Clw@terizclon of tL*Mi. ,1cid in Di&tu',t Pho@dicd Dotuge Fw.d tn ...

DRUG.DRUG INTERACTION STUDIES OF<br />

CETIRIZIIIE<br />

THESIS PRESENTED FOR THE DEGREE<br />

OF<br />

DOCTOR OT PHILOSOPHY<br />

BY<br />

ttr|{nsJa.vaa Ir{,Sc,<br />

DEPARTMENT OF CIIEMISTRY<br />

TJNIVERSITY OF KARACH1<br />

JULY 2009

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Deparrnent <strong>of</strong>chemisry<br />

University <strong>of</strong>Krrachi<br />

CERTIFICATE<br />

Cddtrd rhar Mh3 I.&! sL|t.lra h3 @id out ho B*rt od .,qcrirmrsl rqt d<br />

thc iopic €trdtld as Drug-Irrug Int rsctioD Sludi€! <strong>of</strong> Cetliltlm, mdd ou<br />

suid.!€ 'd rrDcrvki@ i! BFolJ lab I at lh. &!3arcb bsdnn <strong>of</strong> Pbro@|dcd<br />

S.i@..+ F&dty <strong>of</strong> Pt |r@y dd rib 9, D.!rr!la. <strong>of</strong> Cbc6ify, Unicnrt <strong>of</strong>l

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Hisiory<br />

Slrrcturc @livity Eldliotrsbip<br />

Cdi.izi@ .nd @tiond<br />

Doqge ,41 ./6rnidion<br />

CONTENTS<br />

INTRODUCITON<br />

Calcim cblml block€r<br />

NoDst rcid.l dti-<strong>in</strong>flmnarory drugs (NSAID'<br />

NIDDMS<br />

EMtid dd Fe eldents<br />

Immboddalilg &tility<br />

PEpetion <strong>of</strong> deioni*d qd.i<br />

E (PERIMENTA|-<br />

Uv/vhible sp€cbo$opic ealysis<br />

PEpdlion <strong>of</strong> solutioN <strong>of</strong>cernizirc<br />

Conslrwion <strong>of</strong> lh. calibolro! cw6 <strong>of</strong> @liriz<strong>in</strong>e<br />

0l<br />

02<br />

03<br />

05<br />

6<br />

06<br />

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01<br />

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iii<br />

II<br />

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T<br />

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iv<br />

I<br />

II<br />

CosEucio! <strong>of</strong>th. cilibdi@ crc <strong>of</strong>i.Lnct<strong>in</strong>g dtugt<br />

1, v<strong>tn</strong> dailalililie <strong>of</strong> celiri2iE dihydnhloridc<br />

Qu itatiotr <strong>of</strong>drugs u<strong>in</strong>g R'P-HPLC tatuiq*s<br />

Asy <strong>of</strong>e<strong>tn</strong>izirc B<strong>in</strong>S RP- HPLC<br />

M€rhod dev€lopoat.!d optibizarioo<br />

DruB- drw <strong>in</strong>tera.don $udi6<br />

Dng-m€t l<strong>in</strong>r.E tior snrdiq<br />

sp€crospi. sludis <strong>of</strong> complqB<br />

Chflilm<strong>in</strong>esM say<br />

T

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E<br />

F<br />

CairiziE witb NSA.ID'3<br />

S<strong>in</strong>uli'eB &ranitudon <strong>of</strong>cditiziE lrd NSAIIX by RP- HPLC<br />

hl.d.rid <strong>of</strong>caniziE wirb NSAID3<br />

C.tiriziac with eliD.lui.ls<br />

sihuli!@B d.hiralior <strong>of</strong> edririe i! p(e@ <strong>of</strong> utiDLnds<br />

lft.ddon <strong>of</strong> cani2i@ qitb etibdr.i.ls<br />

C.tirizi4 {ilh eftrhDalic drlgt<br />

S<strong>in</strong>'nt.rcoa rLaditrrion <strong>of</strong> et .izilc <strong>in</strong> peqe <strong>of</strong> utunhtulic dt!8r<br />

l lEtio! !tudre <strong>of</strong>Er<strong>in</strong>drl *ith utiadndic ddgt<br />

C.tiri"j& *itt c4tdorpor<strong>in</strong>!<br />

Si[uftlFN d.L@i!.lid <strong>of</strong>elidziF i! F!s.nc. <strong>of</strong>c.pnd69oriB<br />

l .racnon <strong>of</strong>cdni?i!. *itl c.lhrlo.podnj<br />

Cltirizi!. wilt NIDDMS<br />

S<strong>in</strong>ult!@u dcLm<strong>in</strong>dior <strong>of</strong> eliri2im i! pG.rE <strong>of</strong> NIDDM3<br />

bt Elion slldi6 <strong>of</strong> rlirtjF i! ri!$@ <strong>of</strong> NIDDM3<br />

lnt edoi <strong>of</strong> c.ririzirc witb Bsdrl cl66ts<br />

Uv-visibL 3pccrrodDlobcty<br />

HP[,C<br />

Syn{Bk <strong>of</strong> drug{ru8 @rdqd<br />

Synlh6b<strong>of</strong> d.rivdiv€ <strong>of</strong> canizi@<br />

Ch.Elcrialid <strong>of</strong> ddiv.tiB<br />

b-vivo edvity <strong>of</strong> d.ridivcs<br />

Orid.tirc bult $dy fd &.lFi! <strong>of</strong> ROS Dodul.lo6<br />

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REFERENCES<br />

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180<br />

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RESEARCII PUBLICATIONS ANT' PRESENTATTONS<br />

SulirD N, Any@ MS .d Sl.n t.n g QC@, l, etttu thrdi* 4 fu i'tttuiu b.ts@n<br />

eti.izie ard E2 rcept@ .tagonhts ai"g Weophotowiy a".l d@rse&phe ,tgL<br />

p.4@@rc. liqdd.h@logqlV,M.diciNl Clmiliry R.5@h, l.ll.<br />

Suf|.m N, A6ye MS, N.v6d S md Si.!<strong>tn</strong>.d g (2@9) ,{.rro, D.wlop,,.,tt ad<br />

Vali.latid 4 EeliF, ,laa Cluonaogqhi@ 0,.e/za<br />

Suftm N, An F MS.d Sl..'!.d l| (21,1,9) StD!ta@6 tLio.l D.wlopnzd,<br />

vdl.ldtor .,t l ln vitrc lden tb6 Sttdif ol Cetuizid ut h PhryIePbiE, CMiJtEsit<br />

@dl&dr.tdaJr, rouful <strong>of</strong> Phllrmy dd Pheeuti*l S.i.@s lst?rrrr.4r,<br />

S!ffi.r. N, AEyn. MS &d Sl.o.'!ii'i12008) Maltdtbvlopwt <strong>of</strong>cettrt2ltu lntull<br />

&ts, dwweuttcal htuulatton a".l utu, w, J. cta. s4c. Pd. JX4).<br />

Sutt tu N, AnyF MS .nd Sl.@d g lzc,,) )1 RP-HPLC MetM hr h. S<strong>in</strong>ttu@a<br />

D.t.rnt@d@ <strong>of</strong> C.tiritiE <strong>in</strong> Prcse <strong>of</strong> Iti$Iotut h Bth Mdoid, Plwwutical<br />

FMsldtM ard tt@, S.M. Eth atrdl N.rioMl Conf@E Sai.ty ol<br />

Ph@vigjlre (lNDlA) SoPIC 6 Kd*m Jsu{y } | l.<br />

Su|!E N, A6yrc MS, Ne S .!!d St|dlrd II (2009) PJyical ad Cl*6tc4l<br />

<strong>Clw@terizclon</strong> <strong>of</strong> <strong>tL*Mi</strong>. ,<strong>1cid</strong> <strong>in</strong> Di&<strong>tu'</strong>,t <strong>Pho@dicd</strong> <strong>Dotuge</strong> <strong>Fw</strong>.d <strong>tn</strong><br />

Stattlt|, Sat liet Un,E Nowl W-EPIC tr rod Eth Amul N.tidl C@f@M Sai.lv<br />

<strong>of</strong> Ph.m@vigihne (lNDlA) SoPIC o Koltrr!, .teury ll L<br />

Suliim N, Anync MS ud S[@W tl Q0O9) Slfrtlt@ou d.Ediaatid oIcarirE,<br />

Dlhta.n od At' o.lipiE wit:4 R,',futat<strong>in</strong> I a IN.ml Slat lod t" DoPe. FMlldior<br />

aul EM *M by W-EPLC 2d InEhlriodl w@khop Cun-Tn<strong>in</strong><strong>in</strong>g Co@ on<br />

MoLcul& Mcdicim .d Drus RqEh (MMDR-2) Jxulty 12'15, 2009, l(lrchi.<br />

Sullr N, Anyn. MS.d S!.D.|.d g (200E) ti4d. Sr4rl,.rJ oJC.n'EiE t$loAes<br />

Int cdf oi olsdic Sy.rndir. ,e 22, 200E, sod K@. PR- lEo-<br />

Sulr.E N, Aurs MS id $r.!O.n'npooq Sifitrlt4@4 D.bmitatiu oIcaniziE,<br />

Ph.,r'LptitiE, C@it{.Esk h,n Mtttulutd Unng RP-EPIE 19 Cod@mi. d.<br />

Quldiq Dcp.d.n6to dc Qllmio Univ6id.d d. Oricnc Soli.go d. Cuh., 28 M.yo<br />

2@E. TLmr3.<br />

SllnE N, Anyn MS rnd Snrolltd I QoOD l" vitu llt Nti6 Sadht <strong>of</strong> Cei,aE<br />

\.tth Ea Edpt@ .1d.C@itu B<strong>in</strong>g Vcnopltutoo"I'y anl RP-HPIE ln|.rrnnl<br />

Chstrify Conf.llc: Rlqr Adv@3 <strong>in</strong> Chchislry, LlhoE Coll.!. lor Woh.n<br />

uiiecBity, L.toF Novobq 2-3.<br />

Sullrd N, Anle MS ud SLul.n n 1206) t, vItu ttu dio" 9tdi4 <strong>of</strong> Ceti.i.lte<br />

vik &*nlial a,td Tw Ele@Nt Uti"g Wcnopl-brcnic and W.EPLC T.clhICEs<br />

kr Inr.tuli@l Ch.nic.y C<strong>of</strong>@@ CC Unir6ity, F.iel.hq4 Ptrisb. Novcnh.r l-1.<br />

P8<br />

'lo<br />

suluD N, AnyG MS 4d Sl|@\d fl l7(M). oPttkbcton d @itatiE aMW oI<br />

C.EritiE Uti"a Mtltiwiat. Wcnal Calib,atlon <strong>tn</strong> tuh Dq dd DosC. Fotuulcto<br />

f l .mdol & lf Mtion l Clstrisrry Conf@M EMlLnl Thrcugn lmv.don<br />

Dc.mbq 26 - 23, 2(x)7 D.p.rtrd <strong>of</strong>ch.nisiry, Cmd Unav6ity, D.r ls.il Kne,

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ACKNOWLEDCEMENT<br />

My deet€sr lhelG ges to thc only suprlh. aurhority <strong>of</strong> thc wholc Univ@, tb. nosr<br />

b€rcvol€nl {d thc mGl hftitul, rhe foun

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ABERf,VIATIONS<br />

Alnl An odip<strong>in</strong>e PMA Phorbol 12- hfsr.c tl-<br />

Alor Aroryanad!<br />

BCP BoncEslpn ple PHA Phyrohodegtul<strong>in</strong><strong>in</strong><br />

BPB Bmnoph@lblw PBMC PeripLent blood<br />

C.l Cdi.izie nomNdd ells<br />

C.nii Ce&iore Pot Po.""y<br />

Cip Cipsfloeir NADPH Redu.€dfm<strong>of</strong><br />

CIM Cimetid<strong>in</strong>e d@tilmide aden<strong>in</strong>e<br />

CNS CentEl ndou systeh d<strong>in</strong>@lolide pnospharc<br />

Chl Cbloroqu<strong>in</strong>e MN Rnird<strong>in</strong>e<br />

Conc Conenrarion P€f Refe@cs<br />

R' Cor€larionc@fIcie RtU Rqdilg pq lm<strong>in</strong>onert<br />

CPM Coui Fr mi.ure<br />

CDCL3 Deutenl€d chlor<strong>of</strong>om ROS R@lile oxyee, sp6ies<br />

DMSO D<strong>in</strong>ethylsulfoxide Rec Reov€ry<br />

Dil Dilti@ RSD Relarive shdard deviation<br />

EIMS Eleclron ionialion nds Rosu Rosuvaslat<strong>in</strong><br />

sFctos@py RPMI Roswell parknmoriol<br />

Eno EooE<strong>in</strong> irodute nedim<br />

aS E ropy SPAR SpdrflokciD<br />

FAM Fmolidift SOz s€M opsdnlg zyDos<br />

AG Gibbs ae €Mry S E. shrl'd mr<br />

Ou c@fm6ir S.E.E. st nd"xlmr<strong>of</strong> eslima@<br />

HBSS tlmts bol@salt slution Spo Spado@<strong>in</strong><br />

Illd Inrqdly TMs TeFdetbylsiLe<br />

InEa Indlday EliN Tri.tbylam<strong>in</strong>e<br />

ISD lmmoglob <strong>in</strong> E Vet VeFPmil<br />

ICr Inhibitory@nenElion<br />

ICH Io€mtional Confffi€. on<br />

Hmonialion <strong>of</strong> Technical<br />

Requimenls fol<br />

ReSistration <strong>of</strong><br />

Pn@aceuticals for HulM<br />

Levo bv<strong>of</strong>lo@<strong>in</strong><br />

McCN Methyl cyeid€<br />

No! Norflore<strong>in</strong><br />

NIDDM Non bsul<strong>in</strong> Dep€trd€trt<br />

Da,b€ric Mell<strong>in</strong>!<br />

NSAIDS Nonsrereidaldtii4flatuurory<br />

dngs<br />

NMR Neldnagncriclgme<br />

Pd Pddiadn

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ABSTRACT<br />

S*ond ee.enrion erihisLm<strong>in</strong> s N p.glycoprote<strong>in</strong> subsrdles. Drugs i.nibn<strong>in</strong>e oi <strong>in</strong>du<strong>in</strong>g<br />

Fglycoprcie<strong>in</strong> nodoldtion day l€ad io drug-dog <strong>in</strong>ierrctions. C€iriz<strong>in</strong>e dihydrochbnde. a<br />

sond c4oation dtihist h<strong>in</strong>ey' b also a potenr substdie <strong>of</strong>p,glycoFore<strong>in</strong>s.<br />

In th€ presenl wort, e attenpl yas madc ro devclop a nunb.r ol HPLC nelhods for<br />

simullan€ous q@<strong>tn</strong>alion <strong>of</strong> c.ti z<strong>in</strong>c ed orher drugs, ehi.h my posibly be<br />

coadnirbted. fte lali dqss <strong>in</strong>clud. Hrr€@pror dragooisi G<strong>in</strong>etitt<strong>in</strong>e, rmolidire and<br />

miid<strong>in</strong>e), st ris (al<strong>of</strong>latat<strong>in</strong>' Guvalai4 pr.var.r<strong>in</strong> dd simvsbr<strong>in</strong>), qu<strong>in</strong>oloie<br />

etibscterial asotr (lcvonoxac<strong>in</strong>. o0ow<strong>in</strong>, cip.<strong>of</strong>lorciD, .@x&ir, sprfloxd<strong>in</strong> dd<br />

rcrflosc<strong>in</strong>), c.lciM chmcl blocreu (dilli@m, v.rpdil. mlodip<strong>in</strong>o, non nmidal etii.flmalory<br />

drues (ri,t<strong>of</strong>cn& &id, dicl<strong>of</strong>.n& sodih 0ubiprcfeq ibup<strong>of</strong>eD. m€f€mic<br />

&id and ndonm} etimrluiak (prrio.thM<strong>in</strong>e qd cholorcquim), dridrhnadc druss<br />

Guifencsia phmyl€phi<strong>in</strong>. &d noncluLsd), ccph.losporitu (@toid@, cphlt xitr ed<br />

ertuim.) od dtuss ued <strong>in</strong> non iBul<strong>in</strong> deFndcnr diab.Ls mllirur (re{omia<br />

slibeklamid€ ard elqudone, Th. /d.v.toF!l mdhodi *4 validaEd 4d w mpid.<br />

on@icd and w€E fourt sujratte tor orri"e JJysi"_or d*s druss' iiom 6w nateri.tsphrm@tical<br />

doss. foru ed ir hltlfu etu.<br />

G<strong>tn</strong>iziF is 0!e m6t widely pdsibcd drus for allcteic dierd€s ed is .vail.bL <strong>in</strong><br />

@mb<strong>in</strong>adon with l|ny olhr drugs <strong>in</strong> mny couries. Due lo rhe po$ibiliiy <strong>of</strong> cedri<strong>tn</strong>e<br />

<strong>in</strong>k&don * r othd drugs, dng <strong>in</strong>r.tuti@r <strong>of</strong> ednz<strong>in</strong>e r@ sMi.d wi$ atl lhe abov€<br />

sLt d dogs. The abore Dstior.d m.rhods w.E appli.d 10 sndy thc po$ible r" rfo<br />

i erurions B<strong>in</strong>g uv visible s!E*Aii*c. -o HpLc r.€hiiqoe <strong>in</strong> s<strong>in</strong>ulated body<br />

aviremmIs at 3?!c ed ar pH I Gimular<strong>in</strong>s mFy sbhach), pH 4 (s<strong>in</strong>ulatjng tuu<br />

slol@h), pH 7.4 Gimulat<strong>in</strong>s bl@d pH) dd ar pu 9 Gimuj.t<strong>in</strong>s <strong>in</strong>rclr<strong>in</strong>al pH).<br />

From <strong>tn</strong>€* <strong>in</strong>reEtion studies. ir 6 cvidenr $ar rh.rc wss no chsge irff,ailabihy <strong>of</strong><br />

.el<strong>in</strong>/<strong>in</strong>e <strong>in</strong>tpRsence ol b, <strong>of</strong> $.s. drusr cxcept srmv6Et<strong>in</strong> ud NSA|Ds. Itese<br />

i erulioE wre futher v.dfied by 3ynrhesiz<strong>in</strong>g conptei€s <strong>of</strong> ceilizie wiln th€s druss<br />

which llw.hdaderizd by us<strong>in</strong>g FT-IR ed |H-NMR. Encryy m<strong>in</strong>imiation studi€s ed<br />

k<strong>in</strong>dics <strong>of</strong>th€e comDl€x€s werc also studicd,<br />

In orde! lo study lbe struduE elivity relafioNhip, vdious d.logu$ ol cet<strong>in</strong>z<strong>in</strong>€ wer€<br />

plepded. The rcagenls <strong>in</strong>chded ph.nyl.n€didi.., phlbalimid., thioacelmide, thioua md

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d ephthyld<strong>in</strong> . Th. rca.tion mh&bm for th. fm.tion <strong>of</strong> atirizirc d.rivarives follow.d<br />

nrclophidc subsdtution re&tion3. Th. piodwr. obtr<strong>in</strong>cd wft.hdet ri2.d by FT-IR rH-<br />

NMR od rc specroi$<br />

'll'.$ d.rivativcs w€E furrha subjercd for lh. posibt. eti<strong>in</strong>U.maiory miiviry .s r€l.s<br />

<strong>of</strong> hjri.nift dd podrction <strong>of</strong> crlotie by mst c.lb {d bephih e thoudt ro b. doely<br />

<strong>in</strong>slrcd <strong>in</strong> Uc p.thog.eeis <strong>of</strong> .llclgic dis.es. All.Eic dilcdg my <strong>in</strong>volv. irfl'mlrory<br />

Dediatoa 3rch a hisi.nirc, .ttoLiFs ed msy difIGMr c.ll rtlcs iNlud<strong>in</strong>s T c.ttsr oasr<br />

c.Un bqophils, n umphih, naophagG .r.. An etihist mic sho$ ori,<strong>in</strong>fl.lmliory<br />

efrecrs at thmp.uric conc.nr.tioN thn ruy nodiry !h€ .fla|3 <strong>of</strong> idmmabry bedi.roB tt<br />

r,w at dos @Bp.6ble !o 6os !s.d cl<strong>in</strong>ically. Lhiml .nleed chmilM<strong>in</strong>*r@ @y<br />

*w F.fodr.d, th. pal<strong>in</strong>iE y $tailg BuX! <strong>of</strong> wholc blood lnowd rhal .onlouds<br />

7t4, 119 &fl 121 .xlribn d sigrifimr oxiddiE burn Espo.3. (eri-i.flumarory) !r<br />

coNotltioB l.rcl <strong>of</strong> l00, 50, 12.5 F8nLi, Eiell.nr irhibirory &riviri6 <strong>of</strong> lt!*<br />

compo@dt wd @.dcd !r t2.5lrghli i... %, 92.5 snd 9t.E Eq.criv.ty. th€*<br />

@npounds *4 rhm l6rcd for a.dviri6 otr i$ldcd m&Fph.8. elts on liv. @nmr.riotu<br />

l*L 50,25. 12.5.6.1atd 3.llrgnfr. lr s found lh.r all ddvdrv€{hlv€.ettdr .tr{G<br />

m nll@ph.e6 .d G nuch |tm potan rha eririzjl. 6c.'r 7l a, Funh6<br />

phmolosicrl rctiviti.s @old fiMlly d.rmim lhcn.kr mhdism <strong>of</strong> edon .d .ner<br />

clrororic &ivni6 th* d.rirdiv.i could rdly povc cGllcfi rh.Epcutic !g6rs <strong>in</strong> arhm<br />

Ihc sbitivity <strong>of</strong> c.&izie ad its dqiEriv6 io r nonllolif.rdis .r!d tmlif.ntiv. BFn$<br />

ro r!. ditogsr phrto[.ba€8luril<strong>in</strong> (PHA) rad Bilogc.-ilduccd prelif.ati@ <strong>of</strong> Tlloplers<br />

M rt$ c!rl@&d. SuppBsiE .fcct <strong>of</strong> ohFurd 7l4 M obs.d.d o Tslt<br />

Folife..{o[ simild] 719 $o*!d .xellcnr Tall $ppr6sir &rivides- C@pould ?27<br />

shoved s <strong>in</strong>t mcdid. !.tiviIy. Th. Gulll fval.d rhn conDounds ?lr, 719 dd 727<br />

dhibiled dtic.Gr activity .rd @uld b. prcv.d l€ad coopoundr i. th.6p.uic qorld aRcr<br />

turha srudi6. AnihsrM<strong>in</strong>ic &livi(6 <strong>of</strong> rh.,Jb96 ompoundi @uld rci be @ndEl€d<br />

drc !o ler <strong>of</strong> fei{iry.<br />

1-,tr& lur'r,

---

-y,,'11'4"- a1! t n,/-'t;;vL !"t-rtLet,-/--Jv i.t<br />

'tz '<br />

-11!n{,ru.6! rntf \;v L<br />

tb<br />

4r e!,'iJi-+ asubstf at€ L,r 4 tr,t 4,!<br />

*-ft7"'!oth J"<br />

, 4l qz/ -q t ot d Gta i,,"r - " a i-t,)r?,''i {" li |<br />

ldJ'J.-+ substmteed, /,4J"t 4{yl/" 't "tc.<br />

tr $<br />

t" d t,'f<br />

o 1, I !'u.- { {q -e,,t -ts; v4 I }L oe ct t 1,6 I' k J q "t'<br />

-t!"i- ''2., " ."---tt, t' r6'J r rtlJP =t,!.J-\'"Jv"<br />

-q Jc -\,t Jtt''t i1,,1 l\),2,'t, N"t l"','tt" Ja,,t/ ia. a, ;Av<br />

i9 aie L t)t 1 lL'i'$ d,9,! -r ", i u'"<br />

"'tz z 4 -a't, :i,l- fe t<br />

+v L F +lz.r€v..-vL!cr-l 4'v'aa,o,)s'!'lt,!'-. f,-,<br />

;,,iu,,t,.t,;-?Lv,', n,ntA4 J'L -', ett6. -q Lr Jr>\'{<br />

-Lt f t; t/e L,iLJ,t oi J\ J,ti!)-. ,-t .' iu-. -Lj,ia Lt)tz -"]<br />

-t ; v L - L,t \J,v a 2- L o {a1 t! 6 ) /z 1..t Ja t-' I i - - "1, 2<br />

i" "iJ.:--'J.,','f'f,!* 4cz tr- Ja-.,e.t/a Lb'JtL6ol<br />

{L.rU"( sttucrurc-Acri\ity Retatio^ship - L ivt{'\ ,t Lt' -<br />

i' J o: "' j u j' t J E, rlot . t,t g A,"r1,J, ctt I I'v rtur-' v -,..<br />

;rlev 6{6 ctfttr{-;lc/-t'r/,t:,!L ' 1,.t * L-ttot-.1Jt:<br />

i, t q t ; iu" -4 i\ t- rtt lu-, *';tt L L 1 v', v'! -0' r; a t - LV'!<br />

- a i{J lva $: rlw u d -!'t -(J {r'.1 w o u t, J y. *<br />

entr<strong>tn</strong>.:,annarory'ctt t I {. 4r ,! -{/ }} | z- 'Pl - rl r?<br />

J-!727 ,171s.714. J. /J+" ur, - 6r' iw-* r{i.u ovlt<br />

!- '-.\f.-)t L 'Jl/ iVV'a 7 -q Jv L df/ Antt<strong>in</strong>ttannato.v<br />

J. ti.v a',!; - u-z ?;!- c' -r! {./a?-N'|[-v J zts.rtttJ. 7<br />

-4{tec

---

INTRODUCTION

---

II\IRODUCTION<br />

nisianitu is a subsree thar is widely dktriburcd io body tilsB &d d on k\<br />

Elw ftod sronge sites. exen a vriery <strong>of</strong> phmlod".l "r"* "f ;]*<br />

,a4,n8 'nknsu) HrtM nesR uru.lb rcspoNibl. ior alkl8r dsod*s,n Y<br />

th€ body. Il stmulat s the prcdetion <strong>of</strong> nNN dd .lilafion <strong>of</strong> blod v.sb. I<br />

sufra or.11..$/ @osda hi$rnie .fr.crs s r 'lmy nose dd smlLn nael pdesd {l I.<br />

2 U<strong>in</strong>6lr.4.pt4r<br />

Hislan<strong>in</strong>e bdns3 irs clf@r nmwl rhe e$vnid tw @prors, H, ed H, rtDi ditr rl oi tl)e<br />

bais <strong>of</strong>theii difier<strong>in</strong>g ensiliviry ro agon<strong>in</strong> od mbgorists, Hr have been foud <strong>in</strong> b6ii [2]<br />

Ht rcceptar dtaqonists<br />

H1 r€cepto. slagon<strong>in</strong>s compelililely bl@k nis@n<strong>in</strong>e at Hr reeptor dd.d b. depicted o<br />

suhslitut <strong>of</strong> .lhylmiE @Dpouds. Bov€r &d collabontoB pl ws€ th. fi61 *ho<br />

disvcFd Hr Gcplor dragonisr* Aner itt disuy mdy @npounds sF fou.d io show<br />

hi8} ar,sonist pocfty ar this deptor [4 s]. R6ulls ftom @ly snrdid wirh rh* analosou<br />

dsiwtiv* <strong>of</strong> cthylcftdidire sueacsEd . cl<strong>in</strong>jc€l potcnlial io. rc.t<strong>in</strong>g .lLrgic ad<br />

irnallrmb.r di&de6 [6].<br />

In rhe b€siM<strong>in</strong>g. thc rctiv€ hi$m<strong>in</strong>e H | @.plor dtaeonists r,s s,6*n by a g.n 6l fom<strong>tn</strong>a<br />

onFis<strong>in</strong>s two Nmadc sreuF [Dr.d by r shon chl<strong>in</strong> <strong>of</strong><br />

t" I I<br />

c atod b ! l.ni.ry Mi@ sreDp. Arr is drlor h.r.re aryl, l-:-i-""'"'<br />

I<br />

\tich nay b.6[th.r subsl<strong>in</strong>tsl Al is *@na aryt,<strong>in</strong>go.<br />

" ^"<br />

m aryl netrrl goup. The Mo aryl soup Arr dd Al @y be bnds.d |o fom ticlclic<br />

derivativ6, X is a sp: or spr hybridized cebon, a niroeen or a spr @bon with d oxyee.<br />

(€th€t [Dr coMect<strong>in</strong>g the side cha<strong>in</strong> ro the donaiic r<strong>in</strong>gr, C-C r€psents a short cha<strong>in</strong> <strong>of</strong><br />

cabon atom which may b€ sat@ted, uneturaLd, b@ched or fom pan <strong>of</strong> r<strong>in</strong>g systen.<br />

\R'R? t g46lly. Gniary d<strong>in</strong>o ercup whi.h my bc pa.t <strong>of</strong> a nng 3t!i.n. tl ws loud<br />

dEt activity @!ld b. iftEded nEk dly wiln the iftodwtiotr <strong>of</strong> a sond mtudc or<br />

hetemyclic .<strong>in</strong>g i o rhc $tutur ad ths,ndbq <strong>of</strong> adlosB wa syndEsird and

---

€valutcd. The nosl aDnug smup is d<strong>in</strong> rhyl m<strong>in</strong>o {d prrmlid<strong>in</strong>o. Tb€F sEucrws do<br />

@l hav.. dos ch.mical rcsnblmce lo hblm<strong>in</strong>e exc@t thai thcy do app@ |o she ihc<br />

f61G <strong>of</strong> m .lmoniM 6lkyl chaio. It is pr6h.d thal Ihey b<strong>in</strong>d to Ur€ se dionic sne at<br />

th. @pror,6 dc hisr.siF, but 0B1rLe @nadc r<strong>in</strong>g b<strong>in</strong>ds ro a Fa|bya*$ry cgion<br />

Howvd, th.E N no* lmy @nFuds *hich lhow hgh potdcy jllo nor fit <strong>in</strong> otrs<br />

IE Hr elasoniss @ cleitid <strong>in</strong> b fiBl gmdtiotrjg.6i&d s@nd sq@tion.scnrs<br />

Fibi g.ndlion dngs e chsedad by srong s.dadng cflels ard nDy ale bl@*<br />

aubnonic 6epb6. Sonc <strong>of</strong> lhe dsgs ircluded <strong>in</strong> thb gFup m cdbihoxo<strong>in</strong>€.<br />

dimerh<strong>in</strong>den€, triprclid<strong>in</strong>e, cl.n&*i&, neobenod<strong>in</strong> , chloryh.niru<strong>in</strong>e elc. S€cond g.neEtio.<br />

ag.nts do€s not obllet ly distribule <strong>in</strong>ro $. d!!l moa system srd rh.y e<br />

cnr@l€dad by $en ls s.dal<strong>in</strong>g efaa. Som. <strong>of</strong> lle dru83 ircluded <strong>in</strong> this grcup @<br />

ebsl<strong>in</strong>., @ilast<strong>in</strong>e, l@itll<strong>in</strong>., cetizire, astoniale @d m€quit z<strong>in</strong>e €rc [tl].<br />

AI <strong>of</strong> th€ Hr &rrsonhs e s6bl€ uim9 Du<strong>in</strong>g dr lasr d.cad6, dive nebboln€s <strong>of</strong><br />

seEl dtihislnifts hav. b*n us€d G &riv. dngs. Th* agoE @ npidly .bsrH<br />

follow<strong>in</strong>S oral adh<strong>in</strong>istradon, wiil pet blood co@traliod @cudi.s <strong>in</strong> l-2 hou6. They<br />

ee widely distiibuted ttrough out the body. The Hrseplor elagonisls blGk lhe acions or<br />

hi$dn<strong>in</strong>c by rcve^ible compcdlive ei.gonhn al the Hr @.Ptot. TlBy have ncgliSibl€<br />

po&rcy ar rhe H, Gepror sd lid. at fi. Hr @pld [ ]. Hoq.c, ih* dr!$ a onry<br />

iilibir rhc BpoMs nedis|d by thc El€4 <strong>of</strong> hjltdift. They ca nol blak ltstu<strong>in</strong> liom<br />

Eled<strong>in</strong>g or pGvent hisiMirc len b<strong>in</strong>d<strong>in</strong>g lo hisum<strong>in</strong>e (ED @pioi. tho€by block<strong>in</strong>s th€<br />

B<br />

ceddziie k the founh dddition ro a nry s.nention <strong>of</strong> audsy m€diation call.d 'non<br />

*dat<strong>in</strong>C' mlihisr@<strong>in</strong>e. Thcs. @w dlihisl'n<strong>in</strong>4 @ clsified s nor-edar<strong>in</strong>s agenls<br />

b€.ac lh.y caue 163 sedarion lh6 their pnd@sB tBl. c€$n<strong>tn</strong>e displals a sries <strong>of</strong><br />

ad@trg6 over its pEd@so6 s n is Ae <strong>of</strong> both sjalee ed choliftryic efers ed h6<br />

poi€ni mlialLtgic aciivily. Howev.r, it is noF sdatilg the lhe olhq non-sedlt<strong>in</strong>g

---

4tihislamic. Cdirizi@ wa mong thoe dNg! $,hich w€E wid.ly pEsrib.d ir EmF for<br />

aldey befoF it B <strong>in</strong>rodlc.d <strong>in</strong> Am.rica.<br />

Cetiriz<strong>in</strong>e dihydrccl ond€ anla<strong>in</strong> noi les 1h.n 99plo ed not<br />

hor thcn 100.5% or (R5).2-[2-l+l(a{hbbphcnyltpborl<br />

tr|I)l)lpiF@iD-l-rllerhoxyl*ric &id dihrdMhbnd(.<br />

cdculaled qiih Ffe€nce lo dd€d subsl&ce [al. II G@mic compoud) is p'<strong>in</strong>eily mid<br />

nel..bolite <strong>of</strong> hydrexyzir€ tsult<strong>in</strong>g Aom compl.t. on{btion <strong>of</strong> prib!ry alohol noiety ed is<br />

auilaue d a vhil€ crrslall<strong>in</strong> po*der dut is valr-eluble. This onpoud is zw<strong>in</strong> rionic<br />

ud elatilely pold &d Zyn* is the br&d nm. <strong>of</strong>€dnizire [I5]. Th€ drug is isolubl€ it<br />

eebn€ md <strong>in</strong> n€thylene chlo.ide, les soluble <strong>in</strong> lipid, bui soluble <strong>in</strong> meli'anol hav<strong>in</strong>g<br />

mol4dtr s.i8hr <strong>of</strong> 461.89. Its m.lliog Doi b 218-220 0C &d pH <strong>in</strong> solnlio. fom is 1.2-<br />

L8.lt@nra<strong>in</strong>s hslamelal nol moE tbtu l0 ppln, moistN con|c nor moE $d 0.5% w/w<br />

dd sulphated ah not norc rhd 0,2370 vlx. Cctirizire loss on dryirg is rol moE lhe 0.5%<br />

dw md 6$y is not l€ss thd 9% w [61. C€tiiiz<strong>in</strong>e partly ecouls for lhe i, viw eile.ts<br />

t Sttctaft..lttitrElorio6,b<br />

ce&iz<strong>in</strong>e hs dboxyl group which h3 reducc &@$ ro th€ e al neoous syst m (CNs) 6<br />

conpred lo thc hydsxyz<strong>in</strong>.. \vhs daly3is ws condud€d on thc lipophilicity bchavior <strong>of</strong><br />

ce<strong>tn</strong>iz<strong>in</strong>e, pdial <strong>in</strong>ta nol€cula chege naddiation *a obsned <strong>in</strong> the Gtanol/sater md<br />

.lode@e/wrd.y$etu. The ionic Fflirion dilgm i.dicaled lhat cdnizie &t 6 a pbid<br />

rasponer &o$ <strong>in</strong>t rfaces wd.r c@<strong>in</strong> @ndilions oI pH Il?l ln coEb<strong>in</strong>aljon Nifi one <strong>of</strong><br />

$e bsic nilroge.s <strong>of</strong> pipe@i.e r<strong>in</strong>g, rcid fuction.lily tules ihis conpound a very uique<br />

n terion. Ceboxylic SDup <strong>of</strong> @<strong>tn</strong>tirc <strong>in</strong>lttul with th. tsic nitroS.n via folded<br />

@.fotl'@, thqdolE, il Fsi.ss Elativ.ly hjgh lipopbilicity at physioloei.il pH (LogD-<br />

1.5). Phmscot<strong>in</strong>€iics orcelidziDc sisn<strong>in</strong>@ y dif€$ fiom lho* <strong>of</strong>the baic ed lipophilic<br />

hydroxyz<strong>in</strong> . Duc to ryitterionic attuctE dd ils P-gly6prol.<strong>in</strong> etility. cetiiiz<strong>in</strong>. h4 onch<br />

low CNS D.netrarion thq hydtuxyz<strong>in</strong> . Ccliddft display3 d<strong>in</strong><strong>in</strong>d a&mlae€s over the<br />

b6ic hydmrytre <strong>in</strong> sv.El c.r.gon6 sNh d slow E@ptor diswiaiion ntc, hieb<br />

sel€cliviq od ncgliSible liv€r enzyG <strong>in</strong>r.Erio. [r8]. Ih snall sE@tudl cheg6 <strong>in</strong><br />

hydoxlz<strong>in</strong> l€d to th€ difd€nl phm@k<strong>in</strong>ctb prcnle ed the phtuodr@ic sDectu<br />

M al$ ch&8.d. In ev€rl i, v,D i61 modcb, c.tirizire prorrd to be poLnl conDourd

---

wilh l@g le*iDg .ctivily. h I ob*o€d lltrl al dos tblr .lletirrl, bl@l tLe &don <strong>of</strong><br />

httrnift <strong>in</strong> thc ak<strong>in</strong> ed luB @tuizire ldn<strong>in</strong>isr.tion clicir.d l<strong>in</strong>le or no s€dation or<br />

el€ct@ocephalosrm {EEc)che8q [19].<br />

4 C.fuaru 6d.Nndo6<br />

C€ririzl!. ii a chir.l dsg ed .Mtion6 @ pE$ot a .&rly l: r nixte. Snrdi.! 6i.d<br />

on th. n6d r€sist&e b @mwE the €freB <strong>of</strong> rdmic. R ad S edriz<strong>in</strong>c <strong>in</strong>dioied thlt S<br />

€Mtion6 docs mt exl bir anihi$d<strong>in</strong> cfretl N shou by bo<strong>tn</strong> @nic .nd R.<br />

e@tion6. IE emat€ dd R cMrioIM irldbicd histrsi!. ed <strong>in</strong>duced e <strong>in</strong>clEe i.<br />

6al rsisra&e, thw irdietilg the andhisi.n<strong>in</strong>e Plopenies <strong>of</strong> R aliriz<strong>in</strong>e 1201.<br />

CdiriziF hav€ b..n sFtbesizd by vqiour ncihods <strong>in</strong> licBnre [21-2!], Detk et ar,<br />

dielo$d th€ p@tical laluolo8y ro. lh. pepetion <strong>of</strong> (,t)-cdir'ane 2Hcl v,a<br />

dis€It@letivc orsrnonelallic addilid to x4..r-bui.n6ulfDyl sld<strong>in</strong>iB [24].<br />

r""r<br />

\4.^."<br />

tv ru o."- *S**

---

fY*.<br />

iO<br />

h<br />

s I<br />

...6., !t f,t<br />

rvii rot-rcrYn nm<br />

.4, U z.c c,4/ V c'*y' \t<br />

r^ria .s\ tlL (fi<br />

t<br />

lr'^u,<br />

14ris<br />

,IrI!<br />

roalff<br />

2'C<br />

tl<br />

.<br />

PtlotlIo'Ff<br />

9<br />

r-tr<br />

I<br />

0<br />

tl<br />

"_"oT<br />

t8t{ , {ior<br />

a.^fl<br />

r'l<br />

6 MdLe {art<br />

i Spcnoscopic mthods<br />

IE a<strong>in</strong>€rioni€ &tihi!Ln<strong>in</strong>e cctiriz<strong>in</strong>e sd ib p@nt &[g hyd&xyz<strong>in</strong> a c&&M<br />

@nF ad lw @i..d fd U.i! 3D rrirres rrd dr|mie. th. rm b6sic pK! ldues,<br />

lhc mosl @@or @rfomlrioc for .a.h clatF! sFci* \Nft dlit milcd by molaul{<br />

dlMica s<strong>in</strong>ulationr &d €onnmd by NMR h6l!4cnG. Fo @tiriz<strong>in</strong>e, lh. re$lls<br />

d.noBhr.d that tlE eitt ri6 qhicb v@ rh. pr.donimr spe.a6 d r,bsiologic.l pH<br />

.xilred a foldcd @nfomlts, wh@a irl nomqtiouc sFcic! dtpl.y.d folded @nfom6<br />

to

---

sllbiliad by <strong>in</strong>ta holecurd hydrcgd bonds. 'Dr€e fbd<strong>in</strong>es were iD full asdmenr wirh<br />

pEvious r€sulk on 1he ljpopbilicity behalior <strong>of</strong> ceiriz<strong>in</strong>e <strong>in</strong> isolropic solvenr syscos ed<br />

tata roB.rha could expla<strong>in</strong> lhe favorable pbm@k<strong>in</strong>eti. poFni.s <strong>of</strong> the dde [25]<br />

C€t<strong>in</strong>z<strong>in</strong>e ha be.n detm<strong>in</strong>ed i. druC, blood &d *tum 6<strong>in</strong>g fluorimeaic 1261, @bnnert<br />

[2?] rd crpilldy elsEopnoEsis pbcelws [281. Two siDple ed mpid, ssiile cxr.&tile<br />

speclrophon€Eic medotls wde dd.loped for the &ntuioation <strong>of</strong> cedriz<strong>in</strong>e <strong>in</strong> bulk md <strong>in</strong><br />

phmelticals. TlEs m.thods w.rc bard on fomation oa chlobfom sol ion conplcxed<br />

bet$q elirj<strong>tn</strong>e with brcm@@l purpl. @CP) or bmnoph.nol bl@ (BPB) ar pH 2.64<br />

w n e absorydon aI409 ad at 414 m for BCP md BPB. resp@tively. R@clion ondirioro<br />

wet opt<strong>in</strong>ized to obk<strong>in</strong> ibe Mimh color <strong>in</strong>tensity. The .bs<strong>of</strong>toce i.cE6ed l<strong>in</strong>.dly<br />

wi<strong>tn</strong> d <strong>in</strong>crede <strong>in</strong> @nc..rarion <strong>of</strong> cednz<strong>in</strong>e, yhich ws corcboded by lhe catculdled<br />

corel.tiotr wfrd€m val@. llE sysld ob€yed Bd6 l:w il th. Mge ot l-16 dd t.5-21<br />

lgnlr lor ACP & BPB, mp.crively. Thc ldiou dalysh pddetes w€rc evaluard 1301.<br />

With salicylic acid b <strong>in</strong>t€hal srdddd qwrit.rioo wd achieved wilh UV derem<strong>in</strong>ation at<br />

210 m ba.d o. rhc peal n ighl drios. Bd s lar B obey€d <strong>in</strong> a conce r'rion Ms€ <strong>of</strong>l-<br />

15 lgnl-r qd th. Fgrsio! lirc equlli@ w d*ived wil[ . @tarion @m€ial <strong>of</strong><br />

0,9999. Tle lalidirt <strong>of</strong>the ncihod wa tufthd confift.d us<strong>in</strong>e rle sledad sddirion berhod.<br />

The popoFd procedu€ ws 3uc@stutly appti.d b <strong>tn</strong>€ dcrem<strong>in</strong>adon <strong>of</strong> ca<strong>in</strong>z<strong>in</strong>e <strong>in</strong> bult<br />

ald tablet fom, with hien pc.irrge <strong>of</strong> Ecov..y, good acc@y dd pEision l2?1.<br />

Ce<strong>tn</strong>nne ws qwdt t d <strong>in</strong> pEs@ <strong>of</strong> H, @pror ehgonisis uirg s<strong>in</strong>ult r@u €qulion<br />

ed derivarive specroeopic teclDiqE [t0]. UV abrorption v6 monilored at 230 nft dd<br />

oxarid<strong>in</strong>e wa enploy.d as lhe <strong>in</strong>lmat $mdsd for qedti.arion. (+)c) ccdnz<strong>in</strong>e dd 1he<br />

dal shrd,rd wm.luiert 6t rslorion l<strong>in</strong>cs <strong>of</strong> t2, 16 dd t2 mjnuls, rcspe.riv€ly. I.he<br />

'<br />

deterion limir ior cet<strong>in</strong>nhe enetioners ws 4OO ognl-' <strong>of</strong> u<strong>in</strong>c. A phs@cok<strong>in</strong>dis srudy<br />

w6 conducred with rhe h€lp 5 healiby tftale lolules who were adh<strong>in</strong>istercd lnh a s<strong>in</strong>gle<br />

oBl doe <strong>of</strong> memic eririz<strong>in</strong>c €@rim.6 ov.r a conenrarion tuge <strong>of</strong> 2.5 200 rsDL r.<br />

Tlt. p.!r <strong>of</strong> lle cxmt d eridziE @rliollB appeEd <strong>in</strong> the u<strong>in</strong>e sple duilg the<br />

penod l-2 hous followiry ihe adm<strong>in</strong>ttralion <strong>of</strong> tiE oEt doe. The ex€rcred tevet <strong>of</strong> i+t<br />

cdirizi.e was slightly highq thd C) cednz<strong>in</strong>e bu1 lh€ diffcMce was nol s!.tisti.allv<br />

sisn<strong>in</strong>cdl [3U. In sorher sF.r.ophoiom.rlic n rhod Bels law B obeyed ovq rhe<br />

@Mn! ron Mge 2.5-20.0 |rgDL' wi$ d lpp@nt mol& aberDtiviry <strong>of</strong> Lllrlo 4<br />

L.mol..hrod Sed€lls sensitvny <strong>of</strong> 0.038 pgcmt. This nedod ws applied lo lhe<br />

d.ted<strong>in</strong>ation <strong>of</strong> cd<strong>in</strong>z<strong>in</strong>e <strong>in</strong> rablers ed based on lhc neu<strong>tn</strong>lizrlion €action. <strong>in</strong>volvi!. rhe<br />

II

---

c*boxyl grcup <strong>of</strong> cctirizilc ad edim hyd@xid. <strong>in</strong> 6qh6 mediu. Th€ lalidity <strong>of</strong> lne<br />

hetlDds M tuiher aerta<strong>in</strong>.d by pdallel detcnn<strong>in</strong>aiion s<strong>in</strong>g 6 Eferenc. melhod md by<br />

Eorc'l nudiq F2J. S<strong>in</strong>plc, prcis &d €cononicd rpelrphoroncEic nelho& *w<br />

develoD€d ior lhe simulla@s esiimtion ol cefiizift dd mbroxol <strong>in</strong> t bler fomulaioN.<br />

The 6d ndhod *6 brsd on th€ B <strong>of</strong> nultidmp<strong>of</strong>t mod€ urlysis dd sd nedod<br />

wa based on fist dailative sp€cual salysis, while lhe thnd De<strong>tn</strong>od was baed on Qoalysis,<br />

i... tlp ab$rba@ dlio merhod. Boln druss ob.yed B@"s la* <strong>in</strong> lhe 6I@!a!io.<br />

6ge <strong>of</strong> 5-10 ssDL-' for etiriz<strong>in</strong>e dd IG60 psml-' for dboxol [3]351. A derivative<br />

speEopholoneEic m.thod w6 ddcloped for 1h. asy ol thG biMry nixlws <strong>of</strong><br />

pstudo@hedr<strong>in</strong>e with fq<strong>of</strong>oadirc, cdiriz<strong>in</strong>e dd lonlad<strong>in</strong>€, nrc ne6od h bed on $e *<br />

<strong>of</strong> lhe nrsl d.dvativ. <strong>of</strong>lh. qlio spetrM [36].<br />

ii HiAhper|almrce th<strong>in</strong>larechrudatogtdpll, (HPTLC)<br />

A Epid od *6itiv. mTLC 6sy had been d.velopcd fo. the m6l!@dl <strong>of</strong> eririz<strong>in</strong>€ <strong>in</strong><br />

hmd plasnd dd irs utihy for phmek<strong>in</strong>eics srldy had b€d cvrl@red. In this nelhod<br />

q@tifi€ on M done vilh ihe h.lp <strong>of</strong> a d@l wvclcngd TCL @n.r. The prcpoFd<br />

tElhod had a Ecovery <strong>of</strong> 9E% an l Ur€ low.sl houl <strong>of</strong> c.tiriz<strong>in</strong>e thal €ould be d.t d.d ws<br />

50 ne. Thc medod *a applied for <strong>tn</strong>c d.ldielion <strong>of</strong> th. plasm lqel ed phjm@kirelic<br />

pdmeteB <strong>of</strong> cetriz<strong>in</strong>€ an€r oral adm<strong>in</strong>idration <strong>of</strong> lwo na*elcd pr@drtions <strong>in</strong> h.alhy<br />

vol@ie4, The deted<strong>in</strong>ed merhods eE <strong>in</strong> agenenl with previocly rcp<strong>of</strong>ted lalucs [37]<br />

Ps.ld6phdiift dd edriz<strong>in</strong> @ wid.ly uled <strong>in</strong> the remot <strong>of</strong> allergic ih<strong>in</strong>njs. A Fpid<br />

*lecdve &d slability <strong>in</strong>dic.t<strong>in</strong>e HPTLC m€rhod *6 develot d md rElidaled lor then<br />

s<strong>in</strong>ulrosN dekmimtion <strong>in</strong> phm@uricalr. The bernod dployed TLC al@<strong>in</strong>m plaret<br />

pr€c@ted wilh silica Sel u $e slarioney phse. The elvot syst€m onsisred <strong>of</strong> EIOAo-<br />

MCOH-NHj (7:1.5:l). Spetrc

---

iii High pre$we liquid chtohatogaph, (HPLC)<br />

Nmb€r <strong>of</strong> nelho& for th. dermimtion ol ednziG h6 b.cn rcpon.d 6<strong>in</strong>g HPLC<br />

tehniquc, Thee nehods dd dEn .l.lails e pEsr€d <strong>in</strong> rabl€ l. L<br />

HPLC Mhods o!@tihire<br />

HyprsilBDS C0(5 A25 cn x 3.9<br />

mn)@lumn, isriic n d. H,O:<br />

M.CN:Er,N (61:r7r02) DH 7.t.<br />

lnensil-C3 (250 x 4.6 mm) 5 FB<br />

dislill.d Mb, .c.loniril. ud<br />

l.idny|ln<strong>in</strong> (a):40:.0.|) pl{ - 3.5<br />

CtrNovpak@lunn{l50n9nm:<br />

,tFn) <strong>tn</strong>6y'Enc & elutid<br />

:.enibiL (6l:39) pn 2.8<br />

Novi-P.l{ Ctrcolumi O50 x 39m,<br />

4lrn) M.CN 0.02 nolLr $dim<br />

d jhydsSo rldphd.$dryLn<strong>in</strong><br />

Nov!-Pot Cl8 4 m Edial<br />

@mDE$io oluh|l 5()91 M.CN-<br />

5eZ phosph& buF6 (pH 1.07) lo<br />

which 0.011 sol Ll EtlN<br />

(50:t0,0.15)edO.ol05 noll I<br />

s.dium dodeyl sdfo@ r.E !ddd.<br />

HIT€6il BDS C I3, 5 nu column<br />

i4.5 x 250 mml mobile pl@. <strong>of</strong> 0.05<br />

M dihydrcgd Dholphd.: @di'ile:<br />

hernmol t.hhydrcf<strong>tn</strong>n (12:t:2: l,<br />

v/v/v/v) .. . pH <strong>of</strong> 5.5<br />

I-icht@tb Rl-18 colub4 KHTPO.<br />

M.CN (55:!5) {v&)<br />

Lich@|b cr colmi. M9CN 4.01<br />

moll | 3€diuD hydbgen phoehde.<br />

002 moll edium h.mlulfo@<br />

Sfi<strong>in</strong> p.cl CLC-ODS @hdn (250x<br />

4.6 nm), MeCN - 0.01 M KHrmr<br />

(46:54, tunbii<strong>in</strong>! 0.02 M N.<br />

hept n6ulfon'., pH 6.1)<br />

sDhdi$rb 5 OD92 olmn (5 mM<br />

aqt rn buryl @onium phosPn{o -<br />

nclonol kraa hydb lu@(33:65:2<br />

Th. irn@e <strong>of</strong> rnp.|@. .!d El{iv. hrmidiry on rbbiliry <strong>of</strong> dirizirc dihydrcchbn{b jn etid<br />

slale wa follos.d bt a HPLC melhod <strong>in</strong> on€ <strong>of</strong>th€ sludy [,t9].<br />

12<br />

,tl<br />

,18<br />

ll

---

Cetiriz<strong>in</strong>e is the &1i!e netabolile <strong>of</strong> htdoxyz<strong>in</strong>e, rirh gr€a$ affiiry fo. Hr @eplor. tcs<br />

df<strong>in</strong>ity for elciw chm.ls, a{dr@rsic, D2-dopsD<strong>in</strong>e, stlTt-@ion<strong>in</strong> dd hus<strong>in</strong>ic<br />

t@prots day deEse plostaglmdirs or leukouioe poduction [s0]. Ir is mpidly abso$ed<br />

fton sarrlo<strong>in</strong>|sliEl r&t ano or.l adn<strong>in</strong>i$6lio[ pet phsm @nqratior b.irg atu<strong>in</strong>cd<br />

wi$ jn about I hou. Food dclays rhe rihe to pest ple. @n€dhation but d@s not decrese<br />

th. u@t <strong>of</strong>drue ab$rbed. Ir is higbiy bodd ro plam prereb rrd ha e .t<strong>in</strong>iurion half-<br />

li& <strong>of</strong>about 10 hous. Celidz<strong>in</strong>e is exc€led p<strong>in</strong>sily i! rhe u<strong>in</strong> na<strong>in</strong>ly as dchdged.<strong>tn</strong>B<br />

dd dG @1 .r'F{ !o frs th. bloo

---

kela.@n@le withoul ihc <strong>in</strong>cEbed nlk <strong>of</strong> head iGguldiiies @mo! to 0$6 rcn-sedal<strong>in</strong>s<br />

&li hLlte<strong>in</strong>* 1561. How*o, MAO irnibiloE ifttte the cfel <strong>of</strong> synpalbomim.tic<br />

dires sd may prolong md ifldsiry the.frec' <strong>of</strong> dlibislan<strong>in</strong>$. No dde irt @lions had<br />

bei Eponed wilh th. @ <strong>of</strong> poa.eihol [57]. Il is hishly $letivc i! tu <strong>in</strong>rc@tion *irh<br />

v&ious boooml b<strong>in</strong>d<strong>in</strong>g sir6 md hiShly porenr krfenad<strong>in</strong>€ d well. No wdio roxic eflcrs<br />

wE ob*ncd wiih rh. nw &ug wncn u*d al its e@m€nded or hi8ns do*s or whd<br />

adn<strong>in</strong>ht€rcd with imidaale ednDeal od n&olide edbiotics. How.ver. orher rypical<br />

drug <strong>in</strong>l€rutioro <strong>of</strong> Hr odnistdire applr 10 eriiz<strong>in</strong>e. As.ltiriz<strong>in</strong>e is a edalive drug, e il<br />

should not be talen along wilh alcohols or CNS supprc$<strong>in</strong>e drugs I58l,<br />

The ccdnz<strong>in</strong>e l0 ng do noi <strong>in</strong>te@t wilh al@hol ir two studics bul some dighr addnive<br />

efects wre .Lt@led <strong>in</strong> morhd [59-61]. Uha e <strong>in</strong>rcBction @cured, it appeed lo he due<br />

to d!. @rb<strong>in</strong>.d or lddifie enrd neryos d.DMl.ffet5 <strong>of</strong> both lhc atcohol od th€<br />

mdnist.m<strong>in</strong>e 1621. lr had bee. obsened that both c€tiliz<strong>in</strong>e t0 mg alone <strong>in</strong> onb<strong>in</strong>ation with<br />

ni@sulide 100 ng d.c@d wheal !d fle Esrone sisrifi@tly !r 2 hou6 and lhe<br />

€spose cont<strong>in</strong>u€d to decr€ase dll 6 how post dosilg. Th€ d4re6e M nuch hore wh€n<br />

onbi..ri@ <strong>of</strong> cet<strong>in</strong>nne ed nimdulid€ @ 8iyo 3 @mp.Fd lo c.ridt@ alotre. This<br />

sugSesl€d a synergistic €if*t ot cetiriz<strong>in</strong>e ed nimdulid€ therc sd no study reporle'l $ fr<br />

show<strong>in</strong>g dy phmcody.uic dd ph.@oL<strong>in</strong> ti6 i e@don beiwcq n<strong>in</strong>6did. &d<br />

cetuizjne. PhmMdynmics <strong>in</strong>e@tion wa noE Dlausible for resulrs obla<strong>in</strong>ed 4<br />

n<strong>in</strong>esulide h.d ben aponed to hav. borh dli <strong>in</strong>Jldnsrory and $rihi$an<strong>in</strong>ic actilities<br />

[63]. Dose rDponion l cmd valEs wd€ @hi.ved wirh<strong>in</strong> I hor <strong>of</strong> onl adh<strong>in</strong>ist.arion or<br />

arnizie. CoBisre wit! rbe polr @tur <strong>of</strong> this @tbxtlic @id dru& l.s th& I tr^ <strong>of</strong> p.d<br />

pldna ld€ls had b€en m@rd io th. bm<strong>in</strong>. Celirirne m.ol €xlosilel! nebboliad ed<br />

70qlo <strong>of</strong>the l0 ns w6 excrclcd <strong>in</strong> th€ u<strong>in</strong> an

---

&d no dN adj$uned <strong>of</strong> c€0rizim wa n*ssy. Thc €lecuocddiogdphic eilst ot<br />

@tiriz<strong>in</strong>e w6 studied <strong>in</strong> l0 HIV subjecls. No parient hod signifimt eleclroctrdiognphic<br />

chug$ du<strong>in</strong>g cetiriz<strong>in</strong>e adn<strong>in</strong>islntion. So, edriz<strong>in</strong>e *s efc &dhislam<strong>in</strong>e drus <strong>in</strong> palienk<br />

rEat d wirh ph [65]. Ir€ Ecc .tr@rs <strong>of</strong> cairizirc wft sludied <strong>in</strong> nomal subi6.s dd<br />

a

---

C Int nctilgdrug!<br />

Cet<strong>in</strong>z<strong>in</strong>e is widely prceritEd

---

static (HMC-coA lldElas irhibibE) @ on. <strong>of</strong>lnc bcr widely prc$nbed chs <strong>of</strong><br />

.lrugs d&ueholn tb. wodd, b6au. <strong>of</strong> lheir 4@ll@1 cholor.rolloEirg cffecr &d ov€ratt<br />

sfely prclile ex@pi for @ but fat l rhabdomyolysh &is<strong>in</strong>g eider dir€ctly or <strong>in</strong>dnedly by<br />

phdllr@tirdic irl@doN wirh enatu olnq drugs F8l. SrdjE m ptomm€d dlugs rsed<br />

<strong>in</strong> th. hcat hdt <strong>of</strong> hypdlipid@i.. They m f&st posEs<strong>in</strong>g ed 6s<strong>tn</strong> drugs. Siovsi|rilr<br />

pnvatai<strong>in</strong>, cdivdraf<strong>in</strong> fld alorvstad. de sm. <strong>of</strong>lhe doSs <strong>in</strong>clud€d <strong>in</strong> this category [79].<br />

Nmb.R <strong>of</strong> <strong>in</strong>teaciotu <strong>of</strong> slari$ h.w ben Epon d wirh diff@r

---

Resfuh on 4{u<strong>in</strong>olon.-3.carboxyhr€s had l.d to th€ dieovery <strong>of</strong> a fmily <strong>of</strong> 6-flum-7,<br />

pip€ru<strong>in</strong>yl4-qu<strong>in</strong>olon s &live aea<strong>in</strong>st bur.ti. i, ytuo s well s ui!@lluld palhosqs ed<br />

t <strong>in</strong>ethoF<strong>in</strong> eisl' micrebes tEa9al. Coudrivcly. rh* @Dpouds \,ft called<br />

fdoqu<strong>in</strong>oloes [E51. 'fte qu<strong>in</strong>ol<strong>of</strong>t adbet!.ials e p|lE to l@y <strong>in</strong>r.Ecriotu vith other<br />

&!gs. Qu<strong>in</strong>ol<strong>of</strong>t .beDlion b nEledly Edw.d wnh mrtri& and rh.r.p.uric failw my<br />

resull. OilM nelallic ion-contaiong drugs 6.ls r€dwe abso+rion. Som. <strong>of</strong>ue newer<br />

qu<strong>in</strong>olones <strong>in</strong>libned tbe ct1@hrcne P450 systen.<br />

T.bL l,r<br />

Qukot B &kd.dJor tiktdiLr I7+1n<br />

(phs d m<strong>in</strong>6|+fl mF2Jnihydrc3-m€$yl-l014n.rlyl.!pipq@<strong>in</strong>yt>7oxo-7<br />

H- pyrido{ l:,3- de l- l,4,b.naE<strong>in</strong>.-6-<br />

€lb.r)lic,c'd:( rHrfNo. aprle)elto\orbnShr ' . _<br />

t.llow, cryshll<strong>in</strong>e poNder, slightly soluble <strong>in</strong> wdr€r,<br />

glioirl reric ei4 slighlly solubl. mdhylere chlolid.<br />

ItttlopDpyl+nlre l,1.diht de{{xc 7{ | tip.e'nt l) 3{urnon*<br />

catorylic eid; C'HdNIO I Solubl. <strong>in</strong> *e.<br />

ifilil,fr"lt**""'""'cubreisrn'<br />

l-.lhyl-6-fl uorc-1.4-dihydc4-oxo-7-(l-pipsr<strong>in</strong>ylll,&naghlh yridirc-3-<br />

@boxylio eidj CTHDFNaOT, il foms cry$ls<br />

<strong>in</strong> dhsovnetiyleF chlori(|q tr nelr<strong>in</strong>g poirn<br />

is 220-224"C.<br />

(cir!5-m<strong>in</strong>Gl4rclop'qyu{l,<strong>tn</strong><strong>in</strong>dhyll-pip.djnyll6,8iillrcl,4dihyde-4{xc3-quimli'@!6oxylic<br />

ci4<br />

CFHlFrNlOr, Y€llow n .dl6 iom 95%<br />

rl6hol, mell<strong>in</strong>g poii 263!C , lolubl. <strong>in</strong><br />

!lk!li.s, hot alcohal, pEoric.lty iMluble <strong>in</strong><br />

I -.thyl-6.fl uorl,4-dihydD-.4{x67{ lpiFEz<strong>in</strong>yl}3-qu<strong>in</strong>ol<strong>in</strong>obox ylic<br />

&i4 C6Htr FN: Or, molcult *.ighr irll9.l,<br />

A Bhit q palcyellow. hyg@pic,<br />

phd@.sniv., cry$llic po*d.r, v..t sliehdy<br />

slubl. <strong>in</strong> tur, slighly s.lubl. <strong>in</strong> dm and<br />

l9

---

Cipt<strong>of</strong>l(eia @e<strong>in</strong> rd pc0oeir 6 im|!s rlsphylli!. @nqrllrioN 10 ioxic<br />

vdB, atrnity <strong>of</strong> quirolores fq the ga|ldd<strong>in</strong>obItldc &id 6.Fl0r nay <strong>in</strong>due CNS<br />

adv* efrets [9sl. Qu<strong>in</strong>olord have beo Epon d ro poss con{Isr &riviry [96-9].<br />

4 Cd6M.h.nr.t ukttus<br />

calciu chonel blockB e a hetercge@s sreup <strong>of</strong> dres 0lD, r0l I Fp|lgtilg a ldge,<br />

siMff.lly di!re gbup <strong>of</strong> chdiqb l|i.13h& lle lbilfty ro <strong>in</strong>libil calciu 6ry i o<br />

nusl. c.ns <strong>tn</strong>ftush &doo on rhe calciw-$l4dve ion llml. Th. ddss <strong>in</strong>clurted <strong>in</strong> |hi!<br />

careso.y re phoylalkylm<strong>in</strong>q (v€Bp.dil), bc@dj.apiE, (dilti@n), dihydopyid<strong>in</strong>c<br />

(mlodipire). diarylm<strong>in</strong>opopylmiE (tcpridil) t1031. v@pmil, diltim ed nicardip<strong>in</strong>e<br />

w fomd to <strong>in</strong>libii h.ldic dug-m.t bolizjng .Dr-_ym. SMica on ircE tion b€tw*n<br />

digox<strong>in</strong> ed dlciM.h.@l bl@t6 shoped ihn vdrdil <strong>in</strong>crled pl.sm digoxile<br />

@E@hrio6 [r04] Oth* <strong>in</strong>ra!.tioB @udd <strong>in</strong> prt.ere <strong>of</strong> @t nu2.pie, cyctGporirc<br />

and c<strong>in</strong>elid<strong>in</strong>e have ale b.d rcporr€d 005-rl0l.<br />

Trbl.l.3<br />

caL.t@ bbta' vled.nh/ idenctiN l7t11l<br />

(2S.lSf l r2 d<strong>in</strong>diylmiRrhyll2.l.4.5-bhhld@2{..n<strong>in</strong>oxy<br />

Dh.nyl)4{rel,5-h.nrc diepim<br />

.3.yle.Lt. h}dehlori&, rnjG,<br />

crylbll<strong>in</strong> po*der, solubl. <strong>in</strong> a.&.,<br />

m.0!rol rnd nedrylo. chldide,<br />

dishlly slubL <strong>in</strong> .ttdol, h n.lE<br />

1 atbul 2llcc with d..onm.ili@.<br />

Alphllt-l P{ J.{-d<strong>in</strong>.rhdtdEnrlLrhrl lDdnrbhirdprlpyU-J+<br />

ndhylaiyl)a.nanaeroniril.;t.<br />

(3,4ii-<br />

Ddhox}?herelnyl)Bdhyld<strong>in</strong>ol-2-<br />

(3,4.dim.dbxyph.nyl>2.i$.<br />

pFpylvaldnitilqcrH,NP. Flubl.<br />

ii *d.r dd m.deol, sp.<strong>in</strong>sly<br />

-v<br />

(r"<br />

I -<br />

2-l{2s<strong>in</strong>odno(}nndhylH.{2{hlotudbrl}r...dihtdrc-GD.rtyL<br />

,,5-pldd<strong>in</strong>dio6oxylic *id r

---

3 Notst@idd .ttiJnfunmto,f dr.tt (NSAIDt)<br />

Irre uLdo8enic popenies <strong>of</strong>NSAIDs sr€h fto6 the fact rhat they ft orBei. &id!, which<br />

@ <strong>in</strong>itat. rhe gsEic nu@e and ale non th€n <strong>in</strong>hibiiory .frec& on prosLglddir<br />

biosyntlElb. NSAIDS h8. ben @mi.lly tsilable lior decad.s ed e wll ttum to<br />

Ed@ pah lDd <strong>in</strong>nMado! [rr] cbD.ic us.s. <strong>of</strong> rh* drugs h|! b@ assidcd wnt<br />

lhe poFnlity for sid€ .fi€cts such N gsbo<strong>in</strong>t$tiral idilalion ed slppE$ion <strong>of</strong> Enal<br />

fiNlion <strong>in</strong> prn <strong>of</strong> the popularioi U 12- 1141.<br />

Ns,lIDs 3.t.tuI Jq i"!@jN Ot11l<br />

5-benayLa-sedtyl 2rhioDh.n.rc.lic &id. CxHuOls<br />

<strong>of</strong> 260.3 & whit micrccryslrllii., <strong>in</strong>soluble <strong>in</strong><br />

we, n6ly eluble b don., .lohol rd<br />

2{2,6iic!lr!pt ryl) ditul tq|e @ric<br />

c l,Cl,NMq. mokcuLr eaghr ir 313- l.<br />

h is 6<strong>in</strong>dy y.llowish *hirc ro ligl'r b€ige.<br />

viftdly odod.$, rluble ir wat r, alcohol,<br />

f,dnyl al@hol diglrtly elubl. <strong>in</strong> &.1onn<br />

iNlubL <strong>in</strong> .d6, chlobfdn ed dilut Gid.<br />

(9 l. llbiplknylF.dic rid, 2 fl'|l)@.ncrhyl ed (!) 2.(2.<br />

Aumbiph.nyl-4.y1)prpiaic<br />

cDHlrFo. ool.culo wigh. is 2rl4.rg,<br />

whne b dighdy yellop, cryr.ltirc<br />

Powdr, exirl .r ! tuemt <strong>of</strong> tho two<br />

optcal ism.ri irslublc <strong>in</strong> wrt r, ftely<br />

sluble ii !l..lbl, .rner, aon.. m.rhmot Md<br />

rid, CDH'P), Nhir.. .rysll<strong>in</strong>.<br />

r'r'-f'-"<br />

(2i&2-14{2-n.dtlpmpyD phdyupoFmic<br />

powder or cdoudd .ry$ti Ptuticdly<br />

irslubl. <strong>in</strong> Mt r, frly $l!bl. <strong>in</strong><br />

oeloe, m..heol .!d m.thyl.n<br />

ohldirle, Il di.slves <strong>in</strong> dild€ &lulions oialt li<br />

2-(2<strong>in</strong>iDcrhyl phoyl mjnol b@i.<br />

eid odl N- (2,3-rylayl) rdlErilie eid<br />

nolall& rci3hr is 241.1, el Ed<br />

dnd whit oddl6 micetsdl<strong>in</strong>c<br />

pow.r.r, en h4twpiq <strong>in</strong>slubk <strong>in</strong><br />

hyddides ad @boml4.<br />

qrter, solubl. <strong>in</strong> olcohol, nerlyl ilcohol, spannsly iolubl. <strong>in</strong> dhn md<br />

Meloxien i! 4-hydrcxy,2.hodyl,N{5,nelhyl-l.Srhiuol2-yD-2 H.1,2bgmrhiuiFlraboxmidcl,<br />

liioxid.<br />

havj4 l5l 8 noloLr eiShr Prldi.,lly Frri<br />

iMlubl. <strong>in</strong> ldr, :lishrt $tubk <strong>in</strong> er<strong>of</strong>t,<br />

2l

---

Typical re(tioN <strong>in</strong>clud. cpigbFic pdn, n.u.a vonit<strong>in</strong>g, didheo, bled<strong>in</strong>g .<br />

Frforaion <strong>of</strong> slomh, sm.ll or lrge i esriD., Fplic ular, hmouhlgc dd Frloniioi.<br />

Drug resislance <strong>in</strong> Eal{ia h a vit lly <strong>in</strong>por.or public h.alrh concem. E&h ye&, d<br />

est<strong>in</strong>atd 0.?-2.7 nillion people die <strong>of</strong> m.lria. The developm.nt <strong>of</strong> Esi$ance had d<br />

siSr<strong>in</strong>si <strong>in</strong>flue.e o! thc <strong>of</strong>iol <strong>of</strong> Daldi. <strong>in</strong> afi.cled @uaid, R6istte. ol pldnotlim<br />

/aLb@@ to.lnobqu<strong>in</strong> , ! 4u<strong>in</strong>oqui@lioc, B fi6r oberyed dmn 50 )td ago. Now<br />

r tlay, chlolquir€ qi5rff. @6 .lD@t iD d€ry EgioD *fi.p P lalcipatun @M,<br />

Stra<strong>in</strong>s <strong>of</strong>/z/.{Mza pa*ir6 hdd develoFd Fsistalce to mosr <strong>of</strong> the comonly usd<br />

edmaldials. <strong>in</strong>clld<strong>in</strong>g sulfadox<strong>in</strong>e-plr<strong>in</strong>elhm<strong>in</strong>e (Fssirt r) &d d€floqu<strong>in</strong> 1115-r2ll.<br />

T.bl.l.7<br />

tdiNtaials set*t.d fu i@iorc p'n)<br />

t-(4-oholorophdyl}6.ctlyl-2,4-pyriDid<strong>in</strong> di.n<strong>in</strong>c. cDHnclNa,<br />

practi€lly irsolublc <strong>in</strong> wder,<br />

eluhle <strong>in</strong> e<strong>tn</strong>uol sd dighdy<br />

$lubl. <strong>in</strong> cbn , I*t-7.3,<br />

pdnjon cfficicnr 2.7 <strong>in</strong><br />

!4us ejd od 2.86 <strong>in</strong> rqllos<br />

lI -(?-chlosqu<strong>in</strong>ol<strong>in</strong>-1-yllM,lV-diedylp.nr.lr1.4diM<strong>in</strong>.bisldihydog.n<br />

phGphd). whiE or nd *nite,<br />

crysu<strong>in</strong>e po*ds, hygbspicj 6ely $lubl. <strong>in</strong> wis, slightly<br />

srubl. <strong>in</strong> alahol Md<br />

mdnuol lt dis <strong>in</strong> 2 fmi<br />

orc <strong>of</strong> *hich n.lts .hour<br />

I95 "C rd .h€ olh.r .t lhour<br />

218.C.<br />

7 Antiath.tttL tbust<br />

Irt cpiBlolt dng rD*cl is domiMcd b, jusr te <strong>in</strong>diddotuJ 6dn ond chrcnic<br />

ob.tructjle pulno.lry dis.e. Alth.uel rh* dis.s m rr€.r.d with thc me drugs. rhey<br />

difci significanlly <strong>in</strong> th.L sderly<strong>in</strong>s etiology, Borh & ch@d.dad by loe <strong>in</strong>flallmtioD.<br />

tlow.vr, patimrs with arhna suff€r lars.ly fron wdible aidlow obstrurio., wh@d<br />

padd$ wi<strong>tn</strong> chrcnic obsriuclive pulbonary di3.e qpqierce a @Dr<strong>in</strong>uou dslire <strong>in</strong> lug<br />

tu ction 6 rhen disc4 P'ogffi [lr]. Asrhm-Elll€d lait' bctud. ct<strong>in</strong>i€l synp{om <strong>of</strong><br />

22

---

dslhma swh s cough<strong>in</strong>S, whez<strong>in</strong>g, dd dyspneai bronchial hyp.r.sponsivo*s (BHR) as<br />

aesd by nedacholift chill€trge lesti $M lgE ldelsj aropy; 6d stopic dermariis.<br />

motclulosl is l€ulorri.ne modifia. guif.BiD is & qFctom! ph.nylcphdne<br />

hydr@hlorid. is a dMrgdarr ed a . mydriatic <strong>in</strong> ophth.lni. appli€tioB [r2]-r251<br />

T.bl. l,<br />

,lntilthnatics slect d ht bne@tiots 113-11)<br />

112'nahoryph.mxyll,2- DdpoEdiol, C'oHkO{<br />

crysbll<strong>in</strong>. po*dsj $lublc <strong>in</strong> wab, ..hmol,<br />

cholorolom, <strong>in</strong>sluble <strong>in</strong> pctol.un ertd,<br />

p<strong>tn</strong>ioD e@m.i. (@hnotwri.r) 1.4, rquous<br />

..>

---

. ihclcri.l sFcrruD .rd sutdi iN al Fcirion 3 <strong>of</strong> 0E dilydorhi&ire rirs dr.r i[.<br />

phm(ot<strong>in</strong>.ric! sd m.cbol( pamdeu <strong>of</strong> rh. dxs It2t]<br />

c.pktrNpqi$ kb.kd fu MM 11+111<br />

Disdiqr 6/t,7rt!7-{ltzX2{iiorfi iMr,l-ylIm.6qy<strong>in</strong><strong>in</strong>o, Gryll.D'nol<br />

i\*<br />

CtrHbNrNilqSr.3%H,, tcly $hhle <strong>in</strong> *!r.', lplmrly eluble <strong>in</strong> m.thml,<br />

q 3liddv $lublc <strong>in</strong> .thel.<br />

[6 R .[6,lpha'bad R''ll.?.ltM<strong>in</strong>ophntlr.!ld<strong>in</strong>o]-l.m.rhyr.3-oxo-5.<br />

lhi!-l-@bicyclo l,t,2.0let2-.n.-2c.rboxylic<br />

eid; CduNlO.s,<br />

nol@Lr *i8ht ir 14239, Th. Disq<br />

or c.rhilcpc<strong>in</strong> exnibib noF<br />

biologicol @livity lhd de L-ismq. Ceph.ld<strong>in</strong> is d€sEd.d by sfons.cid.,<br />

alLli, ulFaviolc lirnt Md Bl.drhs.<br />

J6 R. [6dDn47bdr Z )ll U('.cryloxrrncrh rl]7{l(2s'nor,<br />

rhiuolyl)(Dethoxyim<strong>in</strong>o)dlryl jeiDol-8.<br />

oxo-5rhi.-l@bicycle{4.2.01{cl-2ar-2qboxylic<br />

rid; C,dl,?\qs:, Bdd<br />

+.ctum .hird 8.Mior .th.lcp.r<strong>in</strong><br />

dtibi

---

Hist.oc./melabolic s}t'dmne, which confen a p.diculdly high nsk <strong>of</strong> cardiovdculd d.aih.<br />

CeIMlly.tiab€1e e.llitu c.mt b. culd bui only @!iroll.d. Curutly &ailablc glucG<br />

low<strong>in</strong>g a8ats v..y @triddally i! th.n .bil y ro rldu e mic@lbd<strong>in</strong>di4 Tbe<br />

sullbnyluo sppq to hav. cflet on nidoalbu<strong>in</strong>uia expEsed d udndy<br />

alhmidcMtirim Etio, *trile iltc rhi@lidiclioG b.ve sic@ e$dr on rhis isk f&bi<br />

<strong>in</strong> pa'all.l qilh dEn ef.cts or iGulir 6isl.@ {rtq.<br />

NtDDLk yl6t d l* itudiN 11911<br />

NN- dim.lhylimidodiqrbonimidio dimide, I,l -dim.rhylbraumid.r<br />

C.HrClNjj FEly slublc <strong>in</strong> rlc.,<br />

tlighdy elubl. <strong>in</strong> .Lohol, Fdielly<br />

<strong>in</strong>elubl. <strong>in</strong> &.tonc .nd <strong>in</strong> m.rhyl.n.<br />

ohlorid., m.lt<strong>in</strong>8 po<strong>in</strong>l is 222 - 226<br />

l-[a-[2'ft 5+hl@2{rhdybd"iyl)dn<strong>in</strong>o]anylp66ylFulphonyll-3-<br />

.ycloh.xyluEr, crHrclNrors; wnn.<br />

or dmosl *hit, ciysrlllire pdwd.r,<br />

pncriolly iNoluble <strong>in</strong> w!l.., spar<strong>in</strong>gly<br />

$lublc <strong>in</strong> m.tftylec cnbiL, stghly<br />

slubL <strong>in</strong> .LdDl dd s.rlml.<br />

isoqu<strong>in</strong>olyl)chyll<br />

D E&ltLl ...1 tre .LEdt!<br />

c'HjNrOlS; *hit. or rlmo{<br />

shia po[d.r, pdci€lly iMlublc <strong>in</strong><br />

(96%) &d ir h.rh.!ol, elubL<br />

i d!':i:C<br />

rTr--<br />

uLr ; dighdy $luble <strong>in</strong> ethool<br />

i. .@rc, fi*ly slubl. <strong>in</strong><br />

M<strong>in</strong>dls esenli{l 10 hcdtb @ <strong>in</strong>rclv€d <strong>in</strong> Fifotu<strong>in</strong>g r&ious fiNlioE <strong>in</strong> body. thcy re<br />

oslly adh<strong>in</strong>il&Ed, s wll alonS wilh ditreHt food ddnk or 6 drugs, Tl|n defici.ncr oi<br />

ex6 My lad ro vsrioE dilrub'l6 b body. Irs. N .bout l?-20 (d.pdd<strong>in</strong>g oi dE<br />

$t@) niffids @Nn|a .ssd.l ro hl||@.utrition.<br />

Mircds e genmlly clssified ar Major or b.N nimr.k de ond rcfeftd b a 6&ntial<br />

niadis rquir€d <strong>in</strong> mouls ol l0{ bg or mrc ps d!t. nE$ @ catcim. chlorid€,<br />

25

---

dEgnesim. phosphotus, pot sium, sdim dd sul6n. Mico or tracc m<strong>in</strong>e€k e uoally<br />

rqlircd io eodts le$ lho 100 ng pq day. n'e$ m €brcmiu, oball, copps. fluoride,<br />

iodiE, ion, ndrga.e, nolybddh, slaiD &d zim-<br />

Ultu tre€ mile,als e lhose thar e pobably esential but d required only <strong>in</strong> h<strong>in</strong>ute<br />

mouts (l6s th& I ng p€' day) md uually tr be adequlely snppli.d <strong>in</strong> $e dis wi$out<br />

add.d $pplel@btior, ft* iftlud. oMiq boml' hrom<strong>in</strong> , @dnim, lad, lirhi@.<br />

nickel. sili@n. t<strong>in</strong> ed v&adiM.<br />

MaAn€sim is the founl oost abuddl n<strong>in</strong>eral <strong>in</strong> rhe body ed arprcx<strong>in</strong>al.ly 50elo oi total<br />

body daen€siu h found <strong>in</strong> bonc The olhq half is food prcdomiMlly i.side celh <strong>of</strong> body<br />

tsls od orsu. Only I % <strong>of</strong>m8rEsim is found <strong>in</strong> blood, brt tbe body *orb vdy hed ro<br />

kep blood ld€ls <strong>of</strong> nagn6im .onslaft Ir301 clta vesaabl€s swb as spiMch c good<br />

ews or m8!€sim, some lesw.s 0e4 ed p€6). nuis ad *e& ed whole.<br />

'mfDed<br />

sEiB e de sood $'@s <strong>of</strong> magciu 0311. Mag!.siM <strong>in</strong> the body sd.s sreal<br />

<strong>in</strong>po@r metabolic tunctions ad plays a iol. iD the produclion ed tr nspon oI€Mgy. Ir is<br />

also import nl for the @nirerion ed relMtion <strong>of</strong> m$l€s Masnesium is <strong>in</strong>volvcd <strong>in</strong> rhe<br />

smlhBis <strong>of</strong> pmr.<strong>in</strong> od it aisc <strong>in</strong> lhe n4cdos<strong>in</strong>e <strong>of</strong> c€rLjn €.zyn r <strong>in</strong> de body U32l<br />

Macnesim deficiency ce afed v<strong>in</strong>ually d.ry orSe sys!.b <strong>of</strong>th€ body. Wilh rcgdd ro<br />

skelelal nwle, one Day exFdoe rwilch.r, €rdps, nwle r€mion, nNle soEness.<br />

<strong>in</strong>clud<strong>in</strong>g b&k eh€s, reck pair, Lrsion hqdache ed jaw jo<strong>in</strong>l (or TMJ) d'sturclio.. Tn€<br />

@htral n.Noa sy$.m nay al$ be nwt€dly atfeted. Synploms <strong>in</strong>cludc <strong>in</strong>somia, &xiery,<br />

hlT€@tivity and catlc$Bs wiltr onslrrt movd€4 panic atra.ks, ag@phobia dd<br />

p<strong>tn</strong>€.srrlal iEitabilig, MagBiM dcfici€dcy synploms <strong>in</strong>volv<strong>in</strong>g th. Fdptehl rcdo6<br />

syslqn <strong>in</strong>clude nMbn $, t<strong>in</strong>gl<strong>in</strong>g &d o<strong>tn</strong>€r abnotml eostio6, such s zips. aps ed<br />

vibFlory *Nlio6 o331.<br />

The nosi aburdrdr d<strong>in</strong>.ral h th. hl!@ bod,, h6 sev€ral <strong>in</strong>porrel aucions. More thd<br />

9ryo <strong>of</strong>bt.l body cdciM is srocd <strong>in</strong> tbe boms srd t€el[ wh@ ir nDdiotu ro suppon rhen<br />

$ruct'e ll34l. nrc Rma<strong>in</strong><strong>in</strong>e l% h found rhmughour rbe body <strong>in</strong> bl@d, nBl. &d 1he<br />

fluid be$*n celh. Colcim is essntjd for he.llhy bon€s, il is n ed€d for mNle contr&rioq<br />

harr ato|! blood v*l @trtretion ed exp66ioa nomal blood clolr<strong>in</strong>g, t)wo6 syst m<br />

26

---

mirlende. rh. sErion <strong>of</strong> homones ed .nzycs dd send<strong>in</strong>g n€ss8es lhNugh rh€<br />

neryols sy$ed [35]. Cal€iw h added to bon6 by ells c.Ued ostoblsts ed is renolcd<br />

iion bons by *lls called osrclclsB [36]. CrlciM days e <strong>in</strong>porLnl rcle <strong>in</strong> a nmbd <strong>of</strong><br />

physiologicd pc6*s a <strong>in</strong> de qcir.bility <strong>of</strong> .elemsulr mesblaG. Ir is ale <strong>of</strong><br />

critical importance <strong>in</strong> excitaiion conuedon @upl<strong>in</strong>S <strong>in</strong> musle. Ihe mncenlration <strong>of</strong> ionic<br />

calcim ir plam is clGely rcgulal€d ed ilvolv.e onrol <strong>of</strong> i .sr<strong>in</strong>al ed renal trmpon<br />

ochdis dd mormqr ben€i bo.e &d ECF 1134. Calcim is a <strong>in</strong>poriant ct<strong>in</strong>icd<br />

pslm.Lr <strong>in</strong> tlF di.gosis <strong>of</strong> ihbalaGs <strong>in</strong> n<strong>in</strong>sal nerabolim o?ically Miard with<br />

bone di*ses, di$rdes ol pd.thrroid sle&, Mal failw or cdco [l!El. nE besr f@d<br />

ews e d.iry pr.ducts, b.$r, @uliflow.r, cg8 yo& nolaer lary g@i reselllki<br />

*d<strong>in</strong>6, clom md oysr6. Dailr Fquim.ot <strong>of</strong>carcim is E00-t200 me [139].<br />

Chrcmim is now @ognir

---

ld.ls <strong>in</strong> vidually .ll dieb. R.sadls <strong>of</strong> brrke, eioals g.n Btty mai s<strong>in</strong> si.ble dsse<br />

mdgd€F leveb s a resull <strong>of</strong> honosblic mehmius that ightly Fgulai. rh€ absorltion<br />

and .x@tion <strong>of</strong> this meta.l. Howv€r, high.doe exposG e s6i.r,:d wirh irctted<br />

liss Mge.F l.vels, €B<strong>in</strong>g adw E@lo8i.al. ep@ducivc ad rsliElory .flal' In<br />

hmds, m&ge.s.-<strong>in</strong>d@d n.wbn€rty is dsilr€d with a mobr dys{ucrion s}nlron ,<br />

comnonly efded b d nalgdism or Pehnsonis, which b <strong>of</strong> parmout concen ed is<br />

@aid.Ed ro b. ore <strong>of</strong>rhc nolt $6itiE odpo<strong>in</strong>6 [r4]. Mdg&* is lbelb€d noD lh.<br />

smdl <strong>in</strong>resl<strong>in</strong>e and th€n F.Npolr.d via blood <strong>in</strong> rhe tival€ f@ houd lo r baa gtobut<strong>in</strong>.<br />

lraomegei!, lt h exceled <strong>in</strong> th. bil. and thro!€I the <strong>in</strong>rcat<strong>in</strong>al wall. Th€ eour.xcr.tcd<br />

<strong>in</strong> uir. is v€ty sndl [lrl4].<br />

Ircn hs the capeiry ro ecepl ed do&re €Lctrons Eadily, <strong>in</strong>t''rconverl<strong>in</strong>8 between fdri.<br />

(Fcr) od re@u (Fe'?) fom. This capabilig @la ft a Btul oopomr <strong>of</strong> cr{oheDci<br />

oxygo-b<strong>in</strong>d<strong>in</strong>g oolcule .rd nmy ozlm.s. Howr, ire. 6 ale dm!s. tissG by<br />

cslalyz<strong>in</strong>g thc convesior <strong>of</strong> hydrog€n pqoxid. io n@-udic.l ios thfi anrck elluld<br />

hmbr@s! prci.iG ud DNA. Ircn pnbpo.phydD O€be) .d ibn+ultu cluI€s sF. a<br />

@yme @feloB 0:l5l-<br />

Each crydmyte @ntaiB billioa.iohs <strong>of</strong> iren| r norml nEs <strong>of</strong><br />

tllmv{, rnis @Mntrariotr€or..pon& ro d€ iturpoErion <strong>of</strong> 2 x Ido abN <strong>of</strong> iM pdday<br />

0{61. Conseq@ntly, ddia is fie cnd<strong>in</strong>al sign <strong>of</strong> ircn d€fici.ncy. Mqr <strong>of</strong> rh€ rna<strong>in</strong><strong>in</strong>g<br />

body ircn is fould i! hepddtts sd Eticulendotb€lisl tuIophagd, which we s srodge<br />

d.poL. The livd ha firsl-ps.c.* to di€ra.y nurriols a.d @@dily tak up&mour <strong>of</strong><br />

circula<strong>in</strong>g ircn dit €xc4

---

e$enrid fuciion ol cob.h is rs a conponenr <strong>of</strong> vir BD. Cobalt uually @Nid.Ed a nonbnc.<br />

hower. *!er€ c&.lie failue od some ddths <strong>in</strong> mm have icsuli.d fron<br />

ct)llsmflior <strong>of</strong> legc moun <strong>of</strong> b€r @ a<strong>in</strong><strong>in</strong>g 1.2 1.5 pprn @bal104ll. Both exe$ dd a<br />

deficioc, <strong>of</strong> obdlt ce irhibn lbt@id activity ed ob6ll s virom<strong>in</strong> Ba €anses p€nicious<br />

d6ia. High lweh <strong>of</strong> cobalr ce pod@ a polycrdcni! <strong>in</strong> mmy sFcies[lso]. Laee<br />

uod <strong>of</strong> @b6ltou ct oride d@B dE producljon <strong>of</strong> .rtallmttd [r5ll.<br />

Nickel 6 eliv'l|€ ccna<strong>in</strong> qzyn s ,r urro. allhouSh lhir ef€cl is mosl preblbly mn<br />

specific. HisI concenlrldos <strong>of</strong> Cr md Ni, th.ir fm b<strong>in</strong>d<strong>in</strong>e <strong>in</strong> nucleic *ids m

---

dcficimy @ b€ b€st d€teted tbougl a pos'tiv. 6IoM to $ppl.henrllion rridr. Zirc<br />

supplcm.ntltion h6 ben shom b bav€ a p6iriv..f€.t on <strong>tn</strong>e <strong>in</strong>cidae oadieba ord<br />

pnemonia md nigh lead lo a da@e <strong>in</strong> thc <strong>in</strong>cideM <strong>of</strong> mal&io. Z<strong>in</strong>c hs de prolen lo<br />

d€cr€6e lh. duradon <strong>of</strong>diuhea by 15% [1591. ft€ impondce <strong>of</strong>z<strong>in</strong>c for huna hql<strong>in</strong> wa<br />

fist docmentcd <strong>in</strong> 1963. Du<strong>in</strong>g ttr€ p6l 25 yds, denci€ey <strong>of</strong> z<strong>in</strong>c <strong>in</strong> hhm due 10<br />

nutritiomlfrctos dd Fvenl dist* sl!l$ h6 now be@ !@cniz!d. Z<strong>in</strong>c is rcquiFd for<br />

ndy biologicsl turctioN imlnd<strong>in</strong>g DNA synthcais, kll divisiotr ed gde dpcssion. ll is<br />

r€quircd for th. activny <strong>of</strong> tIEy.My@s <strong>in</strong> biologic.l sysrem. R@ studics <strong>in</strong>dicaE th4<br />

z<strong>in</strong>c is nad.d for @ll-n dial€d ilmuity. U601, d.ily EquiEne is l0lo l5 h& l0lo40<br />

% <strong>of</strong> the di.lary z<strong>in</strong>c is abe.bed ftom lhc arDll i.Gsti@, the absQtion appea to be<br />

Mi.r.d wirh nuiilionrl $ars [16l]. Absolprion <strong>of</strong> ntr ba b@ d€cEa.d wilh rhe<br />

fomalioD <strong>of</strong> <strong>in</strong>soluble mmpldB wilh phrlli. (@rcrlt, calciu, villln<strong>in</strong> D, prctc<strong>in</strong> dd<br />

fib.r. hc@ed copper <strong>in</strong>laks m also suppFss zi.c ab$rplion by @npelition fot albunio<br />

b<strong>in</strong>d<strong>in</strong>s sites 1162l. It h excEled <strong>in</strong> the f.ces wirh only tr@s apFd<strong>in</strong>g <strong>in</strong> the u<strong>in</strong>. s<strong>in</strong>ca th€<br />

kidrcys h.v€ liul€ or no rcle <strong>in</strong> rcsulat<strong>in</strong>s the cont nt <strong>of</strong>zi@ <strong>in</strong> lhe body 0631.<br />

l0<br />

CadniM is ! hana meral with a high roxicity, it is loxic ar v.ry lo* qposw lev.ls ed has<br />

eulc ed chrcnic clfdrs od halll dd dvimmo. CadniM is .ol d€gmdabl. <strong>in</strong> tutft<br />

dd will ths, on@ lelq$d lo rhe envirmen|, stay <strong>in</strong> cionstion. Nw elcss add lo $e<br />

alaady .xist<strong>in</strong>e d.posis <strong>of</strong> @dsim <strong>in</strong> rhc e.vircm.ni. Csdmim tud codniu conpobds<br />

m, @np@d !o other h€avy b.lals, relatilely MLr sluble. They N th€Efore also noE<br />

Dobile <strong>in</strong> €.s. soil, senerolly more bioavailabl. &d t€nd lo bi@mulat€. Chonic @dnim<br />

exposw produc.s a wi.l€ vdiely <strong>of</strong> &u. &d ctronic €fsrs <strong>in</strong> hdm. cadniw<br />

umulat.s <strong>in</strong> tlE humm body dd €sFcially <strong>in</strong> rhc tidn ts [164]. Cadrbim sulphid. ed<br />

cidniM sdd.tc had betr used for rh€ r,lsl,ndt <strong>of</strong> st<strong>in</strong> @ndition &d cy. iritclion,<br />

Gpetilcly 1165l A suficior @@E tid (200 l1r/s) dabasd ilE Lidney cell, Gultiry <strong>in</strong><br />

preximal ruhle i.juty and Fote<strong>in</strong>uia U66l- ln rh. GI te! rhe abGotplon <strong>of</strong> cldniE is<br />

poo', studies <strong>in</strong> $e laboFtory e<strong>in</strong>als <strong>in</strong>diqLd tht enenr <strong>of</strong> absorydon lo b€ only l.t%<br />

[167] md limit d sludies <strong>in</strong> M <strong>in</strong>dlcated d valu. <strong>of</strong> 6bout 5%. Appoximolely 50vo <strong>of</strong>$e<br />

toral body bu.den, aner dhtdbution is foud <strong>in</strong> lhe liver dd kidneys. Livei dd kidney<br />

cont <strong>in</strong>s n.tallolhion€n, which is <strong>in</strong>d@ible by .xposw $ cadsiM [68].<br />

t0

---

tdd hody kd.a d.r diliihdm ir tutld h dr liE .!d tidE r Liw rd kidDy<br />

old E t![oltio@4 *hici i, irdu.iblc by deore ro cldoiun [r6t].<br />

E Inn.m.d.Ldq ..tirirt<br />

tfidei.. d€* .!d q,totiD Fo.tud!6 by oa c.{t .rd b..o0tit. & rho!8h !o t<br />

ilslv.d h t r.dosrori. <strong>of</strong>.lt .sic dir.r... Ir t8 b€.n ra0ord ttd dlagic didg<br />

e i!tdt!.d by corylicrrd ibfunc Espord .ad ory iMlve itrtl|noltqy o.dhr.6 &ch<br />

u HrlrDir. rd.nli&oic.cid uarloli4a crbt<strong>in</strong> r.!d o.sy dift.ed ccn typ6<br />

iocldi.g T cd|!' ur ocr4 brrorhr., ialtqbiL\ |tryqt gd a. trral. T cdtr e<br />

i@h4d i! lh. ''Fr'.i@ .ad ngl!!l[ <strong>of</strong> .lld8i. <strong>in</strong>trdn|li@ .!d .Ey phy rotc i. tt<br />

ctrcoicity <strong>of</strong>6. dir..$ tltrt r.gdlde tt iDEM .€+@e ro for.ig! t i!€o! od p|nioipCte<br />

i! it 'Dridr{@ <strong>of</strong> Fipt...|.!d o..Ld loLr|e [r?1]. A etd.dhl ho

---

Filuily iNolv.d <strong>in</strong> <strong>in</strong>flmato,y dises <strong>of</strong> $. l@s. Ii hd b€en povcd that lnsldn<strong>in</strong>e is<br />

d efi@tile siimulus for cx@tlosis ed cyioldne prod@lion nom hlllm lwg merephages,<br />

h hs also b.en suggelled <strong>tn</strong>al hislaoi@ nay conidbute to tbe longrm dolltion <strong>of</strong> lug<br />

<strong>in</strong>flal1mrion ed tissre emod.l<strong>in</strong>8 <strong>in</strong> allcrgic di*s by nodulat<strong>in</strong>g $e pildwion <strong>of</strong><br />

prc<strong>in</strong>n@torr and imuoEgdatory ned<strong>in</strong>oF by mrepbasd. tl?51.<br />

1r'<br />

0 ., - \J,-J,, ,-!<br />

:<br />

".'.t:<br />

A mild peenc. <strong>of</strong> <strong>in</strong>llmolory celb dd ICAM.I deprors oo epirhclidl cell h6 b€en<br />

demoNtrat€d even dur<strong>in</strong>g dymploMtic p€riods ih au.leic subje.ts. So lh. comt uearnefi<br />

<strong>of</strong>auergic disordeB should addrcss alle4ic <strong>in</strong>ndmtio. ed notjst $e sydploms. AUersic<br />

d<strong>in</strong>jtis ad bbnchial a1hm frequntly co'exist. Thu n is elf{vidcor that alrhoush<br />

otihislam<strong>in</strong>B (s@nd g€re61i@ Hl bldtcu) e th€ dost eidcly u!.d lsdrs for t[e<br />

rrqln@t or alldgic 6ndiio6 0?61. h ws rh. obj4tive <strong>of</strong> U. p!!sr <strong>in</strong>@rion ro<br />

synthesia nov€l sdhbbm<strong>in</strong>ic, arni-allcrgic dd dti<strong>in</strong>flasnDtory ealogrcs <strong>of</strong> ccdnz<strong>in</strong>e<br />

J2

---

the h@d imw sysid pDi€ct lion dipe, Th€r e tlo typ.s <strong>of</strong> imuiiy.<br />

A hrd. 0 no^-tpalft: btun r<br />

IEEG imuily @mfiis <strong>of</strong> n€hanicd brri6 &d c[oic€l bdis. Sk<strong>in</strong>,lhe @m <strong>of</strong><br />

th. eyq ed the mcmbffi l<strong>in</strong>iry tle reAi6tory, dig€niv€, ui@y .nd EFoductire tr*at<br />

do6 not allow nicob6 to Fr€nat<br />

nno body !d thu acl N m@hdical b.trieF. T@ <strong>in</strong><br />

rhe eyes &rl Fcr€lions <strong>in</strong> the digestive r&l dd vag<strong>in</strong>a cont <strong>in</strong>iog eMyms such s lysozrme<br />

that 6 desiroy b@tciil dd small mol€cule s <strong>in</strong>lcrf@ft e oI ansidqlbl. importarce <strong>in</strong><br />

pde. on agtoNl Infcdion ed N ampl6 <strong>of</strong> ch.n'*l bsie^.<br />

X ds i*ludes ph.g6Ics (MEopbils, @s<strong>in</strong>ophils dd mmcyrdtu bph.g6 <strong>in</strong> blood ud<br />

<strong>in</strong> Dany h.dy li$urs) whic[ @ @gniz. p60Dg6-a!siat d @leulr prrrem rhal m<br />

pEmt @ mi.bbc! but rcl on hosl cells. Ihc .bility for th€ <strong>in</strong>rale imuc Fspone to have<br />

$is Ecognition k on. factor that shos th. clo* Ebtionshjp berweo ih. iMte &d adaptive<br />

r.spoN. I e.f.'oN md @nmi rila NK cdh) kiu vFD-iDJ*t d ed cmcq *lls.<br />

Inflmalion aileis lcuk6r16 to th€ <strong>in</strong>Jation sne, *tE <strong>in</strong>nale imu. Gpos6 Mui.<br />

Irtc eni€ blood c.lls irvolved h @nsDeilic imuiry N mo@ycs (\trich develop ilio<br />

@Fph,ss), rorropnib, @sitropbils, b€ephik .rd en]6l kill6 elb I lt4.<br />

Th. €nldgenent md shifr<strong>in</strong>g <strong>of</strong> nonoc)res ftoh blood s[em 10 tissuca duc ro <strong>in</strong>fection @<br />

crlled mcrcphag.s, Th.y {e gr&t'les oEt @ nlbd pith eizytrs that h.lp !o dig6t baclerit<br />

Ncurropbils re pt€e <strong>in</strong> blood sa.am, Th€y d attet€d lo*{ds b&t ri. rDd ots ri$u€s<br />

qher they <strong>in</strong>gest bet ria dd oth€r foreign @lls by a proes rmm a chholaxis.<br />

Frs<strong>in</strong>ophils e lc$ etive .g.<strong>in</strong>sl b6.icria th6 neuuopbils dd tubphag.s. -IrEn m<strong>in</strong><br />

f<strong>in</strong>aior bar be lo .rh.h ro bacraia rd lhs h.lp imobilize rnd ldll p.ruirca. E*hophils<br />

ale p6nicip.te i, all.lgic Eactio6 ($ch a NthDa).<br />

l3

---

iy nLtophiLt url Mt c.lb<br />

Bsophils ed mst cells <strong>in</strong>ili.t hyF6ensnivny by rclca<strong>in</strong>g hist n<strong>in</strong>e thal <strong>in</strong>dues<br />

<strong>in</strong>ilamlion and snoolh nuscl. @nir.crio.. BMphils al$ piodlce substanes lhal attrsl<br />

n€ulrophils md ss<strong>in</strong>ophils towdds forig. subsidcB <strong>in</strong> ord€r to phygocytes thm.<br />

I Notunl Llller c.llt<br />

Naiual killd (NK) ceUs dc onc typ. <strong>of</strong> lyhphoctls thrt afix io stmge celh md Elese<br />

@yns that damage oure! hemb@cs <strong>of</strong> thar microorgaism. NK cells hill cd.io<br />

nic@teeisi abnom.l celh dd ells <strong>in</strong>&d.d by viruFs. 'ftey pdu@ c)iok<strong>in</strong>6 ihar<br />

€gdaie $ne <strong>of</strong> lhe fucrioG <strong>of</strong> T lymph@rt s, B lyhph@ytA ad l@rcphages.<br />

B spaifE bM.arr<br />

Speific o adapiive imnuny is 6.lquiEd imuiry rclpr*nt ai the dne ol b<strong>in</strong>ll. ll<br />

develops a0d ed€ lime <strong>of</strong> iriliol expcG <strong>of</strong> ns &d!en od a mnory is fomed. l&t<br />

cpoIB ro a peviouly 6@ul.iEd eligcn e moE €f.cliv. ed moE npid lh41hN<br />

g4nt d by i!@L iMuity. T lymphetl.s ,nd Blynphdlte. @ tro bporr! €ll<br />

i olv€d <strong>in</strong> a.quiFd im6iy.<br />

Bone l|r.mw sffit6 B-lynph@rlq hd<strong>in</strong>g spccific @For on snich panicdd &tige6<br />

m b<strong>in</strong>d. \vhm s eligcn amch6 to th.F sitai B lymphdyt s gd nimulslio4 <strong>in</strong> Bdr<br />

lbey e coNened irto plas@ ccll ehich pr

---

u CwrhaealdttutirB<br />

Whia Dlood ard eru<strong>in</strong> otlF cdL <strong>of</strong> dr imu. ry.i.d F!du. crr.ldn€ vba D utiSo<br />

k d.tet d. Cyrokir6 ed cl|aDkiB e i*gnSd <strong>of</strong> im@ synd d.y e <strong>in</strong>volEd <strong>in</strong><br />

grewth diffaaniltioo rd *tiyEtio., .k plsy ibpo(rrnr oL <strong>in</strong>,lLiSic rcrior!. Tb.y<br />

$irullL qt io vnirc blood clls ro b.com nort ctrccri!€ tillcrs.rd 1o $t-t otha whir.<br />

bl@d ells 1o . tolblc rpot CtrotiG .i$ priri.ipd. <strong>in</strong> 3Fific imuity .<strong>tn</strong> @ b.<br />

divid.d <strong>in</strong>io <strong>in</strong>laL'ti$ (k), i dftrcG (lf&), @lolr-sdDd.rils n 106 (CSF3) dd<br />

nloN c$i. f,rro.l (INF!).I!t6&oB iot6fa! vill th l?licdid <strong>of</strong> vitls lr?1.<br />

35

---

EXPERIMENTAL

---

Raw @&ituls a.d wft <strong>of</strong> Dtmr.uticd pwily, obhired Aon difi@nr pb@.@tic.l<br />

but€ds (t bl€ 2.1). ThG Eblcrs rft prc[,$d fon 16.l plrmdy dd B l!h.led.<br />

NIDDMs<br />

EXPERJMENIAL<br />

T.bl.2.l<br />

D st, b4dt dn M{@t@s<br />

x-<br />

Phm&.utio.l irduslry (Lrd.)<br />

Yugsh<strong>in</strong> Phlmx.{icd Ind.<br />

50 ahbont b6tro.i6lP.tid.n)<br />

It<br />

250<br />

200 Abbon tihombri.s (Pd,itu)<br />

Smilh Kl<strong>in</strong> B.rchm<br />

r50 Beh Phm.€uricak (P{)<br />

2m<br />

.:00<br />

20<br />

l0<br />

l0<br />

.]0<br />

Atbon lrhoddi6 P.Iitu)<br />

Brd Hod8s P itu(P{)<br />

Abbon L.bomtoi6(P itu)<br />

Bondr Hods$r Palib (Pd)<br />

36

---

Analtlical gmde Eagedl3 lle ued dur<strong>in</strong>g the whole €xFr<strong>in</strong>enlal prccedws. Melhsol &d<br />

&.lonitrile w* <strong>of</strong> (1iILC gtad.) {TEDlAo. USA), OUr€r @gefis <strong>in</strong>cluded hydrccnbri.<br />

rcid. nera dd pda pbaelm€diMire, ue!" thiouea, &ewni.le, sodim hydrend€, sdim<br />

chbnd., polassiu dihy&ogd onlophosphrlc, di$diu hydrDga onhophcphare,<br />

.@oni@ chlodde, loEo NHr $lutio4 phosphodc @id 85% (Merct, Gmy) Lm<strong>in</strong>ol<br />

(3-oimphhrlhydr@<strong>in</strong>e) M prchr*

---

AllD( 500 MHz spetron i.r s<strong>in</strong>g IMS s e <strong>in</strong>i€hal sllndad, Melt<strong>in</strong>g po<strong>in</strong>ts 1r@<br />

ieco.d.d on a Galbnnmp neh<strong>in</strong>g po<strong>in</strong>r .pp@ru. Cbdilw<strong>in</strong>csence sd T.Cell<br />

Foliieration 6ey weE pqfom€d at Pejw&i Cot r for Molcculd Medic<strong>in</strong>e dd Drus<br />

Rwh. us<strong>in</strong>g Lmh6ke RS, A-$<strong>in</strong>tillalion courer (B@knm mutd USA LS 6500).<br />

'| PEpandoa oJ.lelonlz.d toler<br />

D.-iodad wter *a pr.pald by pasirg doubl€ disilled wltd brcugb lhc d.ioiid<br />

(s1de csw 300). while monib<strong>in</strong>S th. @trdwrs@ <strong>of</strong>rle .mu.!r.<br />

2 PtuNrrtionolbrfiB<br />

Prepantion <strong>of</strong> 0.1N hta/ochlorlc 4cld (s<strong>in</strong>ulat d gBttic juice)<br />

Andlrical gndc (l I N) 9 d[ hydmblodc &id M r.km <strong>in</strong> ! lil' volumeEic 0ast ed lhc<br />

volM. w hade up lo thc n rt with deioniz.d s!r.r.<br />

Papdtutiok ol I M so.litk Mtotid.<br />

sodim hydrcnde pellers (40 g) were ratd io 1000 nr volMelric fl6k, dislvsd <strong>in</strong> deionizd<br />

wllr .rd rbe vdu. w bad. up ro UF Drlt *ith deioniud M!d.<br />

Prcp@a,ior ot0.2 Mpol8tiw c @id.<br />

14.91 g po&ssim chloride dilslved <strong>in</strong> d€-io.ied wler <strong>in</strong> I L lolMeiric flsh &d ihe<br />

volud€ made up lo the ddi wilh de-ionizd wa!.r.<br />

Pnpanion <strong>of</strong> lM potastim dihydnger uthoph6ph4.<br />

PotasiM dihydseen onlopholphaE (136.09 g), dislv€d <strong>in</strong> a litilc

---

Btf.t pH 7.a (pb''phare btt t)<br />

0.6 g <strong>of</strong> poi.siM dihydro8.D orlhophosphrtc, 6,4 g <strong>of</strong> di$dim hydrog€n orthophosphale<br />

&d 5.85 g <strong>of</strong>edim chlorid. we disslved iD suffici€nl d€-iooized watd 10 prcducc 1000<br />

rrl- dd th. pH .djusLd if M6sary.<br />

Batet pH E and g(Mm,na bufet)<br />

4.98 g <strong>of</strong> almonim chloiid. M dis$lv. <strong>in</strong> l00O triL <strong>of</strong> deionized water ed pH w4<br />

adjuled qith l0% almonia.<br />

E Uv/viibh.Frt!@pi..ldtlL<br />

I Asat ol c..bbhE shts Vl,-tilttd. sp.ctrophotoadda it tod<br />

P p pa rct io n <strong>of</strong> s a I ln io h r <strong>of</strong> c. I tr| z I re<br />

1 DM solulion <strong>of</strong> @<strong>tn</strong>izje w pr4olrd by dislvilg 0.0461 g <strong>in</strong> 100 ol <strong>in</strong> 3<strong>in</strong>ul.l€d<br />

safic jui@ .Id volMe w m.dc up with thc l.rc elv6r |o lh. @L 25 mL <strong>of</strong> priony<br />

slution w flnld dilurcd to 250 rI wirh simulated srsiric juice 10 rEl. ih. f<strong>in</strong>rl<br />

con€mt.lion <strong>of</strong>o-l bM, rcsFclively, In a s<strong>in</strong>ild way the solutiore w€r€ Flp!rcd<br />

Cohntution <strong>of</strong> ttlt .otibtution c@t <strong>of</strong> cetui2itu<br />

<strong>in</strong> the<br />

Dif&rent dilulioB rme<strong>in</strong>s liom 0.01 10 0.I nM wcrc pEpsrEd by dilut<strong>in</strong>g the $ock slulions<br />

(0.1 nM) vilh difrsert buf* ell'ioN oI pH l -9. F<strong>of</strong> rhis purpoe 5, 10, 15, 20, 25, 30, 35,<br />

,lO, 45 .nd 50 6L <strong>of</strong> slact elidzif slutioo *s eFrr.ly piFn d out <strong>in</strong> leo diff.Mt 50<br />

nL voldetric llaks &d dilllld *il[ <strong>in</strong>dividusl hfftr $lurio6 up ro lbe b!* to F!pd.<br />

rhe solulions <strong>of</strong> 0.01-0.I mM. Ih. ab6o6dce ruim w@ emqd <strong>in</strong> th€ Esion <strong>of</strong> 190-700<br />

m for th.& &lutions agaiNt O. eagent blark. Th€ @ima rlFaFd at 231 M. Gophs<br />

w ploltld for ab6o$rne asa<strong>in</strong>i @nqr.don dd sniish l<strong>in</strong> @ obl,.iftd $,hich<br />

ob€yed Ber lr$err's l3*. Epiilo valB qe ..lcllll€d n@ tF obsemric.<br />

2 conttra.tlon <strong>of</strong>th..atbtutirDc4Molltutuct<strong>in</strong>s.trugs<br />

To pl€p@ calibdrion cunes <strong>of</strong> <strong>in</strong>t€@l<strong>in</strong>8 do8!, difreHt lir€&ity dges wrc seledcd dd<br />

@ p@r.d i! laue 2.2. Gnphs 9@ plon d for .bsbs. .gd.n @r..lio. .!d !<br />

sfaieli lie m oha<strong>in</strong>ed enich oberd th. BaR |ry.<br />

39

---

T.bl.2l<br />

LMit rdgd <strong>of</strong>@lra ob.yirls Bwt lqb.n tre<br />

NIDDMS<br />

3 In eUtu awitobititi.s <strong>of</strong>..tuEii. dthrtltu rbnd.<br />

0 0t,0 |<br />

0.0t412<br />

01405t<br />

0.1-0.0.6<br />

0.1-0.6<br />

0.t4.6<br />

Th€ i, r,to availabilily sludid <strong>of</strong> celniz<strong>in</strong>c dihydncl onde dd NSAIDS were studled<br />

<strong>in</strong>dividualy <strong>in</strong> sihllared srsic juie (pH l), s<strong>in</strong>uladn3 frrll stonacn OH a), siDurldnc

---

loo

---

solutiors. Con@.nadon tug€3 <strong>of</strong> all ealytes &e givm <strong>in</strong> t2bl. 2.3. FEsh etk<strong>in</strong>8 slntios<br />

v@ peprEd daily. All $lutioB w fil|.cd (0.45 !n) aDd d.gr$cd ui.g eni€ror<br />

Clv.ktutdr,b @a.<strong>tn</strong>itu<br />

McOH HP<br />

I 1.2,50<br />

I I t2-50<br />

20 l.JJ.ll.l<br />

50 t0 3.1 I 2 5.t0{<br />

75 .18 I 2.5-100<br />

NIDDMs t0 u 2.4 I 2.5-t00<br />

2.7<br />

5 3.2 2.5-100<br />

70 l0 I 2.5.100<br />

l0 2.3 2.t100<br />

Prep@ation oI phqw.e{icat dosee fu n $npls<br />

Phm@ical fotuulatiotr <strong>of</strong> lhe Bp€.tiv. b6ds, com.rcially avaiLbl. h Polislar<br />

w€@ evalutcd. In d€n cde, sreup€ ol lwty i.blels Me <strong>in</strong>dividurlly *iel|d &d ff@ly<br />

povd.tEd <strong>in</strong> a @i{- W.i8h.d ponio! <strong>of</strong> 0E po}dd €q!i!al.d b rhe $iilbl€ moud <strong>of</strong><br />

dog (@!d<strong>in</strong>g lo tu lab.lcd cllihed) vs tusfeftd <strong>in</strong>to a 100 mL volwlric 0art. The<br />

drug m nnly dhelved <strong>in</strong> nobilc phe drd thcn dilulln wirh thi! $lvdt !p to thc ndlc a<br />

ponion <strong>of</strong>thjs $luton @ lilt Ed tbrcugl a dispoeble 0.45 trm lihd and 1nen <strong>in</strong>j€cled.<br />

Ptep@t<strong>in</strong> <strong>of</strong> sand@d drug plqru tolutifu<br />

Blood mplcs elrE sllcred fron h€althy volunim md th.n entriirged ai 3000 Am for<br />

I0 m<strong>in</strong>utes. The sup@ianl obta<strong>in</strong>ed m stor€d at -20oC Aner $rs<strong>in</strong>g, lelm ws<br />

d@rctiEted by &elonitrile ard spited dlily rith work<strong>in</strong>g $lulio6 to Fod@ d6iEd<br />

o.erhliom <strong>of</strong> ce<strong>tn</strong>tire dihldcnhide md <strong>in</strong>teEct<strong>in</strong>g drugs. l0 FL rclmc <strong>of</strong> *h<br />

mple I irjcct d ed chsmtosraphed ud.r rbove @nditioN.<br />

2 Mctlodd.v.lopn€ni.ldoptimklrion<br />

HPLC neuods wre de€lop.d ald opddizd fd @ita<strong>in</strong> pomreE b.foe nelhod<br />

validatio!. 'ft'. opt<strong>in</strong>iution <strong>of</strong> rh. erltti.al pFcdw bc b*n @ied our by varyj.g the<br />

mobile ph6e coiposirioa flow nb, pH <strong>of</strong> tlr nobile phe, dil@ts <strong>of</strong> $lutiors md<br />

42

---

wveldgth <strong>of</strong> ealyl.s <strong>in</strong> ord€r ro &hi.vc aym.<strong>tn</strong>cal p€15 wilh good rcsolulion at<br />

Ee@ble ret€niioo iime.<br />

All Blirlatiotr sr.ps wE cMi.d oor eord<strong>in</strong>S !o dE ICH guid.lirct swh s sysrem<br />

sunabilitr. *letivny, sFciticiry, lilEity (conelrlrioFdere.lor 6poM rlaio.ship),<br />

@l@y, pEisior dd sdilivi9 i,e. dctatio! Dd qurifietioa limit.<br />

Syslem suilability <strong>of</strong> the medod m evalutcd by &alyz<strong>in</strong>g fiv€ eplicale mlys.s <strong>of</strong> de<br />

dru8 .t a sFcific concenftdon for Ep.dabilily, peks slrn€Fy Gy.u.Fy facroO,<br />

th@rerical pl.l6 <strong>of</strong> O. @ll@, tululion b.t*an thc pal! <strong>of</strong> cairiz<strong>in</strong>c dihydr@bloridc<br />

&d orba d!$, llB disaibutiotr Etio (cap.cig f&tor) rld rcladv. r.rorioi.<br />

The druBs w* spik d wilh phtueuticrl fomulaiions conta<strong>in</strong><strong>in</strong>g difreient excipienls.<br />

ft. li@iry <strong>of</strong> thc h.rhod v6 evalured al dill.Mt @rcdFdtioN <strong>in</strong> dr. tuS. deib€d <strong>in</strong><br />

t bL 2.l. LilE @rclarion coeficioq i<strong>tn</strong>cMpi ad sloF vd6 lft c.lcuhr.d for<br />

'Ihe &cu€y <strong>of</strong> th. n.thod @ cal.dded d thE conenlration lwels (80, 100 and 120%)<br />

by spikj4 hDM q@titis <strong>of</strong> th€ &!s &dr,L' Dre idetiom <strong>of</strong> €acb slution weE<br />

<strong>in</strong>j€ted b SPLC ayst@ ud % @v.rt sr cdctl.l.d <strong>in</strong> @h w.<br />

For th€ p@ision <strong>of</strong> $. metho

---

3 Dmg- dru! i .ncriob srndi6<br />

The D v,r4 <strong>in</strong>tedction srudies <strong>of</strong> celiriz<strong>in</strong>e sd rll <strong>tn</strong>e o-adn<strong>in</strong>isLrcd dlu8s were cdied out<br />

ar dilfeEnl buffq medims a enpv srom&h (pH l), tull slommh (pH 4), s<strong>in</strong>ulared blood<br />

(!H ?.4) md simdaicd <strong>in</strong>tesdnal juice (!H 9). For rhis purpo$ I oo rsnl r lrock solnlions <strong>of</strong><br />

aw t r€ial or.etjrizi& .nd oltq &ues (<strong>in</strong>dividlrlly) vw pr@d.d and nixed b rEke<br />

fiml orc.nt?lion oa 5olr8bl-'' fd @h @nnnu.r Th.* l,4 kcpt on ulcr barh for 120<br />

n<strong>in</strong>ules at lfc. Ar dliquol <strong>of</strong> 5 DI ws qithdsu a116 every 15 m<strong>in</strong>ur.s im€ryals ed an€r<br />

n kile suitable dilurions wft $med on Uv-visible specirophotomcid. ln the sme<br />

mamr for sludy<strong>in</strong>g <strong>in</strong>renctio.s on HPLC, ih. supl.s w@ filt€r€d through 0,45 Fn fill€r<br />

paper anr mrtirg .ppopriat€ diltjoB rd thE. rsPlicals we <strong>in</strong>jcrad <strong>in</strong> to the srsrem.<br />

Th. co@Fation <strong>of</strong> @h drg rc d.lem<strong>in</strong>ed dd % @vdy itr @h c& w6 c.lculal€d.<br />

4 Dng {.t!l i.rcnctio! rrldid<br />

l,rr'to availability <strong>of</strong>c.ririz<strong>in</strong>e <strong>in</strong> pEerce <strong>of</strong> n llh ws detem<strong>in</strong> d by disslv<strong>in</strong>S l0 ne <strong>of</strong><br />

c.t iz<strong>in</strong>e <strong>in</strong> 100 mL mixtue <strong>of</strong>90:10 n€thsol ed wat r. enicated for l0 Fioul$. Sbct<br />

elulion <strong>of</strong> th€ <strong>in</strong>mai sian.hrd, pmpyl peab.n, ws sihilely p@psed. 'nF @e.nl.ation <strong>of</strong><br />

bolh sto.k $tunons ws .quiEtot ro 100 |r8DL'. Slek elurioE <strong>of</strong> n rab srlc<br />

(M8cb.6HtO, caclr.2Hro, crc|i6Hro, M'CD.HrO, F.Cl3.6HrO, CoClr.6HrO, Nicl!6tl,o.<br />

cuclz.2H?o. zich ald CdCl:.Hro) w prcpscd by dislv<strong>in</strong>s 5De <strong>of</strong>ech <strong>in</strong> 100 mL <strong>of</strong><br />

de-ionizd water ro gilc @ocntradoc <strong>of</strong> 50 FgoLr.<br />

Equivolme slock elutioB <strong>of</strong> Delal ud @ti.iz<strong>in</strong>e wrc nixed togedt r ro give f<strong>in</strong>al<br />

@dcentdion <strong>of</strong> 50 Fgmlr <strong>of</strong> edriz<strong>in</strong>e &d 25 lrgnrr <strong>of</strong> m.tsl salts for dng-neral<br />

<strong>in</strong>t@tior Th6e elurioB wrc pl&€r! <strong>in</strong> wdd.ba$ na<strong>in</strong>b<strong>in</strong>€d ar l1a 5"C for d hou, rh.n<br />

lillcEd lbrcugh a 0.45 rrn lihlr @pe ed <strong>in</strong>jered for 4al'sis.<br />

G SD..rtuopt ltudla <strong>of</strong>orpld.r<br />

Cdirizire md its conpld$ weE chlEredzd by FT-IR sp€lrophobD.u <strong>in</strong> the Egion <strong>of</strong><br />

409000 qr The <strong>in</strong>fftd rpetr! w@ @rdcd s a Dorasim brenid€ dis nellod.<br />

Polon NMR sludics wF cdied our on a Brukd i$nrnent <strong>in</strong> deutcrared wrr. m€<strong>tn</strong>mol<br />

ed cblo<strong>of</strong>om u<strong>in</strong>8 l MS .s d <strong>in</strong>leml slsdrd.

---

g Srarn6i! <strong>of</strong> d.riv.tivd<br />

I I g <strong>of</strong> cedriz<strong>in</strong>€ m reacted Mrh 0.5 8 n€io md pm phoylen.dim<strong>in</strong>e wnh out my<br />

elvenl at 140.160'C on sd b.th. ItE eclion ws modloEd ai.r.very 30 n<strong>in</strong>utes by<br />

applyiq TLC. The prcduct M lh€n c@l€d dd kn for .r'sLlliztio. m

---

la* dd HBSS+ *s !dd.d to @h wll to oblAi! . 200 pjl volM./wll. 'ft. lhrgoclrosis<br />

k<strong>in</strong>elic sludies vc monitored with lm<strong>in</strong>on rd for 50 n<strong>in</strong>utes <strong>in</strong> th. Fpeated $tu nod€.<br />

P€at ad told <strong>in</strong>l.gral ch.milmiMqce cld<strong>in</strong>8s w@ .xprcssd <strong>in</strong> rhc cl.tively liSh un.<br />

J T-C.[ Foli|<strong>in</strong>tio! ery<br />

l0 nL blmd E @lletcd by vei! puactw h h.D6r<strong>in</strong> @drd<strong>in</strong><strong>in</strong>g lub. nob a n,thy<br />

volute€r. 50 mL sLdlc hl@n nrb€ m pla.d <strong>in</strong> stuy.€!ber (.r liditc @ndirio6) to 1nie<br />

wa added blood, ficoll paque ed RPMI <strong>in</strong>@mpl.t n€dia iwnho fctll boliie stm) <strong>in</strong><br />

equal lolme. 5 nL li@U paque wa added <strong>in</strong> rhr@ 15 nL stenb enpty cenrritug€ lub€s md<br />

enbituged d 4{0xs for 20 m<strong>in</strong>ut€s at room reDp.nrN with no brcak. Pqiph.nl blood<br />

homrEl@ eus (PBMCS) apFared n th! junclion <strong>of</strong> trc layeF, th. upp6 layd @<br />

di$arded ord ln. lowd @d!i!i.g tb€ PBMC5 vs Fesf€d.d ir @lnd slllil. tub., *trs&d<br />

qnh RPMI ir@hpler! nldia ed @Eifucd $dn sl 300xg for l0 n<strong>in</strong>ults !r 4qC. The<br />

$pe@lant wa dhddcd dd r€susp€nded pcuct <strong>in</strong> I DL RPMI <strong>in</strong>@mpl.i. ncdia ed sroed<br />

on ie. The viability <strong>of</strong> the cells @ chect€d by Lyp.n bl@ ed cclls w.e coured by<br />

hm6'tonEler. 50 pL <strong>of</strong> 5% conpl€te RPMI w6 add€d <strong>in</strong>to @h qcll <strong>of</strong> . sterile 96 well<br />

plate io srdiL cnviom. B<strong>in</strong>s saf€ry ob<strong>in</strong>a follosrcd by spl. dD$ h|<strong>in</strong>g ln€<br />

@Mftrim berw.n 6.25 ed 100 psnl-_r adjcdng dlc fidl wll@ ro 0,1 mL. wlile wlt<br />

'A @trla<strong>in</strong>ed only 5% @npl.a &PMI ro bc u*d a @!irol. 50IL PBMC ells (lxl06hL)<br />

sF added <strong>in</strong> !6posion ot 5% onpl.t RPMI ro @h wll €xcept blarl follosed by th€<br />

addiiion <strong>of</strong> 50 !L PHA ex@pi negadv€ @Dtol dd bldk dd volme <strong>of</strong> well wd nade up lo<br />

0.2 nl by 5% compl.t RPMI .Ille mixrw wa <strong>in</strong> ubat€d for 72 ho$ <strong>in</strong> CO, <strong>in</strong>cubald at<br />

3?qc. And ircub.tion 25 lll otthldidim *as ad.led <strong>in</strong> @h wel €icept bl& ard the plsre<br />

aa<strong>in</strong> ircubared <strong>in</strong> cq <strong>in</strong>cutoro..t 3?oc for lE hoE. An r <strong>in</strong>cublrion @us wE hdeled<br />

s<strong>in</strong>g ela 6b.r 6Iq 6d lhe all b.rcnd, In @ll haFdl<strong>in</strong>g rhe plar.s \m sash€d witr<br />

70% ethdol 5 tim.s, fih.r€d .nd leff 6dl $cy \^@ @npl€l€ly dry, thcn dislved <strong>in</strong><br />

sepanle vi.ls us<strong>in</strong>g thc sc<strong>in</strong>tillador elution md 6cmd by s<strong>in</strong>rillaiion .ouid.

---

RESULTS & DISCUSSION

---

RESULTS AND DISCUSSION<br />

The possibiliiy <strong>of</strong> druss ro <strong>in</strong>i uence each orhos sfety or emecy is <strong>tn</strong>oM as drug-drug<br />

ifletudon, Th€ esuhs <strong>of</strong>a r€ce.r Egi$ry stldy ildicated thal ar l.st 250,000 Fsos die<br />

q.h y@ 6 r E dr <strong>of</strong> @s Eade Btilc thcy e hospnaliad. 'Ilt. hnk <strong>of</strong> fice do6<br />

itrvolvcd nbadv€trtws pith lhmpeulic drugs 0E31. Drng i .r.clioB @nnonly @cu<br />

with multipls medications, may nate drug less e,Iecdve, csuse uncxp.cted side efTects. or<br />

ilqess lhe action <strong>of</strong> a panicule dsg. Son. ddg <strong>in</strong>tetutions 6 clen be hmtul dd hay<br />

bre pl&. due to @ion <strong>of</strong> dlugs with @h oth.r. This r'rusnrug <strong>in</strong>re@don my o@ to<br />

.xF i.n* & uexpelted sidc eff6a Dru-food,bev@g€ <strong>in</strong>tcnctios esuh from dnCr<br />

Eml<strong>in</strong>g wilh fmds o. b€v.rd8cs 0841. Most <strong>in</strong>te@tioG r€ma<strong>in</strong> t!@ognird b€cdue drugs,<br />

b gei.rrl, havc a wide ndgio <strong>of</strong> sfety or b€cause the exlenr <strong>of</strong> chdge <strong>in</strong> drug leveh is<br />

sall wh.n compded with vdiadon nomally s6 <strong>in</strong> cl<strong>in</strong>ical thdpy. All drw <strong>in</strong>tcdcions<br />

hat t phm@k<strong>in</strong>etic or phmaodylmic b6is [85]. on rh.s€ tes a pmc€duE rc<br />

adaptcd ro study the - vlz <strong>in</strong>lerulior olceiriz<strong>in</strong> *irh difreMr @ adnidstqed dDgs. Fo!<br />

thjs purpose diilf<strong>tn</strong>l sp€clrosopic lechniqu.s w.rc ued md conpoEd. S<strong>in</strong>ullaneous<br />

nethod! wer€ als d€v€lop€d dd vali.bt d tor th€ .lelemimtion <strong>of</strong> ednz<strong>in</strong>e <strong>in</strong> Pl€eoce <strong>of</strong><br />

dif€E dtues 6<strong>in</strong>s RP-HPLC lEhniqE. AI <strong>tn</strong> F n€thods wd late. on used 10 sludy rhe<br />

p6\iblcr, v,i.o <strong>in</strong>tetulion<strong>of</strong> er<strong>in</strong>ttr widdificrnt dngs<br />

A UY-Vilible3p..lolcopy<br />

aralysis <strong>of</strong> cdniz<strong>in</strong> hs b.d snrdi€d qt€6iv.ly by UV spetrcs@py [27-29] blt all $e$<br />

n rho

---

e this wveldgth {a cbos fd ou o,lyric.l<br />

@ <strong>of</strong> li.@ rcgEssior fdcdon obla<strong>in</strong>ed by<br />

plonirg @n@ii.tior vesB abc<strong>of</strong>tdre <strong>in</strong> lhe<br />

rorEDg @n@tlrion tuge<br />

Suiiability <strong>of</strong> lhe nethod M ch*ked by<br />

ddynnS lhe li@iiy ai $e 3.r coicefadon<br />

drgc a pFncd <strong>in</strong> rable 3. | . Thcs drh sir<br />

w@ .pplied 10 lirca rcgEssion tunction, ed<br />

fie r$ulis ohl<strong>in</strong>ed @ givd id l.ble 3.2, *hich<br />

cldly iodica&d thar the n€thod *a sunalb for<br />

all romulations. ft€ soodms-ortu (i1 wq<br />

studiB. nis nel[od <strong>in</strong>rclv.d simullrn@N<br />

T.bl.3,l<br />

% R@t ry <strong>of</strong> dni'k2 h btdza <strong>of</strong> pH<br />

1.2 atd 7.1d 23lm<br />

foud ro b. 0.99E sr pH 1.2 md 0.999 al pH 7.4. In ords b detcm<strong>in</strong>e &cuey <strong>of</strong> Lhe<br />

method, kloM qrdtiii€s <strong>of</strong> ccii.izi@ wd spik d<br />

sr.nd!.& md wa salyzed <strong>in</strong> <strong>tn</strong>@ Epli€a1*.<br />

It ha bd ohcdlcd $al th. ndlod B dui.<br />

*i$ io the eivo m8c. The nc<strong>in</strong>od pds*d fic icst<br />

for repalability a delem<strong>in</strong>ed by M<strong>in</strong>g six<br />

epliotB <strong>of</strong> thc 100% esr $lution @rd<strong>in</strong>g ro<br />

ICH glid.lic. Thc daltticd E$lts oh.jncd<br />

non thee <strong>in</strong>v€sligations for both nethorb @<br />

sllr)mkld <strong>in</strong> t!bl. 3,1. ft. ddation l<strong>in</strong>it or<br />

(LoD) ad l<strong>in</strong>it <strong>of</strong> qua ihdon (LoQ) lor<br />

ceriiizi.e *d ch.ck d al two pH l€v€ls i.e. pH 1.2<br />

&d pH 7.4, LOD for e<strong>in</strong>z<strong>in</strong>e at pH L2 wN foud<br />

1o bG 0.04 lrgml,'od 0.01 fgnL''ar pH 7.4, For<br />

Ev na,1erid <strong>of</strong> ceririzire th. LOQ volc wa<br />

fowd 10 be 0.14 pgml ' al pH 1.2 ed 0.1 1 pgnl '<br />

DHI2<br />

Lir.o wsiq tNti.w adttEtrs@ .al,Mtat<br />

9.21 ,9.3<br />

9t.t8<br />

I3.57 t03.t6 91.23<br />

.11.09 107.34<br />

27.7 | 96.57 93.0E<br />

t2.tl 100.01 t02.65 l02.ll<br />

s.E.E.t<br />

l0l..r2 r01.91<br />

<strong>in</strong> the dtug poduct fouow<strong>in</strong>g USP 2009<br />

r.bh 33<br />

,awat ad Prchl$ oJth. propaed<br />

23_09<br />

LOD LOQ<br />

2I 0.62<br />

2ll 0.t2 0_01 0_l I<br />

l{D.63<br />

l3_95 102.65<br />

lo65<br />

23.06<br />

21.0t<br />

.2106 99.83<br />

)t 07<br />

.2105<br />

100.36<br />

002<br />

at pH 7.4. Similely thc LoD od LoQ <strong>in</strong><br />

48

---

s€@ we obs.led to b. 0.04 l!gn[ 'and 0.15 llgnl- ' esp.criv€ly. Equiul.@ sludy w6<br />

perfomed al difeEnl bmds ol celniz<strong>in</strong>e rablets availdble jn Potjsllr The svajlabihy <strong>of</strong><br />

eii.iz<strong>in</strong>c fion @n@rially wrilablc dosg. fo@ vft ..tculared (rdlc 3,4) dd w<br />

foud to be <strong>in</strong> asebot *irh lhe lab.led claim!.<br />

allco|et! o1(lnitk aJifere lqnulaho8 rn tE 7 4<br />

r@j 96.23<br />

t3.9 t008 93..18 97.25<br />

97 27 92 t2 u.26 t2.t2<br />

2lL t05 3 t0t.83 t0.2.78 t02.73<br />

Mo@va, no pturou@d eff€d wo obsred <strong>in</strong> cG <strong>of</strong>pH 1.2 ad<br />

foud ro b€ pH <strong>in</strong>deF.denr i..., sc !r pH t.2 ud pH 7.4, The<br />

on@halion l.vels <strong>in</strong> pH 7,4 (simula<strong>in</strong>e btood pH) wft sl€ded<br />

ldr qwdtador <strong>of</strong> c.friz<strong>in</strong>e <strong>in</strong> sfu. I1!. 6ov€ry val@s $<br />

obrair.d @ givcn <strong>in</strong> bble 3.5 idi@tii8 suirability <strong>of</strong> melhod. Ite<br />

etulls <strong>of</strong>th€ abor nudy <strong>in</strong>dicrd rtu <strong>tn</strong> dlrhod @utd b€.r,ptied<br />

to st<strong>in</strong>ale cdiriz<strong>in</strong>e <strong>in</strong> bul* dtue s wI 6 iD d6!s. fomuEioB<br />

aal <strong>in</strong> sfu This h€lhod is doe Etiabte thd ot!.i tJv<br />

speEophorohelric nelhodr &d it en@mgs onc io alply tor oulirc ellsis<br />

B RP-qPLC reblho.<br />

.1,2..t1 103,95<br />

J6_9t 1 ,.2<br />

HPLC is a *tuitile ed sFcific lahriqu. rhroush which pra@@kn€ric arudi€s ce be<br />

@alucr.d on a lergc vdi.ty <strong>of</strong> rh.Ep.uric ag.rrs. ft ce ,le b. u.d foi cli c.t t€s@h and<br />

for lhdnFuiic drDg monitoriog. A s.lecdve ed Epid HPLC De<strong>tn</strong>od 16 d.liFd for rhe<br />

q@ril'rion <strong>of</strong> c€<strong>tn</strong>t<strong>in</strong> <strong>in</strong> &tive, fmulaijoN &d hul@ sm. s,nulr.r€ou HPLC<br />

nello& <strong>of</strong> c4iriz<strong>in</strong>e <strong>in</strong> pr6.nce <strong>of</strong> o ldm<strong>in</strong>istdr

---

ibuF<strong>of</strong>eD, nefelmic &id dd m.loxicd), dt<strong>in</strong>deials (pynmdhqile dd choloroqu<strong>in</strong>e),<br />

etuslnmatic dru8s (guifffi<strong>in</strong>, phdylcphriie md donlehr.n), cephatospor<strong>in</strong>s<br />

(efriuone, &phalel<strong>in</strong> ed c<strong>of</strong>oa{<strong>in</strong>e) ed druss ued <strong>in</strong> non iNut<strong>in</strong> dependot diabetes<br />

mdh6 (m.dom<strong>in</strong>, glib.ncLmide ad 8tiquidone) wft atso d.veroFd atd lrlidar€d. Tt*<br />

laii.lal€d merhods ww utili2ld for qqtifiutio. <strong>of</strong> ddgs i! phameudc.t prcpd!|ioru tud<br />

m hlM stu, Mo@va, $es. nelhods w.F <strong>in</strong>lh.r @d ro snrdy rhe <strong>in</strong>.litro <strong>in</strong>r.Bcrions<br />

<strong>of</strong> etidzirc with l!* .lrues.<br />

t Opthnh.tion oI ahnMtoetuptic .Mthtians<br />

In RP-HPLC. compouds stict !o cott!@ <strong>in</strong> hish aquos nobile phse &d e €lutcd 6on<br />

@llm <strong>in</strong> pNne <strong>of</strong> hiel orgeic nobile ple. h R? HPLC @npobdj e w.reil d@<br />

!o rhei hydtuphobic ch@crr [186].'nEre @ iwo na<strong>in</strong> clals <strong>of</strong> .olMn: .!oml'sd<br />

'Evss.d' phd. Mcdr, EvE*d phe @lu|m @ used, p&t€d wft ch.nicrlty bonded<br />

odad€cylsilyl coEt d silic4 such colum de Efercd io e C_t8 md m very .on-pols<br />

Other phe olums have @lasityl, cya@Flpyt ard ph€rytsilyt pdt<strong>in</strong>gs, t is Epon d rhal<br />

lhe den on t<strong>in</strong>e <strong>of</strong> aaltr is clared b llen hydrophobicity ed will be r€idned noe <strong>in</strong> ihe<br />

@llm [87]. Hoy€v.r ioniarion ds(t*s rL hydiophobic chdclf aod th€cfoE_ n<br />

dc|eas Ele ion. Acids looe a lr.bn ott bsE. iotriz.d whs pH irc'las &d b6ss<br />

ga<strong>in</strong> a proton ed becohe ionikd wnen pH d!cEs*. Ttr@forc, adj$t<strong>in</strong>s pH <strong>of</strong>1h€ mobilc<br />

phc us<strong>in</strong>g d appiorriar. bufrc' js neccqry <strong>in</strong> ordr b ehicve r.p.odeible 6utrs ll8al.<br />

Dtugs woe speded at low pH b6ause at hi8ne, plt the ptubl€o <strong>of</strong> p€ok bbaden<strong>in</strong>g tud<br />

f.ilirg lNw .o@ur.Ed 6 eidic dtogs jnt @Ld et@6ric.lty ro sibtrot gllups.<br />

TheEIoE. oper.t<strong>in</strong>g al . low pH @duces ft Enoves d.tetenous s@pE,suppolt nr,acrDDq<br />

&d Foduced *.ll,shapcd, drcw psll fd host spl6. A3 eall1.s wrc lipophilic dd<br />

ionic <strong>in</strong> dt@ rh€ eidic mobitc pba ptuvid.d besl pak shrp.s dd aptuducible $D.ation<br />

<strong>of</strong>conponeors lor long cna<strong>in</strong> alkyt bonded-phse cotLms. Nuber <strong>of</strong>daSs could be besl<br />

E$tvel by 25 d long cot@ dd 5 l1h panicle size p,ovided @m!te qprciry f&to. In<br />

ord.r to scl*t a popq mobil. ph$ for alt rhe nethodj hocraric elution sb appli€d. Th€<br />

mbil€ ph!$ uscd vilh B€E d p[G mllms e Etarirely pola,, c.s. MGOwHZO Th.<br />

hoE pold coDponenh <strong>of</strong> a nixr@ eluie fisr, s<strong>in</strong>ce these padjtion Eladv€ly unlsvorably on<br />

rh. hiENy mn-pot& p.ctdn8. tel$ils <strong>tn</strong>e potdig <strong>of</strong> the $lvat mcE6.d rhe rctotion<br />

time <strong>of</strong>d patticlk @npon@i Acid is Eed io <strong>in</strong>preve rhe ct onabgmphic pel sh.pe od<br />

lo pmydc a sol@ <strong>of</strong>prerom <strong>in</strong> Ev@ phc [189j, Mobil. phe composition is dr most<br />

50

---

povatul My <strong>of</strong> opt<strong>in</strong>iz<strong>in</strong>g sel*dvny \neM tempente hs a mi.or .ffecr dd would<br />

o.ly ehiae mll slcliviiy ch&lg€s. pH *illort, signfi@rty afrer ih. rcrdtion <strong>of</strong> w€ll<br />

scids and b*s. Opr<strong>in</strong>um coidid<strong>of</strong>f to ad€qulely r€ll<strong>in</strong> all ealtlcsi thal is, to e.s@ thal<br />

rc an ltt ha a c€p.city f&!or <strong>of</strong> les lhe 0.5 (!oor raorioo could 6ult <strong>in</strong> pert<br />

ovdlalp<strong>in</strong>g) ad rc ealtle h.s a ccpaciry f&!or gEatr ih.n lo-t5 (€xa$ive r.l€ jon<br />

lads 10 lolg s.lysis 1im. md br@d Fals wirl poo' dere!6bility) Il90]. Affq seestul<br />

@hpl€ti@ <strong>of</strong> merhod dd€lopm€nt ir *s vdid,cd a@rdjng ro lhe euide ft6 e1 by<br />

Intemrional CodfeEnc. on Hhoni?nion tt9tl.<br />

Acc@y n€aues lh€ closen€$ <strong>of</strong> rh. .xF<strong>in</strong>enral rcsut8 to ihe trn€ vdue. A{uacy<br />

sudies for dng slbslsnc. ed drug prodNt e ft@nhended to be D.rfo@.d al l4t @h <strong>in</strong><br />

rr'plislc dt rhe 80, l0O ad l2@/o lev.ls <strong>of</strong> t.bel claim. An u!@y 1e$ ats Ev.,ls the<br />

speifcily <strong>of</strong>thc hethod <strong>in</strong> prcene <strong>of</strong> the eicipiats udd nre chroDabgEphic @oditions,<br />

Th. 0,6RSD <strong>of</strong> $. rcpli@rai ale prcvid6 de balysis prcision *t ch h@ws tb€ cto$res<br />

<strong>of</strong> dala for a nubd <strong>of</strong> meswdars bdq thc tue eal',1ical oadilions. pFcisions should<br />

b. esrimt.d bt thr @npomnts E!.alllitjry, irr.media@ p@isiotr ad EprodEibitiry.<br />

Rep€mbility cM be s*ssed by <strong>in</strong>ject<strong>in</strong>s mutdpte ,utu <strong>of</strong> homoeenou smDte md th€n<br />

c.lcul,r<strong>in</strong>s lhe % RSD. trren diare pEcision cm b. cei€d our by catcutarjng rhe % RSD <strong>of</strong><br />

the sples on nulripl. days, by diffeht dstys$ &d <strong>in</strong>srrmenls elc, R€producibility<br />

qprcs3 th€ pEcision b.tq€m t.bodlories 6 <strong>in</strong> coll.bontiv. $!di€s.<br />

Detediot and quantitdion t<strong>in</strong>it<br />

Dcre.don limi is <strong>tn</strong>e bw€sl cooenrrqrion <strong>of</strong>e anatyr. <strong>in</strong> a tude lhat cfl be dete€l€d. bur<br />

nol M€srily b. q@rihted wdq 0!. sral€d.xFr<strong>in</strong>gt l @ftlitioE. e@titadon l<strong>in</strong>ir i3<br />

thc lor€si onc.nr'aiion <strong>of</strong> daltle <strong>in</strong> a spl€ lhar @ bc det m<strong>in</strong>eil wirh acceprable<br />

pFisor ed dl@y hdq th. $ard exFrimdtsl @ndiroN.<br />

Liftaily Ual ob.ys Be',s Law is depcndd on ln. conpoud be<strong>in</strong>g ealyzd &d th. k<strong>in</strong>d <strong>of</strong><br />

d.rector Ned, qort<strong>in</strong>g htle conefilation e{i mplcs teslld for a@cy sboutd b. <strong>in</strong> thc<br />

l'r@ mge. Rage is lhc <strong>in</strong>t€rvat h€rw..n the hisn md bw levcls <strong>of</strong>dalvle sfudi€d.<br />

5l

---

RobusuEs c& b. ssssd by m.&<strong>in</strong>g delibrar€ chme6 <strong>in</strong> rhe ncrhod p.:usrm, IE<br />

nelho2) is a nBW <strong>of</strong> sep@tion b€tw@n n o !slG.<br />

The dum.y <strong>of</strong> q@drlrion @dd trol be mhicved wirh <strong>in</strong>cr.le i. Fak lait<strong>in</strong>g. ThoEtiql<br />

plate nMbd is a d€aue ol @lum .ffi€i€ey U9l, l9l.<br />

iit Me,ho.t dNlopwtt an t wtddnn o!..ti,ht . s<strong>in</strong>s Rp-EpLC<br />

Nmbss <strong>of</strong> HPLC mcrlbds <strong>of</strong> c.<strong>tn</strong>itrc hare b.€n eponed <strong>in</strong> litqalE (rdt. t.l). Z.spte<br />

.? u1.. [39] dcleloped a sidpte tsr ed p@ise Rp HPLC m€thod for th. s<strong>in</strong>llt n6us<br />

dchiDtion <strong>of</strong>cedntF and psud@pheddE <strong>in</strong> abt.s A hrT.Eit BDS Ctr (5 U. 25 €b x<br />

3.9 m) ollm <strong>in</strong> i$@tic Dode. wjth ihe nobil€ ph6e H,O-MeCNB-EiN (631?:0.21dd<br />

pH adjwred to 7.5 wi<strong>tn</strong> 5% pnosphoric eid w€E us.d d 2j4 M. The floq nl. ws r<br />

nlm<strong>in</strong>r ed |td.

---

m. xrcjD ., d. t{31 dd€lop.d d R!-HPLC m.rhod fo. the d€r.miuior <strong>of</strong>etdz<strong>in</strong>e <strong>in</strong><br />

s<strong>in</strong>e uiry Nova-Pal Cr 6ll@ wirh a hobitc I'has <strong>of</strong> 50oZ M.CN-50% phosphat buifo<br />

<strong>in</strong> lo which EtrN dd sodih dodccyl sutfoEt! were .lso ,rtded. Thc dd.ctor *as opqlred at<br />

Uv 229 m, wnn &dox<strong>in</strong>n 6 e i emal $ddatd wality .r 4t. [27] d€rm<strong>in</strong>ed ! simple<br />

HPLC say <strong>of</strong> etiiizirc <strong>in</strong> pr$nce <strong>of</strong> one <strong>of</strong> it5 synrheti. precues (hy.rroxrz<strong>in</strong>e Hc0.<br />

Bondapal C l8 colum ws u*d wilh a mobile phae <strong>of</strong> .c.bnftit€ dd almoniu<br />

dihydtuger sulfde al a flow rr. <strong>of</strong> 2 nLbjn r. L ord.r to dct.mirc s<strong>in</strong>ulr,n@Bly, (+) & ("<br />

) etiriz<strong>in</strong> i! hulM u<strong>in</strong>e, choi tud coulbodros l3ll dev€tor.d a chirar $pedon method<br />

by HPLC. A chiEl srarioEy phe <strong>of</strong> alphat -&id gtyoprere<strong>in</strong>, . AGp-CSp, ws ued 10<br />

eparare <strong>tn</strong>c .ndtromeB. Mobil. pI4 @Bisr€d <strong>of</strong> phospbac btfer 4d erodrite for<br />

u'rc ssys. Jel<strong>in</strong>sta {4Sl ad CowotkeB develoFd ed validsled &o1h€, HPLC nelhod for<br />

fie

---

stsftl,rd w6 4.2 n<strong>in</strong>ut s Estectively. The sylt m suiLbility <strong>of</strong> the nethod ss esr.blished<br />

by <strong>in</strong>jddrs six Fpli@r.s <strong>of</strong> ! edd.rd slurion dd nNitre r[. BFBS (!6t a6) <strong>of</strong><br />

The Elative sl$dard d.viation <strong>of</strong>d. six pek Espon$s ws nol foud gEaler rbe 2%<br />

vrhich colfimed tte suitrbility <strong>of</strong> ihe mrbod. SFciflciry <strong>of</strong> ttE m€rhod ws d.boBilaet by<br />

gerdtlg rcprelcniarive .hrcmdoerms (Iigre 3.1) ro lhow ihal rhe othe. conDoncnh thai<br />

@uld b. p@nl <strong>in</strong> r[. mdc mrit @ @tv.d tm de p.mt edyc.<br />

No signifiHr cheges <strong>in</strong> AUC or rcre ion r<strong>in</strong>e <strong>of</strong> ttE d{8s <strong>in</strong> p,.sncc &d abence <strong>of</strong><br />

.xcipients clorly <strong>in</strong>dic.lcd rbd specificiry <strong>of</strong> rh€ De$od. For limairy siudi€e. dle *ri6 <strong>of</strong><br />

@nqlra$o6 <strong>of</strong> the d$g <strong>in</strong> t. mge 3.12-50 lrgbt L w€E prcpard, calibotion cwe fol<br />

Ors m8. w$ dal@ted, Th. t<strong>in</strong>@ Eg6sion .q@rion foud for 1his mg. ws y = l0o89x<br />

+ 19100 ed lild @mcis1 valE b foud ro be 0.999. Thc del[od peision w<br />

p.rfom.d by fou iepaFdalive s@plcs on c&h <strong>of</strong> 2 days, The ..rimaled prection (toi.l<br />

vdation) non virh<strong>in</strong> day qFd|Mr h ob*d€d io bc ls rhd 2% RSD. Th. nerhod<br />

p6s.d lhe lest for rcpealabiliry N deren<strong>in</strong> d by 0/oRSD <strong>of</strong> $e rca <strong>of</strong> rbe peaks <strong>of</strong> six<br />

Gpliclr. <strong>in</strong>j€.rioB d t00/. t s c()l@r{ion hbte 3.6. nle csutts <strong>of</strong> <strong>in</strong>tedcdiare pRisio,<br />

Aeu@y <strong>of</strong> the ndhod *s cv.turd<br />

thc ditrtul <strong>in</strong>depod.nl onadrdions<br />

i,c. 8, 10. 12 !g EIr for dl 0E degs<br />

(n=6) by drlt<strong>in</strong>g lnom q@rili$ <strong>of</strong> rhe<br />

.ubL io rhe drug Pl0der Th. 6ult <strong>of</strong><br />

a€'@y (llble 3.7) Ev€sled lhat ft€<br />

h.tl'od vs det€ for all oSoE pu.pos.<br />

w.E der.mircd (rlbte 3.7).<br />

l0 25 20 3t2<br />

0.22 1.05<br />

0.62 088<br />

Icbl.' (q"RsDJ 021 065<br />

0.25 t12 0ll<br />

t02.45<br />

8f,<br />

l9Der and e8n^ ity ohh. n.thad<br />

%RSD LOD L()()<br />

0.8.1<br />

019<br />

0_22<br />

ne LOD dd LOQ v.tks for drllf<strong>tn</strong>r drnes

---

Ruggedrs ol ihc medod @ hld.!.d by dcr.mil<strong>in</strong>g rbe<br />

which ws deiem<strong>in</strong>€d bt <strong>in</strong>ject<strong>in</strong>s lhe srandlrd md Mple<br />

*.c rcrd 6 Fat ea. In sotution ws<br />

allowed !o s&nd ar mbicnt remp€raiue for 24<br />

ho6 md th6 lhe slurions were daly&d<br />

r8ai4I ihe nEshly pEpoEd 3lad!rd. Ille<br />

aveFge value <strong>of</strong> lhe ag.d elurions r.spoNs<br />

tsl lB) E obad.d ro aeE with rhe<br />

ii€sn sbtior rcspotuca, wiihb r3%. IrE<br />

d.velop.d Dahod @ appli.d for rhe<br />

d.leni&rion <strong>of</strong> dilf€Ent dng @otcnB ir<br />

st biliry <strong>of</strong>d. &alyt elurioa<br />

solulions ed detector Espon$s<br />

m&teldl fomulado$. The 6!ay esltl3 shoh <strong>in</strong> lable 1.6, denonstFred lhe $itabitity <strong>of</strong><br />

ne6od. Sihil&ly rhe %t@vqi6 od R, <strong>of</strong> dtugs jn PI€ge <strong>of</strong> stu (bblc 3.6) F€ded<br />

th. applicability <strong>of</strong> nedod for lh.raleuric pu'loses.<br />

C Dngdrug ila.mrio! rrrdi6 lritr, ,pernFopi. .!d Rp_HpLC ictliqr6<br />

Seod dd rhird somtion alihi$.d<strong>in</strong>es ft FSly@pbr€<strong>in</strong> subsrat€s. If Fslycopbte<strong>in</strong> is<br />

iolibited or i.du@d by othq drues, deceasad emc&y or enldced side ef€crs <strong>of</strong>$cond or<br />

tbitd g.ieotio. erihirteiB my c lt93l. Modutarion <strong>of</strong> p-cty@Plorei. tbtuugh<br />

i.Iibition or <strong>in</strong>ducdon @ lsd io drug-dtug <strong>in</strong>te@lios by alr,er<strong>in</strong>g <strong>in</strong>test<strong>in</strong>al, CNS. rnal or<br />

biliary emu [9{]. Tlc nor-ed.r<strong>in</strong>a erilislan<strong>in</strong>6 shov a divcsiry <strong>of</strong> fa1es <strong>in</strong> lhe b.dy &d<br />

$e tMent dngs ed netabolites Eay .lifio <strong>in</strong> rhei biologic.t prcpeni6. Cl<strong>in</strong>ically<br />

significdt <strong>in</strong>i@clios with iriibitoE <strong>of</strong> cyl@hrlne p45O hlvc b€a repon€d pnn{ity for<br />

lerfenadioc [1951. P-glycopbr.<strong>in</strong> irnibhoE, al$ cdled .e!c6al agcnE o. Fgly@pete<strong>in</strong><br />

nodulato$, thcy modulab P-glycoprct <strong>in</strong> turcdon by comFr<strong>in</strong>g with $e b<strong>in</strong>d<strong>in</strong>s aid<br />

tespon <strong>of</strong>th. dhs o. ilrcugh nor@hpetitivc b<strong>in</strong>d<strong>in</strong>g [r96.t9Si_ p-slyopbreh i.hjbils a<br />

wtde @ge <strong>of</strong> cobpounds, <strong>in</strong>clud<strong>in</strong>S hydrophobic dphipathic drugs, catcim chM€l<br />

bl@k6, dtilislanitus, Ffljde ad st€Dj4s [r99l. C€{dzire bc<strong>in</strong>g . Fglycoprete<strong>in</strong><br />

substrale ce lleEforc i e6cr with a nmbq <strong>of</strong> o-adm<strong>in</strong>isLrld &u8s. In rh€ p@sdl wort<br />

@tiri<strong>tn</strong>. w qMtiriii.d <strong>in</strong> pEs@e <strong>of</strong> orbd co@only co ldm<strong>in</strong>is&rcd dnss Fbn th.<br />

sLach& it is €!id6t thai edriz<strong>in</strong>e show.n I@ly all rcrls <strong>of</strong> possiblc rmsiriG o. &out<br />

<strong>of</strong> pr€scc <strong>of</strong> rcniary m<strong>in</strong>o 8rclp &d @boryl grcup whicn g,<br />

55

---

n-n. bMsilions. S<strong>in</strong>ce ode <strong>of</strong> the @mtic rjry is disubslitut .t wirh bod el4ron donar<strong>in</strong>g<br />

erelp i... Cgr ed chlodre (with pd! snbslitulior), Knd <strong>of</strong> dnel Es@e <strong>in</strong>aEdon<br />

@cs b€rw€eh subsriiucnl grcups. As methyl and chlor<strong>in</strong>e both 4t s autrttrones lhey<br />

it|l,te @njleation. S<strong>in</strong> e chlor<strong>in</strong> po3s ushffid d6aoo pan, Iw.4c <strong>in</strong>t @rior <strong>of</strong><br />

thjs l<strong>of</strong> peir with double bond <strong>in</strong>cl€es th€ l.ngth <strong>of</strong> @njugabd syscD. So s a Esutt Oc<br />

non-bond<strong>in</strong>e eletron beon€s psn <strong>of</strong> r lyst m <strong>of</strong> noleuld o.bilal <strong>in</strong>ci*<strong>in</strong>g iB t.ngrh b, I<br />

dtb orbilal. In l[€ similar fathioD, nethyt grcu9 do nor he uslrFd elenon rhc<br />

is thoughr ro r€sult fom olcilop <strong>of</strong> CH bond<strong>in</strong>g<br />

'nler&lioo<br />

odilal wirh r sysrem rcsult<strong>in</strong>g <strong>in</strong><br />

nt?€Mnjugarion. *dich culrt <strong>in</strong> exI. ion oar synms. So E @ slre @ d@ bsij<br />

rhlt de ctuohophoG group i! dlis ce may be dtubsliluled b@ne riry shoy<strong>in</strong>g ,-r.<br />

lrssition. The lvo t chniqws w€E ed fo, <strong>in</strong>teelion srudi.s i,.. spet ospy art Rp.<br />

HPLC. The spetrophobm.r.ic asy <strong>of</strong> dngs @ty <strong>in</strong>volvee rhe n€lj@m.fi <strong>of</strong> ab$rbde<br />

<strong>of</strong> smpl.s .onra<strong>in</strong><strong>in</strong>S onty on ibsrb<strong>in</strong>S conpondr. The ba.is <strong>of</strong>alt rh€ sp.cnopboloneuic<br />

IahrjqB fd mltioEpoMt $Dd* is rbe FoFrry oEr ar dt Mvcldstbl, the a!&rba@<br />

<strong>of</strong> a solurion is lhe suD <strong>of</strong> abslbece <strong>of</strong> tr€ <strong>in</strong>dividurl omponors o! rhe n*@d<br />

absrb6ft. is rh. ditrccne h.rvH rhc tor.t abelbdrce <strong>of</strong> |he eluiio, <strong>in</strong> 0E sDte ett<br />

ed llal <strong>of</strong>lhe $lutio! ir the cfeEnce cell [200].<br />

In odq to q@tiry cedrizi@ ir Fche <strong>of</strong> oth.r cea.!,n<strong>in</strong>ister.d dru$ rm difeF.t<br />

@uarc, prer$ tud @enicd appm&hs \@ us.d for th. cstimtior.<br />

I Siddrrr€ous €quadon<br />

2 Daivarivc spetrlspy<br />

A* {tlhultanfu .qutuN<br />

A helhod ws designed on Uv-vhibt. sre.rrophoroneter to s<strong>in</strong>ullan@sty nesw g.<br />

q!.!rni6 <strong>of</strong> cririz<strong>in</strong>€ <strong>in</strong> pEqe <strong>of</strong> cmonly @.dhidnq.d ttrugs pEhr <strong>in</strong> th. @c<br />

soluto!! without Fp@r<strong>in</strong>g dEn. lor thic pu.pos . D.rhmaricd rctadoship wE! Ds.d<br />

which gav. Oe corc@rlrioa <strong>of</strong> r*o ddgs s<strong>in</strong>ulbn€ouly. wh.n m€auEd ar th.ir ab$rprion<br />

c!=<br />

56

---

Hce, b = lldr logth <strong>of</strong> $e ell ( I cn <strong>in</strong> ou *pcr<strong>in</strong>mts), c = @Denration <strong>of</strong>$lurion.<br />

However sihdlan@us equri<strong>of</strong>t could ontt bc applied wh€n 1n. <strong>of</strong>the two dnes e<br />

lE&nauy dis<strong>in</strong>ild dd ln. rs! drugs do ,ot <strong>in</strong>!.Ect ch@icaut ^f,_<br />

lh.Eby n.ga<strong>tn</strong>g dE<br />

<strong>in</strong>nid ssMprion that lhc rot l sbsbae is rhc sm <strong>of</strong>the <strong>in</strong>dividual also,bma [20tl. For<br />

lne 6say <strong>of</strong> cetiriz<strong>in</strong>e, stock soluioru <strong>of</strong> I nM \r@ p,epe€.t <strong>in</strong> bu'Ic6 nnS<strong>in</strong>g &oh pH I -9<br />

dd dilu&d to @ratrFalion 6gc <strong>of</strong> 0.09,0.t nM u<strong>in</strong>g rlE M€ slvor &d sDFd <strong>in</strong> th€<br />

rcgion <strong>of</strong> 200-700 m dgaiGt $c reagar bla,L Th. abs$ee .t Lu vas rc@rd€tl (rable<br />

3.8) ed caiibation wcs <strong>of</strong> ab@lbaM ag.iBt .<strong>of</strong>t.lr"tion wcE plon d Bhicn ob.ycd<br />

B4fs law <strong>in</strong> {E orco&ltion rdg. <strong>of</strong> O.O9-O.I mM. Mole aberltiviris \@ also<br />

cd.ulat d ed wd la&r <strong>in</strong> catculalioc.<br />

otphon at u<strong>tn</strong>i,<strong>in</strong>. EJcr.4. std,lad at wba ,11<br />

2 0.129 0..155<br />

0.112 0.155 0.2 0.164<br />

0.595<br />

5 0.828 0.861 0.134<br />

0.912 L0.]l<br />

0.462<br />

133 1.209 1.031 |.072 r.133<br />

r..,93 I t3l t.lt t.2.16 t.251 t.142 t.2M I t45<br />

9 t..148 1.371 tl76 1.361 I 568 I 16l<br />

l0 l.6l I 482 | 501 t.5t9 t.481 t.6.12<br />

D€riladve sp.cFophorom.hy <strong>in</strong> the Uv-visibl. €Cjon is a etul techniqw for qudnadve<br />

dd q@turiv. 3rudy <strong>of</strong> ov.rtlpp<strong>in</strong>g bands <strong>of</strong> the mlfes &.1 <strong>in</strong>rerfeEnces. Und€r<br />

ahputer controllcd irs[uaradoA ddivari!€ speci.ophoroDcEy is play<strong>in</strong>g a v..y<br />

important rcl€ b ihe nutli.coDponor eatr3is <strong>of</strong>nixrG by Uv/vhibte spetrophobm€try.<br />

It coBisE <strong>in</strong> difie@dari4 nomat sF.dun by @th€naricd dq5fotmt@ <strong>of</strong> qecrnr<br />

cwc <strong>in</strong>ro 6 drivarile (n'sl or highd dcdvativ6). nft bchnique implov$ r€siution beds,<br />

.lieimies rh. idluc@ <strong>of</strong> baclqro@d and prcvjdq nor d.fbed f<strong>in</strong>eerpr<strong>in</strong>8 lii& di@t<br />

esorumce specra. Derivadvc lr&sfomali@ F@itl di$.<strong>in</strong>ierion .s.<strong>in</strong>s b@dbad<br />

nlerf.ron s eis<strong>in</strong>g lion brctSFbd abso+rioo md n tends ro enphdia sublte sDecrm<br />

fal@, allow<strong>in</strong>g lhe ennM.nr <strong>of</strong> dE s4irivity. Denvadve UV spedrospy ha ben<br />

51

---

witdt d.d s . tool br f .di-riE &lytir ch.|.|dianon !d<br />

!8.ioh!r.l, phr.rfiqnicd &d U6h.dicd ffelds. This dndrndi&<br />

l@lbiq6 ha @iv6.t <strong>in</strong>@<strong>in</strong>g<br />

&alib <strong>in</strong> !'irgl. .id @lri-<br />

@trpd.nt q@rlii|riE afilysiq<br />

.4@irlly <strong>in</strong> w-$5b<strong>in</strong>8 ndic6<br />

[202] vriae daiv ivg <strong>of</strong><br />

cairtir. re pr.p€r.d ir tb.<br />

b!6.6 <strong>of</strong>ptl l, 4, 7.4 .nt 9<br />

I C.{.6. rtr X, Hoddr<br />

I SitutttpM.btmh,ed<strong>of</strong>etiririE <strong>in</strong>prewqH,wpte aqqisrs<br />

Ir Dod <strong>of</strong>rb. .{dgic di!..s Onat .d flrr! unidit {d daEdognpnim), @.oEir&r<br />

&<strong>tn</strong><strong>in</strong>idntion <strong>of</strong>e Hr .-.Fd lrlrgdic with<br />

a rI1 Gc.p(f d.gdilr B raEd b b. Ie<br />

.trdiw tls di. adD<strong>in</strong>i.h.li@ <strong>of</strong> !n Hdi.sd<strong>in</strong><br />

c e rL ld.gdie &E ErL206l<br />

FunlEDoE, n w.! .to o66arc{t ttlrl @bb<strong>in</strong>cd<br />

FtLtut with & Dd tlr {r.gai!& @!.d .<br />

gcda <strong>in</strong>nibirion <strong>of</strong> h<strong>in</strong>m<strong>in</strong>ciaduc€d nud<br />

R.sENt6 thdtdd an le&Mt, oJ<br />

|,oA LOD<br />

0103 0.031<br />

0.132<br />

0.0t4<br />

bloc&.g. tlu did Hr drgois .foe [262011. tr qpaB ltlr !ff&d, 6GH,4tl<br />

pf|lnmy I cpdriblc ao. th. 6itu t i.!.1 btoc*rg., luggdl<strong>in</strong>g e@ d.A@ <strong>of</strong> itrtqldion<br />

ba*a th. E &d rL d.dulat !d[*ry! I2raj. Fd ddi€,n E d@id.ddt &.fcaiw<br />

.

---

n<strong>in</strong>'mM detectable l<strong>in</strong>it <strong>of</strong> 5 lenl, r, fte c@fiicienh <strong>of</strong> vdiation <strong>of</strong> thh nerlod for i.t€r<br />

ed ilFanly ey wrc fobtl ro b€ ls 6an E%-<br />

Radolph {2151 dsoibed d H?Lc hedod for rhe<br />

cxt &1ion <strong>of</strong> c<strong>in</strong>did<strong>in</strong>e, ton whole blood dd<br />

u<strong>in</strong>e, nrc method neasurd concenlrarioB <strong>of</strong><br />

cimelid<strong>in</strong>c s loq s 0.05 ug nL r. A rlpid. Fnlilive<br />

dd rcbust rcv.F pha HPLC h.thod wilh<br />

collnm swirchiig t*hniqw for the derm<strong>in</strong>ation <strong>of</strong><br />

fdotid<strong>in</strong>e ir hMd plsha B d*rib.d by<br />

znons md Yeh [216]. 'nE <strong>in</strong>ftd.y @emdeiK <strong>of</strong><br />

tl3!F 3,,r: R.prcs@iv. chrnnosm<br />

wialion !r all @n@na on lw.k t* L$ ihtu tQplo, Thc l<strong>in</strong>ir <strong>of</strong> o@i<strong>in</strong>odor for<br />

f@otidioe h hwd plama ws I n8DLr, How.rer, no m.thod foi siDulla.@Ds<br />

---

nln<strong>in</strong> r. RepEeoradle chrc@toglrm w€r€ gm€rat€d lo show rhat o1h€r conponenrs lnat<br />

@uld be presit <strong>in</strong> rhe sple tuEix e Fsolvcd ftom the p@ni edlyte. No sisniticmt<br />

ch.!g6 b AUC d rreltion rihe <strong>of</strong> rh. dr!8s <strong>in</strong> ptls.G &d ab*e <strong>of</strong> pbDtllohb.n<br />

(<strong>in</strong>t.dl iudard) cldly <strong>in</strong>dic.Ld lF speifci9 <strong>of</strong> rhe mdlod (6grc ].5).<br />

F<strong>of</strong> lim&ity srudi* 6 ditrdd cotr@rftdoB (33,33, 16.66, u.33, 10, 6,66.l,3l |lgDL-')<br />

<strong>of</strong> 6 mixl@ <strong>of</strong>each dtu& ii presnce ol ituenal sandard wer asaycd. TIE l<strong>in</strong>e&it otlh€<br />

nelho

---

The develoted nelhod M lppli.d tor rh. d.tmimdon <strong>of</strong> difl@nt dng con!.nt <strong>in</strong><br />

ndkeled fomulaiios, The say resulb show iD labte 3.32, dchorstftled th€ suilsbitiiy <strong>of</strong><br />

th€ m.thod. Sidildly th. o4@ved6 ed R' <strong>of</strong> Ih. drugs <strong>in</strong> pB.k <strong>of</strong> sfu shou <strong>in</strong><br />

utblc l.ll Ev.,l.d rhc .!'pl'c!bility <strong>of</strong> @edod for rhonpedic purFs.<br />

rrbb JJI<br />

'6 Rtcowia <strong>of</strong>Alid bnnat<br />

1.t., 10t.93 12,0J t04_3 10_t2 31.72 34.45<br />

102.32 r6 t5 96.t,2 tr.2t 102.13 t5.25 l7.ll<br />

B.l t2.5 ll.Jl 13.19<br />

10053 10.62 lm.3 9.71 105 t9 9.49<br />

I00.2.2 6.59 6,3<br />

l.t6<br />

25 20 I5 5 n:<br />

99.24 10t.65 t(M I<br />

96.91 t0t_19 t02.5<br />

95.52 l0l.t3 102.15<br />

t01.75 r0t.t!<br />

It l,tret@tion studies <strong>of</strong>cetiri2i@ with H, bloctzrs<br />

Fmotidilc allEs ro bc a P-glycopbteh lub6ra1ei th@ is posibitiry <strong>of</strong> ili.tutioc<br />

rhmud irlibiriotr or <strong>in</strong>dErion <strong>of</strong> this raspond [2r4_ rr hs .bo ben repon d rh.r<br />

Mitidirc dd c<strong>in</strong>did<strong>in</strong> cs act 6 eb€rrares lor rhis pnle<strong>in</strong>. tr hs bed susis€sled rh.r rhe<br />

balec. b.tw€en absQtiv. md sret ry mehehhs 6 a fdlor <strong>in</strong> derm<strong>in</strong><strong>in</strong>g <strong>in</strong>reslihal<br />

absorytim Blds to b€ a ourire @Niddtotr 4€n fd @mpoudr exFcred ro hav. a<br />

Fdmiir ly elluld llloDriotr rcule d lh. msl <strong>of</strong> dnsr ab$lb€d by s{ft bui. I2tEl.<br />

6I

---

Th! .bsrbuce mdim <strong>of</strong> ciociidire al &idic pH i... I &d 4 \|@ foud 10 be 218 M<br />

whft 4,.r pH 7.4 n 6 217 ed ar pH<br />

9, 216 m. Simulk@6 equatio! B<br />

.lplied fo. lhe deremiMtion <strong>of</strong><br />

ikmrd@dtu M^<br />

c.dridr <strong>in</strong> pes.tB <strong>of</strong> c<strong>in</strong>didiE,<br />

Th. .Filon vatB <strong>of</strong> llc drugs d th.ir<br />

10393.31<br />

tfi42.95<br />

186t t29<br />

E F.tiE cf@ and on th€<br />

<strong>in</strong>t et<strong>in</strong>g drugs Efelt@s ar v&ioq<br />

t6350 10371.91<br />

16350 r0t68 l4l5l.05<br />

pH lcv€h (i.ble 1.34) wft calcdsled dd !i.d for cslculgr<strong>in</strong>s the o/dvailabilily <strong>of</strong> dsss aftei<br />

thc i, lito <strong>in</strong>teradions. The % e@very <strong>of</strong> cdiriz<strong>in</strong> ed cimetid<strong>in</strong>e at all pH leveh mg€d<br />

bels.a 97-l04yo, This itrdi€aled th.r bo$ the &usr @ available rnd oone <strong>in</strong>rdfered wilb<br />

TrbLlJs<br />

IM.M rceib <strong>of</strong> etiitirc vth e ielAiw N Uy tpectophuowty ed<br />

HPLC<br />

pHl<br />

HPLC HPL' HPI-C HPI-c<br />

t<strong>tn</strong>27 100.t2 100,45 98,/tl _u lmi6<br />

l5 99.52 l0o,4J loo.t3 96.f2 98.54 t@?8 r0o.r2<br />

99.57 98.45 100.74 91.25 94.t2 t0t.14<br />

97.25 t0l.6l 97.33<br />

t0056 r0082 100.31<br />

99.t4 101.98 93.12<br />

l0t.2l 99.12 100.46<br />

I05 100.87 102.t4 99.6J 10071<br />

t20 100 t.] l00,ll l0l.ll t00.81 98.9 t01.46 I01.39 100.39<br />

105<br />

100.24 r04.l8 91.12<br />

t0l.t2 91.07 98.78 101.33<br />

t00.70 93.33<br />

98.32 r00.62 t02.45 9431 l0r ll<br />

94.41 99_t7 t00tl t01.65 10058 t00.23<br />

94.55 l0o.J4 9.t6 100.9 t@?8 101.34<br />

l0o.7l tot.62 10t.37 tmiT<br />

t20 t01.62 r00.J2 Im.03 I0t.39<br />

62

---

Irr &nltri.al nsim for feotidirc .t stomh pH i,c. I sd 4 w fou[d 10 b.266 m<br />

vh.@, .t blood ad <strong>in</strong>t4t<strong>in</strong>li pH it wB !r 284 m. S<strong>in</strong>c. th. spccr! <strong>of</strong> f.sotidirc did nor<br />

<strong>in</strong>tcrfdc wilh thc ru<strong>in</strong>. <strong>of</strong> cdnizirc<br />

h@e 3imllllEoa cqulrion w6<br />

.p!li.d to qutit t thc rrc dru$ <strong>in</strong><br />

th. mixtuF. Th. .pilotr vdB lr@<br />

€lcol.t d a pBdt d <strong>in</strong> rh. rdL<br />

1.36,<br />

pHl t6t0o QN 761.6<br />

l3t0() 3I4I 625.51<br />

16350 755t.91 1718 l|lt.56<br />

pH9 l6rr0 7157_99 5565 186.59<br />

T.!h ljt<br />

na I W q*bopletoNtr dd EPLC<br />

tl PH<br />

HPLC HPI.C HPt' HPLC<br />

9E,n 10t.9 t00,2 99,,1t l0t.? tm.7 tott<br />

It 96_51 9.52 91.52 t0t,7 t01,3 9E.54 91.5,t<br />

JO t02.0 9t.05 t00,6 98,J' t00.4<br />

Ll n.25 10t.3 91.12 9.tl 98_n to2t<br />

r@.6 9,23 98.31 9n7 9t.75<br />

15 t00.5 t00.2 I0t.9 93.t9 99.t! 98A2<br />

90 9.28 l0t.l 94,61 t00,3 9t,57 100.3 99.55<br />

t05 r(x).8 100.4 r0t.l ,9E3 9E,t2 100.7 I00.3<br />

r20 t00.! t0t,4 roo.5 (x).O 9.0t t00.7 91.25<br />

0 9,,52 100.7 tot.9 .12<br />

It 94.67 100,8 9tt 9t.09 t0t,6 9t.6t t00.6<br />

30 9,12 l0o,l 9t.u, t00,8 9t.12 t00.8<br />

99.24 9.12 91.4! 99.65 l0!.t<br />

6o t00,6 98.?l 100.., 9.t0 99t8<br />

97,00 9t.l! 98.,16 rm_8 I00.7 !00.1 99,2t 99l0<br />

98.2t 100.2 t00.8 t0t-7 tt.52 t00.7<br />

105 l03J t00.5 t0o,? t00.t roo_t<br />

t2o 100.1 I00.3 100,3 tl.il5 99,71 I(x}JI t0t_8<br />

Ihe <strong>in</strong> dcti6 sfu(|i$ p.rfodiFd on W spoctup[otomcrry .nd HPLC (r!bt. 3.]r) ddty<br />

irdiorcddr.tceri.iz<strong>in</strong> w!v.il.bt.upio97-104%<strong>in</strong>.Id!.buflcrn di@.Inrh.e.<br />

hy t[. wailalility <strong>of</strong> fo&otidir. E fould io h. 96- 103% by ul<strong>in</strong>g borb rb. t chdqrcs.<br />

6l

---

'nE .citm mvcblgt[ d pn I *u 2Z ud 313 M wls! s .,t ,tl thc orlE mdilm<br />

Os 4, 7-4 .!d e) l[. ffiidr r@ bund lo b.228 |ntl 313 M. A. rra I dp 'is!.I .tD6<br />

lna.pplyitrB fird d6ivdiv. lor odiriz<strong>in</strong>o rnd nnitidi@ ww 224.84 rd A1.26 m<br />

.atp€.liEly. Al pH 4, 74 ud 9, 22E.43 rd 3!6.93 n|! qr obEvcd for c.ri.iriE r.d<br />

l|E aa: DlndiE.t .ti. ordnni! rrrtib<br />

rxl<br />

lur tattdq <strong>of</strong>dtlr*t atdMrlM<br />

tll7.4<br />

pll9 ,- l! !7lr-0.0t01 0.996<br />

pl|l<br />

pH7a<br />

I!. i!t6!.lion @lr rbos! <strong>in</strong> rlbL 3.t9 cldly <strong>in</strong>dicrod rhrt m i!n€.!.ri@ o€utld<br />

b€.96 it $l.oi.d ddg!_ Tt t@v.ry <strong>of</strong>cdniziF .l dl ptl t v6l, rw 6t d lo b. itr tls<br />

tuge <strong>of</strong>9A-l0l7o. Itr rlF !'m w|y ttF i.coy..y rdw <strong>of</strong> miridiio s@ ftold to b.9?-<br />

101% i'di6!i.g @ E tioo b.t*6 Gt d.tga<br />

t'

---

tbh aS9<br />

Ituftti@ r.s,Ls otethxiE with MiltliE N w speciophdmt.y a'd ttprc<br />

pHl pH4<br />

HPLC HPLC HPLC HPLC<br />

9.60 l@,45 98.56<br />

98.56 tm95 I00.14<br />

93.Il t8.45 Lt2 99.8t 93.21 93L]<br />

45 1rr.26 9,92 t@.78 100.?5 10t93<br />

93.72 98.!' 100.85 100.21<br />

r00.78 ,9.t2 tol.64 93.17<br />

r00.82 100.6r 93.33<br />

10t.72 99.22.<br />

10t.35 t00.24<br />

I00,62<br />

r00,.ll 99,96 98.78 100.33 98.7J<br />

99.39 t00.75 99.U 99. r0 99.32<br />

93.45 9.11 t.6l 9992<br />

97.13 93.31 93,3t<br />

93.12<br />

100.88 l0o.l1 100)2 93.52<br />

l0t 99.t3 98,65 100.89 lm,l 9a_16<br />

lt0 1m29 t0t.6l t00.36<br />

I S<strong>in</strong>ulteeoB detem<strong>in</strong>ation <strong>of</strong>c.tuiziw <strong>in</strong>pres.nce <strong>of</strong>tatirc<br />

A badirl <strong>of</strong> ce rporrs <strong>of</strong> irr!€sNiliviiy io seriE havc appe.rd <strong>in</strong> ihe lft@nre. Ihe<br />

@lio.s h.v. <strong>in</strong>clud€d st<strong>in</strong> @tiois, jo<strong>in</strong>l pe!!, egio-@d€na left vatricute<br />

dysru.tionl pullMary srrprons (@ugh, dyspdo€. dDd pnel@litit [2r9]. st tiN d. rhe<br />

nolt colmo! ttF <strong>of</strong> cbol6iebl-lok<strong>in</strong>g drugr us.d <strong>in</strong> cl<strong>in</strong>i.at pr&rice. R4a16emh<br />

sugS.sl€d lnat liiey may also have &ri-<strong>in</strong>flffidory prep.nies ir psaicul& by iohibidor <strong>of</strong><br />

d <strong>in</strong>portal <strong>in</strong>flamabry cell .alled ! T lynphoc',t . Th€* fmd<strong>in</strong>ss d@Btrared th.<br />

th.nFuric potendal <strong>of</strong>srd<strong>in</strong>-*tuitiv. p.thways <strong>in</strong>.lldgic aiMF djsee [220]. Ir @rher<br />

3ttdy, it @ ale oncluded th,r st tiB havc dli,<strong>in</strong>imro., dd IEWprcr@Uv.<br />

Fop.ni6 vtich my b. beneficirl ir rhc rla[rcnr <strong>of</strong> mulripL sLmsis 6 w[ s orlFr<br />

@16l idou sls.d (cNs) n 'rod.sffiliv. di!..s [r2r].<br />

65

---

NilBh [222] rL$rib.d e RP-mLc m€rhod for 3imulrar@u en<strong>in</strong>gliotr or s<strong>in</strong>vs!.r<strong>in</strong> 8d<br />

cz.l<strong>in</strong>ibe i! onb<strong>in</strong>ed &eAc fm. Th. mcrhod s loud ro b. Iilk <strong>in</strong> th. mge ot l-50<br />

pgnlr Mth m@ @ovcry <strong>of</strong> 99.21% foi simvaiai<strong>in</strong> ed 99.50plo for czl<strong>in</strong>ibe. Ihe<br />

@Fclriion ceffici€nls for.ll @mDonmte 4 €los to L Shah.r al, [223] dev€lop.d<br />

s<strong>in</strong>ult.mu Deihod on RP-HPLC lor the d.t mimdotr oI atosNtarh calcim erd Gpir<strong>in</strong><br />

<strong>in</strong> opsuL doegc foms. Th. @te ion r<strong>in</strong>€s <strong>of</strong>.tonasrat<strong>in</strong> cddu ed sDif<strong>in</strong> weE 5.4 dd<br />

1.4 n<strong>in</strong>u6, 6Fcriv.ly. TIE liMity tur doryBtati! c.lcim dd s?irh wtr <strong>in</strong> th. BnB.<br />

<strong>of</strong>0.5-4 ard 5-25 nsml ', 6p€1iv€ly. Lsa .r al, [224] doelop.d s<strong>in</strong>dl.'rcoN belhod for<br />

thc dd€mimtion <strong>of</strong> thc bcia.blekG (alenolol, sot lol, meropblol, bisoprelol, proptuolol<br />

dd ceedilol), calcim{haDel elasonkis (dih@, dlodip<strong>in</strong>e ed vmpmil),<br />

rngiotqs<strong>in</strong>li d|gonbis (losn & irbddtan, ulefian dd r€thisarr{) ond rh.<br />

ddery$nic dns (Rcritri.lc) itr stole blood sple &m fomic auoFi6. wirh 0E<br />

.x@ptio! or dlodipift' de l<strong>in</strong>it <strong>of</strong> qhificlrion @ve!d lov lh.r.p.ulic @Ilqrrlrim<br />

l.v.ls for all lhe mmpouds. zrl<strong>tn</strong> dd Ucal(uk [225] develop.

---

et dt. [22E] q@rifi.d rhe s<strong>in</strong>vlsrlr<strong>in</strong> dd p,o{ihydoxysid simvslar<strong>in</strong> libehtcd ftom<br />

s<strong>in</strong>varad( The nethod ws chd&tdized by good liMity ovq th. n .iuM.nl rsg€ oI<br />

Hower, i. order to d.t€m<strong>in</strong>e ed qhit for the<br />

fi$r t<strong>in</strong>e efiriz<strong>in</strong>e <strong>in</strong> pr.s.m <strong>of</strong> stliils n€e m.thod<br />

6 dry.lop.d and vali&led- For anl<strong>in</strong><strong>in</strong>e oF<strong>in</strong>iz.d<br />

@ndition <strong>of</strong> lhe ncthod veious rados ol n $uol:<br />

wrer (90:10,85:15,80:20) wre lii.rt. lt M<br />

ob6dld lh.l i@ <strong>in</strong> lL. m.lhMl 6lio <strong>of</strong> tbe<br />

nobile pbse r€sulled i. pmr $laniion betwd<br />

Ju--'l<br />

chM&sm <strong>of</strong> €<strong>in</strong> a rh.rurD,<br />

c.liriz<strong>in</strong>. rnd aloNsral<strong>in</strong> ad <strong>in</strong>cGe <strong>in</strong> tb.6tio <strong>of</strong><br />

Ba&I Brhcd ii tail<strong>in</strong>g and lda c|cntio dnc <strong>of</strong> dogs. H.@. a rew ol84ic elrcnt m<br />

irnoduc.d <strong>in</strong>io the sFGm. DiffeFnr nixtud <strong>of</strong> &c4loniFil., n thdol &d watd (5,E0:15,<br />

10:70:15,20r60:lt,20:50:20,20145125, v/v/v) q@ iried. ln dl iGr.nc€s, sotr <strong>of</strong> iobil€<br />

phas caull.d <strong>in</strong> For *?aEtid sd i! enc thc p.ar slmEy w6 disbncd-<br />

%RSD<br />

o.l5 10019<br />

0.13 I00.23<br />

0.33<br />

o.24<br />

0.53<br />

0.25<br />

101.25<br />

t.2l 103.35<br />

t2v/. 1.52 t04.17<br />

Ho@, only &etonihiL: Mrq wa |an€d 4 lh. nohle pbe, lt B obefl€d thrl tt: 25<br />

*.eroniEil.: wats gavc lhe besr Esults with pop€r *p6Fri@ <strong>of</strong>.€tiriz<strong>in</strong> , aloryst t<strong>in</strong>,<br />

61

---

osuvsrarjn &d sihBraril Howvd, evd at this mobil. pha* pnv.slar<strong>in</strong> colld not b.<br />

$?!Et d <strong>in</strong> pEse bsuvaeat<strong>in</strong> e pEratlt<strong>in</strong> m tu ep€Ei.ly ?nolg with ceririz<strong>in</strong>e.<br />

IbuFo&n wa chosen as & <strong>in</strong>letul slardard. It m.lso obswed d.t all slal<strong>in</strong>s w€e pH<br />

ldilive ad h€de pH 2.8 va $l4tcd giv<strong>in</strong>r lhc b6t tglution rrd symccy <strong>of</strong> peals.<br />

The El€nlion t<strong>in</strong>e <strong>of</strong> 4tirizioe, aroweladn, rosuvadad.! phvslstir dd s<strong>in</strong>vasLlh wr€<br />

found to be 2.05,3.45,4.45 md l0 biNles, EsD.ciively.<br />

Mctlo

---

Intudide pr*iriN <strong>of</strong> the Ntho.l<br />

% RSD %RSD 9'RSD<br />

II t2 II t2 II t2 II t2 tl t2<br />

2.25 05, LI3 Lf2 0.t6 t.t7<br />

0.24 08t 0.3 1.55 t.2<br />

t, 0.82 0.71 0.34 0.56 0 l.I 0.99<br />

,:0 02t 0.ll l.l2 0.13 0.91 t.87<br />

0.59 0.87 o.16 0.12<br />

50 0.03 0.4 0_87<br />

The % RSD ed found was calculqled <strong>in</strong> .&h cs, The above validared delhod w used fot<br />

all lhe drug. asy detemimtion <strong>in</strong> rhc phMudc.l ttp@lion. TIE %@ov.ri6 <strong>of</strong> all<br />

tE dng! wd found ro b. with h l[e a.pr.blc mgq1l!. sFcificiry <strong>of</strong> the m.1hod ws<br />

al$ cdfn.d <strong>in</strong> rhii t!).mr a m id.rGr.r.. tom ih. ddDidrs ct@lv <strong>in</strong>dicd.d rn<br />

sFcifi city <strong>of</strong> thc method.<br />

I0l l 2.51 106.8 2,67<br />

1026 5.13 t0l.l 4.n 97.22 5.42<br />

t5 100.8 I5.ll 98,16 102.6<br />

20.96 I9.97 96 t6 20.01 100.8 20.1?<br />

103.6 25.91 u.25 25.19 21.91<br />

50.39 9333<br />

91.16 10t.2 101.2 101.7<br />

R@very <strong>of</strong> c.<strong>tn</strong>iz<strong>in</strong>€ B al$ p€rfo@ed <strong>in</strong> ffi s<strong>in</strong>e spiked drus-E€€ seM st five<br />

diffdnl cot@ttlrioB. Th. y.|@vai6 <strong>in</strong> 5fu for aI rhc dru$ wE fould ro b. <strong>in</strong> the<br />

@A. <strong>of</strong> 97.55-108.94% thu irdi€ri.g rl€ .pplicirion <strong>of</strong> rlE mrhod for dEnp.utic<br />

pnrpoes, MoE over thh .pplhation onc. .gs<strong>in</strong> irdicaLd th. 3peificiry <strong>of</strong>d. n.$od <strong>in</strong><br />

rclafion lo endogdou @npon€nrs.

---

2 5 l5 20 25<br />

t00.!.t 103 99 10159 tot.32 l0l.2l<br />

t0o.t 99 33 l@ 7l t01.45<br />

91.66 106.7,1<br />

n.55 l0? 5<br />

l05..ll 102 65<br />

It lttqd

---

tbn ct .[dtttEadtu<br />

r=ll3!7i+0.0017<br />

R.<br />

0 9925<br />

DH 9.0 0.9808<br />

pH 1.0<br />

pll9.0<br />

0 9993<br />

o.t 62<br />

.4do4 t t'rd <strong>of</strong>di@ dh atot1,.tui,6 W t<br />

DHI Dll9<br />

HPt' HPLC rflc HPI'<br />

t00.10 99,6 93.24 9t.t5 96.30<br />

l5 93.t4 99.62 t0!.21 l0l.12<br />

3{' 103.t6 98.50 t0013 91.6t<br />

r02.E2 98.66 lm 5t _12 lol.33 t01.78 22<br />

60 lm_73 t0178 105 76 9{.79 99.22 Ll9<br />

15 9t.ta 94.72 t03.66 100.n l@.L tm 5a<br />

90 lm.7t l02.2l t0t.76 9l.l0<br />

l0J ,t.53 9.62 vt 62<br />

t2t) 101.32 tt2.69 f3 rcj_71 1m.69 t00.25<br />

t(n.!l t@.91 t9 3l t0t.5J<br />

l5 100.92 97.01 93.62<br />

30 100.92<br />

10t.33 l0o.t3 l0t.t2 !*21<br />

l@.6s l0l tt l@,69 96.2t t0t.42 100.97<br />

15 10163 t01.90 96.2E l0o.7r 101,45 98.46 97.62<br />

t0t.95 r@.4t 93.5t 93.r7 t00.73 99.t0<br />

93.11 10t.88 lm 32 t00.t2<br />

120 t00 56 t05.52 t04.3, 95.51 loi_u t(D.t6<br />

Th..Elydc.l !i8dh o6.avd d try {c.rrt<br />

6. .ll tlt ptt E di!tu sw fdrd b b. d<br />

21o M. Abelot vdE <strong>of</strong> ddivriv. rig6t.<br />

fo. eti.iz<strong>in</strong> a pII t,4 ?4 ud 9 9@<br />

nlstld !1 221.9,24059,24t.36 std<br />

223.01 m. In rt mc dy $. ddir,|rirc<br />

7l

---

c$!6r.r<strong>in</strong>.i pH l. 4, ?.4 md 9 \r@ 51 23t.33, 210.81, 230.95, 230.E6 M, Esp41i!ely.<br />

Tb. i,-rrto irctution Bdls <strong>of</strong> eririui* Mth Mwlsrai<strong>in</strong> r all pH d*igmred thd<br />

a<strong>tn</strong>iziE did @l <strong>in</strong>tcrf@ with oslBl.r<strong>in</strong> ,r rcidic or bsic pH. Thc 96!sil.biuli6 <strong>of</strong><br />

@<strong>tn</strong>iziE at .lf buff.Ed nedims v@ foud ro tE i^ the tugE <strong>of</strong> 9.60-IM.WA<br />

(detemioed by Uv speftpboton t r) ald 95.60-101.22% Oy HPLC).<br />

R.wih tu1aict <strong>of</strong> c.tlzire @'d rctwM<strong>in</strong><br />

pH 1.0<br />

srnB olati.iziN ,ith rdue.lcE d W r<br />

0.gvn<br />

HPIC HPIC HPLC<br />

10068 r00.4t 9.8r 93.35 r00.48 t00.0t<br />

94.24 99..10 lot 0 96.82 98.26<br />

l0 95.21 98.?l 1007:<br />

99.48 100.69 9t,24 100.22<br />

99 6l 101.32 101.61 r0r.85 97..:.1 10.1.57 99.69<br />

15 102.69 101.62 95.61 99.12 I01.23 l0l.3l<br />

90 97.EE 101.87 I01.69 97.0E I0o.l2 101.87<br />

105 t02.t5 94.2\ 93_7.] 98.2' 102_70 100.85 t0o.0i<br />

r20 r00.6l 102.1t 104.9<br />

94.62 9922 t01.22 tm.7l 99.29<br />

t5 97.28 99.21 t01.29 93.t'<br />

l0\,26 10,0.73<br />

98.06<br />

60 100.64 95.E1 100,69 104,78 t00.64<br />

15 99.61 100.91 98,?0 9,80 9.72 I0070<br />

90 97.82 10t.23 98,90 t00.62 98.18 100.91 100.75<br />

I0t 9.87 102.18 98.47<br />

120 10t.35 I00.73 100.48 %,70 r03.48 99.'<br />

12

---

Tr! Mid risr.l ohriBt ftr l[. <strong>Fw</strong>.drli! w<br />

fqnd b b.235 @ i! .[ d. b.dil@. rlolffi,<br />

&.ivdiE dg!.k cb€ for o.anni!. rdd<br />

F.v.ta<strong>in</strong>.r pH I ed 4 pa! 235.55 |nd 2t9.tl<br />

4 F.p..riidy si@ildly r. pH 7.:t od 9 rtE<br />

|IlFl'rr: DdidiE@d<br />

dntbdFd.i.<br />

dgrdr rd.a.d 9@ ?9 Dd 219.()? d ir cai.izim ed Fng.ti, ,!.p..ridy (6CE<br />

3.1D.<br />

pH 1.0<br />

pHta<br />

cr r.0<br />

td <strong>of</strong>etun4 dn wtui,<br />

y- |.652r - 0.02ln<br />

t.Db l!2<br />

iMMelttdd@ sitwddiu W tsd@htu@at tEprc<br />

II l9<br />

rlPlc HPI,C qna HPT'<br />

.24 99.28 l@.42 91.67<br />

l5 93.73 t00.45 10t.54 97.31 98.r8<br />

JO 105 63 Lt0 100.41 100.73 lm.6l<br />

9.24 10t.22 103,4 100.61 1m.73 qm vt.4<br />

9931 t01.34 t01.44 lc2 56 lm<br />

15 l0l-5,t tot_17 t01.9 99.rr 99.62 vt.2l<br />

l0l.8l l0l.09 m42<br />

q_n t(D_32 q_12 tmjl 10163<br />

l2l) 101.68 10t.63 9t.62 qt t0l.t] t@.84<br />

100.25 r02.96 99.25 96..11 103.21<br />

l5 n73 too.a l0t.a2 rcL2t 99?9 98.3t<br />

l{, ltD.05 r3.t0 l0l3a 9_20 9913<br />

96 t9 l('2.35 9t.9 too R t00.@ 9lL t0o.2t<br />

t01.36 too.t3 9t.96<br />

99.t I Im.3l t0?..n lo2_t9<br />

rcl.t1 99 3l 99 75 t0163<br />

9a f2 9.62 9J.60 10176 100.3t<br />

t20 l@.56 10165 9913<br />

73

---

Tb E rl a icdi@

---

l :l<br />

&rF1(,: Chudo'u.<strong>of</strong> iGdon .r Ct a,7.a d r Etd N rr.tdd srt dd<strong>in</strong>d|c<strong>in</strong><br />

T.D|.lL<br />

I"t @iM@tt <strong>of</strong>etttun etk ttMdt d ul/tp@ebyot t<br />

pH4 ellT 4<br />

HPI4 HPLC HPT,C<br />

9!.75 912l 93.U 95 22<br />

l5 92.t3 9.5' 92.99 9512 9r_51<br />

8t.t5 I10,12 ||5.89 119.32<br />

|2.42 1t7.9 t2o.?3 120.lrl<br />

t6.90 4532 1t6.8, ll9vt tzt_1t t26.ll<br />

15 35ll $.9 12064 t22.t9 t3192 lJo_t2<br />

tt.5.l t2a_15 t23.92 ttgs7 lJ5_J5<br />

105 n.a2 |]3 t3 t43.33 l.lt 35<br />

120 ,l_n 7J.tl t3t.al t15.72<br />

4.23 a).tl 53 45<br />

l5 !{2r 33.46 @13 53I n.lr<br />

lo 6t.t6 54.26 6t 05 70.22 7l tl<br />

{5 51.23 6l.tl 5a.l I 65.t' 61t2<br />

53.99 53.()7 63.22 6t)]<br />

6t_66<br />

50.n 52.61 J3.3a<br />

t05 40.!l q.32 55 {l<br />

120 41.t4 rt5.28 lan 50.n<br />

DosHa€@r irt qdi@ @ t fod <strong>of</strong> lddhiod qdio.. thlt do mr nr lbd.I rut6 <strong>of</strong><br />

v.ldy t!'o!@E, pr!(ird! 6y odl. ooly <strong>in</strong> rolnion fo.u rr .qitibiub wir[ rh.<br />

.oqod mhods laxrl. T!. lifd<strong>in</strong>c <strong>of</strong> dl. cdglq (rotri@ <strong>of</strong> dotr! rd a.c.otor5)<br />

d|c bo sdretrly dort B. |i-Iftlddrlld (B-rD e..hod i. t ' .rr u..d 4pN.6 for<br />

ddqDilirg lh. I.i.i<strong>in</strong> .'y ud .quilihi@ 6or.d. <strong>of</strong> @ hood.d itrrd!.tis $ticb i!<br />

b.td 6 rt 6@'l<strong>in</strong> lbr wt6.irh.. @ <strong>of</strong> dt .a.ri. (hod d s!.!r) ir FE d i!<br />

d.d leld. oq lle orha rad.d, tt dr..dqidic .t 0rl'.@ ,!@r. <strong>of</strong> lt. ortd<br />

15

---

anot eill b. trstrFor i. dE @lleriv. .butdcc/.||issio! tugc <strong>of</strong>lbc E$1io 3Frm<br />

[234]. It 6 h. cdclld.d u<strong>in</strong>g dF foll <strong>in</strong>s €qlrdo.<br />

tDlo/Ah = (l/talo) ( lr

---

3 C.dddr. rttt qrbolon6<br />

I Shrtt@Bd.tmttutionoletbbltu <strong>tn</strong>F.nrc.<strong>of</strong>qr<strong>tn</strong>lms<br />

Cdidnrc is @nln<strong>in</strong>tuldld with qu<strong>in</strong>oloB <strong>in</strong> nubq <strong>of</strong> c.g howE; .!'rg-irduc.d<br />

ulti*ia hls bei Fron d *ith r wi& d|8c <strong>of</strong> dru$ &d v@iB NSAIDs dd edbiotie<br />

e dE dru$ don @oly .ssoci.r.d wnh unic{i., .lrlDugD rltirbtc d.tji nDm<br />

prlrpcdirly @noollcd sfudiB i! $!n 12351. QrimlG eribiodcs <strong>in</strong>d@ mBp6cifc<br />

hid.mirc El.itc t2361. lt E rF sdl cpotu <strong>of</strong> d$phyt-tic rliN eirh<br />

cipFflon<strong>in</strong>. n&y *ilh ti61 hoM cxpoG, which 3ronSly $88.3rt M-imlF<br />

n di.t d hi$.mitu El.a [234. h ha d$ b€n FFd.d dt t mo.r D.ddrs wit buttipt<br />

dnlg dld$, sydllm &d hoG rh.D @ dnd <strong>of</strong> eubj.cb with . hidory <strong>of</strong>hypa*Niriviry<br />

!, . lilglc adih..idid dng w@ ch.Eariad by l[c F€4! <strong>of</strong> ciFut.rirS htur<strong>in</strong>ic<br />

cl€dig f*loB enich bi8ht DIry . relc ir &lS-idrxrd ldw.s erioB ob*ry.d ii Oasc<br />

p.tidis t23tl. Monova,0F ldh<strong>in</strong>ilE ti@ <strong>of</strong> e@t drl83 (six HrE lror btoctcr+ ffi<br />

baMdmrgic etlgonll!, fou d'dg6icr lctr diuraie sd fw gu<strong>in</strong>oloi!) whi.t modutdc<br />

lh. turctid <strong>of</strong> P-slycoprelc<strong>in</strong> lo pdriftt3 may ldllely afan rhc onul f<strong>tn</strong>did <strong>of</strong> rhi!<br />

.mu pmp rtrd Dy oe dngnDs itrr.drim <strong>in</strong>du.d sidc.re|3 1239!. Oi. <strong>of</strong> tE<br />

sndi.s confncd tbc polani.l fdrility hlzlds <strong>of</strong> @only $.d druss tuh $ Hr Fcpror<br />

e!.8d<strong>in</strong>g eric?il.ptics {d edbioriB I!,t01. P.ria|! rrli!8 ciplolloreir @ cully<br />

tdvk d to pbtccr 6.ir s*itr froD di@r iu!'li8hr l2,ltl.<br />

O. lhb b8b n b*{E lpp.Mr ro &rclop &d latidal! for rI. fir$ rirc . nErhod fd<br />

3iDulr.M{a d.idEilatid <strong>of</strong> ccririd4 <strong>in</strong> p|!*. <strong>of</strong> quildoB Mait! e, ar, [r,a2]<br />

dcEl@ . siDplc. siriv. isi.lic ndhod for tlt d.larion ud oMdfic.too <strong>of</strong><br />

.iFotld&i! <strong>in</strong> plalm lrd qiE. Thc osy conrisrld <strong>of</strong> twB.d-Dle HPLC with<br />

ulE viola

---

H&id! ?r ar, [246] develop.d d HPLC n rhod. for th. say <strong>of</strong> gatifloxrcb h aw tuaterial<br />

aid tableb. M€$od wa l<strong>in</strong>w ftom 4-14 FgDLn. Thc i cr sd ild"day p@isio. w6 less<br />

rha 1,05%. Bne a al. [24?] d.v.lop.d md<br />

wlidoled HPLC method for th. detlm<strong>in</strong><strong>in</strong>g<br />

golifloxe<strong>in</strong> @ncnlradons <strong>in</strong> selw sd u<strong>in</strong><br />

by nem <strong>of</strong>cl8 Ev€re-pha!. colhn wirh a<br />

nobile phde cosh<strong>in</strong>g <strong>of</strong> l0 mM SDS, l0<br />

nrM TBAA ad 25 nM citiic acid wirh 5070<br />

aebn<strong>in</strong>ile ir d€ioni4d w.t r at 293 ft. Thc<br />

LOQ B lo0 nsnl-i ir sfu dd I pgnlr<br />

lltun 314: R.pFenndv. chmabsm<br />

otquirclon., ca<strong>in</strong>z<strong>in</strong>. ed <strong>in</strong>t h.l tuddd<br />

Howvq, no n€tLod for sioulLn@u &r.dii.rion <strong>of</strong> qu<strong>in</strong>olo!.r D pBae <strong>of</strong> c.ririzift<br />

w FF.led. HenG h th. pFent &* a n4hod ws &rclop

---

Rerendon l<strong>in</strong>e obw.rl for ou<strong>in</strong>oton.s. a<strong>tn</strong>iz<strong>in</strong>c dd <strong>in</strong>t€nal .rd.rd ws foud to b€ 2.5.<br />

3-5 md 9.5 m<strong>in</strong>utcs, BFctivcly,<br />

Corbli@ @etrcio& od s.nsilivny <strong>of</strong><br />

dE Delhod e pr€*nt d <strong>in</strong> rsbt. 3.56.<br />

The 3p€cilicily ed rcbuln6s <strong>of</strong> lh.<br />

m€rhod ws also stablished. It was foud<br />

that lne prcposed m.thod p&scd the r€sl<br />

Ior mbuires dd sp€cit:city, Th.<br />

EsFcliv€ chrcm.togm d.mostFtcd<br />

dar dE nerhod m speific. TIE<br />

chrcmlogtm obtaired fion sLn

---

Th &.uey &d pEbion <strong>of</strong> lh. EElhod d. pBat d <strong>in</strong> trbl. 1,57. For er€tu.rio! <strong>of</strong> thc<br />

<strong>in</strong>m-diy pacbion s.y<strong>in</strong>s spl.r s@ F.p.rcd at six l4.k <strong>of</strong>conc€ r.tid on difrd€n<br />

d.ys, Th. Eladr. srandrd ddi.ti6 otr ah dBy wa cslculard .nd foud @.DLblc with i!<br />

'6<br />

T.bL3ll<br />

tu$E ld. pebt tt <strong>of</strong> tb Ntlbd<br />

RSD 2.5 t It 20 50<br />

0.29 0.19 0.ll 0,75 t,2l<br />

0.lt 0,59 0,56 0,96 1.55 0.62<br />

o,t9 L09 0.12 0.t<br />

0.67 0.2t t.r6 0.89 093 1.03<br />

0.54 0.13 0.lt<br />

0.55 l.2l I.]I Lt,<br />

o-008 0,1 0.m5 t.2<br />

0.12 0,16 0,25 0.lt t.t 0.89<br />

0.tl 0,17 0.03 0.15<br />

0.12 0.5,t 0,92 t.2 t.5<br />

t,27 0-37 oa) o.16 0,15 0,22<br />

2.0t o.8l 0.96 t.23 1.09<br />

o.5l oxn 0.95 0.82 071<br />

0.n 0,92 t,01 t,05 t.7t<br />

xR@i.trtMciN<br />

2 t5 20<br />

t05.21 100.9 to2t7 9t.tl<br />

2.tt 5,m t5.t4 b.19 2t.53<br />

tol.2, r04,5J t04.22 l0l.?il 95.J6<br />

2.02 t6,2t 20.!5 2t.u<br />

t00,25 t0t.54 to2.15 t00.t? too.t2<br />

2.01 t.o8 lt.4l m,t1 ,t.0.'<br />

t00lt 99.45 99.0'<br />

1.95 1,82 t5,oJ t9.89<br />

9t.5J 99,15 t00.02 l00.ll 100.45<br />

197 I5 20.o1 25.t1<br />

99,33 96.25 t00,04 t0t.57<br />

2 4_86 20.01 25.J9<br />

97,t2 9.62 100.26 10t.45<br />

L'4 4,9J 20,05 25.16<br />

80

---

LaLt al<br />

t*tdhl nattqedtur dh lo@t6 Wtpdnb*iy.nHptE<br />

Dll l !H 1.1 rll9<br />

HPI' H''T.c H?L HPLC<br />

9t.14 9.15 tm.@ ,4.22 ,.n 94.t2<br />

IJ 99.t v,.2 ta.z 96.u 12l tl,0.3a t01.23<br />

30 9.21 96.32 tot.aJ cr_l l0t,5a tm.t<br />

tt.r1 r01.32 9i. 9.0t 10l,.,5 r0i}.al<br />

60 9t.r I 9,t5 t@,5a 96_ll 96?l 99.ni, tm.t3<br />

,5 99.11 l|n.23 t00_?r 9r.t ll|o.tJ 96.t1 9a.ra<br />

too_0, l0t_ta lr9.3t 9t:l l@.ll l0lJa 9.ta 521<br />

t0J l(x).65 td,.75 q_12 99.6 tm.69 1029| 9..6 q.25<br />

t20 l0o.7t l@.49 ,t.tl 1@.n t0l.ta t0o.t5 96<br />

0 951' 9?.aa t0.?5 too,t2 9.11 9t.65 t0o.ll t0l<br />

t5 99.I1 t0l}.ol 965 9t.3 LX q.25 94.7J<br />

30 96.32 tm.2J .rt,72 l@_la ttt.6 98.?a<br />

,tt yt.tl tol.|l 90.t lB.$ ltD_tl tq,.t6<br />

,2.11 to2,75 99.5! loo.06 9ljt l(D_o1 lot.22 r0l,5t<br />

,5 ltD.lt ,4.1J l(D.tB l0t.I9 rn33<br />

9l.tt l@.06 t6.u 9t_57 totJt l0ll' l(l).,1{<br />

l0t 99.11 lto ItlJ tuJ.69 102 lot.52<br />

ta) lo0.l2 ,24 It 3.65 t00,3t lx.t7 to0.7J<br />

Sililr rr r E!oigr.d oI|I,l. i.a tt lu|E <strong>of</strong>c.iririB r4.d laE 95.!llol.tay{<br />

rt.r tt ralr.t v.t|. 6. tcvlfod. d r[ dI v.t! od W<br />

r9..lt rtdd.. |ld Bn s!! tud io b. <strong>in</strong> r!. os. <strong>of</strong> 92.|l-lo5.t7%. Th. nda.<br />

cldiy idict .rld c.irizi!. it ltiLaL i! rt rF ic c.|Fr*roo ft. n phE .otoriol<br />

dtoo i! Fr.@ <strong>of</strong> ldldordc<br />

Nqfor&n r- r Y.ris rH [.Ert s<br />

d.@i!.4 n pfl | n E tu&d io b.3t5.5 .!d<br />

T,, @\a dla3*trs d|n 6.arlr1.a<br />

192t34213 o,',25 M.dn ps 9b b.3<br />

315, 32!, 2tl dd A 1.00 d E! rqrd.il<br />

lir rkivaiE rp..'orqy e.r r!.d lo<br />

olorlr. tt % raqi.. <strong>of</strong> elgr r ir zdo<br />

drl6 l!. l|vdagtl olcatidD s. oQtady<br />

ovtttPilg li. no.foEdn pat .d n E 6r<br />

Fnibb to d.a.dn n by .<strong>in</strong> .6l| oqrdid<br />

tlF! t |!l Dsidrr F oacnirt<br />

Al pH l, a, ?.a .d 9 rh. qldagtt<br />

82

---

el@t€d for eririzi.e \|@ 242.6r,240.81, 226.50 ed 240 M, resFcriv€ly &d rh€<br />

walelcigrh for mrooe<strong>in</strong> ]6 2A.14,2a7,40, 284.A7 ed 2AI m, Est@tively (fisu€<br />

Llt.<br />

The EgIKion nadstiG for ln. applicd d.nv!d!. spocrsspic rechriqE @ Fegr.d <strong>in</strong><br />

rable 1.63. Frcn ilt @rion cut! (labl. l.6a) obnb.d by u<strong>in</strong>g tw tecbriqs i_e. UV<br />

spetophoronet y ard llPL. lt wa clid.nl rh.t tu irt.n tior muft€d berwd rbe ddss.<br />

Thc @very mg6 fo. cairiziG .r dl pH lcv.ls v@ fould to b. 91.5G 108.0ry, S<strong>in</strong>jlrly<br />

mrfloxe<strong>in</strong> E8.d betw@ 9l.77105.I f4.<br />

Ikt.$io, tdiatu af.4<strong>in</strong>irc ad no lor<br />

v=00121r+00007<br />

srtd dettiiE wilh"trllw u W @rcDlttwtu<br />

942l<br />

HPLC<br />

99.16 98.2t<br />

HPT'<br />

t0ol7 lOO.],1<br />

HlT<br />

t00. l0l.2l<br />

HPIC<br />

I00,<br />

l5 r00.20<br />

l0t.tl<br />

91.t0<br />

95.41<br />

9t.26<br />

100.13<br />

l0l.6l 97_29<br />

9308<br />

100.30 100.76<br />

91.50 99.82 93.43<br />

l0t.7l<br />

97.2\ 99,10<br />

t00,63<br />

98,52<br />

97,22 99.t3<br />

93.20 99.21<br />

t01.26 10t.66<br />

l0t.25 r00.18 100.18 100.t0<br />

t20 t00.19 98,17 9E 5l t02.66 t00.12<br />

t00,:1 98.t1 t00.22 99.1.1<br />

l0 I00.20 r00,03<br />

l0l.6J 9818<br />

15<br />

93.25<br />

t<strong>tn</strong>.62<br />

t00.72<br />

106.82<br />

98_24<br />

91.20<br />

993\<br />

100,98<br />

I0l.2l 93.93<br />

t03.c2<br />

102_66<br />

t0{_n<br />

10t.52 102.08 9a_62 t00_01 I00.33<br />

94.12<br />

t00.25<br />

I20 105 19 r00.87 r00.2t<br />

83

---

ft. r* <strong>of</strong><strong>of</strong>otu<strong>in</strong> .t pH I w fold ro<br />

b 29a urd t6 n4 a f,l 4 w 32n, 29a<br />

..d 227 oo. d pH 7.4 X* $., d 324<br />

291 .d 27.00 m |nd .r plt 9 i1 w<br />

@ d,3az 244.255, uE d nE<br />

m. TrE nv.logth. Fl.dd for<br />

cdirizile ud o0oMr<strong>in</strong> .td agptirg fftlr<br />

(kiv.tirc lp€dm!.opy !r ptl I 9@<br />

226.49 d 2a2.@ .t6, t fll 4 td 1,4<br />

ww 227.00 rd 102.30 m .nrt .! ptl 9<br />

c{r drl<br />

ftc l.IC Ddivd4 e.da oa.dnizi& ad<br />

otrMt<br />

r* 226.8? ed 276 ni, Fec.ti\llly (fu@ 3.16). Tb % |lcosy <strong>of</strong>c..iriz<strong>in</strong>c i, Fg&<br />

<strong>of</strong> <strong>of</strong>oei! @tt..d..a.d qelaSlt ! dt pH t vdt uiig boat tt lctuiqud rc bu.d<br />

b b. ir ib. r!qg. <strong>of</strong>9.6O-lOZ55% r o.dior.d h nDlo 3_65_ Si,litrty ib |Fv..y v.l6<br />

orddr.<strong>in</strong> d .[ tlf bvd. !y fra (kivniv. !..ld{! 9w foq,.t ro b. ct.4?-103.48%.<br />

ltlir .nt !y ujlg tt. rs a.cLiq8 cLdy tbsEit tu o <strong>in</strong>6.db!<br />

drr0<br />

dra.0<br />

pg ?.4<br />

pH 4.0<br />

9fl t.4<br />

y=0.01r +5&l?<br />

u

---

od<br />

ry..elt, ntdtt 4n Ernth oltur,6 w tsd,@t tuE<br />

pr 1.4<br />

HPT' xPtc HPI,C HPIC<br />

cr,tt ,t.11 l0l.'7 td,.8J v2.& 9ttt t00.0t<br />

l5 E.1l 9a_a lra,6 101.36 95.8t 96.82<br />

JO 95.23 99.!O 99_59 t@.62 98.66<br />

a5 ct.90 Ln tm.25 99.tt t0l.a5 1m.22<br />

9.53 t0l.t2 too,tt 96.61 r('o.9a t00.6t yt.u<br />

10t.62 t0t.62 9t,41 10t.0 t00.90 r0l.3t 94.24<br />

9o loo.6, r06.56 99.61 tm.l2 Ln 9j1<br />

105 tgt.55 9t.21 Im.al 97.t18 r0o.t6<br />

120 rot.6, 99.f2 LA t(D_2t 9,.r0 l0l,.,lr Im.t tm.6l<br />

ln52 loo.t6 l(x).?t t@ lr9.x l(D.4 99.8<br />

IJ vt zl ,t.la 94.6a t00.tB tm.7l<br />

30 c5.6t 9..65 t0l.tt<br />

n.7t 9t.30 1m.71 t0o.?0<br />

9.21 t0,J,72 t0t.59 91.4 l0l./A<br />

75 1,0.91 too, Itrr,Tl t00., tol5<br />

,t.2t 10t.2, yr,tl lot.t7 '9.0 ,t.10 r@.t5 tm.qt t@.1t<br />

t@.?' l0t.u <strong>tn</strong>269<br />

ln' t0l.t5 1t2.99 l03.al 99 5l<br />

Es..ttr tbecd n! 1- <strong>in</strong> rtdb di|d !<br />

3{,, 266 !d 219 m. b tb !c uy tt lr<br />

otri.d b. doufi ir rae.t .d b.dc<br />

6.dim ''@ !46, 265 d 2E @,<br />

'tl pll 7.4 rd q l!. Fl <strong>of</strong> .odrn<br />

octqg.d rlE rp..n <strong>of</strong>caiirrE.!d i s<br />

Dr FdbL ro c.lotd. th. ffiid <strong>of</strong><br />

er &!g qil dr id6fr.@ 6.tbr! wc<br />

lppiied fi.d dda d..irdiE t (tlrcopy ft'<br />

f<strong>tn</strong> 3.lt: Dqivriw p.dr- d<br />

dl d.diM.. Ar pH I tlF rt t<strong>in</strong>S Bst.lsrt br c..iriri!. .nd .!|oeia !n . {oty<strong>in</strong>s ffi<br />

d.iivairc {e 232.74 r.d 257.2he. r..p.dirdy. A ptl 4 catundrc w .rdr"rcd d 22!.57<br />

m .!d .tw<strong>in</strong> !r 276,64 d TL urd.oatb clc b.c.t!i.js .t oll z4 w 223.57<br />

.d .r pH 9 w 226.62 m wn*.{ &r s|Ni! rt pH 7.4 e&Etd$i pr.tur.d w 27664<br />

dtl d prl 9 r|! 2?7 d4 clpGdiv.ly (69@ !. | 7).<br />

E5

---

Rcg$sion sbdnics re sboh <strong>in</strong> tablc<br />

3.6?. IrF o/dqilalilig lrlEs <strong>of</strong><br />

cairiz<strong>in</strong>e {d ooE<strong>in</strong> <strong>in</strong> diffffil<br />

buff6 neditm cl@ly <strong>in</strong>diored lhal<br />

drugs e nor eff*red by drc prele <strong>of</strong><br />

this qd@l(E a wll dd quiNlo!.<br />

did nol <strong>in</strong>te.f@ rhe dislibulion ed<br />

abs+don <strong>of</strong> drug .| ey body<br />

mvircmentol nedim (1abl€ 3.68). 'ne<br />

@ovcry yalu6 <strong>of</strong> €.tifizile io .tll rhe<br />

m€dims on uV sp4trephoton€ny reg.d<br />

lwvery vals w@ 97. l9n 0l.96%.<br />

Trble 3. 67<br />

RtsE tion $distics oldiEire aad enMir<br />

0.9982<br />

0 086.4<br />

bciwcd 96,48-106.78% dd o. HILC lh.<br />

.tturu Etdb ol@luh.,4,.nodh on w secnnhdon tu a'd I<br />

I<br />

xptr HPLC HPI.C HPLC<br />

101.26 99.E1 I03.43<br />

91.22 t00.31 97.t1<br />

30 t0t.72 105.89 t&_21<br />

t02.69 99.24 10i.72 9t.12 tot 55 10t.25<br />

l@52 t00.43<br />

97.10 tol 58 lo0.2l<br />

yt.l2 100.80 105.t2<br />

105 l0l.4t t01.22<br />

t20 tm. t01.26 I00.20<br />

91.25 t01.78 97.88 t0o.t2<br />

l5 93.6.1 97.21 105.54 98.29 101.32 97.31 100.58<br />

l0 103.26 99.61 99.62 10265<br />

101.53 l01.l.l 98.12 102.57<br />

10J.72 98.26 IOI36 r00 85 I01.33<br />

99.62 101.0 l0l.3t 100.91<br />

l00.r.I<br />

105 99.32 I0l.N7 98.94<br />

1.20 I01.32 r02.36 100.52 99tl<br />

Tlrc I* obsed lor cipmllok<strong>in</strong> !l pH I ed 4 € found to b€ 3 15 ad 277 M. Simitdly<br />

.r pH 7.4 sd 9 6e liE obrl<strong>in</strong>cd we 314, 1t,27t &d 227 M, Bp6riv.ly. The<br />

weclcDgtts pFtu for cdnizi4 ed ciprotloxa.h an4 .pplyiq frn ddiv.tiw r@llliqE<br />

^ pH I w 2)9.20 &d 2a1 .61 d! a1 pH 4 w choh .r 222.t 5 ed 230.9 rD, rr DH 7.4<br />

86

---

obwe,l d, 224.72 tl 2@.91 M lad ft pH 9 ir<br />

w *let d !r 22t .!d 262 nn! rcll'.diEly (fig.<br />

3 19)<br />

Th. Egrcsion 3t ridi$ lffi .Eludcd ($to<br />

3.69). The 'svtry dudk <strong>of</strong> cairiz<strong>in</strong> <strong>in</strong><br />

pl!g@ <strong>of</strong> cipr<strong>of</strong>loeh <strong>in</strong>diot€d m cbtrg. <strong>in</strong><br />

.vlil.bilitt vdu6 <strong>of</strong> borh !h. dtug!. TtE/.<br />

Ewil.lility <strong>of</strong> .tftizi@ <strong>in</strong> F.!.M <strong>of</strong><br />

cipr<strong>of</strong>,oeia d .[ pH la.lt<br />

ru foud to b. b.t9a<br />

9425-t05.61%. SiDilrly ttk<br />

% adihlility <strong>of</strong> ciF<strong>of</strong>oxt itr<br />

d .[ pll l4k B ot6/.it<br />

to b. ir tlE 6!9. <strong>of</strong> 9.&<br />

cip<br />

fi.rE 3.rt: rr.ridiE qcfu orccniziE<br />

eitc<strong>in</strong>ooe<strong>in</strong><br />

t8ttfu ttdnka <strong>of</strong>sw an d<br />

fltE ottuw,It ctptulMn d Uv t4rDd,t em6tI EPLC<br />

Dlt I<br />

t5<br />

t0<br />

9a.u<br />

t02.n<br />

XPLC<br />

tot 77<br />

l00.Jl<br />

93.09<br />

101.00<br />

t04.32<br />

t05.6.!<br />

t00.37<br />

HPI-C<br />

t@.to<br />

99 53<br />

.21<br />

10t.36<br />

t(x).al<br />

vt.u<br />

HPI,C<br />

.n<br />

l(x) ?3<br />

93 39<br />

HPIC<br />

99n<br />

l0t.5a 100.61 99t0 99 7l<br />

120<br />

0<br />

l5<br />

94.25<br />

9412<br />

99.8!<br />

102.35<br />

97.21<br />

99 tO<br />

too.30<br />

93.26<br />

t00.77<br />

9at2<br />

9t.62<br />

t0l.t9<br />

98 40<br />

t@.n<br />

10t.33<br />

10t.76<br />

104.35<br />

101.09<br />

t@t3<br />

t03 6t<br />

to.t.2J<br />

1m.73<br />

t01.4.2<br />

t00.t3<br />

99.31<br />

t03.21<br />

93.30<br />

9962<br />

t(x)73<br />

t01.36<br />

10t.53 100.02<br />

10t.65 10t.66<br />

t00.92 102.96<br />

10t.22 9.2t 100.05 100.25<br />

t01.33 100.82 100.98 99.64<br />

93?t<br />

100.68<br />

tm12<br />

100 73 101.9<br />

l(x)3l<br />

105<br />

93.7E 99.3 | 98.79 tm.55<br />

120 99.t I 99.31 100,71 100.42 101.63<br />

a7

---

T1E r'- <strong>of</strong> 3pd0oeir at pH I w'16I, 296<br />

ald 224 at pH 4 w obs&d io bc .t 368, 298<br />

ttd 232 n\ Gp.ctircly. TIF odtricd<br />

ww.ldgtb cho6 an6 .pply<strong>in</strong>g 6.!t dlriv.lirr<br />

4.drc@pic ahdi.r for clttiz<strong>in</strong> .nd<br />

3p&Soe<strong>in</strong> rt pII I ll@ el.dd ! 224.t4 Dd<br />

8r,s6, rt pH 4 w fotdl ro b. |r 245.57 |nd<br />

287.46 d\ d pH 7.4 w ob6lrd ! 2A.l4.nrt<br />

300 m..d n plt 9 qr foli ro t! 24.46 |nd tot Er cedrivdy (6ge 3.20). m.<br />

FgBi'..ql|nid ud Rltd6 @.hom <strong>in</strong> idL 3.7l. Tl|. qddlr @fici@it turftl<br />

b.l[. iatod w oh.<strong>in</strong> d i6 tlF r!9. <strong>of</strong> 0.98O?-0.99j7.<br />

&Fs46 'd1'd6 oJa<strong>tn</strong> E @d 'i,tt@t R:<br />

dr1<br />

Dtl7.a<br />

pll9<br />

ptll<br />

rH4<br />

htdldid lndilr f,i.d orrt ! wici! hfta. rdi,r'nr rtonEd drla io ida.dioor , ey <strong>of</strong><br />

Ite plt lcvd!. TlD.AEiLbiliry <strong>of</strong>e<strong>tn</strong>iri@ ! dl rlE pB lcv.! d W !rc.t optoton i.y<br />

rDg.d b.*sq 92.41-10!.86% sd d tlp|-c I fqfit ro bG b.rl6 96 Eo-t01.42%<br />

'h€rcfor., n w 6n lud.d rh cdirizii. outd b. dcty u!.d yith flu.oquiDloei .od<br />

tlF. fu.oqli@l{lG did et iflct !d wirh ir, ditr.ihdid or $e.ptidj, ior d.ttyqt l[.n<br />

rd..& io brb &y !o.t <strong>of</strong>|.lr,<br />

33

---

H?LC HPLC H?tc<br />

100.5 | 9ll3 t0t.66 96 80<br />

l5 101.78 qt.62 99n2 tm.56<br />

30 99.t2 t0r.36 98.50 93.33<br />

98.66 98.71 108)8 r0r.88 98_22<br />

9.68 I00. t0 10092<br />

99.23 98.06 92,41<br />

t02.66 I01.33 93.14 95.63<br />

105 9815 t00,32<br />

120 99.24 100.25<br />

0 93.45 100 2.1 100.54 99.22 101.42<br />

t5 t01.35 100 l.l 98.61<br />

.t0 91.25<br />

9a_29 t01.7, 95.02 91.65 t00_1]<br />

96.11 t02.42 100.68 101,45 10t.73<br />

75 99.69 lot m 96.28 9612 100.91<br />

100.41 tol.54 94.27 10t,63 93.46<br />

t05 I0t.29 98.t1 t05.76 99.86 10042 t00.1.2<br />

t20 10{.78 100.52 t04.tt l00m 93.09<br />

4 Cedrnir. ritb qLi@ .hun.l blo.k E<br />

I Sihtlt@B d.t m<strong>in</strong>at<strong>in</strong> <strong>of</strong> ethbttu <strong>in</strong> ws@ ot@lcim chael bl@te6<br />

C.lciw iotu @ cntcr dE en lhsueh volragc dcpodot chdn ls .nd rh. povo€tim <strong>of</strong><br />

brolchosp€sn with oewoEN<strong>in</strong>er acetylcholirc eoton<strong>in</strong> or hhramirc nay &tivar<br />

speific rcalos ibat opeo c.lcim chmels [250]. Calcim-chmel bl@kcF w.rc loud io<br />

ptud$e Eiobl. <strong>in</strong>nibilory etrecb on all.Aic ard non-all€rgic hisdift krelion [251].<br />

Mo@q,fihitir B ale found to h. stonlly eirr.d with sys:rolic blood pllss@ aad<br />

hrFr.Bion b mr t2521. ln tulbs rtl

---

M .@onim @tate. aceroniuile and l'ielhyle<strong>in</strong>e (2:2:l:0.04 v/v/v). dete.don l<strong>in</strong>it ws<br />

ls tha E ngbln lo. atl @mpounds , *irb ctrrciots <strong>of</strong> wi.rion lN thD 19o (for <strong>in</strong>bed<br />

i ra.day) ovd lh€ co.c.nrration rtus€ <strong>of</strong> I-IOOO ngmln, MBtaf.1216l develop.d ed<br />

vrlidared HPLC ncthod for th. simultaFu aDtysis <strong>of</strong> mlodipi@ ed v.lsrna <strong>in</strong> mpls<br />

for liv€r p€rfisiod s1udi6. This Eerhod ws foud to bc li.@ with<strong>in</strong> ih. rug! <strong>of</strong>0,05 !o 60<br />

!snI--I, LOD ed LOQ v.lu6 \re 0.02 snd o.o5 llgnrr for bolh lDlodipire ed v.isdt n.<br />

VoE and kdav [251 daclop€d R.P-H]LC nethod for s<strong>in</strong>ultlmu d.lediution <strong>of</strong><br />

bispelol fiddaL dd ulodip<strong>in</strong>e bBylale <strong>in</strong> i.bleis, L<strong>in</strong>@ity wa e$ablished <strong>in</strong> lhe arse<br />

<strong>of</strong> 8-31 ,!8DL-r. Md l@very w6 9.1% ed 98-6yo for bisoFotol fr||]qt .!d<br />

drnodip<strong>in</strong>e b€sylsL, r€sperively. chaldh6i ,/ at, I25El desib.d e RP.HPLC method foi<br />

thc s<strong>in</strong>ul|InoE .stimdon <strong>of</strong> aroMqat<strong>in</strong> ed dlodipift fibh th€n cmbiInios dn8<br />

prcdDct. A sability <strong>in</strong>dicadng RP-HPLC me<strong>tn</strong>od h6 bcn da.loped ard s$lequatly<br />

vdid.t d for simultllHB .si<strong>in</strong>ation <strong>of</strong> mlodipim pEnt s lnlodip<strong>in</strong> b6ylar. ed<br />

h..mpril ny&ochlorid€ frcn fien @nb<strong>in</strong>arion Dtuducr. The d.sqib.d n thod ws Un€e<br />

ovc . ran8. <strong>of</strong> G l4 pgnLi for sblo

---

lgnl-n for sll drugs wcE s<strong>in</strong>ulileouly prpsed. All $lutio6 @ntailcd 5 !gml--' <strong>of</strong><br />

F$$t!th (<strong>in</strong>t @l standard). Ee[ ehrion m id.ded <strong>in</strong> tdplior€. C.tibBlion c@es<br />

lNft @dlrnctcd by plonirg @!@<strong>tn</strong>lio! v.ts dtu p.d( ag dio. Ihe @retadon<br />

c@6ci.nts wrc calcular.d (bble Ltl) 6d l<strong>in</strong>tu Egc$ion .qutio.e found fd v€rapenil<br />

B y = 2l0J4x + 10493, dilrian B<br />

y = 7918 8x + 41587, ulodip<strong>in</strong>c re y = l8ltox<br />

+ 27?31 &d cairizirc B t-l6l45i+58960.<br />

'Ibe sleciticity <strong>of</strong> e daltlical method @y b.<br />

d.6,€d a th€ lbitty to ureqlilRlUy &redie<br />

lh. anallte <strong>in</strong> pFse <strong>of</strong> additional coDporcnis<br />

swh a <strong>in</strong>puities. degndarioi pldrcrs.<br />

SF.<strong>in</strong>cig, B evalul.d by pFFr<strong>in</strong>g $e<br />

ealltic.l spik d mpl.s &d it @ o.fid.d<br />

tul Oe rie.al m6u€d 6 @ue€d onty by rh.<br />

malytes, Tn€ FpEsnutive chtl)mtogllm did<br />

not slow oy od.r F.lc, which @ med lhe<br />

specificity <strong>of</strong> thc helnod.<br />

Lltunenke Fdirie oltJt @ba<br />

8W. l.l8 98.12<br />

l0t.5l<br />

O.JJ]<br />

80y. t_6t<br />

tuo/.<br />

9. RSD %RSD %RSD<br />

2.5 0.21 0.98 0.99 0.1 055<br />

5 01t 0.t2<br />

l5 0.t2<br />

Lll<br />

t.t5<br />

033<br />

1.59<br />

|.47 0.23<br />

l.l I l.t5<br />

0_92<br />

0.35 0.t2 t.0l l.t6<br />

t2@/, 0.t2<br />

l,0l 9a.n<br />

0.82t l0l<br />

t00.]9<br />

t.l9<br />

Aeley (&}|. 3.74) rtudy *s pdfmed by spiti.g 80, IOO &d I20yo <strong>of</strong> e*<strong>in</strong>s<br />

slandsd. The pr.cision <strong>of</strong> rh. hethod lru sdsfadory s c/oRSD w6 nol mor $e 2%,<br />

Rsfl3 <strong>in</strong>dicjr.d tb!. r[. hdividu.l @ecry <strong>of</strong> .I it dngs mgld t't'w6 9E,72-tOl.r2%.<br />

PFcisioa (bble 3.74 ed 3,75) @ nBWd <strong>in</strong> r.ms <strong>of</strong> rcpeahbiliry ot.ppti@rion ed<br />

D4ll@or. -nE <strong>in</strong>er{ay p@isi@ dala $!F obra<strong>in</strong> d by .gyilg @plca prEplld ar<br />

9l

---

ihe ld.b <strong>of</strong> co@manon o. difrer d.F. Rlpealability <strong>of</strong> sr.idad appticarion B<br />

ffi.d our Bilg sir Gpliqrs <strong>of</strong> ilE t00./.ld $tutiotr. nE y,RSD <strong>of</strong> Del !16 foraI Oe<br />

.hes wa foud 1o be vdy low.<br />

Thc bbul<strong>tn</strong>ss dd rugs€.L.ss <strong>of</strong> rhe hcrhod M €6rabtish.d s the yd.vilrion iom m.d<br />

ey valE- It *6 tur€d dw m degndlrio <strong>of</strong> &, dng blrt ecuftd <strong>in</strong> rh€ @nccd<br />

fdnuLtion l!.1 9@ &dtys.d by Ihir ncIhod (l!U. 3.?6). IF low %RSD ul@ <strong>in</strong>diclt d<br />

the suitability <strong>of</strong> lht m€6od for but<strong>in</strong> halyris <strong>of</strong> aI drugs <strong>in</strong> phmaceuliql dosge fom.<br />

Th. l@rcri6 <strong>of</strong> dru8! ir pE*nc€ <strong>of</strong> s@ fd dt <strong>tn</strong>. ddgs qd r6r€d for Dcm@ <strong>of</strong><br />

.ldos€ooB @npordrs rtdch hiShr <strong>in</strong>r.rf.E wiit rhe drgs b.i,g oalr2.d (labl. 3.?7).<br />

Cl[onsroSrms <strong>of</strong> blel plMa ed a pta3tu @plc spiked wiih all ile drugs wce<br />

@mp@d to show rh. 3peificity .!d $Lcrivit <strong>of</strong> th. FoFed p@!dw.<br />

% ?c@wn6 oldg?ad bnn&<br />

l02.tl 99.52<br />

5 98,97 to5_21 s.02<br />

l5 104.u r0r.2 lt.l8 95.14 1412<br />

t02.11 t9,97 19.E6<br />

25 t0t.l? 25.29 24.6J<br />

r0l.2r t00 25 44.29<br />

2 20 25<br />

93.52 l0t.2l 93.75 100.12<br />

95.26 96.1t 96,53<br />

93.65 t03_54<br />

100,16 lor.02 102.66 r00.88<br />

ll C. rizia. <strong>tn</strong>ieraction studie, with catciw chtuet btute|<br />

oIE <strong>of</strong>rlE msl srudi.d 6isr,@ nehqis b m.did€d by p_8tyoDrere<strong>in</strong>, which ce,t$<br />

be noddated b, .atciuh chanel bl@lc6 12601. Ddss such o dilri@h ad v@p€n e<br />

nodulators <strong>of</strong>borh CYP3A4 ed p-glycoprcte<strong>in</strong>. Horev€r, ilE roL <strong>of</strong>p_gtycopoteh i! rh*e<br />

speifi. d$s <strong>in</strong>l.o.nod mdc wl€.r 12291. vmpaDit tuy ord phan@ caidane.<br />

92

---

Fli.d| toF <strong>of</strong> <strong>in</strong>9ltrtd d4rc cdd dE b n! lor.did pdy.op{cadn itbibir,o., efcd!<br />

[r6t].<br />

vd|lrnil rhortd ir n|xit|M $!ort.e d 27E Dd 229 m <strong>in</strong> dl lrudi.d pB 6€

---

.5t lt9<br />

Itur@tt@ wltt <strong>of</strong>qd^nN db <strong>tn</strong>p,tt u W tp.noptoown, a,t<br />

HPI,C HPIC rfLc urrr<br />

99.25 91.65 99 6l<br />

It 99.62 94.74 992t<br />

lo 98.12 98.t2 93.2 lm 06 97.24 lo0 5<br />

100.r t0t.2<br />

9ta 102 105.5 yr.t5<br />

15 t03 1(B6 10t.3<br />

1027 l0l t00.J8 l0l t(x).2<br />

105 l0t 9i3 10t.7 98.63<br />

tm 98.73 100.2 t03 l0l t6 98.69 94.72 l@.3<br />

0 102.7 t03.J4 9t.l I !03.3 9ta<br />

t5 l0l9 l0l toz.vl lot 3<br />

to2 lm37 98.t5 lo0 I<br />

t0l 933 l0t.t I0t.2<br />

fi ct,t5 t03 l0l3 100.7 lm7<br />

15 t01.96 t02.1 9947 t0lJ to2_a<br />

tm.l 100 53 104 %32 100 2<br />

l0J 99_ra tg2 tm.7<br />

l.t0 100.3 y, t7 l0l l0t 3<br />

Ia.I t!. hlfr*d Ddiutu (r,H t, { 7. !d 9) s&.rag<strong>tn</strong> Dryitu <strong>of</strong> il|n,.5 E<br />

ob!..v!d ro bc at 236 M. So <strong>in</strong> dda ro r@tve d,. c Et ppD8 lIErrA <strong>of</strong> .aniziE od<br />

dihtu&m th. frn dajldjE Bpons<br />

I pH I r@ rBt&d d 223.43 .d<br />

Sibilrly rt cponB d pH d Z.a<br />

&d 9 fo. eridt4 B4 224.14<br />

223.77 .rd 216 9a n4 c.p..riEly.<br />

Fo diti.zcm rhe !!rtri@t<br />

hEr@gtb4 !.t dcd fo. qu.btrdd<br />

e6. 219.34,2t6-9t Dd 2lr.oo orr r6!.direty. Tt ,/d@vay <strong>of</strong> canizie .@..t<br />

b.twn Ll5.lot 7s% wtFE { rhd <strong>of</strong> ditt.*d E foud ro be <strong>in</strong> dx 6,rse <strong>of</strong> 9.};5.

---

t05.65% Th. |@rst ddic. <strong>of</strong> bo$ rt drug' clarty stow.d rt|tt d <strong>in</strong>ra.dion.r |Iy pH<br />

bv.h Ou! both {E dosr c@ld bc d.ly 6.<strong>tn</strong><strong>in</strong>i!tq!d.<br />

DI<br />

t4ktu 4nnt oJ 4dtur rhh dtt@- tu w tp.dtupteto&nr @d EpLa<br />

pH9<br />

HPLC HPII HPLC urrr<br />

%.la<br />

t5 98 35 97.42<br />

l@.02 101.22 99 55<br />

105.75 l(x) 96 r@.03 l@tl 101.43<br />

92.t5 t02.65 10016 l03.la<br />

93 5t lm 5.t<br />

t00.69 9t.36 t0t.23 l0l.2l<br />

t05 102.15 9a l'l<br />

120 y, t5 r@.J6 93.13 101.37 t(D.63<br />

0 Iot .}t tm.9l 93. t3 rot.n<br />

t5 1m.56 100.87 l0l 16 1m.85 9t.36 101.23<br />

t01.26 22 I02 35<br />

102.5a 100.68 %.tJ<br />

l&99 96.1,t l@31 yr.t2 l@ 33<br />

15 102.54 l0l.2l 10t.57 100 36 93.41<br />

l0l. q_tl rct.n tot.92<br />

t00.03 100.26<br />

tm 9125<br />

Th. Niru6 3pc.r..l ri8fi,tr fo..blodipi@.t dl<br />

th. pn le obkEd b be !r 366 !|d 236m.<br />

IIde h ordr io strc rh. ddiqtiv. sp€r. <strong>of</strong><br />

cdiri2i@ .rd .Dtodip<strong>in</strong> it|. fiis &ivdiE<br />

lp€ro@pic t€hriq@ wa .ppli.d. A,.lrricd<br />

ng..|3 n6!r&d 1 pH 1 fo. cai.izi@ &d<br />

mroi'F4 rc.! 225.t 19.d 23r a3 @. r pn<br />

ll - !/a\<br />

n..E 3.2rr DeridtiE Srcn dcc .Dd r,il<br />

4,2ta.M @ 2t9.tZ, tt pttT.4 rhe .DtFicrl esrct.tgrt Fl.dd *$ 22.9t at! 210.74 m<br />

!,.t .r plt 9 ir $.! d 224.95 ud 2t9.53 m (fi8@ 3 24). Th. Gg.eion r.ri!ri..! e<br />

-<br />

95

---

.pfstd ttdiei3 ol c.tizitu dd z'todiDi4<br />

pHl<br />

0j9r<br />

o-9956<br />

'fte 6ult5 (la!I. 3.83) <strong>of</strong> anlodip<strong>in</strong>q showed rhlr no <strong>in</strong>teredon dt oy pH lclels. The rry<br />

sF.iropnobtErcric valus <strong>of</strong> eririzjE rnd dlodipirc ar all pH l*ls @8ed b.rven 90l0l%<br />

md 95- 109%. rspecti!.ly md on HPLC rtuged belw@n 9t- l Ot "/o for bolh th€ dru8s.<br />

r.b|. 313<br />

In@E iM /6ulB oJdirizke vith an!.dip<strong>in</strong> on UV tpzcnoplotmtry dd<br />

EPLC<br />

PH9<br />

HDLC HPLC HPT' HPLC<br />

97.24 99.82, 98.45 91.20 98.82<br />

I5 91.20 9.25<br />

l0 98,15 t00.5) I00.3t 96.J4 t00 7l 93_62<br />

100 8.1 t00.?.1 93.19 r00.90<br />

94.42 t00.41<br />

98.48 93.33 93,51<br />

90 99.07 99.52 101.65 98.71 100.41 97.84<br />

95.16 t00.3t 9l.ill<br />

99.42 93.55 l0t.5l<br />

99.1| r00.31<br />

I5 99.11 93.t5 9n 89 t00.42 rol &<br />

t0 95.0E r00.9t 96.2t 9,78 r0o,7l<br />

99.20 96.54 97.49 93.92 t01.4 |<br />

97_t8 100.61 93_3J<br />

91.51 99.43<br />

99.85 94.71 100.08 100.89 99.85<br />

105 l{x)91 100.62 t0t.65 98,72 100.26 97.O1<br />

Cdniri!. ri.n NSAID'!<br />

98.54 100.37 96.88 100.86<br />

S<strong>in</strong>uhdtuow zleterkituioa <strong>of</strong>@tirlzltu ihyeMA@ <strong>of</strong>NSA|DS b, Rp- H.LC<br />

96

---

It hs ben 6bblish.d drt s'n.rgisli. €tre.t ws .xlibit€d by th. .ombired e <strong>of</strong> c*nizim<br />

wilh ni@didc [262] dd <strong>in</strong> cl<strong>in</strong>ic,l triats cctirizire had b6 saf€ly adDilbl.r.d wjlh<br />

NSAID9 12631, Topial dlihist m<strong>in</strong>ic agenls not ody povirL f&rrer od suFrior ctief thd<br />

syslenic etihistm<strong>in</strong>es, bu1 th.y hay also ,osses a longd dualion <strong>of</strong>@lion rhan orler<br />

.lNs i.clud<strong>in</strong>g vM<strong>of</strong>fificlo6, lul cell 31$ilisea, NSAIDS ed coni@st€roids. M&y<br />

&tihi$mircs hve eli<strong>in</strong>llamatory pnFni.t s rell. Som. ol6rs dli.iif{M.tory<br />

.tra1 s6 with 'pw dnhi$lhiG pE C.v@lbast<strong>in</strong>e ed mcd.sr<strong>in</strong>e) nay b. diE tly<br />

.nribnl€d lo rh. bl@k<strong>in</strong>g <strong>of</strong> th. hislaniie rcccptor ihar hs been shom to dom rcgulat€<br />

<strong>in</strong>t@lllld .dh$ion noLcul..l expEsion &d <strong>in</strong> nn4 liajr chemoiaxis <strong>of</strong> <strong>in</strong>fl&rnarory<br />

elh. Ym ed Ju [264] dcvclopcd a siriv. &d yd siopl. RP-IiPLC o.rhod for tbe<br />

d€l€mimlion <strong>of</strong> ibuprcfed <strong>in</strong> b.agle doeh plMa by 6<strong>in</strong>e $lid phae €xlticrion. Avd.ge<br />

qbelnle @overies w€E 88% for ibuo<strong>of</strong>en dd 96% Ior <strong>in</strong>remal slanddd. N.soji [265],<br />

d.velop.d a 3impl€. *letiv€, Epi4 peis ud .@nonic.l rcv.e phAe HPLC 6€lhod for<br />

simulr{oE .srim.rion <strong>of</strong> n<strong>in</strong>dulide dd dicl<strong>of</strong>eMc $diu 6!n eesul6. Thc l<strong>in</strong>@<br />

dtMic tu8. lor bod nib.sulide md dicl<strong>of</strong>.ne edim ws 0,5,30 psnl-_'<br />

dd 2.0-lO Agml-r Especlilcly by lhis<br />

m.rhod. l'l@lanol *a @.t 6 m<br />

<strong>in</strong>tqml st afd. Heelala d a/., [2d6]<br />

d€sib€d a sihple, sp.c<strong>in</strong>c, &cuar€<br />

4d pei* RP-HPLC method for th€<br />

siDdr.ms detemiedon <strong>of</strong><br />

n<strong>in</strong> sulide ed riaitl<strong>in</strong>e froD |!ble!s.<br />

Coefici.nts <strong>of</strong> cod€lolion obr.<strong>in</strong>ed for<br />

n<strong>in</strong>esulide &d tiai

---

ft. n€thod for rh€ dcim<strong>in</strong>ation <strong>of</strong><br />

cetiiizift (slion B-iii) B seleted lo<br />

qudt NSAIDS <strong>in</strong> &1i!., ph'Mnlical<br />

pr.te.liom dd <strong>in</strong> tu. Rehrion rirc <strong>of</strong><br />

clt riz<strong>in</strong>., tiap<strong>of</strong>en@ &id, fllrlir<strong>of</strong>en,<br />

iblprcfcn ed nefendic acid \^@<br />

sibllr.!@Bly de|em<strong>in</strong>ed elnl<strong>in</strong>g our .r<br />

2.5, 3.E, 4.8, 5.10, and 7.1 m<strong>in</strong>nt s,<br />

Gp

---

t1M<br />

%RSD<br />

0_52<br />

I01.72<br />

9.62<br />

l0l.l I<br />

to0.8,r<br />

0.1,t 9.8.]<br />

t02..,6<br />

96.15<br />

93.|l<br />

t0l-55<br />

lO,l.87<br />

t20% 0.33 t0'4.t2<br />

0.12 t02,66<br />

100,22<br />

101.99<br />

to0_2 |<br />

0.21 93.77<br />

0.8?<br />

<strong>tn</strong>@t"edii@ sei:;ta oltlz nethd<br />

%RSD YORSD<br />

I l.I 2.25 l.t3 o.97 0.7., t.72<br />

6.25 o.21 0.r6 0.t6 t.55<br />

12.5 0,&2 0.ll 0.62 0.11<br />

t0 0.2 | 0Jl5 It2 0.88 018<br />

)5 0.t99 0.21 0.29 o.,<br />

0.82 0.72<br />

99

---

mon dtd. pra*tu <strong>of</strong>tlz nhd<br />

%RSD<br />

0.16 Ll 0.45 t.t2<br />

0.lt t.6 0.37 t.2 r12<br />

t2.5 0.56 0.t2 l.l,l<br />

20 0_91 1.37 l.2l<br />

0_t2 0.55 0.17<br />

l0 0.37 087<br />

M.thod bb6hs with Fgld to vdi.tiotr <strong>in</strong> wav.Lngth ir lh. slgc <strong>of</strong> 230,240 M ws<br />

$dic.l. P.!l a6 lrd Et ntion tire chdg6 l4 ob*nEd. R6uhs ctdly <strong>in</strong>didr.d rhrr<br />

Frr c rd6 lrw irflEnccd lN, up to 2% fd .ll rbe d gs .seyed- Momh, rh.<br />

epeation M foud ro bc sulficidt. Th. m.thod B suc6stuUy applisbL for pla.rical<br />

ue, To cv.lule ihe i.ledivity <strong>of</strong> developcd m.rhod for ihe aEl$is <strong>of</strong> fomulat d prodwrs.<br />

c.tidz<strong>in</strong>c, tilpbfen c si4 nuhprefea ibuprefqr m.fendic @id ed @toxi@ rablcrs<br />

rw &dyz.d .!d c!rcDtogtu v@ dp.rtd *ir[ de $.Dd'd etution <strong>of</strong> rh* dtugs<br />

*IFF m irterf@ne <strong>of</strong>cxcipidts B ob{.F.d,<br />

wecowh, ol dltete4, b@'ds<br />

102.13 lt9 LI 10t.78 Ll3<br />

6.25 6.2C t02.13 98.2X 93.25<br />

12.5 12.61 101.45 t2.93 t2.45 96..]6 12.05<br />

N 99.88 19.93 20,3t t01.99 98.48<br />

x 21J9 25.67 10.,78<br />

l0 96.21 24.45 29_41 28,10 r03.65 ILl<br />

t02,44 5t.22 t0.1.65 5t.El 98,21 49.11 105.15 52.]J<br />

I00

---

%Rwn* oldtf.Eit bru,&<br />

It) t05.25 3.24 I02.12 Ll9 107,88 1.37<br />

98.32 107J, I02.t6<br />

t2.5 12.02 105 22 ll l5 12.63<br />

r0136 20.21 100.23<br />

102.69<br />

l0l.2l 97.6t<br />

96.21<br />

IrF sFc<strong>in</strong>cig <strong>of</strong> th€ n.Ood qs also ddonsraled by spik<strong>in</strong>g $tm smpl.s <strong>in</strong> fik<br />

dif.Ht @netreadoN qd calculatiry th. lwrcr, (r.ble 1.93), which for .tt the drugr M<br />

found b b. <strong>in</strong> lhe @g. 92.45- 107.45 showirg th. fi.Epartic siglli@ce <strong>of</strong>lh. Ddnod,<br />

ll Interactiob<strong>of</strong>cetbizire thNMtDs<br />

t.t2 6.25 12,5 20 25<br />

10t.54<br />

t$.22 t0t.99 102.66 r00.29<br />

I03.57 98.6t 98,64<br />

,9 t2 101.44 I0l<br />

10521 96.21 96ll l03<br />

107.23 99.21 97.65<br />

92.45 9a.D<br />

NSAIDS may eflst P-glycopol€<strong>in</strong> expE$ion [258], ir qs foud thai both celecoxib ed<br />

diclo&@ haE <strong>tn</strong> lDr.oli.l ro <strong>in</strong>libn rh. tunction ot p-gtyopot <strong>in</strong> ir ECC 6i,s<br />

Aodqi.c !p&le sd .flu ,sF [269].<br />

Thc ab$rption lmima <strong>of</strong> risprfemc &id a1 pH 4 wd foud b b€ 3 I I nr! howwer at pH?.4<br />

md 9, it w at 315m. Simulr.nos €qutioD ws lpplied o qu&rilate the two dtug! <strong>in</strong><br />

$lulioq <strong>in</strong>0.drion ruults cldly iDrlic$cd th.r % availabiliry <strong>of</strong> cctirizift M ml.dly<br />

rffc.tcd ir F€..@ <strong>of</strong> riap<strong>of</strong>.m &id. ft. yc lv.ilabitiry <strong>of</strong> eririzire wa foud lo b€<br />

168.l5-748,93 ed 121.46.128.8? % by Lry sp.clrcsopy ald HPLC eFctively.<br />

t0l

---

Epsilaau c wiw t'ft^<br />

15100 t29\7<br />

t68t0 ]65t t4742<br />

l6lt0 l5r0 tlotl<br />

TIF % avaihbiliry orcdirizi!. <strong>in</strong> pBace <strong>of</strong>ri.prcf@ eid ys nor fodd looyo. S<strong>in</strong>itdly<br />

ti.prcfoe rcid b also sf&ctcd <strong>in</strong> presc. <strong>of</strong> c.liiizi!.. D!. Esults al vebs DH lev.h<br />

a peeld <strong>in</strong> ubl€ 3.95 cldly <strong>in</strong>dicat€d th. @tid bellrg thc two drugs.<br />

Tianbfon&<br />

qPl! HPI,c HPLC<br />

t02 100 t03.t6 9.68 I02.91<br />

It 90,05 93.1 l0E.5o t01,92 36.36 33.66<br />

l0 9t.60 l0o 84 t0{.95 3I<br />

1t5 80 5.61 lt42t 1t609 11218 I I9.96<br />

0. t2 |1.7 I t3.64 t\6.97 10886 I I0.t6<br />

II9.t2 l r8.62 ll6.15 I I7.tt 102l) I Ia.t7<br />

I26.tl t29.43 I20.66 t25)1 1t5,63<br />

105 r30,9 I2l.3l t2t.75 t21.99 llt.57 Il3.4l<br />

I15.20 r21,34 I15.70 \25.42 t20,69<br />

t04.J9 100 1084 98.48 115.53 |l9.68<br />

t5 93_lt t06.3 t09.21 t06.6<br />

9l.lt 109.3 107.59 t02.3 t00.2t<br />

1t5,95 |2.52 ro7.9l ll2.l3 I t3. r.l<br />

l6t,.t' ll6.5l 8.r4 r08,7 D1.24<br />

t25.1t I I3.6.] |1,17 2t5.97 I19.07<br />

l50i.l t20.19 20o.ll tr0,8l t20.ll<br />

105 12t.3 t24_62 122.61<br />

120 t6t It t21.46 r28.87 244.91 r28.81<br />

i Dicl<strong>of</strong>e@ sotliu<br />

'ft. absrption lwiM <strong>of</strong>dicl<strong>of</strong>cn c ediu .t DH 4 ald 7,4 qd fourd ro bc n 27lm ud<br />

al pH 9 al 276M, Th€ <strong>in</strong>I@lion study <strong>of</strong> c.tiriziE @ p6fom.d <strong>in</strong> pt€ge <strong>of</strong> di.l<strong>of</strong>en&<br />

sdim c<strong>in</strong>g simulia!@s equdons, The eplilon vd!6 w. cdt llared dd 6e D6e.led<br />

t02

---

Thc <strong>in</strong>tmctlon rcsuh oI c€t<strong>in</strong>z<strong>in</strong>c<br />

<strong>in</strong> pFs€M <strong>of</strong> dicl<strong>of</strong>.N $dim<br />

cldly <strong>in</strong>dic.Ld thd @tion<br />

@oE!d al sll rhc pH la€k. Il<br />

w obswed that rvailability <strong>of</strong><br />

dicl<strong>of</strong>cu. $dih (@id€obly deElsed i! pt*re <strong>of</strong> etirizire. TIE iolc6.rioD Mg€<br />

obercd for did<strong>of</strong>@ $diu .r.il dE bufld n diu tug.d b.r@ 26,2&56.1070 on<br />

Uv -lisible spectrophotomelq, s<strong>in</strong>ild rend was obsw€d on HPLC, which w6 5o.EE-<br />

7E.45% I! lhc s. my, tbc itr&cdon Bults for c€<strong>tn</strong>iziF .i .ll pH lcrcb wE ir lh.<br />

tu9. <strong>of</strong> 157.13- | 61.94% d uv-visiblc sp.ctrqhorom.&r &d E0,45-2t 0,03% on HPLC.<br />

T.bL 3,!,<br />

Epiton wtt6 d wio6 b,I.B<br />

D<br />

t5100 9237<br />

16850 l0l7l I t57<br />

pHo 16350 10t35 9804 .l l7<br />

HPLC HPI' HPLC<br />

IM lod.t2 t0().t5<br />

It 67.95 93.91 96.91 9!.86<br />

l0 72.59 26.62 8?.88 4.1.0J 37.52<br />

65.92 24.20 35.24 t3.69 88.i8<br />

5524 54.U 20.62 n.1a 54.29 91.54<br />

75 5E.77 Itol 16_t5<br />

53.00 t4|l 1068 3l7l<br />

t2.17 681 5t.61<br />

120 t0.88 2626 69.89<br />

|l0.t3 95.3) 9n.18 93.1|<br />

r5 35<br />

16986 8.t.]6 87.35 31.19<br />

130.24 r85.51 46.12 88.5J lIl.36 31.72<br />

|l5.]6 |1.66 37.t9<br />

I5 t70.92 187,2t |r1_t t25.83 3713<br />

90 170.31 192.\4 10.08 t29.27 34.33<br />

l0t l98.ll 5.33 81.16 3t.69<br />

r20 2ro.0l t2n.76 5t.tt<br />

ftc MimM .r.lyticd sign l ob@ed for flubipreIer w !r 246 m ir all pH bedi@.<br />

H.M limiramB .qu.rio! B lppli.d to. th. q@riialion <strong>of</strong> I[* drugs <strong>in</strong><br />

l0l

---

Ite <strong>in</strong>i.@rion reeultr <strong>of</strong> nubipr<strong>of</strong>€n at veiou pH l*ls <strong>in</strong>dic.lcd s <strong>in</strong>ct€e <strong>in</strong> availabiliry<br />

<strong>of</strong> flubiprefd whi.h 6dged b.twen 125.I I'l68.9t % or UV spenosly ed o. HPLC. In<br />

tb. 9m v!y, .vaiLhlfty <strong>of</strong> cdnizi@ ift@s.d dEsrioly <strong>in</strong> p|!$M <strong>of</strong> Rutbipbfto b lLe<br />

tuEe o:I 25 1.y2444. | 5yd..<br />

Epi<strong>tn</strong> uot4s d was btfus<br />

J286 l4r.l<br />

16350 2t94<br />

16150 .21650<br />

il H<br />

4<br />

HPLI HPLC HPLC<br />

9t.10<br />

l5 95 5.] 98.i 91.13 91.t6<br />

100.48 94..t5<br />

Il1.33 98.16 99.02 9t.32<br />

ttt.24 147.8' |5_27 t02,98<br />

15 |]6.50 150.71 102.t7 II5J3 103.31<br />

154_42 l26.ll t20.55 I I8. t9<br />

t0t 146.t9 159.84 lll.46 I21.58 l]6..:0 12t.96<br />

120 I55.96 168.9r 112.90 \25.67 112.46 I25.ll<br />

t00.t5 t00 I.]I 97.26 22J_6 Imil<br />

r5 t0,.9 2242\ t03.tt<br />

9t.2t, I l t.44 97.1E 110.69<br />

121.5r tot42 2@.59 102.17 .I13.76<br />

341.14 26t.74 90l9<br />

]69.r1 15988 nn_27 I|0.91 93.31<br />

.]89,01 143.28 5.67 98.72<br />

105 ll8.46 250.93<br />

29432 lr0 8l

---

Th. iaitutiotr srurlr <strong>of</strong> c€rnizirc 6 Frfom.d i! prls€re <strong>of</strong> ticp<strong>of</strong>e@ &id 6<strong>in</strong>s<br />

s<strong>in</strong>ulLn@B equtioBi €psilon vdG l@ cilculded dd @ prcml.d <strong>in</strong> lable 3, t00, The<br />

irt€@tion resulls <strong>of</strong> cdir<strong>in</strong>re <strong>in</strong><br />

Fel.re <strong>of</strong> ibDprcf.n ihos thd<br />

d. Eaclion ccued !t all th. pU<br />

lw€h ed ihe % availability <strong>of</strong><br />

both thc drngs @Nid€Ebly<br />

Eprtlo, vdus d woa bSe6<br />

333<br />

16350 t 7|l2 254<br />

t0012<br />

% mihbilitr <strong>of</strong> ilru6 .r wis DH lo.l<br />

H'<br />

H?LC HPL,c HPLC<br />

100.16 t00.88 100.01 93.63 t01.69<br />

t5 l0o.3l 65.37 23t.45 lt2_14<br />

88,97 98i6 27t.ll t2t.03<br />

269.a4 l15 43<br />

I26.94 261.21 t2a 11 125_75<br />

12089 42t.66 t42.41<br />

t35.39 t22.11<br />

t05 145.78 116.78 411.88 123.7<br />

120 150.69 140.33 419.45 129.4J<br />

98..]6<br />

l5 r02.89 t06.13 93.61 \02.26<br />

120 219.77<br />

115.96 92.t5 120.46 t64.'l 106.54 96 82<br />

t2o.5a | 70ll t2E_11 192.47 I I3.43<br />

l]8.9 101.09 It9.37 82 68<br />

t30.2)<br />

r37.61 t94..33 211.87 113.44<br />

218.15 I35.43 288_12<br />

'rlE .b$rptiotr l|uim. <strong>of</strong> tuftui. &id B fould ro b. st 285@ h.e s<strong>in</strong>utr$os<br />

eqution sa usd to q@tit r€ th. rvo dnss <strong>in</strong> pEstre <strong>of</strong> @h orher (iabl€ 3.102).<br />

105

---

Th. % availability <strong>of</strong> ednzie<br />

ra4.d bdwco 44,73-45.tt9 Y. on<br />

UV rp.clrophotorc&r &d 66.26-<br />

?3.58 % @ tlPLC. S<strong>in</strong>ildly<br />

@isi.Loble dtit B ob6dcd for<br />

Eps on r:dw d wiN btd.A<br />

16350 tt2l0 1219 105<br />

15ll r27<br />

n.f.Mic rcid wherc availability <strong>in</strong>dEs.d up r,o 124.25.135.84% on Uv spcct opholob.ily<br />

.r1d 265.9G27A-1Po on IIPLC,<br />

tlr. nwimm si8tul at all ih. pH<br />

lels for oebncd M foud to b.<br />

ai 162 m h.ne s<strong>in</strong>ulr.ncoE<br />

eq@iid 6 alpli.d io qMritlr. the<br />

tw dnrgs <strong>in</strong> nixtw (bbl. 3.104).<br />

% llro .btti, oldt zt a wios tE L|.b t9<br />

HPI' HPLC<br />

I5 31.71 870l 97.15<br />

l0 23,50 8t.39 25.44<br />

8t.72 lt_57 37_95<br />

60 87.19 35.71 3,1.19<br />

75 87.43 18.29<br />

90 41.18<br />

7t98 12.69<br />

t20 7t.54 6_26<br />

0 93.25 t00 99.18<br />

97.56 105.59 106.89<br />

t0 7938 t22.lt u3.20<br />

t64.31<br />

t21.16 t70.86 2t0.39<br />

t26.62 t92_11 r5t,78 220.96<br />

90 tu.74 l9t.m 157.69 267.28<br />

r0t t2t_52 210 135.56<br />

l20 115.34 265.96 t21.25 278.n<br />

Eryilon w|tur d wnw btli\<br />

11904 22<br />

t2152<br />

t\54<br />

t06

---

For cctiriz<strong>in</strong>€ th€ o/dv.jlability ieged berwan 120.96182.11 % sd I15.62-191.?3 % by<br />

UV spebophotoneter ed H?LC Esp€ctiv.ly, Thc % avanatiliq <strong>of</strong>mcbn@ ir pr.se<br />

<strong>of</strong> ccti.irift dsased 10 c aignif@t qr.!! N.ihlilirt <strong>of</strong> c.ririAft @ 2_06{6.2e W<br />

lJv-vi3ible stFtophoromacry and 42.6t68.49.a bJ HILC.<br />

I.bl.3J05<br />

tr4 t9<br />

HPI' HPt,c<br />

t0o.t2 91_Zl .r9.39<br />

I5 91tl t2_6 88.15 36.71 6l.tl aJ6<br />

30 57.11 l5 34 39. t9<br />

27.47 56.23<br />

19i 35.49 102.5 65.67<br />

2.11 33.11 64.67 78 88<br />

2.25 63.9t 7t.tt<br />

105 63.It<br />

r20<br />

100 10008 96,59<br />

l5 2.9 I10.99 l0l24 110.25 1t2.55<br />

30 t30.16 79.33 103.07 |]0.62 ll6.2l<br />

t2t.t1 tu.32 105.13 I6t.5?<br />

\t2.17 l.l4.tJ t24.t6 I09.21 l1t_62<br />

7t 113.6 ltt.78 115.84 t06.41 141.3<br />

I14,06 r40.88 t26.62 1t0.87<br />

r05 I17.63 178 6 112.88 143.9 149.32<br />

t20 t20 96 I9l.7l t2t.75 ll5 62 l82.rt<br />

Inl @lion nudi6 s@ fsnhd supponed by th.modynmic d!t!. lt ws obsd.d ftom<br />

themodyMi€ dal, thai sponhrcous qcrio. have ocared be$e€n NSAIDS ad etiriz<strong>in</strong>e,<br />

6 dl itr. Cibbs Ge o65, vdu6 \'@ fo6d 10 b€ rcg.tivc.In s simild ey, helI 6nLnr<br />

vdB *w .lso fould to b. eg.tiv., *I|icn shoved rh.r @hdd fotuio! is duc b<br />

cb.l.li@. En$oDy val6 for all de <strong>in</strong>i.*ti@s *w fourd ro b. positiw qc.pr for<br />

b.loxicM <strong>in</strong> pH 4 at all thrc. r€mFEtc. N.gaiive €ntopy v.luca <strong>of</strong> meloxi.m <strong>in</strong>dic.red<br />

doror eepbr mnpl€x forrutio. due lo hydrcgc. bondiq dd ch.larion.<br />

107

---

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s .? .r<br />

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T T E €<br />

2 E 8 E € e<br />

I 1<br />

2 s<br />

.1 J a<br />

F s<br />

F a i R e s T<br />

? .t e .t<br />

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E t Y I E E I F €<br />

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---

6 C.tirizib. ritb r imrl.d.lt<br />

I S<strong>in</strong>tLa@ts detem<strong>in</strong>atiok oIcefthift l, preleace <strong>of</strong>antltularlah<br />

In om <strong>of</strong> thc an|di6 a ce <strong>of</strong> d.l.y.d Fss@ urtiwi. w p@l.d <strong>in</strong> whjch<br />

,dihistuiG g+ rct efedre. tlo**r, drrbddid E found 10 prldue positiv€<br />

imF.i [270]. In eolhd .& or aut uiidia dd algio€dqE onl etihisrabiB showed<br />

no dier <strong>of</strong> sydploos. rbwv.r, 06l chlobqu<strong>in</strong>e shoqed ! .lrmatic <strong>in</strong>povtuot <strong>in</strong><br />

patie condition t2?ll. ln solr uniceio dimalrial tptrn€ M .fiecdve [2?2]. nE<br />

ddotdtids, c oroqu<strong>in</strong>*, hydnxychlooqu<strong>in</strong>€. ed quim.nn€ e usd prihdily lot<br />

maldia but th.y cd b. b.n ficial for c!ran6$ lupu dtlhmatoss (LE), pollmoQhoB<br />

liclt duptioo, el& uni@i! &d Frph"ia cur8@ I'd. t273l. siftc etmldi.is e efely<br />

coado<strong>in</strong>islcEd dnSs <strong>in</strong> pEpM <strong>of</strong> er<strong>in</strong>2irc .d haw shoM . poitivc cull <strong>in</strong> dr<br />

l@rndt <strong>of</strong> liliwi. hene a nov€l &P-HPLC F.thod m develop€d [o simultaMuly<br />

q@dry cdni<strong>tn</strong> <strong>in</strong> presm <strong>of</strong> ml<strong>in</strong>aldials. Nu€rcN RP-HPLC h.thods have b€a<br />

Fported for the d€tem<strong>in</strong>adon <strong>of</strong> dtiDalaials. B.ll a ar, [2?4] dev€lop.rl HPLC melhod for<br />

th€ qu.ndrsdr! detcrnilalio! <strong>of</strong> @mon etimaldials, they q@tificd stdfado<strong>in</strong>e,<br />

pyrimlb@i@, chlorcqui!.c, dodirqui& &d .16.:thyldodiaquift lion wbol€ blo.d.<br />

Cdibdion crc wcc l<strong>in</strong>@ (rL0-9t <strong>in</strong> dE MS6 5 l0O llSnl-], 5O-IOOO, 150 1500,<br />

100 1000 and 100-1000 ngml r for sutfadorirc, p}T<strong>in</strong>dhtuift, chlobquiE, dodiaquift<br />

ed desihylmodiaquire. Esp€.tively. ,&. dr 4t, [2?5] de$ib.d mcilFd for ihe<br />

d€t mi@lion <strong>of</strong> pyrimethd<strong>in</strong>e, sulfadie<strong>in</strong>c sd its melaboliL N-acdyl-lllf.diuiE <strong>in</strong><br />

plama mpl.! fom rconals, s@ple tftp@tion wa bded on proreio pdipitadon. The<br />

dalysis s perf<strong>of</strong>r.d usila HPLC with UV md ns spet onmic dcEcrion.<br />

Ii tbe plffir *ort, ! w merbod B<br />

dcvelopcd .rd $lidn

---

sym€F <strong>of</strong> p€ali. The reteition t<strong>in</strong>.s <strong>of</strong> pydh€$m<strong>in</strong>e, cflotoqui@ ed eririz<strong>in</strong>e at rhis<br />

mbil. phe 6 foud to be 2.5, 3.6 md 6.2 njlurcs, 6F.rively, TLe d.r..rior ws<br />

perf@ed.r 210 M with 1.5 mLnitir. Rosuvslalir ws choq to be & <strong>in</strong>l€h.l slandlrd<br />

elut<strong>in</strong>S ou1 at 9.3 niml6. Itu Fp6dt tive l<strong>in</strong>@ cqudoB fo. plr<strong>in</strong> lhdiF.<br />

chlooquioe dd c€tiriz<strong>in</strong>e w.E foud ro h€ y =80262x-24975, y = 54715x + 5861l8 &d y<br />

= 6622?x -200861, Esl,e.iiEly. Th. corelidon @ffici€nls, LOD nd LOO Elc @<br />

PzgtstN id6tLt @d kBt\'ly oI th. n4hod<br />

LOQ toD<br />

0 999 0.00r<br />

0,04t 0.0800<br />

Th. $t<strong>in</strong>Et d p@isiotr (torsl laialion) EDh wilh<strong>in</strong> dNy expsjn€ w ob$Ned 6 l6s<br />

thd 2%. Thc m.rbod p6s€d th€ r6t for etc.Lbiliry a d.r.m<strong>in</strong> d by %RSD <strong>of</strong>d. d.a <strong>of</strong><br />

t& peks <strong>of</strong> six rcplic.tE iljadoc.r toop/o rs1@lc.nEation (raue LtO8). ,nE Esulr, ot<br />

<strong>in</strong>rmcdiare p@ision @ s[M ir labtc 3.109. The lKti <strong>of</strong> a@@y (r..bL ]. | 0s) Ev..l.d<br />

lhil lbe meurod wN ecwte for .I abov€ purpoFs.<br />

ccttt dnd wisiM olrtE netbd<br />

% RSD<br />

100.t4<br />

0.ll I00.12<br />

t0ty4 I.23 t0l<br />

tle/. 98.75<br />

l@ 12<br />

99.11<br />

t2e/o 100.t9<br />

ll0

---

Iir'4ne.Iitte p4bid oJth. h.tkd<br />

50 0|l 0.78<br />

y.RSD %RSD<br />

25 0.15 0.26 0.01<br />

t2.5 25 0.05<br />

o,072 0.75 0.08] IJ6<br />

2.5 0.92<br />

0.12 ) 0.61<br />

t5 0.21 1.25 0.032<br />

fte av€Es. v.lws <strong>of</strong> thc ag€d $lution 6poB6 (!eal d6) sed obseFed ro be asE d<br />

wnh <strong>tn</strong>e Alsh $turid sFls, with<strong>in</strong> i2%. Tlle 7o rccoEns <strong>of</strong> tue, h pr6e@ <strong>of</strong><br />

s@ (bble 3,I l0) reveal.d the applicabiliry <strong>of</strong> |nelnod for rhemFrric &d cl<strong>in</strong>icd pu+osg<br />

ll <strong>tn</strong> ranio, <strong>of</strong> c.ftlzire vith @timl@iats<br />

t2.5<br />

to2_34 t01.37 95_1a<br />

50 25 2<br />

I00.ll<br />

t0115 t0t.u r00.85<br />

P-8ly@prctci, honologw I (?Bhl), noddaL s@irivity io a tuge <strong>of</strong> eiiftat&iat<br />

@npouds. In th€ sc atudy, mdloqu<strong>in</strong> ws shoM ro be . Fi.nr irhibftc <strong>of</strong> p-<br />

glycoprob<strong>in</strong> tespon acdvity, <strong>in</strong>crcs<strong>in</strong>g the sositivity <strong>of</strong> drus{esistdftmoi c.ll li@s to<br />

cfotonc agdts [276]. Mc0oquift hlve both pFiosty b.e! sbou ro bird diFrty to p-<br />

glycopret i4 alrhowh it des e with rhigha.6nity rh{ vP I2?4. TtF e.tsi! D€ruit 's<br />

P-glycopDb<strong>in</strong> hobolog!., iDllMe d. sitiviry <strong>of</strong> malqia p@ircs to a div* tuge ol<br />

&tiDaldiai druss bul lh. Mhetum by which n do6 e hs @i!cd obs@ [2?s].<br />

Mdim <strong>of</strong> pyrihethmic dt aI pH \N* obedql !r 272 {rd 223 m. And .gply<strong>in</strong>g 661<br />

d.dv.tiw techniq@ th. i&lttical wvelagth Ft{red for dI pH t.v.ls \r@ obee€d ro be<br />

.l 240,53 m for cdnizbc sd 224,84 M fd pyribelldii*.<br />

|ll

---

R.snt@ lotiurs ol.attN dA pnn4tmme<br />

pHl<br />

y-0.026r+00007<br />

Thc <strong>in</strong>t.rerion Esulis shou <strong>in</strong> tlble 3.I|2 d.moBrar€d rhd nudied druF did nor i erfft<br />

with *h otb.s qwtitaion <strong>in</strong> .omb<strong>in</strong>rdod, C.riririre E avaihble <strong>in</strong> E tuse <strong>of</strong> 95.EE-<br />

l0l.35clo and 97,16-100.98% by both the t chriqB. Sihil{ly pydmcilm<strong>in</strong>e awilabiliry<br />

a 97.l0-l 12.86010 lrd 9?.2G 100.82% uilg sp.clropnotoh.try 6d H!LC.<br />

Irnk 3.112<br />

hteretih nsths oJdnbiv eah N@tttunke d W tp.ctrcp<strong>tn</strong>!@try o.d<br />

EPLC<br />

HPI.C HPIf HPI'<br />

9932 Im_76 td).2a IOIiI<br />

93.66 lo0 78 91.t6 100.58 l0o.8r<br />

94.72 98.42 98.71 9a.29 99.41<br />

95.88 93.99 93.36<br />

93.32 99.8.] 98.79<br />

$.q) I00.43<br />

100.7J<br />

r0l.lt 99.69<br />

120 9348 98..t?<br />

l@.65 lm.at 100.02 94,51 94.96 t00.61<br />

l5 100,98 93.11 I@ 7l l00.ll 2.86 98.69<br />

I00,69 r00 8.r 10t.74 98.66 97.42<br />

t0t.93 t01.65 100.84 91.t6<br />

100.99 t00,.]l 10t.87 t(x).63 97.31<br />

99.1I<br />

99,82 100.69<br />

105 100.68 I00.72 93.36 yt.42<br />

120 %.42 t00.t9 r@.86 100.32<br />

ll2

---

Th. .bdliE tuiD <strong>of</strong> cuoroqli4 d ptl I *@<br />

d 342, 237 aA 223 M hd. dqirdi$<br />

{od@Py e.! {rli.d ft. il, al32 m fd<br />

€liriz<strong>in</strong> dd 219.39 m r€r! d@tr tur cnbFquie<br />

lftq fiBt ddi$ti@ t6nniqu. Tle iddciim r$!h<br />

I<br />

l|arr Jl': DqirriE .0ds ordlr!<br />

.r pB I idi.!.d rbd o ida..rid @n!d Bod tt drugr w@ .nit.u. |rc.rd t6,<br />

lo@,t thugh cit dr. oqqilt rnd ooddni@ (irbl. l. I l4),<br />

6 tffid dtenhtEdn<br />

Ri<br />

pll I 0.9181<br />

Pl|| y=1552x-0.0208<br />

r.U.!.t!l<br />

ht Md6 Enltt deiM* Nnth.rto,t4tdre q Wtp.tot',tolonhyda<br />

'LC<br />

ctl<br />

t5 15 10, tm<br />

9r.t 93.12 10t.7!<br />

rtrta 93.t7 100.17 100.73 101.37<br />

,s_tl lu).54 100.35 95.t I 101.82<br />

ltPL l@-,rr l0()..t7 94.24 1m.42 100.03 t00.16<br />

C.drld@ rto ..d.xlE.d. dat<br />

$@tbEtu .Len,tdld dedtidE h pew olo taatiAt azgs<br />

It .di.<strong>in</strong>neidory lrd |di{rhric .6icr <strong>of</strong> .#hiirds td b6 ddut d <strong>in</strong><br />

prri.d. wirh bodr dlrSic |.!hM ,'d lh<strong>in</strong>hi! t279l. Cliridt bsrdit| <strong>of</strong> II, r.c.oror<br />

dr.gooid *4 +F qr i! 6od.rd! tdor t2tol. n hd d.o b€ rss.|t.d ih.airLtu.<br />

drld b. u.dl &r 6. !!6.d <strong>of</strong> oitd ro Eoddd..tttD rrd .q &. rt Flv.d<strong>in</strong> <strong>of</strong><br />

lh. di&4 t2rl1. Co rlhpy <strong>of</strong> u.dihi{miF *ir! ! t.utoii@ 6.910r .l|l.eoi<strong>in</strong> w<br />

tuid ro Flde Srcdq dti{.bDrb.r.d du rhlr <strong>of</strong>.iths ds8 gim aroD t2r9}<br />

Adilir.riq or 6ly FEvldtd tt Fog(5iE <strong>of</strong>dtae, ha rb.y E! ftod ro db4<br />

d! .frdry pta @d<strong>in</strong>ql *irh loLdiiF rd.g6id. t2r2l. r! rdtm rx{d.i,<br />

@nDiE srpy <strong>of</strong> Hr a|rrgoixi ietudi.g .rniz<strong>in</strong> wnh r6!iE!dy ddg! sh s<br />

I t.,

---

gu<strong>in</strong>fenesir dd hont€lntal weE nostly €o'mon [28!]. Momw, et<strong>in</strong>z<strong>in</strong>e is rlso<br />

.lailable <strong>in</strong> c<strong>of</strong>tbimtion wirh rcspirabry drugs such 6 pFudoephedrirc [2E4] ed elhedr<strong>in</strong>.<br />

[2t51. N@@s HPLC melho& have ben rporred ror th€ d.himtior or rhe sp<strong>in</strong>rory<br />

drurs. Phoylephir<strong>in</strong>c ed rropicuide lN* sihltrad@uly dclemitrd n€thod <strong>in</strong> nl|l@<br />

aqueus hmor by HPLC Sepetion w6 p€rfon€d o. d CN coll)m wi$ 0.01 M Pic 88<br />

(ochne sulfonic acid)-rcelo.nrib (65:15, v/v) s mobile phe. The stdddd cwes weE<br />

Un@ <strong>in</strong> th. ddad@ tuge Tn Feisio! <strong>of</strong> O. melhod (.xpta*d by Glariv€ srandlrd<br />

ddiatior) ed th. sccuocy (m.e €mr <strong>in</strong> per c.o0 w*

---

Tl@foe, a 3<strong>in</strong>ple @u.& od p@ie HPLC<br />

mlhod for situlllM6 delgbiEtion <strong>of</strong> rh.s<br />

drues ws dt loFd. 115 rhc* drugs &e<br />

availabl€ <strong>in</strong> coDb<strong>in</strong>alion ed e nostly @<br />

dmiNler.d $ a medod wb Foposd lor $.<br />

simdran@s deLmimtion <strong>of</strong> de drugs <strong>in</strong> <strong>Fw</strong><br />

materials, dosg. fom'nalionr ed <strong>in</strong> b@4<br />

elm us<strong>in</strong>S ibupr<strong>of</strong>en as e i eml staidald.<br />

Ihe d€velop€d ne6od w6 foud lo b€ wid.ly<br />

lppli€ble trd @dd be usd for U.r@utic Dd cl<strong>in</strong>icd purp.*r.<br />

ChM.rogm <strong>of</strong> dnas, r=<br />

Fsuoifd.s<strong>in</strong>, c=et<strong>in</strong>zirc,<br />

Ssi6 <strong>of</strong> exlqimmis w@ .ondu€i€d lo .srablish d. oFimM hlE <strong>of</strong> rh. &allric.l<br />

vdiabl6- 'Ir,e pam.LB optimizd imludcd mobile pl@ vdietions dd $me physical<br />

v&iau6, irclud<strong>in</strong>s th€ fiow 8L &d the s!1. lolue adjuun€rt oI pH. MoE over. ir<br />

B obscd lhar lolg th. conccnF.rior <strong>of</strong> w{€r ln. shonq Uc rererlio! rim. <strong>of</strong> rl de<br />

dDgs esuh<strong>in</strong>g <strong>in</strong> overlapp<strong>in</strong>g <strong>of</strong> peaks. hcr€se <strong>in</strong> oMnlration ot wate. upro l? triL,<br />

Gsulted <strong>in</strong> fal.r 6d b€tLr s.p@lion <strong>of</strong> p€.ks <strong>of</strong> atl lhe drugs. However, DoF <strong>in</strong>cMe <strong>in</strong><br />

orenFatior ol *arq 6uhd <strong>in</strong> very lorg fr.nlon dne for no el&6t. HeMfonl\ th.<br />

opt<strong>in</strong>m @hFsilion <strong>of</strong>d. nobile pb& w.chided ir a otio <strong>of</strong> 17 vateij 4 ebdrrite<br />

ed 75 neteol fo! shdp ed well Fsolv.d p.ats. Acard<strong>in</strong>8ly, the flow or. q6 ale<br />

adjuled e thai lor lbe drugs it w6 sr al L I hlniri' dd for monteluk6l ir w6 et ar L5<br />

ml-m<strong>in</strong>'r. ThG oPliru @nposition <strong>of</strong>de nobilc ph* @sisr.d <strong>of</strong>metheol: *eronirriL:<br />

sre (79:4:17) drd s pE 2.7, sdjusred by orrlophcphdic &id for mpid dd wlfEelv€d<br />

peets <strong>of</strong>all lhe drugs, Ac@rd<strong>in</strong>gly,lhe gradie nowmle system wd utiliad fornonitor<strong>in</strong>g<br />

<strong>of</strong> chMulogms by <strong>in</strong>todrc<strong>in</strong>r ptugllm<strong>in</strong>8 <strong>in</strong> sftwe. So lh. flow Ele wd adjuled <strong>in</strong><br />

srch . uy rhat for th@ drugs i... cdniz<strong>in</strong> , phayl.phni!. a.d erdnfdEsio n *s l l<br />

mlmir'r dd for monteluld it *6 1.5 Dln<strong>in</strong>r. The !€r61ion (mes <strong>of</strong> rb. druss w@<br />

foud lo bd 2.5 D<strong>in</strong>utes for phenyl€phldne, I m<strong>in</strong>ules for gui.f€n€s<strong>in</strong>, 3.6 miNtes fo!<br />

c€lirizi@, l0 m<strong>in</strong>ulB for @orclulsl dd ibup<strong>of</strong>o (<strong>in</strong>i.mal stadd&d) €lur<strong>in</strong>g out al 7.2<br />

h<strong>in</strong>ut s. Thc Uv spetE <strong>of</strong>ildividud drugs vw @ord.d ald @mFld <strong>in</strong> lhe wv.L.sth<br />

tuse non 200 ro 400 m. Th. choice lo w isb€stic Fid sa ar 230 M B .onsidd€d<br />

satisfacbry, p€milt<strong>in</strong>g the dekcrion <strong>of</strong> all dogs wirh adequre eosiliviry.<br />

ll5

---

IlF rhtive $andard &virtion <strong>of</strong> th€ six FaI F6DDNs wu lot found grater th& 2%. Ihe<br />

rc$luljon p,@elea w.E found for phayl.thirift lo be 2.58, guitrfeG<strong>in</strong> 2.00, ca<strong>in</strong>z<strong>in</strong><br />

2.20 <strong>tn</strong>d fdmor&l ai 1.98.<br />

No signiflcor cfi"ngd ir ftd uorLx cw. or rcLtlti@ li@ <strong>of</strong> th. dngs <strong>in</strong> preeo@ ed<br />

abenc. <strong>of</strong> ercipidls cl€arly th.<br />

qEiliciiy <strong>of</strong> the me6od.<br />

'ndicared<br />

Th. re!resdrativ.<br />

li!@.quati6 <strong>in</strong> de @n@dr.ri@ @ge <strong>of</strong><br />

2.5-100 |rgDl,r<br />

(2-5, 5, 15, 20, 25, 50, IOO)<br />

for c.tirizirc 16 foud to b. t-17955x +<br />

52233. for guifoes<strong>in</strong> wa r-22164x +<br />

5,1&19. ph@yhtk<strong>in</strong> w6 r

---

dt t die Ntitio, olrk tuthod<br />

%RSD %RSD<br />

2 0.35 t5l<br />

0.ll 021 0.1 Ll8<br />

t5 015 416 0.25 051 76.25 0.t2<br />

20 0. r8 0.52 0. r5 6.08 It<br />

t.0l<br />

IlE sv€88. v.lres <strong>of</strong> the aecd slurion Bpos.s Geak als) w.re ob66rd ro .€!re with<br />

lhe f.$h slution respons8, with<strong>in</strong> 13%. S<strong>in</strong>ce montelutsi i! lighl sGitive d.ug hence it<br />

M stor.d <strong>in</strong> tidtly qppcd n.sk pEpp.d ii alm<strong>in</strong>m foil. Tlrc develo!.d mcdbd s<br />

lppli€d for th€ de&miMdon <strong>of</strong> difrmr dog @nreor <strong>in</strong> ph.@udcal fomut.lioro. Th.<br />

4sy sulls shom <strong>in</strong> l:blc 3.118 demoNtrat d lhe suirabilily oi nedod, Simildly the<br />

o/<strong>of</strong>coverid dd @ftlation co.fiicie or dru8s <strong>in</strong> pmence <strong>of</strong> !e@ {bble 3.119) Eveal€d<br />

dE appli€biuty <strong>of</strong>medDd fo. the.nleudc &d cl<strong>in</strong>ical purps6.<br />

IkcoEn i" tt@wdkot hn'tuIotiM<br />

93.63 t.91 209<br />

8.75 tm.9l lo.4.I 5.l,l<br />

2,6.25 101.73 15.57<br />

35 t9l3<br />

26.6 22.71<br />

87.t t0.t.02<br />

25 20 t5 5 2.5<br />

102.14 t01.87<br />

I(x).31<br />

t02.45 10t.24<br />

1.5 3.75 2625 t5 4.t.t5 87.5<br />

t04.21 lot 73 100,J4<br />

027<br />

|1

---

It beraato., e@.s dedtutu vih qd$tlnadc dagt<br />

A'|tIh. ir u idl$rlddy di|.& lyopr.d & FeE <strong>of</strong> coqgb 6 siajtrt' !d !n<br />

,p.ci6qly dlctic wlE<strong>in</strong>g or iodn l d€h Bitl C..p di&!tdc.. Cdtuiz<strong>in</strong>. i. r pot6.<br />

od long{.1irg ..cond-g.s.lion Iftt 6i@ HFre.lror &r!gni!r u!€d br rh. relrndr <strong>of</strong><br />

.ll6si. di-rq rlrl s dirsic ,lti!f<strong>tn</strong> .nd c&oric ilio!.ttic unnrh rdd e. |lh.' doa<br />

d <strong>in</strong> ..it'dio. rit[ ortd di{dDri. 6 .di dlasic d!gr. A th-+a!ic.lt, .fic(riF<br />

.anot <strong>of</strong> ..tiriri& ir u!.d to F!i!d d drd @!.r <strong>of</strong> x .tu! drd. It doag.<br />

d.padt ds.idly d tt .p..ifE n tt d <strong>of</strong> .do<strong>in</strong>il<strong>tn</strong>lbn !d @ ttc purDoc <strong>of</strong> {|e<br />

Flonr|dn t2tl. Ir r.. ford tu !l-*A dyoogrd.io Ftf6!di.[y ilitiEd lt.<br />

pndykrhirei.dEd cod.did ttt3l<br />

AI .li pll l.edt tt lqio <strong>of</strong> 8u.ie{ai! w<br />

obhEd rt 2?3 rd 27j @ lI.@ d.[ !.d<strong>in</strong>!<br />

lh. ddivdiv. lign l ctos for c.rnizirc ws<br />

223.11 M ud for @ift!6<strong>in</strong> w 230.69 m. Tb.<br />

ttgGio Gqldid Tb. idq.dlF Bl <strong>of</strong><br />

canira i. FE.@ <strong>of</strong>gurifaxio rlbrEd rh.. rh.<br />

rqihbihy <strong>of</strong> dogs a uqFcd.d <strong>in</strong> pr.6.icc <strong>of</strong><br />

oh otbd. IlE ./. .Eihbilhy <strong>of</strong> @ri.izi.. pd<br />

frrd to b. <strong>in</strong> l[. rug. <strong>of</strong> 9cl0l% brh64<br />

sy gqrif.dat! w eiLU. <strong>in</strong> 6. rug! 96.1+<br />

l0l.98P, by lriig both thc rclniq@r.<br />

ttc rx: Dqn?riE rdr d<br />

!HI0<br />

Plt40<br />

pll7 a 0.9945<br />

l18

---

T.lb3.lll<br />

ttt6ct<strong>tn</strong> Eturtt tedtueith gtdf8n @ WtPdft'fuMo<br />

pHl pH,l pH t.a !x9<br />

HPI,C HPIC HPI' tfLc<br />

lm.2l 100.53 94.25 .47 9t tl<br />

l5 99.23 9.25 99 63<br />

93.15 9_A 9.6 t00.59 9t.15 9.6., 93 at<br />

99.62 t00.?3 t0o.ol 96ll 93.15<br />

@ t(D 3t 95.3t<br />

15 93 35 l0l3t 100.75 9t.87 t00.06 9ai5 99ll<br />

10145 99.57 9.ll lm 30 100.08<br />

10t.6, 93.t7 94.2i lm.fl<br />

t20 10175<br />

tm15 93.1t lmft 99.a1 93.47<br />

l5 98.51 t0t.67 t00.73 91.9 t00.0, 99 5l 99.1!<br />

.73 101.93 9t.7t lm36<br />

100 7l<br />

93.1,4 l0l.,ll<br />

100.t6 .91 9a.15 9t.6! 1013,<br />

93l4 10175 LA1 9911 t00.t3<br />

105 100.t0 l(n 09<br />

l!o t0o.5r<br />

Ar pH I dd a dE @na <strong>of</strong> Phatl.?hri* 6<br />

&!d to b. d 214 !d 27] @ lbqlE .t pH ?.4 .od<br />

pH q th. .qiu *@ ob@cd tl ,8 and 273 m.<br />

Daiv.tis ecdD..ogt w rfPli.d to E$lv. tlE<br />

ochpooS FL' 23761 m ft). c.tirizi@ !6d<br />

283 07 m for ph..tl.pbnft q@ chos for rn.<br />

qulditdioo a! edrc pH rt@ a.. pll ?.4 !d 9,<br />

240.61 br cantc ttd 2a3.66 m tu<br />

phaybft<strong>in</strong>c vtr! cto!.n (fgurc 3.31).<br />

dr l d{a<br />

L.

---

(ztxi@ twiiiu .lr.t<strong>in</strong>iw ad Dhpnv:|.<br />

0.998'<br />

y - 0.1258x+0.0153 0.9987<br />

0.9959<br />

'ft. Tdvailability <strong>of</strong>c.tiliz<strong>in</strong>e <strong>in</strong> all butre ws obw€d to be <strong>in</strong> th. rug€ <strong>of</strong>96-10l% by<br />

s<strong>in</strong>g boih lh€ l€chniqucs, In the sm€ wy phcnylephr<strong>in</strong>€ w6 9?-loto/o avaitabt. ai ihc cnd<br />

<strong>of</strong> cxFri|Mt *trich slowld dlr l[e dn$ did aor ifierfec qi0r .&h otLa.<br />

lnbdiontuuh<strong>of</strong>.ahi.iEenhde.rkplrk q W tp.cttupldMtl @t t ITPLC<br />

HPI,C HPLC ljv HPT,c HPI-c<br />

94.23 99.38 98.11 98..12 100.54 9j6 93.t6<br />

It 94.67 100 5l 93.53<br />

roo.8? 9a_27 94.29<br />

9388<br />

9lo 98.24 I00,53 97.49 100.81<br />

75 93.37 t00.85 98.16 t00.56 t00.79 r00.63<br />

90 91.45 98.68 94.25 I00.46 93.26<br />

t20 t(x)_31<br />

99.51 t0091 9t 8) 98.t0<br />

I5 I00.76 93.37 98. t6 91.24<br />

t0 100.42 99 l.] 98.01 I00.63 93.t1<br />

60 t00.55 98.89 l00.ll I00.91 l(x).87 99.58 93.14<br />

r0l. t9.97 98.87 10t.47<br />

I00.15 908 94.26<br />

l0t tm.63 98.1t 93.03<br />

t20 100.88 98.73 101.43 99.10 l00.tl<br />

120

---

Mdima <strong>of</strong> montcluksr ar pH 9 s€E<br />

folrd lo be ai 145, 328 ed 28lm<br />

espcliwly- S<strong>in</strong>uhar@u equdd m<br />

applicd to q@dt{€ eririz<strong>in</strong>c &d<br />

monlelulal h ih. nixrE. The<br />

16150 I9103.67 294.0952<br />

awiht'ility <strong>of</strong>c.tilizirc 6 foud ro be <strong>in</strong> (h. Elge <strong>of</strong>96.9 . Molelutln @ avaihbL<br />

it lh. Dng. <strong>of</strong> 90.87-99.437.. However @6t.nr d€cEe <strong>in</strong> rlE lwitabilirv <strong>of</strong> mo ehbsr<br />

M ohw.d which is anributed lo irs brable behavior.<br />

hrtu6A ts oJariuN vth Mtdut6! 6 W tpectophanty ad HPLC d pH g<br />

l5 30 15 r20<br />

93.33 93.21 94.12 91.32<br />

91.t2 93.93<br />

97.17<br />

HPLC 9t l.] 94.t2 91.12 9J 22 92.47<br />

E C.airi.ir. vi<strong>tn</strong> cpn brporiu<br />

I S<strong>in</strong>ultatuous d2temiNtio, olcetuizire <strong>in</strong> prcserce d ceplvlosryi8<br />

c€ririz<strong>in</strong> ha bc.n safelr adhiiilte&d qith @phalosporic [294]. However, r tue <strong>in</strong>sriM<br />

<strong>of</strong> @ntrcI-tyF unidia sull<strong>in</strong>S fion d a.guiFd sdirizrion lo @tbdcpol<strong>in</strong> @nlDund.<br />

<strong>in</strong> . chenist lab M Epod.d t29t. In arcrhr sludy admi.ieririon <strong>of</strong> c@batoth<strong>in</strong>,<br />

c@hal*i4 celedrcxil od cefdalih <strong>in</strong> rEnicill<strong>in</strong>{tlergic t6tients E ssociated wior a<br />

si8lifi@l itrcr€4 <strong>in</strong> the 61e <strong>of</strong> all€rgic arctioN shc@ adnitrifiadon <strong>of</strong> afDDzil,<br />

eturcx<strong>in</strong>€, e&odoxi@, eneidime ard eftrido@ did nor. on rhis bsis ! tr .d fo.<br />

simult reoN d.lhod qa f€X which could b. ed irnh.r ro snrdy th. possible a v,ltu<br />

ut @tioc <strong>of</strong> @tirizire i! pretue o{ @.dm<strong>in</strong>isrrd 4phrlospori6. Sqml HPLC<br />

aaho& har hdn Epolt.d for @ph,lospdiB. A hid Fsft liquid chmbatosE hic<br />

ncthod B deenbcd fo. the ad.lysc <strong>of</strong> a wid. @gc <strong>of</strong>cphalospor<strong>in</strong> con8.n6, uils only<br />

th@ Faeots for ex<strong>tn</strong>clion ed drug alalFis, Compoud. sn lyzd <strong>in</strong>cluded @phalcx<strong>in</strong>,<br />

e&mandole c.lhdothi[ @fotax<strong>in</strong>e, ef@li4 €th.loddire, efoxitii! efelor,<br />

aplt pir<strong>in</strong> ad efopa@lq Esh anribioli. &mstrated cxette li@ny rhroughoul thc<br />

)21

---

Lalence [29?] developed s HPLC techniqud <strong>in</strong>volv<strong>in</strong>S a radial @mpqsion hodule for<br />

nesur<strong>in</strong>g chlormphoicol md five cephaloslori. mlibiotics: efotar<strong>in</strong>e. cefel<strong>in</strong>,<br />

ccfori<strong>in</strong>, cephap<strong>in</strong>n, md efdodol. Sbndard cwes \l@ l<strong>in</strong>a 10 at l6t tOO n8ur. The<br />

lbsorb&c€ <strong>of</strong> chiompn€li@l wa nooitoEd ar 254 and 280 M. Ydututu er ,1., [29E]<br />

4pli.d<br />

HPLC nethod for ile tLt @iErion <strong>of</strong> Bidlsl €pbdcporiG i! b.Gf nea. Th.<br />

'@!ai.s vw ar levels <strong>of</strong> 78.3 ro 91.6%. A6ync .r al, [299] dev.lop.d e emte<br />

*6niw &d l@l lime @sm<strong>in</strong>8 RP-HPLC ncrhod for lbe 6:tiD,tion <strong>of</strong> efpiomc <strong>in</strong> rh€<br />

pr*ic. <strong>of</strong> €slial ed tae mdal. The d.rfttion l<strong>in</strong>ir <strong>of</strong> c.bimn @ tO ng. nrce<br />

srudies w@ rcpon€d lo b€ b€n ficial lor deEm<strong>in</strong><strong>in</strong>e rhe ddg <strong>in</strong> dEnpedic concod{ion3<br />

ituid. hlll@ body d w€I 6 ns complexalion wilh n t l calions. Sh<strong>in</strong>de e, a/., I3O0l<br />

d.v.lo!.d a simple, priF md taDid, RP-HPLC mdnod fo.1he simulranos dermiBtion<br />

<strong>of</strong>.ephdex<strong>in</strong> ed prcbdeid ir t bteis, The m<strong>in</strong>ihm d.t€clion l<strong>in</strong>it obra<strong>in</strong>ed for borh th.<br />

dngs Ns 2 F8nLr.<br />

In this melhod nifedip<strong>in</strong>e !s lsed 6 m <strong>in</strong>r€nal srardtrd.<br />

In ord.r to develop a dovel RP-HPLC method for the d€l€mimlior oI elnizire <strong>in</strong> prcsdce<br />

<strong>of</strong> c@hdGporic Eiou mobile phe @mbiEtioru wF tied. For ihe $pdtion, Cl8<br />

@lum a us€d s<strong>in</strong>ce th. cn @tdistic r<strong>in</strong>S s1rucrw ed ioaizble side gbup6 <strong>of</strong><br />

eph.lsporiB tulG r[d id.d edidales for Ev.e pn4 mLC. The lipophitic Mrw <strong>of</strong><br />

c.phal6por<strong>in</strong>s ormd ex@U.or areftior on Gv.M-phe coll|lM porl.<br />

Prcl<strong>in</strong><strong>in</strong>dy €xF <strong>in</strong>eo!3 <strong>in</strong>dicaled lhdr B<strong>in</strong>g<br />

dif.am corcsrrariotu <strong>of</strong> neth{ot and war' ir<br />

was nol posible to sp&at€ the rEals oa<br />

e<strong>in</strong>'z<strong>in</strong>e dd ceph.losporiN or to oha<strong>in</strong> suillbl.<br />

rercn$oh md lFal shap€. In orde lo abi€ve<br />

&celkblc peak shaFs ed perform dc<br />

ep@ion or a suirable tu r<strong>in</strong>e ed b kep ihc<br />

n Iho

---

T!. chrcdatosm obrliftd toB slandad $lurid w idori@l eirh rhx oblliEt tm<br />

spik d solution cont jn<strong>in</strong>S m .quivalot co.cen<strong>tn</strong>lion. Th€ cprcmradv. chematogms<br />

(ngw 3.22) show.d no olhd pe.Is on fi€ Fteniion rihe <strong>of</strong>..tiriz<strong>in</strong>€ dd cQhrlospotiB ih.<br />

eidtion tih6 did m| clang.. A@.d<strong>in</strong>ely, rb. proFsd tulhod @ b. @ili&Ed<br />

sl€ctiv€. Th€ coGlarion c@fficimls (!blc 3,126)<br />

detcm<strong>in</strong>ed Ior ell the degs denoNtr4r.d .xcell@r<br />

l<strong>in</strong>tuig <strong>in</strong> th. tugc <strong>of</strong> 2-50 ,rghl r.<br />

y=@856x 66123<br />

y=11909x+59194<br />

y=l7l22x+19A92<br />

y=l392Jr+65711<br />

kge$im std<strong>in</strong>ix @1d tNitirit!<br />

LOa t,oD<br />

0.211<br />

00t6<br />

0.012<br />

Th. cnsirivity <strong>of</strong> rh. me<strong>in</strong>od w.s.valnated (rablc Ll26) by ddm<strong>in</strong><strong>in</strong>g the LOD md LOQ<br />

fot dl lhe druSs asyed. The LOD eslisaied s ihe mowi <strong>of</strong>dtugs fdjrh<strong>in</strong>g a siglal thra<br />

r rbe $c noi$ (s^=3/l) and LOQ 6 @cidd.d s tbe low*r @m!iri@<br />

l<strong>in</strong>6 sFt<br />

a!.lyad widr @.piahL @ufuy md<br />

pFction (20olo) for all th. ealyes.<br />

Psision M n4ued <strong>in</strong> tcm <strong>of</strong><br />

GF.ralility <strong>of</strong> appliedon {d<br />

n.!ll@@1. A.cur&t dd pEcision \m<br />

dct m<strong>in</strong>ed six i<strong>in</strong>es per concarra,liod<br />

(r.blc 3.127). with<strong>in</strong>- ard b.r*qiay<br />

pEcisior rElre! e giv6 <strong>in</strong> r.bl€ 3.128.<br />

%R.cov€nes ed %RSD valEs weE used<br />

10 .xpB @l@y &d P@ision. stad:rd<br />

addition and @ovat €xFircnrs wG<br />

al$.ond@ted !o deh<strong>in</strong>e the accuacy <strong>of</strong><br />

lh. pFst medod for the q@rific*ion <strong>of</strong><br />

cairiziE, cephalq<strong>in</strong>, efotaxitr dd etoidorc.<br />

aewet @d paniu <strong>of</strong> tlf tulod<br />

0.23<br />

l2@/, 100.1<br />

968<br />

t2tt%<br />

0.61<br />

0.ll<br />

0.21<br />

LI5 100.!<br />

0.34<br />

0.73 100.21<br />

Mcthod mbwlls! md ruggedncls w@ derem<strong>in</strong>cd by dat,zirS sm€ smple ar mmal<br />

op€Btitrg @ndilio6 &d also by ch&g<strong>in</strong>g son opd.liDg analtlical conditi<strong>of</strong>f s*h Es<br />

qv.laglh, oobil. ptas @npositiol! llow '!1e, i.srul@r .nd a!.tr!r IlE Ehrire<br />

staftiad devi.riotr ir @h ce es foud mr norc rhd 42yo. IrE n.rhod @ fttthd<br />

0.001<br />

t23

---

nbi..r.d to l! r!.llrir i! F@ (r.btc 3.129). Tt b!$od w tudd io be $ir!bt. for<br />

httcri.dtu ptdtton <strong>of</strong>tb *th'.l<br />

II D II lt II a n u<br />

0.31 0.@ o.a2 t.7 0.93 LlI<br />

2..13 2.63 0.t t.23 I 0t6<br />

t5 o21 l1l on<br />

0.u23 013 1.35 2.O1 0.72 0.79<br />

25 0.47 0.87 0.87 t13 0.81 0.36<br />

LbL3.lr9<br />

100 02 104.37 95.56 95,05<br />

ll Itu ttlid olennth. eib @pt arrsrt8<br />

n.42 103.09 94.12 93.31 98.67<br />

yr_2t<br />

9t_6t 101.53<br />

t03.!2 l0lia 10t.25<br />

C.phdolporii! e . flnily <strong>of</strong> kmi .y hdh rtibiodo!, sm <strong>of</strong> rhich htw 3uucrul<br />

fc.tru .!d4n qnh rlbi.d6 br i!. Nti ddg !&,po,ta, p-Stycoprdtir s.tu <strong>of</strong>rh.<br />

c+[.lo.pori! .dilioti€ .h!! ,tiudrd cbsr<strong>in</strong>ils vil[ .g.d! bom ro oodd.r. <strong>in</strong><br />

!!Ei!8 @l|ii dug cid.@ tL2l<br />

l'-. otc.nrimre.t dl pg l.Ek wd fouDd io b..r<br />

2al d q.€pr d pH I which w{ n 262 @. Horlg,<br />

d.gc <strong>of</strong> otqlapi"g w ot€6,rd itr dE 23t no<br />

l.g<strong>in</strong> 0- <strong>of</strong>oaiizie). So it s .t5 dotv.d by<br />

.pply<strong>in</strong>S ilqivdire .p.do@pic t ctliqE Dqirii€<br />

r'8trlk cho@ fo. €tirizim lNd etoidoE .t DH I<br />

rq! 215.2t 3!d 231.3t m. Sioildt |t .t ri. dtd<br />

pH l.!€b ri8!.k ldcd.d e.! 2a1.85 d 6. eririziE<br />

.!.1 230.84 m 6r eftit:@<br />

:l<br />

50<br />

lu

---

.p.sw ednks oletitiae ad celtid<strong>in</strong>e<br />

!= 1652r'0.0208<br />

R'<br />

0.9942<br />

'fu % availability <strong>of</strong> @ddz<strong>in</strong>e <strong>in</strong> pEsence <strong>of</strong> celfuidore ws foud lo be <strong>in</strong> $e mgc 94.I2-<br />

102.54% by Uv-visiblc lp.clro@py dd 96.87-101.32% by II?LC. The q/dvlilaliliry <strong>of</strong><br />

enridor i! aI thc buft6 ws i! the tuge <strong>of</strong> 96.36-103.65% lad 93.56-lol.58t6 by UV-<br />

viliblc .nd HPLC, ctFrirclt. ft ss did.nr hom lle 6drs 6rr m <strong>in</strong>ia&lion @ur.d ai<br />

sut4 <strong>of</strong>ca<strong>tn</strong>zke \|ith.trno|n an W ttec<br />

PH 9<br />

HPIC HPI'<br />

95.1|<br />

t5 98.21 100.31 I0l.l2 100.5t 9a_D<br />

99.31<br />

100.14 100.73 9C.22 98.28 96,25 100.85 1007E<br />

96.21 100.69 102.54 91.64 96.1\<br />

l00.lJ 97.11 96.r8 100.13<br />

r00.73 t0l.t2 l00.ll t0t.39<br />

I00.17 94,22 t3.25<br />

tlt tm.06 tfi.t2 ntl 94.2\<br />

t00.It 96.28 98.6' I00.1I r0l<br />

l5 96.36 102,96 101.69 99.25<br />

l0 102.98 93.25 98.12 100.14 98,66<br />

94.58 93.1 101.29 105.37 91.69<br />

99.61 91.56 I0l.t7 tot.22 I01.58<br />

tm.0l ro0 29<br />

tol 2.1<br />

10t.23 t01.58 98.t5 t02<br />

I20 100.26<br />

nD <strong>in</strong>t Ectiotr <strong>of</strong>@li.i2i* vith efo|axim &picr.d e c&ang6 jn .v.ilalifty elc <strong>of</strong> rh.<br />

two dnlgs, Elotl rbe dngs rft avaihblc wirh <strong>in</strong> d. Mae <strong>of</strong> 9t. I n 01.72% <strong>in</strong> a[ ttc bufcnd<br />

t25

---

Trbl.3.ll2<br />

HPLC HPLC HPI' Hptc<br />

97.tt 91.54<br />

I5 9t.73 100.09 99.87<br />

99.E2 lot.63 97.82 r00.76<br />

45 r00.06 91.63 98.63 97,6t1<br />

60 9.62 95.71 98.66 9E.t2<br />

97.n 91,81 t00.tt<br />

r{,0.56 t00,69 91.6t 100.06<br />

105 98.48 t00,43<br />

t20 r0t..]l tol.72 97_l<br />

r00.46 96.r6 97_46<br />

I5 96.18 10t,96 91.24 97.81<br />

JO 97.42 r00.16 ,8.76 98.87<br />

r00,59 97.18 t01,48<br />

60 96.12 t00.63 l00.ot<br />

,8.71<br />

94,21 93.t9 99.]'<br />

t05 r00.2 | l0o.o5 99,61 94,71<br />

120 100,3 r00_16 roo_09 99.42<br />

T!. Rrlri rt wi@ pH lcEL .r 3?qC <strong>in</strong>dic.rd no ch..gcs i! % .EiLbitili6 <strong>of</strong>lhe &ss,<br />

bol[ d.ugs }e avtil&|. lp io 96.02-102.76%, stich sheld tlt c€tiriziF 6 h. !.f.ty<br />

{udn<strong>in</strong>iilnd *ith c.phalq<strong>in</strong>.<br />

T.n|. J.||t<br />

rtuion telB oldttltie vfi, c.<br />

gprr HPLC HPI' HPLC<br />

9,62 t00,81 ro0_,<br />

t5 91.U t0l.64 9.6 99.6r<br />

30 96.3' 98.42 t0o.l<br />

97.11 91.2E t0t.58<br />

60 t0o.o9 t0lzl 98.3r<br />

to0.7l 100.63 91,1t 91,E<br />

l0r.r8 91.54 93.t5 9!.71<br />

100,9? 97,52 97.42 93.1<br />

t20 9l.lt 98.t1 9E.45 99.6r<br />

0 99.36 97.I 91,4E<br />

l5 91.t9 t00-55 94.52 98.42<br />

l0 I00.09 91.t1 91,63<br />

to0.tr 97_21 98.11 98.,1<br />

t00.25 %.t6 99.78 99r8<br />

r01.96 r{,0.09<br />

90 I01.69 tot,12 101.9<br />

99.21 102,3, 100,t2<br />

t20 96,02 t02,74 t02.ll<br />

t26

---

9 C.dridn. ri<strong>tn</strong> MDDMS<br />

I SituLtuous.letemiMtion otcetuxire <strong>in</strong> preprce <strong>of</strong> NIDDl,lt<br />

Tl}tph@t16 may prcfmntially ditr@ i.t€ lo*srds a Thl ebBF, which b thowht ro b€<br />

<strong>in</strong>volvcd <strong>in</strong> th. autoimre .spets <strong>of</strong>diabd.r or a In2 subtt!., whjch is thought ro d.dial€<br />

aueryic dbeses [3{3]. orc <strong>of</strong> the sudies<br />

@nfim.d $. sk<strong>in</strong> ndifesLtions <strong>of</strong><br />

diab€Es n llits to b. a co@on<br />

@u!r!@ 'lquir<strong>in</strong>g a sios appr@h &d<br />

Ednar It w Eval€d tbar pEv.L4 <strong>of</strong><br />

diab.l6 Fllitu rclatcd stir disr

---

I! th. deib.d pc.d!n, sp{rtio <strong>of</strong> ildieidud<br />

NIDDMT t!qui!.d oodifi.tlid <strong>of</strong> th.<br />

hlf.r/oryeic aolvcd r.lio. Ho*vq, no mahod for siEult.FB d.t@i..lio <strong>of</strong> edririd<br />

i! plBdc <strong>of</strong> NIDDMS w nudi.d ro fr.<br />

InlI|? p|!s.! vqt..d RP-HPLC mdhod<br />

for siDull{|ds catitutioo <strong>of</strong> caidnrc <strong>in</strong><br />

F*@ <strong>of</strong> mcdmiA sliquidom d|d<br />

glibcelcni& a dcElopcd. In th<br />

Fll<strong>in</strong><strong>in</strong>ry qrdimnrs difrst tr.ri6 <strong>of</strong> dE<br />

iiobil. p[e *E t6r.d. h B ob.dcd rhll<br />

ntio @tukr<strong>in</strong>s <strong>of</strong> (90:10) mrhdDl: qard<br />

R.8@bn notbls ct l witb r <strong>of</strong> tb<br />

8!E @ sf.rolioE <strong>of</strong> F.ri b.t96 c.ttti4 dd Dcrftdi!. HG@ o{hd ddo! vw.l$<br />

ti.d. TL &:20 su!.d <strong>in</strong> good symaricd F.lr wiu -api.bL 3?.mi6 .bons dl<br />

&ugi Hos.lq, dcBioe rhc &mul <strong>of</strong> hcihlsl fidtd <strong>in</strong> th. nobil. pt|'!c Bttrd ir<br />

itsgscd raqnio dDc for sliguidorc. H.ncc, r*o conpolrcd FobiL pha w chos.n for<br />

tE 3ndy. t w'! .le ob.dvcd d .djusi.s 0F pH <strong>of</strong> mbib plw ro 2.E Bltr.d i!<br />

oltr@d {.ltlc paL ryt|Way and<br />

!6oluti@ for ltl tb. .!s.ycd druss. Th.<br />

r.cn{on liB for mdomill cctirizi@,<br />

slibqFlui& ed gliqlidoc wc<br />

foud b b. 2.5, l,t, 5,5 rrd t2 niNt 3"<br />

n$.ctislr. ln lhk retlod diclolqE<br />

3odtue q,!! r!.d a e <strong>in</strong>rdnrl lrllddd<br />

cluliog ord .r 7.5 rn<strong>in</strong>qt6. Th.<br />

..libr$ion crw6 for .ll dE dn$ wE<br />

@6h&Ld ud.r o?dhu @nditi@<br />

&d dF li|Eiry <strong>of</strong> d! mthod w6<br />

erBt d by Frfo.niq <strong>in</strong>jetiom.l<br />

toa toD<br />

o.2r3<br />

0,95 0.t69 o.26<br />

0.01 0,(x)3<br />

0.393 0.|l7<br />

r|lLJ,Dj<br />

%RSD<br />

o.12 91,88<br />

0,56 t0l_22<br />

o.52 91,3t<br />

807. 0.3 to2.1J<br />

l00tt 0.16 106.1<br />

t20x 0.tl 10t,78<br />

wl 0J,l 102.36<br />

t@'4 0,6 l0t.8t<br />

0.65 t0t.7'l<br />

80tr o.52 t0t.t8<br />

l00ra 0_J6 9,94<br />

t20rl l00.l,a<br />

*q difr@nt con @lEtid l*b <strong>in</strong> thc l<strong>in</strong>d mgc ov.r 2 diffctqr d.rs. Ttu D.d( !n$<br />

<strong>of</strong> dl th. doa3 wa plo!.d lgr<strong>in</strong>sr lh. @FsFodi!8 lmiol @nc.oL|ri@ io obr.<strong>in</strong><br />

cdibdrion gtlph. Th. @blion @mci@ls oad tt sitivity <strong>of</strong> dl dE ddSs v4<br />

e!r.bli!h.d od e p@ncd h l!U. 3. | 14, Th. FgBid .qurriou obtdrEd for ncdmit!<br />

elniziE, slib@cbni& md sliqddo@ lw y-E0609(+38188, r=332E9x-t tEt6,<br />

F58303x-12E27 ald r {390x+51842, Fg.crisly. Thc sitivhy <strong>of</strong> lk &.t}ri.!t<br />

t2E

---

nethod wa.v.lu&d by.letemil<strong>in</strong>e thc limir! <strong>of</strong> dete.lion ard q@tiLtion. nF signalro<br />

@ie nti6 <strong>of</strong> I rl ard l0: I Ec lato 6 LOD ed LOQ EsP€ctircly- Th. Fpcsulrire<br />

%RSD %RSD<br />

II t2 II tz l t2 II t2<br />

2.25 05t It3 t7t<br />

25 035 0. t6 0.3 0.1I<br />

20 0.32 0ll 0.71 0.56<br />

t5 l. t2 0.13 0.91 |.87<br />

5 0.599 022 0.t2 0.t5<br />

2.5 0.3? 0.87<br />

cbmd,roSe i! ihou b 8gw 1.24 show<strong>in</strong>g th. speificity <strong>of</strong>1h. m.dod. No Gndog.@u<br />

@mpon€ i <strong>in</strong>tdf.n.8 wilh alalttes ed rhe <strong>in</strong>r.mrl siardards wrc foud i. rhe<br />

chrcmtoslams obla<strong>in</strong>ed. Prccision dd a@dey were 6*sed <strong>in</strong> @nju.tion wi$ the<br />

liEeit !tudid uils thre sliked shplca at €a.h <strong>of</strong> thre @M ratios (E, l0 and 12<br />

!srnln). PFlion ws asss€d <strong>in</strong> t ds <strong>of</strong>%RSD. Accu!.y *s d.L@itFd li@ th. bis<br />

R@vqy tclr <strong>in</strong> fmul.lioG -@ pe.fmcd by $c drlda.d additioo d.thod .r six difeMr<br />

@lmtaio6 for delfomiq c.lirizift. glib.nclmide ar(l gliquidonc, In dl c!s, dE<br />

@overy P€tcn!A8. values raged b€tw€m 92.01 6d lu954% with el.live slandard<br />

deviation

---

23 m t0 l5 5<br />

t01., 97.58 lfi 55<br />

9t.38 1o2.35<br />

t01.36 105.33 t03 56<br />

98.22 t03.54 t06.98 t0? 33 93,5<br />

+t.d lauo io dE f..d p..l !A f|ths <strong>of</strong> .quivrleot ,4l|de iaitrrd &tuti$.<br />

Speciioity <strong>in</strong> lBlirid lo.ndog@u cmpomnr! w$ d.rcrlrdt d by aEblis <strong>of</strong> i sia <strong>of</strong><br />

tutlonJt 3d.d.d ddg-&* @|n mpt.| (rrbtc 3. | 38).<br />

B. bnereli@ stubes <strong>of</strong> @tirt.te <strong>tn</strong> Ws@ INDDMS<br />

Th. rcdble gly@pFtdn PGI <strong>in</strong>nibir.d iiri<strong>in</strong> rccdor tyui@ tile .id pt y.d . ole<br />

.. L.d io p..t <strong>in</strong> l[. iul<strong>in</strong> .sii.rd. <strong>of</strong> NIDDM. Alrhough ir. .n l pnyiiotoeiol mte<br />

llMitturho*q imd.'r <strong>in</strong> 8ly@prddn rc-l ir aqir8 nlidly' b@E <strong>of</strong> it3 Dodibl. ti.j(<br />

si|[ lt Fthog@ir <strong>of</strong> di.t'..6 .rl olg. P@iM nootr. @at d lh bdt|@<br />

glycoprddtr I€-l ldiviry *i..ldra.d <strong>in</strong> qdn!.d ftrott dt too NIDDM D.ri.d! qitb<br />

i&l<strong>in</strong> Gn!.@ t3ro, trr}<br />

At tII I th. '4i@ <strong>of</strong> E rftrDh w<br />

hrldto be.r 205 m &d r. pH 4, ?.4 ai<br />

9 $. n'nni <strong>of</strong> bcthmir s rlco8t d b<br />

be d ,3 m. Fd ridlhElt<br />

dcamifttim <strong>of</strong> .dniz<strong>in</strong>. rd @rfmii<br />

ddivatic !q.d.o!co9ic t cl'liqE v.!<br />

ptl I pg1<br />

appli.d by *l€d<strong>in</strong>g 212.88 m for odirizirc<br />

ed 219.34 M for m.tbm<strong>in</strong>. Ito*€vd d<br />

pr I dr*lcrcdurctaglhw2%02m forc.&izim.d2ta99mfor'ft.foE n<br />

-<br />

l -/-- J\ ---t\'!-i':<br />

pll1.4 pH9<br />

rIa.E Lrt DciEliE rp..iE d dntiE dit<br />

130

---

.@tt iaitat d r.thzn. ai N<br />

pH7.4<br />

Ih* <strong>in</strong>rdr.rion 3tudid show€d tu i qacrio bd*@ D€trm<strong>in</strong> ,!d ciririrc ar &y pH<br />

ldels. Ir'e dv.ilabiliy <strong>of</strong> cdniz<strong>in</strong>. rt rll pH lcvcls 6ged bet$an 97.17100.98%.<br />

S<strong>in</strong>ildly th. % w.ilabili9 <strong>of</strong> mefom<strong>in</strong> tug.d bctwEn 97,1+101,59y., Th€$ resuhs<br />

<strong>in</strong>dic.t d rhat th. availability <strong>of</strong>.erid<strong>tn</strong>e is uitrar.d <strong>in</strong> Desoe <strong>of</strong> nerfom<strong>in</strong>.<br />

Trbl.3.133<br />

I'x@io, witt <strong>of</strong> e<strong>tn</strong>tire wxh NfMk on w qtuphdoret, aha<br />

pH9<br />

HPI.C HPT,c HPTC HPTC<br />

0 IU).93<br />

I5 93..I1 I00.36 9_t7 94.f9<br />

l0 98.26 100.69 9851 98.81 99.19<br />

t00.81 93.39<br />

93.t4 99.14<br />

15 98.89 r00.87 93.53 9'l3<br />

Ll0 98.38 93.63 97.52<br />

105 98 75 99.63 9E18 97.t7<br />

t20 91.21 t00.75 93.11 9E.19<br />

98 29<br />

EPLC<br />

91,24 99.31<br />

98.16 99.63<br />

60 100.23 100.78 100.76 99,t2 98.73<br />

100.4J 100,J8 96_U I00.43 100.72<br />

100.37 93.06 97.24 I00.45 98,57<br />

lmil 93,|l 9'.3t<br />

l3l

---

fi. l4itu <strong>of</strong> gliquido* d pH 9 a obsEd ro b. d<br />

225 m .ad 2l8 m Afta rtply<strong>in</strong>g ff<strong>in</strong> odd dqitltirc<br />

th. lfuiru oldl€d for cai.idn. dd gliquidm (fullft<br />

3-26) 1@ 210.01 i.d 230.9 .b, r.!p.di!dt Th.<br />

r.gcaid rnbi6 .la llPlyhg ddivni€ r..hiq6<br />

@ dDM <strong>in</strong> nbL 3,138. Tb. id6.dioi 3bdy <strong>of</strong><br />

gliquidonc with c.<strong>tn</strong>iz<strong>in</strong> w @i.d on & pll 9. No<br />

ftE3.x: D6il|liF E eor<br />

.6.rg6 <strong>in</strong> Tt uiLbility <strong>of</strong> dr d.rgr s! obFad i' prq.c or *h olta (t bL<br />

Lll9). Ita % MiLbility <strong>of</strong>o.ridr<strong>in</strong> *.. b@d to b. i! tlE ds. <strong>of</strong> 97.51-1m.98./a<br />

'nnc<br />

v. $ril.bilhy <strong>of</strong>Slhuid@ irs found lo b. b l[. tu8! <strong>of</strong>9E.0l-100.EE r'o.<br />

uI@ tundq <strong>of</strong>*d,ttE dn t<br />

dt9<br />

!H9<br />

tu an@ wnt oIdlruEvii<br />

I5 15 lm<br />

93J? 100 65 100.98 99.42 t00.42<br />

HPI' 9t.88 98.t6 93.32 t@.42 l00.al 9E.{l<br />

94 53 9.t5 94.74 98.03<br />

HPT' lo0.(' 93 55 1m.6, to0.,r<br />

TIp $lorption maiM <strong>of</strong> glib@ldid. w$ otdred 10<br />

b t 22a n wnich a ovalrppiiS lt. .p..16 <strong>of</strong><br />

ritiri?ie lttr E lb |qs rld daitdiE tttuioa I<br />

u!.d ro sl€ rh. ddt p9<strong>in</strong>8 !F.1a b3,2s n 2219.52<br />

m wft sl6Ld 8). c.tirizir. &d slibtuluid. a<br />

tlaE 3|? : Dqn/riw s.6<br />

.!drri6l dt!.h <strong>of</strong> fnt &.ivdiB. Th. .@t <strong>of</strong><br />

Slitdldid. d !H 9 3h',!d th drug' did tr.r iddfcld<br />

vitl @t otlE !.d w@ .dLble <strong>in</strong> rh.6ngc <strong>of</strong> 97 5&100,85%. Th.'/dwl.lility <strong>of</strong><br />

c€drizb. wa rvlilrbl. <strong>in</strong> lh. fi€. &gaalloDA3%.

---

sitD tdi\iB olaiziE @d qlib.rct<br />

T.bt 3.l,|o<br />

Lttukn B,/B <strong>of</strong> et 12itu vith stibmt^rle u w spdnophdomtry ad EpLc<br />

o l5 15 105 t20<br />

tm.9l 93.61 t00.08 98.51 .1t 9aAl 100.73<br />

HPI-C lm_41 t00.oo 99,61 9t.88 99,31<br />

93.32 99.4t 97.58 9.92 100.72 99.6t<br />

93.63 93.14 98,19 100.78 100,7r 100.35<br />

InLEctiDr <strong>of</strong> .diii!i. q t *qti.l .|.ndii<br />

W- <strong>in</strong> . W.ctrophotod.lr!<br />

Mci.Uic salts e <strong>in</strong>volved <strong>in</strong> F.fom<strong>in</strong>g vdoc nndion3<br />

dn<strong>in</strong>jsr.r.d, 6 w[ .long with diffdent food dr<strong>in</strong>l$<br />

or a drugs. Then d.ffci.ncy or .xc6 @t l.!d to<br />

vdiou disluba@s itr Ihc body and D6r <strong>of</strong> the<br />

m.tals @ <strong>in</strong>yolv..l <strong>in</strong> @t<strong>in</strong>g wioN k<strong>in</strong>dr <strong>of</strong><br />

all€rgic readioN [312-3151. A h4othsir @<br />

led{y pul foNBrd ttal diffurion <strong>of</strong> pbsm<br />

hirtrnic i.lo tlE dvit|mdrl rissB, <strong>in</strong> e,ldch lhc<br />

m.diaior b €labolizd. nighl oro pssivety <strong>in</strong> thc<br />

fod <strong>of</strong> z<strong>in</strong>chisid<strong>in</strong>€{ysteimle @mpLx. It<br />

<strong>in</strong> body. They e o6Uy<br />

% ,lwdan iD o[caiEw d 37C<br />

0 52.2<br />

l5 9t.2 89.4 365<br />

97.0 54.1 93.1<br />

95.2 a7_2 53.4 10t.7<br />

9l_0 t02.1<br />

33.7 1l.2 r05.1<br />

accordoc. wirh ftb hypoitEsis, dy padn r ligaod<br />

for zi@ ad hisLnirc <strong>in</strong> $,lrich nisiig pLsa<br />

@Mneltior Nuld .ntail . bend mbilialion <strong>of</strong> bist'oiF <strong>in</strong>to @ral dimtsiblc ftl'l<br />

onpLxq wdd al$ favor thc hisldjnc 6r.bolisF. Metal io6 phy a vilal rele du<strong>in</strong>g rhc<br />

biological pM$ <strong>of</strong> drug utiliaiid <strong>in</strong> de body, In rhe trE <strong>tn</strong>€nl <strong>of</strong> emi4 iron is oElly<br />

adm<strong>in</strong>bl@d 'tile zirc, copptr ed tulee de peqt <strong>in</strong> nullivir.m<strong>in</strong> mixtws,<br />

t316Jrtl. Hower, <strong>in</strong> on <strong>of</strong> rhe studis e<strong>tn</strong>iz<strong>in</strong>. B <strong>in</strong>re@r.d *irh d.l!b <strong>in</strong> preec. <strong>of</strong><br />

dicl<strong>of</strong>c@ $diu od n a @lcluded lbll only dicl<strong>of</strong>erc sodiu h.d lh. alilit, for ncial<br />

t03.4<br />

I05 93.5 9l.l 9.1.8 101,1<br />

I20 94.7 t09.2

---

<strong>in</strong>d<strong>in</strong>g. Cctirizire s<strong>in</strong>ply dbpl.c.d the net l ions ad its Cl- ion neuraliad ilE positive<br />

c.rt . <strong>of</strong> $. rclal iNolv.d. MoHE, n m ale @&l!d.d thar d@ to dr. pl€ge ot<br />

eith€r lwo or tlue moleuLs <strong>of</strong> dicl<strong>of</strong>€E sdiu, stdic hndme efrcts Dmhibil€d ihe<br />

<strong>in</strong>ter&1ion <strong>of</strong> nor tho ooe e<strong>tn</strong>izjn€ molccule [3r8]. So ir b€cde appMr io <strong>in</strong>leret<br />

etiiz<strong>in</strong>e with <strong>in</strong>dividual n€llls <strong>in</strong> ords 10 krow ih€ deg@ <strong>of</strong>.omplexation. nr€ objet <strong>of</strong><br />

pretrr puL *a ro obanc lle lNibl. ctr@t! <strong>of</strong> mg.6iM, calcid. chFniub,<br />

nanedeF, ircn, 6bal! nickel, cupFr, z<strong>in</strong>c dd cadn'm on ltE ,tvir, .v.ilabiliry <strong>of</strong><br />

celiriz<strong>in</strong>e alooe ed h lheir pr*M sd d€t mimlion <strong>of</strong> rh.ir @nplq6 by RP-HPLC.<br />

Metal mnpl.x6 <strong>of</strong> c.tilizim e <strong>of</strong> grc.l importae for udeBtand<strong>in</strong>s drug-metal<br />

<strong>in</strong>readiotr and for th.n F|.nrial pb.m@logicrl E. L y ro El€s <strong>of</strong> c.tirizim aloE<br />

(iable 3.141) sd i! pse@ <strong>of</strong> meral i@ .$oiisl ro hul@ body like nrgn.sim. .alciu,<br />

chrcmim, neSese,Idic, fenou, cobalt, nick€I, apper, nnc &d cadhim studies B<strong>in</strong>s<br />

BP 2007 disolulion t61 aprenB weE srrdj.d <strong>in</strong> dpty sto@h pH, n $oo&h pH, blood<br />

pH dd iri.sliul pH al37C, It m okwed thsl avlilabilig <strong>of</strong>cdnizire a unafi€drd <strong>in</strong><br />

pEs@ <strong>of</strong>all th. neials erd cedrizi!. did nor b<strong>in</strong>d silh dy <strong>of</strong>thc studi€d hel'l!.<br />

N EPLC<br />

validal€d @thod

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E Sydh6l! oldrugirg oupL!6<br />

Ir ha b€n di$us.d <strong>in</strong> *rio! C (2 &d 8) drar eftiziG <strong>in</strong>r€tuled *ilh NSAID'S dd<br />

nnvaiat<strong>in</strong> Bull<strong>in</strong>g chdges <strong>in</strong> % availabililies <strong>of</strong> dn8s. Hoe e attempi hd b€en h6d€ lo<br />

synihaiz€ the conpl€x.s <strong>of</strong> <strong>in</strong>i@tiDg dru8s <strong>in</strong> pEs@ <strong>of</strong> @tiriz<strong>in</strong>e. ItE* .onplexes<br />

9@ synth$iz.d <strong>in</strong> meth4ol for rte hoN .rd th.n GrFralliud, Tb. synlhAiz.d<br />

cmplqs *E ch,rut{ized by {ren physi.rl p.@.&F s sll s by thc techniqes <strong>of</strong> IR<br />

dd NMR.<br />

The Nigmats <strong>of</strong> lR ba|ds \N* md. by @Dpd<strong>in</strong>e d. 3Fc<strong>tn</strong> <strong>of</strong> rhe p@ d$g ed<br />

<strong>in</strong>i@ijng sFcics Mlh lhe @Dplq6, mjor aberptior bdds for the <strong>in</strong>nzred ftcquenci.s<br />

dd ihe @mpond<strong>in</strong>g asigmdll e diicus.d.<br />

In rcpon€d speti or e&izir, OH s[n h<strong>in</strong>g nbde <strong>of</strong> wr.r.nd oH dimd <strong>of</strong> 0!. m<strong>in</strong>e<br />

@hoxylic eid @ ob*ryeif al 1417.6 &d 262a.8 2354.9 cb-r. Gtetively. B@d bdd<br />

obsred al (3110 3000 cm r) md 2985.6 2914,2 cn ' is 6sign.d io Oe eoaric CH dd<br />

.liphlric CHr 8tuup, EsFcrircly. Tlte qu,t duiy nirogen atom srelch obsded al -30?0<br />

cn-' dd a vlry slak t6!d at 2216.1 d I b sigD€d to hytlrochlodde. The OH diF. is<br />

shou b bc ! nono-$bsrituti@ to a C&crlOCHr by th. ?58 or. Sbiffs rr 84F808.1<br />

.n ' showed the peme <strong>of</strong> tso sdj@i boa. rir8s. TIF cdboxylic C-O bond frcquncy<br />

]6 obwed ar 1456.2- 1319,2 ed 1214.9-1242.1 n1 , bdo8.n substitulion ( l?39.? cn ')<br />

appe6 s a ho@-$bs<strong>tn</strong>rdon d | 078- I 6 ' ir rh. p@Gposition wilh ! rirS sr,lrch bcrren<br />

1650-14q.? cm-t teqE&y tuBe. Aliphalic chrjn C-O bond <strong>in</strong> CHTCHTOCHTCOOH<br />

app@ ar r 186.1 and ar 740 cnr I!r9, ?61.<br />

DLloleM 3Fc!u showed dE NH ffih<strong>in</strong>s band al l2?6.8cmr ud NH,,,O bad or<br />

<strong>in</strong>ta'noladd hydng.n bodhg .1 3421.5 @-r [r2o]. s€v.dl splir boG lilm 1604.? ro<br />

1388-7cm' e si$ed to the slb.liruied ph.nyl grcup6. Brnds at 1454.2 ed 869.8<br />

621cn '<br />

<strong>in</strong>dicaied a dihalogeMtcd substituted bemne r<strong>in</strong>g ed ittr€e adj@nt hydbga<br />

6toms. Al 1604.? mi band b sigled to d <strong>of</strong>rro-disuh6{ilution, .1 1234-Ll20l.6 @r and<br />

682.916.6.m-r is shou 1.2+uls<strong>in</strong>nid ir thc s@!d.<strong>in</strong>g. TIE o.lbnyl sdup arFa6<br />

bdwtr l8OO lrd l95O cn I s a ee!} ahaorbe@ dd aga<strong>in</strong> s th. neurraliad .ntiiy <strong>of</strong> $e<br />

wboxylic acid <strong>in</strong> rhe @s6 l610-1554.s ed t 409.9-1292 .mr [3r9 ]-<br />

tJ7

---

The !R spccta ol nubipr<strong>of</strong>d showed chucr.dstic brcad p€a& h the nnec 2500 10 3500<br />

cn ' dE to hydmsa bordils. The p€I! .l 1698 ald 290 cm-' vft d@ b orbonyt ed<br />

hytltoxyl sf achils, espelilely [32r].<br />

Mebnc@ show.d chdictciislic psks at t 620 cn-r (C.O strcrch<strong>in</strong>e), 3292 cnr (econdary<br />

-NH or -OH) dnd sne ploni&nr b.!ds su.h s 84656? d-r (.cH emlric r<strong>in</strong>s bad<strong>in</strong>g<br />

dd [.1soNm.d6) and 1346 io I 163 cb:' G=O 3rachirg) [32t].<br />

Mcf@mi. &id shos€d Fdls ar 3300 cmr (N-H srdch). 1647 cn ' (C=O sEetch), t 572 cn<br />

| (N-H b€nd<strong>in</strong>g), l5O4 cmi (c{ sterh),757 cm | (e@dc str.!ch) [32!].<br />

IR s!€trn <strong>of</strong> ibl4bfd @ntritu a stoog sbslptid bond at t7O8 di dE to erboxyl<br />

Creup dd thc btds @ntstodiDg 1o vibdtioN <strong>of</strong> the NEtrc r<strong>in</strong>g &d dF i$bntyl<br />

ftagne s(1608,1512, r044, ed 1020 mj) t3241.<br />

S<strong>in</strong>6lriD show€d petl ^r 3546 d4 1422 @'r <strong>of</strong> &c ed eiated O-H slretch,<br />

Fsp.criwly. It sbowd p6k .l l0l I d_' <strong>of</strong> otcnnic C-H irctch. 'Ihe Ffs ob@ed ar<br />

2969.2929,2811 ard 1459 .D r wft d@ ro Ihe psoe <strong>of</strong> mcihyl C-H 6)1Mclric od<br />

slmetric afttch. Simwlar<strong>in</strong> showed checr.rishc p€aks at 1261 dtd 1225 ch't iue ro<br />

prsce <strong>of</strong> lrcrole C.OC aGl.h The p.its d lTOl dd I 106 ch' we egn d b eG<br />

C{ and 6td C.O-C stErch, Bpdrirely- Th. F k ar l3E9 .!d 1369 cm'' E signed ro<br />

ihep6en@ <strong>of</strong> gm{im€thyl C-H st€tchard .r 1056. 870 &d5?0cD' wft <strong>of</strong> $@rdary<br />

slcohol, tri substituted oLf<strong>in</strong>ic C-H ed cis olel<strong>in</strong>ic C-E sr.etch$, rerpecdvely F251.<br />

In the <strong>in</strong>fFrcd sp@t|u <strong>of</strong> lh. c@pl.x foded bet*q cdnizift ed dicl<strong>of</strong>orc<br />

sodiu, th! Ng di@ <strong>of</strong> mim &id Aon 2?0G2.100 m-r diepFaEd ed dF qutorty<br />

nitrogs alom siretch<strong>in</strong>g 3h<strong>in</strong>.d froh 30?0 to 3040 cnI, Simildly ihe mmtic CH and<br />

aliphati. CHr lbsrltion ban& sh<strong>in</strong> d Aom 3l10-3000 ad 2985.6 2914.2 |o1165 j024<br />

tld 2v25.11-2847.61 d-1 Bpetir€ly. NH rftr.b<strong>in</strong>8 bdd snd de carboiyl gour iD<br />

dicl<strong>of</strong>@ shii.d Aob 3276,8 ard l8OG.l95O co:r ro 3320.1 rid at 1315.32-1147 ,19 ffi-t .<br />

A nodifi€d b&d appad.t l63E.l4 mj stich bdiated n ur.siiati@ <strong>of</strong> itE {boxylic<br />

Stoup i.to a carbolyl gFup, Th. &bend<strong>in</strong>S c&bonyl nodc sh<strong>in</strong>cd fton 1421,57-1200.91<br />

cDj b 1409.31-123?.68 mi, Fon lbe aborc 6&s, n !s bd @clurled rls! kak<br />

chrg€ E&sfd i erE rion qtE bcl9@ 6e doubly charged pipc@im noiery <strong>in</strong> ei<strong>in</strong>z<strong>in</strong>e<br />

dd dicl<strong>of</strong>drc, Cetiriz<strong>in</strong>e er a @ elst on ac€ptor [319], C.tiriz<strong>in</strong>enubipr<strong>of</strong>cn comtlex<br />

sho*.d th.t lhc quat€nsry nntu8.n aioE streichng sbii€d fron 3O7O 10 3O4l cm-'. Th€ NH<br />

diffi <strong>of</strong> m<strong>in</strong>o aid non 270G2,100 m- ap!.ir€d a . xik sig.al with cFd ro<br />

138

---

cciiriz<strong>in</strong>e, Ch&&lensd€ broad p.alc <strong>in</strong> lhe rege <strong>of</strong> 2500-3500 ed 2920 cm' due io<br />

hydrcgen bond<strong>in</strong>g dd hydroxyl slr.lchiq diepFed whfta cdrtonyl peal sh<strong>in</strong>ed lion<br />

| 698 lo 1654 cn-' wit! dim<strong>in</strong>bhcd <strong>in</strong>lensity.<br />

Conplex fomed betw@n cdirizile dd ncloxicd shosed quar€mary liitogd atom<br />

stFlch<strong>in</strong>g at 3070 cm I md NH d<strong>in</strong>tu <strong>of</strong> M<strong>in</strong>o eid <strong>in</strong> rh. r€gion <strong>of</strong> 2700-2400 cb_l<br />

coDplelely di$ppc&rd with EslEt ro dntiDa Cb@Ldnic F.rs <strong>of</strong>mdoxi@ d 1620<br />

dd 3292 m-r foi C{ ed s@lda.y ,NH or -OH strsrchirg disllFir€d whil., otho ers<br />

In tlE conplex <strong>of</strong> mefe@ic &id NH d<strong>in</strong>d <strong>of</strong> uilo &id ed lhe quateddy niEosetr atom<br />

sftLhitrg nom 270G2400 m-' and 3070 ro 3040 d ' dieppdr€d. Sh<strong>in</strong><strong>in</strong>A <strong>of</strong> somc<br />

meswd peek werc obsNcd wilh r€sp.d ro m€feMic acid, p€.Is <strong>of</strong> neu<strong>tn</strong>liad<br />

.ntiiy oI0!e wboxylic acid shiftcd liom 16l0-1554.5ed 1409.9-1292.2 cn-rlo 1654-158t<br />

IR 3pefu <strong>of</strong> elnizirc-ibuF<strong>of</strong>@ prcved th|t th. quar.nary litroga arom stFtch<strong>in</strong>g ard<br />

NH d<strong>in</strong>er <strong>of</strong> m<strong>in</strong>o rcid f@m 2?00-2400 cnir md 3070J040 cm I conpleicly dhappearcd.<br />

Srong absorption beds drc lo wboxyl grcu! shii€d fion l70E !o 1768.90 cn r,<br />

IR sFn.rdn <strong>of</strong> eti.iz<strong>in</strong>e*imlardid @mpl.x pmv€d that rhe qurtury ntuogd atom<br />

$elchiry nd NH dimr <strong>of</strong> mi@ &id at -30?O cE ' ed 270G2400 cn I rclF€rively,<br />

dhdppedd sill] Espar to @tiriz<strong>in</strong>€- Ch{erqblic Fab <strong>of</strong> l&1ore C-O-C arr.tch<strong>in</strong>g <strong>of</strong><br />

3iFvasladn sh<strong>in</strong>cd froo 1267 srd 1225 qr ro l24l cn'. Sihil&ly fiftire <strong>of</strong> 6r€r C=O<br />

ard csrcr {4C sterch<strong>in</strong>s toil Tot ad | 166 chr !o 1728 6d I135 mr !p?.dtd. orhq<br />

s4! <strong>of</strong> siCnals we sme.<br />

'It. rU NMR sFcoa <strong>of</strong> eririz<strong>in</strong>e @.6ned th. abov€ Gulls. The srgrrh <strong>of</strong> c€<strong>tn</strong>iz<strong>in</strong>e<br />

sholEd a s<strong>in</strong>gl.i ai d 2,8 dd at 4,09 ppn deliSraddg tsr poto6 for lhe CH, attached ro N<br />

iD the NCHTCH,O grelp ed t$! polo6 <strong>of</strong> the CH, adjeelt ro lhe ceboxylic acid,<br />

$perivel, Th. Dirog.n prclon <strong>in</strong> pipepjn w6 obtrn€d .t , 121 3.47 ppd. A rripLl<br />

B ob6n€d a1 d 3.65 3.86 pPn for i& pdro6 i! 6e CH, nd ilE O <strong>in</strong> CHrCIlrO. ItE<br />

pdlon <strong>of</strong>lhe CH <strong>in</strong> lhe n€thyl diphdyl ercup showed a bro.d si.gld ol d 4.6 ppm. fte<br />

nultiplel ar d ?.1 ?.6 ppD @ drc to nile prctoB <strong>of</strong> the enatic.i!es ard.t d 10,8 ppd a<br />

el bbad s<strong>in</strong>gl.t 6 shoM for @ pDton <strong>of</strong> ih. e|boxylic eid IroW.<br />

l]9

---

The deshi€ld<strong>in</strong>! efl*t ws .x.ned <strong>in</strong> @npl.xes on l!€ somalic NH pmior via <strong>in</strong>rdnolsula<br />

chrge n4Gr eu<strong>in</strong>g lhe @M@ ro b€ do$rft€td shifled to d ?.6 ppn. nN,<br />

lhis prelon app€tEd <strong>in</strong> the troad nullipl€r b.$@ , 6.27 &rd 7.56 ppn shov<strong>in</strong>g sixreq<br />

aomdt CH pDloN dd thc t$b Ntf pnlons. A s<strong>in</strong>glel qs ob&ned ar d 3.3 ppm for<br />

nethyl diphenyl CH proion, Triple! al ,3.7t ppm ws obviou dE to fou prctoos on rhe<br />

&yclic CH, Sbups adj&ot to NH- <strong>in</strong> $e piF@ire riDe md at , 3.16 DpD @ obsdcd for<br />

the grclps .dja.enr to lhe nftogd hydebbnde dnfty. A dou-fietd ob$n€d for acyctic<br />

oliphalic CH, <strong>in</strong> NII'CHTCHTO from d 2.8 ro 3.4 ppn d irs proror w6 ir ihe plee <strong>of</strong> lh€<br />

cdbonyl grcup. Anothd s<strong>in</strong>glei .t d 3.61 ppn with tM prctons w6 shoM for iie CE, <strong>in</strong><br />

CH,CHIO.ntily, The CE? <strong>in</strong> th€ CHTCOOH gdu! a9peFd s ! siDgLt,l.7t ppn. A very<br />

aEt s<strong>in</strong>glcr B Dltgt ar d 10.8 ppd for ri. oF pmroD <strong>of</strong> th. o.tFxylic eid grcup In<br />

sp€ct? <strong>of</strong> ncfcn4ic scid coDplq, dosrfi.ld lhifr w obsacd lor emaric pbro6.<br />

Tnpbts at d 3.16 ed l.5l pph obswed for proioB on the &yclic CH, g@ups adj&enl ro<br />

NIf ir the pipc@ire r<strong>in</strong>g. S<strong>in</strong>gl€r .l d 10.8 pln ws presr for one pbron <strong>of</strong> lhe cdboxylic<br />

&id greup. Simild 6u! *s obs.ird tur @dn?<strong>in</strong>c,flurbipr<strong>of</strong>.n 6rplq ir, s<strong>in</strong>glel <strong>of</strong><br />

@boxylic gtuup pbton m<strong>in</strong>cd ai, lo.E mn &d domfield sh<strong>in</strong> obered for Nmatic<br />

poio6. nF piotoN <strong>of</strong> pip@<strong>in</strong> w@ obs€n.

---

7ll \< a "e<br />

722<br />

7t2<br />

70E<br />

710<br />

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f<strong>tn</strong>bl.l43<br />

Posibl shat@ ad clsetqianifu ol@wba<br />

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siclttly I t2"C

---

F Synrb6ir <strong>of</strong> d..lr.tivs ol.dirlrim<br />

In !l6t y6 l€s€ah wrt ha ben cei.d oul for $e strtheis <strong>of</strong> potent @Dpouds<br />

vhich codd b€ uwd to tFat all€rei. ed <strong>in</strong>nmmtory di$ideB s<strong>in</strong>ultlmuly [3t6, 32?],<br />

t M! .t a/, Il2El lnrcd tu lisllnire Hr@pror er.gdi$ cdnt<strong>in</strong>e to No{el6<strong>in</strong>g<br />

spe* ercups, 'ft. Hrb<strong>in</strong>d<strong>in</strong>g $lffolds <strong>of</strong>@titizirc, eflednz<strong>in</strong>e, erl lodr.d<strong>in</strong>e werc l<strong>in</strong>ted<br />

to a lilbpbilic N-hydroxyE4 th! 5-LO <strong>in</strong>hibitils noiay <strong>of</strong> ziLuton [329]- Nubs <strong>of</strong><br />

ddiEtiw <strong>of</strong> .l<strong>tn</strong>izie wE pFpsrd io lMif6l llc dli-irtldmlo.y !.tiviry <strong>of</strong> c*nizire.<br />

Duc 10 laat <strong>of</strong> Gaili1i6, etihistam<strong>in</strong>ic activity <strong>of</strong> cetiriz<strong>in</strong>€ could dot b€ esbblhhed. Ibe<br />

@mpou& elel.d D lhis ce vw cbos oD tb€ bsis <strong>of</strong> lh€n dtii<strong>of</strong>ldabry elivities<br />

such 4 thiolM t3301, @taeide [331], phdyLnqdiui* [$2], n phthylto<strong>in</strong>. [3$].<br />

Th€ re&tion n€chmis for ihe fomalion <strong>of</strong> etrizirc ddivatives poc..ded via ait .t by lh.<br />

l<strong>of</strong>t p6is peol d niEogo <strong>of</strong> thiour.a $i@.tdi&. phcylenedi@<strong>in</strong> , MPhthyldie<br />

ed pthaldidc, njtogcn @ts s . nEl@phjl. ed aneks rhe catboxyl wbon <strong>of</strong> the acid<br />

vhich lads to th! fmtion <strong>of</strong> e akonde ioi Gi.! 1). A3 a o$dl@M, a poto! 's losl<br />

8!b d NH: g6up (step 2). An nslurld d6!u pan on th. altqid. oxygd ion moB <strong>in</strong><br />

to h.lp disple. dr l.lv<strong>in</strong>g gbup Gtep 3). th. r4tion follows th. NU'l .lclophillic<br />

G_-,O *t'r:i<br />

:{ -6 i- 'i' ,f*-<br />

(--"-_,-t n . _<br />

.9.\'/-<br />

-2!H'R<br />

L'r :dF<br />

-,,"---::s,<br />

->-q-/&<br />

I<br />

-t?<br />

.Fp<br />

-'c(:r<br />

cdH<br />

\_"-ifi*<br />

t-"..-.H",. i_"_ -il<br />

i,<br />

7r. R{rfl'N(nrt6yr.n d!hi*) 72J R-qHls CIr @id.)<br />

719 R=clHrNcpbdlldodilmh.) 7A R-CsrNsaftiourc.)<br />

12 r R{r}t No:(phrt.l<strong>in</strong>ido 727 R=€d4(Drpbu'ybn<strong>in</strong> )<br />

,f<br />

t42

---

Thjs D.lhod.!lov!d Uc idrodudid <strong>of</strong> . v&i.ty <strong>of</strong> subslir@r! sEh a c-naptbyldift, m'<br />

phm.Lndim<strong>in</strong> , p-phoelddimirc, lhio@s, thioacetadi.lc ad phth.l<strong>in</strong>i& <strong>in</strong>to tle core<br />

sirucrw <strong>of</strong>eiiriz<strong>in</strong>.,.t carbo*ylic ercup, <strong>in</strong> ! quick and simpL way, Funn r oor, n 3l3o<br />

.lloq.d 6e sFlh*is with s hieh y.[d foanmbd <strong>of</strong>edoS!* <strong>in</strong> thc sFt m.<br />

Chs..rdhati

---

M6iqn dat updQn47U<br />

'y1 .^"-"-r" *<br />

\.- a l.n_., -,-"*:r I<br />

@ .-"""_____"-* [a._ a*]<br />

|"ry:l---{"rl

---

Trbl.l.l44<br />

?hrsical ahd spe.E^copic .lata <strong>of</strong>compothd 7 t4<br />

N{4-miroph.nyl}2{2{4{(44hlorcptdyDonenylFcthyl)pipqu<strong>in</strong>r<br />

1742\<br />

o<br />

'0-'"x<br />

.173.(2.?D, 388,1(4.06), 301,(3.01), 2tl4.l(5.22) 201,0(100 0)<br />

T$le 3.145<br />

Physical and tp.cnMopi. dato oJ conpound 719<br />

N-(4tr<strong>in</strong>orhoyl!2-{2{4{(4{hldoDh.nylxplsyl)<strong>tn</strong>.lhylhipdz<strong>in</strong>-l<br />

47421<br />

aN--.vcr,-c-NH<br />

N-2 -/,<br />

478,1(2 ?tr, l'&l(1.06), ]01.\l.olr, 244 l(5.12).201.0(100 0l<br />

c=O <strong>of</strong>didd appe.ed <strong>in</strong> lLe tum <strong>of</strong>i e8ificd pat al I?Il69m_'i.c. itte dymclrical<br />

3trrch<strong>in</strong>g whilc 6'1mehcd esler stRh<strong>in</strong>g appercd al l5o7cm lh. mturic chtur<br />

is Dw! moE ptunidr !t 3182.75c6i qbilc N.C apFaed s! l273cm' md lh@ *s no<br />

!..1 tur c{toxylic s@p.<br />

Th€ Eoction iite is dboxylic grcup <strong>of</strong>cctlizim s <strong>in</strong> NMR sPecl&m <strong>of</strong>coFpoud 721 th€e<br />

B rc p€al at lo.8ppm ald .dditiord fou pdoa <strong>of</strong> pbth.l<strong>in</strong>id. noi.ty.ptor.d b trc<br />

fom <strong>of</strong> muttiplcr al ?.83-?.86 ppb wfil€ mbatic Folou <strong>of</strong> eftiz<strong>in</strong>c noieiy opp.d€d at<br />

t45

---

7,21-7.7 ppm, Pre1on for th€ CII, sft&hed io N h NCH,CH2O goup app€@d al 1.54 and<br />

3.4 ppn, tLc pblon <strong>of</strong>pipeFiG !i!g app€e.d .i 2.50!'pm.<br />

Mas fasm,tdtid patted oJ72 !<br />

c "'^ o<br />

o^o o^c--rr<br />

!<br />

_.!-.--\<br />

r-- r'Y"\,-\,<br />

\,i\-2 "<br />

T|bL 3.la6<br />

Pttsiql ond tp.cttMopic eb <strong>of</strong>anpoud 121<br />

2-(2-(2-(4-benzhydrylpip@<strong>in</strong>-l<br />

143.22<br />

25r(r 22), r68.09\r2 t9),92.06(19.19)<br />

_yl).thoxv)a@lvl)iso<strong>in</strong>dol<strong>in</strong>e_ I<br />

Tlr F6de <strong>of</strong> Fsk al 3350 &d l300otrt iddic$.d i!. Pt..4. <strong>of</strong> Fhtrv dim *nich<br />

lFongly @nfm.d th€ stret@3 <strong>of</strong> @bFuad 4d ole .vi&M M the shii<strong>in</strong>g <strong>of</strong> C=O<br />

p.ats lov:rd the lower 8eqrcNy i... ar l6oocm r. Asmalic grcup ahsorh€d at 3l50cd ' with<br />

ituifed fom .!d dplEtic cb,@rq @Fe!d d 2850co r'<br />

146

---

Si.elel <strong>of</strong> NHt apptud at 2.49 ppm, {ni|. signrl for s@dsry @ir6 ,pFed ai 6.3ppn.<br />

'fte Foto! <strong>of</strong> piFmzie risg .ppcrEd !l 1,83 .!d .t 4.67 ppD. A rripLt obsd ar 3.?4,<br />

3,?9 ppn for tB! FotoE <strong>in</strong> th. CH, ar rh! O ir CHTCHTO. ]h. prc1on <strong>of</strong> CH <strong>in</strong> lhe<br />

nelhyldiph.nyl group is shoM by ! broad but vslt s<strong>in</strong>glet at 5.6ppb. nF enaiic n<strong>in</strong>e<br />

proloB app@d ai 7.14-7.32 ppn whil€ tb€rc b lot sileL 1 at 610.8ppm fd th. .aboxylic<br />

&id goup thd coDnriEd the 3it <strong>of</strong>@ctioo.<br />

M6t ltustu,ttdtio, pdtEm oJ 72J<br />

C-JY\-*<br />

r -- r'r<br />

!-_\ r-\<br />

-n4.-<br />

)<br />

r'n--r<br />

T.bL!.147<br />

Physical or.l specn@copic data olco pornd 723<br />

,v{3{2{+bcnrhydylpip.@i& l-ylFlhoxy)-2{xopopylFthddhrmi<br />

l17C<br />

25r(' rl, r6809(r.0t, ?3.0J(9 86)<br />

The FoIs at 3358 ed 3lO?,25 mj dE to slrctch<strong>in</strong>S <strong>of</strong> NH: we ob6.sed which b slrong<br />

<strong>in</strong>dicadd <strong>of</strong> a c@pl.x G thi F* is a!.dt <strong>in</strong> U. plr€nr obpound. The Nmric ch@le.<br />

r47

---

k meh Fon<strong>in</strong> !t at 3145.9? di , dipbdic chl<strong>in</strong> is obedcd at 2913 @r .nd C=O bond<br />

ot6.(!d ar 159?-28 mn. Th. €k ab$btion fo. es obs€d al2030 d'' v6 drc ro<br />

h.aw weidt <strong>of</strong> sulphu grup. C=O stdch<strong>in</strong>g w obeped at loM fr€quency a conpcd<br />

to p.Mt &!g i... ar 1597,28 m''.<br />

S<strong>in</strong>elct <strong>of</strong>^'tl, apFared .t 2,49 ppm, etile signrl for s@nddy dircs sppened !t 6.3ppm.<br />

Th. ptoton <strong>of</strong> pipeE<strong>in</strong>. nng app€.red d 3-83 and at 467 ppn. A t ipld obs.d€d at 3.84l.9t<br />

ppo for t$o preront ir dE Cft M dt O i! cH2CtUO. Th. Foron <strong>of</strong> cH thc<br />

nc<strong>in</strong>yldilh.nyl grup is shoM by ! broad bul *$l s<strong>in</strong>gl.t *<strong>tn</strong>ch app.!r.d al5 4lPpn. Th€<br />

ehad. Dift protos appqlld at 7.147.32 ppi while O.F is m s<strong>in</strong>elci at 6l0jppm for<br />

th. cdboxylic eid eroup llrl c@68.d th! sa <strong>of</strong> @dio!<br />

Ma ttugtuntation spectw <strong>of</strong>TU<br />

G^CT<br />

TrbL 3JlE<br />

P|r*tcal and spectscopic daa olconPound n4<br />

l.(2{2{+b.n2hrdrrlpiFE<strong>in</strong>- | -yl/.lhoxyF@tyllhio@<br />

412.5t<br />

lTfc<br />

l9?.r 3(1.36, 133.2(6.32), 2tr.r5(16.21).<br />

148

---

Boad budi ot6ad, 3l lO-3000 .!d 29E5,6-2914.2 d-' e sigtEd to ih. @tic<br />

CH ald alip[rlic CtL sro,4, r!.p.cliEly. Th! C{ <strong>of</strong> mid6 4percd i! tlF fm <strong>of</strong><br />

<strong>in</strong>leEifi.d bed at 1620 cn' whil€ emltio lb$rb€d .t 3l5O wilh ircNided f<strong>of</strong>r &d<br />

alphalic ch.@t* app{€d at 2E50,<br />

'IrE tH NMR sF.r6 <strong>of</strong> @Dto@d 727 w .@Fr€d *ith lhe spef<strong>tn</strong> <strong>of</strong> lhe fiF drug.<br />

Pip€@<strong>in</strong>e, chlob beMre ed Nrrtic Foton! lhowd no dl4t, a s<strong>in</strong>glct @curcd !t 6 8.0<br />

pPm Epca.nlilg ih. Pl.@ <strong>of</strong> ffii& goup.<br />

M6s Jragneitation pattfl <strong>of</strong> 727<br />

a]r<br />

Y r.".N, \--'<br />

---

Emrs n<strong>in</strong>nnbdiN .elalatiM oldtMtvt<br />

B.E.<br />

.1.9106 t4 2425 2_7159<br />

7t9 29.95 J.9516 21202<br />

121 65.1523 20,t l6a<br />

21.3498 4.3015 0.7113 2.5182<br />

124 21.691 2.4131<br />

121 t0.5525 -2.677 .2.1 780 0.653r ,.6.]16<br />

G In-yt@ acdrtt otd.nElbs<br />

Ii is w.ll knoM rhat remtive oxygo spc.i6 (ROS) @ <strong>in</strong>limal.ty rclevdr lo ihe <strong>in</strong>duction <strong>of</strong><br />

<strong>in</strong>Jlamation. Tle Ros geD@red io tucDph.g6 m) pDdue pcE2, No, €yrot<strong>in</strong>e (lLr0,<br />

II--6, TNI{), l.adilg ro tbe dd€loptMr ot i!flalrmtion 13341. F@ Fdicds d€riwd from<br />

m.cbolites <strong>of</strong> unsnrIld fdty &ids or moDhift \r@ sbou ro <strong>in</strong>drce hisidnjre at6e<br />

ton rat @t cells [33s,336]. Evid.@ suge.sred dat 1h. conr<strong>in</strong>@t El%e <strong>of</strong> hisianire<br />

lirD ludg cells <strong>of</strong> astbna pari€nts @y @ntiburc to lqe iis@ bfl€|rmii@ ,nd<br />

lmodel<strong>in</strong>e, dd @y af*r ltoph@tr.s, monoctlcs, ba&phils, .pirhetisl elts, &d<br />

Mbphag6 by moduldiDg rh. El€e <strong>of</strong> pohfllmdory ed imuoEgutalory n€dilroE<br />

dd .y1okjrcr [337], IIE eri-<strong>in</strong>fl@atory &riviris <strong>of</strong> *coi.l &d rhhd_genc@tio! Hr<br />

l@pio. atagonisis h.ve bc! daluli.d t vt o_ Irre studis sho*.d tbr n ny s@nd_<br />

8o@lion Hr-Ecepror anrlgonisls aad thnd-ge@rion HFrec@to, dtasodsr. <strong>in</strong>nibited<br />

relea d g€rcution <strong>of</strong> Dulriplc iD{.rnD,rory hediatoB, <strong>in</strong>clud<strong>in</strong>g IL-4, IL{, IL8. .d tL<br />

l3j PGD2; LTC4j tt?lae; hktam<strong>in</strong>q dd lhe TNF-d.<strong>in</strong>duc€d chemok<strong>in</strong>e RAIITES. s wU<br />

a @s<strong>in</strong>oplil .hmonxis rld adb6i@ [331. S€od dd Oid-s*anid odbisruj*s<br />

ll@ afreted on rhe all€ryic irisDnaiory r€spo$e ar hign ddg con .drlrioB 133&!401,<br />

Fd .@tic, oE t yrm sludy <strong>of</strong> lle *end-g€rcntior drug cdnizi!. otr tb. <strong>in</strong>hiltton <strong>of</strong><br />

Il-s{.pended @sircphit swi}€.I EquiRd s concmrtirion <strong>of</strong> rhe deg (l0O umoll.r) rhat<br />

E nrch highr rhar rhat u*d ctidcaly t3401.<br />

t50

---

', I<br />

TT<br />

lrrndEF€,!.i{erU'dEi'0E r!t)<br />

l!<br />

l.!A6.6us,.@<br />

Il<br />

rl3uE r,T1. Esp<strong>in</strong>lory hfltudory .@da ft<strong>in</strong>|ly aiNly .. utt rcsp<strong>of</strong>t6 ro dldgdr gdeEs<br />

!.rritu dd ritld diviriG eEn ! .6iDo9hit 'bi|IM Dd D'difdiA 'nodis<br />

lldpho.y6, dd deEnljilio <strong>of</strong>ddr crb l3atl.<br />

<strong>of</strong> IsE by B<br />

Aldgic aiMy ElpoNs ielud.d rt tldirn m dd hfiL.rid <strong>of</strong> rH2+ lFpt@'rex B<br />

lymphocttcs, tut c€Is, b6ephil!, ard osi&phits, c&h<br />

<strong>of</strong> enich degmrlrr€d q ws a.tiv.tcd to Et@e<br />

b€{tiato6, crlot<strong>in</strong>cs, ald cnenokiB tbsr @lrdbrncd 10<br />

Bpihlory <strong>in</strong>flamErion. AriihiflaD<strong>in</strong>6 that slD*ld<br />

dti-iro@rErory .tr6t3 !t rb.r4.uric ct)!@tradotu<br />

Day modiry the .fl@ts <strong>of</strong> <strong>in</strong>0al)@bry Dediaros u vivo<br />

ar dls @n|r@bl. b rlt@ us.d ctioi.dly [3a21. h rhe<br />

lighl oI lbove faa8 wc srnd4i4d a nMbd <strong>of</strong> ddivarivB <strong>in</strong> or.l€r io ielle 0!.<br />

<strong>in</strong>flmtory adivity <strong>of</strong> clritizirc dd rhftfoiq w did nor Frfon .nrihislm<strong>in</strong>ic elivity <strong>of</strong><br />

ddivltive bur D@ opbsiad d bd-<strong>in</strong>rn.m'lory md imuohodulrlory adviijs <strong>of</strong><br />

Mdonv ba6. sttqlo. @'!rt& oJ ROS tu lrt to6<br />

This rd allo{€d ddmiDrio! <strong>of</strong> tetoc'r onddiE hrn <strong>in</strong> ncpsioizd enob bloo

---

€stosiblc for prcd@i!8 sup@xidc aio!, which w6 quickly @Nen d to hydogen<br />

Forid. ad hldDryl Edic.k. AbnoDAliti6 <strong>in</strong> lhe @Bdt@t p4tidd <strong>of</strong> tb€ NADPH<br />

oxiddc ozyme Bysth lead to dy!functros chand€tistic <strong>of</strong>CGD, N€urrophils ton CGD<br />

p{dot! fliled to podw a 3iedfi@t oxidatirc busl follow<strong>in</strong>g stimulation. n. oxidalive<br />

bu61 <strong>of</strong> gruuloclr.s s <strong>in</strong>psird <strong>in</strong> laspler€d palicnis ald patierrs with AIDS on th€<br />

orher hmd. li wa highly .Lv.i.d <strong>in</strong> <strong>in</strong>flaMatory dierd6. veios imuomodulaloa<br />

G.e., cytokia (GM-CSF, G.CSF, dd TNFo) or doss) !.@ to hN. effdrs or rhe oxidqriv€<br />

bu.si. Siimulaiory compouds @uld hare oppon$ity <strong>of</strong> be<strong>in</strong>g i@uomodulale or dhmce<br />

imle imm 6pon* o. Uc oiltq hld $ppcsiog @mpou& @ h. us.d eitha ed<strong>in</strong>flMatory<br />

or im@suppr*$vq The test pr<strong>in</strong>ople M dEl ph.goctrosis by polymoryh-<br />

Gnrcld Eutrophib, non@t16 &d t'r,@phlgs @nsrhr.d a stial e <strong>of</strong> hosl<br />

defense agaidsi beterial or irgal i<strong>of</strong>.ctio6. The phagoc,,tic prcc.$ e be s@a.tcd ir o<br />

*vEE1 mjd sLs6; ch@ouxjs (Eisrltid <strong>of</strong> phagayes to irnmtubit sit s), .nehndl<br />

<strong>of</strong> paniclcs to thc ccl suf&e <strong>of</strong> phaeocltes, <strong>in</strong>g.stion (ph.sayt6b) and <strong>in</strong>tlellule killiq<br />

by oxyscn{epoddi (onddivc b!d) lnd oxys*<strong>in</strong>de!.nderl m..hmis. Upon<br />

stimulalior, g6ul@tas &d mo@yt6 prod@d l@tirc oxyg€n mddohd <strong>in</strong> calde <strong>of</strong><br />

eM$ si.ded with p.oduction <strong>of</strong> luFbxid€s, sup.oxide &ion, hydrogo pcDxide.<br />

hno.NobG, eid wbich ddrcy€d b&tei, iEide rhe phlsoeme Fodadon <strong>of</strong> th. @ctiE<br />

oriddL dr<strong>in</strong>g the ond.tiv€ bubl car be DoritoEd by tlE addirion <strong>of</strong> ld<strong>in</strong>ol or lucigenir<br />

In su@!ry, ph.goclrosis &d rbe 3ubs€q@r digdrion e a nutisr.p ed mDllifeldial<br />

Ldiml cda|8l cbenilhil].s@ 'sy lw F.fod€d s deib€d by Hered [18r]<br />

ed Eakld sr zr, [182]. Ilte prcliD<strong>in</strong>dy sFn<strong>in</strong>s @ulB <strong>of</strong> whole blood showed th.t<br />

@nDouds 714, ?19 8d ?2? cxl bited lign<strong>in</strong>qr ondadve bursr BF@ (eti<strong>in</strong>flamatory)<br />

at concentilioB Lv.l<strong>of</strong> 100,50. 12,5 Fgor'' wilh ICe < 12,5 !gnt'.<br />

Exellent <strong>in</strong>libitory a.rivitis <strong>of</strong>th.* obpollds *F t@ded at 12.5!gmli i.e, 96,92,6<br />

dd 94.E rcsp..tivcly (i.bl. LI50). nEs onpouds *ft thcn t6t d for acdlnis on<br />

isldlttl drrepbsge @Is on fiw concat6i6levek 50,25, 12.5,6.3 ed 3.l|l8rnlr &d<br />

Mph,s6 a@ &iiEd by SOz 0uiEl-b3s€d) (l!bL 3.l5l). Ir a found $at all<br />

ddjvativca hale *€elenl€il4rs otr @rcphrgB aid aF nuch mo€ potent thd @tiriz<strong>in</strong>e<br />

dcpl ?19. IEe @.deourds posssed vsy lN ICs vnich lN* 6.6, 11.3,

---

cylcioxio raivitiQ tl* d.dvdiq q rally <strong>Fw</strong>o s@lb.t tlsrpodc !g.ds i! alrhma<br />

T.U.3.13)<br />

s.enh8 <strong>of</strong>dhnre @d t d.,lwdw ldnE vtbt. bktdJu chatrl/n!@ @nit<br />

26.5 191.9 yt.t<br />

12.5 50 t2.5<br />

23.8 3tl 335 5 97.5 926<br />

721 1206 623.f l6a5 -t7.1<br />

n1 224.7 3t7 12.9<br />

rc50<br />

lSD<br />

33.4 214.5 12l I 92.8 29.3<br />

m 2t.0 1J5.2 u.5

---

T.U.3Jl<br />

*n6tttc <strong>of</strong> eniziu atd iE t r1!tE t .d d.nnnw Ldns M4rec., <strong>tn</strong> tbir @hidlaMdr<br />

719<br />

nl<br />

.7zx!<br />

I<br />

drso<br />

RIU<br />

lc 50<br />

+sD NLU<br />

4629 am.2<br />

&||I 25.O 3L2<br />

t2.s lr5<br />

6.ZS t3l4J 1105 0<br />

3l 21225 12.6!4.1 ll16.0<br />

23<br />

lt.5<br />

35.1<br />

2(bJ<br />

721<br />

250<br />

125<br />

20r.3<br />

625<br />

3l t2625<br />

10r5.0<br />

1t70.5<br />

x 25.0<br />

t53.'<br />

t63.1<br />

lL3 nl<br />

12.5 62,5 4 51.5t4.4 l2.J 6512<br />

+sD<br />

t293.0 to26.l<br />

3.1 16t5.5 ll 2t48.5 ll.&13<br />

50 83.r{t.J<br />

I2.5<br />

711.2<br />

tc 50<br />

1SD<br />

122

---

ft. $Bitivit <strong>of</strong> eftizirc &d ia (kivatiB lo s Mp'olif@tirc dd prolif.nrire 6poe<br />

!o thc nitogo phttohem.gglutidn (PHA) &d mitogen-<strong>in</strong>duccd ttulifsenio. <strong>of</strong> T-<br />

lynph@,r6 wE w.lulr.d. Polif.Elir E po@ @ FiioglB w mailoEd at<br />

conc.ntations <strong>of</strong> 3.12, t2.5 and 50 rgml, r, SuppFsiv. .ff*l <strong>of</strong> compoud ?14 (lcs =<br />

4-l+0.5 |r8nl') E obs.d d T+U polifcutioa s<strong>in</strong>ih.ly ?19 lhoerd cxaldt Tall<br />

suppcaire activi9 dd it! ICs is 7.149 tgEL'' stich is duch grsLr the fi. plE l drug-<br />

Compourd ?27 showd e <strong>in</strong>t€medi.t &iivity, It exlibitcd ilhibitory aclivity (98,7 %) with<br />

& lco l?.0 rgnl-j. Pqid 8l@ to lhc obri<strong>in</strong>cd @ll3 (rlble 1.45 & fig@ 3.1lo) l*lt d<br />

ihai the @npounds 714, 719 ed 727 d.hibitcd mtic4q &dvity ed.ould b. preved l.ad<br />

@pourds <strong>in</strong> th.rqeudc snd and tu th studiB,<br />

T. .1rJ3<br />

ftrmihs dtuhhe nd ifi t<strong>tn</strong>tfuttBd d.ttudh.t aW nM. uoaa fur hen <strong>in</strong>tu@ nodllatks<br />

ithibitoty popetw<br />

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t390_0 10580.7 t9306,5<br />

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215r9.0 24U3.7 2$tz.n 22,1 t1.6 12.5<br />

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1t2 14503.' ,0285.6 2132t.0 -23.5 I5.3 1.2<br />

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t56

---

CONCLUSTON<br />

CaniziE is s@!d gder.rion Hr cAior d&sonisq us.d <strong>in</strong> thc leried <strong>of</strong> .wbq <strong>of</strong><br />

audgic disordd &d ce b€ saf€ly coldn<strong>in</strong>isrored with nubd <strong>of</strong> dngs ed supplddk.<br />

Fd {iruSiDg ald dtug-hel,l <strong>in</strong>ter&tion snldi6 <strong>of</strong> etiriziE, i,ilially !s HII,C ncthods<br />

for lhe &temiMtion <strong>in</strong> dw D.i.riak, dosa. fodularions ed <strong>in</strong> tu 9@ .LveloFd,<br />

'nre mthods sw validai.d @rd<strong>in</strong>g to ICH 8!id.li6 ed pha@opoeial p.meleB<br />

dd 1l* foud to b€ eGitiv., 6pid, Eliabl., <strong>in</strong>€xrmiv., 6y !o follow and wjdety<br />

Thes s<strong>in</strong>ullaneous nedods ll@ thcn appli.d for th. i, vr.o <strong>in</strong>le@tion snr(|i$ <strong>of</strong> Hr<br />

Eepror dlagodn (cimetd<strong>in</strong>e, 6no0dift dd tuiddirc), slati$ (arorvstati!. b$v'st ti4<br />

rerdsla<strong>in</strong> and simv.sr.r<strong>in</strong>)j quilolon€ eriber€riat agotl 0do0oei4 <strong>of</strong>loecio,<br />

ciprcfloeit! emeia spdfloe<strong>in</strong> ed @.flo&i!), cilcim chtuel bl@keB (dilrid,<br />

vdpuil, e odip<strong>in</strong>e), non ilbitlrl erj-<strong>in</strong>nallmbry druss (ris{@f.@ &i4 dict<strong>of</strong>@<br />

$dim flurbiprcfcn, ibupr<strong>of</strong>d, m.fodh eid ed metoxim), etiDaldials<br />

(tyrioethdir. aad cholooqui@), &rildldllj. ddss (cujfffi'a phoyt@l[ift ed<br />

mont€luk !0, elhalospor<strong>in</strong>, (cetoisone, cephsld<strong>in</strong> arxt erohx<strong>in</strong>€) and drugs lsed ih non<br />

iisth d.poddr digbete mclitls (e.tfodia gtib€trctMi.le dd gliqujdoe) ,!d .sgial<br />

md tree Derals. These <strong>in</strong>rencion sludi6 werc ne.rioned on HpLC m

---

i o lne @F sh&te <strong>of</strong> eririziE with d a<strong>in</strong> !o i6pft dtijnfldturory 4rivitid <strong>of</strong><br />

cetiriz<strong>in</strong>e, s<strong>in</strong>ce ceihiz<strong>in</strong>e hs bm foud <strong>in</strong> nuber <strong>of</strong> c66 to pos*s sti-<strong>in</strong>llm@rory<br />

edvftid. on rh. b6is <strong>of</strong> sleao@ic acbriqc (w, Fr,t& |HNMR {d ns<br />

spebospy), n wa! stablbh€d thar c.ririz<strong>in</strong> fm.d @npl.x6 fouoMns nud@phittic<br />

sub6tiMd E tic 3l @tbxtli goup,<br />

All dE dsivativd wft foud to pos6s si8lifi@l mtiiondrDrory activity ed also<br />

shosrd €xelLd .llcls on D.mpl|g* AI lb. @Epou& wft fobd io be nEt noc<br />

pote Ure @tirizjne. Howq N

---

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t63

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l7l

---

Mcthod d.velopE nt ed bbuslDs t sr<strong>in</strong>g by expqimenbl d6ir;r, Iounal <strong>of</strong><br />

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236 Gillid MS (2003) Hn l!@iriviry R.!.tioE ro Drues: Evatualion dd MlEsmo!<br />

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237 Asoud M, willcoit RJ and Cedns ?H 0995) Araphyl&bid ecliohs to<br />

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251 cbaid \ P.rhact rL, DiMtis Jw lld S<strong>of</strong>ia RD (t985) Heleroscmiry <strong>of</strong> catciu<br />

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Rh<strong>in</strong>iris is eiat d *ith iftFqed sysbtic blmd pBW h m6 a !6putation-ba$d<br />

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ch@.j bler.n nd orhr agm6 on p6siE olarcous saphylAn <strong>in</strong> rhe Fr Drug<br />

ddeloph.nl re*3rch, 3(4). ]l I tt?.<br />

25,1 Jm6 HS 0973) T@ otBervcd .ssirri@ bcr96 6pirdo.y aldsi€s e.l<br />

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---

255 Gmia MA, Solis C, AtuyoD JJ, F 6ile U. BFgdre MA fld Cstilto JR {t998)<br />

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HILC syscn wirh ulhqoler d€l€crjoq TalaDt4 4?, t 24 t. | 254<br />

256 Murafa Q, MBla.fa SK, Saide A atd se<strong>tn</strong>a g (200E) vatidaled HpLc nerhod<br />

d€v.lopnert The simultan€ous salysb ot mlodip<strong>in</strong>e 8d valslan <strong>in</strong> mples tor<br />

liver perision studis, Ha@nepe Univdsiry Jomdl <strong>of</strong> fte f&dry <strong>of</strong> ph'my,<br />

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174

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---

286. Oalmid MI, F@y AM, M6Li S, Bct.s E, Petir J, Ai&h. JM dd taigue C<br />

(2000) Hiellpe|fom.nc. liquid chrodltosnphjc d€r@imtion <strong>of</strong> ph€ryl.phr<strong>in</strong>e dd<br />

tropi@jde <strong>in</strong> hum rq!66 huor, Biomedical chrcmrosnphy, 14(3),202 - 204.<br />

287 Hudeovd T, Hat lk S. Zimov! N dd HarAret E (2002) Vali.tation <strong>of</strong> thc HPLC<br />

ncdorl <strong>in</strong> rhe d.tmimtion <strong>of</strong> dioxopronelbzire .nd phcnytephr<strong>in</strong>e <strong>in</strong> .t! drops<br />

sihulr!@Ldy &cm<strong>in</strong>d dioxormDans<strong>in</strong>e ard phoyl.phrift iD €r€ drcD3, C6ka<br />

Slov Fm,5re),9l-5.<br />

288 Savs MA, S.Dah SA, Mosraf! AS dd Nahcd MA (200t) Simulmou<br />

detefrirution <strong>of</strong> phcoyl.phr<strong>in</strong>e hydMhloride, guifod<strong>in</strong>, dd chlorph€.imie<br />

ruloie <strong>in</strong> cough srop by gndient liquid chomtognphy, Jomol <strong>of</strong> AOAC<br />

bt rodon l.9(2). 276-284.<br />

289. Radh.kisb.r T, N@ju A R sakirbe M a sarr@yea A (200j)<br />

Simdta@u ddmimrior <strong>of</strong> nonrhlosl ed lonladir. by HpLC and daivrriw<br />

sD€lrophoton€tic m.thods! JoMal <strong>of</strong> Phallt@uiical ed Biom€dicat A)alvsis.<br />

3(2),359-368.<br />

290 Pat6r S, Bugon K ed Au&n S (2008) A siDpl. bioealttical ssay for<br />

.Lt mietiotr <strong>of</strong> horclllal <strong>in</strong> h@a pls@: Appli€1iotr to s pb@k<strong>in</strong>dic<br />

sludy, Joumal <strong>of</strong>ChDmarosE hy B, E69(t-2),18-44.<br />

291 Mchdi A, Maryu K ud MohMm.d S (2006) Sihutr.neoB ehtitrtion <strong>of</strong><br />

'Ir'eophyu<strong>in</strong>e od Cusifen€s<strong>in</strong> <strong>in</strong> S,"up by HPLC, Deiivalirc dd Derivariv. Rario<br />

SpectophotoEetry for Qualiry Conrol Purpo*q ltui.n Joumat <strong>of</strong> Phmmotogy<br />

and TheEleulics, 5, 67-72.<br />

292 Uyl.nbeek Lu, D. Long@ilL, Wilme A dd Dc Cletc J Us Of Cdirizift For<br />

PEvat'rg the olBt Of Ae[Da USA D6Enr LP I I 09557.<br />

293. Yoshiko T, Shig.hio O, Kuuati M, Mlsaki O, Karsuhid. N dd N&tumi T (2003)<br />

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<strong>of</strong> Ph'fuIo$/, 47(2). l37-14l.<br />

294 hnp//w-aporex.@tr/c€/@!rcducttprilatelalevcednz<strong>in</strong>.dp<br />

295 rrubTun(1975)Co ..rUrti6i!fre6C@halorpori^!ArchDemalol, IIt, |609.<br />

296. Stcven AS, Thona MF ed.,e6 ST (1984) Hid-PG3e Liquid Chrcrnr,toSEphic<br />

M€dod for AnalysG <strong>of</strong> Caph.lospor<strong>in</strong>s, Anl<strong>in</strong>icrobial Agcnls and Ch.noth€Epy,<br />

26(5).652-655.<br />

29?. Larele AD (19E3) Liquid chrcmaio8nphjc derdi@tion <strong>of</strong> ephdosDoriB dd<br />

chiompb€ni@l <strong>in</strong> s€u, Cl<strong>in</strong>ical Ch6i5ny, 29(5), 856EjE<br />

298 Ya!tulo K Makiy@ I, Fuh<strong>in</strong>olo A.nd Oshi@ H 099) D€temitudon <strong>of</strong><br />

Ccphalospor<strong>in</strong> Andbiorics <strong>in</strong> Bef Mear uirg HiSh-perf(md.e Liqnid<br />

Chmmaioglalhy. Jou@l <strong>of</strong> t!€ Japm Vdd<strong>in</strong>aly Medicgl Ajrcciaiioo, S2(5), 3il-<br />

325<br />

299 A6yr. MS, Sulte N rad Na*u M (2006) A D-HPLC Dellod for th. lsy <strong>of</strong><br />

elbiltre and irs alplicrliotr <strong>in</strong> drug-nctat iDrftctior studics! p.ll J phm Sci.,<br />

19fl).39-44.<br />

176

---

300<br />

301<br />

302<br />

Shilde vM. d6ai BS .rd T..dollr NM (199t) Simlr.r@u dct mi!,tion <strong>of</strong><br />

c9baldir & prcb€nsid A@ r.btcrs by RP-HPLC,Ildie jouE l <strong>of</strong> phill]@diol<br />

Gi@ Rw (1983) Tcchnical @sidc6tio6 <strong>in</strong> lhe @ <strong>of</strong> "high-p.rfoddce liquid<br />

chrcnaiogaphy <strong>in</strong> rh.Ep.uric deg nonitor<strong>in</strong>s. Cl<strong>in</strong>. Chfl., 29, l33l -l143.<br />

Micbal PG, B.n LL 4d BmiDn IS (1989) Rev6al by Cefope$an orR$islalcc<br />

lo Etopcide Doxoubici4 ed Virblssr<strong>in</strong>e ir Mdridng R.sistaat Hl!@ saMtu<br />

C€Is', C!@r R.qrb- 49- 690H 105.<br />

303 Y@ C, Mei L, J@b K and Rob.n D (2005) Ite Asi.lion B.rw.n Allersl dd<br />

Diab€te i! thc C3rErlia!, EwIe JoMsl <strong>of</strong> Epid.dioloen 20(8), 7l3.717.<br />

304 S<strong>in</strong>m M, Poj. C, Budim€i€ D, Psic A, Md<strong>in</strong>ovic B, Bsia.Jub6ic A, Boleca-<br />

Bmbd s, MMt-Suic S, Bdicevic B dd Mmovic D (1998) sk<strong>in</strong> diedes <strong>in</strong><br />

diab€dc patien$: . five-y* study. S.laq 4.<br />

305. DebE M@lla RN (2001 wlai Should I Take for ny Cold od nu sympto@?<br />

Cold &d Flu S!{eon and Dia!.t s, Evicw br ncdi€l ho&d.<br />

306. Kdei J, Hi6m s, MirEt S, Saibh A ed onod@ K (2005) Effds orn61-.rd<br />

5@nd-g..mlion hbramile-Hl-Eepror atsgonjns on dr p.nbbebilal-<strong>in</strong>duc.d<br />

lGs <strong>of</strong> l,\. light<strong>in</strong>g Fflq h sf€ptoe!@<strong>in</strong>-<strong>in</strong>duc.d diabdic ni@, J Phm@l Sci.,<br />

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307. AmtDe MS, Suliea N od Zubdi MH (2006) D€Elopme.t sd validation <strong>of</strong> RP-<br />

HPLC nelhod for th€ ealysis <strong>of</strong> m.tfomilr Prtista! JounEl <strong>of</strong> th@dcal<br />

scimes, r9(3),231-215<br />

108. Jitrg rm, s[i ya-qiD, Li detun8 ald J<strong>in</strong> Sh+HoDs (200?) D.vclopDent <strong>of</strong>a RP-<br />

H?LC nethod for smirg porddally couterfeit dti-diab€dc druss, Joual <strong>of</strong><br />

.hrchatoghphy B, 85!(2), 254-259.<br />

309. Abdel-H.did ME, Sdeim MS, Elssy.d YM, Najib NM ed H8u MM (200E) s<br />

npid high.perfodEn@ liquid chrcmatography say <strong>of</strong> glibenclmide <strong>in</strong> em,<br />

Jomd <strong>of</strong> Cl<strong>in</strong>ical Phm@y ed 'nEnpani6, 14(3), | 8l-188.<br />

310. Mlddu ae SbFei! P ad KuAaB S (195) Mdb|@ glycopsreio PCI od<br />

<strong>in</strong>siir Bi5tae. ir rcn-<strong>in</strong>sdi .F!&nr diatcre belirB, Nrtur,l7l,448 451.<br />

3ll Belf@ A, Colrddno A ald Fti$ F 096) OvdprE$i@ <strong>of</strong> @b!4<br />

glr@uoldn PC- I <strong>in</strong> MDA-MB23I bEasl c4.. els is s@i.r.d wi$ <strong>in</strong>lib<strong>in</strong>on <strong>of</strong><br />

i6d<strong>in</strong> Eapior itrosire kiEe elivig, Mol. Endqilol., 10, l3l8-1326.<br />

312 Juij I. Hosrynek!,b, K!ftd<strong>in</strong>e E. R68!I. &d Howard IM (2002) Diasnosric Tsrilg<br />

for Nickel Allagic HD€Euitivityr Patch T.sr<strong>in</strong>g vcrs Lldphoc),re<br />

Ttudo@rion T6! ExoS D.@rol, (2), 5363_<br />

ll3 KANM M (199) Chenical srls|!D6 fd m.rrl5 cuilg dembsis. Rubb.r<br />

glov6 : Alla$/ qout tu.ase.nicl.!, Hitubyo Shidyo,21, I lGl l3<br />

314 hnp//ww.yo@thmaii€1bdt..oE|/lll.Ey-@u€iicam€tab.hrn<br />

315 hftp:r\rw.&t ga<strong>in</strong>stdleryy.codraa/l l2+act-6sl<strong>in</strong>sr-aUeryy-hoD.page.hlrnl<br />

316 Ber<strong>in</strong>on G, V4midis A, BlaquieE C ed RiSal D (198?) Hi6tam<strong>in</strong>e 6 a ligdd j.<br />

blood pldna. P.n 7.Matate, ndlorlr., mal.lre dd r,rrai! s adjuvurs <strong>of</strong> z<strong>in</strong>c to<br />

t11

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favou histmiG tisE diftlion thtuw)r nixcdlised @rdiDdid.In viho t sts on<br />

lynph@,ft prclifffitiotr, Infl@tion R.s.shn, 2(l-4), 231-24?.<br />

317 Liwne D 6d Kryst<strong>of</strong>K (2009) on pFsciiption ed ov{-1heeuLr hhtan<strong>in</strong>e<br />

<strong>in</strong>vese agonists <strong>in</strong> ih<strong>in</strong>itis l}eEpy, Cu€ All.rgy &d AsiJ'M R@ons, 9(2), 140"<br />

148.<br />

318 Ihsd MK, BlMm NB and M.ba AY (2005) C€nriz<strong>in</strong>e dihydrochloridc <strong>in</strong>Lrulion<br />

wilh sone dicl<strong>of</strong>@ @bplq6, EwFs JoM'l <strong>of</strong> Phai@utical ScicncB, 25 (3-<br />

4L341.348.<br />

ll9 lhs MK, Baeu NB &d Mr!! AY (2005) Drus drug <strong>in</strong>tcdrion b.tl{M<br />

dicl<strong>of</strong>.@. cat<strong>in</strong>ne dd milidirc. Jou<strong>tn</strong> l <strong>of</strong> Pb,@utic.l dd Biodldictl<br />

Ardysis, 37, 655{61-<br />

320 f<strong>in</strong>i a, Glruri !! F&io G, Alv@-Fulnas J &d Eolgado ltlA (2001) Dicl<strong>of</strong>@<br />

sal!. L liactrl ad thm.l analtsis <strong>of</strong> sdiM lrd Ftasi@ dicl<strong>of</strong>@ stlis .,,<br />

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321 PeEdke A lvfih.shMi M, Tyasi AIq Chauh& B ed Kad@ SS (2003) Pcp@lion<br />

ed Chdact€dation <strong>of</strong> FlurbipDfcn Bcads by Melr solidific.tion T*hDiq@, AAPS<br />

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322 Shmo S, shd P, Badv€ s ed P.w AP {2005) Aderpton orM€loxicm on Poroa<br />

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PhmsciTdh., 6{4). E6l8-E625.<br />

323 D.rlc DV, B.L M &d ksli*ql N (2008) 1, tto md itr vtu cv.luldon <strong>of</strong><br />

rcf.lmic &id ad its obdd6 with i4tclod*t<strong>in</strong> and HP-Fcyclodexrr<strong>in</strong>. Alie<br />

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324 c.wil<strong>in</strong> Mv lrd PogFbrr?t AV (2001) Sy h€sis, cbE!.1€iizalion, dd rytlultion<br />

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Ph.m@lnical chdjsfy Johd, 35(?), 395-396<br />

325 Florcy K (1985) &alr'lrcal PrcfiL Drug Subsrdce 17, Acadmic Pc$ London<br />

326 Sh{if NA, xu Sx ald Ymi JM, En.d.si<strong>in</strong>e A (1994) Pore , Hish Amnity<br />

Histlm<strong>in</strong>€ Hl-R@eptd-Seleciive Antlgonist for Ocule use: R€c€plor B<strong>in</strong>d<strong>in</strong>g md<br />

S@nd M.sosq snrdies, J. O.ul. PheMl., l0 (4),65H64.<br />

327 ToMa Y, Kubo H, H@e]fhi & I\r@rr T rnd Futuok! M (2001) Eflois <strong>of</strong><br />

luplata( rosih& zItD C.pslLfl/ oD rh. prodlcrid <strong>of</strong>@tiv. oxyg.n by @utophils<br />

!d <strong>of</strong>lL-8 by oononuclw elh ltri. tmbophdn I(6),I181-1187.<br />

328 Laetr A-K Fu.srli !, DiCEnl@ ,\ Ad.tls lil, Ludh.rg J, Ed.nis C,<br />

Govoni M, Monopoli A, Sab A" D| an S-E. dd lol@ G C (200n A tw clN <strong>of</strong><br />

nitdc otderld<strong>in</strong>g d6ivaliv6 <strong>of</strong> dnizirc; ph@losicd prcfil. <strong>in</strong> ve'ilr dd<br />

.iMy s@rh mwle pEpontioB, , & J Ph!d&ol., r5r(l), 35-44.<br />

329 Timothy Al, Mich.Ie AY, Msk PA, L)tu B. xiong C, Philippc C, Jo$ph BE,<br />

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(2004) Cetidz<strong>in</strong>. ed lo€radi@.bd.d mtihilran<strong>in</strong> s wirh 5-lipoxygo6e <strong>in</strong>libilory<br />

erivity, Biodeaic & Mediciral ch.nhrry !en6, r4@2),5591.5594,<br />

178

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330 Baltaba UA, MaklMov Ac, ZdkiFv UB, Bab.ev ID !d Shututl@ K (2002)<br />

phm&euticd ct@isrr jouhal, ftc eri<strong>in</strong>nlmabry acdvity <strong>of</strong> rew ,ryt ,nd<br />

@yll[iotuw d€dv.dve$ 36(2).<br />

331 Kai W, Hu-he S, ru{hu C ard Zhong C (2005) PulrFnary Pbm@logy,<br />

Inlibnory etr c1<strong>of</strong> etdid€4s on aiMy <strong>in</strong>namadotr ed phoslhodi$ree* 4 <strong>in</strong><br />

allergic ois! A.ia Phmeologica S<strong>in</strong>ic4 26, t 492-t 496.<br />

332 v@a M. T.ipaihi M, Sq€B AK.nd Shdld K ( 1994) Anri<strong>in</strong>ilamaiory .diviry <strong>of</strong><br />

lovel <strong>in</strong>dole dqivativ$, Ewpee jowal <strong>of</strong> mcdic<strong>in</strong>al chemislry, 29(12), 941-946.<br />

313 Dolgld GD, Gmrse DM, Jo*ph.lP,Io& ES, willim O ed Rich.rd RH (1990) 2-<br />

Subslituted-l-mphd@ls d Pol.iit 5.Lipoxyg.nse Inlibirob wir\ Topical<br />

Amiir1ls@alory A.iivity, Jomal <strong>of</strong> M.dic<strong>in</strong>il Chemisty. 33 ( l), 36G370.<br />

134 leng L, xa Y, C@i. Oq Hwes D od Wlson CB (1995) InvolMot <strong>of</strong> r*tive<br />

oxyge! iri.mediales <strong>in</strong> cyclooxyg@.2 dprcsion <strong>in</strong>d@d by <strong>in</strong>terl€ulir- 1, rnor<br />

Mbsis fa.loF, od lipopolysMhdide, J- Clii- lnv.s1., 95, 1669- 1675.<br />

135 Mon H, AEi T,llirra K, khiiH, Eodo N, Mrtilo K 6d Fukuda K, (2000) Etrects <strong>of</strong><br />

Gfomylpt ril! a hd<strong>in</strong>e oxila$ <strong>in</strong>libiior ad ! supercnde smg6 @<br />

pnnucijor <strong>of</strong> nitic onde h Rr{\v 264,7 n1!@ph!96, BiehiD. Biophrs. Acia, 1474,<br />

91-99.<br />

336 lulagmi Y, Ydo S, Hori. S, Tsliya S. Ikcgmi I, S.t<strong>in</strong>c T, Y@oto Y,<br />

Fljimdi H, Trt Doto K ard w!|rE!. K (195) Ar.ls6ic, rewDl ct+ ct!fuI,<br />

blct<strong>in</strong>s rnd tu@tt 6us.l. Eh@r erivitie <strong>of</strong> nidlglnie, d <strong>in</strong>

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alioi H, Mepbr snbsoni$ is us.d tu rh!<br />

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hum lff w n mii<strong>tn</strong>un <strong>in</strong>blf4nc, fM rmm endog.rdr @r|Funr Ttu<br />

*oid probLm wcs rh. .hoie ot prcp.r .hrcnrbgnphi. loidtrion. ro obbir<br />

&pdtion ot me dE @mporma fon rh..idosdNs onrouidr.<br />

Th. hrir sM<strong>in</strong>. ..!rir<strong>in</strong>. dihydehbndc @yn{ t0 m0 dd rb. r,, e.por<br />

aqoEr om.ridjn. (uk.rd 4m n9. hmdid<strong>in</strong>e tHits 20 nl!), miridii.<br />

(N!lq 150 m!), rlld iftmil sbdr'd ptufylp.nben <strong>of</strong> rllm@dal Fn9<br />

*E oti|jn.r tmm vdio6 phr@ukd @mpcni6. Th. dnftt u.d rs <strong>of</strong><br />

sPra 3rd. An dE nri.r usd e.d or olrrrid s'r& iEl'djn! hr&eNdic<br />

*id (E. Mnr). lorsium cNodq $di!n hydoxid., pdsium dihynmi.i<br />

dhoprt6ph&, ud dhoph$phori. eid (8, M.rk). Deio 4d w.b w6 ftshty<br />

Trrddic.r b!l|r. (M.nkr Tokno jABra, cotmhs, usA), ot tu(rr.nlr<br />

Tor.do rlP 220. cotumbus, usA), uv.viribte 160l sn<strong>in</strong>&u ddbLjce<br />

NFhpnorom.tr, r4m rcchsute qumz !€ns. dcioriry (Sbd.c csw_30,<br />

Jr ' ,CFt t)F 20ot 2. Cmd!, rtr &d<br />

Ihsi'nrd'uHPLCr*m,i

---

uor fron I b 9, ud rd lk Fq dutb: cl .oluriB <strong>of</strong> o I <strong>in</strong>br<br />

"-i *.4. wcrmc ."'d.d -r"u<br />

* i..ia r a,u"g r. "p.p"'E rNJtr o' ur oruuon m .n. ** butr'<br />

QffiaMa ol dtus| n 'tu@.aa<br />

To did. d*. dr3r. . Gri.d 6ii! th. w<strong>in</strong>lbl. rpdEdlM *B<br />

ddieEd b d@c qm<strong>in</strong>6 o<br />

'h. m For rht Pnipos 3 h.rh@ric'l Eh d_<br />

lhip *s ued rhi gay. $. .onentdrioi or rwo drug. smuraourv wFn<br />

mud d et rbsrprion malni<br />

*h.E b n d* ldh Lnsrh or lll. ..ll (r cd <strong>in</strong> ff .rp.ncits) 'd c n &<br />

cididiE, rd lmdidm <strong>in</strong> ln. Fs<br />

(D<br />

\1)<br />

r&oIt<strong>in</strong>g I dhtircdY difi*nr<br />

*lv.ldgrhs tridy ld lod dch o$d<br />

Ba.E rc6$ng ddivniv. tp..n is rhe mdt .olmd prdm ror<br />

<strong>in</strong>s sF.h i' birry mn@ (Ab&l .t .1"<br />

2m5), &. 6{ daivlM srhp*Mhc ndnod P5 qcli.d fd siml|@<br />

didim <strong>of</strong> ov.ilrpp<strong>in</strong>s spc6 <strong>of</strong> eftizir. od dildlE h e p.ffi. ot<br />

oP'iiiand 4 h. aobb Ptu.<br />

To &Elo D n}.HPr-c mlnod. idrlly qxtuol qu r90 ro, E b.d fa<br />

ihuhu!ru d<strong>in</strong>rtd <strong>of</strong> @'n,ii. x h H, 'Epb sLgon'u 'crdn'jne<br />

miridjn. md fMidii.) lidividtrd dtus $lutions *d i!j4r.d <strong>in</strong>b $. oruhi<br />

.! a @htsdoi ol lLto !e/n -. sid borh rhe eluboi p4En dd e 6drtd<br />

h Phe .x 'hr Hr 'efls lotlM srtr<br />

* a"i.a -,' * *."i'oi rR i. :rnrl d m Fd*rd<br />

.fid % ob*i.d {irh E djudtr<br />

d.d f( d. quiF! pulpoe Fd rhii ft$trd:lrb 13020) vs ti.4 ad<br />

iidius shorcd rhr 4 rhis drio, rh. H<br />

Hotrv.r. r lunhd dec@e <strong>of</strong> mdh<br />

-

---

phft hrd no crfd oi $. H, s.rror 'rqoi;r bur onty <strong>in</strong>cEcd e @dM<br />

rjtu <strong>of</strong>erirtirc Ti. pH.nd lbrrd rhr opr<strong>in</strong>jz.d.ddiooo e tuLd !h.n<br />

o. pH vdE 3 r.5. glde<strong>in</strong>g *ll-c.olv.d [d stu,p F.tc fd dt dius sly.d<br />

ri iddirion, $e w ry..h or <strong>in</strong>diri<br />

r03c <strong>of</strong> 200 ro 4o0 im dnd .onpr&d. Th. choie b R h. lobdri. poi .a ar<br />

227 nm ** .@id.Ed &$shcbry. prmhri.s rhe de@do <strong>of</strong> jl &r$ *o<br />

M.$hd:yad (30 20) 16 rh. !mpk$ mbit. phe fd nDid sd ,nu6ds<br />

4rirutim or ..riri!<strong>in</strong>. *irl H: H€prd dbsonisr pmpyl pmbcr pa @n b<br />

J n<strong>in</strong>. Tn. ff<strong>in</strong>m imt w robd o h.<br />

2.5 mii ro! dE Hi e.'td uras@rh !d 3 5 fh ror cr<strong>in</strong>zii., *nh , €8 nE<br />

S.pu& t@r siuror d c zi( $d omudi. qer dipcd by d,s<strong>tn</strong>lg<br />

lohg or eri dns ir rm d s04 4rdr Ddhmj o lhn |n. i!.1<br />

@nhrid wa loo lEn wdrms stukn rs $eE pEp.Fd sFd.ty bj<br />

d,ruu4 rmm ,rr $drd {rrnotu L obum Lo.dw;;bd@i rrr ud<br />

33.33 lrc/'br F6wv.. iiamrr drd M:d<br />

oNbr (i., 16.66 |3/nL) ii r[ rh. hdiig drnd.rd stlriois. rr. @<br />

pc.dua wa Ep.!r.d for hmdd<strong>in</strong><br />

To!.!m<strong>in</strong>. dr sb' oI bodr &uu tr o. romudod rL.m.ldra fuoddim,<br />

s. cor{.d rnd .{udor b ro oE <strong>of</strong><br />

€riizr.d|o'm!<strong>of</strong>H)Dtrgdtrb'wE*q!lBl',ndlh.€|utronlsd.!p<br />

b r(lo dL * h eoq 4hr crhoot Th. nrk,ns €rron w 6tkr!d.: ri.<br />

4ord<strong>in</strong>sly dirucd *ft rh. qme yi{m 6.d <strong>in</strong> nrd.td oturid ro oo,cn<br />

eruood. yid' rh. t<strong>in</strong>{l .on.enf&on A shpb and xbndrd ,olurjm rm<br />

nltdEd rbnlsb 0..r ! ,ilk, Fp.r b.rm qdum dd ,lE ry*m a pturo<br />

6rc .l,o ea lubF.d b df, $ nE pcdbrtry d<br />

*'p6 mM<br />

'n<br />

h drr5 *B {ni.d<br />

Phhr.mp s obbrmd.rcn hq<strong>tn</strong> ..,hmR^ re ! , ckd rd iod lrun.<br />

--

---

l ni[ rh.n annilused fdr 10 nii n 10,000 rth. TIE rlp.rmbr wt ilr.t d bv r<br />

tunh.n! fiha wirh r pft .iz. ot 0 45 |ls. Ad aliqbl ..lm rMplc t t fdi6'd<br />

Mh e.h drus b eh d. Llt turl .onaNdiotr<br />

-!ar( F h. r. J rt ol 6 h rmPl. i(<br />

I b r'rr [g/ml weE p,tpslr. dd l0 lt|- or<br />

r.rdid ws jij..red dd chrcmdosnph.d. Fon dr' l<strong>in</strong>.dnv and p.@n!!. <strong>of</strong><br />

Eldir lbndtd .Lviarior (*RsD) !<br />

To mR bund q'b pH 1.v.." ol I rnd | ! 0 | rovl olurion or poB'un<br />

ch|;d; "* etFd qrh qd'dtri1. a d<br />

iplap ab pH *6 araiEd F<strong>of</strong> prcPlrdiotr or pH ?4 poedun dihvdbg.i<br />

onhophdphe (0.6 s), dMdium hvdrug.n onhophosph.b (6 4 g) rid !di!m<br />

cbls& ri 35 s sge d,"shd h rltu(i' d.rookd $M b Dr.d*. 1000 d -<br />

*i,i ,h. oH ;Ned i R!6s<br />

! a3 s or m'um<br />

dbe;Ldilelv.drr.0oomLorq& tr h rrE pH<br />

'di'!.d b o uD, r'qu'd<br />

Tr. i'lt.rurjd odls vse Fdon*d<br />

by pt'ariis 2ol}|g^nl tck $lutiotr or<br />

oh dtu! itr bufieG ot an dp{y sonrh pH ol l , tull sMeh pH or 4 t<br />

iiea<strong>in</strong>d DH ol9.6d r blood pH <strong>of</strong> ? 4 Ndt.20 ftr or d$k cc<strong>tn</strong>rne lorltd<br />

ws rftf.dld <strong>in</strong> r cooE.l fldh, did ro rhir es ad&d 20 o[ ot rd] cid$ddlF<br />

$tunoi Tnc @Dic,l f,a3t !s plsc.d h r "!rd br$ r r7r fd r h Th€ spia<br />

sF vi$d:nen.!.4 hrlt hor rid rn y7.d ulidg the Lw Yiribl. stdropho'<br />

orub ed gPLc ardr sir$I. diluriN\ rud b. made. Aboturc.s d p.4<br />

I{ *4 n orJ.d 2nd rmm un d<br />

TL !m Bi!.!dm wr E .:rd rd ouw Ht c.p6 tusdjlB 6 {.lL Ir'<br />

€n! lnE otritr d bv u<strong>in</strong>! bdn ft Ehiiqu @ 6nFr.d. !n cc|ui6<br />

@ d..s b.'.d oD tu lg16. T1F<br />

Uvrkibl. rp.rbphoromtr<br />

Caltb.ad Md .ohrbtb$<br />

tu lhdiq .ndi6 ro difidr d..r<strong>in</strong>ris or d ds 14 Fr.d u<br />

dirdr nir6 rd $dn!d ftE lhqprDi nsitr or@idtm Dd ciisi'liE<br />

ts o{xdld d 21r m dd !16 nn Fn f sdG rlE rb6ol'to |u<strong>in</strong>d<br />

I

---

. {heu u! nm % ok ftd d pH ?.4 Dd<br />

Th.* dru$ *a carn.ros rms ,<br />

*dudbi6|{ldnu$.qudti'i.toIliA!dnsjiasolutiotr<strong>of</strong>unloow'<br />

.d..ihron. Tn 'bsprio ry<strong>in</strong>un oI dniridii. ws rolnd 6 hc ar 225 nm,<br />

whioh oErhpFd rh. r&ihum or alid?<strong>in</strong>c (23 | ii) Th(dc, 'n* lppliaron<br />

<strong>of</strong> !eoid{edvlriE(Fis ?)'p.crophorm.ticnrlhod,rhediflditab$prton<br />

tu<strong>in</strong>r ror EfnziE !.d mitid<strong>in</strong>. wR eod.d d dffeE pH Lv.h.<br />

Irr qlihr.riq .N.s rrs wrc rolnd b b. tiB'r lnhh dr .tre.u!!m<br />

dl. ot 0 0r ro 0.1 n)mr/r- td d<strong>in</strong>ri* .!d tuirdjn.. TtE prcdua * ldrd<br />

b e rhpr.. n!id. d'i r.rBbt. <strong>tn</strong> jt 'h. c*,. rh. crn. i.br or .$1e B<br />

,d'dbb.dllrcdEr2*<br />

R.pl.!.Iulivechrcndogramswe(<br />

P6tlb]ypl.Fd<strong>in</strong>lhesnp|?mf<br />

si$ii.! chriscs ji 4a undd rh! c$o rAU() or fu DD ljme <strong>of</strong> qE {qj ,n<br />

.bo' (iiotu nadrrd) ctdty idiclr.d rtE<br />

sDe'n i! ot oE n <strong>in</strong>od Gi!. r)<br />

t t@tt, <strong>tn</strong>rn ol d2k n2^ (roD\ a d ti,'tit o! 4btuddiil Qno)<br />

rs fiMity !Ndi6. d difrdr mirrur dEnmjms (13 31 16.66. t3-t3, lO,<br />

t66.3.13 Ig/nL)<strong>of</strong>@rdru!, ii p!.sR orrh. iikn n drd wE sy.n<br />

TrE [Miry <strong>of</strong> rh. trd]od *s o6c^qr *irh<strong>in</strong> rh. .iFd.n limcrrnom tu$i<br />

li<br />

t'<br />

:<br />

J<br />

@

---

i.!r.IFliEdMJennd'd,4<br />

JLD$ ftt ' 'om !$r' rop. 'ME PL ',ld<br />

.*r*"."-.rn "" "i *.*'.a<br />

or tu For ru tSlnn the om.ddion *se $'l. it agEsiotr $'h'i' LoD<br />

xd l-oQ @ lhom iD rabL l<br />

f|hmcsdsF6jubdrlhEdful<br />

'a-a.i ;**" " " *'irr' 'o :s .na z. *hr bv rdd'* rem<br />

q""itu or,r'. .,ry,. . ,n. a.e p..a<br />

nddd *! @urE ror rLl Lh. rbov<br />

Trx mftod Drxd 'r 6r ro .P.'rh<br />

or tu Fr! or rL Eplar mrdnft n r'^ 4 r{.on rnmtrd Th' rqrL ror<br />

i'rd.dnE pdi6m m showi ii Trbk r<br />

ftre.FhUftsftd'0is. Fopo$d ndhod. d.rtud. dsditotid i! pH<br />

vicr ot th. tubil. Phs$ !4<br />

lrE ohtbdbgraphc paEmetB<br />

E

---

*! lblnd b b. ?65 mdpg r rnd 4, vh.@ 234 nm w6 ahrd.d d pH 7 4,.d<br />

TlEe dogs wd *rimEd uiig !i Malr .bsorprivnhs<br />

*cr u8d ror catcula<strong>in</strong>s ln. qudiri.r <strong>of</strong> rh.r. drurs ii r pturioi or unuo*n<br />

!h ot ffirid<strong>in</strong>. was rotrd ro be !r 225 nn.<br />

rnich oh hpp.d numum <strong>of</strong> dh.m Uj I M rnRrm. rna lppjddon<br />

'nr ' '<br />

<strong>of</strong> ri. @DdieJildr rFu. 2r {dhoohft h.ridt, tu drn.t@ !ryon<br />

dni rd €Iirizir ad tuiddiE w @d.d !r difiamr pH Lv.ls<br />

rE drt riu ffi ,tio rw fold b h. tiE[ *nn<strong>in</strong> Ihe crc.did<br />

nI3. <strong>of</strong> 0ol b ol rmt/L fa dniziE !n dnidiE. rh ,E i'r. rs foua<br />

b b. !hpL, npi4,!d Eridt |! ru d. c. rb. .cficid <strong>of</strong> ,arr|E w<br />

rdndbb.d@<strong>tn</strong>d295.<br />

R.ptrnbdr .hlmrbglm3 $.a<br />

polroLy p.ud r k spk T&,r E Boh.d IDm ft. prd, ,nJrE No<br />

ngnrnqd cbr4.r u 'E udq lh. .@. i AL c) tr leron M <strong>of</strong> rl! ders h<br />

ft. enEtu o abd.G oi pneytpobo rti@.t sbidd/.rdy ndsrd rr.<br />

l'e'f(i" <strong>of</strong> r]l m'5od c'! rr.<br />

edry. rr<strong>in</strong> otdaai,n tttDI .,n t .t ol q@neh (rro)<br />

Fo.liEiry sbdia rdx difidr oir@ @oHj* (3j.lt, 16.64 t3.jr, lO,<br />

t64 3 33 u/bt) <strong>of</strong> sn doC, ir !@ oa rh. iihl ,r.ndzd wc &ey.d.<br />

nr liMiy <strong>of</strong> dE dtod E orqv.n $&<strong>in</strong> rh. aFcr.d (:lrlllfuid d!..<br />

rb.t k*e,!v:Fde'hd,dd,Br<br />

!ib..ir.l<br />

@

---

n.'tr'ddn.nq!t4-d.F<br />

ut rr!-orre@dma<br />

e'eq.!<br />

@hld&dr,ohtdFdd<br />

dr.lit 4 h. ulbility ld dtt"t ll. r8hd @.L?e 'nct'!' d<br />

@lud .odftkit *G .L&di.d Fd cd.!l!lm ol 'n' t|Ifu c@ D6<br />

or u eor,<br />

.dlrQe tlm i. T|l* I<br />

-.r.-<br />

u *mt- @ u'd It qdtio' sid€ r'OD<br />

I1E i'd.v Fitim.!d clrv <strong>of</strong> rt re ddud d |!F t'irtod<br />

'D.dod<br />

'J-.&.i i*-u-, *nv. lo. 25. !d 20 |JIh|- hv r'dl! hbn<br />

;;ddr or 6. &dvE o dE dot F.dd Ti. dli ra mv ji''td $a6'<br />

ddhod *u c@ f4.ll thl $oE Mh*d prlPc<br />

T1rdiodost drr6rdF{alhlir) .ddan$.dbv*RSDrdr*@<br />

or d. Frr. or rir E L*rFUdur1004dcoeimd TbtuLrd<br />

'ncm.dLE @rm G ihoM h r|t& r'<br />

Fbr rh. .!hos*$ ddy or tb.<br />

v.lc or fi. nbb,rc de **<br />

dE cbena.<strong>tn</strong>rruc Fnl|'6<br />

E<br />

mmd i.rhod. &llt & b.dtiorior i! pH<br />

;j.!. I o b. s lhd r& .E Y otririio ut 4<br />

e h uldrE *iot rh. ..rtiitlF! vrl*, a

---

:t0.1{ir pH ch&3. <strong>of</strong> .!or 3.JO (,H or ri. ,FriL ph&) hd m cdj@*<br />

unFd d dEni.rnpht Ff(me.<br />

I]'.d.Eop.dmllFd*cr!p|'.db<br />

'n 6.d In nhilrl, or$. rlab6 rn dE I oj 6e dngl u d: ltEE d<br />

Em dbiEd <strong>in</strong> T$k a sbor rh.l?jf,:ni|i|' ot $. mdod ta uEi&c<br />

appletqorftxmu/b.st{u<br />

bdx6 tu( rd H, bbr.u. s!rutu<br />

tdc lft o!6ay.d .tta k ohdr.d trm Hplf<br />

'rir<br />

nk rnLD|t,ty vjE<br />

d dirtft Dd I! bbrft n Fee <strong>of</strong> tr rdtd @ Ioud b b. tfir&,<br />

sb b .tulq ir Nrir$ihy du fd r|l d..E a F*E <strong>of</strong> jr 4h db.r n<br />

d dE b{ff.n sdj.4 . rh*. h Trbk 5<br />

tEr

---

wdEldaNPlh.iffu&!nd@ry<br />

Modv.., our m.dod wd rNid o b. wid'lv applic'bL ond Gplod*ible Fd<br />

df .!.!. nou.d l!ls\ is.thn w'h ..dvss um e* or oF !d d<br />

**.Dd *.t.u't"r . .*",.t<br />

'dnfttu s d'nv&E c'PlbiljrLv uF<br />

'n<br />

.r-'l.r a**,.o,uu$ old add bnrq@ Fdhaff<br />

6. ii!d; "'.-a*;n.. .df- t ubbite dd p'!cd!s rc tudB or<br />

"f "'rv$<br />

*-* i'o r, *,.' -":-. -rr* -d b h eurp'( or d'lds 15'<br />

prlrudiql des. <strong>of</strong> rhe &u!..<br />

iE ddH 'aP'n mu€onB! *d srffi<br />

i* u' ii**. . '* ;"ry". 6.rd B"* d or tb' su'r* $'ftd<br />

ri-,i,*,**.l *,i^. .g* i, wr orr'd.d ,rd dri 'v".{ir'c 'rd<br />

rcr", N".d"*. t.*"d b.*fi' rDn co'dn<strong>tu'</strong>tun <strong>of</strong>iMndir lirb<br />

sivsriic. ..tiriz<strong>in</strong>a and ldahdim i<br />

*s obercd (ch.i d ar . l99a)<br />

l" -"+. 'r,. --.^**,.<br />

q.*-.r *-;a *. *a'"-v<br />

-

---

Ae ,uppErsid, $us co.idiig rh. dioi.t tor r ad ot d.!. rarc4rc6<br />

.dniii3rEd coEomihrry ro sn. rri.ii! wirh .lnonic udicd, utulp,ur. ro<br />

@dn d wid f Hr aMgonhr ilorc Ir w6 .ondud.d rhn $d n no rcraEum<br />

uriomr. b, cocdnidknns..un.R *,rh !,m.ud m fq F. kdmn o";(&!<br />

sd da ure n.didimr my b. coodlntibkrd sf.ty wjrhour fd or m.djorid<br />

iildum rNirsu ? c/.. t999, Hc64. rhit syn.ryrj! .na, *s nor rNnd,n<br />

dr rh. dudis (Er.rL a a/.. ,95. cor<br />

I!.d q <strong>tn</strong>. 6d pd ol dE sdt. r {hurll@s ru-riPr_c rs d.v.loFd sd<br />

viidlr.d rc ur dd.tueq or drotr <strong>in</strong> rlr Fffi d Hr iaFa<br />

&4djrB ftopylpc,xn D w!reLc<br />

'id Ed mdy s r F*djE <strong>in</strong> rr,&G. Trr<br />

(hnfugnphictr'hod*av.ld!.{b'|lgsnslifutr'Itrny''|.dlqly'<br />

rF. *rdrE d q@ddiE. Tn mlhod ra fiq oj rd.'tc rrem<br />

.rcipi.ib. ft wa u&d b .vrlub $. p6ribl. <strong>in</strong> vjh idbrerions bqwai<br />

ehn* ,nd H, Ecpt6 ebgonkt<br />

h h sfd pd orrh.sudy, rh. uv,vilibt. lp@hnpic r..hijqu. w ued<br />

b 3rrd, d! <strong>in</strong>lfmioL Fo' tur rtr qlu. *E ldldaE nw \rluo *.8<br />

non, b.r*en ln. dnss, fd sds sc<br />

.onprd *d rl'e ot firl_c. Fbf rh. Erulr4 ir *s ctsnv .vjddr lnr rc<br />

hbla:ru M,i,!d <strong>in</strong> Dy <strong>of</strong> n. b{If*. rd m .hrns. ,n p*dus. ol<br />

Arrhd{ft nis @n djd d .bp. b ii6ia& d. j. vid n,di4 ri.<br />

ffi dlnod otd b. ea{u y b ttE sd, oj sDp|.s <strong>in</strong>ojql! ir<br />

vi6 rbr6B Frcn "9t'.d d! Be3td.d,hd rr. syEBiloc.fld<br />

Fd@d b' fr.mbi.Jm 'hclumrody.,r <strong>of</strong> lh4 dr!33 lhodd b. rud,e! d lbr Iw or<br />

Atur .ll th. rcs'nb obrriR! by HPI-C odl.r hd b..i oaty*!, ir *a .oicrud.d<br />

rDwr | tosh p.Mn{s. or doErid. ed tr Ln{ !p ro I qde rus. ot<br />

i. <strong>of</strong> ,nkrucuon Eutb ohdd tom bod<br />

eh'qua. n vs orrud.d rhr no <strong>in</strong>hnon @uftd bdGi d<strong>in</strong>zjn. Dd u:<br />

lIE

---

vi4l.slocl?@'fud!@e@dd'd,(D''ih)'dyiteii|!bE'<br />

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-

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J.cd.s(P'r.. yor Jq Nq.., !a<br />

Oltimirrion <strong>of</strong> Qrzrrir.riv. AnrlyrL <strong>of</strong> C.tari.hc i. Bulk Dngt D<strong>of</strong>g.<br />

F.16ul.rjd rnd Hum.r s.ruD UsirsSp.c.ro<strong>tn</strong>.ron.try<br />

NAJMA SULTAIiA. IMUHAMMAD SAEEO ATAYNE' AND IHINA S'{AMSHAO<br />

' R^,otch kilid. at phoncIlttcct s.i.rc6. Foah, ot t\moq.<br />

u, q:itt af Xdtutt Xd@hi-75)70<br />

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lc'6P|ti'd1i'Fi@'^'dEnni'dElqd&iEd!UjE*bft<br />

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ro rh. burk drus, dos4. fomur'rions aid for hrro<br />

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ph@h.ticdlr rhl pmpod n.rhod n3.ppli.d ro<br />

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rrr pH .lf!d. Trr n4hod q3 .ppli.d ro rh. miyljr<br />

<strong>of</strong> dtu8lpik.d ii $run as v.ll.

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56,|J'ciri's.c'.'|',vo|I.No'4.!04<br />

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obl,<strong>in</strong>d by Plon trg d. oi"nrdrion <strong>tn</strong>6 $$r<br />

bde <strong>in</strong> Ih. wllliis cunc.nranoi dBc<br />

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nh) eirh qu@.dL ol rcnn p.rl' kiah Th.<br />

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---

)<br />

\1<br />

pcio\<br />

2nd International Symposium<br />

Cum Tra<strong>in</strong><strong>in</strong>g Course on Molecular Medic<strong>in</strong>e<br />

Drug Research (MMDR-2)<br />

Janurrr l2- 15,2009, Krrachi, Pakistan<br />

Abstract Book<br />

I)r. I'aniwrni Ccnlcr tor Molecular MediciDc and Drug llcsearch<br />

Intcrnalional Ccnter tbr Chcmical and lliological Scicnces<br />

Ulivcrsity <strong>of</strong> Krrachi. Karachi-752?0, Pakistan

---

Simultrnoous Dcterm<strong>in</strong>ation <strong>of</strong> Cctiriz<strong>in</strong>e, Diltiazc nnd<br />

Anlodip<strong>in</strong>c Us<strong>in</strong>g Rosvast!(<strong>in</strong> $ In tc<strong>in</strong>al Strnderd <strong>in</strong> Dosrgc<br />

l.ormohtion ,nd lhman Scfl<strong>in</strong>| by RP-HPLC<br />

I l<strong>in</strong>a slnpslpdr, 14. S@d AnynC atrd N.jrtr slll!<strong>tu'</strong><br />

't,b r, D@t*tu Eckdiitt, ud.Biry 4r,4hi xftN,752?a, Iolbb. iR.trqct td tu. ol<br />

Phdtdkaikd sdqat, D,Ntr.N {tr ,mtuid ckEhw f..'ltt 4rtu 44.<br />

udkhit otb6hi ks@^l, 75r74 Poltt@<br />

PO-31<br />

ir bci &Erq.d sd uiida.d for ric dddniiflii or dkr.rn. ti<br />

[$uc ordrciln.rnii.r blcr.B (di *4 rnrodipii.) Grig @4prc k<br />

idnrosnd rc *tsnrlq hdhrn 'h'r<br />

t. dc, (6ttid rrnrdror l i wi<br />

diod ws roL nd b e .nicicir ud ks c<br />

dftJ!Jrogln'|*Da@'idF'djNdsp|6'I'..mhdlidlIE<br />

I re d@t,ryr@i @r4Mn4 n. r a

---

ADR,<br />

imLe<br />

Pror. K C Strghal<br />

SOCIE?Y OF pt{ARMACoVtctLANCE (lNDlA}<br />

Executlv€ Comhittee (2008.09)<br />

ChletEdti.r<br />

S.cr.trry - <strong>tn</strong>i.m.dor||t R.hrrbn.<br />

r,r, PDe8€ 8bB<br />

organt hca.Jnt ry<br />

Oi S:nl!ru K Tdp.tft;<br />

1l!<br />

Yl \

---

P49 An RP-HPIC m.lhod tor tte slnullar.ous d.temlnauo. ol celi.L<strong>in</strong>e ln<br />

pEsence ol qulnolon$ <strong>in</strong> bulk maletul, phamaceulidl lonnulations and human<br />

U!!:S!!!$3!, NaJm. sultana and M. saeld A'.yno<br />

Rese.rch Inslitule ot Plamaceuti*l Scienca, F cully <strong>of</strong> Pham.cy lt tab 9,<br />

0eparlmenl olChemiBlry UnlveFity ol Xaracht, Ka.achi.75270, Pakistan<br />

An acc"rale. sens lNe and easr Ine mlsum.T RP.FPLC reh;d to'rhe estmahol ol<br />

c€Inz<strong>in</strong>e <strong>in</strong> lhe presence ot qu<strong>in</strong>otones i.e cip<strong>of</strong>loxac<strong>in</strong> on<strong>of</strong>lonc<strong>in</strong>, spamoxac<strong>in</strong>,<br />

norfiorec<strong>in</strong>, levolloxac<strong>in</strong> and olloxac n was devetoted and vatidated <strong>in</strong> active, dosage<br />

tomurations .nd <strong>in</strong> h! man seah Ceridn n. €tuled tom purcspher Srar, C 1 8 (5 nm. 250<br />

t 4 6 nm) column al room temperature us ng mob te phase <strong>of</strong> melhanot: scelon ldte:<br />

waier (50:20:30 vA/) at a fld .ale <strong>of</strong> lml n<strong>in</strong>urei $hite W deteclion l!?s periomed al<br />

?25 nm. The .elention lime <strong>of</strong> celiiz<strong>in</strong>e was tound Io be 4.00n<strong>in</strong> and that ot ou<strong>in</strong>otones<br />

wes 2 5rri The LOO and LOO vatues ro, @, ?r @e tound ro be OOI and O 0l<br />

mqnnLi. The method ,as va rdared tor accuracy, sensitiul, pecision, spe.jktry and<br />

ruggedness. Calibralion cuft€s were tound to be l<strong>tn</strong>eff wilh<strong>in</strong> the Enge ? 5-50 mgmriL.<br />

, Mlh regressjon coeficient t2) O 999 The esrabtished H pLC method sas tou; to b€<br />

Eo'd ac.urate a.d seled ve be(else or 'rs se-5nv(yat Rpbduc,bilt Moreo/er, rhe<br />

D.esenl rethod was found ro be etiecl,vF tor rhe,aDeulc olrooscs

---

.i-'<br />

P.10 Pnvsical ard chenidl cha'act€tizttion ol mli'namic tcld <strong>in</strong> difrerent_<br />

t", , $eir stabititv studles u'lng novel RP tlPlc '<br />

"nd<br />

',t1"-..1,"""i1*"s"<br />

ff"jltto*, .*"0 o.te' Hlnasham3had mtalir Asla Naz shari<br />

'Nishar<br />

iiiiiiEt-ii urza ". ana srruna raz st'at'<br />

1"",-"rw ne*atctr ldlitute ol Pharmtceuxcal scloncs I l'b I'<br />

o;prr<strong>in</strong>enl<br />

"ipr'"ma"v, olch€mistrt, univet3'tvol Krrachi haacht 75270 P'kist<strong>tn</strong><br />

A n@l RP-HPLC melhod ,s lhe estimalion ol mfenamic acid <strong>in</strong> rd maleri'l difier€nl<br />

bhamaceutiel dosaoe l<strong>of</strong>ms and <strong>in</strong> human serum io' rculircb analysls' lherapeulc<br />

irroos"s anO tor statit'ry sruO'es Ms deve'oped Presenl w* is elso a cllkclion or<br />

!"i.r o"rr"-"4 - tr'" pr'yo""t ,nd oemical asper ls o're'enarrc acid The m€lhod<br />

;ewooed consl ur€s L_i oDs Io nf, (25 cm x 4 6mm)column sth mobilF Ph'se<br />

;;Br'rd"972s%6@ronit.e, I%a(eric.Ld ?b5%wale'el279ndelul'9oulat42<br />

m<strong>in</strong>ure Th€ 0164l method or HPLC ms also compadd wilh fte UV visible tsnnque<br />

end ir was oljserued thal HPLC melhod is more pGcise, sensitve and accuhle<br />

1<br />

{

---

Ilt<br />

3'7i--<br />

L:; -_I<br />

i'<br />

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---

PR-180<br />

SrEd. Syntl.|b <strong>of</strong> C.lirLln. .nrloeua<br />

shr gnrdbd,, N{if Sdbn', ld<strong>tn</strong> Xrr,r .ut nt, &-a AnF<br />

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r.rr.Fd durr |Id.j.r6ordlrE: i.r b{r tl4!d Tr. ffi <strong>of</strong> itE,t <strong>in</strong>rvtr<br />

wdlmcd b, uj4 |,..ruo|*) !c[r{E,{.6dtelt NMR<br />

cl<br />

'Q*'--*'"<br />

C.ddn.. dllrd r..r |. rd.<br />

Cdnic, dod- 4dE a|*h-a!! II}mL

---

Intenational Clenistry Conference<br />

Recent Advances <strong>in</strong> Chemistry<br />

E-3 Novernbel., aocrT<br />

Lqhore - pqjdsfqn<br />

ABSTRACTS<br />

:GWg HEC csP<br />

{oMr,tNG;" "#i,:iffi.- *"i:Ylitj:.*

---

thtu$ro^t chnbl4 hrf,.zht!- Ruut )tiax! h crt|rj|<br />

I/irro ttrlersction Sludi6 <strong>of</strong>Cetirizirewith Hi Re"Ptor Atrtagorkls<br />

Nltrg SpeFoPhotomctry !id RP-HPLC<br />

N',mSulbn, M. Stad /dvnel<strong>tn</strong>d ltiDr Sbrmthld<br />

i:l;;;i;;i ;;*;io'-d'v D'p'nn'dorPhrnderu'ci'm<br />

Phms. UtrN.i,ry <strong>of</strong> Knd'i<br />

rD.D, ;-' .rck."'ry. !'""i'v ,<br />

q fi'rh o<br />

*:C.ridz<strong>in</strong>c, $cond sd.htio HI d.ptordttsonitt, rs usl fo' rhc rra<strong>tn</strong>c or'llclgn<br />

i'dirodqs. In eh. <strong>of</strong> tlE dis4@ comb<strong>in</strong>cd lheEPv <strong>of</strong> III and Ir2 is lcNrallv norc<br />

fictrdiv. tlE ii the ro'@.r orHr and H2 alone ahhoush rhG svnctsrsric cIlecr b's tol<br />

qtien found i. all studi6 Motovct, dl.nsiw t vD stldier ha!' bd catried dur oi<br />

!: lhe efilcLs <strong>of</strong> coadm<strong>in</strong>ismtion <strong>of</strong>rhe rD tu.ptor antasooist on lhe pnamacok<strong>in</strong>cr:cs<br />

r<strong>tn</strong>d phEn&odynmics <strong>of</strong>lh. Hl tccp@r dilgonisG so i!<br />

i"liln@h w6 adopcd 1o sludy lhe <strong>in</strong>craclion or cctiriznrc wi<strong>tn</strong> comnonlt admrnisteft'l<br />

(hc p'csc'l l)a €r a r/r'<br />

''<br />

| tl2re.plor antagonhls ie c<strong>in</strong>irid<strong>in</strong>c, tuirid<strong>in</strong>c sd f.nordirc <strong>in</strong> simul'r<strong>in</strong>B bodv<br />

i 'nu{s !r diflercnt pH .nd al 3?oc c<strong>in</strong>g RP_HPLC and Uv sD€chpholometv An RP'<br />

Fi. HPLC ncrhod was aho dev.loped and v'lidded for rbe s<strong>in</strong>uhmsus dcrcm<strong>in</strong>rtion or<br />

:l <strong>tn</strong>ce dtuls.--r'hc nobil. phs.onsisred <strong>of</strong>n lhlnol: w!r.r (80:20) punp€d ar, flo*<br />

r.t. ol lmlmirll tlt€ ctuomotostam verc monilcrcd al 210 nm Th. rc$'lb tom llv<br />

spd1tophobmclry and HPLC clc.rly i.dic.kd thal lh. availabilnv ol tclniz<strong>in</strong>c wa{<br />

unnlfc&d bt sn.ulhncou adn<strong>in</strong>islmion <strong>of</strong> H2 reeplor anlalonisl Uctrcc rc lwo<br />

drugs euld bc aar.ly adn<strong>in</strong>islorcd wirb each olher '<br />

'X.y vor.t: Cedriz<strong>in</strong>c, IJI Kcnbr anlrgonist, lI2 rcccp(or mr|gonirr' ci'nitid<strong>in</strong>c,<br />

tuifti.. dd [motid<strong>in</strong>e, i.r.Fcrion sludics, UV spcctoPhobmclry and I II'LC<br />

D.paiad o/

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AB,S RACTS<br />

7'I INTERIATIoNAL &I7,, NATIoNAL<br />

'|{r.€llco.e Tirougi Inrovirion"<br />

Februsry 2G28,2007<br />

Under<br />

Chemical<br />

the auspices<br />

<strong>of</strong><br />

Society <strong>of</strong> Pakistan<br />

Orarnized Bv<br />

Depannant <strong>of</strong>Ch;mtutrv<br />

comrl Udversitv.<br />

Dem Isnall Xhrn (NwFijpikisran

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tionrl o.udrt .rntafut,. Pa <strong>tn</strong>t,<br />

OP4IMIZ4TION OF QU NTITATIV!] ANALYSIS oT<br />

CEI'IRJZINE USING MULTIVARTATE SPECIR^L<br />

CALIBDITTONS IN BULK DRUG AND DOSAGE<br />

TORMUL TIONS<br />

N.jmnsuirano , M, Saed Aiay.e, and H<strong>in</strong>! Shamshad'<br />

Itrrcmch lnslitute <strong>of</strong> Phameeuljcrt Scicnc.s, Fncllry ot ph nrcy,<br />

UilvcNity ol Kdrochi. K,rachi.7527O. prkhlan.<br />

Dcplnmcnt <strong>of</strong>Chcmlsrry, Univcail! ot Xtlch , Kuraohr.75270, prtrr|i0j<br />

A !implc muhvsare sp€crmt cahbr on Incrt,oJ t4r rne quJnrnr,,\(<br />

rnrlysj! ol ccuhz'nc wrs ,leyctopcJ ,t hJr bccn loDpaEJ wnh rh.<br />

llNicll ull'rvnt.r sp.dmphoromerric ftrhoJs tor rhe 6umalor ul<br />

@dnnm.Thc n.thod was d€vctop€! <strong>in</strong> butf.^ <strong>of</strong> sjmutarcd sasrncju,cc<br />

dd r<strong>in</strong>uh@d blood pH. Th. I'n* Egrssion cqurlon wJs uscd d ',vc<br />

dfl.rcnr wJv.i.n8rhs. To lrtidlc '<strong>tn</strong>s n.rhoJ. <strong>in</strong>Jbnc,,t prtumere s<br />

luci 6 siccrrvr). 4-Jii!) MJ pr.rkiun ho\e beer e{rbhJco lrl<br />

djlfcrcnt br.nG <strong>of</strong> tobleb and have b.cD .yatoitcd datsricany ro r$e$<br />

lh. eplic!rion <strong>of</strong> rhe nrrhod. This ncthod js rupid,c$y, rnexpensive dxl<br />

a powcdui t@l wnh very s<strong>in</strong>pie ndrhcmuricut ;onb ; ror sy(ems. Thc<br />

mrhod hos bem jourd ro hJ\e ,,t\.ntJ8c tor ,,mp,r.r.). j..ti,,r.).<br />

rnririvtry l0 56,-B), rrpndu! 'b'hry,n-lO, !nd rcdfu, tor E.r3 L\cL: \<br />

rn .rcnrlc to rhe crisr<strong>in</strong>g ,nermnhnromrnc mcrtroJs ro, rtc rrrtr,.<br />

aialysis ot ti. drg ns ph@@dcat tomutarjons and for cknical<br />

dudi6. Euivalcrce uudie we4 dso pcrfomcd ror difaeEm btunds ol<br />

cdniz<strong>in</strong>c rvail$lc <strong>in</strong> Pnkishn