2.2. BSA–VLM cocrystal (1:1)  

BSA (100 mg, 0.636 mmol) and VLM (63 mg, 0.636 mmol) were ground well in a mortar and pestle for 20–30 min by adding 4–7 drops of EtOAc (liquid-assisted grinding or LAG; Shan et al., 2002 ; Trask & Jones, 2005 ; Friščić et al., 2006 ). The ground material was kept for crystallization in 5 ml of an EtOAc–THF mixture as well as in individual solvents at room temperature. Good diffraction-quality crystals were harvested under ambient conditions after 3–4 d; m.p. 79–81°C.

2.3. BSA–CPR cocrystal (1:1)  

BSA (100 mg, 0.636 mmol) and CPR (72 mg, 0.636 mmol) were ground well in a mortar and pestle for 20–30 min by adding 4–7 drops of EtOAc. The ground material was kept for crystallization in 5 mL of an EtOAc–THF solvent mixture as well as in individual solvents in a 25 ml conical flask at room temperature. Good quality crystals were harvested under ambient conditions after 3–4 days; m.p. 80–83°C.

2.4. BSA–AZL (1-aza-2-cyclooctanone) cocrystal (1:1)  

BSA (100 mg, 0.636 mmol) and AZL (80.87 mg, 0.636 mmol) were ground well in a mortar and pestle for 20–30 min by adding 4–7 drops of EtOAc. The ground material was kept for crystallization in 5 mL of an EtOAc–THF mixture as well as individual solvents in a 25 ml conical flask at room temperature. Good quality crystals were harvested under ambient conditions after 3–4 days; m.p. 76–81°C.

2.5. 2ClBSA–VLM, 4ClBSA–VLM cocrystal (1:1)  

ClBSA isomer (100 mg, 0.521 mmol) and VLM (51.6 mg, 0.521 mmol) were ground well in a mortar and pestle for 20–30 min by adding 5 drops of EtOAc. The ground material was kept for crystallization in 5 mL of an EtOAc–THF mixture as well as individual solvents at room temperature. Single crystals were harvested under ambient conditions after 3–4 d; m.p. 80–82°C; 90–91°C

2.6. 2ClBSA–CPR, 4ClBSA–CPR cocrystal (1:1)  

ClBSA isomer (100 mg, 0.521 mmol) and CPR (59 mg, 0.521 mmol) were ground well in a mortar and pestle for 20–30 min by adding 5 drops of EtOAc. The ground material was kept for crystallization in 5 mL of an EtOAc–THF mixture, as well as separate solvents at room temperature. Single crystals were harvested under ambient conditions after 3–4 d; m.p. 80–82°C; 82–83°C.

2.7. 4BrBSA–VLM cocrystal (1:1)  

4BrBSA (100 mg, 0.423 mmol) and VLM (51.6 mg, 0.423 mmol) were ground well in a mortar and pestle for 20–30 min with solvent assistance by adding 4–7 drops of EtOAc. The ground material was kept for crystallization in 5 mL of an EtOAc–THF mixture, as well as individual solvents at room temperature. Single crystals were harvested under ambient conditions after 3–4 d; m.p. 92–94°C.

2.8. 4BrBSA–CPR cocrystal (1:1)  

4BrBSA (100 mg, 0.423 mmol) and CPR (58.95 mg, 0.423 mmol) were ground well in a mortar aand pestle for 20–30 min through solvent-assisted grinding by adding 5 drops of EtOAc. The ground material was kept for crystallization in 5 mL of EtOAc–THF mixture as well as separate solvents. Single crystals were harvested at ambient conditions after 3–4 days; m.p. 90–92°C.

2.9. OTSA–VLM, PTSA–VLM cocrystal (1:1)  

OTSA/PTSA (100 mg, 0.584 mmol) and VLM (57.89 mg, 0.584 mmol) were ground well in a mortar and pestle for 20–30 min through solvent-assisted grinding by adding 5 drops of EtOAc. The ground material was kept for crystallization in 5 mL of an EtOAc–THF mixture as well as separate solvents. Single crystals were harvested under ambient conditions after 3–4 days; m.p. 70–72°C; 74–75°C.

2.10. SNA–VLM, 2ABSA–VLM cocrystal (1:1)  

SNA/2ABSA (100 mg, 0.580 mmol) and VLM (65.63 mg, 0.580 mmol) were ground well in a mortar and pestle for 20–30 min through solvent-assisted grinding by adding 5 drops of EtOAc. The ground material was kept for crystallization in 5 mL of an EtOAc–THF mixture as well as separate solvents. Single crystals were harvested at ambient conditions after 3–4 d; m.p. 95–97°C, 87–91°C.

2.11. Single-crystal X-ray diffraction  

A single crystal obtained from the crystallization experiment was mounted on the goniometer of an Oxford Diffraction Gemini X-ray diffractometer equipped with an Mo Kα radiation source (λ = 0.71073 Å). Data reduction was performed using CrysAlisPro 171.33.55 software. The crystal structure was solved and refined using Olex2-1.0 with anisotropic displacement parameters for non-H atoms. H atoms were experimentally located through the difference-Fourier electron density maps in all crystal structures. Data was reduced by SAINT-Plus (Bruker, 1998 ) and further continued with SHELXTL (Sheldrick, 2008 ). A check of the final crystallographic information file (CIF) with PLATON (Spek, 2009 ) did not show any missed symmetry. X-Seed was used to prepare the figures and packing diagrams. Crystallographic parameters of all the cocrystals are summarized in Table 2 . Hydrogen bond distances (see Table S1 of the supporting information) are neutron-normalized (O—H 0.983, N—H 0.82, C—H 1.083 Å). CIF files are also deposited with the CCDC (Nos. 1039188–1039200).

Table 2

Crystallographic data summary and classification of sulfonamidecarboxamide cocrystals and isostructurality (see Table 3 for full crystallographic data)

S. No.	Cocrystal	Cell parameters (a, b, c, in )	Crystal system	Synthon observed
1	BSAVLM	a = 7	Orthorhombic, P212121
2	BSACPR
3	4ClBSACPR	b = 1213		Synthon 1
4	4BrBSACPR	c = 1415		Catemer chain
5	SNACPR
6	4ClBSAVLM	a = 25	Monoclinic, C2/c
7	4BrBSAVLM	b = 7
		c = 19
8	2ABSACPR	a = 7	Monoclinic, P21/n	Synthon 2
9	BSAAZL	b = 1617		DimerCyclic ring
		c = 1213
10	2ClBSAVLM	a = 910	Monoclinic, P21/c	Synthon 3
11	2ClBSACPR	b = 1314		DimerCatemer
		c = 10
12	PTSAVLM	a = 5	Monoclinic, P21/n
		b = 16
		c = 16
13	OTSAVLM	a = 5	Triclinic,
		b = 8
		c = 16

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Some single-crystal diffraction data were collected at 298 K on a Bruker SMART APEX-1 CCD area-detector system equipped with a graphite monochromator, Mo Kα fine-focus sealed tube (λ = 0.71073 Å) operated at 1500 W power (40 kV, 30 mA). The frames were integrated with SAINT (Bruker, 1998 ) software using a narrow-frame integration algorithm. Data was corrected for absorption effects using the multi-scan method (SADABS; Bruker, 1998 ). The structure was solved and refined using SHELXTL (Sheldrick, 2008 ).

2.12. X-ray powder diffraction  

Bulk samples were analyzed by X-ray powder diffraction on a Bruker AXS D8 diffractometer (Bruker-AXS, Karlsruhe, Germany). Experimental conditions: Cu Kα radiation (λ = 1.54056 Å); 40 kV; 30 mA; scanning interval 5–50° 2θ at a scan rate of 1° min⁻¹; time per step 0.5 s. The experimental PXRD patterns of the BSA, 4Cl BSA and 4Br BSA cocrystals were compared to confirm the isostructurality (Fig. S4 of the supporting information).

3.2. Synthon 1, catemer chain  

Among the 13 cocrystal structures studied (Table 1 ), seven structures contain the sulfonamide–syn-carboxamide catemer synthon of C ₂ ¹(4) notation. The catemer chains are assembled by sulfonamide N—H donors hydrogen bonding to the carboxamide acceptor. The structures are isostructural upon altering the auxiliary functional groups of benzene sulfonamide, such as Cl/Br/NH₂/CH₃. BSA–VLM and BSA–CPR have the same unit-cell parameters, whereas p-substituted BSA molecules (such as 4ClBSA, 4BrBSA and SNA) showed a 0.5 Å increase in the crystallographic b- and c-axis. BSA–VLM, BSA–CPR, SNA–CPR, 4ClBSA–CPR and 4BrBSA–CPR are three-dimensional isostructural. There are two more sets of isostructural cocrystals, 4ClBSA–VLM and 4BrBSA–VLM, with the same synthon.

3.2.1. BSA–VLM, BSA–CPR, SNA–CPR, 4 ClBSA–CPR and 4BrBSA–CPR (1:1)  

The crystal structures of all these multi-component systems were refined in the orthorhombic space group P2₁2₁2₁. The sulfonamide NH₂ donates an N—HO hydrogen bond to both sides of the carbonyl group of the lactam acceptor in the synthon 1 catemer (Fig. 4 a). The hydrogen-bonded C(4) chain runs along the a-axis and in a corrugated sheet-like structure parallel to the (011) plane (Fig. 4 , Fig. S1) and exhibits three-dimensional isostructurality in crystal packing.

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Figure 4

Crystal structures of sulfonamide–lactam cocrystals with catemer synthon 1. Two-dimensional packing diagrams are drawn with the asymmetric unit showing benzene sulfonamides (in green) and lactams (in blue) (VLM, CPR).

3.3. Synthon 2, dimer–cyclic ring  

3.3.1. BSA–AZL cocrystal (1:1)  

The crystal structure was refined in the monoclinic space group P2₁/n. Glide-related sulfonamide molecules are flanked between dimers of lactam through N—HO (N1—H1BO3: 2.12 Å, 158°; N1—H1AO3: 2.03 Å, 158°) hydrogen bonds (sulfonamide NH donors) to give R ₂ ²(8)R ₄ ²(8) ring motif synthon 2 (Figs. 5 a and b), similar to that in N-oxide cocrystals (Goud et al., 2011 ). The structural units extend along the a-axis in a one-dimensional pattern. The meta H atoms of BSA form C—HO interactions with S=O along the a-axis (Fig. 5 c) resulting in corrugated layers of sulfonamide chains separated by coformer molecules (Fig. S2).

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Figure 5

Dimer–cyclic synthon 2 in cocrystals BSA–AZL, 2ABSA–CPR and two-dimensional layer packing. Two-dimensional packing diagrams are drawn with the asymmetric unit showing benzene sulfonamides (in green) and lactams (in blue) (VLM, CPR).

3.4. Synthon 3, dimer–catemer  

3.4.1. ClBSA–VLM cocrystal (1:1)  

Equimolar quantities of the components were ground and crystallized from EtOAc to give single crystals which were solved in the monoclinic space group P2₁/c. Catemer chains connect glide-related 2ClBSA molecules that assemble via homodimers of VLM through N—HO (N1—H1AO3 = 2.03 Å, 169°) hydrogen bonds in synthon 3, or dimer–catemer synthon R ₂ ²(8)C ₁ ¹(4)D (Figs. 6 a and b). In this synthon the coformer dimers are sandwiched between sulfonamide catemer chains. Halogen bonding (ClO, ClN) provides auxiliary support to the structure (Metrangolo et al., 2005 , 2008 ; Saha & Nangia, 2007 ; Desiraju, 1989 ; Mukherjee et al., 2014 ). The catemer chains of 2ClBSA extend along the c-axis and homodimers of VLM connect adjacent chains of sulfonamides via C—HO interactions to make two-dimensional stacks in the ab-plane (Fig. 6 c).

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Figure 6

Dimer–catemer synthon 3 in cocrystals 2ClBSA–VLM, 2ClBSA–CPR, OTSA–VLM, PTSA–VLM and two-dimensional hydrogen bond motifs. Two-dimensional packing diagrams are drawn with the asymmetric unit showing benzene sulfonamides (in green) and lactams (in blue) (VLM, CPR).

3.5. Isostructural and isomorphous systems  

Two crystals are said to be isostructural if they have the same structure, but not necessarily the same unit-cell dimensions nor the same chemical composition, with a comparable variability in the atomic coordinates to that of the cell dimensions and chemical composition (IUCr, 2014 ). Isostructurality depicts the arrangement of different molecules in a similar way in the crystal structure, but not necessarily their unit-cell parameters (Fábián, Argay & Kálmán, 1999 ; Fábián & Kálmán, 1999 , 2004 ; Kitaigorodsky, 1961 ). Certain substituents in the molecule can be replaced with others without altering the crystal packing as well as cell values and the space group (Brink & Kroese, 1952 ; Perutz, 1956 ; Kroon et al., 1965 ; Sauer et al., 1997 ; Dikundwar et al., 2012 ). Such a functional group exchange leads to isostructural and isomorphous crystal structures (Berzelius, 1844 ; Melhado, 1980 ; Mitscherlich, 1822 ; Morrow, 1969 ). The recent literature on molecular cocrystals (Cinčić et al., 2008a ,b ; Dubey & Desiraju, 2014 ) and pharmaceutical multi-component systems, e.g. lamotrigine and olanzapine cocrystals and salts, provide examples of isostructurality (Ebenezer et al., 2011 ; Galcera et al., 2012 , 2013 ; Galcera & Molins, 2009 ; Clarke et al., 2012 ; Thakuria & Nangia, 2013 ; Chitra et al., 2012 ). The importance of isostructurality is that similar cocrystals can be designed depending on the geometry and shape and molecular composition of the starting materials. Isostructurality is also a useful guide in the crystal structure prediction of multi-component systems (Schmidt, 1971 ; Desiraju, 1989 ; Braga et al., 1998 ; Desiraju et al., 2011 ). Different guest molecules may be incorporated into the host lattice without substantially changing the crystal structure, i.e. isostructurality. The formation of isostructural cocrystals with the same synthon (isosynthon) and this study of sulfonamides with VLM, CPR shows how synthon similarity can lead to isostructural cocrystals (Fig. 3 ). There are four sets of isostructural cocrystals along with three types of synthons found in this set of cocrystals. Interestingly, a unique set of isostructural cocrystals shows isosynthons. Out of the 13 cocrystal structures in this study, four contain the dimer–catemer synthon, two result in the dimer–cyclic motif and seven gave the catemer synthon. Synthon 1 cocrystals exhibit two isostructural sets: set one of BSA–VLM, BSA–CPR, 4ClBSA–CPR, 4BrBSA–CPR, SNA–CPR and set two cocrystals 4ClBSA–CPR and 4BrBSA–CPR. These are three-dimensional isostructural systems and show isostructurality due to the Cl/Br/NH₂ exchange (functional group) and VLM/CPR (homolog; Table 4 ). Further, the same trend continues for synthons 2 and 3 cocrystal sets also, i.e. isostructurality for Cl/Br and VLM/CPR. Furthermore, despite changes in molecular structures, the PXRD line patterns of synthon 1 cocrystals match quite well (Fig. S4) confirming their isomorphous nature.

Table 4

Unit-cell similarity index () of cocrystals

Cocrystal†	Crystal system/space group	Cell values	Cell values summation
BSAVLMa	Orthorhombic, P212121	7.104, 12.793, 14.030	33.928	0.0253
BSACPRa		7.070, 12.762, 14.977	34.809
4ClBSACPRa		7.156, 13.369, 15.276	35.801	0.0082
4BrBSACPRa		7.156, 13.538, 15.406	36.100
SNACPRa		7.095, 13.128, 15.342	35.566	0.0147 (SNACPR, 4BrBSACPR)
4ClBSAVLMb	Monoclinic, C2/c	25.701, 6.809, 19.177	51.900	0.0016
4BrBSAVLMb		25.914, 6.8687, 19.202	51.984
2ClBSAVLMc	Monoclinic, P21/c	10.521, 13.7661, 10.340	34.627	0.0085
2ClBSACPRc		9.878, 14.172, 10.875	34.925
2ABSACPRd		7.273, 15.905, 12.776	35.954	0.0223
BSAAZLd		7.302, 17.189, 12.2835	36.774

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^† a, b, c, d are the different isomorphous systems as detailed in Table 1 .

Isostructurality was calculated on the basis of unit-cell parameters. Monoclinic and orthorhombic crystal structures show the unit-cell similarity index goes to zero (isostructurality) (see Table 2 )

where a, b, c and a′, b′, c′ are orthogonalized lattice parameters of the related structures.

3.6. Classification of sulfonamide synthons  

A survey of the Cambridge Structural Database (CSD, Version 5.36, 1 November 2014 update; Allen, 2002 ) furnished 220 hits of primary sulfonamides (after eliminating hydrates, solvates, salts and duplicates) and 2160 hits of secondary sulfonamides (Table 5 ). These reported structures were analyzed to classify the known supramolecular synthons for sulfonamides and named as the anti catemer, syn catemer, finite catemer; continuous dimers, alternative dimers (Fig. 7 b), dimers making rings, finite dimers; tetramers, three point synthons, and finally a miscellaneous cluster of mixed motifs (Fig. 7 , CSD refcodes are provided in Table S2). The presence of multiple donors/acceptors on the SO₂NH₂ group together with conformational flexibility (syn/anti) leads to many possible hydrogen bond synthons. In contrast, the syn amides are more predictable and show mainly dimer and to a lesser extent catemer synthons. The synthons in Fig. 7 (c) suggest that the known heterosynthon between sulfonamide and N-oxide may be replaced by amide with the same graph set to provide a crystal engineering strategy for sulfonamide–carboxamide cocrystals.

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Figure 7

(a) Classification of primary sulfonamide synthons reported in CSD and (b) their hydrogen bonding and frequency. (c) Synthons in cocrystals of primary sulfonamides with N-oxides and amides. The latter analysis suggests that sulfonamide–N-oxide synthons may be replaced by syn-amides to give a new strategy for sulfonamide–carboxamide cocrystals.

A CSD search for the binary systems (cocrystals) furnished 33 hits for primary sulfonamides and 39 hits for secondary sulfonamides along with the starting materials of this study (Fig. S5). The almost equal numbers of primary and secondary sulfonamide cocrystals means that there are no steric issues with cocrystal assembly. Among the primary sulfonamide cocrystals, there are a few N—HO hydrogen-bonded structures with amides, e.g. celecoxib-valerolactam trimorphs and nicotinamide cocrystals (see Fig. 7 ). Among the primary sulfonamide drugs, celecoxib, furosemide, acetazolamide and hydrochlorothiazide are notable for making cocrystals with amide coformers (Bolla et al., 2014 ; Harriss et al., 2014 ; Ueto et al., 2012 ; Arenas-García et al., 2010 ; Sanphui & Rajput, 2014 ; Remenar et al., 2007 ), e.g. nicotinamide, isonicotinamide and picolinamide with different sulfonamide–amide syn­thons (see Fig. S9).

There are 2046 sulfonamides in the CSD but only 72 binary systems (cocrystals) in the CSD. The fewer number of sulfonamide cocrystals compared to say those for carboxylic acids and amides could be due to the enthalpy penalty for disrupting the strong sulfonamide homosynthon in the parent crystal structures with an even stronger hydrogen bond in the cocrystal. The activated oxygen acceptor of N-oxides, and to a lesser extent carboxamide functional groups, has been successfully used for sulfonamide cocrystals. The present study presents a crystal engineering approach to sulfonamide–carboxamide cocrystals analogous to the sulfonamide–pyridine-N-oxide heterosynthon.

GB and SM thank the UGC for a fellowship. We thank the DST-SERB scheme on APIs (SR/S1/OC 37/2011), JC Bose Fellowship (SR/S2/JCB-06/2009) and CSIR project on Pharmaceutical Cocrystals (01-2410/10/EMR-II) for funding. UGC and DST (UPE and PURSE funding) are thanked for providing instrumentation and infrastructure facilities.