Binary and ternary cocrystals of sulfa drug acetazolamide with pyridine carboxamides and cyclic amides

The first report of a ternary cocrystal acetazolamide–nicotinamide–pyridone (1:1:1) for a sulfonamide drug with amide coformers.


Introduction
Hydrogen bonding is the key adhesive to construct supramolecular synthons for the design of crystalline architectures by using multiple functional groups (Desiraju, 1995). From a crystal engineering perspective, binary and ternary adducts are formed due to robust heterosynthons in the cocrystal, compared with homosynthons in the constituent molecules (Walsh et al., 2003). It has been shown over more than a decade that crystal engineering of multi-component phases offers rational approaches to systematically tune the physicochemical and pharmacokinetic properties of active pharmaceutical ingredients (APIs, Fig. 1). The matching of functional groups and supramolecular synthons together with size and shape factors of molecules offers an approach to assemble three different molecules in the same crystal lattice (Tothadi & Desiraju, 2013Chakraborty et al., 2014;Aakerö y et al., 2001Seaton et al., 2013;Aitipamula et al., 2013). Ternary cocrystals are relatively less studied and the sulfonamide group is a 'structural gap', even as SO 2 NH 2 is the key functional group in the most populated sulfa drugs category. These considerations encouraged us to systematically study binary and ternary cocrystals of the sulfonamide group . The assembly of three different molecular components in the same crystal lattice is challenging because it hinges on a balance of intermolecular interaction strengths, chemical recognition, geometric fit and overall shape complementarity (Tothadi & Desiraju, 2013). There is more than one possible outcome of a three-component cocrystalli-zation; it may result in one of the components, its solvates or hydrate, a new polymorph of the molecule, binary systems, starting materials, or the ternary product (Fig. 1).
Recent success in the deliberate construction of ternary cocrystals  and our work on binary sulfonamide cocrystals (Bolla et al., 2014 served as the background for the present study. The Cambridge Structural Database (CSD version 5.36, May 2105 update) contains about 75 X-ray crystal structures of ternary systems. Recently, we reported the assembly of ternary components using amides and the sulfonamide group along with a carboxylic acid . In the present work, the sulfonamide and acetamide groups of acetazolamide are the starting point to demonstrate the sulfonamide-lactam supramolecular synthon for the assembly of ternary systems.

Experimental
All the coformers used in this study were purchased from Sigma-Aldrich, India. All chemicals are of analytical and chromatographic grade. Acetazolamide was purchased from Yarrow Chemicals, Mumbai, India, and its purity was confirmed by NMR and DSC.
2.1. ACZ-NAM (1:1) ACZ (100 mg, 0.45 mmol) and NAM (54 mg, 0.45 mmol) were ground well in a mortar and pestle for 20-30 min by adding 4-5 drops of EtOAc. The ground material was kept for crystallization from a solvent mixture of EtOAc and THF (5 ml) as well as in individual solvents in a 25 ml conical flask at room temperature. Good quality crystals were harvested at ambient condition after a week; m.p. 180 C. Chemical structures of ACZ as A, coformers pyridine carboxamides and syn-amides, aromatic COOH compounds as B and C used in cocrystallization.

Figure 1
Multiple possibilities of solid forms during cocrystallization to give single, binary and ternary products.

ACZ-VLM (1:2)
ACZ (100 mg, 0.45 mmol) and VLM (45 mg, 0.45 mmol) were taken in a 1:1 ratio and ground well in a mortar and pestle for 20-30 min by adding 4-5 drops of EtOAc. The ground material was kept for crystallization in EtOAc (5 ml) at room temperature. Good quality crystals were harvested at ambient conditions after a week. Even though the components were taken in an equal molar ratio, the product crystallized in a 1:2 ratio from solution; m.p. 93 C.
2.3. ACZ-CPR hydrate (1:1:1) ACZ (100 mg, 0.45 mmol) and CPR (50 mg, 0.45 mmol) were taken in a 1:1 ratio and 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 from a solvent mixture of EtOAc and THF (5 ml) as well as individual solvents at room temperature. The ground material crystallized from solution as a hydrate after one week; m.p. 80 C. Solvents used here are analytically pure and crystallization was carried out at room temperature (ca 30 C) in an open evaporation flask, which gave the cocrystal hydrate product.

ACZ-2HP (1:2)
ACZ (100 mg, 0.45 mmol) and 2HP (42 mg, 0.45 mmol) were taken in a 1:1 ratio and 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 from a solvent mixture of EtOAc and THF (5 ml) as well as individual solvents at room temperature. Good quality crystals were harvested at ambient conditions after a week. The ground material crystallized from solution in a 1:2 ratio; m.p. 160 C.

ACZ-2HP (1:1)
ACZ (100 mg, 0.45 mmol) and 2HP (42 mg, 0.45 mmol) were ground well in a mortar and pestle for 20-30 min by adding 4-7 drops of EtOAc in the presence of NAM or INA to obtain a ternary system. Even though the attempts to obtain an ACZ binary cocrystal with isonicotinamide (INA) were not successful, experiments were carried out to obtain a ternary ACZ-INA-2HP adduct in a trial attempt. A binary product ACZ-2HP (1:1) was obtained. A unit cell check of randomly selected crystals showed that the majority are ACZ-2HP (1:1), while a few crystals had 1:2 stoichiometry. The ground material of 1:1 stoichiometry was kept for crystallization from a solvent mixture of EtOAc and THF (5 ml) as well as individual solvents at room temperature. Good quality crystals were harvested at ambient condition after a week; m.p. 180 C.
2.6. ACZ-MeHP (1:1) ACZ (100 mg, 0.45 mmol) and MeHP (49 mg, 0.45 mmol) were ground well in a mortar and pestle for 20-30 min. The ground material was kept for crystallization in 5 ml of EtOAc at room temperature to obtain good quality single crystals at ambient conditions after 1 week; m.p. 130 C.

Single-crystal X-ray diffraction
A single crystal was mounted on the goniometer of an Oxford Diffraction Gemini X-ray diffractometer equipped with Cu K radiation source ( = 1.54184 Å ) at 298 K. Data reduction was performed using CrysAlisPro 171.33.55 software (Oxford Diffraction, 2008). The crystal structure was solved and refined using Olex2-1.0 (Dolomanov et al., 2009) 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 were reduced by SAINT-Plus (Bruker, 1998) and further continued with SHELXTL (Sheldrick, 2008). A check of the final CIF file with PLATON (Spek, 2009) did not show any missed symmetry. X-Seed (Barbour, 2001) was used to prepare the figures and packing diagrams.
The crystallographic parameters of all the cocrystals are summarized in Table 1 and hydrogen-bond distances are listed in Table S1. CIF files are deposited at CCDC Nos. 1436978-1436985. Single-crystal Xray diffraction data were also collected at 298 K on a Bruker SMART APEX-1 CCD areadetector system equipped with a graphite monochromator Mo K fine-focus sealed tube ( = 0.71073 Å ) operating at 1500 power, 40 kV, 30 mA. The frames were integrated by SAINT (Bruker, 1998) software using a narrow-frame integration algorithm. Data were corrected for absorption effects using the multiscan method (SADABS; Bruker, 1998). The structures were solved and refined using SHELXTL (Sheldrick, 2008).

Crystal structures of binary cocrystals
The crystal structure parameters are summarized in Table 1 and hydrogen-bond parameters in Table S1 of the supporting information. The synthons and molecular packing of binary cocrystals is presented first and then the build up to the ternary system is described.  3.2.1. ACZ-NAM (1:1). The cocrystal structure (space group P1) contains N-HÁ Á ÁN homodimers R 2 2 ð8Þ of ACZ, similar to those observed in polymorph (II). However, the sulfonamide dimer of ACZ is replaced by N-HÁ Á ÁO and N-HÁ Á ÁN hydrogen bonds to nicotinamide. Two ACZ and two NAM molecules form a tetramer ring motif R 4 4 ð16Þ via N-HÁ Á ÁO and N-HÁ Á ÁN hydrogen bonds (Fig. 4a). The overall structure has a layered two-dimensional pattern (Fig. 4b).
3.2.2. ACZ-VLM (1:2). In the crystal structure (P2 1 /c) VLM forms a R 2 2 ð9Þ motif of sulfonamide, thiadiazole and amide groups (Fig. 4c). A second equivalent of VLM connects such heterosynthon units via N-HÁ Á ÁO hydrogen bonds. Such onedimensional chains extended parallel to the c-axis via N-HÁ Á ÁO hydrogen bonds in a two-dimensional array (Fig. 4d). The inclusion of a second VLM in the cocrystal structure suggested that if this latter molecule could be replaced by a different amide, then a ternary system will result. In other words, the binary system has a tendency to include a third partner from solution. The same phenomenon is observed in the next structure.
3.2.3. ACZ-CPR hydrate (1:1:1). The ground material of ACZ and CPR in a 1:1 ratio was crystallized as a hydrate (1:1:1) in space group P1. CPR homodimers R 2 2 ð8Þ are sandwiched between the SO 2 NH 2 and water molecules in a R 4 4 ð12Þ ring motif (Fig. 4e). Such discrete clusters extend via the water O-H donor (Fig. 4f). Even though the water is serendipitously included, it makes three components in the crystal lattice.
3.2.5. ACZ-2HP (1:1). The cyclic ring motifs, such as the N-HÁ Á ÁN dimer of ACZ polymorphs (Figs. 3a and b), are interrupted in the presence of 2HP to give an amide-imino-diazole R 2 2 ð8Þ motif (Fig. 4i), similar to the previous structure. The extended motifs via N-HÁ Á ÁO catemer chain C(4) in this structure (Fig. 4j) obviate the need for the 2HP dimer noted in the 1:2 structure (Fig. 4g). This binary structure suggests that 2HP should be a good partner for ternary assembly because the crystal structure is heavily disturbed compared with the ACZ structure, as well as other cocrystals. Moreover, both 1:1 and 1:2 combinations were routinely observed. A strong heterodimer between the two components is a prerequisite for ternary assembly (Aakerö y et al., 2001;Aakerö y & Salmon, 2005). The presence of the symmetry-independent 2HP dimer in the 1:2 structure appears to be optional and it could be replaced by another component of similar size, shape and hydrogen-bonding groups to yield a ternary cocrystal. We note that there is a similar NAM amide dimer in the ACZ-NAM (1:1) structure (Fig. 4a) and this gives a logical lead towards the ternary combination.
3.2.7. ACZ-OMeHP hydrate (1:1:1). The ground product of ACZ and OMeHP in a 1:1 ratio crystallized as a hydrate (1:1:1) in space group P1. The dimer of ACZ diazole and OMeHP amide in ring motif R 2 2 ð8Þ (Fig. 3a) and water molecules connect such units (Fig. 4m) in the inter-layer region (Fig. 4n). It appears that the inclusion of water was mandated as a spacer between the ACZÀOMeHP dimer units to accommodate the OMe group. This means that the bonding between ACZ and 2HP is strong enough to override steric groups which were overcome by the inclusion of a water molecule in the binary cocrystal.
The above crystal structures are described in the natural sequence of crystallization being carried out and the experimental results analyzed.

Crystal structure of ternary cocrystal ACZ-NAM-2HP
(1:1:1) After screening several binary combinations and their crystal structures, we have decided to replace the second equivalent of the coformer in ACZÀ2HP (1:2) with NAM, given that nicotinamide can form an amide R 2 2 ð8Þ dimer similar to 2HP. Moreover such dimers are present in ACZ-NAM (1:1). Grinding of ACZ, NAM and 2HP in an equimolar ratio and recrystallization of the crystalline product gave the ternary cocrystal ACZ-NAM-2HP, as confirmed by single-crystal X-ray diffraction (1:1:1 stoichiometry). The ternary cocrystal structure has resem-research papers IUCrJ (2016). 3, 152-160 Bolla and Nangia Cocrystals of sulfa drug acetazolamide 157 Figure 5 (a) Synthons in ternary cocrystal ACZ-NAM-2HP (1:1:1). The macrocycle ring motif R 2 2 ð20Þ of ACZ are novel to the ternary structure and NAM further extends these units with hydrogen bonding to the dimers of 2HP. (b) Two-dimensional packing of the ternary cocrystal shows that ACZ molecules (green) are separated by NAM and 2HP (blue, red). blances with the binary structure ACZ-2HP (1:2) as expected. Hydrogen bonds between the sulfonamide NH and acetamide C O groups of ACZ result in dimer pairs R 2 2 ð20Þ (Fig. 5a), which were noted previously in polymorph (I) of ACZ as well as in ACZÀ2HP (1:2). The R 2 2 ð8Þ dimers of 2HP are also present here. The link between these ring motifs is that the amide NH of ACZ bonds to the pyridine N of NAM and the NH of NAM is bonded to the 2HP amide dimer. Thus, while the A and C dimers are repeating motifs, the linkage through the B molecule is somewhat different in the ternary structure compared with the previous binary cocrystals. Propagation of the centrosymmetric motifs via N-HÁ Á ÁO and N-HÁ Á ÁN hydrogen bonds is shown in Fig. 5(b). There is considerable 'carry over' of synthons from the binary to the ternary cocrystal, yet there are unexpected motifs as well. Overall, the element of design and crystal engineering appears to be a consistent thread in this family of structures.

Supramoleculer synthons in this study
The three hydrogen bonding sites in ACZ are acetamide (donor-acceptor), sulfonamide group (donor-acceptor) and thiadiazole ring (acceptor only) (Fig. 6a) The main stream of our approach and objective was to understand the long-range synthon Aufbau modules (LSAM; Ganguly & Desiraju, 2010;Mukherjee et al., 2014a,b) in the ternary cocrystals . However, because we were successful in crystallizing only a single ternary structure in this family, a supramolecular build-up or LSAM model for the ternary assembly of ACZ is difficult to analyze due to insufficient data. The ternary cocrystal suggests the ACZ amide bonds with NAM pyridine via N-HÁ Á ÁN and the Hydrogen-bonding synthons of ACZ observed in this study. (a) Molecular diagram showing the hydrogen bonding groups as rigid or flexible (according to Arenas-García et al., 2010, 2012. (b) Synthon 1 between the acetamide and thiadiazole ring of ACZ with carboxylic acid, carboxamide, syn-amide, respectively. (c) Synthon 2 between the sulfonamide group of ACZ and pyridine carboxamides, e.g. NAM, PAM, to give large ring motifs. (d) Synthon 3 connects sulfonamide, thiadiazole N and lactam conformer C. The graph-set notations of ring motifs are given for identification.

Figure 8
Different types of (a) sulfonamide-amide, (b) sulfonamideÀpyridine and (c) sulfonamideÀacid supramolecular synthons. programs) are thanked for providing instrumentation and infrastructure facilities.