Multiple Crystal Forms of p‑Aminosalicylic Acid: Salts, Salt Co-Crystal Hydrate, Co-Crystals, and Co-Crystal Polymorphs Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju Pramod Kumar Goswami, † Ram Thaimattam,* ,‡ and Arunachalam Ramanan* ,† † Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi-110016, India ‡ Ranbaxy Laboratories Ltd., Chemical Research, Plot-20, Sector-18, Udyog Vihar Industrial Area, Gurgaon-122015 (Haryana), India * S Supporting Information ABSTRACT: Crystallization of p-aminosalicylic acid, an anti- tuberculosis drug, in the presence of pyridine derivatives as coformers led to formation of nine multicomponent solids that include salts, a salt co-crystal hydrate, co-crystals, and co-crystal polymorphs. Seven of them are new solid forms. The influence of the COOH···N heterocycle synthon is examined in dictating the various crystal forms, the manifestation of which depends on solvent of crystallization and API-coformer composition in solution. ■ INTRODUCTION Active pharmaceutical ingredient (API) co-crystals have demonstrated the ability to modify physicochemical properties of the APIs. 1 p-Aminosalicylic acid (PAS) is a well-known antibiotic in tuberculosis (TB) treatment and also a promising anticancer drug. 2 Recently, there is a renewed interest in obtaining the multicomponent crystals based on this molecule to explore its solid state chemistry. 3 PAS is also a potential ligand in the context of coordination polymers with multi- dentating functionality to stabilize metal ions in solution, and along with bridging ligands such as like 4,4′-bipyridine (bpy) or its analogues, it can lead to multidimensional extended structures. 4 PAS is one of the components of the anti-TB combination drug used in second-line therapy. Recently PAS is reported to form an unexpected salt co-crystal with bpy and interesting drug-drug co-crystals with other anti-TB drugs, isoniazid and pyrazinamide, used in first-line treatment to prevent multiple drug-resistant TB. 2,5,6a The reported crystal structure of PAS with bpy is quite unusual in that both charged and neutral bpy species are present in the same crystal. 5a There is a single hydrogen bond, COOH···N heterocycle synthon, 6b between PAS and bpy that is distinct from the commonly found two-point hydrogen bonded COOH···N heterocycle interaction wherein the interacting moieties are in the same plane. The COOH···N heterocycle synthon is also found to be the driving force for the formation of PAS-isoniazid and PAS-pyrazinamide drug-drug co-crystals. 6a A 2:1 PAS/bpy salt/co-crystal involving PAS···bpy···PAS trimer connected by COOH···N heterocycle is generally expected if they are co-crystallized. For instance, this is demonstrated in ibuprofen-bpy co-crystals. 7 This prompted us to further explore the structural landscape of the PAS- pyridine/bpy derivative system. Therefore, co-crystal formation of PAS with bpy, 4-amino pyridine (pap), 3-hydroxy pyridine (mhp), 1,2-bis(4-pyridyl)ethane (bpe), and 1,2-bis(4-pyridyl)- ethylene (bpee) were explored. In this paper, we describe 2:1 co-crystal of PAS and bpy (1), 2:3 co-crystal of PAS and bpy (2), 1:2 salt co-crystal monohydrate of PAS and bpy (2a), 1:1 salts of PAS and pap (3), and PAS and mhp (4), 2:1 salt of PAS and bpe (5), two polymorphs of 1:1 co-crystal of PAS and bpe (6 and 6a), and 1:1 co-crystal of PAS and bpee (7). ■ EXPERIMENTAL SECTION All reagents and solvents were used as received from commercial suppliers without further purification. All nine of the solid forms were obtained by slow evaporation of acetone or acetone-MeOH mixtures. The solutions were prepared by dissolving the components in the solvent or solvent mixture, or by slowly adding a clear solution of the coformer to the API solution. Stoichiometry of the components in the solution had an effect on the outcome (Table 3). Synthesis of PAS·(bpy) 0.5 , 1. PAS (0.65 mmol, Merck 99%) was dissolved in 7 mL of acetone (Merck 99%) followed by the addition of 4 mL of solution of bpy (0.32 mmol, Merck 99%). The resulting yellow color solution was stirred and kept at room temperature for crystallization. Yellow plate shaped crystals of 1 after 4-5 days in about 85% yield (based on PAS) were filtered and dried in desiccators. Elem. Anal. (%) Calcd for 1: C, 62.06; H, 5.21; N, 12.06. Found: C, 62.41; H, 4.73; N, 12.18. IR (cm -1 ): 3460 (s), 3366 (s), 3233 (s), Received: October 18, 2012 Revised: November 14, 2012 Article pubs.acs.org/crystal © XXXX American Chemical Society A dx.doi.org/10.1021/cg3015332 | Cryst. Growth Des. XXXX, XXX, XXX-XXX