4‑Aminosalicylic Acid Adducts Suryanarayan Cherukuvada, † Geetha Bolla, † Kanishka Sikligar, ‡,§ and Ashwini Nangia* ,† † School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India ‡ Networking Resource Centre, School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India § Bhaskar Pharmacy College, Yenkapally, Hyderabad 500 075, India * S Supporting Information ABSTRACT: 4-Aminosalicylic acid (p-aminosalicylic acid, PAS), an antituberculosis drug, is a model active pharmaceut- ical ingredient to study salt and cocrystal formation in a multiple hydrogen-bonding functionality molecule with carboxylic acid, amine, and phenol groups. A cytosine salt CYT + -PAS - , salt cocrystal hydrate CYT + -PAS - -CYT-H 2 O, and nicotinamide cocrystal hydrate PAS-NAM-H 2 O, are described in this article. Furthermore, X-ray crystal structures of PAS sodium dihydrate, sulfate, and mesylate salts and dehydration/rehydration behavior of the sodium salt by powder X-ray diffraction are discussed. ■ INTRODUCTION 4-Aminosalicylic acid, commonly known as p-aminosalicylic acid (abbreviated as PAS, Figure 1), is a second-line drug used in the treatment of multidrug-resistant tuberculosis (MDR- TB) 1 and is on the World Health Organization Model List of Essential Medicines. 2 PAS was found to be also effective toward ulcerative colitis 3 and Crohn’s disease, 4 but the more potent drug in these latter ailments is its isomer 5-aminosalicylic acid 4,5 (5-ASA, common name mesalazine or mesalamine, Figure 1). Both these aminosalicylic acids are amphoteric molecules, and surprisingly, there are no polymorphs reported for these classic drugs. Interestingly, PAS exists in an unionized state as 4- NH 2 C 6 H 3 (OH)COOH, whereas 5-ASA is a zwitterion/inner salt 5-NH 3 + C 6 H 3 (OH)COO - in the crystal structure 6 (Figure 1). In buffer solutions, PAS is known to exist in different ionic states: (a) as a diprotic acid (NH 3 + C 6 H 3 (OH)COOH) below its pK a1 (= 1.79), (b) as a zwitterion (NH 3 + C 6 H 3 (OH)COO - ) at its isoelectric point (pI = 2.71), and (c) as a diprotic base (NH 2 C 6 H 3 (OH)COO - ) above its pK a2 (= 3.63). 7 PAS decarboxylates to 3-aminophenol (NH 2 C 6 H 4 OH) through the zwitterionic species 7 and also upon melting. 8 There is a renewed interest in the chemistry of p- aminosalicylic acid. It was recently shown that PAS inhibits dihydropteroate synthase in M. tuberculosis by acting as a replacement substrate and a prodrug that releases active forms by the enzymes that they eventually inactivate. 9 Cocrystals of PAS with pyrazinamide, isoniazid, 10 and sulfadimidine 11 are examples of drug-drug cocrystals, which can become multi- drug, fixed-dose formulations in the future. An amorphous form, 12 several salts (sodium, 8b potassium, hydrochloride, sulfate, mesylate, ammonium, etc.), 13 molecular salts 14 (piperazinium, morpholinium), and a dioxane solvate 15 of PAS were reported by different groups, and among these, the ammonium salt is polymorphic. 16 However, crystal structures of many of these salts are not reported. Because of its rich functionalities (carboxylic acid, amine, and phenol), PAS could form a multitude of adducts 17 with coformers depending on the pK a , 18 and thereby offer a better understanding of salt and cocrystal supramolecular assembly. 10,14b,18,19 Salts, cocrystals, and salt cocrystal hydrate of PAS with pyrdine coformers were Received: December 7, 2012 Revised: February 18, 2013 Published: February 19, 2013 Figure 1. (a) 4-Aminosalicylic acid (PAS) exists in an unionized neutral form and (b) 5-aminosalicylic acid (5-ASA) is a zwitterion in the crystal structure. Intramolecular O-H···O hydrogen bond is present in both structures. The molecular structure of 4-ASA is extracted from the CSD (refcode AMSALA01). 6 The reported structure of 5-ASA (refcode SAQJAV) has no H atoms, and hence, its X-ray crystal structure was redetermined with 3D coordinates (.cif file is deposited to CCDC). Article pubs.acs.org/crystal © 2013 American Chemical Society 1551 dx.doi.org/10.1021/cg301798s | Cryst. Growth Des. 2013, 13, 1551-1557