Pharmaceutical Organic Salts of Isoniazid, Nicotinic Acid, and Their Isomers: Structure, Aqueous Solubility, and Biological Studies

Utilization of the understanding of intermolecular interactions for the development of functional materials is a key feature of crystal engineering. Based on the understanding of sulfonate–pyridinium synthon, we report the design and development of organic salts of a series of pyridyl-based pharmaceuticals such as isoniazid (ISN) and nicotinic acid (NA) and their isomers: nicotinic hydrazide (NCH) and isonicotinic acid (INA) with naphthalene disulfonic acid (NDSA-2H). Single-crystal X-ray diffraction studies validate crystallization of ISN and NCH, as hydrated organic salts: [(NDSA)2-(ISN-2H)2+·3H2O] (1) and [(NDSA-H)-(NCH-H)+·3H2O] (2), while INA and NA crystallize as anhydrous salts: [(NDSA)2-(INA-H)2+] (3) and [(NDSA)2-(NA-H)2+] (4), respectively. Proton transfer between sulfonate and pyridyl functionalities is observed in all crystal forms and is substantiated by structural parameters. The ionic nature of crystal forms provides them with very high thermal stability and a striking increase in aqueous solubilities reported at pH values of 2.1, 7, and 8.2. The solubility increases by 5- to 20-fold for the drug precursors in their mixed crystal forms. The products have been further evaluated for their biological activity using a 2-fold microdilution assay against M. tuberculosis and M. smegmatis. Compound 1 showed potent and selective activity (MIC: 0.5–1 μg/mL for M. tb H37Rv, 0.5 μg/mL for M. tb H37Ra, 64 μg/mL for M. smegmatis), indicating enhanced efficacy through cocrystallization.