Drug-drug cocrystals of antituberculous 4-aminosalicylic acid: Screening, crystal structures, thermochemical and solubility studies

Abstract

Experimental multistage cocrystal screening of the antituberculous drug 4-aminosalicylic acid (PASA) has been conducted with a number of coformers (pyrazinamide (PYR), nicotinamide (NAM), isonicotinamide (iNAM), isoniazid (INH), caffeine (CAF) and theophylline (TPH)). The crystal structures of 4-aminosalicylic acid cocrystals with isonicotinamide ([PASA+iNAM] (2:1)) and methanol solvate with caffeine ([PASA+CAF+MeOH] (1:1:1)) have been determined by single X-ray diffraction experiments. For the first time for PASA cocrystals it has been found that the structural unit of the [PASA+iNAM] cocrystal (2:1) is formed by 2 types of heterosynthons: acid-pyridine and acid-amide. The desolvation study of the [PASA+CAF+MeOH] cocrystal solvate (1:1:1) has been conducted. The correlation models linking the melting points of the cocrystals with the melting points of the coformers used in this paper have been developed. The thermochemical and solubility properties for all the obtained cocrystals have been studied. Cocrystallization has been shown to lead not only to PASA solubility improving but also to its higher stability against the chemical decomposition.

Keywords: 4-Aminosalicylic acid (PubChem CID: 4649); Acetone (PubChem CID: 180); Acetonitrile (PubChem CID: 6342); Caffeine (PubChem CID: 2519); Cocrystal; Crystal structure; Desolvation; Dissolution rate; Ethanol (PubChem CID: 702); Isoniazid (PubChem CID: 3767); Isonicotinamide (PubChem CID: 15074); Melting points; Methanol (PubChem CID: 887); Nicotinamide (PubChem CID: 936); Pyrazinamide (PubChem CID: 1046); Screening; Tetrahydrofuran (PubChem CID: 8028); Theophylline (PubChem CID: 2153).