Salts of Antifolate Pyrimethamine with Isomeric Aminobenzoic Acids: Exploring Packing Interactions and Pre-Crystallization Aggregation.

Pyrimethamine (PYR), a drug approved for the treatment of infections caused by protozoan parasites, is a multifunctional API based on 2,4-diaminopyrimidine scaffold. The present study aims toward the development of novel solid forms of PYR, by combining it with three isomeric aminobenzoic acids-2-aminobenzoic acid (2NH2-BA), 3-aminobenzoic acid (3NH2-BA), and 4-aminobenzoic acid (4NH2-BA). Solution crystallization led to the formation of three new solvated salts of PYR (PYR/2NH2-BA/EtOH/H2O, PYR/3NH2-BA/EtOH, and PYR/4NH2-BA/EtOH/H2O). The detailed physicochemical properties of the formed compounds were characterized by single-crystal X-ray diffraction (SC-XRD), FTIR, PXRD, thermogravimetry (TG), and differential scanning calorimetry (DSC). Additionally, the pre-crystallization solutions of PYR with 2NH2-BA, 3NH2-BA, and 4NH2-BA were studied by electrospray ionization mass spectrometry technique (ESI-MS), which enabled the observation of peaks corresponding to noncovalently bonded molecules, providing insight into their specific aggregation in a solution/gas phase environment. We identified different non-covalent aggregates, including self-aggregates of aminobenzoic acids and PYR/aminobenzoic acid associates of different stoichiometries.