Salts, Binary and Ternary Cocrystals of Pyrimethamine: Mechanosynthesis, Solution Crystallization, and Crystallization from the Gas Phase

A series of salts and binary and ternary cocrystals of the antimalaria drug pyrimethamine (PYR) are reported. PYR has a donor–acceptor–donor (DAD) and a donor–acceptor (DA) binding site, and cocrystallization experiments were performed with coformers with complementary acceptor-donor-acceptor (ADA) and acceptor-donor (AD) H-bonding functionalities. Three different preparation techniques were compared, namely, solution crystallization, crystallization from the gas phase, and liquid-assisted grinding. In several cases different solid-state forms were obtained depending on the crystallization method. The molecular ionic cocrystals PYRH+BAR–·PYR (BAR = barbituric acid) and (PYRH+SAC–)2·GLU (GLU = glutarimide, SAC = saccharin), the binary cocrystal PYR·GLU, the salt PYRH+NIC– (NIC = nicotinic acid), and two polymorphs of PYRH+SAC– could be crystallized by sublimation. Two other ternary molecular ionic cocrystals, (PYRH+BEN–)·PYR·SUC and (PYRH+SAC–)2·SOR (SUC = succinimide, BEN = benzoic acid, SOR = sorbic acid), were obtained by solution crystallization. Attempts to crystallize ternary cocrystals from solution also yielded a number of new two-component cocrystals including four new solvates of PYRH+SAC–, thus extending the structural landscape of the PYR/SAC system. Liquid-assisted milling was performed as a one-pot reaction and with the stepwise addition of the coformers. The (PYRH+SAC–)2·GLU cocrystal formed when the coformers were milled in one step and when they were added to the mill stepwise. For other systems the outcome of the two-step milling experiment depended on the order in which the coformers were added. The PYR-coformer interactions were analyzed using the PIXEL program.