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Polymorphic Cocrystals of the Antimalarial Drug Pyrimethamine: Two Case Studies

Authors: Baptista, JA; Castro, RAE; Rosado, MTS; Maria, TMR; Silva, MR; Canotilho, J; Eusebio, MES

Ref.: Cryst. Growth Des. 21(7), 3699-3713 (2021)

Abstract: Polymorphism is known to have significant implications in the pharmaceutical industry. However, there are relatively few studies of polymorphic pharmaceutical cocrystals, and contributions to the systematic assessment, structural, and thermodynamic characterization of cocrystal polymorphs are of great relevance. This work reports cocrystal formation between pyrimethamine, a multifunctional API with a 2,4-diaminopyrimidine scaffold, common to many dihydrofolate reductase inhibitors, and two structurally related coformers, caffeine and theophylline, differing in their hydrogen-bonding donor ability. Two (1:1) enantiotropic cocrystal polymorphs were identified for both pyrimethamine:caffeine and pyrimethamine:theophylline. The contribution of differential scanning calorimetry to guide the cocrystal polymorphs discovery should be emphasized. The different hydrogen-bonding abilities of the coformers have consequences for the crystalline structures obtained. The crystalline structure of pyrimethamine:theophylline polymorph II, previously solved by Delori et al., is determined by the N-PMA center dot center dot center dot H-N-THEO bond. Both pyrimethamine:caffeine polymorphs, whose crystalline structures were solved in this work, although differing in packing and synthon, share a common 2,4-diaminopyrimidine hydrogen-bonded chain pattern which has quite close similarity with pyrimethamine polymorph I. A similar infrared pattern in the N-H stretching region is observed for these three solid forms, and also for pyrimethamine:theophylline, polymorph I, which may anticipate a similar arrangement in this polymorph.

DOI: 10.1021/acs.cgd.1c00005