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Differences in coformer interactions of the 2,4-diaminopyrimidines pyrimethamine and trimethoprim

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posted on 2024-02-22, 11:15 authored by Lamis Alaa Eldin Refat, Ciaran O'Malley, John M. Simmie, Patrick McArdle, Andrea Erxleben

The identification and study of supramolecular synthons is a fundamental task in the design of pharmaceutical cocrystals. The malaria drug pyrimethamine (pyr) and the antibiotic trimethoprim (tmp) are both 2,4-diaminopyrimidine derivatives, providing the same C–NH2/N═C/C–NH2 and C–NH2/N═C interaction sites. In this article, we analyze and compare the synthons observed in the crystal structures of tmp and pyr cocrystals and molecular salts with sulfamethazine (smz), α-ketoglutaric acid (keto), oxalic acid (ox), sebacic acid (seb), and azeliac acid (az). We show that the same coformer interacts with different binding sites of the 2,4-diaminopyrimidine ring in the respective tmp and pyr cocrystals or binds at the same site but gives H bonding patterns with different graph set notions. Pyr·smz·CH3OH is the first crystal structure in which the interaction of the sulfa drug at the C–NH2/N═C/C–NH2 site with three parallel NH2···N, N···NHsulfonamide, and NH2···O═S H bonds is observed. The main synthon in (tmp+)(keto).0.5H2O and (tmp+)2(ox2–)·2CH3OH is the motif of fused R21(6) and R12(5) rings instead of the R22(8) motif typically observed in tmp+ and pyr+ carboxylates. Tmp/az is a rare example of cocrystal-salt polymorphism where the two solid-state forms have the same composition, stoichiometry, and main synthon. Theoretical calculations were performed to understand the order of stability, which is tmp·az cocrystal > (tmp+)(az) salt. Finally, two three-component tmp/sulfa drug/carboxylate cocrystals with a unique ternary synthon are described.

Funding

Synthesis and Solid State Pharmaceutical Centre (SSPC)

Science Foundation Ireland

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History

Publication

Crystal Growth and Design, 2022, 22, pp. 3163-3173

Publisher

American Chemical Society

Other Funding information

This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) and is co-funded under the European Regional Development Fund under grant number 12/RC/2275. The Irish Centre for High-End Computing (ICHEC) is thanked for the provision of computational resources under projects nuig02 and ngche102c

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  • Synthesis and Solid State Pharmaceutical Centre

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  • (3) Good Health and Well-being

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