The discovery of new cocrystals of 5-fluorocytosine using amine–carboxylate supramolecular synthon

Abstract

Supramolecular synthon strategy is an often-employed principle to guide the discovery of novel pharmaceutical cocrystals. The amine–carboxylate (N–H···―OOC) intermolecular interaction has been confirmed as a member of the supramolecular toolbox, and a cocrystal of 5-fluorocytosine (FC) with L-proline (FC–L-PRO) containing this heterosynthon was previously harvested. Herein, two new cocrystals of FC with sarcosine (SAR) or dimethylglycine (DMG) were successfully screened out. Similar to FC–L-PRO, the N–H···―OOC synthon presents as the most important hetero-molecular interaction between FC and SAR/DMG in their crystal structures. And the FC molecular ribbons via homo-molecular N–H⋯N and N–H⋯O hydrogen bonds were observed in all of the cocrystal structures, which also exist in the structure of FC. Theoretical calculations show that the formations of FC–L-PRO and FC–DMG are thermodynamically favorable. While for FC–SAR–MeOH, the calculated result is not applicable. The coformer competitive experiments reveal that FC–L-PRO and FC–DMG have similar relative stability and FC–SAR–MeOH is the relative unstable form. These cocrystals exhibit weakened physical stability under high humidity condition (75% RH), then should be stored in controlled humidity conditions (≤50% RH). Additionally, FC–L-PRO demonstrates reduced intrinsic dissolution rate (IDR) in pH 1.2 medium (simulated gastric fluid), which may provide positive contribution to alleviate its toxic side effects.