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

Supramolecular synthon strategy is an often-employed principle to guide the discovery of novel pharmaceutical cocrystals. The amine-carboxylate (N-F center dot center dot center dot-OOC) intermolecular interaction has been confirmed as a member of the supramolecular toolbox, and a cocrystal of 5-fluorocytosine (FC) with L-praline (FC-L-PRO) containing this hetemsynthon 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 center dot center dot center dot-OOC synthon presents as the most important hetem-molecular interaction between FC and SAR/DMG in their crystal structures. And the FC molecular ribbons via homo-molecular N-H center dot center dot center dot N and N-H center dot center dot center dot 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.

Automated summary

The supramolecular synthon strategy was used to screen two new pharmaceutical cocrystals of FC with SAR or DMG, with N-H···OOC and N-H···N/N-H···O hydrogen bonds identified as important interactions. These cocrystals exhibited decreased physical stability under high humidity conditions and should be stored in controlled humidity conditions.