Posaconazole Cocrystal with Superior Solubility and Dissolution Behavior

This work reports the first cocrystal of the basic drug posaconazole (PSZ). PSZ is poorly water-soluble and has low and erratic bioavailability based on its large positive food effect and high solubility-pH dependence. The structure and enhanced properties of the discovered 2:3 cocrystal with 4-aminobenzoic acid (4ABA) are presented in this study. Single-crystal X-ray diffraction revealed that the two non-superimposable PSZ molecules interact with three 4ABA molecules through O-H center dot center dot center dot O, N-H center dot center dot center dot O, and N-H center dot center dot center dot N hydrogen bonds. Cocrystal and drug solubilities were measured in biorelevant media, and the cocrystal solubility advantage (SA = S-cocrystal/S-drug) was calculated to be 139 in FaSSIF and 48 in FeSSIF. Cocrystal dissolution generated supersaturation levels (sigma(max) = C-max/S-drug) of 16 in FaSSIF and 8 in FeSSIF and resulted in relative area under the curve (RAUC = AUC(cocrystal)/AUC(drug)) increases of 4 and 13 times, respectively, compared to drug. This study demonstrates the utility of cocrystals to improve the solubility and dissolution behavior of drugs with poor biopharmaceutical properties.