• Cocrystal dissolution pH-shift studies in vitro are good predictors of the superior bioavailability of cocrystal with a dibasic drug and diacidic coformers. • Cocrystals of weakly basic drugs with acidic coformers mitigate the negative effects of elevated gastric pH on drug absorption. • Cocrystals sustain drug supersaturation in vitro and improved in vivo absorption in beagle dogs. • The cocrystal approach reduces pH effects on dissolution and absorption. It is well documented that weakly basic drugs, such as ketoconazole (KTZ), will exhibit reduced oral absorption and lower bioavailability in elevated gastric pH conditions. Because this occurs frequently in patients taking medicines to reduce stomach acid, it is crucial to identify formulation strategies that ensure adequate drug exposure. The purpose of this work was to evaluate the in vitro and in vivo effects of KTZ cocrystals with acidic coformers in mitigating the negative effects of elevated gastric pH on KTZ dissolution and absorption after oral administration. Dissolution-supersaturation-precipitation in vitro studies were performed with drug and three KTZ cocrystals with fumaric (FUM), adipic (ADP), and succinic (SUC) acids, under a two-stage pH-shift micro dissolution method, to mimic the transfer from gastric to intestinal compartment. All cocrystals exhibited less sensitivity to elevated gastric pH than the drug. In vitro , cocrystals reduced the area under the curve (AUC) 2.6-fold compared to drug where AUC decreased 6.7-fold. Based on the superior performance observed during in vitro studies, the KTZ-SUC cocrystal was selected for bioavailability evaluation in beagle dogs treated with pentagastrin and famotidine to simulate normal and elevated gastric conditions. The cocrystal mitigated the negative effects of elevated dog gastric pH on KTZ absorption. It reduced the pH sensitivity of AUC (1.3 times) and C max (1.4 times). The drug exhibited high pH sensitivity with reduced AUC (12.3 times) and C max (7.5 times). These findings demonstrate that cocrystals of weakly basic BCS-class II drugs with acidic coformers promise to improve therapeutic outcomes that are otherwise limited by disease states or co-administration of drugs and food that increase gastric pH.
Tucci et al. (Fri,) studied this question.