Control of Dissolution and Supersaturation/Precipitation of Poorly Water-Soluble Drugs from Cocrystals Based on Solubility Products: A Case Study with a Ketoconazole Cocrystal

This study demonstrates in vitro and in vivo controlof cocrystaldissolution with drug supersaturation/precipitation based on the solubilityproduct of a cocrystal. As a cocrystal model, KTZ-4ABA (ketoconazole,KTZ, a poorly water-soluble drug cocrystal, with 4-aminobenzoic acid,4ABA, a coformer) was used. The presence of 4ABA in the dissolutionmedia dramatically reduced the dissolution rate of KTZ-4ABAand regulated the supersaturation/precipitation of KTZ, supportedby the solubility product of KTZ-4ABA. In the in vitro dissolutionstudy, the combined solid form of KTZ-4ABA and a ten-fold amountof 4ABA significantly lowered the degree of KTZ supersaturation withoutprecipitation and further cocrystal dissolution. To confirm cocrystaldissolution control in the gastrointestinal tract with the same compositionas the in vitro study, an in vivo oral administration study with ratswas conducted. When KTZ was coadministered to rats in the cocrystalform, an excess of 4ABA coadministered with KTZ-4ABA in thesolid form reduced the maximum plasma KTZ concentration (C (max)), prolonged the time to reach the C (max), but did not influence the area under the plasma concentration-timecurve. These results demonstrate that both in vitro and in vivo cocrystaldissolution can be regulated by adding an appropriate amount of coformerbased on the solubility product, which can be one of the promisingstrategies for the oral use of cocrystal formulations.

Automated summary

This study demonstrates the control of cocrystal dissolution in vitro and in vivo by utilizing drug supersaturation/precipitation based on the solubility product. A cocrystal model, KTZ-4ABA, was used and the presence of 4ABA in the dissolution media significantly reduced the dissolution rate of KTZ-4ABA and regulated the supersaturation/precipitation of KTZ. In vitro dissolution study showed that the combined solid form of KTZ-4ABA and a ten-fold amount of 4ABA lowered the degree of KTZ supersaturation without precipitation. An in vivo study with rats confirmed the control of cocrystal dissolution in the gastrointestinal tract. Overall, this study demonstrates the promising strategy of using cocrystal formulations for oral use.