RESUMEN
Pharmaceutical cocrystals have attracted increasing attention over the past decade as an alternative way to modify the physicochemical properties and hence improve the bioavailability of a drug, without sacrificing thermodynamic stability. Our previous work has demonstrated the viability of in situ formation of ibuprofen/isonicotinamide cocrystal suspensions within a matrix carrier via a single-step hot melt extrusion (HME) process. The key aim of the current work is to establish optimized processing conditions to improve cocrystal yield within extruded matrices. The solubility of each individual cocrystal component in the matrix carrier was estimated using two different methods, calculation of Hansen solubility parameters and Flory-Huggins solution theory using a melting point depression measurement method, respectively. The latter was found to be more relevant to extrusion cocrystallization because of the ability to predict miscibility across a range of temperatures. The predictions obtained from the F-H phase diagrams were verified using ternary extrusion processing. Temperatures that promote solubilization of the parent reagents during processing and precipitation of the newly formed cocrystal were found to be the most suitable in generating high cocrystal yields. The incorporation of intensive mixing/kneading elements to the screw configuration was also shown to significantly improve the cocrystal yield when utilizing a matrix platform. This work has shown that intensive mixing, in combination with appropriate temperature selection, can significantly improve the cocrystal yield within a stable and low viscosity carrier during HME processing. Most importantly, this work reports, for the very first time in the literature, the use of the F-H phase diagrams to guide the most appropriate HME processing window to drive higher cocrystal yield.