Continuous, one-step synthesis of pharmaceutical cocrystals via hot melt extrusion from neat to matrix-assisted processing - State of the art.

Use of hot melt extrusion (HME) as continuous manufacturing process in the cocrystal synthesis is of increasing interest from both industrial and academic perspective and it is seen as a newly developing branch of mechanochemistry with possible broad application in single step synthesis and formulation of pharmaceutical cocrystals. Furthermore, one-step formulation of pharmaceutical products results in combined processing of pharmaceutical cocrystal mixtures with polymers using HME, which may result in phase change or formation of amorphous solid dispersions during the material processing. The manuscript aims at providing selection guidelines and understanding of processing parameters and instrumental setup of importance to design the HME process for cocrystal synthesis. Furthermore, importance of stoichiometry control of the final product and the matrix selection criteria in simultaneous synthesis and formulation of pharmaceutical cocrystals via HME are provided. The first part of this review, introduce mechanochemical methods of cocrystals synthesis along brief explanation of the possible molecular mechanisms of cocrystal synthesis via mechanochemical approach. Subsequently, the critical process parameters i.e. temperature, screw speed, screw configuration or material feed rate of importance in successful synthesis of high quality product are described followed by literature examples of the processing of neat cocrystal compounds or matrix assisted cocrystallisation.