Matrix Assisted Cocrystallization as an example of continuous and scalable method of obtaining pharmaceutical cocrystals on an industrial scale

Cocrystals can be defined as crystalline solids composed of at least two compounds in a stoichiometric ratio which interact nonionically. While one of the components is an active pharmaceutical ingredient (API) the term ‘pharmaceutical cocrystal’ could be applied. These are the subject of interest in academic and industrial research as they offer better control over physicochemical, mechanical and pharmacokinetic properties of API while its therapeutic activity remains intact. Commercial success of this approach can be confirmed by the number of marketed pharmaceutical cocrystal drug forms. Despite the range of cocrystallization methods introduced, it is challenging to propose a technique meeting industrial requirements such as scalability or continuousness of the process with respect to ‘green chemistry’ principles being reduction of solvents use. This paper covers the criteria of cocrystallization method selection and presents techniques potentially applicable for large-scale purposes such as Hot Melt Extrusion, Matrix Assisted Cocrystallization and spray congealing with advantages and limitations of those. Within mechanochemical methods of obtaining cocrystals, Matrix Assisted Cocrystallization (MAC) is a promising candidate for industrial-scale use as it is a continuous, one-step, solvent-free technique offering high control over process parameters (e.g. temperature, feed rate, screw speed, screw configuration, extruder type) in order to increase the efficiency of the synthesis and provide high quality product. The addition of polymer facilitates the extrusion and enables conducting the process at lower temperature to prevent degradation of thermolabile substances. Furthermore, cocrystals embedded in polymeric matrix can exhibit the improvement of dissolution rate or compressibility. Additionally, the MAC can be coupled with Process Analytical Technology (PAT) tools to provide real-time data for manufacturing process monitoring and control of product quality.