(645g) Cocrystallization Process Development of Benzoic Acid – Apremilast Cocrystal

In this work, we have designed several new cocrystals and solvates of a pharmaceutical molecule apremilast. Out of these new multicomponent forms, the cocrystal with benzoic acid is particularly promising due to its improved intrinsic dissolution rate (approximately 400%) and comparable thermal properties to marketed apremilast B. The crystal structure of this cocrystal was solved using single-crystal X-ray diffraction to provide further insight into the cocrystal formation. Cocrystallization process was explored to simplify further scale up. Utilizing the ternary phase diagram, constructed by the combination of specific experiments and a solid-liquid equilibria model, we were able to significantly decrease the experimental efforts compared to traditional approaches such as discontinuous isoperibolic thermal analysis (DITA). Methylehtyl ketone was chosen as a solvent for the cocrystallization experiment. This was performed in a 100ml reactor, were we investigated the impact of process parameters included cooling rate, stirring speed, impeller, concentration and seeding on the size and morphology of the apremilast-benzoic acid cocrystal. Obtained results confirmed strong impact of operating conditions on the crystals sizes and shapes. These crystals were consequently tested during dissolution and it was observed that significant improvements in the dissolution rate can be achieved by varying the crystal sizes and well as shapes.