A new co-crystal of pharmaceutical active ingredient Apremilast was successfully designed in this work. The discovered co-crystal with benzoic acid significantly improves key properties like the dissolution and stability of an otherwise poorly soluble Apremilast. A crystallization process was developed, which includes efficient solvent selection and ternary phase diagram construction to minimize risks during scale up. To increase efficiency, we propose that both steps be combined into a single methodology based on solubility data. A suitable solvent for the co-crystallization process was selected and ternary phase diagrams were constructed using three different modifications of thermodynamic model of solid-liquid equilibria. Based on the obtained information, the co-crystallization process was scaled-up to 100 mL. This provides a feasible process to produce larger amounts of this promising pharmaceutical solid form of Apremilast necessary for further drug development.

Department of Chemical Engineering University of Chemistry and Technology Technická 3 166 28 Prague 6 Dejvice Czech Republic

Department of Physical Chemistry University of Chemistry and Technology Technická 5 166 28 Prague 6 Dejvice Czech Republic

Zentiva k s U Kabelovny 130 10237 Prague 10 Czech Republic

Zentiva k s U Kabelovny 130 10237 Prague 10 Czech Republic; Department of Solid State Chemistry University of Chemistry and Technology Technická 5 166 28 Prague 6 Dejvice Czech Republic

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Surface Defects and Crystal Growth of Apremilast Benzoic Acid Cocrystals

Apremilast Cocrystals with Phenolic Coformers

Structure-property relations of a unique and systematic dataset of 19 isostructural multicomponent apremilast forms