A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles

Herein, we report the development of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance (DS) of the commercial product Otezla. This development effort was motivated by the desire to create an alternative manufacturing configuration with a significantly smaller footprint and to impart intensification resulting in a more sustainable process. Three primary aspects of the existing batch process had to be addressed to achieve this goal: (1) long reaction time, (2) low solubility of the starting materials and intermediates in the primary reaction solvent (THF), and (3) extensive postreaction unit operations contributing to significant solvent waste. Key features of the intensified CM process include the following: (1) use of a plug-flow reactor (PFR) to access increased reaction temperatures (130 °C), resulting in a shorter reaction time to reach the target conversion (>18 h in batch to 30 min in flow); (2) replacement of THF with DMSO to solve solubility issues related to starting materials and reaction intermediates, and (3) development of a multistage continuous MSMPR (mixed-suspension, mixed-product removal) crystallization upon addition of water as antisolvent to the end-of-reaction stream containing apremilast. This intensified CM process reduced the number of primary unit operations from nine to three (67% reduction). Moreover, it can be executed at commercial scale using a compact manufacturing skid. Part I of this manuscript series highlights the effort to develop the novel process and the corresponding kg-scale demonstration of the optimized process. Part II describes the process characterization and development of a control strategy in detail to ensure process efficiency and robustness of the small-footprint continuous skid.