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

Abstract

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.

Supervised Machine-Learning Algorithm using Low Data Sets: Flow Chemistry Optimization of the Key Urea Moiety Construction in Larotrectinib

“…Addressing this while restricting the reaction of 4 with 3 within the confines of a flow reactor would have required us to either drastically increase the residence time of stage 1, which would have been counter-productive, or increase the length of the reactor coil in stage 2. The latter option was unwieldy, prompting us to adopt a more practical approach of using a surge tank to ensure the completion of the reaction between 4 and 3 (see Figure for the modified continuous flow experimental setup).…”

A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy

“…Scheme provides an expanded view of the penultimate step in the Apremilast synthesis, redeveloped to enable CM, with Figure providing a full process flow diagram (PFD) . This process begins with the reaction of ( S )-Aminosulfone and 3-Acetamidophthalic Anhydride (3-AA) in a plug flow reactor (PFR) to yield Apremilast in crude solution.…”

“…This process begins with the reaction of ( S )-Aminosulfone and 3-Acetamidophthalic Anhydride (3-AA) in a plug flow reactor (PFR) to yield Apremilast in crude solution. The crude reaction solution is then collected in a surge tank prior to direct antisolvent crystallization of Apremilast executed using a series of continuous mixed-suspension mixed-product-removal (MSMPR) vessels. − Finally, semicontinuous isolation is achieved via the application of a dual centrifuge configuration in which the slurry is continuously fed and filtered, and then the isolated Apremilast cake is washed, spun down, and discharged in discrete batches.…”

“…In Part I (10.1021/op3c00400) of this series, we reported the development of an integrated CM process for the penultimate step in the synthesis of Apremilast, − the drug substance for Otezla (Scheme ). That development effort led to significant intensification and enabled a minimal-footprint manufacturing skid for production of this product at a small manufacturing site . In this article, Part II of the series, we report details of the process characterization conducted for the Otezla CM process.…”

PAT-Enabled Automated Feedforward Control: An Application to the Continuous Manufacture of Apremilast

“…In developing and characterizing the integrated CM process shown in Figure , we proposed a parametric control strategy and a five-two operating strategy (operating over a five-day workweek, with a two-day shutdown/preparation over the weekend). This has a number of advantages: the control strategy is straightforward and only requires monitoring of process parameters, rather than collection and processing of IPC samples during continuous runs, operations are not required to be staffed over the weekend, and the continuous manufacturing skid can be cleaned out each week to ensure no long-term fouling or solid build-up in the transfer lines or on the centrifuge filters.…”