Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 2: Step 2 Synthesis

The pharmaceutical manufacturing sector is steadily transitioning from batch to continuous operations, as the drawbacks of batch operations and the advantages of continuous operations have increasingly provided compelling motivation for change. This study, which details the Step 2 synthesis of baloxavir marboxil (from S-033447 to S-033188), provides an example of how continuous manufacturing implementation can offer significant operational benefits. The process includes four unit operations (i.e., reaction to S-033188, crystallization and purification of S-033188, continuous rotary filtration of S-033188, and continuous wet milling and drying of S-033188). S-033188 was formed in a three-stage 500 mL CSTR cascade with a ReactIR in the third stage. The total residence time was 10.5 h, and the high-performance liquid chromatography (HPLC) area% of S-033188 and S-033447 in the third stage was 96.6 and 0.6%, respectively. The continuous crystallization of S-033188 was performed in a three-stage MSMPR system, and the crystallization yield was 97.1% with a 15-fold antisolvent addition. Focused beam reflectance measurement (FBRM) was located in the third stage to monitor the start-up and steady state during the run. A continuous rotary filter was used to process the S-033188 slurry, and it operated with a vacuum pressure of approximately −15 kPa and a cake height of 4 mm after reaching a steady state. Wet milling was applied to achieve the required quality attribute of S-033188 on particle size distribution (PSD), and heptane/ethyl acetate (50:1, v/v) was selected as the resuspension solvent. After wet milling, S-033188 was dried with a continuous drum dryer, resulting in desired Form I.