End-to-End Continuous Synthesis and Crystallization of Clopidogrel Bisulfate: Process Intensification and Solid-Form Control

The conventional batch manufacturing of clopidogrel bisulfate is constrained by low process efficiency and poor control over pharmaceutically preferred yet metastable Form I. Herein, we report an end-to-end continuous manufacturing process that combines multistep synthesis with a nucleation–growth decoupled crystallization strategy to address both challenges. Through the integration of solid-acid-catalyzed esterification, three-feed sulfonylation, phase-transfer catalyst (PTC)-enabled S_N2 reaction, membrane-based phase separation, inline solvent exchange, and continuous crystallization, this integrated platform directly converts commercially available starting materials into spherical Form I crystals with a narrow size distribution (Span = 0.42) without isolation of intermediates. The system operated continuously for 7.5 h, achieving a 70% overall isolated yield and 97% S-enantiomeric purity. Compared with batch processing, the platform reduces total processing time by 3.8-fold, halves the E-factor and process mass intensity (PMI), and increases space-time yield (STY) by 20-fold. The integrated process offers a scalable approach for continuous production of pharmaceutical solids while maintaining control over both the molecular synthesis and product solid form.