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

Abstract 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 SN2 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.