Polymorph Control by Investigating the Effects of Solvent and Supersaturation on Clopidogrel Hydrogen Sulfate in Reactive Crystallization

Reactive crystallization and polymorphic transformation of clopidogrel hydrogen sulfate (CHS) in nine pure solvents were studied at 313.15 K. It is found that thermodynamically stable polymorphic form tends to be obtained in solvents with higher solubility of CHS and the conversion rates from form I to form II are also mainly increased with increasing solubility. The solvent hydrogen bond donor ability is essential for determining the solvent effects on solubility and polymorphic formation of CHS. Besides, the reactive crystallization of CHS at different supersaturations in 2-propanol and 2-butanol was monitored online by using ATR-FTIR and FBRM with a calibration-based approach. The results indicate the nucleation induction period is the kinetic-determining stage and supersaturation is a direct factor to determine the polymorphic formation of CHS: form II was obtained with s under 18 while form I was produced when s increases above 21.