Teng Zhang, Yumin Liu, Shichao Du, Songgu Wu, Dandan Han, Shiyuan Liu, and Junbo Gong, “Polymorph Control by Investigating the Effects of Solvent and Supersaturation on Clopidogrel Hydrogen Sulfate in Reactive Crystallization”, Cryst. Growth Des, 2017, 17, 6123−6131.
The authors state that metastable polymorphic drugs, which frequently exhibit improved bioavailability, can be challenging to produce and maintain due to potential conversion to a more stable polymorph. The focus of their research was reactive crystallization of clopidogrel hydrogen sulfate (CHS) and investigating the two forms of the compound with respect to solvent and supersaturation levels. To determine the connection between solvent-solute interactions and consequential polymorphism, in-situ ATR-IR (ReactIR ) was used to continually monitor solute concentration and control supersaturation during crystallization and FBRM (ParticleTrack) was used to monitor particle numbers. The polymorphs were investigated in nine different solvents with different supersaturation and the reactions were performed in an automated laboratory reactor (EasyMax).
Data was presented for supersaturation and polymorphic formation of CHS in 2-propanol and 2-butanol to yield form II and form I, respectively, and ATR-FTIR and FBRM monitored the kinetics and real-time concentration of the CHS reactive crystallization. Different supersaturation levels were obtained by changing the amounts of clopidogrel and sulfuric acid. From this work, the authors determined that the nucleation induction period is the kinetic-determining step and supersaturation is the major driver for polymorphic formation of CHS reactive crystallization in the two different solvents. For the conditions and solvents used in these experiments, they found that the thermodynamically stable polymorph is obtained at s < 18, while the metastable form is formed at higher supersaturation level (s > 21).