Particle design of the metastable form of clopidogrel hydrogen sulfate by building spherulitic growth operating spaces in binary solvent systems

Abstract Clopidogrel hydrogen sulfate occupies a large market share of antithrombotic drugs. Its metastable form I has the advantages of high solubility and bioavailability. However, the poor powder properties and stability limit its application. This work solved the issue by building spherulitic growth operating space in “isopropyl acetate + lower alcohol” binary solvent systems. The systems were selected by the indicators of solubility and isosteric adsorption heats. By investigating crystal morphologies, polymorph transformation, and gelation with supersaturation gradient experiment, ATR-FTIR spectroscopy, and inverted tube method, these binary solvent systems follow the supersaturation-dependent spherulitic growth mechanism providing operating spaces significantly larger than the reported single solvent system. Hence, an optimal crystallization process was designed to prepare high-quality spherulites of form I avoiding polymorph transformation and gelation. Compared with the reported single solvent system, the optimized product presents better powder properties with residual solvent decreased by 59% and operating time decreased by 75%–90%.