Particle Design Of The Metastable Form Of Clopidogrel Hydrogen Sulfate By Building Spherulitic Growth Operating Spaces In Binary Solvent Systems

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 ap-plication. 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 gra-dient 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%. ? 2021 Elsevier B.V. All rights reserved.