Three-solvent spherical crystallization method with a model drug: Clopidogrel hydrogen sulfate

Abstract

A novel three-solvent spherical crystallization method for producing monodisperse spherical particles with potential use in industry has been presented in this work. By combining the advantages of quasi-emulsion solvent diffusion (QESD) and spherical agglomeration (SA) method, the new approach adds another solvent as diffusion agent which can form a partially miscible zone with good and poor solvents in their phase diagram, changing the diffusion driving force into the transformation of composition point of solvent system from immiscible to miscible region in phase diagram of solvents system. This study presents a detailed process and characterization of obtained spheres in terms of size distribution and morphologies by using clopidogrel hydrogen sulfate (CHS) as a model drug. The effects of process parameters on spheres size and morphology are also investigated experimentally. The results show that particles of defined size and morphology can be prepared precisely by tuning the process conditions. Furthermore, the morphologies exhibit a continuous structural transition from polycrystalline to single crystal. This approach overcomes the shortage of QESD requiring large amount of poor solvent, and also breaks through the main difficulty of selecting suitable bridging liquid of SA method. Although CHS is used as model drug, this method is easily generalized to other drugs.