Solution-mediated polymorphic transformation from risperidone form II to form I

Abstract

Polymorphism widely exists in the pharmaceutical industry and can significantly affect the quality of the products. Investigating the transformation between different polymorphs is crucial for obtaining high-purity active pharmaceutical ingredients (APIs). In this study, the solution-mediated polymorphic transformation (SMPT) from risperidone form II to form I was systematically investigated. The solubility of risperidone form II in methanol, ethanol, ethyl acetate and acetone was measured via a dynamic method. The solubility of form I and form II were compared to determine the relative stability of different polymorphs. It turns out that form I is more stable over the selected solvents and temperature range. The rate-determining step of the SMPT was determined by combining the offline powder X-ray diffraction (PXRD) and the gravimetric method. The nucleation and growth of risperidone form I are found to be the rate-determining step of the transformation. In addition, the effect of several operating factors on the SMPT was investigated, including solvent, temperature, solid loading, agitation rate and seed addition amount. The results show that the above factors can influence the SMPT speed to different degrees. The molecular dynamic (MD) simulations were also performed, and the radial distribution function (RDF) analysis was used to explain the SMPT from the perspective of solute–solvent interactions. It turns out that the strong interaction between the solvent and the O2 and H2 atoms on the solute molecule may prevent the nucleation and growth of risperidone form I, thus resulting in a slow transformation rate in acetone and ethyl acetate. This study can give references for manufacturing pure risperidone form I in the pharmaceutical industry and is helpful in understanding the SMPT between polymorphs.