Polymorphic and kinetic investigation of adefovir dipivoxil during phase transformation

Abstract

To search polymorphs of adefovir dipivoxil (AD), the polymorphic transformation approach in solution was developed. Also, the kinetics of polymorphic transformation was investigated to effectively control polymorphs. The AD crystals were obtained by crystallization at -10°C, and then the polymorphic transformation was induced by raising temperature. The polymorphs of AD were confirmed using DSC, XRD and solubility analyses. The polymorphic fraction during transformation was monitored for kinetic investigation. Via polymorphic transformation in solution, four polymorphs of AD were found and two of them were new (NF-I, NF-II). The DSC analysis revealed that solvate form (NF-I) was changed to form-V in solid state, and then re-crystallized to NF-II at 93°C, and finally became form-I at 97°C. This serial change of polymorphs in DSC was identical to polymorphic transformation sequence in solution. The kinetic rates of polymorphic transformation described by nucleation and mass transfer theories were well matched with experimental measurement. The polymorphic transformation approach was effective to search polymorphs of which the structure was changed to the other one in the solution. The kinetic information of polymorphic transformation predicted by Volmer's nucleation model and Stokes-Einstein diffusion equation was valuable for exact control of polymorphic purity.