(707f) Polymorphism in Dabigatran Etexilate Mesylate: Nucleation and Transformation

The active pharmaceutical ingredients (APIs) can exist as different solid-state forms including polymorphs, solvates, hydrates and amorphous form. Different solid-state forms of a drug usually exhibit different physical and chemical properties, such as stability, dissolution rate, bioavailability, etc. Therefore one of the primary goals of solution crystallization is to generate particles with desired crystal form in a reproducible manner. To accomplish this goal, one has to establish control over crystallization, which is a complex process including crystal nucleation and growth. The early stages of solution crystallization from the supersaturated solution to the formation of crystal nucleus play a decisive role in determining the crystal form. In this work, the solution-mediated polymorphic transformation (SMPT) process of dabigatran etexilate mesylate Form I occurring through dissolution of the metastable phase and crystallization of the stable phase was investigated by using several offline and online tools, such as PXRD, DSC, TGA, FBRM, Raman, and ATR-FTIR. The influence of solvent, temperature and supersaturated ratio were analyzed in detail. Because of the different solvent-solute interactions, SMPT process of Form I is prone to occur in alcohols rather than esters and ketones. Temperature is a key factor which will influence nucleation of different polymorphs and a new solvate was found. The supersaturated ratio could also have an effect on the nucleation of the new polymorphs which may result from the different conformations of the dabigatran etexilate mesylate molecular. It was confirmed by transformation experiments that the polymorphic transformation of Form I was controlled by the crystallization of the stable phase.