Impact of Pre-Heating On Nucleation Kinetics and Polymorph

Polymorphs play an important role in pharmaceutical development as they can impact the stability and bioavailability of the active pharmaceutical ingredient (API). However, isolating and stabilizing the desired form can often be a challenging task as several factors can affect the crystallization of a particular polymorph. In this study, the impact of thermal history of the under-saturated solution on the nucleation kinetics was studied for an API. It was found that pre-heating a solution of the API at a temperature higher than the dissolution temperature could significantly increase the induction time or suppress the nucleation temperature during cooling crystallization. In addition, pre-heating was also found to have an effect on the polymorph that nucleated. While typically the metastable form would nucleate during cooling, pre-heating resulted in concomitant nucleation of the metastable as well as stable form, with a correlation between the duration of pre-heating and the proportion of the stable form in the polymorphic mixture. This suppression of nucleation by pre-heating may due to a conformational transition at higher temperatures. Conversion to the wrong conformer(s) would not only reduce the effective supersaturation but might also inhibit nucleation. Spectroscopic studies are under way to study the conformers and pre-nucleation aggregates in solution.

Communication number: IPDO IPM-00269