Concomitant Polymorphism of Prasugrel Hydrochloride in Reactive Crystallization

Abstract

Concomitant polymorphism of prasugrel hydrochloride was investigated in reactive batch crystallization experiments at 20 and 40 °C. The solubility of prasugrel hydrochloride form I and form II was experimentally determined. To understand the effects of reaction kinetics, supersaturation ratio, and nucleation kinetics on the behavior of concomitant polymorphism of prasugrel hydrochloride and the solvent-mediated transformation process, online techniques such as attenuated transform reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Raman spectroscopy, and focused beam reflectance measurement (FBRM) were used to in situ monitor the reactive crystallization of prasugrel hydrochloride. It was found that prasugrel and hydrochloric acid react promptly and the designed supersaturation can be established almost instantly. The interfacial energies and thus relative nucleation rates of prasugrel hydrochloride form I and form II were calculated, and it was concluded that, at all investigated supersaturations, the nucleation rate of form II is always higher than the nucleation rate of form I. At lower supersaturation, thermodynamics dominated the crystallization process and form I was obtained, while at higher supersaturation, kinetics was critical in the crystallization process and form II was produced. At moderate supersaturation, both thermodynamics and kinetics played important roles and concomitant polymorphism of form I and form II was observed. Solvent-mediated transformation experiments were performed with and without seeding. It turns out that the transformation cannot happen without seeding of form I. Therefore, not reaction kinetics and polymorphic transformation but the concomitant nucleation should be the inherent reason for the observed concomitant polymorphism.