The role of phosphoric acid in the crystallization of lenalidomide form DH–water system

Abstract

In this work, we studied the effect of phosphoric acid (0–10 v%), acting as an additive, on the thermodynamics and nucleation kinetics of the lenalidomide (LDM) latest form (DH). It was found that the solubility of form DH in water increased with the increasing amount of phosphoric acid. The solute–solvent interactions were further investigated by the NRTL model. The nucleation of form DH is complicated as the nucleation rate is fast in low-concentration phosphoric acid and slow in both pure water and high-concentration phosphoric acid. The experiments involving induction time and metastable zone width yielded similar results. This interesting phenomenon was analysed through the classic nucleation theory and modified Sangwal's theory. Combined with DFT calculations and molecular simulation, the mechanism of crystallization behavior of LDM form DH in both pure and impure systems has been revealed systematically.