Solution versus Crystal Hydration: The Case of γ-Amino Acid Pregabalin

Abstract

Understanding the link between solution chemistry and nucleation is essential to control crystallization processes, in particular regarding pharmaceutical compounds. In the present work, the link between the solution hydration state and crystallization of the γ-amino acid pregabalin is presented. Pregabalin is a blockbuster pharmaceutical drug having broad therapeutic effects. Using induction time experiments in combination with the classical nucleation theory, we show that the ease of nucleation increases with solubility and water fraction of the solvent. Water was found to enhance both the kinetic and thermodynamic processes of forming a nuclei. As a result, larger clusters which represent the hydrate form were measured using dynamic light scattering in pure water. Once in the solid state, the hydrate form of pregabalin was found to be physically unstable, as it rapidly converted back into its anhydrate form, as rationalized using in-line Raman spectroscopy. Thus, the hydration and nucleation of pregaba...