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

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 pregabalin in solution is highly favored, as opposed to the solid-state situation, where the anhydrate is the stable form. Despite these differences, a solution-crystallization link could still be established in our work. Knowledge of the solution chemistry and structural landscape of pharmaceutical compounds is essential for the development of manufacturing routes and patent protections, and we foresee that the presented approach can be used to further reveal relationships among self-association in solution, crystallization, and hydration of a wide range of organic compounds.