Discovery and Selective Nucleation of Polymorphs of Flexible GABA Molecules: Solvation Effects and Conformational Rearrangement

We designed a solvent mixture composed of carboxylic acid solvents and water as the crystallization medium for the selective preparation of three distinct γ-aminobutyric acid (GABA) conformational polymorphs (Form-I, Form-II, and the newly discovered Form-IV). By adjusting the carbon chain length and content of carboxylic acid solvents, we were able to finely tune the solvation environment, leading to the formation of the desired polymorphs. Crash-cooling crystallization experiments demonstrated that with the carbon chain length (C1–C6) and content (0–30%) of carboxylic acid increasing, the polymorphic outcomes gradually change from Form-I to Form-II and ultimately to Form-IV. Interestingly, four different conformations were observed within these three polymorphs. DFT calculation indicated that the stability order of these conformations is conformer-IVβ > conformer-IVα > conformer-II > conformer-I. Based on solution FTIR analysis and solvation free energy calculation, the solvation effect on GABA molecules diminishes with an increasing carbon chain length and content of carboxylic acid solvents. A lower solvation effect makes the desolvation process of GABA molecules much easier so that GABA molecules can undergo sufficient conformational rearrangement during the nucleation stage, thereby adopting a more stable conformation during the molecular assembly process. In this crystallization conditions, Form-IV with a more stable conformation in its crystal structure has the potential to replace Form-II and Form-I through preferential crystallization.