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

We designed a solvent mixture composed\nof carboxylic acid solvents and water as the crystallization medium\nfor the selective preparation of three distinct γ-aminobutyric\nacid (GABA) conformational polymorphs (Form-I, Form-II, and the newly\ndiscovered Form-IV). By adjusting the carbon chain length and content\nof carboxylic acid solvents, we were able to finely tune the solvation\nenvironment, leading to the formation of the desired polymorphs. Crash-cooling\ncrystallization experiments demonstrated that with the carbon chain\nlength (C1–C6) and content (0–30%) of carboxylic acid\nincreasing, the polymorphic outcomes gradually change from Form-I\nto Form-II and ultimately to Form-IV. Interestingly, four different\nconformations were observed within these three polymorphs. DFT calculation\nindicated that the stability order of these conformations is conformer-IV<sub>β</sub> > conformer-IV<sub>α</sub> > conformer-II\n> conformer-I. Based on solution FTIR analysis and solvation free\nenergy calculation, the solvation effect on GABA molecules diminishes\nwith an increasing carbon chain length and content of carboxylic acid\nsolvents. A lower solvation effect makes the desolvation process of\nGABA molecules much easier so that GABA molecules can undergo sufficient\nconformational rearrangement during the nucleation stage, thereby\nadopting a more stable conformation during the molecular assembly\nprocess. In this crystallization conditions, Form-IV with a more stable\nconformation in its crystal structure has the potential to replace\nForm-II and Form-I through preferential crystallization.