Surprising Effect of Carbon Chain Length on Inducing Ability of Additives: Elusive Form-II of γ-Aminobutyric Acid (GABA) Induced by Sodium Carboxylate Additives

Abstract

Herein, we developed the strategy of additive-induced polymorph, realizing the selective crystallization of elusive Form-II of γ-aminobutyric acid, a potent bioactive compound. A series of sodium carboxylate additives with different carbon chain lengths (C2–C8) were identified to induce the crystallization of Form-II. It was found that additive molecules will inhibit the growth of the centrosymmetric Form-I at two opposite ends, thereby precluding it, but they will inhibit the growth of the polar Form-II at only one end so that it survives. Notably, these sodium carboxylate additives exhibited distinct inducing ability for Form-II; that is, the effective critical addition amount required to induce Form-II increases with the increase of carbon chain length. However, the sodium formate is an exception and it cannot induce the Form-II. The difference of the inducing ability of additives was rationalized based on the competition of attachment and detachment behavior of additives on the growth end of Form-I. When the extent to which the attachment is more favorable than the detachment is larger, the corresponding additive exhibits a better inhibition effect on Form-I and more remarkable inducing ability for Form-II.