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.

Additive‐Induced Selective Crystallization of the Elusive Form‐II of γ‐Aminobutyric Acid

“…Our previous work suggested that the balance between attachment and detachment of additives on the GABA growth end may determine their inducing ability . On the one hand, due to the electrostatic interactions between the –COO − group of additives and the –NH 3 + group exposed on GABA growth ends, additive molecules will be attached on the growth ends.…”

“…Two levels of additive concentration were set (0.582 and 1.455 mol L −1 ), which corresponded to the concentrations in the cooling crystallization experiment where the molar ratios of additive to GABA were 4 % and 10 %, respectively. The detailed apparatus and procedures were described in previous publications of our group . The measurement procedures were repeated three times and the arithmetic average was taken as the final solubility value.…”

“…In our previous work , we adopted the strategy of additives‐induced polymorphs, successfully achieving the selective crystallization of GABA Form‐II. A series of sodium carboxylate compound (CH 3 (CH 2 ) n COONa, n = 0–7) with straight‐chain alkyl were identified as effective additives to induce Form‐II.…”

Green Mechanochemical Strategy for the Discovery and Selective Preparation of Polymorphs of Active Pharmaceutical Ingredient γ-Aminobutyric Acid (GABA)

“…29 Moreover, Form-II is an elusive polymorph and its selective crystallization in solution requires the aid of tailor-made additives. 30 In this work, we utilized a mechanochemical strategy to explore the polymorphic diversity of GABA and attempt to selectively prepare its various polymorphs. Notably, a new polymorph of GABA (Form-III) was identified by mechanochemical milling and its crystal structure was also obtained through the crystal structure prediction (CSP) method.…”

“…In addition, because of the biological importance of GABA, a wide knowledge of possible crystal structures of GABA as well as molecular conformation and hydrogen-bonding sites in these structures will be helpful to understand the specific recognition mode of GABA participating in the biological process. , To date, however, only two polymorphs of GABA have been reported: Form-I in 1973 by Tomita and Form-II in 1996 by Dobson . Moreover, Form-II is an elusive polymorph and its selective crystallization in solution requires the aid of tailor-made additives …”