Polymorphism and Multi-Component Crystal Formation of GABA and Gabapentin.

This study exploits the polymorphism and multi-component crystal formation of γ-amino butanoic acid (GABA) and its pharmaceutically active derivative, gabapentin. Two polymorphs of GABA and both polymorphs of gabapentin are structurally revisited, together with gabapentin monohydrate. Hereby, GABA form II is only accessible under special conditions using additives, whereas gabapentin converts to the monohydrate even in the presence of trace amounts of water. Different accessibilities and phase stabilities of these phases are still not fully clarified. Thus, indicators of phase stability are discussed involving intermolecular interactions, molecular conformations, and crystallization environment. Calculated lattice energy differences for polymorphs reveal their similar stability. Quantification of the hydrogen bond strengths with the atoms-in-molecules (AIM) model in conjunction with non-covalent interaction (NCI) plots also shows similar hydrogen bond binding energy values for all polymorphs. We demonstrate that differences in the interacting modes, in an interplay with the intermolecular repulsion, allow the formation of the desired phase under different crystallization environments. Salts and co-crystals of GABA and gabapentin with fumaric as well as succinic acid further serve as models to highlight how strongly HBs act as the motif-directing force in the solid-phase GABA-analogs. Six novel multi-component entities were synthesized, and structural and computational analysis was performed: GABA fumarate (2:1); two gabapentin fumarates (2:1) and (1:1); two GABA succinates (2:1) and (1:1); and a gabapentin:succinic acid co-crystal. Energetically highly attractive carboxyl/carboxylate interaction overcomes other factors and dominates the multi-component phase formation. Decisive commonalities in the crystallization behavior of zwitterionic GABA-derivatives are discussed, which show how they can and should be understood as a whole for possible related future products.

Maleic Acid as a Co-Former for Pharmaceutically Active GABA Derivatives: Mechanochemistry or Solvent Crystallization?

In this study, we compare the mechanochemical and classical solvent crystallization methods for forming maleates of GABA and its pharmaceutically active derivatives: Pregabalin, Gabapentin, Phenibut, and Baclofen. Common characterization techniques, like powder and single crystal X-ray diffraction, IR-spectroscopy, differential scanning calorimetry, thermogravimetric analysis and 1H-NMR spectroscopy, are used for the evaluation of structural and physicochemical properties. Our work shows that maleate formation is possible with all investigated target compounds. Large increases in solubility can be achieved, especially for Pregabalin, where up to twentyfold higher solubility in its maleate compared to the pure form can be reached. We furthermore compare the mechanochemical and solvent crystallization regarding quickness, reliability of phase production, and overall product quality. A synthetic route is shown to have an impact on certain properties such as melting point or solubility of the same obtained products, e.g., for Gabapentin and Pregabalin, or lead to the formation of hydrates vs. anhydrous forms. For the GABA and Baclofen maleates, the method of crystallization is not important, and similarly, good results can be obtained by either route. In contrast, Phenibut maleate cannot be obtained pure and single-phase by either method. Our work aims to elucidate promising candidates for the multicomponent crystal formation of blockbuster GABA pharmaceuticals and highlight the usefulness of mechanochemical production routes.

Supramolecular networks by imine halogen bonding.

Halogen bonding of neutral donors using imine groups of porous organic cage compounds as acceptors leads to the formation of halogen-bonded frameworks. We report the use of two different imine cages, in combination with three electron-poor halogen bond donors. Four resulting solid-state structures elucidated by single-crystal X-ray analysis are presented and analysed for the first time by plane-wave DFT calculations and QTAIM-analyses of the entire unit cells, demonstrating the formation of halogen bonds within the networks. The supramolecular frameworks can be obtained either from solution or mechanochemically by liquid-assisted grinding.