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.
Keywords: API; GABA; crystallization; gabapentin; hydrogen bond; multicomponent crystals; non-covalent interactions; pharmaceutical crystal engineering; polymorphism.