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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A structural study on the solid, microcrystalline chromophore roseolumiflavin was carried out. Based on rational design considerations three binary co-crystals were prepared with a primary focus set on utilizing the imide functional group. Therefore, robust supramolecular synthons, including a carboxylic acid–amide dimer, halogen bonding, as well as a hydrogen-bonded three-point binding motif, were successfully incorporated into the multicomponent systems. All the co-crystals showed a blue-shifted fluorescence in the red range compared to the near-infrared-emitting solid roseolumiflavin. Solvatochromic studies finally elucidated that the degree of close packing between the flavin molecules within the crystal structures was decisive for the emission colour. These results render new possibilities to investigate flavins in the aspect of crystal engineering to tune optical properties of organic chromophores in the solid state. [ABSTRACT FROM AUTHOR]

Crystallization and multicomponent crystal formation of active pharmaceutical ingredients Baclofen and Phenibut with dicarboxylic acid co-formers are discussed. The crystallization process of several crystalline entities is elucidated via single crystal—as well as powder X-ray—diffraction, followed by thermal analysis and phase stability studies over time. Both APIs form increasingly complex crystalline phases with co-formers malic and tartaric acid, where phase purity of a desired compound is not necessarily a given. Therefore, the influence of different solution and milling environments during crystallization on the outcome is studied. Emphasis is laid on how molecular influences such as the chirality, propensity to form hydrates as well as low solubility of Baclofen and Phenibut impede attempts to gather high-quality single crystals. The results highlight that targeted crystallization of these compounds with dicarboxylic acids can be difficult and unreliable. [ABSTRACT FROM AUTHOR]

The low melting compounds 3-fluoropyridine, 3,5-difluoropyridine,2,3,5-trifluoropyridine, and 2,3,5,6-tetrafluoropyridine were crystallizedin situ on the diffractometer and analyzed by X-ray diffraction. Thecomparison with pentafluoropyridine shows a consecutive dependenceof the arrangement of pyridine molecules with the increasing fluorinesubstitution. Starting with the monosubstituted representative, thecrystal packing changes stepwise from herringbone packing to parallelarrangement of the molecules in the trifluorinated pyridine and thenswitches back to the edge-to-face form by the perfluorinated compound.To get a deeper insight into the aggregation behavior of the flourinatedpyridines, the crystal packing motives were also analyzed on the basisof ab initio quantum-chemical calculations of the intermolecular interactionenergy, using the MP2/6-311G(d,p) method. This approach allows theindication of energetically rich fragments in the crystal structures,called basic structural motifs, and the very weak attractive or ratherrepulsive nature of F···F interactions. [ABSTRACT FROM AUTHOR]

Abstract: The influence of fluorine substituents on the crystallisation behaviour of pyridine was investigated by crystal structure determinations. The low melting compounds 2-fluoropyridine, 2,6-difluoropyridine and 2,4,6-trifluoropyridine were crystallised by in situ crystallisation directly on the single crystal X-ray diffractometer. [Copyright &y& Elsevier]