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 H-1-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.

Automated summary

In this study, the mechanochemical and classical solvent crystallization methods for maleates formation were compared for several GABA derivatives. Various characterization techniques were used to evaluate the properties of the obtained compounds. The results showed that maleate formation was possible for all investigated compounds, with significant increases in solubility observed for Pregabalin. The method of crystallization affected certain properties and the formation of certain forms for some compounds, while for others it did not play a significant role. The study aimed to identify promising candidates for multicomponent crystal formation and highlight the usefulness of mechanochemical production routes.