Supramolecular modification of baclofen in the solid state

Abstract

Baclofen (BAC, (R/S)-4-amino-3-(4-chlorophenyl)butanoic acid), a γ-amino acid, was used to form multicomponent crystals (MCCs) with coformers (CFs) of different acidic strength and molecular size. Crystallisation of BAC with oxalic acid (OXA), salicylic acid (SAL), phenoxyacetic acid (POA), 2,4-dichlorophenoxyacetic acid (2,4ClPOA), 4-picoline (4PIC) and 3,4-lutidine (3,4LUT) yielded seven MCCs, [BAC+][OXA-]·w, BAC·SAL·w, [BAC+][POA-], [BAC+][2,4ClPOA-], [BAC+][2,4ClPOA-]·w, 2BAC(4PIC)·w and 2BAC(3,4 LUT)·w, respectively. The bulk materials were analysed by thermoanalytical methods (thermogravimetry and differential scanning calorimetry), powder X-ray analysis and Fourier transform infrared spectrometry. Liquid assisted grinding (LAG), as a green chemistry method, was also applied to form the MCCs. X-ray analysis of the single crystal structures revealed that BAC exists in zwitterionic or cationic form in these crystals, and the MCCs represent a large variety of crystal classes, such as salts, salt solvates, cocrystal salt solvates or solvates with different stoichiometry. It was noted that BAC appeared in many different conformations in the MCCs and the crystal [BAC+][2,4ClPOA-] represents a new conformer of BAC found in the solid state. Comparative crystal packing analysis revealed similarities in the packing arrangement of the MCCs, with the exception of the oxalate salt, where the hydrogen bonded layers formed by the polar functional groups of the BAC and the CFs alternating with the hydrophobic aromatic layers. Contrarily, the polar layers show great variety in their hydrogen bonding pattern. In conclusion, BAC is a good candidate to form MCCs with the selected CFs, but the predictability of the nature of interactions formed between the BAC moieties or between the BAC and CF molecules are poor and this makes BAC a challenging target when crystal engineering techniques are used.