A Solubility Comparison of Neutral and Zwitterionic Polymorphs

Several amphoteric model compounds and drugs, such as isomers of aminobenzoic acids (ortho, meta, and para), N-aryl-2-amino-nicotinic acids (three isomers), amino-salicylic acids (meta and para), clonixin, and niflumic acid, were selected to obtain their zwitterionic and neutral polymorphs with the objective to study their X-ray crystal structures, solubility and dissolution rate, and stability. We were successful in crystallizing neutral and ionic polymorphs for 2- and 3-aminobenzoic acid (ABA), 2-(p-tolylamino)nicotinic acid (TNA), and clonixin (CLX), as well as 4- and 5-aminosalicylic acid (4-ASA as neutral and 5-ASA in ionic form). The neutral and zwitterionic crystalline polymorphs were differentiated by their distinctive powder Xray diffraction (PXRD), Fourier transform infrared, Raman and ss-NMR spectroscopy, and further quantified by Hirshfeld surface analysis. Phase transitions were monitored by differential scanning calorimetry and variable temperature powder X-ray diffraction. The difference in solubility and dissolution rates of the neutral and zwitterionic polymorphs were correlated with their hydrogen bonding (O-H···O, O-H···N, and N+-H···O-). The faster dissolution rates of the ionic forms were ascribed to stronger, attractive interactions between the solvent molecules and the zwitterionic functional groups. Even as there is no general strategy yet to crystallize ionic polymorphs of amphoteric molecules, the present study shows the advantages of zwitterionic forms for solubility enhancement.