ABSTRACT
Amino acids have shown promising abilities to form complexes with poorly water-soluble drugs and improve their physicochemical properties for a better dissolution profile through molecular interactions. Salt formation via ionization between acidic drugs and basic amino acids is known as the major contributor to solubility enhancement. However, the mechanism of solubility enhancement due to non-ionic interactions, which is less pH-dependent, remains unclear. The aim of this study is to evaluate non-ionic interactions between a model acidic drug, indomethacin (IND), and basic amino acids, arginine, lysine and histidine, in water. At low concentrations of amino acids, IND-arginine and IND-lysine complexes have shown a linear relationship (AL-type phase solubility diagram) between IND solubility and amino acid concentration, producing â¼1 : 1 stoichiometry of drug-amino acid complexes as expected due to the strong electrostatic interactions. However, IND-histidine complexes have shown a nonlinear relationship with lower improvement in IND solubility due to the weaker electrostatic interactions when compared to arginine and lysine. Interestingly, the results have also shown that at high arginine concentrations, the linearity was lost between IND solubility and amino acid concentration with a negative diversion from linearity, following the type-AN phase solubility. This is indicative that the electrostatic interaction is being interrupted by non-electrostatic interactions, as seen with histidine. The IND-lysine complex, on the other hand, showed a complex curvature phase solubility diagram (type BS) as lysine self-assembles and polymerizes at higher concentrations. The freeze-dried drug-amino acid solids were further characterized using thermal analysis and infrared spectroscopy, with results showing the involvement of weak non-ionic interactions. This study shows that the solubility improvement of an insoluble drug in the presence of basic amino acids was due to both non-ionic and ionic interactions.
ABSTRACT
A number of amino acids (AA) has been investigated as promising hydrotropes to improve the solubility of biopharmaceutics classification system (BCS) class II drugs carbamazepine (CBZ) and indomethacin (IND) via specific complexations in aqueous solution. The aim of this work is to understand the molecular basis of these hydrotropic interactions by investigating the two model drugs combined with 12 amino acids including phenylalanine, tryptophan, isoleucine, proline, valine, glycine, serine, threonine, arginine, lysine, histidine and aspartic acid in water at 25 °C, 30 °C and 45 °C. The amino acids were chosen based on their different side chains (neutral aromatic, aliphatic, polar charged or uncharged) to investigate their hydrotropic performance. A linear solubility curve was observed between indomethacin and mono-neutral hydrophobic amino acids (phenylalanine, tryptophan, isoleucine, proline and valine) well beyond 1:1 molar ratio indicating the interaction is predominantly non-ionic between the drug and the hydrotropes. Interestingly, the aqueous solubility of carbamazepine (a neutral compound) was enhanced by neutral, charged basic or acidic amino acids, confirming the presence of hydrophobic interactions that involve H-bonds, H/π and π/π stacking and the results were confirmed by UV-Vis spectroscopy. A combination of multiple neutral amino acids showed additive hydrotropic effect in indomethacin solubility with up to 7-folds increases. This study demonstrates for the first time the potential of amino acids as hydrotropes to improve aqueous solubility of poorly water-soluble drugs, which is important for pharmaceutical development.
