TY - JOUR
T1 - Mechanistic study of the solubilization effect of basic amino acids on a poorly water-soluble drug
AU - Alsalhi, Mohammed Suleiman
AU - Royall, Paul G.
AU - Chan, Ka Lung Andrew
N1 - Funding Information:
The authors would acknowledge the Faculty of Pharmacy at King Saud University (KSU), Riyadh, Saudi Arabia for financial support.
Publisher Copyright:
© 2022 The Royal Society of Chemistry
PY - 2022/6/29
Y1 - 2022/6/29
N2 - 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 ∼1 : 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.
AB - 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 ∼1 : 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.
UR - http://www.scopus.com/inward/record.url?scp=85134349104&partnerID=8YFLogxK
U2 - 10.1039/D2RA02870K
DO - 10.1039/D2RA02870K
M3 - Article
SN - 2046-2069
VL - 12
SP - 19040
EP - 19053
JO - RSC Advances
JF - RSC Advances
IS - 30
ER -