Ternary systems of naproxen with hydroxypropyl-beta-cyclodextrin and aminoacids.
The purpose of the present study was to investigate the combined effect of hydroxypropyl-beta-cyclodextrin and different aminoacids (L-lysine, LYS; L-valine, VAL; L-iso-leucine, LEU; and L-arginine, ARG) on the solubility of naproxen, a poorly water-soluble anti-inflammatory drug. Aqueous solubilities of naproxen in binary and ternary systems with hydroxypropyl-beta-cyclodextrin and each aminoacid were determined. The pH was measured in all solubility studies and its role on drug solubility variation was evaluated. Arginine was the most effective aminoacid in improving drug solubility and the only one which showed a synergistic effect when used in combination with hydroxypropyl-beta-cyclodextrin. In contrast, some reduction with respect to the theoretical drug solubility (i.e. the sum of the solubilities in the presence of cyclodextrin and aminoacid separately) was observed in ternary combinations with the other aminoacids. This occurred also in the case of lysine, despite the higher solubility of its ternary system in comparison with the binary cyclodextrin complex at pH 7. Phase-solubility experiments showed that the ternary system with arginine (pH approximately 7) exhibited a stability constant 3.6 times higher and was about 5.5 times more effective in improving drug solubility than the binary complex in buffered (pH approximately 7) aqueous solutions. These results demonstrated that the high increase in the drug solubility shown by ternary systems with arginine was not simply due to a favorable pH change but to multicomponent complex formation. Solid products of naproxen with hydroxypropyl-beta-cyclodextrin, and/or arginine, prepared by different methods, were characterized by Differential Scanning Calorimetry (DSC), Hot Stage Microscopy (HSM) and Scanning Electron Microscopy (SEM).
Mura
Paola
P
Department of Pharmaceutical Sciences, University of Florence, Via G. Capponi 9, 50121 Firenze, Italy. mura@unifi.it
Maestrelli
Francesca
F
Cirri
Marzia
M
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000596:Amino Acids / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D003505:Cyclodextrins / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007532:Isoleucine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D009288:Naproxen / Q000737:chemistry*; D012995:Solubility; D014633:Valine / Q000737:chemistry; D047392:beta-Cyclodextrins
D000596:Amino Acids; D000893:Anti-Inflammatory Agents; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D007532:Isoleucine; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D009288:Naproxen; D001120:Arginine; D014633:Valine; D008239:Lysine