Paper
BAI Lei1, LI Yingxia1, XU Hui2, LIU Dongchun1*, TANG Xing2
This paper investigated the stability of the ester drug triamcinolone acetonide acetate (TAA) in ionic Carbopol 940 (CP) and in nonionic hydroxypropyl methylcellulose stearoxy ether (Sangelose 90L, SGL) hydrogels to provide the basic guideline for gelling formulation. The content change of TAA (1 mg/g) dispersed in either CP (0.5%) or in SGL (0.5%) was examined during the storage at 60 ℃ for 10 d. To explore the possible reasons for the changes in content of TAA in CP and SGL gels, the stability of dissolved TAA (20 μg/ml) in respective solvents (water, phosphate buffers of pH 4.7, 5.8, 7.4 and 9.18, sodium chloride solutions of 0.01, 0.1 and 1 mol/L) containing 30% methanol was investigated during the storage at 25 ℃ for 10 d. The effects of pH value and neutral salts on the hydrolysis of TAA were studied. In the SGL and CP hydrogels, TAA decreased to 82.0% and 74.4%, respectively. In respective solutions (water, phosphate buffers of pH 4.7, 5.8, 7.4, and 9.18, sodium chloride solutions of 0.01, 0.1 and 1 mol/L), TAA reduced to 92.1%, 25.0%, 30.5%, 33.9%, 4.38%, 89.5%, 85.8% and 82.8%. TAA was stable in methanol-water but unstable in acidic, especially in alkalic solutions. The stability of TAA decreased as the ionic strengths (concentrations of sodium chloride) of the solution increased in a neutral solution. By the catalysis of H+, OH- or Lewis acid and salt effect, the ester bond could be induced to polarize and accelerate the hydrolysis. The triethanolammonium cation in CP hydrogel, as a Lewis acid, induced the ester bond of TAA polarizing and nucleophilic (OH-) attacking to the carbonyl group resulting in promoting the hydrolysis of TAA. We concluded that TAA was more stable in the nonionic SGL hydrogel than in the ionic CP hydrogel. For ester drugs, it was suggested that nonionic polymer should be considered and electrolytes should be avoided in the hydrogel formulations.