Kinetics of thermal degradation of betamethasone valerate and betamethasone dipropionate in different media

Abstract

The effect of pH, media, phosphate concentration and ionic strength on the kinetics of thermal degradation of betamethasone valerate and betamethasone dipropionate has been investigated. A validated HPLC method has been used to determine the parent compounds and their major thermal degradation products identified in the reaction. Betamethasone-17-valerate gave rise to two major products, namely, betamethasone-21-valerate and betamethasone alcohol, and betamethasone dipropionate degraded into three major products, namely, betamethasone-17-propionate, betamethasone-21-propionate and betamethasone alcohol, in different media. Betamethasone valerate showed maximum stability at pH 4-5 while betamethasone dipropionate was maximally stable at pH 3.5-4.5. The degradation of betamethasone valerate and betamethasone dipropionate was found to follow first-order kinetics and the apparent first-order rate constants (k(obs)) for thermal degradation in different media range from 0.399-9.07×10(-3) h(-1) and 0.239-1.87×10(-3) h(-1), respectively. The values of the rate constants decrease with increasing solvent polarity, phosphate concentration and ionic strength. The second-order rate constants (k΄) for the phosphate ion inhibited reactions lie in the range of 3.02-1.30×10(-6) M(-1) s(-1).

Keywords: Betamethasone valerate; betamethasone dipropionate; kinetics; thermal degradation.

Fig. 1

HPLC chromatograms of betamethasone valerate and betamethasone dipropionate along with their degradation products. (a) HPLC chromatogram showing betamethasone-17-valerate (peak 2, 5.671 min) and its thermal degradation products, betamethasone-21-valerate (peak 3, 7.265) and betamethasone alcohol (peak 1, 2.487 min) with internal standard beclomethasone dipropionate (peak 4, 10.015 min), (b) HPLC chromatogram showing betamethasone dipropionate (peak 4, 8.201 min) and its thermal degradation products betamethasone-17-propionate (peak 2, 3.726 min), betamethasone-21-propionate (peak 3, 4.348 min) and betamethasone alcohol (peak 1, 2.345 min) with internal standard beclomethasone dipropionate (peak 5, 9.945)

Fig. 2

Degradation pathways for the thermal transformation of betamethasone valerate. Degradation pathway for the thermal transformation of betamethasone-17-valerate into betamethasone-21-valerate and betamethasone alcohol

Fig. 3

Degradation pathways for the thermal transformation of betamethasone dipropionate to their degradation products. Proposed degradation pathways of betamethasone dipropionate to give betamethasone-17-propionate, betamethasone-21-propionate and betamethasone alcohol. Thick arrows indicate major pathways

Fig. 4

pH-rate profile for analytes. pH-rate profile of (a) betamethasone valerate and (b) betamethasone dipropionate at 40°

Fig. 5

Dependence of the rate constant of degradation for the analytes. Dependence of the rate constant of degradation of (a) betamethasone valerate and (b) betamethasone dipropionate on solvent dielectric constant. (●) Methanol (♦) Acetonitrile (■) Water (Phosphate buffer, pH 7.5)

Fig. 6

Plots of k_obs vs phosphate concentration for the degradation. Plots of k_obs vs phosphate concentration for the degradation of (a) betamethasone valerate and (b) betamethasone dipropionate at pH 7.5

Fig. 7

Plots of k_obs vs ionic strength for the degradation. Plots of k_obs vs ionic strength (μ) for the degradation of (a) betamethasone valerate and (b) betamethasone dipropionate at pH 7.5