M. Powell, A. Magill, A. Becker
Jun 1, 1988
Citations
0
Influential Citations
3
Citations
Journal
International Journal of Pharmaceutics
Abstract
Stability of the anti-psoriatic naphthyl diester, 1,4-diacetoxy-6-chloro-2,3-dimethoxynaphthalene, 1 (lonapalene) was studied in various alcohols and in propylene carbonate (PC) at 50°–100°C. For comparison, lonapalene was also incorporated into a propylene glycol-based ointment formulation and the drug reactivity was monitored from 40 ° to 80 ° C. In several of the alcohols, biphasic kinetics were observed where a slower phase occurred after the initial 20–60% of reaction. This second, slower phase is due to a lowering of the solution acidity by acetic acid, one of the degradation products. When 0.1 mg/ml citric acid was added to the reaction solution, the initial ‘pH’ dropped from ca. 6–7 to ca. 4–5 resulting in an approximate order of magnitude increase in drug stability. A good linear correlation between log kca (when 0.1 mg/ml citric acid was present) and the solvent hydroxyl group concentration was observed for the degrActation of 1 at 80 ° C. This diester also degraded slowly in pure PC showing apparent first-order kinetics. In the ointment formulation, lonapalene degrActation closely paralleled the reactivity observed in alcohol solutions with respect to kinetic order, Arrhenius behavior, and influence of citric acid on stability. Taken together, these results were interpreted as follows: (i) a change in mechanism occurs from specific base catalysis in neutral ‘unbuffered’ alcohols to one involving reaction of the alcohol with ester directly in solutions containing citric acid (where specific base catalysis is suppressed), (ii) lonapalene degrades in PC at a rate comparable to the rate of reaction in some alcohols, even though the hydroxyl group concentration (due to traces of water present) in propylene carbonate is negligible, and (iii) lonapalene reactivity in alcohols closely models drug degradation in a glycol-based ointment indicating common reaction pathways for these solution-phase and semisolid media.