dc.description.abstract |
The present work involves an investigation of the thermal and photochemical degradation
of betamethasone esters i.e. betamethasone valerate and betamethasone dipropionate
under various conditions and the evaluation of the photoxicity of these compounds. The
thermal degradation (40oC) of betamethasone-17-valerate leads to the formation of
betamethasone-21-valerate
and
betamethasone
alcohol
whereas
betamethasone
dipropionate gives rise to betamethasone-17-propionate, betamethasone-21-propionate
and betamethasone alcohol at pH 2.5-7.5, betamethasone-21-propionate being an
intermediate in this reaction. The betamethasone esters on photodegradation, using a UV
radiation source (300-400nm), yield two major unknown products in aqueous and organic
solvents. The detection of the photodegradation products of betamethasone valerate and
betamethasone dipropionate has been carried out by HPLC and the tR values of the
unknown products have been reported.
The USP HPLC method, after proper validation, has been used for the assay of
betamethasone esters and their thermal and photodegradation products. The analytical
data have been used to evaluate the kinetics of thermal and photochemical reactions. In
both reactions the betamethasone esters have been found to follow the first-order kinetics
under the conditions employed. The apparent first-order rate constants for the thermal
degradation of betamethasone valerate and betamethasone dipropionate in various media
lie in the range of 0.339-9.07x10-3 hr-1 and 0.239-1.87x10-3 hr-1, respectively. The values
of these rate constants for the photodegradation of betamethasone valerate and
betamethasone dipropionate are in the range of 1.617-11.303x10-3 min-1 and 1.101-
7.657x10-3 min-1, respectively. The buffer and ionic strength effects on the rate of thermal
and photodegradation have also been studied. It has been found that phosphate buffer
inhibits the rate of degradation of both esters at pH 7.5. This could be due to deactivation
of the thermal and photo-excited species involved in the reaction .An increase in the ionic
strength of the phosphate buffer also leads to a decrease in the rate of reaction.
Attempts on photostabilization of betamethasone esters in cream and gel formulations
using compounds causing spectral overlay (vanillin and butyl hydroxytoluene) and light
scattering agent (titanium dioxide) show promising results. However, the use of titanium
dioxide was most effective in the photostabilization of the esters, causing 39.62-42.56 %
and 33.84-35.70 % greater protection in cream and gel formulations compared to the
control formulations of betamethasone valerate and betamethasone dipropionate,
respectively.
An important aspect of this work has been the evaluation of in vitro phototoxicity of
betamethasone
esters. This involved the application
of the tests including
photohemolysis, lipid photoperoxidation and protein photodamage. The results indicate
that betamethasone esters and their photodegradation products are toxic to mouse red
blood cells under UV irradiation. Photodegradation products of the esters are toxic in the
dark also, therefore, appropriate precautions may be taken in their clinical applications to
avoid any adverse effects. |
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