EVALUATION OF HEAT-CONDUCTION MICROCALORIMETRY IN PHARMACEUTICAL STABILITY STUDIES .7. OXIDATION OF ASCORBIC-ACID IN AQUEOUS-SOLUTION

Heat-conduction microcalorimetry at 25.0-degrees-C has been evaluated as a method of predicting the stability of a drug undergoing complex degradation in aqueous solution. The oxidation of ascorbic acid was used as a model reaction. The influence on the microcalorimetric response of various amounts of ascorbic acid, oxygen and hydrogen ion in the solution, and of the addition of a metal complex binder or an antioxidant was investigated. In general, the appearance of the heat flow curves and the calculation of the heat evolved gave a clear indication of how the stability was influenced. The accuracy of the microcalorimetric response was investigated by comparing it with an HPLC assay technique. A linear relationship between the cumulative heat and the amount oxidized was obtained. The slope, described as the apparent enthalpy change, was 224 kJ/mol. It is concluded that microcalorimetry can be used as a simple stability indication technique, at normal storage temperatures, for a complex degradation reaction. However, for reactions that include an antioxidant (sodium metabisulfite), which in itself undergoes a continuous major chemical reaction, the appearance of the heat flow curves cannot be related to the stability of the ascorbic acid.