The determination of drug stability by HPLC assay of degradation products

This work evaluates the advantages in drug stability testing of following the decomposition by analysis of decomposition products. Conventional methods of drug stability testing are criticised and the limitations are shown to be largely a result of analysing for un-decomposed drug. Using simulated analytical results incorporating various levels of precision, the use of product concentration is shown to be capable of producing conventional rate constants in shorter times, by utilising smaller extents of reaction than use of intact drug analysis. The simulation is applied to single, parallel, consecutive and reversible reactions. The findings of the simulated decompositions are supported by practical decomposition studies on several drugs. HPLC with ultraviolet detection is used as a single analytical method for both reactant and product. Aspirin and diiodoaspirin represent single-decomposition product systems; tetracycline is examined as a drug decomposition involving parallel, consecutive and reversible reactions. Nafimidone is studied to establish the advantages and limitations of product and reactant measurements, where all decomposition products have not been identified. The oxidation of 5-hydroxymethylfurfural is also examined to determine the usefulness of product analysis in limit testing and in establishing reaction pathways. In all cases where product identity is known, it is shown that the initial rate method employing product concentrations provides more rapid determination of rate constants. It is suggested that reaction order is overemphasized in shelf-life determination of drugs and that the initial rate method with analysis of product can minimise - and in certain cases, eliminate - the need for temperature stressing to determine shelf-life. HPLC is shown to be very generally applicable in product measurement. New criteria for stability-indicating assays that allow use of the initial rate method are demonstrated for the above drugs, and for succinylsulphathiazole, diphenhydramine and chloramphenicol. The separations obtained are described in terms of current ion pairing ideas.