results of Evaluation of the lKB 2277 Calorimeter for stability testing of Pharmaceuticals

BaCKGrounD At the preformulation stage of product development, estimates of chemical and/or physical stability are normally derived from accelerated stability tests and occasional use of thermal analysis (DSC, DTA, TGA). Although thermal analysis is ideally suited for study of first and second order phase transitions, kinetic studies of either chemical reactions or physical changes are normally limited to extremely high temperatures where the data obtained are of dubious utility in predicting kinetics at temperatures of interest (25o and 40o). Accelerated stability tests are subject to the same criticism if the temperatures are high enough to complete the stability test in a reasonable time (i.e. approximately one week). Further, accelerated stability tests are quite labor intensive due to the need for assay work.. Clearly, a rapid method for estimating rates of chemical and physical changes at temperatures near ambient would be of great utility. LKB-Produkter AB has recently introduced a versatile calorimeter system, the Bioactivity Monitor, which has a unique combination of high sensitivity and high sample capacity. Although the instrument is currently viewed as a tool for microbiological and biochemical research, for example, studies of the effect of cephalosporins and other antibiotics on various microorganisms, it has also found application in shelf-life stability estimation for explosives, a problem similar to that faced by the pharmaceutical industry in estimating the stability of preliminary pharmaceutical formulations. The utility of the calorimetric technique in kinetic studies depends on the sensitivity of the calorimeter and on the heat of reaction for the change under study. For energetic reactions such as amorphous to crystalline physical changes, acid-base reactions and oxidation reactions, it appears that reaction rates as low as 5% per year could be measured. However, for reactions giving essentially zero heat of reaction, calorimetry would be useless. For many reaction types of potential interest to pharmaceutical research, such as cephalosporin decompositions, the magnitude of the heat of reaction is unknown. An assessment of the utility of the LKB 2277 Bioactivity Monitor in studying the stability of pharmaceutical systems was performed in the LKB Application Laboratories in Stockholm in co-operation with Dr. Jaak Suurkuusk. The major objective was to determine whether the heat produced during decomposition of representative pharmaceutical systems was sufficient to be quantitatively determined by the calorimeter system at temperatures between 25° and 40°.