Stability testing of pharmaceuticals by high-sensitivity isothermal calorimetry at 25°C: cephalosporins in the solid and aqueous solution states

Present methodology for preliminary stability testing requires high temperatures and therefore suffers from the uncertainty of extrapolation of results to the temperature of interest. Clearly, a rapid method for estimating chemical decomposition rates at the temperature of interest would be of great utility. The recent introduction of a high-sensitivity isothermal calorimeter, the LKB 2277 thermal activity monitor (TAM), allows measurement of the rate of heat production, or thermal activity, from a sample (i.e., arising from a chemical reaction) with a sensitivity of about 10⁴ greater than is possible with a conventional differential scanning calorimeter. Since the power is equal to the product of the reaction rate and the heat of reaction, ΔH_r, the sensitivity of a calorimetric method depends on the magnitude of ΔH_r. From TAM and chemical assay data on the same samples, ΔH_r data were evaluated for a number of cephalosporins in aqueous solution and in various solid forms (i.e., crystalline forms and the amorphous form at selected water contents). Heats of reaction are exothermic and large in magnitude, several hundred kj/mol for the solids, yielding a sensitivity to detect decomposition rates as low as ≈ 1% year with an overnight experiment. For crystalline solids and amorphous samples of low to moderate moisture content, ΔH_r is roughly independent of temperature, water content, and polymorphic form. High-moisture amorphous solids and aqueous solutions of all concentrations have a heat of reaction about a factor of 5 less than the corresponding “dry” samples. However, variations in ΔH_r for a series of samples, including solutions, is less than the variation in chemical stability. Consequently, decomposition rate correlates well with thermal activity for a given compound, and TAM data are generally a valid measure of chemical stability. Exceptions to this generalization may arise when thermal activity from physical changes dominate, and if systems which undergo parallel endothermic and exothermic reactions are studied. The stability studies suggest two generalizations of particular interest. (1) The decomposition rates of amorphous cephalosporins increase with increasing water content in highly non-linear fashion, the rates increasing sharply as the water content increases beyond “intermediate” levels. (2) Stability in a series of crystalline pseudo-polymorphs is found to be quantitatively related to the heat of crystallization, and a theoretical model is proposed to interpret this observation.