Solid-State Stability Testing of Drugs by Isothermal Calorimetry
A new technique has been developed to calculate rapidly the solid-state room-temperature degradation rate of drugs and drug candidates. The technique utilizes measurements of the initial rate of heat output at several elevated temperatures by isothermal calorimetry and the degradation rate of the compound determined at a single elevated temperature by chromatography. The activation energies and degradation rates at 25°C calculated by conventional methods and by isothermal calorimetry are compared and discussed. The compounds studied were phenytoin, triamterene, digoxin, tetracycline, theophylline, diltiazem, and several proprietary ICI compounds.
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, ΔHr, the sensitivity of a calorimetric method depends on the magnitude of ΔHr. From TAM and chemical assay data on the same samples, ΔHr 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, ΔHr 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 ΔHr 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.
Implementation of Tourism Satellite Account: Assessing the Contribution of Tourism to the Croatian Economy
Compiling the indicators of tourism consumption and the output of tourism industries, Tourism Satellite Account (TSA) provides a framework for internationally harmonized measurements of direct macroeconomic contribution of tourism. Ivandic and Marusic provide a detailed methodological approach for the transfer of TSA theoretical concepts to the assessment of tourism economic contribution on the case of the Croatia. Giving that the TSA compilation is still characterized by a surprisingly wide range of ‘styles’ used, the chapter contributes to a better understanding of the issues related to measurement of direct tourism impacts. It also gives a set of baseline criteria for resource allocation within tourism policy and the further evaluation of its effectiveness.