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.
Determination of physical and chemical stability in pressurised metered dose inhalers: potential new techniques
Introduction: Pressurised metered dose inhalers (pMDIs) are subject to rigorous physical and chemical stability tests during formulation. Due to the time and cost associated with product development studies, there is a need for online techniques to fast screen new formulations in terms of physical and chemical (physico-chemical) stability. The problem with achieving this is that pMDIs are by their definition, pressurised, making the direct observation of physico-chemical properties in situ difficult. Areas covered: This review highlights the characterisation tools that can enhance the product development process for pMDIs. Techniques investigated include: laser diffraction, Raman spectroscopy, isothermal ampoule calorimetry, titration calorimetry and gas perfusion calorimetry. The operational principles behind each technique are discussed and complemented with examples from the literature. Expert opinion: Laser diffraction is well placed to analyse real-time physical stability as a function of particle size; however, its use is restricted to suspension pMDIs. Raman spectroscopy can be potentially used to attain both suspension and solution pMDI spectra in real time; however, the majority of experiments are ex-valve chemical composition mapping. Calorimetry is an effective technique in capturing both chemical and physical degradations of APIs in real time but requires redevelopment to withstand pressure for the purposes of pMDI screening.
Stability and Compatibility Testing Using a Microcalorimetric Method
Abstract A microcalorimetric method is used for compatibility and stability studies. The high sensitivity of the instrument permits measurements at 60°C or even lower, i.e. under more realistic conditions than offered by conventional techniques like DTA and vacuum stability tests. The instrument consists of four independent calorimeters with a short thermal relaxation time, high sensitivity and excellent baseline stability. The calorimeters are placed in a common, precisely thermostated water bath. In compatibility studies, heat flow curves are recorded for the pure components and a mixture of these. A theoretical curve is constructed, which simulates a non-interacting system. The difference between the theoretical and the experimental curve for the mixture reflects the degree of interaction between the materials. A number of compatibility problems are discussed, including interactions in mixtures of TNT with amine/amide type polymers, polycarbonate — double base propellant interactions under various conditions and the influence of an anaerobic sealant on a high explosive and a propellant. Some results from stability measurements on an igniting compound are also presented.