Drug substances thermal stability

The storage conditions and the length of the studies should be sufficient to cover storage, shipment, and subsequent use. Both drug substances and products should be evaluated under storage conditions that test for thermal stability (temperature effect) and moisture sensitivity (humidity tolerance). 

As part of the preformulation activities, investigations include physiochemical character, purity, solubility, stability, and optimal pH studies. In preparation for clinical studies, potential product formulations considering route of administration and solution stability are also studied. Unique to dosage form development studies for lyophilized products, thermal analysis of the drug substance and product formulations are also necessary. Data generated during this phase of product development is useful for future development activities, along with validation. 

Polymorphism is customarily monitored by melting point or infrared spectral analysis. However, other methods, such as X-ray diffraction, thermal analytical, and solid-state Raman spectroscopy, also can be used. It is expected that the sponsor will conduct a diligent search by evaluating the drug substance recrystallized from various solvents with different properties. Either the basis for concluding that only one crystalline form exists, or comparative information regarding the respective solubilities, dissolution rates, and physical/chemical stability of each crystalline form should be provided. 

Thermal stability studies on pharmaceutical formulations have been formalized for many years. Specific protocols have been developed to provide data from which a shelf-life determination can be made (Carstensen, 1995). Thus, procedures followed in one laboratory are readily reproduced in another, and shelf-life is a consistent estimation for the product, independent of the laboratory in which the data were gathered. In thermal stability studies, the principal consideration is how long the drug substance or formulation is exposed to a particular temperature. The nature of the apparatus to be used is not important as long as the temperature of the sample is uniform. Thus, the sample may be contained in a flask, bottle, or tube, or held in a water thermostat or an air incubator — whatever is most convenient for the study. Also, the concentration of the drug studied is not crucial because a thermal degradation usually proceeds by first-order kinetics for which the half-life is independent of the starting concentration. 

Photochemical reactivity of drug formulations is an important aspect to consider during development, production, storage, and use of pharmaceutical preparations. However, photochemical stability of drug substances is rarely as well documented as thermal stability of the compounds. For instance, in order to obtain a high sterility assurance level of the product, a parenteral preparation is sterilized in its final container if possible. Steam sterilization at minimum temperature of 121°C for... 

In practical terms, terminal sterilization of liquid parenteral products means sterilizaticMi by saturated steam. Production of free radicals in water prohibits the application of radiation sterilization to aqueous products, but radiation sterilization may be suitable for some solid dosage forms. Dry heat and ethylene oxide are unlikely to be of any value. In the first instance, therefore, saturated steam should be the process of first choice for sterilization of thermally stable drug substances dosage forms should not be formulated in ways that compromise thermal stability. 

Thermoanalytical techniques have had a major application in the understanding of transitions in the skin and of drug penetration of the skin. The application of thermoanalytical techniques to prosthetics and implants is also discussed, as are recent DSC investigations of the oesophagus that provided the information on thermal stability required for successful stent implantation. The use of thermoanalytical techniques such as modulated temperature differential scanning calorimetry (MTDSC) has been be used to characterise polymeric material in order to determine whether there are interactions with drug substances to control and predict drug delivery. 

Drug substance properties should be carefully evaluated. These property will dictate the excipients, method, and process selection for ASD product. The properties to be considered are solubility in organic and aqueous solvents, miscibility with polymers, melting point, particle size, and thermal stability. These properties determine manufacturability, product performance, and long-term stability. For example, hot melt extrusion cannot be used for thermally labile drug molecules (Forster et al. 2001 Vasconcelos et al. 2007 Leuner and Dressman 2000). Qn the other hand, for spray drying process, drug solubility determines the selection of the solvent as well as inlet process temperature (Vasconcelos et al. 2007 Leuner and Dressman 2000). 

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