Estimation of molecular mobility of disaccharides

In pharmaceuticals amorphous state can be obtained either intentionally or unintentionally. Intentional production is used, for example, to improve the dissolution of poorly soluble compounds, to stabilize the structure of proteins, or to improve the mechanical properties of excipients (e.g., lactose). Unintentional introduction of amorphous phases can result from general manufacturing procedures of pharmaceuticals, such as coating, granulation, drying, milling, and compression. The presence of amorphous regions, even in small quantities, can exhibit a significant influence on the physical and chemical stability of pharmaceutical products. Molecular mobility in formulation with amorphous content is believed to be the key factor of their stability. Therefore, evaluating of molecular mobility is an important step in pharmaceutical product development. The aim of this study was to estimate molecular motions in amorphous disaccharides using calorimetric approach at temperatures below the glass transition temperature (Tg), where relaxation process is very slow as compared to the time of experiment. When temperature is low enough, the initial relaxation time parameter (τi) can be used as an estimate for relaxation process on the timescale of pharmaceutical product shelf life. The results of the present study revealed similar trend in stability of amorphous forms for the disaccharides (sucrose experiencing the fastest structural relaxation), which can be assumed on the basis of Tg alone, where higher Tg would result in more stable glassy state (Tg of sucrose is the lowest). Storage temperature of Tg - 55oC or lower would suffice for amorphous trehalose, melibiose and cellobiose to achieve at least 2 year's relaxation time, while for sucrose the temperature is Tg - 70oC. Fragility has been used as a helpful mean for classifying amorphous materials. All the compounds can be classified as fragile. Fragility ranking in the present study contains some degree of uncertainty, while 3 different approaches revealed somewhat different results for ranking the disaccharides. The variation in the results can be attributed to the overall sensitivity of DSC. The method described in the present study is quite difficult to apply without supportive information from other techniques. The results, obtained with the method, are very dependent on the slope in plotting ln q vs. 1/Tg, and even small fluctuations in the estimation can lead to different fragility values and consequently to different relaxation times. However, the final results reveal values for relaxation times well below Tg, which are in reasonable agreement with modern theoretical understanding of glassy state dynamics.