Structural relaxation and molecular mobility in organic amorphous pharmaceutical compounds

The strong molecular mobility of amorphous materials, in relation to their crystalline counterparts, is widely considered as one of the major factors responsible for the reduced stability of low molecular weight, organic pharmaceutical compounds in the amorphous form. An accurate evaluation of molecular mobility in these materials is critical for the development of amorphous pharmaceutical products with acceptable shelf lives. This study is aimed at providing a comprehensive characterization of molecular mobility in amorphous compounds through the measurement of the characteristic relaxation time. Based on calorimetric methods, an in-depth investigation of the structural relaxation in amorphous systems is presented. Within the framework of the Adam-Gibbs theory of configurational entropy, differential scanning calorimetry (DSC) is used to develop a methodology to estimate the temperature and time dependence of molecular mobility in several model pharmaceutical compounds. Amorphous pharmaceutical compounds demonstrate the ability to undergo fast changes in molecular mobility under isothermal conditions, even at temperatures well below the glass transition temperature. In order to a priori characterize molecular mobility in amorphous pharmaceutical compounds, a computational approach is presented. The approach, built on the Boltzmann superposition of the non-exponentiality and the non-linearity character of structural relaxation, effectively simulates the response of amorphous systems to changes in their thermal history. The study shows that the comprehensive thermal characterization of amorphous pharmaceutical compounds is possible when a specific set of parameters is known. The parameter set includes: (i) the fragility of the material (ii) the non-exponentiality of the relaxation, (iii) the Kauzmann temperature and (iv) the heat capacities of the crystalline and amorphous forms. These experimentally obtainable parameters provide a complete, theoretically consistent set of variables for a common mathematical expression describing the time and temperature evolution of the relaxation time in both the glass and liquid forms. Furthermore, if the heat capacities (item iv above) are known, the theoretical simulation can be used as an invert model to obtain the other parameters (i through iii above). This means that from careful measurements of heat capacity, it is possible to estimate the molecular mobility of a given amorphous compound under any designated set of time and temperature conditions. Through the analysis of structural relaxation, an improved DSC-based method to measure the enthalpy loss during the isothermal relaxation is proposed. Experiments using amorphous salicin show that this method can provide accurate estimation independently of the experimental conditions. In addition, the phenomenology and theoretical explanation of the impact of annealing, heating/cooling rate, and material properties on the glass transition behavior is given in detail in this study