(321aa) Estimating Molecular Mobility in Amorphous Organic Pharmaceutical Compounds

The amorphous state of drugs is gaining increased consideration as an effective alternative for enhancing the bioavailability of otherwise crystalline, poorly soluble pharmaceutical compounds. One of the major concerns precluding amorphous formulation from entering the mainstream of formulation strategies is the stronger molecular mobility in amorphous forms compared to the crystalline counterparts, situation that often leads to unwanted physical and chemical transformation during processing and storage. Evaluating molecular mobility of amorphous pharmaceutical compounds under different conditions is the first step toward controlled production of amorphous drugs with desired stability. This research is intended to provide a comprehensive characterization of molecular mobility, obtainable through DSC experiments, for amorphous pharmaceutical compounds as a function of storage temperature and time.

A comprehensive computational platform, capable of estimating the temperature and time evolution of molecular mobility in amorphous pharmaceutical compounds, was developed (Fig. 1). Such a platform has as its basis calorimetric experiments focused on the behavior of amorphous materials about the glass transition event. Specifically, a theoretical model is built based on Boltzmann summation to represent changes in fictive temperature upon the heating/cooling of an amorphous compound as a series of small temperature steps followed by isothermal holds. The relaxation at each step is described using the Kohlrausch-Williams-Watts (KWW) equation, where the relaxation time t is obtained from the Adam-Gibbs-Vogel equation. The use of very short temperature steps allows the model to clearly differentiate between different paths leading to the formation of the glass from the equilibrium supercooled liquid. The equations of the model allow for the identification of all parameters needed to characterize an amorphous material as it undergoes a glass transition, including glass transition temperature Tg, fragility, non-exponentiality index b, and heat capacity (Cp) differences between glassy and crystalline forms. It also accommodates all thermal treatments experimentally attainable by DSC, such as different heating/cooling rates.

Amorphous salicin, nifedipine and felodipine were used as model compounds. The aforementioned characteristics of the pharmaceutical glasses were obtained by fitting the model to the actual Cp values measured using DSC. Studies indicate that all compounds tested exhibit similar fragility (Angell's strength parameter D within 7 - 8) and similar non-exponentiality (b value between 0.5 - 0.6). It was also found that amorphous pharmaceutical compounds can exhibit strong molecular dynamics even below Tg, where changes in t by 2 - 3 orders of magnitude are possible within the timescale of experiment. This approach reveals that a pharmaceutical glass prepared by cooling the supercooled liquid at a higher cooling rate exhibits greater molecular mobility and faster relaxation kinetics than the one cooled at a slower rate, suggesting that quench cooling may lead to a less stable pharmaceutical amorphous solids.

The approach developed in this study enables a full characterization of the molecular dynamics in amorphous pharmaceutical compounds by incorporating all features relevant to structural relaxation, as reflected on calorimetric measurements. Integration of the theoretical and computer models of this work into a widespread analytical package for research and educational uses will provide a useful tool for the development and understanding of pharmaceutical amorphous formulations.