Microstructure evolution and the physical stability of amorphous materials

David A Engers, Purdue University

Abstract

The long term stability of amorphous solids formulated as dosage forms is a significant concern due to the inherent instability of the amorphous state and the potential for structural changes during storage. Initiation of changes such as those observed on appearance of a more stable crystalline phase, leads to the spontaneous and often catastrophic decrease of critical product performance attributes, including solubility and dissolution rate, which are prerequisite to realizing the bioavailability benefit of amorphous materials used as pharmaceuticals. One aspect of particular interest to understanding pharmaceutically relevant amorphous solids is the phenomena of structural relaxation. Structural relaxation in this context refers to the physical changes in the locally preferred packing arrangement of molecules or groups of molecules attributed to aging or annealing. It is believed that the packing arrangement of molecules and groups of molecules, including the presence of a secondary (crystalline) phase, influences the physical state and the observed changes in the viscoelastic properties of an amorphous solid during storage. Further, the anisotropy or 'shape' of the molecules that comprise these disordered materials plays an integral role in the maintenance of this microstructure. Effects of time and isothermal storage temperature on the physical state and viscoelastic properties of quench-cooled amorphous indomethacin were investigated using as-quenched and powdered preparations. When stored at greater than 12°C below its glass transition temperature (45-47°C), the as-quenched solid displays no evidence of crystalline indomethacin, whereas a measurable increase in crystalline content is detected for the powdered solid over the 24 h period examined. For storage temperatures greater than 22°C below the glass transition temperature of the as prepared material, the data suggest that the extent of relaxation and the relative width of the glass transition region are equal to or greater than the powdered preparation over all temperature conditions studied. At storage temperatures closer to the glass transition temperature, these parameters are observed to decrease and approach the magnitude observed at lower storage temperatures. An initial assessment of structural change in quench-cooled amorphous indomethacin on isothermal storage was examined using pair distribution functions (PDF) derived from measured x-ray powder diffraction (XRPD) data. Structural change was examined relative to the PDF obtained for the as-quenched sample. The data suggests that a higher packing density is achieved after isothermal storage as indicated by the decrease in the width of the nearest-neighbor and next nearest-neighbor PDF peaks. The greatest change was observed at Tg-22 C, which corresponds with observations made from thermal analysis. Effects of molecular anisotropy on the packing patterns and structure relaxation behavior of quench-cooled amorphous solids were also investigated using four structurally-diverse model compounds—salicin, indomethacin, felodipine and nifedipine. A simple physical description of each molecule and its corresponding packing pattern in as-quenched specimens were obtained by methods of direct observation and from total scattering using pair distribution functions. Thermal parameters were acquired by differential scanning calorimetry (DSC). The data suggest that the molecular packing coefficient and the aspect ratios of the molecule and the common packing distances are related to parameters commonly used to assess structural relaxation by thermal methods. Further, the as-quenched materials with the lower degree of packing (and presumably the greater free volume), as determined from the aspect ratio of the packing distances were found to change to a greater extent and at a more rapid rate on storage. Of particular interest, a power law relationship that relates the shift factor required for superposition of the structural relaxation rate data with the elapsed storage time was established. This evidence lends support for the fundamental role of molecular shape in determining the structural relaxation behavior on storage. A conceptual model for the structural evolution of an amorphous solid during isothermal storage below the glass transition region is proposed. In this model, a quench-cooled amorphous solid immediately after preparation is viewed as comprised of non-periodic, locally stable domain structures, which emerge as a direct consequence of the excess strain created in the microstructure during quench-cooling and the anisotropy of the constituent molecules. The dynamic structures maintained at equilibrium in the liquid phase persist during quench-cooling below the glass transition region, and increase in size as the system volume decreases with decreasing temperature. On impingement of these locally stable structures, two physical characteristics, which are important in the physical stability of the amorphous material during storage, result as a direct consequence of non-periodic structures packing in a reduced volume; high-energy interfaces resulting from unsatisfied bonding and defects or 'voids' structures due to the incomplete filling of space.

Degree

Ph.D.

Advisors

Morris, Purdue University.

Subject Area

Pharmacy sciences

COinS