EFFECT OF COMPRESSION FORCES ON THE STRUCTURAL STABILITY OF AMORPHOUS SYSTEMS

The failure of most new chemical entities to reach the market is mainly due to their drugability problems. The main causes of their drugability problem is poor bioavailability as the result of poor solubility or/and poor permeability through the GI wall. Various formulation strategies showed their capability to improve the kinetic solubility and dissolution rate of poorly water soluble drugs. The general introduction section merely focused on solid form modifications as a formulation strategy for poorly water soluble drugs. Solid dispersions are comparably discussed in detail including their preparation methods, stabilization mechanisms and the hurdles for the success of ASD in commercialized drug products with elaborate literature examples. Alternate solid forms, polymorphic forms and amorphous forms can also lead to differences in molecular, particulate and bulk level properties of the drug which can affect the bioavailability and processability of the drug. Therefore the relation of solid forms on physicochemical properties is also discussed briefly with practical examples. In addition, the solid form of drugs may also change during manufacturing which is briefly covered in the introduction section. An overview of pharmaceutical tableting, popular models to study the volume-pressure relation during compression and the mechanism and the consequences of plastic deformation of glassy polymers are also discussed.The general and specific objectives are further pointed out in chapter 2. The main objective of the project was to understand the role of compression on the structural and physical stability of amorphous solid dispersions and amorphous forms of pure drug. The glass forming properties and the glass stability of the amorphous form of pure drugs may play a role on the physical stability of amorphous solid dispersions. Indomethacin is a good glass former with relatively good physical stability. Amorphous indomethacin was prepared by cooling the molten sample rapidly (25°C/min) or slowly (0.2°C/min) to room temperature. The experimental protocols were devoid of stresses applied during sample transfer and preparation for analysis since compression and further analysis by thermal, vibrational spectroscopy and PXRD techniques were performed in the primary containers (DSC standard aluminum pan). Amorphous indomethacin generated from the gamma polymorphic form showed aging time dependent non-isothermal crystallization first predominantly to the stable gamma f