Phase Behavior of Amorphous Solid Dispersions during Hydration and Dissolution

Amorphous solid dispersions (ASDs) which are primarily comprised of drug(s) dispersed within a polymeric matrix are becoming increasingly prevalent as a formulation strategy to enhance the in vivo performance of poorly soluble compounds because of their ability to generate supersaturated solutions upon dissolution. The drug in an ASD typically has higher free energy relative to its crystalline counterpart/s and therefore can undergo a variety of phase transformations, which are accelerated upon contact with water, for instance, during storage or during dissolution. In the solid ASD matrix, the absorbed water molecules can cause crystallization and/or amorphous—amorphous phase separation (AAPS). In AAPS, a molecularly mixed ASD matrix phase separates and drug—polymer concentration gradients develop throughout the dispersion, with the components retaining their amorphous nature. The resultant drug-rich domains will be more susceptible to crystallization due to the lower polymer concentration, which can adversely affect the dissolution performance of the dispersion. In the solution phase, it has been observed that ASDs upon dissolution can lead to apparent concentrations higher than the amorphous solubility. The dissolved drug in excess of the amorphous solubility forms a second submicron amorphous drug-rich phase in the solution, and this phenomenon is referred to as liquid-liquid phase separation (LLPS). The drug-rich phase is in metastable equilibrium with the free drug in the solution, and both phases are supersaturated with respect to the crystalline solubility. In the gastrointestinal tract, LLPS may lead to higher absorption as the colloidal drug-rich phase can serve as a drug “reservoir” and can quickly replenish the free drug that is absorbed in the blood stream. Thus, from a performance standpoint, LLPS can be advantageous whereas AAPS can be detrimental. Currently, there exists a knowledge gap about the relationship between AAPS and LLPS and the factors that govern them. One of the reasons for the lack of understanding in the inter-relationships of the solid and solution state phase transformations is that it is analytically challenging to study drug-polymer miscibility in an ASD especially in a hydrated state. In this research, new fluorescence-based analytical approaches to characterize drug-polymer miscibility in ASDs were explored and developed. The newly developed methodologies were verified using established orthogonal analytical techniques. Once developed, the fluorescence-based techniques were used to study the impact of the polymer type and drug loading in an ASD on phase transformations such as AAPS and LLPS. A mechanistic understanding on the interplay between AAPS and LLPS and their impact on the observed supersaturation upon ASD dissolution was established. Understanding of the phase transformations provided through this research can offer insights into why some ASDs might show better performance with certain polymers. The results provide a guide to rational polymer selection to obtain better overall performance by manufacturing optimally performing ASDs at higher drug loadings which can help in decreasing the pill burden, thereby increasing patient compliance for chronic medication therapies