Optimization of Dissolution Performance for Amorphous Solid Dispersions

2019-12-03T13:51:48Z (GMT) by Chailu Que

Many newly discovered drugs have low aqueous solubility leading to poor dissolution behavior and inefficient drug absorption, resulting in low bioavailability. Generally, for oral dosage forms, there are two major routes of drug absorption in the gastrointestinal (GI) track: passive diffusion and carrier-mediated transportation. Regardless of the primary route, drug absorption is highly dependent on the amount of free drug present in the aqueous solution. One formulation strategy to enhance solubility is the formation of an amorphous solid dispersion (ASD), where the drug is dispersed in a hydrophilic polymer. Supersaturation can be achieved following dissolution of an ASD, which significantly increases the free drug concentration. Recent research shows that dissolution of an amorphous solid dispersion can lead to a concentration above the maximum supersaturation concentration, also known as amorphous solubility. When this occurs, the drug and solution undergo liquid-liquid phase separation resulting in the formation of a drug-rich colloidal phase. This can only be obtained when the drug and polymer undergo polymer-controlled dissolution. During polymer-controlled dissolution the dissolution rate of the drug is limited by the intrinsic dissolution rate of pure polymer and not the drug dissolution rate. This brings forth two advantages over physically stable ASD formulations that exhibit polymer-controlled dissolution. The first is that the dissolution rate of the drug is orders of magnitude higher, which allows for quick attainment of maximum supersaturation in vivo. The second advantage is that the drug-rich colloidal phase can serve as a reservoir with very fast replenishing rates. This extends the duration of maximum flux across biological membranes, allowing for higher bioavailability. In order to achieve the optimal dissolution performance for an ASD formulation, it is critical to understand how to achieve polymer-controlled dissolution, as well as the impact of any crystallization events, which can deplete the supersaturation advantage. Thus, my PhD research focuses on mechanistically understanding the elements that prevent apparently stable ASD formulations from attaining their optimal dissolution performance. The conclusions drawn from the research may significantly improve the bioavailability of amorphous drugs and provides fresh insight into new drug molecule candidate optimization and excipient selection when an ASD is the preferred formulation strategy.