Optimization of Dissolution Performance for Amorphous Solid Dispersions
Chailu Que
10.25394/PGS.11301389.v1
https://hammer.purdue.edu/articles/thesis/Optimization_of_Dissolution_Performance_for_Amorphous_Solid_Dispersions/11301389
<p>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 <i>in vivo</i>. 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.</p>
2019-12-03 13:51:48
Amorphous solid dispersion
Dissolution
Drug polymer interaction
Residual Crystallinity
Pharmaceutical Sciences