Evaluation and enhancement of physical stability of amorphous solid dispersions

A major concern during formulation development has been to enhance the dissolution rate and bioavailability of poorly water-soluble drugs.[1],[2] The amorphous forms of APIs have attracted considerable attention as the amorphous forms tend to exhibit significantly higher levels of supersaturation in aqueous media when compared to the crystalline forms.[3],[4] For drugs which bioavailability is limited by aqueous solubility (biopharmaceutical classification system (BCS) class II drugs), which is a significant number of recently discovered drug candidates, the improved solubility may lead to enhanced bioavailability.[5-7] Oral absorption of APIs depends on two broad, but crucial, events, namely drug solubilization and gastrointestinal permeation.[8] Amorphous solid dispersions have been widely investigated to increase the gastrointestinal permeability, and the roles played by polymers and other excipients were also studied.[9],[10] However, even after 40 years of active research there have not been many commercial products that have reached the market based on amorphous solid dispersion technology. [11, 12] The primary reason for this is a combination of the stability and scale up issues associated with this approach, which has been reported by several authors.[13-15] Hot-melt extrusion currently stands as the most promising approach for solving the scale up issues associated with amorphous solid dispersion systems.[16] Unfortunately, amorphous solid dispersion systems still face the issue that the amorphous form is, in general, thermodynamically unstable relative to its crystalline counterpart(s), [17], [18] and therefore may ultimately result in unacceptable changes in the API’s physical properties. [19] The most comapproach of preserving the solubility/bioavailability enhancement imparted by the high-energy amorphous form is to kinetically stabilize the drug substance in the amorphous state for the duration of the anticipated shelf life. Amorphous solid dispersions can be stabilized as such if there exists a sufficient energy barrier provided by the polymer(s) with a high glass transition temperature, or by way of molecular interactions between the API and the polymeric carrier, such as hydrogen bonding. So the study to evaluate and enhance the physical stability of the amorphous solid dispersions is with great importance for the pharmaceutical industry. This thesis would focus on the evaluation and enhancement of the physical stability of amorphous solid dispersion.

Name thesis:degree_name

Ph.D. in Pharmaceutical Sciences

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomolecular Sciences

Year dc:date.available

2016

Author dc:creator

• Feng, Xin

Contributors dc:contributor

• Michael A. Repka
• Samir A. Ross
• S. Narasimha Murthy

• amrphous
• hot melt extrusion
• polymer
• recrystallization
• solid dispersion
• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://egrove.olemiss.edu/etd/1471

OAI identifier oai:identifier

oai:egrove.olemiss.edu:etd-2470