Release Mechanisms of Amorphous Solid Dispersions
As the pharmaceutical industry moves towards molecular obesity with the use of high throughput screening for identification of promising candidates, the low aqueous solubilities of new chemical entities pose significant challenges to achieving adequate oral absorption and bioavailability. Enabling formulations are often needed to address this issue. Amorphous solid dispersion (ASD), where an amorphous drug and a polymer are molecularly mixed, has gained popularity as a dissolution/solubility enhancing strategy over the years. Upon ASD dissolution, the release rate of drug is much higher than that of the neat amorphous form of the drug. More importantly, the apparent concentration of drug in the solution can exceed its amorphous solubility through the formation of a drug-rich colloidal phase in the solution, also called nanodroplets. The presence of nanodroplets has been shown to be beneficial for oral absorption and bioavailability and their formation during release is therefore desirable. However, such release profiles are only achieved at relatively low drug loadings (DLs) and release tends to drop with increasing DL. For ASDs based on polyvinylpyrrolidone/vinyl acetate (PVPVA), drug release drops drastically once the DL exceeds a certain value, called limit of congruency (LoC). The low DL at which the ASD demonstrates good release also presents additional challenges since it can create a pill burden for patients due to the large amount of polymer needed in the formulation. Therefore, to achieve optimal drug product performance, it is crucial to understand the mechanisms of drug release. Therefore, this thesis focuses on understanding the factors affecting, and the mechanisms of ASD drug release, as well as enhancing drug release through addition of surfactants.
The glass transition temperature of a drug and its interaction with the polymer were identified as important factors affecting the drug release and LoC. Another phase transition occurring during ASD hydration/dissolution, amorphous-amorphous phase separation (AAPS), was shown to affect drug release from ASD significantly. During dissolution, water-induced AAPS occurs, and the initially miscible ASD separates into two phases, an insoluble drug-rich phase and a soluble water/polymer-rich phase. The formation of a continuous drug-rich phase at the ASD-solution interface was shown to be detrimental to drug release as it could act as barrier that blocked any further drug release. When the drug-rich phase formed adopted a discrete morphology or when phase separation occurred in the solution outside of the dissolving ASD matrix, good release could be achieved. Surfactants could interrupt the formation of the continuous drug-rich both kinetically and thermodynamically, improving drug release as a result. Other mechanisms of release enhancement by surfactants included increased polymer release rate, increased water ingress and plasticization. The findings in this thesis will provide insight into ASD release mechanisms, and facilitate rational excipient selection when designing ASD formulations.
- Doctor of Philosophy
- Industrial and Physical Pharmacy
- West Lafayette