자료유형  

 학위논문

Control Number  

0016932901

International Standard Book Number  

9798379851620

Dewey Decimal Classification Number  

660

Main Entry-Personal Name  

Yang, Ruochen.

Publication, Distribution, etc. (Imprint  

[S.l.] : Purdue University., 2022

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2022

Physical Description  

1 online resource(288 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-01, Section: B.

General Note  

Advisor: Taylor, Lynne S.

Dissertation Note  

Thesis (Ph.D.)--Purdue University, 2022.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약As 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.

Subject Added Entry-Topical Term  

Surfactants.

Subject Added Entry-Topical Term  

Polymers.

Subject Added Entry-Topical Term  

Humidity.

Subject Added Entry-Topical Term  

Spectrum analysis.

Subject Added Entry-Topical Term  

Nuclear magnetic resonance--NMR.

Subject Added Entry-Topical Term  

Microscopy.

Subject Added Entry-Topical Term  

Crystallization.

Subject Added Entry-Topical Term  

Molecular weight.

Subject Added Entry-Topical Term  

Statistical significance.

Subject Added Entry-Topical Term  

Hydration.

Subject Added Entry-Topical Term  

Drug dosages.

Subject Added Entry-Topical Term  

Analytical chemistry.

Subject Added Entry-Topical Term  

Atmospheric sciences.

Subject Added Entry-Topical Term  

Chemistry.

Subject Added Entry-Topical Term  

Medical imaging.

Subject Added Entry-Topical Term  

Optics.

Subject Added Entry-Topical Term  

Polymer chemistry.

Added Entry-Corporate Name  

Purdue University.

Host Item Entry  

Dissertations Abstracts International. 85-01B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:641989