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Solid-State Chemistry of Drugs: Chiral Separation, Polymorphism, and Surface Enrichment of Formulation Components
Solid-State Chemistry of Drugs: Chiral Separation, Polymorphism, and Surface Enrichment of Formulation Components
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103522
- ISBN
- 9798314884249
- DDC
- 615
- 서명/저자
- Solid-State Chemistry of Drugs: Chiral Separation, Polymorphism, and Surface Enrichment of Formulation Components
- 발행사항
- [Sl] : The University of Wisconsin - Madison, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 144 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
- 주기사항
- Advisor: Yu, Lian.
- 학위논문주기
- Thesis (Ph.D.)--The University of Wisconsin - Madison, 2025.
- 초록/해제
- 요약This dissertation focuses on several areas concerning solid-state chemistry of drugs: (1) chiral resolution by crystallization, (2) effect of surfactants on polymorphism and crystallization, and (3) surface enrichment of formulation components in an amorphous solid dispersion.Chirality is everywhere in nature. The natural amino acids are the L form, while the natural sugars are the D form. When a drug interacts with a living system, a change of chirality can make a medicine into a toxin. Among the methods to obtain enantiopure compounds, crystallization is the most economical. We first show that the relative energies of the chiral and achiral crystals influence the success of chiral separation by crystallization. In the cases where crystallization can generate chirality, the chiral crystal usually has lower energy than the achiral, while the opposite is true if no chiral separation occurs. This simple result helps assess the potential for a given system to undergo chiral separation by crystallization. We then investigate arabitol, showing it satisfies the rule we developed previously and that it indeed shows chiral separation by crystallization, using a seeding method to control the course of crystallization.Amorphous solid dispersions (ASDs) can be used to enhance the solubility and bioavailability of poorly soluble drugs. An ASD typically contains a drug, a surfactant, and a polymer. The surfactant is often present to aid wetting and dissolution, but can reduce the glass transition of the system, thus promoting the drug's crystallization and reducing its solubility. We investigate the effect of two common surfactants, Span 80 and Tween 80, on the crystallization and polymorphism of the antifungal posaconazole. We find that posaconazole, known to crystallize as only Form I in the bulk when pure, crystallizes Form I and Form II when doped. When either surfactant is present, the growth rates similarly increase but does not cause proportional increase of the polymorphs' nucleation rates, as observed for many ASDs where nucleation and growth are both under kinetic control. The effects are quantitatively accounted for by the Classical Nucleation Theory where surfactants are treated as ideal diluents of the host molecules.Work on binary ASDs has observed significant differences between the surface and bulk compositions, with impact on the wettability and stability of the material. In the final part of this thesis we extend the previous work to a realistic ternary ASD composed of posaconazole, Span 80, and a dispersion polymer (PVP or PVP/VA). The surfactant loading was fixed to 5 wt% and the drug/polymer ratio was varied. Using X-ray photoelectron spectroscopy, we observe strong enrichment of the surfactant at the surface with simultaneous depletion of the drug. Between the two polymers, the more hydrophilic PVP causes a larger enhancement of the surface enrichment effect. This effect already exists in the binary drug-surfactant mixture and is substantially enhanced by the addition of the polymers. The results demonstrate the importance of component interactions in altering the surface concentrations of ASDs and their performance.
- 일반주제명
- Pharmaceutical sciences
- 일반주제명
- Chemistry
- 일반주제명
- Materials science
- 일반주제명
- Biochemistry
- 키워드
- Chirality
- 키워드
- Crystallization
- 키워드
- Polymorphism
- 기타저자
- The University of Wisconsin - Madison Pharmaceutical Sciences
- 기본자료저록
- Dissertations Abstracts International. 86-11B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798314884249
■035 ▼a(MiAaPQ)AAI32038821
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a615
■1001 ▼aBorchardt-Setter, Kennedy A.
■24510▼aSolid-State Chemistry of Drugs: Chiral Separation, Polymorphism, and Surface Enrichment of Formulation Components
■260 ▼a[Sl]▼bThe University of Wisconsin - Madison▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a144 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-11, Section: B.
■500 ▼aAdvisor: Yu, Lian.
■5021 ▼aThesis (Ph.D.)--The University of Wisconsin - Madison, 2025.
■520 ▼aThis dissertation focuses on several areas concerning solid-state chemistry of drugs: (1) chiral resolution by crystallization, (2) effect of surfactants on polymorphism and crystallization, and (3) surface enrichment of formulation components in an amorphous solid dispersion.Chirality is everywhere in nature. The natural amino acids are the L form, while the natural sugars are the D form. When a drug interacts with a living system, a change of chirality can make a medicine into a toxin. Among the methods to obtain enantiopure compounds, crystallization is the most economical. We first show that the relative energies of the chiral and achiral crystals influence the success of chiral separation by crystallization. In the cases where crystallization can generate chirality, the chiral crystal usually has lower energy than the achiral, while the opposite is true if no chiral separation occurs. This simple result helps assess the potential for a given system to undergo chiral separation by crystallization. We then investigate arabitol, showing it satisfies the rule we developed previously and that it indeed shows chiral separation by crystallization, using a seeding method to control the course of crystallization.Amorphous solid dispersions (ASDs) can be used to enhance the solubility and bioavailability of poorly soluble drugs. An ASD typically contains a drug, a surfactant, and a polymer. The surfactant is often present to aid wetting and dissolution, but can reduce the glass transition of the system, thus promoting the drug's crystallization and reducing its solubility. We investigate the effect of two common surfactants, Span 80 and Tween 80, on the crystallization and polymorphism of the antifungal posaconazole. We find that posaconazole, known to crystallize as only Form I in the bulk when pure, crystallizes Form I and Form II when doped. When either surfactant is present, the growth rates similarly increase but does not cause proportional increase of the polymorphs' nucleation rates, as observed for many ASDs where nucleation and growth are both under kinetic control. The effects are quantitatively accounted for by the Classical Nucleation Theory where surfactants are treated as ideal diluents of the host molecules.Work on binary ASDs has observed significant differences between the surface and bulk compositions, with impact on the wettability and stability of the material. In the final part of this thesis we extend the previous work to a realistic ternary ASD composed of posaconazole, Span 80, and a dispersion polymer (PVP or PVP/VA). The surfactant loading was fixed to 5 wt% and the drug/polymer ratio was varied. Using X-ray photoelectron spectroscopy, we observe strong enrichment of the surfactant at the surface with simultaneous depletion of the drug. Between the two polymers, the more hydrophilic PVP causes a larger enhancement of the surface enrichment effect. This effect already exists in the binary drug-surfactant mixture and is substantially enhanced by the addition of the polymers. The results demonstrate the importance of component interactions in altering the surface concentrations of ASDs and their performance.
■590 ▼aSchool code: 0262.
■650 4▼aPharmaceutical sciences
■650 4▼aChemistry
■650 4▼aMaterials science
■650 4▼aBiochemistry
■653 ▼aAmorphous solid dispersion
■653 ▼aChiral resolution
■653 ▼aChirality
■653 ▼aCrystallization
■653 ▼aPolymorphism
■653 ▼aSurface composition
■690 ▼a0572
■690 ▼a0794
■690 ▼a0485
■690 ▼a0487
■71020▼aThe University of Wisconsin - Madison▼bPharmaceutical Sciences.
■7730 ▼tDissertations Abstracts International▼g86-11B.
■790 ▼a0262
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357509▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
