uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The influence of drug loading and drug-polymer interactions on physical stability and supersaturation of spray-dried solid dispersions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-390257OAI: oai:DiVA.org:uu-390257DiVA, id: diva2:1341196
Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-08-14
In thesis
1. Molecular Mechanisms Influencing the Performance of Amorphous Formulations for Poorly Water-Soluble Drugs
Open this publication in new window or tab >>Molecular Mechanisms Influencing the Performance of Amorphous Formulations for Poorly Water-Soluble Drugs
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crystallisation is a concern for amorphous formulation because it compromises the solubility-enhancing benefit gained from amorphisation. Traditionally, amorphous formulation had been designed primarily based on trial-and-error approach. The success rate for amorphous formulation is unimpressive, due to a poor understanding of the formulation itself, especially with regard to its crystallisation behaviour. Therefore, this thesis aimed to propose a strategic approach for rational design of amorphous formulations, as opposed to the trial-and-error approach. This can be achieved by understanding what drives the crystallisation of amorphous drug, and when and how the amorphous drug crystallises. The information can guide the selection of drugs, excipients and preparation method to achieve amorphous formulations with favourable features.

In the first part of the thesis, a systematic protocol was proposed to identify mechanisms via which crystallisation takes place when amorphous drug is dissolved. The stabilisation strategy of supersaturation produced upon dissolution of amorphous drug was then recommended depending on the crystallisation mechanisms. A molecular dynamics (MD) simulations was used to understand drug-polymer interaction during supersaturation. It was revealed that hydrogen bond interaction is an important in stabilising supersaturation. The factors affecting glass-forming ability and long-term physical stability such as preparation method and humidity were then highlighted in the second study. A follow-up study was performed to elucidate the potential complications in using a standardised differential scanning calorimetry to classify promiscuous glass formers into any specific glass-forming ability/glass stability class. In the subsequent study, the effect of physical aging and/or crystallisation of amorphous drugs during storage on supersaturation potential was addressed. It was shown that, minor crystallisation of amorphous drug upon storage did not have a significant impact on the supersaturation potential during dissolution. Instead, the crystallisation pathway of the amorphous drug during dissolution plays a more important role in determining the supersaturation behaviour of some drugs. Finally, the impact of (i) drug loading on physical stability, supersaturation, drug/polymer miscibility, and (ii) the physical aging and/or crystallisation upon storage on supersaturation potential of spray-dried solid dispersions with HPMC-AS were discussed in the last study. It was observed that the effect of drug loading on physical stability and supersaturation, and the effect of physical aging and/or crystallisation during storage on supersaturation potential is highly drug-dependent. Similarly, the stabilisation effect of HPMC-AS varied across model drugs, drug loadings and crystallisation pathways (i.e. in solid or during dissolution). The Flory-Huggins interaction parameter calculated using MD simulations revealed good miscibility between the drugs and HPMC-AS at drug loadings investigated. In the presence of water molecules, various structural organizations of the drugs and HPMC-AS complexes were observed. Taken together, this thesis provides an improved understanding of crystallisation behaviour of amorphous formulations, which is useful to guide a rational design of amorphous formulations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 276
Keywords
Amorphous formulation, crystallisation, supersaturation, glass-forming ability, physical stability, glass stability, spray-dried solid dispersion, dissolution, promiscuous glass former, poorly-soluble drug, solid-to-solid, solution-mediated, particle-associated
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-390579 (URN)978-91-513-0717-6 (ISBN)
Public defence
2019-09-27, Room B21, Biomedical Center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-09-04 Created: 2019-08-14 Last updated: 2019-09-17

Open Access in DiVA

No full text in DiVA

Authority records BETA

Edueng, KhadijahKabedev, AlekseiMahlin, DennyBergström, Christel

Search in DiVA

By author/editor
Edueng, KhadijahKabedev, AlekseiMahlin, DennyBergström, Christel
By organisation
Department of Pharmacy
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 51 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf