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Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media
Luleå University of Technology, Department of Health Sciences, Medical Science.ORCID iD: 0000-0002-2273-457X
Departments of Pharmacology and Clinical Neuroscience, Umeå university.
Luleå University of Technology, Department of Health Sciences, Medical Science.ORCID iD: 0000-0002-0654-5410
Number of Authors: 32017 (English)In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 1, p. 79-88Article in journal (Refereed) Published
Abstract [en]

The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25˚C and 37˚C) were investigated in this work. Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry, modulated differential scanning calorimetry, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions. All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25˚C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried solid (SD) dispersions and supersaturation was maintained. However, at 37˚C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures. Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25˚C may not predict the supersaturation behavior at physiologically relevant temperatures.  

Place, publisher, year, edition, pages
Taylor & Francis, 2017. Vol. 43, no 1, p. 79-88
National Category
Other Health Sciences
Research subject
Health Science
Identifiers
URN: urn:nbn:se:ltu:diva-10634DOI: 10.1080/03639045.2016.1220566ISI: 000394022300009PubMedID: 27487184Scopus ID: 2-s2.0-84984655366Local ID: 97717bba-7cba-45dd-96f0-e41d826a95acOAI: oai:DiVA.org:ltu-10634DiVA, id: diva2:983579
Note

Validerad; 2017; Nivå 2; 2017-01-30 (andbra)

Available from: 2016-09-29 Created: 2016-09-29 Last updated: 2018-11-15Bibliographically approved
In thesis
1. In vitro-solubility and supersaturation behavior of supersaturating drug delivery systems
Open this publication in new window or tab >>In vitro-solubility and supersaturation behavior of supersaturating drug delivery systems
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
In vitro-löslighet och övermättningsegenskaperhos övermättat läkemedels-administrationssystem
Abstract [en]

The development of new pharmaceutical products has been challenged by the growing number of poorly water-soluble drugs, which often lead to suboptimal bioavailability. Various approaches, such as the use of amor-phous solid dispersions and cocrystals, have been used to improve the solu-bility, and subsequent bioavailability, of these drug molecules. Supersaturat-ing drug delivery systems (SDDSs) have potential for achieving adequate oral drug bioavailability by increasing the drug solubility and creating a su-persaturated state in the gastrointestinal tract. However, there is a need for better understanding of the supersaturation behavior in SDDSs and of the factors affecting supersaturation. The main objective of this thesis was to improve understanding of the supersaturation solubility behavior in SDDSs with a particular focus on rapidly dissolving solid forms (amorphous forms/cocrystals).

In the course of the work, a new formulation for ezetimibe using an amorphous solid dispersion was prepared, cocrystals of tadalafil were pre-pared, and oral films of silodosin were formulated for the first time. These new formulations were thoroughly characterized using a number of solid-state and pharmaceutical characterization techniques.

The dissolution and supersaturation behavior of the prepared SDDSs were studied. The effects of various factors on the supersaturation and precipita-tion characteristics were investigated. These factors included the preparation method, the temperature of the dissolution medium, the type of dissolution biorelevant medium (gastric/intestinal) used, the permeability of the relevant gastrointestinal membranes, the addition of polymers, and the addition of surfactants. The amorphous solid dispersions, cocrystals and oral films that were prepared represent new drug formulations that provide significantly higher dissolution rates and supersaturated solubility than crystalline drug forms. Solid dispersions prepared by the melting method had better super-saturation properties than those prepared by spray drying. The precipitation kinetics of the solid dispersion were faster at 37 ̊C than at 25 ̊C in bio-relevant media. Implementation of an absorption tool during in vitro evalua-tion of supersaturation levels could improve the prediction accuracy of su-persaturation and precipitation. A better understanding of the effects of ex-cipients on the supersaturation and precipitation behavior of these types of formulation was obtained in this thesis. The improvement in supersaturation solubility obtained by adding polymers and surfactants was not proportional to the amounts of excipient used.

This thesis has made notable contributions to the field of pharmaceutical science by advancing our understanding of the supersaturation solubility behavior of the newly prepared SDDSs.

Place, publisher, year, edition, pages
Luleå: Luleå University of Technology, 2018
Series
Doctoral thesis / Luleå University of Technology 1 jan 1997 → …, ISSN 1402-1544
National Category
Other Health Sciences
Research subject
Health Science
Identifiers
urn:nbn:se:ltu:diva-68787 (URN)978-91-7790-154-9 (ISBN)978-91-7790-155-6 (ISBN)
Public defence
2018-06-19, D770, Luleå, 10:00 (English)
Opponent
Supervisors
Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-06-08Bibliographically approved

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Al-Hayali, Amani Ibraheem YounisVelaga, Sitaram

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