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In vitro-solubility and supersaturation behavior of supersaturating drug delivery systems
Luleå University of Technology, Department of Health Sciences, Medical Science.ORCID iD: 0000-0002-2273-457x
2018 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
In vitro-löslighet och övermättningsegenskaperhos övermättat läkemedels-administrationssystem (Swedish)
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: urn:nbn:se:ltu:diva-68787ISBN: 978-91-7790-154-9 (print)ISBN: 978-91-7790-155-6 (electronic)OAI: oai:DiVA.org:ltu-68787DiVA, id: diva2:1206930
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
List of papers
1. Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe
Open this publication in new window or tab >>Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe
2018 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 117, p. 147-153Article in journal (Refereed) Published
Abstract [en]

The interplay between supersaturation, precipitation and permeation characteristics of the poorly water-soluble drug ezetimibe (EZ) was investigated. Supersaturation and precipitation characteristics of EZ in the presence of Caco-2 cells were compared to those in a cell-free environment. The effect of the water-soluble polymer polyvinyl pyrrolidone (PVP-K30) on the supersaturation, precipitation and transport of EZ was also investigated and the amount of drug taken up by Caco-2 cells was quantified.

A one-compartment setup without Caco-2 cells (i.e. in the wells of cell-culture plates) was used to mimic a non-sink in vitro dissolution chamber. The two-compartment Caco-2 cell monolayer setup (with apical and basolateral compartments) was used to investigate how the absorption of EZ affects supersaturation. EZ in varying degrees of supersaturation (DS; 10, 20, 30 and 40) was introduced into the one-compartment setup or the apical chamber of the two-compartment setup. Samples were collected at specific times to determine supersaturation, precipitation and permeation. At the end of the study, Caco-2 cells were lysed and the intracellular amount of EZ was quantified.

In the one-compartment setup, a high DS was associated with rapid precipitation. Supersaturation was maintained for longer time periods and precipitation was lower in the presence of Caco-2 cells. There were no significant differences in the absorption rate of the drug, even at high concentrations on the apical side. Permeability coefficients for all supersaturated solutions (i.e. DS 10–40) were significantly (p < 0.05) different from those when EZ was present in crystalline form. Both concentrations of PVP-K30 (i.e. 0.05% and 0.1% w/v) improved solubility and supersaturation of EZ when added to the apical side, however, the increase in absorption at the higher concentration was not proportional. The amount of intracellular EZ increased with increasing DS in the apical side, until the saturation limit was reached in the cells (i.e. at DS 30 and higher).

This study demonstrated that precipitation of EZ could be overestimated when supersaturation was investigated without the implementation of an absorption compartment in vitro, both in the absence and in the presence of polymer.

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Other Health Sciences
Research subject
Health Science
Identifiers
urn:nbn:se:ltu:diva-67527 (URN)10.1016/j.ejps.2018.01.047 (DOI)000430368800018 ()29408604 (PubMedID)2-s2.0-85042182339 (Scopus ID)
Note

Validerad;2018;Nivå 2;2018-03-01 (andbra)

Available from: 2018-02-06 Created: 2018-02-06 Last updated: 2018-06-11Bibliographically approved
2. Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media
Open this publication in new window or tab >>Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media
2017 (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.  

National Category
Other Health Sciences
Research subject
Health Science
Identifiers
urn:nbn:se:ltu:diva-10634 (URN)10.1080/03639045.2016.1220566 (DOI)000394022300009 ()27487184 (PubMedID)2-s2.0-84984655366 (Scopus ID)97717bba-7cba-45dd-96f0-e41d826a95ac (Local ID)97717bba-7cba-45dd-96f0-e41d826a95ac (Archive number)97717bba-7cba-45dd-96f0-e41d826a95ac (OAI)
Note

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

Available from: 2016-09-29 Created: 2016-09-29 Last updated: 2018-05-18Bibliographically approved

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