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Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
2010 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 7, 1309-1317 p.Article in journal (Refereed) Published
Abstract [en]

Purpose. To evaluate the usefulness of a miniaturized rotating disk equipment for the determination of factors influencing the in vitro dissolution rate, G, of a model basic drug substance (terfenadine) in different aqueous media, using experimental design and multivariate data analysis. The apparent solubility, S, was included in the chemometric study.

Methods. The dissolution rate was determined with a miniaturized rotating disk apparatus and the solubility by shake-flask methodology. Media were based on acetate, phosphate or maleate buffers. The later used in fasted state simulated intestinal fluid (FaSSIF-V2). The chemometric analyses included fractional factorial design, principal component analysis (PCA) and orthogonal partial least squares (OPLS). Quantifications were made with a RP-HPLC-DAD system.

Results. The most influential factor for both G and S of terfenadine in the different media was pH. Apart from the ionic strength and sodium chloride concentration in the acetate medium, the effects of the other variables were insignificant implying no wetting effect of the surfactants.

Conclusions. The miniaturized rotating disk equipment was suitable to use, in conjunction with the chemometric analyses, in the evaluation of the factors affecting the in vitro dissolution rate. The apparent solubility was found to be influenced by the same factors as G.

Place, publisher, year, edition, pages
2010. Vol. 27, no 7, 1309-1317 p.
Keyword [en]
dissolution media, dissolution rate, solubility, chemometrics, miniaturized rotating disk equipment
National Category
Medicinal Chemistry
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-112089DOI: 10.1007/s11095-010-0111-0ISI: 000278694400012PubMedID: 20358263OAI: oai:DiVA.org:uu-112089DiVA: diva2:284902
Available from: 2010-01-08 Created: 2010-01-08 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Evaluation of a Miniaturized Rotating Disk Apparatus for In Vitro Dissolution Rate Measurements in Aqueous Media: Correlation of In Vitro Dissolution Rate with Apparent Solubility
Open this publication in new window or tab >>Evaluation of a Miniaturized Rotating Disk Apparatus for In Vitro Dissolution Rate Measurements in Aqueous Media: Correlation of In Vitro Dissolution Rate with Apparent Solubility
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The general aim of this thesis was to evaluate a newly designed and constructed miniaturized rotating disk apparatus for in vitro dissolution rate measurements of different drug substances from all of the classes in the Biopharmaceutical Classification System (BCS). The new equipment is based on a low volume flow-through cell of Plexiglas, a gold plated magnetic bar and a special designed press. The disk of drug substance (approx. 5 mg) is placed eccentrically in the bar. Rotation speeds were set with a graded magnetic stirrer. An external HPLC pump delivered a continuous flow of aqueous medium to the flow-through cell during dissolution testing.

A reversed phase high-performance liquid chromatography system using diode array detection (RP-HPLC-DAD) was coupled online to the new equipment. The injections from the miniaturized rotating disk outlet into the quantifying HPLC system were controlled by a six-position switching valve. The injection volumes from the valve and the autosampler, used for the external standards, were statistically evaluated to match each other volumetrically. No analyses were longer than three minutes, using isocratic mode.

A traditional USP rotating disk apparatus was used as a reference system and the two instruments were shown to be statistically dissimilar in the numerical dissolution rate values probably due to different hydrodynamics, but had approximately the same precision/repeatability. When correlating the logarithmic values of the in vitro dissolution rate (G) with the apparent solubility (S), using shake-flask methodology in the solubility studies, the two apparatuses gave the same correlation patterns. Further correlation studies were done where the media components were altered by the use of different buffer species or additives into the buffers, such as inorganic salts.

Chemometric tools, e.g. orthogonal partial least squares (OPLS), were used to better evaluate the most influential factors for G and S in different media. The most significant factor for a model basic drug substance (terfenadine) was pH, followed by the ionic strength (I) and added sodium chloride in one of the media. However, the surfactants in the Fasted State Simulated Intestinal Fluid (FaSSIF-V2) were found to be insignificant for G and S in this study (using a 95% confidence interval).

The new miniaturized apparatus is a promising prototype for in vitro dissolution rate measurements both for early screening purposes and in dissolution testing during drug development, but needs further instrumental improvements.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 118
Keyword
analytical methods, HPLC (high-performance liquid chromatography), miniaturization, in vitro dissolution rate, apparent solubility, physicochemical properties, dissolution media, correlation study, chemometrics
National Category
Medicinal Chemistry
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-112257 (URN)978-91-554-7708-0 (ISBN)
Public defence
2010-02-26, B22, BMC (Uppsala Biomedicinska Centrum), Dag Hammarskjöldsväg/Husargatan, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2010-02-04 Created: 2010-01-12 Last updated: 2010-02-22Bibliographically approved

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Persson, Anita MariaPettersson, Curt

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