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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

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ABSTRACT

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 latter 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.

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Abbreviations

ACN:

acetonitrile

BCS:

biopharmaceutical classification system

CMC:

critical micelle concentration

DAD:

diode array detector

DoE:

design of experiments

G:

in vitro dissolution rate

GI:

gastrointestinal

I:

ionic strength

IVIVC:

in vitro/in vivo correlation

NaCl:

sodium chloride

NaTC:

sodium taurocholate

OPLS:

orthogonal partial least squares

PCA:

principal component analysis

RP-HPLC:

reversed phase high-performance liquid chromatography

RSD:

relative standard deviation

S:

apparent solubility

TFA:

trifluoroacetic acid

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ACKNOWLEDGEMENTS

The authors would like to thank Walter Lindberg, AstraZeneca Mölndal, Sweden, for letting us borrow the miniaturized rotating disk equipment. Anders Sokolowski, AS Consulting Uppsala, Sweden, is thanked for all the exceptional help in the media and buffer calculations/recipes used in this study. Expressed gratitude is made to Eva M. Karlsson, Anders S. Carlsson and Anders AS. Karlsson, AstraZeneca Mölndal, Sweden, for the generous donation of the surfactants (NaTC and lecithin). Johan Gottfries, Gottfries Medicinal AB Göteborg, Sweden, is thanked for all constructive discussions of the multivariate data analysis. Financial support from the Carl Trygger Foundation, Sweden, is gratefully acknowledged.

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  1. Division of Analytical Pharmaceutical Chemistry, Uppsala University, BMC, 751 23, Uppsala, Sweden

    Anita Maria Persson & Curt Pettersson

  2. Divison of Pharmacognosy, Uppsala University, BMC, 751 23, Uppsala, Sweden

    Josefin Rosén

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  1. Anita Maria Persson
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Correspondence to Anita Maria Persson.

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Persson, A.M., Pettersson, C. & Rosén, J. Multivariate Data Analysis of Factors Affecting the In Vitro Dissolution Rate and the Apparent Solubility for a Model Basic Drug Substance in Aqueous Media. Pharm Res 27, 1309–1317 (2010). https://doi.org/10.1007/s11095-010-0111-0

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