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Multivariate Methods in the Development of a New Tablet Formulation: Excipient Mixtures and Principal Properties
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2006 (English)In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 32, no 1, 7-20 p.Article in journal (Refereed) Published
Abstract [en]

A tablet formulation for direct compression has previously been studied using multivariate design. An optimization study of one of the most important tablet properties, disintegration time, revealed that excipients with Principal Properties (PP's) that were predicted as suitable by the model were not represented within the studied material.

The feasibility of using mixtures of excipients in the multivariate approach to tablet formulation to solve this problem has been investigated in the present study. By mixing different excipients of the same excipient class, it should be possible to obtain mixtures with the predicted PP's, which in turn should give a formulation with the desired properties. In order to investigate the utility of this approach, separate mixture designs were applied to both binders and fillers (diluents).

As reported here, the Partial Least Squares Projections to Latent Structures (PLS) model developed in the previously published screening study has been validated in the sense that the interesting region of the PP space identified in it has been shown to contain excipients, pure or mixed, that give the formulation suitable properties. Formulations with suitable properties were found with the mixture experiments. The local models also offer several alternatives for the composition of the formulation that yield the desired disintegration time.

Place, publisher, year, edition, pages
New York: M. Dekker , 2006. Vol. 32, no 1, 7-20 p.
Keyword [en]
Mixture design, D-Optimal, Excipient, Tablet formulation, PCA, PLS
National Category
Chemical Sciences
URN: urn:nbn:se:umu:diva-3959DOI: 10.1080/03639040500410823OAI: diva2:142880
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2013-03-19Bibliographically approved
In thesis
1. Multivariate methods in tablet formulation
Open this publication in new window or tab >>Multivariate methods in tablet formulation
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the application of multivariate methods in a novel approach to the formulation of tablets for direct compression. It begins with a brief historical review, followed by a basic introduction to key aspects of tablet formulation and multivariate data analysis. The bulk of the thesis is concerned with the novel approach, in which excipients were characterised in terms of multiple physical or (in most cases) spectral variables. By applying Principal Component Analysis (PCA) the descriptive variables are summarized into a few latent variables, usually termed scores or principal properties (PP’s). In this way the number of descriptive variables is dramatically reduced and the excipients are described by orthogonal continuous variables. This means that the PP’s can be used as ordinary variables in a statistical experimental design. The combination of latent variables and experimental design is termed multivariate design or experimental design in PP’s. Using multivariate design many excipients can be included in screening experiments with relatively few experiments.

The outcome of experiments designed to evaluate the effects of differences in excipient composition of formulations for direct compression is, of course, tablets with various properties. Once these properties, e.g. disintegration time and tensile strength, have been determined with standardised tests, quantitative relationships between descriptive variables and tablet properties can be established using Partial Least Squares Projections to Latent Structures (PLS) analysis. The obtained models can then be used for different purposes, depending on the objective of the research, such as evaluating the influence of the constituents of the formulation or optimisation of a certain tablet property.

Several examples of applications of the described methods are presented. Except in the first study, in which the feasibility of this approach was first tested, the disintegration time of the tablets has been studied more carefully than other responses. Additional experiments have been performed in order to obtain a specific disintegration time. Studies of mixtures of excipients with the same primary function have also been performed to obtain certain PP’s. Such mixture experiments also provide a straightforward approach to additional experiments where an interesting area of the PP space can be studied in more detail. The robustness of a formulation with respect to normal batch-to-batch variability has also been studied.

The presented approach to tablet formulation offers several interesting alternatives, for both planning and evaluating experiments.

Place, publisher, year, edition, pages
Umeå: Kemi, 2004. 56 p.
Organic chemistry, PCA, statistical experimental design, multivariate design, PLS, excipients, direct compression, tablet formulation, robustness testing, Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
urn:nbn:se:umu:diva-268 (URN)91-7305-653-7 (ISBN)
Public defence
2004-05-28, KB3B1, KBC, Linneaus väg, Umeå, 09:00
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2011-03-10Bibliographically approved

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Gabrielsson, JonSjöström, Michael
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