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Multivariate methods in tablet formulation
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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.
Keyword [en]
Organic chemistry, PCA, statistical experimental design, multivariate design, PLS, excipients, direct compression, tablet formulation, robustness testing
Keyword [sv]
Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-268ISBN: 91-7305-653-7 (print)OAI: oai:DiVA.org:umu-268DiVA: diva2:142882
Public defence
2004-05-28, KB3B1, KBC, Linneaus väg, Umeå, 09:00
Opponent
Supervisors
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2011-03-10Bibliographically approved
List of papers
1. Multivariate methods in developing an evolutionary strategy for tablet formulation
Open this publication in new window or tab >>Multivariate methods in developing an evolutionary strategy for tablet formulation
2000 In: Drug Development and Industrial Pharmacy, Vol. 26, no 3, 275-296 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3956 (URN)
Available from: 2004-05-07 Created: 2004-05-07Bibliographically approved
2. Multivariate Methods in the Development of a New Tablet Formulation
Open this publication in new window or tab >>Multivariate Methods in the Development of a New Tablet Formulation
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2003 (English)In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 29, no 10, 1053-1075 p.Article in journal (Refereed) Published
Abstract [en]

The overall objective of this article is to use an efficient approach to find a suitable tablet formulation for direct compression. By using traditional approaches to statistical experimental design in tablet formulation, the number of experiments quickly grows when many descriptive variables or many excipients are included. To facilitate the screening process, a multivariate design, which allows a systematical evaluation of a large number of excipients with a limited number of experiments, was implemented. Formulations with acceptable values for disintegration time and crushing strength were obtained with some of the formulations in the present study. The multivariate experimental design strategy yielded PLS models that will be used to identify a region of interest for the optimization. The strategy is general and can be applied in many different areas of pharmaceutical research and development.

Place, publisher, year, edition, pages
New York: Marcel Dekker, 2003
Keyword
Multivariate design, Principal properties, PCA, PLS, Excipient, Tablet formulation
National Category
Chemical Sciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-3957 (URN)10.1081/DDC-120025864 (DOI)
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2017-12-14Bibliographically approved
3. Multivariate methods in the development of a new tablet formulation: optimization and validation
Open this publication in new window or tab >>Multivariate methods in the development of a new tablet formulation: optimization and validation
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2004 (English)In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 30, no 10, 1037-1049 p.Article in journal (Refereed) Published
Abstract [en]

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.

Place, publisher, year, edition, pages
New York: M. Dekker, 2004
Keyword
Multivariate design, Validation, Disintegration time, PCA, PLS
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-3958 (URN)10.1081/DDC-200040243 (DOI)
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2017-12-14Bibliographically approved
4. Multivariate Methods in the Development of a New Tablet Formulation: Excipient Mixtures and Principal Properties
Open this publication in new window or tab >>Multivariate Methods in the Development of a New Tablet Formulation: Excipient Mixtures and Principal Properties
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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
Keyword
Mixture design, D-Optimal, Excipient, Tablet formulation, PCA, PLS
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-3959 (URN)10.1080/03639040500410823 (DOI)
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2017-12-14Bibliographically approved
5. Robustness testing of a tablet formulation using multivariate design
Open this publication in new window or tab >>Robustness testing of a tablet formulation using multivariate design
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2006 (English)In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 32, no 3, 297-307 p.Article in journal (Refereed) Published
Abstract [en]

A total of 45 experiments were carried out to evaluate the robustness of two similar tablet formulations--a product of two strengths--with respect to normal batch-to-batch variation of the excipients and the active pharmaceutical ingredient. The formulations consist of 10 ingredients. Because of the differing amounts of active pharmaceutical ingredients, the two formulations also differ in the amounts of two of the diluents and one of the binders. The excipients and active pharmaceutical ingredient were characterized in terms of multiple variables, and principal properties were calculated with principal component analysis. A Plackett and Burman design was applied to the principal properties. The relationships between the design factors and two responses, mean disintegration time and mean crushing strength, were evaluated by using regression methods. Both formulations were found to be robust under controlled conditions.

Place, publisher, year, edition, pages
Taylor & Francis Group, LLC, 2006
Keyword
Robustness testing, Plackett-Burman design, multivariate design, PCA, PLS
Identifiers
urn:nbn:se:umu:diva-19041 (URN)10.1080/03639040500518823 (DOI)16556534 (PubMedID)
Available from: 2009-03-03 Created: 2009-03-03 Last updated: 2017-12-13Bibliographically approved

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