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A Quality by Design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Computational Life Science Cluster (CLiC))
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Computational Life Science Cluster (CLiC))
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2013 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 447, no 1-2, 47-61 p.Article in journal (Refereed) Published
Abstract [en]

Roll compaction is a continuous process for solid dosage form manufacturing increasingly popular within pharmaceutical industry. Although roll compaction has become an established technique for dry granulation, the influence of material properties is still not fully understood. In this study, a quality by design (QbD) approach was utilized, not only to understand the influence of different qualities of mannitol and dicalcium phosphate (DCP), but also to predict critical quality attributes of the drug product based solely on the material properties of that filler. By describing each filler quality in terms of several representative physical properties, orthogonal projections to latent structures (OPLS) was used to understand and predict how those properties affected drug product intermediates as well as critical quality attributes of the final drug product. These models were then validated by predicting product attributes for filler qualities not used in the model construction. The results of this study confirmed that the tensile strength reduction, known to affect plastic materials when roll compacted, is not prominent when using brittle materials. Some qualities of these fillers actually demonstrated improved compactability following roll compaction. While direct compression qualities are frequently used for roll compacted drug products because of their excellent flowability and good compaction properties, this study revealed that granules from these qualities were more poor flowing than the corresponding powder blends, which was not seen for granules from traditional qualities. The QbD approach used in this study could be extended beyond fillers. Thus any new compound/ingredient would first be characterized and then suitable formulation characteristics could be determined in silico, without running any additional experiments.

Place, publisher, year, edition, pages
Elsevier, 2013. Vol. 447, no 1-2, 47-61 p.
Keyword [en]
orthogonal projections to latent structures, mannitol, dicalcium phosphate, experimental design, principal component analysis, roll compaction, tablet manufacturing, quality by design, critical quality attributes, excipient quality
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-66681DOI: 10.1016/j.ijpharm.2013.02.036PubMedID: 23434544OAI: oai:DiVA.org:umu-66681DiVA: diva2:608198
Available from: 2013-02-26 Created: 2013-02-26 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Multivariate Synergies in Pharmaceutical Roll Compaction: The quality influence of raw materials and process parameters by design of experiments
Open this publication in new window or tab >>Multivariate Synergies in Pharmaceutical Roll Compaction: The quality influence of raw materials and process parameters by design of experiments
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Roll compaction is a continuous process commonly used in the pharmaceutical industry for dry granulation of moisture and heat sensitive powder blends. It is intended to increase bulk density and improve flowability. Roll compaction is a complex process that depends on many factors, such as feed powder properties, processing conditions and system layout. Some of the variability in the process remains unexplained. Accordingly, modeling tools are needed to understand the properties and the interrelations between raw materials, process parameters and the quality of the product. It is important to look at the whole manufacturing chain from raw materials to tablet properties.

The main objective of this thesis was to investigate the impact of raw materials, process parameters and system design variations on the quality of intermediate and final roll compaction products, as well as their interrelations. In order to do so, we have conducted a series of systematic experimental studies and utilized chemometric tools, such as design of experiments, latent variable models (i.e. PCA, OPLS and O2PLS) as well as mechanistic models based on the rolling theory of granular solids developed by Johanson (1965).

More specifically, we have developed a modeling approach to elucidate the influence of different brittle filler qualities of mannitol and dicalcium phosphate and their physical properties (i.e. flowability, particle size and compactability) on intermediate and final product quality. This approach allows the possibility of introducing new fillers without additional experiments, provided that they are within the previously mapped design space. Additionally, this approach is generic and could be extended beyond fillers. Furthermore, in contrast to many other materials, the results revealed that some qualities of the investigated fillers demonstrated improved compactability following roll compaction.

In one study, we identified the design space for a roll compaction process using a risk-based approach. The influence of process parameters (i.e. roll force, roll speed, roll gap and milling screen size) on different ribbon, granule and tablet properties was evaluated. In another study, we demonstrated the significant added value of the combination of near-infrared chemical imaging, texture analysis and multivariate methods in the quality assessment of the intermediate and final roll compaction products. Finally, we have also studied the roll compaction of an intermediate drug load formulation at different scales and using roll compactors with different feed screw mechanisms (i.e. horizontal and vertical). The horizontal feed screw roll compactor was also equipped with an instrumented roll technology allowing the measurement of normal stress on ribbon. Ribbon porosity was primarily found to be a function of normal stress, exhibiting a quadratic relationship. A similar quadratic relationship was also observed between roll force and ribbon porosity of the vertically fed roll compactor. A combination of design of experiments, latent variable and mechanistic models led to a better understanding of the critical process parameters and showed that scale up/transfer between equipment is feasible.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2014. 69 p.
Keyword
Roll compaction, dry granulation, mannitol, dicalcium phosphate, design of experiments, orthogonal projections to latent structures, critical quality attributes, tablet manufacturing, quality by design, design space, near-infrared chemical imaging, texture analysis, modeling, scale up, instrumented roll, Johanson model
National Category
Other Chemistry Topics Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-96441 (URN)978-91-7601-162-1 (ISBN)
Public defence
2014-12-12, KB3A9, KBC-huset, Umeå universitet, Umeå, 10:00 (English)
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Available from: 2014-11-21 Created: 2014-11-20 Last updated: 2014-11-21Bibliographically approved

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