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Multivariate Synergies in Pharmaceutical Roll Compaction: The quality influence of raw materials and process parameters by design of experiments
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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 [en]
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: urn:nbn:se:umu:diva-96441ISBN: 978-91-7601-162-1 (print)OAI: oai:DiVA.org:umu-96441DiVA: diva2:764715
Public defence
2014-12-12, KB3A9, KBC-huset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2014-11-21 Created: 2014-11-20 Last updated: 2014-11-21Bibliographically approved
List of papers
1. A Quality by Design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction
Open this publication in new window or tab >>A Quality by Design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction
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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
Keyword
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:nbn:se:umu:diva-66681 (URN)10.1016/j.ijpharm.2013.02.036 (DOI)23434544 (PubMedID)
Available from: 2013-02-26 Created: 2013-02-26 Last updated: 2017-12-06Bibliographically approved
2. Design Space Estimation of the Roller Compaction Process
Open this publication in new window or tab >>Design Space Estimation of the Roller Compaction Process
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2013 (English)In: Industrial & Engineering Chemistry Research, ISSN 0888-5885, E-ISSN 1520-5045, Vol. 52, no 35, 12408-12419 p.Article in journal (Refereed) Published
Abstract [en]

Roller compaction (RC) is a continuous process for solid dosage form manufacturing within the pharmaceutical industry achieving similar goals as wet granulation while avoiding liquid exposure. From a quality by design perspective, the aim of the present study was to demonstrate the applicability of statistical design of experiments (DoE) and multivariate modeling principles to identify the Design Space of a roller compaction process using a predictive risk-based approach. For this purpose, a reduced central composite face-centered (CCF) design was used to evaluate the influence of roll compaction process variables (roll force, roll speed, gap width, and screen size) on the different intermediate and final products (ribbons, granules, and tablets) obtained after roll compaction, milling, and tableting. After developing a regression model for each response, optimal settings were found which comply with the response criteria. Finally, a predictive risk based approach using Monte Carlo simulation of the factor variability and its influence on the responses was applied which fulfill the criteria for the responses in a space where there is a low risk for failure. Responses were as follows: granule throughput, ribbon porosity, granules particle size, and tablets tensile strength. The multivariate method orthogonal partial least-squares (OPLS) was used to model product dependencies between process steps e.g. granule properties with tablet properties. Those results confirmed that the tensile strength reduction, known to affect plastic materials when roll compacted, was not prominent when using brittle materials. While direct compression qualities are frequently used for roll compacted drug products because of their excellent flowability and good compaction properties, this study confirmed earlier findings that granules from these qualities were more poor flowing than the corresponding powder blend.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-71222 (URN)10.1021/ie303580y (DOI)
Funder
Swedish Research Council, 2011-6044
Available from: 2013-05-23 Created: 2013-05-23 Last updated: 2017-12-06Bibliographically approved
3. Near-infrared chemical imaging (NIR-CI) on roll compacted ribbons and tablets - multivariate mapping of physical and chemical properties
Open this publication in new window or tab >>Near-infrared chemical imaging (NIR-CI) on roll compacted ribbons and tablets - multivariate mapping of physical and chemical properties
2015 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 483, no 1-2, 200-211 p.Article in journal (Refereed) Published
Abstract [en]

Near-infrared chemical imaging (NIR-CI) is an attractive technique within the pharmaceutical industry, where tools are continuously in demand to assess the quality of the intermediate and final products. The present paper demonstrates how NIR-CI in combination with multivariate methods was utilized to spatially map physical properties and content of roll compacted ribbons and tablets. Additionally, extracted textural parameters from tablet images were correlated to the design parameters of the roll compaction process as well as to the physical properties of the granules. The results established the use of NIR-CI as a complementary nondestructive tool to determine the ribbon density and map the density distribution across the width and along the length of the ribbons. For the tablets, the compaction pressure developed during compression increased with the lateral distance from the center. Therefore, NIR-CI can be an effective tool to provide information about the spatial distribution of the compaction pressures on the surface of the tablet. Moreover, low roll compaction roll force correlated to a heterogeneous type of texture in the API chemical image. Overall, texture analysis of the tablets enabled efficient investigation of the spatial variation and could be used to advance process understanding. Finally, orthogonal projections to latent structures (O2PLS) model facilitated the understanding of the interrelationships between textural features, design parameters and physical properties data by separately joint and unique variations.

Keyword
Near-infrared chemical imaging, Roll compaction, Orthogonal projections to latent structures (O2PLS), Grey-level co-occurrence matrices, Texture analysis
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:umu:diva-96433 (URN)10.1016/j.ijpharm.2015.02.006 (DOI)000350454200023 ()
Available from: 2014-11-20 Created: 2014-11-20 Last updated: 2017-12-05Bibliographically approved
4. Roll compaction process modeling: transfer between equipment and impact of process parameters
Open this publication in new window or tab >>Roll compaction process modeling: transfer between equipment and impact of process parameters
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2015 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 484, no 1-2, 192-206 p.Article in journal (Refereed) Published
Abstract [en]

In this study the roll compaction of an intermediate drug load formulation was performed using horizontally and vertically force fed roll compactors. The horizontally fed roll compactor was equipped with an instrumented roll technology allowing the direct measurement of normal stress at the roll surface, while the vertically fed roll compactor was equipped with a force gauge between the roll axes. Furthermore, characterization of ribbons, granules and tablets was also performed. Ribbon porosity was primarily found to be a function of normal stress, exhibiting a quadratic relationship thereof. A similar quadratic relationship was also observed between roll force and ribbon porosity of the vertically fed roll compactor. The predicted peak pressure (Pmax) using the Johanson model was found to be higher than the measured normal stress, however, the predicted Pmax correlated well with the ribbon relative density/porosity and the majority of downstream properties of granules and tablets, demonstrating its use as a scale-independent parameter. A latent variable model was developed for both the horizontal and vertical fed roll compactors to express ribbon porosity as a function of geometric and process parameters. The model validation, performed with new data, resulted in overall good predictions. This study successfully demonstrated the scale up/transfer between two different roll compactors and revealed that the combined use of design of experiments, latent variable models and in silico predictions result in better understanding of the critical process parameters in roll compaction.

Keyword
Roll compaction modeling, Dry granulation, Scale up, Instrumented roll, Johanson model, Orthogonal projections to latent structures
National Category
Other Chemistry Topics Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-96435 (URN)10.1016/j.ijpharm.2015.02.042 (DOI)000351317400023 ()
Available from: 2014-11-20 Created: 2014-11-20 Last updated: 2017-12-05Bibliographically approved

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