Pirjo Tajarobi - Academia.edu (original) (raw)

Papers by Pirjo Tajarobi

Research paper thumbnail of Bench to batch: Linking pharmaceutical powder flow characterisation, intermediate bulk container discharge and video observations

International Journal of Pharmaceutics

Research paper thumbnail of Modelling the effect of L/S ratio and granule moisture content on the compaction properties in continuous manufacturing

International Journal of Pharmaceutics

Research paper thumbnail of Rheological properties and the state of water of microcrystalline cellulose and silicified microcrystalline cellulose wet masses

Rheological properties and the state of water of microcrystalline cellulose and silicified microc... more Rheological properties and the state of water of microcrystalline cellulose and silicified microcrystalline cellulose wet masses

Research paper thumbnail of Effect of shape on the physical properties of pharmaceutical tablets

International Journal of Pharmaceutics

Research paper thumbnail of Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation

European Journal of Pharmaceutical Sciences, 2022

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be... more In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

Research paper thumbnail of Robustness of a continuous direct compression line against disturbances in feeding

International Journal of Pharmaceutics, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of A quality by design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction

International journal of pharmaceutics, Jan 15, 2013

Roll compaction is a continuous process for solid dosage form manufacturing increasingly popular ... more 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 r...

Research paper thumbnail of Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction

International journal of pharmaceutics, Jan 15, 2011

Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat ... more Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response....

Research paper thumbnail of Roll compaction process modeling: Transfer between equipment and impact of process parameters

International Journal of Pharmaceutics, 2015

In this study, the roll compaction of an intermediate drug load formulation was performed using h... more 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.

Research paper thumbnail of Design Space Estimation of the Roller Compaction Process

Industrial & Engineering Chemistry Research, 2013

Roller compaction (RC) is a continuous process for solid dosage form manufacturing within the pha... more 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.

Research paper thumbnail of Continuous manufacturing of extended release tablets via powder mixing and direct compression

International Journal of Pharmaceutics, 2015

The aim of the current work was to explore continuous dry powder mixing and direct compression fo... more The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems.

Research paper thumbnail of Characterization of microcrystalline cellulose spheres and prediction of hopper flow based on a μ(I)-rheology model

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2019

The objective of this study was to characterize the rheology of a pharmaceutical material in the ... more The objective of this study was to characterize the rheology of a pharmaceutical material in the context of the µ(I)-rheology model and to use this model to predict powder flow in a manufacturing operation that is relevant to pharmaceutical manufacturing. The rheology of microcrystalline cellulose spheres was therefore characterized in terms of the μ(I)-rheology model using a modified Malvern Kinexus rheometer. As an example of an important problem in pharmaceutical manufacturing, the flow of these particles from a hopper was studied experimentally and numerically using a continuum Navier-Stokes solver based on the Volume-Of-Fluid (VOF) interface-capturing numerical method. The work shows that the rheology of this typical pharmaceutical material can be measured using a modified annular shear rheometer and that the results can be interpreted in terms of the μ(I)-rheology model. It is demonstrated that both the simulation results and the experimental data show a constant hopper discha...

Research paper thumbnail of Twin-screw granulation and high-shear granulation: the influence of mannitol grade on granule and tablet properties

International journal of pharmaceutics, 2020

Granule structure has a key influence on tablet critical quality attributes. The ability to contr... more Granule structure has a key influence on tablet critical quality attributes. The ability to control this structure through excipient choice is an important part of formulation development. Mannitol is a popular diluent and the choice of input grade has been shown to impact granule properties. Allopurinol formulations containing two grades of mannitol (Pearlitol 160C and 200SD) were prepared by wet-granulation (twin-screw and high-shear) at different liquid / solid ratios (0.3 and 0.6 g/g). The particle and bulk properties were characterised by a range of techniques and linked to flow performance and tablet tensile strength during compression on a rotary tablet press. During granulation, 200SD underwent a polymorphic transition from a mixture of α and β to predominantly β. This transition was accompanied by a morphology change. Mannitol needles were formed, giving more porous granules with a higher specific surface area, which led to poorer flow properties but higher tablet tensile s...

Research paper thumbnail of Comparison between twin-screw and high-shear granulation - The effect of filler and active pharmaceutical ingredient on the granule and tablet properties

Research paper thumbnail of Powder flow from an intermediate bulk container – Discharge predictions and experimental evaluation

International Journal of Pharmaceutics

Research paper thumbnail of Drying in a continuous wet granulation line: Investigation of different end of drying control methods

Research paper thumbnail of Continuous Twin Screw Wet Granulation and Drying – Control Strategy for Drug Product Manufacturing

Journal of Pharmaceutical Sciences

The use of Continuous Manufacturing has been increasing within the pharmaceutical industry over t... more The use of Continuous Manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This paper focuses on development of appropriate control strategies for Continuous Wet Granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The paper also discusses the use of Process Analytical Technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique. Thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process like wet granulation compared to direct compression process.

Research paper thumbnail of Tableting performance of various mannitol and lactose grades assessed by compaction simulation and chemometrical analysis

International Journal of Pharmaceutics

Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several co... more Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several commercial grades that are produced using different manufacturing processes. These grades significantly differ in particulate and powder properties that impact tablet manufacturability. Choice of sub-optimum type or grade of excipient in tablet formulation can lead to manufacturing problems and difficulties, which are magnified during a continuous manufacturing process. Previous characterization of tableting performance of these materials was limited in scope and under conditions not always realistic to the commercial production of tablets. This work seeks to comprehensively characterize the compaction properties of 11 mannitol and 5 lactose grades using a compaction simulator at both slow and fast tableting speeds. These include tabletability, compressibility, tablet brittleness, die-wall stress transmission, and strain rate sensitivity. A chemometrical analysis of data, using the partial least square technique, was performed to construct a model to provide accurate prediction of tablet tensile strength for mannitol grades. Such knowledge facilitates the selection of suitable tablet filler to attain high quality tablet products.

Research paper thumbnail of Comparison between integrated continuous direct compression line and batch processing – The effect of raw material properties

European Journal of Pharmaceutical Sciences

Abstract There is a current trend in pharmaceutical manufacturing to shift from traditional batch... more Abstract There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing. Graphical abstract Figure. No Caption available.

Research paper thumbnail of A systematic study of the impact of changes of roller compactor equipment on granule and tablet properties

Powder Technology

Abstract Typical industrial development of roller compaction processes include changes in scale f... more Abstract Typical industrial development of roller compaction processes include changes in scale from laboratory to pilot and then further to production scale and also changes in equipment design due to equipment availability in different manufacturing facilities. Transfer and scale-up of roller compaction processes based on conservation of ribbon density is relatively well established, although different equipment designs, such as side seals and ribbon milling systems can lead to changes in downstream quality attributes, including granules and tablets. The aim of this study was to investigate this transfer/scale-up approach by systematically comparing the ribbon, granule and tablet properties between three different roller compactors from the vendors: Hosokawa, Alexanderwerk and Gerteis. A larger amount of uncompacted material was observed for the Hosokawa compared to Alexanderwerk and Gerteis, partly due to side seal leakage. To reduce the material bypass fraction, the Hosokawa was modified by using tight polymer cheek plates and concave rolls although the granules still exhibited a large amount of fines. One cause is the key difference in the roll force control. The roll force on the Hosokawa is controlled by proportional–integral–derivative (PID) regulation of the feeders, which leads to large force variations. In contrast, the Alexanderwerk and Gerteis achieve an almost constant force by using a hydraulic pressure system. Granules from all roller compactors were successfully pressed into tablets, and there was no correlation between the particle size and tabletability. However, the tabletability was better for granules from ribbons with higher porosity, which indicated an effect of granule hardening in the roller compaction step. This work demonstrates that conserving ribbon porosity when moving between different roller compactors is not sufficient to achieve granules with identical properties, indicating that a more advanced approach is needed for scale-up or transfer.

Research paper thumbnail of Bench to batch: Linking pharmaceutical powder flow characterisation, intermediate bulk container discharge and video observations

International Journal of Pharmaceutics

Research paper thumbnail of Modelling the effect of L/S ratio and granule moisture content on the compaction properties in continuous manufacturing

International Journal of Pharmaceutics

Research paper thumbnail of Rheological properties and the state of water of microcrystalline cellulose and silicified microcrystalline cellulose wet masses

Rheological properties and the state of water of microcrystalline cellulose and silicified microc... more Rheological properties and the state of water of microcrystalline cellulose and silicified microcrystalline cellulose wet masses

Research paper thumbnail of Effect of shape on the physical properties of pharmaceutical tablets

International Journal of Pharmaceutics

Research paper thumbnail of Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation

European Journal of Pharmaceutical Sciences, 2022

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be... more In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

Research paper thumbnail of Robustness of a continuous direct compression line against disturbances in feeding

International Journal of Pharmaceutics, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of A quality by design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction

International journal of pharmaceutics, Jan 15, 2013

Roll compaction is a continuous process for solid dosage form manufacturing increasingly popular ... more 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 r...

Research paper thumbnail of Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction

International journal of pharmaceutics, Jan 15, 2011

Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat ... more Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response....

Research paper thumbnail of Roll compaction process modeling: Transfer between equipment and impact of process parameters

International Journal of Pharmaceutics, 2015

In this study, the roll compaction of an intermediate drug load formulation was performed using h... more 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.

Research paper thumbnail of Design Space Estimation of the Roller Compaction Process

Industrial & Engineering Chemistry Research, 2013

Roller compaction (RC) is a continuous process for solid dosage form manufacturing within the pha... more 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.

Research paper thumbnail of Continuous manufacturing of extended release tablets via powder mixing and direct compression

International Journal of Pharmaceutics, 2015

The aim of the current work was to explore continuous dry powder mixing and direct compression fo... more The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems.

Research paper thumbnail of Characterization of microcrystalline cellulose spheres and prediction of hopper flow based on a μ(I)-rheology model

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2019

The objective of this study was to characterize the rheology of a pharmaceutical material in the ... more The objective of this study was to characterize the rheology of a pharmaceutical material in the context of the µ(I)-rheology model and to use this model to predict powder flow in a manufacturing operation that is relevant to pharmaceutical manufacturing. The rheology of microcrystalline cellulose spheres was therefore characterized in terms of the μ(I)-rheology model using a modified Malvern Kinexus rheometer. As an example of an important problem in pharmaceutical manufacturing, the flow of these particles from a hopper was studied experimentally and numerically using a continuum Navier-Stokes solver based on the Volume-Of-Fluid (VOF) interface-capturing numerical method. The work shows that the rheology of this typical pharmaceutical material can be measured using a modified annular shear rheometer and that the results can be interpreted in terms of the μ(I)-rheology model. It is demonstrated that both the simulation results and the experimental data show a constant hopper discha...

Research paper thumbnail of Twin-screw granulation and high-shear granulation: the influence of mannitol grade on granule and tablet properties

International journal of pharmaceutics, 2020

Granule structure has a key influence on tablet critical quality attributes. The ability to contr... more Granule structure has a key influence on tablet critical quality attributes. The ability to control this structure through excipient choice is an important part of formulation development. Mannitol is a popular diluent and the choice of input grade has been shown to impact granule properties. Allopurinol formulations containing two grades of mannitol (Pearlitol 160C and 200SD) were prepared by wet-granulation (twin-screw and high-shear) at different liquid / solid ratios (0.3 and 0.6 g/g). The particle and bulk properties were characterised by a range of techniques and linked to flow performance and tablet tensile strength during compression on a rotary tablet press. During granulation, 200SD underwent a polymorphic transition from a mixture of α and β to predominantly β. This transition was accompanied by a morphology change. Mannitol needles were formed, giving more porous granules with a higher specific surface area, which led to poorer flow properties but higher tablet tensile s...

Research paper thumbnail of Comparison between twin-screw and high-shear granulation - The effect of filler and active pharmaceutical ingredient on the granule and tablet properties

Research paper thumbnail of Powder flow from an intermediate bulk container – Discharge predictions and experimental evaluation

International Journal of Pharmaceutics

Research paper thumbnail of Drying in a continuous wet granulation line: Investigation of different end of drying control methods

Research paper thumbnail of Continuous Twin Screw Wet Granulation and Drying – Control Strategy for Drug Product Manufacturing

Journal of Pharmaceutical Sciences

The use of Continuous Manufacturing has been increasing within the pharmaceutical industry over t... more The use of Continuous Manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This paper focuses on development of appropriate control strategies for Continuous Wet Granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The paper also discusses the use of Process Analytical Technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique. Thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process like wet granulation compared to direct compression process.

Research paper thumbnail of Tableting performance of various mannitol and lactose grades assessed by compaction simulation and chemometrical analysis

International Journal of Pharmaceutics

Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several co... more Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several commercial grades that are produced using different manufacturing processes. These grades significantly differ in particulate and powder properties that impact tablet manufacturability. Choice of sub-optimum type or grade of excipient in tablet formulation can lead to manufacturing problems and difficulties, which are magnified during a continuous manufacturing process. Previous characterization of tableting performance of these materials was limited in scope and under conditions not always realistic to the commercial production of tablets. This work seeks to comprehensively characterize the compaction properties of 11 mannitol and 5 lactose grades using a compaction simulator at both slow and fast tableting speeds. These include tabletability, compressibility, tablet brittleness, die-wall stress transmission, and strain rate sensitivity. A chemometrical analysis of data, using the partial least square technique, was performed to construct a model to provide accurate prediction of tablet tensile strength for mannitol grades. Such knowledge facilitates the selection of suitable tablet filler to attain high quality tablet products.

Research paper thumbnail of Comparison between integrated continuous direct compression line and batch processing – The effect of raw material properties

European Journal of Pharmaceutical Sciences

Abstract There is a current trend in pharmaceutical manufacturing to shift from traditional batch... more Abstract There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing. Graphical abstract Figure. No Caption available.

Research paper thumbnail of A systematic study of the impact of changes of roller compactor equipment on granule and tablet properties

Powder Technology

Abstract Typical industrial development of roller compaction processes include changes in scale f... more Abstract Typical industrial development of roller compaction processes include changes in scale from laboratory to pilot and then further to production scale and also changes in equipment design due to equipment availability in different manufacturing facilities. Transfer and scale-up of roller compaction processes based on conservation of ribbon density is relatively well established, although different equipment designs, such as side seals and ribbon milling systems can lead to changes in downstream quality attributes, including granules and tablets. The aim of this study was to investigate this transfer/scale-up approach by systematically comparing the ribbon, granule and tablet properties between three different roller compactors from the vendors: Hosokawa, Alexanderwerk and Gerteis. A larger amount of uncompacted material was observed for the Hosokawa compared to Alexanderwerk and Gerteis, partly due to side seal leakage. To reduce the material bypass fraction, the Hosokawa was modified by using tight polymer cheek plates and concave rolls although the granules still exhibited a large amount of fines. One cause is the key difference in the roll force control. The roll force on the Hosokawa is controlled by proportional–integral–derivative (PID) regulation of the feeders, which leads to large force variations. In contrast, the Alexanderwerk and Gerteis achieve an almost constant force by using a hydraulic pressure system. Granules from all roller compactors were successfully pressed into tablets, and there was no correlation between the particle size and tabletability. However, the tabletability was better for granules from ribbons with higher porosity, which indicated an effect of granule hardening in the roller compaction step. This work demonstrates that conserving ribbon porosity when moving between different roller compactors is not sufficient to achieve granules with identical properties, indicating that a more advanced approach is needed for scale-up or transfer.