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Pharmaceutics
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Continuous Twin Screw Granulation
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Continuous Twin Screw Granulation

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 35542

Special Issue Editors

Prof. Dr. Valérie Vanhoorne

E-Mail Website
Guest Editor
Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg, B-9000 Ghent, Belgium
Interests: pharmaceutical technology; continuous manufacturing; 3D printing; additive manufacturing; pellets; twin-screw granulation; direct compression; material science
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ashish Kumar

E-Mail Website
Guest Editor
Universiteit Gent, Ghent, Belgium
Interests: process modeling and simulation; equipment design; continuous manufacturing; pharmaceutical engineering

Special Issue Information

Dear Colleagues,

Today, granulation is frequently applied to improve the flowability, homogeneity and/or compressibility of formulations prior to tableting or capsule filling. A wide variety of granulation techniques is available for this purpose. However, driven by the advantages offered by continuous manufacturing, there is an increasing interest in continuous twin-screw granulation.

Complying with the quality-by-design principles requires identification and thorough knowledge of the interaction between critical process parameters, critical equipment settings, critical material attributes and critical granule attributes. As the residence time during continuous twin-screw granulation is of a different time-order than during batch-wise wet granulation, different formulation strategies are needed. Furthermore, integrating the unit operation of twin-screw granulation into a fully continuous tableting line requires advanced process control, the implementation of PAT and an understanding of the interaction between upstream and downstream unit operations.

This Special Issue aims to bring state-of-the-art research-related continuous twin-screw granulation to the attention of a wide audience. We would be delighted to receive submissions of articles related to formulation and/or process development, PAT implementation and the modeling of twin-screw granulation.

Prof. Dr. Valérie Vanhoorne
Prof. Dr. Ashish Kumar
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tablets
  • granules
  • PAT
  • process control
  • formulation
  • continuous manufacturing
  • quality-by-design
  • process modeling and simulation
  • process optimization

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 166 KiB  
Editorial
Advances in Twin-Screw Granulation
by Valérie Vanhoorne and Ashish Kumar
Pharmaceutics 2022, 14(1), 46; https://doi.org/10.3390/pharmaceutics14010046 - 27 Dec 2021
Viewed by 1876
Abstract
Twin-screw granulation (TSG) is an emerging process technology that allows both wet and dry granulation of powders with a wide range of properties [...] Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)

Research

Jump to: Editorial, Review

14 pages, 4792 KiB  
Article
Particle-Scale Modeling to Understand Liquid Distribution in Twin-Screw Wet Granulation
by Ashish Kumar, Stefan Radl, Krist V. Gernaey, Thomas De Beer and Ingmar Nopens
Pharmaceutics 2021, 13(7), 928; https://doi.org/10.3390/pharmaceutics13070928 - 22 Jun 2021
Cited by 7 | Viewed by 2632
Abstract
Experimental characterization of solid-liquid mixing for a high shear wet granulation process in a twin-screw granulator (TSG) is very challenging. This is due to the opacity of the multiphase system and high-speed processing. In this study, discrete element method (DEM) based simulations are [...] Read more.
Experimental characterization of solid-liquid mixing for a high shear wet granulation process in a twin-screw granulator (TSG) is very challenging. This is due to the opacity of the multiphase system and high-speed processing. In this study, discrete element method (DEM) based simulations are performed for a short quasi-two-dimensional simulation domain, incorporating models for liquid bridge formation, rupture, and the effect of the bridges on inter-particular forces. Based on the knowledge gained from these simulations, the kneading section of a twin-screw wet granulation process was simulated. The time evolution of particle flow and liquid distribution between particles, leading to the formation of agglomerates, was analyzed. The study showed that agglomeration is a rather delayed process that takes place once the free liquid on the particle surface is well distributed. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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22 pages, 3892 KiB  
Article
Improvement of a 1D Population Balance Model for Twin-Screw Wet Granulation by Using Identifiability Analysis
by Ana Alejandra Barrera Jiménez, Daan Van Hauwermeiren, Michiel Peeters, Thomas De Beer and Ingmar Nopens
Pharmaceutics 2021, 13(5), 692; https://doi.org/10.3390/pharmaceutics13050692 - 11 May 2021
Cited by 11 | Viewed by 2613
Abstract
Recently, the pharmaceutical industry has undergone changes in the production of solid oral dosages from traditional inefficient and expensive batch production to continuous manufacturing. The latest advancements include increased use of continuous twin-screw wet granulation and application of advanced modeling tools such as [...] Read more.
Recently, the pharmaceutical industry has undergone changes in the production of solid oral dosages from traditional inefficient and expensive batch production to continuous manufacturing. The latest advancements include increased use of continuous twin-screw wet granulation and application of advanced modeling tools such as Population Balance Models (PBMs). However, improved understanding of the physical process within the granulator and improvement of current population balance models are necessary for the continuous production process to be successful in practice. In this study, an existing compartmental one-dimensional PBM of a twin-screw granulation process was improved by altering the original aggregation kernel in the wetting zone as a result of an identifiability analysis. In addition, a strategy was successfully applied to reduce the number of model parameters to be calibrated in both the wetting zone and kneading zones. It was found that the new aggregation kernel in the wetting zone is capable of reproducing the particle size distribution that is experimentally observed at different process conditions as well as different types of formulations, varying in hydrophilicity and API concentration. Finally, it was observed that model parameters could be linked not only to the material properties but also to the liquid to solid ratio, paving the way to create a generic PBM to predict the particle size distribution of a new formulation. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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16 pages, 2847 KiB  
Article
Parametric Study of Residence Time Distributions and Granulation Kinetics as a Basis for Process Modeling of Twin-Screw Wet Granulation
by Timo Plath, Carolin Korte, Rakulan Sivanesapillai and Thomas Weinhart
Pharmaceutics 2021, 13(5), 645; https://doi.org/10.3390/pharmaceutics13050645 - 01 May 2021
Cited by 5 | Viewed by 4191
Abstract
Twin-screw wet granulation is a crucial unit operation in shifting from pharmaceutical batch to continuous processes, but granulation kinetics as well as residence times are yet poorly understood. Experimental findings are highly dependent on screw configuration as well as formulation, and thus have [...] Read more.
Twin-screw wet granulation is a crucial unit operation in shifting from pharmaceutical batch to continuous processes, but granulation kinetics as well as residence times are yet poorly understood. Experimental findings are highly dependent on screw configuration as well as formulation, and thus have limited universal validity. In this study, an experimental design with a repetitive screw setup was conducted to measure the effect of specific feed load (SFL), liquid-to-solid ratio (L/S), and inclusion of a distributive feed screw on particle size distribution (PSD) and shape as well as residence time distribution of a hydrophilic lactose/microcrystalline cellulose based formulation. An intermediate sampling point was obtained by changing inlet ports along the screw axis. Camera-based particle size analysis (QICPIC) indicated no significant change of PSD between the first and second kneading section, except for low L/S and low SFL where fines increase. Mean residence time was approximated as a bilinear fit of L/S and SFL. Moreover, large mass flow pulsations were observed by continuous camera measurements of residence time distribution and correlated to hold-up of the twin-screw granulator. These findings indicate fast granulation kinetics and process instabilities for high mean residence times, questioning current standards of two kneading compartments for wet granulation. The present study further underlines the necessity of developing a multiscale simulation approach including particle dynamics in the future. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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19 pages, 2857 KiB  
Article
A Semi-Mechanistic Prediction of Residence Time Metrics in Twin Screw Granulation
by Shashank Venkat Muddu, Lalith Kotamarthy and Rohit Ramachandran
Pharmaceutics 2021, 13(3), 393; https://doi.org/10.3390/pharmaceutics13030393 - 16 Mar 2021
Cited by 5 | Viewed by 2760
Abstract
This work is concerned with the semi-mechanistic prediction of residence time metrics using historical data from mono-component twin screw wet granulation processes. From the data, several key parameters such as powder throughput rate, shafts rotation speed, liquid binder feed ratio, number of kneading [...] Read more.
This work is concerned with the semi-mechanistic prediction of residence time metrics using historical data from mono-component twin screw wet granulation processes. From the data, several key parameters such as powder throughput rate, shafts rotation speed, liquid binder feed ratio, number of kneading elements in the shafts and the stagger angle between the kneading elements were identified and physical factors were developed to translate those varying parameters into expressions affecting the key intermediate phenomena in the equipment, holdup, flow and mixing. The developed relations were then tested across datasets to evaluate the performance of the model, applying a k-fold optimization technique. The semi-mechanistic predictions were evaluated both qualitatively through the main effects plots and quantitatively through the parity plots and correlations between the tuning constants across datasets. The root mean square error (RMSE) was used as a metric to compare the degree of goodness of fit for different datasets using the developed semi-mechanistic relations. In summary this paper presents a new approach at estimating both the residence time metrics in twin screw wet granulation, mean residence time (MRT) and variance through semi-mechanistic relations, the validity of which have been tested for different datasets. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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14 pages, 3088 KiB  
Article
The Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation
by Alexander Ryckaert, Michael Ghijs, Christoph Portier, Dejan Djuric, Adrian Funke, Chris Vervaet and Thomas De Beer
Pharmaceutics 2021, 13(2), 293; https://doi.org/10.3390/pharmaceutics13020293 - 23 Feb 2021
Cited by 15 | Viewed by 3288
Abstract
The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying process is, [...] Read more.
The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying process is, however, still lacking. A first major goal was to investigate the breakage and attrition phenomena during transport of wet and dry granules, the filling phase, and drying phase on a ConsiGma-25 system (C25). Pneumatic transport of the wet granules after TSG towards the dryer induced extensive breakage, whereas the turbulent filling and drying phase of the drying cells caused rather moderate breakage and attrition. Subsequently, the dry transfer line was responsible for additional extensive breakage and attrition. The second major goal was to compare the influence of drying air temperature and drying time on granule size and moisture content for granules processed with a commercial-scale ConsiGma-25 system and with the R&D-scale ConsiGma-1 (C1) system. Generally, the granule quality obtained after drying with C1 was not predictive for the C25, making it challenging during process development with the C1 to obtain representative granules for the C25. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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17 pages, 4822 KiB  
Article
Evaluation of Binders in Twin-Screw Wet Granulation
by Claudia Köster, Sebastian Pohl and Peter Kleinebudde
Pharmaceutics 2021, 13(2), 241; https://doi.org/10.3390/pharmaceutics13020241 - 09 Feb 2021
Cited by 8 | Viewed by 4045
Abstract
The binders povidone (Kollidon 30), copovidone (Kollidon VA64), hypromellose (Pharmacoat 606), and three types of hyprolose (HPC SSL-SFP, HPC SSL, and HPC SL-FP) were evaluated regarding their suitability in twin-screw wet granulation. Six mixtures of lactose and binder as well as lactose without [...] Read more.
The binders povidone (Kollidon 30), copovidone (Kollidon VA64), hypromellose (Pharmacoat 606), and three types of hyprolose (HPC SSL-SFP, HPC SSL, and HPC SL-FP) were evaluated regarding their suitability in twin-screw wet granulation. Six mixtures of lactose and binder as well as lactose without binder were twin-screw granulated with demineralized water at different barrel fill levels and subsequently tableted. A screening run with HPC SSL determined the amount of water as an influential parameter for oversized agglomerates. Subsequent examination of different binders, especially Kollidon 30 and Kollidon VA64 resulted in large granules. All binders, except Pharmacoat 606, led to a reduction of fines compared to granulation without a binder. The molecular weight of applied hyproloses did not appear as influential. Tableting required an upstream sieving step to remove overlarge granules. Tableting was possible for all formulations at sufficient compression pressure. Most binders resulted in comparable tensile strengths, while Pharmacoat 606 led to lower and lactose without a binder to the lowest tensile strength. Tablets without a binder disintegrated easily, whereas binder containing tablets of sufficient tensile strength often nearly failed or failed the disintegration test. Especially tablets containing Pharmacoat 606 and HPC SL-FP disintegrated too slowly. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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19 pages, 2369 KiB  
Article
Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin Screw Wet Granulation Process
by Lise Vandevivere, Maxine Vangampelaere, Christoph Portier, Cedrine de Backere, Olaf Häusler, Thomas De Beer, Chris Vervaet and Valérie Vanhoorne
Pharmaceutics 2021, 13(2), 210; https://doi.org/10.3390/pharmaceutics13020210 - 03 Feb 2021
Cited by 6 | Viewed by 3408
Abstract
The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, [...] Read more.
The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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Review

Jump to: Editorial, Research

19 pages, 1887 KiB  
Review
Continuous Twin Screw Granulation: A Review of Recent Progress and Opportunities in Formulation and Equipment Design
by Christoph Portier, Chris Vervaet and Valérie Vanhoorne
Pharmaceutics 2021, 13(5), 668; https://doi.org/10.3390/pharmaceutics13050668 - 07 May 2021
Cited by 26 | Viewed by 5044
Abstract
Continuous twin screw wet granulation is one of the key continuous manufacturing technologies that have gained significant interest in the pharmaceutical industry as well as in academia over the last ten years. Given its considerable advantages compared to wet granulation techniques operated in [...] Read more.
Continuous twin screw wet granulation is one of the key continuous manufacturing technologies that have gained significant interest in the pharmaceutical industry as well as in academia over the last ten years. Given its considerable advantages compared to wet granulation techniques operated in batch mode such as high shear granulation and fluid bed granulation, several equipment manufacturers have designed their own manufacturing setup. This has led to a steep increase in the research output in this field. However, most studies still focused on a single (often placebo) formulation, hence making it difficult to assess the general validity of the obtained results. Therefore, current review provides an overview of recent progress in the field of continuous twin screw wet granulation, with special focus on the importance of the formulation aspect and raw material properties. It gives practical guidance for novel and more experienced users of this technique and highlights some of the unmet needs that require further research. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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22 pages, 601 KiB  
Review
Twin-Screw Melt Granulation for Oral Solid Pharmaceutical Products
by Seth P. Forster, Erin Dippold and Tiffany Chiang
Pharmaceutics 2021, 13(5), 665; https://doi.org/10.3390/pharmaceutics13050665 - 06 May 2021
Cited by 12 | Viewed by 4556
Abstract
This article highlights the advantages of pharmaceutical continuous melt granulation by twin-screw extrusion. The different melt granulation process options and excipients are described and compared, and a case is made for expanded use of twin-screw melt granulation since it is a flexible and [...] Read more.
This article highlights the advantages of pharmaceutical continuous melt granulation by twin-screw extrusion. The different melt granulation process options and excipients are described and compared, and a case is made for expanded use of twin-screw melt granulation since it is a flexible and continuous process. Methods for binder selection are profiled with a focus on rheology and physical stability impacts. For twin-screw melt granulation, the mechanism of granulation and process impact on granule properties are described. Pharmaceutical applications of melt granulation ranging from immediate release of soluble and insoluble APIs, taste-masking, and sustained release formulation are reviewed, demonstrating the range of possibilities afforded by twin-screw melt granulation. Full article
(This article belongs to the Special Issue Continuous Twin Screw Granulation)
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