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Pharmaceutics
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Powder Processing in Pharmaceutical Applications
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Powder Processing in Pharmaceutical Applications

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 43053

Special Issue Editors

Prof. Dr. Arno Kwade

E-Mail Website
Guest Editor
Institut für Partikeltechnik, Technische Universität Braunschweig, Braunschweig, Germany
Interests: particle comminution; particle formulation; product design; bulk solids handling; battery process engineering; pharmaceutical engineering; battery recycling
Special Issues, Collections and Topics in MDPI journals
Dr. Jan Henrik Finke

E-Mail Website
Guest Editor
Institute for Particle Technology, Technische Universität Braunschweig, Braunschweig, Germany

Special Issue Information

Dear Colleagues,

In all production processes of solid dosage forms, powders with a multitude of distributed properties must be processed. Starting with the handling for dispensing and weighing, over blending, dosing, comminution, and granulation, up to capsule filling or tableting, powder properties crucially determine the process performance and product quality. In any case, each powder in pharmaceutical formulations brings along distributions of various microscopic properties such as particle size, morphology, and surface energies as well as macroscopic properties such as flow behavior and bulk densities. Along the process chain, multiple powders are blended or more fundamentally change their properties, e.g. by granulation, causing complex changes that will affect their behavior in subsequent processes. Additionally, transportation and packaging of intermediates and final products can cause changes due to aeration, abrasion, or compaction. The determination of powder properties such as particle, surface, and flow properties require sophisticated, methodologic approaches to measure meaningful parameters under representative conditions. The deep knowledge of powder properties and quick and reliable measurement techniques become a prerequisite in the context of continuous process chains that need to immediately respond to material property changes to keep processes and product quality stable within specified ranges. To achieve this, well-developed model approaches need to be derived to predict and control any complex powder processing operation.

This special issue is dedicated to in-depth studies and reviews, presenting fundamental advancement in the scientific field of powder processing in pharmaceutical applications. Contributions addressing thorough insight into unit operations, innovative measurement methods for powder properties, model approaches providing prediction of effects such as demixing, segregation, overmixing, abrasion, deagglomeration, particle breakage, and residence time distribution based on material properties and process parameters, as well as research on continuous process chains are especially encouraged.

Prof. Dr. Arno Kwade
Dr. Jan Henrik Finke
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

  • Powder processing/handling
  • Process modelling
  • Powder properties
  • Flow behavior
  • Process performance
  • Continuous processes
  • Demixing/Segregation
  • Granulation
  • Tableting
  • Capsule filling

Published Papers (9 papers)

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Editorial

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3 pages, 159 KiB  
Editorial
Powder Processing in Pharmaceutical Applications—In-Depth Understanding and Modelling
by Jan Henrik Finke and Arno Kwade
Pharmaceutics 2021, 13(2), 128; https://doi.org/10.3390/pharmaceutics13020128 - 20 Jan 2021
Viewed by 1656
Abstract
In all production processes of solid dosage forms, powders with a multitude of distributed properties must be processed [...] Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)

Research

Jump to: Editorial

18 pages, 5771 KiB  
Article
Influence of Formulation Parameters on Redispersibility of Naproxen Nanoparticles from Granules Produced in a Fluidized Bed Process
by Martin Wewers, Stefan Czyz, Jan Henrik Finke, Edgar John, Bernard Van Eerdenbrugh, Michael Juhnke, Heike Bunjes and Arno Kwade
Pharmaceutics 2020, 12(4), 363; https://doi.org/10.3390/pharmaceutics12040363 - 16 Apr 2020
Cited by 16 | Viewed by 5638
Abstract
The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient’s convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the [...] Read more.
The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient’s convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the influence of several formulation parameters (i.e., type of carrier material, type and amount of additional polymeric drying excipient in the nanosuspension) on the redispersibility of naproxen nanoparticle-loaded granules produced in a fluidized bed process was investigated. The dissolution rate of the carrier material (i.e., sucrose, mannitol, or lactose) was identified as a relevant material property, with higher dissolution rates (sucrose > mannitol > lactose) resulting in better redispersibility of the products. Additionally, the redispersibility of the product granules was observed to improve with increasing amounts of polymeric drying excipient in the nanosuspension. The redispersibility was observed to qualitatively correlate with the degree of nanoparticle embedding on the surface of the corresponding granules. This embedding was assumed to be either caused by a partial dissolution and subsequent resolidification of the carrier surface dependent on the dissolution rate of the carrier material or by resolidification of the dissolved polymeric drying excipient upon drying. As the correlation between the redispersibility and the morphology of the corresponding granules was observed for all investigated formulation parameters, it may be assumed that the redispersibility of the nanoparticles is determined by their distance in the dried state. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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18 pages, 2980 KiB  
Article
Scaling Tableting Processes from Compaction Simulator to Rotary Presses—Mind the Sub-Processes
by Isabell Wünsch, Irene Friesen, Daniel Puckhaber, Thomas Schlegel and Jan Henrik Finke
Pharmaceutics 2020, 12(4), 310; https://doi.org/10.3390/pharmaceutics12040310 - 31 Mar 2020
Cited by 25 | Viewed by 4305
Abstract
Compaction simulators are frequently used in the formulation and process development of tablets, bringing about the advantages of flexibility, low material consumption, and high instrumentation to generate the most possible process understanding. However, their capability of resembling general aspects of rotary press compaction [...] Read more.
Compaction simulators are frequently used in the formulation and process development of tablets, bringing about the advantages of flexibility, low material consumption, and high instrumentation to generate the most possible process understanding. However, their capability of resembling general aspects of rotary press compaction and their precision in simulating or mimicking sub-processes such as feeding and filling need to be systematically studied. The effect of material deformation behavior, blend composition, and feeding on tensile strength and simulation precision as compared with rotary presses of different scales is evaluated in this study. Generally, good simulation performance was found for the studied compaction simulator. Compaction profile-sensitivity was demonstrated for highly visco-plastic materials while shear-sensitivity in feeding was demonstrated for lubricated blends of ductile particles. Strategies for the compensation of both in compaction simulator experiments are presented by careful investigation of the compaction stress over time profiles and introduction of a compaction simulator-adapted shear number approach to account for differences in layout and operation mode between compaction simulator and rotary press, respectively. These approaches support the general aim of this study to provide a more straightforward determination of scaling process parameters between rotary press and compaction simulator and facilitate a quicker and more reliable process transfer. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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19 pages, 4813 KiB  
Article
Impact of Particle and Equipment Properties on Residence Time Distribution of Pharmaceutical Excipients in Rotary Tablet Presses
by Daniel Puckhaber, Sebastian Eichler, Arno Kwade and Jan Henrik Finke
Pharmaceutics 2020, 12(3), 283; https://doi.org/10.3390/pharmaceutics12030283 - 21 Mar 2020
Cited by 12 | Viewed by 4177
Abstract
Paddle feeders are devices commonly used in rotary tablet presses to facilitate constant and efficient die filling. Adversely, the shear stress applied by the rotating paddles is known to affect the bulk properties of the processed powder dependent on the residence time. This [...] Read more.
Paddle feeders are devices commonly used in rotary tablet presses to facilitate constant and efficient die filling. Adversely, the shear stress applied by the rotating paddles is known to affect the bulk properties of the processed powder dependent on the residence time. This study focuses on the residence time distribution (RTD) of two commonly applied excipients (microcrystalline cellulose, MCC; dicalcium phosphate, DCP), which exhibit different flow properties inside rotary tablet presses. To realistically depict the powder flow inside rotary tablet presses, custom-made tracer powder was developed. The applied method was proven to be appropriate as the tracer and bulk powder showed comparable properties. The RTDs of both materials were examined in two differently scaled rotary tablet presses and the influence of process parameters was determined. To analyze RTDs independent of the mass flow, the normalized variance was used to quantify intermixing. Substantial differences between both materials and tablet presses were found. Broader RTDs were measured for the poorer flowing MCC as well as for the production scale press. The obtained results can be used to improve the general understanding of powder flow inside rotary tablet presses and amplify scale-up and continuous production process development. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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23 pages, 8754 KiB  
Article
The Challenge of Die Filling in Rotary Presses—A Systematic Study of Material Properties and Process Parameters
by Ann Kathrin Schomberg, Arno Kwade and Jan Henrik Finke
Pharmaceutics 2020, 12(3), 248; https://doi.org/10.3390/pharmaceutics12030248 - 10 Mar 2020
Cited by 13 | Viewed by 3197
Abstract
For the efficient and safe production of pharmaceutical tablets, a deep process understanding is of high importance. An essential process step during tableting is the die filling, as it is responsible for a consistent tablet weight and drug content. Furthermore, it affects the [...] Read more.
For the efficient and safe production of pharmaceutical tablets, a deep process understanding is of high importance. An essential process step during tableting is the die filling, as it is responsible for a consistent tablet weight and drug content. Furthermore, it affects the results of subsequent process steps, compaction and ejection, and thus critical quality attributes. This study focuses on understanding the influences of process parameters and material properties on die filling on a rotary tablet press. By the systematic variation in process parameters as the turret and paddle speeds as well as the fill and dosing depths, five formulations with differing properties are processed. Analysis of the normalized tablet weight, called filling yield, revealed different limitation mechanisms of the filling process, i.e., incomplete filled dies for certain parameter settings. Kinetic limitations occur due to a short residence time under the feed frame (filling time) caused by high turret speeds, which additionally induce high tablet weight variation coefficients. Characteristic maximum turret speeds at certain paddle speeds can be found to still achieve complete filling. At low turret speeds, densification of the powder inside the dies takes place, induced by two mechanisms: either high paddle speeds or high overfill ratios, or a combination of both. The challenge to fill the dies completely as well as avoid densification is dependent on material properties as the flowability. The mass discharge rate from an orifice was found to be in a linear correlation to the filling results of different formulations below complete filling. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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19 pages, 3970 KiB  
Article
Application of Multiple Linear Regression and Artificial Neural Networks for the Prediction of the Packing and Capsule Filling Performance of Coated and Plain Pellets Differing in Density and Size
by Panagiotis Barmpalexis, Ioannis Partheniadis, Konstantina-Sepfora Mitra, Miltiadis Toskas, Labrini Papadopoulou and Ioannis Nikolakakis
Pharmaceutics 2020, 12(3), 244; https://doi.org/10.3390/pharmaceutics12030244 - 08 Mar 2020
Cited by 6 | Viewed by 2555
Abstract
Plain or coated pellets of different densities 1.45, 2.53, and 3.61 g/cc in two size ranges, small (380–550 μm) and large (700–1200 μm) (stereoscope/image analysis), were prepared according to experimental design using extrusion/spheronization. Multiple linear regression (MLR) and artificial neural networks (ANNs) were [...] Read more.
Plain or coated pellets of different densities 1.45, 2.53, and 3.61 g/cc in two size ranges, small (380–550 μm) and large (700–1200 μm) (stereoscope/image analysis), were prepared according to experimental design using extrusion/spheronization. Multiple linear regression (MLR) and artificial neural networks (ANNs) were used to predict packing indices and capsule filling performance from the “apparent” pellet density (helium pycnometry). The dynamic packing of the pellets in tapped volumetric glass cylinders was evaluated using Kawakita’s parameter a and the angle of internal flow θ. The capsule filling was evaluated as maximum fill weight (CFW) and fill weight variation (FWV) using a semi-automatic machine that simulated filling with vibrating plate systems. The pellet density influenced the packing parameters a and θ as the main effect and the CFW and FWV as statistical interactions with the coating. The pellet size and coating also displayed interacting effects on CFW, FWV, and θ. After coating, both small and large pellets behaved the same, demonstrating smooth filling and a low fill weight variation. Furthermore, none of the packing indices could predict the fill weight variation for the studied pellets, suggesting that the filling and packing of capsules with free-flowing pellets is influenced by details that were not accounted for in the tapping experiments. A prediction could be made by the application of MLR and ANNs. The former gave good predictions for the bulk/tap densities, θ, CFW, and FWV (R-squared of experimental vs. theoretical data >0.951). A comparison of the fitting models showed that a feed-forward backpropagation ANN model with six hidden units was superior to MLR in generalizing ability and prediction accuracy. The simplification of the ANN via magnitude-based pruning (MBP) and optimal brain damage (OBD), showed good data fitting, and therefore the derived ANN model can be simplified while maintaining predictability. These findings emphasize the importance of pellet density in the overall capsule filling process and the necessity to implement MLR/ANN into the development of pellet capsule filling operations. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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18 pages, 4411 KiB  
Article
Along the Process Chain to Probiotic Tablets: Evaluation of Mechanical Impacts on Microbial Viability
by Karl Vorländer, Ingo Kampen, Jan Henrik Finke and Arno Kwade
Pharmaceutics 2020, 12(1), 66; https://doi.org/10.3390/pharmaceutics12010066 - 15 Jan 2020
Cited by 16 | Viewed by 4267
Abstract
Today, probiotics are predominantly used in liquid or semi-solid functionalized foods, showing a rapid loss of cell viability. Due to the increasing spread of antibiotic resistance, probiotics are promising in pharmaceutical development because of their antimicrobial effects. This increases the formulation requirements, e.g., [...] Read more.
Today, probiotics are predominantly used in liquid or semi-solid functionalized foods, showing a rapid loss of cell viability. Due to the increasing spread of antibiotic resistance, probiotics are promising in pharmaceutical development because of their antimicrobial effects. This increases the formulation requirements, e.g., the need for an enhanced shelf life that is achieved by drying, mainly by lyophilization. For oral administration, the process chain for production of tablets containing microorganisms is of high interest and, thus, was investigated in this study. Lyophilization as an initial process step showed low cell survival of only 12.8%. However, the addition of cryoprotectants enabled survival rates up to 42.9%. Subsequently, the dried cells were gently milled. This powder was tableted directly or after mixing with excipients microcrystalline cellulose, dicalcium phosphate or lactose. Survival rates during tableting varied between 1.4% and 24.1%, depending on the formulation and the applied compaction stress. More detailed analysis of the tablet properties showed advantages of excipients in respect of cell survival and tablet mechanical strength. Maximum overall survival rate along the complete manufacturing process was >5%, enabling doses of 6   ×   10 8 colony forming units per gram ( CFU   g total − 1 ), including cryoprotectants and excipients. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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18 pages, 4556 KiB  
Article
Improved Understanding of the High Shear Wet Granulation Process under the Paradigm of Quality by Design Using Salvia miltiorrhiza Granules
by Yi Zhang, Brian Chi-Yan Cheng, Wenjuan Zhou, Bing Xu, Xiaoyan Gao, Yanjiang Qiao and Gan Luo
Pharmaceutics 2019, 11(10), 519; https://doi.org/10.3390/pharmaceutics11100519 - 09 Oct 2019
Cited by 13 | Viewed by 4284
Abstract
Background: High shear wet granulation (HSWG) is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. However, study of HSWG is complex and challenging due to the relatively poor understanding of HSWG, especially for sticky powder-like herbal [...] Read more.
Background: High shear wet granulation (HSWG) is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. However, study of HSWG is complex and challenging due to the relatively poor understanding of HSWG, especially for sticky powder-like herbal extracts. Aim: In this study, we used Salvia miltiorrhiza granules to investigate the HSWG process across different scales using quality by design (QbD) approaches. Methods: A Plackett–Burman experimental design was used to screen nine granulation factors in the HSWG process. Moreover, a quadratic polynomial regression model was established based on a Box–Behnken experimental design to optimize the granulation factors. In addition, the scale-up of HSWG was implemented based on a nucleation regime map approach. Results: According to the Plackett–Burman experimental design, it was found that three granulation factors, including salvia ratio, binder amount, and chopper speed, significantly affected the granule size (D50) of S. miltiorrhiza in HSWG. Furthermore, the results of the Box–Behnken experimental design and validation experiment showed that the model successfully captured the quadratic polynomial relationship between granule size and the two granulation factors of salvia ratio and binder amount. At the same experiment points, granules at all scales had similar size distribution, surface morphology, and flow properties. Conclusions: These results demonstrated that rational design, screening, optimization, and scale-up of HSWG are feasible using QbD approaches. This study provides a better understanding of HSWG process under the paradigm of QbD using S. miltiorrhiza granules. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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19 pages, 3064 KiB  
Article
A Mathematical Approach to Consider Solid Compressibility in the Compression of Pharmaceutical Powders
by Isabell Wünsch, Jan Henrik Finke, Edgar John, Michael Juhnke and Arno Kwade
Pharmaceutics 2019, 11(3), 121; https://doi.org/10.3390/pharmaceutics11030121 - 15 Mar 2019
Cited by 42 | Viewed by 8695
Abstract
In-die compression analysis is an effective method for the characterization of powder compressibility. However, physically unreasonable apparent solid fractions above one or apparent in-die porosities below zero are often calculated for higher compression stresses. One important reason for this is the neglect of [...] Read more.
In-die compression analysis is an effective method for the characterization of powder compressibility. However, physically unreasonable apparent solid fractions above one or apparent in-die porosities below zero are often calculated for higher compression stresses. One important reason for this is the neglect of solid compressibility and hence the assumption of a constant solid density. In this work, the solid compressibility of four pharmaceutical powders with different deformation behaviour is characterized using mercury porosimetry. The derived bulk moduli are applied for the calculation of in-die porosities. The change of in-die porosity due to the consideration of solid compressibility is for instance up to 4% for microcrystalline cellulose at a compression stress of 400 MPa and thus cannot be neglected for the calculation of in-die porosities. However, solid compressibility and further uncertainties from, for example the measured solid density and from the displacement sensors, are difficult or only partially accessible. Therefore, a mathematic term for the calculation of physically reasonable in-die porosities is introduced. This term can be used for the extension of common mathematical models, such as the models of Heckel and of Cooper & Eaton. Additionally, an extended in-die compression function is introduced to precisely describe the entire range of in-die porosity curves and to enable the successful differentiation and quantification of the compression behaviour of the investigated pharmaceutical powders. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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