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19 pages, 6982 KiB

Open AccessFeature PaperArticle

Discrete Element Method Evaluation of Triboelectric Charging Due to Powder Handling in the Capsule of a DPI

by

Francesca Orsola Alfano

,

Alberto Di Renzo

and

Francesco Paolo Di Maio

Pharmaceutics 2023, 15(6), 1762; https://doi.org/10.3390/pharmaceutics15061762 - 18 Jun 2023

Viewed by 863

Abstract

The generation and accumulation of an electrostatic charge from handling pharmaceutical powders is a well-known phenomenon, given the insulating nature of most APIs (Active Pharmaceutical Ingredients) and excipients. In capsule-based DPIs (Dry Powder Inhalers), the formulation is stored in a gelatine capsule placed [...] Read more.

The generation and accumulation of an electrostatic charge from handling pharmaceutical powders is a well-known phenomenon, given the insulating nature of most APIs (Active Pharmaceutical Ingredients) and excipients. In capsule-based DPIs (Dry Powder Inhalers), the formulation is stored in a gelatine capsule placed in the inhaler just before inhalation. The action of capsule filling, as well as tumbling or vibration effects during the capsule life cycle, implies a consistent amount of particle–particle and particle–wall contacts. A significant contact-induced electrostatic charging can then take place, potentially affecting the inhaler’s efficiency. DEM (Discrete Element Method) simulations were performed on a carrier-based DPI formulation (salbutamol–lactose) to evaluate such effects. After performing a comparison with the experimental data on a carrier-only system under similar conditions, a detailed analysis was conducted on two carrier–API configurations with different API loadings per carrier particle. The charge acquired by the two solid phases was tracked in both the initial particle settling and the capsule shaking process. Alternating positive–negative charging was observed. Particle charging was then investigated in relation to the collision statistics, tracking the particle–particle and particle–wall events for the carrier and API. Finally, an analysis of the relative importance of electrostatic, cohesive/adhesive, and inertial forces allowed the importance of each term in determining the trajectory of the powder particles to be estimated. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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26 pages, 17953 KiB

Open AccessArticle

Bulk Flow Optimisation of Amorphous Solid Dispersion Excipient Powders through Surface Modification

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Pharmaceutics 2023, 15(5), 1447; https://doi.org/10.3390/pharmaceutics15051447 - 09 May 2023

Viewed by 1123

Abstract

Particulate amorphous solid dispersions (ASDs) have been recognised for their potential to enhance the performance of various solid dose forms, especially oral bioavailability and macromolecule stability. However, the inherent nature of spray-dried ASDs leads to their surface cohesion/adhesion, including hygroscopicity, which hinders their [...] Read more.

Particulate amorphous solid dispersions (ASDs) have been recognised for their potential to enhance the performance of various solid dose forms, especially oral bioavailability and macromolecule stability. However, the inherent nature of spray-dried ASDs leads to their surface cohesion/adhesion, including hygroscopicity, which hinders their bulk flow and affects their utility and viability in terms of powder production, processing, and function. This study explores the effectiveness of L-leucine (L-leu) coprocessing in modifying the particle surface of ASD-forming materials. Various contrasting prototype coprocessed ASD excipients from both the food and pharmaceutical industries were examined for their effective coformulation with L-leu. The model/prototype materials included maltodextrin, polyvinylpyrrolidone (PVP K10 and K90), trehalose, gum arabic, and hydroxypropyl methylcellulose (HPMC E5LV and K100M). The spray-drying conditions were set such that the particle size difference was minimised, so that it did not play a substantial role in influencing powder cohesion. Scanning electron microscopy was used to evaluate the morphology of each formulation. A combination of previously reported morphological progression typical of L-leu surface modification and previously unreported physical characteristics was observed. The bulk characteristics of these powders were assessed using a powder rheometer to evaluate their flowability under confined and unconfined stresses, flow rate sensitivities, and compactability. The data showed a general improvement in maltodextrin, PVP K10, trehalose and gum arabic flowability measures as L-leu concentrations increased. In contrast, PVP K90 and HPMC formulations experienced unique challenges that provided insight into the mechanistic behaviour of L-leu. Therefore, this study recommends further investigations into the interplay between L-leu and the physico-chemical properties of coformulated excipients in future amorphous powder design. This also revealed the need to enhance bulk characterisation tools to unpack the multifactorial impact of L-leu surface modification. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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13 pages, 2200 KiB

Open AccessArticle

Experimental Elucidation of Templated Crystallization and Secondary Processing of Peptides

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Pharmaceutics 2023, 15(4), 1288; https://doi.org/10.3390/pharmaceutics15041288 - 20 Apr 2023

Viewed by 975

Abstract

The crystallization of peptides offers a sustainable and inexpensive alternative to the purification process. In this study, diglycine was crystallised in porous silica, showing the porous templates’ positive yet discriminating effect. The diglycine induction time was reduced by five-fold and three-fold upon crystallising [...] Read more.

The crystallization of peptides offers a sustainable and inexpensive alternative to the purification process. In this study, diglycine was crystallised in porous silica, showing the porous templates’ positive yet discriminating effect. The diglycine induction time was reduced by five-fold and three-fold upon crystallising in the presence of silica with pore sizes of 6 nm and 10 nm, respectively. The diglycine induction time had a direct relationship with the silica pore size. The stable form (α-form) of diglycine was crystallised in the presence of porous silica, with the diglycine crystals obtained associated with the silica particles. Further, we studied the mechanical properties of diglycine tablets for their tabletability, compactability, and compressibility. The mechanical properties of the diglycine tablets were similar to those of pure MCC, even with the presence of diglycine crystals in the tablets. The diffusion studies of the tablets using the dialysis membrane presented an extended release of diglycine through the dialysis membrane, confirming that the peptide crystal can be used for oral formulation. Hence, the crystallization of peptides preserved their mechanical and pharmacological properties. More data on different peptides can help us produce oral formulation peptides faster than usual. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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20 pages, 7020 KiB

Open AccessArticle

Numerical Investigation of the Particle Dynamics in a Rotorgranulator Depending on the Properties of the Coating Liquid

by

Philipp Grohn

,

Stefan Heinrich

and

Sergiy Antonyuk

Pharmaceutics 2023, 15(2), 469; https://doi.org/10.3390/pharmaceutics15020469 - 31 Jan 2023

Viewed by 1081

Abstract

In the pharmaceutical industry, the coating of particles is a widely used technique to obtain desired surface modifications of the final product, e.g., controlled release of the active agents. The production of round, coated particles is particularly important, which is why fluidized bed [...] Read more.

In the pharmaceutical industry, the coating of particles is a widely used technique to obtain desired surface modifications of the final product, e.g., controlled release of the active agents. The production of round, coated particles is particularly important, which is why fluidized bed rotor granulators (FBRG) are often used for this process. In this work, Computational Fluid Dynamics (CFD) coupled with the Discrete Element Method (DEM) is used to investigate the wet particle dynamics, depending on the properties of the coating liquid in a FBRG. The DEM contact model was extended by liquid bridge model to account for capillary and viscous forces during wet contact of particles. The influence of the relative contact velocity on the maximum length of the liquid bridge is also considered in the model. Five different cases were compared, in which the particles were initially wetted, and the liquid loading as well as the surface tension and viscosity of the liquid were changed. The results show that increasing viscosity leads to a denser particle bed and a significant decrease in particle rotational velocities and particle motion in the poloidal plane of the FBRG. Reducing the liquid loading and surface tension results in increased particle movement. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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27 pages, 6351 KiB

Open AccessArticle

Impact of Vertical Blender Unit Parameters on Subsequent Process Parameters and Tablet Properties in a Continuous Direct Compression Line

by

Marius J. Kreiser

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Christoph Wabel

and

Karl G. Wagner

Pharmaceutics 2022, 14(2), 278; https://doi.org/10.3390/pharmaceutics14020278 - 25 Jan 2022

Cited by 2 | Viewed by 2998

Abstract

The continuous manufacturing of solid oral-dosage forms represents an emerging technology among the pharmaceutical industry, where several process steps are combined in one production line. As all mixture components, including the lubricant (magnesium stearate), are passing simultaneously through one blender, an impact on [...] Read more.

The continuous manufacturing of solid oral-dosage forms represents an emerging technology among the pharmaceutical industry, where several process steps are combined in one production line. As all mixture components, including the lubricant (magnesium stearate), are passing simultaneously through one blender, an impact on the subsequent process steps and critical product properties, such as content uniformity and tablet tensile strength, is to be expected. A design of experiment (DoE) was performed to investigate the impact of the blender variables hold-up mass (HUM), impeller speed (IMP) and throughput (THR) on the mixing step and the subsequent continuous manufacturing process steps. Significant impacts on the mixing parameters (exit valve opening width (EV), exit valve opening width standard deviation (EV SD), torque of lower impeller (T_L), torque of lower impeller SD (T_L SD), HUM SD and blend potency SD), material attributes of the blend (conditioned bulk density (CBD), flow rate index (FRI) and particle size (d₁₀ values)), tableting parameters (fill depth (FD), bottom main compression height (BCH) and ejection force (EF)) and tablet properties (tablet thickness (TT), tablet weight (TW) and tensile strength (TS)) could be found. Furthermore, relations between these process parameters were evaluated to define which process states were caused by which input variables. For example, the mixing parameters were mainly impacted by impeller speed, and material attributes, FD and TS were mainly influenced by variations in total blade passes (TBP). The current work presents a rational methodology to minimize process variability based on the main blender variables hold-up mass, impeller speed and throughput. Moreover, the results facilitated a knowledge-based optimization of the process parameters for optimum product properties. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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29 pages, 11481 KiB

Open AccessArticle

Conceptualisation of an Efficient Particle-Based Simulation of a Twin-Screw Granulator

by

John P. Morrissey

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Kevin J. Hanley

and

Jin Y. Ooi

Pharmaceutics 2021, 13(12), 2136; https://doi.org/10.3390/pharmaceutics13122136 - 12 Dec 2021

Cited by 4 | Viewed by 2919

Abstract

Discrete Element Method (DEM) simulations have the potential to provide particle-scale understanding of twin-screw granulators. This is difficult to obtain experimentally because of the closed, tightly confined geometry. An essential prerequisite for successful DEM modelling of a twin-screw granulator is making the simulations [...] Read more.

Discrete Element Method (DEM) simulations have the potential to provide particle-scale understanding of twin-screw granulators. This is difficult to obtain experimentally because of the closed, tightly confined geometry. An essential prerequisite for successful DEM modelling of a twin-screw granulator is making the simulations tractable, i.e., reducing the significant computational cost while retaining the key physics. Four methods are evaluated in this paper to achieve this goal: (i) develop reduced-scale periodic simulations to reduce the number of particles; (ii) further reduce this number by scaling particle sizes appropriately; (iii) adopt an adhesive, elasto-plastic contact model to capture the effect of the liquid binder rather than fluid coupling; (iv) identify the subset of model parameters that are influential for calibration. All DEM simulations considered a GEA ConsiGma™ 1 twin-screw granulator with a 60° rearward configuration for kneading elements. Periodic simulations yielded similar results to a full-scale simulation at significantly reduced computational cost. If the level of cohesion in the contact model is calibrated using laboratory testing, valid results can be obtained without fluid coupling. Friction between granules and the internal surfaces of the granulator is a very influential parameter because the response of this system is dominated by interactions with the geometry. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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20 pages, 1989 KiB

Open AccessArticle

A Hybrid Model to Predict Formulation Dependent Granule Growth in a Bi-Component Wet Granulation Process

by

Indu Muthancheri

and

Rohit Ramachandran

Pharmaceutics 2021, 13(12), 2063; https://doi.org/10.3390/pharmaceutics13122063 - 02 Dec 2021

Cited by 3 | Viewed by 1877

Abstract

In this study, a hybrid modeling framework was developed for predicting size distribution and content uniformity of granules in a bi-component wet granulation system with components of differing hydrophobicities. Two bi-component formulations, (1) ibuprofen-USP and micro-crystalline cellulose and (2) micronized acetaminophen and micro-crystalline [...] Read more.

In this study, a hybrid modeling framework was developed for predicting size distribution and content uniformity of granules in a bi-component wet granulation system with components of differing hydrophobicities. Two bi-component formulations, (1) ibuprofen-USP and micro-crystalline cellulose and (2) micronized acetaminophen and micro-crystalline cellulose, were used in this study. First, a random forest method was used for predicting the probability of nucleation mechanism (immersion and solid spread), depending upon the formulation hydrophobicity. The predicted nucleation mechanism probability is used to determine the aggregation rate as well as the initial particle distribution in the population balance model. The aggregation process was modeled as Type-I: Sticking aggregation and Type-II: Deformation driven aggregation. In Type-I, the capillary force dominant aggregation mechanism is represented by the particles sticking together without deformation. In the case of Type-II, the particle deformation causes an increase in the contact area, representing a viscous force dominant aggregation mechanism. The choice between Type-I and II aggregation is determined based on the difference in nucleation mechanism that is predicted using the random forest method. The model was optimized and validated using the granule content uniformity data and size distribution data obtained from the experimental studies. The proposed framework predicted content non-uniform behavior for formulations that favored immersion nucleation and uniform behavior for formulations that favored solid-spreading nucleation. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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11 pages, 3052 KiB

Open AccessArticle

Effect of Mixer Type on Particle Coating by Magnesium Stearate for Friction and Adhesion Modification

by

Wei Pin Goh

,

Ana Montoya Sanavia

and

Mojtaba Ghadiri

Pharmaceutics 2021, 13(8), 1211; https://doi.org/10.3390/pharmaceutics13081211 - 05 Aug 2021

Cited by 2 | Viewed by 2480

Abstract

Glidants and lubricants are often used to modify interparticle friction and adhesion in order to improve powder characteristics, such as flowability and compactability. Magnesium stearate (MgSt) powder is widely used as a lubricant. Shear straining causes MgSt particles to break, delaminate, and adhere [...] Read more.

Glidants and lubricants are often used to modify interparticle friction and adhesion in order to improve powder characteristics, such as flowability and compactability. Magnesium stearate (MgSt) powder is widely used as a lubricant. Shear straining causes MgSt particles to break, delaminate, and adhere to the surfaces of the host particles. In this work, a comparison is made of the effect of three mixer types on the lubricating role of MgSt particles. The flow behaviour of α-lactose monohydrate, coated with MgSt at different mass percentages of 0.2, 0.5, 1, and 5 is characterised. The mixing and coating process is carried out by dry blending using Turbula, ProCepT, and Mechanofusion. Measures have been taken to operate under equivalent mixing conditions, as reported in the literature. The flow resistance of the coated samples is measured using the FT4 rheometer. The results indicate that the flow characteristics of the processed powders are remarkably similar in the cases of samples treated by Turbula and Mechanofusion, despite extreme conditions of shear strain rate. The least flow resistance of samples is observed in the case of samples treated by the ProCepT mixer. High-velocity collisions of particles round off the sharp corners and edges, making them less resistant to flow. The optimal percentage of magnesium stearate is found to be approximately 1% by weight for all mixer types, as the addition of higher amounts of lubricant does not further improve the flowability of the material. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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17 pages, 3533 KiB

Open AccessArticle

Impact of Powder Properties on the Rheological Behavior of Excipients

by

Pauline H. M. Janssen

,

Sébastien Depaifve

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Aurélien Neveu

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Filip Francqui

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Bastiaan H. J. Dickhoff

Pharmaceutics 2021, 13(8), 1198; https://doi.org/10.3390/pharmaceutics13081198 - 04 Aug 2021

Cited by 14 | Viewed by 4807

Abstract

With the emergence of quality by design in the pharmaceutical industry, it becomes imperative to gain a deeper mechanistic understanding of factors impacting the flow of a formulation into tableting dies. Many flow characterization techniques are present, but so far only a few [...] Read more.

With the emergence of quality by design in the pharmaceutical industry, it becomes imperative to gain a deeper mechanistic understanding of factors impacting the flow of a formulation into tableting dies. Many flow characterization techniques are present, but so far only a few have shown to mimic the die filling process successfully. One of the challenges in mimicking the die filling process is the impact of rheological powder behavior as a result of differences in flow field in the feeding frame. In the current study, the rheological behavior was investigated for a wide range of excipients with a wide range of material properties. A new parameter for rheological behavior was introduced, which is a measure for the change in dynamic cohesive index upon changes in flow field. Particle size distribution was identified as a main contributing factor to the rheological behavior of powders. The presence of fines between larger particles turned out to reduce the rheological index, which the authors explain by improved particle separation at more dynamic flow fields. This study also revealed that obtained insights on rheological behavior can be used to optimize agitator settings in a tableting machine. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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24 pages, 30727 KiB

Open AccessArticle

Process Modeling and Simulation of Tableting—An Agent-Based Simulation Methodology for Direct Compression

by

Niels Lasse Martin

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Ann Kathrin Schomberg

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Jan Henrik Finke

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Tim Gyung-min Abraham

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Arno Kwade

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Christoph Herrmann

Pharmaceutics 2021, 13(7), 996; https://doi.org/10.3390/pharmaceutics13070996 - 30 Jun 2021

Cited by 8 | Viewed by 3388

Abstract

In pharmaceutical manufacturing, the utmost aim is reliably producing high quality products. Simulation approaches allow virtual experiments of processes in the planning phase and the implementation of digital twins in operation. The industrial processing of active pharmaceutical ingredients (APIs) into tablets requires the [...] Read more.

In pharmaceutical manufacturing, the utmost aim is reliably producing high quality products. Simulation approaches allow virtual experiments of processes in the planning phase and the implementation of digital twins in operation. The industrial processing of active pharmaceutical ingredients (APIs) into tablets requires the combination of discrete and continuous sub-processes with complex interdependencies regarding the material structures and characteristics. The API and excipients are mixed, granulated if required, and subsequently tableted. Thereby, the structure as well as the properties of the intermediate and final product are influenced by the raw materials, the parametrized processes and environmental conditions, which are subject to certain fluctuations. In this study, for the first time, an agent-based simulation model is presented, which enables the prediction, tracking, and tracing of resulting structures and properties of the intermediates of an industrial tableting process. Therefore, the methodology for the identification and development of product and process agents in an agent-based simulation is shown. Implemented physical models describe the impact of process parameters on material structures. The tablet production with a pilot scale rotary press is experimentally characterized to provide calibration and validation data. Finally, the simulation results, predicting the final structures, are compared to the experimental data. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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14 pages, 4615 KiB

Open AccessArticle

Numerical Simulation of Particle Dynamics in a Spiral Jet Mill via Coupled CFD-DEM

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Pharmaceutics 2021, 13(7), 937; https://doi.org/10.3390/pharmaceutics13070937 - 23 Jun 2021

Cited by 8 | Viewed by 2180

Abstract

Spiral jet mills are ubiquitous in the pharmaceutical industry. Breakage and classification in spiral jet mills occur due to complex interactions between the fluid and the solid phases. The study of these interactions requires the use of computational fluid dynamics (CFD) for the [...] Read more.

Spiral jet mills are ubiquitous in the pharmaceutical industry. Breakage and classification in spiral jet mills occur due to complex interactions between the fluid and the solid phases. The study of these interactions requires the use of computational fluid dynamics (CFD) for the fluid phase coupled with discrete element models (DEM) for the particle phase. In this study, we investigate particle dynamics in a 50-mm spiral jet mill through coupled CFD-DEM simulations. The simulations showed that the fluid was significantly decelerated by the presence of the particles in the milling chamber. Furthermore, we study the particle dynamics and collision statistics at two different operating conditions and three different particle loadings. As expected, the particle velocity was affected by both the particle loading and operating pressure. The particles moved slower at low pressures and high loadings. We also found that particle–particle collisions outnumbered particle–wall collisions. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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Review

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48 pages, 53576 KiB

Open AccessReview

Reviewing the Impact of Powder Cohesion on Continuous Direct Compression (CDC) Performance

by

Owen Jones-Salkey

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Zoe Chu

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Andrew Ingram

and

Christopher R. K. Windows-Yule

Pharmaceutics 2023, 15(6), 1587; https://doi.org/10.3390/pharmaceutics15061587 - 24 May 2023

Cited by 1 | Viewed by 1988

Abstract

The pharmaceutical industry is undergoing a paradigm shift towards continuous processing from batch, where continuous direct compression (CDC) is considered to offer the most straightforward implementation amongst powder processes due to the relatively low number of unit operations or handling steps. Due to [...] Read more.

The pharmaceutical industry is undergoing a paradigm shift towards continuous processing from batch, where continuous direct compression (CDC) is considered to offer the most straightforward implementation amongst powder processes due to the relatively low number of unit operations or handling steps. Due to the nature of continuous processing, the bulk properties of the formulation will require sufficient flowability and tabletability in order to be processed and transported effectively to and from each unit operation. Powder cohesion presents one of the greatest obstacles to the CDC process as it inhibits powder flow. As a result, there have been many studies investigating potential manners in which to overcome the effects of cohesion with, to date, little consideration of how these controls may affect downstream unit operations. The aim of this literature review is to explore and consolidate this literature, considering the impact of powder cohesion and cohesion control measures on the three-unit operations of the CDC process (feeding, mixing, and tabletting). This review will also cover the consequences of implementing such control measures whilst highlighting subject matter which could be of value for future research to better understand how to manage cohesive powders for CDC manufacture. Full article

(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)

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