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Tableting Science, QbD and simulation

A Mathematical Approach to Consider Solid Compressibility in the Compression of Pharmaceutical Powders

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.

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Breaking pharmaceutical tablets with a hole: Reevaluation of the stress concentration factor and influence of the hole size

Mechanical strength is an important property for pharmaceutical tablets. Its study using the theory of linear elastic fracture mechanics has been introduced in the pharmaceutical field through the Brittle Fracture Index (BFI). This index is based on the stress concentration factor (SCF) and contradictory results have been published in the pharmaceutical literature about the value of the SCF during the diametral compression of a disc with a hole.

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Calibration and interpretation of DEM parameters for simulations of cylindrical tablets with multi-sphere approach

Finishing and transport operations of pharmaceutical tablets such as coating and conveying processes can qualitatively be improved with a better understanding of the interplay of process parameters and product quality attributes. This study provides a first step towards the simulation of these processes with the calibration of the motion modelling of uniaxial-compressed cylindrical tablets using the multi-sphere approach (MS) within the Discrete Element Method (DEM). Only high accuracy in the representation of cylindrical tablet shape, especially regarding edges, yields a good agreement between simulated and experimental packing fraction.

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Comparative study between Drucker-Prager/Cap and modified Cam-Clay models for the numerical simulation of die compaction of pharmaceutical powders

Numerical simulation with finite element method is commonly used to model the process of die compaction. In pharmaceutical field, the Drucker-Prager/Cap (DPC) model is by far the most used to study the mechanical behavior of the powder. Another classical model but less used model, the modified Cam-Clay (MC-C) model, is introduced in this study. The main advantage is that the model parameters are easier to determine for MC-C model than for DPC model.

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Comparison of breaking tests for the characterization of the interfacial strength of bilayer tablets

The bilayer tableting technology is gaining more acceptance in the drug industry, due to its ability to improve the drug delivery strategies. It is currently assessed by the European Pharmacopoeia, that the mechanical strength of tablets can be evaluated using a diametral breaking tester. This device applies a force diametrically, and records the tablet breaking point. This approach has been used to measure the structural integrity of single layer tablets as well as bilayer (and multi-layer) tablets.

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Development of a new test for the easy characterization of the adhesion at the interface of bilayer tablets: Proof-of-concept study by experimental design

Although, adhesion at the interface of bilayer tablets is critical for their design it is difficult to characterize this adhesion between layers. In view of this, a new test with an easy implementation was proposed for the characterization of the interface of bilayer tablets. This work is presented as a proof-of-concept study to investigate the reliability of this new test with regard to the effects of some critical process parameters (e.g., compaction pressure applied on each layer) and material attributes (e.g., elasticity of the layered materials) on the interfacial adhesion of bilayer tablets.

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Effect of friction between powder and tooling on the die-wall pressure evolution during tableting: Experimental and numerical results for flat and concave punches

Tablet final properties are mainly determined during the compaction process by the evolution of the stresses applied to the powder. Any process or product parameter that may influence this stress evolution may have a direct impact on the tablet final properties. In this article, we studied the influence of the friction between the tooling and the powder on the evolution of the die-wall pressure during compaction using flat and concave punches.

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Effect of the Curvature of the Punches on the Shape of the Interface and the Delamination Tendency of Bilayer Tablets

Bilayer tablets are of special interest in the pharmaceutical industry. The main problem during their manufacturing is the occurrence of delamination during or after the ejection from the die. This work studies the influence of using punches with a curvature on the interfacial strength and thus on the delamination tendency of bilayer tablets. Bilayer tablets were produced with a compaction simulator using different flat and concave punches with different radii of curvature.

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Evolution of the Die-Wall Pressure during the Compression of Biconvex Tablets: Experimental Results and Comparison with FEM Simulation

Capping is a classical manufacturing problem for tablets, which is known to affect more biconvex tablets than flat-faced ones. One reason could be the development of a higher residual die-wall pressure during unloading. Unfortunately, contradictory results were published on the subject. In this work, the evolution of the die-wall pressure during the compaction of biconvex tablets was studied experimentally and using finite element method (FEM) modeling.

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FEM simulation of the die compaction of pharmaceutical products: Influence of visco-elastic phenomena and comparison with experiments

This work studies the influence of visco-elastic behavior in the finite element method (FEM) modeling of die compaction of pharmaceutical products and how such a viscoelastic behavior may improve the agreement between experimental and simulated compression curves. The modeling of the process was conducted on a pharmaceutical excipient, microcrystalline cellulose (MCC), by using Drucker–Prager cap model coupled with creep behavior in Abaqus® software.

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Influence of the Punch Speed on the Die Wall/Powder Kinematic Friction During Tableting

Influence of the compaction speed on the final tablet properties is an important challenge during the scale-up of a solid dosage form. This strain rate sensitivity is generally attributed to the time dependent deformation behavior of the powder. In this work, we studied the influence of the speed on another important factor during compaction: friction between the tablet/powder and the die.

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On the links between elastic constants and effective elastic behavior of pharmaceutical compacts: importance of poisson's ratio and use of bulk modulus

The elastic properties of pharmaceutical powders and compacts are of great interest to understand the complex phenomena that occur during and after the tableting process. The elastic recovery after compression is known to be linked with adverse phenomena such as capping or delamination of tablets. Classically, the elastic behavior is modeled using linear elasticity and is characterized using only Young's modulus (E), often by using a value extrapolated at zero porosity.

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Quantitative evaluation of different rotary tablet presses by compaction velocity based on compaction simulation study

This study evaluated differences in rotary tablet presses quantitatively using a compaction simulator. First, we calculated the compaction velocity for each rotary tablet press. As a result, rotary tablet press B showed higher compaction velocity than rotary tablet press A regardless of having the same compaction conditions. It was also confirmed that the compaction velocity was changed depending on the rotation speed.

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Role of the elasticity of pharmaceutical materials on the interfacial mechanical strength of bilayer tablets

The effect of the elasticity of various pharmaceutical materials on the interfacial adhesion in bilayer tablets was investigated. The elastic properties of five pharmaceutical products were characterized by their total elastic recovery. To test the interfacial strength of the bilayer tablets a new flexural test was proposed. Thanks to the test configuration, the experimental breaking force is directly correlated with the interfacial layer strength.

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Evolution of the Die-Wall Pressure during the Compression of Biconvex Tablets: Experimental Results and Comparison with FEM Simulation

Capping is a classical manufacturing problem for tablets, which is known to affect more biconvex tablets than flat-faced ones. One reason could be the development of a higher residual die-wall pressure during unloading. Unfortunately, contradictory results were published on the subject. In this work, the evolution of the die-wall pressure during the compaction of biconvex tablets was studied experimentally and using finite element method (FEM) modeling.

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Hybrid modeling of roll compaction processes with the Styl'One Evolution: Granule size distribution

Roll compaction/dry granulation (RC/DG) is a widely used method in pharmaceutical industry. Nevertheless, in R&D problems can occur because it is a time and material consuming process. In previous trials it was shown that hybrid modeling of RC with the Styl’One Evolution can identify the settings to obtain ribbons with the desired solid fractions(SF).

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Use of roller compaction and fines recycling process in the preparation of erlotinib hydrochloride tablets

This study focuses on improving the manufacturing process for a generic immediaterelease tablet containing erlotinib hydrochloride by adding a fines recycling process during roller compaction. Due to the large fraction of small-sized API particles, the starting powder mixture was inconsistently fed into the roller compactor. Consequently, poorly flowing granules with a high ratio of fines were produced. A fines recycling step was, therefore, added to the existing roller compaction process to minimize the risks caused by the poor granule flow.

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Estimation of nip angle by roll compaction simulation

On a roll compactor (RC), the space between the rolls is divided into a slip, a compaction and a release zone. The angle between the beginning and the end of the compaction zone is called nip angle. This angle is an important parameter for the process understanding. There are several approaches to determine the nip angle but they are laborious and difficult. The aim of this study was to use a uniaxial compaction simulator (Styl‘One Evolution, Medelpharm) for the nip angle estimation and to evaluate the influence of the specific compaction force, gap width and roll speed on the nip angle of different excipients.

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Studying the feeding system impact on tablet properties using STYL'One

The impact of the force feeder on tablet tensile strength depends on the amount of lubricant, the compaction behavior of the material (deformation vs. fragmentation) and the rotation speed of the feeder. This can be easily and quickly evaluated on a Styl’One™ using only small amounts of powder early in R&D stages, ensuring appropriate tablet properties during scale-up.

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Tablet-in-cup drug delivery device Drug release modification by tablet geometry

AIMS: Development of TIC devices Elaboration of the potential of the TIC design for drug release modification In-silico simulation of TIC drug release

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Troubleshooting, capping, lamination, lubricationbleshooting

Early detection of capping risk in pharmaceutical compacts

Capping is a common mechanical defect in tablet manufacturing, exhibited during or after the compression process. Predicting tablet capping in terms of process variables (e.g. compaction pressure and speed) and formulation properties is essential in pharmaceutical industry. In current work, a nondestructive contact ultrasonic approach for detecting capping risk in the pharmaceutical compacts prepared under various compression forces and speeds is presented. It is shown that the extracted mechanical properties can be used as early indicators for invisible capping (prior to visible damage)....

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Influence of the unloading conditions on capping and lamination: Study on a compaction simulator

Capping and lamination are classical industrial issues that can be challenging during the scale up of solid dosage forms. Previous publications showed that changing the unloading conditions (triaxial decompression, loaded ejection) made it possible to mitigate capping. In the present study, a systematic study of the effect of the unloading conditions on capping and lamination was performed using a compaction simulator. One model formulation for capping and one for lamination were studied.

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Lamination of biconvex tablets: Numerical and experimental study

Capping and lamination are common industrial problems during the manufacturing of pharmaceutical tablets. Even if they are commonly treated together, these phenomena correspond to different failure patterns of the tablet and, as a consequence, to different mechanisms of cracking. In this work, a specific case of lamination of biconvex tablets was studied. It corresponds to a breakage into two parts of the tablets along a failure plan normal to the compression direction and located approximately at the center of the tablet band.

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Lamination of pharmaceutical tablets due to air entrapment: Direct visualization and influence of the compact thickness

Capping and lamination are two problems that are often faced during the industrial manufacturing of pharmaceutical tablets. Several reasons have been proposed to explain these phenomena. Among them, air entrapment is supposed to play a role in some cases. Nevertheless, no direct proof were given to prove that air entrapment can promote lamination or capping and various publications have questioned this hypothesis.

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Shear strength of pharmaceutical tablets: Theoretical considerations, evaluation and relation with the capping tendency of biconvex tablets

Capping is a major industrial issue during pharmaceutical powder compression, especially in the case of biconvex tablets. Several articles proposed that capping was in fact a failure in shear. Shear strength should thus be interesting to study the capping tendency of a formulation. In this work, the ratio between the shear strength and the tensile strength obtained by diametral compression was first studied from a theoretical point of view considering different failure criteria.

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Evaluation of the performance of an external lubrication system implemented in a compaction simulator

Internal lubrication is often associated with decreasing tensile strengths and increasing disintegration times. Using external lubrication, the lubricant is sprayed on tablet tooling, thereby minimizing the negative effects involved with internal blending of the lubricant.

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Studying the impact of lubrication on tablet properties using STYL'One

 

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Unravelling capping issues using STYL’One Dwell Time or Punch Speed

Capping is a common problem encountered during tablet formulation and industrial production; whose origin has been attributed to several causes as air entrapment, compression speed, viscoelastic recovery; and stress and density distribution. The speed at which the punch travels during the compression influences tablet properties.

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Excipient and API characterization

Chitin’s Functionality as a Novel Disintegrant: Benchmarking Against Commonly Used Disintegrants in Different Physicochemical Environments

Disintegrants are used as excipients to ensure rapid disintegration of pharmaceutical tablets and further ensure proper dissolution of the active pharmaceutical ingredient. This study investigates disintegration mechanisms of chitin and common disintegrants. Swelling assessment (swelling force and swelling ratio) in different media, and compaction behavior (pure or mixed with other excipients) tabletability, deformation (Heckel modeling), and compact disintegration times were investigated on the tested disintegrants (alginic acid calcium salt, crospovidone, sodium starch glycolate, croscarmellose sodium, and chitin). ...

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Compaction of food powders: The influence of material properties and process parameters on product structure, strength, and dissolution

During pressure agglomeration of food powders, it is often difficult to control the final product properties due to their complex material behaviours. The current study aims to better elucidate how the quality of a compact is impacted by the material characteristics of the raw materials as well as the process conditions applied. An amorphous powder was compacted under various conditions to investigate the influence of material properties, such as water activity and molecular weight, and process parameters (pressure and dwell time) on tablet porosity, tensile strength, and dissolution time.

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Compaction of functionalized calcium carbonate, a porous and crystalline microparticulate material with a lamellar surface

In the present study, we aimed to characterize the compressibility and compactibility of the novel pharmaceutical excipient, functionalized calcium carbonate (FCC). We studied three FCC modifications and compared the values for compressibility and compactibility with mannitol, microcrystalline cellulose (MCC), and ground calcium carbonate (CC 330) as well as mixtures of paracetamol and MCC or FCC at drug loads of 0%, 25%, 50%, 75%, and 100% (w/w). We used Heckel analysis, modified Heckel analysis, and Leuenberger analysis to characterize the compaction and compression behavior of the mixtures.

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Development of Coprocessed Chitin-Calcium Carbonate as Multifunctional Tablet Excipient for Direct Compression

Owing to the increasing interest in multifunctional excipients for tableting, coprocessing of individual excipients is regularly used to produce excipients of improved multifunctionality superior to individual excipients or their physical mix. The use of chitin as an excipient in tablet formulation is limited because of certain drawbacks such as poor flowability and low true density. The objective of this work is to improve these properties through coprocessing of chitin with calcium carbonate (CaCO3) by precipitating CaCO3 on chitin particles using different methods. In addition, optimization of the coprocessed chitin was carried out to improve the excipient's properties.

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Study of the Lactobacillus rhamnosus Lcr35® properties after compression and proposition of a model to predict tablet stability

The beneficial effects of probiotic bacteria on human health are now widely acknowledged, and this has prompted growing interest in research and development in the pharmaceutical field. However, to be viable when they reach their target, the bacteria must be able to survive during the manufacturing process and the biological pathway. Tablet form best meets the requirements for protecting acid labile drugs, but the tableting process could be an additional stress for the bacteria. This study evaluated the initial effect of compression pressure on the Lcr35® strain in a vaginal (Lcr regenerans®) and an intestinal (Lcr restituo®) formulation.

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The influence of isomalt particle morphology on tabletability after roll compaction/dry granulation

The influence of different isomalt particle morphologies on dry granule and tablet properties was investigated. Primary crystals, milled particles and agglomerates were tableted after roll compaction/dry granulation and compared to the directly compressed powders. Afterwards, the changes in tabletability were evaluated. Particle size distribution and specific surface area were measured for powders and granules. The influence of different specific compaction forces on granule and tablet properties was investigated.

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Tricalcium citrate – a new brittle tableting excipient for direct compression and dry granulation with enormous hardness yield

Poster as presented on 11th Worldmeeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology 2018, Granada, Spain

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