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Relaxation tests are often used in the pharmaceutical field to assess the strain rate sensitivity of pharmaceutical powders and tablets. These tests involve applying a constant strain to the powder in the die and then monitoring the stress evolution over time. Interpreting these tests is complicated because different physical phenomena, mainly viscoelasticity and viscoplasticity, occur simultaneously. These two phenomena cannot be distinguished by observing the evolution of the axial pressure alone, as it decreases in both cases. In this work, it was shown that monitoring the evolution of the die-wall pressure during relaxation can help separate the effects of these phenomena. Theoretical considerations revealed that during viscoplasticity, the die-wall pressure also decreases, whereas an increase in the die-wall pressure during relaxation indicates a viscoelastic relaxation. This was confirmed experimentally using specially designed compaction cycles on four different pharmaceutical excipients. Experimental results indicated that at low pressure, viscoplasticity was predominant, whereas at high pressure, viscoelasticity became more prominent. These results suggest that at low pressures, relaxation tests can be used to assess the viscoplastic properties of different products. However, the use of high pressure should always be avoided as viscoelastic phenomena might become more significant, and the combination of both phenomena might compromise the interpretation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Among the various pharmaceutical forms, tablets offer numerous advantages, like ease of administration, cost-effectiveness in production, and better stability of biomolecules. Beyond these benefits, the tablet form opens up possibilities for alternative routes for the local delivery of biopharmaceuticals such as oral or vaginal administration, thereby expanding the therapeutic applications of these biomolecules and overcoming the inconvenients associated with parenteral administration. However, to date there is limited information on the feasibility of developing biomolecules in the tablet form. In this study, we have evaluated the feasibility of developing monoclonal antibodies in the tablet form while preserving their biological properties. Different excipients and process parameters were studied to assess their impact on the antibody's integrity during tableting. ELISA results show that applying compression pressure up to 100 MPa is not detrimental to the antibody's binding properties when formulated from a lyophilized powder containing trehalose or sucrose as the major excipient. This observation was confirmed with SPR and ultracentrifugation experiments, which demonstrated that neither the binding affinity for both Fc and Fab antibody fragments nor its aggregation rate are affected by the tableting process. After compression, the tablets containing the antibodies have been shown to be stable for 6 months at room temperature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Most of biopharmaceuticals, in their liquid form, are prone to instabilities during storage. In order to improve their stability, lyophilization is the most commonly used drying technique in the pharmaceutical industry. In addition, certain applications of biopharmaceutical products can be considered by oral administration and tablets are the most frequent solid pharmaceutical dosage form used for oral route. Thus, the tableting properties of freeze-dried products used as cryo and lyoprotectant could be a key element for future pharmaceutical developments and applications. In this study, we investigated the properties that might play a particular role in the specific compaction behavior of freeze-dried excipients. The tableting properties of freeze-dried trehalose, lactose and mannitol were investigated and compared to other forms of these excipients (spray-dried, commercial crystalline and commercial crystalline milled powders). The obtained results showed a specific behavior in terms of compressibility, tabletability and brittleness for the amorphous powders obtained after freeze-drying. The comparison with the other powders showed that this specific tableting behavior is linked to both the specific texture and the physical state (amorphization) of these freeze-dried powders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Capping and lamination are common defects occurring during the manufacturing of pharmaceutical tablets. Several studies showed that tablet anisotropy can play a role in the occurrence of such defects. In this work, we propose a new and easy methodology to characterize the anisotropy of flat-faced cylindrical tablets, which are considered as transversally isotropic due to the process, through the study of their elastic properties using impulse excitation technique and finite-element method (FEM) simulations. The study was performed for tablets with a thickness-to-diameter-ratio between 0.160 and 0.222. FEM simulations showed that it was possible to determine three out of the five elastic constants of the tablet using the first three natural vibration modes. An anisotropic index was then built as the ratio of the two apparent shear moduli. Moreover, in order to simplify the estimation of tablet anisotropy and to avoid the systematic use of FEM simulations, an analytical model was also developed. It only requires the measurement of the tablet dimensions and of the first three natural frequencies. Using this technique, experimental measurements on tablets made of classical pharmaceutical excipients were done and found coherent with the existing literature. This indicates thus that this methodology is a quick, easy and reliable characterization method in order to access tablet anisotropy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Evolution of the compaction properties of powders with the compaction speed (strain rate sensitivity, SRS) is a common phenomenon during the manufacturing of pharmaceutical tablets. Nevertheless, several different phenomena can be responsible of the SRS like friction, viscoelasticity, viscoplasticity or air entrapment. In this work, an original experimental methodology was developed to characterize specifically the viscoelasticity of tablets using a compaction simulator. After various compressions, tablets were finally loaded elastically at different constant strain rates. This methodology made it possible to measure the apparent bulk and shear moduli as a function of the strain rate. The methodology was successfully applied to microcrystalline cellulose (MCC), Starch, Lactose monohydrate (GLac) and Anhydrous Calcium Phosphate (ACP). No significant evolution of the moduli was found for Lac and ACP as expected. On the contrary, for MCC and Starch, both shear and bulk moduli were found to increase along with the strain rate. The viscoelastic behavior was then successfully modeled using prony series. Assessment of the model parameters was achieved by inverse identification using an analytical model and a finite element analysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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. Experimental studies were performed on microcrystalline cellulose as well as numerical studies using finite element method (FEM) simulation. Both methodologies indicate that increasing the friction between the powder and the tooling promotes an increase in the die-wall pressure during tableting. This is in contradiction with results that can be found in the literature. Moreover, the results of this study showed that for flat punches, the stress evolution is mainly driven by the die/powder friction. On the contrary, for concave punches, changing the punches/powder friction have also a consequence in the evolution of the die-wall pressure. This could have practical consequences in sticking situations where, due film formation on the punches, the friction between the punches and the powder may change during tableting., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Finite elements method was used to study the influence of tablet thickness and punch curvature on the density distribution inside convex faced (CF) tablets. The modeling of the process was conducted on 2 pharmaceutical excipients (anhydrous calcium phosphate and microcrystalline cellulose) by using Drucker-Prager Cap model in Abaqus(®) software. The parameters of the model were obtained from experimental tests. Several punch shapes based on industrial standards were used. A flat-faced (FF) punch and 3 convex faced (CF) punches (8R11, 8R8 and 8R6) with a diameter of 8mm were chosen. Different tablet thicknesses were studied at a constant compression force. The simulation of the compaction of CF tablets with increasing thicknesses showed an important change on the density distribution inside the tablet. For smaller thicknesses, low density zones are located toward the center. The density is not uniform inside CF tablets and the center of the 2 faces appears with low density whereas the distribution inside FF tablets is almost independent of the tablet thickness. These results showed that FF and CF tablets, even obtained at the same compression force, do not have the same density at the center of the compact. As a consequence differences in tensile strength, as measured by diametral compression, are expected. This was confirmed by experimental tests., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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. This was investigated using a design of experiment approach and the results obtained were in good accordance with those obtained with other tests and thus, confirms the potential of such a method for the measurement of the interfacial adhesion of bilayer tablets., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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 visco-elastic 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. The experimental data were obtained on a compaction simulator (STYLCAM 200R). The elastic deformation of the press was determined by performing experimental tests on a calibration disk and was introduced in the simulation. Numerical optimization was performed to characterize creep parameters. The use of creep behavior in the simulations clearly improved the agreement between the numerical and experimental compression curves (stresses, thickness), mainly during the unloading part of the compaction cycle. For the first time, it was possible to reproduce numerically the fact that the minimum tablet thickness is not obtained at the maximum compression stress. This study proves that creep behavior must be taken into account when modeling the compaction of pharmaceutical products using FEM methods., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: The aim of this work was to develop a quantification method based on image analysis, able to characterize sticking during pharmaceutical tableting. Relationship between image analysis features and relevant mechanical parameters recorded on an instrumented tablet press simulator were investigated., Methods: Image analysis, based on gray levels co-occurrence matrices (GLCM), generated textural features of the tablet surface. The tableting simulator (Stylcam® 200R, Medelpharm), instrumented with force and displacement transducers, provided accurate records. The tablet defects and compaction process parameters were studied using three pharmaceutical powders (Fast-Flo® lactose, anhydrous Emcompress® and Avicel® PH200 microcrystalline cellulose), five compression pressures (60 to 250 MPa), five lubricating levels, and three types of punches (standard steel, amorphous hard carbon and anti-sticking punches)., Results: Texture parameters made it possible to quantify with precision tablets’ aspect. The selected parameter IC2 (Information on Correlation 2) plotted versus the ratio between the ejection shear stress (Esh) and the compression pressure (Cp) let appear a relevant knowledge space where it was possible to identify a normal and a degraded tableting mode. A positive link between those two parameters was shown., Conclusion: Since the Esh/Cp ratio was related to image analysis results, it proved to be an interesting defect tag.

During pharmaceutical compaction, the interaction between the punch and the powder determines the formation and the aspect of the surface of the compact. In industry, the properties of the punch surface, which play a key role in this interaction, are sometimes changed by fixing an intermediate layer onto the punch to prevent sticking problems. In this article, the case of a polymer insert layer was studied. Firstly, sugar spheres were compacted with and without the polymer insert fixed onto the punches. After compaction with uncovered punches, the surface particles, which had been subjected to high deformation, were flattened on one side. However, it was observed, using confocal X-ray microfluorescence, that this kind of deformation was limited to the surface and that the bulk particles, which underwent a more isotropic deformation, still exhibited an approximately round shape. Secondly, the influence of the surface structure on the mechanical properties of the compacts was studied. The indentation hardness and the tensile strength of compacts of microcrystalline cellulose (MCC) and anhydrous calcium phosphate (aCP) were studied. No differences were found for the compacts of MCC produced with the two kinds of punches, but the compacts of aCP obtained with uncovered punches presented a higher hardness and a higher tensile strength than those obtained with covered punches., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In the pharmaceutical industry, tablets are obtained by the compaction of two or more components which have different physical properties and compaction behaviours. Therefore, it could be interesting to predict the physical properties of the mixture using the single-component results. In this paper, we have focused on the prediction of the compressibility of binary mixtures using the Kawakita model. Microcrystalline cellulose (MCC) and L-alanine were compacted alone and mixed at different weight fractions. The volume reduction, as a function of the compaction pressure, was acquired during the compaction process ("in-die") and after elastic recovery ("out-of-die"). For the pure components, the Kawakita model is well suited to the description of the volume reduction. For binary mixtures, an original approach for the prediction of the volume reduction without using the effective Kawakita parameters was proposed and tested. The good agreement between experimental and predicted data proved that this model was efficient to predict the volume reduction of MCC and L-alanine mixtures during compaction experiments., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: The aim of this work is to study the effect of compaction on the specific surface area of tablets composed of various pharmaceutical materials (microcrystalline cellulose, lactose, and anhydrous calcium phosphate) compacted under seven degrees of compaction pressure., Methods: In a first part, the influence of the deformation behavior of the compacted materials on the evolution of the specific surface area is observed. In a second part, the brittle and ductile abilities of the materials are calculated using the specific surface area values. The experimental results are used to calculate the number and the force of interparticulate bonds inside the tablet., Results and Discussion: Tablets made of microcrystalline cellulose, which deform plastically, have specific surface areas that fall under pressure. In the case of lactose, the tablet specific surface area first increases to reach a maximum value at a pressure of 150 MPa. At higher pressure, however, the specific surface area decreases. The specific surface area of tablets composed of anhydrous calcium phosphate consistently increases, whatever the compaction pressure applied. Moreover, the evolution of the specific surface area is correlated with the tensile strength of the corresponding tablets. The number and the force of interparticulate bonds make it possible to classify the materials according to their deformation behavior and to quantify their ability to form cohesive tablets.

The Stylcam 100R, a rotary press simulator, was designed to simulate speed profiles of rotary tablet presses. Such a simulator was qualified by numerous laboratories and, actually, its ability to be used for studying the behaviour of powders under pressure should be examined. Then, the purpose of this work was to investigate the performances of the Stylcam 100R for characterizing the compaction behaviour and the tabletting properties of pharmaceutical powders. The compressibility of three pharmaceutical excipients (microcrystalline cellulose, dicalcium phosphate dihydrate and alpha-lactose monohydrate) was studied. Four compression speeds were used on the compaction simulator. Force-displacement cycles were associated with two energy parameters, the specific total energy (Es(tot)) and the specific expansion energy (Es(exp)). The mean yield pressure was calculated from Heckel's plots obtained with the in-die method. The diametral tensile strength of compacts was measured in order to evaluate mechanical properties. To evaluate the accuracy of all these parameters, a comparative study was carried out on an eccentric instrumented press. The values of energy parameters and tensile strengths of tablets are close between the eccentric press and the compaction simulator, whatever the compression speed on the latter. The mean yield pressure values obtained using the two presses are different. Finally, the Stylcam 100R seems to be a good tool for characterising tabletting properties of powders, except for the Heckel's model probably due to an unadapted equation of deformation and a lack of accuracy of the displacement transducers. Future improvements should allow correcting these two points., ((c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association)

Abstract: The development of predictive models for the pharmaceutical compaction process is of great interest for not only the formulation step but also in the context of the quality by design development. This paper deals with the prediction of the compressibility, i.e. the prediction of the evolution of the density and the porosity of the compact along with the compaction pressure, both “in-die” (during the compaction) and “out-of-die (after the ejection of the compact). For this purpose, four different mixtures composed of five different pharmaceutical products were studied using a rotative press simulator. The excipients and formulations were chosen to be as near as possible to real industrial formulations. Using the volume as an additive property and a reformulation of the Kawakita equation as a function of the density, it was possible to predict the density of the compact both “in-die” and “out-of-die” with a good accuracy (residuals <3.5%). In most of the cases, for the pressure levels used in the pharmaceutical industry, the absolute error on the prediction of the porosity was below 2%. This study demonstrates that this approach could be well suited to predict the compressibility of real pharmaceutical formulations in the industrial context. [Copyright &y& Elsevier]

Abstract: The compressibility of three pharmaceutical excipients (microcrystalline cellulose, lactose and anhydrous calcium phosphate) and their binary mixtures was studied. The aim of this work was to observe the impact of the mass composition of the mixture on the compressibility. The single-compound materials and their mixtures were compacted using instrumented presses. It allowed obtaining compression cycles (i.e., force–displacement curves) which were associated with energy measurements (specific compaction energy, E spcp and specific expansion energy, E spexp). It was observed that for the mixtures studied, the change of E spcp with the mass composition could be fitted using a linear relationship (it was not the case with E spexp). A linear relationship between the porosity of mixture’s compacts and the mass composition was also obtained. Heckel’s plots were then obtained for the three excipients and the mixtures. The mean yield pressure was calculated with the “in-die-method” and the “out-of-die method”. A proportional relationship was not valid for the mean yield pressures. But, a predictive approach was proposed in order to obtain indirectly the mean yield pressure of a binary mixture if the data of the single materials were known. It used the linear mixing rule observed with the porosity. The validity was verified and compared with the experimental values. This comparison showed that it was possible to predict the mean yield pressure of binary mixtures from the accessible data of the single excipients. [Copyright &y& Elsevier]

Abstract: Three pharmaceutical excipients (microcrystalline cellulose, lactose, anhydrous calcium phosphate) and their binary mixtures were compacted to form compacts of various mean porosities. Some mechanical properties (Young’s modulus, tensile strength and Brinell hardness) were studied on these compacts. The mechanical properties of the binary mixtures were not proportional to the mixture composition expressed in mass. More, for all the properties, a negative deviation was always observed from this linear relationship. In reference to a composition percolation phenomenon, critical mass fractions were detected from the graph mechanical property vs. mass composition of a mixture. The results obtained with Brinell hardness differed from the results of the Young’s modulus and the tensile strength, i.e. the most plastic material in the binary mixture controlled the mixture behaviour. Secondly, a predictive model based on a statistical approach was proposed for the Young’s modulus and the tensile strength. The validity of this model was verified on experimental data, and an interaction parameter used to characterize the affinity of the two compounds was calculated. Finally, the X-ray tomography technique was applied to the compacts of cellulose/phosphate mixtures to obtain cross-sections images of the compacts. The analysis of the cross-sections images allowed explaining the no linear relationship of the different mechanical properties results observed on these binary mixtures. [Copyright &y& Elsevier]