The effect of unloading and ejection conditions on the properties of pharmaceutical tablets.

This study investigates decompression and ejection conditions on tablet characteristics by comparing compact densities and tensile strengths made using regular rigid dies and custom-built die systems that enable triaxial decompression. Die-wall pressure evolution during decompression and ejection stresses did not meaningfully impact the density and tensile strength of the materials tested: microcrystalline cellulose, crystalline lactose monohydrate, and mannitol. Furthermore, the apparent differences in tensile strength between rectangular cuboids and cylindrical compacts are unrelated to decompression and ejection conditions, but rather a consequence of their shapes and of the test configurations. This suggests that elastic and plastic deformations that may occur during decompression and ejection are not significantly influenced by die-wall pressure evolution. We thus conclude that while triaxial decompression and constraint-free ejection may allow the production of defect-free compacts for materials that otherwise are defect prone using a rigid die, they seem to pose no benefits when the materials already produce defect-free compacts using a rigid die.

Tableting behavior of freeze and spray-dried excipients in pharmaceutical formulations.

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.

Consolidation of Spray-Dried Amorphous Calcium Phosphate by Ultrafast Compression: Chemical and Structural Overview.

A large amount of research in orthopedic and maxillofacial domains is dedicated to the development of bioactive 3D scaffolds. This includes the search for highly resorbable compounds, capable of triggering cell activity and favoring bone regeneration. Considering the phosphocalcic nature of bone mineral, these aims can be achieved by the choice of amorphous calcium phosphates (ACPs). Because of their metastable property, these compounds are however to-date seldom used in bulk form. In this work, we used a non-conventional "cold sintering" approach based on ultrafast low-pressure RT compaction to successfully consolidate ACP pellets while preserving their amorphous nature (XRD). Complementary spectroscopic analyses (FTIR, Raman, solid-state NMR) and thermal analyses showed that the starting powder underwent slight physicochemical modifications, with a partial loss of water and local change in the HPO42- ion environment. The creation of an open porous structure, which is especially adapted for non-load bearing bone defects, was also observed. Moreover, the pellets obtained exhibited sufficient mechanical resistance allowing for manipulation, surgical placement and eventual cutting/reshaping in the operation room. Three-dimensional porous scaffolds of cold-sintered reactive ACP, fabricated through this low-energy, ultrafast consolidation process, show promise toward the development of highly bioactive and tailorable biomaterials for bone regeneration, also permitting combinations with various thermosensitive drugs.

Image analysis quantification of sticking and picking events of pharmaceutical powders compressed on a rotary tablet press simulator.

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.

Indices for the brittleness of pharmaceutical tablets: A reassessment.

Brittleness is an important mechanical property. In the classical sense, a material is considered brittle if, during loading, it behaves elastically until failure. Nevertheless, it is also sometimes understood as the fact to be resistant to breakage. In the case of pharmaceutical tablets, three different indices have been defined to measure brittleness: the brittle fracture index (BFI), the brittle/ductile index (BDI) and the tablet brittleness index (TBI). The aim of this work was to reassess the meaning of the different indices that are known to give contradictory results. Using theoretical considerations, numerical modelling and experiments, it was possible to show that the only index that unequivocally measures the brittleness of the tablet understood as elastic until failure is the BFI. If the other two indices can be useful, for example to assess the friability of the tablet in the case of the TBI, they do not make it possible to measure tablet brittleness in the classical sense, i.e. as opposed to ductility.

Effect of geometrical features on the capping behavior of biconvex tablets.

Capping is a common industrial issue during the manufacturing of pharmaceutical tablets. It is influenced by both process and formulation parameters. In this work, a systematic study of the influence of the geometrical features of biconvex tablets on capping occurrence was performed on a model formulation, using a design of experiment. Capping was characterized by the pressure at which half of the produced tablets were capped. The influence of the tablet geometry was assessed by varying three parameters: the diameter (D), the band thickness (W) and the ratio between the radius of curvature (R) and the diameter, i.e. R/D. Results showed that having a large diameter, a low band thickness and a high curvature (i.e. a low R/D) favored capping occurrence. Moreover, the effects are not independent as cross-effect were detected. Finally, even for homothetic tablets (i.e. same R/D and W/D) it is shown that a large diameter increases capping occurrence. These results could be used in the future as a guideline for punch selection during tablet development.

Comparing failure tests on pharmaceutical tablets: Interpretation using experimental results and a numerical approach with cohesive zone models.

The mechanical strength is an important quality attribute of pharmaceutical tablets. It can be determined using different failure tests like the Brazilian test or the three-point bending test. Nevertheless, literature shows that different failure tests often give conflicting values of tensile strengths (TS), which are generally calculated using the maximum stress criterion as a failure criterion. This work started from the hypothesis that these discrepancies are in fact due to the application of this criterion which is not suited to study pharmaceutical tablets, first due to heterogeneity of the stress distributions during the tests and second due to the quasi-brittle nature of pharmaceutical tablets. As an alternative, a numerical fracture criterion which is known to be well-suited for quasi-brittle solids (cohesive zone model, CZM) was used and calibrated using experiments. Using this approach, the breaking forces obtained numerically were shown to be in fair agreement with the experimental ones. Above all, the numerical results made it possible to catch the trends when comparing the different failure tests one to another. Especially, the model made it possible to retrieve the factor 2 between the TS obtained by three-point bending and by diametral compression found in the literature.

Tableting properties of freeze-dried trehalose: Physico-chemical and mechanical investigation.

Freeze-drying of biopharmaceutical products is the method of choice in order to improve their stability and storage conditions. Such freeze-dried products are usually intended for parenteral route administration. However, many biopharmaceutical materials administered by parenteral route are used to treat local diseases particularly in the gastro-intestinal tract. Therefore, many studies concentrate nowadays their effort on developing alternative dosage forms to deliver biopharmaceutical molecules by the oral route. Tablets are the most popular solid pharmaceutical dosage form used for oral administration since they present many advantages, but poor informations are available on the possibility of tableting freeze-dried powders. In this study, we evaluate the compaction behavior of freeze-dried trehalose powder since trehalose is one of the most used cryo and lyoprotectant for the lyophilisation of biopharmaceutical entities. Results show that freeze-dried trehalose powder can be tableted while remaining amorphous and the obtained compacts present very specific properties in terms of compressibility, tabletability, brittleness and viscoelasticity compared to the crystalline trehalose and compared to classical pharmaceutical excipients.

Influence of the punch shape on the core and shell structure of press-coated tablets.

Press-coated tablets are a key technology to achieve delayed releases in chronotherapeutics. The drug release properties of this kind of tablets are linked to its unique core-shell structure. It is thus important to understand the influence of the process parameters on this structure. As different shapes can be used in the industry, we focused, in this study, on understanding the influence of punch shape on the final structure of a press-coated tablet. Experiments were performed using flat, bevel-edged and concave punches for the coating-compression to study the effect of the punch shape on the final properties of the core but also on the density distribution in the shell. The experiments were supported by numerical simulation to understand the mechanical effects in the powder compression process. It was found that the radial and axial stress state in the shell and in the core during compression is very dependent on the punch shape. The use of concave punches results in a more hydrostatic stress state compared to flat punches. The consequences on the structure are a more homogenous shell and less deformation of the core, which confirms that the tooling shape is a critical parameter to consider for the production of press-coated tablets.

Controlling the lag-time and release kinetics of press-coated tablets using process parameters and tablet geometry.

Press-coated tablets are an advantageous technology to achieve delayed releases of active ingredients. They are characterized by a core-shell structure, that makes it possible to tune the lag-time and release kinetics in order to meet the chronotherapeutical goals. Thus, these features are the most important quality attributes to be controlled when designing a press-coated tablet. Many studies have focused on the influence of the formulation on the release attributes. This work aims to study the influence of geometrical and process parameters on the release attributes of press-coated tablets, while keeping a constant formulation. In particular, the variation of compression pressure, layer thickness and band thickness made it possible to vary the lag-time from 1 h to 10 h. These parameters also have an influence on the release kinetics after the lag-time. Indeed, two main opening modes were observed during the dissolution test that correspond to fast or slow release rates. The opening mode obtained depends on the density distribution in the shell, which is directly influenced by the process parameters.

Breaking patterns of press-coated tablets during the diametral compression test: Influence of the product, geometry and process parameters.

Press-coated tablets are a high-interest technology in chronopharmaceutics, for modified release applications. As for any kind of tablet, the test of the mechanical resistance is of primary importance at the industrial level during both the development and production steps. For this purpose, the diametral compression test is commonly used in the industry for press-coated tablets. Nevertheless, the result of this test can be much more complex compared to the case of single layer tablets. This work aims to study the applicability of this test to press-coated tablets. Diametral compression tests were performed on press-coated tablets obtained with different products (shell/core), shell sizes and compaction pressures. Four types of breaking profiles were found: total diametral, shell diametral, around the core and laminated depending on the process parameters/products used to obtain the tablet. Digital image correlation was used in order to understand the breaking patterns especially in terms of failure initiation and propagation. The kind of breaking pattern obtained is dependent on the final structure of the tablet in terms of density distribution and thus of elastic properties. To confirm the findings, numerical simulations by the finite element method was used to visualize the stress distribution inside the tablet and confirm the influence of the process parameters. The multiple failure profiles obtained imply that the output value of the diametral compression test applied to press-coated tablets should be taken with caution.

Beyond Brittle/Ductile Classification: Applying Proper Constitutive Mechanical Metrics to Understand the Compression Characteristics of Pharmaceutical Materials.

Active pharmaceutical ingredients (API) and excipients are often classified as 'brittle' or 'ductile' based on their yield pressure determined through the Heckel analysis. Such a brittle/ductile classification is often correlated to some measure of elasticity, die-wall stresses, and brittle fracture propensities from studies performed with a handful of model excipients. This subsequently gives rise to the presumption that all ductile materials behave similarly to microcrystalline cellulose (MCC) and that all brittle materials to lactose, mannitol, or dicalcium phosphate. Such a 'one-size-fits-all' approach can subsequently lead to inaccurate classification of APIs, which often behave very differently than these model excipients. This study compares the commonly reported mechanical metrics of two proprietary APIs and two classical model excipients. We demonstrate that materials classified as 'ductile' by Heckel's 'standards' may behave very differently than MCC and in some cases may even have a propensity for brittle failure. Our data highlight the complexity of APIs and the need to evaluate a set of mechanical metrics, instead of binary assignments of ductility or brittleness based on quantities that do not fully capture the tableting process, to truly optimize a tablet formulation as part of the overall target product profile.

Polymorphic transformation of anhydrous caffeine under compression and grinding: a re-evaluation.

Polymorphic transformations that may occur during mechanical treatment are of great interest for the production of pharmaceutical solids. Anhydrous caffeine is a well-known example of such transformations but a careful reading of the already existing literature shows that published results are contradictory. In this study, both forms of caffeine, form I and form II, respectively metastable and stable at ambient pressure and temperature, were submitted to compression in an instrumented alternative press and to grinding, and were studied before and after treatment by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Compression experiments showed no changes of form II during compression, whereas form I was partially transformed into form II. Nevertheless, this transformation did not happen immediately. Form II appeared after a kinetically slow transformation and was clearly detectable only after a few days, fact that was never mentioned by previous authors. Same phenomenon was observed after the grinding of form I but also after an extensive grinding of form II. DSC and XRPD measurements indicated that polymorphic transformation did not happen directly, but that a new intermediate form was obtained after mechanical treatment, which slowly turned into form II within a few days.

Effect of the compaction parameters on the final structure and properties of a press-coated tablet (Tab-in-Tab): Experimental and numerical study of the influence of core and shell dimensions.

With increasing interest in chronopharmaceutics, press-coated tablets have become a key technology in the field of modified release drug delivery systems. Although their benefits in terms of drug release have been largely studied, the comprehension of the compaction process of press-coated tablets is yet to complete. Particularly, the effects of geometrical parameters like the ratios between the thickness/diameter of the core and the thickness/diameter of the whole tablet were so far not much considered. Moreover, there is only few studies in the literature about the effect of the press-coating compression on the final structure and properties of the core. The present work consists in a joint experimental and numerical study that aims to assess these points. The study revealed high stress concentrations on the core during compression, causing high permanent deformations of the core, especially when the ratio between the core thickness and the total tablet thickness was high. The mechanical properties of the core tablet were also shown to be impacted: its density and strength were found to decrease before increasing again along the coating-compression. This effect was highlighted to be dependent on the triaxiality of the stress state (i.e. the ratio between the stresses in the different directions), itself depending on the two studied geometrical parameters. As the properties of the core affect the release attributes, ratios between the dimensions of the core and the dimensions of the whole tablet (thickness, diameter) should be taken into account as critical parameters for the manufacture of press-coated tablets.

Anisotropic porous structure of pharmaceutical compacts evaluated by PGSTE-NMR in relation to mechanical property anisotropy.

PURPOSE: The pore space anisotropy of pharmaceutical compacts was evaluated in relation to the mechanical property anisotropy. METHODS: The topology and the pore space anisotropy were characterized by PGSTE-NMR measurements. Parallelepipedical compacts of anhydrous calcium phosphate (aCP) and microcrystalline cellulose (MCC) were tested on top, bottom and side faces. A microindentation and three-point single beam tests were used to measure Brinell hardness, tensile strength and Young's modulus. All the data were submitted to a statistical analysis to test for significance. RESULTS: The porous structure of MCC compacts was anisotropic, contrary to those of aCP. The analysis of the pore space by PGSTE-NMR method showed that its structural anisotropy was controlled by the behaviour under compaction of the excipients. At the same time, the Young's modulus and the tensile strength were the same whatever the direction of testing. For the aCP compacts, all the faces had the same Brinell hardness. With MCC compacts, only the bottom face showed a lower Brinell hardness. CONCLUSIONS: Except for Brinell hardness measured on MCC compacts, the tested samples were characterized by anisotropic mechanical properties when its porous structures were sometimes anisotropic. Then, there is not a straight link between porosity anisotropy and mechanical properties.

Role of Precompression in the Mitigation of Capping: A Case Study.

Capping is an important industrial problem that can arise during the manufacturing of pharmaceutical tablets. It corresponds, for biconvex tablets, to the detachment of one of the cups of the tablet during the ejection from the press or after relaxation. Solutions to this problem remain mainly empirical. Among them, precompression is widely used. One of the most popular explanation of the role of precompression in the mitigation of capping is that it increases the total time under compression. Following this interpretation, press manufacturers developped devices or machines that make it possible to maintain the pressure between precompression and main compression. In this note, we present a case study of capping. For the formulation proposed, a precompression that was maintained until the compression gave similar results as no precompression at all, i.e. capping of all the tablets. On the contrary, if the precompression was released before compression, capping stops completely. In this case, the effect of precompression is thus due to the separation of two compression events. Moreover, results prove that this separation must last long enough for the precompression to be efficient. This example shows that effect of precompression is more complex than often described in the literature.

Applicability of impulse excitation technique as a tool to characterize the elastic properties of pharmaceutical tablets: Experimental and numerical study.

Elastic properties are of particular interest during the development of tablets especially for the definition of the formulation and of the process parameters. Impulse excitation, which is used in several industrial fields to determine elastic properties of materials, is presented in this article as a new fast and relatively cheap technology for the determination of elastic constants of pharmaceutical tablets. This technique is based on the detection of the natural resonance frequencies of solids. It was found in the present work that, for tablets obtained using different products under different compaction pressures, it was possible to detect clearly at least 3 resonance frequencies. Moreover, the shape of the resonance peaks obtained in the spectrum could be a sign of the viscoelastic nature of the tablet. With the two first resonance frequencies, it was possible, under the assumption of isotropy, to calculate Young's modulus and Poisson's ratio for each tablet using the methodology presented in the norm ASTM E1876-01. The values obtained were found independent of the tablet size as expected, and were consistent with those presented in the literature using other methodologies. Moreover, using FEM simulation, it was found that the difference between the experimental value of the third resonance frequency and the value obtained numerically was well correlated with the expected anisotropy of the tablet. Impulse excitation could thus be an interesting methodology to study tablet anisotropy.

Characterization and modeling of the viscoelasticity of pharmaceutical tablets.

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.

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. An original experimental methodology was developed to study the evolution of the kinematic friction coefficient between the tablet and the die as a function of the sliding speed of the tablet on the die wall. This methodology made it possible to separate the speed used to make the tablet from the speed used to measure the friction coefficient. Results indicate that the kinematic coefficient of friction increases with the sliding speed following a logarithmic trend. This trend was observed for 4 different pharmaceutical excipients. Moreover, it was proved that the speed dependency is an intrinsic property of the friction between a tablet and a die lubricated using magnesium stearate.

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. When symmetrical decompression was performed, as on a rotary press, capping (on both side of the tablet) and lamination were obtained. Asymmetrical unloading (fixed lower punch during unloading) made it possible to suppress lamination and to limit capping to the upper face of the tablet. This unloading condition is similar to the unloading on an eccentric press with a stationary lower punch. Finally, loaded ejection (small pressure on both sides until the end of ejection) made it possible to eliminate both capping and lamination. By changing the unloading condition, it is possible to obtain defect free tablets even for formulations with a high capping or lamination tendency. Moreover, experiments performed on an eccentric press showed results similar to those obtained for asymmetrical unloading on a compaction simulator. Anticipation of tablets defects during the development on eccentric presses might thus be complicated especially in the case of lamination.