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Predicting tablet defects, such as capping, that might occur during manufacturing, is a challenge in the pharmaceutical industry. In the literature, different parameters were presented to predict capping but no general consensus seems to have been reached yet. In this article, we chose to study a wide range of products (18 formulations, 8 of which presenting capping) to predict capping on biconvex tablets using the properties characterized on defect-free flat-faced tablets (tensile strength, solid fraction, elastic recovery, etc.), made using the same process parameters. Single parameters and predictive indices presented in the literature were evaluated on this set of formulations and were found not suitable to predict capping. A predictive model was then developed using a decision tree analysis and was found to depend only on three in-die tablet properties: the plastic energy per volume, the in-die elastic recovery and the residual die-wall pressure. This model was tested on another set of 13 formulations chosen to challenge it. The capping behavior of 29 out of the 31 formulations studied in total was well estimated using the developed model with only two products which were predicted to cap and did not. This shows the potential of the used approach in terms of risk analysis and assessment for capping occurrence.

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Capping is a common defect that can occur during the manufacturing of pharmaceutical tablets. Several studies showed that decreasing the unloading speed of the manufacturing cycle plays a role in the occurrence of such defects. Following this idea, we study in this work the influence of the unloading step on capping using a compaction simulator. Measuring the die wall pressure made it possible to detect precisely that tablets capped just after the unloading (some milliseconds only). To evaluate the impact of the unloading speed on capping, we developed a two-step unloading phase controlled by three manufacturing parameters. It was possible to mitigate capping by decreasing the speed at which the contact between the punches and the tablet was lost. Capping seemed due to dynamical effects related to the release of the axial pressure. The modification of the unloading step to mitigate capping led to significant changes in tablet density but no clear trends were found for the residual die-wall pressure and tablet strength. This work made it possible to improve the understanding of capping. Moreover, the two-step unloading cycle gave a new idea for possible modifications that could be done on rotary presses in order to mitigate capping.

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Lamination is a common industrial problem during the production of pharmaceutical tablets. It corresponds to a failure of the tablet in one or several planes parallel to the surface and passing through the tablet band. But different kinds of lamination exist, and a classification of the different cases is proposed in this work. Type 1 corresponds to a multiple fracture caused by air entrapment. Type 2 occurs because of the shear stresses developing when the tablet goes out of the die. Type 3, which is limited to convex tablets, is due to a tensile stress developing at the center of the tablet at the end of the unloading that further propagates toward the band. One case of each type was studied experimentally in order to test three solutions classically used at the industrial level: slowing down the press, using a precompression and using a tapered die. Results shows that, in coherence with the proposed mechanisms, lamination type 1 can be mitigated by slowing down the press or using a precompression. For type 2, only the tapered die solution stopped lamination. None of the solutions completely solved lamination type 3. Nevertheless, the use of a tapered die decreased the severity of the problem avoiding the propagation of the crack until the surface.

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Pharmaceutical tablets can be produced on different kinds of presses that may have very different compaction kinematics. Strain rate sensitivity (SRS) is thus an important property for the powders used to produce pharmaceutical tablets. Viscoelasticity is one of the aspects of the SRS and can be sometimes difficult to characterize. In this work, impulse excitation technique was used as an easy-to-implement method for characterizing viscoelasticity using the fact that this property induces damping which can be detected on resonance spectra as peak enlargements. A damping ratio, related to the first flexural vibration mode, was determined on impulse excitation frequency spectra using the half-power bandwidth method on tablets made with different products. This method made it possible to obtain reproducible results for the damping ratio. As viscoelasticity is not the only phenomena that can promote damping, tests were made in order to assess the influence of other parameters: viscoplasticity, porosity and tablet dimensions. Results indicated that the influence of these phenomena could be considered as negligible. Finally, the damping ratios determined were in good accordance with the known viscoelastic behavior of the studied products. This made it possible to confirm that impact resonance is an easy and quick way to characterize the viscoelastic nature of pharmaceutical tablets.

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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.

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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.

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Liquid vaccine formulations present some disadvantages such as stability problems, cold chain requirement or administration by trained personnel. Vaccine formulated as tablets would present a wide range of progress such as an increase stability that would facilitate the administration, the distribution and the storage of vaccine formulations. This work investigates the possibility to develop a mucosal tablet vaccine for human influenza viruses. The tablets were tested in vitro for biological efficacy and stability and in vivo in swine as a model for influenza A virus immunity. First, the ability to produce by compaction a stable vaccine with a preserved antigen was demonstrated. In a second part, vaccine tablets were used to immunize pigs. After positioning the tablets on the buccal mucosa, the animals were challenged by inoculation of the A/H1N1 pandemic virus. The responses were compared to those observed in animals vaccinated intramuscularly with the commercial liquid vaccine. It was observed signs of priming of the pig's immune system with vaccine tablets, even if the immune response stayed lower than vaccination by intramuscular route. Thus, we present attractive results that indicate a promising potential for mucosal vaccine tablets.

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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. Then, a shear test usually performed on bilayer tablets was adapted to monolayer tablets. The shear strength obtained for 5 products, 2 of them having a known capping tendency, were compared with the strengths obtained during diametral compression test and uniaxial compression test. The results indicated that, for the formulations with a capping tendency, the ratio between the shear strength and diametral compression strength was lower than for the other products. Considering the mechanism of capping, the weakness in shear of these formulations explained their capping tendency. This was also linked with the mechanical anisotropy of the same formulations which was shown in the literature. In the cases studied in this article, the fundamental reason for the capping tendency was the anisotropic strength of the tablets.

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Mechanical strength is an important critical quality attribute for tablets. It is classically measured, in the pharmaceutical field, using the diametral compression test. Nevertheless, due to small contact area between the tablet and the platens, some authors suggested that during the test, the failure could occur in tension away from the center which would invalidate the test and the calculation of the tensile strength. In this study, the flattened disc geometry was used as an alternative to avoid contact problems. The diametral compression on both flattened and standard geometries was first studied using finite element method (FEM) simulation. It was found that, for the flattened geometry, both maximum tensile strain and stress were located at the center of the tablet, which was not the case for the standard geometry. Experimental observations using digital image correlation (DIC) confirmed the numerical results. The experimental tensile strength obtained using both geometries were compared and it was found that the standard geometry always gave lower tensile strength than the flattened geometry. Finally, high-speed video capture of the test made it possible to detect that for the standard geometry the crack initiation was always away from the center of the tablet.

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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. In this article, using a model product compacted on a compression simulator, a direct proof of the implication of air entrapment during lamination was given. In fact, at the surface of the compact, defects with a spherical shape, clearly linked with an entrapped bubble of air, began to appear on the surface of the compact just below the pressure level to which lamination was observed. Moreover it was also observed that, when the compact thickness increased, the lamination pressure decreased, meaning that the compact thickness can promote lamination. As a conclusion, contrary to what is said in some publications, air entrapment can be involved when problems of lamination occur, and, in this case, powder desaeration should be considered.

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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.

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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.

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The aim of this study was to better understand the effects of the curing conditions on the resulting drug release patterns from pellets coated with aqueous polymer dispersions. Diltiazem HCl was used as model drug, ethylcellulose as polymer, triethyl citrate (TEC), dibutyl sebacate (DBS), and distilled acetylated monoglycerides (Myvacet) as plasticizers. Interestingly, the effects of the curing conditions strongly depended on the coating level and the type of plasticizer: in the case of TEC, the drug release rate monotonically decreased with increasing harshness of the curing conditions (time, temperature, and relative humidity), irrespective of the coating level. In contrast, in the case of DBS and Myvacet, this type of relationship was only observed at low coating levels (5%). At intermediate coating levels (around 7.5%), the curing conditions had virtually no effect on drug release. At high coating levels (10%), the release rate initially increased and then decreased with increasing harshness of the curing conditions. This more complex behavior might be attributable to the superposition of two competing phenomena: improved film formation and drug migration into the polymeric membrane. Furthermore, it could be shown that the type of plasticizer had a major effect on drug release in not fully coalesced and equilibrated film coatings, whereas the release profiles were similar for all plasticizers in the case of completely formed and equilibrated film coatings. Importantly, the latter systems were stable for long term even during storage under stress conditions.

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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.

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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.

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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, Esp cp and specific expansion energy, Esp exp). It was observed that for the mixtures studied, the change of Esp cp with the mass composition could be fitted using a linear relationship (it was not the case with Esp exp). 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.

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Lead soaps can be found in archaeological cosmetics as well as in oil paintings, as product of interactions of lead salts with oil. In this context, a better understanding of the formation of lead soaps allows a follow-up of the historical evolution of preparation recipes and provides new insights into conservation conditions. First, ancient recipes of both pharmaceutical lead plasters and painting lead mediums, mixtures of oil and lead salts, were reconstructed. The ester saponification by lead salts is determined by the preparation parameters which were quantified by FT-IR spectrometry. In particular, ATR/FT-IR spectrometer was calibrated by the standard addition method to quantitatively follow the kinetics of this reaction. The influence of different parameters such as temperature, presence of water and choice of lead salts was assessed: the saponification is clearly accelerated by water and heating. This analysis provides chemical explanations to the historical evolution of cosmetic and painting preparation recipes.

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Physico-chemical properties of a substance including the compaction behaviour are directly connected with the crystalline structure. The aim of this work is to compare the compaction behaviour in a group of excipient and in this first part, to display the influence of lactose structures on the compressibility. alpha-Lactose monohydrate (LalphaM), anhydrous beta-lactose (LbetaA), anhydrous alpha-lactose (LalphaA) and partly amorphous lactose (FF) were compressed using instrumented presses to investigate the densification behaviour under pressure. Force-displacement curves were associated to two energy parameters, specific cycle energy and specific expansion energy. This approach was used to class the four lactose species. It is possible to differentiate three groups with the specific energy cycle, FF, LalphaA/LbetaA and LalphaM in decreasing order of this energy. At the same time, the values of specific expansion energy are relatively low for FF and LalphaA contrary to LalphaM and LbetaA. Then, Heckel's plots were obtained with two compact geometries and the mean yield pressure was calculated from the in-die-method and the out-of-die-method. Two lactoses seem to differ, LalphaM appears to be the most ductile whereas LalphaA is more brittle than the others. Finally, it is concluded, that in the case of lactoses, pseudopolymorphism seems to affect the compressibility more than anomerisation or partial amorphisation.

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Magnetic Resonance Imaging (MRI) was used to study the mixing process of binary mixtures of free flowing sugar beads in a Turbula mixer. In order to make particles MRI-sensitive, some reference beads were doped with an organic oil. Doped and undoped particles were mixed and MRI was used to non-destructively image the particle bed for a given number of mixer rotations (NR), bead diameter ratio (R=d(ref)/d(i)) and rotation speed (V). All the results were quantified on the basis of image analysis to characterise the degree of mixing. Studies showed that for binary mixtures of identical particle size, the mixing was complete after 30 rotations, whereas for beads of different size (R=2.8) a segregated steady state was obtained after nearly 10 rotations. Experiments revealed that segregation appeared as soon as R=0.9. Moreover, the lower the rotation speed, the more segregated the final state was. It appeared that for a filling level greater than 80%, dead regions appeared in the centre of the powder bed. In conclusion, when the particles are non-cohesive, the Turbula blender perfectly mixes identical beads but segregation occurs for beads of different size after just a few rotations.

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Most of the pharmaceutical processes involved in the manufacturing of so lid dosage forms are connected with powder flow properties, at least for some of the intermediate steps. Powder flow characteristics are commonl y investigated by various measurements, such as handling angles, tap tes ting, shear cell measurements, etc. All these approaches allow the calc ulation of indices characterising powder flowability. Unfortunately, th ese methodologies are highly product consuming, which is a limitation in the first steps of a novel drug development, when only a small amount of product is available. The use of mercury porosimetry to evaluate compre ssibility and flow properties of powders could be a new and alternative approach to obtain insight in the rheological properties of granular med ium by the interpretation of the first part of programs (low pressures) . We have developed such an evaluation and compared the results obtaine d with those given by tap testing and shear cell measurements, applied t o four excipients for direct tabletting and three different drugs. Merc ury porosimetry turned out to be a sensitive technique, able to providequantitative information about powder flow properties, complemen ted by an evaluation of particles micro porosity and size distribution, in a single step. These characterisations are obtained with only approx imately 250mg of bulk powder compared to high quantities ( >100g) needed for other methods.

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