On the complexity of predicting tablet capping.

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.

Impact of unloading kinematics on the occurrence of capping during the production of pharmaceutical tablets.

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.

Characterization of the viscoelasticity of pharmaceutical tablets using impulse excitation technique.

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.

Lamination of Pharmaceutical Tablets: Classification and Influence of Process Parameters.

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.

Use of impulse excitation technique for the characterization of the elastic anisotropy of pharmaceutical tablets.

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.

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. 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.

Development and pre-clinical evaluation in the swine model of a mucosal vaccine tablet for human influenza viruses: A proof-of-concept study.

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.

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. 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.

Reevaluation of the diametral compression test for tablets using the flattened disc geometry.

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.

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. 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.

The surface layer of pharmaceutical compacts: the role of the punch surface and its impact on the mechanical properties of the compacts.

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.

Blooming of Irganox 3114® antioxidant onto a medical grade elastomer. Impact of the recrystallization conditions on the antioxidant polymorphism, on the film wettability and on the antioxidant leachability.

Studying the blooming and recrystallization of additives onto the surface of polymer medical devices is of a great interest because it can affect the biocompatibility of the material. The polymorphism of a phenolic antioxidant (Irganox 3114(®)) used as an additive in medical devices and pharmaceutical packaging was studied: two different polymorphs were characterized by differential scanning measurements, FTIR and X-ray diffraction analyses. Then, the behavior of the additive in medical grade polyurethane films was described: a recrystallization into the stable polymorphic form was observed onto the polymer surface after annealing at different temperatures. The morphology observed depends not only on the additive/polymer ratio but also on the whole amount of additive in the polymer film. Depending on the recrystallization morphology, the wettability with water could be lowered and the leachability of the additives into aqueous media could be favored.

Prediction of the compressibility of complex mixtures of pharmaceutical powders.

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.

The microscopic (optical and SEM) examination of putrefaction fluid deposits (PFD). Potential interest in forensic anthropology.

This article describes the potential interest in physical and forensic anthropology of the microscopic analysis of residues of putrefaction fluid, a calcified deposit frequently found associated with bone rests. Its sampling and analysis seem straightforward and relatively reproducible. Samples came from archeological material (Monterenzio Vecchia, an Etruscan necropolis from the north of Italy dated between the fifth and third century B.C.; body rests of Agnès Sorel, royal mistress died in 1450 A.D.; skull and grave of French King Louis the XI and Charlotte of Savoy dated from 1483 A.D.). All samples were studied by direct optical microscope and scanning electron microscopy. Many cytological, histological, and elemental analysis were possible, producing precious data for the identification of these remains and, in some cases, the cause of death.