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The incorporation of siRNA into nanocarriers is mandatory to facilitate its intracellular delivery, as siRNA itself cannot enter cells. However, the incorporation of these nanocarriers into oral, solid dosage forms and their fate in the gastrointestinal environment is yet to be explored. In the present work, the fate of, (i) naked siRNA, (ii) freshly prepared siRNA lipoplexes, and (iii) tableted siRNA lipoplexes, in simulated gastric and intestinal fluids was studied. The siRNA, either released from or protected within the lipoplexes, was quantified by gel electrophoresis and siRNA efficacy was assessed in cell transfection. The freshly prepared lipoplexes kept their siRNA load and transfection efficiency totally preserved during 1 h of incubation in simulated gastric fluid at 37 °C. However, in simulated intestinal fluid, despite no release of siRNA from lipoplexes after 6 h of incubation, gene silencing efficacy was dramatically decreased even after 1 h of exposure. The lipoplexes obtained from tablets efficiently protected siRNA in simulated gastric fluid, thus preserving the gene silencing efficacy, whereas their incubation in simulated intestinal fluid resulted in a marked siRNA release and decreased gene silencing efficacy. These results provided a detailed explanation for understanding the fate of siRNA in gastrointestinal conditions, when simply loaded in lipoplexes or formulated in the form of tablets.

Probiotics are of great current interest in the pharmaceutical industry because of their multiple effects on human health. To beneficially affect the host, an adequate dosage of the probiotic bacteria in the product must be guaranteed from the time of manufacturing to expiration date. Stability test guidelines as laid down by the ICH-Q1A stipulate a minimum testing period of 12 months. The challenge for producers is to reduce this time. In this paper, a mechanistic approach using the Arrhenius model is proposed to predict stability. Applied for the first time to laboratory and industrial probiotic powders, the model was able to provide a reliable mathematical representation of the effects of temperature on bacterial death (R(2)>0.9). The destruction rate (k) was determined according to the manufacturing process, strain and storage conditions. The marketed product demonstrated a better stability (k = 0.08 months(-1)) than the laboratory sample (k = 0.80 months(-1)). With industrial batches, k obtained at 6 months of studies was comparable to that obtained at 12 months, evidence of the model's robustness. In addition, predicted values at 12 months were greatly similar (±30%) to those obtained by real-time assessing the model's reliability. This method could be an interesting approach to predict the probiotic stability and could reduce to 6 months the length of stability studies as against 12 (ICH guideline) or 24 months (expiration date).

Graphical abstract Abstract 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. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]