Shear stress computation in a millimeter thin flat panel photobioreactor: Numerical design validated by experiments.

Flat panels are the most spread type of photobioreactors for studying light effects on a microalgae culture. Their low thickness, usually between 1 and 3 cm, aims at ensuring light homogeneity across the culture. Yet because optical density has to remain very low, studies are still limited to low cell density cultures. To alleviate this problem, even thinner photobioreactors can be designed. Nevertheless, thin flat panel reactors are very prone to induce high shear stress. This work aimed at designing a new millimeter thin panel photobioreactor to study light effects on Chlorella and Scenedesmus genera. We proposed a numerical workflow that is capable of assessing the shear stress intensity in such a reactor. The numerical predictions were validated at three different levels: 2D preliminary simulations were able to reproduce bubble commonly known behaviors; close to the nozzle, the predictions were successfully confronted to shadowgraphy experimental reference; at the mini bioreactor scale, experimental and numerical mixing were found to be close. After these throughout validations, shear stress intensity in the photobioreactor was calculated over 1000 Lagrangian tracers. The experienced shear stress was agglomerated at the population level. From the computed shear stress, it was possible to choose the minimal reactor thickness that would not hinder cell growth.

Processing-induced-transformations (PITs) during direct compression: impact of compression speeds on phase transition of caffeine.

For pharmaceutical industry, understanding solid-phase transition of the active pharmaceutical ingredient (API) induced by the manufacturing process is a key issue. Caffeine was chosen as a model API since it exhibits a polymorphic transformation during tableting. This study investigated the impact of the compression speed on the phase transition of anhydrous Form I (CFI) into Form II. Tablets were made from pure CFI and binary mixtures of CFI/microcrystalline cellulose, with an electric press well instrumented at three different compression speeds (50, 500 and 4500 mm min(-1)). For each velocity of the mobile punch studied, tablets made from three compression pressures (50, 100 and 200 MPa) were analyzed. The determination of the CFI transition degree was performed using a Differential Scanning Calorimetry (DSC). The CFI transition degree was monitored during three months in order to obtain the transformation profile of the API in tablets and in uncompressed powder. The modeling of the profile with a stretched exponential kinetic law (Johnson-Mehl-Avrami model) was used for the identification of the transition mechanism. The direct compression process triggered the polymorphic transformation in tablet when a sufficient compression pressure is applied. The velocity of the punch did neither impact the transition degree just after compression nor the transformation profile. The transition mechanism remained driven by nucleation for several operating conditions. Consequently, the punch velocity is not a decisive process parameter for avoiding such phase transition in tableting. As already observed, the compression pressure did not influence the transition whatever the compression speed and the velocity.

Processing-induced-transformations (PITs) during direct compression: Impact of tablet composition and compression load on phase transition of caffeine.

In the pharmaceutical field, solid-state transitions that may occur during manufacturing of pharmaceuticals are of great importance. The phase transition of a model API, caffeine Form I (CFI), was studied during direct compression process by analysing the impacts of the operating conditions (process and formulation). This work is focused on two formulation parameters: nature of the diluent and impact of the caffeine dilution, and one process parameter: the compression pressure that may impact the phase transition of CFI. Tablets were made from pure CFI and from binary mixture of CFI/diluent (microcrystalline cellulose or anhydrous dicalcium phosphate). A kinetic study performed during six months helped to highlight the influence of these parameters on the CFI transition degree. Results showed a triggering effect of the direct compression process, transformation was higher in tablets than in uncompressed powders. Whatever the pressure applied, CFI transition degree was almost constant and uniformly occurring throughout the tablet volume. Nevertheless, several differences on the evolution of the CFI transition degree were observed between binary mixtures of CFI/diluent. An analysis of the transition mechanism with a stretched exponential law of the Johnson-Mehl-Avrami model shows that tableting accelerates the polymorphic transition without modifying its mechanism controlled by nucleation only.

Comparative scale-up of three methods for producing ibuprofen-loaded nanoparticles.

The lack of information related to the scaling-up of technologies used for preparing polymeric nanoparticles (NP) might hinder the introduction of these colloidal carriers into the pharmaceutical market. In the present study, the scale-up of ibuprofen-loaded NP produced by three manufacturing processes--salting-out, emulsification-diffusion and nanoprecipitation--was assessed at pilot-scale by increasing 20-fold the laboratory-batch volume from 60 ml to 1.5l. Eudragit L100-55 and poly(vinyl alcohol) (PVAL) were used as polymer and emulsifying agent, respectively. The influence of the hydrodynamic conditions on the NP characteristics such as mean size, drug content, residual PVAL and morphology was also investigated. At pilot-scale, stirring rates of 790-2000 rpm lead to NP mean sizes ranging from 557 to 174 nm for salting-out and from 562 to 230 nm for emulsification-diffusion. An increase in the stirring rate enhances the droplet break-up phenomenon which leads to the formation of finer emulsion droplets and thus smaller NP. Moreover, the influence of the stirring rate on the mean size of NP can be predicted using a model based on a simple power law. The continuous method used for nanoprecipitation scale-up allows production of NP in a reproducible way over a relatively short time. Finally, for the three methods, NP characteristics were reproduced well at both scales. However, the scale-up process induced a slight reduction in the size and drug loading of NP.

Predictive model for tensile strength of pharmaceutical tablets based on local hardness measurements.

In the pharmaceutical field, tablets are the most common dosage forms for oral administration. During the manufacture of tablets, measures are taken to assure that they possess a suitable mechanical strength to avoid crumbling or breaking when handling while ensuring disintegration after administration. Accordingly, the tensile strength is an essential parameter to consider. In the present study, microscopic hardness and macroscopic tensile strength of binary tablets made from microcrystalline cellulose and caffeine in various proportions were measured. A relationship between these two mechanical properties was found for binary mixture. The proposed model was based on two physical measurements easily reachable: hardness and tablet density. Constants were determined from the two extreme compositions of this given system. This model was validated with experimental results, and a comparison was made with the one developed by Wu et al. (2005). Both models are relevant for this studied system. Nonetheless, with this model, the tablet tensile strength can be connected with a tablet characteristic at microscopic scale in which porosity is not needed.

Process induced transformations during tablet manufacturing: phase transition analysis of caffeine using DSC and low frequency micro-Raman spectroscopy.

The phase transition of a model API, caffeine Form I, was studied during tableting process monitored with an instrumented press. The formulation used had a plastic flow behavior according to the Heckel model in the compression pressure range of 70-170 MPa. The quantitative methods of analysis used were Differential Scanning Calorimetry (DSC) and low frequency Micro Raman Spectroscopy (MRS) which was used for the first time for the mapping of polymorphs in tablets. They brought complementary contributions since MRS is a microscopic spectral analysis with a spatial resolution of 5 µm(3) and DSC takes into account a macroscopic fraction (10mg) of the tablet. Phase transitions were present at the surfaces, borders and center of the tablets. Whatever the pressure applied during the compression process, the transition degree of caffeine Form I toward Form II was almost constant. MRS provided higher transition degrees (50-60%) than DSC (20-35%). MRS revealed that caffeine Form I particles were partially transformed in all parts of the tablets at a microscopic scale. Moreover, tablet surfaces showed local higher transition degree compared to the other parts.