A Multiscale Approach for the Characterization and Crystallization of Eflucimibe Polymorphs: from Molecules to Particles

We present in this paper a generic multiscale methodology for the characterization and crystallization of eflucimibe polymorphs. The various characterization techniques used have shown that eflucimibe polymorphism is due to a conformational change of the molecule in the crystal lattice. In addition, the two polymorphs are monotropically related in the temperature range tested and have similar structures and properties (ie. interfacial tension and solubility). Consequently, it was found that for a wide range of operating conditions, the polymorphs may crystallize concomitantly. Induction time measurements and metstable zone width determination allow to infer the origin of the concomitant appearance of the polymorphs. A predominance diagram has been established which allows to perfectly control the crystallization of the desired polymorph. However, even if the stable form can be produced in a reliable way, the crystal suspension went toward a very structured gel-like network which limits the extrapolation process. Based on microscopic observation of the crystallization events performed in a microfluidic crystallizer, we propose a range of operating conditions suitable for the production of the stable form with the desired handling properties

Fractal dimension of fumed silica: Comparison of light scattering and electron microscope methods

Due to the enormous increase in nanopowder production, it becomes necessary to find and develop adapted characterization techniques. In the case of nanostructured agglomerates, the structure of these particles has a direct impact on flowing, and handling, but also on end-use final product properties. In this work, a fractal approach is used to characterize the agglomerate structure using two different, commercially available and widely used, methods: static light scattering (SLS) and image analysis of scanning electron microscope (SEM) photographs of the aggregates. Fumed silica aggregates are used for this comparison. The results by image analysis show that fumed silica aggregates have a two-level structure, made of compact aggregates of open aggregates of nanoparticles. This structure is not detected by SLS. For such a structure, SLS seems to be less accurate than image analysis method, although it could be an interesting technique in more simple cases, since it is a much less time-consuming technique

Crystal nucleation in adroplet based microfluidic crystallizer

The study presented in this paper deals with the determination of eflucimibe nucleation rate in a droplet based microfluidic crystallizer. The experimental device allows the storage of up to 2000 monodispersed droplets to get nucleation statistics and crystal growth rates under static conditions. Supersaturation was generated by quenching the droplets down to 273 or 293 K. To determine the nucleation kinetics of eflucimibe, the number of appearing crystals is recorded as a function of time. At low time scale, it was found that eflucimibe in the droplets containing active centers (impurities) crystallizes first and thus yields a rapid initial rate. At higher time scale, once all the droplets containing impurities have crystallized, leaving only the droplets that are free of impurities, the nucleation rate falls allowing the determination of the homogeneous nucleation rate. The crystal–solution interfacial energy found in this system σ=3.12 mJ m−2 is in good agreement with the previously published results. Using the crystalnucleation and the growth rate determined experimentally, simulations were performed using a Monte Carlo method. Even if this method correctly predicts the number of droplets that remains empty during the experiments, it was not possible to predict correctly the number of crystals per drop obtained experimentally. The relationship between the growth and nucleation rates and the resultant number of crystals per drop is likely to be complex and dependent on a number of system parameters. The failure of the model may be attributed either to an overestimation of the crystal growth rate or to an enhancement of the nucleation rate due to the presence of seed crystals

Biologically induced phosphorus precipitation in aerobic granular sludge process

Aerobic granular sludge is a promising process for nutrient removal in wastewater treatment. In this work, for the first time, biologically induced precipitation of phosphorus as hydroxyl-apatite (Ca5(PO4)3(OH)) in the core of granules is demonstrated by direct spectral and optical analysis: Raman spectroscopy, Energy dispersive X-ray (EDX) coupled with Scanning Electron Microscopy (SEM), and X-ray diffraction analysis are performed simultaneously on aerobic granules cultivated in a batch airlift reactor for 500 days. Results reveal the presence of mineral clusters in the core of granules, concentrating all the calcium and considerable amounts of phosphorus. Hydroxyapatite appears as the major mineral, whereas other minor minerals could be transiently produced but not appreciably accumulated. Biologically induced precipitation was responsible for 45% of the overall P removal in the operating conditions tested, with pH varying from 7.8 to 8.8. Major factors influencing this phenomenon (pH, anaerobic phosphate release, nitrification denitrification) need to be investigated as it is an interesting way to immobilize phosphorus in a stable and valuable product

Ultrafine aerosol generation from free falling nanopowders : experiments and numerical modelling

In the last few years, the interest on nanomaterials and their applications have increased in a considerable way. Hence, the knowledge of the possible hazards on human health becomes necessary. Besides the description of the toxicological effects of nanomaterials, the exposure level on the worksites is one of the key data of the problem. The present work aims at studying the resuspension of ultrafine particles in the air during the falling of nanostructured powders. A numerical approach has been developed aiming at simulating the free falling of a powder cluster. The results show that a resuspension of particles occurs following the powder cluster deformation during the free fall of the particles in the air. Isolated particles remain suspended in the air for a long time

An evaluation of thermodynamic models for the prediction of drug and drug-like molecule solubility in organic solvents

Prediction of solubility of active pharmaceutical ingredients (API) in different solvents is one of the main issue for crystallization process design. Experimental determination is not always possible because of the small amount of product available in the early stages of a drug development. Thus, one interesting perspective is the use of thermodynamic models, which are usually employed for predicting the activity coefficients in case of Vapour–Liquid equilibria or Liquid–Liquid equilibria (VLE or LLE). The choice of the best thermodynamic model for Solid–Liquid equilibria (SLE) is not an easy task as most of them are not meant particularly for this. In this paper, several models are tested for the solubility prediction of five drugs or drug-like molecules: Ibuprofen, Acetaminophen, Benzoic acid, Salicylic acid and 4-aminobenzoic acid, and another molecule, anthracene, a rather simple molecule. The performance of predictive (UNIFAC, UNIFAC mod., COSMO-SAC) and semi-predictive (NRTL-SAC) models are compared and discussed according to the functional groups of the molecules and the selected solvents. Moreover, the model errors caused by solid state property uncertainties are taken into account. These errors are indeed not negligible when accurate quantitative predictions want to be performed. It was found that UNIFAC models give the best results and could be an useful method for rapid solubility estimations of an API in various solvents. This model achieves the order of magnitude of the experimental solubility and can predict in which solvents the drug will be very soluble, soluble or not soluble. In addition, predictions obtained with NRTL-SAC model are also in good agreement with the experiments, but in that case the relevance of the results is strongly dependent on the model parameters regressed from solubility data in single and mixed solvents. However, this is a very interesting model for quick estimations like UNIFAC models. Finally, COSMO-SAC needs more developments to increase its accuracy especially when hydrogen bonding is involved. In that case, the predicted solubility is always overestimated from two to three orders of magnitude. Considering the use of the most accurate equilibrium equation involving the ΔCp term, no benefits were found for drug predictions as the models are still too inaccurate. However, in function of the molecules and their solid thermodynamic properties, the ΔCp term can be neglected and will not have a great impact on the results

Organic pollution selective degradation by adsorption on high silica zeolites and regeneration by ozone

This study concerns the treatment of industrial airstreams polluted with volatile organic compounds (VOCs), and focuses on highlighting the experimental feasibility of a new hybrid process combining VOC adsorption on hydrophobic zeolites and regeneration by an ozonated airstream in a single reactor. A preliminary study of high-silica zeolites has shown the different kinds of interactions between gaseous ozone and two mineral zeolitic adsorbents, a faujasite Y (FauY) and a ZSM-5 type silicalite (SilZ), and the conservation of the solids adsorption properties (capacities and selectivity) after their contact with ozone. Here, results concerning the contact of gaseous ozone and zeolites saturated with adsorbed VOC are presented. Using temperature measurements inside the fixed bed, oxidation of two models VOC, methyl ethyl ketone (MEK) and toluene (TOL), was observed on both zeolites. Adsorbents were fully regenerated, and the adsorption capacities of the zeolites after their contact with ozone were not affected when used in a discontinuous adsorption / oxidation mode. In addition, the adsorbed VOC were totally mineralized. Detection and identification of oxidation sub-products traces using mass spectrometer - gas chromatography (formic, oxalic, acetic acids, and acetaldehyde for TOL and 2,3-butanedione and acetic acid for MEK) makes possible the indentification of oxidative species. Moreover, a mass balance on oxygen showed that all the produced ozone was used for organic compounds oxidation. There was no or very little ozone lost via side-effect decomposition/deactivation mechanisms. At last, using the zeolites selectivity determined in a previous study toward a binary MEK-TOL mixture, the adsorption / ozonation cyclic process enables the recovery of the minor compound and the selective oxidation of the other component. The great interest of this new process is clearly highlighted, and the technology transfer to industrial operating plants is now studied

Location and chemical composition of microbially induced phosphorus precipitates in anaerobic and aerobic granular sludge

This work focuses on combined scanning electron microscopy and energy dispersive X-ray analysis (SEM-EDX) applied to granular sludge used for biological treatment of high-strength wastewater effluents. Mineral precipitation is shown to occur in the core of microbial granules under different operating conditions. Three dairy wastewater effluents, from three different upflow anaerobic sludge blanket (UASB) reactors and two aerobic granular sequenced batch reactors (GSBR) were evaluated. The relationship between the solid phase precipitation and the chemical composition of the wastewater was investigated with PHREEQC software (calculation of saturation indexes). Results showed that pH, Ca:P ratios and biological reactions played a major role in controlling the biomineralization phenomena. Thermodynamics calculations can be used to foresee the nature of bio-precipitates, but the location of the mineral concretions will need further investigation as it is certainly due to local microbial activity

Parameters influencing calcium phosphate precipitation in granular sludge sequencing batch reactor

Parameters influencing calcium phosphate precipitation in Calcium phosphate precipitation inside microbial granules cultivated in a granular sequenced batch reactor (GSBR) has been demonstrated to contribute to phosphorus removal during wastewater treatment. Whereas hydroxyapatite (HAP) is proven to accumulate in the granule, the main calcium phosphate precursors that form prior to HAP are here investigated. A separate batch reactor was used to distinguish reactions involving biological phosphate removal from physicochemical reactions involving phosphateprecipitation in order to establish the kinetics and stoichiometry of calcium phosphate formation. Experiments and simulations with PHREEQC and AQUASIM software support the assumption that amorphous calciumphosphate (ACP) is the intermediary in HAP crystallization. The results provide the kinetic rate constants and thermodynamic constants of ACP. The formation of bioliths inside biological aggregates as well as the main parameters that drive their formations are discussed here. Finally, the influence of pH and calcium and phosphate concentrations in the influent was also assessed, in order to determine the contribution of precipitation in the different operating conditions

Impact of downstream processing on crystal quality during the precipitation of a pharmaceutical product

In pharmaceutical industries, active pharmaceutical ingredients (API) are made of crystals whose properties must be controlled because they influence the end-use properties of the drug. Even if crystal quality is mainly determined during the precipitation step, downstream processing also has an influence. In this study, the influence of washing on the crystal size and shape was analyzed. For the API being considered, different impurities have to be removed from the final suspension by filter cake washing. The efficiency of the washing steps was measured by different types of characterization on the solid phase (differential scanning calorimetry, scanning electron microscopy, and size distribution) and on the remaining filtrate (concentration of impurities). A second component also coprecipitates with the API. A specific study has been carried out on the withdrawal of this by-product and on its impact on the evolution of the crystalline form during washing steps. It was found that three filter cake washings allow us to remove all the impurities and to obtain a pure crystalline form