A critical review of the published literature regarding the computational fluid dynamics (CFD) modelling of single-phase turbulent flow in stirred tank reactors is presented. In this part of review, CFD simulations of radial flow impellers (mainly disc turbine (DT)) in a fully baffled vessel operating in a turbulent regime have been presented. Simulated results obtained with different impeller modelling approaches (impeller boundary condition, multiple reference frame, computational snap shot and the sliding mesh approaches) and different turbulence models (standard k − ε model, RNG k − ε model, the Reynolds stress model (RSM) and large eddy simulation) have been compared with the in-house laser Doppler anemometry (LDA) experimental data. In addition, recently proposed modifications to the standard k − ε models were also evaluated. The model predictions (of all the mean velocities, turbulent kinetic energy and its dissipation rate) have been compared with the experimental measurements at various locations in the tank. A discussion is presented to highlight strengths and weaknesses of currently used CFD models. A preliminary analysis of sensitivity of modelling assumptions in the k − ε models and RSM has been carried out using LES database. The quantitative comparison of exact and modelled turbulence production, transport and dissipation terms has highlighted the reasons behind the partial success of various modifications of standard k − ε model as well as RSM. The volume integral of predicted energy dissipation rate is compared with the energy input rate. Based on these results, suggestions have been made for the future work in this area.Nous présentons un examen critique de la littérature concernant la modélisation de la dynamique des fluides numérique (DFN) de l'écoulement turbulentà une phase dans les réacteursà cuve agitée. Dans cette partie de l'examen, nous présentons les simulations de DFN de turbinesà ecoulement radial (principalement des turbinesà disque (TD)) dans un réservoir entièrement cloisonné effectuées dans un régime turbulent. Les résultats des simulations obtenus grâceà différentes approches de modélisation des turbines (couche limite turbulente, méthode des référentiels multiples, snap-shot de modélisation numérique, maillage glissant) età différents modèles de turbulence (modèle standard k-e, modèle RNG k-e, modèle aux tensions de Reynolds et simulation des grandeséchelles) ontété comparés aux données expérimentales internes d'allocation de Dirichlet latente (ADL). De plus, les modifications des modèles standards k-e récemment proposées ontégalementétéévaluées. Les prédictions du modèle (de toutes les vitesses moyennes, de l'énergie cinétique turbulente et de son taux de dissipation) ontété comparées aux données expérimentales relevéesà différents endroits de la cuve. Une discussion présente les points forts et les points faibles des modèles de DFN actuellement utilisés. Une analyse préliminaire de la sensibilité des hypothèses de modélisation liées aux modèles k-e et RSM aété menée en utilis...

Crystallization is the primary process used to purify synthetic drug substances and intermediates as well as to control bulk properties, including particle size, surface area, and flowability. Accordingly, new or improved tools to aid crystallization design are of central importance to drug development. In this Perspective, we provide a brief review of the state of the art, identify current challenges, and highlight key opportunities within different aspects of crystallization process development for synthetic pharmaceutical compounds.

The published literature on the liquid-phase mixing in a turbulent flow regime has been critically reviewed and analyzed. Experimental techniques for mixing time have been described together with their relative merits. The effects of the impeller design (blade number, blade angle, blade and disk dimensions, and blade shape), the location of the impeller (off-bottom clearance, distance from the vessel center, i.e., eccentricity), and the vessel size on the liquid-phase mixing have been critically analyzed. The mixing performance dependency on the internals such as baffles (number, dimension, and position) and the draft tube has been presented in detail. Further, an extensive review on the mathematical models proposed for the liquid-phase mixing has been presented, and the utility of the computational fluid dynamics modeling for the mixing optimization has been illustrated. Finally, suggestions have been made for the selection of an energy-efficient impeller-vessel configuration, and directions have been given for future studies.

Glecaprevir was identified as a potent HCV NS3/4A protease inhibitor, and an enabling synthesis was required to support the preclinical evaluation and subsequent Phase I clinical trials. The enabling route to glecaprevir was established through further development of the medicinal chemistry route. The key steps in the synthesis involved a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle and a challenging fluorination step to form a key amino acid. The enabling route was successfully used to produce 41 kg of glecaprevir, sufficient to support the preclinical evaluation and early clinical development.

In the first part of the review, published literature regarding the CFD modelling of single-phase turbulent flow in stirred tank reactors with radial flow impellers was critically analysed. A brief overview of different turbulence models (standard k − ε model, RNG k − ε model, the Reynolds stress model and large eddy simulation) as well as impeller baffle interaction models has been presented in the previous part. This part is concerned with the review of literature regarding CFD simulation of axial flow impellers. Comprehensive simulations have been carried out using various turbulence models and the model predictions (of all the mean velocities, turbulent kinetic energy and its dissipation rate) have been compared with the experimental measurements at various locations in the tank. The strengths and weaknesses of various turbulence models for axial flow impellers is presented. The quantitative comparison of exact and modelled turbulence production, transport and dissipation terms has highlighted the reasons behind the partial success of various modifications of standard k − ε model as well as Reynolds stress model. Literature efforts on multiple impeller systems and multiphase systems have been discussed in a separate section. Based on these results, suggestions have been made for the future work in this area.Dans la première partie de l'étude, on a procédéà une analyse critique de la littérature concernant la modélisation de la dynamique des fluides numérique de l'écoulement turbulentà une phase dans les réacteursà cuve agitée dotés de turbinesàécoulement radial. Une vue d'ensemble rapide des différents modèles de turbulence (modèle standard k-e, modèle RNG k-e, modèle aux tensions de Reynolds et simulation des grandeś echelles), ainsi que des modèles d'interaction des déflecteurs de turbine, aété présentée dans la partie précédente. Cette partie se concentre sur l'analyse de la littérature concernant la simulation de DFN de turbinesàécoulement axial. Des simulations complètes ontété effectuées en utilisant plusieurs modèles de turbulence et les prédictions des modèles (de toutes les vitesses moyennes, de l'énergie cinétique turbulente et de son taux de dissipation) ontété comparées aux données expérimentales relevéesà différents endroits de la cuve. On a présenté les points forts et les points faibles de plusieurs modèles de turbulence concernant les turbinesàécoulement axial. La comparaison quantitative des données exactes et modélisées de la production, du transport et de la dissipation de la turbulence a mis enévidence les raisons qui expliquent la réussite partielle de plusieurs modifications apportées au modèle standard k-e ainsi qu'au modèle aux tensions de Reynolds. Une partie distincte est consacréeà la discussion des résultats indiqués dans la littérature concernant les systèmesà roues multiples et les systèmes multiphases. Sur la base de ces résultats, desétudesà venir dans ce domaine ontété suggérées.

A new technique for the measurement of 3D crystal morphology and identification of its polymorph using tomographic images is proposed. Confocal microscopy is used for the first time to obtain tomographic images of crystals that are coated with a suitable fluorescent dye. A convex polyhedron is fitted through a stack of tomographic images of a crystal to obtain the normal vectors of each facet and their corresponding perpendicular distances from the center of the crystal. The angular patterns are generated from the measured normal vectors and are matched with the master angular patterns of each polymorph. It is shown that the matching of the angular patterns is unique and provides a simpler way to identify polymorphs. An image-analysis program that can be integrated with conventional confocal microscopes was created to sequentially perform image processing, morphology measurement, and polymorph detection. This program was used to measure morphologies and identify polymorphs of 2D and 3D acetaminophen crystals. Detailed directions are provided to enable the application of the methodology without the need for special-purpose software. The image-analysis program is also suitable for repeated measurements to produce morphology distributions. This technique will provide an effective platform for measuring the 3D shapes of materials of interest to many applications.

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While the conventional screening techniques suffer from depletion of supersaturation, the continuous-flow microfluidic device screens crystalline materials at controlled supersaturation.