ARR - Annual Report

The objective of this research project is to assess and enhance the ability of a recently advanced high-fidelity modeling framework for spray formation to model complex liquid break-up and predict drop size distributions in high viscosity and non-Newtonian liquid atomization systems, such as found in spray drying applications. This framework, which has been developed by the PI’s research group, hinges on two key components:

1. a fully conservative Eulerian interface tracking technique with the ability to capture sub-grid scale liquid features such as thin films and thin ligaments, known to be of critical importance in the break-up of viscous and non-Newtonian fluids, and
2. simple physics-based break-up models to convert these thin liquid features into spray droplets that can be tracked in a Lagrangian fashion.

The focus of the work to date has been studying how complex fluid rheology (e.g., liquids with high viscosity and non-Newtonian behavior) alters atomization physics. Preliminary analysis of high viscosity liquid atomization in a pressure-swirl configuration has shown conventional liquid-gas interface techniques lead to break-up that is not physics-based (i.e., the break-up is caused by numerical errors) while our newly developed interface tracking method is able to maintain the thin-conical sheet that occurs during pressure-swirl atomization of high viscosity liquids. Additionally, non-Newtonian constitutive models have been implemented and tested in benchmark flow configurations with initial verification and validation matching published works. These models were implemented in a smaller scale flow configuration and were shown to have significant impact on liquid structure break-up, and for the case of high viscosity liquids, impact the mean droplet size.

Going forward, the focus will be to continue studying how complex rheology impacts liquid structure break-up and using those lessons and observations as guidance for how our current model can be adapted to account for complex liquid rheology. An updated model will then be implemented in large-scale, industrial-type atomization systems, which in turn, will allow for comparison with experimental measurements for drop size distributions.

The state of the art of capillary suspensions was described in a review paper published in Current Opinion in Colloid & Interface Science [1]. Our model system for capillary suspensions consists of fairly monodisperse, spherical, silica particles fluorescently labeled with rhodamine B isothiocyanate in a mixture of 1,2-cyclohexane dicarboxylic acid diisononyl ester (Hexamoll DINCH) and n-dodecane, with added aqueous glycerol. Capillary suspensions are prepared using a two-step ultrasonication: an emulsification of both liquids after which the particles are added and sonicated again. The three components are all index matched and the silica contact angle can be modified [2]. The attractive interaction strength can be modified by tuning the contact angle, and fraction of secondary liquid, and, by changing the particle roughness. This lets us access both granular-like systems with weak interactions and strong attractive gels using the same model system. During the project, we switched from using porous silica particles to nonporous particles as there were problems noted with adsorption of the secondary liquid into the pores. This means the particles are detected on the images as red rings rather than filled circles. To detect the particles, a self-coded particle detection algorithm based on edge detection and Hough transform was designed. The algorithm includes a simple graphical user interface for both local detection and manual addition or removal of missing or misdetected particles to improve the final detection efficiency. Using consecutive images on the rheoconfocal, the displacement of the particles can be detected as a function of the applied shear. AI tools have also been used to detect the particles.

Our initial goal of the project was to track microstructural changes in the network in response to external shear applied via a linear shear cell. These structural changes were correlated with the rheological response of the material. Application of external shear via the linear shear cell, however, was unsuitable. Due to the very low yield strain in capillary suspensions, the applied shear was often above the flow point and specific changes during yielding could not be adequately captured. Furthermore, the prior setup only allowed for the deformation profile to be captured in one shear plane. While this has provided valuable information, proving that capillary suspensions tend to undergo solid-body movement, where the rotation of particles around their respective bridges is resisted through both the structure of the network and the extra torque provided by the contact angle pinning and/or the contact angle hysteresis, full 3D tracking is necessary. Therefore, a rheometer was mounted onto a highspeed confocal microscope in 2022. The improved setup has allowed us to directly compare bulk, rheological changes with local, microscopic changes to the clusters and network, as discussed further in Section 2.1.

Experimental Approach to Investigate the Rheology of Powders

We propose an experimental approach to investigate the rheology of powders and their behavior during compaction and aeration processes. The first step is to develop protocols to synthetize and characterize model cohesive granular materials. The aim is to synthetize particles with tailored properties (stiffness and adhesion) using two technics (micro-polymer particles, or polymer coated silica particles).

Steps Involved

1. The first step involves developing protocols to synthetize and characterize model cohesive granular materials.
2. The second step involves developing tools to characterize particle properties and their bulk rheology.
3. The third step will involve studying different flow configurations encountered in packaging processes.
4. The final step concerns the coupling with air.

Executive summary

The main objective of this project is to apply a pneumatic nozzle design, the Air-Core-Liquid-Ring (ALCR)-nozzle, for spray-drying of highly viscous liquids and pastes. The project is divided into three main working packages (WP). WP 1 aims to validate the ACLR atomizer technology to enable spraying of highly viscous liquids, using both experimental measurements and CFD simulations. WP 2 aims to evaluate the impact of the composition and morphology of the atomized droplets on the drying kinetics, for highly concentrated feeds. WP 3 aims to join the results of both packages to investigate the applicability of the ACLR nozzle for spray-drying of highly viscous liquids. The followings findings were achieved in the present funding period.

WP 1: Atomization with the ACLR nozzle

• A model system of maltodextrin solutions was chosen and characterized for different dry-matter concentrations, which reaches viscosities up to 3 Pa·s at 20°C at 103 s-1.
• The experimental analysis of the ACLR nozzle internal flow instabilities was extended for viscosities up to 1.3 Pa·s.
• An automated algorithm for measuring the spray angle in real time was developed.
• Experimental droplet size distributions were measured for MD solutions with a dry-matter concentration of up to 57%. The distributions show that atomization is, in principle, possible. The bimodality of the DSD, the high number of large droplets and the apparent time-instability of the distribution still need to be further investigated.
• A CFD model was implemented to represent the internal flow of the ACLR, and has been validated for viscosities up to 0.14 Pa·s.

WP 2: Evaluation of the impact of the composition and morphology on the drying kinetics and model development by single droplet drying

• Hanging-droplet experimental setups were identified to be an appropriate method due to their advantages in measuring drying kinetics. CFD was employed to investigate the flow characteristics within the drying channel and to ensure an even and stable airflow. Pressurized air is utilized for drying, permitting volume flow rates of up to 850 cm³·min and temperatures of up to 200 °C. Droplets are generated using a syringe and are then transferred to the 0.3 mm thickness glass filament.
• Exploratory experiments were conducted to evaluate the experimental setups viability in determining drying kinetics, showing good results for solid contents of up to 20 wt.%.
• Particle morphologies and particle contour area were successfully captured using a high speed camera.

WP 3: Proof-of-concept of industrial applicability of the ACLR nozzle for spray-drying of highly viscous liquids

• This WP is planned to start on the funding year 2024-2025.

This project aims in developing a system engineering approach for understanding, optimizing and scaling industrial dry grinding processes, with a special focus on the manipulation of the material properties and, thus, the grinding and classification efficiency by the use of grinding aids. In terms of process units, the project deals with a pilot scale dry grinding circuit consisting out of a ball mill and air classifier. During milling operations, grinding aids affect the milling process mainly in: tendency of fine particle agglomeration; amount of material coated on equipment surfaces; powder flowability; total mass of product inside the mill and residence time; product fineness after grinding.

The project work for the initial three years was divided in four main work packages:

1. Identify which aspects of the ball milling process are affected by different GA
2. Identify which aspects of the air classification process are affected by different GA
3. Modify process models from the literature to account for the presence of GA, implement a flowsheet simulation tool and validate the flowsheet with mill-classifier circuit data

In the first year of the project (2020) batch grinding tests and powder flowability measurements of the product were conducted in order to assess grinding aid contribution to the breakage aspect of milling, without powder transport. The second project year (2021) focused on the air classification step of the circuit. Trials in two air classifiers, in laboratory and industrial scales, were conducted. It was compared which aspects of this process are influenced by grinding aids and which are determined by machine design.

The third project year (2022) dealt with two aspects. First, continuous milling trials in passage mode to study the effect of grinding aids on powder transport, mill holdup and process dynamics and stabilization. Second, modification of process models from the literature to consider the effect of GA. The main conclusion of the open-circuit milling trials can be summarized as:

1. Powder flowability should be kept within an intermediary range (easy-flowing). Both excessive and too low flowability should be avoided in order to improve throughout and process stability.
2. High flowability can be detrimental to the amount of stressed material and energy transfer from ball to product particles.
3. Beyond flowability GAs should be selected in order to reduce caking on equipment surfaces and reducing ball coating. Once an amount of powder is stressed between two balls, it should be readily fall off to allow another sample of powder to be stressed.

The mill model proposed is formulated as mechanistic population balance for media mills capable of predicting grinding of particles sizes from the lower millimeter size range down to the sub-micrometer scale. The mechanistic approach to media mill models is a very flexible tool that allows full separation of material and process aspects. The proposed mill model assumes stead-state operation, requires input from Discrete Element Method (DEM) simulations and accounts for impact of powder flowability on powder stressing.

Wet granulation is a key process used to make formulated particulate products across a wide range of industries. Granular products typically have at least one desired function, and in many cases there are several key performance characteristics which are required. Recent work has shown great improvement in the ability to model granulation process to predict granular properties such as size, however the ability to predict granular function is lacking, as is the ability to design processes to give desired granular function.

The primary aim of this work is to develop linked process and product performance models for wet granulation, and to initiate the inverse problem solving process, i.e. to investigate the ability to predict required process parameters to give desired performance characteristics. This is being performed for a case study of a high shear wet granulation process, coupled with a new model which describes granule disintegration.

Due to the relative immaturity of granular product performance models, much of the focus of this work has been on the development of a model to describe granule disintegration. Of particular importance is the suitability of this model for coupling with existing population balance models to enable model linking.

In this report, an improved model for granule disintegration is presented, which has been simplified to reduce the number of parameters required. A local sensitivity analysis is shown, which shows that decreasing granule porosity and constituent particle size contribute to smaller granule populations over time, due to an increased number of breakage events. Increasing the maximum absorption ratio of disintegrants in the model acts to decrease particle size. The effect of starting granule size is somewhat more complex, but indicates a potential threshold in normalized granule size behavior, above which the normalized size distribution becomes independent of the starting granule size. This however requires further research to confirm.

Initial experimental validation has been presented using a bespoke flow cell, optical microscopy and Optical Coherence Tomography (OCT), alongside a new image analysis app to provide data required for model parameterisation and validation. Preliminary parameterization has been performed, and a good fit to experimental data is demonstrated, however further work is required to verify, validate and parameterise the model.

A summary of the mechanistic high shear wet granulation model is presented, which is well developed and implemented in gPROMS FormulatedProducts. Tasks for the remainder of this project will focus on experimental validation of the new disintegration model, global sensitivity analysis, linking of the process and product performance models, and inverse problem solving. Additional resources at the University of Sheffield and the University of Strathclyde are being used to assist in the experimental validation, global sensitivity analysis and inverse problem solving.

In the first year of this project, we had derived a mechanics-based model for the feed rate in a single-screw feeder, making several simplifying assumptions. The model makes the prediction that the feed rate is maximum at a particular value of the ratio of pitch to diameter p/2R of the screw. This prediction matches exactly with the results obtained by DEM simulations under the same conditions. When the simplifying assumptions are relaxed in the DEM simulations, the dependence of the feed rate on p/2R was found to be qualitatively similar, suggesting that the simple model captures the essential physics of the problem.

In the second year, our work was extended in several directions:

• experimental measurement of the feed rate for different p/2R, the stress at the barrel surface using sensitive force sensors, and the velocity profile adjacent to the (transparent) barrel surface by flow imaging;
• application of a newly developed non-local constitutive model to the screw feeder problem and solving the governing equations to obtain the velocity and stress fields;
• DEM simulations to study the effect of particle cohesion on the feed rate and obtain the detailed spatial variation of the stress and velocity in the particulate medium.

Overall, we found good agreement between results of the DEM simulations, model predictions, and experimental data. The important conclusion was that combination of the three components of our investigation, namely theoretical analysis, DEM simulations and experiments, led to substantial insight.

In the third year (for which this report is written) we have further extended our experimental studies in some directions: we first completed the determination of the feed rate for a larger range of p/2R for glass beads and confirmed the existence of a maxima in the feed rate at an optimum value of p/2R. We then measured the feed rate for two cohesive powders – though measurements for sufficient large p/2R are yet to be made, the data strongly suggest the presence of the maximum in the feed rate. The experiments also throw light on the feed rate fluctuations, which are quite different for non-cohesive and cohesive powders. Our earlier DEM simulations restricted the feeder length to one pitch and assumed periodic inlet and outlet conditions. We have now conducted simulations for the full feeder, from the inlet hopper to the feeder exit. The results show a gradual fall in the fill level with axial distance from the inlet, as observed in the experiments.

Our ongoing work is to obtain solutions of the non-local model for the more general cases of finite screw friction in the presence of gravity. We are measuring the feed rate of cohesive powders for a large range of p/2R to confirm the presence of the maxima. We will soon conduct DEM simulations for cohesive powders for the full length of the feeder.

This report summarizes the main achievements during the year 2022 of the project with the aim of developing process systems engineering approaches for improved crystal size and purity control during crystallization processes. The successful crystallization process and system design requires an interdisciplinary effort, which ranges from population balance model (PBM) development of the system concept, through efficient implementation of model equations to soft-sensor development, which is required for the model predictive control (MPC) design as well. This report gives a deeper insight into these interdisciplinary development efforts, which also highlights the achievable improvements enabled by the combination of process modeling, high performance process simulation and optimization.

This year was focused on designing a novel, integrated crystallization system capable of establishing increased control of the properties of crystalline materials. The attainable region of crystal size distribution (CSD) is widened by the application of a recirculation stream and multiple MSMPR units as well as the integration of a downstream wet mill and classification units with recirculation stream(s) for continuous operation. This approach was then applied in finding an attainable region for a commercial active pharmaceutical ingredient (API) to observe real life application of the system. Also, a Quality-by-Control (QbC) guided framework is developed for crystallization processes to meet the CQAs of studied processes. QbC allows for control over techno-economics of the system through productivity and yield in addition to properties such as crystal size and narrow distribution.

The last part of this work focuses on production of Atorvastatin calcium with higher yield and lower cost. To address the limitations that the conventional batch manufacturing possesses, operating end-to-end in a continuous mode to shorten and strengthen product supply chains and add agility and flexibility to manufacturing is proposed. This leads to an integrated cascade of crystallizers that control polymorphism and agglomeration to be the connection between reaction and continuous filtration and drying in carousel (CFC) device.

1. Development of an integrated continuous crystallization system, wet mill, classifiers with recycle
2. Development of attainable regions for model and commercial compounds
3. Robustness studies via kinetic parameter uncertainties and inlet seed distribution
4. Validation experimental results for continuous crystallization with wet mill, classifier and recycle

Achieved Deliverable

In this report, we provide an update on the progress of the second part of the IFPRI Robin. In our Part 1 report, we quantitatively assessed the effectiveness of discrete element method (DEM) calibration methods utilised by 8 industrial DEM practitioners for a number of differing experimental geometries, particulate media, and combinations thereof. The accuracy of the methods was assessed by comparing the outputs of simulations performed following the procedures of 8 industrial participants with detailed experimental data produced using Positron Emission Particle Tracking (PEPT), a technique which allows the dynamics of particulate systems to be imaged, in three dimensions, with sub-millimetre spatial resolution and sub-millisecond temporal resolution. Strikingly, of all the participants surveyed, no two institutions adopted the same practices, highlighting the need for a more standardised approach and best practice. Our results showed that while most contemporary calibration methods were able to successfully capture the dynamics of simple, free-flowing, spherical particles under low-shear conditions, and a reasonable percentage of participants could correctly predict the dynamics of angular particles, the majority of procedures tested were unable to correctly reproduce the behaviours of smaller, more cohesive particles, or higher-shear environments. For the latter case, though qualitative agreement and visual similarity between simulated and experimental systems could be observed, deeper and more quantitative analysis using PEPT revealed significant disparities. Of the calibration methods examined, the most effective – indeed the only one to consistently reproduce the experimentally-measured dynamics of the cohesive systems tested – involved the combination of both static and dynamic powder characterisation tests, suggesting this to be the best practice for multi-parameter DEM calibration.

In the second part of the project, we will assess the ability of DEM, and the practitioners thereof, to handle a series of still more complex particles, including binary systems whose components possess strongly differing PSDs; fine particles (both free-flowing and cohesive); and highly elongated particles. We will also explore additional industryrelevant test systems (a Resodyn acoustic mixer and a Pascall mixer), and create additional digital twins of characterisation tools used by our industrial project partners (a Granutools GranuPack, Granutools GranuFlow. aerated Freeman FT4, and Anton Paar powder rheometer). We will also use detailed sensitivity analysis to assess the suitability and efficacy of all characterisation tools explored for the determination of different DEM parameters. This brief report highlights progress made so far toward these aims, and showcases a selection of the new tools developed and data obtained. All tools and data are available, free and open source, to IFPRI members upon request.

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Our goals within the IFPRI project are threefold

1. To explore how, moving away from model systems containing spherical colloids with near hard interactions, we can widen the range of rheological responses by changing the properties of the building blocks of the suspensions, so that even in simple formulations a wide range of behaviors can be ”built in”, i.e. obtaining formulation guidelines to do “more with less” or simplifying formulations from within. The properties aimed for, after discussing with IFPRI members, are the control of shear thinning/thickening and the control of the thixotropic response.

2. To further develop a limited number of rheological and structural tools to interrogate the rheological response of the such dispersions, focusing on

• Advanced rheological methods which allow for stress deconvolution such as high frequency rheometry and superposition rheometry, which help identify the nature of the stress during flow (elastic or viscous), which helps to identify which aspect of the particles or formulation controls the rheology
• High resolution confocal microscopy to probe structural development in situ during flow (4D imaging)
• Local scale tribological measurements using AFM.

3. Apply these methods to simplified industrial dispersion by industrial partners and compare with the formulation guidelines obtained from (1).

The present report discusses the progress made in the last 12 months.