Particle Formation

Crystal morphologies are governed by growth conditions such as supersaturation and temperature as well as by the bonding structures of growth units within the crystal lattice. The vast majority of organic crystals of interest exhibit noncentrosymmetric growth units which feature anisotropic bonding interactions. Bonding anisotropy results in the presence of multiple distinct growth units within the unit cell which generate complex periodic bond chains and edge stability phenomena, presenting a significant challenge for contemporary morphology prediction tools. In this report, we consider the case of noncentrosymmetric molecules with two distinct growth units present in the unit cell (Z = 2).

Current Funding Period Advances

• Extended the use of kinetic Monte Carlo (kMC) simulations to predict the morphology of noncentrosymmetric organic crystals grown from solution.
• Expanded the development of a novel crystal growth model for asymmetric organic molecules with two molecules in the unit cell.

Spray drying is an advanced drying technology that is used in various industries. The development of the spray drying process is closely linked to the dairy industry and is require for longer shelf life of many food products. The origins of spray drying date back to the 1800s, but it was not until the 1850s that the process began to be used on an industrial scale. This method was further developed, and today a wide range of products are spraydried, with capacities ranging from a few kg/h to several dozen tons/h. Spray dryers are currently used for research and commercial purposes for drying agrochemical and biotechnological products, fine and heavy chemicals, dairy products, colorants, mineral concentrates and pharmaceuticals.

Spray-dried products

Spray-dried products can be divided into three groups, depending on the morphological structure of the particles (Walton & Mumford, 1999):

• skin-forming;
• porous;
• with crystalline structure.

As a rule of thumb, organic substances belong to the group of skin-forming materials, water-soluble inorganic substances to materials with crystalline structure, and water-soluble inorganic substances to porous materials. However, it is important to remember that this is only a general classification and that there are exceptions (Walton, 2000).

Skin-forming materials

Skin-forming materials are spherical and have a relatively smooth surface, which is usually filled with gas. With this type of material, drying initially takes place on the surface of the droplet, resulting in a thin, hard outer layer known as the "skin" or "shell". The thickness of the skin is usually between 50 and 130 µm. During the process, the skin thickens and a solid or hollow particle is formed, depending on the material being dried. Hollow particles tend to collapse after drying, while solid particles retain their shape. At a higher drying temperature, around 200 °C, the skin is quickly formed, whereupon the gas trapped inside the particle ruptures and causes it to collapse. At this temperature, the thickness of the "crust" is between 30 and 50 µm. In some materials, secondary bubbles can form in the original particle. This is caused by a certain amount of residual moisture inside the particle.

Skin-forming materials include: Sodium silicate, sodium dodecyl sulfate (SDS), potassium nitrate, gelatin, skim milk, chicken eggs (Walton & Mumford, 1999) or maltodextrin (Zbiciński & Kwapińska, 2003).

Porous materials

Porous materials, also known as agglomerates, consist of individual particles bound by submicron dust or a binder. The particles generally have a regular, spherical shape. Drying of this type of material is achieved by gradual evaporation of moisture from the interior of the particles. The highly porous structure allows water vapor and gasses to flow freely from the inside of the particles to their surface. This explains the high degree of sphericity of the particles and the rare occurrence of irregularities on their surface.

If the initial particle size of the suspension is much larger than 1 µm, the particles tend to form a solid structure upon drying, while the resulting particles are hollow if the initial particle size is less than 1 µm.

In contrast to skin-forming materials, the morphology of porous materials practically does not depend on the drying temperature. Only the drying speed changes with the temperature. Porous materials include, among others: Silica, colloidal carbon, cocoa and some detergents (Zbiciński & Kwapińska, 2003).

Materials with crystalline structure

Materials with crystalline structure are characterized by a highly ordered structure of their atoms or molecules. The solid phase is formed by the growth of crystals on nucleation centers on the droplet surface. In this type of material, the morphology of the particles depends largely on the type of substance. Sodium chloride, for example, forms large, cubic crystals, while sodium benzoate forms small, elongated crystals. Both solid and hollow particles can occur, and a relatively large shell thickness of the hollow particles is observed, namely 200-300 µm.

At a higher drying temperature, over 200 °C, a phenomenon analogous to that observed with skin-forming materials is observed, namely the disruption of the particle structure and the secondary formation of nucleation centers. In addition, materials dried at a higher temperature are characterized by much lower shell thickness of the empty particles, i.e. 50-100 µm.

Materials with crystalline structure include, among others: Sodium chloride, sodium carbonate, zinc sulfate, sodium pyrophosphate, sodium benzoate, sodium formate (Walton & Mumford, 1999).

Research program

The research program presented for IFPRI assumes finding the relationship between the rheological properties of the solution as well as the drying speed on the morphology of the particles obtained by the spray drying method. For this purpose, in the second year of the project, the following tasks were assigned:

• Carrying out spray drying experiments on the semi-industrial scale.
• Analysis of the physicochemical properties of the obtained powder samples.
• Preparation of a monodisperse droplet generator to construct devices to measure drying kinetics.

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.

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.

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.

The focus of the report is on development of a contact model for usage in CFD-DEM simulations. Great effort is placed in this step since it provides a basis for all future results upon which the continuum model will be built.

We present a contact model able to capture the response of interacting adhesive elastic-perfectly plastic particles under a variety of loadings. The model is built upon the Method of Dimensionality Reduction which allows the problem of a 3D axisymmetric contact to be mapped to a semi-equivalent 1D problem of a rigid indenter penetrating a bed of independent Hookean springs. Plasticity is accounted for by continuously varying the 1D indenter profile subject to a constraint on the contact pressure. Unloading falls out naturally, and simply requires lifting the plane indenter out of the springs and tracking the force. By considering the incompressible nature of this plastic deformation, the contact model is also able to account for the nonlocal effects of neighboring contacts, including formation of secondary contacts from outward displacement of the free surface. JKR type adhesion is recovered easily by simply allowing the springs to ‘stick’ to the 1D indenter’s surface. Additionally, we account for the rapid stiffening in the force-displacement curve under high confinement (e.g. during powder compaction) by triggering a superimposed bulk elastic response based on a simple criterion related to contact area.

Given that the model arises from rigorous contact mechanics formulations and simple geometric arguments only a few physical inputs are needed to run the model. Namely, the average radius of the particles Ro, Young’s modulus E, Poisson ratio ν, yield stress Y, and effective surface energy Δγ. An outline of the numerical implementation of the model is included. Every aspect of the contact model is validated, either through comparison to finite element simulations or in the case of adhesion directly to the JKR theory of adhesion. These comparisons show that the proposed contact model is able to accurately capture plastic displacement at the contact, average contact stress, contact area, and force as a function of displacement under a variety of complex loadings. This gives us confidence in the predictive capability of the contact model and its ability to reflect reality when used in the upcoming CFD-DEM simulations.

Objectives:

• To establish a predictive criteria
• To identify the key factors
• To establish a test methodology

The original aim and objectives of the project remained unchanged: to design a diagnostic tool to determine if a powder formulation will stick to the punch-face during tablet production.

Timeline

Work on the project started effectively in August 2021 with the arrival of PhD student Ahmad Ramahi. In February 2022 PhD student Vishal Shinde joined the project. The first two objectives have been completed and work on the third objective is ongoing aiming to complete by the AGM in June 2023.

Approximately 20 characterisation techniques were employed or explored at different levels of detail as described in this report. Measurement of the % area of the punch covered by the sticking powder was selected as the main method to quantify sticking. Following regular monthly project meeting with the IFPRI advisory group, given the complexity involved in the sticking phenomena (summarised in Section 1), the focus was maintained on empirical studies to identify the relevant mechanisms for the materials of interest and on creating a database of approximately 20 powder materials (including sticking and non-sticking APIs, sticking and non-sticking excipients, powder formulations and lubricated formulations), and delve into the science of each mechanism in the follow-on proposal.

The database contains material properties including chemical information (formula, structure, molecular weight), physical characteristics (particle size distribution, density, shape, morphology of the particles, bulk density of powders), mechanical properties of particles (Young’s modulus, Poisson’s ration, yield strength), interaction properties between particles (friction coefficient between particles, surface energy), thermal properties (conductivity, heat capacity, thermal expansion coefficient) and humidity related properties (water adsorption isotherms, water activity).

The sticking behaviour of powders during single compression events is characterised considering 4 processing parameters: compaction pressure, temperature, humidity, and compaction rate. Work is ongoing, only 4 materials were characterised so far. The compression tooling used was provided by iHolland (B tooling). Long term sticking (multiple compaction events) are planned.

The deliverable the end of the 3 years is a predictive toolkit comprising of the database analysed using Principal Component Analysis to extract functional relationships between material properties, process parameters (compaction pressure and rate) and environmental conditions (temperature and RH) and finally assign a risk for sticking.

A proposal is being developed for a follow-on project to extend the database for new materials to further validate the predictive capability, establish the science base to understand the underlying mechanisms, link molecular level information to sticking behaviour and develop mitigating strategies for sticking at early stage product development. A collaboration with Professor Jerry Heng at Imperial College is proposed to cover the Chemistry/Chemical Engineering aspects.

This project sought to develop physically realistic models for atomization processes relevant to particle production, such as in spray-drying processes, with a focus on high viscosity and non-Newtonian fluid atomization. The goals of this work were to generate a spray database and to develop understanding and correlations for the accurate pilot-to-production scaleups. We divided the work to focus on two nozzle types: pressure-swirl, and two-fluid nozzles.

In the current funding period we have made advances on three fronts:

1. use of kinetic Monte Carlo (kMC) simulations to predict the morphology of organic crystals grown from solution for cases where the solution is pure and also when it contains growth inhibitor molecules,
2. completed incorporating three new all-atom force fields into ADDICT in order to test the sensitivity of our morphology predictions with respect to different estimates of intermolecular interaction energy, and
3. developed a new crystal growth model for asymmetric organic molecules with two molecules in the unit cell. This is a precursor to developing a more general model with many molecules in the unit cell.

We report progress on all three topics.

We have continued to develop our kinetic Monte Carlo (kMC) modeling codes to predict the morphology of organic crystals grown from solution both with and without the inclusion of impurity molecules on the crystal surfaces. We have used these codes to make morphology predictions for naphthalene grown from ethanol solvent at increasing supersaturations in impurity-mediated solutions. The results were quite satisfactory and are reported in more detail later in the report.

In addition to the Generalized Amber Force Field (GAFF) which is already included in ADDICT, we have added three new all-atom force fields to ADDICT. They are the Coulomb-London-Pauli (CLP) force field, the Consistent Force Field (CFF), and the Universal Force Field (UFF). Each has its own specific advantages and limitations.

• CLP is the most general with over 90 atom types (similar to GAFF).
• CFF is specific to organic molecules containing intermolecular hydrogen bonds, especially carboxylic acids and amines.
• UFF has one atom type for every element in the periodic table - it is very general but with only one atom type for each element it is not very accurate.

Later in the report we describe these force fields in more detail and show new results for predicting the morphology of five organic crystals using the CLP force field. We continue to develop a new crystal growth model for asymmetric organic molecules under the restriction of that the unit cell contains exactly two molecules. This allows us to make a big leap from essentially one (symmetric) molecule per unit cell to two asymmetric molecules. Once this theory is fully tested and validated on real molecular systems it will lead to further extensions to 4 molecules in the unit cell, and then many.

• Design of particle-free fall SDD measurement system.
• Adaptation of the existing equipment to the project requirements.
• Measurements of rheological properties of aqueous solutions of selected materials.
• Selection of suitable experimental media and determination of quality criteria.

The research program presented for IFPRI assumes finding the relationship between the rheological properties of the solution and the drying speed on the morphology of the particles obtained by the spray drying method. For this purpose, in the first year of the project, the following tasks were assigned to be implemented:

Spray drying is a complex process. Many process parameters affect not only the operation of drying towers but also the final properties of the product. This complexity makes modelling of spray drying difficult, and the developed mathematical models are usually dedicated to the specific processes and materials (Filkova et al., 2015). Even though the spray drying process has been used for over a century in the industry, mathematical models are still elaborated to predict the physicochemical properties of powders, based on drying process parameters and rheological properties of the sprayed solution.

Spray drying is one of the basic techniques for the formation of particles from liquid solutions, suspensions or slurries. The process involves spraying a solution in the stream of a hot drying medium, usually air. As a result of the rapid spray extension, intensive moisture evaporation takes place without a significant increase in dried material temperature. Short drying time and low product temperature in spray drying are beneficial in many industries, from pharmaceuticals, through food, to chemicals, especially for drying heat-sensitive materials.