Particle Formation

Executive Summary

to extend our work to other model compounds.

since the methodologies worked out in our studies to date have been effective, we consider

become relevant for the development of molecular dynamics simulations. Furthermore,

With that knowledge, we are now in the course of collecting new data that we hope will

first results are quite exciting and warrant further in-depth studies of these phenomena.

the project, we are on target with achieving the goal of the original project brief. These

ACM on SAMs as revealed by in situ synchrotron x-ray experiments in the third year of

By providing first insights into the earliest formation stages of the crystallization of

these early stages.

nucleation and growth, pointing to the possible existence of structural transformations at

along scattering vector, q, of isolated scattering peaks at the earliest time points of crystal

spontaneous crystallization events in a simple droplet of form I we identified unusual shifts

verified that crystallization originates at the substrate-solution interface. Studying

crystals and moving the x-ray beam vertically through the elongated film sample we

Energy Synchrotron Source (CHESS). Using seeded crystallization events of form II

means of time-resolved in situ wide-angle x-ray scattering (WAXS) at Cornell’s High

have studied the early formation stages of these form I and II crystallization events by

dioxane produce the less favored orthorhombic form II. In the third year of this project, we

thermodynamically stable, monoclinic polymorph form I, while mixtures of water and 1,4-

hydrophobic SAMs, pure solvent systems such as ethanol, water, and 1,4-dioxane yield the

• (i) both solvent and substrate work together to control crystal polymorph, and that
• (ii) on (gold, silicon oxide/silicon). In the first two years of this project, we have established that

and -silanes, with different terminal (omega) functional groups, on various substrates

(ACM) as our model system, on arrays of self-assembled monolayers (SAMs) from alkanethiols

We have successfully worked with a pharmaceutical compound, acetaminophen

understanding of early crystal formation pathways and mechanisms are highly desirable.

a polymorph is determined at the nucleation of a crystal, methods that lead to an advanced

(crystalline solids with different arrangements of the same constituents) is difficult. Since

a number of industries. To date, however, the experimental control of polymorphs

organic as well as inorganic compounds is scientifically and technologically important to

Understanding and control of crystallographic polymorphism and crystal habit of

Executive Summary

One of the long term barriers to particulate modelling of particulates is the lack of suitable test particles that can be used for model validation. This IFPRI project presents a new 3D printing approach to creating test agglomerates with “tunable” properties. Agglomerates were designed using EDEM or CAD software and printed on a polyjet 3D printer. Materials with different mechanical properties were used to print the particles and the inter-particle bonds, allowing combinations of bond strength, particle strength and agglomerate structure to be tested. Quasi-static compression tests (including cyclic loading) and high strain rate impact tests were performed to investigate the breakage behaviour of the printed agglomerates in terms of structure, orientation, bond properties and strain rates.

Agglomerate deformation and breakage was simulated via Discrete Element Method (DEM) using the Timoshenko Beam Bond Model (TBBM) with bond properties matching the 3D printed agglomerates. For the two main types of agglomerate structures used in this project, the simulation and experiment showed similar qualitative breakage patterns. Mechanical testing of the sub-structures (the polymers using in the printer, and single bond “doublets” tests were performed to characterise the bond stiffness and strength in agglomerates. FEM analysis of doublet compression was performed to identify the elastic limit of the bonds, to be within the validity of the TBBM model. Qualitatively the DEM produced accurate predictions of the macroscopic breakage behaviour, and was able to quantitatively predict the compressive load during the initial deformation of the agglomerate. Although some issues were identified - possible anisotropy of agglomerate strength due to the 3D printed layers depending on the polymer selected, and the non-linear behaviour of the polymers used by Stratasys - these reflect the kind of complexities found in industrial agglomerates, and identifies clear directions for future work.

This IFPRI projects has demonstrated, for the first time, how new 3D printing technology can be used to bring “in silico” particles into the physical environment, to enable rigorous testing of agglomerate deformation and breakage that has not previously been possible.

A review of the literature on the atomization of high viscosity fluids is provided. The review starts with a brief presentation of various atomization models, which are used to predict the spray droplet sizes. Next, atomization results using different types of atomizers are reviewed. These include plain orifice, splash plate, swirl, and twin-fluid atomizers.

Generally, most studies show that the Sauter Mean Diameter of a spray (SMD) increases with viscosity. This increase can be compensated by increasing the energy input to the atomizer (such as increasing the atomizing gas pressure or velocity). However, even in the cases that SMD does not change significantly, the size distribution changes with viscosity. In sprays of high viscosity liquids, larger droplets take up a larger proportion of the spray size distribution, resulting in the deterioration of the spray quality. The primary atomization of high viscosity liquids generates longer liquid ligaments and filaments, which have to be atomized during a secondary atomization process. This later process is intimately related to the coflowing gases. The secondary atomization of the long ligaments can be expedited by having high velocity coflowing atomizing gas. The review ends with a case study for the prediction of the droplet size distribution using a detailed numerical modeling that considers the exact design of the atomizer.

Executive Summary IFPRI Report Powder structure control FRR 62-07 2017

Process Engineering and Food Powders, University of Hohenheim, Stuttgart, Prof. Dr.-Ing. R. Kohlus

Particle structures can be characterized by stereological methods. In case of granulation, systems with a high and low volume fraction of primary particles should be distinguished when choosing the analysis method. Systems with a high volume fraction, close to the maximum packing density, are characterized by the possibility to move of the primary particles. This can be expressed by an average particle-to-particle distance. The non-particle phase of such systems is preferably described by its covariance function, allowing a prediction of specific surface area and average capillary diameter. Dissolution speed as well as crushing strength of these systems show a dependency on particle-particle distance, which strongly decreases with increasing distance to level off at a critical distance. This behavior is however superimposed by the size ratio of primary particle to granule diameter.

In systems with a low volume fraction, the covariance function of both phases, particle as well as binder phase, is of interest. In these systems, the effect of particle size, i.e. both points of the two-point correlation being in the same particle, does not dominate. Primarily, the distance distribution of the primary particles is reflected. The covariance function will be a valuable measure for adapting statistical distribution models, e.g. Poisson distribution, or serve directly as basis for computer simulations of the granule structure. In addition, the covariance function can be analyzed to reveal nearest neighbor distribution.

In both systems, dense as well as dilute, the chord length distribution of the non-particle phase is a direct size measure of the structure.

Mainly, Limestone-PEG systems with varying particle size distribution of the primary particles have been studied. High shear mixer granulation, casting and fluid bed granulation have been applied. NaCl particles have been used as second solid phase. With respect to structure dependent granule properties, the focus was on single particle crushing strength and dissolution behavior. The applied characterization method of analyzing particle structures still needs more validation and applications to shows its full potential as well as its weaknesses. Especially the interaction with simulation tools is an unexploited field. This includes the computer generation of structures of a given stereological description, i.e. covariance function, as well as the simulation of properties. First simulations for the simplest case of stagnant dissolution have been conducted.

With the extended availability of high resolution µXRT systems, more 3D data of granule structures will be generated in the coming years, allowing to prove the benefit of using the proposed structure characterization method. This will also allow to investigate the validity of the found approximations and predictive relations.

The interpretation of the covariance function and chord length distribution, with respect to more intuitively comprehensive measures like coordination number and nearest neighbor distribution, would lead to a method that has its value from a mathematical as well as an engineering point of view.

Executive Summary

The understanding and control of crystallographic polymorphism and crystal habit of organic as well as inorganic compounds is scientifically and technologically important to a number of industries. To date, however, the experimental control of polymorphs (crystalline solids with different arrangements of the same constituents) is difficult. Since a polymorph is determined at the nucleation of a crystal, methods that lead to an advanced understanding of early crystal formation pathways and mechanisms are highly desirable. Towards this aim, in this project we employ arrays of self-assembled monolayers (SAMs).

Self-assembled monolayers (SAMs) are well-defined surfaces that can be used to study the relationship between the nucleation event and the final polymorph selection. Furthermore, by tuning the substrate-crystal interface energy, potentially crystalline order of SAMs can promote the nucleation of polymorphs not accessible via solution methods. It is these two advantages, i.e. the establishment of scientific correlations between nucleation and observed polymorph and access to polymorphs not accessible via solution methods, that have led us in this project to choose heterogeneous surface nucleation via SAMs as the primary means to study polymorph selection.

In the second-year of work, we examined 1-undecanethiol (UDT) and 11-mercapto-1-undecanol (MUOH) SAM chemistries on gold, and trichloro(octadecyl)silane (OTS) and trichloro(phenyl)silane (PTS) on oxide bearing silicon substrates in the presence of various solvent systems to investigate their ability to influence the nucleation, polymorph selection and crystal growth of acetaminophen (ACM). We found that for evaporating solvent from a single droplet on SAMs, both solvent(s) and SAM substrate work together to control crystal polymorph selection. On hydrophobic surfaces (UDT, OTS, PTS), use of pure solvents resulted in ACM form I (monoclinic), while a mixture of water and dioxane produced form II (orthorhombic). In addition to polymorph selection, under these conditions we found that for form II different SAM surface chemistries influence crystal orientation. Finally, by introducing a doctor-blading process, for first experiments of PTS SAMs on a silicon waver, polymorph selectivity could be achieved varying the solvent from 1,4-dioxane to ethanol. This opens the door to similar experiments at the Cornell High Energy Synchrotron Source (CHESS) in the third-year period. By studying at CHESS the known relationships between the structure of the crystal on one side, and the nucleating surface and conditions (quiescent versus shear) on the other, we hope to gain insights into the early formation pathways of crystallographic polymorphs.

Project resources: A first PhD student (Wael Ebrahim) started on the project in April 2017, his work and that of supporting Master’s student projects is reported here. Funding was also secured from the University of Leeds for a second student who will start in November 2017 (Tien Nguyen), his primary focus will be the introduction of mechanical models into the single drop drying framework. Funding has also been received from the EPSRC for a collaborative project, with Durham and Bristol Universities, looking at the fundamentals of structure formation when single drops are dried. This project has just started and wil

Objectives:

This project seeks to develop experimental and modelling methods that enable dried particle structure, properties and drying rate to be predicted based on droplet drying history. The project will focus on effects driven by boiling and look to develop material independent models which capture behaviors of industrial interest. In particular it will look to address key limitations in current understanding:

1. the impact of a non-isothermal drying history on particle structure and consequently drying rate;
2. improved measurements of material properties under the non-equilibrium conditions experienced during drying;
3. extension of models to include the mechanics of structure formation.

Approach:

Initially, material classes and materials will be identified. Novel experimental rigs and methods will be developed to allow unsteady drying behaviour to be investigated and material properties to be measured under relevant conditions. Established models will be extended to include better material models and mechanical deformation. We will bring this together into a regime map(s) which links material properties, particle size, initial moisture content and drying history to morphology.

Recent Technical Progress:

• Benchmarking dryer/drop tube operation – the pilot spray dryer from ProCepT was investigated to check the accuracy of the inlet temperature measurement, check the inlet temperature distribution and to investigate the heat loss. A significant offset in inlet temperature was recorded and a distinct profile in the inlet temperature across the system was measured. Large drops in heat loss were mitigated by insulating the dryer. The dryer will be used as a basis for the drop tube.
• Evaluation of mono-dispersed atomization technologies – several mono-dispersed atomisers were assessed, a customised atomiser from Leeds will be tested on the drop tube.
• Behaviour of HPMC (one of the model systems identified) has been mapped - the ProCept spray dryer was used to dry HPMC droplets across a range of droplet sizes and dryer temperatures. At all temperatures we saw highly deformed structures, there was no clear, discontinuous, change when the droplet exceeded the boiling temperature. However two distinct structures were noted, a highly deformed, deflated, structure and a smoother spherical structure.
• Single drop drying rig development – overall design has been defined and support and pipe work structure complete. The heater control is due to be finished in January and initial commissioning will start then.
• Models to estimate the composition distributions of atomised slurry droplets have been developed – a stochastic model has been developed that enables the composition distribution of slurry droplets to be estimated. At low concentrations of solids the solid particle number in each droplet shows a Poisson like distribution.
• Models to investigate the prediction of boiling have been developed – a CDC model has been used to estimate the bulk moisture concentration at the droplet boiling temperature. This will be extended to diffusion based models to enable the link between material properties and diffusion to be explored.
• Initial experiments into microwave droplet drying have been made – a method for material characterisation by puffing droplets using microwaves has been explored. Initial attempts have proved unsuccessful and work is in progress to develop the technique.

Future Focus - 2017

• Rig build and commission: The initial version of the single drop rig is due for commissioning Jan 2017. A mono-dispersed nozzle for the drop tube will be tested in the spray dryer Jan 2017.
• System mapping: The work with the HPMC highlighted the need to do this for a mono-dispersed drop tube system; consequently this will begin once capability in place. Opportunities to work with alternative techniques at collaborators are also being investigated.
• Material properties: Measurement and technique development due to start Q2 2017.
• Model development: Approach defined for incorporation of mechanical properties by end of Q2.
• Associated work: CFD modelling of the ProCept pilot scale spray dryer which will enable better understanding of the droplet trajectories and drying histories. (Masters project completion May 2017).

One of the long term barriers to advanced and accurate modelling of particulates is the lack of a suitable set of test particles that can be used to validate particle models. Generally the approach has been to take a specific, simplified particle system, measure the mechanical and surface properties as accurately as possible, and input these parameters into a model. The model is then used to estimate a property of the agglomerate – for instance agglomerate strength – and compared to experimental measurements on the simplified particle system. Whilst some of these approaches have produced some elegant simulation results, they often fail to produce an accurate prediction of the full distribution of behaviour of the simple particle system, let alone the behaviour of far more complex industrial powders.

There are two key limitations with the existing approach. Firstly, we collapse our experimental data to an average particle shape, average roughness, average surface energy etc. and eliminate the complexity of real particles very early in the process. The final model becomes "an average of averages", and the important effects of the structure, interactions and distributions are lost. Secondly, the destructive experimental tests can only ever test a single agglomerate in a single test condition and a single (usually unknown) orientation. The structural details of the agglomerate and the test conditions (particularly orientation) are never precisely modelled and the experimental test can never be replicated with an identical particle under identical conditions. Thus we are never sure if the model is insufficient to describe the behaviour, or if the model was accurate but the number of experimental testing replicates was insufficient to statistically converge to the average behaviour predicted by the model.

Real agglomerates produced by spray fluidised beds and high shear mixers in industrial processes have complex structures and irregular shapes which are difficult to study directly. At a basic level, general terms such as porosity or its complementary solid fraction are used to define the structure of the agglomerates [1-3]. These terms can also be related to variables such as coordination number or envelope density [4-6]. However, more advanced and useful analytic tools, such as X-ray microtomography technique, are recently available to study the structure of the agglomerates. Farber et al. [7] used X-ray microtomography to characterise pharmaceutical granules. Total porosity, pore size distribution and geometric structure were obtained by this technique. Rahmanian et al. [8] have also used X-ray microtomography to characterise the granule structure evolved in a high shear granulator. Due to complexity of the agglomerate breakage analysis in some cases, such as characterisation of internal stresses by experimental work, numerical simulation using Distinct Element Method (DEM) has been widely used by different researchers to provide a basis for sensitivity analysis of different factors affecting the agglomerate structure, and hence the breakage of agglomerates [9-11]. Golchert et al. [12, 13] for the first time studied the failure of the agglomerates with their structures characterised by X-ray micro-tomography, and their strength analysed by DEM models. The 3D spatial locations of particles of real agglomerates were obtained and implemented into the simulation code to generate simulated agglomerates. The effects of agglomerate shape and structure on breakage patterns during compression were analysed. A similar piece of work was carried out by Moreno-Atanasio et al. [14]. More recently, Dadkhah et al. [15, 16] characterised the internal morphology of agglomerates produced by a spray fluidised bed using X-ray micro-tomography. The 3D volume images of agglomerates were analysed in terms of porosity, coordination number, coordination angle. For the first time, they separated the solidified binder morphology of these agglomerates using this imaging technology. Although structural details of agglomerates can be obtained by X-ray micro-

Karen Hapgood ARR67-02 Page 4

tomography, the destructive breakage tests can only be carried out on a single sample under a single orientation.

The effect of structure details has hardly been investigated and the breakage test can never be replicated under identical conditions. The complexity of the agglomerate structure, arising from different parameters such as primary particle size distribution, void fraction, inter-particle bond characteristics and material properties of both primary particles and bonds, makes it difficult to establish a full map of agglomerate breakage regimes. Overall, the agglomerates can break in different patterns, depending on their properties and loading conditions leading to various failure modes. Several pieces of work have been done on classification of patterns of agglomerate breakage [17, 18]. Subero and Ghadiri [17] made agglomerates using glass ballotini as primary particles bonded together by bisphenol-based epoxy resin. In order to explore the effect of agglomerate structure on agglomerate impact strength, the agglomerates were made with different levels of porosity by making different number and size of the macro-voids. The particles were impacted at different impact velocities and angles. In order to elucidate the fracture patterns, the shapes of the fragments were observed. They reported different patterns of breakage for agglomerate impact breakage obtained in their work, such as localised damage, fragmentation, multiple fragmentations with localised damage and disintegration. In order to study the effects of structure on agglomerate breakage, it is desirable to produce multiple identical test agglomerates with controlled structures, and then study their breakage behaviour in detail with the aid of mathematical models and experimental instruments.

In this project, 3D printer-Objet Connex 500 is used to print multiple customised agglomerates. The Objet 500 is an eight jet "PolyJet" printer which can print multiple materials simultaneously in a single print run, including rigid or rubber-like flexible materials with well-defined mechanical properties. Liquid photopolymer is printed on a build tray to form the object and cured with UV light. It can also print a removable support gel to support overhangs and/or complicated geometry. PolyJet prints simultaneously different materials with varied mechanical properties to represent the particles and/or dried liquid bridges between the particles. There are five broad material classes available, some with sub-variations: rigid opaque materials (2 variations); rubber-like materials (3 variations); transparent materials (2 variations); a polypropylene-like material and a high temperature material. The properties of each material are well defined and detailed datasheets are available [19], specifying density, hardness, tensile strength, elongation at break, elastic modulus, water adsorption and glass transition temperature Tg (where relevant), and other properties as well as the ASTM test method used to measure each of these properties. This permits a broad spectrum of agglomerates to be produced with "tuneable" physical properties.

In year one, quasi-static compression tests and drop weight impact tests were carried out using a spherical symmetrical agglomerate to investigate the agglomerate breakage behaviour at different strain rates. Preliminary experiments to determine the influence of agglomerate orientation, bond properties and strain rates were conducted to demonstrate "proof of principle" for the approach. An updated description of this work is included in this report, and the first "proof of principle" paper has recently been published in Powder Technology in late 2016. In year two, two different agglomerates were designed (cube shaped tetrahedral agglomerate, and a spherical shaped randomly structured agglomerate) and both breakage tests and DEM modelling were conducted. This report summarises the progress to date and the remaining work for year 3.

The focus of the recent work was on the generation of different types of structure. Random

close structured granules as presented in previous years were investigated more

detailed regarding the packing density and primary particle distance distribution inside

a granule. Additional random loose structures were generated allowing porosity as additional

phase. Porous systems were generated using two different methods: fluid bed

granulation and a sintering method. Layered systems or core/shell systems were generated

using a fluid bed; a fine particle suspension was sprayed on larger core particles.

Additionally the particle-particle distance of coarse primary particles that was presented

as suitable structure measure last year was investigated more detailed. The goal was to

develop a theoretical calculation of particle-particle distance based on the known primary

particle size distribution. Results show a good agreement between values calculated

from X-ray micro-tomography images and values from theoretical calculations. Therefore

this theoretical particle-particle distance was used as structure measure in random close

structured granules.

The dissolution measurements of different sets of experiments showed that the dissolution

speed is dependent on two factors: amount of soluble material (fraction of surface

occupied by soluble material) and pore size or phase width of soluble materials. These

two factors are strongly connected and it is difficult to investigate one without the other.

Together a high fraction of soluble material and a high phase width leads to a faster dissolution

compared to granules with smaller phase width (or pore size) and fraction.

The mechanical strength of random close structured granules showed no explicit results

and was difficult to evaluate. Random loose structured granules on the other side showed

a higher strength for lower effective porosities. These results were as expected, the development

of a network of solid bridges between primary particles leads to stable granules

if more and thicker bridges are build.

Executive Summary

The understanding and control of crystallographic polymorphism and crystal habit of organic as well as inorganic compounds is scientifically and technologically important to a number of industries. To date, however, the experimental control of polymorphs (crystalline solids with different arrangements of the same constituents) is difficult. Since a polymorph is determined at the nucleation of a crystal, methods that lead to an advanced understanding of early crystal formation pathways and mechanisms are highly desirable. Towards this aim, in this project we employ arrays of self-assembled monolayers (SAMs).

Self-assembled monolayers (SAMs) are well-defined surfaces that can be used to study the relationship between the nucleation event and the final polymorph selection. Furthermore, by tuning the substrate-crystal interface energy, potentially crystalline order of SAMs can promote the nucleation of polymorphs not accessible via solution methods. It is these two advantages, i.e. the establishment of scientific correlations between nucleation and observed polymorph and access to polymorphs not accessible via solution methods, that have led us in this project to choose heterogeneous surface nucleation via SAMs as the primary means to study polymorph selection.

In the first-year of work, we have selected three types of SAMs, two hydrophilic (carboxylic acid terminated surface and hydroxyl terminated surface) and a hydrophobic (methyl terminated) surface to investigate their ability to influence the nucleation, crystal growth, and polymorph selection of a common drug, acetaminophen (ACM). It turns out that the hydrophilic surface tends to promote the formation of the monoclinic form of ACM, while the hydrophobic surface induces the formation of the less thermodynamically stable orthorhombic form of ACM. We hypothesize that this selection is due to the energetic preference of certain crystal facets interacting with the chemically specific SAMs surface. By studying the known relationships between the structure of the crystal and the nucleating surface, we will gain insights into molecular-scale recognition events that can lead to polymorphism which is a promising step to the final goal: understanding early formation pathways of crystallographic polymorphs.