Particle Formation

Executive Summary

groups, including carboxylates and amines, and other solvents.

crystals on the SAM surface, as well as exploration of other SAM surface functional

steps will include changing sample angle in order to increase the low number of observed

of yellow needles (YN), while methyl SAMs preferred red prisms (R). Next experimental

for selection of additional polymorphs. Besides Y, hydroxyl SAMs preferred the nucleation

surfaces. However, hydroxyl and methyl terminated SAMs showed a different tendency

that yellow crystal (Y) was the dominating polymorph on both -OH and -CH3 terminated

polymorph characterization of nucleated crystals. First experimental results demonstrated

jump at three different levels of supersaturation. Raman microscopy was applied for

solution and the nucleation was induced on the SAM surface by generating a temperature

project, control over the degree of supersaturation. SAMs were placed vertically in the

Crystallization by cooling experiments were conducted to allow, for the first time in this

[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) in toluene as solvent.

groups (-OH and -CH3) as nucleating surfaces for the organic model system 5-methyl-2-

based self-assembled monolayers (SAMs) with different terminal (omega) functional

number of industries. This project has moved to the formation of alkane-thiols on gold

as well as inorganic compounds are scientifically and technologically important to a

Understanding and control of crystallographic polymorphism and crystal habit of organic

Abstract

Coating, or layering, is the process of applying a secondary layer of solid to a solid host substrate, for instance a core or carrier particle. The process is applied in many industries, like food and feed, pharmaceuticals, fuels or fertilisers, to design the functionality of the coated material. This report gives an overview of process technologies and their capabilities for the coating of core particles smaller than 200 µm in characteristic size.

Executive Summary

The renewal IFPRI project revolves around utilizing 3D printing as a means to procure tuneable particles for the purpose of advancing particle technology. There are a number of advantages to this approach. Firstly, it provides accurate data for the particle properties which can be entered into a simulation, for comparison against the real experiment. This provides more precise results than the typical approach of measuring existing, non-identical particle properties. Secondly, an infinite number of experiments destructive in nature (i.e. breakage, dissolution) can be replicated to test a particle under the identical conditions.

In the previous IFPRI project, only agglomerate breakage was investigated and validated with a DEM simulation.

In year one of this project, the quasi-static compression tests of a random spherical agglomerate 3D printed in colour was carried out to investigate the distribution of strength. Soft, rigid and a hybrid mixture of both soft and rigid materials were used for the agglomerate bonds to determine the optimum bond material to prevent individual particle breakage, something which had not been previously observed. Further tests were undergone on agglomerates containing internal voids within the structure. X-ray tomography of our 3D printed particles as well as real granules were obtained for set up future projects.

In year two of this project, we report progress on 3D motion tracking of particle breakage, photoelastic polymer discs and 3D printed porous substrates for analysis of the wetting behaviour. All 3D printing files for the particle models have been uploaded onto our Thingiverse account. This report summarizes the progress made in the second year of the renewal project and provides a summary of the remaining work for the final year.

Abstract

We report our recent results on the effect of impurities or ‘imposter molecules’ on the crystal growth process and developing mechanistic models describing the mechanisms by which impurities influence crystal growth. Impurities affect growth kinetics at the scale of kink attachment and detachment events, which are too fine to examine experimentally in real time. Thus, simulations are used to study the proposed mechanisms for growth inhibition/promotion and the results will be compared to experimental data available in the current literature. As a starting point, Kinetic Monte Carlo (KMC) simulations are utilized to simulate the time evolution of centrosymmetric organic crystal growth. Rare event rates are determined as functions of energetic barriers for desolvation and attachment/detachment works. Various mechanisms have been proposed to explain the growth-inhibiting effect of impurities, including step-pinning and spiral-pinning, which are described herein. These mechanisms will be incorporated into the KMC simulations, and compared to experimental values for validation. Once we have established effective working models, we will look to publish our results and ideally incorporate them into ADDICT3 (Advanced Design and Development of Industrial Crystallization Technology - version 3), an engineering tool which predicts relative growth rates and crystal morphology of solution-grown faceted crystals [1].

Additionally, we report on some new developments in ADDICT3 to improve the workflow during conceptual design of crystalline solid processes. ADDICT3 is capable of predicting the shape and morphology of crystalline particles using only the following input data, (1) crystal structure, (2) atom-atom force field, and (3) specified solvent and growth conditions. The key outputs are the steady-state growth shape and morphology of the crystals, and the “shape triangle” which gives graphical information about the influence of design variables (temperature, supersaturation, solvent) on the resulting shape and morphology of the crystal. More detailed outputs are also provided (e.g., periodic bond chain networks, growth spiral shapes, etc.) for use by the more sophisticated user. The tool can be used alone or in combination with other tools that have been developed recently to aid in the design of crystallization processes.

Executive Summary

Understanding and control of crystallographic polymorphism and crystal habit of organic compounds is scientifically and technologically important to several industries. Since a polymorph is determined at the early stages in crystallization, methods that lead to an advanced understanding of early crystal formation pathways and mechanisms are highly desirable. In this work, we have introduced time-resolved in situ wide-angle X-ray scattering (WAXS) at Cornell’s High Energy Synchrotron Source (CHESS) to study the early formation stages of the Form I and II crystallization events of a pharmaceutical compound, acetaminophen (ACM). Studies were informed by results from earlier investigations that both the surface chemistry of self-assembled monolayers (SAMs) as well as solvent conditions work together to control crystal polymorph. Studying crystallization of Form II by seeded nucleation, we verified that crystals grow faster at the substrate-solution interface than in the bulk above, and that the PTS (trichloro(phenyl) silane) SAM surface is taking over in controlling crystal growth by directing the (002) planes from slightly out-of-plane to a totally in-plane orientation. Studying crystallization of Form I by spontaneous nucleation, we identified unusual shifts along the scattering vector, q, of the earliest peak occurring in the in-situ scattering patterns. Further analysis and corroboration by other data sets pointed to the possible existence of structural transformations at these early crystal formation stages. Our results indicate that our methodologies are effective to gain insights into the earliest formation stages of the crystallization of ACM and are now being extended to other model compounds.

Figure 1. Take home message from the first year.

A first statistical classification was established for thirty powders. Four categories (green, yellow, orange and red) corresponding to various reconstituabilities were identified and summarized in the take home message (Figure 1). Long wetting time was associated to high particle surface hydrophobicity, small particle size, high protein and fat contents in the powder bulk. Long reconstitution time was linked to the powder manufacturing process (grinding) and low sugar content in the powder bulk.

• Green group: short reconstitution time and short wetting time,
• Yellow group: short reconstitution time and long wetting time,
• Orange group: long reconstitution time and short wetting time,
• Red group: long reconstitution time and long wetting time.

(3) First statistical correlations between the various powder characteristics and reconstituability ranking

(2) For selected powders: reconstitution kinetics in different conditions of temperature, stirring, etc.

(1) Powder classification according to their reconstitution behavior

Achieved deliverables:

The first year of the PhD work deals with the systemic physicochemical analysis of powders and their classification according to their reconstitution ability. It will be achieved at the end of January 2020. The PhD work has met the three stated deliverables for thirty powders.

(PhD duration: 1st February 2019 – 31th January 2022)

Executive Summary until the tenth month

Executive Summary

This project seeks to develop physically realistic models for spray-drying as used in industry with a focus on high viscosity and non-Newtonian fluid atomization. The goal of this work is to develop understanding and correlations for the accurate pilot-to-production scaleup of spray-drying. We divide the work to focus on two nozzle types: pressure-swirl, and two-fluid.

A testing facility is setup for experiments with swirl nozzle. Various types of pressure swirl nozzle with different scales are selected to be tested with different fluids at relatively high pressure. An imaging system is used to take near-nozzle images to analyze the atomization process. It is also used to measure the droplet size downstream and report number distribution and SMD at various radial positions. An atomization process is proposed by observing near-nozzle images. Physics model is being developed and its predictions will be compared with all the experiment results for further improvements.

Preliminary tests of two-fluid nozzles reveal the similarity to single-droplet breakup, thus detailed experimentation and analysis on single droplet atomization by an air jet was conducted. A working hypothesis that the rate of droplet deformation determines the mode of droplet breakup is being studied, and models for the underlying breakup processes have been compared to the experiments with reasonable agreement. The next phase for this branch of the project will be to apply the developed models for single-droplet breakup to the two-fluid atomization geometry.

Executive Summary

2 and 3.

publication in Q1 2019. This report summarises the progress to date and the remaining work for years

of this work is included in this report, and the first “proof of principle” paper will be ready for

out for the first time which showed the layer by layer detail of the 3D printing process. A description

something which had not been previously observed. X-ray tomography of the agglomerate was carried

agglomerate bonds to determine the optimum bond material to prevent individual particle breakage,

more detail. Soft, rigid and a hybrid mixture of both soft and rigid materials were used for the

orientation, individual particles and observe the breakage behaviour with much more accuracy and in

agglomerates in colour. By dividing the agglomerate into coloured sections, it will be possible to track

of strength behaviour at different strain rates. A Stratasys Object 500 Connex 3 was used to print the

identical spherical agglomerates 3D printed in colour were carried out to investigate the distribution

ideas and implement them broadly. In year one of this project, quasi-static compression tests of

work from this project would enable the particle technology worldwide community to take up the

disintegration and powder flow and segregation using the newly developed approach. The published

The new IFPRI project contains three sub projects which focus on agglomerate breakage, agglomerate

successfully conducted and the results were highly reproducible.

structure. For the first time, experimental tests on “perfect” particles with tuneable properties were

and the breakage behaviour was compared with a DEM simulation of an agglomerate with an identical

techniques. In the previous IFPRI project, identical copies of agglomerates were designed and printed

orientations. To date, this has not been possible via experimental agglomeration production

under the same condition/orientation and then repeated for various other conditions and

3D printing technology allows mass fabrication of identical agglomerates that can be tested repeatedly

from a ‘single’ individual agglomerate can never be replicated.

possibility of reproducing the data under the same conditions. Therefore, experimental data produced

destructive nature of the experimental tests i.e. breakage, dissolution etc., which would eliminate the

inability to capture the true complexity of the agglomerate structures in simulations and 2) the

actual experimental measurements. The two key drawbacks of the current approach are 1) the

entered into a computer for imprecise estimates of the model simulations, then compared against the

measure the relevant properties of existing non-identical particles. These parameters are then

due to lack of suitable test particles. To date, the cumbersome approach has been to individually

Accurate and systematic validation of particle systems with a simulated model has not been possible

structures collected from a lab scaled spray dryer.

Structures obtained from the single droplet drying experiments showed high similarities to

The differences in these drying metrics have been related to key material properties.

final particle size, moisture content at locking were collated at different drying conditions.

encountered above boiling. Several drying metrics including relative size at locking, relative

further understand the differences in drying behaviour and morphology evolution route

conditions collected from the single droplet drying rig have been extensively investigated to

deflation, inflation and puffing. Drying kinetics and morphology time-series at different drying

different drying mechanisms, boiling without any inflation/deflation cycles, inflation and

concentrations using a filament single droplet drying rig. The three materials showed three

and drying kinetics have been investigated across a range of air temperatures and initial solid

sucrose, sodium silicate and Hydroxypropyl Methylcellulose (HPMC). The drying behaviour

and morphology evolution. Three skin forming materials were chosen for this study namely,

The aim of this study is to investigate the effects driven by boiling on the drying behaviour

Wael Ebrahim

above boiling point

An experimental investigation of the drying mechanisms of single droplets

The solution of this model is currently underway.

expression for the expansion of a single centralized bubble within a liquid droplet was derived.

transfer on the expansion of a single bubble in an infinite liquid media was conducted and an

to the asymmetric pressure and velocity field. An initial assessment of the influence of mass

An off-centre bubble was also investigated and a self-centering behaviour was observed due

oscillations which decayed with time. The rate of decay increasing with increasing viscosity.

dynamics of a initially over pressured bubble, behaved as anticipated showing bubble

constructed and solved to allow for asymmetry to be investigated. The 2-D model, of the

spherically symmetric 1-D equations were derived and solved and a 2-D model was also

derived from the mass and the momentum balances and the Navier-Stokes equation. Both

The governing equations for the oscillations dynamics of the bubble and the droplet are

within a droplet, which is termed as ‘bubble-droplet system’ in this report, are investigated.

The effects of mass transfer on the oscillation dynamics of a single bubble centrally located

Tien Nguyen

BUBBLE DYNAMICS INSIDE A DROPLET

Executive Summary

hydrates/solvates, and cocrystals crystallized from solution.

we plan to continue with the remaining modifications required to implement models for organic salts,

ADDICT v3.0 against molecular crystals with multiple molecules in the asymmetric unit. Following this,

Upon completion of this new architecture, we will demonstrate improved functionality by testing

co habit predictions of organic salts, cocrystals and solvates grown from solution.

quires a complete rewrite of the existing codes, these modifications lay the groundwork for rapid in sili-

lographic complexity. We are currently implementing this redesign within the software. Although it re-

of the solid-state interactions that is independent of the asymmetric unit and applicable to any crystal-

solvates and cocrystals). With our redesigned input preparation architecture, we can build a description

sponds to the growth unit itself, many systems do not satisfy this criterion (including all organic salts,

from the asymmetric unit. While this approach is feasible for systems where the asymmetric unit corre-

architecture for acquiring this information is to apply crystallographic operations to generate a unit cell

growth models is to calculate and organize solid-state interactions between growth units. The typical

salts, cocrystals and solvates. A necessary, but not sufficient, condition to enact mechanistic crystal

shape-prediction design aid that is applicable to all crystalline solids, from organic molecules to organic

vanced Design and Development of Industrial Crystallization Technology). Our goal is to produce a

important solid forms, and especially drug substances. We call our software design aid Addict (Ad-

morphology software tool in order to generalize the methodology to a much broader class of industrially

In the first year of this project we have used IFPRI funds to redesign and rewrite our crystal growth and