FRR - Final Report

Summary

This report documents the work performed during the last 36 months funded by IFPRI. It covers the following four aspects: 1) suction filling; 2) Rotary die filling; 3) Forced die filling with a paddle wheel; and 4) Segregation during die filling.

For suction filling, a model suction filling system was developed. Die filling efficiency was evaluated in terms of fill ratio, and four different types of pharmaceutical powders were used and. Effects of filling and suction velocities, as well as powder properties, on the efficiency of die filling were systematically investigated. It was observed that for a given die filling system an optimal ratio of filling to suction velocity (i.e. the optimal velocity ratio, v*) could be defined. Therefore, three distinctive phases in suction filling could be identified: i) a filling to suction velocity ratio (vr) below v* would result in piston reaching the specified terminal position before the shoe completes its transit over the die; this is referred to as slow filling ii) when vr = v*, the suction and filling synchronise so that the piston reaches the terminal position precisely when the trailing edge of the shoe starts transiting over the die, which is referred to as the synchronised filling; iii) when vr > v*, the piston reaches the terminal position after the shoe has completed the transit over the die, and this is referred to as fast filling. In slow filling, cohesive and free flowing materials showed two distinctive die filling behaviours: cohesive materials produced a gradual increase of fill ratio, reaching its maximum value at v*, whereas for free flowing materials the fill ratio decreases slightly as the vr increases and at v*, 5-10% reduction in fill ratio was observed. In fast filling, the die filling behaviour is similar to that of gravity filling at high filling velocities, where the fill ratio decreases as vr increases.

For rotary die filling, a model rotary die filling system was developed to mimic the die filling process in a typical rotary tablet press. The system consists of a round die table of 500 mm diameter, equipped with a rectangular die. The die table can rotate at an equivalent translational velocity of up to 1.5 m/s. The filling occurs when the die passes through a stationary shoe positioned above the die table. Using this system, die filling behaviours of 7 commonly used pharmaceutical excipients with various material characteristics (e.g. particle size distribution, sphericity and morphology) and flow properties were examined. The efficiency of die filling is evaluated using the concept of critical filling velocity. It was found that the critical filling velocity is strongly dependent on such properties as cohesion, flowability, average particle size and air sensitivity index. In particular, the critical filling velocity increases proportionally as the mean particle size, flow function, air permeability and air sensitivity index increase, while it decreases with the increase of specific energy and cohesion.

For forced die filling with a paddle wheel, the flow behavior of powders was studied systematically using a model die filling system. The fill effects of different turret speed and paddle speed were carried out using a simulated system with four cylindrical dies. Three grades of microcrystalline cellulose powders were examined to explore the effect of particle size and shape on die fill. Flow properties were quantified using the concept of critical fill speed. It was found that critical filling speed and parameter n depend on not only the properties of powders but also the size and shape of die. The ratio of powders entering the die was primarily influenced by turret speed, while paddle speed has a slight impact. High speed video was used to discuss the trait of flow pattern. Mass uniformity was positively correlated with critical fill speed. The powder bed is loosened when the last die through the fill area and consequently it was filled more than others. The researched critical process parameters help optimize powder formulation and process design.

For segregation during die filling, particle size-induced segregation during die filling of binary pharmaceutical blends, consisting of fine and coarse particles in various fractions, was investigated. Coarse fraction was made of milled and sieved acetylsalicylic acid, whereas the fine fraction was mannitol. The die filling process was carried out in gravity filling and suction. The segregation was assessed through determination of the coarse component concentration using UV-Visible spectrophotometry. The obtained values of concentration, determined for ten units of identical volume inside the die, were used to calculate the Segregation Index (SI), which was an indicator of uniformity of the powder blend deposited into the die. It was found that high segregation tendency was generally observed during suction filling at low velocity, due to the effect of air drag, and during gravity filling at low velocity, as it was carried out through three consecutive filling steps. The lowest segregation tendency was observed during suction filling, irrespective of the filling velocity and concentration. The horizontal segregation was mostly observed in the top layers of the die, due to mainly two mechanisms: coarse particles cascading down the heap formed by the powder in the final steps of die filling, which produces higher coarse concentration in the near side of the die, observed at low coarse concentration; or coarse particle cascading down the top surface of the flowing powder stream into the die, which increases the coarse concentration in the far end of the die.

Executive Summary

We summarise the findings of our second three-year project on the long-term stability of colloidal gels. In our first three-year project, we showed that it was processes occurring at the top of gels that appeared to control the way these materials collapsed under gravity, and that simulations without hydrodynamic interactions could not reproduce any of the plethora of observed phenomenology. These findings form the starting points of our second three-year project. First, we use lattice-Boltzmann simulations that take into account hydrodynamic interactions to study a variety of local phenomenology, revealing the subtle but important ways in which such interactions affect gel properties via the kinetics of aggregation. Secondly, experiments show that a curved meniscus gives rise to dense ‘debris’ on the top of gels, precipitating collapse. Eliminating curved menisci, of either sign, significantly increases gel life times. Finally, towards the end of our project, we studied a colloidal gel containing large, non-Brownian particles, mimicking how colloidal gels are used in many industrial formulations. Unexpectedly, we find that the behavior of this system depends on preparation protocol, so that using colloidal gels to suspend large particles introduces complexities that are not revealed by studying the colloidal gels alone.

Executive Summary

of the proposed DEM-PBM multiscale method for the optimization of milling devices.

predictions of product size distribution is achieved, which indicates a promising application

experiments at different rotary speeds. A good agreement between the tests and the

model was then used to predict the milling outcomes for the other three set of milling

12000RPM using a constraint optimisation technique. The DEM-PBM coupled multiscale

i.e. particle material dependent parameters, were evaluated from the milling test at

parameters and mill operating dependent parameters. The remaining parameters of PBM,

scale. Variables in the PBM kernel were classified into particle materials dependent

operating dependent parameters in the Population Balance Model (PBM) at the process

velocity distributions obtained through DEM simulations were utilized to inform the mill

the particle dynamic and stressing conditions inside the pin mill. Furthermore, the impact

and feed rate. DEM simulations were then performed to understand the fundamentals of

The UPZ100 pin mill experiments were conducted to study the effect of rotary speed

Timoshenko beam theory considering axial, shear and bending behaviour of the bond.

model by Brown et al. (2014) was utilized in which the bond contact is based on

which is then compared to experimental results. A recently developed new bonded contact

breakage subject to impact loading was conducted to evaluate the breakage propensity

of numerical results. A Discrete Element Method (DEM) simulation of single particle

comminution characteristics of the test solids, which provides the basis for the validation

experiments were carried out using the UPZ100 impact pin mill to measure the

component to be rationalized. In particular, the contribution of tangential component velocity was incorporated in the new model using the mobilized dynamic friction. Milling

a new breakage model, which enables the contribution of the normal and tangential velocity

velocity identified from experiment, the effect of impact angle is considered in developing

in predicting breakage under oblique impact and the significance of tangential component

crack accounts for the chipping mechanism. Considering the limitation of existing models

velocity. A new particle breakage model was proposed assuming that the subsurface lateral

velocity plays an increasingly important role in particle breakage with increasing impact

impact tests. It was found from the zeolite particle impact test that tangential component

by single particle loading experiments, including indentation tests and single particle

elucidate the particle breakage mechanics. The material grindability was first investigated

A hybrid of experimental, theoretical and numerical methods have been adopted to

particle breakage model calibrated against the defined grindability.

etc. pertaining to a milling process, which in turn will provide the basis for an improved

capable of analysing particle breakage subjected to particle impact, compression, and shear

provide the fundamental scientific basis for developing appropriate grindability measure

and how they relate to the mechanical properties and the final size distribution. This will

fracture and breakage mechanisms of individual particles under different loading regimes,

stressing events. The material grindability will require a detailed study of the fundamental

prevail in a milling operation and establishing material grindability in the context of the

in mill performance optimization. This involves characterizing the stressing events that

grindability with particle dynamics in a mill in order to provide an innovative step-change

reduction. In this project, we aim to develop new ideas and methodologies to link material

Milling is commonly deployed in many industrial sectors for intended particle size

EXECUTIVE SUMMARY

depends on both the particle shape and material.

while the local rheological parameter is largely independent of particle-shape, the nonlocal parameter

from material properties such as the coefficient of friction or elastic modulus. We observe that

shape of the interparticle contacts (rounded vs. angular) is an important control on s, separate

with three different elastic moduli, and small range of particle sizes. We have observed that the

parameters, using particles of three different shapes (circles, ellipses, and pentagons), materials

We have successfully performed experiments to test how the particle properties affect the model

observing that it corresponds to a drop in the susceptibility to force chain fluctuations.

yield criterion. Finally, we newly identify the physical mechanism behind this transition at s by

the prediction that there is growing lengthscale at a finite value s, associated with a frictional

collected once we account for frictional drag with the bottom plate. Our measurements confirm

successfully find that a single set of model parameters is able to capture the full range of data

We obtain (I) curves for several different packing fractions and rotation rates, and

and the inertial number I through the use of a torque sensor, laser-cut leaf springs, and particle tracking.

The apparatus is designed to measure both the stress ratio (the ratio of shear to normal stress)

photoelastic particles.

quasi-2D annular shear cell with a fixed outer wall and a rotating inner wall, including using

different packing fractions, shear rates, and particle properties, we performed experiments in a

model [gradient model, Bouzid et al. 2013]. To validate the efficacy of these two models across

nonlocal theory [cooperative model, Kamrin and Koval 2012], and added a comparison to a second

Through the three years of this project, we have have conducted laboratory testing of one

to macroscale behaviors.

to bulk data for a particular flow geometry and particles, we aim to connect grain-scale parameters

of granular materials, independent of the flow geometry. Rather than using empirical relations fit

and thereby provides an improved understanding of how particle properties control the rheology

best describe such flows. Therefore, there is a need for experimental data which tests these theories,

aside adhesion, which is more challenging still). It is an open question what constitutive equations

predicts its rheological response as a function of particle size, shape, and friction (even leaving

Currently, there is no first-principles, general theory of intermediate dry granular flow that

EPILOGUE TO THE PROJECT

density.

components and the individual components when compacted to the same pressure or the same

compacts. This work has clearly demonstrated the differences between a mixture of two

develop during compaction of powder mixtures as well as the residual stresses in the resulting

(2) We employed the Discete Element Method (DEM) to explore the distribution of forces that

pharmaceutical formulations) because it may replicate their interaction with moisture.

be considered as a model material for soluble crystalline components in mixtures (e.g., APIs in

of X with the appropriate properties (in this case matching of the elasticity modulus). NaCl can

controls strength in NaCl-X mixtures allows us to optimize their properties deliberate selection

material interactions. The most important result is that understanding the mechanism that

(1) The work in the NaCl system, in terms of in depth understanding of the mechanisms and the

In this report we present the results of the last year in particular:

paramount importance to the understanding of interacting mixtures.

In general, a mechanistic understanding of the ingredients and their interactions is of

the non-interacting mixtures.

received attention in the literature and was misinterpreted by studying it in the context of

this kind of behavior within the framework of the NaCl-Starch system, which had

during post compaction property evolution. We have attempted to demonstrate some of

stages of the processing of the mixtures, for example during milling of the mixture or

properties or the behavior of the others. This interaction can take place in any of the

• Indirect interactions, where the presence of one of the ingredients in the mixture alters the

such as those involving moisture transport, or local interdiffusion

• Direct interactions, such as chemical reactions between the powders, physical interactions

possible type of interactions. To begin with we attempt to classify them into:

- Directly interacting mixtures. This is a very broad category of problems because of the

mixtures is can be tricky.

high density regime. Therefore utilizing it to more complex problems such as the one of the

substantial effort (which was part of our project) is still relatively new and untested, in the

The problem here is that the DEM approach, even for single components, despite our

approach. We have presented this first order approach and have highlighted its weakness.

no trivial. This is the problem that we have attempted to address using the discrete element

Even in this case the direct comparison between the individual constituents and the mixture is

not the process of mixing affect the physical and chemical characteristics of the powders.

- Non interacting mixtures. This is the simplest case in which neither the powder themselves

mixtures according the possibility and the type of interaction between their constituents:

important concept that became obvious in the early days of the project is the classification of

some ideas that will provide the scientific basis for the exploration of this problem. The most

the years by the academic and scientific community. We attempted in the project to explore

The problem of compaction of powder mixtures and their properties has received attention over

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.

Executive Summary

Segregation model development holds promise for translation of academic research into industrial practice. Two significant issues that hamper the applicability of models in industry, however, are (1) the inherent difficulty in measuring segregation rates (especially in an experimental setting) for validation purposes and (2) the significant dearth of validated scale-up studies for these models. In this project, we seek to alleviate these two shortcomings of segregation research through a combined theoretical, computational, and experimental program. One unique aspect of our work is that we use flow perturbations to establish an “equilibrium” between segregation and mixing in free surface granular flows in order to alter the steady-state distribution of particles. By achieving this balance between the rate of segregation and the perturbation rate, we can combine the model expressions that we are interested in testing with dramatically simplified experiments to ultimately deduce the segregation rate (and validate the expressions). Moreover, by exploring a novel view of the interplay between granular rheology and segregation, we aim to introduce a new way of structuring segregation rate models that will make them inherently more scalable than any models previously reported. Thus far we have demonstrated which models from the literature may be considered state-of-the-art, but, more importantly, we have begun theoretical development of novel inherently-scalable models based on rheologically-relevant dimensionless groups. As this project continues to mature our ultimate aim is (experimentally) validated segregation models that can be incorporated into device-level transport equations in order to supply quantitative prediction of segregation at process scale.

Executive Summary

Building on preliminary results obtained at the end of our first three-year project, we have confirmed that curved menisci of whatever origin limit the life time of depletion-induced colloidal gels. Optical imaging reveals that rapid structural collapse is always initiated at these curved interfaces. Having shown that hydrodynamics is crucial for simulating realistic collapse in our previous project, we have now implemented the lattice-Boltzmann method for simulating gels, in which far-field flows are fully accounted for. Exploration of hydrodynamic interactions is now possible on desktop graphics processing unit (GPU) machines. Results to date show that such interactions are crucial for the aging of the gel structure before large-scale collapse, and speed up such collapse by generating back flows.

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.