Particle Formation

New Classification Of Drying Processes Based Upon the Option Used for the Protection of Heat Sensitive Ingredients:

• A Low temperature
• B Short drying time (by high drying rate)
• C Even distribution of temperature in the particles
• D Equal residence time for all particles, if they are of equal size
• E Residence time adapted to the size of the particles, if they are of unequal size
• F Adapted dryer atmosphere, especially absence of oxygen

One of the long term barriers in understanding granule breakage is the lack of a universally accepted test method or test granules to systematically evaluate agglomerate breakage propensity and mechanism. Computer simulations are often used but are limited by the lack of identical, controlled agglomerates to test and validate simple models, let alone replicate the complex structure of real industrial agglomerates.

This report summarises progress to date on a new 3D printing production method of test agglomerates with defined and "tuneable" properties. Agglomerates were designed using Solidworks 2014 software and printed by an Objet500 Connex 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. Compression and impact tests were performed to investigate the breakage behaviour of printed agglomerates in terms of agglomerate orientations, bond properties and strain rates.

The compression and impact results reveal different agglomerate breakage characteristics. For compression tests under low strain rate, breakage occurs at the bond between primary particles, and the compressive strength is influenced by the bond strength significantly. In future, it is worth to further relate the microscopic particle-particle and particle-bond interactions to the macroscopic compressive strength. For impact tests with high strain rate, the agglomerates with flexible bond show rebound behaviour, while the agglomerates with rigid bond fracture. Under the same impact conditions, the rubber materials have high fracture toughness and the rigid materials behave in a more brittle manner that can fracture easily. For the fractured agglomerates, clear fracture planes can be observed with low impact energy. At high impact energy, a large amount of small debris occurs, and the breakage extent increases accordingly.

Now that proof of principle for the approach has been established, the next stage of the project is to conduct systematic studies of agglomerate strengths varying structure, material properties, under various breakage forces, orientations and strain rates.

During the third year of this project we focused on the following activities:

• We have completed the study of the force displacement law for high densities which was also part of a parallel leveraging project funded by Abbvie. This work has demonstrated that the utilization of DEM to high relative density compaction problems requires a completely different approach to the force displacement law than traditional DEM. The contact response between particle was found to depend on the overall triaxiality of the contact deformations on of the particle. A new deformation fabric tensor was proposed based on the deformation and direction of all contacts on a particle. These results form the basis for more appropriate force-displacement laws at contacts that can be implemented in discrete element simulations for high density problems.

• A detailed study was conducted on the contact problem between dissimilar spheres (different radii and different materials cases). This problem is central in the cases of powder mixture compaction. New results are presented in the report.

• An experimental study was conducted in the NaCl-Starch system – a binary system with peculiar behavior in terms of the strength of mixtures. We have first repeated the experimental results to verify them. We have identified a different method of milling that produces completely opposite trends. Our analysis of results indicates that there is a strong coupling between the milling process and the microstructure of the compacts. The milling process results in essentially a change of the particle size that depends on the materials of the mixture.

Ongoing work focuses on (a) the introduction of failure models in DEM, (b) the extension of the large relative density approach for DEM for multi material systems, (c) understanding the role of shear motions in multi material systems, (d) parametric studies for powder mixtures (d) model validation.

In previous years the experimental set-up was about granules composed of only two phases, a particle phase and a binder phase. The particle phase consisted of insoluble limestone particles with different particle size distributions. The particle size distribution was varied systematically by changing the ratio of coarse to fine primary particles. It was found that the composition of primary particles plays an important role for the granule properties, especially the amount and distribution of coarse primary particles.

The aim of this years project

was to amplify the knowledge about structure - functionality correlation. Therefore a set of experiments with two different primary particle phases was investigated. The materials were chosen to have a soluble and an insoluble particle phase. As soluble particle phase sodium chloride was chosen because it allows the measurement of conductivity during dissolution. The insoluble particle phase was again chosen to be limestone. Also the binder was hold constant to be polyethylene glycol but it was now used in a melted state and not in concentrated solution as before.

Granulation method

Additionally the granulation method was changed into a two step method involving casting and milling. This step was necessary because it was aimed to generate a random close structure of primary particles in binder. In more detail a mixture of primary particles was mixed with melted binder and casted on a plate for cooling. The amount of binder was adapted to generate a saturated system without porosity. Afterwards the hardened plate was milled down to the desired granule size between 250 and 710m.

Investigation of granules

The granules were investigated in two ways as done in previous work. The structure was determined from X-ray micro-tomography images calculating structure measures like chord length distribution, covariance function and star volume of different phases. The granule properties were determined by different measurements including single particle crushing and dissolution behavior.

The review focusses on progress in understanding, measuring and modelling the structures formed when single droplets dry. In the initial period of drying concentration gradients are formed, these establish the basis for subsequent transformation to the solid particle structure. The Péclet number is becoming established as a useful metric for evaluating the magnitude of these concentration gradients and therefore interpreting trends seen in the final particle structure. The structures formed after drying depend on the nature of the phase transition of the material being dried.

Three broad classes are discussed:

• colloidal suspensions
• crystallising materials
• skin forming materials

Recently significant progress has been made in the understanding of colloidal suspensions. Quantitative analysis and careful experimentation in the field has helped quantify and predict effects in model systems. These give insights that help the particle engineer design particles with the desired structure. That said there are still many open questions for this class of material, and micro-scale-modelling techniques are available and should be used to help address these questions.

Crystallisation and film forming systems have seen less progress. Some work has been done looking at alternative crystallisation models, which give some interesting insights into amorphous-crystalline transitions; however there is a lot of opportunity to extend these further. Film forming systems have received little fundamental activity in recent years, however researchers are beginning to characterise material properties and link these to behaviour to explain observed phenomena.

The whole area of materials characterisation in the non-equilibrium conditions seen during drying is a priority area for all material types, as the value of current modelling capability is limited by lack of reliable physico-chemical properties. The aerosol community has been active in developing new methods to address this need and their application should be extended to materials of industrial interest. Some of the recent developments in measurement techniques for free droplets has also been pushed by the aerosol community, beyond these methods there is still a need to extend and develop the state of the art in the area for better measurements of internal composition profiles. Drying of other particle systems is also discussed and key differences in the mechanisms driving the structure of dried thin films and sessile droplets are highlighted.

Submicron crystals have the potential to enhance dissolution rates and absorption efficiency of active ingredients with low aqueous solubility used in pharmaceutical formulations and in a wide range of specialty chemicals. Precipitation from solution offers a direct and cost effective method to produce micron-sized and submicron particles. However, a precise knowledge of the particle formation mechanisms, involving the primary process of nucleation and crystal growth, is essential to control crystallization in this size range. Producing submicron crystals of organic compounds by antisolvent or reactive precipitation methods, as compared to inorganic crystals (ionic salts and metal oxides), is even more challenging due to their relatively slow nucleation rates at moderate supersaturation levels. Further, the presence of directional H-bonding in molecular crystals can lead to faster growth along certain facets resulting in crystals with higher aspect ratios.

In this research work, nucleation and growth phenomena of organic crystals from solution were investigated experimentally, with the aim of understanding the effects of solution conditions and process variables on submicron crystallization process. Initially, nucleation kinetics of the model compound, naproxen (a poorly water-soluble drug), was determined at various solute concentrations and in the presence of polymeric additives that are typically used to stabilize colloidal crystal dispersions. Nucleation rates were calculated from multiple induction time measurements at a constant supersaturation using a statistical approach. The results showed a reasonably good agreement between experimentally determined nucleation rates and that predicted using classical nucleation theory relationship. While the polymeric additive polyvinylpyrolidone (PVP) significantly promoted the nucleation kinetics in the entire range of supersaturation studied, the effect of hydroxypropyl methyl cellulose (HPMC) on the nucleation kinetics was supersaturation dependent. Thermodynamic and kinetic parameters for nucleation of naproxen crystals were derived from the experimental data and, in turn, linked to the mechanisms underpinning the effects of polymeric additives in producing submicron crystal dispersions.

1. Introduction

The earlier parts of the project were focused on the implementation of structure descriptors and determination of physical parameters of model granules and their correlation to structure parameters. The first results were intensified and finding checked for correctness.

Model granules were generated containing different size distributions of primary particles to achieve different internal structures. A series of bimodal particles size distribution of fine and coarse limestone particles were granulated with polyethylene glycol binder. Three dimensional X-ray micro tomography images of the model granules were recorded and used for further calculations of structure descriptors. The structure descriptors that were evaluated include volume and surface fraction, star volume, chord length distribu- tion and covariance function.

For the determination of physical properties the techniques established last year were applied. Mechanical strength is measured by single particle crushing and the dissolution or disintegration behaviour by conductivity measurements and online particle sizing respectively. The structural as well as the physical parameters provide results that are suitable to distinguish between differently structured granules.

A complete experimental determination of the drying and degradation kinetics to get better knowledge of the mechanisms involved in transforming a droplet to the particle is the main aim of the whole project. Accomplishment of this task requires the application of a special equipment which would make it possible to take samples and to ensure residence time long enough. The main difference of our approach and the approach encountered in the literature in a systematic investigation of spray drying process for chemical and biological systems is involving in situ analysis of the properties of continuous and dispersed phases from atomization to collection of dry product.

A typical systematic analysis of a spray drying process contains the following steps (Nath and Satpathy, 1998):

• atomizer performance studies,
• parametric sensitivity of spray dryer studies,
• powder property studies,
• thermal inactivation studies,
• post drying studies.

We proposed to make an additional step for deeper analysis of the spray drying process; to study spray and heat carrier properties during drying process (inside the dryer). Only this kind of analysis enables understanding of transferring mechanisms from droplet to particle connecting operational parameters of the process (temperature, humidity, moisture content) and current structure of spray (particle size distribution, particle velocities, etc.).

Spray drying is one of the best theoretically developed drying methods, particularly in the area of calculation of hydrodynamics in the two-phase flow: solid particles-gas. The process of spray drying is, however, such a complex phenomenon that so far no model describing it correctly has been proposed. The gravest errors in the calculation of spray drying are caused by an incorrect determination of drying kinetics and improper model of flow turbulence (Bahu, 1992).

Due to broad variety of materials being dried in spray dryers, it seems difficult to develop general principles concerning the kinetics of water removal from these materials (Masters, 1991). It is necessary to determine individual drying kinetics for each material separately. In a typical schematic of spray drying, a particle stops shrinking and the formation of a rigid structure starts when a critical moisture content is reached. Since that moment on the particle may not change its size, it may break down, disintegrate and agglomerate. All these phenomena affect the coefficients of aerodynamic drag and heat and mass transfer which have a significant influence on the drying process. Some materials may behave in a quite different way, e.g. the colloidal-capillary-porous bodies reveal high resistance to vapour diffusion on the surface; this may cause swelling of the particle in the initial period of drying (particles of milk).

The key problem in spray drying which has not been solved yet is the determination of drying kinetics and degradation kinetics for heat sensitive products. The lack of appropriate experimental investigations is due to technical problems in carrying them out. The residence time of particles in the spray dryer does not usually exceed 30 seconds, and is often even shorter. Thus the whole process of dehydration, formation of solid structure, degradation, etc. takes a very short time. Therefore, a few attempts made so far to determine the kinetics of product drying and degradation have been restricted to the analysis of relevant parameters only at the dryer inlet and outlet, e.g. Alizondo and Labuza (1974), Johnson and Etzel ( 1994).

Step I of this project is a preliminary stage to enable extensive studies on kinetics and degradation of dewatering of selected products in a disperse system when particle residence time does not exceed a few seconds.

As follows from the research we have carried out so far, the range of measurements performed in the experimental rig must be extended by increasing the residence time of sprayed material in the measuring section and reducing the risk of material deposition on the walls. To achieve this the diameter of the measuring section should be changed from 30 to 50 cm which would enable drying in a broad range of initial process parameters (mainly in a wide range of feeding rates and atomization angles).

The project steps and related milestones for the first year period as defined in the project proposal are:

1. Set up of model suspension systems and of basic laboratory analytical procedures for testing microstructure, rheology and mechanical extrudate product properties (6 months) described in chapters 1-3
2. Set-up / adjustment of extrusion system and first experiments with the selected model systems (6 months) described in chapters 4 and 5