ARR - Annual Report
The aim of this project is to enhance our understanding of how solvents and supersaturation affect the nucleation of polymorphic forms of compounds. Polymorphism is very important to the pharmaceutical industry as a compound’s polymorph can exhibit different physical properties, some more desirable than others. Being able to control which polymorphic form is nucleated is thus very important. In the first year of this project, the dimorphic enantiotropic compound p-aminobenzoic acid was selected as the model compound due to the availability of its solubility data and the relatively low transition temperature between its and polymorphs. The second year of the project has been focused on the precise location of the transition temperature and measuring the relative nucleation rates of and at different temperatures.
Background
Research background
There have been few studies of the relative nucleation rates of two polymorphic forms. Figure 1 shows a schematic phase diagram for an enantiomorphic system of Polymorphs I and II, it is characterised by a transition temperature at which the relative solubility and hence stability of forms switches. At the transition temperature
EXECUTIVE SUMMARY
The aim of the project is to establish a relationship between the product properties and feed material and the mill functions for milling of organic solids. The specific objectives are:
- a) To characterise the physical, mechanical, and thermal properties of organic feed materials (material function) at the single particle level, and to examine the effects of temperature and humidity on these properties,
- b) To investigate the breakage behaviour of single organic particles at quasi-static and dynamic conditions under the influence of temperature and humidity,
- c) To investigate the bulk milling behaviour of model organic solids and mill hydrodynamics (mill function),
- d) To characterise the properties of milled product, and to correlate the product properties to material and mill functions.
Model materials planned and approved for use in the project by the TC of IFPRI include aspirin, á -lactose monohydrate, sucrose or sorbitol, starch, and microcrystalline cellulose. These materials cover a fairly wide range of physical, mechanical and thermal properties, hence ensuring generality of the results to be achieved. This report summarises the work done over the second year of the project. The work includes the single particle breakage studies using the impact tester under both ambient and sub-ambient conditions, surface characterisation of the product particles using the Dynamic Vapour Sortion (DVS) device, measurements of Young’s modulus and hardness of single aspirin crystals using the nano-indentation method, analysis of the bulk milling behaviour of aspirin under both ambient and sub-ambient conditions, analysis of the mill dynamics, the use of a flow aid Aerosil to prevent re-agglomeration of milled products during the bulk milling, and population balance modeling of the milling of aspirin in collaboration with Du Pont. An attempt has also been made to relate the characteristics of the milled products in terms of particle size to the properties of feed material - the primary aim of the research. The single particle impact tests at the ambient conditions show that data on the breakage extent fit well to the model developed by Ghadiri and Zhang (2002) for semi-brittle materials. The aspirin particles used in this work are non-spherical but very close to the cubic shape. High speed digital video recording suggests that aspirin particles impact on the target from edges/corners of the particles. SEM analysis of particles after the impact testing shows that the failed surfaces under the ambient conditions are fairly smooth, suggesting possibility of particle failure at the cleavage planes. A reduction in temperature has a marked effect on the single particle breakage behaviour of aspirin. The new surfaces at the sub-ambient conditions are rougher than that in the ambient conditions, suggesting that the particle failure may be not at the cleavage planes under the sub-ambient conditions.
Fine and ultra-fine grinding is of great interest to many industries. Examples of applications are fillers for paper and plastic coatings, pigments, ceramics for abrasive and structural applications, toners for photocopy and printing machines. Besides the direct synthesis of these materials by chemical methods, wet grinding in stirred media mills is a suitable method for the production of sub-micron particles. In the sub-micron size range the behaviour of the product suspension is more and more influenced by increasing particle-particle interactions. Due to these interactions, often spontaneous agglomeration of product particles occurs and the viscosity of the product suspension increases [1] [2]. To overcome this problem the milling suspension has to be stabilized by means of electrostatic, steric or electrosteric stabilization.
In this study, milling of electrostatically stabilized alumina particles in water, sterically stabilized alumina particles in water and ethanol has been accomplished. Preliminary to the milling experiments of sterically stabilized alumina particles in different media, adsorption isotherms of the polymer DAPRAL GE 202 on alumina particles in water, ethanol, 2-butanol and toluene has been explored. These adsorption isotherm curves show that the amount of adsorbed polymer on the surface of the alumina particles in 2-butanol is higher than in ethanol, water and toluene. This indicates that the affinity and conformations of the hydrophobic and hydrophilic parts of the polymer chains are oriented differently according to the nature of the solvents.
The median particle sizes of the milled product particles of sterically stabilized alumina in ethanol is less than the milled product particles of sterically stabilized and electrostatically stabilized alumina F-320 particles in water at the same milling conditions. This is supported by different measuring techniques like DLS, SEM and BET. SEM pictures show a particle size of 50 nm for the milled sterically stabilized particles in ethanol. Mechanochemical changes from alumina to alumina hydroxide have been observed during wet grinding of sterically and electrostatically stabilized particles in water. The amount of the hydroxide phase is the same regardless of the stabilization method. This point is supported by characterizing sample with the DSC method.
In contrast to milling experiments with alumina particles in water no mechanochemical changes occur for sterically stabilized alumina milled in ethanol. In this system the obtained median particle sizes are the result of pure mechanical grinding, because the formation and dissolving of an hydroxide layer is not observed. This fact is supported by different characterizing methods like XRD, DSC and FTIR analyses. And also in this study with the help of Whole Powder Pattern Modelling, the microstructural study of the materials based on the analysis of the X-ray diffraction patterns of the milled samples has been carried out. The particles are breaking at the interface of the crystallites leading to smaller particles until a critical domain size is reached, which we believe is the real grinding limit.
In case of tin oxide the critical domain size or grinding limit is reached at 2 nm. Whereas, the critical domain size of tin oxide obtained from Rietveld and Scherrer methods are 5 and 15 nanometers.
IFPRI Research on Attractive Colloids and Gelling Systems
IFPRI members have selected ‘attractive colloids and gelling systems’ as a possible priority topic within the general area of ‘wet systems’. As a start, a small one-year project was set up, in which 6 leading research groups accepted to collaborate in order to explore/demonstrate the potential, as well as possible routes, for IFPRI research in this domain. Here, the groups report their contributions with experiments on common model systems which where specifically prepared for this project.
The results demonstrate that a wide range of experimental techniques is available that can be applied to gelling systems. Various rheological techniques have been used; they can be applied to all kinds of industrial systems. Other techniques probe the structure and the dynamics of the particles. Some of them operate time-resolved and/or during flow. They include e.g. confocal microscopy and scattering techniques (here light and X-rays have been used), these can be applied during flow. Also micromechanical tools are available, using e.g. optical tweezers.
One of the groups put the results in a theoretical perspective, pointing out how such data could provide a basis for further theoretical modelling of gelling systems. On the basis of the results it can be concluded that IFPRI-stimulated research in this area could provide industrially relevant results at this stage.
This report presents the results of a ten month ongoing research on 3D size and shape characterization of particles. This work has been performed at the GeMMe Laboratory under the responsibility of Prof. Eric Pirard and was supported by a research grant from the International Fine Particle Research Institute. This research has two main aspects, firstly reviewing and validating the existing 3D imaging techniques and secondly developing 3D dedicated image analysis and 3D dedicated size and shape parameters.
3D Imaging Techniques
The first part is dedicated to 3D imaging techniques. A set of powder samples with different physical properties was gathered and tested on three optical imaging techniques and two imaging techniques based respectively on x-ray and electron beams.
- The structured lighting is an optical imager based on the Moiré principle.
- The infinite focus is a reflected light microscope coupled with a digital image processing taking advantage of the finite depth of focus.
- The confocal microscope is based on laser reflection and is also associated with a digital image processing.
All three techniques are surfometric imaging instruments giving the elevation for the entire image. X-ray and electron tomography are imaging from sections techniques. Their scales of investigation are respectively micrometric and nanometric. The advantages and drawbacks of each 3D imaging technique were enumerated regarding particle characterization specifications.
3D Image Analysis and Measurement
The second part of the report is about 3D image analysis and measurement. Programs were implemented to compute size and shape parameters of individual particles. At this stage of the research, volume, surface area, sieve diameter, aspect ratios and convexity index can be calculated for a particle. All the programs were validated on synthetic particles for which the geometry is completely known. Then, they were tested on 3D images of real powder samples obtained from x-ray and electron tomographies.
Ongoing Researches
The last part presents the ongoing researches with intermediate results and the perspectives for the short and medium terms.
The objective of this third year was to collect data from a pilot plant for control testing. A team of 4 visiting researchers joined the existing particle research group in Queensland (Jim Litster, Ian Cameron, Fu Yang Wang, David Page, Rachel Smith) for an experimental campaign: Jonathan Poon and Rohit Ramachandran, both PhD students at Imperial College London, supervised by Charles Immanuel; Thomas Glaser a diplomarbeit student from Stuttgart who stayed in Frank Doyle's group in Santa Barbara for a year; and Constantijn Sanders a post doc in the Doyle group. Thomas recently graduated and Jonathan is writing up his PhD thesis.
The team had 2 objectives while in Queensland:
- Operate the continuous drum granulator to improve the continuous plant model
- Study the chosen formulation in a batch granulator to extract rate constants and improve process understanding for the purpose of improved modeling.
After the experimental phase, the Imperial team returned to London to further analyze the experimental batch results and to improve the 3 dimensional process model (papers 2 and 4 in section 8: Publications Resulting from Support) in collaboration with Frantisek Stepanek. The UCSB team returned to Santa Barbara to analyze the continuous data and experiment with several model predictive control algorithms. The team reunited in November in Salt Lake City at the Annual AIChE meeting to present 2 papers and discuss overall progress.
The pilot plant is now ready to be used and fully controlled by MATLAB: it is a good test bed for controllers. However, Jim Litster moved to Purdue this year, and the future of the pilot plant is unclear. Frank Doyle and Constantijn Sanders started experimental work in collaboration with Hong Sing Tan (Newcastle) and Paul Mort (Cincinnati) both of Procter & Gamble. The aim for this collaboration is to demonstrate an MPC setup on an industrial process.
This report is divided in three sections:
- Batch granulation experiments and modeling
- Continuous granulation experiments and modeling
- Continuous granulation control
Work carried out this year is essentially focussed on 3-D image analysis. New 3-D shape descriptors completing the range of those introduced last year are defined. A dissolution index is first proposed. It gives an information of how morphology influence the dissolution process. We also implement the decomposition of a particle within its maximum inscribed spheres. From this, we extent in 3-D the computation of particle roundness and roughness. In parallel, we define a new method to quantify and to illustrate the uncertainty related to the assessment of particle size distribution using image analysis.
The two year research have allowed the definition of 3-D size and shape descriptors with a range equivallent to the 2-D one. The 3-D descriptors are optimised in terms of sensitivity and robustness. It will constitute practical tools for the future 3-D size and shape characterization. The methodology developped to quantify particle size distribution uncertainty will be useful for practionners using image analysis (either 2-D or 3-D) to determine the number of particles that must be analysed.
On the other hand, we completely finish the evaluation of 3-D imaging techniques regarding particle characterization specification. Future work will be dedicated to the creation of a new 3-D imaging technique adapted to routine 3-D particle characterization. Finally, X-ray micro-tomography and 3-D image analysis are applied on a real case, size and shape characterization of Zn particles used in battery. Thanks to a satisfying 3-D particle dispersion, the size and the shape of 4500 particles are characterized. The comparaison of the results with 2-D image analysis results and prior knowledges gives credence to the 3-D size and shape characterization.
During the third year of the research, we plan to perform 3-D size and shape characterization of severals real samples. This will fully validate the methods implemented. Another field for future research is the quanfication of cristallinity both in 2-D and 3-D. This issue have not been fully resolved even if it is important in pharmaceutic application.
This report addresses the properties of flow in a funnel or hopper. One aspect of this work is to better understand and interpret results using the Flowdex tester. This device is used to characterize flowability, and in particular to characterize that property for various powders of interest to P&G. This work has benefitted from collaborative interactions with Paul Mort of P&G.
The Flowdex tester consists of a cylinder with a small hole at the bottom. The material to be tested resides in this cylinder. The typical dimensions are a half dozen centimeters for the cylinder diameter, and about 10 cm for its height. A release mechanism provides a rapid opening mechanism for the plug at the bottom of the cylinder.
1. Introduction
A proposal of the Swiss Federal Institute of Technology Zurich (ETH), Laboratory of Food Process Engineering (years 4-6) on the topic "Quantitative Analysis of Structural Transformation in Extrusion Processing" has been accepted for support by IFPRI in June 2005 and started in April 2006. The present report covers the time frame from December 06 to May 2008.
Background to Surface Forces
In the first part of this report we provide some background to surface forces in order to explain the main considerations that apply when high concentration of electrolytes are present. That is the electrostatic component of the surface force is greatly reduced and the surface forces and therefore the stability of a system is dependent upon the balance between the repulsive hydration force and the attractive van der Waals forces.
Investigation of Interaction Forces
An investigation of the interaction forces in NaCl solutions at both low, intermediate and high salt concentrations illustrates this point further. Additionally the frictional forces in these systems have been measured in order to test the proposed approach of using the frictional and adhesive forces to characterize the hydration force in systems where the hydration force cannot be easily measured directly. This approach is validated.
New Technique for Solvent Structure Evaluation
The development of a new technique for the sensitive evaluation of solvent structure is described, termed photon pressure AFM. This technique is able to resolve the solvent structure adjacent to a solid material and observe alterations to that structure arising from the presence of cations in solution. It promises to provide exquisite detail on the interaction of ions with mineral surfaces.
Challenges and Future Directions
A major challenge has been to produce mineral surfaces that are sufficiently idealized in terms of geometry and surface finish to employ in these studies. To this end the technique of ALD is very promising. Funds from IFPRI have been employed to apply for a research grant to acquire this instrumentation.