Size Reduction

Nanotechnology applications in the pharmaceutical, materials and chemical industries has renewed interest in the use of wet grinding in stirred media mills for the production of nanoparticles. However, challenges arise in the production of sub-micron particles that are, in part, due to colloidal surface forces influencing slurry stability and rheology. As often observed in the literature, a grinding limit in the range of 0.5 µm is reached despite high energy inputs and aggressive milling conditions. Furthermore, the product size can even increase with increased energy input, a seemingly counterintuitive result that is attributed to aggregation of fine particles during the milling process. By producing particles smaller than a median particle size of 1 µm a steady state between breakage and agglomeration exists in the milling process. This equilibrium is controlled by interparticle interactions as well as the milling conditions. In this report we demonstrate that this steady state particle size is independent of the feed particle size and can be reached by agglomeration of small particles as well as by real breakage of large particles.

Furthermore, we extended our studies to non-aqueous systems, because of the high industrial demand on nano particles in organic solvents. Milling studies with steric and electrostatic stabilization showed that the size of the particles milled in organic solvents is conspicuously smaller than the size of the particles milled under the same conditions in the aqueous phase. However, ions dissolved from the media wear and impurities in the suspension can destabilize the suspensions if the electro-static stabilization mechanism is chosen. This is not the case for steric stabilized systems.

An important question is whether the mechano-chemical activation which was observed in aqueous media is crucial to obtain nano-particles. Differential Scanning Calorimetry (DSC) and X-ray difraction (XRD) measurements showed no mechano-chemical changes during milling in ethanol and toluene. In the aqueous phase the stabilization mechanism has no influence on the amount of hydroxide phase. A protecting polymer cover around the particles does not prohibit the mechano-chemical changes.

The production of submicron and nanometer sized particles by wet grinding in stirred media mills was investigated. Small grinding media and, thus, small stress energies are required for an effective grinding, i.e. for a minimization of the specific energy. Moreover, the relations, particularly the so-called stress model, derived for grinding of coarser particles in stirred media mills are also valid for grinding of nanoparticles. However, for the production of alumina particles with sizes below approximately 200 nm an effective stabilization of the particles against agglomera-tion is necessary, especially, if yttrium-stabilised zirconium oxide grinding media are employed. An electrostatic stabilization with anorganic acids is effective if the surface charge is near the one of neutral chloride. This behaviour can be described by the so-called Hofmeister series. In case of organic acids the hydrocarbon chain should be as short as possible.

Beside a high grinding efficiency a low product contamination by grinding media wear is important. As known from grinding coarser particles grinding media wear at different operating conditions can be described by a so-called wear energy. Moreover, the grinding media wear can be minimized by optimizing the suspension viscosity and, thus, by adjusting the pH-value: If the viscosity is too low, the collisions of the grinding media are not damped and, thus, the wear is high. If the viscosity is too high, high concentrations and packing of the grinding media in front of the separation device occur causing high wear of the grinding media. Besides optimizing the viscosity the product contamination can be minimized by using coarse alumina particles as grinding media. First results show that nanoparticles can be produced by such an autogenous grinding process.

Besides the investigations on nanogrinding the mechanism of capturing particles between two grinding media were investigated using a specially designed model apparatus. Among others the measurements with this model apparatus showed that adhesion of product particles at the grinding media surface and decreasing product particle sizes increase the number of particles caught at one stress event.

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.

Nanomilling is of great interest to many industries. Anosize particles are gradually being incorporated into a broad range of application fields, examples are fillers for paper and plastic coatings, pigments, ceramics for abrasive and structural applications, toners for photocopy and printing machines, pharmaceuticals. Advanced devices include electronic packages, ultra-thin-film optical devices, advanced fuel cell catalysts, molecular conductors, and biochips. 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. The main advantage of using wet grinding in stirred media mills over alternative grinding methods is the possibility to apply higher power densities necessary to produce very fine particles [1].

The overall aim of the project is to elucidate the effect of feed material properties, mill dynamics and prevailing environment on milling of organic materials. This requires the use of a multi-scale approach covering molecular scale, to single particle scale and the bulk scale.

The recently concluded IFPRI programme (IFPRI FRR 52-03) addressed the effect of material properties on single particle breakage and bulk milling, which enabled establishment of a relationship between the single particle properties and the bulk milling. The main aims of this follow-up programme are to understand single particle breakage behaviour from the molecular scale, and to bridge the gap between the properties and behaviour at the single particle scale and those at the molecular scale. The principle methodology used in the follow-up programme is to investigate the single particle breakage behaviour as a function of temperature, humidity and strain rate. The work over the past 12 months has led to the following results:

• Effect of temperature was investigated at a relative humidity of ~30%. The results show that the extent of impact breakage of aspirin particles increases with increasing temperature, whereas little effect of temperature is seen for sucrose.

• Effect of humidity was studied at the ambient temperature (20oC). The results show no clear influence of the relative humidity for sucrose and aspirin particles on their single particle breakage behaviour.

• Effect of repeated impacts on single particle breakage (fatigue tests) was investigated using sucrose at the ambient temperature and ~30% relative humidity. The results show that the extent of breakage increases first with increasing number of impacts, reaches a maximum after a certain number of impact, and then followed by a slow decrease with a further increase in the number of impacts. The impact velocity has a great effect on the maximum value of the cumulative extent of breakage; a higher impact velocity gives a higher peak breakage extent; however, the number of impacts needed to reach the peak breakage extent also increases with increasing impact velocity.

Despite considerable efforts that have been made in the past with regards to milling, no single model has the capability to predict the milling behaviour of materials. The objective here is to further understand the role of material properties in breakage, under the influence of temperature. The methodology is to characterise the mechanical properties of materials at the single particle level using quasi-static nano-indentation and dynamic impact tests. The effect of temperature on the breakage behaviour of these materials is investigated under dynamic impact conditions and the effect of temperature on mechanical properties indirectly inferred. Furthermore, dynamic impact breakage is compared to bulk milling behaviour, under the influence of temperature. A widely used pharmaceutical active ingredient, Aspirin, and two excipients sucrose and -lactose monohydrate (-lm) are chosen as model materials. All three are regarded as semi-brittle materials with different mechanical properties.

EXECUTIVE SUMMARY

Milling is a common unit operation deployed in many industrial sectors for particle size reduction. In this project, we aim to develop a robust methodology to link material grindability with particle dynamics in a mill in order to provide an innovative step change in mill fingerprinting and optimisation. This involves characterising the stressing events that prevail in a milling operation and establishing material grindability in the context of the stressing events. The material grindability will require a detailed study of the fundamental fracture and breakage mechanisms of individual particles under different loading regimes, and how they relate to the mechanical properties and the final size distribution. This will provide the fundamental scientific basis for developing appropriate grindability tests capable of analysing particle breakage subjected to particle impact, compression, shear and abrasion etc. pertaining to a milling process, which in turn will provide the basis for an improved particle breakage model calibrated against defined grindability.