Particle Formation

The overall objectives of the project are to model and experimentally verify fundamental aspects of the mechanically actuated granulation processes using binders, with focus directed to surface free energy approaches coupled with the experimental technique of mixer torque rheometry (MTR). Further general aims, building on the surface interaction and MTR knowledge, are to develop predictive relationships which can be applied to address scale up in high shear mixer--Granulators and dry granule characteristics. In all sections of the project, MTR is regarded as a pivotal experimental method.

The surface free energy model utilism, spreading coefficients and interaction parameters between substrate and binder components has been shown in previous reported project (J and spreading phenomena during granulation by mechanical agitation. Both model and a range of representative substrates with selected binders have been evaluated and predictions verified experimentally using mean torque granulation profiles from MTR. This knowledge enables formulation components to be selected in a more rational manner than is current practice, based on sound, physicochemical principles. A key requirement, however, is to link the wet mass torque (rheology) with dry granule properties.

Results of studies probing such relationships are presented. A testing method has been developed which defines a friability index, a measure of the relative ease with which dry granules fragment and fracture in a standardized procedure. For three representative granule formulations, similar trends between mean torque and friability index were observed, indicating that data from MTR for wet massed samples provide an indicator of mechanical characteristics of dry granules prepared from the wet mass. These observations have clear practical and industrial relevance, since, together with selection criteria for formulation components mentioned above, procedures which accommodate both granulation component properties and final granule characteristics are being worked to explain wetting, to couple other practically important dry granule properties to wet mass rheology and material properties is indicated.

In considering scale up issues it was considered critically important to test developed relationships at realistic industrial levels and capacity. This has been achieved through extensive collaboration and liaison with mixer-granulator equipment manufacturers as well as by the generous supply of large quantities of experimental materials by Zeneca Pharmaceuticals. Based on a dimensionless number principle linking power number with three other dimensionless groups (Reynolds number, Froude number, and a fill ratio term for the mixer-granulator--bowl) a scale up function was developed. This enables a master curve for a specified formulation to be generated when granulated in geometrically similar equipment. Consistency of wet mass density and rheological characteristics are key parameters in providing linkage between laboratory, pilot and large scale processes.

These studies, combined with those reported previously, show that in a series of fixed bowl high shear mixer-granulators where geometric similarity is respected, scale up to a selected end point can be predicted over the range 25-1800 litre bowl capacity. This is the first time a predictive scale up strategy has been successfully demonstrated to hold over this full range of capacity range for such mixer-granulators.

In a practical situation for scale up prediction, the sequence of events would be to define the formulation master curve (i.e. power number correlation) using a small scale mixer-granulator, identify the optimal density and rheological consistency for dry granule properties and performance, use these values and mixer-granulator variables to calculate power requirements on large scale equipment, run the process at defined setting, and check product for density and consistency.

This report also details further scale up studies on high shear removable bowl and low shear planetary mixer-granulators. In the former, geometric similarity was not respected in bowl dimensions for the 75L and 600L equipment and, as expected, parallel power number correlations curves were not found. However, for two bowl sizes of a planetary mixer granulator, although limited in scale up factor, the relationship was verified. Further studies are indicated to probe the breadth of application of these rules, considering additional terms for non-geometric similarity and material and formulation factors.

Single and Twin Screw Extruder Based Continuous Processing Techniques

Single and twin screw extruder based continuous processing techniques offer significant advantages in the processing of pastes in comparison to batch mixers. These advantages include high surface to volume ratio and hence better heat transfer characteristics, tailorable mixing behavior, and ability to work with modular elements i.e., flexible manufacturing capabilities. The extrusion technologies also offer the facility to process and compact solids, melt, mix, deaerate/devolatilize, pressurize, react and shape within the confines of a single machine. In this report the fundamentals of the processing of pastes in extruders are reviewed and elucidated using both single and twin screw extruders. The applications of the extrusion technology in various industries are further outlined by summarizing the technical journal and patent literature available.

Methodology and Mathematical Modeling

The review also includes a methodology for proper characterization of pastes and a mechanism and framework for mathematical modeling of the processing of pastes in single and twin screw extruders. One, two and three dimensional mathematical models of the extrusion processes are covered. Important findings and experimental methods to verify the modeling results are discussed.

Conclusions and Future Directions

The review concludes that the basic failing of the available techniques, both in mathematical modeling and experimental studies, involves the inability to incorporate and characterize the microstructure of the paste as it evolves in the extruder. Future directions of research in this area are provided.

Zirconia (ZrO,) particles are one of the most important materials for refractory ceramics. However, commercially available ill-defined powders prepared by milling of calcined agglomerates or by gas-phase reaction of ZrCl, and 0, are normally difficult in preparation of crack-free compact for sintering or need high sintering temperatures above 1700 “C. On the other hand, the monosized amorphous powders of a high sinterability prepared by hydrolysis of the alkoxides are not free from the economical problem of their low productivity (< 0.2 mol dmm3 in final concentration).

The objectives of our project are to develop a new method for preparation of unagglomerated ultrafme crystalline spheres of ZrO, of a narrow size distribution with the mean diameter of the order of ten nanometers or less in large quantities on the basis of the gel-sol technique developed in our laboratory, to elucidate the formation mechanism, and to examine the sintering properties. The standard procedure is as follow.

• Zirconium (IV) n-propoxide (ZNP: Zr(OC,H,),) is mixed with triethanolamine (TEOA: N(CH,CH,OH),) at a molar ratio of ZNP:TEOA = 1:3 in a dry box filled with dry air to form a stable compound of Zr”’ against the exceedingly rapid hydrolysis of Zr4’.
• After aging the solution at room temperature for 24 h, doubly distilled water and NH, solution are added to the solution in order to make a solution of 0.5 mol drnm3 in Zr4’ and 1.0 mol dmw3 in ammonia. In this stage no reaction takes place.
• The resulting solution is then aged at 200 “C for 3 days without stirring in a preheated oil bath to nucleate and grow the zirconia particles.

From the UV spectra of the mixed compounds of ZNP and TEOA in n-propanol and FT-IR spectra in chloroform, it was found that the propoxy groups of ZNP were all replaced by ethoxy groups of TEOA. With the elevation of the internal temperature which took ca. 30 min to reach 200 + 1 “C, hydroxide gel was formed and the nucleation occurred on the gel network in 20 min. The nuclei were grown to fairly uniform particles of ca. 15 nm in mean diameter at the expense of the gel until, finally, the gel completely disappeared in 1 h. In this stage the particles were of a rough surface, but as they were further aged, they became spherical with a smooth surface due to the intra-particle recrystallization. When the aging was prolonged to 72 h, the particles were somewhat grown by Ostwald ripening. It is noteworthy that so-prepared particles were tetragonal ZrO, after 30 min as determined by X-ray diffractometry, even at the rather low temperature, 200 “C, while particles prepared at high pH (-13) in the absence of ammonia or those prepared in the presence of acetate ions at neutral pH (-7) were both monoclinic. Also, high-resolution transmission electron microscopy revealed that the produced particles were mostly single crystals.

From the analysis of growth mechanism it is concluded that the fairly uniform unagglomerated ultrafme particles are nucleated on the gel network of the hydroxide, and grown by dissolution of the gel without significant coagulation owing to the gel network holding each particle. In addition, extensive renucleation is inhibited due to the lowered supersaturation by the formation of the gel precursor.

The so-prepared powders (-15nm and -2.5nm) showed an excellent sinterability, as compared to power prepared by gas-phase reaction (-6Onm) or monosized amorphous powder by hydrolysis of zirconium butoxide at 50 “C (-250nm).

This report summarizes the activities conducted under IFPRI support from November 97 to November 98. The main target of our work is to understand, characterize, and quantify the behavior of powders in the early stages of compaction attendant to the intrinsic properties of the material and the processing conditions. The project involves theoretical, numerical, and experimental components. It is framed within a collaborative effort with concentration on pharmaceutical manufacturing, but the results are relevant to powder compaction in many other industries.

Topics Addressed

• Die pouring (Section 2)
• The reaccomodation process of Region I of the compaction curve (Section 3)
• The mechanics of regular aggregates as they obtain in pre-compaction structures (Section 4)
• The deformation process of Region II of the compaction curve (Section 5)
• An ongoing experimental program aimed at verifying our theoretical and computational results (Section F)

In the Introduction these topics are motivated in the context of the overall goals of the project.

This report summarizes the research activities for the project “Optimal Quality Control of Industrial Crystallizers,” ARR 32 - 01, during the period 1 September 1996 to 31 August 1997. The goal of this project is to develop on-line measurement technology and predictive crystallization models so that advanced on-line crystallizer control can be implemented to enhance precise control of crystal size and shape.

During the current year, we have demonstrated model identification and control strategies to improve filtration of a problematic photochemical of industrial interest. In order to analyze crystal shape as well as size, we have purchased and installed an Olympus BX60 microscope, image capturing hardware, and Image Pro Plus image analysis software. We have further developed our stochastic modelling capabilities so that models with new and complex crystallization mechanisms can be simulated quickly and accurately. We currently can simulate the following mechanisms:

• size dependent nucleation
• size dependent growth
• growth rate and nucleation rate fluctuations
• growth rate dispersion
• size dependent agglomeration

Plans for the next year are to test and commission the new image analysis equipment on a relatively simple system, and identify a model chemical system that is particularly relevant to industrial practice, for which improvements in particle size and shape measurement and control would provide large potential benefit. We will construct a flow cell and circulation loop to monitor the crystal size and shape in real time during crystallization experiments.

This research work addresses the correlation between tht material properties and the processing conditions to the final characteristics of powders and granular materials compacted at low and medium pressures. This correlation is based on the study of the microstructural characteristics and evolution during the compaction process. The materials (powders, granules, binders and lubricants) selected for this study are representative of those used mostly by pharmaceutical and household consumer companies.

The main objective of this study is focused on providing guidelines to improve rationally and systematically the current compaction operations by helping in the optimal selection of particles, binder, lubricants as well as compaction pressures and compaction speeds.

Rutgers University offers a unique environment, to conduct, this investigation. This university provides first hand access to current research on fundamental aspects relat,ed to compaction such as granulation, milling, mixing and blending, within a co- herent and collaborative effort with concentration on Pharmaceutical Manufacturing. Also, it provides the state-of the-art in characterization techniques and computational facilities, and ad-hoc testing facilities such as the Compactor Simulator Laboratory.

This report includes the current work since the beginning of the grant in October 1996 (some results were reported previously informally).

EXECUTIVE SUMMARY

This report presents a use of an electrical capacitance tomography (ECT) system to study the dynamic behaviour of various modes of fluidization. The results showed that the system can provide instantaneous information on solids distribution for a wide range of gas-solids flow patterns. An application of the ECT system is illustrated here by measurements of the instantaneous behaviour of a fluidised bed. The experimental programme focused on measuring both discrete and continuous parameters which characterise the interaction between the gas and emulsion phases. The first included bubble sizes, their velocities and time scales characterizing a bubble coalescence growth. Solids cross-sectional distribution at various positions in a riser and in a dip leg were measured for a wide range of superficial gas velocities and circulating solids mass fluxes. Instantaneous images showed a flow morphology which is crucial for modelling the heat transfer process. This included details of wall coverage by solids clusters and thickness of the annular layer.

Part of this project was concerned with the development of both hardware and software for capacitance tomography. During the project the software was extended by including a new iterative algorithm and a computer aided procedure for sensor design was developed. As a result the sensors can be designed in different ways to meet differing industrial needs. The data from the ECT system can provide, for the first time, the continuous and on-line information required by the control loop.

The software developed provides the data to the control loop from each individual electrode or from the whole set of electrodes and can be used in in two ways. The first includes images showing solids distribution within a pipe cross-section and the second is based on the statistical analysis of data gathered by a multiplicity of sensor. This can include averaged values, standard deviation and other parameters based on Fourier analysis like spectra or correlation functions. The choice of one of these parameters depends on the particular aim which can be defined by the industrial user.

Granulation is a size enlargement process generally involving the agglomeration of particles often with liquid binders using specialised processing equipment. The dried granules in some cases, are further processed into compacts or tablets. Whilst widely used throughout industry the granulation process and related aspects, such as formulation design and scale-up procedures, are in general inadequately described.

With increasing industrial need for directed formulation design linked to prediction, of processing performance and efficient scale-up of granulation, specific project objectives were defined, and several inter-related study areas identified with a view to providing much needed insight to address these issues. The research areas were the physico-chemical interactions between components to aid directed formulation design, the rheology of the wet-mass during granulation for process evaluation knowledge, and scale-up strategies for specific types of processing equipment. Within the project remit of granulation by mechanical agitation, high shear mixer-granulators were selected for the scale-up studies. This project has successfully researched several key aspects in these areas, generated valuable information and knowledge, and developed practically useful guidelines for industrial application.

From an extensive literature review, it was recognised, that the physicochemical interactions between granule components, whilst critically important during granulation, were poorly understood. Through a surface free energy (SFE) approach to derive a group of spreading and interaction coefficients, a model has been developed to predict the nature of material interactions which direct the structure and properties of granules. The model was tested with model systems using both physical evaluation and mixer torque rheometry, then successfully applied to a number of experimental particulate substances of diverse chemical composition granulated with two typical polymeric binders - HPMC and PVP. This procedure thus provides the basis of a rational approach to material selection in granule formulation design.

Zirconia (ZrO,) particles are one of the most important materials for structural ceramics used at high temperatures. However, commercially available ill-defined powders prepared by milling of calcined agglomerates or by reaction of ZrCl, and O, in gas phases are normally difficult in preparation of crack-free compact for sintering or need high sintering temperatures above 1700 degrees C. On the other hand, the monosized amorphous powders of a high sinterability prepared by hydrolysis of the alkoxides are not free from the economical problem of their low productivity (< 0.2 M in final concentration).

The objectives of our first project are to develop a new method for preparation of unagglomerated ultrafine spherical particles of a narrow size distribution with the mean diameter of the order of a few ten nanometers or less in large quantities on the basis of the gel-sol technique developed in our laboratory, to elucidate the formation mechanism, and to examine the sintering properties. The “gel-sol method” essentially differs from the popular sol-gel method. The standard procedure for the preparation of ZrO, particles and their growth mechanism have already been reported in detail in the annual report of the last year (ARR 31-02).

Executive Summary

This is the first annual report for the IFPRI project 37 Powder-Binder Agglomeration. The aims of this project are to:

• Define the controlling groups for each of the following classes of granulation process (1) binder dispersion, wetting and nucleation (2) consolidation and growth (3) attrition and breakage;
• Use appropriate models to link these groups to key product attributes eg. size, size distribution, density (porosity);
• In each case, qualify the models for the effects of complicating powder-binder interactions eg. dissolution, reaction, drying.

The report summarises progress in both wetting and nucleation, and consolidation and growth. Drop penetration time and dimensionless spray flux are proposed as two controlling groups for wetting and nucleation. The drop penetration time, which depends mainly depends on formulation properties, is a promising tool for studying nucleation processes. Preliminary studies show that penetration time varies widely, particularly with binder viscosity. Combining the existing models for drop penetration (Denesuk, 1993) and nuclei growth (Schaafsma, 1998b) will create a more complete picture of nuclei formation and morphology, and the effect of material properties. Ex-granulator experiments demonstrated different nucleation regimes from drop-controlled nucleation to caking. In the drop controlled regime, each drop forms a single nucleus and the nuclei distribution can be controlled by controlling the drop size distribution form the spray. A single dimensionless group, the dimensionless spray flux, characterises the main process parameters with respect to spraying. An experimental plan and methodology for studying wetting and nucleation is presented.

For granule growth and consolidation, a regime map of granule growth behavior is proposed based on granule deformation during collision and the granule liquid content measured as the maximum pore saturation. The granule deformability on collision is represented by a deformation number, which is a ratio of granule impact energy to the plastic energy absorbed per unit strain. Granule growth regimes such as steady growth, induction, nucleation, crumb, and slurry are defined. This regime map qualitatively explains the variations in granulation behavior. Laboratory drum granulation experiments were used to test the regime map. Increasing granule yield stress by decreasing particle size and increasing binder viscosity caused the system to move from steady growth to induction behavior as predicted by the regime map. Preliminary validation with literature data was also encouraging. More work, however, is required to better quantify the boundaries between different growth regimes and to investigate the effect of process agitation intensity. This regime map has great potential to help design and control granulation systems, because it is based on properties of the powder/binder system that can be measured or estimated without performing any granulation tests.