Agglomeration of hydrophobic powders via solid spreading nucleation

Wet granulation of a highly hydrophobic fine powder was investigated to elucidate the granule nucleation and growth processes in systems in which distribution of granulating fluid in the granulating mass is complicated by poor wetting. A mixture containing approximately 70 wt.% (90% by volume) of a micronized poorly wetting powder was granulated in a high-shear mixer using water and the microstructure of resultant agglomerates (granules) was studied using optical and electron microscopy as well as X-ray computed tomography (XRCT). The study revealed that granules are typically spherical or elliptical in shape and range in size from 200 to 500 μm. They are strong and consist of a consolidated powder shell and an empty core. Based on the microstructure, a nucleation mechanism for such a hydrophobic system is proposed. Implications for controlling granule growth and granule properties are discussed. This study demonstrates that well-controlled nuclei formation and subsequent granule growth is achievable in a highly hydrophobic system.     

Evolution and structure of drying material bridges of pharmaceutical excipients: studies on a microscope slide

An experimental procedure was developed to study directly the process by which liquid bridges between small particles in a granule form and solidify. The evolution of saturated solutions of such pharmaceutical excipients as lactose and mannitol in a liquid bridge was studied on a system situated on a microscope slide. Solidification and crystallization kinetics and phase composition during and immediately following bridge formation were observed directly. It was shown that bridges on the microscope slide and in the granule behave very much the same regardless of the different length and diffusion-scales of the two systems.We found that solid bridge formation takes place in several consecutive but distinct steps. In the case of lactose, considerable shrinkage of the initial liquid bridge takes place prior to the onset of crystallization. Further bridge solidification at ambient conditions occurs via simultaneous crystallization and vitrification within minutes. As a result, a “solid” bridge usually contains both a crystalline and a non-crystalline phase, the crystalline phase being predominately α-lactose monohydrate. Most of the non-crystalline phase eventually converts to crystalline β-lactose but the process may take many hours or even days. Results for this process are compared for samples obtained from different manufacturers of commercially available lactose. In the case of mannitol, different polymorphic forms crystallize as the drying/crystallization process progresses. A formed “solid” bridge usually contains several polymorphs of mannitol. The relevance of the behavior of the two model systems (pure lactose and pure mannitol) to a real granulation and tabletting process is discussed.     

Steady states in granulation of pharmaceutical powders with application to scale-up

Theoretical and experimental evidence is given to show that steady states can be reached during agglomerate growth and break-up in high-shear granulation of fine powders. An earlier theoretical model [G.I. Tardos, I.M. Khan and P.R. Mort, Critical parameters and limiting conditions in binder granulation of fine powders, Powder Technology, 94, 245-258 (1997).], based on simple energy-dissipation considerations hinted at the existence of these states at the point where growth is counterbalanced by breakage. Further theoretical evidence is obtained from molecular dynamic simulations of wet and dry particles situated in a constant shear field [I. Talu, G.I. Tardos and M.I. Khan, Computer simulation of wet granulation, Powder Technology, 110, 59-75 (2000).], where the size distribution of initially identical particles, shifts in time to reach a dynamic steady state. Under the conditions of this steady state, the number of breaking agglomerates approximately equals the number of forming ones to yield a time independent final-size distribution.Experimental evidence to support the theoretical findings is obtained during the present research by measuring particle size distributions at line at crucial points during granulation of a typical pharmaceutical powder in a high-shear mixer. In order to reach a steady state, binder addition has to be slow enough and wet massing has to be long enough so that neither has an influence on the final properties of the granules. We show experimentally that if binder is spread properly and homogeneously in the powder and continuous shearing of the wet mass ensures homogeneous, equal growth of the granules, the steady state will only be a function of the total amount of fluid added provided that the shear forces in the machine are maintained constant.These findings are important in that they show that under carefully controlled conditions of binder addition and shear in the mixer, the granulation process is robust and controllable and can, in principle, be scaled up with ease once the powder ingredients and the total amount of binder are fixed.     

Effect of process parameters on the crush strength of granular fertiliser

The granulation characteristics of nitro-phosphate-based NPK fertiliser have been investigated in a bench scale drum granulation unit. It was found that the granulation of the fertiliser took place in the growth regime. Crush strength analysis of the final granulate was undertaken and was correlated with particle size and fractional saturation. The experimental data and analysis in this study indicate that that the rounded, regular-shaped granules produced by granulating with higher liquid phase ratio and fractional saturation result in the granules having stronger bonds between sub-granules and lower porosity.     

Effects of process parameters on granules properties produced in a high shear granulator

Results of a study on the influence of process parameters such as impeller speed, granulation time and binder viscosity on granule strength and properties are reported. A high shear granulator (Cyclomix manufactured by Hosokawa Micron B.V., The Netherlands) has been used to produce granules. Calcium carbonate (Durcal) was used as feed powder and aqueous polyethylene glycol (PEG) as the binder. The dried granules have been analysed for their strength, density and size distribution. The results show that increasing the granulation time has a great affect on granules strength, until an optimum time has been reached. The underlying cause is an increase in granule density. Granules are consolidated more at higher impeller speeds. Moreover, the granule size distribution seems not to be affected significantly by an increase in impeller speed. Granules produced with high binder viscosity have a considerably lower strength, wide strength distribution due to poor dispersion of binder on the powder bed. Binder addition methods have showed no considerable effect on granule strength or on granule size distribution.     

Wet granule breakage in a breakage only high-hear mixer: Effect of formulation properties on breakage behaviour

Wet granule breakage can occur in the granulation process, particularly in granulators with high agitation forces, such as high-shear mixers. In this paper, the granule breakage is studied in a breakage only high-shear mixer. Granule pellets made from different formulations with precisely controlled porosity and binder saturation were placed in a high-shear mixer in which the bulk medium is a non-granulating cohesive sand mixture. After subjecting the pellets to different mixing time in the granulator, the numbers of whole pellets without breakage are counted and taken as a measure of granule breakage. The experimental results showed that binder saturation, binder viscosity and surface tension as well as the primary powder size have significant influence on granule breakage behaviour. It is postulated that granule breakage is closely related to the granule yield strength, which can be calculated from a simple equation which includes both the capillary and viscous force of the liquid bridges in the granule. The Stokes deformation number calculated from the impact velocity and the granule dynamic strength gives a good prediction of whether the granule of certain formulation will break or not. The model is completely based on the physical properties of the formulations such as binder viscosity, surface tension, binder saturation, granule porosity and particle size as well as particle shape.     

Effect of process parameters on the melt granulation of pharmaceutical powders

Co-melt granulation of lactose and PEG was investigated in a fluidised bed granulator. The effect of process parameters such as binder content and binder viscosity were correlated to granulation time and particle size distribution. The experimental data indicated that after initial nucleation the granulation mechanism was dependent upon binder content and binder viscosity. When the binder content was increased above 18% (w/w) de-fluidisation of the bed occurred and granulation moved to the slurry regime. As the process involved the melt granulation of relatively high molecular weight (6-20 k) and thus high viscosity PEG (500-19000 mPa s), it was found that binder viscosity had a significant affect on the granule growth mechanism. Granulation with a binder viscosity of 500 mPa s resulted in granule growth by coalescence, however, an increase in binder viscosity resulted in less coalescence and a lower granule growth rate. Furthermore, the granulation data were characterised by Stokes number analysis.     

Manufacturing pharmaceutical granules: Is the granulation end-point a myth?

The moist agglomeration process by high-shear mixing/granulation, i.e. the wet massing, screening and subsequent drying is a wide spread but critical unit operation. Since for decades formulators are looking for the correct “end-point” of this important process, i.e. when do you need to stop massing or stop with the addition of granulating liquid? What is the correct amount of granulating liquid? A similar situation exists in case of the moist agglomeration in fluidized bed equipment. In the latter case the simultaneous drying of the still moist granules have to be taken into account. Recently a science-based virtual equipment simulator could be developed mimicking the granule size evolution in a fluidized bed granulator during the addition of granulating liquid. For the simultaneous drying the Mollier chart is used. With this virtual equipment simulator it is possible to simulate “crash situations”, i.e. by overwetting or by an incorrect use of the parameter setting. However the determination of the “end-point” depends only on the operator, who desires a certain granule size distribution and a well-defined final moisture content of the batch. Thus the existence of a process intrinsic “end-point” has to be questioned. The same situation can be reported in case of high-shear mixing/granulation based on many years of research. In fact nobody could clearly show the existence of an intrinsic “end-point”. However during the continuous addition of a granulating low viscous liquid a sudden increase in power consumption can be measured, which levels off. Such a measurement depends on the formulation and leads to an “early signal” not to the “end-point”. This signal can be used for a tight control of the granulation process and leads to a low batch to batch variability in the final granule size distribution. The latter is the goal of the PAT (Process Analytical Technology) Initiative emphasizing “Quality by Design”.     

An experimental study of the variability in the properties and quality of wet granules

For wet high-shear granulation, there can be a considerable variability in product quality in terms of the size, binder content, porosity, and appearance. Using the same equipment and feed material, it has been shown that such variability can be reduced by optimising the operating protocol. The associated narrowing of the range of mechanical properties for granules formed using an optimised procedure is exemplified by measurements of a number of parameters such as the coefficient of restitution.     

Behaviour of soft granules under compression: Effect of reactive and non-reactive nature of the binder on granule properties

Granulation is a process where primary powder particles are made to adhere to form multi-particle entities called granules and this is achieved by using a binder. The binders can be broadly classified into two categories viz. reactive (reacts with base powder) and non-reactive (does not react with the base powder). The effect of various parameters related to binder liquid (binder viscosity, addition rate, distribution over the bed etc.) on the mechanism of granulation and physical/mechanical properties of granules is well studied. However, comparison of physical and mechanical properties of granules made via reactive and non-reactive binder using the same base primary particles has not been reported. In this paper, granulation of sodium carbonate primary particles under reactive and non reactive conditions was studied. The mechanical properties of sodium carbonate granules were characterized using single granule compression measurements. The average single granule apparent strength of reactive granules was higher compared to non-reactive granules. It was observed that granules formed using non reactive binder were brittle and showed multiple breakages. However granules made using reactive binder showed single breakage followed by significant plastic flow. In addition, bulk granule compression measurements were also carried out. Known models of Heckel, Kawakita and Ludde, and Adams et al. (developed mainly for pharmaceutical and metal powders) were used to predict mechanical properties of soft detergent granules. The bulk granule compression measurements also showed that reactive granules have higher strength compared to non-reactive granules. However, the absolute values of granule strength obtained from the empirical models were lower than the granule strength obtained from single granule compression measurements.     

Breakage in granulation: A review

The study of breakage in granulation is important from a process and from a product quality perspective. Breakage is considered an important rate process in granulation, and plays roles in granule homogeneity and strength. Understanding this rate process has important implications in the design and control of the granulation process. From a product perspective, the study of breakage has important implications for the subsequent processing, transport, handling and final use of granular products. Breakage behaviour of granules can be a strong signature of the consistency of properties between nominally identical granular products. This paper reviews the study of breakage from the process scale down to the single granule and sub-granule scale, discussing largely experimental results complemented with some modelling results.     

Flowability of moist pharmaceutical powders

The effect of moisture content on four pharmaceutical powders (an active pharmaceutical ingredient (API), Aspartame, Hydroxypropyl Methylcellulose (HPMC), and Respitose ML001) has been investigated. The API and Respitose powders were found to be nonhygroscopic and were tested at their native moisture contents only. The Aspartame was tested at moisture contents of 0%, 2%, 5%, and 8% and the HPMC was also tested at moisture contents of 0%, 2%, 5%, and 10%. Powder flowability was measured using the Jenike shear index, the Hausner Ratio, the Carr Index, and the static and dynamic angles of repose. The flowability of Aspartame increased with an increase in moisture content, which is attributed to the formation of large, round agglomerates. The flowability of HPMC decreased with an increase in moisture content, attributed to the increasing strength of liquid bridges. The Jenike shear index was the only flowability indicator to capture this complex behaviour.     

Applying dry powder coatings to pharmaceutical powders using a comil for improving powder flow and bulk density

A method for applying nano-sized silicon dioxide guest particles onto host pharmaceutical particles (a.k.a. “dry-coating” or “nanocoating”) has been developed using conventional pharmaceutical processing equipment. It has been demonstrated that under selected conditions, a comil can be used to induce sufficient shear to disperse silicon dioxide particles onto the surfaces of host particles such as active pharmaceutical ingredients (API) without significant host particle attrition. In accordance with previous studies on dry coating, the dispersed silicon dioxide adheres to the host particle surface through van der Waals attractions, and reduces bulk powder cohesion. In this work, laboratory and pilot scale comils were used to dry coat pharmaceutical API and excipient powders with 1% w/w silicon dioxide by passing them through the mill with an appropriate combination of screen and impeller. In general, the uncoated powders exhibited poor flow and/or low bulk density. After dry coating with a comil, the powders exhibited a considerable and in some cases outstanding improvement in flow performance and bulk density. This coating process was successful at both the laboratory and pilot scale with similar improvements in flow. The superior performance of the coated powders translated to subsequent formulated blends, demonstrating the benefit of using nanocoated powders over uncoated powders. This particle engineering work describes the first successful demonstration of using a traditional pharmaceutical unit operation that can be run continuously to produce uniform nanocoating and highlights the substantial improvements to powder flow properties when this approach is used.     

Agglomerate strength and dispersion of pharmaceutical powders

This study aims to investigate quantitatively the direct correlation between the mechanical strength of powder agglomerates and their dispersion into aerosols by a dry powder inhaler. Agglomerates of mannitol as a model drug-only formulation were prepared by a rolling method followed by exposure to various relative humidity (RH: 55%, 82%, 86% and 90%). The agglomerate strength was obtained from the compression of single agglomerates at a selected speed rate using an Instron testing machine. The dispersion performance (FPF_Loaded) was determined at flow rates of 60 and 100 l min^?1 using an Aeroliser^® coupled to a multistage liquid impinger. Results showed an inverse linear relationship between the agglomerate strength and the dispersion performance. An increase in strength from 3 to 183 kPa resulted in a significant drop (P<0.05) of 18% in the FPF_Loaded. Agglomerates containing ‘solid bridges’ exhibited higher strength (three to eight times) and lower FPF (5–15%, corresponding to 86% and 90% RH) compared to those containing ‘liquid bridges’. These results have provided direct information on the agglomerate strength and its quantitative relationship with powder aerosol performance.     

Impact breakage of fertiliser granules

Systematic data are presented for the single impact failure of 3.2, 5.3, and 7.2 mm fertiliser granules over a wide range of impact speeds and angles. The probability of failure was found to change only slowly between 90° (normal) impact and 50°, but decreased rapidly below 50°. The probability of failure increased with increasing size of granules. The effect of impact velocity on the mean, median and the proportion of the largest-sized fragments were examined. Two distinct forms of normal impact damage were identified, corresponding to low and high impact velocities, and the mechanisms of failure are discussed.     

Microwave-convective drying characteristics of pharmaceutical powders

Common pharmaceutical excipients and active ingredients, wetted with specific solvents, were dried in a combined microwave-convective system (2.45 GHz, 90 W). The drying curves showed a constant drying rate period, followed by two falling rate periods. Cross-flow air velocity had little effect on solvent evaporation rate in the initial stages; however, an increase in drying rate was observed during the falling rate period. Increasing air temperature increased the drying rate throughout the entire process, with reductions in drying time of up to 78% being observed. Average and maximum sample temperatures were found to decrease on addition of air-flow, the extent of which was dependent on material and operating conditions.     

Fluidised-bed jet milling of pharmaceutical powders

Jet milling is often employed to produce very fine product or to tackle materials that are difficult to mill. This paper analyses particle breakage in a single jet region in a fluidised bed with a view to identify the role of jet hydrodynamics and material properties. By making a number of simplifying assumptions, the particle breakage in the jet can be estimated by coupling a hydrodynamic model of the jet with the kinetics of single-particle impact breakage. This approach works satisfactorily for a number of particulate solids, e.g., α-lactose monohydrate, but poorly for some others, e.g., paracetamol.The underlying cause of this feature is unclear, although it is likely to be due to the hydrodynamic mechanism. In this work, a sensitivity analysis has been carried out which highlights the importance of some of the hydrodynamic parameters on particle flow and breakage in the jet region. A more general model of jet hydrodynamics is needed to predict reliably the particle behaviour in this region.     

The kinetics of the granulation process: Right from the early stages

In this study, experimentation and modelling were carried out to understand the granulation process. This work assesses whether there is a significant difference in the aggregation rate of the wet granulation process between the very early stages and later stages of high shear granulation. Measurements of the size distribution and binder content from the beginning of the process, just after liquid binder addition, were carried out. A population balance model based on two different kernels, the Equi Kinetic Energy (EKE) kernel and two-dimensional population balance equations with a Size Independent (SI) kernel, was applied to the high shear granulation process. It was concluded that the population balance equations with SI kernel best described the aggregation in the high shear granulation process. The value of aggregation rate constant in the early stages is smaller than aggregation kernel in the later stages.     

Flow of granules through cylindrical hopper

The gravity flow characteristics of pharmaceutically important granules were studied in a cylindrical hopper with attachable orifice disk at the bottom. Results indicate that materials property and orifice diameter play key role in determining mass flow rate while keeping environmental condition (temperature) at fixed range. A new dimensionally analyzed equation was developed to predict gravity flow of pharmaceutically important granules. The developed correlation agreed well with the experimental data. Calcium gluconate and lactose were used for preparing granules. Generally, glidant/lubricant materials are added to pharmaceutical granules during tablet manufacturing process, in order to improve physical property of granular material. Hence, the effect of glidant/lubricant on mass flow of granules through hopper was also studied. Magnesium stearate (1.5%) was added as glidant before granulation.     

Morphology and structure characterization of ceramic granules

For the production of brittle materials like technical ceramics it is important to prohibit big defects in the material to achieve high mechanical strength. Due to that already the granule properties are important because they can cause defects in the final product. Characterization and quantification of the granule properties are important steps for improving the production process and properties of the granules for further processing. In this work a novel method for the characterization and quantification of granule morphology, especially sphericity, and internal structure like the ratio of macro pores is provided via digital microscopy. The new quantitative characterization method can be done in an academic and industrial field with appropriate effort. Differences between granules can be characterized, quantified and be used for further development.