Granulation of hydrophobic powders

Granulation of hydrophobic powders is frequently required in the pharmaceutical industry. The structural complexity of new drug molecules mean that is increasingly common for entire classes of drug compounds to be highly hydrophobic. This creates considerable difficulty in understanding, controlling and trouble-shooting these industrial granulation processes.There have been many recent advances in granulation theory. Essential to this theory is that wetting and spreading of the fluid through the powder particles is a prerequisite for good granulation. The possibility of a fine, hydrophobic powder spreading over the surface of the liquid during nucleation has been identified theoretically based on surface chemistry and as a potential nucleation mechanism. Recently, investigation confirmed that nucleation can occur by spreading of the sub-micron particles around the template drop to form a “liquid marble”. The hollow granule structure formed by the “solid-spreading” nucleation mechanism suggests the possibility of using the controlled, open granule structure to manufacture designer structured agglomerates with advantageous properties, including controlled granule structure and size and excellent ideal flow and handling properties. This paper describes single drop solid-spreading nucleation experiments where single fluid droplets are placed onto loosely packed powder beds of hydrophobic powders and the formation of the powder shell observed. Experimental results and observations for some model systems are presented, together with a preliminary framework for liquid marble formation.     

Foam granulation: Liquid penetration or mechanical dispersion?

There have been significant advances in the understanding of wet granulation processes. Foam granulation is the latest development and an emerging area of interest for pharmaceutical manufacturing.Single foam penetration experiments were carried out on static powder beds, followed by short-nucleation experiments (where nuclei are formed by a nucleation-only mechanism) and full foam granulation experiments (where nucleation, growth and breakage are occurring simultaneously). All experiments were performed with lactose monohydrate powder using a 5 L high shear mixer–granulator. The foam penetration/dispersion behaviour was examined and the granule size distributions were investigated as a function of foam quality (83–97% FQ), impeller speed (105–515 rpm) and wet massing period (0–4 min).Nucleation in foam granulation is postulated to undergo either “foam drainage” or “mechanical dispersion” controlled mechanisms. For “foam drainage” mechanism, the foam penetrates the powder bed to form coarse and broad granule size distributions. For “mechanical dispersion” mechanism, the wetting and nucleation conditions are governed by the powder mixing conditions and similar granule size distributions are produced. Regardless of the mechanism, the initial wetting and nucleation behaviour controls the initial nuclei size distribution, and this initial distribution is retained in the final granule size distribution. This work demonstrated the critical importance of the nucleation and binder distribution in determining the granule size distributions for foam granulation process.     

Fluidized bed granulation of a microdose pharmaceutical powder

The influence of some process variables on the size distribution and drug content of granules prepared in a fluidized bed has been investigated using a powder mix of 5% phenylbutazone in lactose. Using a 10% aqueous solution of polyvinylpyrolidone (PVP) as the granulating agent, granule size increased with volume of solution and rate of spraying and decreased with increasing temperature. In addition, as granule size increased, so did the homogeneity of phenylbutazone distribution in the granules. This was explained on the basis of increased wetting of the large granules which then pick up fine drug particles. Also, large granules are able to break up phenylbutazone agglomerates by a “ball milling” action. When two successful batches were compressed, the tablets produced complied with official and non-official standards. Under the conditions exmployed, granulation using a 10% alcoholic PVP solution was unsuccessful.     

Quantitative proof of liquid penetration-involved granule formation in a high shear mixer

Previous work of the authors [K. van den Dries, H. Vromans, Qualitative proof of liquid penetration-involved nucleation in a high shear mixer, Eur. J. Pharm. Sci. 58 (2004), 551–559.] revealed that the granule formation in a high shear mixer depends on a balance between the rate of liquid penetration and binder dispersion. Three distinct nucleation mechanisms could be qualified; (I) granule formation by liquid penetration followed by granule breakage or (II) absence of granule breakage and (III) complete dispersion of the binder liquid. The aim of this study was to quantify the mechanisms of granule formation. A substandard amount (1.5% w/w) of binder liquid was added to a lactose mixture, while the mixer was operating. The powder mixture was frozen with liquid nitrogen after 15 s and analysed by sieving. The results show that, despite the minimal liquid amount, granules are formed under most conditions. It is argued granules are being formed by a liquid penetration process. These freshly formed granules are broken down at low viscosity (< 1 Pa s) and remain intact at higher viscosity (> 1 Pa s). Only at extreme conditions (viscosity > 30 Pa s) hardly any granules are formed. In this case penetration of the liquid becomes practically impossible and the binder is completely dispersed. A model based on the processes of liquid penetration, binder dispersion and granule breakage, confirms the observed nucleation behaviour. It is conclusively shown that an increase in viscosity results in a transition from nucleation mechanism I→II→III.     

Strength and morphology of solid bridges in dry granules of pharmaceutical powders

This is an experimental study of the tensile strength of solid bridges between primary particles comprising granules of lactose or mannitol. We report on two systems: granules prepared with ethanol granulating solutions, in which the base powders were at most sparingly soluble, and aqueous granulating solutions, in which the base powder solubility was large. Both systems were studied with and without hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP) or surfactants (Triton-X100, sodium lauryl sulfate or polysorbate 80) added to the granulating solution. The interparticle bridge strength was determined from the granule crush strength with a simple model that assumes that solid bridges form by evaporation of solvent from liquid bridges that maintain their shape during drying.Lactose granules prepared with pure ethanol are very weak, with crush strength comparable to that predicted by JKR theory, consistent with its negligible solubility. Mannitol, which is sparingly soluble, forms granules with bridge strength similar to the theoretical (Griffith) strength of a pure mannitol. Addition of HPC or PVP to the granulating solution produces bridges with strength comparable to that of pure polymer films. In comparison, the behavior of granules prepared with aqueous granulating solutions was much more complex due to the high saturation concentration of base powder. Granules produced with pure water had bridge strength approximately 20% of the theoretical strength. Addition of HPC or PVP to lactose granules increased the bridge strength modestly, but the strength was much smaller than that of the corresponding pure polymer films. Addition of HPC to mannitol granules had little effect on bridge strength, while PVP reduced bridge strength by approximately 30%. Addition of surfactants to the granulating solution also reduced dry bridge strength. These results reflect the complex microstructure and resulting mechanical properties of dry bridges produced by coprecipitation of the sugars and polymers (or surfactants).     

Foam granulation: Binder dispersion and nucleation in mixer-granulators

Traditional wet granulation method involves spraying of liquid binder onto a moving powder bed to granulate the powder particles in the granulator. A new alternative method of wet granulation has been developed where foam delivery of binder is used to granulate the powder particles.This study investigated binder distribution in wet granulation and focused on the nucleation stage, where nuclei are formed during the initial binder distribution. Nucleation experiments were used to study the formation of nuclei by the foam and spray delivery methods in a high shear mixer-granulator. The distribution of foams on a dynamic powder bed were also investigated by filming small portion of foams as they penetrated into moving powder beds under different powder flow conditions in a high shear mixer-granulator.Nucleation experiments in this study show that foam delivery tends to create a narrower nuclei size distribution during the early stage of wet granulation process compared to spray delivery at the same processing conditions, demonstrating the potential of foam granulation in achieving improved binder distribution. For foam delivery, the nuclei formation is influenced by the foam properties and powder flow conditions in the granulator. The experiments show that the narrowest nuclei size distribution is obtained by granulating with high-quality foam and intensive powder mixing conditions. Coarser nuclei are formed when low-quality foam is dispersed in a less intensively agitated powder. The interactions of foam quality and the powder flow pattern are discussed and two distinct wetting and nucleation mechanisms are proposed: (1) under bumping flow, a low-quality foam tends to induce localised wetting and nucleation. The wetting and nucleation is “foam drainage” controlled. (2) Under roping flow, foam will be dispersed by the motion of the agitated powder. The wetting and nucleation is “mechanical dispersion” controlled.     

Formation of hollow granules from liquid marbles: Small scale experiments

Research into formation of hollow granules from liquid marbles is an emerging field in hydrophobic granulation. A liquid marble is formed by a network of self-assembled hydrophobic powder around a droplet, and this paper investigates the conditions required for forming hollow granules from a liquid marble precursor.Single drops of fluid were produced using a syringe and placed onto loosely packed powder beds of hydrophobic powders. Liquid marbles formed from several powder/liquid combinations were dried at several conditions to investigate the drying conditions required for formation of a stable hollow granule.The formation of stable hollow granules was found to depend on drying temperature and binder concentration. For HPMC and PVP binder, formation of hollow granule is proportional to binder viscosity and for HPC binder, this relationship is constant. Different combinations of powder and binder at both drying temperatures - 60 °C and 100 °C - had mixed success rates in forming hollow granules, but generally the success rate was improved by using higher drying temperatures, smaller particles or higher viscosity binder fluids.     

Origin of profound changes in powder properties during wetting and nucleation stages of high-shear wet granulation of microcrystalline cellulose

The aim of this work was to understand the evolution of powder tabletability and flowability during wetting and nucleation stages of high-shear wet granulation (HSWG). Microcrystalline cellulose (MCC) was granulated with water using a high-shear process. Granule morphology, surface texture, size, porosity, specific surface area, tabletability, and flowability were characterized. MCC granulated with 5% water showed no change in tabletability but significantly improved flowability, corresponding to smoother surfaces and lower surface area. From 5% to 25% water, tabletability decreased by 1/4 but flowability remained unchanged. Granule shape and porosity remained unchanged while surfaces were smoothened, leading to decreased surface area. From 25% to 35% water, MCC granules became more round. There was another sharp decrease in tabletability but powder flowability remained unchanged. Forty-five percent of water led to more particle rounding and commencement of nucleation, which only slightly impacted tabletability and flowability. From 0% to 45% water, granule size decreased slightly and could not explain the significant changes in powder tabletability and flowability. Deteriorated tabletability was instead caused by surface smoothing, granule densification, and granule rounding. Enhanced powder flowability was caused mostly by surface smoothing with granule rounding as a minor contributor.     

Advanced 3D and 4D microstructure study of single granule formation for pharmaceutical powders using synchrotron x-ray imaging

Monitoring the microstructure of the granule in the wet granulation process could play a decisive role in obtaining high-quality granules. Due to the complex, fast and opaque nature of wet granulation, it cannot be captured by conventional methods. In this study, synchrotron x-ray imaging was employed for the first time to investigate the internal real-time pore evolution during the granule formation process, based on the single droplet impact method. It was found that granules from coarser and more homogenous powders experienced a higher rate of pore evolution during nucleation with a more uniform pore distribution. Dynamic wetting studies showed the granule formation mechanisms, the crater mechanism was found for most binary mixtures with 50 wt. % excipients. According to the physical tests, the granules with lower porosity and finer pores exhibited higher hardness and a slower dissolution rate.     

Effects of granule density on strength and granule related defects in zirconia

A suspension of zirconia powder (TZ3YSE) with a solids loading of 50 vol% was prepared by ball milling. Binders were added and some of the suspension was diluted to 40, 30 and 20 vol% before freeze granulation was performed. A spray dried material (TZ3YSEB) was used as a reference. The pore size distribution of the different granules was evaluated and from the microstructure it was shown that inhomogeneities were present in both the freeze granulated as well as in the spray dried granules. In addition, the density, microstructure as well as the strength of sintered materials prepared from the granules were studied. The results showed that a high green density or sintered density was not sufficient in order to achieve a high strength material. It was further shown that the strength was significantly influenced by the granule density and not by the inhomogeneities found in the granules.     

Drop penetration time in heterogeneous powder beds

Wet granulation is a technique in which enlarged particles or ‘granules’ are produced from the coalescence of fine particles, with the intention of improving the powder properties. High shear granulators are often used to carry out the granulation process where the powder mass is agitated in a vessel by mechanical means while liquid is sprayed from above onto the powder bed surface. When the binder droplets impact the powder surface, the drop penetration time of the droplet into the powder is important for uniform binder dispersion and the prediction of the formation of granule nuclei from the nucleation map, which depends on the dimensionless spray flux. Previous studies on the drop penetration time were carried out on predominantly hydrophilic powder beds. Although this gives a good prediction of the nucleation behaviour in granulation, it does not reflect the condition where hydrophobic drugs are used in the formulation without surfactants. This paper aims to look at the effects of powder bed hydrophobicity on the drop penetration time.Single drop nucleation experiments using a syringe and a small powder bed were carried out on varying ratios of salicylic acid and lactose powders to study the kinetic of drop penetration. As expected, the drop penetration time increased as the proportion of hydrophobic component increased in the powder mixture. However, long drop penetration times were observed for low degrees of drug loading, showing that hydrophobicity strongly influences the drop penetration time. The wettability of the powder mixture also has a pronounced affect on the granule properties in which the hydrophobicity of the powder mixture is proportional to the granule strength and inversely proportional to the granule size. These findings have important implications in terms of the design of the granulation process where conditions of minimum spray flux or efficient mechanical forces are recommended to produce a more uniform granulation batch.     

Influence of the interaction between binder and powders on melt agglomeration behavior in a high-shear mixer

The purpose of this study was to investigate the effects of the different surface properties of powders on granular agglomeration in a high-shear mixer. Polyethylene glycol 6000 (PEG 6000) was used as the melting binder. Three different powders, with mean granule sizes of 75-150 μm were used as the raw materials: calcium carbonate, calcium sulfate, and sodium carbonate. The wetting properties of the raw materials were measured with a contact angle instrument. The results indicate that the speed at which the droplets sink into the powder bed and the contact angle of binder droplets on the powder surface play important roles in determining the progress of the agglomeration process. Several types of agglomeration were found: a slurry state, heterogeneous nucleation, snowballing, and induction growth behavior. Heterogeneous dispersion leads to induction behavior and subsequent growth, but a homogeneous dispersion leads to little or no nucleation and growth of agglomerate size.     

粗糙疏水表面冷凝形核特性研究

为了研究疏水基底粗糙度对形核特性的影响规律,采用腐蚀及修饰的方法得到具有不同粗糙度的疏水基底,通过对基底表面粗糙度因子的计算和表观润湿角的测量,考察了基底粗糙度对基底表面水的表观润湿角的定量关系;在制备的粗糙基底上进行了冷凝蒸汽形核实验,利用统计方法得到基底粗糙度因子与冷凝液滴数量的关系。结果表明:基底微观形貌对水在基底表面的表观润湿性和形核特性具有显著影响,对于疏水基底,随着基底粗糙度的增加,水滴在其表面的表观润湿角增大;相同的基底过冷度下,越粗糙的基底表面蒸汽冷凝形核点越少。分析认为,基底微观形貌通过影响液胚在其表面的表观润湿角,进而改变异质形核功,造成了粗糙基底表面形核特性的改变。实验现象与基于Wenzel模型的粗糙基底异质形核理论取得了一致。     

Breakage of drop nucleated granules in a breakage only high shear mixer

Wet granule breakage is a significant mechanism, particularly in high shear mixer granulation. This paper presents a study of the wet breakage mechanism using a Breakage Only Granulator. Granules with varying powder and liquid binder properties were created using single drop nucleation. These granules were inserted in a Breakage Only Granulator, a high shear mixer granulator with non-granulating cohesive sand as the bulk medium. Two different impellers were used at impeller speeds of 500 and 750 rpm. An 11° beveled edge impeller was used to create both impact and shear in the granulator, and a flat plate impeller was used to minimize impact and maximize shear in the granulator. The fraction of granules which broke during the granulation process was used as a measure of granule breakage within the granulator. These results were compared with Stokes deformation numbers calculated using mean dynamic peak flow stresses measured in unconfined uni-axial compression tests. Results for the beveled edge impeller blade show increasing breakage with increasing Stokes deformation number. Significant breakage was observed at high Stokes deformation number. Increasing impeller speed increased the magnitude of breakage. The Stokes deformations number appears to be a reasonable predictor for granule breakage within the granulator. Results for the flat plate impeller show very little breakage at 500 rpm, and significant breakage for only one formulation at 750 rpm. This suggests that either impact is dominant over shear for breakage within the granulator, or that the two impeller designs give substantially different collision velocities in the granulator. The impeller speed, type and shape have a profound effect on granule breakage in high shear mixer granulators.     

Progression of wet granulation in a twin screw extruder comparing two binder delivery methods

The two available wetting methods for twin screw granulation, namely foam delivery and liquid injection, were studied in detail by examining granule development along the screws as powder formulation and screw design were varied. Granulation profiles were determined by particle size analysis of samples along the screws collected using the “screw pullout” technique. Analysis of the particle size and porosity of produced granules revealed only minor differences between the two methods of wetting despite the larger dropsize of liquid injection compared to foam delivery. Excipients like microcrystalline cellulose or hydroxypropyl methyl cellulose with poor spreading properties, quantified by their specific penetration time and nucleation ratio, made the differences more apparent. The general similarities in granulation independent of wetting method implied that binder dispersion in an extruder was dominated by mechanical dispersion. Screw design (i.e., location of kneading block) had the dominant effect on the granulation process in this study. © 2014 American Institute of Chemical Engineers AIChE J, 61: 780–791, 2015     

Mapping of regimes for the key processes in wet granulation: Foam vs. spray

The evaluation of foam and spray granulation mechanisms and their performances in achieving uniform liquid distribution in a high‐shear mixer‐granulator is presented. A regime map is presented to describe the granulation mechanisms for the foam and spray systems. Foam and spray granulation are shown to successfully create granules of well‐distributed moisture at the end of wet massing despite there was a deviation from the theoretical moisture content at the end of binder addition. In the wetting and nucleation regime, spray granulation involves drop penetration nucleation outside of the drop‐controlled regime, whereas foam granulation operates favorably in the mechanical dispersion regime. For foam granulation, mechanical dispersion produces more uniform granule‐size distributions below the overwetting limit. Spray granulation exhibits steady granule growth, whereas foam granulation shows induction granule growth followed by rapid granule growth. The regime map provides a basis to customize formulations and compare the different foam and spray granulation mechanisms. © 2013 American Institute of Chemical Engineers AIChE J, 59: 2328–2338, 2013     

Stress measurements in high-shear granulators using calibrated “test” particles: application to scale-up

Granulation is a process by which fine powders are agglomerated into larger particles using a liquid binder. In high-shear granulation the powder–binder mix experiences intense agitation inside a mixing vessel as binder is dispersed and granules form and strengthen under the influence of shear and compacting forces in the device.

It is an implicit assumption that in a “high shear” mixer, large forces are transmitted to the powder and this results in a short and efficient granulation process. Owing to these desirable characteristics, high-shear granulation was adopted by several industries including pharmaceuticals and detergents where the process is used almost exclusively. In the work reported here, we attempt to measure shear forces in a moving powder inside a mixer-granulator. The method is based on previous numerical simulations [Powder Technology 110 (2000) 59] and experiments [Journal of Fluid Mechanism 347 (1997) 347] where we showed that at equilibrium between stresses in the mixer and the yield strength of the particles, granules attain a characteristic elongated shape. The measuring method adopted is indirect in the sense that pellets with well-defined mechanical properties were used to interrogate forces inside the granulating vessel at the point where they attain their characteristic elongated shape. We subsequently used the condition of equal shear forces in the device as a scale-up criterion so as to preserve the magnitude of stresses at both scales and thereby to expose forming granules to similar forces in both the small- and large-scale machines.

We found that shear forces in a “High-Shear” mixer-granulator with a vertical axis (Fielder) are actually not always high. The mixer has the potential to produce high shear forces but these forces are transmitted to the powder mass only if the powder is sufficiently cohesive or becomes cohesive due to binder addition. Shear forces in the granulator are strongly wet-mass-dependent and they increase rapidly as soon as a “granulation limit” is achieved, i.e., at the point where granules start to form in the shearing powder mass. We found that granulators with geometrically similar bowls can be scaled to generate comparable shear forces by decreasing the impeller rotational speed of the large machine by the factor (D/d)ⁿ, where D and d are the impeller diameters of the large and small machine, respectively, and n is a scaling index that depends on impeller geometry but not on wet mass properties. For the equipment studied in this work, the coefficient n was obtained as 0.80<n<0.85. We also propose an improved granulation process in which dry powders are pre-wetted before introduction into the main granulating device. This scheme has the potential to produce larger shear forces during wetting and binder introduction and thereby improve homogeneity and consequently final granule properties.     

A study of fly ash-lime granule unfired brick

In this paper, the properties of fly ash-lime granule unfired bricks are studied. Granules were prepared from mixtures of fly ash and lime at fly ash to hydrated lime ratios of 100:0 (Ca/Si = 0.2), 95:5 (Ca/Si = 0.35) and 90:10 (Ca/Si = 0.5). After a period of moist curing, the microstructure and mineralogy of the granules were studied. Microstructure examination reveals that new phases in the form of needle-like particles are formed at the surface of granule. The granules were used to make unfired bricks using hydrothermal treatment at temperature of 130 ± 5 °C and pressure of 0.14 MPa. The microstructures, mineralogical compositions, mechanical properties and environmental impact of bricks were determined.The results reveal that the strengths of unfired bricks are dependent on the fineness of fly ash. The strength is higher with an increase in fly ash fineness. The strengths of the fly ash-lime granule unfired brick are excellent at 47.0-62.5 MPa. The high strength is due to the formation of new products consisting mainly of hibschite and Al-substituted 11 Å tobermorite. The main advantage of utilization of granule is the ability to increase the pozzolanic reaction of fly ash through moisture retained in the granule. In addition, the heavy elements, in particular Cd, Ni, Pb and Zn are efficiently retained in the fly ash-lime granule unfired brick.     

Mechanisms in high-viscosity immersion-granulation

An atypical high-shear granulation process is investigated in which a fine inert powder is bound with a highly viscous surfactant paste. The mechanism comprises adsorption of powder particles onto paste fragments, breakage of powder-coated paste granules, micro-mixing of the granules with incorporation of the powder, granule growth via coalescence, and finally granule consolidation. These stages are supported by micrographic and granule size distribution data. The agglomeration process features two main mechanisms, namely binder distribution followed by granule consolidation and coalescence, the transition between which is shown to be dependent upon the operating parameters.A number of time-dependent consistency regimes can be identified and quantitatively described using bulk tapping compaction tests. Of particular interest is the trend in Hausner ratio, which provides information on the inter-granular friction and cohesivity. Various pseudo-steady state tapping parameters are used to track the agglomeration process, the results of which are consistent with the Iveson et al. (2001a, Powder Technology 117, 83-97) steady state agglomeration regime maps. The effects of paste/powder composition, paste rheology and mixing speed upon the agglomeration rate can be explained physically in terms of adsorption, viscous and mechanical energy dissipation mechanisms. In summary, the work introduces a preliminary analysis of an immersion-granulation mechanism in which a number of key features are identified.     

A kinetic study on the electrodeposition of nickel nanostructure and its electrocatalytic activity for hydrogen evolution reaction

The electrodeposition of nickel was studied using electrochemical techniques in different electrolytes and various agents. The voltammetry analysis clearly showed that the electrodeposition of nickel was a diffusion-controlled process associated with a typical nucleation process. The current transients represented instantaneous nucleation with a typical three-dimensional (3D) growth mechanism. Scharifker’s equations were derived for instantaneous and progressive nucleation of the 3D growth of the spherical centers under diffusion-controlled condition. The number of nucleation sites increased with the increment in overpotential and Ni²⁺ concentration. Atomic force microscopy was used to confirm the presumed model. Also, the electrocatalytic activities of the Ni films were investigated for hydrogen evolution reaction (HER). The electrocatalytic activity of the Ni nanostructure was three times higher than the 2D Ni microstructure when the overpotential of −1.2 V was applied. The HER current density at −1.4 V for Ni nanostructure (−20 mA cm⁻²) was considerable with respect to the Ni microstructure (−8.46 mA cm⁻²) too.