An investigation on process of seeded granulation in a continuous drum granulator using DEM

Numerical simulation of wet granulation in a continuous granulator is carried out using Discrete Element Method (DEM) to discover the possibility of formation of seeded granules in a continuous process with the aim of reducing number of experimental trials and means of process control. Simple and scooped drum granulators are utilized to attain homogenous seeded granules in which the effects of drum rotational speed, particles surface energy, and particles size ratio are investigated. To reduce the simulation time a scale-up scheme is designed in which a dimensionless number (Cohesion number) is defined based on the work of cohesion and gravitational potential energy of the particles. Also a mathematical/numerical method along with a MATLAB code is developed by which the percentage of surface coverage of each granule is predicted precisely. The results show that use of continuous granulator for seeded granulation is promising provided that a high level of shear is considered in the granulator design, i.e. using baffles inside drum granulators is essential for producing seeded granules. It is observed that the optimum surface energy for seeded granulation in scooped granulator (used in this study) with rotational speed of 50 rpm is 3 J/m², which is close to the value predicted by the concept of Cohesion number. It is also shown that increasing the seed/fine size ratio enhances the seeded granulation both quantitatively (60% increase in seeds surface coverage) and qualitatively (more homogeneous granules).     

Investigations at an industrial scale on granule and tablet attributes in high shear rapid mixer granulator

Particle agglomeration by granulation was a very ubiquitous operation that finds applications in various industries such as pharmaceutical, food, chemical, fertilizer, etc. Among many granulators, the high shear rapid mixer granulator (RMG) was a very commonly used wet granulator in pharmaceutical industry. The wet granulation process was sensitive to the process parameters and the input product variables. The flow pattern, fill ratio, cohesive forces, velocities, and the kinetic energy of the particles have impact on the granular and the tablet properties. In this work, solid dosage formulation integrated with the RMG process has been studied at an industrial scale. The total formulation of the tablet was kept constant and the impact of various critical operating and process parameters of RMG viz., impeller design, impeller speed, batch size, binder concentration, and binder type on granule and tablet attributes has been studied and analyzed. The optimal set of process parameters to achieve the desired granular and tablet attributes viz., bulk density, compressibility (Carr index) flow properties (Hausner ratio), particle size distribution, texture, tablet hardness, dissolution, and disintegration times were found in the study.     

Scale-up and endpoint issues of pharmaceutical wet granulation in a V-type low shear granulator

A 3² factorial experiment is conducted in a 57 liter low shear granulator to evaluate the influence of changes in binder strength and agitator speed on the response variables of granule size, granule morphology, granule density and torque input. Results are compared to previous work in a 2 liter granulator and scale-up issues between the two granulators are addressed.     

Stage-wise characterization of the high shear granulation process by impeller torque changing rate

Fine cornstarch powders are wet granulated in a lab-scale high shear granulator. The torque required for maintaining the impeller passing through the bed with a constant rotating speed is monitored during the continuous binder addition granulation process. A new method is proposed to identify 6 stages during the granulation process based on the fraction of the positive impeller torque changing rate in a characteristic period of time. The morphologies and the behavior of the bed are found intrinsically different in the identified 6 stages. The influence of the impeller blade inclined angle on the impeller torque in each stage is initially reported. The impeller with planner 45° blades requires higher torques in Stages I and II due to the overall powder bed mass loading. The impeller with steeper 60° blades requires higher torques in Stages III and IV due to the higher collision frequencies between the blade and granules. The suitable granulation liquid binder to solid powder mass ratio can be readily identified in Stages II and III, and its range is found to increase with the increasing of the impeller rotational speed and is independent to the blade inclined angle.     

Comparison of low shear, high shear, and fluid bed granulation during low dose tablet process development

Three processing methods were compared to develop a low dose (0.1%) immediate release tablet. Similar formulations were used to evaluate low shear, high shear, and fluid bed granulation methods. For each granulation process, the drug was dissolved or suspended in the granulating fluid and sprayed into the granulator. Both water and methanol were evaluated as granulating fluids. The low shear granulation was performed in a Patterson-Kelley V-Blender with I-bar. The high shear granulation was performed in a GRAL (top entry impeller) and a Diosna (bottom mounted impeller). Fluid bed granulation was also performed using top-spray. Acceptable content uniformity was obtained using each technology. The type of granulator and granulating solvent affected the granulation particle size distributions and bulk/tap densities. However, the addition of extragranular microcrystalline cellulose minimized the effect of variable granulation properties and allowed similar tablets to be produced from each granulation process.     

Influence of process variable and physicochemical properties on the granulation mechanism of mannitol in a fluid bed top spray granulator

This study investigated the influence of specific process variables, including the hydroxypropyl cellulose (HPC) binder solution atomization, on the fluidized bed top spray granulation of mannitol. Special attention was given to the relationship between wetting and the granule growth profile. The atomization of the HPC binder solution using a binary nozzle arrangement produced droplets of decreasing size as the atomization pressure was increased, while changes in the spray rate had little effect on the mean droplet size. Increasing the HPC binder concentration from 2 to 8% w/w increased the binder droplet size and was most likely attributed to higher solution viscosity. The top spray granulation of mannitol showed induction type growth behavior. Process conditions like high spray rate, low fluidizing air velocity and binder solution concentration that promote the availability of HPC binder solution at the surface of the particles appeared to be key in enhancing nucleation and growth of the granules. Increasing the bed moisture level, up to a certain value, reduced the contribution of attrition to the overall growth profile of the granule and, more significantly, produced less granule breakage on drying. It was observed that the mean granule size could be reduced as much as 40% between the end of granulation and the end of drying for lower initial bed moisture level despite a shorter drying phase. High atomization pressure, especially when maintained during the drying phase, contributed substantially to granule breakage.     

Extrusion granulation and high shear granulation of different grades of lactose and highly dosed drugs: a comparative study

Formulations containing different lactose grades, paracetamol, and cimetidine were granulated by extrusion granulation and high shear granulation. Granules were evaluated for yield, friability, and compressibility. Tablets were prepared from those granules and evaluated for tensile strength, friability, disintegration time, and dissolution. The different lactose grades had an important effect on the extrusion granulation process. Particle size and morphology affected powder feeding and power consumption, but had only a minor influence on the granule and tablet properties obtained by extrusion granulation. In contrast, the lactose grades had a major influence on the granule properties obtained by high shear granulation. Addition of polyvinylpyrrolidone (PVP) was required to process pure paracetamol and cimetidine by high shear granulation, whereas it was feasible to granulate these drugs without PVP by extrusion granulation. Granules prepared by extrusion granulation exhibited a higher yield and a lower friability than those produced by high shear granulation. Paracetamol and cimetidine tablets compressed from granules prepared by extrusion granulation showed a higher tensile strength, lower friability, and lower disintegration time than those prepared from granules produced by high shear granulation. Paracetamol tablets obtained via extrusion granulation exhibited faster dissolution than those obtained via high shear granulation. For all lactose grades studied, extrusion granulation resulted in superior granule and tablet properties in comparison with those obtained by high shear granulation. These results indicate that extrusion granulation is more efficient than high shear granulation.     

Influence of melting and rheological properties of fatty binders on the melt granulation process in a high-shear mixer

The preparation of granules by melt granulation was investigated using a laboratory-scale high-shear mixer (Pellmix PL 1/8) and binary mixtures containing lactose and different lipidic binders, namely, Compritol® 888, Cutina® HR, or Precirol® ATO5. During the process, the product temperature and the impeller motor power consumption were monitored. On the other hand, the melting behavior (thermal analysis) and the rheological properties (controlled stress capillary rheometer) of the different lipophilic binders were also determined. The granule formation was shown to be quite effective at product temperatures even below the melting point of the lipidic binder, that is, when the binder is sufficiently softened to be deformed by the very high shearing forces developed in the high-shear mixer. On the other hand, the performance of lipidic binders during the melt granulation process was shown to be closely dependent on their melting and rheological properties. The granule growth rate was shown to be higher when the binder melting range is narrow and the influence of temperature on the viscosity of the unmelted product is high.     

Investigation of the effect of impeller speed on granules formed using a PMA-1 high shear granulator

Impeller speed was varied from 300 to 1500?rpm during the wet high shear granulation of a placebo formulation using a new vertical shaft PharmaMATRIX-1 granulator. The resulting granules were extensively analysed for differences caused by the varying impeller speed with emphasis on flowability. Microscopy showed that initial granules were formed primarily from microcrystalline cellulose at all tested impeller speeds. At low impeller speed of 300?rpm in the “bumpy” flow regime, forces from the impeller were insufficient to incorporate all the components of the formulation into the granules and to promote granule growth to a size that significantly improved flowability. The “roping” flow regime at higher impeller speeds promoted granule growth to a median particle size of at least 100 µm that improved the flowability of the mixture. Particle size distribution measurements and advanced indicators based on avalanching behavior, however, showed that an impeller speed of 700?rpm produced the largest fraction of optimal granules with the best flowability potential. This impeller speed allowed good development of “roping” flow for sufficient mixing, collision rates and kinetic energy for collisions while minimizing excessive centrifugal forces that promote buildup around the bowl perimeter.     

Investigation of the effect of impeller speed on granules formed using a PMA-1 high shear granulator

Impeller speed was varied from 300 to 1500?rpm during the wet high shear granulation of a placebo formulation using a new vertical shaft PharmaMATRIX-1 granulator. The resulting granules were extensively analysed for differences caused by the varying impeller speed with emphasis on flowability. Microscopy showed that initial granules were formed primarily from microcrystalline cellulose at all tested impeller speeds. At low impeller speed of 300?rpm in the "bumpy" flow regime, forces from the impeller were insufficient to incorporate all the components of the formulation into the granules and to promote granule growth to a size that significantly improved flowability. The "roping" flow regime at higher impeller speeds promoted granule growth to a median particle size of at least 100 μm that improved the flowability of the mixture. Particle size distribution measurements and advanced indicators based on avalanching behavior, however, showed that an impeller speed of 700?rpm produced the largest fraction of optimal granules with the best flowability potential. This impeller speed allowed good development of "roping" flow for sufficient mixing, collision rates and kinetic energy for collisions while minimizing excessive centrifugal forces that promote buildup around the bowl perimeter.     

Influence of the initial volume fill ratio of the granulator on melt agglomeration behavior in a high-shear mixer

The purpose of this study was to investigate the effects of different initial volume fill ratios of the granulator on granular agglomeration in a high-shear mixer. Calcium carbonate powders, with mean granule sizes of 75–150 μm were used as the raw material. Polyethylene glycol 6000 (PEG 6000) was used as the melting binder. The initial liquid to solid weight ratio was fixed at 0.15. Four different initial granulator fill ratios were used 11%, 14.7%, 18.4% and 22%. The results showed that the granules that formed during the nucleation stage were a little larger when the initial fill ratio was lower than higher. In the rapid-growth stage, the agglomeration growth rate increased as the initial fill ratio increased. The range in granule size at the end of agglomeration also increased as initial fill ratio increased. SEM images of the surface structure of the granules during the nucleation and final stages are shown.     

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations

The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and in vitro dissolution were also studied. Following post-granulation drying at 60?°C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25?°C/60% RH and 40?°C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.     

Solventless-mixing layering using a high shear mixer for preparing drug pellets: A feasibility study using acetaminophen

Our aim was to investigate the feasibility of mechanical-mixing layering using a high shear mixer, which can produce drug pellets by simply mixing drug crystals and inactive seed particles without the need for solvents or binders. Acetaminophen crystals and microcrystalline cellulose spheres were mechanically mixed using various impeller speeds and the resulting composite particles were characterized. Acetaminophen particles were separated from the spheres using a low impeller speed and deposited on the surface of the spheres at a higher impeller speed. The diameter of the acetaminophen crystals in the composite particles decreased as the impeller speed increased, due to increased collision impact between the spheres. The correlation between drug content and drug particle diameter in the composites indicates that acetaminophen particles were layered on the cellulose spheres due to their pulverization during the mixing treatment. We examined additional mixing treatments to enhance drug loading: after mechanically mixing acetaminophen crystals and cellulose spheres, fresh acetaminophen crystals were added and mechanically mixed with the composite particles. Additional mixing increased the loading of acetaminophen particles without lowering the layering efficiency. In conclusion, mechanical-mixing layering can be accomplished using a high shear mixer.     

Influence of chopper and mixer speeds and microwave power level during the high-shear granulation process on the final granule characteristics

Although microwave drying technology has been used extensively, detailed studies in the pharmaceutical field are necessary to model the different operational parameters involved in microwave drying in combination with the high-shear granulation processes. The implications of the chopper and the mixer speeds during the granulation step and the microwave power level during the drying step on the final granule characteristics were investigated. alpha-Lactose monohydrate and microcrystalline cellulose were granulated at three different mixer and chopper speeds in a laboratory-scale high-shear mixer (Mi-Mi-Pro) and dried at three microwave power levels. The dried granules were characterized by friability tests, particle size analysis, bulk and tapped density studies, and porosimetry. Neither the mixer speed nor the chopper speed had a significant influence on the granule friability, which was low for all batches produced. The selected materials and experimental conditions induced a very robust granulation process, but the granule size distribution was influenced by the microwave power level. The reciprocal relationship between the dust formation and the microwave power level was analyzed using a central composite factorial design. The amount of dust remained low in all batches, but it influenced some of the inherent density properties and the volume reduction behavior of the granulation mass. In almost all cases, the Carr index decreased slightly with increasing microwave power. The major granule characteristics were not changed when different mixer or chopper speeds were changed, although the mixer speed did alter the intragranular pore size distribution.     

High shear wet granulation: Improved understanding of the effects of process variables on granule and tablet properties of a high-dose,high-hydrophobicity API based on quality by design and multivariate analysis approaches

High shear wet granulation (HSWG), as a widely used granulation technology, has been studied extensively. However, for the HSWG of formulations containing hydrophobic components, the influence of process variables on the properties of granules and tablets has not been reported. In the present study, based on a combination of quality by design and multivariate analysis (MVA) approaches, quercetin with high-dose and high-hydrophobicity was used to study the relationship between process variables, granule properties, and tablet properties in HSWG systematically. Control and response variables were determined using risk assessment. The optimal fitting empirical models established by Box-Behnken design showed that the liquid to solid ratio and impeller speed were the most important factors, which affected all product properties except Carr’s index and yield pressure. Instead, the influence of wet massing time was relatively small (only the effects on yield, granule size, granule hardness, and compression ratio were significant). Then, the process design space was obtained by limiting the related critical quality attributes, which was verified effectively. Scanning electron microscope images showed that smooth granules were produced using higher process parameters, whereas rough and porous granules resulted at lower process parameters. Furthermore, the MVA results demonstrated that increasing the granule hardness led to an increase in the compression ratio and a decrease in tensile strength of the tablets. Tablet fragility and disintegration time were mainly affected by granule density and bulk density, respectively, and both were negatively correlated. The established research paradigm is not only conducive to the successful development of quercetin products, but also provides valuable guidance for improving HSWG–based product development with such formulation characteristics.     

Numerical analysis of similarities of particle behavior in high shear mixer granulators with different vessel sizes

This paper deals with the numerical analysis of kinematic and dynamic similarities of particle behavior in high shear mixer granulators with different vessel sizes. The three-dimensional particle motion in high shear mixer granulators with four different vessel sizes was calculated using a discrete element method (DEM). The geometrically similar mixer granulators equipped with a flat-shaped impeller blade were used as simulated mixer granulators.Kinematic and dynamic similarities of particle behavior in various vessel sizes under a constant normalized agitation power were numerically analyzed. In various vessel sizes, dynamic similarity expressed by the particle collision energy was confirmed under a constant normalized agitation power, while kinematic similarity expressed by the particle velocity was not confirmed. These results indicate that the dynamic similarity should be maintained for successful scale-up of high shear mixer granulators.     

Monitoring and evaluation of process parameters in a plunge grinding operation

Plunge grinding, like other grinding operations, is a complex process because of a large number of factors that are involved. This often makes it difficult to determine the optimal grinding parameters in pursuit of a certain product quality and cost, based upon the existing generic knowledge and experience about the process. However, the combined effect of the large number of factors and therefore, the performance characteristics of a given grinding system (including grinding wheel, component, grinding machine as well as workpiece holding system) can be learned by monitoring the grinding process. This can then help in the determination of optimal or near optimal grinding parameters. The paper describes a computerised system for the analysis of a plunge grinding operation based on the monitored power traces. This analysis yields data on important parameters such as grinding power (P), specific energy (E?s?), grinding force (F?t?), system deflection (Δy) and stiffness (K?s?). The paper also discusses the evaluation models used in the system, in particular, the model proposed for evaluation of system deflection and stiffness. The effect of the system stiffness on grinding process is analysed and a method to determine spark-out period, required to eliminate the system deflection, is proposed in the paper.