High Shear Mixer Granulator Research Articles

Characteristics of residence time distribution in a continuous high shear mixer granulation using scraper rotation

Characteristics of residence time distribution (RTD) in a continuous high shear mixer granulation were investigated to promote the development of a continuous manufacturing process in the pharmaceutical industry. A continuous granulator with an impeller and a scraper was utilized. The tracer behavior in the continuous wet granulation was verified in impulse-response experiments with acetaminophen. The RTD of acetaminophen changed depending on the scraper speed (15–50 rpm), and the mean residence time could be adjusted by the scraper speed in the wet granulation. The impact of changes in the liquid-to-solid ratio (0.10–0.20) and the addition of binder were also examined, and the variance of RTD was influenced by both. The degree of axial mixing was quantitatively evaluated with a dimensionless index, the Peclet number (Pe). Higher scraper speed was found to suppress fluctuations of the axial mixing that occurred with changes in the liquid feed. Moreover, the transition of granule size distribution with the change in liquid feed reached a steady state more quickly under the higher scraper speed. These results show that scraper rotation can help to adjust the RTD and the axial mixing, leading to a more robust continuous granulation.

Fabrication of extended-dissolution divalproex tablets: a green solvent-free granulation technique

Objective: Divalproex sodium (DVS) is a challenging drug owing to its hygroscopicity, bitter taste, and short in vivo half-life. This study aims to produce stable taste masked DVS once daily tablets using solvent free hot melt granulation (HMG) process.Methods: A lab scale high shear mixer granulator employing six meltable lipid binders (compritol®888 ATO, beeswax, gelucire®50/13, precirol® ATO5, stearyl alcohol, and geleol®) was used for the preparation of tablets. Quality control tests were performed on granules and tablets, and Box–Behnken’s design was adopted to investigate the effect of binder concentration, impeller speed, and granulation time on the drug dissolution. Shelf and accelerated stability evaluation, taste assessment, and in vivo pharmacokinetic study were conducted on the selected batches.Results: Results revealed that DVS tablets were successfully prepared, and that the in vitro dissolution of the drug was inversely proportional to the binder concentration. Beeswax and compritol® tablets showed similar dissolution profiles to the marketed product Depakote® 500 ER tablets (F1 < 15 and F2 > 50). The selected batches showed lower moisture content (<2%) and successfully masked the bitter taste compared to uncoated tablets based on a hydrophilic matrix. The in vivo pharmacokinetic study delineated relative bioavailability values for Beeswax and Compritol® tablets of 95.6% and 118%, respectively, compared to the marketed product.Conclusion: The solvent free HMG process can be employed to formulate 24 h extended dissolution DVS tablets with masked bitter taste and high stability, and comparable or higher bioavailability than the marketed product.

Preparation and characteristics’ evaluation of zeolite/activated carbon composite granules, using high shear mixer granulator

In this work, zeolite/activated carbon composite granules were produced in a prototype high shear mixer granulator, using wet granulation method. The main objectives of the study were to investigate the effect of granule size and composition on its compression behavior and crushing strength. The porous granules were prepared to be used, in another study, as adsorbent of air/water pollutants. The Fourier transform infra-red (FTIR), scanning electron microscopy (SEM), x-ray diffraction (XRD), and quasi-static single particle crushing strength tests were employed to characterize chemical, physical, and mechanical properties of the granules. The results showed that smaller granules with the lower content of activated carbon achieved higher mechanical strength. Considering these results, it was possible to produce composite granules with the crystalline and porous structure, as well as suitable mechanical strength.

Continuous high-shear granulation: Mechanistic understanding of the influence of process parameters on critical quality attributes via elucidating the internal physical and chemical microstructure

Over the past decade, continuous wet granulation has been emerging as a promising technology in drug product development. In this paper, the continuous high-shear mixer granulator, Lӧdige CoriMix® CM5, was investigated using a low-dose formulation with acetaminophen as the model drug. Design of experiments was deployed in conjunction with multivariate data analysis to explore the granulator design space and comprehensively understand the interrelation between process parameters and critical attributes of granules and tablets. Moreover, several complementary imaging techniques were implemented to unveil the underlying mechanisms of physical and chemical microstructure in affecting the tablet performance. The results indicated that L/S ratio and impeller speed outweighed materials feeding rate in modifying the granule and tablet properties. Increasing the degree of liquid saturation and mechanical shear input in the granulation system principally produced granules of larger size, smaller porosity, improved flowability and enhanced sphericity, which after compression generated tablets with slower disintegration process and drug release kinetics due to highly consolidated physical microstructure. Besides, in comparison to batch mixing, continuous mixing integrated with a conical mill enabled better powder de-agglomeration effect, thus accelerating the drug dissolution with increased surface area.

Mixing of low-dose cohesive drug and overcoming of pre-blending step using a new gentle-wing high-shear mixer granulator

The objective of this study was to examine the influence of drug amount and mixing time on the homogeneity and content uniformity of a low-dose drug formulation during the dry mixing step using a new gentle-wing high-shear mixer. Moreover, the study investigated the influence of drug incorporation mode on the content uniformity of tablets manufactured by different methods. Albuterol sulfate was selected as a model drug and was blended with the other excipients at two different levels, 1% w/w and 5% w/w at impeller speed of 300 rpm and chopper speed of 3000 rpm for 30 min. Utilizing a 1 ml unit side-sampling thief probe, triplicate samples were taken from nine different positions in the mixer bowl at selected time points. Two methods were used for manufacturing of tablets, direct compression and wet granulation. The produced tablets were sampled at the beginning, middle, and end of the compression cycle. An analysis of variance analysis indicated the significant effect (p < .05) of drug amount on the content uniformity of the powder blend and the corresponding tablets. For 1% w/w and 5% w/w formulations, incorporation of the drug in the granulating fluid provided tablets with excellent content uniformity and very low relative standard deviation (∼0.61%) during the whole tableting cycle compared to direct compression and granulation method with dry incorporation mode of the drug. Overall, gentle-wing mixer is a good candidate for mixing of low-dose cohesive drug and provides tablets with acceptable content uniformity with no need for pre-blending step.

A novel co-processed directly compressible release-retarding polymer: In vitro, solid state and in vivo evaluation

Directly compressible (DC) co-processed excipient capable of providing nearly zero order release with improved functionality was developed without any chemical modification by employed various techniques such as physical mixing, high shear mixer granulation and spray drying. Co-processed excipient was developed by using release retarding polymer Eudragit RSPO, separately, in combination with different concentration of hydroxyl propyl methyl cellulose 100 cps (Methocel K100 LV, HPMC), ethyl cellulose (Ethocel N50, EC) and hydroxyl propyl cellulose (Klucel EF, HPC). All co-processed excipients were evaluated for their flow properties in terms of angle of repose, bulk density, tapped density, compressibility index and Hausner's ratio. Out of eighteen combinations, the nine co-processed excipients exhibited promising flow properties were found suitable for direct compression and formulated as tablets. Metoprolol succinate, a BCS Class I drug, was selected as a model drug and the formulation was developed employing direct compression approach. The developed tablets were evaluated for physical parameters like uniformity of weight, thickness, hardness, friability and assay. In vitro dissolution study confirms that formulation prepared using co-processed excipient showed sustained drug release. The optimized tablet formulation was characterized by DSC, FTIR and PXRD which confirms the absence of any chemical change during co-processing. The optimized formulation was kept for stability study for six months as per ICH guidelines and found to be stable. In vivo pharmacokinetic study of optimized formulation in rats showed similar pharmacokinetic behaviour as was observed with the marketed brand. Study revealed that co-processed excipient has advantage over polymers with single property and can be utilised for sustained release formulation.

Effects of Process and Design Parameters on Granule Size Distribution in a Continuous High Shear Granulation Process

Wet granulation is widely used in the pharmaceutical industry. This advantageous technology is capable of enhancing compression and powder handling, decreasing ingredient segregation, and promoting blend and content uniformity. Currently, a high level of interest exists in the continuous version of this technology, both by the US Food and Drug Administration (FDA), and by pharmaceutical manufacturers. In this paper, a continuous high shear wet granulation process was examined based on a placebo formulation comprising 70% ∂-lactose monohydrate and 30% microcrystalline cellulose (Avicel® PH101). Granulation was then carried out in a continuous high shear mixer granulator, Glatt GCG 70. The impact of two process variables (rotation speed and liquid/solid (L/S) ratio) and two design parameters (blade configuration and nozzle position) were evaluated via an I-optimal design. Multi-factor analysis of variance (ANOVA) indicated that rotation speed and L/S ratio dominated the granulation process and had the most significant effects on granule size distribution (GSD). The largest granule mass median diameter was obtained at the lowest rotation speed and highest L/S ratio. The granulation mechanism underlying this continuous process was examined using a wetting and nucleation regime map. For the cases studied here, the mechanical dispersion regime controlled the formation of granule nuclei, leading to a broad GSD and a limited growth ratio.

The effects of fluidised bed and high shear mixer granulation processes on water adsorption and flow properties of milk protein isolate powder

The effects of fluidised bed (FB) and high shear mixer (HS) granulation processes on water adsorption and flow properties of milk protein isolate powder (MPI) were investigated and compared. The agglomerated granules were characterised by different size fractions. It was found that granules produced from the HS process adsorbed less moisture, with slower adsorption kinetics, compared to those produced from using the FB. Granulation reduced the cohesiveness of the MPI powder, with HS having a significant greater impact due to the formation of the particles with higher bulk density and larger size. Particle size played a critical role that influenced water adsorption and flowability. Granulation processes contributed to different degrees to reducing the minimum outlet diameters of hoppers based on either mass-flow or core-flow discharges. HS granules had large wall friction angles, suggesting a need for steeper hopper walls for effective discharge.

High shear mixer granulation using food grade binders with different thickening power

Mixer agglomeration, in particular high shear wet granulation, is a unit operation typically used in the pharmaceutical industry to improve the flowability, the compressibility, the dosing accuracy during tableting or the content uniformity of a blend. Thanks to its advantages (production of spherical and dense granules, reduction of production time), this technique can be potentially successful also in the food industry as for example in the production of dietary supplements. In this work four thickening agents (povidone, maltodextrin, k-carrageenan and xanthan gum) have been tested to study their effects on the granule growth behavior and on some technologically relevant granule properties (size, shape, strength and flowability). Experiments highlighted the full feasibility of the process and the possibility of using these agents to get products with satisfactory technological properties. The dependence of product properties on the formulation variables (water and binder amount) has been analyzed according to a multivariate approach and a robust predictive tool for the granule size has been developed. Furthermore it was observed that a reduced amount of binding liquid (water) can be used in the presence of strongly thickening binders with a reduction up to 25%. This would decrease drying time and energy requirement and be beneficial especially in the food and food supply industry where products have generally lower added value than in the pharmaceutical one and reducing production costs is critical.

The rheology of dense granular flows in a disc impeller high shear granulator

The aim of the present study is to evaluate the new approach to dense particulate systems proposed by Jop et al. [1], in the dense regions of a High Shear Granulator (HSG). Wet granulation in high shear mixers is a common process in pharmaceutical technologies and a good understanding of the local mixing and flow patterns is a pre-requisite for this step. In the aforementioned model a dense granular flow is characterized as a visco-plastic fluid. Therefore the local rheology of the system can be predicted assuming averaged and virtual properties and a constant solid volume fraction.A simple disc impeller granulator with glass spheres was chosen for this study. The dynamics of the system have been studied using several techniques including PIV analyses, CFD simulation and image processing. The flow behaviour has been characterized for various impeller speeds and particle loads. Several cases have been analyzed from different aspects both in experiments and through equivalent simulations to evaluate the validity of the model in these particular applications.Results look promising in spite of the simplicity of the model. The model was found to give a good general description of the flow field and bed shape. On the other hand the model is insufficient in some aspects; mostly related to the regions with low volume fraction. The next step would be to combine the model with conventional models on rapid granular flow such as Kinetic Theory of Granular Flows (KTGF).

Synthesis of alumina granules by high shear mixer granulator: Processing and sintering

Abstract Alumina powders were granulated in a prototype high shear mixer granulator as primary particles. The produced green granules were then sintered in an electric furnace. The sensitivity of the granule characteristics to the wet granulation parameters and sintering post-processing temperature was studied. The results showed that increasing the liquid binder to solid ratio led to the wide size distribution of granules. Furthermore, increasing the binder concentration could enhance the attrition and bulk compression strength of sintered granules. The strengths of the granules were strongly improved by increasing the sintering temperature due to densification progress and porosity decrease. In general, performing the granulation/sintering process by water (rather than PVA) binder, at the higher levels of the liquid to solid ratio, would improve the bulk compression strength, employing a proper sintering temperature.

Regime map development for continuous twin screw granulation

A promising method for continuous wet granulation is to pass powdered solids and binder through a twin-screw extruder, usually, as in this case, with co-rotating screws. In the current work, the relationship between operating conditions and product granule properties has been investigated using the same materials (microcrystalline cellulose and polyethylene glycol) as in an earlier study of conventional batch granulation using a high shear mixer-granulator (Tu et al., 2009), enabling a direct comparison to be made. Two extruder configurations were used: with barrel diameter/length dimensions of 16mm/16mm and 16mm/64mm. Two regimes (granulation and extrusion) were recognised for the short mixing geometry, while three regimes (granulation, extrusion and blockage) were recognised for the long mixing geometry and the staggered geometry. The resulting regime maps suggest that optimal granulation (narrow granule size distribution and large mean granule size) can be achieved with a higher liquid-to-solid ratio and a higher screw speed. The uniformity of size distribution can be improved by reprocessing and/or more aggressive mixing.

Comparison of granule properties produced using Twin Screw Extruder and High Shear Mixer: A step towards understanding the mechanism of twin screw wet granulation

Abstract The wet granulation process plays an important role in the pharmaceutical industry. With the introduction of a Twin Screw Extruder (TSE), it allows the possibility of wet granulation to be run continuously in contrast to a conventional batch process using a High Shear Mixer (HSM). However, the mechanism of Twin Screw Extruder wet granulation is not well understood and the aim of this study is to investigate this process and compare it with the High Shear Mixer granulation process with regard to the granule properties. Granules of pure microcrystalline cellulose (MCC) were produced using a Twin Screw Extruder and a High Shear Mixer with water as liquid binder under different process conditions and formulations. The properties (particle size distribution, shape, surface morphology, internal structure, internal porosity and strength) of the granules were then compared. It was found that the granules produced by the two methods have different physical properties. Granules produced by the HSM are spherical in shape and are made up of smaller granules through coalescence process. It is believed that the granules produced by HSM in the present study are over-granulated which leads to the production of strong dense granules. On the other hand, granules produced by TSE have irregular shapes with tiny pores spread uniformly throughout the granules. The granules produced by HSM are affected by process conditions and are stronger at higher impeller speed. However, granules made by TSE are consistent in strength and relatively independent of process conditions. Due to over-granulation in HSM process, the granules produced result in the production of weak tablets whilst granules made by TSE manage to produce stronger tablets. Finally, by observing the structure of the granules, it is believed that the mechanism of HSM and TSE granulation is different. Although the granules made by HSM were over-granulated, it shows the existence of consolidation process that is apparently absent in TSE granulation. Nevertheless, more work will be needed to further understand the mechanism in continuous TSE wet granulation process.

Scale-up of high shear mixer-granulator based on discrete element analysis

For developing a scale-up method based on the kinematic and dynamic similarities of particle behavior, motion of particles in a commercial high shear mixer-granulator with different vessel sizes (2 to 112 L) were simulated using a three-dimensional discrete element method (DEM). Effects of the vessel size on the internal particle flow and the particle collision energy were analyzed. It was found that under the constant impeller tip speed magnitude of the internal particle shear flow can be nearly maintained at different vessel sizes. This implies that the constant impeller tip speed should be employed to achieve the kinematic similarity when scaling-up the high shear mixer-granulator. However, under the constant impeller tip speed the cumulative particle collision energy per unit time significantly decreased with an increase in the vessel size. This suggests that in order to achieve the dynamic similarity the granulation time should be adjusted so that the cumulative particle collision energy over the granulation time can be maintained at different vessel sizes. Based on the simulation results, we proposed a scale-up method in which the optimal granulation time can be determined to achieve the same cumulative particle collision energy at different vessel sizes while maintaining the same impeller tip speed. This method can provide both the kinematic and dynamic similarities between different vessel sizes. Validity of the proposed scale-up method was confirmed by an experiment of wet-granulation using a commercial high shear mixer-granulator with different vessel sizes (2 to 216 L). Effects of the vessel size on the particle motion in a high-shear mixer granulator were analyzed using a DEM. Based on the simulation results, two constant rules for the successful scale-up were proposed: i.e., the constant impeller tip speed and the constant cumulative particle collision energy. The experimental results well supported validity of the proposed scale-up method. ► DEM simulation of particle motion in a high shear mixer-granulator was conducted. ► Effects of the vessel size on the particle flow and collision energy were analyzed. ► The kinematic similarity can be maintained under the constant impeller tip speed. ► The dynamic similarity can be maintained by adjusting the granulation time. ► The experimental results supported validity of the proposed scale-up method.

The Use of Response Surface Methodology to Evaluate the Impact of Level 2 SUPAC–IR Changes on the In Vitro Release of Metronidazole and Ranitidine from a Fixed-Dose Combination Tablet

The purpose of this study was to evaluate the effect of differ ent levels of disintegrant (croscarmellose sodium, CCS), binder (polyvinylprrolidone K30, PVP–K30), and lubricant (magnesium stearate) on the in vitro release of metronidazole (MTZ) and rantidine (RTD) from a solid oral fixed-dose combination tablet. The excipient levels investigated were Level 2 changes in component and composition described in the Scale-Up and Post Approval Changes for Immediate Release (SUPAC–IR) guidance (1). Batches of tablets (1000 units) were manufactured by wet granulation using a Saral high-shear mixer granulator and a Manesty B3B rotary tablet press. Weight uniformity, friability, and disintegration of all tablets were assessed, and all batches complied with compendial specifications. The amount of drug released (Q) at ten minutes was dependent on the levels of CCS in the formulation, and the effect of PVP–K30 and magnesium stearate was dependent on the levels of CCS. Synergistic interactions between independent variables were observed for the Q10 value for RTD, whereas PVP–K30 and magnesium stearate exhibited an antagonistic effect on the Q10 values for MTZ and RTD. The use of response surface methodology facilitated an investigation into the effect of Level 2 component and composition changes, as described in SUPAC–IR, on the in vitro release of MTZ and RTD from a fixed-dose combination (FDC) solid oral dosage form (SODF).

Foam granulation: Effects of formulation and process conditions on granule size distributions

The use of foam to achieve granulation is a new development in wet granulation processes. This paper studies foam granulation by investigating the impact of formulation and granulation process conditions on the granule size distribution in a high shear mixer-granulator. Experimental studies were performed in a high shear mixer-granulator on a lactose and microcrystalline cellulose (PH-101) formulation. The granule size distributions were determined as a function of foam quality (83% or 91%), primary powder particle size (75 μm or 150 μm), HPMC binder concentration (4% or 8%), liquid to solid ratio (20–60%), and impeller rotational speed (295 rpm or 515 rpm). The results showed that decreasing foam quality, or increasing the lactose particle size, liquid binder concentration or liquid to solid ratio increase the average granule size, but the effect is interconnected with impeller speed. Transformation maps were proposed to explain the changes in granule size distribution in response to changes of the studied parameters on the basis of wetting and nucleation mechanisms for foam granulation process.

Effect of high shear granulation process parameters on the production of granola cereal aggregates

Granola is an aggregated cereal food product which can be used as a breakfast cereal or snack comprised of ingredients such as cereals, nuts and honey. A high shear mixer granulator was used to produce granola in a wet granulation process followed by oven drying. The aim was to investigate the effect of granulation parameters; impeller speed, binder addition rate and wet massing time on key granola physical properties. Experiments were carried out at impeller speeds of 150, 200 and 300 rpm during binder addition and wet massing. Binder addition rates of 0.22, 0.33 and 0.65 g s −1 and wet massing periods of 6, 9 and 12 min were applied respectively. The granola was then dried on an oven at 160 °C for 10 min. Granule size distribution and granule strength were measured using a digital image analyser and texture analyser respectively. Regarding the process variables, the agglomeration behaviour was found to vary greatly with impeller speed. Granules formed at low impeller speed were found to have low apparent density. The results enabled the optimal ranges of impeller speeds, liquid binder addition rate and the wet massing time to be established for this system, thereby aiding the manufacturing process in terms of controllability and reproducibility. ► High shear mixer granulator was used to produce granola breakfast cereal. ► Effect of impeller speed, binder addition rate and wet massing time investigated. ► Impeller rotational speed is the single most important process parameter. ► Highest impeller speed and lowest binder addition rate gave highest hardness and crispness.

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.

Effects of Blade Design in Wet Granulation in a High Shear Mixer Determined by Positron Emission Particle Tracking

Wet granulation in high shear mixer is important in reducing potential environmental and safety hazards. A complex mechanism dominates high shear mixer granulation because there is an enormous range of geometries and designs for the mixer. This study is the first report of the effects of blade design on wet granulation in high shear mixer. In this study, two designs of blade were used to compare the granulation, and it was determined that the flat blade resulted in no granule or lump formation, while the beveled blade resulted in good granule formation. Positron emission particle tracking was used in order to investigate the effects of different impeller designs in wet granulation in a high shear mixer. These results should prove useful in improving process design in order to optimize the final granules, and in improving the quality of the resultant product.

Novel extended-release formulation of lovastatin by one-step melt granulation: In vitro and in vivo evaluation

The objective of this study was to apply a one-step melt granulation method to develop an extended-release formulation of lovastatin (LOV-ER). We prepared a formulation using PEG 6000 as binder agent in a laboratory scale high-shear mixer. In vitro dissolution studies showed that the release of the drug from the new formulation followed a zero-order kinetic with no differences in the release profile with either the pH media or the agitation rate. The pharmacokinetic of lovastatin and its metabolite lovastatin acid was evaluated after the administration of the new formulation to Beagle dogs in fasted conditions and after a high-fat meal, and compared to the marketed formulation Altoprev®. After the administration of LOV-ER, extended plasma profiles of lovastatin and its active metabolite were achieved in both fasted conditions and after the high-fat meal. Plasma levels of lovastatin and lovastatin acid were always higher when the LOV-ER formulation was administered with the high-fat meal. A high variability in plasma levels and pharmacokinetic parameters was obtained, being this variability higher when the formulation was administered under fasting conditions. Our results suggest that there is an increase in lovastatin bioavailability when the formulation is administered after the high-fat meal. When we compare LOV-ER and Altoprev®, both administered after the high-fat meal, we found significant differences (p<0.05) in Cmax of lovastatin and in AUC0–∞ and MRT of lovastatin acid. No differences were detected between both formulations in fasting conditions. In this regard, the high-fat meal seems to increase the absorption extent of lovastatin from LOV-ER formulation and to delay the absorption rate of the drug from Altoprev®. In conclusion, we developed a lovastatin formulation that provided extended plasma levels that confirm that one-step melt granulation in high-shear mixer could be an easy and cost-effective technique for extended-release formulation development.