High-shear Granulation Research Articles

Highly Soluble Drugs Directly Granulated by Water Dispersions of Insoluble Eudragit® Polymers as a Part of Hypromellose K100M Matrix Systems

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide

This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufacturing using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing experiments on the scale of 5 and up to 100 kg/lot, using the same raw materials. Three technologies were tested and compared: (i) batch technology using fluidized bed granulation, (ii) batch technology using high shear granulation, (iii) continuous technology using high shear granulation. In the full-scale experiment, in all three technologies including continuous technology, the quality of the tablets fulfilled the target values regarding hardness, active pharmaceutical ingredient content, and dissolution. The granules produced by different technologies, however, presented varying attributes regarding granule size distribution, loose bulk density, or scanning electron microscope images. The process performance, more specifically the yield, was slightly better for batch technologies than for the continuous technology, mainly due to losses in the start-up operation. Notably, this study has shown that continuous technology, which is generally believed to not entail scale-up procedures, could in fact, require parameter adjustment for prolonged operation. The results provided suggestions for improvements to implement large-scale continuous technologies in the pharmaceutical industry.

Dimensionless criteria as a tool for creation of a model for predicting the size of granules in high-shear granulation

This work deals with the creation of a mathematical model which will predict with sufficient accuracy the size of granules in the high-shear granulation process. The aim of the paper was to create a model created with dimensionless criteria to give the size of granules as a function of selected process parameters, equipment, and experimental material. Microcrystalline cellulose granules were manufactured in an experimental granulator of our own construction using a high amount of granulation liquid (absolute humidity >40%). The work also focuses on the study of granule size distribution and the yield of the process in achieving the target granule fraction (0.4–3 mm). Particle size and particle size measurement were performed using 3 D dynamic image analysis (PartAn 3 D, Microtrac). The granules were analyzed with respect to their shape and width of distribution. Using the created model, it is possible with high probability, 89.4%, to predict on our device the median value of the granule size of microcrystalline cellulose, with ±0.1 mm precision.

Determination of significant factors in high-shear granulation process of sucrose with aqueous solution of sodium lauryl sulphate using partial least square regression approach

Sucrose as one of the most commonly used raw materials in pediatric formulations is soluble and sticky excipient and its manipulation in high shear granulators may be very difficult. Therefore, to determine the correct amount of liquid binder is very important because it falls in a very narrow range and may vary due to small variations in the material properties or environmental conditions. The possibility of using the sugar as powder for granulation may be very challenging because of solubility and moisture adsorption properties of crystalline sugar, especially if the binder solution is water. The aim of this study was trying to solve these problems and produce sucrose granules using high share granulation and water as a binding liquid, with properties required for final product good performance. By reducing the sucrose particle size and improving the uniformity of the size distribution, the differences of the processes of nucleation and growth for small and large particles might be reduced. According to the variable importance or VIP scores from the developed partial least square (PLS) model, raw material particle size is as influential variable as the quantity and composition of the granulation liquid (Gra), granulation time (Grn) and impeller rate (Imp). Keywords: sucrose, particle size distribution, high-shear granulation, partial least square

A DEM model-based study to quantitatively compare the effect of wet and dry binder addition in high-shear wet granulation processes

Wet granulation is widely used in many particulate industries for its capability to improve flowability and handling of powder substances. A mathematical model using discrete element methodology (DEM) was developed to study two kinds of binder addition approaches commonly used during wet granulation in a batch high-shear granulator: wet binder addition (WBA) and dry binder addition (DBA). To define the complex interactions in the systems, a novel integrated DEM algorithm that incorporates powder wetting behavior, capillary and viscous liquid bridge formation as well as binder dissolution was developed. DEM simulation results show a significant difference between the viscous regions in the particle bed for the two systems: the WBA approach quickly wets the majority of the particle bed with a low viscosity fluid, while in the DBA approach fewer particles with higher viscous surface liquid are generated that are responsible for a delayed but faster granule growth rate. The difference in the viscosity of the surface liquid in the two systems lead to varying strengths and numbers of the liquid bridge formed between particles as well as particle velocities. In general, the high viscous areas are dependent on the binder and liquid dispersion which are affected by the mechanical agitation.

Novel, lean and environment-friendly granulation method: Green fluidized bed granulation (GFBG)

The Green fluidized bed granulation (GFBG) technology is based on the moisture activated dry granulation (MADG) technique and consists only of a mixing and a spraying process using a fluidized bed granulator, requiring no heating process. This provides a less energy-consuming and environment-friendly granulation method compared to current fluidized bed granulation (FBG) and high-shear granulation (HSG) methods. The aim of this study is to compare and evaluate the manufacturability, and granule and tablet properties among GFBG, MADG, FBG and HSG.The GFBG process time took less than 20 min for producing final blends at a 700 g scale, which was comparable to MADG. This process time was significantly shorter than that of FBG and HSG. GFBG not only had the shortest process time but also reduced the number of manufacturing machines compared to FBG and HSG.The Hausner ratio (HR) of granules from GFBG (1.30) indicated a good flowability, and no problems were observed in the tablet mass variability during compression.Tablets produced using GFBG achieved sufficient tensile strength (>1.5 MPa) even at a low compression force and demonstrated the fastest disintegration time compared to the other manufacturing methods. Tablet disintegration is related to wettability and porosity, therefore the tablet wettability (initial and capillary wetting) and tablet porosity were investigated. As a result, the capillary wetting of the tablets produced using GFBG was 3.6 times higher than the tablets produced using FBG, which might have affected the fast disintegration of the tablets produced using GFBG.

Impact of Different Dry and Wet Granulation Techniques on Granule and Tablet Properties: A Comparative Study

Four granulation techniques were compared evaluating their impact on granule properties and the tablet tensile strength. A common formulation was chosen to be processed with both wet and dry granulation techniques: roll compaction/dry granulation, high-shear granulation, twin-screw granulation, and fluidized-bed granulation. The produced granules were characterized in terms of granule size distribution, X-ray powder diffraction, scanning electron microscopy, porosity, and strength. Granules were tableted, and the tablets were evaluated in terms of tensile strength and mass variation. A particular focus was given to granule strength measurements. Granule strength showed to be strongly affected by the used granulation technique. Moreover, a nonlinear inverse correlation was identified between granule strength and tablet tensile strength. High-shear granulation produced the densest and strongest granules, which presented the lowest tablet tensile strength. Granules manufactured by roll compaction/dry granulation showed no loss in tabletability with the used formulation even for the more compacted and strong granules. Tablets produced by the fluidized-bed granulation showed the best properties in terms of tensile strength and mass variation. However, twin-screw granulation presented comparable results for the specific formulation evaluated in the study, thus revealing a great potential of this technique.

High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties

Context: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation.Objective: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer.Methods: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the ‘out-of-die’ Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4 L, 300 L, and 600 L.Results and conclusion: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.

Homogenization of Amorphous Solid Dispersions Prepared by Electrospinning in Low-Dose Tablet Formulation.

Low-dose tablet formulations were produced with excellent homogeneity based on drug-loaded electrospun fibers prepared by single-needle as well as scaled-up electrospinning (SNES and HSES). Carvedilol (CAR), a BCS II class compound, served as the model drug while poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was adopted as the fiber-forming polymer. Scanning electron microscopy (SEM) imaging was used to study the morphology of HSES and SNES samples. Different homogenization techniques were compared to maximize homogeneity: mixing in plastic bags and in a high-shear granulator resulting in low-shear mixing (LSM) and high-shear mixing (HSM). Drug content and homogeneity of the tablets were measured by UV-Vis spectrometry, the results revealed acceptably low-dose fluctuations especially with formulations homogenized with HSM. Sieve analysis was used on the final LSM and HSM powder mixtures in order to elucidate the observed differences between tablet homogeneity. Tablets containing drug-loaded electrospun fibers were also studied by Raman mapping demonstrating evenly distributed CAR within the corpus.

Multivariate modeling to evaluate effect of fabricating process on product profile of high shear granulation

ObjectiveTo investigate the feasibility of high shear granulation (HSG) for agglomeration of Crataegi Folium extract (Chinese edible herbal), and explore the effect of process variables on granule critical quality attributes (CQAs) by three different models, i.e., response surface methodology (RSM), multilayer perceptron neural networks (MLP), and partial least squares method (PLS). MethodsRSM, MLP, and PLS complementary to design of experiment (DoE) were utilized to investigate the influence of granulation time, impeller speed, and binder amount on the products. Crataegi Folium extract was employed as granulation powder. RSM was further carried out to develop design space of HSG. ResultsThe results indicated that RSM, MLP, and PLS modeling techniques enhanced the understanding and controlling of granules produced via HSG. The granule CQAs were mainly influenced by granulation time, impeller speed, and binder amount. Overlay plots of the RSM indicated that design space for the operating ranges of impeller speed and binder amount at high levels of granulation time was the smallest. ConclusionThe study showed that these models were useful to characterize the granulation process, and was particularly important to understand the process.

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.

Use of Mixer Torque Rheometer to Clarify the Relationship between the Kneading States of Wet Mass and the Dissolution of Final Product in High Shear Granulation

The properties of wet mass, which indicate the progress of high shear granulation processes, usually have an effect on final product properties, such as tablet dissolution. The mixer torque rheometer (MTR) is a useful tool for quantitatively measuring the 'kneading state' of wet mass and detecting differences in granules. However, there have been no studies of the relationship between the MTR torque and the final product properties to date. In this study, we measured the MTR torque of wet granules at different kneading states, which were prepared by changing the granulation conditions. We then evaluated the relationship between the MTR torque and the dissolution rate of the final product properties. The amperage of the high shear granulator is usually monitored during granulation, but we could not detect a difference in the kneading state through the amperage. However, using MTR torque we were able to quantify the difference of the wet mass. Moreover, MTR torque showed a high correlation with dissolution, compared with the correlations with other intermediate properties, such as granules particle size and tablet hardness. These other properties are affected by following processes and are not properties that directly relate to the kneading state. Thus, MTR torque is a property of wet mass after granulation, and it can be used to directly evaluate differences of the kneading state, and as a result, dissolution. These results indicate the importance of controlling the kneading state, i.e., the progress of granulation, and the utility of MTR for detecting differences in wet mass.

Mechanism of the formation of hollow spherical granules using a high shear granulator

Recently, we have developed a novel granulation technology to manufacture hollow spherical granules (HSGs) for controlled-release formulations; however, the mechanism of the granulation is still unclear. The aim of this study is to determine the mechanism of the formation of the HSGs using a high shear granulator. Samples of granulated material were collected at various times during granulation and were investigated using scanning electron microscope and X-ray computed tomography. It was observed that the granulation proceeded by drug layering to the polymer, followed by formation of a hollow in the granule. In addition, it was also found that generation of a crack in the adhered drug layer and air flow into the granules might be involved in forming the hollow in the structure. Observation of the granulation of formulations with different types of drugs and polymers indicated that negative pressure in the granules occurred and the granules caved in when the hollow was formed. The hollow-forming speed and the shell density of the hollow granules depended on the particular drug and polymer. Taken together, the granulation mechanism of HSGs was determined and this information will be valuable for HSGs technology development.

Microstructure of micro-crystalline cellulose based granules produced by high-shear wet granulation with long wet-massing time

Design and scale-up of batch high-shear granulation is complicated by the interplay of granule nucleation, growth, and breakage and their non-linear dependence on liquid binder addition rate and granulation time. In an earlier paper, we demonstrated that during extended wet massing times, granule growth and breakage rates become equal (pseudo-steady-state granulation), and the ultimate granule size distribution depends only on agitation intensity and granulating fluid level. This significantly simplifies scale-up. The granule size distributions produced in these long granulation times were quite narrow compared to those produced in more typical granulation times.This work provides additional characterization of the granules produced in “steady-state” granulation. We observe an interesting microstructural change in granules comprised of microcrystalline cellulose and lactose. During extended wet massing, these granules evolve from typical agglomerates comprised of primary MCC and lactose particles to a bi-continuous structure with a skeleton of porous cellulose with pores filled with the remaining formulation components. The soluble components can be removed from the pores by dissolution, leaving the porous MCC skeleton. The dependence of the microstructure on wet massing time, liquid level, and MCC content is reported.

An investigation on the evolution of granule formation by in-process sampling of a high shear granulator

Understanding the growth mechanisms in granulation process is an important topic, providing valuable insights and supports control strategies. Typically, observations in high shear granulators are made after stopping the process. In this work, an in-process sampling technique is described and applied to a high shear wet granulation process. Different samples can be collected over the cause of the high shear granulation process. This allowed observation of the evolution of granules during addition of water at a constant flowrate. For a typical pharmaceutical formulation, we observed that granules nucleate in the first 2min after starting the water addition and then grow to an average size of 200–1200μm at 12.5min, corresponding to a sharp increase in torque. Longer water addition times lead to oversized granules and eventually a paste and highly fluctuating torque. Sampling was also continued after stopping water addition which showed with time larger formed granules smoothen, whilst the smaller ones disintegrate. The work shows the in-process sampling can facilitate the identification of the granule growth kinetics and required binder quantity in high shear granulation.

In-Line Monitoring of a High-Shear Granulation Process Using the Baseline Shift of Near Infrared Spectra.

Although near infrared (NIR) spectra are primarily influenced by undesired variations, i.e., baseline shifts and non-linearity, and many applications of NIR spectroscopy to the real-time monitoring of wet granulation processes have been reported, the granulation mechanisms behind these variations have not been fully discussed. These variations of NIR spectra can be canceled out using appropriate pre-processing techniques prior to spectral analysis. The present study assessed the feasibility of directly using baseline shifts in NIR spectra to monitor granulation processes, because such shifts can reflect changes in the physical properties of the granular material, including particle size, shape, density, and refractive index. Specifically, OPUSGRAN®, a novel granulation technology, was investigated by in-line NIR monitoring. NIR spectra were collected using a NIR diffuse reflectance fiber optic probe immersed in a high-shear granulator while simultaneously examining the morphology, particle size, density, strength, and Raman images of the mixture during granulation. The NIR baseline shift pattern was found to be characteristic of the OPUSGRAN® technology and was attributed to variations in the light transmittance, reflection, and scattering resulting from changes in the physicochemical properties of the samples during granulation. The baseline shift also exhibited an inflection point around the completion of granulation, and therefore may be used to determine the endpoint of the process. These results suggest that a specific pattern of NIR baseline shifts are associated with the unique OPUSGRAN® granulation mechanism and can be applied to monitor the manufacturing process and determine the endpoint.

Chemical looping with oxygen uncoupling (CLOU) and chemical looping combustion (CLC) using copper-enriched oxygen carriers supported on fly ash

An experimental investigation on chemical activity and stability of innovative CuO-based oxygen carriers (OC) supported on coal fly ash, towards Chemical Looping Combustion (CLC) and Chemical Looping Oxygen Uncoupling (CLOU) is presented. The materials were prepared by granulation of fine powders of CuO and fly ash (FA), with 40–60–80wt% CuO loading (Cu40FA, Cu60FA and Cu80FA), using a high shear granulator. CLC and CLOU activities were investigated in a thermogravimetric analyzer (TGA) in the presence of a reactive fuel or an inert atmosphere, respectively. A rather stable CLOU capacity (Ro-CLOU) in the range of 4–8g O2/100g OC was found over 42 redox cycles, in agreement with the stoichiometry of the prepared samples. CLC oxygen carrying capacity (Ro-CLC) with gaseous fuel, on the other hand, has evidenced a quick decline for the material with higher copper loading (80wt% CuO). Furthermore, both oxygen carriers with 40–60wt% CuO were tested for combustion of coal in a macro-TGA rig using CO2 as carrier gas and different OC:fuel ratios. First, a blank test in the absence of the OC was carried out to characterize the fast devolatilization and slow gasification reactions taking place due to the exposure of the fuel to high temperature and CO2-rich atmosphere. The comparison of the weight loss curve evolution with and without oxygen carrier, and the measured residual carbon after test, enabled to extract the CLOU effect for each combination of material/solid fuel.

Application of continuous twin screw granulation for the metformin hydrochloride extended release formulation

This study focuses on evaluating the potential of transferring from a batch process to continuous process for manufacturing of the extended release formulation. Metformin hydrochloride (HCl) was used in the model formulation which was intended to contain the high amount of hydrophilic drug. The effects of barrel temperature, binder type, powder feed rate, and screw speed on granule properties (size and strength) and torque value in twin screw granulation were investigated. Due to the high content of hydrophilic model drug, the granules prepared at a higher temperature with HPMC binding solution had the narrower size distribution and greater strength than the granules prepared with distilled water as a binding solution. After continuous drying and milling steps, the granules (continuous process) satisfied the fundamental purpose of granulation with size and flowability, despite different shape compared with the granules (batch process). Furthermore, there were no significant differences between two granulation processes in tablet properties, such as tablet hardness and in vitro release. The considerations and strategies used in this study to transfer from a batch to continuous process can be applied to other existing formulations based on high shear granulation to enable rapid process transfer in the pharmaceutical industry.

Integrating the physics with data analytics for the hybrid modeling of the granulation process

A hybrid model based on physical and data interpretations to investigate the high shear granulation (HSG) process is proposed. This model integrates three separate component models, namely, a computational fluid dynamics model, a population balance model, and a radial basis function model, through an iterative procedure. The proposed hybrid model is shown to provide the required understanding of the HSG process, and to also accurately predict the properties of the granules. Furthermore, a new fusion model based on integrating fuzzy logic theory and the Dempster‐Shafer theory is also developed. The motivation for such a new modeling framework stems from the fact that integrating predictions from models which are elicited using different paradigms can lead to a more robust and accurate topology. As a result, significant improvements in prediction performance have been achieved by applying the proposed framework when compared to single models. © 2017 American Institute of Chemical Engineers AIChE J, 2017

Analysis of mesoscale effects in high-shear granulation through a computational fluid dynamics–population balance coupled compartment model

There is a need for mesoscale resolution and coupling between flow-field information and the evolution of particle properties in high-shear granulation. We have developed a modelling framework that compartmentalizes the high-shear granulation process based on relevant process parameters in time and space. The model comprises a coupled-flow-field and population-balance solver and is used to resolve and analyze the effects of mesoscales on the evolution of particle properties. A Diosna high-shear mixer was modelled with microcrystalline cellulose powder as the granulation material. An analysis of the flow-field solution and compartmentalization allows for a resolution of the stress and collision peak at the impeller blades. Different compartmentalizations showed the importance of resolving the impeller region, for aggregating systems and systems with breakage. An independent study investigated the time evolution of the flow field by changing the particle properties in three discrete steps that represent powder mixing, the initial granulation stage mixing and the late stage granular mixing. The results of the temporal resolution study show clear changes in collision behavior, especially from powder to granular mixing, which indicates the importance of resolving mesoscale phenomena in time and space.