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.     

Process intensification in particle technology: Intensive granulation mechanism and granule characteristics

The mechanism and processing characteristics of a novel intensified granulation technique are evaluated. This intensification technique is based on the non-isothermal flow induced phase inversion (FIPI) phenomenon. Poly(ethylene glycol) (PEG) with an average molecular weight 10⁴ and calcium carbonate powder (mean particle size 2.7 m) were used as binder and filler to prepare granules. The granulation experiments were carried using a Haake extruder (Rheomex 252) which connected to a granulator of a new design. The extruder produced a homogenous PEG and calcium carbonate paste and fed it to the granulator. When the paste was subjected to a temperature gradient field with a superimposed repeated shear and extensional deformation, solidification, granule nucleation and subsequent macroscopic fragmentation (referred to as crumbling) occurred to give granular particles. The mechanism of granulation has been discussed. The granule size and size distribution characteristics under different process conditions have been evaluated. The novelty of this research lies in the granulator design and the mechanism of the granulation process. Temperature differential and repeated deformation are the two primary factors for the granulation process. Particle size distribution and crumbling area depend on the concentration of PEG, the clearance between rotor and stator, and the extrusion speed. If a so called crumbling agent, in the form of fine particles, is added to the newly formed granules, these granules are coated with the crumbling agent forming a core-shell type of granulated particles.     

Physical aspects of wet granulation III. effect of wet granulation on granule porosity

Abstract

The porosity of granules produced by wet granulation has been studied using mercury porosimetry. Granule pore size distribution appears to be bimodal, with a population of micropores and macropores. Pore surface area varies with kneading time, going through a maxima at a point where physical properties such as flow and bulk density also exhibit a maxima. True granule density displays a direct relationship to rate of flow. The information in general supports the postulate that equilibrium microporous granules are formed first in the wet granulation process, followed by consolidation with subsequent formation of microporous twins and agglomerates.     

Physical aspects of wet granulation III. effect of wet granulation on granule porosity

The porosity of granules produced by wet granulation has been studied using mercury porosimetry. Granule pore size distribution appears to be bimodal, with a population of micropores and macropores. Pore surface area varies with kneading time, going through a maxima at a point where physical properties such as flow and bulk density also exhibit a maxima. True granule density displays a direct relationship to rate of flow. The information in general supports the postulate that equilibrium microporous granules are formed first in the wet granulation process, followed by consolidation with subsequent formation of microporous twins and agglomerates.     

Evaluation of the influence of granulation processing parameters on the granule properties and dissolution characteristics of a modified release drug

Understanding the relationship between high shear wet granulation processing parameters and the characteristics of intermediate and final products is crucial in the ability to apply quality by design (QbD) and process analytical technologies (PAT) to secondary pharmaceutical processes. This research examined a high shear wet granulation process and subsequent manufacturing of a tablet containing a biopharmaceutics classification system (BCS) class II drug, gliclazide (low solubility, high permeability). Previous studies have concentrated on either granulation or tabletting but not both together; this work brings together the analysis as a single large multivariate process. The design of experiment (DoE) was performed according to an L9 Taguchi method with three replications, in total; thirty-six runs were performed. A full statistical analysis relating both granule and tablet properties to selected process parameters were carried out. The research illustrates that mapping a highly multivariate process is possible. Statistically significant critical process parameters were identified for granule hardness, granule density and granule particle size. These granule properties were also identified as contributing to the dissolution release characteristics. Dissolution modeling and prediction was achieved within the DoE structure. Process noise was identified and measured across the entire production and specifically with respect to the milling process.     

Modelling effects of processing parameters on granule porosity in high-shear granulation

When trying to meet final product specifications for porosity of granules made using high-shear granulation there are many choices for the formulation recipe and processing conditions. This paper presents the concept of a Critical Packing State of the primary particles forming a granule and the associated Limiting Binder Ratio, which allows granule consolidation to be modelled. The effect on consolidation of varying the following processing parameters is explained: Mixing intensity, mixing time and binder addition method. The effects of varying the following aspects of the formulation recipe are explained: Primary particle type, shape and size distribution, binder type and binder: solid ratio.     

Multiphase versus single pot granulation process: influence of process and granulation parameters on granules properties

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes.

The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.     

Comparison of low-shear and high-shear granulation processes: effect on implantable calcium phosphate granule properties

Background: Calcium phosphate porous ceramics present a great interest not only as complex bone defect fillers but also as drug delivery systems. Most of the methods described in the literature to fabricate pellets are based on compaction, casting into spherical molds, or on processes such as liquid immiscibility or foaming. Despite wet granulation is used in a wide range of applications in pharmaceuticals, food, detergents, fertilizers, and minerals, it is not applied in the biomaterial field to produce granules. Methods: In this study physicochemical and in vitro drug delivery properties of implantable calcium phosphate granules, produced by two wet agglomeration processes, were compared. Pellets obtained by high shear granulation (granulation in a Mi-Pro apparatus) were shown to be more spherical and less friable than granules elaborated by low shear process (granulation in a Kenwood apparatus). Although Mi-Pro pellets had a slightly lower porosity compared to Kenwood granules, ibuprofen loading efficiency and dissolution profiles were not statistically different and the release mechanism was mainly controlled by diffusion, in both cases. Conclusion: Mi-Pro pellets appeared to be better candidates as bone defect fillers and local drug delivery systems as far as they were more spherical and less friable than Kenwood agglomerates.     

The effect of process parameters on audible acoustic emissions from high-shear granulation

Product quality in high-shear granulation is easily compromised by minor changes in raw material properties or process conditions. It is desired to develop a process analytical technology (PAT) that can monitor the process in real-time and provide feedback for quality control. In this work, the application of audible acoustic emissions (AAEs) as a PAT tool was investigated. A condenser microphone was placed at the top of the air exhaust on a PMA-10 high-shear granulator to collect AAEs for a design of experiment (DOE) varying impeller speed, total binder volume and spray rate. The results showed the 10 Hz total power spectral densities (TPSDs) between 20 and 250 Hz were significantly affected by the changes in process conditions. Impeller speed and spray rate were shown to have statistically significant effects on granulation wetting, and impeller speed and total binder volume were significant in terms of process end-point. The DOE results were confirmed by a multivariate PLS model of the TPSDs. The scores plot showed separation based on impeller speed in the first component and spray rate in the second component. The findings support the use of AAEs to monitor changes in process conditions in real-time and achieve consistent product quality.     

基于铰刀厚度的陶瓷干法造粒混料过程数值分析

基于铰刀厚度对陶瓷干法造粒混料过程的影响,采用计算流体动力学方法建立干法造粒混料过程欧拉-欧拉双流体模型,数值模拟分析混料过程粉体颗粒的体积分布、合成速度大小和运动轨迹,同时实验分析验证数值模拟的正确性。结果表明:当铰刀厚度分别为16、14、12、10、8 mm时,有效颗粒占比依次为82%、84%、90%、83%、81%;铰刀厚度对陶瓷干法造粒混料过程具有一定的影响,厚度为12 mm时,混料过程粉体堆积现象不明显,速度相对较均匀,分散性及流动性较好,有效颗粒占比最大,造粒效果最佳。     

Flash calcines of kaolinite: Effect of process variables on physical characteristics

The physical transformation of powdered kaolinite associated with rapid dehydroxylation during flash calcination has been followed using pycnometry, thermogravimetry, electron microscopy, X-ray powder diffraction and infrared spectroscopy. 116 partially dehydroxylated kinetically-frozen calcines were produced in a laboratory flash calciner covering the following ranges of process variables: calciner temperature 700–1000 °C, rate of heating to calciner temperature 4700–15000 Ks^–1, residence time at the calciner temperature 0.1–1.5 s, He or N₂ calciner atmosphere. From the analyses of these calcines a picture of the changes in physical characteristics caused by flash heating of kaolinite has emerged and is described.     

The conductivity of the damp mass during the massing stage of the granulation process

A Planetary mixer has been modified so that the conductivity of the damp mass could be studied during the process of wet-massing in granulation. The technique makes it possible to follow the distribution of the binder liquid and possibly also the changes in packing that occur during massing.     

The conductivity of the damp mass during the massing stage of the granulation process

Abstract

A Planetary mixer has been modified so that the conductivity of the damp mass could be studied during the process of wet-massing in granulation. The technique makes it possible to follow the distribution of the binder liquid and possibly also the changes in packing that occur during massing.     

Effect of three-dimensional melt pool convection on process characteristics during laser cladding

A three-dimensional heat transfer model is developed to simulate the cladding process that include the different physical phenomena such as heat transfer, phase changes, addition of powder particles and fluid flow due to Marangoni–Rayleigh–Benard convection. It is found that the Rayleigh–Benard convection is insignificant and Marangoni–Benard convection is dominant for the studied cases. By varying the scanning speed and Marangoni number the melt pool size and strength of convection are changed and its influence on clad built-up geometry, dilution level, maximum and average melt pool temperatures and the form and scale of the microstructure of the solidified clad track has been studied.     

An experimental study on the spray characteristics of pressure nozzle in a fluid bed granulation

The particles with a narrow size distribution are proper products in a fluid bed granulation and coating. As well, the process efficiency is one of the most important parameters, and the wall deposition of sprayed liquid reduces it. The modality of spray volume distribution is a key parameter in the definition of particle size distribution and process efficiency. This work is done in two steps: In the first step, an experimental study on spray characteristics including spray flux distribution, spray cone angle, and discharge coefficient is conducted. Based on the experimental data, the curves of liquid volume flux versus nozzle pressure and height are obtained. The results indicate that the flux distribution changes significantly with even small pressure and height changes. In the second step, the granulation process is carried out in a semi-industrial conical fluid bed, and the particles size distribution curves and the deposited mass on the bed wall are obtained. The results show that the precise determination of the spray flux distribution is an appropriate way to predict the well-advised nozzle pressure/height in order to achieve the narrow particle size distribution and high efficiency of the process.     

Using experimental design to optimize the process parameters in fluidized bed granulation

In this study many parameters were screened for a small-scale granulation process for their effect on the yield of granules between 75 and 500 μm and the geometrical granule mean size (d50). First a Plackett-Burman design was applied to screen the inlet air temperature, the inlet flow rate, the spray rate, the nozzle air pressure, the nozzle spray diameter, and the nozzle position. The Plackett-Burman design showed that the key process parameters were the inlet flow rate and the spray rate and probably also the inlet air temperature. Afterward a fractional factorial design (2^5-2) was applied to screen the remaining parameters plus the nozzle aircap position and the spraying time interval. The fractional factorial design showed that the nozzle air pressure was also important. As the target values for the granule yield (between 75 and 500 μm) and the geometric mean granule size (between 300 and 500 μm) were reached during the screening experiments, further optimization was not considered necessary.     

Latent structure analysis in the pharmaceutical process of tablets prepared by wet granulation

Background: Granule characteristics are some of the important intermediate qualities that determine tablet properties. However, the relationships between granule and tablet characteristics are poorly understood. The aim of this study was to elucidate relationships among formulation factors, granule characteristics, and tablet properties using a non-linear response surface method (RSM) incorporating a thin-plate spline interpolation (RSM-S) and a Bayesian network (BN).

Method: Tablets containing lactose (Lac), cornstarch (CS), and microcrystalline cellulose (MCC) were prepared by wet granulation. Ten formulations were prepared by an extreme vertices design. The angle of repose (Y₁), compressibility (Y₂), cohesion force (Y₃), internal friction angle (Y₄), and mean particle size (Y₅) were measured as granule characteristics. Tensile strength (TS) and disintegration time (DT) were measured as tablet properties.

Results: RSM-S results showed that TS increased with increasing amounts of MCC and Lac. DT decreased with increasing amounts of MCC and CS. The optimal BN models were predicted using four evaluation indices –Y₃ was shown to be the most important factor for TS, whereas Y₂, Y₃, and Y₄ were relatively important for predicting DT. Moreover, tablets with excellent tablet properties (i.e. high TS and low DT) were produced by relatively high Y₁, low Y₂, high Y₃, high Y₄, and middle Y₅ values, and resulted from the middle of MCC, middle-to-low CS, low Lac, and middle-to-low magnesium stearate (Mg-St) amounts.

Conclusion: The RSM-S and BN techniques are useful for revealing complex relationships among formulation factors, granule characteristics, and tablet properties.     

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).     

Study of granule growth kinetics during in situ fluid bed melt granulation using in-line FBRM and SFT probes

Objective: The aim of this work was to study the granule growth kinetics during in situ fluid bed melt granulation process using real-time particle size measurement techniques. In addition, the usefulness of these techniques during scale-up of melt granulation was evaluated.

Materials and methods: Focused beam reflectance measurement (FBRM) and spatial filtering technique (SFT) probes were used within the process chamber of fluid bed granulator for real-time in-line granule size analysis.

Results: The results demonstrated that the use of in-line particle size probes in fluid bed granulator during the process offers an insightful view of granule growth and allows in-process monitoring of granule chord length changes. The effect of selected critical parameters (binder content, inlet air temperature and product endpoint temperature) on the granule growth was clearly presented by in-line measurements in a laboratory scale. A comparison of granule size measurements from both FBRM and SFT probes showed similar particle growth trends, which were in close correlation to the product temperature. Comparable trends in end granule particle size were observed when comparing different in-line, at-line and off-line particle size measurements.

Conclusion: The in-line FBRM and SFT probes were successfully employed in in situ fluid bed melt granulation process to study the influence of critical formulation/process parameters on the granule growth kinetics. The scale-up experiment confirmed the potential of these in-line granule size measurement techniques as a viable tool for process monitoring during the transfer of granulation to the larger scale or another manufacturing site/equipment.     

Preliminary report of the discovery of a new pharmaceutical granulation process using foamed aqueous binders

Spray granulation is commonly used to improve the flow of drug formulation powders by adding liquid binders. We have discovered a new granulation process whereby liquid binders are added as aqueous foam. Initial experiments indicate that foam granulations require less binder than spray granulations, less water is added to the powder mass, rates of addition of foam can be greater than rates of addition of sprayed liquids, and foam can be added in a single batch to the surface of the powder mass for incorporation at some later stage in the process. This new process appears to have no detrimental effects on granulate, tablet, or in vitro drug dissolution properties. In addition, the elimination of spray addition reduces the complexity of the process and avoids the plugging problems associated with spray nozzles. Several formulations were successfully scaled up from laboratory scale (1.5 kg) to pilot scale (15 kg). Process control was good and there was no detrimental effect on tablet and drug dissolution properties. This paper also proposes a working hypothesis of the mechanism by which foam granulation operates.