A study of foam granulation and wet granulation in a twin screw extruder

This research investigated a new technique known as foam granulation for the continuous manufacturing of pharmaceuticals by a twin screw extruder. Six grades of hypromellose were compared as binders in the trials, using two addition methods: foam injection by auxiliary side stuffer feeder and liquid injection directly into the extruder. The produced granules were tested for particle size, Carr compressibility index and characteristic fracture strength. It was found that granulation using foam injection improved powder lubrication inside the extruder and wetting uniformity of the lactose, as well as produced granules having lower Carr indices. © 2012 Canadian Society for Chemical Engineering     

Foam granulation: Binder dispersion and nucleation in mixer-granulators

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

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

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

Foam and drop penetration kinetics into loosely packed powder beds

Foam granulation is a new liquid delivery method for wet granulation, where the liquid binder is delivered as an aqueous foam, rather than as an atomised spray to the powder bed. This paper reports for the first time the similarities and differences between wet granulation via foamed and sprayed binder addition methods.The kinetics of single foam and single drop (of HPC and HPMC solutions) penetrations into loosely packed powder beds (of glass ballotini and lactose powders) were studied. Specific penetration time (defined as penetration time per unit of binder mass) and nucleation ratio (defined as the ratio of nuclei granule mass to liquid binder mass) were compared between foam and drop nucleation methods. The impact of particle size and binder concentration on both parameters was also studied.The results indicate that the foamed binder addition method allows a greater mass of binder fluid to be absorbed into the particle bed and uses less liquid binder to nucleate the same number of gram of powder, which indicates improved nucleation efficiency compared to the drop addition method.     

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.     

The effect of wetting liquid droplet size on the growth of agglomerates during wet drum granulation

Results of investigation of the effect of wetting liquid droplet size on the growth of agglomerates during wet drum granulation of dolomite flour of selected grain-size composition which guaranteed geometrical similarity were discussed.

The process of granulation was carried out batch-wise in a drum granulator 0.5 m in diameter and 0.4 m long at rotational speed 0.33 s⁻¹ and constant volumetric drum filling degree =0.1. On the bed tumbling in the drum, the wetting liquid (distilled water) was supplied at a constant flow rate Q_w=12×10⁻³ m³/h. The size of wetting droplets was changed using various air flow rates through pneumatic spray nozzles in the range Q_a=1.0 to 3.0 m³/h and applying a sprinkler which supplied (drop-wise) the liquid uniformly along the entire drum length. In the whole experimental cycle, constant mean saturation degree of the feed equal to S=0.293 was used. Relationships determining the effect of wetting droplet size and particle size distribution of the raw material on the rate of agglomerate growth during drum granulation were developed.     

Evaluation of the physical and mechanical properties of high drug load formulations: Wet granulation vs. novel foam granulation

The purpose of this study was to evaluate the influences of intrinsic drug mechanical properties and different granulation binder delivery processes on the physical and mechanical properties of high drug load granulations after wet granulation. Formulations (80% w/w) of acetaminophen (APAP), metformin and aspirin, which are brittle, viscoelastic, and ductile, respectively; were granulated by high-shear wet granulation. Two modes of binder delivery for wet granulation, either conventional or binder foam, were investigated. Particle size, surface area and pore size of the granulations were characterized. Compacts were prepared at a solid fraction of 0.9 under tri-axial decompression and Hiestand indices (worst-case bonding index (BI_w) and brittle fracture index (BFI)) of the compacts were determined. APAP formulations exhibited the smallest geometric mean particle sizes (d_g) and showed only slight differences in d_g values between the two granulation processes. Binder delivery mode affected mechanical properties of the granulated model drugs differently. Foam granulation appeared to enhance the granule plasticity for APAP while aspirin showed a mixed deformation mechanism based on both its high BI_w and high BFI values. The higher BI_w value for aspirin after foam granulation may be attributed to improved binder distribution among particles during granulation. On the other hand, conventional wet granulation improved the plasticity of metformin as measured by the higher BI_w and lower BFI values. Therefore, conventional wet granulation process conferred advantages in manufacturability and product quality for metformin; as compared to foam granulation which did not enhance plasticity for metformin. Based on this study, a wet granulation process can be selected based on knowledge of the intrinsic drug mechanical properties.     

双螺杆湿法制粒关键质量属性调控机理模拟研究

针对我国造粒工艺存在关键质量属性（粒径分布均匀性、颗粒表观质量和制粒收率）难以调控的行业共性问题,基于Edinburgh Elastic?Plastic Adhesion接触模型,构建了连续异向啮合双螺杆高剪切湿法制粒过程的仿真方法,模拟研究了过程参数?粒径分布均匀性和收率的协同耦合演化规律,以此诠释了双螺杆湿法制粒关键质量属性的调控机理。结果表明,连续异向啮合双螺杆高剪切湿法制粒机能制备表面光滑的球化颗粒,粒径与粉体喂料速度呈正关联关系,而与螺杆转速呈负关联关系,制粒收率与粉体喂料速度、螺杆转速均呈现先增后减的演化规律;在粉体喂料速度为360 kg/h或螺杆转速为1 400 r/min时,制粒收率处于最佳状态,其最优制粒收率值分别为87.9 %和83.91 %;制粒粒径主要受控于颗粒平均停留时间和持有颗粒质量,且呈正关联关系,以此提出了通过粉体失重喂料装置螺杆和异向啮合双螺杆高剪切湿法制粒机螺杆的变频转速控制,在线实时调控合格颗粒粒径和收率的技术方法。     

Study of dynamic multi-dimensional temperature and concentration distributions in liquid-sprayed fluidized beds

A physically based model was developed for heat and mass transfer processes in liquid-sprayed fluidized beds. Such fluidized beds are used for granulation, coating and agglomeration. The complex correlations of a number of microprocesses, spraying, wetting, drop deposition, heat transfer, drying and mass transfer were studied, and transient three-dimensional distributions of air humidity, air temperature, particle wetting efficiency, liquid film temperature, particle temperature, local liquid loading and local evaporation rate were calculated. For the evaluation of the model, the stationary spatial air temperature distributions were measured at a fluidized bed pilot plant of the institute. The fluidized bed of monodisperse wood- or glass beads was sprayed with clear water. Conclusions are drawn on the relevance of particle dispersion, spraying and drying to simulating temperature and concentrations distributions.     

Wettability study for pigmentary titanium dioxide

Wetting is the first step in the dispersion process of any powder. Understanding how the powder surface and the liquid properties affect the speed and intensity of the wetting process provides a set of tools to determine the dispersion efficiency as a whole, and an effective dispersion allows the reduced use of the powder to achieve the specified final properties. This article reports experimental results on the wetting behavior of five different TiO₂ samples by liquids with different values of surface tension [deionized (DI) water and DI water containing surfactants] and its effect on the dispersion process. The selection of the TiO₂ samples was based on different particles sizes with similar surface properties, and similar sizes with different surface properties. The samples were characterized in terms of their specific surface area and particle size distribution. The wetting behavior was evaluated by a capillary rise technique (Washburn) to measure liquid penetration height and rate, and the time evolution of the particle size distribution. The results show that larger particles presented faster wettability and that liquids with lower surface tension facilitate the wetting of the powder. The energy required to deagglomerate the powder is inversely proportional to the wetting speed: the faster the wetting the easier it will be to disperse the particles, with less energy required.     

Fractionation of Nanocellulose by Foam Filter

The foam fractionation method was applied for nanocellulose. Experiments were carried out with enzymatically pretreated nano-fibrillated cellulose (NFC) from softwood, as well as commercial products. Narrow channels (plateaus) between bubbles prevent the flow of coarse particles along the water, so that foam acts like a filter. The advantage of the method is no risk of clogging, which could be a big problem for conventional filters or screens. Mean particle size (effective size by means of dynamic light scattering measurement) was reduced by foam fractionation, and the reduction range depended on the cellulose grade and the type of surfactant. The yield turned out to be low, probably because of particle aggregation due to the interaction with surfactant.     

Microstructure and rheologic development of polypropylene/nano‐CaCO3 composites along twin‐screw extruder

Polypropylene/nano‐calcium carbonate (PP/nano‐CaCO₃) composites were prepared by using an intermeshing, co‐rotating twin‐screw extruder. Two different screw configurations, denoted by screws A and B, respectively, were employed. The former provided high dispersive mixing and the later provided high dispersive and distributive mixing. Effect of mixing type on microstructure and rheologic development of nanocomposites was investigated by taking samples from four locations along screws A and B. Transmission electron microscopy results show that in the sample at the exit of extruder, the percentage of nano‐CaCO₃ particles with the equivalent diameter lower than 100 nm along screws A and B is 66.5 and 79.0%. respectively. Moreover, for screw B, the number‐averaged diameter at four sampling locations is smaller than that for screw A. This means that the distributive mixing, provided by screw B, favors the size decrease of nano‐CaCO₃ in the PP matrix. In addition, rheologic results show that the decrease of complex viscosity for the nanocomposites is deeply related to turbine mixing elements, which provides distributive mixing. The online melt shear viscosity of the nanocomposite at the exit of extruder prepared by screw B is lower than that of pure PP. This is related to the dispersion of nano‐CaCO₃ in PP matrix. Finally, the relationship between rheologic properties and microstructure was analyzed. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Process intensification in particle technology: Characteristics of powder coatings produced by nonisothermal flow‐induced phase inversion

The characteristics of powder coatings manufactured through a novel processing technique based on nonisothermal Nlow‐induced phase inversion granulation enhanced by fluid injection to promote phase inversion and particle formation from melt state is summarized. Experiments were carried out in a purpose‐built granulator, which operates in a parallel disk rotor‐stator arrangement, so that the mechanism of granulation could be studied. The product of this intensive granulation was compared with that of the conventional powder coating manufacturing process. Understanding the mechanism of intensive granulation helped to redesign the equipment that resulted in smaller particles. Pigment dispersion characteristics were improved by intensive granulation. Also, the particle size span can be significantly reduced by dry granulation and gas‐phase granulation, and the flowability can be improved by wet granulation. Chemical analysis of particles by Fourier transform infrared spectroscopic analysis showed that the injection of coolant fluid had no effect on the chemical composition. © 2011 American Institute of Chemical Engineers AIChE J, 2012     

Agglomeration in suspension of salicylic acid fine particles: Analysis of the wetting period and effect of the binder injection mode on the final agglomerate size

Agglomeration in suspension is a size enlargement method which facilitates the operations of solid processing such as filtration, transport and galenic while preserving the solubilisation properties of fine particles. A small quantity of binding liquid is added into a suspension of microparticles, directly in the stirred vessel where the precipitation or crystallisation took place. With optimised quantity of binder injected and optimised injection mode, spherical and dense agglomerates can be obtained. This paper analyses the first step of the agglomeration process, i.e. the wetting period, which corresponds to the injection of the binder liquid and its dispersion within the particle suspension. The system studied is the agglomeration of salicylic acid microparticles using chloroform as binder. A visualisation cell was developed in order to observe under optical microscope the interactions between a liquid binder droplet and the particles to be agglomerated. Clearly, an immersion mechanism was observed. Experiments were also carried out in a stirred vessel to visualise the wetting phase within the reactor using an image acquisition probe. The effect of the injection mode and quantity of binder on the agglomerate size was analysed. A fast binder injection under high stirring and an optimum quantity of binder favour the formation of small agglomerates.     

Monitoring quality attributes for high-shear wet granulation with audible acoustic emissions

Continuing development of process analytical technology (PAT) tools is needed in the pharmaceutical industry to provide more flexible processing and achieve products of consistent quality. For high-shear wet granulation, audible acoustic emissions (AAEs) have shown potential as a PAT tool for monitoring changes in physical properties related to product quality. This article develops the relationship between AAEs and two critical quality attributes, size and density, and investigates the potential for monitoring product quality online. Condenser microphones were placed inside the air exhaust of a PMA-10 high-shear granulator to collect AAEs for a design of experiment (DOE) where particle size and density were varied by changing the grade of Avicel in the formulation. The results showed increases in particle size and density affect the observed decreases in the AAEs at granulation end-point and during over wetting. In addition, the changes in size and density could be represented by different combinations of 10 Hz frequency groups and the trends in the multivariate scores support online monitoring.     

注塑螺杆计量段槽深和导程的模拟及优化

首先建立注塑螺杆的模拟及优化平台,该平台以Injection Molding Plastification(IMP)软件为基础,结合DOE(实验设计)方法,将不同螺杆的模拟结果进行DOE分析和优化。重点对常规三段式螺杆的计量段结构进行了研究,分别采用模拟优化和实验优化的方法对计量段槽深和导程进行了优化。并将两种优化方法的优化结果进行对比,结果分析表明:模拟与实验优化结果比较接近,初步形成模拟与实验相结合的优化思路。在螺杆的模拟优化之前,对IMP软件的可靠性和准确性进行初步验证,通过比较模拟和实验获得的螺杆沿程压力、螺杆扭矩,结果表明该软件基本上能够较准确地反映实际加工过程。     

场协同对PP/PS复合体系传热传质性能的影响

从动量和能量守恒方程出发,提出速度场与温度场的协同耦合作用对聚合物流动与换热具有重要影响,并以此为依据设计了新型扭转螺杆结构和场协同螺杆。以聚丙烯(PP)和聚苯乙烯(PS)为原料制备PP/PS复合材料体系,通过挤出试验对比研究了常规螺杆与场协同螺杆的传热传质性能。结果表明,相对于常规螺杆,设置有扭转螺杆结构的场协同螺杆的数均粒径更小、粒径分布密度和平均停留时间更大,提高了挤出机的混合能力;场协同螺杆的对流换热系数更大、径向温差更小,提高了挤出机的换热能力。     

注射螺杆熔融过程的可视化研究

讨论了注射螺杆和挤出螺杆熔融过程的差异；并研究了工艺条件、螺杆参数和结构对注射熔融过程的影响；观察了熔融延迟点的位置变化；同时测量了注射熔体的轴向温差，并对其影响因素进行了讨论。结果表明：注射螺杆工作的全过程是在轴移和静止两种状态下交替进行；塑料在注射螺杆上相变点的位置是变化着的，变化条件有背压、转速、行程、温度、树脂、停留时间等；注射螺杆某螺槽内的树脂聚集状态，随注塑周期呈周期性变化；螺杆参数和结构设计，直接关系到熔料温差和塑化能力；合理的设计和创新螺杆结构是获得低温差、高混合和高塑化能力的主要途径。     

Granulation rate processes in the kneading elements of a twin screw granulator

To characterize the granulation rate processes in the kneading section of the twin screw granulator, separate experiments were conducted using exclusively conveying elements as the baseline in addition to different configurations of kneading elements. The configuration parameters examined were the length of the kneading section, the advance angle, and the angle direction. Granule size, shape and liquid distribution were measured. Two main rate processes were observed (1) breakage and layering, and (2) Shear elongation and layering. Breakage was dominant in the 90° configuration while shear elongation dominated in the 30° reverse configurations, with other configurations giving some combination of the two rate processes. The distinct three‐dimensional (3‐D) shape characteristics of granules obtained from each configuration were crucial in elucidating the dominant granulation rate process in each case. The proposed granulation mechanisms explain the events leading to particular granule attributes, but more importantly provide insight into future optimization of twin screw granulation process. © 2013 American Institute of Chemical Engineers AIChE J, 59: 4100–4115, 2013     

Effect of screw design on hopper drawdown of spherical particles in a horizontal screw feeder

Screw feeders are used to remove material from hoppers and bins at a controlled rate. The evenness of the flow in the bin depends on the drawdown pattern, which in turn depends on the screw and hopper design, shape of the particles and wall friction effects. A key design requirement is to ensure that a progressive increase in the screws volumetric capacity is achieved along the entire length of the hopper's opening so as to produce even drawdown. If this is not achieved then compositional variations in the outgoing stream and other operational problems (such as caking) can be created. Screw designs to date have been generally based on analytical models and at times the predicted flow pattern is not achieved. In this study, the Discrete Element Method (DEM) is used to predict particle transport in a horizontal screw feeder system for a range of conventional screw designs including a variable screw pitch, variable screw flight outside diameters and variable core diameters. The influence of screw choice on the particle mass flow rate, the evenness of particle drawdown from the hopper, power consumption, screw wear and wall friction variations are all investigated. Important features captured by DEM that are not accounted for by the analytic model and which vary strongly between competing screw designs, include the particle circulation in the hopper, shearing of the particle bed in the trough just outside the screw and the spatially varying particle force along the hopper which leads to non-uniform drawdown and to the existence of large stagnant or slow moving zones. The screw design and consequent flow patterns also strongly affect the power draw with variations up to a factor of three and screw wear with large changes in their distribution and magnitude. Finally, the surface frictional properties of the screw are shown to strongly influence the rate of bed compaction within and along the screw leading to strong variation in mass flow rate, uniformity of drawdown and power draw.