Multi-component granulation in a fast fluidized bed

The granulation of multi-component particles was conducted in a fast fluidized bed with an atomizing binder solution. The effects of gas velocity and binder droplet diameter on granulation rate, granule size distribution and granule composition were studied. The granulation rate and granule yield were determined by the balance between the agglomeration rate of feed particles and the disintegration rate of granules because there was no secondary granulation. With the increase in gas velocity and the reduction in binder droplet size, the agglomeration rate of feed particles decreased but the disintegration rate of granules increased, resulting in a reduced granule yield. Despite the larger fraction of small particles in the granules, the homogenous granulation of multi-component particles was achieved.     

Strength and morphology of solid bridges in dry granules of pharmaceutical powders

This is an experimental study of the tensile strength of solid bridges between primary particles comprising granules of lactose or mannitol. We report on two systems: granules prepared with ethanol granulating solutions, in which the base powders were at most sparingly soluble, and aqueous granulating solutions, in which the base powder solubility was large. Both systems were studied with and without hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP) or surfactants (Triton-X100, sodium lauryl sulfate or polysorbate 80) added to the granulating solution. The interparticle bridge strength was determined from the granule crush strength with a simple model that assumes that solid bridges form by evaporation of solvent from liquid bridges that maintain their shape during drying.Lactose granules prepared with pure ethanol are very weak, with crush strength comparable to that predicted by JKR theory, consistent with its negligible solubility. Mannitol, which is sparingly soluble, forms granules with bridge strength similar to the theoretical (Griffith) strength of a pure mannitol. Addition of HPC or PVP to the granulating solution produces bridges with strength comparable to that of pure polymer films. In comparison, the behavior of granules prepared with aqueous granulating solutions was much more complex due to the high saturation concentration of base powder. Granules produced with pure water had bridge strength approximately 20% of the theoretical strength. Addition of HPC or PVP to lactose granules increased the bridge strength modestly, but the strength was much smaller than that of the corresponding pure polymer films. Addition of HPC to mannitol granules had little effect on bridge strength, while PVP reduced bridge strength by approximately 30%. Addition of surfactants to the granulating solution also reduced dry bridge strength. These results reflect the complex microstructure and resulting mechanical properties of dry bridges produced by coprecipitation of the sugars and polymers (or surfactants).     

The effect of granule microstructure on dissolution rate

The relationship between the microstructure of granules and their dissolution rate has been investigated. Granules consisting of mannitol primary particles and PVP aqueous binder have been prepared by top-spray fluid-bed granulation, and granules consisting of sucrose primary particles and PEG binder by in-situ melt fluid-bed granulation. Granule microstructure has been systematically varied by manipulating the primary particle size distribution and the binder content in each case. In both cases granule porosity was found to be a decreasing function of binder content and a minimum of porosity as function of the fine/coarse primary particle mixing ratio has been observed, in line with theoretical expectations. Granule microstructures have been analysed using X-ray computed micro-tomography and compared with three-dimensional “virtual granules” generated by a computer simulation of the agglomeration process. The dissolution rate of granules has then been measured. While porosity was found to have a strong effect on the dissolution rate of mannitol granules, the dissolution rate was found to be practically independent of porosity in the case of sucrose granules. The formulation-microstructure and microstructure-dissolution correlations established in course of this work are in line with previous computer simulation results and form part of a computer-aided granule design methodology.     

Particle design for dry powder inhalation via binderless powder coating by pressure swing granulation

Novel formulation for dry powder inhalation (DPI) particularly appropriate for very dilute drug concentration was developed based on the pressure swing granulation (PSG) technology. PSG was applied to the granulation of excipient lactose particles and to the coating/dusting of lactose granules with fine model drug particles. Size distribution and granule strength as well as the dispersibility of the drug particles for DPI were found to be successful for practical use. The drug particles dispersed into the respirable aerodynamic size range of 1-7 μm from the E-haler® was 53.9% for 1% coating/dusting (i.e. 1% drug in product granules) and 46.3% for 2%. E-haler® was capable of emitting 89.8% and 83.2% of drug particles charged for cases for 1% and 2% coatings, respectively.     

Designing slurry conditions to control size distribution of spray-dried dense YSZ granules

This study suggests approaches to achieve the desired size and size distribution of highly dense spherical granules by investigating the effect of slurry conditions on size distribution. Highly dense spherical granules were prepared with a solid content of over 77 wt% by spray-drying the slurry. A prolonged deagglomeration time of 64 h provided adequate flowing ability by breaking up almost all aggregates and improved dispersibility, resulting in reduced granule sizes and narrow size distributions. The optimum slurry conditions for maintaining dispersibility were 1 wt% of the dispersant and a strong basic pH, which had the greatest effect on size distribution. Based on these considerations, the 10.6 µm sized 3 mol% yttria-stabilized zirconia granules were synthesized with 99.83% density, 97.17% sphericity, and uniform size with fraction yield of 80.01% at 10–20 µm. These dense granules have significantly higher hardness and modulus values of 19.19 and 206.68 GPa, respectively, than that of pellet and film types. To the best of our knowledge, the relationship between the slurries and the span of the size distribution of ceramic granules during spray-drying has been demonstrated for the first time.     

浆液体系中木薯淀粉乙酰化反应均匀性及基团分布特征

以木薯淀粉为原料、乙酸酐为酰化剂，在浆液体系中制备乙酰化淀粉，采用4.3 mol·L^-1 CaCl₂溶液对乙酰化淀粉颗粒进行化学表面糊化处理，获得不同表面糊化程度的剩余淀粉颗粒，通过SEM、XRD表征剩余颗粒的形貌及结晶结构，采用皂化法测定剩余颗粒的乙酰基含量，并利用最小二乘法拟合取代基含量在淀粉颗粒径向上的分布曲线，考察乙酰化反应均匀性和乙酰基分布的影响因素。结果发现：乙酰基团在淀粉颗粒中呈现外高内低的非均匀分布，30%以上的乙酰基分布在对比半径0.9~1.0的外部区域，而在0~0.7比较大的范围内仅占28%左右；反应温度升高、反应时间延长和酰化剂用量增大，乙酰基含量在淀粉颗粒内的分布离散程度减小，有利于乙酰化反应和乙酰基团分布更趋均匀；随着表面糊化程度增大，剩余颗粒均能保持木薯淀粉的形貌和“A”型结晶结构特征，但粒径稍有减小，结晶度整体呈现下降趋势，部分稍有突跃。以上结果说明，结晶结构与非晶结构在木薯淀粉颗粒内交替存在，且各区域结晶区和非晶区比例存在一定差异，适当改变反应条件可改善木薯淀粉颗粒内乙酰化反应和乙酰化基团非均匀分布的状况。     

The effect of primary particle surface energy on agglomeration rate in fluidised bed wet granulation

The effect of primary particle surface wettability by a binder solution on the rate of agglomeration in a fluid-bed top-spray granulation process was investigated. A model system consisting of hydrophilic and hydrophobic spherical primary particles with a narrow size distribution, and an aqueous solution of hydroxy propyl-cellulose (HPC) as binder, was used. The surface energy of the primary particles was measured by inverse gas chromatography (IGC) and their wettability was characterised by static and dynamic contact angle. Granulation was carried out in a desktop fluid-bed granulator and the resulting granule size distribution and granule microstructure were analysed. The hydrophobic particles gave a wider granule size distribution (larger maximum granule size) than hydrophilic ones under otherwise identical conditions, and the granules were notably rounder and more compact. However, the fraction of un-granulated fines was also higher in the case of hydrophobic primary particles. SEM analysis of granule microstructure revealed that the hydrophilic particles were coated by the binder solution, which left a smaller amount of binder available to form bonds at particle contacts. On the other hand, all of the binder was found to form solid bridges in the case of hydrophobic primary particles. A population balance model was used to explain the observed granulation behaviour.     

Effects of process parameters on granules properties produced in a high shear granulator

Results of a study on the influence of process parameters such as impeller speed, granulation time and binder viscosity on granule strength and properties are reported. A high shear granulator (Cyclomix manufactured by Hosokawa Micron B.V., The Netherlands) has been used to produce granules. Calcium carbonate (Durcal) was used as feed powder and aqueous polyethylene glycol (PEG) as the binder. The dried granules have been analysed for their strength, density and size distribution. The results show that increasing the granulation time has a great affect on granules strength, until an optimum time has been reached. The underlying cause is an increase in granule density. Granules are consolidated more at higher impeller speeds. Moreover, the granule size distribution seems not to be affected significantly by an increase in impeller speed. Granules produced with high binder viscosity have a considerably lower strength, wide strength distribution due to poor dispersion of binder on the powder bed. Binder addition methods have showed no considerable effect on granule strength or on granule size distribution.     

The effect of powder size on induction behaviour and binder distribution during high shear melt agglomeration of calcium carbonate

Growth mechanisms in high shear mixer granulation were observed over a wide range of particle size and liquid-to-solid (L/S) ratio. The materials used were calcium carbonate (CaCO₃; size fractions in the range 1.5 to 85 μm) with a binder of polyethylene glycol 6000 (PEG 6k). The binder, solid at room temperature, was added by the “melt-in” method. A 10 L vertical-axis granulator was used, with a chopper and a four-bladed impeller.

The mean granule size and granule size distribution were measured at regular intervals during the agglomeration process by careful sampling and sieving. The uniformity of binder distribution among the granules was also measured.

The growth behaviours of each grade of primary particles were classified and compared. An induction type mechanism was observed with an initial period of slow growth in mean particle size that lasted 2 to 3 min (the induction period). This was followed by a short rapid growth phase lasting 1 to 2 min. The final stage was a plateau of more or less zero growth. Interestingly, the end of the induction period and the onset of rapid growth corresponded to a change in the granule size distribution from bimodal to monomodal and a similar change in the distribution of binder. Induction period growth rate tended to be lower for granules of finer particles, but these grew more rapidly during the rapid growth stage and produced larger granules than the coarser primary particles.

The liquid-to-solid (L/S) ratio had a significant effect on the growth rate during the rapid growth stage but a minor effect on the granule size distribution and binder distribution. Primary particle size had a significant effect on the final average size of granules, the growth rate during the rapid growth stage and the distribution of granule size and binder.     

The relationship between surface properties and binder performance in granulation

A crucial stage in the granulation of pharmaceutical products is the selection of the most appropriate formulation of drug/excipient/binder. The binder must not only wet both solid species sufficiently to form (liquid) bridges to hold them together so that granules can then proceed to grow, but also must distribute homogeneously amongst the particles in the mixture to ensure a uniform distribution of each species in the resultant granules.This paper reports a micro-scale study to elucidate the wetting behaviour of binder solutions on paracetamol crystals in order to provide a low-cost and effective selection procedure for the optimal binder solution. A previous study has determined the spreading behaviour of two commonly used binders, hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), on paracetamol crystals. This study is focussed on the additional use of wetting agents, namely sodium lauryl sulphate and sodium docusate, to improve the wetting behaviour and distribution of the binders on the particles. The balance between binder adhesion (with the solid surfaces) and cohesion (for itself) in relation to granule growth is inferred from the interaction forces and the binder wetting behaviour.     

Agglomeration of hydrophobic powders via solid spreading nucleation

Wet granulation of a highly hydrophobic fine powder was investigated to elucidate the granule nucleation and growth processes in systems in which distribution of granulating fluid in the granulating mass is complicated by poor wetting. A mixture containing approximately 70 wt.% (90% by volume) of a micronized poorly wetting powder was granulated in a high-shear mixer using water and the microstructure of resultant agglomerates (granules) was studied using optical and electron microscopy as well as X-ray computed tomography (XRCT). The study revealed that granules are typically spherical or elliptical in shape and range in size from 200 to 500 μm. They are strong and consist of a consolidated powder shell and an empty core. Based on the microstructure, a nucleation mechanism for such a hydrophobic system is proposed. Implications for controlling granule growth and granule properties are discussed. This study demonstrates that well-controlled nuclei formation and subsequent granule growth is achievable in a highly hydrophobic system.     

Scaling of continuous twin screw wet granulation

Scaling rules were developed and tested for a continuous twin screw wet granulation process using three scales (11, 16, and 24 mm barrel diameter) of twin screw granulators (TSG). The distributive feed screw configuration used produced high porosity granules (50–60%) with broad bimodal size distributions, especially in the 16 and 24 mm TSGs. Three dimensionless numbers, Froude number (Fr), liquid‐to‐solid ratio (LSR), and powder feed number (PFN), were identified and their effect on granule size distribution (GSD), porosity and liquid distribution tested. Granule size increased with increasing LSR as expected. However, Fr and PFN had no significant effect on d₁₀ or d₅₀ and only a small effect on d₉₀. In contrast, granulator scale had a strong effect on GSD, with d₉₀ increasing almost linearly with barrel diameter. This is consistent with breakage of large granules being a dominant mechanism and directly controlled by the geometry of the screw. © 2016 American Institute of Chemical Engineers AIChE J, 63: 921–932, 2017     

Granule performance of zirconia/alumina composite powders spray-dried using polyvinyl pyrrolidone binder

Polyvinyl pyrrolidone (PVP) was used as a binder in spray-drying a slurry containing zirconia/alumina composite powder and its influence on granulation and granule deformability was compared with those of polyvinyl alcohol (PVA) and polyethylene glycol–hydroxyethyl cellulose cobinder (PEG–HEC). Although the most spherical solid granules were obtained from the slurry containing PEG–HEC, the granules containing PVP were the most deformable during compaction. It was apparent that a high-viscosity organic additive mixture added to the slurry resulted in highly spherical solid granules, and a low T_g of the mixture led to a high deformability. The flexural strengths of composites prepared from granules containing PVP, PEG–HEC, and PVA were 634, 578, and 468 MPa, respectively, which corresponds to the ascending order of T_g of the binders mixed with plasticizers.     

微米级单分散聚苯乙烯微球的制备

以苯乙烯(St)为单体、偶氮二异丁腈(AIBN)为引发剂、聚乙烯吡咯烷酮(PVP)为分散稳定剂,在乙醇-水反应介质中,采用分散聚合法制备了微米级单分散聚苯乙烯(PS)微球。分别用电镜扫描和激光粒度仪表征了PS微球表面形貌、粒径及粒度分布,探讨了影响PS微球粒径及粒度分布的诸多因素。结果表明,AIBN用量(以单体质量计,下同)大于5.0%或PVP用量(以单体质量计,下同)小于2%时,PS粒子间有聚并现象;当St浓度为10%、AIBN用量为2.5%、PVP用量为5.5%、醇水质量比为90∶10、聚合温度为70℃时,制备的PS微球粒径为1.612μm、粒度分散系数为0.357,微球单分散性及球形度最佳。     

EPDM分布形态对动态硫化PP/EPDM共混物增韧效果的影响及其机理的研究

采用扫描电子显微镜（ＳＥＭ）技术研究了乙烯质量分数分别为０５３,０４５和０７５的３种ＥＰＤＭ与ＰＰ组成的动态硫化共混物的形态结构特征及其增韧效果。结果表明,当ＥＰＤＭ中乙烯质量分数在０４５～０５５之间时,ＥＰＤＭ的结构规整性差、熔融粘度高、与ＰＰ相容性小,动态硫化的实质是使ＥＰＤＭ分散颗粒由大变小、粒度均化、分布均匀,增大共混剪切强度有利于提高这种ＥＰＤＭ的增韧效果。当ＥＰＤＭ中乙烯质量分数达到０７５时,ＥＰＤＭ中因出现均聚ＰＥ序列结构而呈现部分结晶性,熔融粘度低,与ＰＰ相容性增大,动态硫化后ＥＰＤＭ分散颗粒由小变大,并同时形成“亚网结构”,强化化学交联反应可提高网络密度及网络连续性,从而提高增韧效果,而提高共混剪切强度,反而会使增韧效果下降     

An investigation of the effects on agglomeration of changing the speed of a mechanical mixer

A study that focussed on the effects on agglomeration of changing the rotational speed of a vertical-axis high shear mixer is reported. The design of the mixer was such that, at high impeller speeds, the power input was high. The agglomeration behaviour was found to vary greatly with impeller speed. At low impeller speed, the extent of size enlargement increased with power input. At high impeller speed, the extent of size enlargement was low relative to the large power input. From examination of the changes in size distributions of the granules and of granule morphology, it was concluded that, at high speed, size enlargement was limited by granule breakage. The observation is important as it may provide an improved means of controlling the process.     

Miscibility and tack of blends of poly (vinylpyrrolidone)/acrylic pressure-sensitive adhesive

In this study, miscibility and tack of blends of poly (vinylpyrrolidone) (PVP)/acrylic pressure-sensitive adhesive (PSA) were evaluated. For this purpose, appropriate amounts of PVP (2–30% w/w) were added to an acrylic PSA to obtain visually homogeneous solution. The resulting solution was evenly applied on a polyethylene terephthalate (PET) film with final specific thicknesses of 10, 40, and 70 μm by using a film applicator and miscibility as well as tack values were evaluated. With the addition of 2% (w/w) PVP the tack value decreased and increased in 5% (w/w) PVP and then continuously decreased up to 30%(w/w). It was found that the tack value was related to miscibility as well as to viscosity and the free functional group such as hydroxyl group of the blend. By the morphological analysis performed through scanning electron microscopy (SEM) and also by the study of thermal analysis using the differential scanning calorimetry (DSC) behavior of blends, it was found that the two distinct phases constituted after adding 5% (w/w) of PVP. This resulted in the acrylic PSA forming the continuous phase, and by increasing the concentration of PVP a dispersed phase was developed. The dispersed phase has a higher viscosity than the continuous phase and therefore cannot wet the adherent and hence result in lowering the tack values.     

PLGA缓释微球的制备及其释药降解性能研究

以巴比妥为球心物质,聚乙烯吡咯烷酮（PVP）为分散剂,采用溶剂挥发法制备了聚（乳酸-羟基乙酸）共聚物PLGA载药微球。透射电镜、光学显微镜测试表明微球球型规则,表面平滑,分布均匀,微球粒径在400nm左右,包覆效果良好,微球载药率1．039％,药物包封率42．34％。红外（FT—IR）分析得知,两种物质互相融为一体。以PH=7．4的PBS缓冲溶液为释放介质,用紫外分光光度计（UV）对微球的体外释药过程进行了实验,微球在前10天有明显的突释,此后缓慢释药,45天后药物释药率在80％以上。实验结果表明：PLGA是一种理想的控缓释材料。     

On the small composite granules formed in a continuous rotating conical vessel containing grinding media: effect of the methods of feeding powder on the size and structure of binary composite granules

To investigate the effect of the methods of feeding SiC and CaCO₃ powders on the size and structure of binary composite granules made of the powders, experiments were performed by a simultaneous operation of granulation, grinding and separation in a continuous rotating conical vessel using two kinds of methods for feeding the binary powder. The structure of a composite granule was characterized by comparing the granule size with the size of the SiC-agglomerates contained in the granule.

It was found that (i) by feeding dry SiC with CaCO₃ powders, it was difficult to obtain composite granules smaller than 0.3 mm in size, and that (ii) by feeding SiC-powder with binder in a slurry state, it was possible to make composite granules of larger than at least 0.13 mm, though the structure of composite granules depended on the concentration of SiC-powder in the slurry.     

Radiolytic synthesis of Pd-M (M=Ag and Ni) and Pt-M (M=Ru and Ni) alloy colloids

Pd-M (M=Ag and Ni) and Pt-M (Ru and Ni) alloy colloids were successfully prepared in aqueous solution by γ-irradiation using poly(vinylpyrrolidone), PVP, as stabilizer. The PVP-stabilized Pd-M and Pt-M nanoparticles were characterized by UV-Vis spectroscopy, Transmission Electron Microscopy (TEM) and Electrophoretic Light Scattering (ELS) analysis. The influence of molecular size of the PVP on the size and size distribution of the alloy nanoparticles was followed. Pd-Ag nanoparticles were formed by employing PVP with different molecular weights. The size of Pd-Ag alloy nanoparticles was determined by TEM photograph and ELS spectra, respectively. From the TEM photographs, the average diameter of Pd-Ag nanoparticles does not show strong dependence on the molecular weight of the PVP. On the other hand, the average diameter of Pd-Ag alloy colloids prepared by PVP with Mw=40,000 was consistently larger than that of Pd-Ag alloy colloids prepared by PVP with Mw=10,000. A plausible scheme is given to explaining this. The size and size distribution of Pt-M (Ru and Ni) alloy colloids are presented.