Scale-up of high shear granulation based on agitation power

Scale-up of wet granulation in a vertical high shear mixer was conducted. Pharmaceutical excipient mixtures composed of lactose, cornstarch and micro-crystalline cellulose, and hydroxypropylecellulose as a binder were mixed together and then granulated with purified water under various operating conditions and vessel scales. Torque of agitator shaft was continuously measured and then agitation power per unit vessel volume was calculated. The agitation power per unit vessel volume showed a good correlation with physical properties of obtained granules, such as mass median diameter, strength and compressibility. This implied that the scale-up characteristics could be well analyzed by means of the agitation power per unit vessel volume. In addition, the effects of agitator tip speed and Froude number on the agitation power per unit vessel volume were investigated. The results showed that the agitation power per unit vessel volume was well characterized by the tip speed rather than the Froude number. This meant that the granule growth mainly progressed by the shear stress from the agitator blade. Dynamic characteristics of high shear granulation were also discussed here.     

Scale-up studies on high shear wet granulation process from mini-scale to commercial scale

A newly developed mini-scale high shear granulator was used for scale-up study of wet granulation process from 0.2 to 200 L scales. Under various operation conditions and granulation bowl sizes, powder mixture composed of anhydrous caffeine, D-mannitol, dibasic calcium phosphate, pregelatinized starch and corn starch was granulated by adding water. The granules were tabletted, and disintegration time and hardness of the tablets were evaluated to seek correlations of granulation conditions and tablet properties. As the granulation proceeded, disintegration time was prolonged and hardness decreased. When granulation processes were operated under the condition that agitator tip speed was the same, similar relationship between granulation time and tablet properties, such as disintegration time and hardness, between 0.2 L and 11 L scales were observed. Likewise, between 11 L and 200 L scales similar relationship was observed when operated under the condition that the force to the granulation mass was the same. From the above results, the mini-scale high shear granulator should be useful tool to predict operation conditions of large-scale granulation from its mini-scale operation conditions, where similar tablet properties should be obtained.     

Development of a novel vertical high shear kneader and its performance in wet kneading of pharmaceutical powders

A novel multi-functional vertical high shear kneader has been developed. Wet kneading of pharmaceutical powders was conducted under various blade components and operating conditions. Compression properties of wet kneaded mass was analyzed and dispersion of hinder liquid (water) among the mass was investigated by assaying tracer aqueous pigment. Pellets were produced through a dome type extrusion granulator with continuous extrusion pressure measurement device and a fluidized bed drier, and then the physical properties were measured. Quantitative relationship between the pellet's physical properties and the binder dispersion condition as well as the compression properties could be obtained. It was found that the newly developed kneader was very effective to uniformly disperse binder as well as impart high shear stress to the wet mass without generating obvious adhesion onto the vessel wall. It was also pointed out that the extrusion pressure could determine the physical strength of pellet. This method proposes a new methodology for continuous monitoring of kneading condition as well as predicting pellet's physical properties.     

Scale-up of wet kneading in a novel vertical high shear kneader

A novel multi-functional vertical high shear kneader has been developed and its performance in wet kneading has previously been reported [Watano et al., Chem. Pharm. Bull., 50(3), 341-345 (2002)]. In this study, scale-up of wet kneading in the novel vertical high shear kneader was conducted. Pharmaceutical excipients composed of lactose, cornstarch and micro-crystalline cellulose were used as powder samples. Kneading operations were conducted under various operating conditions and three different vessel scales. The dried pellets were then prepared by extruding the wet kneaded masses through a dome-type extruder and their drying by a fluidized bed. The physical properties such as strength and disintegration time of the dried pellets were evaluated. It was found that the properties of the dried pellets and their scale-up characteristics were well expressed by an agitation power per unit vessel volume and dimensionless Froude number.     

Investigation of high shear wet granulation processes using different parameters and formulations

This study compared the granulation processes for different formulations using a laboratory-scale high shear mixer. The effects of critical process parameters (impeller speed, chopper speed and kneading time) on granule characteristics were evaluated. The characteristics of the granules studied included the size distribution, friability and morphological properties. The flow profiles of the wet mass and material deposition during the process were also studied. The results obtained showed that the effect of the impeller speed was determined by the starting material system. On the other hand, chopper speeds from 1200 to 3600 rpm and kneading times from 120 to 240 s had a consistent influence on all formulations. Moreover, it was found that the toroidal flow pattern of the wet mass could be maintained for a longer period and granules with a good spherical shape were obtained by removing the chopper during the last 120 s of the granulation process. In addition, the use of the pregelatinized starch in the formulation also led to a reduction in the wall adhesion of the material. It was concluded that the effectiveness of high shear wet granulation could be improved by choosing a proper combination of starting material and process parameters and by monitoring the mass motion during the process.     

Effects of vessel baffling on the drawdown of floating solids

The effects of baffling of an agitated vessel on the production of floating particles suspension are presented in this paper. Critical agitator speed, needed for particles dispersion in a liquid agitated in a vessel of the inner diameter of 0.295 m, was determined. The just drawdown agitator speeds were defined analogously to the Zwietering criterion. Specific agitation energy was calculated from the power consumption experimental data obtained by means of the strain gauge method. The experiments were carried out for twelve configurations of the baffles differing in number, length and their arrangement in the vessels. The following high-speed impellers were used: up- and downpumping six blade pitched blade turbines, Rushton turbine, and propeller. The impeller was located in the vessel in the height equal to two-thirds or one-third of the vessel diameter from the bottom of the vessel. The results were described in the form of a dimensionless equation. Presented at the 35th International Conference of the Slovak Society of Chemical Engineering, Tatranské Matliare, 26–30 May 2008.     

Interaction of microcrystalline cellulose and water in granules prepared by a high-shear mixer

Microcrystalline cellulose (MCC) granules were prepared by wet granulation using a high-shear mixer. Physical characteristics of the granules were investigated using near IR spectrometry, thermogravimetry and isothermal water vapor adsorption. Near IR spectra of dried MCC granules prepared for various granulation times exhibited different peak intensities at 1428, 1772, and 1920 nm, which were assigned to functional groups of cellulose or water. On isothermogravimetric analysis, the rate of dehydration of water was shown to decrease with granulation time. These results suggest that the physical structure of MCC could change during the granulation process, and the interaction between MCC and water was gradually strengthened. The isothermal water vapor adsorption curves suggested that the amorphous region of MCC would be divided by the strong shear force of the impeller, because the high adsorption ability of intact MCC in the low humidity region was diminished in granules collected following 5 and 10 min of granulation. It was suggested that MCC formed a network which caught water within its structure during the wet granulation process.     

Solid suspension and gas dispersion in gas-solid-liquid agitated systems

The aim of the research work was to investigate the effect of superficial gas velocity and solids concentration on the critical agitator speed, gas hold-up and averaged residence time of gas bubbles in an agitated gas-solid-liquid system. Experimental studies were conducted in a vessel of the inner diameter of 0.634 m. Different high-speed impellers: Rushton and Smith turbines, A 315 and HE 3 impellers, were used for agitation. The measurements were conducted in systems with different physical parameters of the continuous phase. Liquid phases were: distilled water (coalescing system) or aqueous solutions of NaCl (non-coalescing systems). The experiments were carried out at five different values of solids concentration and gas flow rate. Experimental analysis of the conditions of gas bubbles dispersion and particles suspension in the vessel with a flat bottom and four standard baffles showed that both gas and solid phases strongly affected the critical agitation speed necessary to produce a three-phase system. On the basis of experimental studies, the critical agitator speed for all agitators working in the gas-solid-liquid systems was found. An increase of superficial gas velocity caused a significant increase of the gas hold-up in both coalescing and non-coalescing three-phase systems. The type of the impeller strongly affected the parameters considered in this work. Low values of the critical impeller speed together with the relatively short average gas bubbles residence time tR in three phase systems were characteristic for the A 315 impeller. Radial flow Rushton and Smith turbines are high-energy consuming impellers but they enable to maintain longer gas bubbles residence time and to obtain higher values of the gas hold-up in the three-phase systems. Empirical correlations were proposed for the critical agitator speed, mean specific energy dissipated and the gas hold-up prediction. Its parameters were fitted using experimental data.     

Volumetric Scalability of Microfluidic and Semi-Batch Silk Nanoprecipitation Methods

Silk fibroin nanoprecipitation by organic desolvation in semi-batch and microfluidic formats provides promising bottom-up routes for manufacturing narrow polydispersity, spherical silk nanoparticles. The translation of silk nanoparticle production to pilot, clinical, and industrial scales can be aided through insight into the property drifts incited by nanoprecipitation scale-up and the identification of critical process parameters to maintain throughout scaling. Here, we report the reproducibility of silk nanoprecipitation on volumetric scale-up in low-shear, semi-batch systems and estimate the reproducibility of chip parallelization for volumetric scale-up in a high shear, staggered herringbone micromixer. We showed that silk precursor feeds processed in an unstirred semi-batch system (mixing time > 120 s) displayed significant changes in the nanoparticle physicochemical and crystalline properties following a 12-fold increase in volumetric scale between 1.8 and 21.9 mL while the physicochemical properties stayed constant following a further 6-fold increase in scale to 138 mL. The nanoparticle physicochemical properties showed greater reproducibility after a 6-fold volumetric scale-up when using lower mixing times of greater similarity (8.4 s and 29.4 s) with active stirring at 400 rpm, indicating that the bulk mixing time and average shear rate should be maintained during volumetric scale-up. Conversely, microfluidic manufacture showed high between-batch repeatability and between-chip reproducibility across four participants and microfluidic chips, thereby strengthening chip parallelization as a production strategy for silk nanoparticles at pilot, clinical, and industrial scales.     

Nanoscale high-frequency contact mechanics using an AFM tip and a quartz crystal resonator

The transmission of high-frequency shear stress through a microscopic contact between an AFM tip and an oscillating quartz plate was measured as a function of vertical pressure, amplitude, and surface properties by monitoring the MHz component of the tip's deflection. For dry surfaces, the transmission of shear stress is proportional to the vertical load across the contact. This provides a measure of the forces of adhesion between the substrate and the tip. When stretching soft polymeric fibers created by pulling on the surface of a pressure sensitive adhesive, the transmitted shear stress decreased linearly with extension over the entire range of pulling. This contrasts with the static adhesive force, which remained about constant until it discontinuously dropped at the point of rupture.     

On-line monitoring of granule growth in high shear granulation by an image processing system

A novel system has been developed to continuously monitor granule growth in a high shear granulation. The system consists of an image processing system and a particle image probe comprising a CCD camera, lighting unit and air purge system. Segregation during powder mixing was investigated experimentally and the optimal positioning of the probe was determined. High shear granulation was conducted using pharmaceutical powders, and granule size and product's yield of various size ranges were continuously measured by the developed system. Sieve analysis of the granulated products sampled out during the granulation was simultaneously conducted, and the obtained data was compared with that by the on-line image processing system. An extremely close relationship could be found between both data, proving that the developed system could monitor the granule growth accurately and continuously throughout the granulation. An on-off control system was developed to control the granulation process, and the performance of the system was confirmed.     

Prediction of granule physical property by a novel compression energy of wet powder

Wet granulation is a very important process and a reliable evaluation method for formulation study; thus it requires appropriate process control. In this study, a novel and effective method that involves a compression test of wet powder is proposed. Here, the compression energy, which could predict the capability of the wet powder for extrusion granulation as well as the physical properties of the final products, is used as a novel characteristic of wet powder. The compression energy was defined as the energy consumption derived from the compression speed and the transmission loss during the compression test. Lactose monohydrate was mixed with various additives such as hydroxypropylcellulose in the mass ratio of 0-10%. Various amounts of water were fed into the mixtures, which were kneaded in a planetary motion mixer to prepare the kneaded wet powders. The characteristics of these powders were evaluated by the compression energy. The kneaded wet powders were then extruded through an extrusion granulator, the electrical loads of the granulator during the operation were analyzed as the extrusion energy, and the physical properties of extruded granules were investigated. As a result, the granule strength and granule size distribution showed a good correlation with the compression energy. A good correlation was also observed between the compression energy of the kneaded wet powder and the extrusion energy regardless of the different additives and water contents. It was concluded that the compression energy of the wet powder could be used for the formulation study and the process control of wet granulation.     

Aerobic Granulation: Advances and Challenges

Aerobic granulation was developed in overcoming the problem of biomass washout often encountered in activated sludge processes. The novel approach to developing fluffy biosolids into dense and compact granules offers a new dimension for wastewater treatment. Compared with conventional biological flocs, aerobic granules are characterized by well-defined shape and compact buildup, superior biomass retention, enhanced microbial functions, and resilient to toxicity and shock loading. This review provides an up-to-date account on development in aerobic granulation and its applications. Granule characterization, factors affecting granulation, and response of granules to various environmental and operating conditions are discussed. Maintaining granule of adequate structural stability is one of the main challenges for practical applications of aerobic granulation. This paper also reviews recent advances in addressing granule stability and storage for use as inoculums, and as biomass supplement to enhance treatment efficiency. Challenges and future work of aerobic granulation are also outlined.     

Degradation of polymers in high speed rotary homogenizers: A hydrodynamic interpretation

Dilute solutions of DNA in neutral phosphate buffer and of polystyrene in toluene are degraded to limiting molecular weights by high speed stirring in a Virtis homogenizer equipped with special thin, highly sharpened blades. Results are interpreted and justified in terms of the hydrodynamic theory of laminar boundary layers. Estimates of critical stress values for chain scission are obtained at various limiting molecular weights for the two polymer systems, and the treatment is used to rationalize the dependence of degradation upon homogenizer speed. The agreement between the hydrodynamic theory and experimental data implies that limiting molecular degradation occurs entirely in the boundary layer region extending a distance equal to approximately the molecular contour length from the leading edge of the blade tip and that laminar flow conditions prevail in this region. It therefore seems likely that polymer molecules subjected to a critical shearing stress are essentially completely extended in the streamlines of flow. The hydrodynamic theory is finally used to explain the peculiar kinetics of molecular degradation in high speed rotary homogenizers.     

Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules V. Release properties of ethylcellulose layered matrix granules

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. In previous papers, a combination of the square-root time law and cube-root law equations was confirmed to be a useful equation for qualitative treatment. It was also confirmed that the combination equation could analyze the release properties of layered granules as well as matrix granules. The drug release property from layered granules is different from that of matrix granules. A time lag occurs before release, and the entire release property of layered granules was analyzed using the combination of the square-root time law and cube-root law equations. It is considered that the analysis method is very useful and efficient for both matrix and layered granules. Comparing the granulation methods, it is easier to control the manufacturing process by tumbling granulation (method B) than by tumbling-fluidized bed granulation (method C). Ethylcellulose (EC) layered granulation by a fluidized bed granulator might be convenient for the preparation of controlled release dosage forms as compared with a tumbling granulator, because the layered granules prepared by the fluidized bed granulator can granulate and dry at the same time. The time required for drying by the fluidized bed granulator is shorter than that by the tumbling granulator, so the fluidized bed granulator is convenient for preparation of granules in handling and shorter processing time than the tumbling granulator. It was also suggested that the EC layered granules prepared by the fluidized bed granulator were suitable for a controlled release system as well as the EC matrix granules.     

不同饥饿时间下稳态好氧颗粒污泥系统的特性和动力学分析

较长的饥饿时间是好氧颗粒污泥驯化形成的关键条件. 但在稳态颗粒污泥系统中, 饥饿时间长短对颗粒污泥的影响还不清楚. 因此本实验采用四个序批式反应器(SBR), 分别在好氧饥饿时间为1、2、3和4 h(R1~R4)条件下运行, 研究了饥饿时间对稳态好氧颗粒污泥系统的运行和特性等方面的影响. 结果表明: 对于稳态的好氧颗粒污泥系统, 较长饥饿时间已不是保持污泥颗粒化的关键因素, 系统在饥饿时间缩短后依然会保持污泥颗粒化和稳定运行效果. 四种饥饿时间条件下反应器中COD去除效果没有表现出明显差异, COD平均去除率都几乎为98%以上. 但在不同饥饿时间条件下, 好氧颗粒污泥的性质有很大差别. 在 35天实验运行中, 与较长饥饿时间相比, 饥饿时间的缩短会使污泥中胞外聚合物含量降 低, 但PN/PS值会提高约6%左右, 好氧颗粒直径增大. 同时, 当饥饿时间大于2 h会使颗粒污泥中丝状菌过度生长, SVI30值升高约1.5倍, 并且导致颗粒的物理性质降低. 但是, 动力学分析指出R1~R4的有机污染物降解速率在0.25~0.29 h^-1之间, 较短饥饿时间的系统虽具有较高的qmax值, 可是并不明显. 并且R1~R4系统的饱和常数(K)和产率系数(Y)分别在5.39~8.45 mg/L和 0.391~0.746 kgMLVSS/kgCOD, 较短饥饿时间的系统会具有较高的COD出水浓度和剩余污泥产率. 综上, 好氧颗粒污泥驯化成功后, 稳态的颗粒污泥系统不再需要在较长饥饿时间条件下运行, 可以适当缩短反应时间, 这不仅仅可以节约运行成本, 降低不必要的能源消耗, 还可以使系统具有较高的稳定性能.     

Quantitative analysis of water dispersion conditions and pressure transmission characteristics of a wet kneaded mass

In our previous paper [Watano S. et al., J. Powder Technology Japan, 37, 362-370 (2000)], a novel compaction tester was developed to quantitatively evaluate the water dispersion condition of a wet kneaded mass prepared by a paddle type kneader. It has been demonstrated that the physical properties of pellets prepared by extrusion granulation after the kneading can be well predicted by the pressure transmission obtained through the compaction tester. This paper describes a more detailed investigation of the water dispersion, its mechanism and pressure transmission characteristics of wet kneaded masses prepared under various operating conditions. First, kneading by a paddle type kneader was conducted to prepare wet masses under various binder contents using different additional methods and different starting materials. Secondly, water dispersion and pressure transmission characteristics of wet masses were investigated. After the wet kneading, the wet kneaded masses were extruded through a dome type extruder and were dried by a fluidized bed to prepare dry pellets. The relationship between water dispersion and pressure transmission can be expressed by a single line, regardless of binder content or methods of addition. This implies that these parameters have no effect on the water dispersion condition of the wet kneaded mass prepared by a high shear paddle type kneader. Different water dispersion characteristics and the mechanism obtained by different starting materials can also be evaluated by the pressure transmission data. Properties of dry pellets can also be predicted by the pressure transmission. It can be concluded that the developed compaction tester can quantitatively evaluate the water dispersion condition of a wet kneaded mass and also predict properties of the final extruded products.     

Granulation of core particles suitable for film coating by agitation fluidized bed II. A proposal of a rapid dissolution test for evaluation of bitter taste of ibuprofen

To prepare powdered drugs that do not have a bitter taste, a film coating covering the surfaces of the core particles is required. The dissolution rate of ibuprofen from the coated particles changes according to the physical properties of the core particles. In this study, the effects of the physical properties of granules prepared by using several scales of agitation fluidized beds on the drug dissolution rate were investigated. The dissolution rate of ibuprofen decreased when the apparent density and shape factor of the granules increased. In contrast, the dissolution rate of the drug increased with the friablility of the granules increased. Thus, the structures of the granules appear to affect the dissolution rate of the drug to a large degree. A rapid dissolution test that can be used to investigate the early dissolution rate of ibuprofen in vitro was proposed to evaluate the taste-masking level of the coated particles. The bitter taste-masking level of the coated particles was successfully confirmed by using this novel test method.     

Microwave drying of granules containing a moisture-sensitive drug: a promising alternative to fluid bed and hot air oven drying

The impact of microwave drying and binders (copolyvidone and povidone) on the degradation of acetylsalicylic acid (ASA) and physical properties of granules were compared with conventional drying methods. Moist granules containing ASA were prepared using a high shear granulator and dried with hot air oven, fluid bed or microwave (static or dynamic bed) dryers. Percent ASA degradation, size and size distribution, friability and flow properties of the granules were determined. Granules dried with the dynamic bed microwave dryer showed the least amount of ASA degradation, followed by fluid bed dryer, static bed microwave oven and hot air oven. The use of microwave drying with a static granular bed adversely affected ASA degradation and drying capability. Dynamic bed microwave dryer had the highest drying capability followed by fluid bed, static bed microwave dryer and conventional hot air oven. The intensity of microwave did not affect ASA degradation, size distribution, friability and flow properties of the granules. Mixing/agitating of granules during drying affected the granular physical properties studied. Copolyvidone resulted in lower amount of granular residual moisture content and ASA degradation on storage than povidone, especially for static bed microwave drying. In conclusion, microwave drying technology has been shown to be a promising alternative for drying granules containing a moisture-sensitive drug.     

Novel method for constructing a large-scale design space in lubrication process by using bayesian estimation based on the reliability of a scale-up rule

A reliable large-scale design space was constructed by integrating the reliability of a scale-up rule into the Bayesian estimation without enforcing a large-scale design of experiments (DoE). A small-scale DoE was conducted using various Froude numbers (X(1)) and blending times (X(2)) in the lubricant blending process for theophylline tablets. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y(1)), tablet hardness (Y(2)), and dissolution rate (Y(3)) on a small scale were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. A constant Froude number was applied as a scale-up rule. Experiments were conducted at four different small scales with the same Froude number and blending time in order to determine the discrepancies in the response variables between the scales so as to indicate the reliability of the scale-up rule. Three experiments under an optimal condition and two experiments under other conditions were performed on a large scale. The response surfaces on the small scale were corrected to those on the large scale by Bayesian estimation using the large-scale results and the reliability of the scale-up rule. Large-scale experiments performed under three additional sets of conditions showed that the corrected design space was more reliable than the small-scale design space even when there was some discrepancy in the pharmaceutical quality between the manufacturing scales. This approach is useful for setting up a design space in pharmaceutical development when a DoE cannot be performed at a commercial large manufacturing scale.