The effect of the wetting droplets size on power consumption during drum granulation

Changes of torque during fine material (foundry dolomite) granulation in a horizontal drum granulator at changing wetting parameters were studied. The variable parameters were droplet diameter and wetting of granular material. The bed of loose material was sprayed during feeding, at a constant liquid flow rate V_l = 0.012 m³/h. The size of wetting liquid droplets was changed using different rates of air flow through pneumatic spraying nozzles in the range from V_p = 1.0 to 3.0 m³/h and applying a sprinkler which supplied (drop-wise) the liquid uniformly along the entire drum length. In each test, instantaneous values of torque on the granulator shaft were measured in 1 s time intervals. The effect of droplet size and moisture content of the bed of granular material on torque in the whole granulation cycle was estimated. It was found that bed wetting conditions had a significant influence on the nucleation and growth of agglomerates. A minimum (boundary) size of liquid droplets, at which the bed is not transformed into granulated material, depends on the total amount of liquid supplied at the wetting stage. Changes of torque during the drum granulation are a good representation of the phenomena related to the transformation of wetted feed into granulated product and can be an easy indicator of the process.The work was carried out within the project no. 4 T09C 023 22. financed by the State Committee for Scientific Research in the years 2002–2005.     

Alternative Granulation Technique: Melt Granulation

Abstract

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Alternative Granulation Technique: Melt Granulation

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Development of Agglomerated Talc. I. Evaluation of Fluidized Bed Granulation Parameters on the Physical Properties of Agglomerated Talc

Studies were conducted to develop agglomerated talc as a tablet diluent using the fluidized-bed granulation method. A complete 2³ factorial experiment was run using a Uniglatt fluidized bed granulator to determine the effects of atomizing air pressure (P), inlet air temperature (T), and the quantity of the granulating fluid (V) upon the characteristics of the resultant agglomerated talc. It was found that the atomization pressure was the most prevailing factor for controlling the growth of the agglomerates in the granulation process. With the decrease of the atomizing air pressure, the geometrical mean particle size and flowability of the agglomerates increased. The volume of the binder solution (dilution effect) affects the properties of the agglomerates in the same direction as did the atomizing air pressure. Droplet size distribution of the atomized binder solution was estimated. The result suggested that the dilution effect altered the properties of the product through its adhesivity. The flowability and hardness of talc were significantly improved by the fluidized bed granulation process.     

Optimization of Disintegration Time and Crushing Strength of a Tablet Formulation

In an experiment with a factorial design, the following aspects were scrutinized: the impact on disintegration time and crushing strength caused by the loss-on-drying of the granulation; the granule-size distribution; the lubricant concentration; the compression force; and the pre-compression. Both with regard to disintegration time and crushing strength, these factors were found to have a significant influence: the loss-on-drying of the granulation; the fraction less than 0.150 mm; the concentration of magnesium stearate; and the compression force. A reduction of the tablet disintegration time was obtained by means of an increase of the granulation moisture; by an increase of the fine fraction; or by a reduction of the lubricant concentration or the compression force. The tablet crushing strength was increased by reducing the deviation of the granulation loss-on-drying from approximately 4.6 %; by a reduction of the fine fraction; by decreasing the lubricant concentration; or by increasing the compression force. The fraction larger than 0.300 mm had no significant influence; nor did the pre-compression. Further, there were no significant interactions.

By means of superimposing contour plots of disintegration time and crushing strength, a region was obtained where the requirements of disintegration time and crushing strength could be satisfied by controlling the processing variables.     

Optimization of Disintegration Time and Crushing Strength of a Tablet Formulation

Abstract

In an experiment with a factorial design, the following aspects were scrutinized: the impact on disintegration time and crushing strength caused by the loss-on-drying of the granulation; the granule-size distribution; the lubricant concentration; the compression force; and the pre-compression. Both with regard to disintegration time and crushing strength, these factors were found to have a significant influence: the loss-on-drying of the granulation; the fraction less than 0.150 mm; the concentration of magnesium stearate; and the compression force. A reduction of the tablet disintegration time was obtained by means of an increase of the granulation moisture; by an increase of the fine fraction; or by a reduction of the lubricant concentration or the compression force. The tablet crushing strength was increased by reducing the deviation of the granulation loss-on-drying from approximately 4.6 %; by a reduction of the fine fraction; by decreasing the lubricant concentration; or by increasing the compression force. The fraction larger than 0.300 mm had no significant influence; nor did the pre-compression. Further, there were no significant interactions.

By means of superimposing contour plots of disintegration time and crushing strength, a region was obtained where the requirements of disintegration time and crushing strength could be satisfied by controlling the processing variables.     

Air-dictated bottom spray process: impact of fluid dynamics on granule growth and morphology

Background: Growing interest in the use of the less-explored bottom spray technique for fluidized bed granulation provided impetus for this study. Aim: The impact of fluid dynamics (air accelerator insert diameter; partition gap) and wetting (binder spray rate) on granule properties were investigated. Method: In this 3³ full factorial study, the results were fitted to a quadratic model using response surface methodology. The air velocity at the spray granulation zone for the investigated conditions was measured using a pitot tube. Results: Air accelerator insert diameter correlated to measured air velocity at the spray granulation zone and was found to not only dictate growth but also influence granule morphology. The partition gap was found to play important roles in regulating particle movement into the spray granulation zone and optimizing process yields, whereas binder spray rate significantly affected granule morphology but not granule size. Conclusions: Unlike conventional fluidized bed granulation, ease of modulation of fluid dynamics and insensitivity of the bottom spray process to wetting allow flexible control of granule size, shape, and flow. Its good drying ability also indicated potential use in granulating moisture-sensitive materials.     

水分散苎麻麻骨饼的制备及其性能

为探索苎麻麻骨治理重金属废水的工业化应用可行性,首先,利用激光粒度仪、SEM和FTIR等表征手段对苎麻麻骨微粒进行微观表征,探明了苎麻麻骨的微观结构;然后在此基础上,将苎麻麻骨微粒与环境友好型天然润湿剂、黏结剂及崩解剂混合,按一定工艺流程加工成水分散苎麻麻骨饼（WDRSC）,在配方筛选过程中,测试了各种助剂质量分数对WDRSC性能的影响,并对苎麻麻骨与WDRSC吸附重金属Cu2+和Cd2+的能力进行了比较。结果显示:苎麻麻骨为具有多孔隙结构的天然物质,表面具有大量的吸附位点和官能团;当WDRSC配方中麻骨、润湿剂、黏结剂和崩解剂的质量比为75:13:2:10时,WDRSC入水后能迅速被水润湿（润湿时间小于60 s）并自动崩解（崩解时间小于60 s）,60 s内悬浮率达80%左右,各项性能均符合水分散颗粒剂的要求;润湿剂、黏结剂和崩解剂均能不同程度地影响WDRSC的相关性能;与苎麻麻骨相比,WDRSC对Cd2+与Cu2+的去除率分别提高了11%和4%。所得结论表明将苎麻麻骨制成WDRSC具有运输和使用方便、成本低廉、制作工艺简单且吸附后废渣处理方便等优点,为苎麻麻骨规模化利用的可行方法。      

Influence of process variable and physicochemical properties on the granulation mechanism of mannitol in a fluid bed top spray granulator

This study investigated the influence of specific process variables, including the hydroxypropyl cellulose (HPC) binder solution atomization, on the fluidized bed top spray granulation of mannitol. Special attention was given to the relationship between wetting and the granule growth profile. The atomization of the HPC binder solution using a binary nozzle arrangement produced droplets of decreasing size as the atomization pressure was increased, while changes in the spray rate had little effect on the mean droplet size. Increasing the HPC binder concentration from 2 to 8% w/w increased the binder droplet size and was most likely attributed to higher solution viscosity. The top spray granulation of mannitol showed induction type growth behavior. Process conditions like high spray rate, low fluidizing air velocity and binder solution concentration that promote the availability of HPC binder solution at the surface of the particles appeared to be key in enhancing nucleation and growth of the granules. Increasing the bed moisture level, up to a certain value, reduced the contribution of attrition to the overall growth profile of the granule and, more significantly, produced less granule breakage on drying. It was observed that the mean granule size could be reduced as much as 40% between the end of granulation and the end of drying for lower initial bed moisture level despite a shorter drying phase. High atomization pressure, especially when maintained during the drying phase, contributed substantially to granule breakage.     

Influence of Process Variable and Physicochemical Properties on the Granulation Mechanism of Mannitol in a Fluid Bed Top Spray Granulator

This study investigated the influence of specific process variables, including the hydroxypropyl cellulose (HPC) binder solution atomization, on the fluidized bed top spray granulation of mannitol. Special attention was given to the relationship between wetting and the granule growth profile. The atomization of the HPC binder solution using a binary nozzle arrangement produced droplets of decreasing size as the atomization pressure was increased, while changes in the spray rate had little effect on the mean droplet size. Increasing the HPC binder concentration from 2 to 8% w/w increased the binder droplet size and was most likely attributed to higher solution viscosity. The top spray granulation of mannitol showed induction type growth behavior. Process conditions like high spray rate, low fluidizing air velocity and binder solution concentration that promote the availability of HPC binder solution at the surface of the particles appeared to be key in enhancing nucleation and growth of the granules. Increasing the bed moisture level, up to a certain value, reduced the contribution of attrition to the overall growth profile of the granule and, more significantly, produced less granule breakage on drying. It was observed that the mean granule size could be reduced as much as 40% between the end of granulation and the end of drying for lower initial bed moisture level despite a shorter drying phase. High atomization pressure, especially when maintained during the drying phase, contributed substantially to granule breakage.     

Influence of filler selection on twin screw foam granulation

The influence of filler selection in wet granulation was studied for the novel case where the binder is delivered as an unstable, semi-rigid aqueous foam to an extrusion process. The work primarily examined the impact of differing concentrations of microcrystalline cellulose (Avicel PH® 101) in a formulation with spray-dried α-lactose monohydrate (Flowlac® 100) in regards to wetting and granule nucleation for this relatively new technique known as continuous foam granulation. Foam stability was varied within the work to change its drainage and coarsening behavior atop these powder excipients, by use of different foamable binding agents (METHOCEL? F4 PLV and METHOCEL? Premium VLV) as well as by adjusting the foam quality. A static bed penetration test was first used to study the foam behavior in wetting these powders without the processing constraints of an extruder which limit possible liquid-to-solids ratios as well as introduce shear which may complicate interpretation of the mechanism. The test found that the penetration time to saturate these powders decreased as their water absorption capacity increased which in turn decreased the size of the formed nuclei. Differences in the stability of the foamed binder had minimal influence on these attributes of wetting despite its high spread-to-soak behavior. The size of granules produced by extrusion similarly demonstrated sensitivity to the increasing water absorption capacity of the filler and little dependency on foam properties. The different liquid-to-solids ratios required to granulate these different formulations inside the extruder highlighted an evolving concept of powder lubricity for continuous foam granulation.     

Polymorphic Changes of Thiamine Hydrochloride During Granulation and Tableting

Thiamine hydrochloride was granulated using an instrumented fluidized bed granulator (Hüttlin HKC 05-TJ). Granules consisting of pure thiamine hydrochloride were produced using an aqueous solution of thiamine hydrochloride as the granulating liquid. The effects of process variables such as inlet air temperature, spray rate, and amount of granulating liquid on granule properties are described. Particle size distributions of granules depended mainly on the amount of granulating liquid sprayed into the powder bed. Granules were tableted on a rotary tablet press at four different compression forces. Crushing strengths and disintegration times of all tablets were found to be very low after manufacture, but increased considerably after 4 months of storage at room temperature. Granular materials showed “caking” under the same storage conditions. These changes could be attributed to alterations of the polymorphic form of thiamine hydrochloride. The water-free form, being present directly after granulation, absorbs humidity very fast and is transformed into the monohydrate, which is stable at room temperature. Loss of water takes place during the drying phase of the granulation process and on storage of the substance at temperatures of 50°C and 80°C. During storage at room temperature while exposed to humidity, a transformation into the hemihydrate was observed. This polymorph is transformed during thermal analysis at about 190°C to a water-free form that is stable at higher temperatures.     

Polymorphic changes of thiamine hydrochloride during granulation and tableting

Thiamine hydrochloride was granulated using an instrumented fluidized bed granulator (Hüttlin HKC 05-TJ). Granules consisting of pure thiamine hydrochloride were produced using an aqueous solution of thiamine hydrochloride as the granulating liquid. The effects of process variables such as inlet air temperature, spray rate, and amount of granulating liquid on granule properties are described. Particle size distributions of granules depended mainly on the amount of granulating liquid sprayed into the powder bed. Granules were tableted on a rotary tablet press at four different compression forces. Crushing strengths and disintegration times of all tablets were found to be very low after manufacture, but increased considerably after 4 months of storage at room temperature. Granular materials showed "caking" under the same storage conditions. These changes could be attributed to alterations of the polymorphic form of thiamine hydrochloride. The water-free form, being present directly after granulation, absorbs humidity very fast and is transformed into the monohydrate, which is stable at room temperature. Loss of water takes place during the drying phase of the granulation process and on storage of the substance at temperatures of 50 degrees C and 80 degrees C. During storage at room temperature while exposed to humidity, a transformation into the hemihydrate was observed. This polymorph is transformed during thermal analysis at about 190 degrees C to a water-free form that is stable at higher temperatures.     

Extrusion granulation and high shear granulation of different grades of lactose and highly dosed drugs: a comparative study

Formulations containing different lactose grades, paracetamol, and cimetidine were granulated by extrusion granulation and high shear granulation. Granules were evaluated for yield, friability, and compressibility. Tablets were prepared from those granules and evaluated for tensile strength, friability, disintegration time, and dissolution. The different lactose grades had an important effect on the extrusion granulation process. Particle size and morphology affected powder feeding and power consumption, but had only a minor influence on the granule and tablet properties obtained by extrusion granulation. In contrast, the lactose grades had a major influence on the granule properties obtained by high shear granulation. Addition of polyvinylpyrrolidone (PVP) was required to process pure paracetamol and cimetidine by high shear granulation, whereas it was feasible to granulate these drugs without PVP by extrusion granulation. Granules prepared by extrusion granulation exhibited a higher yield and a lower friability than those produced by high shear granulation. Paracetamol and cimetidine tablets compressed from granules prepared by extrusion granulation showed a higher tensile strength, lower friability, and lower disintegration time than those prepared from granules produced by high shear granulation. Paracetamol tablets obtained via extrusion granulation exhibited faster dissolution than those obtained via high shear granulation. For all lactose grades studied, extrusion granulation resulted in superior granule and tablet properties in comparison with those obtained by high shear granulation. These results indicate that extrusion granulation is more efficient than high shear granulation.     

On the composite characteristics of small binary granules formed in a continuous rotating conical vessel with grinding media

In order to produce small composite granules having binary components of CaCO₃ and SiC powders, experiments were carried out by the simultaneous operation of granulation, grinding, and separation in a single continuous rotating conical vessel with grinding media. To characterize these composite granules, SiC agglomerates contained in a granule were separated by chemical methods, and the size distributions of granules and SiC agglomerates were measured by an image analyzer through a microscope. The structure of a composite granule was characterized by comparing the size of a composite granule with that of SiC agglomerates in the granule. It was found that composite structures of the granules could be classified into six kinds of structural models, and that the composite structure depended on the size of the granules and the volume fraction of the SiC component in the granule.     

Improvement in the permeability of sintering beds by drying treatment after granulating sinter raw materials containing concentrates

The permeability of the sinter green beds will remarkably deteriorate when magnetite concentrate powder is introduced into the raw blend. To address this problem, a technique of drying after high-moisture granulation is proposed. Using this technique, the permeability can be raised from 40.45 JPU to 46.05 JPU at 7.7 wt% granulation moisture. At the same time, the results show that drying may cause the degradation of granules when the granulation moisture is excessive. Therefore, the final permeability of the stacked bed depends on the combined effect of increasing the bed stiffness and decreasing the average particle size. Fortunately, the addition of hydrated lime (HL) can significantly inhibit granule degradation and improve granulation efficiency, which can further improve the bed permeability to 61.41 JPU with a 2% HL addition level (at 7.7 wt% granulation moisture). Finally, an optimized process is proposed that uses low-grade waste heat during sinter cooling to dry the wet granules. This optimization not only meets the energy needs of drying but also facilitates the grade recovery and cascade utilization of waste heat during the sintering process.     

Stage-wise characterization of the high shear granulation process by impeller torque changing rate

Fine cornstarch powders are wet granulated in a lab-scale high shear granulator. The torque required for maintaining the impeller passing through the bed with a constant rotating speed is monitored during the continuous binder addition granulation process. A new method is proposed to identify 6 stages during the granulation process based on the fraction of the positive impeller torque changing rate in a characteristic period of time. The morphologies and the behavior of the bed are found intrinsically different in the identified 6 stages. The influence of the impeller blade inclined angle on the impeller torque in each stage is initially reported. The impeller with planner 45° blades requires higher torques in Stages I and II due to the overall powder bed mass loading. The impeller with steeper 60° blades requires higher torques in Stages III and IV due to the higher collision frequencies between the blade and granules. The suitable granulation liquid binder to solid powder mass ratio can be readily identified in Stages II and III, and its range is found to increase with the increasing of the impeller rotational speed and is independent to the blade inclined angle.     

Integrated Population Balance Model Development and Validation of a Granulation Process

This study is concerned with the development of an integrated three-dimensional population balance model (PBM) that describes the combined effect of key granulation mechanisms that occur during the course of a granulation process. Results demonstrate the importance of simulating the different mechanisms within a population balance model framework to elucidate realistic granulation dynamics. The incorporation of liquid addition in the model also aids in demarcating the dynamics in different regimes such as premixing, granulation (during liquid addition) and wet massing (after liquid addition). For the first time, the effect of primary particle size distributions and mode of binder addition on key granule properties was studied using an integrated PBM. Experimental data confirms the validity of the overall model as compared to traditional models in the literature that do not integrate the different granulation mechanisms.     

Estimation of agglomerate size of multi-walled carbon nanotubes in fluidized beds

The objective of this study was to determine hydrodynamic characteristics of multi-walled carbon nanotubes (MWCNTs) agglomerates and examine their sizes. The bed collapsing process of MWCNTs agglomerates was found to be closer to that of Geldart group C particles than group A particles. Median diameters of MWCNTs agglomerates determined by sedimentation method at initial superficial gas velocity of 0.120 and 0.190 m/s were 157 and 221 μm, respectively. The size of these MWCNTs agglomerates in fluidization state was measured by image analysis using a high speed camera. Median diameters of these MWCNTs agglomerates in freeboard were increased from 138 to 189 μm as superficial gas velocity was increased from 0.088 to 0.190 m/s at static bed height of 0.16 m. Median diameter and size distribution determined by sedimentation method fitted well with those measured using image analysis. Results were reasonable at superficial gas velocity up to 0.190 m/s.