Melt Granulation in A Laboratory Scale High Shear Mixer

Abstract

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

Melt Granulation in A Laboratory Scale High Shear Mixer

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

The Granulation of Lactose and Starch in a Recording High-Speed Mixer,Diosna P25

Abstract

Lactose 100 mesh was granulated faster than the 350 mesh quality.

Corn starch required large volumes of granulating solution. When agglomerating pure corn starch, its loss on drying influenced the process.

Suitable limits for the end-point determination when granulating a mixture of 2/3 of lactose 100 mesh and 1/3 of corn starch, with povidone as binder, were determined for the liquid addition under controlled conditions.

In a 1/2 ? 2₆ factorial experiment, the influence of the process variables on the response variables was studied. The former are the main impeller and chopper speed; the method of fluid addition; the way of adding the binder; the volume of granulating liquid added, and the wet massing time. The response variables concerned are the fraction <0.150 or >2.00 mm; the granule median diameter; the change in the rotation rate of the impeller shaft; and heat production in the mass. The impeller and chopper speed, the way of adding the binder, and the volume of granulating solution that was added, influenced all the response variables significantly. However, the dominating variables were the volume of solution and the impeller rate. Besides, the granule median diameter was influenced by the method of fluid addition. Also, the heat production during granulation was influenced by the method of fluid addition as well as by the wet massing time.     

集成过程分析技术和群体粒数衡算模拟的药物材料造粒过程决策支持系统

通过集成在线近红外光谱仪、实时图像采集与处理系统和群体粒数衡算模型,开发了高剪切湿法造粒过程的决策支持系统(Decision support system,DSS)。利用近红外光谱仪和图像系统实时测量多个过程变量和产品质量指标,包括粉体混合均匀度、颗粒粘合剂含量、粒径分布以及团聚、破裂行为等,能够快速确定过程操作空间。同时,由过程分析平台得到的信息经分析处理后输入工艺过程模型模块,用于估算和校准群体粒数衡算模型中的团聚和破裂速率常数,以此持续提高模型精度。另一方面,模型可以指导实验体系寻找最优操作空间。该决策支持系统成功应用到了以微晶纤维素和甘露醇为原料,3%聚乙烯吡咯烷酮水溶液为粘合剂的高剪切湿法造粒过程中,对两个粘合剂喷淋速率下的造粒过程进行监测。DSS认定粘合剂喷淋过程分为四个阶段:润湿期、成核期、快速生长期和慢速生长期。不同阶段之间的分界点与粘合剂喷淋速率有关。在较高喷淋速率下,颗粒进入成核期和快速生长期所需粘合剂较少,但是对颗粒最终粒径无明显影响。此外,通过近红外光谱测定混合均匀度,确定了粉体的混合终点。该DSS系统将基于过程分析技术的高效实验和过程模拟结合,可以快速确定操作空间以及颗粒的生长行为,实时提供大量数据用于持续提高模型精确度和稳健性,提高造粒过程的优化效率。     

Investigations at an industrial scale on granule and tablet attributes in high shear rapid mixer granulator

Particle agglomeration by granulation was a very ubiquitous operation that finds applications in various industries such as pharmaceutical, food, chemical, fertilizer, etc. Among many granulators, the high shear rapid mixer granulator (RMG) was a very commonly used wet granulator in pharmaceutical industry. The wet granulation process was sensitive to the process parameters and the input product variables. The flow pattern, fill ratio, cohesive forces, velocities, and the kinetic energy of the particles have impact on the granular and the tablet properties. In this work, solid dosage formulation integrated with the RMG process has been studied at an industrial scale. The total formulation of the tablet was kept constant and the impact of various critical operating and process parameters of RMG viz., impeller design, impeller speed, batch size, binder concentration, and binder type on granule and tablet attributes has been studied and analyzed. The optimal set of process parameters to achieve the desired granular and tablet attributes viz., bulk density, compressibility (Carr index) flow properties (Hausner ratio), particle size distribution, texture, tablet hardness, dissolution, and disintegration times were found in the study.     

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.     

A Comparison Between Binders in the Wet Phase of Granulation in a High Shear Mixer

The effects of binder solutions on granule size, intragranular porosity and liquid saturation in a high shear mixer are examined during the liquid addition phase of the granulation process. The power consumption profiles of impeller motor are recorded. Five different binders (PVP, PVP-PVA-copolymer, hydrolysed gelatine and two HPMC'S) are investigated.

The PVP and hydrolysed gelatine produce granules with a higher mean granule size. This is shown to be due to the higher densification caused by these binders.

The power consumption profiles for PVP are significantly higher than for the other binder solutions. It is suggested that the high power consumption profiles are a result of the strength of mobile liquid bondings caused by the high surface tension of PVP solutions.     

Effect of Binder Concentration and Method of Addition on Granule Growth in a High Intensity Mixer

Abstract

A model system consisting of microcrystalline cellulose and povidone was used to study the effect of binder concentration and method of addition on granule growth in a high intensity mixer. The methods of binder addition include blending the dry binder with the excipient prior to granulating with water and granulation of the excipient with an aqueous solution of the binder. When the binder was dry-mixed with excipient prior to wetting, a good correlation was obtained between granule size and binder level. The growth of granules prepared by this method also appears to be related to the mechanical “resistance” encountered by the mixing blade during wet massing. In general, granules prepared by the addition of aqueous binder solutions are smaller than granules prepared with corresponding concentrations of dry binder and demonstrate a lesser degree of granule growth with respect to increasing binder level. For the wet addition method, the mechanical resistance was found to be essentially constant with respect to binder level.     

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.     

Effect of Binder Concentration and Method of Addition on Granule Growth in a High Intensity Mixer

A model system consisting of microcrystalline cellulose and povidone was used to study the effect of binder concentration and method of addition on granule growth in a high intensity mixer. The methods of binder addition include blending the dry binder with the excipient prior to granulating with water and granulation of the excipient with an aqueous solution of the binder. When the binder was dry-mixed with excipient prior to wetting, a good correlation was obtained between granule size and binder level. The growth of granules prepared by this method also appears to be related to the mechanical “resistance” encountered by the mixing blade during wet massing. In general, granules prepared by the addition of aqueous binder solutions are smaller than granules prepared with corresponding concentrations of dry binder and demonstrate a lesser degree of granule growth with respect to increasing binder level. For the wet addition method, the mechanical resistance was found to be essentially constant with respect to binder level.     

An Evaluation of Process Variables in wet Granulation

Abstract

In wet granulation, determining the process variables which play an essential role in granule quality is crucial for optimizing the manufacturing process. An L16(2⁵) fractional factorial experimental design using the table of orthogonal arrays was employed in order to estimate the relative intensity of the influences of five process variables on granule quality in wet granulation using a high-speed mixer granulator. Total volume and formulation of binder solution, blade rotation speed, granulation time, and amount of powder supplied into the granulator were selected as decisive process variables in the formation of granules. Granule yield, geometrical mean granule size and uniformity of granule size were evaluated as representative properties of granule quality. Experimental results were analyzed according to the analysis of variance (ANOVA).

The results of significance test and contribution ratio in ANOVA indicated that, within the experimental region, only binder solution had a critical effect on the three physical properties of the obtained granules. The effects of other variables were found to be minimal. Further, the contribution of sampling error to total variance was quite small.     

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations

The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and in vitro dissolution were also studied. Following post-granulation drying at 60?°C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25?°C/60% RH and 40?°C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.     

A Comparison Between Binders in the Wet Phase of Granulation in a High Shear Mixer

The effects of binder solutions on granule size, intragranular porosity and liquid saturation in a high shear mixer are examined during the liquid addition phase of the granulation process. The power consumption profiles of impeller motor are recorded. Five different binders (PVP, PVP-PVA-copolymer, hydrolysed gelatine and two HPMC'S) are investigated.

The PVP and hydrolysed gelatine produce granules with a higher mean granule size. This is shown to be due to the higher densification caused by these binders.

The power consumption profiles for PVP are significantly higher than for the other binder solutions. It is suggested that the high power consumption profiles are a result of the strength of mobile liquid bondings caused by the high surface tension of PVP solutions.     

Influence of melting and rheological properties of fatty binders on the melt granulation process in a high-shear mixer

The preparation of granules by melt granulation was investigated using a laboratory-scale high-shear mixer (Pellmix PL 1/8) and binary mixtures containing lactose and different lipidic binders, namely, Compritol® 888, Cutina® HR, or Precirol® ATO5. During the process, the product temperature and the impeller motor power consumption were monitored. On the other hand, the melting behavior (thermal analysis) and the rheological properties (controlled stress capillary rheometer) of the different lipophilic binders were also determined. The granule formation was shown to be quite effective at product temperatures even below the melting point of the lipidic binder, that is, when the binder is sufficiently softened to be deformed by the very high shearing forces developed in the high-shear mixer. On the other hand, the performance of lipidic binders during the melt granulation process was shown to be closely dependent on their melting and rheological properties. The granule growth rate was shown to be higher when the binder melting range is narrow and the influence of temperature on the viscosity of the unmelted product is high.     

Granulation: A Review on Pharmaceutical Wet-Granulation

Abstract

Recent developments in pharmaceutical wet granulation techniques are reviewed with the main emphasis on granulation in fluidized beds and high shear mixers. The following items are dealt with: Fundamentals of granule growth, granulation methods and equipments, granulation variables, scaling-up and end-point control.     

Instrumentation of a Vertical High Shear Mixer with a Motor Slip Monitoring Device

Abstract

The main impeller shaft of a vertical high shear mixer was instrumented with a device which measures motor slip and displays its output in percent horsepower. Response was proportional to mixer load. A warm-up period was required to minimize variability in output. High speed impeller operation showed more consistency in response than low speed impeller operation. During the granulation process of the different test systems, a typical response profile showed a change in percent horsepower as the binder solution was added followed by a plateauing at about the proposed optimum mixing time. Additional studies to correlate this observation with granulation physical and compression characteristics are necessary     

Prospective Validation of High-Shear Wet Granulation Process by Wet Granule Sieving Method. II. Utility of Wet Granule Sieving Method

The general utility of a method for determination of high-shear wet granulation end point by monitoring the wet granule particle size distribution was evaluated. Wet granulation was conducted in a 25-liter high-shear mixer using four model drugs with different solubilities and particle sizes (ethenzamide, unmilled and milled acetaminophen, and antipyrine). For each drug formulation, its wet granule particle size fraction and target range for granulation end point determination were selected based on the tablet characteristics that are known to be influenced by the wet granulation process. Granules manufactured under different conditions (i.e., different main and chopper blade speeds and binder supplying rate) but manufactured to the same granulation end point determined by the selected fraction and range showed very similar granule characteristics and subsequently very similar tabler characteristics. From the fact that there was a good correlation between the wet and dry-sized granule particle size distributions even if the drying method was changed from fluid-bed drying to vacuum drying, the general application of the end point determining method was verified. Further, the method was shown to be sensitive to the critical granulation parameters for granulation progression and to be very capable of determining the granulation extent. Thus, it was suggested that the method is applicable to various drugs and formulations for determination of wet granulation end point.     

Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO

Context: Niacin (vitamin B3) is a micronized active pharmaceutical ingredient (API) with poor flow properties making the production of high-dose sustained-release tablets by direct compression a challenge.

Objective: We evaluated various wet granulation processes as a simple and efficient approach to obtain high-dose (500 and 1000?mg) niacin sustained-release lipid matrix tablets.

Materials and methods: A high melting-point lipid (Compritol® 888 ATO) was used as the sustained-release agent. Tablets were prepared by various wet granulation techniques, with different process parameters and binder concentrations to identify the optimal process conditions.

Results: A binder (PVP) was needed to increase particle bonding and tablet strength. Process parameters, such as spray rate and quantity of liquid, had only a slight impact on the properties of the granules and resultant tablets, in the presence of low binder concentrations. Increasing binder concentration improved granule wetting, resulting in significant granule growth and improved flow properties. Sustained-release over 12?h was observed for all the compacted granules, irrespective of the drug dose. The sustained-release kinetics for 1000?mg niacin matrix tablets with Compritol 888 produced with the identified optimal parameters were similar to those for the market reference product, Niaspan® FCT 1000?mg. The tablets were stable for up to six months when stored at 25 and 40?°C.

Conclusions: Wet granulation with Compritol 888 presents an effective approach to improve material flow and compressibility. High-dose lipid matrix tablets with sustained release profiles can be successfully produced.     

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.