降糖颗粒湿法制粒工艺优化

目的对降糖颗粒湿法制粒工艺进行参数优化,提高收率。方法用正交设计法设计试验,以颗粒收率为考察指标,对影响降糖颗粒湿法制粒过程的因素进行考察。结果正交试验法设计的三个因素中,润湿剂与干物料比例和搅拌桨/制粒刀速度对颗粒收率有比较显著的影响。结论最佳工艺条件为:润湿剂与干物料比例为1∶4,搅拌桨/制粒刀工作速度为120/1000rpm,制粒终点电流值40A。     

阿奇霉素片颗粒湿法制粒的工艺研究

目的 探究阿奇霉素片颗粒湿法制粒的工艺.方法 本次研究在制作阿奇霉素药片时采用了正交试验法,并考察了本次研究过程中药品的搅拌速度;切碎速度;聚维酮浓度和搅拌时间,以此观察上述四种因素对阿奇霉素片颗粒的成品率和水分的相关影响.结果 通过多次研究证明,在制作阿奇霉素片时,效果最好的搅拌速度为75 r/min,切碎速度为33...     

高剪切湿法制粒工艺对利奈唑胺颗粒的影响

目的 考察高剪切湿法制粒工艺对利奈唑胺颗粒质量属性的影响,确定关键工艺参数,为本品工艺放大奠定基础。方法 采用析因设计考察搅拌转速、用水量、制粒时间对利奈唑胺颗粒大小、流动性、片芯溶出的影响。结果 用水量对利奈唑胺颗粒大小、流动性、溶出的影响有显著性差异,搅拌转速、制粒时间对利奈唑胺颗粒流动性、溶出的影响没有显著性差异。结论 用水量是利奈唑胺片湿法制粒工艺关键工艺参数,后续工艺放大需重点关注。     

流化床一步制粒法对清开灵颗粒收率的影响

目的:采用正交设计的方法,研究流化床一步制粒法影响清开灵颗粒收率的因素。经过试验其结论为:影响清开灵颗粒收率的因素大小顺序为:供业电压>润湿粘附剂浓度>粘合剂用量。     

清胆颗粒制粒工艺研究

目的:研究清胆颗粒制粒工艺。方法:制备清胆颗粒喷雾干燥浸膏粉,采用干压法、流化法、高速搅拌法制备清胆颗粒;以颗粒粒径分布、流动性及成品率为评价指标,优选清胆颗粒制粒工艺。结果:高速搅拌制粒主要为20～30目的颗粒,流化制粒主要为30～60目颗粒,干压制粒粒径分布广、细粒多;流动性顺序为高速搅拌制粒>流化制粒>干压制粒清胆颗粒;成品率顺序为高速搅拌制粒>流化制粒>干压制粒。结论:采用高速搅拌制粒法制备清胆颗粒,效果优于干压法和流化制粒法,工艺可行,可为进一步研究提供理论基础。     

JH颗粒流化制粒工艺研究

目的 建立和优化JH颗粒流化制粒工艺参数.方法 以颗粒成品率作为考察指标,分别对浸膏相对密度、进风温度、雾化压力、蠕动泵转速等工艺参数进行考察.结果 优选的最佳流化制粒参数为浸膏相对密度为1.07,进风温度为80℃,雾化压力为0.08MPa,蠕动泵转速为12r·min-.结论 采用流化制粒工艺制备JH颗粒,工艺参数稳定,可于生产中应用.     

湿法制粒压片中的技术改进

湿法制粒压片历史悠久,至今仍被普遍采用,其适用于对湿热稳定的药物。 湿法制粒压片时,首先药物要进行粉碎过筛,粉碎药物的粒度因不同品种而异,通常固体药物的粒度愈细,则溶出速率愈快,药效就愈高。因为一般口服片剂需在胃肠道中溶解及吸收而显现药效,所以难溶性的药物粒子越细,则在体内溶出速率就越快,在胃肠道内吸收速度也就快。 尼莫地平是一个典型的脂溶性药物,当原料粉碎细度为过五号筛时,其片剂溶出度仅为30％～     

湿法制粒工序参数的应用进展

介绍国外最新的湿法制粒工艺和制药设备，包括湿法制粒机的种类、湿法制粒的原则，分析各湿法制粒工序参数对颗粒形成的影响。当今应用高速搅拌制粒机进行湿法制粒最多，应用工艺分析技术和制粒的统计工具是未来的发展趋势。     

正交法改进牛磺酸颗粒制粒工艺

目的：改进牛磺酸颗粒的制粒工艺，提高收率。方法：采用正交法对工艺进行优化。结果：改进后的工艺，制粒收率由原工艺的81．8％提高到94．5％。结论：改进后的牛磺酸颗粒制粒工艺收率和生产效率明显提高，工艺可行。     

蓝芩颗粒干法制粒工艺研究

通过对蓝芩颗粒干挤法制粒工艺的研究,系统介绍干式制粒及其优点详细论述干式制粒过程中存在的问题及具体解决办法.     

End-point detection in a wet granulation process.

The purpose of the experiments in this paper was to evaluate granulation end-point control by power consumption measurement in a 25-L high shear mixer. The effect of impeller design, impeller speed, liquid addition rate, type of binder, and mixing ratio between lactose and starch on the correlation between power consumption and granule growth was investigated in the liquid addition phase of the process using a fractional factorial experimental design. There was found generally a linear correlation between power consumption and mean granule size, but this correlation was dependent on the impeller design, the impeller speed, and the type of binder. However, an end-point control based on power consumption was not found to be sensitive to variations in the lactose:starch ratio. It was concluded that it was possible to control the liquid addition by the level detection method by which the liquid addition is stopped at a predetermined level of power consumption. An end-point control based upon the peak detection method was not generally applicable, because a peak in the differentiated power consumption signal could not be identified in all the experiments.     

A combined experimental and modeling approach to study the effects of high-shear wet granulation process parameters on granule characteristics

The purpose of the current work is to study the effects of high-shear wet granulation process parameters on granule characteristics using both experimental and modeling techniques. A full factorial design of experiments was conducted on three process parameters: water amount, impeller speed and wet massing time. Statistical analysis showed that the water amount has the largest impact on the granule characteristics, and that the effect of other process variables was more pronounced at higher water amount. At high water amounts, an increase in impeller speed and/or wet massing time showed a decrease in granule porosity and compactability. A strong correlation between granule porosity and compactability was observed. A three-dimensional population balance model which considers agglomeration and consolidation was employed to model the granulation process. The model was calibrated using the particle size distribution from an experimental batch to ensure a good match between the simulated and experimental particle size distribution. The particle size distribution of three other batches were predicted, each of which was manufactured under different process parameters (water amount, impeller speed and wet massing time). The model was able to capture and predict successfully the shifts in granule particle size distribution with changes in these process parameters.     

Analysis of wet granulation process with Plackett-Burman design--case study

According to Process Analytical Technology perspective, drug product quality should be ensured by manufacturing process design. Initial step of the process analysis is investigation of critical process parameters (CPPs). It is generally accepted to type the CPPs based on project team knowledge and experience [5]. This paper describes the use of Design of Experiments tool for selection of the CPPs. Seven factors of wet granulation process were investigated for criticality. Low and high levels of each factor represented maximal and minimal settings of wide operational ranges. Granulates were produced in line with Plackett-Burman experimental matrix, blended with extra-granular excipients and compressed into tablets. Semi-products and final products were tested. Out of specification result of any critical quality attribute was treated as critical failure. The high-shear granulation factors, i.e. quantity of binding solution, rotational speed of impeller and wet massing time were considered of critical importance. Operational ranges of the parameters were optimized. The process performance was confirmed in qualification trials.     

Optimization of a high shear wet granulation process using focused beam reflectance measurement and particle vision microscope technologies

Application of process analytical technology in the pharmaceutical industry has led to a great number of studies into inline instrumentation. Near-infrared moisture monitoring in fluid bed drying and content uniformity assurance in blending are gaining acceptance for monitoring and quality control of these processes. Although these techniques are a great improvement over traditional methods, each is performed at points in processing wherein processing is well understood and interfacing equipment is relatively easy. More complex unit operations have largely been unexplored due to complexities interfacing inline analytical equipment to unit operations or a lack of methodologies that can be applied to measure attributes of interest. This paper reports results from a study utilizing a focused beam reflectance measurement system equipped with window scraper technology for the inline measurement and control of a high shear wet granulation (HSWG) process. In addition to this, offline results obtained with a particle vision microscope system are compared to verify the results obtained inline. It is shown that using these technologies in monitoring the HSWG process greatly increases process understanding of physical changes occurring during processing through real-time observation of particle size, leading to real-time control of the process.     

Optimization of the high-shear wet granulation wetting process using fuzzy logic modeling

A fuzzy model has been developed for the optimization of high-shear wet granulation wetting on a plant scale depending on the characteristics of pharmaceutical active substance particles. The model optimized on the basis of experimental data involves a set of rules obtained from expert knowledge and full-scale process data. The skewness coefficient of particle size distribution and the tapped density of the granulated mixture were chosen as the model input variables. The output of the fuzzy ruled system is the optimal quantity of wetting liquid. In comparison to manufacturing practice, a very strong sensitivity of the optimal quantity of the added wetting liquid to the size and shape of the active substance particles has been identified by fuzzy modeling.     

高速剪切湿法制粒工艺制备氯沙坦钾片

目的通过优化高速剪切湿法制粒工艺参数制备氯沙坦钾片。方法采用高速剪切湿法制粒工艺制备氯沙坦钾片,通过对制备工艺参数优化:搅拌桨转速(X_1,r·min~(-1))、加水量(X_2,%)和制粒时间(X_3,s)为考察对象,以颗粒粒径大小(D50,Y_1,μm)、片剂硬度(Y_2,N)、15min药物溶出度(Y_3,%)为评价指标,利用Box-Behnken效应面法优化高速剪切湿法制粒工艺参数。结果方差分析结果显示:搅拌桨转速、加水量和制粒时间对颗粒粒径影响较显著(P<0.05);加水量、制粒时间对片剂的硬度影响较显著(P<0.05);加水量、制粒时间对药物的溶出度影响较显著(P<0.05)。结论通过Box-Behnken实验设计法优化高速剪切湿法制粒工艺,可以提高工艺过程的稳健性和灵活性。     

Effect of physical states of binders on high-shear wet granulation and granule properties: a mechanistic approach toward understanding high-shear wet granulation process, part 3: effect of binder rheological properties

Ternary blends consisting of efavirenz (a model drug compound), lactose monohydrate, and a polymeric binder were investigated to verify the "physical state theory" in which granulation occurs only when binders undergo transition from glassy state to rubbery solution state. Furthermore, it was found that the rheological properties of the binders can significantly affect the granulation process. The blends with binders of viscous flow [polyvinylpyrrolidone (PVP) K17, PVP K25, and PVP K29/32 after exposure to 96% RH] showed an increase in particle size with both binder concentration and mixing time. On the contrary, binders with viscoelastic properties, such as hydroxypropylcellulose (HPC) EXF and PVP K90, did not flow well and thereby, the blends with HPC and PVP K90 did not show much effect of binder concentration and mixing time on their granule size. Moreover, the friability of granules made with HPC EXF and PVP K90 is low, indicating that the strength of the granules largely depends on the viscosity of the binders, as the binders of higher viscosity tend to produce stronger granules. Finally, the viscoelastic state of the polymeric binders upon absorbing water was analyzed using the glass-rubber transition model, which shows five regions with different viscoelastic properties.     

Scaling-up of a lactose wet granulation process in Mi-Pro high shear mixers

The high shear wet granulation upscaling possibilities of a Pro-C-epT Mi-Pro 250 ml with a batch size of 40 g were investigated by down-scaling an alpha-lactose monohydrate wet granulation process from a Collette Gral 10 (8 l batch size) to a Pro-C-epT Mi-Pro with different bowl volumes of 5 l, and 1900, 900 and 250 ml. The wet granulation process was optimised in the Gral 10, next an octagonal design was build around the central point. Two process parameters, the impeller tip speed and the water content, were varied at three levels, which resulted in a two-factor three-level experimental design. alpha-Lactose monohydrate 200 M was granulated using a polyvinylpyrollidone K 30 (2.5% on dry material) binder solution. The granules were dried at 25 degrees C for 24 h, sieved and characterised. The granules were compressed to tablets. In all mixer volumes the used impeller tip speed range did not influence the granule or tablet properties. In all bowl volumes the influence of water concentration on actual yield, particle size distribution and granule friability was similar. All batch sizes resulted in tablets of similar quality. For the selected formulation the lab scale Mi-Pro high shear mixers with different bowl volumes could be used to determine the optimal process parameters and to scale up to the Collette Gral 10 pilot scale.     

Combining formulation and process aspects for optimizing the high-shear wet granulation of common drugs

The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches.A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale high-shear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis).Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.     

Comparison of torque measurements and near-infrared spectroscopy in characterization of a wet granulation process

The purpose of this study was to compare impeller torque measurements and near-infrared (NIR) spectroscopy in the characterization of the water addition phase of a wet granulation process. Additionally, the effect of hydrate formation during granulation on the impeller torque was investigated. Anhydrous theophylline, alpha-lactose monohydrate, and microcrystalline cellulose (MCC) were used as materials for the study. The materials and mixtures of them were granulated using purified water in a small-scale high-shear mixer. The impeller torque was registered and NIR spectra of wet samples were recorded at-line. The torque and the NIR baseline-corrected water absorbances increased with increasing water content. A plateau in the NIR baseline-corrected water absorbances was observed for wet masses containing MCC. This was at the region of optimal water amount for granulation according to the torque results. In the case of anhydrous theophylline, the slope of baseline-corrected water absorbance values increased at the same water amount as the impeller torque started to increase. The hydrate formation of theophylline during granulation was observed as a slight decrease in the impeller torque. In addition, the hydrate formation during granulation affected the granulation liquid requirement. The liquid requirement was different for monohydrate formed during granulation compared to one formed in high relative humidity before the granulation. The results suggest that NIR spectroscopy may be applicable to process monitoring of wet granulation, also in cases where monitoring of impeller torque is difficult to apply.