干湿法制粒技术在片剂生产中的对比应用

目的通过对不同制备工艺制得的曲克芦丁片(以下简称QK片)和复合磷酸酯酶片(以下简称FM片)进行比较,对两种片剂的制备工艺进行调整。方法采用湿法制粒工艺(以下简称SF工艺)和干法制粒工艺(以下简称GF工艺)分别制备QK片和FM片各三批,并对所制得的颗粒进行粒径分布、休止角、颗粒流动性、可压性、含量和效价测定及六个月的稳定性加速实验数据分析和比较。结果与SF工艺相比,GF工艺虽然在颗粒流动性和可压性方面相对不足,却可以明显提高某些热不稳定品种(如FM片)的稳定性。结论GF工艺技术作为近年来在国际上发展起来的新型造粒技术,在很多方面较SF工艺有着一定的优势,加上通过适当调整生产处方中辅料的用量,使其能够得到较为广泛的应用。     

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.     

Novel extended-release formulation of lovastatin by one-step melt granulation: In vitro and in vivo evaluation

The objective of this study was to apply a one-step melt granulation method to develop an extended-release formulation of lovastatin (LOV-ER). We prepared a formulation using PEG 6000 as binder agent in a laboratory scale high-shear mixer. In vitro dissolution studies showed that the release of the drug from the new formulation followed a zero-order kinetic with no differences in the release profile with either the pH media or the agitation rate. The pharmacokinetic of lovastatin and its metabolite lovastatin acid was evaluated after the administration of the new formulation to Beagle dogs in fasted conditions and after a high-fat meal, and compared to the marketed formulation Altoprev®. After the administration of LOV-ER, extended plasma profiles of lovastatin and its active metabolite were achieved in both fasted conditions and after the high-fat meal. Plasma levels of lovastatin and lovastatin acid were always higher when the LOV-ER formulation was administered with the high-fat meal. A high variability in plasma levels and pharmacokinetic parameters was obtained, being this variability higher when the formulation was administered under fasting conditions. Our results suggest that there is an increase in lovastatin bioavailability when the formulation is administered after the high-fat meal. When we compare LOV-ER and Altoprev®, both administered after the high-fat meal, we found significant differences (p < 0.05) in C_max of lovastatin and in AUC_0-∞ and MRT of lovastatin acid. No differences were detected between both formulations in fasting conditions. In this regard, the high-fat meal seems to increase the absorption extent of lovastatin from LOV-ER formulation and to delay the absorption rate of the drug from Altoprev®. In conclusion, we developed a lovastatin formulation that provided extended plasma levels that confirm that one-step melt granulation in high-shear mixer could be an easy and cost-effective technique for extended-release formulation development.     

Influence of granulation temperature on particle size distribution of granules in twin-screw granulation (TSG)

This study investigated an influence of granulation temperature during twin-screw granulation (TSG) on particle size distributions (PSDs). The influence of the granulation temperature on granule size distributions varied, depending on the liquid to solid (L/S) ratio, the kind of binders, the method of binder addition, and the filler material. The PSD of granules was broad and bimodal at a barrel temperature of 30?°C. Granules size distributions became narrow and second height decreased at high barrel temperature. While the L/S ratio had an effect on the sharpness of granule size distributions, this effect was minor compared to the granulation temperature. Granule size distributions were influenced by binder addition methods. When the binder was added as solution, PSD became broad. In formulations using lactose as filler, PSD became broad and bimodal at 90?°C. Much lactose was dissolved in granulation solution at high temperature, because the solubility of lactose rises significantly with the solution temperature leading to higher effective L/S ratio in the granulator. Hence, granulation was proceeded and large granules were formed. From these results, the granulation temperature is one of important parameters to obtain mono-modal PSD in TSG.     

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。     

An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyetilenglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.     

Scaleup of a High-Shear Granulation Process Using a Normalized Impeller Work Parameter

A method was evaluated to accurately identify the granulation end points of microcrystalline cellulose formulations by monitoring impeller work during high-shear processing. Impeller watt meters were calibrated in situ to a common standard to enable direct comparison of power values between equipment. Integration of the impeller power (watts) versus time (seconds) profile provides an energy parameter (watt seconds) or “work of granulation” for correlation with physical changes in tablet properties and performance. Granulation end points were accurately predicted for 25-, 65-, and 150-liter manufacturing scales on the basis of development work run on 5.0- and 10-liter equipment using work values normalized for the weight of dry powders in the granulator (watt sec/g). The ability to arrive at functionally equivalent granulation end points, in different equipment and at different impeller speeds, was established through comparison of cohesion indexes (slopes of the tablet breaking strength versus compression force profiles) and granulation size distributions determined by sieve analysis. Work measured at the impeller correlated quantitatively with changes in the granulation bulk and tapped densities, average particle size of the finished powders, and cohesion index, independent of granulator make or model. The observed changes in granulation properties, however, did not correlate with individual process variables such as impeller power (watts) or process time.     

流化床制粒法制备甲磺酸吉米沙星片

目的：探索流化床制粒法制备甲磺酸吉米沙星片的工艺参数。方法：以崩解时限为指标,对甲磺酸吉米沙星片的处方进行筛选。结果：500g甲磺酸吉米沙星,60gMCC作为填充剂,600m15％HPMC溶液作为黏合剂,20gCMS—Na作为崩解剂．可制得的颗粒能够制备崩解性能良好的片剂。结论：流化床制粒法解决了传统湿法制粒制备甲磺酸吉米沙星片所遇到的困难。     

Importance of excipient wettability on tablet characteristics prepared by moisture activated dry granulation (MADG)

For moisture activated dry granulation (MADG), microcrystalline cellulose (MCC) or silicon dioxide is recommended for the moisture absorption stage. The aim of this study was to assess the suitability of alternative excipients as moisture absorbents with regard to the disintegration mechanism of resulting lactose based placebo formulations. Beside high and low moisture MCC grades, the additions of magnesium aluminometasilicate (MAMS), pregelatinized starch (S1500), crospovidone (Kollidon CL) and carmellose calcium (ECG 505) were evaluated. High shear granulation (HSG) was conducted as a reference process. The overall disintegration time of all tablets produced by MADG was significantly faster whereas hardness yield and mass-variability were equal or superior compared to the HSG process. Powder wettability of the different moisture absorbents was identified to be a key driver for rapid disintegration, whereas tablet porosity had only a minor influence on the target hardness of the tablets.     

Using experimental design to optimize the process parameters in fluidized bed granulation on a semi-full scale

A face-centered central composite design was applied in order to optimize the granulation process on a semi-full scale (30-kg batch) for the geometric mean granule size. The granulation process variables investigated were: inlet air temperature, inlet airflow rate, spray rate and inlet air humidity. Based on the process variables, the theoretical powder bed moisture content after the spraying process and a measure for the droplet size were determined. Multiple regression modeling was used to develop two models for the granule size: an empirical model, based on the four process parameters, and a fundamental model, based on the balance between the granule growth affected by the theoretical powder bed moisture content and the droplet size and the breakage effect of the airflow rate. These regression models were used to optimize the granulation process to obtain a granule size between 300 and 500 μm. Additional experiments confirmed that these models were valid. Other granule properties, namely the geometric standard deviation, the Hausner index, the angle of repose and the moisture content, were evaluated at the optimal operation conditions.     

湿法混合制粒法制备碳酸氢钠片

目的研究以湿法混合制粒法制备碳酸氢钠片的工艺。方法采用淀粉、糊精、蔗糖粉为辅料,以不同配比、不同工艺制备碳酸氢钠片,并用正交设计筛选出了最佳制备工艺参数。结果经过片剂硬度测试证明,淀粉-糊精-蔗糖粉的配比为7∶1∶1,在制粒时加入5%的淀粉浆,压片时厚度控制为4.30mm时所压的片剂硬度最好。讨论A1B2C1配方及工艺得到的片剂硬度较好,适于生产,但没有考虑崩解时限、溶出度等指标。     

Batch statistical process control of a fluid bed granulation process using in-line spatial filter velocimetry and product temperature measurements

Fluid bed granulation is a batch process, which is characterized by the processing of raw materials for a predefined period of time, consisting of a fixed spraying phase and a subsequent drying period. The present study shows the multivariate statistical modeling and control of a fluid bed granulation process based on in-line particle size distribution (PSD) measurements (using spatial filter velocimetry) combined with continuous product temperature registration using a partial least squares (PLS) approach. Via the continuous in-line monitoring of the PSD and product temperature during granulation of various reference batches, a statistical batch model was developed allowing the real-time evaluation and acceptance or rejection of future batches.Continuously monitored PSD and product temperature process data of 10 reference batches (X-data) were used to develop a reference batch PLS model, regressing the X-data versus the batch process time (Y-data). Two PLS components captured 98.8% of the variation in the X-data block. Score control charts in which the average batch trajectory and upper and lower control limits are displayed were developed. Next, these control charts were used to monitor 4 new test batches in real-time and to immediately detect any deviations from the expected batch trajectory. By real-time evaluation of new batches using the developed control charts and by computation of contribution plots of deviating process behavior at a certain time point, batch losses or reprocessing can be prevented.Immediately after batch completion, all PSD and product temperature information (i.e., a batch progress fingerprint) was used to estimate some granule properties (density and flowability) at an early stage, which can improve batch release time. Individual PLS models relating the computed scores (X) of the reference PLS model (based on the 10 reference batches) and the density, respectively, flowabililty as Y-matrix, were developed. The scores of the 4 test batches were used to examine the predictive ability of the model.     

Assessment of spatial heterogeneity in continuous twin screw wet granulation process using three-compartmental population balance model

In this study, a novel three-compartmental population balance model (PBM) for a continuous twin screw wet granulation process is developed, combining the techniques of PBM and regression process modeling. The developed model links screw configuration, screw speed, and blend throughput with granule properties to predict the granule size distribution (GSD) and volume-average granule diameter. The granulator screw barrel was divided into three compartments along barrel length: wetting compartment, mixing compartment, and steady growth compartment. Different granulation mechanisms are assumed in each compartment. The proposed model therefore considers spatial heterogeneity, improving model prediction accuracy. An industrial data set containing 14 experiments is applied for model development. Three validation experiments show that the three-compartmental PBM can accurately predict granule diameter and size distribution at randomly selected operating conditions. Sixteen combinations of aggregation and breakage kernels are investigated in predicting the experimental GSD to best judge the granulation mechanism. The three-compartmental model is compared with a one-compartmental model in predicting granule diameter at different experimental conditions to demonstrate its advantage. The influence of the screw configuration, screw speed and blend throughput on the volume-average granule diameter is analyzed based on the developed model.     

The effect of the amount of binder liquid on the granulation mechanisms and structure of microcrystalline cellulose granules prepared by high shear granulation

The structure of granules changes during the high shear granulation process. The purpose of this research was to investigate the effect of the amount of binder liquid on the structure of the granules and the structural changes which occur during the granulation process, using microcrystalline cellulose (MCC) and water as the model system. The structure is the result of the granulation mechanism; therefore, conclusions can be drawn about the latter by studying the former. X-ray microtomography and scanning electron microscopy (SEM) were applied in order to visualise the densification process of granules, which were first freeze dried in order to preserve their structure. Variations in their porosity were quantified by applying image analysis to the tomography results. In order to link the granule mechanical properties to their structural differences, a micromanipulation technique was used to measure granule resistance to deformation. MCC granules granulated with 100% (w/w) water showed increased densification with time, as expected; detailed examination showed that densification is more pronounced in the core of the granule; whereas the outer part remained more porous. Increased densification reduces deformability, so that granules become more resistant to breakage. The lower deformability of the densified granules in the final stages of granulation might result in establishment of equilibrium between attrition and growth, without substantial gross breakage. On the other hand, when more water was used (125%, w/w), densification was hardly observed; the porosity of the granule core was still high even after prolonged granulation times. This may be explained by the fact that higher water content increases the ease of deformation of granules. This increased deformability led to significant granule breakage even during the final phases of the granulation process. Therefore, for these granules a final equilibrium between breakage and coalescence might be established. This also explains why more granules produced with 125% granulation liquid were composed of fragments of irregular shape.

Our results establish the link between the granulation behaviour of MCC in the latter stages and the material structure of these granules, which is determined by their liquid content. The process conditions (amount of liquid) to be chosen depend largely on the final purpose for which the granular material is produced.     

Process and formulation characterizations of the thermal adhesion granulation (TAG) process for improving granular properties

In this study, we demonstrate the feasibility of using the thermal adhesion granulation (TAG) method to improve granular properties for preparing highly compressible excipients as direct tabletting aids. The TAG method subjects a mixture containing excipients, such as microcrystalline cellulose (MCC), lactose, starch, or dibasic calcium phosphate (DCP), under closed conditions with a low moisture content and low content of polyvinyl pyrrolidone (PVP) as a binder, to heating during mixing by tumble rotation to produce highly compressible granules. Results demonstrated that a closed system is more efficient than an open system at such a low moisture content, and both water and ethanol were able to fulfill the role of a granulation liquid, but water was more appropriate than ethanol for successfully producing granules suitable for use as direct tabletting aids by the TAG method. It was also found that a 5% moisture content in the powder mixture containing MCC and PVP is optimal in the TAG process to produce granules with the desired characteristics for pharmaceutical applications. On the contrary, increasing the moisture content led to further decreases in the mean size and deterioration of the flowability. It was further demonstrated that the TAG process is able to imbue these commonly used diluents with more-desirable physical characteristics of granules for direct tabletting, enabling the processing of these commonly used diluents with 50% PVP into directly compressible matrix materials.     

流化床制粒法制备速释硝苯地平片及其体外溶出度研究

目的:研制具有速释性的硝苯地平(NFP)片并考察其体外溶出度。方法:对NFP原料药先进行微粒化,再加入辅料采用流化床制粒,经压片、包衣制备NFP片。依据2005年版《中国药典》溶出度第2法及高效液相色谱法测定NFP的累积溶出度,并与2种市售NFP片进行比较。结果:所制NFP片为薄膜衣片,其中NFP粒径小于15μm;其10、60min时累积溶出度分别约为85%、99%,而市售样品1约为30%、78%,市售样品2约为70%、93%。结论:采用流化床法制备NFP片方法简单,工艺可行,所制制剂具有速释作用,优于市售片。     

Scale-up of the rounding process in pelletization by extrusion-spheronization

Previously described scaling models for the spheronization process of wet extrudates are incomplete, often concluding with an adjustment of the plate speed according to the spheronizer diameter, but neglecting to give guidelines on the adjustment of the load or the process duration. In this work, existing scaling models were extended to include the load and the process time. By analyzing the final particle size and shape distributions as well as the rounding kinetics for various loads and plate speeds in spheronizers with plate diameters of 0.12?m, 0.25?m and 0.38?m, the found scaling model was validated. The peripheral speed was found to be the main influence on the rounding kinetic, while the load and the plate diameter only showed minor influence. Higher peripheral speeds, higher loads and a larger spheronizer diameter led to an increase in rounding kinetic, allowing for shorter residence times and increased throughput. However, lower peripheral speed, lower loads and lower plate diameters led to particles of increased sphericity.     

Comparison of single pot and multiphase granulation. Part 2: Effect of the drying process on granules manufactured in a single pot granulator and dried either in situ or in a fluid bed dryer

The aim of this study was to highlight the effect of the drying process on granules manufactured in a pilot scale single pot granulator and dried either in situ or in a fluid bed dryer, for formulations differing in drug substance and its concentration (1%; 25%). Although most of raw data were within specifications, single pot drying tended to improve granule comprimability and seemed less sensitive to formulation. Moreover, it was demonstrated that the formulation impacted on granule median diameter, packing ability, comprimability, residual lower punch pressure and tablet dissolution kinetics. Interactions between process and formulation were highlighted concerning tablet tensile strength and uniformity of mass.     

Spray granulation: Importance of process parameters on in vitro and in vivo behavior of dried nanosuspensions

The use of fluid bed granulation for drying of pharmaceutical nanoparticulates on micron-sized granule substrates is a relatively new technique, with limited understanding in the current literature of the effects of process parameters on the physical properties of the dried nanoparticle powders. This work evaluated the effects of spray mode, spray rate and atomizing pressure for spray granulation of drug nanosuspensions through a systematic study. Naproxen and a proprietary Novartis compound were converted into nanosuspensions through wet media milling and dried onto a mannitol based substrate using spray granulation. For naproxen, various physical properties of the granules, as well as the in vitro re-dispersion and dissolution characteristics of the nano-crystals, were measured. It was found that the spray mode had the most drastic effect, where top spray yielded smaller re-dispersed particle sizes and faster release rates of drug from granules than bottom spray. This was attributed to the co-current spraying in bottom spray resulting in denser, homogenous films on the substrate. Similar in vitro results were obtained for the proprietary molecule, Compound A. In vivo studies in beagle dogs with Compound A showed no significant difference between the liquid and the dried forms of the nanosuspension in terms of overall AUC, differences were observed in the t_max which correlated with the rank ordering observed from the in vitro dissolution profiles. These findings make spray granulation amenable to the production of powders with desired processing and handling properties, without compromising the overall exposure of the compound under investigation.     

Combining microwave resonance technology to multivariate data analysis as a novel PAT tool to improve process understanding in fluid bed granulation

A set of 192 fluid bed granulation batches at industrial scale were in-line monitored using microwave resonance technology (MRT) to determine moisture, temperature and density of the granules. Multivariate data analysis techniques such as multiway partial least squares (PLS), multiway principal component analysis (PCA) and multivariate batch control charts were applied onto collected batch data sets. The combination of all these techniques, along with off-line particle size measurements, led to significantly increased process understanding. A seasonality effect could be put into evidence that impacted further processing through its influence on the final granule size. Moreover, it was demonstrated by means of a PLS that a relation between the particle size and the MRT measurements can be quantitatively defined, highlighting a potential ability of the MRT sensor to predict information about the final granule size.This study has contributed to improve a fluid bed granulation process, and the process knowledge obtained shows that the product quality can be built in process design, following Quality by Design (QbD) and Process Analytical Technology (PAT) principles.