Roll Compaction and Tableting of High Loaded Metformin Formulations Using Efficient Binders

Metformin has a poor tabletability and flowability. Therefore, metformin is typically wet granulated with a binder before tableting. To save production costs, it would be desirable to implement a roll compaction/dry granulation (RCDG) process for metformin instead of using wet granulation. In order to implement RCDG, the efficiency of dry binders is crucial to ensure a high drug load and suitable properties of dry granules and tablets. This study evaluates dry granules manufactured by RCDG and subsequently tableting of high metformin content formulations (≥?87.5%). Based on previous results, fine particle grades of hydroxypropylcellulose and copovidone in different fractions were compared as dry binders. The formulations are suitable for RCDG and tableting. Furthermore, results can be connected to in-die and out-of-die compressibility analysis. The addition of 7% of dry binder is a good compromise to generate sufficient mechanical properties on the one hand, but also to save resources and ensure a high metformin content on the other hand. Hydroxypropylcellulose was more efficient in terms of granule size, tensile strength and friability. Three percent croscarmellose was added to reach the specifications of the US Pharmacopeia regarding dissolution. The final formulation has a metformin content of 87.5%. A loss in tabletability does not occur for granules compressed at different specific compaction forces, which displays a robust tensile strength of tablets independent of the granulation process.     

Investigation on Side-Spray Fluidized Bed Granulation with Swirling Airflow

Top-spray fluidized bed granulation with axial fluidization airflow from the bottom of the granulator is well-established in the pharmaceutical industry. The application of swirling airflow for fluidized bed granulation was more recently introduced. This study examined the effects of various process parameters on the granules produced by side-spray fluidized bed with swirling airflow using the central composite and Box–Behnken design of experiment. Influence of the amount of binder solution, spray rate, and distance between spray nozzle and powder bed were initially studied to establish operationally viable values for these parameters. This was followed by an in-depth investigation on the effects of inlet airflow rate, atomizing air pressure and distance between spray nozzle and powder bed on granule properties. It was found that the amount of binder solution had a positive correlation with granule size and percentage of lumps but a negative correlation with size distribution and Hausner ratio of the granules. Binder solution spray rate was also found to affect the granules size. High drug content uniformity was observed in all the batches of granules produced. Both inlet airflow rate and atomizing air pressure were found to correlate negatively with granule size and percentage of lumps but correlate positively with the size distribution of the granule produced. Percentage of fines was found to be significantly affected by inlet airflow rate. Distance between spray nozzle and powder bed generally affected the percentage of lumps.     

Application of powder rheometer to determine powder flow properties and lubrication efficiency of pharmaceutical particulate systems

The objective of this study was to understand the behavior of particulate systems under different conditions of shear dynamics before and after granulation and to investigate the efficiency of powder lubrication. Three drug powders, metronidazole, colloidal bismuth citrate, and tetracycline hydrochloride, were chosen as model drugs representing noncohesive and cohesive powder systems. Each powder was individually granulated with microcrystalline cellulose and 5%PVP as a binder. One portion from each granulation was lubricated with different levels of magnesium stearate for 5 minutes. The powder characterization was performed on the plain powders, nonlubricated and lubricated granules using powder rheometer equipped with a helical blade rotating and moving under experimentally fixed set of parameters. The profiles of interaction during the forcedistance measurements indicate that powder compresses, expands, and shears many times in a test cycle. Test profiles also clearly reveal existence of significant differences between cohesive and noncohesive powders. In all cases lubrication normalized the overall interactive nature of the powder by reducing peaks and valleys as observed from the profiles and reduced the frictional effect. The developed methods are easy to perform and will allow formulation scientists to better understand powder behavior and help in predicting potential impact of processing factors on particulate systems. Published: October 19, 2005     

Effect of Lime Pretreatment on Granulation of Switchgrass

Densification of switchgrass into consistent and high-density solid feedstock will reduce the cost of transport, handling, and storage to produce fuels and chemicals. Development a novel, low-cost densification technology is critical for reducing the delivered cost of feedstock while improving the bulk flow properties of densified products. In this paper, a novel wet granulation technology was proposed to investigate the effect of lime pretreatment on the production of switchgrass granules. Granulation is a process of agglomerating fine powders by wetting powder surfaces with liquid binders and mild application of shear/vibrating forces. Switchgrass was size reduced into fine powders using a knife mill and pretreated with three lime loading rates (0.05, 0.1, 0.2 g/g of biomass) at 121 °C for 30 min and at room temperature (25 °C) for 72 h. The structural modification of pretreated samples was analyzed by scanning electron microscopy and autofluorescence microscopy. Pretreated samples were granulated using a pan granulator with pre-formulated starch binder. Granules made from 20 % (0.2 g/g of biomass) lime loading rate had significantly higher single granule density and angle of repose with lower binder requirement than that of untreated granules. Lime treatment did not significantly increase the bulk density and hardness of granules. Lime-treated granules had significantly higher ash content and lower gross calorific value than that of untreated granules. In overall, lime treatment was not attractive to produce granules for thermochemical conversion platform, but lime-treated granules could be used to produce liquid biofuels and platform chemicals in biochemical conversion platform.     

Roller Compaction of Hydrophilic Extended Release Tablets—Combined Effects of Processing Variables and Drug/Matrix Former Particle Size

The present study shows that roller compaction (RC) can successfully be used as a granulation method to prepare hydroxypropyl methylcellulose (HPMC)-based extended release matrix tablets containing a high drug load, both for materials deforming mainly by fragmentation (paracetamol) as for those having mainly plastic deformation (ibuprofen). The combined effect of RC process variables and composition on the manufacturability of HPMC tablets was investigated. Standard wet granulation grade HPMC was compared with a larger particle size direct compressible HPMC grade. Higher roll pressure was found to result in larger paracetamol granules and narrower granule particle size distributions, especially for formulations containing smaller size HPMC. However, for ibuprofen, no clear effect of roll pressure was observed. High roll pressure also resulted in denser ribbon and less bypass fines during RC. Loss of compactibility was observed for granules compared to powder blends, which was found to be related to differences in granule porosity and morphology. Using the large-sized HPMC grade did in some cases result in lower tensile strength tablets but had the advantage to improve the powder flow into the roller compactor. This work also indicates that when the HPMC level lies near the percolation threshold, significant changes can occur in the drug release rate due to changes in other factors (raw material characteristics and processing).

Electronic supplementary material

The online version of this article (doi:10.1208/s12249-014-0219-3) contains supplementary material, which is available to authorized users.KEY WORDS: dry granulation, extended release, hydroxypropyl methylcellulose, roller compaction, work hardening     

抗病促生复合芽孢杆菌水分散粒剂的研制与应用

【背景】乳油、可湿性粉剂和粉剂等生物制剂含有苯类有机溶剂及粉尘,会对环境造成污染,而水分散粒剂具有环境友好性、附加值高、市场潜力大等优点,被认为是最具发展前景的剂型之一,然而关于复合芽孢杆菌水分散颗粒的研究却很少。【目的】利用解淀粉芽孢杆菌BZ6-1和短小芽孢杆菌SC-12研制成一种复合芽孢杆菌水分散粒剂。【方法】通过生物相容性实验,研究不同载体和助剂对两种芽孢杆菌孢子的影响,以筛选出最佳载体和添加剂。通过质量检测实验,研究不同筛孔直径、干燥温度、干燥时间对水分散性颗粒质量的影响,以优化制粒条件。在辣椒定植后,使用不同剂量的水分散粒剂进行田间辣椒试验。【结果】复合芽孢杆菌水分散粒剂最佳配方：润湿剂4%十二烷基硫酸钠,分散剂6%羧甲基纤维素钠,崩解剂4%硫酸铵,粘结剂4%聚乙二醇,载体82%硅藻土;最佳造粒条件为：筛孔粒径0.8 mm,烘干温度40 °C,烘干时间45 min。研制出的复合芽孢杆菌水分散粒剂含菌量为2.52×108 cfu/g,悬浮率为79.3%,pH 6.8,水分含量为4.5%,湿润时间为19.6 s,崩解时间为86.4 s,颗粒强度适中,符合水分散粒剂国家标准。【结论】研制出的复合芽孢杆菌水分散粒剂能够有效防治辣椒青枯病,并提高辣椒的产量和品质,推荐复合芽孢杆菌水分散粒剂最适用量为3.0 kg/hm2。     

Advances in aerobic granule formation and granule stability in the course of storage and reactor operation

Aerobic granulation is drawing increasing global interest in a quest for an efficient and innovative technology in wastewater treatment. Developed less than two decades ago, extensive research work on aerobic granulation has been reported. The instability of the granule, which is one of the main problems that hinder practical application of aerobic granulation technology, is still to be resolved. This paper presents a review of the literature in aerobic granulation focusing on factors that influence granule formation, granule development and their stability in the context of sludge granulation. The review attempts to shed light on the potential of developing granules with adequate structural stability for practical applications. The possibilities and perspective of using stored granule as inoculums for rapid startup, and as microbial supplement to enhance treatment of bioreactor systems are also discussed.     

Evaluation of the Physicochemical Properties and Compaction Behavior of Melt Granules Produced in Microwave-Induced and Conventional Melt Granulation in a Single Pot High Shear Processor

Recently, microwave-induced melt granulation was shown to be a promising alternative to conventional melt granulation with improved process monitoring capabilities. This study aimed to compare the physicochemical and compaction properties of granules produced from microwave-induced and conventional melt granulation. Powder admixtures comprising equivalent proportions by weight of lactose 200 M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350 under the influence of microwave-induced and conventional heating in a 10-L single pot high shear processor. The properties of the granules and compacts produced from the two processes were compared. Relative to conventional melt granulation, the rates at which the irradiated powders heated up in microwave-induced melt granulation were lower. Agglomerate growth proceeded at a slower rate, and this necessitated longer massing durations for growth induction. These factors prompted greater evaporative moisture losses from the melt granules. Additionally, nonuniform heating of the powders under the influence of microwaves led to increased inter-batch variations in the binder contents of resultant melt granules and a reliance of content homogeneity on massing duration. Agglomerate growth proceeded more rapidly under the influence of conventional heating due to the enhanced heating capabilities of the powders. Melt granules produced using the conventional method possessed higher moisture contents and improved content homogeneity. The compaction behavior of melt granules were affected by their mean sizes, porosities, flow properties, binder, and moisture contents. The last two factors were responsible for the disparities in compaction behavior of melt granules produced from microwave-induced and conventional melt granulation.     

A Comparison of Granules Produced by High-Shear and Fluidized-Bed Granulation Methods

Placebo granules were manufactured by both wet high-shear and fluidized-bed techniques. The granules were compared based on size, shape, surface morphology, and a variety of different flowability measurements. This comparison showed that granule formation and growth were different, with induction growth for high-shear granulation and steady growth for fluidized-bed granulation. Final granules from high-shear granulation were more spherical and dense compared with the irregular granules from fluidized-bed granulation. The high-shear granules demonstrated better overall flow properties.     

State of the art of aerobic granulation in continuous flow bioreactors

In the wake of the success of aerobic granulation in sequential batch reactors (SBRs) for treating wastewater, attention is beginning to turn to continuous flow applications. This is a necessary step given the advantages of continuous flow treatment processes and the fact that the majority of full-scale wastewater treatment plants across the world are operated with aeration tanks and clarifiers in a continuous flow mode. As in SBRs, applying a selection pressure, based on differences in either settling velocity or the size of the biomass, is essential for successful granulation in continuous flow reactors (CFRs). CFRs employed for aerobic granulation come in multiple configurations, each with their own means of achieving such a selection pressure. Other factors, such as bioaugmentation and hydraulic shear force, also contribute to aerobic granulation to some extent. Besides the formation of aerobic granules, long-term stability of aerobic granules is also a critical issue to be addressed. Inorganic precipitation, special inocula, and various operational optimization strategies have been used to improve granule long-term structural integrity. Accumulated studies reviewed in this work demonstrate that aerobic granulation in CFRs is capable of removing a wide spectrum of contaminants and achieving properties generally comparable to those in SBRs. Despite the notable research progress made toward successful aerobic granulation in lab-scale CFRs, to the best of our knowledge, there are only three full-scale tests of the technique, two being seeded with anammox-supported aerobic granules and the other with conventional aerobic granules; two other process alternatives are currently in development. Application of settling- or size-based selection pressures and feast/famine conditions are especially difficult to implement to these and similar mainstream systems. Future research efforts needs to be focused on the optimization of the granule-to-floc ratio, enhancement of granule activity, improvement of long-term granule stability, and a better understanding of aerobic granulation mechanisms in CFRs, especially in full-scale applications.     

Understanding the properties of aerobic sludge granules as hydrogels

Aerobic sludge granules are larger, denser microbial aggregates than activated sludge flocs with a smoother and more regular surface, which facilitates greater wastewater treatment intensity. Factors important in their growth are still poorly understood, which is an impediment to the construction and operation of full-scale aerobic sludge granule processes. Data in this article obtained with granules treating an abattoir wastewater provide evidence that aerobic sludge granules are hydrogels. The results also demonstrate a method for characterizing macromolecular associations. The rheological profile of these granules was found to be analogous with that of typical polymer gels. Water uptake or swelling reflects an equilibrium between granule elastic modulus and osmotic pressure, whereby uptake is increased by reducing solute concentration or the elastic modulus. A weakening of the extracellular polymeric substance (EPS) matrix as demonstrated with mechanical spectroscopy was induced by several environmental factors including temperature, pH and ionic strength. Uniform and elastic deformation was observed at low strain. Enzymatic degradation studies indicate that proteins and alpha-polysaccharides were the major granule structural materials. The aerobic sludge granules in the current study were therefore protein-polysaccharide composite physical hydrogels. While aerobic sludge granules treating an abattoir wastewater are used as a case study, many of the fundamental principles detailed here are relevant to other granulation processes. The paradigm established in this study can potentially be applied to better understand the formation of aerobic sludge granules and thus overcome a hurdle in the acceptance of aerobic sludge granulation as an alternative to more traditional wastewater treatment processes.     

Modeling and optimization of granulation process of activated sludge in sequencing batch reactors

Aerobic granulation is a promising process for wastewater treatment, but this granulation process is very complicated and is affected by many factors. Thus, a mathematical model to quantitatively describe such a granulation process is highly desired. In this work, by taking into account all of key steps including biomass growth, increase in particle size and density, detachment, breakage and sedimentation, an one‐dimensional mathematic model was developed to simulate the granulation process of activated sludge in a sequencing batch reactor (SBR). Discretization methodology was applied by dividing operational time, sedimentation process, size fractions and slices into discretized calculation elements. Model verification and prediction for aerobic granulation process were conducted under four different conditions. Four parameters indicative of granulation progression, including mean radius, biomass discharge ratio, total number, and bioparticle size distribution, were predicted well with the model. An optimum controlling strategy, automatically adjusted of settling time, was also proposed based on this model. Moreover, aerobic granules with a density higher than 120 g VSS/L and radius in a range of 0.4–1.0 mm were predicted to have both high settling velocity and substrate utilization rate, and the corresponding optimum operating conditions were be determined. Experimental results demonstrate that the developed model is appropriate for simulating the formation of aerobic granules in SBRs. These results are useful for designing and optimizing the cultivation and operation of aerobic granule process. Biotechnol. Bioeng. 2013; 110: 1312–1322. © 2012 Wiley Periodicals, Inc.     

食用菌调味品造粒工艺研究

应用压力成型法、搅拌法和沸腾法对食用菌调味品进行造粒,并对制成的颗粒的成型率、颗粒外观、粒度分布、吸湿性和流动性等有关指标进行评价和比较。结果表明,造粒后颗粒成型率达到90%以上,临界相对湿度达到53%以上,比粉状原料防潮性能更强。压力成型法所制颗粒的成型率、吸湿性和流动性均为最好,在3种造粒方法中最适于食用菌调味品的造粒生产。     

Volutin Granules in Zoogloea ramigera

Zoogloea ramigera, a gram-negative bacterium found in activated sludge, formed volutin granules when excess orthophosphate was added to a phosphate-starved culture. These volutin granules were stainable by hydrogen sulfide after lead acetate treatment and extractable by N-perchloric acid but were not adsorbed by activated charcoal. They appeared to consist of inorganic polyphosphate. Optimum granule formation in the arginine broth required 10 g of glucose, 3 mg of phosphate, and 1 to 20 mg of magnesium per liter of medium. At an Mg(2+) concentration of 1 mg/liter, very large granules appeared which often appeared to fill the cell. An excess of glucose, orthophosphate, or magnesium reduced granule formation. In the absence of sulfate, moderate granulation occurred in arginine broth before the addition of excess orthophosphate; granulation did not increase after the addition of phosphate.     

The Effect of the Chopper on Granules from Wet High-Shear Granulation Using a PMA-1 Granulator

Chopper presence and then chopper speed was varied during wet high shear granulation of a placebo formulation using a PMA-1 granulator while also varying the impeller speed. The granules were extensively analyzed for differences due to the chopper. The effect of the chopper on the granules varied with impeller speed from no effect at a low impeller speed of 300 rpm to flow interruptions at an impeller speed of 700 rpm to minimal impact at very high impeller speeds as caking at the bowl perimeter obscured the effect of the chopper on the flow pattern. Differences in the granule flowability were minimal. However, it was concluded that the largest fraction of optimal granules would be obtained at an impeller speed of 700 rpm with the chopper at 1,000 rpm allowing balances between flow establishment, segregation, and centrifugal forces.     

Chemometric evaluation of pharmaceutical properties of antipyrine granules by near-infrared spectroscopy

The purpose of this research was to apply near-infrared (NIR) spectroscopy with chemometrics to predict the change of pharmaceutical properties of antipyrine granules during granulation by regulation of the amount of water added. The various kinds of granules (mean particle size, 70–750 μm) were obtained from the powder mixture (1 g of antipyrine, 6 g of hydroxypropylcellulose, 140 g of lactose, and 60 g of potato starch) by regulation of the added water amount (11–19 wt/wt%) in a high-speed mixer. The granules were characterized by mean particle size, angle of repose, compressibility, tablet porosity, and tablet hardness as parameters of pharmaceutical properties. To predict the pharmaceutical properties, NIR spectra of the granules were measured and analyzed by principal component regression, (PCR) analysis. The mean particle size of the granules increased from 81 μm to 650 μm with an increase in the amount of water, and it was possible to make larger spherical granules with narrow particle size distribution using a high-speed mixer. Angle of repose, compressibility, and porosity of the tablets decreased with an increase of added water, but tablet hardness increased. The independent calibration models to evaluate particle size, angle of repose, and tablet porosity and hardness were established by using PCR based on NIR spectra of granules, respectively. The correlation coefficient constants of calibration curves for prediction of mean particle size, angle of repose, tablet porosity, and tablet hardness were 0.9109, 0.8912, 0.7437, and 0.8064, respectively. It is possible that the pharmaceutical properties of the granule, such as mean particle size, angle of repose, tablet porosity, and tablet hardness, could be predicted by an NIR-chemometric method.     

A Kinetic Study of the Polymorphic Transformation of Nimodipine and Indomethacin during High Shear Granulation

The objective of the present study was to investigate the mechanism, kinetics, and factors affecting the polymorphic transformation of nimodipine (NMD) and indomethacin (IMC) during high shear granulation. Granules containing active pharmaceutical ingredient, microcrystalline cellulose, and low-substituted hydroxypropylcellulose were prepared with ethanolic hydroxypropylcellulose solution, and the effects of independent process variables including impeller speed and granulating temperature were taken into consideration. Two polymorphs of the model drugs and granules were characterized by X-ray powder diffraction analysis and quantitatively determined by differential scanning calorimetry. A theoretical kinetic method of ten kinetic models was applied to analyze the polymorphic transformation of model drugs. The results obtained revealed that both the transformation of modification I to modification II of NMD and the transformation of the α form to the γ form of IMC followed a two-dimensional nuclei growth mechanism. The activation energy of transformation was calculated to be 7.933 and 56.09 kJ·mol⁻¹ from Arrhenius plot, respectively. Both the granulating temperature and the impeller speed affected the transformation rate of the drugs and, in particular, the high shear stress significantly accelerated the transformation process. By analyzing the growth mechanisms of granules in high-shear mixer, it was concluded that the polymorphic transformation of NMD and IMC took place in accordance with granule growth in a high-shear mixer.     

Growth kinetics of aerobic granules developed in sequencing batch reactors

AIMS: This paper attempts to develop a kinetic model to describe the growth of aerobic granules developed under different operation conditions. METHODS AND RESULTS: A series of experiments were conducted by using four-column sequencing batch reactors to study the formation of aerobic granules under different conditions, e.g. organic loading rates, hydrodynamic shear forces and substrate N/COD ratios. A simple kinetic model based on the Linear Phenomenological Equation was successfully derived to describe the growth of aerobic granules. It was found that the growth of aerobic granules in terms of equilibrium size and size-dependent growth rate were inversely related to shear force imposed to microbial community, while a high organic loading favoured the growth of aerobic granules, leading to a large size granule. The effect of substrate N/COD ratio on the growth kinetics of aerobic granules was realized through change in microbial populations, and enriched nitrifying population in aerobic granules developed at high substrate N/COD ratio resulted in a low overall growth rate of aerobic granules. CONCLUSIONS: The proposed model can provide good prediction for the growth of aerobic granules indicated by the correlation coefficient >0.95. SIGNIFICANCE AND IMPACT OF THE STUDY: The kinetic model proposed could offer a useful tool for studying the growth kinetics of cell-to-cell immobilization process. The study confirmed that the growth of aerobic granules and biofilms are subject to a similar kinetic pattern. This work would also be helpful for better understanding the mechanism of aerobic granulation.     

The effects of shear force on the formation, structure and metabolism of aerobic granules

The effect of shear force on aerobic granulation was studied in four column-type, sequential aerobic sludge blanket reactors. Hydrodynamic turbulence caused by upflow aeration served as the main shear force in the systems. Results showed that aerobic granulation was closely associated with the strength of shear force. Compact and regular aerobic granules were formed in the reactors with a superficial upflow air velocity higher than 1.2 cm s(-1). However, only typical bioflocs were observed in the reactor with a superficial upflow air velocity of 0.3 cm s(-1) during the whole experimental period. The characteristics of the aerobic granules in terms of settling ability, specific gravity, hydrophobicity, polysaccharide and protein content and specific oxygen utilization rate (SOUR) were examined. It was found that the shear force has a positive effect on the production of polysaccharide, SOUR, hydrophobicity of cell surface and specific gravity of granules. The hydrophobicity of granular sludge is much higher than that of bioflocs. Therefore, it appears that hydrophobicity could induce and further strengthen cell-cell interaction and might be the main force for the initiation of granulation. The shear-stimulated production of polysaccharides favors the formation of a stable granular structure. This research provides experimental evidence to show that shear force plays a crucial role in aerobic granulation and further influences the structure and metabolism of granules.     

Effect of starting material particle size on its agglomeration behavior in high shear wet granulation

The effect of anhydrous lactose particle size distribution on its performance in the wet granulation process was evaluated. Three grades of anhydrous lactose were used in the study: “as is” manufacturer grade and 2 particle size fractions obtained by screening of the 60M lactose. Particle growth behavior of the 3 lactose grades was evaluated in a high shear mixer. Compactibility and porosity of the resulting granules were also evaluated. A uniaxial compression test on moist agglomerates of the 3 lactose grades was performed in an attempt to explain the mechanism of particle size effect observed in the high shear mixer. Particle growth of anhydrous lactose in the high shear mixer was inversely related to the particle size of the starting material. In addition, granulation manufactured using the grade with the smallest particle size was more porous and demonstrated enhanced compactibility compared with the other grades. Compacts with similar porosity and low liquid saturation demonstrated brittle behavior and their breakage strength was inversely related to lactose particle size in the uniaxial compression test, suggesting that material with smaller particle size may exhibit more pronounced nucleation behavior during wet granulation. On the other hand, compacts prepared at higher liquid saturation and similar compression force exhibited more plastic behavior and showed lower yield stress for the grade with smallest particle size. The lower yield stress of compacts prepared with this grade may indicate a higher coalescence tendency for its granules during wet granulation.