Binderless granulation of pharmaceutical lactose powders

With a binderless fluidized bed granulation method (Pressure Swing Granulation, PSG), jet-milled lactose particles were successfully agglomerated into narrow and spherical granules. This should be the first achievement of binderless granulation from an organic powder indicating the high potential of PSG application to pharmaceutical processes. With a decrease in the mean diameter of primary particles, the granules' mean diameter decreased, and the compression strength of a single granule increased.The size of product lactose granules predicted by the Iwadate–Horio [Powder Technol. 100 (1998) 223] model was in good agreement with the experimental results obtained by sieve analysis.     

Fluidized bed granulation of a microdose pharmaceutical powder

The influence of some process variables on the size distribution and drug content of granules prepared in a fluidized bed has been investigated using a powder mix of 5% phenylbutazone in lactose. Using a 10% aqueous solution of polyvinylpyrolidone (PVP) as the granulating agent, granule size increased with volume of solution and rate of spraying and decreased with increasing temperature. In addition, as granule size increased, so did the homogeneity of phenylbutazone distribution in the granules. This was explained on the basis of increased wetting of the large granules which then pick up fine drug particles. Also, large granules are able to break up phenylbutazone agglomerates by a “ball milling” action. When two successful batches were compressed, the tablets produced complied with official and non-official standards. Under the conditions exmployed, granulation using a 10% alcoholic PVP solution was unsuccessful.     

Granulation of a hardmetal powder for spark plasma sintering

A fluidized bed granulation method, pressure swing granulation (PSG), was applied to granulation of a hardmetal powder without pressing lubricants for making the upstream process of spark plasma sintering (SPS) more efficient.

The properties of the granules were examined and compared with those of spray dried granules and extruded ones under the present system using a sieve.

Spherical granules between 0.15 and 0.84 mm in diameter difficult to obtain by the spray drying were obtained with high yield. The flowability of the granules was far better than that of spray dried granules and similar to that of extruded ones. Iron contamination and oxidization during pressure swing granulation were tolerable to the real production.     

Simultaneous particulate design of primary and agglomerated crystals of steroid by spherical agglomeration in liquid for dry powder inhalation

Spherical agglomerates of steroid KSR-592, consisting of fine primary drug crystals suitable for dry powder inhalation (DPI), were prepared by the spherical agglomeration method in liquid with a bridging liquid. It was found that the particle size of primary crystals increased until the dispersing medium was saturated with the bridging liquid, whereas the spherical agglomeration of primary crystals was continued even after the saturation of medium with the bridging liquid. The growth rates of primary crystals and agglomerates increased with an increase in the temperature and/or a reduction in the agitation speed of the system. The agglomerates were easily disintegrated into the primary crystals depositing ideally on carrier lactose particles for DPI by mixing. The in vitro efficiency of the mixed system of lactose and disintegrated primary crystals of drug was 2 to 3 times higher than that of crystals prepared conventionally. Furthermore, the soft agglomerates disintegrated easily into respirable particles in air stream when emitted from the inhalation device were prepared by reducing the agitation speed after the dispersing medium was saturated with the bridging liquid.     

Adhesion force measurement of a DPI size pharmaceutical particle by colloid probe atomic force microscopy

The method to determine the adhesion characteristics of fine drug particles for dry powder inhalation (DPI) was established using a colloid probe which mounted a 1-3 μm drug particle on a commercial atomic force microscope (AFM) cantilever. A new preparation system of colloid probes for fine particles smaller than 2.5 μm in diameter was developed with the aid of a micromanipulator and a video microscope. Using this colloid probe, adhesion force distribution between a spherical polycrystalline drug particle and a plate of lactose monohydrate representing for DPI carrier materials or stainless steel for device wall materials was measured. Atmospheric humidity as well as the material and surface roughness of a target plate affected the determined adhesion force. With increasing surface roughness of a lactose plate, the adhesion force between a drug particle and the plate distributed more widely and their mean value decreased. Adhesion force increased meaningfully with atmospheric humidity. Adhesion force for stainless steel was higher than that for lactose.     

流化床侧喷技术制备乳糖颗粒的工艺

采用流化床侧喷制粒技术,以羟丙基甲基纤维素K4M为粘合剂制备乳糖颗粒. 以颗粒粒径分布与流动性为主要评价指标,得到优化的制备参数为：粘合剂浓度1.5%,用量2.0%,喷液速度14~18 g/min,雾化压力1.5′105 Pa. 200~355 mm的目标粒子收率在85%以上,颗粒休止角均小于34o,压缩度均小于10%,流动性好,光学显微镜下颗粒呈类球形. 制备工艺稳定,重现性好.     

Granulation of Fe-Al-Ce nano-adsorbent for fluoride removal from drinking water by spray coating on sand in a fluidized bed

A technology for the granulation of Fe-Al-Ce nano-adsorbent (Fe-Al-Ce) in a fluidized bed was developed. The coating reagent, a mixture of Fe-Al-Ce and a polymer latex, was sprayed onto sand in a fluidized bed. The granule morphology, coating layer thickness, granule stability in water and adsorption capacity for fluoride was investigated by analyzing samples for different coating time. The coating amount was from 3% to 36%. With increasing coating amount, granule stability decreased and adsorption capacity increased. FTIR analysis showed that the latex can react with active hydroxyl on the Fe-Al-Ce adsorbent, which led to a decrease of the adsorption capacity. Coated granules with a coating amount of 27.5% had a fluoride adsorption capacity of 2.22 mg/g (coated granules) at pH 7 and initial fluoride concentration of 0.001 M. A column test showed that 300 bed volumes can be treated with the effluent under 1.0 mg/L at an initial fluoride concentration of 5.5 mg/L, space velocity of 5 h^− 1 and pH of 5.8. The coating granulation of the Fe-Al-Ce adsorbent can produce granules that can be used in a packed bed for the removal of fluoride from drinking water.     

Effect of annealing time and addition of lactose on release of a model substance from Eudragit RS coated pellets produced by a fluidized bed coater

The aim of this study was to investigate the effects of annealing time and addition of lactose in coating liquid formulations on the release of a model substance, methylene blue (MB), from pellets coated with Eudragit^® RS 30 D. The microcrystalline cellulose pellets were layered with MB before coating with aqueous dispersions of Eudragit^® RS 30 D using a Wurster-type fluidized bed coater. The coating processes and conditions were validated and optimized before the final coating. The uncoated and coated pellets were characterized for their size, MB content, morphology and MB release. The results demonstrated that a stable coating process can be developed to produce repeatable batches of pellets. The film thickness was calculated and found to be similar to those observed from scanning electron microscope. The increased annealing time led to a more coherent film. The drug release was found to vary depending on the duration of annealing time and the addition of lactose. Addition of lactose gave a faster MB release and without any initial lag period in the release profile whereas the increased annealing time slowed down the MB release and increased the lag period.     

Optimization of a Fe-Al-Ce nano-adsorbent granulation process that used spray coating in a fluidized bed for fluoride removal from drinking water

A coating granulation technology comprising the spraying of a Fe-Al-Ce nano-adsorbent suspension onto glass beads in a fluidized bed was developed. An acrylic-styrene copolymer latex was used as a binder. The granulated adsorbent was used in a packed bed for fluoride removal from drinking water. The effects of coating temperature, latex/Fe-Al-Ce ratio, and coating amount on granule compressive strength and adsorption capacity were investigated. With increased coating temperature, cross linking in the polymer in the coated layer increased, which resulted in increased granule strength but decreased adsorption capacity. With increased latex/Fe-Al-Ce ratio, more active sites were covered by the polymer, which also resulted in increased granule strength but decreased adsorption capacity. The optimal parameters for making high performance adsorbent granules were for the granules to be coated at 65 °C using a latex/Fe-Al-Ce ratio of 0.5:1 and a coating amount of 27.8%. These granules had a fluoride adsorption capacity of 2.77 mg/g (coated granules) for water with an initial fluoride concentration of 0.001 M that was treated at pH 7.     

Drop penetration time in heterogeneous powder beds

Wet granulation is a technique in which enlarged particles or ‘granules’ are produced from the coalescence of fine particles, with the intention of improving the powder properties. High shear granulators are often used to carry out the granulation process where the powder mass is agitated in a vessel by mechanical means while liquid is sprayed from above onto the powder bed surface. When the binder droplets impact the powder surface, the drop penetration time of the droplet into the powder is important for uniform binder dispersion and the prediction of the formation of granule nuclei from the nucleation map, which depends on the dimensionless spray flux. Previous studies on the drop penetration time were carried out on predominantly hydrophilic powder beds. Although this gives a good prediction of the nucleation behaviour in granulation, it does not reflect the condition where hydrophobic drugs are used in the formulation without surfactants. This paper aims to look at the effects of powder bed hydrophobicity on the drop penetration time.Single drop nucleation experiments using a syringe and a small powder bed were carried out on varying ratios of salicylic acid and lactose powders to study the kinetic of drop penetration. As expected, the drop penetration time increased as the proportion of hydrophobic component increased in the powder mixture. However, long drop penetration times were observed for low degrees of drug loading, showing that hydrophobicity strongly influences the drop penetration time. The wettability of the powder mixture also has a pronounced affect on the granule properties in which the hydrophobicity of the powder mixture is proportional to the granule strength and inversely proportional to the granule size. These findings have important implications in terms of the design of the granulation process where conditions of minimum spray flux or efficient mechanical forces are recommended to produce a more uniform granulation batch.     

The relationship between particulate properties of carrier materials and the adhesion force of drug particles in interactive powder mixtures

The influence of particle size, shape, and particle surface roughness of lactose monohydrate carrier particles on the adhesion properties of drug particles in interactive powder mixtures similar in quality of a commercial product (Serevent Diskhaler^®) has been investigated. None of the ten lactose monohydrate batches tested was found to be similar in terms of particle size. To obtain more information about particle shape and surface roughness, mathematical analysis was undertaken to structure the data. The lactose monohydrate batches could be split into four different types of particle shape. In terms of particle surface roughness, as measured by a laser profilometer, three different roughness categories were identified. Two sets of mixtures were prepared to relate the physical properties of the lactose monohydrate particles to the adhesion properties of the drug formulations: (a) constant mixing time and speed (25 min, 42 rpm), and (b) optimal mixing time (speed 42 rpm) to match the adhesion properties of the Serevent Diskhaler^®. All ten lactose monohydrate batches provided different adhesion properties under test condition (a) and the optimum mixing time [test condition (b)] was also different for each batch. Multivariate data analysis showed that the adhesion force between drug and lactose monohydrate increases with a decrease in particle size and for more irregularly shaped, elongated carrier particles. The effect of surface roughness could only be qualitatively assessed and thus no definitive conclusions can be drawn to judge whether adhesion will increase or decrease as surface roughness changes.     

Fluidised bed granulation of an ordered powder mixture reduces the potential for ordered unit segregation

The granulation of ordered powder mixtures formed from salicylic acid (3.5 μm) and spray-dried lactose has been investigated. The proportion of salicylic acid present in the mixtures was 1 × 10^?3. The distribution of salicyclic acid in the granules, as a function of particle size, was significantly more uniform than in the original ordered mixtures. Fluidised bed granulation of an ordered mixture, therefore, presents a method of substantially reducing the effect of segregation when a broad size range carrier is used.Granulation of ordered mixtures also offers a way of overcoming homogeneity problems, caused by differential solubility and hydrophobicity, which can arise during agglomeration of powders for microdose preparations. Agglomeration of an ordered mixture requires the joining of physically similar entities (ordered units), in contrast to a random mixture when agglomeration of physically dissimilar materials must occur. In the latter situation, differences in hydrophobicity and solubility can affect the granule homogeneity.     

Application of hot-melt coating for controlled release of propranolol hydrochloride pellets

Waxes are available in various lyophilicity, and they can be used to regulate the release from multiunit-controlled release pellets. In this study, the application of saturated polyglycolysed glyceride (Gelucire® 50/02) and glycerol palmitostearate (Precirol® ATO5) as drug release regulators for propranolol pellets and the kinetics of release were investigated. Propranolol pellets containing 60% microcrystalline cellulose (Avicel® PH101) were prepared by using direct pelletization technique in a fluidized-bed rotary granulator (Glatt GPCG1). The pellets of 16:18 mesh size were collected and coated with the molten wax(es) at various ratios and thicknesses in a fluidized-bed top spray coater (Glatt GPCG1). The dissolution was determined using test method for Propranolol Extended Release Capsules USP 24 and was found to be very rapid with the uncoated pellets. The dissolution of coated pellet was decreased with the increases in Precirol ATO5 proportion and coating thickness. Plot of log % drug release vs. reciprocal of time showed a good linear relationship. The k value derived from the slope of the plot and designated as a “diffusive resistance constant” linearly increased with the coating level. The findings indicated that drug release could be adjusted by varying the ratio of Precirol® ATO5 to Gelucire® 50/02 as well as the thickness of the coat.     

The effect of powder size on induction behaviour and binder distribution during high shear melt agglomeration of calcium carbonate

Growth mechanisms in high shear mixer granulation were observed over a wide range of particle size and liquid-to-solid (L/S) ratio. The materials used were calcium carbonate (CaCO₃; size fractions in the range 1.5 to 85 μm) with a binder of polyethylene glycol 6000 (PEG 6k). The binder, solid at room temperature, was added by the “melt-in” method. A 10 L vertical-axis granulator was used, with a chopper and a four-bladed impeller.

The mean granule size and granule size distribution were measured at regular intervals during the agglomeration process by careful sampling and sieving. The uniformity of binder distribution among the granules was also measured.

The growth behaviours of each grade of primary particles were classified and compared. An induction type mechanism was observed with an initial period of slow growth in mean particle size that lasted 2 to 3 min (the induction period). This was followed by a short rapid growth phase lasting 1 to 2 min. The final stage was a plateau of more or less zero growth. Interestingly, the end of the induction period and the onset of rapid growth corresponded to a change in the granule size distribution from bimodal to monomodal and a similar change in the distribution of binder. Induction period growth rate tended to be lower for granules of finer particles, but these grew more rapidly during the rapid growth stage and produced larger granules than the coarser primary particles.

The liquid-to-solid (L/S) ratio had a significant effect on the growth rate during the rapid growth stage but a minor effect on the granule size distribution and binder distribution. Primary particle size had a significant effect on the final average size of granules, the growth rate during the rapid growth stage and the distribution of granule size and binder.     

Flow of granules through cylindrical hopper

The gravity flow characteristics of pharmaceutically important granules were studied in a cylindrical hopper with attachable orifice disk at the bottom. Results indicate that materials property and orifice diameter play key role in determining mass flow rate while keeping environmental condition (temperature) at fixed range. A new dimensionally analyzed equation was developed to predict gravity flow of pharmaceutically important granules. The developed correlation agreed well with the experimental data. Calcium gluconate and lactose were used for preparing granules. Generally, glidant/lubricant materials are added to pharmaceutical granules during tablet manufacturing process, in order to improve physical property of granular material. Hence, the effect of glidant/lubricant on mass flow of granules through hopper was also studied. Magnesium stearate (1.5%) was added as glidant before granulation.     

Experimental study of particle trajectory in electrostatics powder coating process

Experimental studies of particle trajectory were conducted in an isolated Plexiglass coating booth. Polyester particles were injected with a Norsdon® electrostatics spray gun with a fixed distance from the gun to a grounded plate. Using a Dantec® Particle Dynamic Analyzer, the particle velocity and size distribution were measured simultaneously. The experimental results showed that the effect of electrostatics charging on the particle trajectory is strong in the close vicinity of the target, but can be neglected at locations away from the target. The influence on particle size and velocity profile due to the electric field between the charged particles and grounded target was weakened as more particles deposited on the target. When no charge is introduced on the coating powder, particle segregation is observed for particles larger than 100 μm. Particle gravitational settlement is noticed even near the gun tip. However, particle charging largely eliminates the segregation at a gun-to-target distance of 25 cm and helps break agglomerates formed in the spray system. The gun-to-target velocities of larger particles exhibited noticeable deviation from those of the flow field as the grounded target was approached. The study revealed that the onset of electrostatic coating is an important period that can affect the transfer efficiency and film thickness.     

Grinding and granulation in a vibratory ball mill

In the grinding of paracetamol, lactose and sucrose in a vibratory ball mill, it is found that an equilibrium is rapidly attained due to the agglomeration of ground particles. The existence of this agglomerative phase of comminution has been extensively reported in the literature. This study investigates prolonged vibratory ball milling as a means of pharmaceutical granulation. The granules are produced from the agglomeration of very fine particles and become more compacted as comminution proceeds.     

Design, simulation, and performance of a draft tube spout fluid bed coating system for aerogel particles

A draft tube spout fluid bed coating system was designed to coat porous aerogel particles in a size range from 0.1 to 2 mm in diameter. Its primary objective was to insure that just the outer surface of the particles was coated. The inner, pore surface area of the particles needed to remain open to preserve their insulating properties. This paper discusses the design, simulation, and experimental results we obtained on the actual coating of 1-3 mm particles. A conventional, pharmaceutical coating, Surelease®, was used as the coating material and the system successfully coated the particles without penetration of the coating material into the particles. The apparatus can be used to coat friable, low density particles as well as those of high density and is well suited for other coating applications including those in the pharmaceutical industry.     

Preparation of CaO granules using the granulation method

ABSTRACT

Improving the hydration resistance of CaO particle in manufacturing and application of free CaO-containing materials has practical significance. In this study, CaO granules was made from Ca(OH)₂ particles, which were fabricated by the granulation method. The results showed that the hydration resistance of the CaO granules which was prepared under 1700?r?min^?1 was the best, the CaO granules was sintered well in calcination process, the shell of CaO granules was relatively dense, which improves the hydration resistance of CaO granules, and the rate of hydration weight increment was 0.58% after placed in the air for 20 days under a temperature of 10–14°C and a relative humidity of 57–81%.     

Hot melt granulation of coarse pharmaceutical powders in a spouted bed

The hot melt granulation of a coarse pharmaceutical powder in a top spray spouted bed is described. The substrate was lactose-polyvinylpyrrolidone particles containing or not acetaminophen as a drug model. Polyethylene glycol (MW, 4000) used as binder was atomized onto the bed by a two-fluid spray nozzle. The granulation experiments followed a 2³ factorial design with triplicates at the center point and were carried out by varying the spray nozzle vertical position, the atomizing air flow rate and the binder feed rate. Granules were evaluated by their pharmacotechnical properties like size distribution, bulk and tapped densities, Carr index, Hausner ratio and tableting characteristics. Analysis of variance showed that granule sizes were affected by the PEG feed rate and atomizing air pressure at the significance levels of 1.0 and 5.0%, respectively, but spray nozzle distance to the substrate bed was not significant. The spray conditions also affected granule flow and consolidation properties, measured by the Carr index and Hausner ratio. Measured densities, Carr indexes and Hausner ratios proved that granules flowability and consolidation properties are adequate for pharmaceutical processing and tableting. Tablets prepared with acetaminophen-containing granules showed good properties and adequate release profiles in in vitro dissolution tests. The results indicate the suitability of spouted beds for the hot melt granulation of pharmaceutical coarse powders.