Suppression of agglomeration in fluidized bed coating. II. Measurement of mist size in a fluidized bed chamber and effect of sodium chloride addition on mist size

It has been reported that the degree of particle agglomeration in fluidized bed coating is greatly affected by the spray mist size of coating solution. However, the mist size has generally been measured in open air, and few reports have described the measurement of the mist size in a chamber of the fluidized bed, in which actual coating is carried out. Therefore, using hydroxypropylmethyl cellulose (HPMC) aqueous solution as a coating solution, the spray mist size of the coating solution in a chamber of the fluidized bed was measured under various coating conditions, such as the distance from the spray nozzle, fluidization air volume, inlet air temperature and addition of sodium chloride (NaCl) into the coating solution. The mist size in the fluidized bed was compared with that in open air at various distances from the spray nozzle. Further, the relationship between the spray mist size and the degree of suppression of agglomeration at various NaCl concentrations during fluidized bed coating was studied. The mist size distribution showed a logarithmic normal distribution in both cases of the fluidized bed and open air. The number-basis median diameter of spray mist (D50) in the fluidized bed was smaller compared with that in open air. D50 increased with the increasing distance from the spray nozzle in both cases. In the fluidized bed, D50 decreased with the increasing fluidization air volume and inlet air temperature. The effect of NaCl concentration on the mist size was hardly observed, but the degree of suppression of agglomeration during coating increased with the increasing NaCl concentration in the coating solution.     

The prediction of variability occurring in fluidized bed coating equipment. I. The measurement of particle circulation rates in a bottom-spray fluidized bed coater

The purpose of this work was to investigate the effect that changes in design and process variables had on the movement of particles around a fluidized bed coating apparatus. To measure the mean and variance of the particle cycle time distribution (CTD), the number of passages taken by a magnetic tracer particle through the spray zone was measured by a detector coil wound around the partition. The reproducibility of the measurement technique was tested by taking repeated measurements of the tracer particle movement, using similar bed operating conditions, and the method was found to give reproducible results. A series of experiments was carried out by varying operating conditions such as the partition gap, fluidizing air rate, and partition diameter and length, and measuring the change in the rate at which the tracer particle circulated in the coating device. The results of the experiments showed that, over the range of parameters tested in this work, the partition gap had the strongest influence on the rate of particle circulation. Moreover, for the 6-in.-diameter Wurster process used in the current work, the mean circulation time for the 1.1-mm-diameter Nu-Pareil particles was found to vary over the range of 2.2-10.4 sec. In addition, the mean and standard deviation of the CTD could be linearly correlated over a wide range of operating conditions, with a correlation coefficient of 0.80. Finally, an estimate of the variability in mass coating uniformity was made based on the results from the cycle time distributions. It was concluded that the effect of variability in the CTD could account for only a small fraction of the variability in the observed mass coating distribution.     

Effects of plasticizers and surfactants on the film forming properties of hydroxypropyl methylcellulose for the coating of diclofenac sodium tablets

Hydroxy propyl methyl cellulose (HPMC) 5cPs, an aqueous soluble polymer was employed for coating diclofenac sodium (DFS) tablets 25 mg for protecting the integrity of the drug yet rendering the drug to release at a faster rate on contact with the gastric environment. Proper optimization for the aqueous based film coating formulation was undertaken primarily employing plasticizers like polyethylene glycol (PEG) 400 and propylene glycol (PG). The defect free selected formulations were further subjected for studying the effects of surfactants like sodium lauryl sulphate (SLS) and Tween-80 along with the plasticizers. The quality of the aqueous film coats or the plasticizer efficiency in case of PEG-400 is in the order 1.5 > 0.5 > 1.0% and for PG 1 > 4 > 3% which can be stated on the basis of less incidence of major coat defects like chipping, cracking, orange peel, roughness, blistering, blooming, picking. The quality of aqueous film coat or the surfactant efficiency in case of SLS + PEG-400 is in the order 0.3 < 0.5 < 0.1% and SLS + PG is in the order 0.5 < 0.1 < 0.3%. In case of Tween-80 + PEG-400 the order is 0.3 < 0.5 < 0.1% and Tween-80 + PG is in the order 0.3 < 0.1 < 0.5%. Elegant film formation can be stated from fewer incidences of coat defects. The obtained coated tablets eventually satisfied all the normal physical parameters like thickness, weights, and weight gain, drug content, crushing strength, percent friability, disintegration time, dissolution profile and possible drug–polymer interactions. ANOVA was undertaken followed by Dunnet multiple comparison for the dissolution profile considering uncoated as the standard. The difference was considered significant at p ⩽ 0.01.     

The prediction of variability occurring in fluidized bed coating equipment. II. The role of nonuniform particle coverage as particles pass through the spray zone

The purpose of this work was to evaluate the relative importance of particle circulation and particle-to-particle mass coating distribution on the overall mass coating distribution obtained in a Wurster process. A series of batch coating experiments was carried out over a range of operating conditions, in order to evaluate the particle-to-particle variation in the mass distribution of coating material deposited during batch coating operations. Results showed that the major component of variance was due to the variation in the amount of coating received per particle per pass through the spray zone. The variation in the number of times a particle passed through the spray zone was considerably less important. Two models were developed to explain the results of the experimental program. The first model categorized particles moving through the spray zone as either receiving coating or not. Thus, the distribution of coating material per particle per pass is described by a Bernoulli probability distribution. Using this picture of the spray process, the number of particles receiving coating during any given pass through the spray zone was found to vary between 2 and 6%. A second model was developed to explain the major cause of variation. This model explains the variation in terms of the hindering or sheltering effect that particles close to the source of the spray have on particles farther away. Although the agreement of model predictions with experimental results is only fair, it is believed that this model captures the main cause of particle-to-particle variation occurring in batch coating operations and thus is the first model to explain this phenomenon.     

Study of the influence of coating methods on lipid spheres manufactured on rotor fluidized bed process

Abstract

Different previous works have shown that various kinds of spheres can be manufactured by rotor granulation in a ‘single-pot process’ using a lipid base: hydrogenated castor oil. This single-pot technology is based on wet granulation where all components are placed in the powder form in the rotor bowl; then, they are continuously suspended in a fluidized air, with a tangentially sprayed liquid solution. This process allows the granulation and manufacturing of sphere during the same time. Previous experiments have studied the influence of the formulation and the manufacturing process parameters on spheres in terms of feasibility and dissolution properties. Both the spraying time and the weight of liquid sprayed were found to be the most relevant parameters that govern the final quality of the sphere. Now, in a second part of the work, a first comparison is made with two different fluid bed methods: the tangential rotor spray and the Wurster bottom spray for coating the lipid spheres previously manufactured with the rotor tangential spray. The external aspect of the coated spheres manufactured has been evaluated with an electronic microscopy analysis and a study of dissolution properties of the active ingredient has been done by USP in vitro dissolution tests.     

A new process control strategy for aqueous film coating of pellets in fluidised bed.

The parameters with effect on maximum spray rate and maximum relative outlet air humidity when coating pellets in a fluidised bed were investigated. The tested variables include type of water based modified release film coating (Eudragit NE 30D, Eudragit RS 30D, Aquacoat ECD) coating principle (top spray, bottom spray), inlet air humidity and type of pellets (sugar spheres, microcrystalline cellulose pellets). The maximum spray rate was not influenced by the coating principles. The highest spray rate was obtained for the film polymer with the lowest tackiness which is assumed to be the controlling factor. The type of pellets affected the maximum spray rate. A thermodynamic model for the coating process is employed throughout the process and not just during steady state. The thermodynamic model is incorporated into a new process control strategy. The process control strategy is based on in-process calculation of degree of utilisation of the potential evaporation energy (DUE) of the outlet air and the relative outlet air humidity (RH). The spray rate is maximised using set points of DUE and RH as control parameters. The product temperature is controlled simultaneously by regulating the inlet air temperature.     

The effect of droplet size and powder particle size on the mechanisms of nucleation and growth in fluid bed melt agglomeration

This study was performed in order to evaluate the effects of binder droplet size and powder particle size on agglomerate formation and growth in fluid bed spray agglomeration using a meltable binder. Three different lactose grades, 100, 125 or 350 mesh, were agglomerated using polyethylene glycol (PEG) 3000 at two different concentrations, 11.5 or 22% (volume/mass), and three spray droplet sizes, 30, 60 or 90 microm were applied. The ratio of droplet size/particle size was found to determine whether the mechanism of nucleation was distribution or immersion. Distribution was promoted by a low ratio, whereas immersion was promoted by a high ratio. Distribution as nucleation mechanism led to a more open agglomerate structure and immersion to a denser structure. When the nucleation phase was terminated, coalescence between rewetted nuclei or agglomerates was the growth mechanism with both preceding mechanisms of nucleation. A larger particle size of the lactose led to larger agglomerates. The difference in the effect on growth between the 30 and 60 microm droplets was generally low. The 90 microm droplets at 22% binder concentration offered a potential for uncontrollable growth giving rise to markedly larger agglomerates and a lower reproducibility than 30 and 60 microm droplets.     

Effects of droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed.

This study was performed in order to evaluate the effects of binder droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed granulator. Lactose monohydrate was agglomerated with melted polyethylene glycol (PEG) 3000 or Gelucire 50/13 (esters of polyethylene glycol and glycerol), which was atomised at different nozzle air flow rates giving rise to median droplet sizes of 40, 60, and 80 microm. Different product temperatures were investigated, below the melting range, in the middle of the melting range, and above the melting range for each binder. The agglomerates were found to be formed by initial nucleation of lactose particles immersed in the melted binder droplets. Agglomerate growth occurred by coalescence between nuclei followed by coalescence between agglomerates. Complex effects of binder droplet size and type of binder were seen at low product temperatures. Low product temperatures resulted in smaller agglomerate sizes, because the agglomerate growth was counteracted by very high binder viscosity or solidification of the binder. At higher product temperatures, neither the binder droplet size nor the type of binder had a clear effect on the final agglomerate size.     

Slow release of drug through deformed coating film: effects of morphology and drug diffusivity in the coating film.

The effects of the morphology and drug diffusivity in the coating film on the slow release characteristics have been analyzed numerically under the constraint that the volume of the coating film and the drug matrix is maintained constant. Two different systems of coated particles with deformed coating films were studied and their release characteristics compared with those of the coated particles having spherical coating films. The average release rate, fractional release, drug concentration profiles, and the initial burst of drug were found to be strongly influenced by the ratio of drug diffusivity in the coating film to that in the drug matrix D(r) (i.e., dimensionless drug diffusivity in the coating film). Increasing D(r) always increased the release rate, the fractional release, and the initial burst of drug, but reduced the initial lag times of drug release. The effect of shape deformation was very significant in the drug concentration profiles and the initial lag times; in contrast, it was not so substantial on the fractional release and the average release rates. The morphology difference in the deformed systems was also found to affect the release characteristics to different extents. Increasing the degree of the shape deformation, represented by the perturbation parameter epsilon, always reduced the effective surface area for the controlled release of drug. Because of the compensation effects between decreasing surface area and the non-uniform mass flux distribution, even though the heterogeneity of surface mass flux distribution would become more considerable, the effects of increasing shape deformation to the overall release rate would be less than expected unless the coating film was deformed significantly enough. The effect of the shape deformation and the morphology difference become less effective to differentiate the release characteristics with increasing D(r).     

Experimental study of wet granulation in fluidized bed: impact of the binder properties on the granule morphology

In this work, the effect of the physicochemical properties of aqueous hydroxypropyl-cellulose (HPC) binder solutions and different pharmaceutical excipients (mannitol and anhydrous CaHPO(4)) on the agglomeration kinetics and granule properties were investigated. First, a particle size distribution (PSD) analysis together with a detailed analysis of morphological properties of the excipient particles were performed. Second, the viscosity, density, surface tension and size of the spray droplets of binder solutions with different HPC concentrations were determined and wetting characteristics of the binders on the excipients were measured. Third, several fluid bed wet granulation experiments were conducted for pure excipients and their blends with binder solution of different HPC concentrations in a pilot plant Wurster granulator. The observed granule growth for different binder concentrations was a strong function of the binder concentration and the excipient solubility. For mannitol, a significant "coating" period followed by a slow granule growth was observed for the case with the diluted 5% binder. The "coating" period was significantly shorter for the 10% HPC binder and did not exist for the 15% HPC for which immediate and fast granule growth was observed. For anhydrous CaHPO(4) (trademark A-TAB), no growth was observed for the 10% HPC binder and a long coating period followed by fast granule growth was observed for the 15% HPC. Simple physically based criteria were also evaluated, which employ the morphological properties of excipients (size and surface roughness) together with physical properties of the used binder for prediction of the coating versus agglomeration regime at given flow conditions (collision velocity). As expected, a preferential coalescence and growth of the mannitol granules from the blend of mannitol+A-TAB was observed. Finally, the mechanical and morphological properties of the produced granules were measured and correlated to the HPC concentration of the binder used in the experiments. A clear correlation between the granule porosity (evaluated by X-ray tomography) and the binder concentration was found for the mannitol granules.     

不同浓度亚硫酸钠对HL-7702肝细胞活性的影响

目的为了对亚硫酸钠的细胞毒性研究提供实验参考,探讨不同浓度的亚硫酸钠(Na2SO3)对正常人肝细胞HL-7702的影响。方法通过不同浓度的Na2SO3对HL-7702染毒24h后,采用四甲基偶氮唑蓝微量酶比色法(MTT法)测定Na2SO3对肝细胞的活性抑制率。结果随着Na2SO3染毒剂量的增加,对细胞的活性抑制率逐渐增高,其中0.625mmol/L组和2.5mmol/L组与对阴性对照组相比,差异有统计学意义(P<0.05)。结论Na2SO3对肝细胞的活性有一定的抑制作用。     

Influence of the atomization time on the properties of ethylcellulose microcapsules of isoniazid prepared by a fluidized bed

Microcapsules containing isoniazid were produced by the fluidized bed method with ethylcellulose by varying the total atomization time. The kinetics of capsules growth during the preparation was discussed on the basis of the distribution of particle size. The quality of the capsules was evaluated using the particle size characteristics, the total content of ethylcellulose, the particle and wall density, and the time needed for the 50 per cent release of the drug. An increase in the atomization time of the ethylcellulose solution gave rise to an increase in the mean diameter of particles and the ethylcellulose content of capsules; it also produced a more dense product with a prolonged release of the drug. The release of the drug from tabletted microcapsules was further prolonged.     

The effect of water-soluble macromolecular binders on the properties of fluidized bed dried granulates and tablets made from them

In order to characterize physicochemical properties of binders rheological behaviour, wetting ability and film-formation tendency of the binder solutions were investigated. The results obtained were related to granule and tablet properties.     

Influence of the aqueous film coating process on the properties and stability of tablets containing a moisture-labile drug

The effects of an aqueous film coating process on the morphology and storage stability of hydroxypropyl methylcellulose-coated tablets containing a moisture-labile model drug (acetylsalicylic acid, ASA) were evaluated using an instrumented side-vented tablet pan coater. Coating parameters studied were inlet air absolute humidity 5 g/m3 and 12 g/m3, spraying air pressure 100 kPa and 500 kPa, pan air temperature 35 degrees C and 55 degrees C, and coating solution flow rate 2.2 g/min and 7.8 g/min. The surface roughness of the coatings was measured with a laser profilometer and the chemical hydrolysis of the model drug ASA with an UV-spectrophotometer. The film-coated tablets were stored at 25 degrees C/60% RH and 40 degrees C/75% RH for three months. The high absolute humidity of the inlet air increased the residual water content and surface roughness of the coated tablets. Using a lower coating solution flow rate, higher spraying air pressure and pan temperature the coatings were smooth and homogeneous. In both ambient and accelerated storage conditions, the roughness of the coatings and the hydrolysis of ASA increased, but this was independent of the film coating process. Uniform and smooth hydroxypropyl methylcellulose coatings can be achieved by improved control of process parameters related to the application of the coating solution and water evaporation of the tablet surface.     

Physicochemical aspects of drug release. IV. The effect of carrier particle properties on the dissolution rate from ordered mixtures

Six different carrier materials (250–425 μm) were used to prepare ordered mixtures of micronized griseofulvin. These mixtures and pure griseofulvin (agglomerates 500–710 μm) were measured on dissolution rate at sink conditions, using a paddle method at two rotational speeds. Highly soluble carrier materials gave an extremely fast dissolution, probably due to the fact that the drug was delivered as free, well-dispersed primary particles, after rapid dissolution of the carrier particles. The surface area utilized for dissolution was shown to be close to the external surface area of the primary particles, as measured by permeametry. Practically insoluble carriers, gave a limited increase in dissolution rate as compared to the griseofulvin agglomerates. This was explained mainly by an increased influence of diffusional transport, and to some extent by ,decrease in the surface area participating in dissolution. The use of a hydrophobic carrier, decreased the dissolution rate compared to griseofulvin agglomerates.     

In vitro release of noramidopyrine methansulfonate sodium from suppository as a function of particle size and concentration.

The effect of particle size and percentage concentration of noramidopyrine methansulfonate sodium on its release from Witepsol H 15 suppository base is studied. It is proved that the finer the drug particles the less its release and the more the drug concentration the more its release.     

Plasticization of cellulose ethers used in the film coating of tablets.

Plasticizer/polymer interactions have been studied by measuring the intrinsic viscosities of both ethyl cellulose and hydroxypropyl methylcellulose in a series of dialkyl phthalates and in a series of liquid glycols respectively. A correlation was found between the intrinsic viscosity of the polymer/plasticizer solutions and the tensile strength, elongation at rupture and work done in stressing to failure of cast films--the mechanical properties being at a minimum when the intrinsic viscosity was at a maximum. This correlation held only within a homologous series of plasticizers and none was found for plasticizers of different structures. A relationship was found between the lowering of a calculated glass transition temperature of hydroxypropyl methylcellulose in the presence of the plasticizers propylene glycol, polyethylene glycol 200 and glycerol and the intrinsic viscosity of the corresponding solutions--the higher the viscosity the greater the lowering of the transition temperature.