The preparation of pellets containing non-ionic surfactants by extrusion/spheronization

The aim of the study was to investigate the possibility of incorporating non-ionic surfactants into pellets produced from microcrystalline cellulose by the process of extrusion/spheronization and the properties of the pellets. A hydrophilic surfactant, polysorbate 60 (PS 60), and two hydrophobic surfactants, sorbitan monostearate (S 60) and sorbitan monooleate (S 80), were included in the water used to form the pellets in concentrations ranging from 5 to 95%. The presence of the surfactants influenced the type of the extrusion profile and improved the ability to provide round pellets, and the addition of the surfactants changed the range of liquid levels required to prepare the pellets. At a low level, i.e., 5%, all the surfactants increased the range of water contents possible, compared to the use of water alone. At high surfactant levels, the level of liquid, which could be used, became restricted. The median size of the pellets was dependent on the type of surfactant and the concentration included in the formulation. The range of sizes produced was generally quite narrow and there were many systems with more than 90% of the pellets in the modal fraction. The highest concentration of the surfactant in water that can be used to form pellets ranged from 50% for S 60, to 80% for S 80 and 95% for PS 60. The maximum amount of the surfactant, which could be incorporated into the final pellet, however, was found to be approximately 22.5% for both the hydrophobic surfactants and 32.5% for the hydrophilic surfactant.     

The preparation by extrusion/spheronization and the properties of pellets containing drugs, microcrystalline cellulose and glyceryl monostearate.

Pellets have been prepared by extrusion and spheronization containing microcrystalline cellulose (MCC) and four model drugs with decreasing order of solubility, paracetamol (P), diclofenac sodium (D), ibuprofen (IB) and indomethacin (IN) at a 10% level with and without the addition of a range of levels of glyceryl monostearate (GMS). The drugs differed in their response to extrusion in that all formulations containing the drug D had a 'steady state' extrusion profile whereas the other three drugs exhibited 'forced flow' indicating the possibility of water migration during the process of ram extrusion. The presence of GMS did not influence this effect. The drug D also required consistently less water to function than the other three drugs. In spite of these differences in extrusion performance, it was possible to prepare satisfactory pellets from formulations of all the drugs with 0, 30 and 60% GMS combined with 90, 60 or 30% of MCC at a range of water levels. It was also possible to prepare pellets containing the drug D with 70, 80 and 90% GMS, with corresponding quantities of 20, 10 and 0% of MCC. It was also possible to prepare the pellet formulations by dispersing the drugs in molten GMS, grinding and processing this with MCC and water. Such systems retained the processing characteristics of the composition made by the blending of the powder. The presence of GMS in all cases reduced the quantity of water required for the process to function. The steady state or the mean of the range of the forces observed during forced flow, were dependent on the composition and the quantity of water added. The surface of the extrudate appeared smooth and measurements of surface roughness established that the value of the rugosity R(a) for any of the extrudates did not exceed 6 microm. The extrudate diameter was found to increase with the quantity of GMS in the formulation. The pellets produced were all within a relatively narrow size range (three sieve fractions of a root two progression), the median value of which increased with the level of GMS. For the drug D, there was a linear increase of pellet diameter with increase in the extrudate diameter. For the three other drugs this relationship was less certain but nevertheless there was a similar trend for the pellet diameter to increase as the extrudate diameter increased, suggesting the mechanism of the process is the same irrespective of the composition. Considering the value of the shape factor e(R), all the pellets produced from the various formulations were well within acceptable levels for further processing and the only observable trend in the values was that the formulations with the lower water contents were the least round. The porosity of the pellets of the different formulations generally decreased with the increase in water used to prepare the pellets, the extent of this decrease being dependent on the drug and the level of GMS. The in vitro drug release from the pellets was controlled by the solubility of the drug, the lower the value of the solubility, the longer the mean dissolution time (MDT). This was not influenced by the presence of GMS or the method of incorporation of the drug into the formulation.     

Production of chitosan pellets by extrusion/spheronization.

Chitosan pellets were successfully prepared using the extrusion/spheronization technology. Microcrystalline cellulose was used as additive in concentrations from 70 to 0%. The powder mixtures were extruded using water and diluted acetic acid solution in different powder to liquid ratios. The effects on bead formation using water and different acetic acid concentrations and solution quantities were analysed. Also, the morphological and mechanical characteristics of the obtained beads were investigated. With demineralized water as granulation fluid, pellets with a maximum of 50% (m/m) of chitosan could be produced. The mass fraction of chitosan within the pellets could be increased to 100% by using diluted acetic acid for the granulation step.     

The evaluation of formulations for the preparation of pellets with high drug loading by extrusion/spheronization

A capillary rheometer was used to evaluate rheological properties and the fluid mobility of mixtures with a high drug loading (80%) of three model drugs (ibuprofen, lactose, and ascorbic acid) when extruded. These drugs have a range of solubility in water, with 20% microcrystalline cellulose (MCC) as the spheronization aid, and water, pH 2.0, and pH 10.0 buffer as the binder liquid. The results were compared with the ability of the systems to form spherical pellets by the process of extrusion/spheronization. It was found possible to produce round pellets with a narrow size distribution by the process of extrusion/spheronization for formulations containing 80% of either lactose or ascorbic acid with MCC as the spheronization aid. It was not, however, possible to form pellets containing the same level of ibuprofen. This appears to be associated with the high level of fluid mobility observed when the wet masses were extruded in a ram extruder. A range of rheological characteristics in terms of shear stress, die entry pressure, angles of convergence, extensional flow, and elasticity were determined, but the variations in the values of these, which were observed, did not give an indication of the ability of the wet mass to form spherical pellets when subjected to the spheronization process. This could be associated with the fact that the selection of the conditions necessary to provide a valid quantification of the extrusion process did not truly represent the stability of the systems in terms of the mobility of the fluid when the wet mass was processed. The formulation of a wet mass with limited fluid mobility appears to be the first priority of formulations used in extrusion/spheronization.     

The influence of model drugs on the preparation of pellets by extrusion/spheronization: II. Spheronization parameters.

Five drug-models, 4-parahydroxybenzoic acid (4HBA), methyl (MBA), propyl (PBA) and butyl (BBA) paraben and propyl gallate (PG), all of similar chemical nature, were mixed in different proportions (50-73.7%) with microcrystalline cellulose (MCC) (26.3-50%) plus various levels of water (26.9-50.0%). The wet powder mass was extruded and spheronized under standard conditions. The pellets produced were evaluated in terms of their median diameter, their modal size range, the % within a given size range (0.7-1.7 mm) and their shape factor. For the majority of formulations, all drug models, except 4HBA, produced pellets. This material only had two combinations of excipients that produced acceptable pellets. For all the model drugs, two combinations of formulations could be identified; (1) a combination, which produced pellets from all the model drugs and (2) a combination, which was too wet to produce pellets with any of the model drugs. Between these two extremes, whether pellets could be made and their quality varied with the model drug. Cluster analysis was able to divide the formulations into 4 clusters. In cluster 1 all the model drugs produced pellets except 4HBA; in cluster 2 all drugs produced pellets except MBA; in cluster3, pellets were produced with PBA, BBA and PG while MBA produced agglomerates and 4HBA was too dry; in cluster 4, MBA and BBA produced pellets, PBA produced agglomerates while 4HBA was too dry to pelletise and PG too dry to extrude. The five drug models showed different relationships between the median pellet size and drug-load and initial water content in the formulation. Cluster analysis indicated that, the level of water and type of model drug were the most significant factors in determining the pellet size. Three clusters could be identified, but the response to water content was drug dependent. It was not possible to identify a relationship between the force required to extrude the wet mass and the ability to produce good pellets nor their median size. All the products, which could be classified as good pellets, when produced, had a shape factor that can be considered to be indicative of a spherical shape. The most consistent material, in terms of spheronization, as represented by median diameter, size range and roundness, was propyl gallate (PG), which throughout all the formulations produced an almost constant value for shape factor and median pellet size, which in the majority of cases fell within a limited pellet size.     

Production of spherical pellets by a hot-melt extrusion and spheronization process

Controlled-release theophylline containing spherical pellets were successfully produced by a hot-melt extrusion (HME) and spheronization process. A powder blend of anhydrous theophylline, Eudragit Preparation 4135 F, microcrystalline cellulose and polyethylene glycol 8000 powder was sieved, blended and then melt-extruded in a Randcastle Microtruder. The hot-melt extruded pellets were prepared by first cutting a thin, extruded composite rod into symmetrical pellets. The pellets were then spheronized in a traditional spheronizer at an elevated temperature. Thermal properties of the pellet formulation components and the hot-melt extrudate were studied to determine suitability of the formulation for HME. Pellets were examined using scanning electron microscopy to determine the effect of spheronization time on surface morphology. The rate of release of theophylline from the hot-melt extruded spherical pellets was characterized using USP 24 Apparatus 2 dissolution testing after initial pellet production and after 1 year storage in sealed HDPE containers at 25 degrees C/60% RH.     

Designing, optimisation & characterization of sustained release matrix pellets prepared by extrusion spheronization containing mixture of proteolytic enzymes

A method for developing sustained release multiple unit dosage form consisting of pellets of a proteolytic enzyme blend using extrusion spheronization as a process is demonstrated in this paper. Effect of Cellulose and Methacrylate based polymers and plasticizers on stability of the enzyme blend are determined. The effect of type & concentration of the sustained release polymer, spheronization rpm and plasticizer on the yield & sphericity of pellets is studied. The results indicated that the SR pellets could be formulated for this enzyme blend using both HPMC K15 and EUDRAGIT RSPO. The best rpm for spheronization turned out to be 1200 rpm. Use of plasticizer improved yield and sphericity. Triethyl citrate was better over polyethylene glycol 400 and EUDRAGIT RSPO was better over HPMC K15 with respect to yield and sphericity of pellets. The pellets could be suitably enteric coated for protection of enzyme blend in lower pH of GIT. The in vitro release profile indicated release extension could be extended up to 12 hours in intestinal condition postulating to an acceptable bioavailablity in vivo.     

挤出滚圆法制备埃索美拉唑镁肠溶微丸

目的研制埃索美拉唑镁肠溶微丸并对其产品质量进行评价。方法用挤出滚圆工艺和流化床包衣法制备埃索美拉唑镁肠溶微丸,并对产品质量进行评价来进行处方和工艺的优化。结果所制得的微丸制剂在人工胃液中耐酸力良好,在人工肠液中的释放迅速且完全。结论有效解决了埃索美拉唑镁的稳定性问题,而且制备工艺简单可行,重现性良好,有望进行工业化生产。     

The evaluation of modified microcrystalline cellulose for the preparation of pellets with high drug loading by extrusion/spheronization

The performance of microcrystalline cellulose (MCC) which had been modified by the inclusion of various levels of sodium carboxymethylcellulose (SCMC) in the wet cake prior to drying, in terms of their ability to form pellets by a standardised extrusion/spheronization process has been assessed. Initial screening of the ability of the modified MCCs to form pellets with an 80% level of lactose as a model drug identified two potential products containing 6 or 8% of SCMC (B 6 and B 8). These two products were compared with a standard grade of MCC (Avicel PH101) in terms of their ability to produce pellets with 80% of model drugs of low (ibuprofen), intermediate (lactose) and high (ascorbic acid) water solubility when subjected to a standardised extrusion/spheronization process. Also assessed was their ability to retain water with applied pressure using a pressure membrane technique and their ability to restrict water migration during extrusion with a ram extruder. The two new types of MCC (B 6 and B 8) were able to form good quality pellets with all three model drugs, whereas Avicel PH101 could not form pellets with this high level of ibuprofen. This improved performance was related to the ability of the new types of MCC to hold higher levels of water within their structure and restrict the migration of water in the wet mass when subjected to pressure applied during the process of preparing the pellets. There is evidence to show that the two new types of MCC can function over a wider range of water contents than Avicel PH101 and that they have an improved performance if the extrusion process is rapid and if, after incorporation of the water into the powder, the sample is stored for some time before extrusion.     

Compression of controlled-release pellets produced by a hot-melt extrusion and spheronization process

The purpose of this study was to investigate the physicomechanical and dissolution properties of tablets containing controlled-release pellets prepared by a hot-melt extrusion and spheronization process. A powder blend of anhydrous theophylline, Eudragit Preparation 4135 F, and functional excipients was melt-extruded, pelletized, and then spheronized. The pellets were compressed into tablets using forces of 5, 10, 15, and 20 kN. Tablet diluents included microcrystalline cellulose, a mixture of spray-dried lactose and microcrystalline cellulose, modified food starch, and soy polysaccharides. The effective porosity of the compressed pellets was measured using mercury porosimetry and helium pycnometry, while the surface area was determined using Brunauer, Emmett, and Teller (BET) analysis. The disintegration time, hardness, and friability of compacts were determined. Drug release studies were performed according to USP 27 Apparatus 3 guidelines in 250 mL of medium (pH 1.0, 3.0, 5.0, 6.8, and 7.4) 37 degrees C and 20 dpm. Samples were analyzed by high pressure-liquid chromatography (HPLC). Effective porosity and surface area determinations of the melt-extruded pellets were not influenced by compression. The percent of theophylline released from rapidly disintegrating tablets was not affected by compression force or excipient selection, but tablets with prolonged disintegration times exhibited delayed drug release in acidic media. However, dissolution profiles of uncompressed pellets and all compacts were identical after transition from 0.1 N HCl to media increasing in pH from 3.0 to 7.4. Furthermore, pellet to filler excipient ratio and filler excipient selection did not influence the rate of drug release from compacts.     

Properties of drug-containing spherical pellets produced by a hot-melt extrusion and spheronization process

The objectives of this study were to investigate the particle size distribution, morphology and dissolution properties of spherical pellets produced by hot-melt extrusion and spheronization and to compare the properties of hot-melt extruded pellets with beads manufactured by a traditional wet-mass extrusion and spheronization method. Spherical pellets were produced by hot-melt extrusion without the use of water or other solvents. A powder blend of theophylline, Eudragit Preparation 4135 F, microcrystalline cellulose and polyethylene glycol 8000 was hot melt-extruded and the resulting composite rod was cut into cylindrical pellets. The pellets were then spheronized in a traditional spheronizer at an elevated temperature. The same powder blend was processed using conventional wet-mass techniques. Unlike wet-mass extruded pellets, pellets prepared from hot-melt extrusion displayed both a narrow particle size distribution and controlled drug release in dissolution media less than pH 7.4. Scanning electron microscopy, X-ray diffraction and porosity measurements were employed to explain the differences in drug release rates of theophylline from pellets produced by the two processing techniques. Theophylline release from the hot-melt extruded pellets was described using the Higuchi diffusion model, and drug release rates from wet-granulated and melt-extruded pellets did not change after post-processing thermal treatment.     

Response surface optimization of high dose pellets by extrusion and spheronization

A radial basket-type extruder and a serrated plate spheronizer were used to prepare spherical pellets containing approx. 80% active drug. A response surface experimental design was employed to address the effects of altering microcrystalline cellulose concentration, water concentration, spheronizer speed and spheronizing time on pelletization of this low density drug. Response surfaces were adequately described by quadratic equations which contained significant interaction terms for two of three measured product characteristics. Optimum ingredient concentrations and process conditions were selected from the response surface equations. Product subsequently manufactured under these optimum conditions met expectations. This results in a well-characterized, reproducible process for manufacturing smooth pellets with adequate potency to provide a 500 mg dose in a ‘0’ elongated capsule.     

挤出滚圆法制备天山雪莲提取物骨架微丸

目的应用挤出滚圆法制备天山雪莲提取物骨架微丸,并研究微丸制备的最佳处方和工艺。方法采用单因素考察和正交设计,用挤出滚圆法筛选天山雪莲提取物骨架微丸最优处方和工艺条件;考察微丸的粉体学性质及累积释放度。结果制得微丸圆整度、均匀度、流动性及堆密度均较好,成品收率高,且30 min内体外释放度均>80%。结论本法制备的雪莲提取物骨架微丸,工艺简便易行,质量可控,收率高。     

Study of the influence of alkalizing components on matrix pellets prepared by extrusion/spheronization

The aim of this study was to investigate the effects of alkalizing components and the nature of the wetting liquid on the properties of matrix pellets prepared by extrusion and spheronization. Atenolol was used as an active pharmaceutical ingredient, ethylcellulose as a matrix former, microcrystalline cellulose as a filler and disodium phosphate anhydrous and trisodium phosphate dodecahydrate as alkalizing materials. Water and a water-ethanol mixture served as granulation liquids. Pellet formation was evaluated via mechanical, dissolution and morphological studies. In order to enhance the dissolution of Atenolol from the pellets, alkalizing components were used and the influence of these components on the pH was tested. Investigations of the breaking hardness, the morphology and the dissolution revealed that the pellets containing trisodium phosphate dodecahydrate and prepared with a higher amount of water as binding liquid displayed the best physico-chemical parameters and uniform dissolution. In in vitro experiments, the dissolution release complied with the texture of the pellets and the effect of pH. The pellets have suitable shape and very good hardness for the coating process and are appropriate for subsequent in vivo experiments.     

Study of the influence of alkalizing components on matrix pellets prepared by extrusion/spheronization

The aim of this study was to investigate the effects of alkalizing components and the nature of the wetting liquid on the properties of matrix pellets prepared by extrusion and spheronization. Atenolol was used as an active pharmaceutical ingredient, ethylcellulose as a matrix former, microcrystalline cellulose as a filler and disodium phosphate anhydrous and trisodium phosphate dodecahydrate as alkalizing materials. Water and a water-ethanol mixture served as granulation liquids. Pellet formation was evaluated via mechanical, dissolution and morphological studies. In order to enhance the dissolution of Atenolol from the pellets, alkalizing components were used and the influence of these components on the pH was tested. Investigations of the breaking hardness, the morphology and the dissolution revealed that the pellets containing trisodium phosphate dodecahydrate and prepared with a higher amount of water as binding liquid displayed the best physico-chemical parameters and uniform dissolution. In in vitro experiments, the dissolution release complied with the texture of the pellets and the effect of pH. The pellets have suitable shape and very good hardness for the coating process and are appropriate for subsequent in vivo experiments.     

Factorial design in the feasibility of producing Microcel MC 101 pellets by extrusion/spheronization

This study evaluates the effects of certain process variables in the feasibility of producing Microcel MC 101 pellets by the extrusion/spheronization technique. A 2³ factorial design was realised to demonstrate the influence of the significant factors and their interactions in the experimental response. The selected process variables such as water content, extruder screen size and spheronizer speed were studied, as well as their influences on the properties of particle size distribution and the densities were determined. The results showed that high levels of the three factors increased sphere size, and low levels decreased it. A strong interaction between water content and extruder screen size is observed for the particle size distribution response. Extruder screen size has a significant effect on the bulk density. Water content and spheronizer speed interaction influence the sphere density.     

The influence of plate design on the properties of pellets produced by extrusion and spheronization

The aim of this work was to produce pellets using a standard formulation by means of extrusion and spheronization. Three different spheroniser friction plate patterns (i.e. cross-hatch, radial, striated edge pattern) have been used in order to investigate whether the plate pattern affects physical properties of the pellets such as pellet size distribution, yield, shape, mechanical strength, density and drug dissolution. Extrusion was performed with a screen extruder and the screen size was varied to determine whether the extrudate produced could affect the physical properties of pellets. The plate load was also varied. Diclofenac sodium was chosen as a model drug. The pattern of the friction plate used in the spheronization of extrudates affected the properties of the pellets. Yield values varied by up to 20%, and for an otherwise optimised formulation the use of a striated edge plate appeared advantageous in this respect. However, these pellets had a reduced mechanical strength despite their lower porosity, which might be disadvantageous. In addition, other factors such as the amount of extrudate loaded into the spheroniser, the maintenance of a constant moisture content within the spheroniser and the size of the extruder screen influenced these findings significantly. The only physical property of the pellets that did not respond to the various changes in the manufacturing process of the pellets is the pellet shape, which remained spherical. The dissolution of the drug appeared to be related to the median pellet size and was only marginally affected by changes in the spheronization process.     

Alginate-based pellets prepared by extrusion/spheronization: a preliminary study on the effect of additive in granulating liquid.

The aim of this study was to investigate the possibility of producing alginate-based pellets by extrusion/spheronization and also to improve the formation of spherical alginate-based pellets by investigating the effect of additive in granulating liquid on characteristics and drug release from resulting pellets. Two types of sodium alginate (30%) were evaluated in combination with theophylline (20%), microcrystalline cellulose (50%) and different granulation liquids. The pellets were then prepared in a basket extruder, then spheronized and dried. The final products were characterized by morphological examination and drug release study. Different additives in the granulating liquid influenced the ability of the extruded mass to form pellets (the processability) with this technique. However, different sodium alginate types responded to shape modifications to a different extent. Long, dumbbell-shaped pellets were obtained with viscous granulating liquids. However, short, nearly spherical pellets were obtained with watery granulation liquid with calcium chloride that reduced the swelling ability of sodium alginate. Improvements in the pellet characteristics were also dependent on the sodium alginate type employed. Most of pellet formulations released about 75-85% drug within 60min and showed a good fit into both Higuchi and Korsmeyer-Peppas equations. Higher amount of 3% calcium chloride, as a granulating liquid, in the formulation showed higher mean dissolution time resulting from the cross-linking properties of calcium ions to the negative charges of alginate molecules.     

The behavior of different carrageenans in pelletization by extrusion/spheronization

kappa-Carrageenan is known as a novel pelletization aid in manufacturing of pellets by extrusion/spheronization. The implentation of kappa-carrageenan as a pelletization aid can overcome several disadvantages of commonly used microcrystalline cellulose (MCC) such as lacking disintegration and adsorption of several actives. The aim of this study was to compare different types of carrageenans from different suppliers: one iota-, five kappa-, and one lambda-carrageenan. The kappa-carrageenans had the best pelletization behavior. Four of the five tested kappa-carrageenans resulted in pellets with acceptable shapes, sizes, and size distributions using a high drug load of 80% hydrochlorothiazide. These pellets have similar properties over a wide range of water contents ranging from 90 to 105%. The filler, dicalcium phosphate, affected the pelletization process and the pellet properties of all investigated kappa-carrageenans.     

Alginate-based pellets prepared by extrusion/spheronization: Effect of the amount and type of sodium alginate and calcium salts

Pellets containing microcrystalline cellulose (MCC), a model drug (theophylline) and a range of levels of sodium alginate (i.e., 10–50% w/w) were prepared by extrusion/spheronization. Two types of sodium alginate were evaluated with and without the addition of either calcium acetate or calcium carbonate (0, 0.3, 3 and 10% w/w). The effects of amount and type of sodium alginate and calcium salts on pellet properties, e.g., size, shape, morphology and drug release behavior, were investigated. Most pellet formulations resulted in pellets of a sufficient quality with respect to size, size distribution and shape. The results showed that the amounts of sodium alginate and calcium salts influenced the size and shape of the obtained pellets. However, different types of sodium alginate and calcium salt responded to modifications to a different extent. A cavity was observed in the pellet structure, as seen in the scanning electron micrographs, resulting from the forces involved in the spheronization process. Most of pellet formulations released about 75–85% drug within 60 min. Incorporation of calcium salts in the pellet formulations altered the drug release, depending on the solubility of the calcium salts used. The drug release data showed a good fit into both Higuchi and Korsmeyer–Peppas equations.