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Modified starch as an excipient for pellets prepared by means of extrusion/spheronisation
Abstract
De focus van dit onderzoeksproject zijn pellets als farmaceutische doseringsvorm. Pellets worden gedefiniëerd als sferische partikels met goede vloei-eigenschappen en met een nauwe deeltjesgroottedistributie (voor farmaceutische toepassingen variërend tussen 500 en 1500 μm). Als multiparticulaire doseringsvorm bieden pellets een aantal belangrijke voordelen ten opzichte van singleunit vormen zoals tabletten. Pellets kunnen via een aantal technieken worden geproduceerd: extrusie/sferonisatie, layering, directe pelletisatie en high-shear pelletisatie. Extrusie/sferonisatie, de techniek aangewend tijdens dit onderzoeksproject, bestaat uit een aantal verschillende stappen: in een eerste fase wordt een poedermengsel van het geneesmiddel en de hulpstoffen bevochtigd door toevoeging van een granulatievloeistof. Vervolgens wordt deze vochtige massa doorheen een extrusiescherm geperst (extrusie) waardoor cylindrische extrudaten worden gevormd. Deze worden daarna in kleinere cylindrische staafjes opgebroken en afgerond tot sferische granules (pellets) door middel van een roterende frictieplaat (sferonisatie). De laatste stap in het extrusie/sferonisatieproces is een droogfase. Op basis van literatuurgegevens is het duidelijk dat het controleren van de procesparameters tijdens de verschillende stappen van het proces essentieel is om de kwaliteit van de pellets te waarborgen.
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A modified starch (high-amylose, crystalline and resistant starch) was evaluated as an alternative excipient to microcrystalline cellulose for pellets prepared via extrusion/spheronisation. Theophylline anhydrous (25%, w/w) was used as a model drug. A binder was necessary to obtain an acceptable yield and the addition of sorbitol improved the surface properties of the pellets. A surface response design with three formulation variables (binder, sorbitol and water level) and one process variable (spheronisation speed) was used to optimise the process and to evaluate pellet yield, sphericity (aspect ratio and two-dimensional shape factor, e(R)), size (mean Feret diameter), friability and disintegration properties. Mixer torque rheometry and solid-state NMR revealed a significant influence of sorbitol on wet mass consistency and pellet properties. A high pellet yield (>90%), acceptable sphericity (AR<1.2), low friability (<0.01%), fast disintegration (<10 min) and complete drug release in less than 20 min for all formulations, demonstrated the potential of this modified starch in formulations intended for extrusion/spheronisation.
In this chapter we examine dosage forms as drug-delivery systems. The scope of the examination will, however, be limited to those oral dosage forms in which the drug is not in solution when taken by the patient. Usually the absorption of drugs from aqueous solutions can be defined by the principles discussed in Chapter 2. However, occasionally drugs in solution may precipitate in the gastrointestinal (GI) fluids and effectively be considered as suspensions. Nevertheless, the dosage forms considered in this chapter are tablets, capsules, and suspensions. In addition, the discussion is limited to drugs absorbed by passive diffusion that thus appear to obey first-order linear absorption kinetics.
The aim of this study was to develop pellets exhibiting a rapid dissolution of propyphenazone. The possibility of dissolution enhancement was studied by means of a mixture design with constraints. Pellets were prepared by extrusion/spheronization. The fractions of powdered cellulose, low-substituted hydroxypropylcellulose and propyphenazone were varied within a wide range. The shape of the pellets was greatly influenced by the formulation. All dissolution profiles could be described by the square root of time law because disintegration was not observed even for pellets with 80% drug load after complete dissolution. Throughout the investigated factor space, the dissolution rate varied by less than a factor of two. Furthermore, destroying the matrix increased the dissolution rate to a great extent.
The dissolution profile of a model drug (indomethacin) in pellets produced by extrusion and spheronisation has been evaluated according to the method described in the USP XXIII, apparatus II. The effects of the speed of the paddles, temperature, pH and size of the pellets, i.e., the surface area have been examined. The study was complemented by coating the pellets with a polymer (ethylcellulose) in an aqueous dispersion and changes in the release of the drug were monitored. The analysis of the results was carried out by determination of two statistical moments mean dissolution time (MDT) of indomethacin and variance of dissolution time (VR) and an associated parameter, the relative dispersion of the concentration-time profile (RD). From these parameters, it was possible to relate the release of the drug to the dissolution mechanisms and models described in the literature. The present study has shown the possibility of analysing the complete release of the indomethacin as opposed to the traditional approach of considering only 40-60% of the drug released. The analysis has also shown that the mechanism of release of the drug changes throughout the test. Finally, for pellets coated with ethylcellulose, the coating altered the rate of release of the drug and changes in the release mechanism were also observed. Under certain conditions a zero order release rate was obtained.
Autohesion is a diffusion controlled mechanism that can be utilized to explain how high molecular weight polymers interact. This mechanism finds its origin in the rubber and plastics industries and has been briefly alluded to in the pharmaceutical literature only in the area concerning film coating of solid dosage forms. Since many pharmaceutical dosage forms contain high molecular weight polymers in their formulations, this review will attempt to introduce the concept and the factors that affect it to the pharmaceutics area. An understanding of autohesion may assist the developer in producing solid dosage forms with desired strength and release characteristics.
The influence of the size of barrier-coated drug cores was investigated using a special experimental design. It was shown that the release rate is directly proportional to the surface area of the coated cores. This means, for example, that four times more coating solution should be needed to maintain the release properties if the particle size is reduced to half of its original value. This large effect of particle size variations is important both concerning product quality and production economy.
A factorial designed experiment has been used to investigate the effect of formulation and extrudate production variables on the properties of spheroids produced by extrusion and spheronisation. The variables were the Avicel and water content of the formulation (which also contained lactose, and indomethacin as a model drug), extrusion speed and die length. The effects that were investigated were the force required for steady-state extrusion (ram extruder), the shape and size distribution of the spheroids, and the drug release profile from the products. The most important variable was found to be the water content, in particular the water content at the die wall during extrusion (and presumably at the surface during subsequent spheronisation) was found to be important. Factors which may be expected to decrease water availability at the die wall (decreased water and Avicel contents, increased extrusion speed and die length) were found to have detrimental effects on the product (in terms of size distribution and shape). All the variables had some effect on the dissolution performance of the spheroids, but those due to die length and extrusion speed were only significant when the Avicel content was low and the water content high.
The change in porosity parameters, i.e., total pore volume, porosity percentage and pore volume size distribution of lactose, glucose and mannitol granules caused by compression with a low force was investigated. In compression, fragmentation of lactose and glucose granules increased total pore volume and porosity percentage, whereas the total pore volume and porosity percentage of mannitol granules was clearly decreased. This was due to the highly porous structure of mannitol granules, which densified easily in compression. Lactose and glucose granules were shown to resist deformation more. The pore volume size distributions of lactose and glucose tablets showed that large pores ( > 14 μm) decreased in size. For mannitol tablets, the large pores vanished and simultaneously the small granule pores ( < 14 μm) reduced in size. The features of the pore structure of granules were detected in the pore volume size distributions of compressed tablets. Mercury porosimetry, assisted by scanning electron microscopy, was shown to be an adequate method to evaluate the deformation of granules in compression.
The characteristics of drvine and contraction (shrinkage) of molded ceramics were expenmentally studied to clarify the effects of drying conditions on contraction behaviors or deformation during drying processes. Mikawa-Shanshu clay molded into spheres or slabs was used as a sample which underwent convective drying by hot air.Three periods of preheating, constanl rate and falling rate existed, and the contraction was observed mainly in the preheating and constanl rate periods for all samples. It is also observed that the behavior of ihe contraction of molded clay is inflienced significantly by drying conditions. The higher drying rate makes the contraction of clay more remarkable in the preheating and constant rate periods. This behavior could not be explained from the difference of the moisture content distribution among runs. However, it is suggested that the inside parts of molded ceramics may be subjected to the strong compressional stresses and the strain-stress in the sample would Influence the contraction behavior when he gradient of moisture content distribution becomes steeper with increase in the drying rate.
Abstract Beginning with binary Avicel-lactose (20/80) mixtures, the present study focuses on the influence of the spheronization speed and the drying process on the porousness, surface condition and the pressure resistance of neutral spheroids prepared by extrusion/ spheronization. Any increase in the spheronization speed provokes a decrease in the porousness and the average diameter of the pores, and gives a greater hardness and a smoother surface condition. In the final production phase, oven drying gives less porous and harder minigranules and a more homogenous surface than those dried by microwaves. In the experiment conditions, a negative correlation between porousness and hardness was established.
Abstract Pellets were prepared from wet granulations using an extruder and spheronizer. Binary mixtures of active ingredient and different types of Avicel micro-crystalline cellulose products have been processed and evaluated to determine the effect of varying the drug, the diluent, and the drug-diluent ratio. Physical properties including in-vitro drug release profiles were evaluated for the uncoated pellets. Anhydrous Theophylline, USP and Quinidine Sulfate, USP were evaluated at drug-diluent ratios from 10:90 to 80:20. Chlorpheniramine Maleate, USP and Hydrochlorothiazide, USP were incorporated into one system to study the influence of more extreme values of aqueous solubility on drug release. Drug release was found to vary with the drug, diluent, and the drug-diluent ratio.
The influence of the degree of wetting, during the granulation step of the pelletisation process, on the drug release from several microcrystalline cellulose-anhydrous theophylline blends was examined. Blends containing 60% theophylline show a release rate inversely related to the amount of water used for granulation. The drug release rate from mixtures prepared with 25% theophylline is less influenced by the degree of wetting. Differences in release rate were correlated with the crystal transition from anhydrous theophylline to theophylline monohydrate.
The influence of water content on the ability of mixtures of a range of proportions of barium sulphate and microcrystalline cellulose to form spherical granules by extrusion spheronisation has been assessed. Producing the extrudate by a ram extruder indicates that a range of steady state extrusion forces, which produce a satisfactory product, can be assigned to formulations. Below 2500 N, the extrudate is too wet and agglomerates, while above 10000 N the product is too dry and fails to round or cohere. The range of moisture contents over which successful products can be prepared is relatively wide for contents of barium sulphate from 20 to 60%. As this level is exceeded, the moisture content becomes more critical and once 80% of barium sulphate is reached, a critical moisture content is required. The quantity of water relative to the microcrystalline cellulose content, which was required to produce a consistent product in terms of particle size, was found to be proportional to the percentage of barium sulphate in the mixture. The ratio ranged from 1:1 for 20% barium sulphate to 1:1.5 for 80% barium sulphate.
The influence of spheronisation process variables of time, load, speed of rotation and plate texture on the properties of size, shape and density of granules has been assessed with a standard extrudate produced by a cylinder extruder. It was found that optimum conditions of load and speed of rotation existed in that too low a speed produced no significant shape changes in the extrudate, while too high a speed resulted in a size reduction of the particles. A low load appeared to give poor particle/particle interaction while a high load produced poor plate/particle interaction. Increase in the length of the die in the cylinder extruder resulted in the inability to spheronise the extrudate under what had been previously optimum conditions of speed and load. No such loss of spheronisation performance occurred with processing of extrudate from two lengths of die of a ram extruder on a spheroniser with different plate textures. The granules produced, however, were significantly larger than those obtained for the same wet mass processed by the cylinder extruder.
This chapter outlines the general requirements for analytical method validation for HPLC analysis of related substances in pharmaceutical products. Most of the discussions are based on the method validation for pharmaceutical products of synthetic origin. The discussion focuses on current regulatory requirements in the pharmaceutical industry. Since the expectations for method validation are different at different stages of the product development process, the information given in this chapter is most suitable for the final method validation according to ICH requirements to prepare for regulatory submissions (e.g., NDA).
The different presentations of the pore size distribution derived from the gas adsorption method and the mercury porosimetry
are connected with some problems. This concerns especially the use of the logarithmically differential pore volume distribution.
The incorrect application of this distribution to bimodal pore systems involves the danger of an apparent overemphasizing
of larger pores. This effect may also occur using the incremental pore size distribution in case the experimental point spacing
considerably increases towards the larger pore radii. The pore volume density distribution defined as the linear derivative
of the cumulative pore volume curve with respect to the pore radius has been found the most convenient form among the various
kinds of pore volume distribution presentations. It has been shown that the direct comparison between this distribution and
the logarithmically differential pore volume distribution is not allowed. Nevertheless, there is a clear connection between
these definitions for the pore size distribution so that they are completely equivalent.
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.
From a previous study it is known that pellets obtained from extrusion/spheronization containing microcrystalline cellulose (MCC) and/or low-substituted hydroxypropylcellulose (L-HPC) are able to shrink during drying. This phenomenon has important consequences for pellet properties. The pellet size is reduced while the shape remains constant. Densification during shrinking leads to a lower porosity. In the actual study, shrinking and swelling phenomena were analysed quantitatively. This paper (part I) describes the manufacturing of the pellets and their shrinking properties together with their porosities, friabilities and liquid saturations. The accompanying article (part II) investigates the swelling and dissolution properties of the resulting pellets. Drying methods are of great importance for the properties of resulting pellets. Parts of the same formulations were dried alternatively by fluid-bed, oven or freeze-drying techniques and analysed with the aid of image analysis. Additionally, image analysis of the wet pellets was performed before drying. Freeze-drying almost suppressed shrinking of pellets. The size distributions of freeze-dried pellets are comparable to those of wet (undried) pellets and their porosities are very high. Fluid-bed and oven drying led to identical shrinking phenomena. The influence of the presence of L-HPC in the formulation on the shrinking process was studied. The extent of shrinking is influenced by the amount of excipients which are able to absorb water, the water content of the extrudate and the manner of drying. Freeze-drying prevents shrinking.
The effects of Spheronization speed and residence time on the size and sphericity of microcrystalline cellulose (MCC)-lactose spheroids were investigated. Generally, spheroids became larger and more spherical with an increase in the residence time and Spheronization speed. With very high speeds or long residence times, small spheroids resulted. It was found that a combination of speeds ranging from 1000 to 2000 rpm and residence times between 5 and 15 min may be used to produce spheroids with a modal fraction in a size range of 0.7–1.0 mm. The effects of varying MCC content and amount of water required for Spheronization were also studied. The addition of a larger amount of water produced spheroids with larger mass median diameters. A higher proportion of MCC required correspondingly a greater amount of water to form spheroids of a certain mean size. An equation could be used to predict the quantity of water needed to produce spheroids of a required size range. Variation in the particle size of the lactose used also affected the size of spheroids formed. The coarser lactose grade produced larger spheroids. Granule size distribution and sphericity were found to be dependent on the operating conditions. Therefore, with a particular formulation, the variable parameters must be suitably adjusted to complement each other for successful Spheronization.
The relationship between the film thickness on a bead, and the bead's size and mass in a polydispersed system was studied. Beads with a size distribution in the no. 14–20 mesh range were coated using Glatt fluidized bed units equipped with a Wurster insert. The coated beads were separated into narrower size fractions and dissolution testing of each fraction was performed using the USP basket method. The larger beads exhibited much slower release rates compared to the smaller beads, and the differences could not be explained by the relative surface areas. Examination of the beads by scanning electron microscope indicated that the larger or heavier beads received a thicker film compared to the smaller or lighter beads. This trend was attributed to differences in the fluidization patterns and velocities of the various sized beads.
Stress—strain relationships of moist samples of dicalcium phosphate qualities with different particle size distributions are determined and compared with the granule growth pattern in a high-speed mixer. It is shown that granule growth by coalescence proceeds when a limiting agglomerate strength is achieved due to densification of the moist agglomerates. In the region of growth by coalescence, the growth rate is improved by an improved deformability of the moist agglomerates, while increasing strength delays the growth rate. The effects of agglomerate strength and plasticity are described mathematically by a model which outlines the main effects of the stress—strain relationship upon granule growth by coalescence.
Modifications to the impeller design of a radial basket extruder resulted in a higher efficiency of the process. β-Lactose and dicalcium phosphate were used as model compounds for a high and a low water-soluble drug, respectively. Due to the impeller modifications the concentration of β-lactose and dicalcium phosphate could be increased from 58 to 67% (w/w) and from 18 to 43% (w/w), respectively. The yield of the extrusion/spheronisation process was independent of the extrusion speed using the modified high efficiency impeller. The perforation method of the extrusion screen and the perforation geometry influenced pellet quality as the maximal β-lactose concentration increased from 67% (w/w) for the punched screen to 72 and 78% (w/w) for the drilled and profile screens, respectively. These differences were due to irregular die filling for the punched and the drilled screen at higher β-lactose concentrations. The same influences were seen when β-lactose was substituted for dicalcium phosphate dihydrate although at higher DCP concentrations the profile extrusion screen blocked due to particle bridging inside the screen.
An experimental design was used to determine the influence of parameters that are important in the extrusion-spheronisation process. The parameters tested were water content of binary mixtures of Avicel PH 101®/water, spheroniser speed and spheronisation time. They appeared to have a significant influence on the quality of the spheres. By using a Pareto analysis, optimal parameter settings for water content, spheroniser speed and spheronising time were obtained.
Recent developments in pharmaceutical wet granulation techniques are reviewed with the main emphasis on granulation in fluidized beds and high shear mixers. The following items are dealt with: Fundamentals of granule growth, granulation methods and equipments, granulation variables, scaling-up and end-point control.
This study was designed to demonstrate that properties of a granulation with a given composition, prepared by the spheronizing technique, could be altered by slight changes in process variables alone to satisfy the requirements of the formulator. A complete factorial experimental design was found satisfactory for demonstrating the range of properties to be expected and for showing statistically significant main effects and any linear interactions between selected variables. Results using two levels of five variables showed that initial water content and spheronizer speed had significant main effects on all primary granulation properties studied. While only one formulation was studied, the data suggest that the factorial design can have utility in predicting the properties of granulations prepared at conditions within the limits imposed by the equipment or formulation.
14C-hydrochlorothiazide (hct) was administered orally (n=4) and iv (n = 2 to healthy subjects. The gastrointestinal absorption ranged between 60% and 80%, most of it took place in the duodenum and the upper jejunum. The radioactivity was eliminated mainly in the urine, while no sigificant biliary excretion was observed. Chromatographic analysis of the urinary radioactivity demonstrated that greater than 95% of the absorbed or injected 14C-hct was excreted unchanged. The radioactivity in plasma during the first 10 hr after oral administration declined with a fast phase but the levels of label thereafter suggested a slow phase. The existence of such a phase was verified in 1 subject given 75 mg hct orally. His plasma levels of hct (determined with gas-liquid chromatography) declined according to a 2-compartment model, the half-lives of the alpha-and beta-phases being 1.7 and 13.1 hr, respectively. Hct accumulated in the blood cells and the ratio between the radioactivity in cells and that in plasma averaged 3.5. The fate of a single dose of 14C-hct in 2 hypertensive patients treated with the drug chronically was similar to that in the healthy subjects. A third patient, who had slightly elevated serum creatinine, eliminated hct more slowly than the others. Like the healthy subjects, the patients eliminated hct to greater than 95% in unchanged form.
A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.
Piroxicam was administered to beagle dogs intravenously and orally at a dose rate of 0.3 mg/kg bodyweight. It had an elimination half-life of 40.2 hours, a volume of distribution of 0.29 +/- 0.02 litres/kg and a body clearance rate of 0.066 litres/hour. When administered orally it was 100 per cent bioavailable and maximum plasma concentrations were achieved quickly (3.1 +/- 1.0 hours). Piroxicam inhibited the generation of thromboxane B2 in the blood of dogs by more than 70 per cent and more than 50 per cent inhibition was maintained in most animals for 48 hours.
A shape factor eR has been devised to describe how the form of spherical particles approaches that of a true spheroid, based on a two-dimensional image analysis. Both the deviation of shape from a circle towards an ellipse and surface irregularities influence the value of eR. Using a set of model figures such as squares, triangles, diamonds and stars, it could be shown that eR clearly differentiates between different polygonally symmetric figures, even in the case where common shape descriptors such as the aspect ratio provide equal values. The value of eR is 1.0 in the case of a perfect spheroid, while ellipticity and surface roughness lead to a significant change in the value.
The use of powdered cellulose instead of microcrystalline cellulose in the extrusion/spheronization process was investigated. The aim of the study was to assess differences between two types of powdered cellulose using a 2(4-1) fractional factorial design. Water content and amount of binder were found to be most important while type of cellulose and screw speed had only negligible influence on the extrusion process and the resulting pellets. Pellets obtained with powdered celluloses showed higher porosities and faster dissolution rates compared with those made with microcrystalline cellulose. Image analysis was found to be an appropriate method for the simultaneous characterization of pellet size and shape.
The aim of this study was to investigate the influence of the granulation liquid on pellet properties.
Pellets containing propyphenazone were obtained by extrusion/spheronization using different 2-propanol/water mixtures as granulation liquids. The pore structure of the pellets was determined by mercury porosimetry. The fractal dimension of the pore system was calculated according to the model of the Menger sponge. Further characterization included SEM-photographs, disintegration, dissolution and tensile strength.
Fractions exceeding 40% 2-propanol in the fluid resulted in rapid dissolution rates of the pellets. This effect was caused by the rapid and complete disintegration of the pellets as compared to those obtained with less 2-propanol in the mixture. These phenomena were interpreted as being due to a change in the particle bonding of the pellets at concentrations of 40% 2-propanol. Evidence for this hypothesis resulted from the spheronization process, the tensile strength measurements and from SEM-photographs. The analysis of the pore system in terms of fractal dimensions implied a dependency of the fraction of 2-propanol in the granulation liquid on the pore structure. High fractions of 2-propanol resulted in lower fractal dimensions close to the dimension of the Menger sponge (2.727).
The structure of pellets can be markedly influenced by the composition of the granulation liquid. Investigations of the pore system in terms of fractal geometry are more useful for the explanation of pharmaceutical properties than if the pure values for the porosity are taken.
The objects of this investigation were (i) to prepare and characterize a new anhydrous theophylline phase that is metastable under ambient conditions, and (ii) to prepare model tablet formulations containing either this metastable anhydrate (I*) or stable anhydrous theophylline (I), store them under different relative humidity (RH) conditions, and compare their dissolution behavior. I* was prepared by dehydration of theophylline monohydrate (II). Variable temperature X-ray powder diffractometry of II revealed the following series of transitions: II-->I*-->I. The metastable anhydrate, I*, which has not yet been reported in the literature, appears to be related monotropically to I. It was characterized by ambient and variable temperature X-ray powder diffractometry, Karl Fischer titrimetry, and thermoanalytical techniques (differential scanning calorimetry and thermogravimetric analysis). Tablet formulations containing either I* or I were prepared and stored at 33 and 52% RH (room temperature). The solid state of the drug was monitored by X-ray powder diffractometry and the tablets were subjected to the USP dissolution test. In tablets, I* completely converted to I in < or = 10 days when stored at either 33 or 52% RH. Scanning electron microscopy provided direct visual evidence of recrystallization. This recrystallization was accompanied by a decrease in the dissolution rate of the stored formulations that was so pronounced in the formulations stored at 52% RH that they failed the USP dissolution test. The in situ solid-state transition appears to be responsible for the decrease in dissolution rate observed following storage. Stored tablets containing I showed neither a phase transition nor an alteration in their dissolution behavior.
Preliminary studies revealed that Carbopol 974P, NF resin could be incorporated into beads manufactured by extrusion and spheronization, and can slow the release of a highly water soluble drug if calcium chloride was included in the granulating fluid to reduce the tack of the wetted polymer. In this study, the same approach was used to produce high quality chlorpheniramine maleate beads with a prolonged release duration. Because of the complex nature of the extrusion and spheronization process and the various components in the bead formulations, a statistically sound factorial experiment was considered for this study. A one-half fraction of a two level factorial design with three center points was employed to estimate the effects of simultaneously modifying multiple process and formulation variables, including the Carbopol concentration, calcium chloride concentration, water content, and the spheronization speed and time. Product yield, average bead roundness, and the drug release profile were selected as responses. Increasing the Carbopol content across the experimental range resulted in a significant (P<0.05) reduction in the percentage drug released at 25, 40, and 60 min. Results suggest that combining the conditions of high Carbopol, high water, and low calcium chloride levels with low spheronization speeds at long spheronization times produce the highest quality bead with the longest drug release duration.
The purpose of this study was to investigate the effect of drying rate during static drying on certain physical properties of pellets. Pellets were prepared from microcrystalline cellulose by granulation with different agglomeration liquids (various ethanol/water ratios) and thereafter dried without agitation at different drying rates. The dry pellets were characterised with respect to their shape, porosity, and compression shear strength and the tensile strength of tablets formed from pellets with low and high drying rates was determined. Drying of the pellets occurred at a falling rate and the reduction in liquid content with time obeyed a first order type of relationship. An increased drying rate did not affect the shape and surface texture of the dried pellets and did not cause them to fracture. However, the drying conditions did affect pellet porosity, with an increased drying rate resulting in more porous pellets. Through a relationship with pellet porosity, the drying rate also affected the deformability of the pellets (as assessed from Kawakita 1/b values) and their ability to form tablets. Owing to a strong effect of porosity on pellet compactability, marked changes in tablet tensile strength with variations in drying rate may be obtained.
The objective of this work was to analyse the influence of the solubility of the drug and the filler on the physical characteristics of pellets prepared by extrusion/spheronization. Different formulations were prepared according to a statistical plan, using five different drugs and five different fillers selected according to their water solubility. The pellets were then obtained by a standardized extrusion/spheronization process and evaluated in terms of their physical characteristics by measuring the pellet size, density, porosity, mechanical strength, residual moisture after drying and shape. The results were first analysed by the analysis of variance to identify the main factors involved. The results were further assessed by canonical analysis and the significant influence factors were quantified in terms of regression equations. It can be concluded that the solubility of materials used (both drugs and fillers) plays an important role in the quantity of water required to form satisfactory pellets and on the physical characteristics of pellets. Quantitative relationships were identified between (a) the extrusion force required to provide extrudate, which would form pellets and the natural log of the filler solubility; (b) the quantity of the pellets in the size range 1-1.4 and the solubility of both the filler and the drug; (c) the apparent pellet density and both the level of drug and filler plus the solubility of the filler; (d) the pellet porosity and the quantity of drug and the inverse function of the filler solubility; and (e) the mechanical strength of the pellets and the square root of the quantity of drug.
Relative rates of dissolution of several crystalline steroids, xanthines, and other solid drugs have been measured to determine the effect of solvate formation on this property. Equations have been derived relating the solubility products and diffusional constants to rates of solution of organic solvates. The results suggest that the tendency of many drugs to form such adducts provide pharmaceutical investigators a powerful tool in effecting rapid dissolution of highly insoluble substances.
Microcrystalline cellulose (MCC) pellets produced by a standard extrusions/spheronisation process with a 40% ethanol/water mixture as the fluid component, were dried by four different techniques, namely: freeze-drying, fluid-bed drying, hot air oven drying and desiccation with silica-gel to less than 5% (w/w) water content. A 1.0-1.18mm size fraction of the dried pellets were characterised structurally and mechanically in terms of, shape, density/porosity (open and closed), pore volume/pore volume distribution, surface area, surface tensile strength, shear strength, deformability, linear strain and elastic modulus. An amount of 600, 700 and 750mg of the same size fraction of each pellet batch were compacted to the same tablet thickness and the tensile strength and volumetric elastic recovery of the resulted compacts were determined. Analysis of variance was used to assess the significance of the drying process on the property of the pellets and their compacts. The drying process did not influence the shape of the pellets, but all the other properties were affected to some extent. Pellets dried by freeze-drying were more porous, with most of the pores open to the atmosphere and had a higher surface area than pellets dried by the other methods. Pellets dried by desiccation contained the highest proportion of closed pores. The decrease in tensile strength of the pellets, which occurred with the increase in porosity could presumably be due to ease of crack initiation and propagation between the MCC fibres. The weaker pellets broke instantly before they were subjected to appreciable strain. The porous pellets needed a higher compressing pressure and work of compaction to produce tablets of the same mass and dimensions. This reflected their compressibility, i.e. relative decrease in volume of the pellet bed during compression. The strength and volumetric elastic recovery of the compacts increased with the increase of their porosity. The drying techniques, which produced porous, deformable and weak pellets, produced stronger tablets. The value of the volumetric elastic recovery of the compacts was also observed to increase with the value of compaction pressure.
Processing-induced transformations in drug formulation may induce adverse biopharmaceutical changes in the finished product. During the drying phase of wet granulation, theophylline monohydrate transforms either the stable (form I), or a polymorphic, metastable (form I(*)) form of anhydrous theophylline. We investigated the effect of two drying methods (multichamber microscale fluid bed dryer MMFD) or variable temperature X-ray powder diffractometer (VT-XRPD) on the relative amounts of the different theophylline forms remaining in the dried granules. Granules were analyzed using XRPD and near-infrared spectroscopy. Form I(*) was the predominant form of theophylline after drying at 40-50 degrees C with both drying techniques. Although drying at temperatures over 50 degrees C produced mostly form I, more than 20% of form I(*) remained even at 90 degrees C when drying in MMFD. In these conditions, humidity had little influence on the amount of form I(*) in the granules. In contrast, drying in a VT-XRPD at 60 degrees C produced form I already during the first 15min. Using additional drying methods, including MMFD, during the preformulation stage can be more informative about the possible polymorphic transformations and their underlying mechanisms, such as triboelectrification or recrystallization, in drug ingredients during the manufacturing process.
The aim of this study was to investigate the influence of formulation and compression parameters on the properties of tablets, containing enteric-coated pellets, and on the integrity of the enteric polymer of the individual pellets after compression. In addition the piroxicam plasma concentrations were determined after single and multiple oral administration of powder, pellet and tablet formulations at a dose of 0.3 mg piroxicam/kg bodyweight to dogs. Tablets consisted of enteric-coated pellets (containing 2.5% (w/w) piroxicam in combination with microcrystalline cellulose and sodium carboxymethylcellulose (using Avicel PH 101 and Avicel CL 611 in a ratio of 1-3), cushioning waxy pellets and 10% Kollidon CL (as an external disintegrator). From the D-optimality experimental design it was concluded that the ratio of coated pellets to cushioning pellets (CoP/CuP) affected all tablet properties evaluated. Variation of the pellet size and the CoP/CuP ratio resulted in different in vitro tablet disintegration times. Enteric coating of the pellets or compression of the coated pellets did not have a significant influence (P >0.05) on AUC(0-->72 h). Cmax values obtained after oral administration of coated pellets and compressed coated pellets were significantly lower than for the other formulations. Differences in in vitro tablet disintegration times were not reflected in the onset of the piroxicam plasma concentrations. A dosing interval of 48 h prevented piroxicam accumulation following multiple dose administration.
The purposes of this study were to investigate the use of chitosan in the manufacture of beads by extrusion-spheronization without inclusion of microcrystalline cellulose, and to study the effect of formulation and process variables on the characteristics of the beads. Beads containing chitosan, fine particle ethylcellulose, hydroxypropyl methylcellulose (HPMC), and caffeine as the model drug were manufactured. Bead size, yield, shape, friability, density, porosity, and release studies were determined. Spherical beads with good mechanical properties could be manufactured without microcrystalline cellulose. Release studies showed that there was immediate release of drug from the beads. A five factor, half fraction screening design was employed to study the effect of formulation variables and process variables on the properties of the beads. Statistical analysis indicated that formulation variables such as the chitosan content, HPMC content, and water content, and process variables such as the spheronizer speed and extruder speed significantly affected the physical properties of the beads. The bead size decreased with an increase in chitosan content. Significant two-factor interactions exist between the variables for several of the measured responses. Beads with high percentage yield and high sphericity can be obtained at high chitosan content, and low HPMC content, water content, spheronizer speed, and extruder speed. Less friable beads can be obtained at high levels of studied formulation variables and low levels of studied process variables. Beads of high density and low porosity can be manufactured at high levels of the studied formulation and process variables. Regression equations were generated using Statgraphics Plus software that can be used to develop formulations with desired bead properties. Chitosan was useful to provide beads of acceptable physical properties using water as a granulating fluid in the extrusion-spheronization process.
Fast drug release from solid dosage forms requires a very fast contact of the vast majority of the drug particles with the solvent; this, however, is particularly delayed in tablets and granulations. Starch and cellulose substances favor the matrix disintegration during the starting phase and the generation of the effective dissolution surface of the drug substance, thereby. To investigate the very complex interrelation between the functionality of commonly used excipients and the structural effects of the production processes, wettability, porosity, water uptake, and drug release rates of several ketoprofen-excipient preparations (powder blends, granulations, tablets) were measured. Significant linear correlation between these parameters, however, was not achieved; only qualitative tendencies of the effects could be detected. In consequence, a general mathematical model describing the mechanistic steps of drug dissolution from solid dosage forms in a fully correct way was not realized. However, the time-dependent change of the effective dissolution surface follows stochastic models: a new dissolution equation is based on the differential Noyes-Whitney equation combined with a distribution function, e.g. the lognormal distribution, and numerically solved with the software system EASY-FIT by fitting to the observations. This new model coincides with the data to a considerably higher degree of accuracy than the Weibull function alone, particularly during the starting, matrix disintegration, and end phases. In combination with a procedure continuously quantifying the dissolved drug, this mathematical model is suitable for the characterization and optimization of immediate drug release by the choice and modification of excipients and unit operations. The interdependence of some characteristic effects of excipients and production methods is discussed.
This work seeks to explore and demonstrate the functionality of cross-linked polyvinylpyrrolidone (crospovidone) as a spheronization aid and a promising alternative to microcrystalline cellulose (MCC).
Pellets were prepared with various grades of crospovidone using both small- and large-scale extrusion-spheronization. A Box-Behnken experimental design was employed to elucidate the effects of operating variables on the quality of the pellets. Size and shape analyses of these pellets were conducted and compared to those prepared using MCC.
Crospovidone was believed to behave like a liquid repository in its interaction with water during extrusion-spheronization, although its binding ability was weaker than that of MCC. Spherical pellets of narrow size distribution could be made from the finer crospovidone grades with different lactose grades. However, crospovidone-based formulations required higher water levels than weight-equivalent MCC-based formulations. Crospovidone pellets were of equivalent quality to those prepared with MCC, especially in the shape, size, and yield.
Crospovidone can be successfully employed as a spheronization aid to produce good pellets without the need of a binder, unlike most of the previously proposed materials. This study exemplified the enormous potential of crospovidone to serve as a competent alternative to MCC in the production of pellets by extrusion-spheronization.
A means to produce extruded-spheronized beads, devoid of microcrystalline cellulose (MCC) and with a high drug load (greater than 80%, w/w), is presented. Immediate release bead product with a high yield (greater than 60% of 1mm diameter beads) and low friability (mass loss less than 4.0%) that were spherical to the naked eye (roundness score less than 1.20) were obtained. The formulation consists only of water-soluble components, taking advantage of the properties of soluble polyethylene oxide (PEO) and methoxypolyethylene glycol (MPEG). This approach incorporates minimal processing aids, with wetted PEO providing the apparent plasticity and cohesiveness, and MPEG550 providing the apparent self-lubricating characteristics necessary for successful extrusion and subsequent spheronization into beads. The success of this approach has important implications in cases where high drug load beads are desired, but where MCC cannot be used due to chemical incompatibility or where complete release cannot be achieved with MCC-containing beads.