Aqueous Ethylcellulose Dispersion Research Articles

Influence of Type and Level of Water-Soluble Additives on Drug Release and Surface and Mechanical Properties of Surelease® Films

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.

Release Characteristics of the Matrices Prepared from Co-spray-Dried Powders of Theophylline and Ethylcellulose

ABSTRACTCo-spray-dried powders of theophylline and ethylcellulose were prepared using aqueous ethylcellulose dispersion. Co-spray-dried powders were directly compressed into the matrices and the release characteristics of the prepared matrices were investigated. The co-spray-dried powders exhibited good matrix formations with high hardness at rather low compression force. The concentration of ethylcellulose in the matrices was, as expected, the rate-determining factor in controlling the release rate of the drug. Increasing the weight fractions of ethylcellulose resulted in a corresponding decrease in the drug release rates in both 0.1 N HCl and phosphate buffer pH 6.8. However, at the same level of ethylcellulose content, the drug release in acidic conditions was higher than in alkaline medium. To modify release characteristics of the matrices, PVP K30 and lactose were employed as channeling agents. At concentrations of 5 and 10%, PVP K30 was found to slow the drug release when incorporated into the co-spray-dried powder formulations containing 5% ethylcellulose. Lactose at a concentration of 15% provided an increasing effect on drug release when added in the formulations. But an increase in lactose quantity from 15 to 25% did not exert much more influence on release characteristics. Higuchi plots were found to be best applicable to all release data. Scanning electron microscopic examinations on the surface and cross-section of the matrices before and after subjection to release testing revealed the formation of porous networks within the matrices by the ethylcellulose fibers. Such polymeric networks would account for the controlled diffusion of the drug from the matrices.

Influence of Plasticizer Type and Coat Level on Surelease® Film Properties

Two commercially available formulations of aqueous ethylcellulose dispersion differing in their plasticizer, i.e., Surelease/E-7-7050 containing dibutyl sebacate (DBS) and Surelease/E-7-7060 containing glyceryl tricaprylate/caprate (GTC), were evaluated and compared for their film properties as a function of polymeric coat level. Ibuprofen tablets were coated at 1, 2, 3, and 5% w/w levels using each Surelease formulation, and the coated tablets were evaluated for their drug release characteristics, coat reflectivity (gloss), surface texture, Brinell hardness, and elastic modulus. The drug release was dependent on the coat level and followed Hixson–Crowell cube-root model at 1% coat level. However, at ≥2% coat levels, the release from tablets coated with GTC plasticized formulation appeared to be best described by non-Fickian release mechanism and that from tablets coated with DBS plasticized formulation appeared to follow apparent zero-order release mechanism. At equal coat levels, tablets coated with GTC plasticized Surelease yielded lower drug release rates, higher reflectivity (gloss), lower surface roughness, higher Brinell hardness, and lower elastic modulus than those coated with DBS plasticized formulation. A good correlation was observed between the drug release rates and the reflectivity and surface texture of the coated tablets. The film-coats of GTC plasticized formulation were harder and more elastic than those of DBS plasticized formulation indicating better mechanical integrity.

Dynamic mechanical thermal analysis studies of polymer films prepared from aqueous dispersion

Dynamic Mechanical Thermal Analysis of cast and sprayed films of an aqueous dispersion of polymethyl methacrylate (Eudragit NE30D) and mixtures with an aqueous dispersion of ethylcellulose (Aquacoat ECD-30) has been undertaken. Such analysis allows the identification of glass transition temperatures and the degree of miscibility of the polymers. It was found that the two polymers formed as cast or sprayed films were not miscible but had an optimal composition of 30% of the ethylcellulose dispersion in the polymethyl methacrylate dispersion.

The influence of core materials and film coating on the drug release from coated pellets

The objective of this study was to analyse the influence of the composition of the core of the pellets on the in vitro drug release profile. The different materials (drugs and fillers) were chosen according to their relative solubility. Pellets were prepared by a standardised process of extrusion/spheronisation. A selected fraction size (1–1.4 mm diameter) of pellets of each preparation was coated with Surelease (an aqueous dispersion of ethyl cellulose) to give 5% weight gain. The dissolution studies were performed and data analysed in terms of the Area under the Curve (AUC) of the % dissolved as function of time and Mean Dissolution Time (MDT). ANOVA was applied in order to identify the influence factors and the relationship of cross effects. Canonical analysis and multiple regression were employed to quantify these relationships. The film coat was found to be the major factor controlling the drug release. The results however, show that both drug and filler solubility influenced the drug release profile. Some of the unusual results could only be explained if consideration was given to the physical characteristics of both powder and pellets. In particular, the specific surface area of calcium phosphate compared with other fillers played an important role on the release profile of the model drug.

Release characteristics of microspheres prepared by co-spray drying Actinobacillus pleuropneumoniae antigens and aqueous ethyl-cellulose dispersion

Using formalin inactivated Actinobacillus pleuropneumoniae antigens and aqueous ethylcellulose dispersions, microspheres of oral vaccines were developed by a co-spray drying process. The present study attempted to determine whether the dosage formulations of microspheres could form enteric matrices. To assess the enteric characteristics, an in vitro dissolution test was performed with the AQ6-AP microspheres; 95% of the A. pleuropneumoniae protein was released within 3 h at pH 7, but there was no release at pH 1.5. The scanning microscopy revealed that the surface structure of AQ6-AP microspheres became porous at neutral pH. The SDS-PAGE analysis showed that the release rate of proteins from the microspheres was pH dependent not only for the AQ6-AP formulation but also when antigens of A. pleuropneumoniae were replaced with porcine serum. The results suggest that the A. pleuropneumoniae antigens were entrapped in the AQ6 microspheres under the acidic conditions. In a mouse model, oral immunization with AQ6-AP microspheres containing A. pleuropneumoniae evoked systemic IgG and mucosal IgA responses against A. pleuropneumoniae antigens. Thus, the present method may further provide an opportunity to develop oral vaccines and mucosal immunity.

Influence of Plasticization Time, Curing Conditions, Storage Time, and Core Properties on the Drug Release from Aquacoat-Coated Pellets

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer, triethyl citrate, was used because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer, acetyltributyl citrate (ATBC), plasticization time (1/2 h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However, a thermal aftertreatment of the coated pellets at elevated temperatures (curing step) reduced/eliminated the effect of the plasticization time with ATBC. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets.

Development of a new ethylcellulose pseudolatex for coating

An ethylcellulose pseudolatex was prepared according to a patented method, “nanoprecipitation,” based on the dispersion of preformed polymers which does not require emulsification or sonication. Free films were prepared using the pseudolatex and compared with those obtained from Aquacoat®, a commercial ethylcellulose aqueous dispersion. The results suggest that nanoprecipitation could be of great interest to prepare ethylcellulose for coating. Drug Dev. Res. 50:157–162, 2000. © 2000 Wiley-Liss, Inc.

Comparative Study of Drug Release from Pellets Coated with HPMC or Surelease

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.

Drug Release from Film-Coated Chlorpheniramine Maleate Nonpareil Beads: Effect of Water-Soluble Polymer, Coating Level, and Soluble Core Material

The purpose of this research was to use a new drug release model to study the effects of formulation parameters on drug release from a film-coated chlorpheniramine (CPM) nonpareil system. The film-coated CPM nonpareils were prepared by using a fluid bed apparatus. A hydroxylpropylmethylcellulose (HPMC) solution was blended with an aqueous ethylcellulose dispersion (Surelease) to adjust the permeability of the film. The apparent permeability of samples was obtained from dissolution data using a previously reported drug release equation. The apparent permeability was plotted versus the film coating level or the HPMC concentration in the film. When the natural logarithm of the apparent permeability versus coating level was graphed, a biphasic plot was observed in the group without HPMC in the film, showing the occurrence of a critical coating level. It was suggested that a mechanically formed porous film (due to an incomplete coating) could change to a nonporous film after the bead was completely coated. However, in the group that contained 12% HPMC in the film, the critical coating level was not observed. A porous film, formed by the leaching out of the water-soluble polymer, would not change to a nonporous film even after the bead is completely coated. Through a mathematical derivation, the decrease of apparent permeability versus coating level was related to the reduction of the total hole area. The apparent permeability was found to increase with the HPMC concentration. After a critical concentration was reached, the further addition of HPMC into the film caused a rapid increase in apparent permeability. The critical HPMC concentration was related to a minimum domain formation concentration (MDFC). A rapid increase of the drug release was observed when the dissolution profile of a sample made from a regular sugar nonpareil core (soluble) was compared with the sample made from a precoated nonpareil core (insoluble), which suggests that the drug release can be enhanced by the dissolution of the core. A minimum concentration of the HPMC was required to effectively modify permeability of the film. The critical coating level and critical concentration of HPMC can be determined from the apparent permeability plot using a previously published equation. The dissolution of a soluble core can greatly enhance the release of the drug from the nonpareil system.

Development of a new ethylcellulose pseudolatex for coating

An ethylcellulose pseudolatex was prepared according to a patented method, “nanoprecipitation,” based on the dispersion of preformed polymers which does not require emulsification or sonication. Free films were prepared using the pseudolatex and compared with those obtained from Aquacoat®, a commercial ethylcellulose aqueous dispersion. The results suggest that nanoprecipitation could be of great interest to prepare ethylcellulose for coating. Drug Dev. Res. 50:157–162, 2000. © 2000 Wiley-Liss, Inc.

Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl-cellulose as coating material for diffusion pellets II: properties of sprayed films

This study investigates the properties of sprayed films prepared from aqueous ethyl cellulose dispersions (ECD) containing hydroxypropyl methylcellulose (HPMC) and plasticizers of different water solubility in order to clarify the drug release mechanisms of pellets coated with the respective material. It is of special interest to measure the migration of the water soluble components as well as the physical properties of the swollen ethyl cellulose film. Swelling experiments with sprayed films in 0.1 N-HCl at 37°C show that fairly water soluble plasticizers and the pore forming agent (HPMC) migrated rapidly and almost completely out of the films. The water insoluble plasticizers remain predominantly in the film and the migration rate of HPMC is reduced in a release medium of high ionic strength. The glass transition temperature ( T g) and the softening temperature ( T s) of these films after swelling are dependent on the water solubility of the plasticizer. The T g of ECD films plasticized with triethyl citrate is above the swelling temperature of 37°C after migration of the plasticizer, transforming the polymer in the glassy state. In contrast, dibutyl phthalate-containing ECD films demonstrate a T g below the swelling temperature, leaving the polymer in the rubbery state. The mechanical properties of dry and wet films are studied as a function of the state of curing of the films and of the swelling temperature. On contact with water, a pronounced shrinkage of ECD/HPMC films plasticized with water insoluble plasticizers is observed. All these results are used to explain the different drug release mechanisms of the coated pellets and to enable the prediction and optimization of drug release-rates from coated pellets.

Aqueous ethyl cellulose dispersions containing plasticizers of different water solubility and hydroxypropyl methylcellulose as coating material for diffusion pellets: I. Drug release rates from coated pellets

The present work investigates release mechanisms of theophylline pellets coated with an aqueous ethyl cellulose (EC) dispersion containing plasticizers and hydroxypropyl methylcellulose (HPMC) as a water soluble pore former. Three different drug release mechanisms from coated pellets can be determined as a function of the water solubility of the plasticizers and the ionic strength of the release medium. Coated pellets with the addition of more hydrophilic plasticizers such as triethyl citrate (TEC) or diethyl phthalate (DEP) show an approximate zero-order-release rate. In contrast, two-phase release profiles can be observed from pellets coated with dispersions containing hardly soluble plasticizers such as dibutyl phthalate (DBP) or dibutyl sebacate (DBS). Only in a release medium of high ionic strength the water soluble pore former will remain in the coating. Thus the drug diffuses through a hydrated swollen membrane containing EC, HPMC and insoluble plasticizer. The release mechanisms depend on the glass transition temperature of the ethyl cellulose and therefore on the migration of the plasticizers and the pore former. This was shown by investigation of the migration of the additives and the influence of the temperature of the release medium on the release. Additionally, the study investigates the effect of curing and storage conditions of coated pellets on the drug release rate.

The Compression of Spheres Coated with an Aqueous Ethylcellulose Dispersion

Tablets were compressed from commercial samples of Sugar Spheres NF, Sucrose NF, Corn Starch NF, as well as ground spheres and a physical mixture of ground sucrose plus cornstarch. Additional tablets were compressed from spheres that had been coated with a water-soluble cellulosic polymer solution followed by an aqueous ethylcellulose dispersion. Tableting parameters measured “in-die” included work of compression, peak offset time, tablet density, and Young's modulus. Following ejection, tensile strength was determined under diametrical loading. Dissolution of a marker contained in the water-soluble layer was determined for both compressed and uncompressed spheres. Porosities at peak pressure and peak offset times or tensile strength as functions of peak pressure did not differ between tablets compressed from pristine spheres or from ground spheres. Tablets compressed from spheres had higher values for porosity, tensile strength, and peak offset time than those compressed from sucrose or the sucrose:starch mixture. Values for work of compression were higher for tablets compressed from pristine spheres or from starch. This was attributed to the work required for particle deformation and for breaking of the spheres. The greatest elastic recovery during decompression was observed for tablets compressed from pristine spheres or starch. More brittle behavior was observed for tablets compressed from sucrose or the sucrose:starch mixture. Tablets compressed from ground spheres were more brittle than those compressed from the pristine spheres, indicating an effect due to grinding. Most mechanical properties of tablets compressed from the coated spheres were comparable to those of tablets compressed from uncoated spheres. An exception was diametric strain for tablets compressed from spheres coated with the aqueous ethylcellulose dispersion. These values increased since the plasticized ethylcellulose allowed greater distortion of the tablet before failure occurred. The dye marker was released more rapidly from tablets compressed from spheres coated with the aqueous ethylcellulose dispersion than from comparable uncompressed spheres. At both the 5% and 10% coating levels, spheres coated with the aqueous ethylcellulose dispersion fused into nondisintegrating matrices during compression. Little difference in release rates was seen between the two tablets.

Drug Release from Film-Coated Chlorpheniramine Maleate Nonpareil Beads: Water Influx and Development of a New Drug Release Model

The purpose of this work was to investigate drug release from film-coated chlorpheniramine maleate (CPM) nonpareils (sugar spheres) and the effect of water influx on the drug release mechanism. The methods used in the study involved the layering of CPM onto nonpareil cores using a fluid-bed apparatus. These CPM cores were then coated with an aqueous ethylcellulose dispersion, which was blended with a solution of hydroxylpropylmethylcellulose (HPMC) at different concentrations. The net water influx was determined by measuring water uptake during dissolution. The film surface area was calculated from bead diameters measured with an optical microscope. Drug release profiles were measured using USP dissolution method I (basket). The results showed that significant water influx occurred, which produced an internal liquid phase ranging from 0 to 1.8 × 103 mm3/g of sample. As a result of the water uptake, an increase in bead size was observed. The bead surface area varied over the range of 40–80 × 103 mm2/g sample because of a combined effect of the water uptake and the release of the bead contents. A bead geometry parameter was proposed as the ratio of the bead surface area to the volume of the internal liquid phase. This bead geometry parameter was measured as a function of time and fit to an equation using a computer curve-fitting technique. This equation was substituted into an existing drug release model to give a more appropriate mathematical model describing drug release from this system. The conclusion drawn from these results is that the influx of water during drug dissolution creates a progressive increase in the liquid phase within the nonpareil bead; this causes a corresponding increase in the bead surface area which influences the drug release rate.

Drug release from beads coated with an aqueous colloidal ethylcellulose dispersion, Aquacoat®, or an organic ethylcellulose solution

The objective was to investigate several factors (composition of the coating formulation, the type and pH of the release medium and curing conditions), which influence the drug release from beads coated with either the aqueous ethylcellulose dispersion, Aquacoat® or an organic ethylcellulose solution. The chlorpheniramine maleate release from Aquacoat®-coated beads was faster in pH 7.4 buffer than in 0.1 N HCl. Increasing the curing time and curing temperature decreased the drug release in pH 7.4 buffer but did not affect the release in 0.1 N HCl. In contrast, the drug release from beads coated with the ethanolic ethylcellulose solution was not affected by the curing step, the release medium or the addition of sodium lauryl sulfate. Scanning electron microscopy and contact angle measurements explained the release data. The differences in the drug release behavior of aqueous – and organic solvent – ethylcellulose – coated beads could be attributed to the differences in the film formation process.

Drug release from diffusion pellets coated with the aqueous ethyl cellulose dispersion aquacoat® ECD-30 and 20% Dibutyl Sebacate as plasticizer: partition mechanism and pore diffusion

The release of the hydrophilic etofylline and the lipophilic propyphenazone (octanol/water partition coefficient PC=0.35 and 119, respectively) from diffusion pellets coated with the aqueous ethyl cellulose dispersion Aquacoat® ECD-30 and 20% dibutyl sebacate (DBS) as plasticizer is investigated as a function of pH. The relatively slow release is not constant, due to the broad distribution of different release rates within the pellet population and the non-linearity of the release of each diffusion pellet itself. The release proceeds according to a partition mechanism at a pH<6. The partition mechanism is not influenced by the osmotic pressure difference between the release medium and the saturated solution within the diffusion pellets. The diffusion coefficients of different drugs in the plasticized coating are in the range 1 to 5×10 −8 cm 2/s. At a of pH>6 an additional hydrophilic pathway without partition exists if the diffusion pellets did not have any contact with an acidic medium. This is due to the strongly increased water uptake of more than 20% by the coatings as a consequence of the dissociation of carboxyl groups in the ethyl cellulose.

Controlled-Release Behavior of Diphenhydramine Hydrochloride Loaded Neutral Microgranules and Coated Using Ethylcellulose Water Dispersion

The development of a loading method of a water-soluble drug using aqueous binding solution to produce microgranules that were then coated with an aqueous ethylcellulose dispersion to sustain drug release is described. The results, in terms of drug used, showed that besides the fluidized bed parameters, the amount of drug dissolved in the binder solution plays an important role in obtaining a satisfying result during the spraying process. Thus, it seems necessary to determine the critical concentration above which the material started to adhere to the interior of the fluidization column, and the possibility of drug layering onto carrier material is aggravated. ANOVA of the time parameter for release of 63.2% of total drug (td) value showed significant influence of ethylcellulose (Aquacoat ECD-30) and dibutyl sebacate concentration on diphenhydramine hydrochloride (DPH) release. The dissolution rate decreased with an increase in polymer concentration. The diffusional exponent n of the Peppas equation indicated that the DPH release kinetic was non-Fickian but approached Fickian diffusion, particularly at higher coating levels.

Ibuprofen release kinetics from controlled-release tablets granulated with aqueous polymeric dispersion of ethylcellulose II: Influence of several parameters and coexcipients

The objective of this study was to investigate the mechanism of ibuprofen (IBF) release from tablets prepared by wet granulation method, using Surelease as a granulating agent. The influence of certain parameters such as the levels of Surelease solids content (SSC), pH of dissolution media, selected dissolution method, and agitation speed on the release profiles of IBF was investigated. The effect of partial replacement of lactose (primary excipient) by various coexcipients such as microcrystalline cellulose, starch, polyvinylpyrrolidone (PVP), sodium alginate, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethyl cellulose (CMC–Na) was also studied. Tablets prepared with surelease as a granulating agent were non-disintegrating and exhibited prolonged release rates as compared to control tablets. The release of IBF from the tablets appears to occur either via water-filled pores or by diffusion through membrane, depending on the levels of SSC. At higher SSC levels pH independent release profiles for IBF were achieved. Dissolution method and agitation speed exhibited no significant effect on the release profiles. All the coexcipients studied enhanced the release rates, irrespective of whether the coexcipients were water-soluble or water-insoluble.

Subchronic Oral Toxicity Study of Aquacoat ® ECD Ethylcellulose Aqueous Dispersion in the Rat

Groups of 20 male and 20 female Sprague–Dawley rats were administered undiluted Aquacoat ® ECD ethylcellulose aqueous dispersion by oral gavage at doses of 903, 2709 or 4515 mg/kg body weight/day (dry weight basis) for 90 days. Control animals received water at the same dosage volume as the high-dose group. Body weights and food consumption were recorded weekly. Blood was collected prior to study termination for haematology and clinical chemistry measurements. Survivors underwent complete necropsies on days 91–94. Selected organs were weighed and histologically examined. The only treatment-related clinical sign observed was pale faeces which was noted among males and females receiving 2709 and 4515 mg/kg/day Aquacoat ECD. No statistically significant differences in body weights, body weight gains, food consumption and organ weights were noted among males and females when compared with controls. No treatment-related effects in haematology parameters were noted. Significantly decreased total protein and globulin levels and increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in male rats receiving 2709 and 4515 mg Aquacoat ECD/kg/day were considered to be treatment related. No gross or microscopic lesions were attributed to Aquacoat ECD treatment. Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for female rats is in excess of 4515 mg/kg/day; the NOAEL for male rats is 903 mg/kg/day.