Compressibility Characteristics of Matrices Prepared with Ethylcellulose Aqueous Dispersion

Granules of acetaminophen (APAP) and Lactose Fast Flo were prepared by wet granulation method using Surelease aqueous dispersion as a granulating liquid. Acetaminophen granules containing different total solids (from Surelease) were compacted into tablets using instrumented tablet press to investigate the effect of the levels of Surelease (total solids) on the compressional properties of various formulations. Measurements were made of their compressibility, force displacement, works and forces analysis during compaction. All formulations containing Surelease utilized the compaction energy better than formulations of the same composition prepared without Surelease. As the level of total solids from Surelease was increased in the formula, the compressibility characteristic was enhanced. Granules with Surelease exhibited better deformation and densification behaviors and gave tablets of better mechanical strength compared to control tablets.     

Compressibility Characteristics of Matrices Prepared with Ethylcellulose Aqueous Dispersion

Abstract

Granules of acetaminophen (APAP) and Lactose Fast Flo were prepared by wet granulation method using Surelease aqueous dispersion as a granulating liquid. Acetaminophen granules containing different total solids (from Surelease) were compacted into tablets using instrumented tablet press to investigate the effect of the levels of Surelease (total solids) on the compressional properties of various formulations. Measurements were made of their compressibility, force displacement, works and forces analysis during compaction. All formulations containing Surelease utilized the compaction energy better than formulations of the same composition prepared without Surelease. As the level of total solids from Surelease was increased in the formula, the compressibility characteristic was enhanced. Granules with Surelease exhibited better deformation and densification behaviors and gave tablets of better mechanical strength compared to control tablets.     

Continuous direct tablet compression: effects of impeller rotation rate,total feed rate and drug content on the tablet properties and drug release

Context: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages.

Objective: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process.

Materials and methods: The tablet formulations consisted of acetaminophen (3–30% (w/w)) pre-blended with 0.25% (w/w) colloidal silicon dioxide, microcrystalline cellulose (69–96% (w/w)) and magnesium stearate (1% (w/w)). The continuous tableting line consisted of three loss-in-weight feeders and a convective continuous mixer and a rotary tablet press. The process continued for 8?min and steady state was reached within 5?min. The effects of acetaminophen content, impeller rotation rate (39–254?rpm) and total feed rate (15 and 20?kg/h) on tablet properties were examined.

Results and discussion: All the tablets complied with the friability requirements of European Pharmacopoeia and rapidly released acetaminophen. However, the relative standard deviation of acetaminophen content (10% (w/w)) increased with an increase in impeller rotation rate at a constant total feed rate (20?kg/h). A compression force of 12?kN tended to result in greater tablet hardness and subsequently a slower initial acetaminophen release from tablets when compared with those made with the compression force of about 8?kN.

Conclusions: In conclusion, tablets could be successfully prepared by a continuous direct compression process and process conditions affected to some extent tablet properties.     

Formulation of Controlled Release Matrices by Granulation with a Polymer Dispersion

The objective of this work was to incorporate an ethylcellulose-based controlled-release coating suspension (Surelease, Colorcon) within a tablet matrix to provide a release controlling mechanism. Anhydrous theophylline, chlorpheniramine maleate, and acetaminophen were selected as model drug entities. Surelease dispersion was incorporated as the granulating agent either to the drug entity alone or to a blended mixture of drug and filler. Control batches included simple aqueous granulations and direct compression mixtures. Tablets were prepared on a single stroke tablet press. Dissolution was performed by the USP Method I (rotating basket) in purified water for the granulations and the resulting tablets. The uncompressed granulations did not exhibit prolonged release. In general, tablets prepared with the polymer suspension as the granulating agent were non-disintegrating, and exhibited slower dissolution than the control tablets. Release profiles were affected by drug concentration and excipient levels. By the dissolution method selected, complete drug release for the various formulations ranged from less than 1 hour to greater than 12 hours. The use of the polymer dispersion appears to enhance the processing characteristics of some materials, and to provide the formulator with control over drug release.     

Surelease as granulating liquid in preparation of sustained release matrices of ethylcellulose and theophylline

Objectives: Use of Surelease as a granulation liquid in preparation of granules and matrices of theophylline and ethylcellulose was evaluated.

Materials and methods: Physical mixtures (at 1:1 or 1:1.5 drug:polymer) were granulated using water, Surelease or diluted Surelease as granulating liquid. The granule characteristics (shape, size, flow rate, mechanical properties, friability and release profile) were studied. Afterwards, matrices were manufactured and their crushing strengths, friability and release profiles were determined.

Results: Granulation produced agglomerated particles with better flowability than physical mixtures. Change of granulation liquid from water to Surelease or diluted Surelease led to the marginal increase in size of granules at 1:1 drug:polymer, however, the flow rate and Carr’s index were considerably improved. The hardness, elastic modulus, friability and rate of drug release were not affected by granulation liquid. Increase in polymer content resulted in reduction in size of granules, flow rate, elastic modulus and rate of drug release. However hardness of the granules was unaffected. Granulation process and granulation liquid did not affect the hardness, and dissolution rate of matrices at 1:1 drug:polymer, while the use of Surelease or diluted Surelease as a granulating liquid, increased the hardness and decreased drug release rate at 1:1.5 drug:polymer. Matrices prepared from Surelease or diluted Surelease showed similar characteristics.

Conclusions: Surelease is a suitable granulating liquid for preparation of ethylcellulose matrices especially when high amount of polymer is used and could not only improve the flow and compatibility of the granules, but also help in reducing the rate of drug release.     

Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--Part II theophylline and cimetidine

The purpose was to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit RS 30D were developed and beads were produced by extrusion-spheronization. Drug beads were coated using 15% wt/wt Surelease or Eudragit NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm(3) and size of 855 mum were quite close to Surelease-coated drug beads. Curing improved the crushing strength and friability values for theophylline tablets containing Surelease-coated beads; 5.7 +/- 1.0 kP and 0.26 +/- 0.07%, respectively. Dissolution profiles showed that the EC matrix only provided 3 h of drug release. Although tablets containing Surelease-coated theophylline beads released drug fastest overall (t(44.2%) = 8 h), profiles showed that coating damage was still minimal. Size and density differences indicated a minimal segregation potential during tableting for blends containing Surelease-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.     

Controlled-Release Matrix of Acetaminophen-Ethylcellulose Solid Dispersion

Abstract

In this study ethylcellulose was evaluated as a carrier for preparation of prolonged release acetaminophen tablets. Solid dispersions containing three levels of ethylcellulose and acetaminophen (1:3; 1:1; 3:1) were prepared by the solvent method. Also physical mixtures at the same level of ethylcellulose and acetaminophen were prepared. Systems composed of solid dispersion or physical mixture containing the equivalent weight of 50 mg acetaminophen, Lactose fast-flo as diluent and 1% magnesium stearate as lubricant were compressed into tablets and tested for dissolution. The dissolution data showed that the drug release decreased as the level of ethylcellulose increased in the solid dispersion formulations. The drug release from tablets prepared with solid dispersion followed the diffusion controlled model for inert porous matrix, while the drug release from tablets prepared with physical mixture followed the first-order kinetic model.     

Controlled-Release Matrix of Acetaminophen-Ethylcellulose Solid Dispersion

In this study ethylcellulose was evaluated as a carrier for preparation of prolonged release acetaminophen tablets. Solid dispersions containing three levels of ethylcellulose and acetaminophen (1:3; 1:1; 3:1) were prepared by the solvent method. Also physical mixtures at the same level of ethylcellulose and acetaminophen were prepared. Systems composed of solid dispersion or physical mixture containing the equivalent weight of 50 mg acetaminophen, Lactose fast-flo as diluent and 1% magnesium stearate as lubricant were compressed into tablets and tested for dissolution. The dissolution data showed that the drug release decreased as the level of ethylcellulose increased in the solid dispersion formulations. The drug release from tablets prepared with solid dispersion followed the diffusion controlled model for inert porous matrix, while the drug release from tablets prepared with physical mixture followed the first-order kinetic model.     

In-Vitro Release of Acetaminophen from Sodium Alginate Controlled Release Pellets

The production of spheres loaded with acetaminophen by the cross linking technique was achieved. The hydrophilic polymer sodium alginate which gels in presence of a cross linking ion was used as a matrix for the spheres production. Two processing variables were studied. The drug load in the formula which varied from 5% w/v to 20% w/v, and the cross linking agents used; calcium chloride, calcium acetate, and aluminum sulfate. Also the effects of the dissolution medium and the rotational speed of the dissolution apparatus on drug release were investigated. Spheres were compacted into 450 mg tablets without the aid of excipients. The drug release from spheres containing 20% w/v drug was 90% after 6 hours, while the drug release from compacts of these spheres was 90% after 12 hours. The mechanism of drug release from spheres and compacts containing 20% w/v drug and prepared with 5% w/v cross linking material     

In-Vitro Release of Acetaminophen from Sodium Alginate Controlled Release Pellets

Abstract

The production of spheres loaded with acetaminophen by the cross linking technique was achieved. The hydrophilic polymer sodium alginate which gels in presence of a cross linking ion was used as a matrix for the spheres production. Two processing variables were studied. The drug load in the formula which varied from 5% w/v to 20% w/v, and the cross linking agents used; calcium chloride, calcium acetate, and aluminum sulfate. Also the effects of the dissolution medium and the rotational speed of the dissolution apparatus on drug release were investigated. Spheres were compacted into 450 mg tablets without the aid of excipients. The drug release from spheres containing 20% w/v drug was 90% after 6 hours, while the drug release from compacts of these spheres was 90% after 12 hours. The mechanism of drug release from spheres and compacts containing 20% w/v drug and prepared with 5% w/v cross linking material     

Development and In-Vitro Characterization of Sustained-Release Acetaminophen Tablets

Abstract

The objective of this study was to evaluate powdered lipids as both granulating agents and retardants in formulated sustained-release acetaminophen tablets. Castor Wax or Durkee 07 powders were premixed with acetaminophen and granulated with boiling water. After cooling, the mass was screened to obtain a 10/20 mesh fraction which was used for tablet production and evaluation. Friability, hardness, dissolution and compression profiles were monitored. As lipid content increased from 5-15% w/w, friability and hardness also increased. Dissolution showed an inverse relationship between level of lipid and release rate. Compression profiles demonstrated good transmission when Castor Wax was employed. This study demonstrated that a high milligram potency tablet could be fabricated with low levels of lipid, to retard drug release, without significantly increasing tablet weight and size.     

Preparation of ethyl cellulose pseudolatex and studies on suitability of it as a binder for granulation

Ethyl cellulose pseudolatices were prepared by an emulsion-solvent evaporation technique, which consisted of dissolving the polymer in a blend of benzene and ethyl alcohol, followed by the addition of adjuvants. The organic, solvents were removed from the emulsion using vacuum distillation. Physical evaluation of the dispersions and the cast films was carried out.

On the basis of characteristics of cast films selected formulations were fused as granulating agents for preparing chlorpheniramine maleate tablets. Good correlation was observed between total solid in the granulating dispersion and the drug release. The possible mechanisms for the drug release from the tablets are suggested.     

Study of Drug Release from Pellets Coated with Surelease Containing Hydroxypropylmethylcellulose

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.     

Study of Drug Release from Pellets Coated with Surelease Containing Hydroxypropylmethylcellulose

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.     

Eudragit(®) RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets

The influence of plasticizer level, roll pressure and sintering temperature was investigated on the granule properties, tablet breaking force and theophylline release from tablets. Nine formulations using theophylline as a model drug, Eudragit(?) RL PO, Eudragit(?) RS PO, or both as a matrix former and triethyl citrate (TEC) as a plasticizer were prepared. The formulations were roller compacted and the granules obtained were evaluated for particle size distribution and flowability. These granules were compacted into tablets at a compression force of 7?kN. The tablets were thermally treated at different temperatures (50 and 75°C) for 5?h and were evaluated for breaking force and dissolution. Increase in roll pressure and TEC levels resulted in a progressive increase in the mean particle size of the granules. The flowability of the granules also improved with increasing roll pressures and TEC levels. Tablet breaking force increased with an increase in TEC levels and sintering temperatures. But these effects were significant only at the highest level of plasticizer and sintering temperature respectively. For the tablets containing Eudragit(?) RS PO, theophylline release decreased proportionately with increase in TEC levels and sintering temperatures. Tablets containing either Eudragit(?) RL PO or a mixture of RS PO and RL PO failed to impart an extended-release property to the tablets at the studied variables i.e. roll pressure, TEC levels and sintering temperature. It was clearly demonstrated that with suitable optimization of these parameters, the release-rate of a water soluble drug from the matrix tablets prepared via roller compaction can be finely controlled.     

Evaluation of Ethylcellulose as A Matrix for Prolonged Release Formulations. I. Water Soluble Drugs: Acetaminophen and Theophylline

In this study ethylcellulose was evaluated as a carrier for the preparation of prolonged release solid dispersions of relatively water soluble drugs, acetaminophen and theophylline. The solid dispersions containing various concentrations (7.5, 15.0 and 30.0 % by weight of drug) of ethylcellulose of different viscosity grades (21, 95, 209 and 350 cps) were prepared by the solvent method. The concentration of polymer in the formulation was the determining factor in controlling release rate of the drug, as the results indicate prolongation in release of the drug with increase in amount of ethylcellulose. The higher the viscosity grade of ethylcellulose, slower the release of drug from the solid dispersions. The release of drug from the tablets was more prolonged compared to the granular solid dispersions. In vitro release of acetaminophen and theophylline was more or less similar in both dissolution media. The viscosity grade of ethylcellulose showed slight influence on the release rate of drug from the tablet formulations, while it was quite noticeable in granular solid dispersions.     

Evaluation of Ethylcellulose as A Matrix for Prolonged Release Formulations. I. Water Soluble Drugs: Acetaminophen and Theophylline

Abstract

In this study ethylcellulose was evaluated as a carrier for the preparation of prolonged release solid dispersions of relatively water soluble drugs, acetaminophen and theophylline. The solid dispersions containing various concentrations (7.5, 15.0 and 30.0 % by weight of drug) of ethylcellulose of different viscosity grades (21, 95, 209 and 350 cps) were prepared by the solvent method. The concentration of polymer in the formulation was the determining factor in controlling release rate of the drug, as the results indicate prolongation in release of the drug with increase in amount of ethylcellulose. The higher the viscosity grade of ethylcellulose, slower the release of drug from the solid dispersions. The release of drug from the tablets was more prolonged compared to the granular solid dispersions. In vitro release of acetaminophen and theophylline was more or less similar in both dissolution media. The viscosity grade of ethylcellulose showed slight influence on the release rate of drug from the tablet formulations, while it was quite noticeable in granular solid dispersions.     

Preparation and In-Vitro Evaluation of Prolonged Release Tablets of Pheniramine Aminosalicylate

Prolonged release tablets of pheniramine aminosalicylate were prepared from co-precipitates of the drug in different types of Eudragit. The hardness of the tablet had a pronounced effect on the release rate of the drug. Tablets (500 mg, hardness 13 kg) and 375 mg tablets (hardness 6.5 kg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100, and 20% of the drug in Eudragit S 100 respectively, showed release rate patterns that were in agreement with Lang primary requirements for drug release from sustained release tablets.

Tablets (500 mg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100 or Eudragit S 100 and 375 mg tablets containing 20% of the drug in Eudragit S 100 showed release rate patterns that were best described by Higuchi equation, indicating that a diffusion controlled mechanism was mainly operative.     

Eudragit® RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets

The influence of plasticizer level, roll pressure and sintering temperature was investigated on the granule properties, tablet breaking force and theophylline release from tablets. Nine formulations using theophylline as a model drug, Eudragit^® RL PO, Eudragit^® RS PO, or both as a matrix former and triethyl citrate (TEC) as a plasticizer were prepared. The formulations were roller compacted and the granules obtained were evaluated for particle size distribution and flowability. These granules were compacted into tablets at a compression force of 7?kN. The tablets were thermally treated at different temperatures (50 and 75°C) for 5?h and were evaluated for breaking force and dissolution. Increase in roll pressure and TEC levels resulted in a progressive increase in the mean particle size of the granules. The flowability of the granules also improved with increasing roll pressures and TEC levels. Tablet breaking force increased with an increase in TEC levels and sintering temperatures. But these effects were significant only at the highest level of plasticizer and sintering temperature respectively. For the tablets containing Eudragit^® RS PO, theophylline release decreased proportionately with increase in TEC levels and sintering temperatures. Tablets containing either Eudragit^® RL PO or a mixture of RS PO and RL PO failed to impart an extended-release property to the tablets at the studied variables i.e. roll pressure, TEC levels and sintering temperature. It was clearly demonstrated that with suitable optimization of these parameters, the release-rate of a water soluble drug from the matrix tablets prepared via roller compaction can be finely controlled.     

Formulation and stability evaluation of ketoprofen sustained-release tablets prepared by fluid bed granulation with Carbopol 971P solution

The objectives of the present study were: (1) to investigate the possibility of using a Carbopol polymeric solution as granulating agent by the fluid bed granulating process; (2) to select a suitable method of tabletting for sustaining the release of ketoprofen for 12 hr; (3) to perform stability studies according to International Committee on Harmonization (ICH) guidelines and photostability on ketoprofen SR tablets; (4) to study the influence of the storage conditions on release kinetics and melting endotherm of ketoprofen; and (5) to predict the shelf-life of the ketoprofen SR tablets. Tabletting ingredients were ketoprofen, anhydrous dicalcium phosphate, Carbopol® 971P, talc, and magnesium stearate. Carbopol® 971P solution (0.8% w/v) was used as a granulating solution in the fluid bed granulator. For comparative evaluation, tablets were also prepared by direct compression and wet granulation, and subjected to dissolution. Tablets prepared by fluid bed granulation technique were stored in incubators maintained at 37, 40, 50, and 60°C, 40°C/75% RH, 30°C/60% RH, and 25°C/60% RH, and in a light chamber with light intensity of 600 ft candle at 25°C. Melting endotherms were obtained for the drug as well as the tablets during stability studies by differential scanning calorimetry. Tablets prepared by fluid bed granulation technique prolonged the release of ketoprofen better than tablets obtained by direct compression and wet granulation. Further, it complied with the requirements of ICH guidelines for stability testing. Higher temperature and humidity (40 ± 2°C/75% RH, 40°C, 50°C, and 60°C) adversely affected the rate and extent of the dissolution. Ketoprofen SR tablets stored in amber-colored bottles demonstrated a good photostability for 6 months at 600 ft candle. The shelf-life of the formulation was predicted as 32 months.