Optimization of Slow-Release Tablet Formulations Containing Montmorillonite II. Factors Affecting Drug Release

The influence of electrolytes, surfactants in the dissolution medium, and particle size of drug and montmorillonite on the in vitro release of the soluble model drug sodium sulfathiazole from directly compressed slow-release tablets containing 20% drug and 30% magnesium aluminum silicate was investigated. The presence of electrolytes in the dissolution media decreased the release from the tablets. A decrease in release was also observed in deionized water when sodium chloride was included in the tablet formulation. The surface tension of the media appeared to have little influence on the dissolution rate of the drug. Varying the particle size of the drug had a greater effect on release rates than varying the particle size of the montmorillonite clay.     

Soluble filler as a dissolution profile modulator for slightly soluble drugs in matrix tablets

The purpose of this experimental work was the development of hydrophilic–lipophilic matrix tablets for controlled release of slightly soluble drug represented here by diclofenac sodium (DS). Drug dissolution profile optimization provided by soluble filler was studied. Matrix tablets were based on cetyl alcohol as the lipophilic carrier, povidone as the gel-forming agent, and common soluble filler, that is lactose or sucrose of different particle size. Physical properties of tablets prepared by melt granulation and drug release in a phosphate buffer of pH 6.8 were evaluated. In vitro studies showed that used filler type, filler to povidone ratio and sucrose particle size influenced the drug release rate. DS dissolution profile could be changed within a wide range from about 50% per 24 hours to almost 100% in 10 hours. The release constant values confirmed that DS was released from matrices by the diffusion and anomalous transport. The influence of sucrose particle size on the drug release rate was observed. As the particle size decreased, the drug release increased significantly and its dissolution profile became more uniform. Soluble fillers participated in the pore-forming process according to their solubility and particle size. Formulations containing 100 mg of the drug, 80 mg of cetyl alcohol, 40 mg of povidone, and 80 mg of either lactose or sucrose (particle size 250–125 μm) were considered optimal for 24-hour lasting dissolution of DS.     

Effect of Formulation Variables on Dissolution Profile of Diclofenac Sodium from Ethyl- and Hydroxypropylmethyl Cellulose Tablets

Abstract

The effects of formulation variables on the release profile of diclofenac sodium from ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC) matrix tablets were investigated. With increase in viscosity of ethyl cellulose used in nonaqueous granulation, a decrease in drug release from the tablets was observed, while the percentage of fines articles passed through 60 mesh) in the granulation had a significant effect on the dissolution profile. Granules containing 15% fines exhibited slow release of the drug in comparison to those containing 30% fines with EC matrices. An analysis of kinetics of drug release from hydrophobic EC matrix showed Fickian diffusion regulated dissolution. Drug release from HPMC tablets followed an apparent zero-order kinetics.     

Some Factors Influencing the Release of Drdg from Nondisintegrating Slow Release Tablets

Abstract

The purpose of this study was to investigate some factors that control the drug release from non disintegrating cylindrical slow release tablets using sodium salicylate as a model drug. The in vitro release of sodium salicylate was described adequately by a previously published cubic equation. It was found that the release of the drug from a nondisintegrating tablet is controlled by the factors such as porosity (e) of the tablet and the mass of drug present (A) per unit tablet volume. On the other hand, pH of the dissolution fluid had no influence on the release of sodium salicylate.     

The Effect of the Wet Granulation Process on Drug Dissolution

Abstract

Wet granulation can be an important processing step for pharmaceutical solid dosage forms. In this investigation emphasis was directed towards the influence of a “simple” wet granulation process on drug release from granules and their resulting tablets. Direct compression blends of the same materials were used as controls. Binary mixtures containing a 5% level of either theophylline, hydrochlorothiazide or chlorpheniramine maleate in microcrystalline cellulose or lactose were granulated with water. Experimentally, the powders were dry blended in a planetary mixer, wet granulated, and subsequently wet milled and dried. No dry milling step was included. Granule characterization consisted of particle size, density, porosity, compression and dissolution testing. Dissolution results varied with the drug, as expected, and dissolution at 10 minutes ranged from 35 to 95 % release. In general, however, the results indicate that dissolution from granules and the corresponding direct compression blend are similar. Although differences in compressibility were observed in the systems studied, granulation was not found to be detrimental to drug release.     

Release of Acetazolamide from Swellable Hydroxypropylmethylcellulose Matrix Tablets

Abstract

Controlled-release swellable tablets were prepared by a simple direct compression process using hydroxypropylmethylcellulose (HPMC) as the matrix former. The effects of the viscosity and concentration of the polymer and the pH of the dissolution medium on the release behavior of acetazolamide were investigated. The influence of the drug particle size was also evaluated. Ten, 15, 20, and 25% of two different viscosity grades of HPMC were dry mixed with acetazolamide, Fast Flo Lactose, and magnesium stearate, then directly compressed into tablets. The experimental tablets were tested for their drug contents, weight variations, and hardnesses. Dissolution tests were carried out under sink conditions at three different pH values: pH 1.2, 5.4, and 7.4. Release rate data were evaluated according to the equation log M/M_w = log k + n log t.     

Effect of Particle Size and Excipients on the Dissolution Rate of Metronidazole from Solid Dosage Forms: II

Abstract

In-vitro dissolution tests were carried out with tablets prepared from different particle size ranges of metronidazole. Influence of tablet binding agents (Methylcellulose, polyvinyl pyrrolidone - (PVP), potato starch and gelatin) on the drug release were investigated under similar conditions. Comprimates containing PVP and drug with particle size 1.75 μm (in lactose mixture) gave optimum results. These findings may open new ways of formulating a metronidazole tablet exhibiting improved drug - liberation, subsequently with a better bioavailability than the KUON^R-Tablet manufactured in Hungary.     

Development of Sustained-Release Tablets Containing Sodium Valproate: In Vitro and In Vivo Correlation

ABSTRACT

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

Fast- and Slow-Release Tablets for Oral Administration of Flavonoids: Rutin and Quercetin

ABSTRACT

Many derivatives of rutin (Rt) and its metabolite quercetin (Q) are employed in clinics for cardiovascular chronic pathology, and are also known for their antiulcer behavior in vivo and antiproliferative and antimutagenic activity in vitro. Unfortunately, the absorption of quercetin and rutin from the gastrointestinal tract is slow and irregular, probably due to their very slight solubility in water and slow dissolution rate.

In this work the dissolution rate of the drugs from oral formulations has been improved using some enhancers such as cross-linked sodium carboxymethylcellulose (CMC-XL), sodium carboxymethylstarch (E), and cross-linked polyvinylpyrrolidone (P). The drugs were loaded on the hydrophilic carriers by different techniques such as mixing or co-milling. The in vitro dissolution profiles of the mixed or co-milled drug/polymer systems, obtained in various media with different pH, were compared. The results show that the drug dissolution rate from the co-milled drug/carrier systems is faster than that from mixed systems, and CMC-XL and sodium carboxymethylstarch systems are able to enhance the dissolution rate. For this reason, these co-milled drug/carrier systems were used for the production of both fast- and slow-release tablets. The co-milled drug/CMC-XL system was used for the preparation of fast-release tablets containing rutin, while three different fast-release tablets were formulated and tested using respectively Q/CMC-XL, Q/E, and Q/P co-milled systems.

The effect of the presence of sodium lauryl sulfate in the aqueous medium on the dissolution profile of flavonoids alone was also studied.

The prolonged-release formulations have been developed using hydroxypropylmethylcellulose (HPMC) of different viscosity grades as retarding polymer. An extended release of the drugs for times ranging from 6 to 14 hr could be obtained, depending on the type and viscosity of the HPMC used.     

The Production and Evaluation of Orally Administered Insulin Nanoparticles

Abstract

Wet granulation of a hydrophilic sustained release matrix tablet formulation has been studied. A fractional factorial experimental design was employed to identify principal influences and interacting factors from the following : granulation fluid volume, mixing time, mixer speed and inclusion of a wet screening step. Fluid volume and mixing time were primary factors affecting mean granule size. Fines in the granulation were reduced at higher fluid levels and by inclusion of a wet screening operation. There were several interacting factors influencing the particle size properties of the granulation. The factors studied had little influence on the bulk density of the granulation.

The influence of granule mean particle size on flow, compressibility and drug release from finished tablets was evaluated. Flow and compressibility were influenced by granule properties and the data generated suggested that should final tablet properties deteriorate on scale up it may be possible to ameliorate the effect by modification of granulation fluid volume or mixing time or both.

The factors studies had no influence on release of drug from finished tablets.     

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     

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.     

Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Abstract

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50–75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Using the Percolation Theory to Explain the Release Behavior from Inert Matrix Systems

Abstract

A novel analysis of drug release process from binary matrix systems has been realized and a study of the initial stage of the process has been carried out. A fast and easy technique has allowed the acquisition of one experimental datum per second. Release data have been analyzed by means of a detailed statistical study. The dissolution profiles were studied applying different kinetic models (zero order, logarithmic, and Higuchi equation). In all the cases studied, a starting process of zero or first order, indicative of a surface-dependent mechanism, has been found. Then, a parameter, named as critical time of kinetic change (t_c), has enabled the authors to establish the instant at which a diffusion release mechanism, according to Higuchi equation, is consolidated. From this time until the end of the process, release mechanism of matrices was shown to be diffusion controlled. The influence of the drug loading and the particle size over the release properties of tablets has also been investigated and it has been evaluated on the basis of percolation theory. The results show a major significance of particle size over the initial drug release and a decrease of its influence along the time. On the other hand, the drug loading variable shows an important influence over the release properties along the whole process.     

Dissolution Characteristics of Polycaprolactone-Polylactide Microspheres of Chlorpromazine

Abstract

Studies were conducted on the preparation of controlled release polycaprolactone-polylactide microcapsules of chlorpromazine and on release of the drug from the microcapsules in pH 7.0 buffer medium. A wide range of release rates of the drug was obtained by simple change in the polymer system. Chlorpromazine was released from the microspheres in a biphasic manner consisting of an initial fast release phase followed by a slow-release phase. Increasing the drug content increased the initial drug release rate but no significant drug loading effect on the second stage dissolution rate was noted. There was no significant effect of particle size on the drug release rate from the microspheres. The swelling property of the microspheres and the agglomerate nature of the sieve fractions may complicate the drug release kinetics and obscure the particle size effect on dissolution rate.     

Solid Dispersion Controlled Release: Effect of Particle Size,Compression Force and Temperature

Abstract

Solid dispersions are dynamic systems, a careful control of processing variables is required to produce desired physicochemical properties of these systems.

The influence of drug particle size, dispersion temperature and compression force on the release rate of theophylline from solid dispersed system tablets was studied. Theophylline base (micronized and granulate) were embedded into a polymeric mixture of PEG and acrylic/methacrylic esters at controlled temperature and shock cooled. Tablets were made at two compressional forces and drug release was measured spectrophotometrically over a period of fifteen hours.

The release rate of drug dispersed in these insoluble matrices was independent of particle size but not of hardness.

However, variations in ratios of polymeric mixture and dispersion temperature controls the drug release rate from inert matrix more effectively than such factors as drug particle size and lower range of tablet hardness. The fast cooling produced excellent reproducibility of drug content throughout the entire entrapment product. X-ray diffraction study demonstrated no changes in crystalline form of theophylline.     

Evaluation of the Flow-Through Cell Dissolution Apparatus: Effects of Flow Rate,Glass Beads and Tablet Position on Drug Release from Different Type of Tablets

Abstract

Several factors affecting the dissolution performance of various solid dosage forms tested using the flow-through cell method have been evaluated in this study. These factors include the flow rate, the position of tablets in the flow through cell and the glass beads, as well as the physical properties of the dosage forms. The experimental results indicated that the flow rate through the cell greatly affects drug release from disintegrating tablets. Drug release increases with increasing the flow rate of the dissolution medium, as expected. However, the flow rate does not significantly influence drug release from tablets which are not disintegratable, for example, an erodible tablet. The position of the tablets in the flow cell without glass beads is also of importance. Drug release from horizontally positioned tablets is different from vertically positioned tablets in the flow-through cell. It was also observed that the use of glass beads in the flow cell can make the flow pattern more laminar. This may help avoid a turbulent agitation within the cell, which could impact on drug dissolution.     

Preparation and Evaluation of Controlled Release Propranolol Hydrochloride Beads

Abstract

Conventional pan coating method was utilized to prepare propranolol-HCl sustained release coated beads. Eudragit RS 100 was used as release controlling materials. Overcoating of the beads with beeswax was also investigated. The beads were characterized for their particle size distribution, drug loading efficiency and their dissolution behaviour in 0.1N HCl, Most of the finished beads (72.4%) fall in the particle size range 800–1700 um. The actual drug content, calcu-lated as opposed to the theoretical drug content were 77.6% and 74.2% of the drug for the beads having particle size range 1700–1250 um and 1250–800 um respectively, The coating level of the polymer, the particle size of the beads and overcoating with beeswax play a major role in determining the release rate of the drug from the coated beads.     

Effect of Storage Conditions on the Hardness,Disintegration and Drug Release from Some Tablet Bases

Abstract

The effect of storage at relatively high temperature and humidity on tablets prepared from different bases was studied for up to eight weeks. Drug release from tablets was followed by measuring the concentration of a marker (amaranth) in the dissolution medium. Lactose and mannitol based tablets showed an increase in hardness and disintegration time, and a decrease in the initial rate of drug release. Sorbitcl based tablets, stored under 50°C/50% relative humidity (R.H.), showed a decrease in hardness and slower disintegration and dissolution. When stored under 40°C/90% R.H., the tablets were completely deformed within three days. Tricalcium phosphate and cellulose-based tablets did not show any storage related changes in hardness, disintegration or drug release.     

Formulation and in Vitro and in Vivo Availability of Diclofenac Sodium Enteric-Coated Beads

Abstract

Diclofenac sodium enteric-coated beads were prepared using the conventional pan coating technique. Eudragit L₁₀₀ was used as a pH-dependent release-controlling polymer. The beads were evaluated for their particle size distribution, drug loading efficiency, flowability, in vitro release in 0.1 N HCI (pH 1.2) and phosphate buffer (pH 6.8), and bioavailability in beagle dogs relative to the commercial enteric-coated tablets Voltaren®. The beads showed a narrow particle size distribution in which 83% of the beads were in the range of 1-2 mm. The actual yield of the beads was 90.5% and their drug loading was 92%. The beads released about 8% of the drug during 2 hr of dissolution in 0.1 N HCI, and the commercial tablets released no drug. In phosphate buffer (pH 6.8) both formulations released their drug content in 1 hr. Both formulations are, therefore, in compliance with the USP requirements for release from enteric-coated dosage forms.

The in vivo availability study in six beagle dogs revealed that the formulated enteric-coated beads filled in hard gelatin capsules had a 197.54% bioavailability relative to that of the commercial Voltaren tablets. The tablets showed a significantly lower (p < 0.05) area under curve for 0—8 hr (AUC_{0-8 hr}) of 13.44 ± 15.02 μg hr/ml compared to 26.55 ± 5.19 μg hr/ml for the capsules. The capsules showed a nonsignificantly (p > 0.05) higher peak plasma concentration (C^max) of 6.77 ± 0.67 μg/ml compared to 5.88 ± 7.38 μg/ml for the tablets. The time to reach peak (T_max) values were 2 ± 1.48 and 2.25 ± 1.08 hr for the capsules and tablets, respectively. The capsules showed less interdog variability with respect to C_max (CV% 34.6) and AUC (CV% 19.55) compared to CV% 79.9 and 111.76, respectively, for the commercial tablets