High-Throughput Evaluation of Non-Swellable Controlled Release Matrix Tablets

Abstract

Drug release from controlled-release (CR) matrix tablets involves the permeation and diffusion of water through the system. In this study, a new methodology is proposed for the measurement of water permeation and simultaneous drug release from the inert, non-swellable CR matrix tablet of diltiazem (DLT) and a correlation is made between these two processes. Cylindrical matrices were readily prepared by direct compression of pellets obtained by extrusion-spheronization. Water transport was studied using tritiated water (HTO) as a permeant in a Franz-diffusion cell and simultaneously drug release was measured. Further, dissolution was performed on USP XXI/XXII dissolution apparatus I using demineralized water. Matrices showed a steady water-uptake up to 6 h and the steady state for HTO permeation lasting from 6-h to 24-h Flux of water permeated and flux of drug released correlated well. Thus, HTO permeation through the matrix tablet and the proposed methodology can be used as a tool and/or surrogate marker for evaluation of controlled release matrix tablets. This methodology can be coined as “high-throughput” in terms of amount of labor and resources required in comparison to that of dissolution.     

Effect of Various Polymers on Formulation of Controlled Release (CR) Ibuprofen Tablets by Fluid Bed Technique

The need for controlled release (CR) formulations of ibuprofen tablet, is well recognized. Some such formulations have been marketed but in general only patented.

The purpose of this study was to develop an air suspension method, using a laboratory scale fluidized bed drier to coat the ibuprofen granules. Different polymers including, Eudragits L100, S100, RL100, RS100, L100+S100 (1:1), RL100+RS100 (1:1), ethyl cellulose (EC) and Eudragit RS100+EC (1:1) were utilized. The drug release medium consisted of buffer pH 1.2 for 1st 2h, buffer pH 4.5 for 2nd 2h and buffer pH 7.5 for remaining period of time in all experiments, but the release behaviour of the drug from some formulations was also studied using distilled water. Of the polymers investigated, Eudragit RS100, EC, Eudragit S100 and Eudragit RS100+EC (1:1) exhibited proper release characteristics when used as coating materials. The release patterns were analyzed from the standpoint of diffusion-controlled processes and as first-order kinetics.     

Effect of Various Polymers on Formulation of Controlled Release (CR) Ibuprofen Tablets by Fluid Bed Technique

Abstract

The need for controlled release (CR) formulations of ibuprofen tablet, is well recognized. Some such formulations have been marketed but in general only patented.

The purpose of this study was to develop an air suspension method, using a laboratory scale fluidized bed drier to coat the ibuprofen granules. Different polymers including, Eudragits L100, S100, RL100, RS100, L100+S100 (1:1), RL100+RS100 (1:1), ethyl cellulose (EC) and Eudragit RS100+EC (1:1) were utilized. The drug release medium consisted of buffer pH 1.2 for 1st 2h, buffer pH 4.5 for 2nd 2h and buffer pH 7.5 for remaining period of time in all experiments, but the release behaviour of the drug from some formulations was also studied using distilled water. Of the polymers investigated, Eudragit RS100, EC, Eudragit S100 and Eudragit RS100+EC (1:1) exhibited proper release characteristics when used as coating materials. The release patterns were analyzed from the standpoint of diffusion-controlled processes and as first-order kinetics.     

Factorial Design of Phenylpropanolamine Prolonged Release Tablets Formulations Using Fluid Bed Dryer Granulator

A two level factorial design approach was applied to the formulation of prolonged release phenylpropanolamine tablets using three factors: Ethylacrylate-methyl meth-acrylate co-polymer (Eudragit NE-40D) concentration, Microcrystalline cellulose (Avicel PH102) addition to the tablets formula, and the milling of the granulations before compression. The release rate of the drug was the measured parameter. The rate of drug release was mainly affected by the level of the Eudragit. Avicel promotes the release of the drug, specially at low Eudragit level concentrations. Tablets prepared from unmilled lots showed slower drug release than the corresponding lots of milled granules.     

A Process to Produce Effervescent Tablets: Fluidized Bed Dryer Melt Granulation

The purpose of the present study was to apply melt granulation in a fluidized bed dryer (fluidized bed dryer melt granulation) to manufacture one-step effervescent granules composed of anhydrous citric acid and sodium bicarbonate to make tablets. This study permitted us to establish that such process parameters as concentrations of polyethylene glycol (PEG) 6000, residence times in the fluidized bed dryer, fineness of PEG6000, fineness of initial mixture effervescent systems, and efficiency of two lubricants markedly affect some granule and tablet characteristics. It is a dry process that is simple, rapid, effective, economical, reproducible, and particularly adapted to produce effervescent granules that are easily compressed into effervescent tablets.     

Direct Compression Controlled Release Tablets Using Ethylcellulose Matrices

Controlled release erodible matrix tablets were manufactured by a simple, direct compression process using ethylcellulose alone as the matrix former. Each of four different viscosity grades of ethylcellulose (10, 20, 45 and 100 cp) was dry mixed with either indomethacin or theophylline and a small amount of lubricant, then directly compressed into tablets. In initial trials, compression force was held constant, resulting in tablets of varying hardness. In a second study, the compression force was varied to produce tablets of equal hardness. Lower viscosity grades of ethylcellulose were more compressible than higher viscosity grades, allowing production of harder tablets for a given drug. Harder tablets resulted in controlled release of the drug over a longer time period. Dissolution studies indicated that tablet hardness is more important in determining dissolution rate than is the polymer viscosity grade. A mathematical model combining diffusion and erosion mechanisms was developed to describe drug release. Improved r² values over pure diffusion, erosion and diffusion/relaxation models were obtained. Examination of residuals indicated that the derived composite model was more appropriate for the data     

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.     

Release of Acetazolamide from Swellable Hydroxypropylmethylcellulose Matrix Tablets

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.     

Evaluation of the Granulation of a Hydrophilic Matrix Sustained Release Tablet

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.     

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.     

Controlled Drug Release from a Compressed Heterogeneous Polymeric Matrix: Kinetics of Release

A physical model of a new matrix-type system is presented where constant drug release can be maintained irrespective of the extent of the tortuosity and receding drug boundary. Theophylline base was dispersed as discrete crystals and fine particles in a matrix formed by the cross-linking of polymeric mixtures consisting of PEG, acrylic resins and ethyl cellulose. DSC analysis was performed to identify any solid state inactivation of the drug. Concave tablets at specified pressures were prepared in order to achieve a wide range of release rates and patterns of release. It was found that the patterns of release could be controlled by the formulation components and the manufacturing procedures. Drug release rates were determined spectrophotometrically under sink conditions and the flux of drug release, dQ/dt, from these matrix-type delivery systems was almost constant over 15 hours, during which time about 85% of the active drug was released. The release rate was devoid of any hydrodynamic boundary effect and environmental pH. The cumulative amount of drug released was found to be in accordance with zero-order kinetics. The system can be modified within broad limits and have flexibility as well as a wide spectrum of applicability with respect to different types of drugs.     

Controlled Drug Release from a Compressed Heterogeneous Polymeric Matrix: Kinetics of Release

A physical model of a new matrix-type system is presented where constant drug release can be maintained irrespective of the extent of the tortuosity and receding drug boundary. Theophylline base was dispersed as discrete crystals and fine particles in a matrix formed by the cross-linking of polymeric mixtures consisting of PEG, acrylic resins and ethyl cellulose. DSC analysis was performed to identify any solid state inactivation of the drug. Concave tablets at specified pressures were prepared in order to achieve a wide range of release rates and patterns of release. It was found that the patterns of release could be controlled by the formulation components and the manufacturing procedures. Drug release rates were determined spectrophotometrically under sink conditions and the flux of drug release, dQ/dt, from these matrix-type delivery systems was almost constant over 15 hours, during which time about 85% of the active drug was released. The release rate was devoid of any hydrodynamic boundary effect and environmental pH. The cumulative amount of drug released was found to be in accordance with zero-order kinetics. The system can be modified within broad limits and have flexibility as well as a wide spectrum of applicability with respect to different types of drugs.     

Chitosan Matrix Tablets: The Influence of Excipients on Drug Release

Abstract

The influence of excipients on drug release from chitosan matrix tablets was investigated, using diltiazem hydrochloride as model drug. Tablets were prepared by direct compression and the effect of different concentrations of the excipients lactose, sodium lauryl sulphate, sodium alginate, carbopol 934, citric acid and hydroxypropylmethyl-cellulose on drug release profiles was studied. Sustained release of the drug was obtained in all cases but the results indicate that both type and amount of excipient used influences drug release rate. The results support the idea that chitosan can be suitable as a basis for sustained release matrix tablets, and that drug release rate can be influenced by the addition of excipients. It is possible to make use of the interaction between chitosan and excipients in the formulation to provide further prolongation of release.     

Chitosan Matrix Tablets: The Influence of Excipients on Drug Release

The influence of excipients on drug release from chitosan matrix tablets was investigated, using diltiazem hydrochloride as model drug. Tablets were prepared by direct compression and the effect of different concentrations of the excipients lactose, sodium lauryl sulphate, sodium alginate, carbopol 934, citric acid and hydroxypropylmethyl-cellulose on drug release profiles was studied. Sustained release of the drug was obtained in all cases but the results indicate that both type and amount of excipient used influences drug release rate. The results support the idea that chitosan can be suitable as a basis for sustained release matrix tablets, and that drug release rate can be influenced by the addition of excipients. It is possible to make use of the interaction between chitosan and excipients in the formulation to provide further prolongation of release.     

Preparation and In Vitro Evaluation of Controlled Release Hydrophilic Matrix Tablets of Ketorolac Tromethamine Using Factorial Design

Controlled release matrix tablets of ketorolac tromethamine (KT) were prepared by direct compression technique using cellulose derivatives as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC) in different concentrations (10–20%). The effect of polymer type and concentration was investigated on drug release by 2³ factorial design. For the quality control of matrix tablets, weight deviation, hardness, friability, diameter–height ratio, content uniformity of KT, and in vitro dissolution technique were performed. UV Spectrophotometric method was used to detection of KT in matrix tablets. This method was validated. Dissolution profiles of the formulations were plotted and evaluated kinetically. An increase in polymer content resulted with a slow release rate of drug as was expected. According to the dissolution results, tablets prepared with HPMC + HEC + CMC (F1 and F8) were found to be the most suitable formulation for KT. About 99.27% KT was released from F8 in 7 h.     

Controlled Release Salbutamol Sulphate Molded Tablets Using Eudragit Retard

Abstract

Permeable acrylic resins were used as efficient retarding materials to prepare controlled release salbutamol sulphate molded tablets. The formulation is simple, efficient, economic and is easily shaped into molded tablets. The effects of two types of acrylic resins, namely: Eudragit RL100 ad Eudragit RS100 in concentrations 1, 2 and 5% w/w on the physical characteristics as well as on the in vitro release patterns of salbutamol sulphate from molded tablets prepared with either polyethylene glycol (PEG) 4000 or 6000 were studied. It was revealed that, as the molecular weight of the PEG increased, the hardness of the tablets increased. Considerable retardation in the drug release was observed by using Eudragit RS100 as compared to Eudragit RL100. The formulation prepared with PEG 6000 and 5% Eudragit RS100 produced much more release time prolongation than the other tested formulations. On the other hand, tablets prepared by the direct compression technique produced a faster release of salbutamol sulphate than those prepared by molding.