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

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.     

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.     

Effect of Processing on Release from an Inert,Heterogeneous Matrix

Abstract

Matrixes containing 40% ephedrine hydrochloride and hydrogenated castor oil are prepared by two processes: (a) compression of a physical mixture and (b) compression of a congealed melt. The release from the melt matrix is slower than from the matrix prepared by compression of a physical mixture. applied pressure on the release profile is studied. For matrixes prepared by both processes as the applied pressure is increased, the release rate is slower; however, this effect is more pronounced for the physical mixture matrix. The effect of comminution of the medicinal compound on release profile is considered. mixture the fastest release occurs from the finer particles suggesting a boundary layer diffusion. In matrixes produced by the melt process as the particle size is decreased, the release is slowed presumably because of an increased tortuosity and more intimate contact between the ephedrine hydrochloride and the hydrogenated castor oil, which produces mass transfer by matrix diffusion.     

Effect of Processing on Release from an Inert, Heterogeneous Matrix

Matrixes containing 40% ephedrine hydrochloride and hydrogenated castor oil are prepared by two processes: (a) compression of a physical mixture and (b) compression of a congealed melt. The release from the melt matrix is slower than from the matrix prepared by compression of a physical mixture. applied pressure on the release profile is studied. For matrixes prepared by both processes as the applied pressure is increased, the release rate is slower; however, this effect is more pronounced for the physical mixture matrix. The effect of comminution of the medicinal compound on release profile is considered. mixture the fastest release occurs from the finer particles suggesting a boundary layer diffusion. In matrixes produced by the melt process as the particle size is decreased, the release is slowed presumably because of an increased tortuosity and more intimate contact between the ephedrine hydrochloride and the hydrogenated castor oil, which produces mass transfer by matrix diffusion.     

Studies on Sustained Release IV: Inert Matrix Tablets of Sulfamethizole, Employing Pdlyvinyl Chloride and Carboxypolymethylene

An inert matrix type sulfamethizole sustained release dosage form is attempted, using polyvinyl chloride and carboxypolymethylene. The release obtained with the flow -through cell is lower than the target profile. With the rotating bottle apparatus, higher release rates were obtained, but based upon our previous findings, the latter method is considered not to be very realistic.

Upon the kinetic assessment of dissolution data, zero order, first order and Hixson-Crowell kinetics were found to give similar fits.     

Channeling Agent and Drug Release from a Central Core Matrix Tablet

A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance-polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates.     

Channeling Agent and Drug Release from a Central Core Matrix Tablet

A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance–polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates.     

Matrix Type Tablet Formulation for Controlled Release of Highly Water Soluble Drugs

Matrix type formulations with dicalcium phosphate dihydrate (DCPD) using a polymeric binder (Eudragit RSPM®) to obtain controlled release of highly water soluble drugs has been investigated.

The drug, DCPD and Eudragit RSPM® were granulated using isopropyl alcohol with and without a plasticizer (Diethyl phthalate, DEP). Addition of Eudragit did not appear to affect the release profile. However, addition of a plasticizer had a significant effect on the rate of release. The release appears to follow first order kinetics and the rate constant decreased linearly with increasing DEP concentration.

A directly compressible mixture was also formulated by coating DCPD particles with DEP with and without Eudragit RSPM®.     

Matrix Type Tablet Formulation for Controlled Release of Highly Water Soluble Drugs

Matrix type formulations with dicalcium phosphate dihydrate (DCPD) using a polymeric binder (Eudragit RSPM®) to obtain controlled release of highly water soluble drugs has been investigated.

The drug, DCPD and Eudragit RSPM® were granulated using isopropyl alcohol with and without a plasticizer (Diethyl phthalate, DEP). Addition of Eudragit did not appear to affect the release profile. However, addition of a plasticizer had a significant effect on the rate of release. The release appears to follow first order kinetics and the rate constant decreased linearly with increasing DEP concentration.

A directly compressible mixture was also formulated by coating DCPD particles with DEP with and without Eudragit RSPM®.     

In Vitro Drug Release from Matrix Tablets Containing a Silicone Elastomer Latex

Abstract

A silicone elastomer latex was evaluated as a wet-granulating agent in preparing controlled release matrix tablets containing a water soluble active ingredient. A one-half fractional factorial statistical design was used to investigate the effect of five different formulation and non-formulation variables on the in vitro release characteristics of the drug from the matrix tablets. Tablets containing a high percent of fumed colloidal silica exhibited a faster drug release rate. A high drug to polymer ratio in the tablets was also shown to result in a faster release of the drug. Granules dried at a higher temperature (80°C vs. 60°C) produced tablets with a slower drug release rate. The release of the drug was shown to be pH dependent. A higher drug release rate was obtained in a dissolution medium with a lower pH (1.2 vs. 6.8).     

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.     

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

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.     

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Investigation of Hypromellose Particle Size Effects on Drug Release from Sustained Release Hydrophilic Matrix Tablets

Selected combinations of six model drugs and four hypromellose (USP 2208) viscosity grades were studied utilizing direct compression and in vitro dissolution testing. Experimental HPMC samples with differing particle size distributions (coarse, fine, narrow, bimodal) were generated by sieving. For some formulations, the impact of HPMC particle size changes was characterized by faster drug release and an apparent shift in drug release mechanism when less than 50% of the HPMC passed through a 230 mesh (63 μm) screen. Within the ranges studied, drug release from other formulations appeared to be unaffected by HPMC particle size changes.     

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.     

The Relationships of Rate and Kinetics of Release of Theophylline from a New Matrix Tablet Formulation with Content of Release Control Agent

Abstract

Theophylline tablet formulations containing 0.48-14.69% of glyceryl stearate as release control agent (RCA) were prepared and evaluated. The rate of release of theophylline from the tablets decreased as RCA level was increased and relative values have been expressed as a nonlinear dissolution coefficient, K, representing the fractional release after lh. Over the range considered, K is proportional to concentration ^-1/2 of RCA (r=0.955, p<0.001). Kinetics representing the mechanism of release also change with increasing RCA level: at low levels of RCA, dissolution follows cube-root kinetics, but at higher RCA levels, the process is diffusion-controlled. These kinetics are related to values of the nonlinear dissolution exponent, n, which shows a proportionality with concentration of RCA (r=0.899, p<0.001). These findings are discussed in relation to recently reported theoretical values of n.     

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.     

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.     

Effects of Compression Force and Type of Fillers on Release of Diclofenac Sodium from Matrix Tablets

Abstract

The influence of compression force and type of fillers on the release pattern of diclofenac sodium from wet-granulated tablet matrices containing Emcompress and lactose as fillers with Eudragit RSPM as a matrix additive was determined. The release pattern of diclofenac sodium from these matrices in USP phosphate buffer pH 7.2 at 37 ° C were found to be independent of compression forces whereas the ratios of insoluble (Emcompress) to soluble filler (lactose) appeared to greatly influence the drug release rate as evidenced in the increased release rate with decreasing Emcompress content. The kinetics of drug release was determined and found to precisely comform to the Higuchi's planar matrix model. A theoretical approach to predict the drug release rate from a designed system was presented and found to be satisfactorily predictive.