Optimization of Sotalol Floating and Bioadhesive Extended Release Tablet Formulations

Abstract

A novel extended release sotalol HC1 tablet formulation which possesses a unique combination of floatation and bioadhesion for prolonged residence in the stomach has been developed. Tablets were produced by direct compression. A two-factor factorial, central, composite Box-Wilson experimental design was employed to develop and optimize the tablet formulation containing 240 mg sotalol HC1. The ratio of two major bioadhesive agents, sodium carboxymethylcellulose (NaCMC) to hydroxypropylmethylcellulose (HPMC), and the ratio of two direct compressible diluents, ethylcellulose (EC) to crosspovidone, were used as formulation variables (independent variables) for optimizing tablets response parameters, such as dissolution bioadhesive capability, tablet density and required compression force for producing 6 Kg hardness tablets. The data were also analyzed by means of quadratic response surface model. Response surfaces were generated as a function of formulation variables. An optimum direct compression, bioadhesive and floating tablet formulation of sotalol HCl was achieved by considering the dissolution characteristic as primary objective and using required compression force, bioadhesive capability as constraints within the experimental region. The surface model was validated for accurate prediction of response characteristics.     

Optimization of Slow-Release Tablet Formulations Containing Montmorillonite III. Mechanism of Release

The release of sodium sulfathiazole from slow-release tablet dosage forms containing 30% colloidal aluminum silicate and 20% drug, appears to follow first-order kinetics. Analysis of the data however, suggests that several mechanisms including hydration of the clay, diffusion of drug through a hydrated gelatinous barrier and attrition of the gel layer may contribute to the dissolution of sodium sulfathiazole from the tablet matrix. The influence of tablet shape and size on the dissolution properties of drug from the dosage forms was also examined.     

Optimization of Tablet Formulations Containing

Abstract

An optimized direct compression tablet formulation of a conventional theophylline tablet was developed using the technique of response surface methodology and successive quadratic programming (SQP). The response surfaces were obtained from fitting data generated from a secondorder uniformprecision rotatable hexagonal experimental design. The tablet formulation was optimized for mean in vitro dissolution time using disintegration time, ejection force, friability and hardness, as constraints within the experimental region by the SQP technique. The response surface model was validated by preparing and evaluating the predicted formulation. The characteristics of the tablet formulation were analyzed by principal component analysis. Sensitivity analysis for the optimal solution was performed for each constraint, while all remaining constraints were held constant. The robustness of the response surface model was evaluated by simulation for error in the compression force values.     

Optimization of Tablet Formulations Containing

An optimized direct compression tablet formulation of a conventional theophylline tablet was developed using the technique of response surface methodology and successive quadratic programming (SQP). The response surfaces were obtained from fitting data generated from a secondorder uniformprecision rotatable hexagonal experimental design. The tablet formulation was optimized for mean in vitro dissolution time using disintegration time, ejection force, friability and hardness, as constraints within the experimental region by the SQP technique. The response surface model was validated by preparing and evaluating the predicted formulation. The characteristics of the tablet formulation were analyzed by principal component analysis. Sensitivity analysis for the optimal solution was performed for each constraint, while all remaining constraints were held constant. The robustness of the response surface model was evaluated by simulation for error in the compression force values.     

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.     

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

Abstract

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.     

Captopril Floating and/or Bioadhesive Tablets: Design and Release Kinetics

Two viscosity grades of hydroxypropylmethylcellulose (HPMC 4000 and 15000 cps) and Carbopol 934P were used to prepare captopril floating tablets. In vitro dissolution was carried out in simulated gastric fluid (enzyme free) at 37°C ± 0.1°C using the USP apparatus 2 basket method. Compared to conventional tablets, release of captopril from these floating tablets was apparently prolonged; as a result, a 24-hr controlled-release dosage form for captopril was achieved. Drug release best fit both the Higuchi model and the Korsmeyer and Peppas equation, followed by first-order kinetics. While tablet hardness and stirring rate had no or little effect on the release kinetics, tablets hardness was found to be a determining factor with regard to the buoyancy of the tablets.     

Oral Sustained-Release Bioadhesive Tablet Formulation of Didanosine

The objective of this study was to formulate a hydrogel-forming bioadhesive drug delivery system for oral administration of didanosine (ddI). The aim of this tablet dosage form is to improve the oral absorption of ddI by delivering it in small doses over an extended period and localizing it in the intestine by bioadhesion. Compressed tablets of ddI using Polyox® WSRN-303, Carbopol® 974P-NF, and Methocel® K4M as the bioadhesive release rate-controlling polymers were prepared. The effect of polymer concentration on the release profile and in vitro bioadhesion of the matrix tablets was studied. Tablet formulations with Polyox WSRN-303 (10%) and Methocel K4M (30%) showed 93 and 90% drug release, respectively, after 12 h. The drug release was found to be linear when fitted in the Higuchi equation (square-root time equation), suggesting zero-order release. Carbopol 974-P-NF was found to inhibit the complete release of ddI because of drug-polymer interaction; hence, is not suitable for formulation of ddI. Drug diffusion and swelling of the polymer (anomalous Fickian release) was found dominant in ddI release. In general, in vitro bioadhesion increased with an increase in polymer concentration. Tablets containing a single polymer can be designed to form hydrogels serving the dual purpose of bioadhesion and sustained release.     

Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

Abstract

With the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.

The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.     

Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

With the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.

The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.     

Use of a Desk-Top Computer in a Search-Type Optimization of Tablet Formulations

The use of a desk-top computer in the field of formulation and process optimization is described. To illustrate an application of this technique, a series of tablets has been prepared according to a classical optimization design to determine the optman levels of process variables which meet pre-established specifications for product variables (hardness, thickness, etc.) based on second order polynomial predictor equations for each measured parameter.     

Use of a Desk-Top Computer in a Search-Type Optimization of Tablet Formulations

Abstract

The use of a desk-top computer in the field of formulation and process optimization is described. To illustrate an application of this technique, a series of tablets has been prepared according to a classical optimization design to determine the optman levels of process variables which meet pre-established specifications for product variables (hardness, thickness, etc.) based on second order polynomial predictor equations for each measured parameter.     

Studies of Floating Dosage Forms of Furosemide: In Vitro and In Vivo Evaluations of Bilayer Tablet Formulations

For the purpose of enhancement the bioavailability of furosemide (FR), a floating dosage form with controlled release of FR was designed in this study. Because of the lower solubility of active material in the gastric medium, it was first enhanced by preparing an inclusion complex of FR with beta-cyclodextrin (β-CD) in a 1:1 proportion using the kneading method. Following the design of dosage form, bilayer floating tablets were prepared. After dissolution rate studies were performed using the continuous flow-through cell method, the formulation that provided delivery of active material near the target profile was given to six healthy male volunteer subjects, and in vivo tests were performed. It was determined by radiographs that floating tablets prepared by adding BaSO₄ stayed in the stomach for 6 hr. Further, values of the area under the plasma concentration-time curve (AUC) obtained with the floating dosage form were about 1.8 times those of the conventional FR tablet in blood analyses; maximum and minimum plasma concentrations were also found to be between the desired limits. In urine analyses, the peak diuretic effect seen in classical preparations was decreased and prolonged in floating dosage forms. Also, a considerably significant correlation was detected between in vivo results and in vitro data of the dissolution rate, and it was concluded that the modified continuous flow-through cell method is usable for in vitro dissolution rate tests of floating dosage forms.     

Optimization of Slow-Release Tablet Formulations: Containing Montmorillonite I. Properties of Tablets

Slow-release tablets containing 20%. sodium sul fathiazole and 30%. magnesium aluminum silicate were prepared by direct compression techniques. Dissolution studies indicated that tablet hardness exerted a negligible influence on drug release from the tablets. During the dissolution process the clay slowly swelled to form a gelatinous hydrated layer around the tablet matrix. At faster stirring speeds, friction between the dissolution basket and the tablet rapidly removed the hydrated boundary region and resulted in a more rapid dissolution rate of the sulfonamide. Faster rates of dissolution were seen in deionized water than in dilute acid since the clay hydrated more readily at the higher pit.     

III. Segregation of Active Constituents from Tablet Formulations During Grinding: Effects on Coated Tablet Formulations

Abstract

Grinding or milling coated tablets in preparation for their assay can cause the physical separation of an active ingredient from the coating and other tablet components. This phenomenon has been shown to partially account for the poor reproducibility between duplicate assays, and for discrepancies among assays for the same group of tablets but which were composited by different methods.

The effect of compositing methods on the assay results is shown with commercial enteric coated aspirin tablets from various manufacturers. Samples for assay were prepared by manual grinding with a glass mortar and pestle, mechanical grinding with an electric tablet grinder, direct dissolution of the tablets in a suitable solvent, and uncoating of the tablets with an organic solvent prior to their manual grinding.

Suggestions are offered to minimize the effects of segregation of an active tablet ingredient during grinding or milling on the assay results.     

III. Segregation of Active Constituents from Tablet Formulations During Grinding: Effects on Coated Tablet Formulations

Grinding or milling coated tablets in preparation for their assay can cause the physical separation of an active ingredient from the coating and other tablet components. This phenomenon has been shown to partially account for the poor reproducibility between duplicate assays, and for discrepancies among assays for the same group of tablets but which were composited by different methods.

The effect of compositing methods on the assay results is shown with commercial enteric coated aspirin tablets from various manufacturers. Samples for assay were prepared by manual grinding with a glass mortar and pestle, mechanical grinding with an electric tablet grinder, direct dissolution of the tablets in a suitable solvent, and uncoating of the tablets with an organic solvent prior to their manual grinding.

Suggestions are offered to minimize the effects of segregation of an active tablet ingredient during grinding or milling on the assay results.     

Drug Release Kinetics from Tablet Matrices Based Upon Ethylcellulose Ether-Derivatives: A Comparison Between Different Formulations

ABSTRACT

The present study involved the preparation of ibuprofen-containing controlled release tablets formulated from either the established granular product, Ethocel®Standard Premium, or the novel finely-milled product, Ethocel®Standard FP Premium. The tablets were prepared by either direct compression or wet granulation. The aim was to explore the influence of different parameters on the kinetics and mechanisms of ibuprofen release from the tablets. These parameters were; polymer particle size, polymer molecular weight, drug : polymer ratio, preparation methodology and partial replacement of lactose with the coexcipient—hydroxypropyl methylcellulose (HPMC). The derived drug release data were analyzed with reference to various established mathematical models while the f₂-metric technique was used in order to determine profile equivalency. It was found that drug release was mostly modulated by several interactive factors apparently exhibiting crosstalk. Nevertheless, it was possible to identify some simple rules. Incorporation of Ethocel® FP polymers and application of the wet granulation technique facilitated greater efficiency in controlling ibuprofen release behavior from the matrices. Furthermore, drug release profiles could be modulated by partial substitution of the primary excipient with HPMC. Polymer concentrations and particle sizes, rather than viscosity grade, were found to be decisive factors in controlling drug release rates.     

Testing of Drug Release from Bioadhesive Vaginal Tablets

Abstract

To establish en in vitro test method that can predict the drug release and dissolution behaviour of vaginal bioadhesive controlled release tablets, a system was developed and its appropriateness to the in situ conditions was examined. For this purpose, the dissolution rates of vaginal bioadhesive tablets were measured by three different methods. These were, USP dissolution apparatus two and a new vaginal dissolution tester (NVDT) which was developed by us with some modification of the vaginal tablet desentegration apparatus of BP 1988 and, testing in cow vaginas in situ. Four different bioadhesive tablet formulations were used being composed of the drug and the anionic polymer, polyacrylic acid (PAA) and the nonionic polymers, hydroxypropylmethyl cellulose (HPMC) and ethyIcellulose (EC). The release profiles of the in vitro and in situ methods were investigated and evaluated kinetically.

It was found that NVDT could be used to investigate the drug release from vaginal tablets.     

Testing of Drug Release from Bioadhesive Vaginal Tablets

To establish en in vitro test method that can predict the drug release and dissolution behaviour of vaginal bioadhesive controlled release tablets, a system was developed and its appropriateness to the in situ conditions was examined. For this purpose, the dissolution rates of vaginal bioadhesive tablets were measured by three different methods. These were, USP dissolution apparatus two and a new vaginal dissolution tester (NVDT) which was developed by us with some modification of the vaginal tablet desentegration apparatus of BP 1988 and, testing in cow vaginas in situ. Four different bioadhesive tablet formulations were used being composed of the drug and the anionic polymer, polyacrylic acid (PAA) and the nonionic polymers, hydroxypropylmethyl cellulose (HPMC) and ethyIcellulose (EC). The release profiles of the in vitro and in situ methods were investigated and evaluated kinetically.

It was found that NVDT could be used to investigate the drug release from vaginal tablets.     

Optimization of Tablet Formulations Based on Starch/Lactose Granulations for Use in Tropical Countries

Abstract

Several granulations consisting of α-lactose monohydrate 200 mesh and native starch (corn, potato, rice or tapioca) were prepared. The influence of starch concentration, storage temperature and relative humidity on the physical properties of the tablets prepared from these granulations was estimated. Two granulations, which resulted in tablets with adequate initial values of crushing strength and disintegration time and with an acceptable physical stability were selected as standard granulations. The selected standard granulations were evaluated by incorporating a drug (diazepam, 2 mg or mebendazole, 100 mg). The tablet properties were determined one day after preparation. The crushing strength, the disintegration time and the microbiological quality were also measured after storage under tropical conditions. Both selected formulations proved to be adequate for the preparation of tablets by wet granulation, suitable for use in tropical countries.