M. Efentakis

Development and Evaluation of oral multiple-unit and single-unit hydrophilic controlled-release systems

This study compared the release behavior of single-unit (tablets, capsules) and multiple-unit (minitablets in capsules) controlled-release systems of furosemide. The swelling and erosion behaviors of these systems, which contained the swellable hydrophilic polymers sodium alginate (high viscosity) and Carbopol 974P, were compared. Swelling and erosion experiments showed a high degree of swelling and limited erosion for the Carbopol preparations, whereas less swelling but greater erosion was observed for the sodium alginate preparations. The sodium alginate preparations were eroded in 6 hours, while Carbopol preparations exhibited limited erosion within this period of time. These results appear to be attributed to the physicochemical characteristics of the polymers used in this study. Polymer characteristics greatly influenced the release of furosemide (model drug) from the formulations prepared and tested. Sodium alginate had a less pronounced sustained release effect compared with Carbopol (ie, in 8 hours all 3 sodium alginate dosage forms displayed complete release of furosemide, while only 30% of the drug was released from Carbopol dosage forms). Finally, all 3 Carbopol dosage forms (single- and multiple-unit) displayed similar release behavior while sodium alginate dosage forms displayed a different and more distinctive behavior. Minitablets and tablets showed a greater sustained release effect compared with capsules. Evaluation of the release data indicates that the release mechanism for sodium alginate formulations may be attributed to erosion/dissolution, while for Carbopol it may be attributed mainly to polymer relaxation and diffusion of the drug from the polymer surface.

Evaluation of high molecular weight poly(oxyethylene) (Polyox) polymer: studies of flow properties and release rates of furosemide and captopril from controlled-release hard gelatin capsules.

The powder characteristics and the effect of the molecular weight of polymers as diluents on the release rate of furosemide and captopril from hard gelatin capsules were evaluated. The high molecular weight polymers studied were poly(oxyethylene) homopolymers (Polyox), with molecular weight ranging from 4,000,000 to 7,000,000. Powder characteristics suggested good flowability for these materials and predicted capsule fill weight uniformity. Swelling experiments showed a very high degree of swelling for these materials in both gastric and buffer solution. These polymers can sustain the release rate of both water-soluble and insoluble drugs from drug delivery systems. The low molecular weight polymers have a less pronounced sustained-release effect compared to the high molecular weight polymer material (i.e., those with 7,000,000 molecular weight). An increase in the content of polymer results in a decrease in the release rate of the drug. The solubility of the drugs clearly influenced the release rate. Release kinetics were evaluated and appeared to be influenced by the molecular weight of the polymer, the solubility of drug, and the ratio of the drug to polymer in the capsule. Bimodal release kinetics were exhibited by a number of furosemide formulations (i.e., F5 and F8).

Release of furosemide from multiple-unit and single-unit preparations containing different viscosity grades of sodium alginate.

The release characteristics and the effect of viscosity of sodium alginate on the release rate of furosemide (a rather poorly soluble drug) from hard gelatin capsules (single-unit), and minitablets (multiple-unit) filled in hard gelatin capsules, were evaluated. Swelling and erosion experiments showed a different behavior for each viscosity grade. Polymer characteristics influenced significantly the release of the drug from the preparations prepared and tested. The results indicate that erosion plays a significant role, accelerates release rate and shortens duration of drug release. Low viscosity formulations exhibited a greater erosion, and drug release was completed in 4 hours. Medium viscosity formulations showed intermediate erosion, while hh viscosity formulations exhibited less erosion, and drug release was completed in 8 hours. The minitablets always displayed lower release and dissolution efficiency values than the capsules, and as the viscosity increased, the difference of dissolution efficiency between the two formulations increased accordingly. The results further indicated that the multiple-unit system demonstrated a more pronounced sustained effect than the single-unit, and therefore, it is a more suitable preparation for sustained release delivery of poorly soluble drugs. Analysis of release data indicate a rather zero–order release mechanism, which may be attributed mainly to swelling and an erosion/dissolution process.

Effects of Excipients on Swelling and Drug Release from Compressed Matrices

AbstractPolymers, and particularly hydrogels, are becoming very popular in formulating controlled-release tablets because they are excellent drug carriers. The effects of hydrophilic and hydrophobic polymers, incorporated in matrices containing soluble (propranolol HCl) or less soluble (flurbiprofen) drugs, on swelling and release kinetics were investigated. The results indicate that swelling and release profiles were affected by the amount of ingredients, the characteristics of the polymer, and the drug substances incorporated in the matrices. Swelling may influence the release rate of the drugs from the matrices. The data obtained from the in vitro dissolution study were evaluated on the basis of a theoretical dissolution equation, by linear transformation of the dissolution curve, and by the Peppas equation. The release mechanisms appeared complex and are affected by the composition of the matrix

Formulation Study and Evaluation of Matrix and Three-layer Tablet Sustained Drug Delivery Systems Based on Carbopols with Isosorbite Mononitrate

The purpose of this research was to develop and evaluate different preparations of sustained delivery systems, using Carbopols as carriers, in the form of matrices and three-layer tablets with isosorbite mononitrate. Matrix tablets were prepared by direct compression whereas three-layer tablets were prepared by compressing polymer barrier layers on both sides of the core containing the drug. The findings of the study indicated that all systems demonstrated sustained release. The properties of the polymer used and the structure of each formulation appear to considerably affect drug release and its release rate. The three-layer formulations exhibit lower drug release compared to the matrices. This was due to the fact that the barrier-layers hindered the penetration of liquid into the core and modified drug dissolution and release. The geometrical characteristics/structure of the tablets as well as the weight/thickness of the barriers-layers considerably influence the rate of drug release and the release mechanisms. Kinetic analysis of the data indicated that drug release from matrices was mainly attributed to Fickian diffusion while three-layer tablets exhibited either anomalous diffusion or erosion/relaxation mechanisms. The advantage of Carbopol formulations is that a range of release profiles can easily be obtained through variations in tablet structure and thus Carbopols are appropriate carriers of oral sustained drug delivery systems for soluble drugs such as the isosorbite mononitrate.

Polymers for use in controlled release systems: the effect of surfactants on their swelling properties.

The effect of an ampholytic surfactant on the swelling properties of polymeric materials was studied, using various swelling liquids. Tablets were prepared consisting of hydroxypropyl methylcellulose, poly(oxyethylene) and sodium alginate. Tego betain was the non-ionic surfactant used as an additive in a series of samples made of the above polymers. Those tablets were immersed in distilled water, phosphate buffer and 0.1 N HCl, and their weight uptake was recorded as a function of time, in order to assess the swelling process. Measurements of the contact angle of the above systems were also carried out for estimating their wetting properties. The results of this study showed a selectivity among polymers, surfactant and surrounding liquid. Clearly, an enhancement of the swelling capacity of hydroxypropyl methylcellulose tablets due to the surfactant was recorded. An unclear effect was observed in the case of poly(oxyethylene), whereas for sodium alginate, the dominant factor is its water solubility that controls swelling behaviour.

The influence of surfactants on drug release from a hydrophobic matrix

Abstract Hydrophobie matrices were prepared using Eudragit RL 100. Flurbiprofen was used as a model drug, with sorbitol as a diluent. The effect of adding each of five surfactants (sodium lauryl sulphate, sodium taurocholate, cetylpyridinium chloride, cocamidopropyl betaine (CDB) and cetrimide) individually to the matrix was investigated. To investigate the mechanism by which the rate of drug release was increased following the incorporation of surfactants, experiments were undertaken to assess the wettability of the different formulations, and to measure drug release in the presence of submicellar and micellar concentrations of the surfactants. Three mechanisms were proposed by which drug release could be increased following the addition of surfactants: improved wetting, solubilisation, and the dissolution of the soluble surfactants to form pores in the matrix. When the surfactant was added to the dissolution fluid, only one surfactant (CDB) did not result in an increase in drug release; for the other surfactants a minor increase in drug release was observed. Therefore, in most cases, wetting plays a small role in aiding dissolution. There was no significant change in release rate when the experiment was performed in the presence of either sub-micellar or micellar concentrations of the surfactants, thus solubilisation of the drug does not seem to be implicated in the drug release mechanism. The most significant increase in drug release rate was caused by incorporating the most soluble surfactants (sodium taurcholate and cetrimide) within the matrix. As the increase was significantly greater than could be explained by wetting alone, it must be concluded that for these matrix systems the major mechanism by which surfactants increase the dissolution rate is by the formation of pores to aid the access of the dissolution fluid and egress of the dissolved drug. It is also possible that the presence of the relatively concentrated surfactant solution in the wetted tablet would reduce interparticle adhesion and thereby speed drug release rate as a result of an increased disintegration.

Swelling properties of various polymers used in controlled release systems.

The effect of powder packing and porosity of specimens on the swelling properties of polymeric materials was studied, in various swelling liquids, such as distilled water and 0.1 N hydrochloric acid solution. Capsules, tablets and films of hydroxypropyl methylcellulose, poly(ethylene oxide) and sodium alginate were prepared and their weight uptake after immersion into the above solutions was recorded as a function of time, in order to assess the swelling process. Measurements of some characteristics of the as received powders were also performed as an attempt to classify the specimens prepared according to their porosity. Within the experimental conditions of this work, it was shown that the porosity of polymeric specimens is a dominant factor that controls their swelling behaviour. Increased porosity leads to fast initial rates of weight uptake and high extent of equilibrium swelling. On the other hand, dissolution and possible degradation of polymers susceptible to acid hydrolysis, results in some variations from the above-mentioned behaviour. With respect to the application in controlled release systems, the overall delivery rate from a polymeric specimen is expected to be a function of both swelling and disintegration characteristics of a specimen and, therefore, the weight uptake can be considered a measure of the release only in the case of polymers with low water solubility and increased stability to hydrolysis.

The formation of an inclusion complex of methocarbamol with hydroxypropyl-β-cyclodextrin: the effect on chemical stability, solubility and dissolution rate

Abstract The inclusion complex of the hydrophobic drug methocarbamol (ML) with hydroxypropyl- β -cyclodextrin (HP β CD) was prepared and characterized in the solid state and in aqueous solution. The prepared complex was studied by chromatographic, spectral and phase solubility methods to determine its structure, solubility, chemical stability and dissolution rate. Host-guest interactions in aqueous solution were studied by proton nuclear magnetic resonance spectroscopy ( 1 H-NMR) and in the solid state by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). The stoichiometry of the isolated complex was determined by reversed phase high pressure liquid chromatography (RP-HPLC), 1 H-NMR spectroscopy and elemental analysis. The solubility and dissolution rate of ML in free and complexed form were examined in aqueous solution. The stability constant of the complex was determined by the classical solubility techniques. The chemical stability of free and complexed ML, in buffered solution at pH 7.4 and at two different temperatures, 37 and 60°C, was monitored using an HPLC method and resulted in a 2-fold increase in the stability of complexed ML compared to free ML.

The influence of surfactants on drug release from acrylic matrices

Abstract Hydrophobic matrices were prepared using Eudragit RS 100, flurbiprofen (as a model drug), with sorbitol as a diluent and magnesium stearate as a lubricant. The effect of adding each of five surface active agents (sodium lauryl sulphate, sodium taurocholate, cetylpyridinium chloride, cocamidopropyl betaine and cetrimide) individually to the matrix was investigated. To explore the mechanism by which the rate of drug release was increased following the incorporation of surfactants, experiments were undertaken to assess the wettability of the different formulations, and to measure drug release in the presence of submicellar and micellar concentrations of the surfactants. The results were also compared to those which have been reported previously for Eudragit RL based matrix formulations. Three mechanisms were proposed by which drug release could be increased following the addition of surfactants: improved wetting, solubilisation, and the dissolution of the soluble surfactants to form disruptions in the matrix. Only sodium taurocholate and sodium lauryl sulphate showed any significant increase in dissolution rate. From contact angle measurements, these were found to be the only two surfactants which increased the wettability of the tablets. Thus it was concluded that increased wettability is a prerequisite to an increase in dissolution rate. The increase in dissolution rates in the presence of surfactant solutions was, however, very small compared to the increase observed when the surfactant was incorporated within the matrix itself. By comparison with data for release from RL matrices, it is likely that the increase in dissolution rate when the surfactant is present in the matrix is related to the solubility of the surfactant. Thus it is necessary for the surfactant to increase the wettability of the tablet surface, to allow the fluid to gain access to the hydrophobic matrix, and then to dissolve. The increased dissolution rate is probably due to either the formation of pores due to the dissolution of the surfactant, or more likely, because of the influence of high local concentrations of surfactant solution, perhaps affecting adhesion within the matrix, leading to disintegration and thus dissolution. The charge of the surfactant also produced a significant effect. The anionic surfactants resulted in lowering of contact angles and increased dissolution rates; the cationic surfactants did not result in changes in contact angle and caused smaller changes in dissolution. It is probable that there is an interaction between the cationic surfactants and the anionic model drug, resulting in an inactivation of these surfactants. Anionic/cationic interactions are not unexpected, but the presence of such an observation for this system (based on Eudragit RS) is surprising because no such interactions were observed for similar formulations based on Eudragit RL (published previously) (Eudragit RL and RS differ only in the extent of the quaternary ammonium substitution; RS being much greater than RL).