Preparation and Evaluation of Eudragit® Acrylic Resin for Controlled Drug Release of Pseudoephedrine Hydrochloride

Abstract

The preparation of a sustained release dosage form for pseudoephedrine hydrochloride was evaluated. Beadlets (PS) containing pseudoephedrine hydrochloride were prepared by spraying a slurry of pseudoephedrine hydrochloride, Eudragit® S-100, dibutyl sebacate and alcohol onto non-pariel seeds via the Wurster column process. The oven-dried PS beadlets were coated with different levels of Eudragit® RS (poorly water permeable) and Eudragit® S-100 (enteric resin). In-vitro dissolution     

Sustained Release from Precirol® (Glycerol Palmito-Stearate) Matrix. Effect of Mannitol and Hydroxypropyl Methylcellulose on the Release of Theophylline

Abstract

The release of theophylline embedded in a Precirol® (glycerol palmitostearate) matrix containing varying amounts of mannitol and/or hydroxypropyl methyl cellulose 4000 (HPMC) was studied. The results indicated that HPMC or mannitol when incorporated alone, the drug release followed the diffusion-controlled matrix model where the quantity of drug released was proportional to the square root of time. The release rate was found to increase with increase in the amount of HPMC or mannitol in the matrix. When both mannitol and HPMC were incorporated in the matrix, the mechanism of release changed from the Higuchi model to a first-order release. A linear relationship was found between the fraction of HPMC or mannitol in the matrix and the rate constant. An optimum combination of Precirol®, mannitol and HPMC was found for a 12 hour theophyll ine sustained release preparation     

Oral Sustained Delivery of Atenolol from Floating Matrix Tablets—Formulation and In Vitro Evaluation

Floating matrix tablets of atenolol were developed to prolong gastric residence time and increase drug bioavailability. Atenolol was chosen as a model drug because it is poorly absorbed from the lower gastrointestinal tract. The tablets were prepared by direct compression technique, using polymers such as hydroxypropyl methylcellulose (HPMC K15M, K4M), guargum (GG), and sodium carboxymethylcellulose (SCMC), alone or in combination, and other standard excipients. Tablets were evaluated for physical characteristics viz. hardness, swelling index, floating capacity, thickness, and weight variation. Further, tablets were evaluated for in vitro release characteristics for 8 hr. The effect of effervescent on buoyancy and drug release pattern was also studied. In vitro release mechanism was evaluated by linear regression analysis. GG- and SCMC-based matrix tablets showed significantly greater swelling indices compared with other batches. The tablets exhibited controlled and prolonged drug release profiles while floating over the dissolution medium.     

Mechanistic Analysis of Drug Release from Theophylline Pellets Coated by Films Containing Pectin,Chitosan and Eudragit® RS

The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit® RS. Pellets (710–840 μm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit® L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.     

Evaluation of pH-Sensitivity and Drug Release Characteristics of (Polyacrylamide-Grafted-Xanthan)–Carboxymethyl Cellulose-Based pH-Sensitive Interpenetrating Network Hydrogel Beads

Novel pH-sensitive interpenetrating network hydrogel beads of polyacrylamide-grafted-xanthan (PAAm-g-XG) and sodium carboxymethyl cellulose (NaCMC) loaded with ketoprofen were prepared and evaluated for pH sensitivity and drug release characteristics. The pH-sensitive PAAm-g-XG copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The grafting and alkaline hydrolysis reactions were confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and X-ray diffraction studies were carried out to know the crystalline nature of encapsulated drug. Scanning electron microscopic study revealed that the interpenetrating polymer network (IPN) beads possess porous matrix structure in alkaline pH whereas nonporous matrix structure was observed in acidic pH. The swelling of the beads and drug release was significantly increased when pH of the medium was changed from acidic to alkaline. The results of pulsatile swelling study indicated that the IPN beads changed their swelling behavior when pH of the external medium was altered. As pH of the medium was changed from 1.2 to 7.4, a considerable increase in swelling was observed for all the beads. However, swelling process was slower than the deswelling. At higher pH values, the carboxyl functional groups of hydrogels undergo ionization and the osmotic pressure inside the beads increases resulting in higher swelling. Drug release followed case II transport mechanism in acidic medium whereas anomalous/non-Fickian transport mechanism was observed in alkaline medium.     

A Review of: “Evaluation of Enzyme Inhibitors in Drug Discovery”

Abstract

The preparation of a new scored 250 mg theophylline tablet is described, for which effects of particle size of the active principle, aspects of granulation and changes in tabletting settings were investigated.

In vitro studies showed the dissolution rate from tablets prepared from theophylline of commercial quality (50 μm) or of selected particle size (30 μm) to be faster than that from tablets prepared from micronized theophylline (10 μm). In vivo studies in dog showed that only the tablet from theophylline of selected particle size has the same bioavailability as an aqueous solution.

The scale up study showed that the characteristics of the tablets, including dissolution rate, are independent of the formulation factors.     

Establishment of a Fault Prognosis Model Using Wavelet Neural Networks and Its Engineering Application

Fault diagnosis is confronted with two problems; how to “measure“ the growth of a fault and how to predict the remaining useful lifetime of such a failing component or machine. This paper attempts to solve these two problems by proposing a model of fault prognosis using wavelet basis neural network. Gaussian radial basis functions and Mexican hat wavelet frames are used as scaling functions and wavelets, respectively. The centers of the basis functions are calculated using a dyadic expansion scheme and a k-means clustering algorithm.     

Formulation Development and Human In Vitro‐In Vivo Correlation for a Novel,Monolithic Controlled‐Release Matrix System of High Load and Highly Water‐Soluble Drug Niacin

Novel, controlled‐release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO‐based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC‐based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner‐Nelson technique, and a level A “in vitro‐in vivo correlation” was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.     

Prediction of Fracture Toughness of Reactor Pressure-Vessel Steels Using the “Master Curve” Concept and Probabilistic Model

Using a probabilistic model and the Master curve approach, the temperature dependence of the brittle fracture toughness of reactor pressure-vessel steel 15Kh2NMFA in the initial state and highly embrittled state is predicted from the results of fracture toughness testing of a cracked Charpy-type specimen at a given temperature. A comparative analysis has shown that for the steel in the initial state the curves calculated by the probabilistic model and by the Master-curve approach are in good agreement. By testing compact-tension specimens of embrittled 2T-CT steel in a wide temperature range the authors have obtained experimental fracture toughness values and compared them with the calculated curves. It is demonstrated that, in the case of the embrittled steel, the curve as calculated by the Master-curve approach fails to describe adequately the experimental results, while the curves plotted by the probabilistic model agree well with the experimental fracture toughness values.     

Evaluation of Scaleup Procedures Using “System” Approach for Pneumatic Conveying of Powders

This article presents results from an ongoing research effort aimed towards developing a validated scaleup procedure for pressure drop for the dense-phase pneumatic conveying of powders. Two existing/popular forms of the “system” approach for scaling up of diameter were evaluated. The validity of the current technique for length scaleup using a “system” approach was also examined. The existing method showed good potential for dilute-phase flow, but resulted in appreciable under-predictions when predicting for dense-phase flow. The effect of bends on the accuracy of the method was also investigated. In this study, steady-state conveying data of four different powders conveyed in various pipes (diameter/lengths) were used for the purpose of scaleup investigations.     

On a Thomas-Fermi Model of “Hollow” Atom

Abstract

A Thomas-Fermi model of a spherical shell of positive charge is investigated, under various boundary conditions. The electron distribution and the ionization charge are given particular attention.     

Stopford and Wells were Right! MNC Matrix Structuresdo fit a “High-High” Strategy

• This paper seeks to address a primary question about matrix structures: under which strategic condition should multinational companies (MNCs) use matrix structures instead of other structures? To answer this question, the seminal Stopford and Wells Model (1972) is re-examined.
• Stopford and Wells (1972) predicted in their model that MNCs tend to use matrix structure to implement high levels of dual strategies??foreign product diversification and area diversification. Their prediction, however, has remained theoretically unclear and empirically unproven.
• To address this gap in the strategy-structure literature, we re-examine and revise the Stopford and Wells Model to explain the strategic condition in which MNCs tend to use matrix. The key of the revision is to use ??corporate integration?? instead of ??foreign product diversification??.
• The revised model is preliminarily supported by the data from a study of German MNCs. This suggests that corporate integration, together with area diversification, are the two over-riding strategies that lead to MNCs?? use of matrix.

     

“Assessment of Metal Matrix Composites for Innovations” — intermediate report of a European Thematic Network

The Thematic Network “Assessment of Metal Matrix Composites for Innovations” (acronym MMC-ASSESS) is a consortium of 21 partners from industry, research organisations and universities involved in research, development and application of metal matrix composites (MMC). The general goal of the project is to increase market acceptance of MMC by collecting and evaluating information related to the engineering potential of these materials. The working groups of the network are referring to production, characterisation and properties as well as modelling and applications of MMC. These topics are considered as well specifically for the four categories of MMC: particulate, short fibre and whisker, continuous fibre, and monofilament reinforced metals. A web page has been established (http://mmc-assess.tuwien.ac.at/) as an ongoing dissemination activity. An intermediate report on the network's activities is presented, which started in October 1998 by funding of the European Commission for a 36 months period.     

Acrylic Resins as Rate-Controlling Membranes in Novel Formulation of a Nine-Day 17β-Estradiol Transdermal Delivery System: In Vitro and Release Modifier Effect Evaluation

The feasibility of transdermal controlled delivery system of 17 β-estradiol was investigated by conducting in vitro release studies. Several new 17 β-estradiol unilaminate adhesive devices capable of releasing 17 β-estradiol in a controlled fashion over a 24-h, 36-h, 96-h, 104-h, 168-h, and 216-h period have been developed using acrylic resins (Eudragits E100, RSPO, and RLPO) as adhesive and rate-controlling polymers. The in vitro release profiles of 17 β-estradiol from various TDS unilaminate devices were characterized in a new developed dissolution tester vessel (total volume 200 ml), using a new paddle. The release of drug from different formulations was measured by a sensitive high-performance liquid chromatographic (HPLC) method. The release of drug from all prepared adhesive devices seems to obey zero-order kinetics (r > 0.98). The effect of two different plasticizers (acetyltributyl citrate [ATBC] and triethyl citrate [TEC]) on the release patterns of 17 β-estradiol from TDS formulations was studied, and they were almost identical. The effect of two different release modifiers, propylene glycol (PG) and myristic acid (MA), on the release pattern of 17 β-estradiol from prepared unilaminate devices was evaluated. It was shown that the use of these release modifiers significantly increased the release of 17 β-estradiol from a TDS unilaminate patch. Furthermore, these data clearly demonstrated that the acrylic resins are suitable polymers for the preparation of 17 β-estradiol TDS adhesive devices.     

Evaluation of Ludipress as a “Multipurpose Excipeent” for Direct Compression: Part I: Powder Characteristics and Tableting Properties

The powder characteristics and tableting properties of Ludipress, a lactose-based, free flowing granule containing povidone and crospovidone have been evaluated and compared to the physical blend of the base materials in Ludipress and to other filler/binders including Cellactose and Avicel PH 200.

The data were determined in order to evaluate flowability, bulk density, tapped density, Hausner ratio, angle of repose and particle size distribution. The particle morphology and constitution were examined using scanning electron microscopy (SEM). Differential scanning calorimetry (DSC) was used to detect differences between lactose based products.

Several Ludipress samples exhibited a good batch-to-batch uniformity and flow characteristics compared to the physical blend and other excipients investigated.

The tableting parameters tested were crushing strength, friability and disintegration time. The ability to form coherent compacts was similar for Ludipress, Cellactose and Avicel PH 200, whereas tablets made from the physical blend resulted significantly softer. Determination of tablet disintegration time revealed a disintegration time minimum at about 100 MPa for Ludipress compacts. By augmenting compaction load from 100 to 185 MPa Cellactose showed an increase in disintegration time to more than 20 minutes. The disintegration times of Avicel PH 200 compacts were nearly constant and were also the shortest in the compaction load range examined.     

HPLC Assay for Basic Amine Drug in Plasma Using a Silica Gel Column and an Aqueous Mobile Phase–Application in a Pilot Bioavailability Study of Chlorpheniramine Controlled-Release Dosage Form

A high performance liquid chromatographic (HPLC) method that involves the use of a silica gel column and an aqueous mobile phase for simultaneous separation of chlorpheniramine, pseudoephedrine and terfenadine in plasma is presented. Alkalized samples are cleaned by extraction with n-hexane, and the extraction is followed by evaporating the solvent and reconstituting the residue in a small amount of mobile phase. An aliquot of this solution is analyzed by a HPLC system with a silica gel column, an aqueous mobile phase containing 55% CH₃CN and 45% (NH₄)H₂PO4(pH 4.0), and UV detection at 210 nm. The low detection limits of the method in plasma are 1 ng, 4 ng and 0.5 ng for chlorpheniramine, pseudoephedrine and terfenadine, respectively. In this study, terfenadine acts as an internal standard. The coefficient of variance on the results of intraday and interday precision and the accuracy on control samples of chlorpheniramine and pseudoephedrine were all within 10%. We have used this method successfully in a pilot bioavailability study of a newly developed controlled-release formulation.     

Measuring “publications output” and “publications impact” of faculty members of a university chemistry department

The publication and citation records of a group of 34 senior members of the faculty of the Department of Chemistry at Technion-Israel Institute of Technology over the period 1980–90 have been analyzed under the contention that dealing with a small group makes it possible for one to pay adequate attention to the methodology of the measurement and analysis processes. Choosing the most suitable index for measuring Publications Output has been considered in detail; it is suggested that it is essential to make allowances for both the number of co-authors and for the lengths of publications in order to obtain a more valid measure than is provided by a simple count of equally-weighted publications. Analogously it is argued that simple citation counts provide an inadequate measure of the impact that publications make on the group outside the authors' immediate circle and thus that it is necessary to subtract self citations and divide the credit for a citation among the co-authors of the publication. Results of the analysis show that in agreement with all previous findings a few members (perhaps less than 20%) produce more than half the publications and receive more than half the citations of the Group as a whole.