The Influence of Polymeric Subcoats and Pellet Formulation on the Release of Chlorpheniramine Maleate from Enteric Coated Pellets

Abstract

The influences of aqueous polymeric subcoats and pellet composition on the release properties of a highly water-soluble drug, chlorpheniramine maleate (CPM), from enteric coated pellets were investigated. Three different aqueous polymeric subcoats, Eudragit® RD 100, Eudragit® RS 30D, and Opadry® AMB, were applied to 10% w/w CPM-loaded pellets that were then enteric coated with Eudragit® L 30D-55. Observed drug release from the coated pellets in acidic media correlated with water vapor transmission rates derived for the subcoat films. The influence of pellet composition on retarding the release of CPM from enteric coated pellets in 0.1 N HCl was investigated. The rate of drug release was greatest for pellets prepared with lactose, microcrystalline cellulose, or dibasic calcium phosphate compared with pellets formulated with citric acid and microcrystalline cellulose. Citric acid reduced the pellet micro-environmental pH, decreasing the amount of drug leakage in 0.1 N HCL during the first 2 hr of dissolution. Polymer flocculation was observed when CPM was added to the Eudragit L 30D-55 dispersion. An adsorption isotherm was generated for mixtures of CPM and the polymer and the data were found to fit the Freundlich model for adsorption. Adsorption of CPM to the polymer decreased with the addition of citric acid to the drug-polymer mixtures.     

Influence of Eudragit NE 30 D blended with Eudragit L 30 D-55 on the release of phenylpropanolamine hydrochloride from coated pellets

The objective of this study was to investigate the influence of Eudragit® NE 30 D blended with Eudragit® L 30 D-55 on the release of phenylpropanolamine hydrochloride (PPA·HCl) from coated pellets. The miscibility of Eudragit NE 30 D/L 30 D-55 blends at different ratios was studied by using differential scanning calorimetry. The release of PPA·HCl from pellets coated with Eudragit NE 30 D alone and a Eudragit NE 30 D/L 30 D-55 blend, when stored at 40°C and 60°C, was determined by UV spectroscopy. Eudragit NE 30 D and Eudragit L 30 D-55 were miscible in ratios greater than 4:1. The curing time that was required to reach an equilibrium state decreased with the addition of Eudragit L 30 D-55. The presence of Eudragit L 30 D-55 also produced a film coating that was less tacky, and a dispersion of Eudragit NE 30 D containing Eudragit L 30 D-55 (5:1) was shown to prevent agglomeration of the pellets during coating and storage.     

Effect of neutralization of poly(methacrylic acid-co-ethyl acrylate) on drug release from enteric-coated pellets upon accelerated storage

The effect of neutralization of poly(methacrylic acid-co-ethyl acrylate) or poly(MA-EA) 1:1 (Eudragit^® L 30 D-55) on drug release from enteric-coated pellets was studied upon accelerated storage. The dissolution rate of un-neutralized poly(MA-EA)-coated pellets decreased while the neutralized polymer-coated pellets maintained a constant drug release rate. Dynamic mechanical analysis showed that both un-neutralized and neutralized poly(MA-EA) films became rigid on aging. However, the un-neutralized films were affected more than those neutralized. Neutralization of poly(MA-EA) significantly changed the mechanical properties of coating films and improved the stability of poly(MA-EA) enteric-coated pellets upon accelerated storage at the studied conditions.     

The influence of formulation on the dissolution profile of diclofenac sodium tablets

In attempts to design delayed-release tablets of diclofenac sodium, seven experimental batches were produced. The influence of super-disintegrant croscarmellose sodium (CCS), the granulation process, and the thickness of Eudragit® L 100 coating film were evaluated. The values of dissolution efficiency and the similarity factor were used to compare the dissolution profiles of each experimental batch and the reference Voltaren®. Both methods appear to be applicable and useful in comparing dissolution profiles. Based on such values four batches were considered similar when contrasted with the reference. The results suggest an optimal relationship between the amount of CCS and the thickness of the coating film, which provides appropriate dissolution rate of diclofenac sodium from the dosage forms.     

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.     

Effect of water-soluble polymers on the physical stability of aqueous polymeric dispersions and their implications on the drug release from coated pellets

Purpose: To investigate the physical stability and drug release-related properties of the aqueous polymer dispersions Kollicoat® SR 30 D and Aquacoat® ECD (an ethylcellulose-based dispersion) in the presence water-soluble polymers (pore formers) with special attention to the potential flocculation of the polymer dispersions. Methods: A precise characterization of the flocculation phenomena in undiluted samples was monitored with turbidimetric measurements using the Turbiscan Lab-Expert. Theophylline or propranolol HCl drug-layered pellets were coated with Kollicoat® SR 30 D and Aquacoat® ECD by the addition of water-soluble polymers polyvinyl pyrrolidone (Kollidon® 30 and 90 F), polyvinyl alcohol–polyethylene glycol graft copolymer (Kollicoat® IR), and hydroxypropyl methylcellulose (Pharmacoat® 603 or 606) in a fluidized bed coater Glatt GPCG-1 and drug release was performed according to UPS paddle method. Results: Stable dispersions were obtained with both Kollicoat® SR 30 D (a polyvinyl acetate-based dispersion) and Aquacoat® ECD with up to 50% hydrophilic pore formers polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® IR) and polyvinyl pyrrolidone (Kollidon® 30). In general, Kollicoat® SR 30 D was more stable against flocculation than Aquacoat® ECD. Stable dispersions were also obtained with higher amounts of water-soluble polymer or by reducing the concentration of the polymer dispersion. Flocculated dispersions resulted in porous films and, thus, in a sharp increase in drug release. Conclusions: Kollicoat® SR 30 D was more resistant to flocculation upon addition of water-soluble polymers than Aquacoat® ECD. The continuous adjustment of drug release from Kollicoat® SR 30-coated pellets was possible with Kollicoat® IR amounts over a broad range.     

The influence of formulation factors on the kinetic release of metoprolol tartrate from prolong release coated minitablets

The aim of this work was to study the possibility to obtain an oral extended-release dosage forms with zero order kinetic release by coating minitablets (containing metoprolol tartrate) with insoluble methacrylate film coating (Eudragit NE 40D) in a fluidized bed system. To achieve this aim a full factorial experimental design with two factors and three levels was used in order to study de influence of the amount of polymer film formatting (Eudragit NE 40D) and the amount of pore generating excipient in polymeric insoluble film (low viscosity hydroxypropyl methylcellulose-Methocel E 15LV) on the in vitro drug release profile.     

The influence of drug solubility and particle size on the pellet formulation in a rotoprocessor

Pellets containing drugs of different properties were prepared in a Rotoprocessor in order to study changes in the formulation process and resulting pellet characteristics. Diltiazem hydrochloride, diclofenac sodium, and theophylline were chosen as model drugs. Pellet size distribution, sphericity, density, hardness, friability, and repose angle were determined using standard methods. The amount of water as a wetting agent necessary for successful pellet formulation was observed for each sample and changed depending on drug solubility, concentration, and particle size. The pelletization of freely soluble diltiazem hydrochloride required 24.8-23.1% of the wetting agent and its amount decreased as the drug concentration increased. The demand for water in the formulation of theophylline pellets was 31.0-34.4% and it increased with increasing drug concentration. The pellet samples containing both drugs were easy to prepare. However, the cohesion of micronized diclofenac sodium particles negatively influenced both the pellet size distribution and the formulation process itself. When the drug concentration exceeded 40%, it was not possible to produce pellets of an appropriate size and the process was not reproducible.     

The influence of diluent on the release of theophylline from hydrophilic matrix tablets

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the drug.     

The effect of pH,buffer capacity and ionic strength on quetiapine fumarate release from matrix tablets prepared using two different polymeric blends

The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel^® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol^® HD5 ATO). The two formulations attained release profiles of QF over 24?h similar to that of Seroquel^® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel^® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro–in vivo correlations.     

The application of pH(stat) leaching tests to assess the pH-dependent release of trace metals from soils, sediments and waste materials

pH is one of the key parameters that determines heavy metal mobility in soils, sediments and waste materials. In many respects leaching behaviour as reflected by the pH(stat) leaching tests provide a better means of assessing environmental impact than analysis of total elemental composition. This paper discusses the use of pH(stat) leaching tests as a tool to assess the potential mobilisation of trace metals from soils, sediments and waste materials. The possibilities of pH(stat) leaching tests are illustrated by means of different examples. The mathematical fitting of metal leaching behaviour from soils and sediments enabled a distinction between 5 groups of elements with a different leaching behaviour, which could be related to 'pools' with different reactivity. Contrary to single and sequential extractions, where pH is difficult to control, the reactivity and mobility of metals at a user-defined pH can be investigated. Moreover, the potential buffering capacity of the sample and its sensitivity to pH changes as a result of external stresses (e.g. soil acidification, liming) can be estimated. A multidisciplinary approach combining mineralogical analysis (X-ray diffraction) with chemical analysis, pH(stat) leaching tests and geochemical modelling (MINTEQA2) can provide information on the solid-phase speciation and reactivity of heavy metals in soils, sediments and waste materials. Besides the influence of pH on heavy metal leaching behaviour, additional information on heavy metal leachability and retention by the solid matrix was obtained from the kinetics of metal release during a pH(stat) test.