Martin Howard Infeld

Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs

Abstract The ability of polyglycolyzed glycerides (PGG) with varying fatty acid and polyethylene glycol (PEG) chain lengths to produce the self-emulsification of oil in water has been investigated. The quality of the resulting emulsions depends on the oil and emulsifier pair selected. These self-emulsifying drug delivery systems (SEDDS) were prepared using various concentrations of PGG as emulsifiers. Two oils, a medium-chain triglyceride (Neobee M5) and Peanut Oil, were chosen as the vehicle for the drug. A lipophilic drug with excellent oil solubility was selected for this study. The droplet size distribution, the release rate of the drug and the oil/water partition coefficient (PC o/w ) of the drug in these systems were evaluated for the SEDDS obtained. The results indicate that PGG are effective emulsifiers for SEDDS. Droplet particle size in combination with droplet polarity in the emulsion are prerequisites for efficient SEDDS. The PC o/w of the drug from these SEDDS is helpful in evaluating these properties. A phase diagram was used to obtain the optimum concentrations of drug, oil and emulsifying agent. The results obtained with PGG were compared with previously reported SEDDS for the efficiency of drug release (Bachynsky et al., (1989) AAPS Annual Meeting). In vitro dissolution and in vivo absorption of a lipophilic drug from SEDDS are compared with those properties of other dosage forms.

Solid-state plasticization of an acrylic polymer with chlorpheniramine maleate and triethyl citrate.

The influence of in situ plasticization of chlorpheniramine maleate (CPM) on Eudragit RS PO from hot-melt extruded matrix tablets, and from compressed granules prepared by thermal processing was investigated. CPM was studied as both a model drug substance and as a solid-state plasticizer for the acrylic polymer. Triethyl citrate (TEC) was incorporated into the polymer blend as a liquid plasticizer for the polymer. The influence of TEC and CPM concentration on the dissolution properties of CPM tablets was investigated. The glass transition temperature (T(g)) of the samples was determined by modulated differential scanning calorimetry (MDSC). The morphologies of the granules formed by hot-melt extrusion and hot-melt granulation processes were investigated by scanning electron microscopy. The addition of 12% TEC to the polymer reduced the T(g) by 32.5 degrees C, while the reduction in the T(g) for the same level of CPM was 16.4 degrees C. The effect of TEC levels on drug release was dependent on the tablet preparation method. At high TEC levels, the release rate of CPM decreased in tablets prepared by direct compression and tablets made from compressed granules that had been prepared by high shear hot-melt granulation. However, the CPM release rate increased from hot-melt extruded tablets with increasing blends of plasticizer in the extruded tablets. An increase in the CPM content in the tablets resulted in an increase in the drug release rate. During high shear hot-melt granulation, the model drug adhered to the polymer to form a porous discontinuous structure. Following hot-melt extrusion, the drug was distributed at a molecular level in the continuous polymeric structure. The influence of both CPM and TEC levels on the drug release rate from these polymeric drug delivery systems was shown to be a function of whether the granules or tablets were formed by either hot-melt granulation or hot-melt extrusion, as well as the plasticization effects of both TEC and CPM on the acrylic polymer.

Physical and enteric properties of soft gelatin capsules coated with eudragit ® L 30 D-55

Abstract The enteric coating of soft gelatin capsules (SGC) containing ibuprofen in either PEG 400 or Miglyol© was investigated. The effects of two plasticizers, triethyl citrate (TEC) and tributyl citrate (TBC), on the physical and enteric properties of SGC coated with Eudragit ® L 30 D-55 were studied. The water soluble plasticizer TEC was found to be a good plasticizing agent for the Eudragit® L 30 D-55 irrespective of the fill liquid, while the TBC provided satisfactory results only for capsules containing the hydrophobic fill liquid, Miglyol ®. The combination of TEC and TBC provided effective plasticization for the acrylic coating regardless of the fill liquid. A subcoat of HPMC showed no effect on the enteric protection of either Miglyol® - and PEG-containing capsules that were stored at room temperature and zero percent relative humidity. The moisture content of the gelatin shell of the film coated SGC stored at room temperature and at 0 or 96% relative humidity was followed as a function of time. The load strength of the capsules was measured during 3 months of storage using an Instron universal testing apparatus, and the physical-mechanical properties of the capsules were correlated with the moisture content of the SGC. As the moisture content of the gelatin decreased, all formulations exhibited an increase in load strength.

Controlled release of a poorly water-soluble drug from hot-melt extrudates containing acrylic polymers.

ABSTRACT Controlled release tablets containing a poorly water-soluble drug, indomethacin (IDM), acrylic polymers (Eudragit® RD 100, Eudragit® L 100, or Eudragit® S 100), and triethyl citrate (TEC) were prepared by hot-melt extrusion. The physicochemical and IDM release properties of the controlled release hot-melt extrudates were investigated. Indomethacin (IDM) was found to be both thermally and chemically stable following hot-melt extrusion processing and displayed a plasticizing effect on Eudragit® RL PO as demonstrated by a decrease in the glass transition temperatures of the polymer. The inclusion of either Pluronic® F68, Eudragit® L 100, or Eudragit® S 100 in the powder blend containing Eudragit® RD 100 prior to processing increased the rate of release of the IDM from the extrudates. An increase in the media pH and a decrease in the granule particle size also increased the rate of release of IDM. The inclusion of TEC up to 8% in the granule formulation or compressing the granules into tablets had no significant effect on the drug release rate. Indomethacin (IDM) was transformed from a crystalline Form I into an amorphous form in the Eudragit® RD 100 granules following hot-melt extrusion. The thermal processing facilitated the formation of a solid solution with a continuous matrix structure that was shown to control drug diffusion from the extrudates.

Influence of plasticizers on the mechanical properties of pellets containing Eudragit® RS 30 D

The influence of plasticizers on the mechanical properties of single pellets containing the acrylic polymeric dispersion, Eudragit® RS 30 D, as a granulating binder was investigated. Microcrystalline cellulose and anhydrous lactose were used as the substrate powders for pellets prepared by the wet massing and extrusion/spheronization technique. The effects of hydrophilic and hydrophobic plasticizers on the mechanical properties of the pellets and thermal properties of free films were investigated. The mechanical properties, including tensile strength and Youngs modulus, of individual pellets were determined by a diametral compression method with a Chatillon® tension/compression apparatus. The results demonstrated that both the tensile strength and Youngs modulus of the pellets decreased as the plasticizer content increased in the pellet formulation, with the exception at low plasticizer levels. The influence of plasticization on the granulating polymer was reflected in the mechanical properties of pellets, indicating that the pellets underwent a cohesive fracture. The unexpected increase in the tensile strength and Youngs modulus of the pellets containing low levels of plasticizers was ascribed to the antiplasticization of the polymer due to the immobilization of the polymer molecules by hydrogen bonding, van der Waals forces and steric hindrance from the plasticizer molecules. Pellets containing low levels of plasticizers exhibited a brittle fracture behavior under compression while a ductile property was observed at higher plasticizer concentrations. The transition of the fracture behavior from a brittle to a ductile pattern was found to take place when plasticizer levels in the acrylic polymer were between 10 and 20% based on the weight of dry polymer. The transition was due to the shift of the polymeric binder from a glassy to a rubbery state, which was verified by the glass transition temperature values of the free films.

Properties of tablets containing granulations of ibuprofen and an acrylic copolymer prepared by thermal processes.

The objective of this study was to investigate the properties of tablets containing granulations of ibuprofen (Ibu) and Ammonio Methacrylate Copolymer, Type B (Eudragit RS PO) prepared by hot-melt processing. Tablets were compressed from granules prepared by hot-melt granulation (HMG) or direct compression (DC). For the hot-melt extrusion (HME) process, tablets were prepared by cutting the extrudate, manually. The physicochemical properties of tablets were investigated using thermal analysis, powder X-ray diffraction analysis, tablet hardness, and drug dissolution. The effect of thermal treatment of tablets on the dissolution characteristics of Ibu was also investigated. The results demonstrated that the Ibu lowered the glass transition temperature (Tg) of the Eudragit RS PO and the softened polymer functioned as a thermal binder in the granulation. Ibu was demonstrated to be an effective plasticizer for Eudragit RS PO in the thermal processes. The efficiency of the granulation process increased with increasing levels of Eudragit RS PO in the powder blend. Higher levels of Eudragit RS PO in the tablets prepared by HMG or HME resulted in a decrease in the dissolution rate of the Ibu. An increase in the amount of Ibu in the tablets prepared by HMG or DC led to a decrease in the initial dissolution rate of the Ibu. Following the thermal treatment of the Ibu tablets prepared by HMG, the dissolution rate was significantly decreased due to structural changes in the tablets that resulted from the fusion and coalescence of plasticized polymer particles, causing a reduction in tablet porosity. The Ibu tablets prepared by HME demonstrated minimal changes in their release properties following thermal treatment even at temperatures higher than the Tg of the polymer. HME was shown to be a novel method to prepare matrix tablets and stable dissolution properties were obtained when tablets were stored at 40°C for 30 days.

Physical-mechanical properties of film-coated soft gelatin capsules

Abstract Soft gelatin capsules containing ibuprofen dissolved in either PEG 400 or Miglyol® 812 were coated with an aqueous dispersion of Eudragit® L 30 D-55 using a Mini Hi-Coater. The physical-mechanical properties of the coated capsules, including tensile strength, Youngs modulus and tensile toughness, were determined using a Chatillon DFGS50 force gauge attached to a Chatillon TCD-200 motorized test stand. The diametral compression tests were conducted at a rate of 12.7 mm/minute. Force-deflection curves were obtained and mathematically manipulated to yield stress-strain diagrams. The influence of two plasticizing agents, triethyl citrate (TEC) and tributyl citrate (TBC), on the physical-mechanical properties was determined. The hydrophilic plasticizer TEC was found to be the best plasticizer for the acrylic films, regardless of the fill liquid. The physical-mechanical properties of the coated and uncoated soft gelatin capsules were a function of the fill liquid. Temperature and humidity were found to influence the physical-mechanical properties of the coated capsules. The adhesion between the gelatin capsule and the acrylic polymer was found to be dependent on both the fill liquid and plasticizer in the coating formulation. Coating dispersions plasticized with TEC exhibited good adhesion with both the PEG 400 and the Miglyol® 812, whereas the TBC plasticized film coating showed good adhesion with the Miglyol® 812 fill liquid. The acrylic film coatings for the PEG-containing capsules and plasticized with TBC exhibited an increased adhesion of the polymer to substrate over time when stored at both high temperature and high humidity.

Citric acid as a solid-state plasticizer for Eudragit RS PO.

The use of solid‐state plasticizers for the hot‐melt extrusion of pharmaceutical dosage forms has been shown to be beneficial compared with liquid plasticizers. The purpose of this study was to determine the suitability of citric acid (CA) as a solid plasticizer for the preparation of Eudragit RS PO extended‐release matrix systems by a melt extrusion technique. The influence of increasing levels of CA monohydrate (CA MH) or anhydrous CA in the powder blend on the extrusion process parameters (screw speed and motor load) was determined as a function of temperature. The solubility of CA MH in extruded tablets was studied by means of modulated differential scanning calorimetry (MDSC) and powder X‐ray diffraction (PXRD). Films were cast from organic solutions to demonstrate the plasticizing effect of CA MH as a change in physico‐mechanical properties (tensile strength, elastic modulus and elongation). The CA release from extruded tablets was studied over 12 h. The monohydrate form was found to distinctly facilitate the extrusion of Eudragit RS PO, whereas the addition of anhydrous CA to the polymer powder was less effective. This divergent behaviour in plasticization of Eudragit RS PO was attributed to the higher solubility of the monohy‐drate in the acrylic polymer. The plasticizing effect of the CA MH reached a plateau at 25% during hot‐melt extrusion, which coincided with the solubility limit of the organic acid in the polymer as shown by MDSC and PXRD results. The CA MH increased the flexibility of Eudragit RS PO films, as demonstrated by a decrease in tensile strength and elastic modulus and an increase in elongation as a function of CA MH concentration. The dissolution of CA from the matrix tablets followed an extended‐release profile, with CA MH exhibiting a faster dissolution rate than the anhydrous form. In conclusion, CA MH was found to be an effective plasticizer for Eudragit RS PO that facilitates the production of controlled‐release matrix systems by hot‐melt extrusion.

Evaluation of Two New Tablet Lubricants -Sodium Stearyl Fumarate and Glyceryl Behenate. Measurement of Physical Parameters (Compaction, Ejection and Residual Forces) in the Tableting Process and the Effect on the Dissolution Rate

AbstractA comparison of two new tablet lubricants, sodium stearyl fumarate and glyceryl behenate, was made with magnesium stearate. Physical parameters such as compaction force, ejection force and residual force were investigated and quantified. The effect of these lubricants on a biopharmaceutical parameter such as dissolution rate was also evaluated. The results indicate that where magnesium stearate cannot be used due to problems of compaction, lubrication, stability or for biopharmaceutical reasons, sodium stearyl fumarate should be used as the tablet lubricant of choice, followed by glyceryl behenate as the next alternative

Influence of Thermal Processing on the Properties of Chlorpheniramine Maleate Tablets Containing an Acrylic Polymer

The purpose of this investigation was to determine the effects of thermal processing and post-processing thermal treatment on the release properties of chlorpheniramine maleate (CPM) from matrix tablets containing Eudragit® RS PO and triethyl citrate (TEC). CPM tablets containing Eudragit RS PO with and without TEC were prepared by direct compression (DC), high shear hot-melt granulation (HMG), and hot-melt extrusion (HME). X-ray diffraction patterns showed that the CPM was distributed in Eudragit RS PO at the molecular level following HME. The thermogravimetry analysis (TGA) profiles of CPM, Eudragit RS PO, and TEC demonstrated that these materials were thermally stable during both the high shear HMG and HME processes. The tablets were subjected to post-processing thermal treatment by storing the tablets at 60°C in open containers for 24 hr. Tablets prepared by DC showed the highest drug release rate constant of 36.2%hr−1/2. When 4% TEC was incorporated into the formulation, the drug release rate constant for the directly compressed tablets decreased to 32.4%hr−1/2. After high shear HMG and HME of the powder blend containing 4% TEC, the drug release rate constant decreased to 30.8 and 13.8%hr−1/2 for the respective processes. The drug release rate constants for all tablets decreased following post-processing thermal treatment. The reduction in release rate was due to an increase in the intermolecular binding and entanglement between drug molecules and polymer molecules that occurred during thermal processing. Post-processing thermal treatment of the hot-melt extrudates had a minimal effect on the drug release rate since the HME process enhanced the drug and polymer entanglement to a greater extent.