Use of Proteins to Minimize the Physical Aging of EUDRAGIT® Sustained Release Films

ABSTRACT

The objective of this study was to investigate the influence of two proteins, albumin and type B gelatin, on the physical aging of EUDRAGIT® RS 30 D and RL 30 D coated theophylline pellets. The physicomechanical properties of sprayed films, thermal properties of cast films, influence of proteins on the zeta potential and particle size of the dispersion, and the release of proteins from cast films under simulated dissolution conditions were investigated. The release rate of theophylline decreased significantly over time from pellets coated with an acrylic dispersion containing 10% albumin when there was no acidification of the acrylic dispersion; however, when pellets were coated with an acidified EUDRAGIT®/albumin dispersion, the theophylline release rate was stable for dosage forms stored in the absence of humidity. The drug release rate was faster for pellets coated with acrylic dispersions containing 10% gelatin compared to the albumin–containing formulations. When sprayed films were stored at 40°C/75% RH, the water vapor permeability decreased significantly for both EUDRAGIT® films and those containing EUDRAGIT® and albumin; however, there was no significant change in this parameter when 10% gelatin was present. Albumin was released from the acrylic films when the pH of the dissolution media was below the isoelectric point of the protein while no quantitative release of gelatin was observed in pH 1.2 or 7.4 media. The effect of gelatin to prevent the decrease in drug release rate was due to stabilization in water vapor permeability of the film. Acidification of the polymeric dispersion resulted in electrostatic repulsive forces between albumin and the acrylic polymer, which stabilized the drug release rate when the dosage forms were stored in aluminum induction sealed containers at both 40°C/75% RH and 25°C/60% RH.     

The Use of Precirol® to Prepare Sustained Release Tablets of Theophylline and Quinidine Gluconate

Abstract

Tablets were made using theophylline, lactose and Precirol by a granulation technique, resulting in more than 12 hours release. Granulation and hot fusion methods were used to prepare admixtures of quinidine gluconate and Precirol at different ratios of Precirol: drug, 1:9, 3:7 and 1:1. Dissolution studies in 0.1N HCl showed drastic differences in the release of quinidine gluconate from tablets made by the two different methods; granulation method gave a faster release while the hot fusion method gave slower and incomplete release at higher Precirol content. The release rate decreases with higher Precirol content.     

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     

High‐Temperature Deposition of Carbon Films

A mathematical model of growth of a carbon film in hightemperature deposition has been constructed in the approximation of the Stefan problem. The influence of different factors on the maximum thickness of the film has been analyzed. It has been shown that the porosity of the film is a factor of fundamental importance which determines the dynamics of its growth in terms of the effective thermal conductivity.     

Process of Cooling of a High‐Temperature Two‐Phase Flow

A technique and a design of a transducer for measuring the enthalpy of twophase flows using the thinwall method have been developed. Working formulas for calculating the heat capacity and the enthalpy of a gas flow are substantiated. Results of a test of the transducer in hightemperature flows of powder gases, including those after the packing of a coolant, are presented. The results obtained show that cooling of powder gases due to an endothermic reaction makes it possible to decrease the enthalpy flux by a factor of 5 and the temperature by a factor of 2.     

Use of extrusion aids for successful production of Kollidon® CL-SF pellets by extrusion–spheronization

Objective: Fine particle ethylcellulose (FPEC) or poly(ethylene oxide) (PEO) addition to a Kollidon CL-SF was investigated to address low yield and poor sphericity in extruded-spheronized pellets.

Significance: The success of crospovidone as a diluent in extrusion–spheronization was dependent on a small particle size of the polymer. FPEC aided production of rugged and spherical pellets using a large particle size grade, Polyplasdone^® XL. PEO acted as an extrusion–spheronization aid when ethylcellulose was the diluent. These extrusion–spheronization aids could serve in this role when Kollidon^® CL-SF (K CL-SF) is the diluent.

Methods: The influence of formulation and process variables on pellet properties was investigated using design of experiments. A planetary mixer was used to prepare powder blends and the wetted mass after addition of water. An EXD 60 extruder produced extrudate that was spheronized in a Q230 marumerizer. Wet pellets were dried in a forced-air oven.

Results: FPEC improved rounding up but reduced pellet yield. Poly(ethylene oxide) imparted desired characteristics to the wetted mass, the extrudate, and the spheronized pellets. Pellet average diameter, yield, sphericity, aspect ratio, friability, and dissolution profile were assessed. Equations for pellet characteristics facilitated discussion of the influences of factors and their interactions. Optimization was performed on pellets that included PEO.

Conclusions: PEO proved to be an exceptional extrusion–spheronization aid in the preparation of pellets using K CL-SF. It facilitated wetted mass extrusion with minimal mass loss to the extruder, and markedly improved the sphericity of the pellets produced by marumerization. Immediate release pellets were obtained.     

Sustained Release Matrix of Mebeverine Hydrochloride Using Polyacrylate Resin “Eudragit Retard” Kinetic of Drug Release and Evaluation of a Kinetic Model

Abstract

In this study Eudragit RS PM and RL PM were evaluated as carriers for the preparation of prolonged release solid dispersions of mebeverine hydrochloride by solvent and melting methods. The prepared tablets were examined for dissolution at pH 1.2 and 7.4, Eudragit RS PM and RL PM were found satisfactory as potential slow release carriers. The solid dispersion prepared by the solvent method showed a slow release pattern. Drug release appeared to fit both, first order and Higuchi matrix model kinetics. However, on application of the differential rate treatments, the evidence supported the Higuchi matrix model. Effect of temperatures on dissolution rate was studied for thermodynamic consideration.

The drug release was pH-independent until pH 7.4.As the pH increased, the release was significantly reduced due to solubility problem.     

Preparation and Evaluation of pH‐Dependent Gradient‐Release Pellets for TCM

This paper is designed to investigate a novel sustained release system for Traditional Chinese Medicinal Compound Recipe (TCMCR) by incorporating three kinds of pH‐dependent gradient‐release coated pellets into capsules. In our study, dosage reform was conducted on the TCMCR model drug–Guanxin Suhe Wan (GSW), which is in the traditional form of honey bolus, comprising Styrax, Borneolumsyntheticum, Olbanum, Radix aristolochiae and Lignum santali albi. In this study, the β‐CD inclusion complexes were prepared separately for Styrax, Borneolumsyntheticum and the volatile oil extracted from the mixture of Olbanum, Radix aristolochiae and Lignum santali albi. Pellets were prepared in a centrifugal granulator using the powder layering technique and then divided into 3 equal weight portions and coated with HPMC, HPMCP HP‐55 and Eudragit L100/S100 to obtain gradient release in stomach, duodenum and jejunum or ileum respectively. On this basis, a pH‐dependent sustained‐release pellets system, “Guanxin Suhe Sustained‐release Capsules”(GSSC), was prepared by mixing the above three kinds of coated pellets at the weight ratio of 1:1:1. Pharmacokinetic (PK) studies between GSW and GSSC were made on male volunteers and isolated guinea pig hearts by plasma drug concentration method and serum pharmacology method respectively. In plasma drug concentration method, T_max was 0.42 h and 1.08 h for GSW and GSSC respectively, while in the serum pharmacology method, T_max was 0.56 h and 0.52 h respectively. The relative bioavailability of GSSC to GSW was 95.62% and 121.82% separately in the above two methods, indicating a similarity between the two methods in predicting the PK behavior of GSSC.     

Rapid Assessment Testing of Polymer Aluminum Electrolytic Capacitors in Elevated Temperature–Humidity Environments

Aluminum electrolytic capacitors with polymer electrolytes were developed to obtain lower equivalent series resistance (ESR) than that is achievable with liquid electrolytes. Replacement of the liquid electrolyte with a solid conductive polymer also overcomes the propensity of the liquid to evaporate over time, which leads to a reduction in capacitance and an increase in ESR values. However, capacitor manufacturers acknowledge that humidity can degrade the polymer, thereby having an adverse effect on the reliability of polymer aluminum (PA) capacitors. In the current study, surface mount and thru-hole PA capacitors from two different manufacturers were subjected to highly accelerated stress testing (110 °C, 85% RH) and elevated temperature–humidity (85 °C, 85% RH) conditions for rapid assessment. The polymer electrolyte in the capacitors was poly(3,4-ethylenedioxythiophene). Failure analysis was performed to determine the observed failure modes and the underlying failure mechanisms. The dominant failure modes observed were an increase in leakage current and an increase in ESR.     

Modeling of the Temperature State of Large‐Size Space Structures

A procedure of modeling of the temperature state of largesize space structures is considered. Results of modeling of the temperature state of a truss structure, the reflector of a reflectortype aerial, and the concentrator of a solar power unit are reported.     

High‐Temperature Radiative‐Convective Heat Exchange on the Surface of Glass‐Reinforced Plastics

The results of experimental investigations of heat exchange on the surface of a thermalprotective material — glassreinforced plastic — in the flows of hightemperature gases have been presented. It has been established that the influence of injection on the value of the heat flux does not exceed 10% in the range of variation of gas temperatures 300–2000 K and Reynolds numbers 350–9800.     

Aqueous Preparation and Evaluation of Albumin‐Chitosan Microspheres Containing Indomethacin

Controlled‐release egg albumin‐chitosan microspheres containing indomethacin as a model drug were successfully prepared by coacervation method. The proposed method can offer a simple method for microsphere preparation in an aqueous system with the elimination of the use of organic solvents that are usually needed in conventional techniques of microencapsulation. The interaction between negatively charged egg albumin molecules in phosphate buffer, pH 7.2, or sodium hydroxide solution and positively charged chitosan molecules dissolved in diluted acetic acid to form an insoluble precipitate was the principle for the formation of the microspheres. The effects of many process variables, such as amount of formaldehyde as a cross‐linking agent, stirring time, final pH of encapsulation medium, initial drug loading, and albumin concentration or albumin‐to‐chitosan weight ratio, on the properties of the prepared microspheres were investigated. Incorporation efficiencies of the microspheres to the drug were high in most cases and ranged between 63.3 ± 3.6% and 92.39 ± 3.2%, while particle sizes were 435.2 ± 12.6 up to 693.9 ± 34.6 µm for the different tested batches. On the other hand, the values of angles of repose and compressibility indices were in the range of 23.5 ± 0.4 to 32.0 ± 0.7 degrees and 11.1 ± 0.7% to 23.6 ± 0.7% respectively, which indicate overall good free flowing nature of the microspheres of all batches. The maximum required amount of the cross‐linking agent was determined to avoid excessive unnecessary chemicals. It was also noticed that excessive time of stirring and excessive initial drug loading are not recommended as it may lead to microspheres of low properties. The pH of the encapsulation media (pH 3.77 up to pH 4.91) significantly affected the properties of the microspheres. As the pH of the encapsulation media was increased, the incorporation efficiency, particle size, and flowability decreased, along with increase of drug release rate, which could be related to incomplete cross linking of the microspheres matrix. It was also observed that high concentration of albumin solution and accordingly the increase of albumin‐to‐chitosan weight ratio were accompanied with increases in incorporation efficiency and particle size with improved microsphere flowability and slow indomethacin release. Thus, the proposed microspheres showed the ability to control the release of indomethacin, and their properties were highly affected by many process variables that could be controlled to obtain an optimized system.     

Effect of Kollidon VA®64 particle size and morphology as directly compressible excipient on tablet compression properties

The study evaluates use of Kollidon VA^®64 and a combination of Kollidon VA^®64 with Kollidon VA^®64 Fine as excipient in direct compression process of tablets. The combination of the two grades of material is evaluated for capping, lamination and excessive friability. Inter particulate void space is higher for such excipient due to the hollow structure of the Kollidon VA^®64 particles. During tablet compression air remains trapped in the blend exhibiting poor compression with compromised physical properties of the tablets. Composition of Kollidon VA^®64 and Kollidon VA^®64 Fine is evaluated by design of experiment (DoE). A scanning electron microscopy (SEM) of two grades of Kollidon VA^®64 exhibits morphological differences between coarse and fine grade. The tablet compression process is evaluated with a mix consisting of entirely Kollidon VA^®64 and two mixes containing Kollidon VA^®64 and Kollidon VA^®64 Fine in ratio of 77:23 and 65:35. A statistical modeling on the results from the DoE trials resulted in the optimum composition for direct tablet compression as combination of Kollidon VA^®64 and Kollidon VA^®64 Fine in ratio of 77:23. This combination compressed with the predicted parameters based on the statistical modeling and applying main compression force between 5 and 15?kN, pre-compression force between 2 and 3?kN, feeder speed fixed at 25?rpm and compression range of 45–49?rpm produced tablets with hardness ranging between 19 and 21?kp, with no friability, capping, or lamination issue.     

Temperature Stabilization of Avalanche Photodetectors in Recirculation‐Type Information Systems

The influence of the temperature on the signaltonoise ratio in the optoelectronic recirculation circuit of an informationmeasuring system with an avalanche photodetector has been analyzed. It has been established that the temperature dependence of the pulse power of an injection laser has an influence on the width and position of the maximum in the temperature dependence of at the output of the photodetector in a recirculationtype system. The methods of maintenance of the avalanche multiplication factor of a photodetector at a given level have been proposed and their efficiency has been estimated.     

Modeling of the Temperature Field on a Thermodiffusion‐Galvanizing Line

Results of mathematical modeling of the temperature field in the working volume of a thermodiffusiongalvanizing unit on the basis of the assumptions of convective heat exchange are given.     

Modeling Temperature in Coupled Electrical and Thermal Simulations of the Electroconsolidation® Process

Electroconsolidation® is a process for densifying complex-shaped parts by using electrically conductive particulate solids as a pressure-transmitting medium. The part is immersed in a bed of the particulate medium contained in a die chamber. Sintering temperature is achieved by resistive heating of the medium while applying compaction pressure. The process is capable of ultrahigh temperatures and short cycle times and offers the potential for low processing costs. Control of the process and selection of process conditions require knowledge of the temperatures within the die. Temperature gradients exist because of the high heating rate and because of variations of density and electrical resistivity of the medium due to the presence of the part. Direct measurement of temperature with thermocouples or other conventional means is impractical because of the high temperatures, high currents, and high pressures that are involved. Therefore, a computer model was developed to predict temperature as a function of time and applied voltage for any location in the die. The computer model is composed of three parts: a geometrical model to approximate the density and resistivity variations in the medium, a finite-element model to calculate the rate of resistive heating within each element, and a finite-difference model to calculate the temperature distribution based on solution of the heat-transfer equations. Predicted temperatures have been shown to be in excellent agreement with measurements, and numerical simulation provided encouraging consistency and reasonably accurate predictions of temperature profiles within the die. The model demonstrated the feasibility of a new process to achieve simultaneous application of pressure and heat to powder densification in Electroconsolidation.     

Influence of a Long Stay of the Heat‐Release Surface in Kerosene on the Critical Heat Flux in Boiling in It under Steady‐State and Step Conditions of Heat Release

Results of experimental investigations of the influence of a long stay of the heatrelease surface in kerosene on the first critical density of the heat flux in boiling under the steadystate and step conditions of heat release are given.     

Evidences of Rubber Grafting on Activated Carbon Surfaces Containing Fullerene‐like Structures

Abstract

It is shown that graphite is converted into an high disordered carbon black by prolonged ball milling. The kinetics of this transformation has been followed by powder x‐ray diffraction, measurements of the crystallinity and of the surface area. Ball milling is able to introduce an high concentration of defective sites in the pristine graphite including the fullerene‐like structures. By mixing with natural rubber both the pristine and the ball‐milled graphite, it is shown by bound rubber measurements that the amount of rubber grafted (chemically linked) on the pristine graphite surface is negligible but reaches a very high level in the ball‐milled graphite. Similarly, ball‐milling of N660 carbon black causes a deep activation of its surface activity which can be measured by a significant increase in the bound rubber level and in the amount of grafted rubber in comparison to the pristine N660 sample. The bound rubber measurement has been performed also on a natural rubber masterbatch with extracted fullerene carbon black (EFCB). Also in this case extremely high levels of rubber grafting have been achieved in comparison to graphite. It is discussed and demonstrated that the fullerene‐like nanostructures in carbon blacks play a key role in the formation of bound rubber phenomenon and in grafting natural rubber on carbon black surface.     

The Limiting Capabilities of Injection‐Laser‐Based Recirculating Optical Range Finders under Actual Temperature Conditions

Using a method of mathematical simulation, it is shown that the maximum range measured by a GaAlAs injectionlaserbased recirculating optical range finder decreases linearly with increase in the environment temperature. The steepness of its decrease depends on the excess of the laser injection current over a threshold value. At temperatures nearly equal to room temperature, the maximum measured range increases nonlinearly with increase in the injection current, and for I > 2.5 I _thr this dependence is close to saturation, but it decreases nonlinearly with increase in the divergence angle of the injection laser radiation.     

Development of Local Injectable Dental Gel: The Influence of Certain Additives on Physicochemical Properties of Glycerylmonooleate‐Based Formulations

The current research study is based on the design and development of a sol‐gel biodegradable controlled‐release formulation for use in the treatment of periodontal diseases. Glycerylmonooleate (GMO) was used as a main composition in the gel base. The influence of various additives, e.g., glycerylmonostearate (GMS), methylcellulose (MC), surfactants, and triglycerides, in GMO formulations on rheologic and swelling properties and release characteristics was described. It was demonstrated that the surfactants and triglycerides affected rheologic behavior, whereas GMS and MC influenced both rheologic and swelling properties of the bases. The release study revealed that drug released from the gel bases depended on the square root of time. The kinetics can be explained by the Higuchi's diffusion theory. Some polyols could enhance drug release from the gel. The stability results suggested that the dental gels obtained should be kept in the low temperature range.