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     

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.     

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.     

Shedding Light on the Role of Misfit Strain in Controlling Core–Shell Nanocrystals

Heteroepitaxial modification of nanomaterials has become a powerful means to create novel functionalities for various applications. One of the most elementary factors in heteroepitaxial nanostructures is the misfit strain arising from mismatched lattices of the constituent parts. Misfit strain not only dictates epitaxy kinetics for diversifying nanocrystal morphologies but also provides rational control over materials properties. In recent years, advances in chemical synthesis along with the rapid development of electron microscopy and X-ray diffraction techniques have enabled a substantial understanding of strain-related processes, which offers theoretical foundation and experimental guidance for researchers to refine heteroepitaxial nanostructures and their properties. Herein, recent investigations on heterogeneous core–shell nanocrystals containing misfit strains are summarized, with a focus on the mechanistic understanding of strain and strain-induced effects such as tuning the epitaxial habit, modulating the optical emission, and enhancing the catalytic activity and magnetic coercivity.     

Effect of the Drug–Excipient Ratio in Matrix-Type-Controlled Release Systems: Computer Simulation Study

The main objective of this work is to study the drug release behavior from inert matrix systems by using computer simulation. This study allowed us to propose a new statistical method to evaluate the drug percolation threshold as a function of the exposed surface area of the device. The matrix system was simulated as a simple cubic lattice. The sites of the lattice were randomly occupied at various drug–excipient ratios. By simulating a diffusive process, the drug was delivered from the matrix system. The obtained release profiles were fitted to two different models: near the excipient percolation threshold, the square root of the time was well fitted, whereas close to (but above) the drug percolation threshold, the power law described accurately the release data. A relationship between the initial drug load and the amount of drug trapped inside the matrix system at infinite time was found. This relationship was conveniently described by an error function. Percolation thresholds in the matrix systems were determined from the latter relationship by using a nonlinear regression method. The assessment of percolation thresholds depends on the exposed surface area of the matrix systems. Moreover, estimated percolation thresholds were in agreement with the predicted values stated in the percolation theory.     

In Vitro–In Vivo Characterization of Release Modifying Agents for Parenteral Sustained‐Release Ketorolac Formulation

One of the prerequisites for a parenteral preparation is that the excipients incorporated are biocompatible and biodegradable. In the present study hydrophilic and hydrophobic excipients were investigated for developing an intramuscular sustained‐release formulation of ketorolac. Kollidon® 17 PF, Peceol (glyceryl monooleate), and castor oil were chosen as the potential release‐retarding agents, each with a distinct mechanism of action. They were evaluated by in vitro drug‐release profiles and in vivo pharmacodynamic and pharmacokinetic study in mice. Cumulative drug release was determined for standard and test formulations in modified Franz diffusion cell. Pharmacodynamic parameter, T?=?70% response of peak analgesic response, was used to compare the performance of test formulations. Based on pharmacodynamic/pharmacokinetic correlation in the animal studies, Css_max and Css_min of 51.39 and 30.0 µg/mL, respectively, were determined and considered as performance markers for pharmacokinetic evaluation of test formulations. The study suggested that the sustained‐release capability of glyceryl monooleate was maximum followed by that of castor oil and Kollidon 17 PF, when compared to conventional ketorolac tromethamine formulation. It was inferred that water soluble excipient, though, showed release retarding property in vitro but could not maintain it in the in vivo environment. Glyceryl monooloeate‐based formulation produced the most favorable drug blood concentration vs. time profile.     

Oral Controlled Release Formulation for Highly Water‐Soluble Drugs: Drug–Sodium Alginate–Xanthan Gum–Zinc Acetate Matrix

An oral controlled release formulation matrix for highly water‐soluble drugs was designed and developed to achieve a 24‐hour release profile. Using ranitidine HCl as a model drug, sodium alginate formulation matrices containing xanthan gum or zinc acetate or both were investigated. The caplets for these formulations were prepared by direct compression and the in vitro release tests were carried out in simulated intestinal fluid (SIF, pH7.5) and simulated gastric fluid (SGF, pH1.2). The release of the drug in the sodium alginate formulation containing only xanthan gum completed within 12 hours in the SIF, while the drug release in the sodium alginate formulation containing only zinc acetate finished almost within 2 hours in the same medium. Only the sodium alginate formulation containing both xanthan gum and zinc acetate achieved a 24‐hour release profile, either in the SIF or in the pH change medium. In the latter case, the caplet released in the SGF for 2 hours was immediately transferred into the SIF to continue the release test. The results showed that the presence of both xanthan gum and zinc acetate in sodium alginate matrix played a key role in controlling the drug release for 24 hours. The helical structure and high viscosity of xanthan gum might prevent zinc ions from diffusing out of the ranitidine HCl–sodium alginate–xanthan gum–zinc acetate matrix so that zinc ions could react with sodium alginate to form zinc alginate precipitate with a cross‐linking structure. The cross‐linking structure might control a highly water‐soluble drug to release for 24 hours. Evaluation of the release data showed the release mechanism for the novel formulation might be attributed to the diffusion of the drug.     

Polyelectrolyte–Drug Complexes of Lambda Carrageenan and Basic Drugs: Relevance of Particle Size and Moisture Content on Compaction and Drug Release Behavior

The interaction between polyelectrolytes (PE) and oppositely charged drugs (D) results in complexes (PE–D) that can be exploited in controlled release drug delivery systems. The aim of this work is to better understand the relevance of some preparative parameters such as moisture content and particle size on the performance of two PE–D complexes to be used in oral controlled release tablets. PE–D complexes containing diltiazem HCL (DTZ) or metoprolol tartrate (MTP) and lambda carrageenan were obtained at two particle size levels (<45 μm and 75–105 μm), maintained at different values of relative humidity (RH) (11, 52, 75, and 93%), and compressed. The tablets were characterized for porosity, hardness, moisture content, and contact angle. Drug release profiles were fitted to the Weibull equation, and a factorial design was used to understand the relevance of particle size and RH% on release rate as a function of medium pH. The results indicated that the hydrophobic character of the complex between PE and D depended on the drug and in the present case was more pronounced for DTZ than for MTP. This in turn affected the possible release mechanism and therefore the importance of particle size and RH%.     

Evaluation of the Tablet Core Factors Influencing the Release Kinetics and the Loadability of Push–Pull Osmotic Systems

Push–pull osmotic systems have been developed to deliver poorly soluble drugs in a modified-release fashion. The aim of this study was to investigate the influence of the tablet core factors on the drug release kinetics and loadability. The release kinetics was efficiently modulated by varying either the proportion of osmotic agent or the drug layer polymer grade as an alternative to change the membrane characteristics. High osmotic agent proportions and viscous-grade polymers were recommended to formulate high drug loads up to 20%?without losing both the release completeness and the zero-order drug release kinetics.     

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.     

Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs – Part 1 Acetaminophen

The aim of this study was to characterize and evaluate a modified release, multiparticulate tablet formulation consisting of placebo beads and drug-loaded beads. Acetaminophen (APAP) bead formulations containing ethylcellulose (EC) from 40–60% and placebo beads containing 30% calcium silicate and prepared using 0–20% alcohol were developed using extrusion–spheronization and studied using a central composite experimental design. Particle size and true density of beads were measured. Segregation testing was performed using the novel ASTM D6940-04 method on a 50:50 blend of uncoated APAP beads (60%EC) : calcium silicate placebo beads (10% alcohol). Tablets were prepared using an instrumented Stokes-B2 rotary tablet press and evaluated for crushing strength and dissolution rate. Compared with drug beads (60%EC), placebo beads (10% alcohol) were smaller but had higher true densities: 864.8 μm and 1.27 g/cm³, and 787.1 μm and 1.73 g/cm³, respectively. Segregation testing revealed that there was approximately a 20% difference in drug content (as measured by the coefficient of variation) between initial and final blend samples. Although calcium silicate-based placebo beads were shown to be ineffective cushioning agents in blends with Surelease^®-coated APAP beads, they were found to be very compactibile when used alone and gave tablet crushing strength values between 14 and 17 kP. The EC in the APAP bead matrix minimally suppressed the drug release from uncoated beads (t_100%?=?2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t_60%= 5 h) compared with calcium silicate-based placebos, some coating damage (～30%) still occurred on compression as release was faster than coated APAP beads alone. While tablets containing coated drug beads can be produced with practical crushing strengths (>8 kP) and low compression pressures (10–35 MPa), dissolution studies revealed that calcium silicate-based placebos are ineffective as cushioning agents. Blend segregation was likely observed due to the particle size and the density differences between APAP beads and calcium silicate-based placebo beads; placebo bead percolation can perhaps be minimized by increasing their size during the extrusion–spheronization process. The GMS- based placebos offer greater promise as cushioning agents for compacted, coated drug beads; however, this requires an optimized compression pressure range and drug bead : placebo bead ratio (i.e., 50:50).     

Ultrasonic Velocity Studies of Drug Parvon-spas in Mixed Alcohol–Water Solvent Systems at 25°C

Ultrasonic velocities and densities of the drug Parvon-spas in binary mixtures of water with methanol (MeOH), ethanol (EtOH), and propan-1-ol (1-PrOH) have been measured over the complete solvent composition range at 10 mol% intervals at 25°C. Various acoustic parameters such as the acoustic impedance (Z), adiabatic compressibility (β), intermolecular free length (L_f), relative association (R.A.), molar volume (V_m), and molar sound velocity (R_m) have been calculated. In addition, excess functions, i.e., excess adiabatic compressibility (β^E), excess intermolecular free length (L_f^E), excess molar volume (V^E), excess ultrasonic velocity (U^E), and excess acoustic impedance (Z^E) for these three solvent mixtures in the absence and presence of the drug have been calculated. A different behavior of these parameters in these alcohol systems has been discussed in terms of the length of the alcohol molecule, the molecular volume, as well as inter/intramolecular interactions of these molecules.     

Gradient-Concentration Design of Stable Core–Shell Nanostructure for Acidic Oxygen Reduction Electrocatalysis

Manipulating the surface structure of electrocatalysts at the atomic level is of primary importance to simultaneously achieve the activity and stability dual-criteria in oxygen reduction reaction (ORR) for proton exchange membrane fuel cells. Here, a durable acidic ORR electrocatalyst with the “defective-armored” structure of Pt shell and Pt–Ni core nanoparticle decorated on graphene (Pt–Ni@Pt_D/G) using a facile and controllable galvanic replacement reaction to generate gradient distribution of Pt–Ni composition from surface to interior, followed by a partial dealloying approach, leaching the minor nickel atoms on the surface to generate defective Pt skeleton shell, is reported. The Pt–Ni@Pt_D/G catalyst shows impressive performance for ORR in acidic (0.1 m HClO₄) electrolyte, with a high mass activity of threefold higher than that of Pt/C catalyst owing to the tuned electronic structure of locally concave Pt surface sites through synergetic contributions of Pt–Ni core and defective Pt shell. More importantly, the electrochemically active surface areas still retain 96% after 20 000 potential cycles, attributing to the Pt atomic shell acting as the protective “armor” to prevent interior Ni atoms from further dissolution during the long-term operation.     

Synthesis of Palladium-Based Crystalline@Amorphous Core–Shell Nanoplates for Highly Efficient Ethanol Oxidation

Phase engineering of nanomaterials (PEN) offers a promising route to rationally tune the physicochemical properties of nanomaterials and further enhance their performance in various applications. However, it remains a great challenge to construct well-defined crystalline@amorphous core–shell heterostructured nanomaterials with the same chemical components. Herein, the synthesis of binary (Pd-P) crystalline@amorphous heterostructured nanoplates using Cu_3−χP nanoplates as templates, via cation exchange, is reported. The obtained nanoplate possesses a crystalline core and an amorphous shell with the same elemental components, referred to as c-Pd-P@a-Pd-P. Moreover, the obtained c-Pd-P@a-Pd-P nanoplates can serve as templates to be further alloyed with Ni, forming ternary (Pd-Ni-P) crystalline@amorphous heterostructured nanoplates, referred to as c-Pd-Ni-P@a-Pd-Ni-P. The atomic content of Ni in the c-Pd-Ni-P@a-Pd-Ni-P nanoplates can be tuned in the range from 9.47 to 38.61 at%. When used as a catalyst, the c-Pd-Ni-P@a-Pd-Ni-P nanoplates with 9.47 at% Ni exhibit excellent electrocatalytic activity toward ethanol oxidation, showing a high mass current density up to 3.05 A mg_Pd⁻¹, which is 4.5 times that of the commercial Pd/C catalyst (0.68 A mg_Pd⁻¹).     

Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs—Part II Theophylline and Cimetidine

The purpose was to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit^® RS 30D were developed and beads were produced by extrusion–spheronization. Drug beads were coated using 15% wt/wt Surelease^® or Eudragit^® NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm³ and size of 855 μm were quite close to Surelease^®-coated drug beads. Curing improved the crushing strength and friability values for theophylline tablets containing Surelease^®-coated beads; 5.7 ± 1.0 kP and 0.26 ± 0.07%, respectively. Dissolution profiles showed that the EC matrix only provided 3 h of drug release. Although tablets containing Surelease^®-coated theophylline beads released drug fastest overall (t_44.2% = 8 h), profiles showed that coating damage was still minimal. Size and density differences indicated a minimal segregation potential during tableting for blends containing Surelease^®-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease^®-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease^® films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.