Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion

The objective of this research project was to determine the physicochemical properties and investigate the drug release mechanism from ethyl cellulose (EC) matrix tablets prepared by either direct compression or hot-melt extrusion (HME) of binary mixtures of water soluble drug (guaifenesin) and the polymer. Ethyl cellulose was separated into "fine" or "coarse" particle size fractions corresponding to 325-80 and 80-30 mesh particles, respectively. Tablets containing 30% guaifenesin were prepared at 10, 30, or 50 kN compaction forces and extruded at processing temperatures of 80-90 and 90-110 degrees C. The drug dissolution and release kinetics were determined and the tablet pore characteristics, tortuosity, thermal properties and surface morphologies were studied using helium pycnometry, mercury porosimetry, differential scanning calorimetry and scanning electron microscopy. The tortuosity was measured directly by a novel technique that allows for the calculation of diffusion coefficients in three experiments. The Higuchi diffusion model, Percolation Theory and Polymer Free Volume Theory were applied to the dissolution data to explain the release properties of drug from the matrix systems. The release rate was shown to be dependent on the ethyl cellulose particle size, compaction force and extrusion temperature.     

Modulation of drug release kinetics from hydroxypropyl methyl cellulose matrix tablets using polyvinyl pyrrolidone

Hydrophilic matrix tablets are widely used to extend the release of a broad range of pharmaceutically active materials. The mechanism and kinetics of drug release are dependent on the solubility of the active moiety and the swelling and erosion properties of the polymer, with water soluble compounds released predominantly by diffusion. The swelling and erosion properties of hydroxypropyl methyl cellulose (HPMC), typically lead to a first order release rate for water soluble compounds as opposed to the more desirable zero-order kinetics. In addition, for compounds with differences in regional absorption within the gastrointestinal tract a dosage form with a bi-modal release profile may be required, which is difficult to achieve with a simple dosage form. The following paper presents a simple, cost effective and elegant solution for achieving a range of predictable release profiles from linear to bi-modal for a water soluble drug (caffeine) from HPMC matrices, through the inclusion of polyvinyl pyrrolidone (PVP). Mechanistic studies using gel rheology, excipient dissolution and near-infrared microscopy (NIR) microscopy are presented which show that the modulation of drug release kinetics is mediated through a reduction in HPMC viscosity in the presence of a critical concentration of PVP, which leads to a break-up of the extended release tablet. A validated mathematical model is also presented which allows drug release profiles to be reliably predicted based on the initial HPMC and PVP content in the tablet.     

Influence of cellulose ether polymers on ketoprofen release from hydrophilic matrix tablets.

The present work reports the study of different ketoprofen:excipient formulations, in order to determine the effect of the polymer substitution and type of diluent on the drug-release mechanism. Substituted cellulose-methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose were used as polymers, while lactose monohydrate and beta-cyclodextrin were tested as diluents. Distinct test formulations were prepared, containing 57.14% of ketoprofen, 20.00% of polymer, 20.29% of diluent, and 1.71% of talc/0.86% of magnesium stearate as lubricants. The tablets were tested for their drug content, weight variation, hardness, thickness, tensile strength, friability, swelling and release ratio. Polymers MC25 and HPC were found not to be appropriate for the preparation of modified release ketoprofen hydrophilic matrix tablets, while HPMC K15M and K100M showed to be advantageous. The analysis of the release profiles in the light of distinct kinetic models (zero-order, first-order, Higuchi and Korsmeyer-Peppas) led to the conclusion that the type of polymer did not influence the release mechanism of the drug. The mean dissolution time (MDT) was determined, the highest MDT value being obtained for HPMC formulations. Moreover, the drug-release process was found to be slightly influenced by the type of diluent, either lactose or beta-cyclodextrin.     

The effect of polymer properties on direct compression and drug release from water-insoluble controlled release matrix tablets

The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon^® SR, Eudragit^® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (T_g), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low T_g (Kollidon^® SR < Eudragit^® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-T_g polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit^® RS < ethyl cellulose < Kollidon^® SR), as the high permeability was counteracted by PVP in case of Kollidon^® SR. Therefore, the T_g and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.     

Swelling and erosion of pectin matrix tablets and their impact on drug release behavior.

The aim of this study was to investigate swelling and erosion behaviors of hydrophilic matrix tablets using pectin and their impact on drug release. The matrix tablets were prepared by direct compression using different types of pectin. Swelling and erosion studies of pectin matrix tablets were carried out in various media. The pectin matrix tablets formed a continuous gel layer while in contact with the aqueous medium undergoing a combination of swelling and erosion. The swelling action of pectin matrices was controlled by the rate of its hydration in the medium. Release studies showed that the swelling and erosion of matrices influenced the drug release. The extent of matrix swelling, erosion and diffusion of drug determined the kinetics as well as mechanism of drug release from pectin-based matrix tablets. The release data showed a good fit into the power law or the Korsmeyer-Peppas equation indicating the combined effect of diffusion and erosion mechanisms of drug release.     

盐酸地尔硫卓缓释片的制备及释药因素考察

目的制备日服1次的盐酸地尔硫卓缓释片并对释药因素进行考察。方法分别单独采用羟丙基甲基纤维素(HPMC)、联合应用HPMC与羧甲基纤维素钠(CMC-Na)作为基本骨架材料制备盐酸地尔硫卓缓释片,并对影响释药的因素进行考察。结果HPMC规格、压片压力对药物的释放几乎无影响;HPMC用量、稀释剂用量对药物的释放产生一定的影响;CMC-Na用量对药物的释放有较大影响。结论HPMC和CMC-Na联合应用可以有效地解决水易溶性药物盐酸地尔硫卓释药快的问题,加入一定比例的微晶纤维素(MCC)能促进药物中后期释放,以制备日服1次的盐酸地尔硫卓缓释片。     

Controlled release of saccharides from matrix tablets.

The aim of this study was to design site specific, controlled release tablets of N-acetyl-d-glucosamine (NAG), maltose monohydrate and maltopentaose by using hydrophobic matrix formers starch acetate (SA) and ethyl cellulose (EC). The optimized matrices, which had either low porosity and high drug load or high porosity and low drug load, released the saccharides within the desired 2-4 h. In general, it was possible to control the release rate of saccharides by altering the relative amount of hydrophobic matrix former in the tablet and tablet porosity. The release type of saccharides from these formulations varied from immediate release to sustained release. In the case of sustained release formulations, it was found that the release of maltose monohydrate and maltopentaose was biphasic and slower than the release rate of NAG from similar tablets. NAG release kinetics followed square root of time kinetics, while in the case of maltose monohydrate and maltopentaose, the release kinetics were zero order in both phases. The biphasic dissolution profile was proposed to be caused by water mediated recrystallisation of the disordered material formed during the dissolution. Both SA and EC matrices were found to represent suitable controlled oral delivery vehicles for saccharides.     

Optimization and prediction of drug release from matrix tablets using response surface methodology and near infrared chemical imaging

The purpose of this work was to understand the formulation effect on the drug release from a hydrophilic matrix tablet of niacin using a multivariate statistical technique and Near Infrared Chemical Imaging (NIR-CI). Tablets were composed of ethyl cellulose (EC) and polyethylene oxide (PEO) as release retarding polymers and lactose as the release modulator. D-optimal experimental design was composed of three formulation variables: the content of EC(X(1)), PEO (X(2)), and lactose (X(3)). Response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to predict the optimal formulation. Results showed that the interaction effect of lactose with the polymers PEO and EC and lactose by itself were the most influential factors on the drug release rate. While lactose enhances the drug release rate by forming pores it also promotes water penetration into the tablet core. This in turn helps the formation of the gel layer which acts as barrier to drug diffusion. NIR-CI showed that tablets with higher level of PEO swells at a faster rate and greater extent than formulations with higher level of EC. NIR-CI was thus found to be a very useful technique to predict the drug release rate from hydrophilic matrix systems.     

Optimization and prediction of drug release from matrix tablets using response surface methodology and near infrared chemical imaging

The purpose of this work was to understand the formulation effect on the drug release from a hydrophilic matrix tablet of niacin using a multivariate statistical technique and Near Infrared Chemical Imaging (NIR-CI). Tablets were composed of ethyl cellulose (EC) and polyethylene oxide (PEO) as release retarding polymers and lactose as the release modulator. D-optimal experimental design was composed of three formulation variables: the content of EC(X₁), PEO (X₂), and lactose (X₃). Response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to predict the optimal formulation. Results showed that the interaction effect of lactose with the polymers PEO and EC and lactose by itself were the most influential factors on the drug release rate. While lactose enhances the drug release rate by forming pores it also promotes water penetration into the tablet core. This in turn helps the formation of the gel layer which acts as barrier to drug diffusion. NIR-CI showed that tablets with higher level of PEO swells at a faster rate and greater extent than formulations with higher level of EC. NIR-CI was thus found to be a very useful technique to predict the drug release rate from hydrophilic matrix systems.     

Correlation between the viscoelastic properties of the gel layer of swollen HPMC matrix tablets and their in vitro drug release

Abstract

Drug release from hydroxypropyl methylcellulose (HPMC) hydrophilic matrix tablets is controlled by drug diffusion through the gel layer of the matrix-forming polymer upon hydration, matrix erosion or combination of diffusion and erosion mechanisms. In this study, the relationship between viscoelastic properties of the gel layer of swollen intact matrix tablets and drug release was investigated. Two sets of quetiapine fumarate (QF) matrix tablets were prepared using the high viscosity grade HPMC K4M at low (70?mg/tablet) and high (170?mg/tablet) polymer concentrations. Viscoelastic studies using a controlled stress rheometer were performed on swollen matrices following hydration in the dissolution medium for predetermined time intervals. The gel layer of swollen tablets exhibited predominantly elastic behavior. Results from the in vitro release study showed that drug release was strongly influenced by the viscoelastic properties of the gel layer of K4M tablets, which was further corroborated by results from water uptake studies conducted on intact tablets. The results provide evidence that the viscoelastic properties of the gel layer can be exploited to guide the selection of an appropriate matrix-forming polymer, to better understand the rate of drug release from matrix tablets in vitro and to develop hydrophilic controlled-release formulations.     

Effect of formulation variables on drug and polymer release from HPMC-based matrix tablets

The objective of this work was to assess the effect of two formulation variables, hydroxypropylmethylcellulose (HPMC)/lactose ratio and HPMC viscosity grade, on the release of a model drug and HPMC, as well as the mechanism of drug release from HPMC-based matrix tablets. A water-soluble compound, adinazolam mesylate, was used as the model drug. Both drug and HPMC release were found to be a function of the formulation variables, with higher drug and HPMC release rates for formulations with lower HPMC/lactose ratios and lower HPMC viscosity grades. However, the K15M and K100M formulations had identical drug release profiles. All the drug release data fit well to the Higuchi expression. By comparing the drug and HPMC release data, it was concluded that diffusion of drug through the hydrated gel layer was the predominant drug release mechanism for most of the formulations studied.     

Swelling and drug release behaviour of xanthan gum matrix tablets

The swelling and drug release behaviour of xanthan gum matrix tablets were studied using three drugs having different properties, i.e., caffeine as a soluble neutral drug, indomethacin as an insoluble acidic drug, and the sodium salt of indomethacin as a soluble acidic drug. Swelling was ascertained by measuring the axial and the radial expansion of matrix tablets following exposure to media of physiological ionic strength. The mean drug dissolution time and swelling rate were calculated from dissolution and swelling experiments, respectively, and were used as responses for comparison under different experimental conditions. The dependence of drug release on the swelling of the polymer matrix and on the type of the drugs added was established. The former is mainly influenced by the ionic strength and buffer concentrations. The latter is affected by the solubility of the drug. The mechanism of matrix swelling follows Case I diffusion, whereas drug release from this polymer matrix conforms to Case II diffusion.     

The effect of the physicochemical properties of a drug on its release from chitosonium malate matrix tablets

The effect of the physico-chemical properties of an active compound (such as solubility and molecular size) on its release characteristics from chitosonium malate matrix tablets has been investigated. For this purpose, the release of 11 drugs of various solubilities (1 in < 1 to 1 in 10000) and molecular weights (138–375) through chitosonium malate matrix tablets was studied. It may be concluded that, in addition to the solubility, the molecular size of drug is of importance in the drug release characteristics from the chitosonium malate matrix. When the release data (< 60%) were fitted to the simple power law equation, the mode of drug release from the chitosonium malate matrix was generally non-Fickian and Super Case II type. These drugs (timolol maleate, ephedrine, propranolol hydrochloride, acetylsalicylic acid, naproxen, sulphadiazine, indomethacin and pindolol) can be released at a nearly zero-order rate through the matrix.     

PH-dependent drug release from certain commercial tablets.

A dissolution-dialysis profile for each of several brands of nitrofurantoin, hydrochlorothiazide and sulfisoxazole tablets was developed at three pH levels. The study used a two-compartment diffusion cell with a semipermeable cellophane membrane. Nitrofuratoin tablets were tested at pH values of 7.2, 4.7 and 1.2; sulfisoxazole tablets at 7.2, 5.5 and less than 1. Studies with hydrochlorothiazide tablets were terminated because the pH of the dissolution medium had no effect of practical significance on dissolution or dialysis rates. The dissolution rates of the nitrofurantoin and sulfisoxazole tablets were highly brand-individualized and complex. The effects of pH upon a particular formulation were unpredictable. The results suggest that dissolution testing at one fixed pH, as commonly practiced, may be insufficient for some products. This pH-dependent release characteristic may not correspond to a change in bioavailability in all cases, but it represents a potential problem which should be considered by the formulator.     

Model drug release from matrix tablets composed of HPMC with different substituent heterogeneity

The release of a model drug substance, methylparaben, was studied in matrix tablets composed of hydroxypropyl methylcellulose (HPMC) batches of the USP 2208 grade that had different chemical compositions. It was found that chemically heterogeneous HPMC batches with longer sections of low substituted regions and lower hydroxypropoxy content facilitated the formation of reversible gel structures at a temperature as low as 37°C. Most importantly, these structures were shown to affect the release of the drug from matrix tablets, where the drug release decreased with increased heterogeneity and a difference in T80 values of 7h was observed between the compositions. This could be explained by the much lower erosion rate of the heterogeneous HPMC batches, which decreased the drug release rate and also released the drug with a more diffusion based release mechanism compared to the less heterogeneous batches. It can therefore be concluded that the drug release from matrix tablets is very sensitive to variations in the chemical heterogeneity of HPMC.     

Biphasic drug release from film-coated tablets

A study was carried out into the biphasic drug release properties of film-coated paracetamol tablets. The tablet cores were formulated without a disintegrant and film-coated with a coating formulation consisting of pectin, chitosan and hydroxypropylmethylcellulose in a ratio of 6:1:0.37. The tablet cores and the film-coated tablets with coat weight gains (CWGs) of 6, 9 and 13% were evaluated for their water absorption (swelling) and drug release properties. All the tablets absorbed water from pH 6.0 Sorensen's phosphate buffer and the amount of water absorbed increased with an increase in tablet CWG. The addition of 100 μl/50 ml pectinolytic enzymes to the medium resulted in at least a 40% reduction in the amount of water absorption by the tablets, as compared to the medium without enzymes. When the enzyme concentration was increased to 200 μl/50 ml, there was a further reduction (8% w/w) in the amount of water absorbed by the tablets. Drug release was controlled in upper gastrointestinal fluids and decreased with an increase in tablet CWG. Drug release was, however, accelerated in the presence of pectinolytic enzymes, consistent with the entry of the tablets in the colon. An evaluation of the drug release data by the Korsmeyer–Peppas equation showed the involvement of molecular diffusion and other factors such as film/tablet erosion and drug dissolution in drug release.