Hydrophilic Matrix Tablets Research Articles

Multivariate statistical approach to optimizing sustained-release tablet formulations containing diltiazem hydrochloride as a model highly water-soluble drug

A multivariate statistical technique was applied to designing a tablet for the sustained release over 24 h of diltiazem hydrochloride, a model highly water-soluble drug. Tablets of a hydrophilic matrix composed of dextran derivatives and hypromellose were prepared. The formulations were optimized using a nonlinear-response surface method incorporating thin-plate spline interpolation (RSM-S). A bootstrap (BS) resampling method was used to estimate the confidence intervals of the optimal formulations. The response surfaces estimated by RSM-S visualized the effects of the formulation factors, and the optimal release profile for diltiazem was predicted quantitatively as a function of the quantities of the formulation factors, using RSM-S. The simultaneous optimal solutions and their confidence intervals were estimated using RSM-S and BS resampling. The results clearly indicate nonlinear relationships between the formulation factors and the response variables. The observed responses of the optimal preparation coincided well with the predicted responses. The optimal hydrophilic matrix tablet allowed almost zero-order release of diltiazem hydrochloride for 24 h. In conclusion, an oral sustained-release tablet formulation, active over a long period, was successfully optimized using RSM-S, and the reliability of the optimal solution was evaluated using BS resampling.

Study of the critical points of experimental HPMC–NaCMC hydrophilic matrices

The purpose of the present work was to study the existence of critical points on the drug release and water uptake behaviour of ternary hydrophilic matrix tablets and to study the possibility of simplifying a ternary to a binary system. The ternary hydrophilic matrix tablets were prepared between 40 and 100% (w/w) of KCl, HPMC and NaCMC. Dissolution studies were carried out using the paddle method and the water uptake studies were measured using the modified Enslin apparatus and the behaviour of the kinetic parameters was studied. According to the percolation theory, both studies confirm the existence of critical points; those were related to the excipients percolation tresholds. The percolation thresholds for the binary hydrophilic matrix tablets were found between 28.7–40.7% (v/v) of HPMC and 38.6–53.9% (v/v) of NaCMC. For the ternary hydrophilic matrix tablets, the existence of a critical barrier between 54 and 61% (v/v) KCl (60–70%, w/w of KCl) was found. In the studied ternary systems HPMC and NaCMC showed that is not possible to simplify the system but they present a partial collaboration in order to establish the gel layer. The knowledge of this critical barrier will be useful in order to optimize the design of the ternary hydrophilic matrix systems.

Influence of Different Polymer Types on the Overall Release Mechanism in Hydrophilic Matrix Tablets

The effect of three different types of polymer chain structures on the polymer release from hydrophilic matrix tablets was investigated by comparing a synthetic semi-crystalline linear polymer (PEO), a branched amorphous polysaccharide (dextran) and an amorphous substituted cellulose derivative (HPMC). The polymer release rates for tablets containing mixtures of high and low molecular weight grades in different ratios were determined by using a modified USP II method and a SEC-RI chromatography system. The results showed that independent of polymer type: (i) plots of the release versus time had similar shapes, (ii) the release of long and short polymer chains was equal and no fractionation occurred during the release and (iii) the release rate could be related to the average intrinsic viscosity of the polymer mixtures. This confirms the hypothesis that the release rate can be related to a constant viscosity on the surface of the hydrophilic matrix tablet and that it is valid for all the investigated polymers.

Application of dynamic neural networks in the modeling of drug release from polyethylene oxide matrix tablets

The main objective of this study was to demonstrate the possible use of dynamic neural networks to model diclofenac sodium release from polyethylene oxide hydrophilic matrix tablets. High and low molecular weight polymers in the range of 0.9–5 × 10 6 have been used as matrix forming materials and 12 different formulations were prepared for each polymer. Matrix tablets were made by direct compression method. Fractions of polymer and compression force have been selected as most influential factors on diclofenac sodium release profile. In vitro dissolution profile has been treated as time series using dynamic neural networks. Dynamic networks are expected to be advantageous in the modeling of drug release. Networks of different topologies have been constructed in order to obtain precise prediction of release profiles for test formulations. Short-term and long-term memory structures have been included in the design of network making it possible to treat dissolution profiles as time series. The ability of network to model drug release has been assessed by the determination of correlation between predicted and experimentally obtained data. Calculated difference ( f 1) and similarity ( f 2) factors indicate that dynamic networks are capable of accurate predictions. Dynamic neural networks were compared to most frequently used static network, multi-layered perceptron, and superiority of dynamic networks has been demonstrated. The study also demonstrated differences between the used polyethylene oxide polymers in respect to drug release and suggests explanations for the obtained results.

Hydration, Erosion, and Release Behavior of Guar-Based Hydrophilic Matrix Tablets Containing Total Alkaloids of Sophora alopecuroides

It is a challenge to deliver water-soluble drug based on hydrophilic matrix to colon because of swelling and erosion of polysaccharides in contact with media. In our study, guar-based hydrophilic matrix tablets containing water-soluble total alkaloids of Sophora alopecuroides prepared by wet granulation technique were evaluated. A novel method was established to investigate the changes of swelling and volume for guar-based tablets in undynamic state, which generally showed a rapid swelling and volume change in the first 9 h, then the hydrated speed slowed down. On the other hand, the influence of different pH of the media on water uptake and erosion of various guar-based formulations in dynamic state indicated that the hydrated constants in simulated gastric fluid (SGF) was higher than that in SIF, which followed varied mechanism of water penetration by fitting Davidson and Peppas model. The extent of erosion was between 22.4 and 32.6% in SIF within 360 min. In vitro sophoridine release studies in successive different mimicking media showed that the guar matrix tablets released 13.5–25.6% of sophoridine in the first 6 h; therefore it was necessary to develop the bilayer matrix tablet by direct-compressing coating 100 mg guar granula on core tablet. The initial release of coated tablet was retarded and the bilayer matrix tablet was suitable for colon target.

Determination of the percolation thresholds for polyethylene oxide and polyacrylic acid matrix tablets

Abstract The purpose of this study was to implement the concepts of percolation theory in the characterization of drug release from hydrophilic matrix tablets. Percolation theory is a powerful statistical tool that enables mathematical insight into geometrically complex and disordered systems. Matrix tablets are effective substrate for the implementation of percolation theory because of their inherent disordered structure. The objective was to predict percolation thresholds of polyethylene oxide and polyacrylic polymers in diclofenac sodium hydrophilic matrices. Matrix tablets were prepared using polyethylene oxide or polyacrylic acid as matrix forming materials and diclofenac sodium was used as a model drug substance. Ten formulations with different drug/excipient ratios were prepared using the direct compression method. Dissolution studies were performed using the paddle apparatus method. For estimating percolation threshold the change of the kinetic parameters in aspect to the volumetric fraction of excipient plus initial porosity of the tablets was studied. Observed critical points with sudden changes in behavior of kinetic parameters can be attributed to the percolation thresholds. Percolation threshold is found to be 60.22% v/v polyethylene oxide + initial porosity and 39.94% v/v polyacrylic acid + initial porosity. The results obtained demonstrate that percolation theory can be used to design and develop matrix tablet formulations. Determination of percolation threshold is a useful tool for preparing robust formulations.

Formulation and optimization of sustained release tablets of venlafaxine resinates using response surface methodology

The aim of the current study was to design sustained release matrix tablets of venlafaxine hydrochloride using ion exchange resin with the incorporation of hydrophilic and hydrophobic polymer combinations. Venlafaxine HCl was loaded onto Indion 244 by batch method and then resinate were wet granulated with ethyl cellulose and blended with hydroxypropylmethylcellulose and compressed. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile at 2 h and at 18 h. Hydroxypropylmethylcellulose and ethylcellulose were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. Resinate shows inadequate sustained release profile. Compressed matrices exhibited the anomalous release mechanism, as the value of release rate exponent (n) varied between 08109 and 08719, resulting in regulated and complete release until 20 h. Validation of optimization study, performed using five confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error as 1.152±1.88%. Regulated drug release study indicates that the hydrophilic and hydrophobic matrix tablets of venlafaxine resinate prepared using hydroxypropylmethylcellulose and ethylcellulose, can successfully be employed as a once-a-day oral controlled release drug delivery system.

Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

The effect of chemical heterogeneity of HPMC on polymer release from matrix tablets

Polymer release from hydrophilic matrix tablets, composed of hydroxypropyl methylcellulose, was studied for seven different polymer batches. A time difference of more than 80 h between fully dissolved tablets was noticed although the batches were of the same pharmaceutical substituent (USP 2208) and viscosity (100 cps) grade. To find the functionality related parameters for polymer release from hydrophilic matrix tablets the polymer samples were characterised according to size and chemical composition. The size of the polymers was characterised by size-exclusion chromatography with multi-angle light scattering and refractive index detection. The average amount of substituents was measured with nuclear magnetic resonance and the distribution of the substituents along the cellulose chain was determined with high-performance anion-exchange chromatography with pulsed amperometric detection after acid and enzymatic hydrolysis. The results indicated that other types of interactions apart from entanglements were present between the polymer chains, which seemed to affect the polymer release. Most importantly, this study has shown a correlation between the polymer release and the substituent pattern, where the samples with slow release also were more heterogeneously substituted along the polymer chain. From this we can conclude that polymer release is very sensitive to alterations in chemical composition.

Investigation of critical polymer properties for polymer release and swelling of HPMC matrix tablets

Four different HPMC batches were characterized to investigate properties related to critical functionality for their use in hydrophilic matrix tablets. In this study, the HPMC batches were chemically characterized and correlated to the behaviour of pure HPMC tablets. Parameters such as the molecular weight, viscosity, intrinsic viscosity and radius of gyration were kept in a rather limited range, which resulted in a weak correlation to polymer release and degree of swelling. The hydrophilic/hydrophobic character of the HPMC samples was elucidated by the degree of substitution and by the clouding behaviour, where an increased hydrophilicity increased the tablet swelling. This phenomenon was interpreted in a refined model for water transport into HPMC tablets. A five times slower polymer release and a considerably larger degree of swelling were found for one batch of HPMC tablets compared to the others, although the characterized average polymer parameters were in the same range. However, the conformation plot displayed a fraction with compact aggregates. In conclusion, the existence of aggregates in aqueous solution seems to perturb the functionality of HPMC tablets and it seems important to understand and characterize these aggregates to fully predict the polymer release and swelling of HPMC tablets.

Dissolution monitoring of hydrophilic matrix tablets by using frequency information of ultrasound echo

Dissolution monitoring of hydrophilic matrix tablets by using frequency information of ultrasound echo

Oral Controlled Release Formulations of Rifampicin. Part II: Effect of Formulation Variables and Process Parameters on In Vitro Release

Hydrophilic controlled release matrix tablets of rifampicin, a poorly soluble drug, have been formulated using hydroxypropyl methylcellulose (HPMC) polymer (low, medium, and high viscosity) by direct compression method. Influence of formulation variables and process parameters such as drug:HPMC ratio, viscosity grade of HPMC, drug particle size, and compression force on the formulation characters and drug release has been studied. Our results indicated that the release rate of the drug and the mechanism of release from the HPMC matrices are mainly controlled by the drug:HPMC ratio and viscosity grade of the HPMC. In general, decrease in the drug particle size decreased the drug release. Lower viscosity HPMC polymer was found to be more sensitive to the effect of compression force than the higher viscosity. The formulations were found to be stable and reproducible.

Preparation and In Vitro Evaluation of Controlled Release Hydrophilic Matrix Tablets of Ketorolac Tromethamine Using Factorial Design

Controlled release matrix tablets of ketorolac tromethamine (KT) were prepared by direct compression technique using cellulose derivatives as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC) in different concentrations (10–20%). The effect of polymer type and concentration was investigated on drug release by 2³ factorial design. For the quality control of matrix tablets, weight deviation, hardness, friability, diameter–height ratio, content uniformity of KT, and in vitro dissolution technique were performed. UV Spectrophotometric method was used to detection of KT in matrix tablets. This method was validated. Dissolution profiles of the formulations were plotted and evaluated kinetically. An increase in polymer content resulted with a slow release rate of drug as was expected. According to the dissolution results, tablets prepared with HPMC + HEC + CMC (F1 and F8) were found to be the most suitable formulation for KT. About 99.27% KT was released from F8 in 7 h.

Oral floating extended release stavudine hydrophilic matrix tablets: formulation design and <i>in vitro</i> investigations

Stavudine (d4T) is a nucleoside analogue reverse transcriptase inhibitor commonly used as part of highly active antiretroviral therapy, which is administered twice a day. Formulation of extended-release (ER) d4T improves patient compliance and minimizes dose related side effects. This study, therefore, aims at formulating once-a-day floating d4T ER hydrophilic matrix tablets using hydroxypropyl methylcellulose (HPMC) as a release-modifying polymer. NaHCO3 and microcrystalline cellulose (MCC), grade Avicel® PH 101, were used as floating aid and release modifier, respectively. The effects of the levels of NaHCO 3 (5 -10%), MCC (25 - 40%) and compression force (CF) (10 - 20 KN) on floating lag time, friability (Fr), release, and other tablet characteristics were assessed. The release kinetics was determined by fitting the data into different models. Floating lag-time, Fr and d4T release were optimized using a 2-level 3-factor full factorial experimental design and the optimum regions obtained were validated and therapeutic levels of d4T release were obtained for a period of 24 h from all formulations. The results indicated that CF has considerable impact on floating lag time. The floating lag-time of the tablets, at a CF of 10 KN and concentrations of MCC and NaHCO 3 indicated above, was below 25 min. However, when the CF was raised to 20 KN, the minimum lag time was 75 min. The effect of NaHCO3 on floating lag time was dependent on the level of MCC, suggesting that its level should be increased with MCC level. For acceptable Fr, MCC should be increased at a lower level of NaHCO 3 . CF significantly decreased Fr. Thus, Fr and floating lag time are absolutely competitive responses. Therefore, an optimum region for these responses was obtained. As evidenced by the similarity factor, the release rate was not significantly affected by the levels of NaHCO 3 , MCC or CF. Nonetheless, optimum region for the desired drug release was obtained which followed first order at 25% MCC level, and Korsemeyer-Peppas model at 40%. Validation of the optimum formulation confirmed the results obtained. Thus, the in vitro results showed that the d4T regimen could be reduced from twice a day to once a day. . Ethiopian Pharmaceutical Journal Vol. 25 (1) 2007: pp. 51-62

Investigation of the Influence of Particle Size on the Excipient Percolation Thresholds of HPMC Hydrophilic Matrix Tablets

In previous papers of our research group, a linear relationship between the drug percolation threshold and the relative drug particle size (drug/excipient) has been found, in the case of the inert matrices. The objective of the present paper is to investigate the influence of the particle size on the excipient percolation threshold in the case of hydrophilic matrices. This influence can have important consequences on the release behaviour of these controlled release devices. Matrix tablets have been prepared using KCl/Lobenzarit Disodium as drugs and HPMC K4M as matrix forming material, employing six different excipient/drug particle size ratios (ranging from 0.42 to 4.16). The formulations studied contain a drug loading in the range of 20-90% (w/w). In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the volumetric fraction of each component at time zero, was studied. The obtained results support the existence of a linear relationship between a component percolation threshold (drug or excipient) and its relative particle size (drug/excipient in the case of the drug percolation threshold or excipient/drug in the case of the excipient percolation threshold). This relationship is valid for different drugs, excipients and systems (inert or hydrophilic matrix tablets).

Substituted amylose matrices for oral drug delivery

High amylose corn starch was used to obtain substituted amylose (SA) polymers by chemically modifying hydroxyl groups by an etherification process using 1,2-epoxypropanol. Tablets for drug-controlled release were prepared by direct compression and their release properties assessed by an in vitro dissolution test (USP XXIII no 2). The polymer swelling was characterized by measuring gravimetrically the water uptake ability of polymer tablets. SA hydrophilic matrix tablets present sequentially a burst effect, typical of hydrophilic matrices, and a near constant release, typical of reservoir systems. After the burst effect, surface pores disappear progressively by molecular association of amylose chains; this allows the creation of a polymer layer acting as a diffusion barrier and explains the peculiar behaviour of SA polymers. Several formulation parameters such as compression force, drug loading, tablet weight and insoluble diluent concentration were investigated. On the other hand, tablet thickness, scanning electron microscope analysis and mercury intrusion porosimetry showed that the high crushing strength values observed for SA tablets were due to an unusual melting process occurring during tabletting although the tablet external layer went only through densification, deformation and partial melting. In contrast, HPMC tablets did not show any traces of a melting process.

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.

Investigation of the Biopharmaceutical Behavior of Theophylline Hydrophilic Matrix Tablets Using USP Methods and an Artificial Digestive System

This work aimed to investigate the biopharmaceutical behavior of hydrophilic matrix tablets of theophylline using different in vitro methods: USP II, USP IV, and a novel in vitro system simulating the gastrointestinal tract in man called the artificial digestive system (ADS). The potentiality of each method was evaluated by establishing in vitro/in vivo correlation. Using USP methods, the drug release was pH-independent and dependent on agitation intensity. Level A IVIVCs could be established using the different in vitro methods but one to one correlation was established only when the ADS method was used. For the prediction of in vivo drug dosage form behavior based on in vitro methods, the ADS showed a high predictability when compared to USP in vitro methods.

Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet

The aim of this work was to investigate the factors influencing the dissolution characteristics of drug substances from hydrophilic polymer matrix tablets. Various kinds of cellulose derivative polymers were used in for matrix formation. Their swelling propertiesy waswere measured. The effects on drug release was firstly carried were studiedout in comparison with lactose. Results showedindicate that drug release characteristics from polymer matrix tablets followed a Higuchi square root time kinetics. It was found that the polymers could retard the release of drugs in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), but at different levels. The dissolution constants of drugs exhibitedwere higher when the pH of the dissolution medium was increased. Results also demonstratedindicate a the linear correlation between the proportions of matrix-forming structures in the tablets and the extent of dissolution retardation. It was found that not only the swelling property of the polymer but also its hydrophobicity and the hardness of the tablet played an important role onin the retardation of drug release. Results also revealedindicate that PVP K30 could supports cellulose polymers so as to improve the release behavior in order keep a better control to maintain a constant drug release in each time interval.in order to better keep drug release constant in each time interval.

Investigation of Hypromellose Particle Size Effects on Drug Release from Sustained Release Hydrophilic Matrix Tablets

Selected combinations of six model drugs and four hypromellose (USP 2208) viscosity grades were studied utilizing direct compression and in vitro dissolution testing. Experimental HPMC samples with differing particle size distributions (coarse, fine, narrow, bimodal) were generated by sieving. For some formulations, the impact of HPMC particle size changes was characterized by faster drug release and an apparent shift in drug release mechanism when less than 50% of the HPMC passed through a 230 mesh (63 μm) screen. Within the ranges studied, drug release from other formulations appeared to be unaffected by HPMC particle size changes.