Hydroxypropyl Methylcellulose Matrix Tablets Research Articles

Continuous Monitoring of the Hydration Behavior of Hydrophilic Matrix Tablets Using Time-Domain NMR.

Time-domain NMR (TD-NMR) was used for continuous monitoring of the hydration behavior of hydrophilic matrix tablets. The model matrix tablets comprised high molecular weight polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG). The model tablets were immersed in water. Their T2 relaxation curves were acquired by TD-NMR with solid-echo sequence. A curve-fitting analysis was conducted on the acquired T2 relaxation curves to identify the NMR signals corresponding to the nongelated core remaining in the samples. The amount of nongelated core was estimated from the NMR signal intensity. The estimated values were consistent with the experiment measurement values. Next, the model tablets immersed in water were monitored continuously using TD-NMR. The difference in hydration behaviors of the HPMC and PEO matrix tablets was then characterized fully. The nongelated core of the HPMC matrix tablets disappeared more slowly than that of the PEO matrix tablets. The behavior of HPMC was significantly affected by the PEG content in the tablets. It is suggested that the TD-NMR method has potential to be utilized to evaluate the gel layer properties, upon replacement of the immersion medium: purified (nondeuterated) water is replaced with heavy (deuterated) water. Finally, drug-containing matrix tablets were tested. Diltiazem hydrochloride (a highly water-soluble drug) was employed for this experiment. Reasonable in vitro drug dissolution profiles, which were in accordance with the results from TD-NMR experiments, were observed. We concluded that TD-NMR is a powerful tool to evaluate the hydration properties of hydrophilic matrix tablets.

Unexpected Stability of a Prodrug to Enzymatic Hydrolysis within a Hydrated HPMC Matrix Tablet.

The uptake of alkaline phosphate present in dissolution medium into a hydrating hydroxypropyl methylcellulose matrix tablet and that its activity was retained therein was demonstrated. This presents a risk to the stability of prodrugs that are substrates of this enzyme such as phosphonooxymethyl derivative prodrugs. It was found that fostemsavir, a phosphonooxymethyl derivative prodrug being developed for the treatment of HIV-1 infection, was unexpectedly resistant to hydrolysis within a hydrated HPMC matrix when subjected to drug release testing in media containing alkaline phosphatase. Studies indicated that this was not due to microenvironmental pH effects, osmolality effects or effective phosphate concentration effects associated with the presence of the prodrug. That the prodrug and not its parent could affect enzyme activity in a concentration dependent manner, and that another phosphate ester prodrug fosphenytoin did not inhibit alkaline phosphatase activity within a hydrated HPMC matrix suggested that the unexpected stability of the HIV-1 therapy prodrug may be associated with the ability of the phosphate group-containing compound itself to inhibit the enzyme at the concentrations it exists at in the hydrated dosage form and so enables the development of the compound in this type of dosage form.

Release Kinetics of Hydroxypropyl Methylcellulose Governing Drug Release and Hydrodynamic Changes of Matrix Tablet.

Hydrophilic Hydroxypropyl Methylcellulose (HPMC) matrix tablets are the standard role model of the oral controlled-release formulation. Nevertheless, the HPMC kinetics for the mechanistic understanding of drug release and hydrodynamic behaviors are rarely investigated. This study aims to investigate the release behaviors of both HPMC and paracetamol (model drug) from the hydrophilic matrix tablet. Two different viscosity grades of HPMC were used (Low viscosity: 6 cps, High viscosity: 4,000 cps). Three different ratios of drug/HPMC (H:38.08%, M:22.85%, and L:15.23% (w/w) of HPMC amounts in total weight) matrix tablets were prepared by wet granulation technique. The release profiles of the drug and HPMC in a matrix tablet were quantitatively analyzed by HPLC and 1H-Nuclear Magnetic Resonance (NMR) spectroscopy. The hydrodynamic changes of HPMC were determined by the gravimetric behaviors such as swelling and erosion rates, gel layer thickness, front movement data,and distributive Near-Infrared (NIR) chemical imaging of HPMC in a matrix tablet during the dissolution process. High viscosity HPMC tablets showed slower release of HPMC than the release rate of drug, suggesting that drug release preceded polymer release.Different hydration phenomenon was qualitatively identified and corresponded to the release profiles. The release behaviors of HPMC and drug in the tablet could be distinguished with the significant difference with fitted dissolution kinetics model (Low viscosity HPMC 6cps; Korsmeyer-Peppas model, High viscosity HPMC 4000cps; Hopfenberg model, Paracetamol; Weibull model) according to the weight of ingredients and types of HPMC. The determination of HPMC polymer release correlating with drug release, hydrodynamic behavior, and NIR chemical imaging of HPMC can provide new insights into the drug release- modulating mechanism in the hydrophilic matrix system.

Raman-based real-time dissolution prediction using a deterministic permeation model

The purpose of this study was to develop a deterministic permeation model (DPM) that predicts the in vitro release profile of an active ingredient (API) embedded in hydroxypropyl-methylcellulose (HPMC) matrix tablets based on Raman spectra. So far in the literature, such mechanistic models were utilized only for formulation optimization (off-line dissolution prediction), while the real-time prediction of dissolution profiles based on Process Analytical Technology (PAT) data was performed by empirical methods such as Partial Least Squares (PLS) regression. Our work represents a novel conceptual approach that utilizes a mechanistic model to predict dissolution profiles based on data yielded by PAT tools. Tablets containing various API- and HPMC-amounts were produced using different compression pressures according to a 33 full factorial design, their Raman spectra were recorded before dissolution testing. The DPM was constructed using one-third of the measured dissolution profiles and is presented as a system of differential equations together with its analytical solution. The parameters of DPM were estimated by the training data set containing the spectroscopically determined API- and HPMC- amounts and the tableting pressures used, then the release profiles of the remaining two-thirds of the tablets were predicted. The Raman spectra-based predictions of DPM were compared with predictions of an Artificial Neural Network (ANN). It was found that the two methods yield similar results, however, the mechanistic approach has the benefit of requiring a lower amount of training samples. Although the model is based on a remarkable simplification of reality, it facilitates a deeper understanding of the behavior of the formulation.The DPM could improve our understanding of the effect of HPMC and tableting pressures on the release kinetics of the HPMC matrix tablets and participate in the development of PAT-based new surrogate dissolution methods for Real-Time Release testing (RTRt).

Exploring the unexpected behavior of HPMC matrix tablets in dissolution media with SDS

In the case of poorly soluble drugs, a surfactant is often added to dissolution media to increase drug release. In this study, diclofenac sodium (DF-Na) release from hydroxypropyl methylcellulose (HPMC) matrix tablets was explored in dissolution media containing different sodium lauryl sulfate (SDS) concentrations. Drug release increased with increasing SDS concentration; however, an unexpected decrease in DF-Na release was noticed in the medium with pH 4 containing 0.03–0.08% SDS, which is just below the critical micelle concentration (CMC). In addition, an inverse correlation between swelling and release was noticed. Measurements of transmittance of multiple HPMC–SDS dispersions showed that with increasing HPMC concentration transmittances are lower at a wider SDS concentration interval. Thus, when using media with low SDS concentrations, especially those with concentrations lower than CMC (0.03–0.08%), DF-Na release from HPMC matrix tablets is decreased due to increased swelling and lack of SDS in the swelled layer, both possibly due to SDS binding to HPMC. However, when using media with a higher initial SDS concentration in the medium, there remains a high concentration of non-bound SDS in the bulk, which can solubilize incorporated drug and thus enhance its release from HPMC matrix tablets.

English

PolyoxTM coagulant (molecular weight 5 × 106 Da) and hydroxypropyl methylcellulose (HPMC) K4M (USP substitution type 2208) were used to identify the composition variables that ensure the production of polyethylene oxide (PEO) matrix tablets with the same dissolution characteristics as those containing HPMC. Based on the dissolution results obtained using Apparatus 3, a 53% concentration of PEO polymer in the matrix tablet generates comparable drug release as matrix tablets containing 37% HPMC. During the dissolution test, several conditions simulating mechanical stresses in the gastrointestinal tract were investigated, in order to assess the robustness of the gel layer formed in selected PEO and HPMC matrix tablets. Increased mechanical stresses enhanced gel erosion from both matrix tablets evaluated and increased the drug release rate by approximately 10% regardless of the polymer type used. The HPMC gel layer formed was more resilient to mechanical stress and resulted in significantly slower drug release when compared to PEO matrix tablets with the same polymer concentration (37%). The research showed that gel robustness and the PEO polymer percolation threshold are dependent on the mechanical stresses applied. The percolation threshold changed from 30 to 37% when different mechanical stress was applied on Apparatus 2 and 3, respectively. The study revealed that the selection of in vitro dissolution method as well as polymer concentration is important for the evaluation of gel mechanical robustness. Key words: Polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), drug release, percolation threshold, matrix tablets. &nbsp

Formulation and In vitro Release Behavior of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Containing Poorly Soluble Fenofibrate

Fenofibrate, a water insoluble drug was used to prepare matrix tablet with four different viscosity grades of Hydroxypropyl Methylcellulose (HPMC) which were Methocel K4M CR, Methocel K15M CR, Methocel K100M CR and Methocel K100LV CR. The concentration of those excipients was 5, 10, 20, and 40% (w/w), respectively. The content of drug in a fixed quantity of powder in every formulation was ranged between 96.47 to 104.78 %. The dissolution study was done by using USP dissolution apparatus II. The kinetics of release was analyzed by using zero-order, first order, Korsmeyer-Peppas, Higuchi and Hixon-crowell equations to explain the drug release mechanism from the matrix tablets. In-vitro dissolution profile of matrix tablets were dependent upon the HPMC concentration and dissolution was rapid for tablets containing lower polymer proportion i.e. 5,10, and 20% Percentage (w/w) HPMC than those containing 40% (w/w) HPMC.
 Bangladesh Pharmaceutical Journal 23(1): 10-16, 2020

IMPACT OF HYDROXYPROPYL METHYLCELLULOSE (HPMC) TYPE AND CONCENTRATION ON THE SWELLING AND RELEASE PROPERTIES OF PROPRANOLOL HYDROCHLORIDE MATRIX TABLETS USNING A SIMPLEX CENTROID DESIGN

Objective: To prepare hydroxypropyl methylcellulose (HPMC) matrix tablets of propranolol hydrochloride (PNL) using a simplex centroid design.
 Methods: HPMC matrix tablets with different amounts and types of HPMC were prepared by direct compression. A simplex centroid design was used to evaluate tablet weight (Y1), thickness (Y2), hardness (Y3), axial swelling time at 0.5–12 h (Y4-Y9), radial swelling time at 0.5–12 h (Y10-Y15), and % released at 1–12 h (Y16-Y19).
 Results: The tablet weight, thickness, and hardness were 397.6–400.4 mg, 3.967–4.029 mm, and 106.9–139.0 N, respectively. The % swelling (axial) and % swelling (radial) at 0.5–12 h were-8.715 to 59.889 and-1.887 to 49.287, respectively. The negative % swelling could be attributed to erosion of the tablets. The in vitro release of PNL from the tablets in buffer solution pH 1.2 (1 h) and pH 7.5 (3–12 h) was 21.12–76.22%. Tables with a high proportion of K100M HPMC had high PNL release, and the mechanism of PNL release was diffusion-and erosion-controlled.
 Conclusion: The simplex centroid design is potentially advantageous for formulating PNL-HPMC matrix tablets.

Design and Optimization of Controlled Release Felbamate Tablets by D-optimal Mixture Design: In vitro-in vivo Evaluation

Felbamate, an antiepileptic drug is administered multiple times a day to obtain proper restorative action against seizures in childhood onset epilepsy (Lennox-Gastaut syndrome), which usually result in poor therapeutic efficacy because of fluctuating plasma levels and low patient compliance. Hence, controlled release hydroxypropyl methylcellulose matrix tablets of felbamate were formulated to overcome these drawbacks. The results of pre-formulation studies such as differential scanning calorimetry and Fourier transform infrared spectroscopy showed compatibility of drug with the selected excipients. The formulation variables were optimized using D-optimal design which can elucidate the effect of all variables simultaneously during formulation optimization. In vitro drug release at the end of 2, 8 and 20 h were taken as the response parameters for the optimization study by D-optimal design. The results enabled selection of the formulation with the desired drug release pattern approaching to zero order. The optimized batch was subjected to in vivo pharmacokinetic studies in rabbits which showed extended release of drug up to 24 h. Thus, the felbamate controlled release tablets optimized by D-optimal design have potential to reduce the dose and dosing frequency, improve therapy and patient compliance.

In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status

PurposeTo develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status.MethodsA nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent.ResultsErosion was best described by a Michaelis–Menten type model. The maximal HPMC release rate (VMAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of VMAX depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm).ConclusionsThe in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.

Influence of HPMC K100LV and Compritol® HD5 ATO on Drug Release and Rheological Behavior of HPMC K4M Matrix Tablets

The objectives of this study were to develop once-a-day oral controlled-release tablets of quetiapine fumarate (QF) and to determine the effect of polymer type, viscosity grade, polymer ratio, and polymer rheological properties on the rate of QF release from hydroxypropyl methylcellulose (HPMC) matrix tablets. Tablets were prepared from low-viscosity-grade HPMC K100LV (K100LV), high-viscosity-grade HPMC K4M (K4M), Compritol® HD5 ATO (PEGylated glyceryl behenate (PGB)), and binary combinations of these polymers. In vitro drug release from all tablets was evaluated over 24 h. In vitro drug release studies revealed that formulations containing K100LV/K4M and PGB/K4M at a ratio of 170:70 resulted in similar release profiles which extended for 24 h (f2 > 50). QF release kinetics followed either diffusion, anomalous transport, case II transport, or super case II transport, as fitted by the Korsmeyer-Peppas model. Tablet swelling and erosion studies were consistent with dissolution profiles. A linear relationship between % swelling and % QF released was observed in tablets containing K4M alone or in combination with K100LV or PGB, indicating the direct role of polymer swelling in controlling the mechanism of drug release. The viscoelastic properties of single and binary polymeric gels made with the three polymers (K100LV, K4M, and PGB) corroborated the in vitro release studies of QF tablets. Our results provide evidence that blending polymers with different viscosities and hydrophilicities can result in unique matrices with tunable release profiles.

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

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.

Poly vinyl acetate and ammonio methacrylate copolymer as unconventional polymer blends increase the mechanical robustness of HPMC matrix tablets

The objective was to investigate poly vinyl acetate (Kollicoat® SR 30 D) and ammonio methacrylate copolymer (Eudragit® RL 30 D) blends as coatings to increase the mechanical robustness of hydroxypropyl methylcellulose (HPMC) matrix tablets. Poly vinyl acetate (Kollicoat® SR 30 D – KSR) was selected for its flexibility and ammonio methacrylate copolymer (Eudragit® RL 30 D – ERL) because of its high permeability. Films based on KSR:ERL blends were prepared by casting or spraying aqueous dispersions of these polymers and were characterized by water uptake, dry mass loss and mechanical properties. KSR:ERL blends were investigated as coating materials to improve the robustness, mechanical strength and drug release from the HPMC matrix tablets containing propranolol HCl, caffeine and carbamazepine as model drugs. Both HPMC and the polymer coating affected the propranolol release. The release and the mechanical properties could be easily adjusted by varying the polymer blend ratio. The flexibility increased with increasing KSR content. At an 8% w/w coating level, a force of 3.2N was required to rupture the coating of the swollen tablet after 16h in the release medium; the coated tablets were thus robust to withstand gastrointestinal forces. The coating level (6%–10%, w/w) and dissolution agitation rate (50rpm to 150rpm) had no effect on the drug release. The water-insoluble carbamazepine was not released from the coated tablets as HPMC erosion, which is necessary for the release of a poorly water-soluble drug was hindered by the coating. The release of the water-soluble propranolol increased with increasing drug content and decreased with increasing HPMC content. ConclusionPoly vinyl acetate and ammonio methacrylate copolymer could be a proper polymer blend for coating HPMC matrix tablets to increase mechanical robustness, which characterized by its flexibility and permeability.

Colon Specific Drug Delivery: Effect of Eudragit Enteric Coating on Hydroxypropyl Methylcellulose Matrix Tablets of Flurbiprofen

Aims: The present research is focused on developing flurbiprofen colon-specific tablets based on timed release and pHsensitivity. Methods and Material: This study is designed to study the effect of eudragit coating on the drug release from hydroxypropyl methylcellulose matrix to achieve the colon-specific release. Hydroxypropyl methylcellulose matrix tablets were prepared by wet granulation method and coated with eudragit S100 using dip coating method. Then the tablets were evaluated for different physical parameters, compatibility studies, in vitro dissolution and in vivo x-ray imaging studies. Statistical Analysis: In the stability studies, paired t-test is employed to determine the significance of difference at 0.05 level. Results: Flurbiprofen colon-specific tablets have been characterized for weight variation, hardness, friability and drug content. Based on in vitro drug release, the formulation F6 showed the low amount of drug release (18.41 ± 0.68%) in the initial lag period followed 100.43 ± 3.33% in 24 h. Compatibility studies revealed that there was no interaction between drug and the polymers. Similarity index value was found as 95.01, which is more than 50 indicates similarity between the dissolution profile before and after storage. In support of the dissolution studies, x-ray imaging studies revealed that tablets reached the colon without disintegrating in the upper gastro intestinal tract. Conclusion: From the above results, it is obvious that the developed flurbiprofen enteric coated matrix tablets are suitable for colonic delivery. Key words: Dip coating, Lag period, pH-sensitive, Timed release, X-ray imaging study.

Determining the polymer threshold amount for achieving robust drug release from HPMC and HPC matrix tablets containing a high-dose BCS class I model drug: in vitro and in vivo studies.

It is challenging to achieve mechanically robust drug-release profiles from hydrophilic matrices containing a high dose of a drug with good solubility. However, a mechanically robust drug release over prolonged period of time can be achieved, especially if the viscosity and amount of the polymer is sufficiently high, above the "threshold values." The goal of this research was to determine the hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer threshold amount that would enable robust drug release from matrix tablets containing a high dose of levetiracetam as a class I model drug according to the Biopharmaceutical Classification System (BCS). For this purpose, formulations containing HPC or HPMC of similar viscosity range, but in different amounts, were prepared. Based on the dissolution results, two final formulations were selected for additional in vitro and in vivo evaluation to confirm the robustness and to show bioequivalence. Tablets were exposed to various stress conditions in vitro with the use of different mechanically stress-inducing dissolution methods. The in vitro results were compared with in vivo results obtained from fasted and fed bioequivalence studies. Under both conditions, the formulations were bioequivalent and food had a negligible influence on the pharmacokinetic parameters C max and area under the curve (AUC). It was concluded that the drug release from both selected formulations is mechanically robust and that HPC and HPMC polymers with intrinsic viscosities above 9 dL/g and in quantities above 30% enable good mechanical resistance, which ensures bioequivalence. In addition, HPC matrices were found to be more mechanically robust compared to HPMC.

The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion–time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed.

Magnetic Resonance Microscopy for Assessment of Morphological Changes in Hydrating Hydroxypropylmethylcellulose Matrix Tablets In Situ–Is it Possible to Detect Phenomena Related to Drug Dissolution Within the Hydrated Matrices?

PurposeSo far, the hydrated part of the HPMC matrix has commonly been denoted as a “gel” or “pseudogel” layer. No MRI-based results have been published regarding observation of internal phenomena related to drug dissolution inside swelling polymeric matrices during hydration. The purpose of the study was to detect such phenomena.MethodsMultiparametric, spatially and temporally resolved T2 MR relaxometry, in situ, was applied to study formation of the hydration progress in HPMC matrix tablets loaded with L-dopa and ketoprofen using a 11.7 T MRI system. Two spin-echo based pulse sequences were used, one of them specifically designed to study short T2 signals.ResultsTwo components in the T2 decay envelope were estimated and spatial distributions of their parameters, i.e. amplitudes and T2 values, were obtained. Based on the data, different region formation patterns (i.e. multilayer structure) were registered depending on drug presence and solubility. Inside the matrix with incorporated sparingly soluble drug a specific layer formation due to drug dissolution was detected, whereas a matrix with very slightly soluble drug does not form distinct external “gel-like” layer.ConclusionsWe have introduced a new paradigm in the characterization of hydrating matrices using 1H MRI methods. It reflects molecular mobility and concentration of water inside the hydrated matrix. For the first time, drug dissolution related phenomena, i.e. particular front and region formation, were observed by MRI methods.

Effect of Alcohol on Drug Release Kinetics from HPMC-Based Matrix Tablets Using Model Drugs

Drug dissolution testing is routinely used to provide in vitro drug release information for both quality control purposes and drug development. For extended-release (ER) formulations, the dissolution test can serve not only as a quality control tool for the manufacturing process but also as an indicator of how the formulation will perform in vivo to establish an in vitro–in vivo correlation. Hydrophilic matrices are a robust ER formulation technology in which the formation of a viscous hydrated polymer layer at the surface provides a diffusion barrier that retards drug release. Hydroxypropyl methylcellulose (HPMC) is the most widely used polymer for this application. The purpose of this study was to investigate the effect of various proportions of alcohol on in vitro drug release from HPMC-based matrix tablets using three model drugs having different physicochemical properties. The percent drug release increased with increasing levels of alcohol for all three model drugs. It was observed that dose-dumping did not occur for drugs that had low solubility; however, for highly soluble drugs, dumping occurred even at low concentrations of alcohol in the media. The impact of alcohol was prominently observed in terms of initial rapid release for all drugs in the first hour irrespective of the concentration of alcohol. Relative swelling studies of HPMC matrix tablets with and without drug suggest that alcohol retarded hydration and swelling of the polymer. The findings also suggest that the release mechanism changes with an increase in the concentration of alcohol.

Drug Release-Modulating Mechanism of Hydrophilic Hydroxypropylmethylcellulose Matrix Tablets: Distribution of Atoms and Carrier and Texture Analysis

Although release profiles of drug from hydrophilic matrices have been well recognized, the visual distribution of hydroxypropylmethylcellulose (HPMC) and atoms inside of internal structures of hydrophilic HPMC matrices has not been characterized. In this paper, drug release mechanism from HPMC matrix tablet was investigated based on the release behaviors of HPMC, physical properties of gelled HPMC tablet and atomic distributions of formulation components using diverse instruments. A matrix tablet consisting of hydroxypropyl methylcellulose (HPMC 6, 4,000 and 100,000 mPa·s), chlorpheniramine maleate (CPM) as a model and fumed silicon dioxide (Aerosil(®) 200) was prepared via direct compression. The distribution of atoms and HPMC imaging were characterized using scanning electron microscope (SEM)/ energy-dispersive X-ray spectroscopy (EDX), and near-infrared (NIR) analysis, respectively as a function of time. A texture analyzer was also used to characterize the thickness and maintenance of gel layer of HPMC matrix tablet. The HPMC matrix tablets showed Higuchi release kinetics with no lag time against the square root of time. High viscosity grades of HPMC gave retarded release rate because of the greater swelling and gel thickness as characterized by texture analyzer. According to the NIR imaging, low-viscosity-grade HPMC (6 mPa·s) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPa·s) formed much thicker gel layer around the tablet and maintained longer via slow erosion, resulting in retarded drug release. The atomic distribution of the drug (chlorine, carbon, oxygen), HPMC (carbon, oxygen) and silicon dioxide (silica, oxygen) and NIR imaging of HPMC corresponded with the dissolution behaviors of drug as a function of time. The use of imaging and texture analyses could be applicable to explain the release- modulating mechanism of hydrophilic HPMC matrix tablets.

Improvement of photostability and dissolution profile of isradipine using inclusion complex

Inclusion complexes using β-cyclodextrin were manufactured by solvent evaporation method. Then, sustained release (SR) hydroxypropylmethylcellulose (HPMC) matrix tablets containing inclusion complex were prepared via direct compression. Isradipine was chosen as a model drug due to its low solubility, photo-instability and short elimination half-life. The physicochemical properties of the inclusion complexes were examined using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The solubility test and dissolution behaviours were also investigated. Based on the solubility experiments, a 1:2 molar ratio (isradipine:β-Cyclodextrin) was best and chosen to prepare inclusion complexes. In addition, the crystal structure of isradipine was converted to an amorphous structure, as confirmed by Fourier transform infrared spectroscopy (FT-IR) and DSC. The photostability of isradipine in the inclusion complex was more stable than pure isradipine after 4 days radiation. By using hypromellose as the hydrophilic sustained release material, the dissolution rate was retarded during 24 h. A combined method of inclusion complex and SR technology showed increased and sustained release profile above that of Dynacirc® SR Cap. 5 mg.