Hydroxypropyl Methylcellulose Matrix Tablets Research Articles

In-vivo evaluation in man of a hydrophilic matrix containing propylthiouracil.

To reduce the number of administrations of propylthiouracil required to treat hyperthyroidism, the bioavailability and sustained-release characteristics of 300 mg propylthiouracil formulated in hydrophilic matrix tablets were evaluated after single oral administration in healthy male volunteers. A conventional tablet was chosen as the reference formulation. For tablets formulated from three different types of hydroxypropylmethylcellulose, K15M, K4M and K100LV, propylthiouracil dissolution in-vitro was 40%, 51% and 100%, respectively, in 8 h. The three matrix formulations showed sustained plasma concentration-time profiles. The relative bioavailability was 50, 51 and 87%, respectively, for K4M, K15M and K100LV hydroxypropylmethylcellulose matrix tablets. When reverse triiodothyronine concentrations were plotted against the corresponding propylthiouracil concentrations, an antihysteresis loop was observed with the conventional tablets and the K100LV matrix tablet. A linear concentration-response curve was obtained for both the K4M and K15M formulations. The results showed that the K100LV matrix tablet gave a sustained plasma concentration-time profile and a bioavailability and extrathyroidal effect similar to that of a conventional tablet.

Swelling of Hydroxypropyl Methylcellulose Matrix Tablets. 2. Mechanistic Study of the Influence of Formulation Variables on Matrix Performance and Drug Release

We characterized the effect of hydroxypropyl methylcellulose (HPMC)/lactose ratio and HPMC viscosity grade (molecular weight) on solute release and swelling of matrix tablets. We used a semiquantitative optical imaging method to monitor the swelling of matrices with HPMC content from 20% to 80% (w/w) and four viscosity grades. Several aspects of the swelling process common to all formulations were revealed: (i) swelling is anisotropic with a preferential expansion in the axial direction, (ii) swelling is isotropic with respect to the gel layer thickness and composition in both axial and radial directions, (iii) the gel layer develops in three stages, and (iv) water penetration is Fickian in nature and essentially constant for all formulations. We monitored simultaneously drug, lactose, and HPMC release. Lactose and drug release rates were superimposed, indicating a similar diffusional release mechanism and no interaction with HPMC. The strong dependence of HPMC release on viscosity grade is explained on the basis of the concept of polymer disentanglement concentration. We analyzed drug release rates using a model for a reservoir-type release system that incorporates swelling kinetics. HPMC/lactose ratio modulates drug release rate by altering drug diffusivity, a function of gel composition. In contrast, HPMC viscosity grade impacts matrix dissolution and gel layer thickness development below a critical molecular weight. For slowly dissolving matrices containing high viscosity grade (>4000 cps) HPMC, similar drug release rates are observed mainly due to the same drug diffusivity as a result of the identical gel composition and thickness. For fast dissolving matrices (≤100 cps) swelling inhomogeneity is proposed as being responsible for a higher apparent drug diffusivity and release rate.

Swelling of Hydroxypropyl Methylcellulose Matrix Tablets. 1. Characterization of Swelling Using a Novel Optical Imaging Method

A novel optical image analysis method was developed to examine the dynamic swelling behavior of hydroxypropyl methylcellulose (HPMC)-based matrix tablets in situ. In addition to providing precise determinations of apparent gel layer thickness and the tablet dimension, this method is also capable of estimating the HPMC concentration profile across the gel layer. The intensity of light scattered from HPMC gels was found to depend on polymer concentration. A mathematical model that describes the relationship between the scattered light intensity and HPMC concentration was derived from Rayleigh scattering theory coupled with the hypothesis that the turbidity of the gel is an exponential function of polymer concentration. The swelling behavior of a matrix tablet containing 80% HPMC, 17% lactose, and 2.5% adinazolam mesylate is characterized. The data reveal that as the matrix swells, the polymer concentration profiles, as well as the gel layer thicknesses, develop equally in both the axial and radial directions. In addition, the expected dominant axial expansion of the tablet was also observed. This optical image method is generally applicable to in situ characterization of the swelling behavior of polymer matrix-based tablets which are commonly used as extended-release dosage forms.

Application of model-independent and model analysis for the investigation of effect of drug solubility on its release rate from hydroxypropyl methylcellulose sustained release tablets

The effect of drug solubility on the dissolution from the sustained release (SR) matrix tablet prepared with hydroxypropyl methylcellulose (HPMC) 2910 4000 cps was investigated using model-independent moment analysis and Higuchi-type model analysis. In this study, seven model drugs which have various solubilities in the dissolution medium were used for preparation of tablets and dissolution studies were then performed. To determine the mechanisms behind the sustained release, the infiltration rate of the medium into the matrix tablet and the erosion rate of the matrix tablet were also investigated. The model-independent moment parameters i.e. mean dissolution time (MDT), mean medium infiltration time (MIT), mean tablet erosion time (MET), mean swelling time (MSWT) and mean diffusion time (MDFT) as well as Higuchi-type model analysis which, based on release mechanisms, were demonstrated for optimization of HPMC matrix tablets. Both in the model-independent and model analyses, the relationships obtained between drug solubility and release characteristics were similar. Regarding the poorly soluble drug, U-78875, the observed dissolution rate is slower than the erosion rate of the matrix tablet, which indicates that the main rate limiting factor for the dissolution is erosion of the matrix tablet. In the case of drugs whose solubilities are between 0.5 mg/ml and 5 mg/ml (methyl-paraben, ethyl-paraben and propyl-paraben), dissolution rates are observed between the erosion rate of the matrix tablet and the infiltration rate of medium into the matrix tablet, and. the dissolution rate increases with increasing drug solubility. Regarding highly soluble drugs, whose solubilities are more than 5 mg/ml (procaine hydrochloride, acetaminophen, and theophylline), the dissolution rates are not influenced so much by drug solubility but show a similar rate of medium infiltration into matrix. In the latter two cases, the primary rate limiting factor of dissolution is infiltration of medium into the matrix tablet. The reported MDT and MDFT values were within the range 3.16-8.75 h and 1.11-6.70 h, respectively, except for U-78875. Also, MIT, MET and MSWT values as device matrix characteristics were 2.05, 12.05 and 10.00 h, respectively. The model-independent moment parameters, MDT, MIT, MET, MSWT and MDFT are directly comparable to each other. Further, these parameters would be applicable in comparing the device and dissolution characteristics of different types of formulation. These model-independent analytical approaches allow us to optimize the SR matrix formulation at the development stage.

Influence of Physicochemical Properties on Drug Release Rate from Hydroxypropylmethylcellulose Matrix Tablets.

An examination was made of the release of isoniazid, anhyrous caffeine, theophylline, salicylic acid and indomethacin from hydroxypropylmethylcellulose (HPMC) matrices, and the results were usually found to follow first order kinetics. the release rate of the drug was influenced by the solubility of the drug, and by the viscosity and the content of HPMC. As the drug solubility increased, the drug release rate also increased, and conversely, as the viscosity and/or the content of HPMC increased, the drug release rate decreased. A multiple regression analysis was used to determine the relationship between response (release rate) and factors (drug solubility, HPMC viscosity and HPMC content), and a statistically significant model was obtained. This model allows not only predictions of the drug release rate from HPMC matrices, but also establishment of the formulation of the target drug without experimental determination.

Effect of Formulation Variables on Dissolution Profile of Diclofenac Sodium from Ethyl- and Hydroxypropylmethyl Cellulose Tablets

AbstractThe effects of formulation variables on the release profile of diclofenac sodium from ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC) matrix tablets were investigated. With increase in viscosity of ethyl cellulose used in nonaqueous granulation, a decrease in drug release from the tablets was observed, while the percentage of fines articles passed through 60 mesh) in the granulation had a significant effect on the dissolution profile. Granules containing 15% fines exhibited slow release of the drug in comparison to those containing 30% fines with EC matrices. An analysis of kinetics of drug release from hydrophobic EC matrix showed Fickian diffusion regulated dissolution. Drug release from HPMC tablets followed an apparent zero-order kinetics.

Influence of formulation change on drug release kinetics from hydroxypropylmethylcellulose matrix tablets.

Examination was made of the release of indomethacin from hydroxypropylmethylcellulose (HPMC) matrices and the results were found to usually follow first order release kinetics. The release mechanism changed with formulation. HPMC content was the predominant controlling factor. As the HPMC content increased, drug release rate decreased, and the release mechanism gradually changed from Higuchi diffusion release to case II transport. Additives increased the release rate and enhanced Fickian diffusion. As drug content increased, release rate calculated from percent release data decreased while that calculated from mg release data increased. When indomethacin content was lower, drug release was diffusion controlled and when higher, non-Fickian transport or case II transport was apparent. Additive effects were also examined. Starch was found to most effectively maintain case II release. Complex additives containing starch were superior to any additive by itself. A multiple regression model was used to determine the relationship between response (release rate) and factors (content of HPMC and diluents), and on the basis of this model a formulation was established and found valid by agreement with data from the regression model.

Hydroxypropylmethylcellulose matrix tablets containing propranolol hydrochloride and sodium dodecyl sulphate

The anionic surface-active agent, sodium dodecyl sulphate, when included into matrix tablets containing hydroxypropylmethylcellulose (HPMC K15M) retarded the release rate of propanolol hydrochloride by the formation of propranolol dodecyl sulphate. The root-time dissolution rates from these tablets were proportional to the unreacted propranolol hydrochloride. Propranolol dodecyl sulphate formed lyotropic liquid crystals on contact with water. On heating, this hydration was lost at 36°C. The estimated solubility product of this compound was less than 4 x 10 −8 M 2. The ternary phase diagram of sodium dodecyl sulphate-propranolol hydrochloride-water was established and confirmed the approximate 1:1 w/w nature of the precipitate. Similar interactions did not occur between propranolol hydrochloride and cetrimide which, when included in HPMC matrix tablets, marginally increased the dissolution rate of propranolol hydrochloride.

Formulation, bioavailability, and pharmacokinetics of sustained-release potassium chloride tablets.

The release of potassium chloride incorporated into hydrogenated vegetable oil and hydroxypropyl methylcellulose matrix tablets was studied in vitro. The formulations containing 20% hydrogenated vegetable oil and hydroxypropyl methylcellulose showed a sustained-release profile comparable to that of a standard commercially available sustained-release preparation, containing 8 mEq potassium chloride embedded in a wax material. The formulated and standard sustained-release potassium chloride tablets were compared to a conventional enteric-coated potassium chloride tablet in 10 healthy subjects. Mean recoveries in 24-hr urine potassium levels from four dosage forms (after subtracting normal urine potassium excretion levels) were 76 +/- 32% from hydroxypropyl methylcellulose, 95 +/- 22% from hydrogenated vegetable oil-incorporated matrix tablets, 91 +/- 29% from commercially available sustained-release tablets, and 97 +/- 13% from enteric-coated tablets. There was no significant difference (P greater than 0.05) in the time to reach maximum excretion rates among the three sustained-release tablets. No significant adverse effect was experienced with any of the preparations.

Temperature Effects on the Dissolution of Promethazine Hydrochloride from Hydroxypropylmethylcellulose Matrix Tablets

Temperature Effects on the Dissolution of Promethazine Hydrochloride from Hydroxypropylmethylcellulose Matrix Tablets

The influence of additives on the cloud point, disintegration and dissolution of hydroxypropylmethylcellulose gels and matrix tablets

The ability of a salt to lower the cloud point of hydroxypropylmethylcellulose (HPMC) gels was found to follow their order in the lyotropic series, i.e. chloride < tartrate < phosphates and potassium < sodium. Anions were more important than cations in lowering the cloud point. The dissolution of propranolol hydrochloride from HPMC matrix tablets into dissolution media containing a number of different phosphate and chloride salts was investigated. As the ionic strength increased the dissolution rates decreased to a minimum before rising to give a ‘burst’ release. Disintegration times of HPMC matrices, without active, also varied to the ionic strength of the disintegration medium. By determining the cloud points it proved possible to predict if a matrix will show burst release in a given solution of electrolytes. Propranolol hydrochloride, promethazine hydrochloride, aminophylline and tetracycline hydrochloride increased the cloud point but theophylline and quinine bisulphate had little effect on the cloud point.

Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropylmethylcellulose matrix tablets

The dissolution of 7 drugs from hydroxypropylmethylcellulose (HPMC) matrices have been examined to determine the time exponent ( t n ) required to produce linear dissolution profiles. A value of n = ~ 0.67 was obtained for time-dependent release for soluble drugs, the precise values being 0.71, 0.65, 0.67 and 0.64 for promethazine hydrochloride, aminophylline, propranolol hydrochloride and theophylline, respectively. The insoluble drugs, indomethacin and diazepam, displayed values of n = 0.90 and 0.82 indicating a near zero-order release. Matrices containing tetracycline hydrochloride, however, showed a value of n = 0.45 and displayed complex release patterns and lower release rates than anticipated on the basis of solubility. Replacement of HPMC by calcium phosphate or lactose increased the dissolution rates of promethazine hydrochloride although the values of n were unchanged. Differences in release rates between lactose and calcium phosphate replacement occurred only when matrices contained high levels of the diluents. A straight line relationship existed between release rates and tablet surface area for HPMC tablets containing promethazine hydrochloride.

Formulation of Once a Day Controlled Release Tablet of Indomethacin Based on HPMC-Mannitol

p&gt;A hydroxypropyl methylcellulose (HPMC K4M, HPMC K15M, and HPMC K100M) matrix tablet containing Indomethacin along with mannitol was formulated as a function of HPMC viscosity, and was compared with the commercial products. The release characteristics of the matrix tablet were investigated in the intestinal fluid, 6.8 pH phosphate buffer for 12 hours. The formulated products and two marketed products as reference sample were studied for its different physicochemical parameters and in vitro dissolution studies. It was found that the drug release profile decreases with increase in viscosity of polymer and, with increase polymer level in the formulations. Matrix tablets formulated employing Drug:HPMC K15M:mannitol::1:0.25:1 and Drug:HPMC K15M:mannitol::1:0.25:2 gave slow release of indomethacin spread over 12 hours and their dissolution profiles were compared with the Indian marketed product. The dissolution profiles of both the formulations were similar to the dissolution profile of the marketed product, the similarity factor being 74.59 and 68.04 respectively. The dissolution profiles of formulations containing same viscosity grade of HPMC in remarkably different concentrations and different viscosity grade of HPMC in same concentrations were different. Key words: Indomethacin; Controlled release; Hydroxypropyl methyl cellulose; Mannitol; Dissolution. DOI: 10.3126/kuset.v4i1.2884 Kathmandu University Journal of Science, Engineering and Technology Vol.4, No.1, September 2008, pp 55-67