Relationseips Between Drug Dissolution Profile and Gelling Agent Viscosity in Tablets Prepared with Hydroxypropylmethylcellulose (HPMC) and Sodium Carboxymethylcellulose (NaCMC) Mixtures

Two varieties of HPMC, two varieties of NaCMC and various HPMC/NaCMC mixtures were characterized with the aim of providing a sound basis for the selection of appropriate mixtures to use as gelling agents in controlled-release tablets for hydrosoluble drugs. For both HPMC and NaCMC, one variety was of high and the other of low nominal viscosity. We also investigated possible relationships between the rheological properties of HPMC/NaCMC mixtures and atenolol release from tablets prepared with such mixtures. The mean molecular weights of each polymer variety were estimated on the basis of determination of their intrinsic viscosities in aqueous dispersions. Rotational viscosimetry of 2% aqueous dispersions of the polymers and polymer mixtures revealed rheological synergism in some mixtures. Drug dissolution trials were carried out in water and 0.1 N HCl. Dissolution medium, gelling agent composition and proportion of gelling agent in the tablet all affected dissolution profiles. Fitting of Korsmeyer et al.'s equation to the data for dissolution in water indicated zero-order dissolution kinetics for all formulations. For tablets prepared with the most viscous HPMC variety, %hour dissolution efficiency was closely correlated with the apparent viscosity (shear rate 0.5 s^-1) of the aqueous dispersion of the polymer mixture used as gelling agent. Assays of tablet erosion rates indicated that the erosion mechanism may contribute to the observed zero-order dissolution kinetics, but that other factors are probably also involved.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro–in vivo correlation was observed for these products.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro-in vivo correlation was observed for these products.     

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

Abstract

The 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.     

Directly Compressed Mini Matrix Tablets Containing Ibuprofen: Preparation and Evaluation of Sustained Release

ABSTRACT

Directly compressed mini tablets were produced containing either hydroxypropylmethylcellulose (HPMC) or ethylcellulose (EC) as release controlling agent. The dynamics of water uptake and erosion degree of polymer were investigated. By changing the polymer concentration, the ibuprofen release was modified. In identical quantities, EC produced a greater sustaining release effect than HPMC. Different grades of viscosity of HPMC did not modify ibuprofen release. For EC formulations, the contribution of diffusion was predominant in the ibuprofen release process. For HPMC preparations, the drug release approached zero-order during a period of 8 h. For comparative purposes, tablets with 10 mm diameter were produced.     

Directly compressed mini matrix tablets containing ibuprofen: preparation and evaluation of sustained release

Directly compressed mini tablets were produced containing either hydroxypropylmethylcellulose (HPMC) or ethylcellulose (EC) as release controlling agent. The dynamics of water uptake and erosion degree of polymer were investigated. By changing the polymer concentration, the ibuprofen release was modified. In identical quantities, EC produced a greater sustaining release effect than HPMC. Different grades of viscosity of HPMC did not modify ibuprofen release. For EC formulations, the contribution of diffusion was predominant in the ibuprofen release process. For HPMC preparations, the drug release approached zero-order during a period of 8 h. For comparative purposes, tablets with 10 mm diameter were produced.     

Influence of hydroxypropyl methylcellulose mixture,apparent viscosity,and tablet hardness on drug release using a 2(3) full factorial design

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3-6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000-19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

In-vitro evaluation of sustained-release dyphylline tablets

Dyphylline tablets were prepared by direct compression of mixtures of the drug, emcompress and different ratios of hydroxypropyl methylcellulose (HPMC) or cellulose acetate phthalate (CAP). Physical properties of the prepared tablets and the drug release in 0.1 N HC1 and phosphate buffer, pH 7.4 were investigated.

All tablets were found to satisfy the USP requirements regarding content, weight uniformity and friability. Hardness was greatly enhanced and thickness was slightly increased by increasing the polymer ratio in tablet formulations. Disintegration time of the dyphylline tablets was delayed by the presence of either HPMC or CAP and there was a direct relationship between the polymer ratio and the disintegration time. Considerable retardation in the rate and extent of drug release from the prepared tablets in both dissolution liquids was observed. As the polymer ratio increased in the tablet formulations, the drug release was significantly inhibited.     

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

The 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.     

Formulation factors affecting drug release from poly(lactic acid) (PLA) microcapsule tablets

A sustained-release (SR) formulation of phenobarbital (PB) microcapsule tablet was prepared using low molecular weight (MW) DL- and high MW L-poly(lactic acid) (PLA) polymer. Microencapsulation of PB showed a unimodal size distribution (375 to 550 microns) of the microcapsules with high loading capacity (> 84%). Drug release from the microcapsule was influenced by the polymer ratios and increased with an increase in L-PLA amount. Microcapsules and physical mixtures of PB and the PLA were directly compressed independently to form microcapsule and matrix tablets, respectively. Drug release from the microcapsule tablets was significantly lowered (p < .001) compared to matrix tablets or free microcapsule (free microcapsule > matrices > microcapsule tablets). We also investigated the effect of tablet adjuvants, compression pressures, and microcapsule loading on the tablet performance in terms of friability, hardness, porosity, tensile strength, and the release kinetics of PB. The drug release rate increased with increasing compression pressure in the case of Emcompress or lactose, but not Avicel. The drug release rate was three- to fivefold increased with sodium starch glycolate compared to tablets without a disintegrant. With an increase in microcapsule loading, a decrease in the drug release rate was observed; however, the tablet performance remained satisfactory. The morphology of the microcapsules was monitored microscopically after the dissolution and the disintegration of tablets. The drug release accelerated with compression pressures and microcapsule loading from the tablets due to mechanical destruction of the microcapsule wall, which was more clearly seen after disintegration and dissolution of the tablets. Our data suggest that the PLA microcapsule can be tableted to make a SR product without significantly affecting its release kinetics.     

Preparation and evaluation of a sustained-release formulation of nifedipine HPMC tablets

A nifedipine (NF) polyethylene glycol (PEG) solid dispersion was prepared. Using this solid dispersion, NF hydroxypropylmethylcellulose (HPMC) matrix tablets were prepared. Both the high-viscosity grade HPMC (Methocel K15M) and low-viscosity grade HPMC (Methocel K100) were applied in the tablets to form the matrix. The dissolution and absorption of NF from the tablet were evaluated as a formulation that had a sustained release over 24 hr. The Hixson-Crowell equation and Higuchi equation were used to investigate the dissolution mechanism, and the erosion and diffusion codependent mechanism was established. Adalat GITS 30 was used as a reference dosage form. Each beagle dog was also administered an intravenous injection to obtain the pharmacokinetics parameters. The Loo-Riegelman method was applied to study the in vitro/in vivo correlation of the tested tablets and Adalat GITS 30, and significant correlation was proved. Absolute bioavailability and comparative bioavailability of the tested tablet were studied. The results indicated that the NF HPMC tablet could be an ideal 24-hr sustained-release formulation.     

Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

Preparation and Evaluation of a Sustained-Release Formulation of Nifedipine HPMC Tablets

A nifedipine (NF) polyethylene glycol (PEG) solid dispersion was prepared. Using this solid dispersion, NF hydroxypropylmethylcellulose (HPMC) matrix tablets were prepared. Both the high-viscosity grade HPMC (Methocel K15M) and low-viscosity grade HPMC (Methocel K100) were applied in the tablets to form the matrix. The dissolution and absorption of NF from the tablet were evaluated as a formulation that had a sustained release over 24 hr. The Hixson-Crowell equation and Higuchi equation were used to investigate the dissolution mechanism, and the erosion and diffusion codependent mechanism was established. Adalat GITS 30 was used as a reference dosage form. Each beagle dog was also administered an intravenous injection to obtain the pharmacokinetics parameters. The Loo-Riegelman method was applied to study the in vitro/in vivo correlation of the tested tablets and Adalat GITS 30, and significant correlation was proved. Absolute bioavailability and comparative bioavailability of the tested tablet were studied. The results indicated that the NF HPMC tablet could be an ideal 24-hr sustained-release formulation.     

Sustained Release Tablet Formulation for a New Iron Chelator

Abstract

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Performance of Multilayered Particles: Influence of a Thin Cushioning Layer

ABSTRACT

Nowadays, oral dosage forms with controlled release kinetics have known an increasing interest. The polymer coating of drug-loaded particles is one of the most common methods used for controlling drug delivery. Such multilayered particles could be either filled into capsules or compressed into tablets for their oral administration. However, many studies have noticed that coating films are damaged during the compression process, leading to significant changes in drug release profiles. The aims of this study were to investigate the effects of a thin cushioning layer [made of HydroxyPropylMethyl Cellulose (HPMC)] applied on coated theophylline particles upon particle characteristics, tablet properties, and then upon their dissolution performance. If no significant effect was shown with particles, this thin HPMC layer played an important role in the tablets. Tablet cohesiveness was decreased due to HPMC cushioning properties and moreover, the theophylline release rate was increased, as HPMC is a water-soluble polymer creating channels in polymer film for dissolution medium. Therefore, a cushioning layer helped to protect polymer coats from fracture during compression but could also affect drug release and so, both effects must be checked in such a drug delivery system.     

Sustained Release Tablet Formulation for a New Iron Chelator

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Formulation of Controlled Release Matrices by Granulation with a Polymer Dispersion

The objective of this work was to incorporate an ethylcellulose-based controlled-release coating suspension (Surelease, Colorcon) within a tablet matrix to provide a release controlling mechanism. Anhydrous theophylline, chlorpheniramine maleate, and acetaminophen were selected as model drug entities. Surelease dispersion was incorporated as the granulating agent either to the drug entity alone or to a blended mixture of drug and filler. Control batches included simple aqueous granulations and direct compression mixtures. Tablets were prepared on a single stroke tablet press. Dissolution was performed by the USP Method I (rotating basket) in purified water for the granulations and the resulting tablets. The uncompressed granulations did not exhibit prolonged release. In general, tablets prepared with the polymer suspension as the granulating agent were non-disintegrating, and exhibited slower dissolution than the control tablets. Release profiles were affected by drug concentration and excipient levels. By the dissolution method selected, complete drug release for the various formulations ranged from less than 1 hour to greater than 12 hours. The use of the polymer dispersion appears to enhance the processing characteristics of some materials, and to provide the formulator with control over drug release.     

Hydroxypropyl Methylcellulose Mixtures: Effects and Kinetics of Release of an Insoluble Drug

Matrix tablets manufactured from a practically insoluble drug using Methocel K4M, Methocel K100LV, and mixtures thereof exhibited non-Fickian dissolution properties governed by both diffusion and erosion (value of diffusional exponent in Peppas's transport equation 0.7). The effects of these two hydroxypropyl methylcellulose (HPMC) varieties were nonlinear and antagonistic.     

Carbamazepine/βCD/HPMC Solid Dispersions. I. Influence of the Spray-Drying Process and βCD/HPMC on the Drug Dissolution Profile

Abstract

The aim of this study was to compare carbamazepine (CBZ) solid dispersions prepared by spray-drying of aqueous dispersions with the corresponding physical mixtures. The influence of the association of β-cyclodextrin (βCD) and hydroxypropyl methylcellulose (HPMC) on the CBZ dissolution profile of the preparations was investigated. Results demonstrated that CBZ release from solid dispersions is dependent on the ratio of βCD and HPMC. The spray-drying process confers better homogeneity to CBZ polymeric dispersions than the physical mixture process. In summary, we demonstrated the feasibility of obtaining a homogeneous polymeric solid dispersion of CBZ from an aqueous media by spray-drying and a clear influence of the βCD:HPMC ratio on the release profile of CBZ.     

Evaluation of Ethylcellulose as A Matrix for Prolonged Release Formulations. I. Water Soluble Drugs: Acetaminophen and Theophylline

Abstract

In this study ethylcellulose was evaluated as a carrier for the preparation of prolonged release solid dispersions of relatively water soluble drugs, acetaminophen and theophylline. The solid dispersions containing various concentrations (7.5, 15.0 and 30.0 % by weight of drug) of ethylcellulose of different viscosity grades (21, 95, 209 and 350 cps) were prepared by the solvent method. The concentration of polymer in the formulation was the determining factor in controlling release rate of the drug, as the results indicate prolongation in release of the drug with increase in amount of ethylcellulose. The higher the viscosity grade of ethylcellulose, slower the release of drug from the solid dispersions. The release of drug from the tablets was more prolonged compared to the granular solid dispersions. In vitro release of acetaminophen and theophylline was more or less similar in both dissolution media. The viscosity grade of ethylcellulose showed slight influence on the release rate of drug from the tablet formulations, while it was quite noticeable in granular solid dispersions.