The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

Abstract

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6000 (PEG 6000), and hydroxyethyl-cellulose (HEC) as possible alternatives to the use of HPMC to control the release of caffeine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most effective for the release of caffeine from the core-in-cup compressed tablets, and that PEG 6000 was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.     

Zero-order release of theophylline from a core-in-cup tablet in sequenced simulated gastric and intestinal fluid

Core-in-cup tablets containing theophylline were evaluated for their dissolution characteristics in sequenced simulated gastric fluid (SGF) followed by simulated intestinalfluid (SIF). Core-in-cup tablets containing 10% w/w, 20% w/w, and 30% w/w acacia as binder were evaluated for their effects on the time course of release of theophylline. This was done to optimize a formula that could release theophylline at a zero-order rate of release for 8-16 hr in simulated gastrointestinal fluids. Theophylline was released and dissolved from the core-in-cup tablets at a rate that is more consistent with a zero-order dissolution rate than a first-order dissolution rate in both SIG and SIF. The dissolution rates of theophylline from the 10%, 20%, and 30% acacia core-in-cup tablets were 0.87 mg/min, 0.53 mg/min, and 0.27 mg/min, respectively in SGF, and 0.61 mg/min, 0.30 mg/min, and 0.20 mg/min, respectively in SIF. The results indicate that a concentration of 32% w/w acacia in the core tablet will release theophylline at a rate of 0.14 mg/min in SGF for 2 hr followed by SIF for 10 hr.     

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.     

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.     

Formulation and Release Kinetics of Sustained Release Phenylpropanolamine Hydrochloride Granules and Tablets

Abstract

Sustained release phenylpropanolamine hydrochloride (PPH) granules and tablets were prepared using HPMC, HPMC and SCMC, Eudragit RS, Eudragit RS+L or HPMC + Eudragit RS matrices. The release pattern of PPH from the prepared granules and tablets was found to be in the following order HPMC > HPMC + SCMC > RS > RS + 1> HPMC + RS. The results revealed that, although the drug concentration was kept constant in all the prepared granules and tablets, the drug release from these formulations was clearly different and depends mainly on the type of matrix used. The presence of Eudragit L with Eudragit RS and Eudragit RS with HPMC resulted in a marked decrease in the drug release compared with that obtained from the matrix containing HPMC or Eudragit RS alone. The release data of PPH from the prepared granules and tablets were treated mathematically according to zero order, first order, Langenbuchar, modified Langenbucher and Higuchi models. The results revealed that no one model was able adequately to describe the drug release profiles from these formulations. In-vivo studies in human volunteers showed that, the peak urinary excretion of PPH occurred over a sustained period from 2 to 6.5 hr in case of HPMC + SCMC tablets and from 2 to 10 hr in case of either RS+L or HPMC + RS tablets.     

Optimization and development of a core-in-cup tablet for modulated release of theophylline in simulated gastrointestinal fluids

A triple-layer core-in-cup tablet that can release theophylline in simulated gastrointestinal (GI) fluids at three distinct rates has been developed. The first layer is an immediate-release layer; the second layer is a sustained-release layer; and the last layer is a boost layer, which was designed to coincide with a higher nocturnal dose of theophylline. The study consisted of two stages. The first stage optimized the sustained-release layer of the tablet to release theophylline over a period of 12 hr. Results from this stage indicated that 30% w/w acacia gum was the best polymer and concentration to use when compressed to a hardness of 50 N/m². The second stage of the study involved the investigation of the final triple-layer core-in-cup tablet to release theophylline at three different rates in simulated GI fluids. The triple-layer modulated core-in-cup tablet successfully released drug in simulated fluids at an initial rate of 40 mg/min, followed by a rate of 0.4085 mg/min, in simulated gastric fluid TS, 0.1860 mg/min in simulated intestinal fluid TS, and finally by a boosted rate of 0.6952 mg/min.     

Drug release kinetics from tablet matrices based upon ethylcellulose ether-derivatives: a comparison between different formulations

The present study involved the preparation of ibuprofen-containing controlled release tablets formulated from either the established granular product, Ethocel®Standard Premium, or the novel finely-milled product, Ethocel®Standard FP Premium. The tablets were prepared by either direct compression or wet granulation. The aim was to explore the influence of different parameters on the kinetics and mechanisms of ibuprofen release from the tablets. These parameters were; polymer particle size, polymer molecular weight, drug : polymer ratio, preparation methodology and partial replacement of lactose with the coexcipient—hydroxypropyl methylcellulose (HPMC). The derived drug release data were analyzed with reference to various established mathematical models while the f₂-metric technique was used in order to determine profile equivalency. It was found that drug release was mostly modulated by several interactive factors apparently exhibiting crosstalk. Nevertheless, it was possible to identify some simple rules. Incorporation of Ethocel® FP polymers and application of the wet granulation technique facilitated greater efficiency in controlling ibuprofen release behavior from the matrices. Furthermore, drug release profiles could be modulated by partial substitution of the primary excipient with HPMC. Polymer concentrations and particle sizes, rather than viscosity grade, were found to be decisive factors in controlling drug release rates.     

Drug Release Kinetics from Tablet Matrices Based Upon Ethylcellulose Ether-Derivatives: A Comparison Between Different Formulations

ABSTRACT

The present study involved the preparation of ibuprofen-containing controlled release tablets formulated from either the established granular product, Ethocel®Standard Premium, or the novel finely-milled product, Ethocel®Standard FP Premium. The tablets were prepared by either direct compression or wet granulation. The aim was to explore the influence of different parameters on the kinetics and mechanisms of ibuprofen release from the tablets. These parameters were; polymer particle size, polymer molecular weight, drug : polymer ratio, preparation methodology and partial replacement of lactose with the coexcipient—hydroxypropyl methylcellulose (HPMC). The derived drug release data were analyzed with reference to various established mathematical models while the f₂-metric technique was used in order to determine profile equivalency. It was found that drug release was mostly modulated by several interactive factors apparently exhibiting crosstalk. Nevertheless, it was possible to identify some simple rules. Incorporation of Ethocel® FP polymers and application of the wet granulation technique facilitated greater efficiency in controlling ibuprofen release behavior from the matrices. Furthermore, drug release profiles could be modulated by partial substitution of the primary excipient with HPMC. Polymer concentrations and particle sizes, rather than viscosity grade, were found to be decisive factors in controlling drug release rates.     

Comparative study of drug release from pellets coated with HPMC or Surelease

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.     

Formulation and release characteristics of hydroxypropyl methylcellulose matrix tablet containing melatonin

A hydroxypropyl methylcellulose (HPMC) matrix tablet containing melatonin (MT) was formulated as a function of HPMC viscosity, drug loading, type and amount of disintegrant, lubricant and glidant, and aqueous polymeric coating level and was compared with two commercial products. The release characteristics of the HPMC matrix tablet were investigated in the gastric fluid for 2 hr followed by study in intestinal fluid. The surface morphology of an uncoated HPMC matrix tablet using scanning electron microscopy (SEM) was crude, showing aggregated particles and rough crystals or pores, but it became smoother as the coating levels increased. As the HPMC polymer viscosity increased, the release rate had a tendency to decrease. As the drug loadings increased, the release rate slightly decreased. When Polyplasdone®XL, Primojel®, and Ac-Di-Sol®, except Avicel®, were incorporated in the HPMC matrix tablet, the release rate was markedly increased. There was no significant difference in release profiles when a mixture of lubricants and glidants (magnesium stearate, talc, and Cab-O-Sil®), except for magnesium stearate alone, was incorporated into low and high viscosity grade HPMC matrix tablets. As the coating level increased, the release rate gradually decreased, giving an increased lag time. The sustained-release HPMC matrix tablet with optimizing formulations may provide an alternative for oral controlled delivery of MT and be helpful in the future treatment of circadian rhythmic disorders.     

Formulation and Release Characteristics of Hydroxypropyl Methylcellulose Matrix Tablet Containing Melatonin

A hydroxypropyl methylcellulose (HPMC) matrix tablet containing melatonin (MT) was formulated as a function of HPMC viscosity, drug loading, type and amount of disintegrant, lubricant and glidant, and aqueous polymeric coating level and was compared with two commercial products. The release characteristics of the HPMC matrix tablet were investigated in the gastric fluid for 2 hr followed by study in intestinal fluid. The surface morphology of an uncoated HPMC matrix tablet using scanning electron microscopy (SEM) was crude, showing aggregated particles and rough crystals or pores, but it became smoother as the coating levels increased. As the HPMC polymer viscosity increased, the release rate had a tendency to decrease. As the drug loadings increased, the release rate slightly decreased. When Polyplasdone®XL, Primojel®, and Ac-Di-Sol®, except Avicel®, were incorporated in the HPMC matrix tablet, the release rate was markedly increased. There was no significant difference in release profiles when a mixture of lubricants and glidants (magnesium stearate, talc, and Cab-O-Sil®), except for magnesium stearate alone, was incorporated into low and high viscosity grade HPMC matrix tablets. As the coating level increased, the release rate gradually decreased, giving an increased lag time. The sustained-release HPMC matrix tablet with optimizing formulations may provide an alternative for oral controlled delivery of MT and be helpful in the future treatment of circadian rhythmic disorders.     

Simultaneous In Vitro Release of Levodopa and Carbidopa from Biocompatible Core-in-Cup Implants

Most implantable drug delivery systems do not release drug at a zero-order rate of release due to their geometry of a decreasing releasing surface. Microcapsules which can release drug at a zero-order rate are very difficult to produce and are prone to dose dumping. The purpose of this study was to test the in vitro release of levodopa and carbidopa from a new core-in-cup bioerodible implantable tablet. Core-in-cup implantable tablets with cups of Resomer® 207, and cores of Resomer RG 746 and Resomer RG 858 were tested. The core-in-cup implantable tablets were tested as to whether they released levodopa or carbidopa at a zeroorder rate. Their rate and extent of erosion in normal saline were also examined. The results indicate that levodopa and carbidopa were released at a zero-order rate in vitro for up to 100 days depending on the inherent viscosity of the polymer used in the core of the implant. It was also found that the rate and extent of erosion of the cup portion of the core-in-cup implantable tablet did not adversely affect the zero-order release of the drugs.     

Performance of multilayered particles: influence of a thin cushioning layer

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.     

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.     

Investigation of the effect of tablet surface area/volume on drug release from hydroxypropylmethylcellulose controlled-release matrix tablets

The purpose of this study was to investigate the influence of tablet surface area/volume (SA/Vol) on drug release from controlled-release matrix tablets containing hydroxypropylmethylcellulose (HPMC). Soluble drugs (promethazine HCl, diphenhydramine HCl, and propranolol HCl) were utilized in this study to give predominantly diffusion-controlled release. Drug release from HPMC matrix tablets with similar values of SA/Vol was comparable within the same tablet shape (i.e., flat-faced round tablets) and among different shapes (i.e., oval, round concave, flat-faced beveled-edge, and flat-faced round tablets). Tablets having the same surface area but different SA/Vol values did not result in similar drug release; tablets with larger SA/Vol values hadfaster release profiles. Utility of SA/Vol to affect drug release was demonstrated by changing drug doses, and altering tablet shape to adjust SA/Vol. When SA/Vol was held constant, similar release profiles were obtained with f2 metric values greater than 70. Thus, surface area/volume is one of the key variables in controlling drug release from HPMC matrix tablets. Proper use of this variable has practical application by formulators who may need to duplicate drug release profiles from tablets of different sizes and different shapes.     

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

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.     

Controlled Release Salbutamol Sulphate Molded Tablets Using Eudragit Retard

Permeable acrylic resins were used as efficient retarding materials to prepare controlled release salbutamol sulphate molded tablets. The formulation is simple, efficient, economic and is easily shaped into molded tablets. The effects of two types of acrylic resins, namely: Eudragit RL100 ad Eudragit RS100 in concentrations 1, 2 and 5% w/w on the physical characteristics as well as on the in vitro release patterns of salbutamol sulphate from molded tablets prepared with either polyethylene glycol (PEG) 4000 or 6000 were studied. It was revealed that, as the molecular weight of the PEG increased, the hardness of the tablets increased. Considerable retardation in the drug release was observed by using Eudragit RS100 as compared to Eudragit RL100. The formulation prepared with PEG 6000 and 5% Eudragit RS100 produced much more release time prolongation than the other tested formulations. On the other hand, tablets prepared by the direct compression technique produced a faster release of salbutamol sulphate than those prepared by molding.     

Controlled Release Salbutamol Sulphate Molded Tablets Using Eudragit Retard

Abstract

Permeable acrylic resins were used as efficient retarding materials to prepare controlled release salbutamol sulphate molded tablets. The formulation is simple, efficient, economic and is easily shaped into molded tablets. The effects of two types of acrylic resins, namely: Eudragit RL100 ad Eudragit RS100 in concentrations 1, 2 and 5% w/w on the physical characteristics as well as on the in vitro release patterns of salbutamol sulphate from molded tablets prepared with either polyethylene glycol (PEG) 4000 or 6000 were studied. It was revealed that, as the molecular weight of the PEG increased, the hardness of the tablets increased. Considerable retardation in the drug release was observed by using Eudragit RS100 as compared to Eudragit RL100. The formulation prepared with PEG 6000 and 5% Eudragit RS100 produced much more release time prolongation than the other tested formulations. On the other hand, tablets prepared by the direct compression technique produced a faster release of salbutamol sulphate than those prepared by molding.