Preparation and Evaluation of Sustained Release Ibuprofen Beads

Sustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.     

Preparation and Evaluation of Sustained Release Ibuprofen Beads

Sustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.     

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.     

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

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.     

Effect of Spheronization Technique on Drug Release from Uncoated Beads

Spheronization techniques are finding increased utility in pharmaceutical research and production. In this investigation emphasis is on the effect of two different spheronization methods (pan versus marumerizer) on drug release from uncoated beads containing acetaminophen and microcrystalline cellulose at a 1:1 ratio. Drug release from the pan beads is much faster than that from the marumerizer beads. The pan beads disintegrate during the dissolution testing, while beads made via the extruder and marumerizer appear to behave as an inert matrix system.     

Influence of Formulation and Other Factors on the Release of Chlorpheniramine Mateate from Polymer Coated Beads

Abstract

Controlled release beads containing chlorpheniramine maleate, coated with Eudragit RL and RS, were prepared using the Wurster process. The effect of membrane thickness, polymer ratio of the coating material, agitation speed and pH of the dissolution medium on drug release were investigated using the USP dissolution basket method. The in vitro release of drug was described adequately by a previously published equation. The release rate constant (K) was dependent on the membrane thickness, the polymer ratio and pH of the dissolution medium. On the other hand, agitation speed used in this study did not have any influence on the release of the drug.     

Influence of Formulation and Other Factors on the Release of Chlorpheniramine Mateate from Polymer Coated Beads

Controlled release beads containing chlorpheniramine maleate, coated with Eudragit RL and RS, were prepared using the Wurster process. The effect of membrane thickness, polymer ratio of the coating material, agitation speed and pH of the dissolution medium on drug release were investigated using the USP dissolution basket method. The in vitro release of drug was described adequately by a previously published equation. The release rate constant (K) was dependent on the membrane thickness, the polymer ratio and pH of the dissolution medium. On the other hand, agitation speed used in this study did not have any influence on the release of the drug.     

Drug Release from Spray Layered and Coated Drug-Containing Beads: Effects of pH and Comparison of Different Dissolution Methods

Based on dissolution profiles of three model drugs on spray layered beads with the same percentage of Aquacoat® coating, it was concluded that in vitro dissolution of oral controlled–release formulations should be performed in both gastric and intestinal media for ionizable drugs. Ketoprofen (weak acid, pK_a 4.8), nicardipine HCl (salt of weak organic base, pK_a8.6), and acetaminophen (very weak organic acid, pK_a9.7, not ionized at physiologic pH) provided different dissolution characteristics in enzyme–free simulated gastric fluid (pH 1.4) and enzyme–free simulated intestinal fluid (pH 7.4), indicating that the rate of drug release was pH dependent and related to drug ionization even though the solubility of the coating (ethylcellulose) is pH independent. In acidic media, ketoprofen release from the beads containing low–level coating (3%) was slower than that of nicardipine HCl, with the opposite holding true in basic media. Acetaminophen was released at approximately the same rate in both acidic and basic media. A comparison of drug release profiles for nicardipine HCl nude beads was also investigated among three different dissolution methods: USP dissolution apparatus I (basket method, 50 rpm), USP dissolution apparatus II (paddle method, 50 rpm), and USP dissolution apparatus III (Bio–Dis®, Van–Kel Industries, 5 and 10 dpm). Release profiles obtained from all methods were similar, indicating that the three dissolution methods were comparable.     

Ibuprofen Microcapsules: the Effect of Production Variables on Microcapsule Properties

Ibuprofen was microencapsulated with ethylcellulose using the solvent evaporation method. The effect of production variables on the properties of the microcapsules and drug release from them is described. Results show that size distribution, drug loading and the amount of free drug on the surface of the microcapsules is affected by production variables. The release of drug from the microcapsules was observed to be strongly influenced by parameters affecting the presence of uncoated drug on the microcapsule surface.     

Aqueous-Based Cellulose Acetate Butyrate Dispersion: Screening of Process and Formulation Variables to Obtain Verapamil HCl-Controlled Release Beads

The objectives of the present investigation were to evaluate the possibility of using a custom-designed cellulose acetate butyrate (CAB) pseudolatex dispersion on Verapamil HCl-loaded beads for sustained release of the drug. Excipient compatibility was studied by thermal analysis, X-ray diffraction, and content analysis. Inert beads (Nupareil) were loaded with verapamil HCl and subsequently coated with CAB pseudolatex dispersion. Process and formulation factors were screened by Plackett-Burman screening design in order to identify the most important factors affecting the amount of verapamil HCl released in 12 hours. X-ray diffraction pattern and content analysis showed no degradation of verapamil HCl and suggested absence of any interaction. However, thermal analysis indicated an interaction between verapamil HCl and excipient. A polynomial equation was developed to show the relationship between dependent and independent variables. The mathematical model fitted the data and explained 98.05 % of variability in the response. The difference between observed and predicated values of any given run did not exceed 6 % of maximum cumulative release at 12 hours. Plackett-Burman screening design identified coating weight gain, duration of curing, and amount of plasticizer as the most important factors determining cumulative percent released in 12 hours. Amount of Polydextrose/HPMC (Opadry II), spray rate, fluid bed coater outlet temperature, and atomizing pressure had no statistically significant (p < 0.05) influence on the response.     

Effect of Polymer Loading on Drug Release from Film-Coated Ibuprofen Pellets Prepared by Extrusion-Spheronization

Many factors are capable of influencing the mechanism of drug release from pellets prepared by extrusion-spheronization. This study was designed to elucidate the effect of polymer type and loading and the effect of processing variables on the rate and mechanism of drug release from ibuprofen pellets coated using aqueous polymeric dispersions. Qualitative and quantitative assessment of the success of the film coating process and the quality of the resultant films is made using scanning electron microscopy and in-vitro dissolution testing. The importance of plasticizer in polymeric film formation is also discussed. Uncoated pellets containing 60, 70 and 80% ibuprofen were coated with aqueous polymeric dispersions of polymethacrylates, ethylcellulose and silicone elastomer films. The high drug loading of these pellets adds special interest to this study. Drug release from uncoated pellets appears to follow first-order kinetics. The application of a polymeric membrane to uncoated cores has the effect of retarding drug release. There appears to be a critical coating level below which core coverage by the polymer is incomplete, drug release is diffusion controlled and first-order release kinetics are observed. Above a defined polymer level, drug release appears to be membrane controlled and zero-order kinetics are observed. The presence of plasticizer in the polymeric film imparts a hydrophilic component to an otherwise hydrophobic membrane. This enhances the penetration of aqueous solvent into the pellet core during in-vitro dissolution testing, increasing the rate of drug release. Scanning electron micrographs reveal the nature of these hydrophilic pores, beneath which a fine tortuous skeletal network of drug-depleted core is exposed.     

Effect of Polymer Loading on Drug Release from Film-Coated Ibuprofen Pellets Prepared by Extrusion-Spheronization

Abstract

Many factors are capable of influencing the mechanism of drug release from pellets prepared by extrusion-spheronization. This study was designed to elucidate the effect of polymer type and loading and the effect of processing variables on the rate and mechanism of drug release from ibuprofen pellets coated using aqueous polymeric dispersions. Qualitative and quantitative assessment of the success of the film coating process and the quality of the resultant films is made using scanning electron microscopy and in-vitro dissolution testing. The importance of plasticizer in polymeric film formation is also discussed. Uncoated pellets containing 60, 70 and 80% ibuprofen were coated with aqueous polymeric dispersions of polymethacrylates, ethylcellulose and silicone elastomer films. The high drug loading of these pellets adds special interest to this study. Drug release from uncoated pellets appears to follow first-order kinetics. The application of a polymeric membrane to uncoated cores has the effect of retarding drug release. There appears to be a critical coating level below which core coverage by the polymer is incomplete, drug release is diffusion controlled and first-order release kinetics are observed. Above a defined polymer level, drug release appears to be membrane controlled and zero-order kinetics are observed. The presence of plasticizer in the polymeric film imparts a hydrophilic component to an otherwise hydrophobic membrane. This enhances the penetration of aqueous solvent into the pellet core during in-vitro dissolution testing, increasing the rate of drug release. Scanning electron micrographs reveal the nature of these hydrophilic pores, beneath which a fine tortuous skeletal network of drug-depleted core is exposed.     

Release of Ibuprofen from Polyethylene glycol solid dispersions:-Equilibrium solubility approach

This work is an attempt to enhance the release of Ibuprofen by improving its aqueous solubility. This was done by dispersing the drug in a water soluble carrier such as polyethylene glycol (PEG). The solubility was found to depend on various factors such as method of preparation, carrier weight fraction and molecular weight and the pH of the medium. It was found that dispersions prepared by the fusion method gave higher solubilities than those prepared by the solvent technique. The solubility was found to vary with carrier molecular weight and its weight fraction. Decreasing the PEG molecular weight resulted in increased solubility. A polymer to drug ratio of 1:1 was found to give the highest solubility. The solubility decreased as the polymer weight fraciton was increased beyond this value. The solubility of the solid dispersion was found to be pH dependent. A greater solubility was obtained at higher pHs than at lower ones. This was attributed to the weakly acidic nature of Ibuprofen. Calculation of the heat of solution of the various systems studied showed that the non dispersed drug had a higher heat of solution than the dispersed systems. This was thought to be the cause of the higher solubility of the dispersions as compared to the original drug.     

Release of Ibuprofen from Polyethylene glycol solid dispersions:-Equilibrium solubility approach

Abstract

This work is an attempt to enhance the release of Ibuprofen by improving its aqueous solubility. This was done by dispersing the drug in a water soluble carrier such as polyethylene glycol (PEG). The solubility was found to depend on various factors such as method of preparation, carrier weight fraction and molecular weight and the pH of the medium. It was found that dispersions prepared by the fusion method gave higher solubilities than those prepared by the solvent technique. The solubility was found to vary with carrier molecular weight and its weight fraction. Decreasing the PEG molecular weight resulted in increased solubility. A polymer to drug ratio of 1:1 was found to give the highest solubility. The solubility decreased as the polymer weight fraciton was increased beyond this value. The solubility of the solid dispersion was found to be pH dependent. A greater solubility was obtained at higher pHs than at lower ones. This was attributed to the weakly acidic nature of Ibuprofen. Calculation of the heat of solution of the various systems studied showed that the non dispersed drug had a higher heat of solution than the dispersed systems. This was thought to be the cause of the higher solubility of the dispersions as compared to the original drug.     

Bead Coating: II. Effect of Spheronization Technique on Drug Release from Coated Spheres

Abstract

The effect of spheronization method on drug release from coated spheres may be evaluated by determining the drug release rate, the critical coating level and the release mechanism. Drug release is faster from pan beads than from marumerizer beads at the same coating level. An equation is proposed which indicates that the critical coating level is inversely proportional to sphere size and sphere density, which in turn results from the different spheronization techniques. From the calculation, the critical coating levels for 14/16 mesh cuts of marumerizer beads and pan beads are 12% and 18%, respectively. Disintegration, pore-control and barrier control are involved in the release mechanisms of drugs from coated pan beads.     

Bead Coating: II. Effect of Spheronization Technique on Drug Release from Coated Spheres

The effect of spheronization method on drug release from coated spheres may be evaluated by determining the drug release rate, the critical coating level and the release mechanism. Drug release is faster from pan beads than from marumerizer beads at the same coating level. An equation is proposed which indicates that the critical coating level is inversely proportional to sphere size and sphere density, which in turn results from the different spheronization techniques. From the calculation, the critical coating levels for 14/16 mesh cuts of marumerizer beads and pan beads are 12% and 18%, respectively. Disintegration, pore-control and barrier control are involved in the release mechanisms of drugs from coated pan beads.     

Study of Drug Release from Pellets Coated with Surelease Containing Hydroxypropylmethylcellulose

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.     

Study of Drug Release from Pellets Coated with Surelease Containing Hydroxypropylmethylcellulose

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.     

Thermal Treatment of Beads with Wax for Controlled Release

Abstract

Beads prepared by extruder/marumerizer technology were formulated with water soluble drugs, microcrystalline cellulose and several waxy materials. The waxes (10 to 50% by weight) were included in an effort to slow drug release. Subsequent thermal treatment of these beads was applied. Beads were processed to determine the effect of varying wax level, excipient, active drug, and effect of heat treatment. In-vitro drug release profiles were evaluated for the untreated and thermal treated beads. In general, the simple incorporation of wax into the granulation did not provide the desired controlled release dissolution profile. Thermal treatment of the finished beads, however, resulted in products which behaved in a different manner during dissolution testing and in general provided slower release. Drug release was found to vary with the type and level of wax, drug, excipient, and the thermal treatment.     

Thermal Treatment of Beads with Wax for Controlled Release

Beads prepared by extruder/marumerizer technology were formulated with water soluble drugs, microcrystalline cellulose and several waxy materials. The waxes (10 to 50% by weight) were included in an effort to slow drug release. Subsequent thermal treatment of these beads was applied. Beads were processed to determine the effect of varying wax level, excipient, active drug, and effect of heat treatment. In-vitro drug release profiles were evaluated for the untreated and thermal treated beads. In general, the simple incorporation of wax into the granulation did not provide the desired controlled release dissolution profile. Thermal treatment of the finished beads, however, resulted in products which behaved in a different manner during dissolution testing and in general provided slower release. Drug release was found to vary with the type and level of wax, drug, excipient, and the thermal treatment.