Studies on the in vitro Release of Ibuprofen from Polyethylene Glycol-Polyvinyl Acetate Mixtures Liquid Filled into Hard Gelatin Capsules

The release of ibuprofen from mixtures of polyethylene glycol (PEG) with polyvinyl acetate (PVAc) has been studied in vitro and complemented by x-ray diffraction measurements, differential scanning calorimetry (DSC), and melting point determinations via hot-stage microscopy (HSM). Results indicate that ibuprofen release can be affected markedly by alteration of the PVAc concentration. The molecular weight of the PEG and the pH of the dissolution medium are also shown to affect the release profile. Visual observation during the drug release process revealed a complex behavior which included emission of liquidlike droplets, formation of a crust around the releasing mass, and/or production of flakes of solid material. This behavior appeared to have a disadvantageous effect on the reproducibility of drug release. Construction of a phase diagram from results of thermal analysis using DSC and HSM indicated the formation of an eutectic mixture with a composition of 35% ibuprofen and 65% PEG 1500 and a melting point of 36°C. The complex behavior of the drug-releasing mass is discussed in terms of this phase diagram. Only the release data for systems containing 4% w/w or more of PVAc could be linearized by plotting against the square root of time whereas data for all of the systems studied could be linearized by first-order plots.     

Properties of Hot-Melt Extruded Theophylline Tablets Containing Poly(Vinyl Acetate)

The objectives of this study were to investigate the properties of poly(vinyl acetate) (PVAc) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. A physical mixture of drug, polymer, and drug release modifiers was fed into the equipment and heated inside the barrel of the extruder. The cylindrical extrudates were either cut into tablets or ground into granules and compressed with other excipients into tablets. Due to the low glass transition temperature of the PVAc, the melt extrusion process was conducted at approximately 70°C. Theophylline was used as the model drug in this study. Theophylline was present in the extrudate in its crystalline form and was released from the tablets by diffusion. The Higuchi diffusion model and percolation theories were applied to the dissolution data to explain the drug release properties of the matrix systems. The release rate was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. Water-soluble polymers were demonstrated to be efficient release rate modifiers for this system.     

Properties of hot-melt extruded theophylline tablets containing poly(vinyl acetate)

The objectives of this study were to investigate the properties of poly(vinyl acetate) (PVAc) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. A physical mixture of drug, polymer, and drug release modifiers was fed into the equipment and heated inside the barrel of the extruder. The cylindrical extrudates were either cut into tablets or ground into granules and compressed with other excipients into tablets. Due to the low glass transition temperature of the PVAc, the melt extrusion process was conducted at approximately 70°C. Theophylline was used as the model drug in this study. Theophylline was present in the extrudate in its crystalline form and was released from the tablets by diffusion. The Higuchi diffusion model and percolation theories were applied to the dissolution data to explain the drug release properties of the matrix systems. The release rate was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. Water-soluble polymers were demonstrated to be efficient release rate modifiers for this system.     

Development and In-Vitro Evaluation of Ethyl Cellulose Micropellets as a Controlled Release Dosage Form for Theophylline

A micropellet dosage form was developed using ethyl cellulose as a polymer with a view to achieve a controlled release oral drug delivery system for theophylline. Drugpolymer ratios and stirring speeds were found to influence the size-distribution of micropellets. Time required for 50% release of theophylline from micropellets was found to vary linearly with the drug content and reciprocal of diameter of micropellets. Invitro release of theophylline from micropellets, having different drug-polymer ratios and different sizes, was found apparently to follow both the First-order release and Diffusion controlled release processes. By differential rate treatment it was found that the overall release, in fact, followed diffusion controlled process.     

Kinetic Release of Theophylline from Hydrophilic Swellable Matrices

The objective of this research was to evaluate the effect of hydroxypropylmethylcellulose (HPMC; Methocel K4M Premium) level and type of excipient on theophylline release and to attempt to predict the drug release from hydrophilic swellable matrices. Formulations containing theophylline anhydrous (10% w/w), Methocel K4M Premium (10%, 30%, and 40% w/w), different diluents (Lactose Fast Flo, Avicel PH-101, and Emcompress), and magnesium stearate (0.75% w/w) were prepared by direct compression at a target weight of 450 mg ± 5% and target hardness of 7 kp to 10 kp. It was found that, as the percentage of polymer in all formulations increased from 10% to 30% or 40%, the drug release decreased. However, there was no significant difference in drug release between formulations containing 30% polymer and formulations containing 40% polymer. At low levels of polymer, the drug release is controlled by the type of diluent used. Avicel PH-101 formulation gave the highest release, while its corresponding Emcompress formulation gave the lowest release. Formulations containing 30% or 40% polymer gave the same release profiles irrespective of the type of diluent used. In all cases, replacement of a portion of Methocel K4M Premium with any diluent resulted in increase of theophylline release. In addition, this investigation demonstrated that the drug release from hydrophilic swellable matrices can be predicted using only a minimum number of experiments.     

Kinetic Release of Theophylline from Hydrophilic Swellable Matrices

The objective of this research was to evaluate the effect of hydroxypropylmethylcellulose (HPMC; Methocel K4M Premium) level and type of excipient on theophylline release and to attempt to predict the drug release from hydrophilic swellable matrices. Formulations containing theophylline anhydrous (10% w/w), Methocel K4M Premium (10%, 30%, and 40% w/w), different diluents (Lactose Fast Flo, Avicel PH-101, and Emcompress), and magnesium stearate (0.75% w/w) were prepared by direct compression at a target weight of 450 mg ± 5% and target hardness of 7 kp to 10 kp. It was found that, as the percentage of polymer in all formulations increased from 10% to 30% or 40%, the drug release decreased. However, there was no significant difference in drug release between formulations containing 30% polymer and formulations containing 40% polymer. At low levels of polymer, the drug release is controlled by the type of diluent used. Avicel PH-101 formulation gave the highest release, while its corresponding Emcompress formulation gave the lowest release. Formulations containing 30% or 40% polymer gave the same release profiles irrespective of the type of diluent used. In all cases, replacement of a portion of Methocel K4M Premium with any diluent resulted in increase of theophylline release. In addition, this investigation demonstrated that the drug release from hydrophilic swellable matrices can be predicted using only a minimum number of experiments.     

Development and In-Vitro Evaluation of Ethyl Cellulose Micropellets as a Controlled Release Dosage Form for Theophylline

Abstract

A micropellet dosage form was developed using ethyl cellulose as a polymer with a view to achieve a controlled release oral drug delivery system for theophylline. Drugpolymer ratios and stirring speeds were found to influence the size-distribution of micropellets. Time required for 50% release of theophylline from micropellets was found to vary linearly with the drug content and reciprocal of diameter of micropellets. Invitro release of theophylline from micropellets, having different drug-polymer ratios and different sizes, was found apparently to follow both the First-order release and Diffusion controlled release processes. By differential rate treatment it was found that the overall release, in fact, followed diffusion controlled process.     

Differential Thermal Analysis of Polyethylene Glycol and Glycerol Monostearate Suppository Bases Containing Theophylline

Water soluble polyethylene glycol 4000 (PEG4) suppositories were prepared containing 4% (w/w) theophylline. Various concentrations of polyethylene glycol 1000 (PEG1) and glycerol monostearate (GMS) were also added. Differential thermal analysis (DTA) of the PEG4 and PEG1 combination suppositories showed no melting endotherm for theophylline. But when theophylline concentration in the base was 12% (w/w) and above, sharp endothermic peak of theophylline was obtained. In contrast, when GMS was added as a base material above 50% (w/w) with PEG4, the melting endotherm of theophylline (4%, w/w) appeared at 273-274°C. The melting endotherm of the suppository bases increased up to 2 to 4°C due to storage at 4°C for six months.     

Release of Tolmetin from Carbomw Gel Systems

Gel-formulations containing a nonsteroidal anti-inflammatory drug, tolmetin, were prepared using three different carbomers namely, Carbopol™ 934, 940 and 941. Effects of cosolvent composition, carbomer type, carbomer concentration and drug concentration on drug release from the gels were analyzed by factorial design. Gels with high aqueous content yielded significantly higher tolmetin release rates than gels with lower aqueous content. Although no significant differences in drug release characteristics were observed between the three carbomer gels, there was a trend in the release profiles; fastest drug release was observed from Carbopol™ 941 gels and the slowest drug release was observed from Carbopol™ 940 gels. Increasing the carbomer concentration from 1% w/w to 2% w/w had no significant effect on drug release from gel formulations prepared with all the three different types of carbomers. However, increasing the tolmetin concentration in the gels from 1% w/w to 4% w/w resulted in a dramatic increase in drug release. An investigation of the mechanism of drug release from the gels revealed that tolmetin release was diffusion controlled, except at the outset.     

Differential Thermal Analysis of Polyethylene Glycol and Glycerol Monostearate Suppository Bases Containing Theophylline

Abstract

Water soluble polyethylene glycol 4000 (PEG4) suppositories were prepared containing 4% (w/w) theophylline. Various concentrations of polyethylene glycol 1000 (PEG1) and glycerol monostearate (GMS) were also added. Differential thermal analysis (DTA) of the PEG4 and PEG1 combination suppositories showed no melting endotherm for theophylline. But when theophylline concentration in the base was 12% (w/w) and above, sharp endothermic peak of theophylline was obtained. In contrast, when GMS was added as a base material above 50% (w/w) with PEG4, the melting endotherm of theophylline (4%, w/w) appeared at 273-274°C. The melting endotherm of the suppository bases increased up to 2 to 4°C due to storage at 4°C for six months.     

Solid Dispersion Controlled Release: Effect of Particle Size, Compression Force and Temperature

Solid dispersions are dynamic systems, a careful control of processing variables is required to produce desired physicochemical properties of these systems.

The influence of drug particle size, dispersion temperature and compression force on the release rate of theophylline from solid dispersed system tablets was studied. Theophylline base (micronized and granulate) were embedded into a polymeric mixture of PEG and acrylic/methacrylic esters at controlled temperature and shock cooled. Tablets were made at two compressional forces and drug release was measured spectrophotometrically over a period of fifteen hours.

The release rate of drug dispersed in these insoluble matrices was independent of particle size but not of hardness.

However, variations in ratios of polymeric mixture and dispersion temperature controls the drug release rate from inert matrix more effectively than such factors as drug particle size and lower range of tablet hardness. The fast cooling produced excellent reproducibility of drug content throughout the entire entrapment product. X-ray diffraction study demonstrated no changes in crystalline form of theophylline.     

Release of Tolmetin from Carbomw Gel Systems

Abstract

Gel-formulations containing a nonsteroidal anti-inflammatory drug, tolmetin, were prepared using three different carbomers namely, Carbopol? 934, 940 and 941. Effects of cosolvent composition, carbomer type, carbomer concentration and drug concentration on drug release from the gels were analyzed by factorial design. Gels with high aqueous content yielded significantly higher tolmetin release rates than gels with lower aqueous content. Although no significant differences in drug release characteristics were observed between the three carbomer gels, there was a trend in the release profiles; fastest drug release was observed from Carbopol? 941 gels and the slowest drug release was observed from Carbopol? 940 gels. Increasing the carbomer concentration from 1% w/w to 2% w/w had no significant effect on drug release from gel formulations prepared with all the three different types of carbomers. However, increasing the tolmetin concentration in the gels from 1% w/w to 4% w/w resulted in a dramatic increase in drug release. An investigation of the mechanism of drug release from the gels revealed that tolmetin release was diffusion controlled, except at the outset.     

The influence of HPMC concentration on release of theophylline or hydrocortisone from extended release mini-tablets

Context: Mini-tablets are compact dosage forms, typically 2–3 mm in diameter, which have potential advantages for paediatric drug delivery. Extended release (ER) oral dosage forms are intended to release drugs continuously at rates that are sufficiently controlled to provide periods of prolonged therapeutic action following each administration, and polymers such as hypromelllose (HPMC) are commonly used to produce ER hydrophilic matrices.

Objective: To develop ER mini-tablets of different sizes for paediatric delivery and to study the effects of HPMC concentration, tablet diameter and drug solubility on release rate.

Methods: The solubility of Hydrocortisone and theophylline was determined. Mini-tablets (2 and 3 mm) and tablets (4 and 7 mm) comprising theophylline or hydrocortisone and HPMC (METHOCEL? K15M) at different concentrations (30, 40, 50 and 60%w/w) were formulated. The effect of tablet size, HPMC concentration and drug solubility on release rate and tensile strength was studied.

Results and Discussion: Increasing the HPMC content and tablet diameter resulted in a significant decrease in drug release rate from ER mini-tablets. In addition, tablets and mini-tablets containing theophylline produced faster drug dissolution than those containing hydrocortisone, illustrating the influence of drug solubility on release from ER matrices. The results indicate that different drug release profiles and doses can be obtained by varying the polymer content and mini-tablet diameter, thus allowing dose flexibility to suit paediatric requirements.

Conclusion: This work has demonstrated the feasibility of producing ER mini-tablets to sustain drug release rate, thus allowing dose flexibility for paediatric patients. Drug release rate may be tailored by altering the mini-tablet size or the level of HPMC, without compromising tablet strength.     

Evaluation of Chitosan Citrate Complexes as Matrices for Controlled Release Formulations Using a 32 full Factorial Design

Chitosan citrate complexes of several viscocity grades were synthesized, isolated, purified and identified. These complexes were found to form viscous gels of varying viscosities, upon dispersion in water. The ability of these complexes in sustaining drug release from matrix tablets was evaluated using a two factor three level full factorial design with theophylline as the model drug. Viscosity and concentration of the polymer complexes were optimized to achieve the desired in-vitro release profile. In-vitro dissolution characteristics were evaluated in deionized water as the dissolution medium. Data were fit to a quadratic model and polynomial equations were generated and used to predict the optimum formulation composition with desired release characteristics. These complexes were found to be very effective in sustaining the release of theophylline and were directly compressible. The release mechanism appears to be diffusion controlled. Excellent correlation was obtained between predicted and actual release profiles of the optimum formula.     

Release of Theophylline from Ethyl Cellulose Mecrocapsues Alone and in Conjuction with Fat Embedded (Precirol®) Granules and Hydroxypropyl Methycellulose

Abstract

Microcapsules of theophylline with ethyl cellulose were prepared by coacervation technique using cabosil® (silicon dioxide) as separant. Tablets were prepared from microcapsules, microcapsules + theophylline fat embedded granules, and microcapsules and hydroxypropyl methylcellulose 4000 (HPMC). Release was studied in vitro by the rotating basket method. Prolonged release of theophylline was observed from microcapsules with no drug dumping. The release from microcapsules was of first-order whereas that from all the tablet formulation was diffusion controlled according to the Higuchi model. Good correlation was found between release rate and core:wall ratio for all the systems. Decrease in hardness of tablets made from microcapsules alone decreased the release rate, indicating damage of microcapsules during compression. The tablets compressed from fat embedded granules, microcapsules with fat embedded granules, and microcapsules with HPMC gave a desired release for a 74 hour sustained release preparation.     

Solid Dispersion Controlled Release: Effect of Particle Size,Compression Force and Temperature

Abstract

Solid dispersions are dynamic systems, a careful control of processing variables is required to produce desired physicochemical properties of these systems.

The influence of drug particle size, dispersion temperature and compression force on the release rate of theophylline from solid dispersed system tablets was studied. Theophylline base (micronized and granulate) were embedded into a polymeric mixture of PEG and acrylic/methacrylic esters at controlled temperature and shock cooled. Tablets were made at two compressional forces and drug release was measured spectrophotometrically over a period of fifteen hours.

The release rate of drug dispersed in these insoluble matrices was independent of particle size but not of hardness.

However, variations in ratios of polymeric mixture and dispersion temperature controls the drug release rate from inert matrix more effectively than such factors as drug particle size and lower range of tablet hardness. The fast cooling produced excellent reproducibility of drug content throughout the entire entrapment product. X-ray diffraction study demonstrated no changes in crystalline form of theophylline.     

Studies on the Release of Theophylline from Polyvinylacetate Microspheres

Polyvinylacetate microspheres containing theophylline were prepared by emulsification and solvent removal method. The release pattern of theophylline from the microspheres was found to be best explained by diffusion controlled process. The rates of release were found to be influenced by drug-polymer ratios, size of microspheres, concentration of surfactant used for the preparation of microspheres, and pH of the dissolution media.     

Physico-chemical properties investigation of cisplatin loaded polybutyladipate (PBA) nanoparticles prepared by w/o/w

cis-Diamminedichloroplatinum(II) (cisplatin) is used against different kinds of cancers. Unfortunately, because of the severe side-effects like nephrotoxicity, ototoxicity, etc., they are administered in small doses at low concentrations. The purpose of this work is to improve injectional controlled release (ICR) of cisplatin that releases drug in the extended temporal periods. In order to access this aim, biodegradable polymeric nanoparticles containing cisplatin as anticancer drug of various ranges from 71 to 661 nm were prepared by a w/o/w double emulsion solvent evaporation technique. Influences of process parameters such as solvent removal technique, type and concentration of polymer, volume of oil phase, volume of external aqueous phase, concentration of stabilizer, drug concentration in the internal and external aqueous phases and power of sonication on morphology, characteristics of the nanoparticles and release profile were investigated. Morphology of the nanoparticles was studied by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and the images indicated that spherical shape of the nanoparticles can be tailored to rod-like shape by changing the reaction parameters. Size of the nanoparticles decreased as polymer concentration decreases. Volume of oil phase, power of sonication and drug concentration in the internal water phase affected the size of nanoparticles. Drug release profiles indicate that polymer concentration in the oil phase and stabilizer concentration in the external water phase have critical role in the drug release process from the nanoparticles. The in-vitro release of the encapsulated drug was observed by using the diffusion models of release from a sphere carrier and the release pattern was shown to be a complex process.     

Evaluation of Chitosan Citrate Complexes as Matrices for Controlled Release Formulations Using a 32 full Factorial Design

Abstract

Chitosan citrate complexes of several viscocity grades were synthesized, isolated, purified and identified. These complexes were found to form viscous gels of varying viscosities, upon dispersion in water. The ability of these complexes in sustaining drug release from matrix tablets was evaluated using a two factor three level full factorial design with theophylline as the model drug. Viscosity and concentration of the polymer complexes were optimized to achieve the desired in-vitro release profile. In-vitro dissolution characteristics were evaluated in deionized water as the dissolution medium. Data were fit to a quadratic model and polynomial equations were generated and used to predict the optimum formulation composition with desired release characteristics. These complexes were found to be very effective in sustaining the release of theophylline and were directly compressible. The release mechanism appears to be diffusion controlled. Excellent correlation was obtained between predicted and actual release profiles of the optimum formula.     

Modified drug release of poloxamer matrix by including water-soluble and water-insoluble polymer

Background: The ability of poloxamer 407 to control drug release was investigated along with the effect of incorporation of a second polymer with poloxamer on dissolution behavior. Methods: Tablets made of 30% w/w/ theophylline and 15%, 25%, 50%, or 69% poloxamer were prepared. Additionally, tablets containing mixture of poloxamer with carbomer or hypromellose in a 1:1 ratio and at different total levels (15%, 30%, and 50%) were also tested. Results: Data show that as the level of poloxamer increased, drug release decreased. Formulations containing poloxamer: hypromellose 1:1 at 50% level and formulations containing poloxamer: carbomer 1:1 at 30% level produced controlled release matrices over 24 hours of testing dissolution. The mechanism of drug release follows anomalous relaxation non-Fickian diffusion model. Conclusions: These results suggest that the combination of poloxamer 407 with hypromellose or carbomer is feasible and has potential to offer the formulator control over drug release.