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.     

Effect of diluents on tablet integrity and controlled drug release

The objective of this study was to evaluate the effect of diluents and wax level on tablet integrity during heat treatment and dissolution for sustained-release formulations and the resultant effect on drug release. Dibasic calcium phosphate dihydrate (DCPD), microcrystalline cellulose (MCC), and lactose were evaluated for their effect on tablet integrity during drug dissolution and heat treatment in wax matrix formulations. A newly developed direct compression diluent, dibasic calcium phosphate anhydrous (DCPA), was also evaluated. Compritol® 888 ATO was used as the wax matrix material, with phenylpropanolamine hydrochloride (PPA) as a model drug. Tablets were made by direct compression and then subjected to heat treatment at 80°C for 30 min. The results showed that MCC, lactose, and DCPA could maintain tablets intact during heat treatment above the melting point of wax (70°C-75°C). However, DCPD tablets showed wax egress during the treatment. MCC tablets swelled and cracked during drug dissolution and resulted in quick release. DCPD and lactose tablets remained intact during dissolution and gave slower release than MCC tablets. DCPA tablets without heat treatment disintegrated very quickly and showed immediate release. In contrast, heat-treated DCPA tablets remained intact through the 24-hr dissolution test and only released about 80% PPA at 6 hr. In the investigation of wax level, DCPD was used as the diluent. The drug release rate decreased as the wax content increased from 15% to 81.25%. The dissolution data were best described by the Higuchi square-root-of-time model. Diluents showed various effects during heat treatment and drug dissolution. The integrity of the tablets was related to the drug release rate. Heat treatment retarded drug release if there was no wax egress.     

Avicel RC-591/Chitosan Beads by Extrusion-Spheronization Technology

Beads were successfully prepared using the combination of Avicel RC-591 and chitosan using extrusion and spheronization technology. The effects of different viscosity grades of chitosan (SEACURE 142, 242, 342 and 442) on bead formation and on release profiles were examined using acetaminophen as a model drug. Incorporation of higher viscosity grades of chitosan yielded beads with rough surfaces and slower release characteristics. Seacure 342 was chosen for further studies using acetaminophen and theophylline as model drugs of different solubilities. Beads were prepared with varying proportions of Seacure 342 and Avicel RC-591 (20% drug loading). Drug release from the beads varied with the dissolution method used. Beads were swollen in 0.1 N HC1 while the bead structure remained intact. In water, the beads exhibited gel-like structures.     

Avicel RC-591/Chitosan Beads by Extrusion-Spheronization Technology

Abstract

Beads were successfully prepared using the combination of Avicel RC-591 and chitosan using extrusion and spheronization technology. The effects of different viscosity grades of chitosan (SEACURE 142, 242, 342 and 442) on bead formation and on release profiles were examined using acetaminophen as a model drug. Incorporation of higher viscosity grades of chitosan yielded beads with rough surfaces and slower release characteristics. Seacure 342 was chosen for further studies using acetaminophen and theophylline as model drugs of different solubilities. Beads were prepared with varying proportions of Seacure 342 and Avicel RC-591 (20% drug loading). Drug release from the beads varied with the dissolution method used. Beads were swollen in 0.1 N HC1 while the bead structure remained intact. In water, the beads exhibited gel-like structures.     

The effect of wax on compaction of microcrystalline cellulose beads made by extrusion and spheronization

The effect of wax on the deformation behavior and compression characteristics of microcrystalline cellulose (Avicel PH-101) and acetaminophen (APAP) beads is described. Beads of Avicel PH-101 and APAP formulations were prepared using extrusion and spheronization technology. A waxy material, glyceryl behenate, N.F. (Compritol), was added to the formulations in amounts ranging from 10% to 70% of total solid weight. Beads with a selected particle size range of 16-30 mesh were compressed with an instrumented single punch Manesty F press utilizing a 7/16-in. flat-faced tooling set. Compaction profiles were generated for the tablets to evaluate the effect of wax on the densification of beads containing wax. Beads made without wax (the control formulation) required greater compression forces to form cohesive tablets. As the amount of wax in the bead formulation was increased, the beads become more plastic and compressible. The Heckel equation which relates densification to compression pressure was used to evaluate the deformation mechanisms of the bead formulations. The analysis shows that as the level of wax in the bead formulation is increased, the yield pressure decreases, indicating that the beads densify by a plastic deformation mechanism.     

Preparation and Dissolution Characteristics of Prolonged Release Mebeverine-HCL Beads

Different batches of slow release mebeverine-HCl beads were prepared by pan coating technique using different release retarding polymers viz Eudragit RL₁₀₀, Eudragit RS₁₀₀ and Ethyl cellulose. The thickness of the coats was controlled by changing the amounts of the added polymers. Pre- and overcoating of the beads with bees wax was also carried out. Mixtures of pre-waxed Eudragit RS₁₀₀ coated and uncoated beads in different ratios were prepared to control both drug content and release.

Dissolution profiles of mebeverine HCl from the prepared beads were investigated using USP XX rotating basket method. Prolonged release of mebeverine-HCl was obtained from different batches of the coated beads with the advantage of no initial dumping of the water soluble drug. The release of mebeverine-HCl from the beads coated with acrylic resins and ethyl cellulose as well as waxed acrylic resins coated beads was diffusion controlled according to Higuchi model. Beads coated with ethyl cellulose showed a different release pattern when pre-or overcoated with wax. By altering the ratios of prewaxed Eudragit Rs₁₀₀ coated and uncoated beads in formulated mixtures, it was possible to control both mebeverine-HCl content and release rate.     

Preparation and Dissolution Characteristics of Prolonged Release Mebeverine-HCL Beads

Different batches of slow release mebeverine-HCl beads were prepared by pan coating technique using different release retarding polymers viz Eudragit RL₁₀₀, Eudragit RS₁₀₀ and Ethyl cellulose. The thickness of the coats was controlled by changing the amounts of the added polymers. Pre- and overcoating of the beads with bees wax was also carried out. Mixtures of pre-waxed Eudragit RS₁₀₀ coated and uncoated beads in different ratios were prepared to control both drug content and release.

Dissolution profiles of mebeverine HCl from the prepared beads were investigated using USP XX rotating basket method. Prolonged release of mebeverine-HCl was obtained from different batches of the coated beads with the advantage of no initial dumping of the water soluble drug. The release of mebeverine-HCl from the beads coated with acrylic resins and ethyl cellulose as well as waxed acrylic resins coated beads was diffusion controlled according to Higuchi model. Beads coated with ethyl cellulose showed a different release pattern when pre-or overcoated with wax. By altering the ratios of prewaxed Eudragit Rs₁₀₀ coated and uncoated beads in formulated mixtures, it was possible to control both mebeverine-HCl content and release rate.     

Preparation and dissolution characteristics of indomethacin sustained release beads

Indomethacin is a nonsteroidal anti-inflammatory agent and has a short half life, and causes gastric irritation. Sustained release beads of indomethacin were prepared and dissolution profiles were investigated. Beads were prepared by allowing drops of a suspension of the drug and excipients in a solution of cellulose acetate phthalate to drop into an acetic acid solution by means of a peristaltic pump. In a previous study¹, sulfadiazine was used as a model drug to prepare beads by a similar method and the effects of various viscosity agents on the properties of these beads were assessed. Glycerin, polymers (Methocel and Avicel), and surfactants (Tween 80 and Span 80) were used as excipients. The incorporation of various viscosity agents and polymers into the suspension yielded beads with different disintegration and dissolution values. A high performance liquid chromatography method showed no indication of drug degradation during the preparation. The dissolution studies of the indomethacin preparations demonstrated differences in drug release properties depending on composition and method of preparation. The preparation with equal quantities of the two surfactants (Tween 80 and Span 80) released the drug at the slowest rate.     

Preparation and dissolution characteristics of indomethacin sustained release beads

Abstract

Indomethacin is a nonsteroidal anti-inflammatory agent and has a short half life, and causes gastric irritation. Sustained release beads of indomethacin were prepared and dissolution profiles were investigated. Beads were prepared by allowing drops of a suspension of the drug and excipients in a solution of cellulose acetate phthalate to drop into an acetic acid solution by means of a peristaltic pump. In a previous study¹, sulfadiazine was used as a model drug to prepare beads by a similar method and the effects of various viscosity agents on the properties of these beads were assessed. Glycerin, polymers (Methocel and Avicel), and surfactants (Tween 80 and Span 80) were used as excipients. The incorporation of various viscosity agents and polymers into the suspension yielded beads with different disintegration and dissolution values. A high performance liquid chromatography method showed no indication of drug degradation during the preparation. The dissolution studies of the indomethacin preparations demonstrated differences in drug release properties depending on composition and method of preparation. The preparation with equal quantities of the two surfactants (Tween 80 and Span 80) released the drug at the slowest rate.     

Bead Compacts. I. Effect of Compression on Maintenance of Polymer Coat Integrity in Multilayered Bead Formulations

Abstract

Little information is available on the comparability of beads for oral sustained-release dosage forms. It is known that polymer-coated beads may fuse together to produce a non-disintegrating controlled-release matrix tablet when compressed. This study evaluates the effect of compression on beads with multiple layers of polymer and drug coat, and the effect of cushioning excipients and compaction pressure on drug release from compressed bead formulations. The multilayered beads consist of several alternating layers of acetaminophen (APAP) and polymer coats (Aquacoat®) with an outer layer of mannitol as a cushioning excipient. Percent drug release versus time profiles showed that the release of drug decreases from noncompacted beads as the amount and number of coatings increases, with only 43% of drug released in 24 hr for coated beads with 10 layers. It was shown that the compacted multilayered beads will disintegrate in gastrointestinal fluids, providing a useful drug release pattern. It was shown that beads of drug prepared by any method can be spray-layered with excipients such as Avicel and mannitol. Spray-layering of the cushioning excipient onto beads can provide an effective way to circumvent segregation issues associated with mixing of the polymer-coated beads and powdered or spherical/nonspherical cushioning excipients. Spray layering of the cushioning excipient can also provide excellent flow properties of the final formulation as visually observed in our experiments. Triple-layered caplets (TLC) were also prepared with outer layers of Avicel PH-101 or polyethylene oxide (PEO), and a center layer of polymer-coated beads. For TLC, the polymer coating on the beads fractured, and nondisintegrating matrix formulations were obtained with both caplet formulations.     

Development of Controlled Release Formulations of Ketoprofen for Oral Use

Microencapsulated forms of ketoprofen were formulated using polymers and polymer combinations and their in-vitro release characteristics were evaluated against pure ketoprofen using Vanderkamp 600 dissolution test apparatus. Suspensions of cellulose acetate phthalate were prepared and various quantities of drug, glycerin, tween 80, span 80, methocel and avicel were added and the resulting solution was passed through a peristaltic pump into a hardening solution. Beads were formed, dried and the release of the drug was studied at various time intervals in a dissolution medium of simulated intestinal pH. The dissolution studies of the ketoprofen demonstrated differences in drug release properties depending on composition and method of preparation. A formulation of Methocel beads with equal proportions of the two surfactants released its drug content over a period of 12 hours in a zero-order fashion. Rapid drug dissolution was seen when the formulations contained Tween 80 as a surfactant. Varying the drug to CAP ratio in the suspension from 0.1 to 0.4 did not appear to alter dissolution. It is concluded that proper control of the formulation can give any desirable release from ketoprofen formulations.     

Melt granulation and heat treatment for wax matrix-controlled drug release

The purpose of this study was to evaluate sustained drug release after melt granulation and heat treatment. Theophylline (anhydrous) and phenylpropanolamine hydrochloride (PPA) were used as model drugs. Compritol® 888 ATO (Glyceryl Behenate NF) was incorporated as the wax matrix material. Formulations with drug:wax in 3:1 and 1:1 ratios were evaluated. Tablets were made by dry blending or melt granulation; some of the tablets were heat treated at 80°C for 30 min. Tablets with or without heat treatment were tested for drug release using in vitro drug dissolution. The results showed that melt granulation gave slower drug release than dry blending. Heat treatment further retarded drug release for both dry blending and melt granulation. The drug release rates for theophylline were slower than for PPA at the same wax level and processing method. The drug release profiles were linear using a square root of time scale. In conclusion, melt granulation and heat treatment slowed drug release for the wax matrix-controlled release tablets. Heat treatment of the tablets made by melt granulation further retarded drug release. Heat treatment redistributed the wax, forming a new matrix system with higher tortuosity. The application of melt granulation or heat treatment can successfully retard drug release.     

Development of Matrix Controlled Release Beads by Extrusion-Spheronization Technology Using a Statistical Screening Design

The objective of this study was to develop beads with inherent modified release characteristics requiring no subsequent controlled release coating. Extrusion-spheronization was chosen to accomplish this goal. The model drug was a zwitterion (isoelectric point ∼pH 5.2) with poor solubility and low bulk density. Preliminary studies indicated that matrix beads with modified micro-environmental pH would result in sustained release of the drug. A Nica extruder and spheronizer were used to manufacture the beads. A Plackett-Burman screening design was employed to isolate critical variables influencing the bead characteristics and drug release. Variables studied included the type of polymeric dispersion, polymer concentration, acid type, acid concentration, plasticizer content, drug concentration and spheronizing time. Responses evaluated included capsule fill weight, drug release rate, micro-environmental pH, yield and friability. Beads were successfully manufactured according to the screening design and exhibited different dissolution characteristics. Polymer type (Eudragit RS 30 D over Aquacoat ECD-30), polymer concentration and acid concentration significantly retarded drug release. However, increasing acid concentration increased bead friability. In addition to drug concentration, higher polymer concentration, appropriate acid selection and longer residence times afforded maximum capsule fill weights and increased bead density.     

Binder effectiveness for beads with high drug levels

Previous reports from these laboratories showed that microcrystalline cellulose (Avicel^R MCC, PH-101) formulations with low and medium drug levels (10 and 50%) produced very uniform beads whereas formulations containing MCC with high drug levels (80%) were difficult to process without special treatment or required the incorporation of alternate excipients. In this study, several binders, at a 2% level, specifically: Carbomer (Carbopol^R 934-P), Sodium carboxymethylcellulose (CMC 7MF), Hydroxypropylcellulose (Klucel^R HXF), Methylcellulose (Methocel^R K-15). Povidone, USP (PVP K29-32) and Pregelatinized starch NF (Starch 1500^R), were evaluated to determine whether they might impart advantages in processing and whether any differences in dissolution behavior would result. Spheres containing 80% anhydrous theophylline, the binders and MCC were manufactured by the extrusion/marumerization technique. In general, beads containing high drug levels produced with these binders are suitable for further processing (coating). Processing ease, bead shape, and bead hardness (friability) varied with the choice of binder. Beads with carbomer, hydroxypropylcellulose, and methylcellulose remained intact during dissolution testing; beads with starch, carboxymethylcellulose, PVP, and the control did not.     

Co-solvent systems in dissolution testing: Theoretical considerations

The situation was considered where a co-solvent, added to enhance drug solubility and thus provide sink conditions for a drug, also resulted in a decrease in solubility and hence dissolution rate of a water soluble excipient present in the dosage form. Theory predicted that, in the absence of disintegration, at sufficiently high excipient content and or co-solvent concentration the drug dissolution rate may decrease, release becoming controlled by the now less soluble excipient. Solubility and dissolution studies using tolbutamide and lactose mixtures in water-ethanol mixtures provided results which were reasonably consistent with theory, indicating that the presence of the excipient may greatly reduce the drug dissolution rate below that expected for the drug alone.     

Binder effectiveness for beads with high drug levels

Abstract

Previous reports from these laboratories showed that microcrystalline cellulose (Avicel^R MCC, PH-101) formulations with low and medium drug levels (10 and 50%) produced very uniform beads whereas formulations containing MCC with high drug levels (80%) were difficult to process without special treatment or required the incorporation of alternate excipients. In this study, several binders, at a 2% level, specifically: Carbomer (Carbopol^R 934-P), Sodium carboxymethylcellulose (CMC 7MF), Hydroxypropylcellulose (Klucel^R HXF), Methylcellulose (Methocel^R K-15). Povidone, USP (PVP K29-32) and Pregelatinized starch NF (Starch 1500^R), were evaluated to determine whether they might impart advantages in processing and whether any differences in dissolution behavior would result. Spheres containing 80% anhydrous theophylline, the binders and MCC were manufactured by the extrusion/marumerization technique. In general, beads containing high drug levels produced with these binders are suitable for further processing (coating). Processing ease, bead shape, and bead hardness (friability) varied with the choice of binder. Beads with carbomer, hydroxypropylcellulose, and methylcellulose remained intact during dissolution testing; beads with starch, carboxymethylcellulose, PVP, and the control did not.     

A Sustained Release Drug Delivery System Using Calcium Alginate Beads

Calcium alginate beads impregnated with sulphamethoxazole as model drug were prepared and characterized. Scanning electron microscope was used to examine their surface with and without the drug. The bead average diameter was 1.25mm and the sulphamethoxazole uptake by the beads was about half of the incorporated quantity. The release behaviour was followed using USP dissolution method. The effect on release of factors such as sodium alginate, calcium chloride concentration, pH, hydration and compression were studied. Sodium alginate concentrations had no pronounced effect on the release. The release was found to be a function of calcium chloride concentration. The higher the concentration the lower the release. The smaller the water content the lower the release from the beads. Compression of the beads yields a deformed beads with an increase in their release. Plain calcium alginate beads were not suitable for sulphamethoxazole loading. Sulphamethoxazole diffusion through calcium alginate film was determined. The dissolution patterns were discussed. The system may offer a simple and efficient sustain release preparation.     

A Sustained Release Drug Delivery System Using Calcium Alginate Beads

Abstract

Calcium alginate beads impregnated with sulphamethoxazole as model drug were prepared and characterized. Scanning electron microscope was used to examine their surface with and without the drug. The bead average diameter was 1.25mm and the sulphamethoxazole uptake by the beads was about half of the incorporated quantity. The release behaviour was followed using USP dissolution method. The effect on release of factors such as sodium alginate, calcium chloride concentration, pH, hydration and compression were studied. Sodium alginate concentrations had no pronounced effect on the release. The release was found to be a function of calcium chloride concentration. The higher the concentration the lower the release. The smaller the water content the lower the release from the beads. Compression of the beads yields a deformed beads with an increase in their release. Plain calcium alginate beads were not suitable for sulphamethoxazole loading. Sulphamethoxazole diffusion through calcium alginate film was determined. The dissolution patterns were discussed. The system may offer a simple and efficient sustain release preparation.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,III. Influence of Filler Excipient.

Abstract

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, III. Influence of Filler Excipient.

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.