Compression of pellets coated with various aqueous polymer dispersions

Pellets coated with a new aqueous polyvinyl acetate dispersion, Kollicoat SR 30 D, could be compressed into tablets without rupture of the coating providing unchanged release profiles. In contrast, the compression of pellets coated with the ethylcellulose dispersion, Aquacoat ECD 30, resulted in rupture of the coating and an increase in drug release. Plasticizer-free Kollicoat SR coatings were too brittle and ruptured during compression. The addition of only 10% w/w triethyl citrate as plasticizer improved the flexibility of the films significantly and allowed compaction of the pellets. The drug release was almost independent of the compression force and the pellet content of the tablets. The inclusion of various tabletting excipients slightly affected the drug release, primarily because of a different disintegration rate of the tablets. The core size of the starting pellets had no influence on the drug release. Pellets coated with the enteric polymer dispersion Kollicoat 30 D MAE 30 DP [poly(methacrylic acid, ethyl acrylate) 1:1] lost their enteric properties after compression because of the brittle properties of this enteric polymer. Coating of pellets with a mixture of Kollicoat MAE 30 DP and Kollicoat EMM 30 D [poly(ethyl acrylate, methyl methacrylate) 2:1] at a ratio of 70/30 and compaction of the pellets resulted in sufficient enteric properties.     

Polymerized rosin: novel film forming polymer for drug delivery

Polymerized rosin (PR) a novel film forming polymer is characterized and investigated in the present study for its application in drug delivery. Films were produced by a casting/solvent evaporation method from plasticizer free and plasticizer containing solutions. Films prepared from different formulations were studied for their mechanical (tensile strength, percent elongation and Young's modulus), water vapour transmission and moisture absorption characteristics. Neat PR films were slightly brittle and posed the problem of breaking during handling. Hydrophobic plasticizers, dibutyl sebacate and tributyl citrate, improved the mechanical properties of free films with both the plasticizers showing significant effects on film elongation. Release of diclofenac sodium (model drug) from coated pellets was sustained with high coating levels. Concentration of plasticizer was found to affect the release profile. PR films plasticized with hydrophobic plasticizers could therefore be used in coating processes for the design of oral sustained delivery dosage forms.     

Compressibility of floating pellets with verapamil hydrochloride coated with dispersion Kollicoat SR 30 D.

The purpose of this study was to work out a method of compression of floating pellets with verapamil hydrochloride (VH) in a dose of 40 mg. It was assumed that this form should reside in the stomach floating for several hours and gradually release the drug in a controlled way. Compression of pellets into tablets, being a modern technological process, is much more perfect than enclosing them in a hard gelatin capsule. Kollicoat SR 30 D was selected for coating. In experiments three plasticizers were examined-propylene glycol, triethyl citrate and dibuthyl sebecate (all at concentration of 10%). It was found that VH release from pellets coated by the films of the same thickness (70 microm), however, containing plasticizers is considerably different. Pellets were prepared by wet granulation of powder mixture, spheronization of the granulated mass and coating of the cores with a sustained release film. Two kinds of cellulose, microcrystalline and powdered, and sodium hydrocarbonate were the main components of pellet core. Proper pellet coating film thickness, ensuring obtaining desirable VH release profile and flotation effect, was defined. X compositions of tablets with pellets were examined in order to obtain formulation, from which VH release would mostly approximate pellets before compressing. The best formulation was evaluated taking into account the effect of compression force an tablet hardness and friability, and pellet agglomeration and flotation. Tablet cross-section photographs were taken confirming necessary coating film thickness preventing their deformation caused by compressing into tablets.     

混合水分散体肠溶迟释薄膜性能研究

目的 采用肠溶型水分散体Eudragit?L30D-55和控释型水分散体Kollicoat?SR30D混合制备一种全新的对周围环境pH值具有响应的,同时具有迟释性能的聚合物薄膜。方法 采用铸膜法制备L30D-55∶SR30D混合水分散体游离膜,采用差示扫描量热法(DSC)测定薄膜玻璃化转变温度(glass transition temperature,Tg),万能材料试验机测试薄膜拉伸性能,杯法考察薄膜透湿性能。考察聚合物比例、附加剂种类和用量对薄膜性能的影响,并以制备泮托拉唑钠(PAZ-Na)肠溶迟释微丸考察包衣膜特性。结果 随着SR30D的增加,薄膜的Tg逐渐降低,强度和刚性变弱,韧性变强,透湿性能先不变后增加。随着增塑剂增加,薄膜刚性减弱,渗透性能增强。不溶性成分的加入可不同程度降低薄膜的渗透性。制备的肠溶迟释微丸在0.1 mol·L^-1盐酸中2 h药物损失量<5%,在pH 6.8缓冲液中可延迟10~20 min开始释放,并至90 min释放完全。结论 L30D-55∶SR30D混合水分散体制备的游离膜和包衣膜具有良好的理化性能,可用于肠溶调释制剂的研究和开发。     

Influence of Plasticization Time,Curing Conditions,Storage Time,and Core Properties on the Drug Release from Aquacoat-Coated Pellets

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer, triethyl citrate, was used because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer, acetyltributyl citrate (ATBC), plasticization time (1/2 h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However, a thermal aftertreatment of the coated pellets at elevated temperatures (curing step) reduced/eliminated the effect of the plasticization time with ATBC. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets.     

Influence of plasticization time, curing conditions, storage time, and core properties on the drug release from Aquacoat-coated pellets

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer triethyl citrate, was used because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer acetyltributyl citrate (ATBC), plasticization time (1/2 h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However a thermal aftertreatment of the coated pellets at eleylated temperatures (curing step) reduced/eliminated the effect of the plasticization time with ATBC. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets.     

Influence of plasticizer type and level on the properties of Eudragit® S100 matrix pellets prepared by hot-melt extrusion

Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit® S100 matrix pellets. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20% level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present.     

Influence of plasticizers on the mechanical properties of pellets containing Eudragit® RS 30 D

The influence of plasticizers on the mechanical properties of single pellets containing the acrylic polymeric dispersion, Eudragit® RS 30 D, as a granulating binder was investigated. Microcrystalline cellulose and anhydrous lactose were used as the substrate powders for pellets prepared by the wet massing and extrusion/spheronization technique. The effects of hydrophilic and hydrophobic plasticizers on the mechanical properties of the pellets and thermal properties of free films were investigated. The mechanical properties, including tensile strength and Young's modulus, of individual pellets were determined by a diametral compression method with a Chatillon® tension/compression apparatus. The results demonstrated that both the tensile strength and Young's modulus of the pellets decreased as the plasticizer content increased in the pellet formulation, with the exception at low plasticizer levels. The influence of plasticization on the granulating polymer was reflected in the mechanical properties of pellets, indicating that the pellets underwent a cohesive fracture. The unexpected increase in the tensile strength and Young's modulus of the pellets containing low levels of plasticizers was ascribed to the antiplasticization of the polymer due to the immobilization of the polymer molecules by hydrogen bonding, van der Waal's forces and steric hindrance from the plasticizer molecules. Pellets containing low levels of plasticizers exhibited a brittle fracture behavior under compression while a ductile property was observed at higher plasticizer concentrations. The transition of the fracture behavior from a brittle to a ductile pattern was found to take place when plasticizer levels in the acrylic polymer were between 10 and 20% based on the weight of dry polymer. The transition was due to the shift of the polymeric binder from a glassy to a rubbery state, which was verified by the glass transition temperature values of the free films.     

Suitability of κ-carrageenan pellets for the formulation of multiparticulate tablets with modified release

κ-Carrageenan is a novel pelletisation aid with high formulation robustness and quick disintegration leading to fast drug release unlike the matrix-like release from non-disintegrating microcrystalline cellulose pellets. Compression of pellets into tablets is cost effective. The feasibility of formulating multiparticulate tablets with coated κ-carrageenan pellets was investigated. Pellets containing a highly soluble drug in acid, namely bisacodyl and κ-carrageenan or MCC as pelletisation aid were prepared, enteric coated with a mixture of Kollicoat(?) MAE 30 DP and Eudragit(?) NE 30 D and compressed using silicified microcrystalline cellulose as embedding powder. The effect of coating level, type of pellet core, compression force and punch configurations on drug release were studied. A sufficient coating thickness for κ-carrageenan pellets was necessary to obtain multiparticulate tablets with adequate resistance in the acid stage regardless of the compression pressure used. While κ-carrageenan pellets and their tablets released over 80% of the drug during the neutral stage only about 20-24% was released from MCC pellets and their tablets. The type of punches used (oblong or round) did not significantly influence the drug release from the prepared tablets. Moreover, sufficient prolonged release properties were obtained with κ-carrageenan pellets containing theophylline as a model drug and coated with Kollicoat(?) SR 30 D using Kollicoat(?) IR as pore former. A lower coating level and higher amount of pore former were needed in case of theophylline pellets formulated with MCC as pelletisation aid. The sustained release properties of both coated pellet formulations were maintained after compression at different compression pressures.     

Quinine sulphate pellets for flexible pediatric drug dosing: formulation development and evaluation of taste-masking efficiency using the electronic tongue.

The purpose of this study was to develop a taste-masked quinine sulphate dosage form as a flexible pediatric formulation tool. Pellets were produced as they offer more flexibility to body weight dose adaptation and therefore represent an alternative to tablet breaking in pediatrics. Quinine sulphate pellets were produced via extrusion-spheronisation. Next pellets were coated using Eudragit E PO to obtain a taste-masked formulation. Using 15% dibutyl sebacate (based on polymer weight) as a plasticizer in the formulation caused rapid pellet agglomeration during storage at 40 degrees C and 75% relative humidity. Using stearic acid (15% based on polymer weight) as plasticizer yielded pellets which were less sensitive to sticking. Quinine sulphate release in water within the first 5 min of dissolution testing: 9.2%, 5.9% and 2.1% of the drug dose was released from pellets coated with 10%, 20% and 30% (w/w) Eudragit E PO, respectively. These observations correlated well with the bitterness score of the formulations determined via the Astree electronic tongue and its Bitterness Prediction Module, showing that 20% (w/w) Eudragit E PO was required to obtain a homogeneous film and to delay quinine sulphate release sufficiently to mask the bitterness after drug administration. In acid medium immediate quinine sulphate release was obtained.     

Aqueous ethyl cellulose dispersions containing plasticizers of different water solubility and hydroxypropyl methylcellulose as coating material for diffusion pellets. I. Drug release rates from coated pellets

The present work investigates release mechanisms of theophylline pellets coated with an aqueous ethyl cellulose (EC) dispersion containing plasticizers and hydroxypropyl methylcellulose (HPMC) as a water soluble pore former. Three different drug release mechanisms from coated pellets can be determined as a function of the water solubility of the plasticizers and the ionic strength of the release medium. Coated pellets with the addition of more hydrophilic plasticizers such as triethyl citrate (TEC) or diethyl phthalate (DEP) show an approximate zero-order-release rate. In contrast, two-phase release profiles can be observed from pellets coated with dispersions containing hardly soluble plasticizers such as dibutyl phthalate (DBP) or dibutyl sebacate (DBS). Only in a release medium of high ionic strength the water soluble pore former will remain in the coating. Thus the drug diffuses through a hydrated swollen membrane containing EC, HPMC and insoluble plasticizer. The release mechanisms depend on the glass transition temperature of the ethyl cellulose and therefore on the migration of the plasticizers and the pore former. This was shown by investigation of the migration of the additives and the influence of the temperature of the release medium on the release. Additionally, the study investigates the effect of curing and storage conditions of coated pellets on the drug release rate.     

Design and study of ibuprofen disintegrating sustained-release tablets comprising coated pellets.

One challenge in tableting of sustained-release multiparticulates is maintaining the desired drug release after compaction. The aim of this study was to design sustained-release ibuprofen tablets which upon oral ingestion rapidly disintegrate into sustained-release pellets in which the integrity of the pellet core and/or coat is preserved. First free films composed of Eudragit RS 30D and RL 30D in 4:1 ratio and containing different levels of triethyl citrate (TEC) were prepared and tested to optimize the plasticizer level. Cured Eudragit based pellets with 60% ibuprofen loading which in our previous study showed proper mechanical properties for compression were coated with Eudragit RS 30D/RL 30D (4:1) containing 20% triethyl citrate at different coating levels. The mechanical properties of the coated pellets were tested. Polymer coated pellets were compacted into tablets either alone or with a blend of excipients comprising Avicel, PEG 4000, cross-linked PVP. A 3(2) full factorial design was used to optimize the filler blend composition. Effects of pellet to filler ratio, compression force and granulation of filler on tablet characteristics were investigated. Results of mechanical test showed that the coating of cured pellets had no significant effect on yield point and elastic modulus of the pellets. In the case of 5% coating level sustained release of ibuprofen over a period of 24h was achieved. The results obtained from tableting procedure showed that by selecting suitable filler blend (60% Avicel, 10% cross-linked PVP and 30% PEG 4000), compression force, and granulation of filler it was possible to prepare sustained-release tablets containing high ratio of coated pellets (even 80%) with desirable strength, disintegration time, and drug release rate. It was observed that compression force, pellet to filler ratio, composition of filler blend and granulation of fillers had no effect on drug release rate from compacted pellets but had significant influence on tablet strength, friability, and disintegration time. SEM graphs and in vitro release profiles for compacted pellets showed no apparent damage to the coated pellets as a result of the compaction process.     

XEDS-mapping for explaining release patterns from single pellets

A common way to formulate controlled-release (CR) pharmaceuticals is to coat pellets of active substance with a polymer film, decrease the size of the pellets and distribute them as multiple-unit dosages in capsules. To increase the understanding of the release mechanism, the pellet shape and surface structure of pellets, before and after release in microtitre plates, have been studied by scanning electron microscope and X-ray energy-dispersive spectrometry. By performing these studies we associate release profiles during the first few hours to the microscopic structure. Pellets were divided into three classes (spherical pellets, dumbbell shaped pellets and twin-pellets) according to pellet form. Cases of burst release occurred for all three shape classes due to “open-window-defects” at the surface. Areas of thinner polymer film in the neck-region of dumbbell shaped pellets broaden the range of intermediate release rates for this pellet shape. The surface of twin pellets and dumbbell shaped pellets showed more defects, which increases the release rates in comparison to spherical pellets. All pellets with high release rates revealed ruptures in the polymer film, whereas only small cracks could be traced for pellets with slow release rates. The information gained is necessary for the development of future formulations and mathematical modelling of release patterns. The pharmaceutical used as model was remoxipride coated with a polymer film of ethyl cellulose and 10 wt.% triethyl citrate.     

Influence of curing on the adhesive and thermomechanical properties of an applied acrylic polymer

The objective of the current study was to investigate the relationship between polymer adhesion and post-coating thermal treatment. A novel adhesion technique was used to quantify the adhesive properties of applied acrylic films. Differential scanning calorimetry was used to determine the glass transition temperature of the applied polymer. Post-coating thermal treatment, or curing, was found to significantly influence the adhesive and thermomechanical properties of the applied film coating. Adhesion of triethyl citrate-plasticized films to tablets increased during storage at elevated temperatures, equilibrating within four hours. The glass transition temperature of the applied triethyl citrate-plasticized coatings also increased during curing. Equilibration of polymer properties was found to be dependent on the hydrophobicity of the plasticizer incorporated into the coating formulation, with longer curing times required for films containing the hydrophobic plasticizer tributyl citrate. The curing temperature was shown to influence polymer properties, with stronger film-tablet adhesion and higher glass transition temperatures resulting when the coated tablets were stored at higher temperatures. Substrate hydrophobicity was also found to influence the curing process, suggesting that the mechanisms involved in film formation and polymer-substrate adhesion may contribute to the internal stresses within the film.     

Effect of substitution of plasticizer dibutyl phthalate with dibutyl sebacate on Eudragit® RS30D drug release rate control

In the current study, the influence of type of plasticizer used with Eudragit^® RS 30D on the drug release was investigated in solid dosage form extrusion/spheronization, and film coating. The drug pellets were coated for controlling drug release with Eudragit^® RS 30D containing dibutyl phthalate and compared with dibutyl sebacate as an alternative plasticizer. To study the influence of pH of the dissolution medium on the drug release profile, capsules are tested for drug release profile at pH 1.2, 4.4, and 6.3. Additionally, the aging effect on the curing of Eudragit^® RS 30D is evaluated by exposing the capsules dosage form to room temperature (25?°C?±?2?°C/60%?±?5% RH) for time 0, 3, 6, and 9?months, accelerated temperature (40?°C?±?2?°C/75%?±?5% RH) for time 0, 3, and 6?months, and intermediate temperature (30?°C?±?2?°C/65%?±?5% RH) for time 0, 6, and 9?months. The replacement of dibutyl phthalate, with dibutyl sebacate for polymer coating system in similar concentration is comparable with respect to plasticization effect. The coalescence of the polymer particles is not changed and requires no additional processing parameter control or additional curing time.     

An investigation into the characteristics of chitosan/Kollicoat SR30D free films for colonic drug delivery

The purpose of the study was to establish the physico-mechanical, digestibility, permeability and swelling properties of chitosan/Kollicoat SR30D films as potential coatings for colonic drug delivery. Free films containing different ratios of chitosan to Kollicoat SR30D were prepared by casting/solvent evaporation method. The resultant mixed films were characterized in terms of puncture strength and elongation (%), glass transition temperature, swellability, polymer miscibility, permeability, and digestibility under different media. The mixed films possessed good mechanical properties, which could be used as film-coating materials for drug delivery. The extent of digestion was directly proportional to the amount of chitosan present within the film. No apparent miscibility was detected between the chitosan and Kollicoat SR30D, regardless of the film composition. The films were found to be susceptible to digestion by bacterial or β-glucosidase enzymes in simulated colonic fluid (SCF). The SCF with rat cecal bacterial enzymes had a more profound hydrolytic activity than that with β-glucosidase enzyme for the digestion of chitosan within the mixed films. Overall, the results indicated that such chitosan/Kollicoat SR30D films had potential as a coating system for drug delivery to the colon.     

Physical-mechanical properties of film-coated soft gelatin capsules

Soft gelatin capsules containing ibuprofen dissolved in either PEG 400 or Miglyol® 812 were coated with an aqueous dispersion of Eudragit® L 30 D-55 using a Mini Hi-Coater. The physical-mechanical properties of the coated capsules, including tensile strength, Young's modulus and tensile toughness, were determined using a Chatillon DFGS50 force gauge attached to a Chatillon TCD-200 motorized test stand. The diametral compression tests were conducted at a rate of 12.7 mm/minute. Force-deflection curves were obtained and mathematically manipulated to yield stress-strain diagrams. The influence of two plasticizing agents, triethyl citrate (TEC) and tributyl citrate (TBC), on the physical-mechanical properties was determined. The hydrophilic plasticizer TEC was found to be the best plasticizer for the acrylic films, regardless of the fill liquid. The physical-mechanical properties of the coated and uncoated soft gelatin capsules were a function of the fill liquid. Temperature and humidity were found to influence the physical-mechanical properties of the coated capsules. The adhesion between the gelatin capsule and the acrylic polymer was found to be dependent on both the fill liquid and plasticizer in the coating formulation. Coating dispersions plasticized with TEC exhibited good adhesion with both the PEG 400 and the Miglyol® 812, whereas the TBC plasticized film coating showed good adhesion with the Miglyol® 812 fill liquid. The acrylic film coatings for the PEG-containing capsules and plasticized with TBC exhibited an increased adhesion of the polymer to substrate over time when stored at both high temperature and high humidity.     

Influence of aqueous coatings on the stability of enteric coated pellets and tablets.

Pancreatin pellets, placebo pellets and tablets containing vitamin B2 were coated with various aqueous and organic enteric polymers, HPMCAS, HP, Eudragit L 100-55, Eudragit L 30 D-55, CAP, CAT, CMEC and PVAP, comparatively investigated and tested for storage stability. With the exception of Eudragit L 100-55 and Eudragit L 30 D-55, higher amounts of coating material were needed to achieve gastro-resistance with aqueous coating than with organic coating. Film formation from aqueous dispersions of micronized HP 55 was affected by the degree of micronization and was improved by reducing the particle size of the polymer. Undercoating was another suitable measure to decrease the amount of coating material required. The choice of plasticizer was of special importance in the aqueous dispersions, and type and quantity must be appropriate for the polymer applied. Non-polymeric plasticizers such as triethyl citrate (TEC) evaporated along with water during the spraying or drying process and high temperatures promoted such losses. The moisture-sensitive pancreatic enzymes were damaged both by humidity and heat during aqueous coating. The extent of damage was dependent on the coating equipment used. Upon storage, coatings obtained from aqueous dispersions showed changes in enteric performance or release characteristics as a consequence of three chemical/physical mechanisms: hydrolysis of ester linkages in the polymer or plasticizer, evaporation of the plasticizer, delayed film formation. The active ingredient pancreatin induced hydrolysis of the ester based film-former hydroxypropyl methylcellulose acetate succinate (HPMCAS). However, even without the influence of enzymes, the phthalic ester groups of aqueous hydroxypropyl methylcellulose phthalate (HP) were partly cleaved after 11 months storage. In HPMCAS-coated pancreatin pellets, the plasticizer glyceryl triacetate was almost completely hydrolyzed by the enzymes, whilst triethyl citrate was lost by evaporation through permeable packaging material at elevated temperatures. Open storage at elevated temperatures and humidities caused changes in the surface structure of HPMCAS coatings, consisting of a smoothing of the originally somewhat porous film and sticking. When applied to vitamin B2 tablets, Eudragit L 100-55, Opadry enteric (PVAP) and Aqoat (HPMCAS) proved to be quite stable aqueous enteric coatings, whereas cellulose acetate phthalate CAP or cellulose acetate trimellitate CAT coatings as ammonia-neutralized aqueous solution or as water-based pseudolatex Aquateric were unstable when stored under stress conditions.     

Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl-cellulose as coating material for diffusion pellets II: properties of sprayed films.

This study investigates the properties of sprayed films prepared from aqueous ethyl cellulose dispersions (ECD) containing hydroxypropyl methylcellulose (HPMC) and plasticizers of different water solubility in order to clarify the drug release mechanisms of pellets coated with the respective material. It is of special interest to measure the migration of the water soluble components as well as the physical properties of the swollen ethyl cellulose film. Swelling experiments with sprayed films in 0.1 N-HCl at 37 degrees C show that fairly water soluble plasticizers and the pore forming agent (HPMC) migrated rapidly and almost completely out of the films. The water insoluble plasticizers remain predominantly in the film and the migration rate of HPMC is reduced in a release medium of high ionic strength. The glass transition temperature (T(g)) and the softening temperature (T(s)) of these films after swelling are dependent on the water solubility of the plasticizer. The T(g) of ECD films plasticized with triethyl citrate is above the swelling temperature of 37 degrees C after migration of the plasticizer, transforming the polymer in the glassy state. In contrast, dibutyl phthalate-containing ECD films demonstrate a T(g) below the swelling temperature, leaving the polymer in the rubbery state. The mechanical properties of dry and wet films are studied as a function of the state of curing of the films and of the swelling temperature. On contact with water, a pronounced shrinkage of ECD/HPMC films plasticized with water insoluble plasticizers is observed. All these results are used to explain the different drug release mechanisms of the coated pellets and to enable the prediction and optimization of drug release-rates from coated pellets.     

Influence of film additives on stabilizing drug release rates from pellets coated with acrylic polymers.

The objective of this study was to investigate the influence of talc and triethyl citrate (TEC) on stabilizing the drug release rates following curing and storage at elevated temperature of pellets coated with an aqueous acrylic polymeric dispersion. Core pellets containing anhydrous theophylline (20%), microcrystalline cellulose, and polyvinylpyrrolidone were prepared by extrusion-spheronization. The aqueous dispersions were prepared by adding up to 30% TEC as a plasticizer and talc up to 200% as an antiadherent to a mixture of Eudragit RS 30D/RL 30D (95:5). The theophylline pellets were coated in a fluidized-bed coating unit and then cured at elevated temperatures. Theophylline pellets were successfully coated with the Eudragit dispersions that contained up to 200% talc, based on the dry polymer weight, and the coating efficiency was greater than 93%. Our results demonstrated that the polymer, which was plasticized by TEC, was able to function as a film-forming agent for dispersions containing high levels of talc. No sticking of the coated pellets was observed during the coating process or during the curing or equilibrating phase, even with high levels of TEC in the film. The dissolution rate of theophylline from the coated pellets was delayed when the film coating dispersion contained high levels of talc. Additionally, the stability of the drug release profiles from the coated pellets after storage was significantly improved. Furthermore, a modified dissolution testing used to simulate mechanical stresses that may be encountered in vivo showed the film coated pellets would have sufficient strength. The results of this study demonstrated that high levels of film additives in the acrylic dispersion contributed to the stabilization of the drug release rates as well as the reproducibility of the coating process.