Use of Colloidal Silica as a Separating Agent in Film Forming Processes Performed with Aqueous Dispersion of Acrylic Resins

Abstract

Aqueous dispersion of polymers are going to take the place of the corresponding organic solution in the film forming process of tablets, pellets and granules, because of some definite advantages.

Among the additives used in formulation techniques, talc, that is normally utilized as an antiadherent and polishing agent, presents some problems connected with its tendency to form sedimentation. For this reason, during the film coating operation, the dispersion must be always kept under constant and proper agitation, however, the danger of blocking the piping and the spraying system of the equipment employed cannot be completely avoided.

On the bases of these observations, the aim of this research work is to evaluate the possibility of substituting talc with colloidal silica as separating agent in aqueous dispersion of film acrylic resins, normally used in the preparation of prolonged release systems.

Results concerning fluid bed coating processes of pellets prepared by extrusion-spheronization technique have been reported, with particular attention to usable concentration of colloidal silica and to possible influence of these on the drug release characteristics of the systems obtained.     

High-Viscosity HPMC as a Film-Coating Agent

The possibility of using high viscosity grades of hydroxypropylmethylcellulose (HPMC) as a film forming agent in a conventional coating process has been investigated. Ethanol/water mixtures having different weight ratios (5 to 18) and containing up to 5 % of HPMC revealed to be suitable.

The influence of some formulation additives (talc, PVP and plasticizers) on both the overall coating process and the in-vitro release profiles of ketoprofen containing coated tablets was also investigated and discussed.     

Studies on modifying the tackiness and drug release of Kollicoat EMM 30 D coatings

In the search for antitack additives for Kollicoat EMM 30 D (ethyl acrylate-methyl methacrylate 30% dispersion, Ph. Eur.) film coatings, various possibilities were investigated. The best results were obtained using a combination of simethicone and talc. This mixture was tested on propranolol, theophylline, and verapamil HCl blank pellets in a previously developed Kollicoat EMM 30 D basic formulation. Almost any desired drug release rate can be obtained with all three pellet formulations by varying the two pore formers hypromellose 3mPas and microcrystalline cellulose type 105. A thin application of colloidal silica onto the coated pellets additionally prevents them from sticking together during storage.     

The MiniWiD-Coater. III. Effect of Application Temperature on the Dissolution Profile of Sustained-Release Theophylline Pellets Coated with Eudragit Rs 30 D

Theophylline pellets were coated with Eudragit RS 30 D in a miniature fluid-bed pan coater called MiniWiD developed recently. The dispersions were plasticized with varying amounts of triethyl citrate (TEC), dibutyl phthalate (DBP), and polyethylene glycol 6000 (PEG) and applied at different temperatures ranging from 25 to 45 °C. Theophylline release was tested by dissolution using the USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours.

At a coating level of 4 % (0.7 mg/cm²) sustained-release profiles were obtained from dispersions plasticized with TEC or DBP. By reducing the amount of plasticizer from 20 to 10%, films with higher permeabilities were obtained. This effect was compensated by tempering the pellets at 50 deg;C for 24 hours. The coating temperature had little effect on the dissolution profiles of TEC-plasticized films and no effect on films with DBP.

Coatings plasticized with 20% PEG were applied at temperatures ranging from 25 to 45 °C. These films required a coating level of about 18 % (3.3 mg/cm²) to provide comparable sustained-release properties. In contrast to DBP and TEC, a strong influence of the coating temperature on the release rates was observed in which higher temperatures led to slower release rates. This behavior can be explained by the minimum film-forming temperature (MFT). Since PEG does not lower the MFT of Eudragit RS 30 D, the application of these films below the MFT of 45 °C is associated with a lower degree of film formation.     

Influence of extrusion-spheronization processing on the physical properties of d-Indobufen pellets containing pH adjusters

d-Indobufen pellets containing pH adjusters (acids, buffer, salt) were prepared by extrusion-spheronization technology.

The interaction effect between some processing variables (feeding/agitator speeds of extruder, plate speed and residence time of spheronizer) was evaluated by comparing the basic formulation pellets with the pellets in which the soluble filler (lactose) was substituted by fumaric, tartaric and citric acids and also sodium citrate.

The criteria of formulation and process evaluation were the reproducibility of the particle size distribution, the density, the hardness and morphological properties, in addition to the reproducibility of the drug dissolution rates.

In all cases, the physical/technological characteristics were not influenced very much by pH adjuster incorporation, but the drug dissolution profiles showed some significant variations in the first hour. As a logical extension of this work, wet granulations with aqueous ethylcellulose and acrylic resin dispersions instead of only water were tested to evaluate the wetting effect of the release modifier inclusion. The results confirmed the validity of polymeric systems in the preparation of pellets and their ability to produce a further delay of d-Indobufen release.     

Technological Evaluation of three Enteric Coating Polymers I. With an Insoluble Drug

The enteric properties of a recent cellulose polymer, cellulose acetate trimellitate (CAT, EASTMAN KODAK) were evaluated on an insoluble substract for comparison, included in this paper are the properties of two other cellulose esters: cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HP55).

The physical properties and disintegration time at pH 1.2 and 6.5 were influenced by the level of coating solution. The gastroresistance was obtained more fastly with CAT and CAP than for HP55.

The influence of coating solution on drug release from tablet was investigated. The dissolution studies were made allowing the variation of pH in the dissolution medium during the kinetics.

Drug release from coated tablets was found to be dependent upon the type of polymers used to form film: higher release rates were obtained with CAT compared to CAP and HP55.     

Acrylic Latices from Redispersable Powders for Peroral and Transdermal Drug Formulations

Aqueous dispersions of acrylic resins may be converted to pow ders by spray or freeze drying. Such solids contain loose ag glomerates of discrete latex particles, that disintegrate easily into the original latex particles of less than 2 µ;m in diameter. No film formation occurs, provided that the minimum film forming temperature of the latex is not exceeded during drying.

Such powders can be redispersed in water in the presence of 3-6 mol% of alkali or organic bases to obtain a stable latex system. This can be used for enteric film coating in the same way as the original latex dispersions.

Redispersed methacrylic acid copolymers can be mixed with neu tral, permeable emulsion polymers to adapt the release profile of drugs more specifically to match their pharmacokinetic prop erties. In this way the pH-dependent solubility of methacryic acid copolymers, which controls the release in the gut by dissolution or increasing permeability can be combined with the pH-independent permeability of neutral acrylic ester polymers, to give time controlled retardation. Similar formulations of acrylic resins can also be used to solve several problems of transdermal delivery systems.

The described redispersable polymer powders are stable under normal storage conditions, so their handling and use as redispersed aqueous coating formulations is much more easier and will open an extended field of application.     

The Strength and Compaction of Millispheres: The design of a controlled-release drug delivery system for ibuprofen in the form of a tablet comprising compacted polymer-coated millispheres

This paper reviews a case study of the design of a controlled-release drug delivery system for ibuprofen in the form of a tablet comprising compacted polymer-coated millispheres (multiparticulate pellets). The particular challenge was to prepare coated millispheres of ibuprofen (a high-dose drug) with the addition of minimal excipients so that the drug-release retarding polymeric membrane surrounding the millispheres remains intact during and after tablet compression, disintegration and release of the millispheres. The study included (a) the design of the uncoated core and its manufacture by wet massing, extrusion, spheronization and drying; (b) the coating of these millispheres with a range of possibly suitable polymers; (c) an assessment of the drug release profiles from these pellets; (d) the quantification by indentation rheology of the mechanical properties of the polymer films used to coat the spheres; (e) the measurement of the mechanical properties of individual uncoated and coated millispheres and f. the design, manufacture and evaluation of compressed tablets containing coated millispheres

The matching of millisphere and polymer mechanical properties was found to be essential in order to ensure minimal damage to the millispheres and the release of virtually intact coated spheres without destruction of their retarded drug-release characteristics. Aqueous polymeric dispersions which formed a film with similar elastic and tensile properties to the uncoated millisphere formulation resulted in the most satisfactory film coating for application to spherical particles which must withstand compaction. Those polymeric films exhibiting significantly greater resilience than the uncoated cores were inappropriate for the film coating of millispheres for compaction into tablets     

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.     

Miconazole and Miconazolenitrate Chewing Gun as Drug Delivery Systems - A Practical Application of Solid Dispersion Technique

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs - incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole - 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Miconazole and Miconazolenitrate Chewing Gum as Drug Delivery Systems - A Practical Application of Solid Dispersion Technique

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs-incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole - 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Evaluation of Thermal and Film Forming Properties of Acrylic Aqueous Polymer Dispersion Blends: Application to the Formulation of Sustained-Release Film Coated Theophylline Pellets

Aqueous acrylic polymer dispersions were blended in order to improve processing and film formation from acrylic polymers with poor film forming properties and/or to obtain sustained-release film coated pellets with optimal barrier properties according to the physicochemical and pharmacokinetic requirements of the active substance.

Heterogeneous film structures are generally obtained from blends containing an association of hard acrylic polymers (Eudragit^* RS30D, S100) with the soft Eudragit^* NE30D when the drying temperature is lower than the minimum film forming temperature (MFT) of the hard acrylic polymers. The Tg and MFT values of the hard acrylic polymers are not modified in the presence of the soft polymer as shown by the thermograms of these blends which are generally characterized by two individual glassy transitions.

On the other hand, a wide range of drug dissolution profiles can be obtained from film coated pellets either by using, in different proportions, the insoluble but readily permeable Eudragit^* RL30D in association with the less permeable Eudragit^* RS30D in order to obtain pH-independent permeability membrane, or by mixing the anionic methacrylic acid copolymers (L30D, S100) with the neutral NE30D in order to obtain pH-dependent permeability film coated pellets showing higher dissolution release rates at intestinal pH values.     

Release of cyclobenzaprine hydrochloride from osmotically rupturable tablets

Osmotically rupturable systems were developed and the release of cyclobenzaprine hydrochloride (model drug) from the systems was investigated. Systems were designed using mannitol (osmotic agent) and increasing amounts of polyethylene oxide (PEO, a water-swellable polymer) surrounded by a semipermeable membrane. When placed in an aqueous environment, osmotic water imbibition into the systems distended and swelled the systems until the membrane ruptured and released the active compound to the outside environment. Tablets with increasing amount of PEO exhibited longer rupture times. This may be due to osmotic pressure-modulating properties of the polymer, changing the rate of water imbibition into the systems.

The integrity of the membranes was investigated using high-pressure mercury intrusion porosimetry. Minimal mercury intrusion into the membrane structure and core tablet indicated membrane integrity and lack of defective areas or pinholes. The results were in agreement with the release profiles where no drug release was detected prior to membrane rupture. Mercury intrusion porosimetry appears to be a promising technique for evaluation of membrane integrity.

Once the systems ruptured, drug was released by osmotic pumping and diffusion mechanisms through the ruptured area. There was a decrease in drug release rate with inclusion of PEO in the core.

The effects of film thickness on rupture and release times were also investigated. Devices with thicker films produced longer rupture times. This is in agreement with the theoretical prediction.     

In vitro and in vivo performance of a multiparticulate pulsatile drug delivery system

The objective of this study was to investigate the in vitro and in vivo drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD. Acetaminophen was used as a model drug, because in vivo performance can be monitored by measuring its concentration in saliva. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Increasing the coating level of outer membrane lag time was clearly delayed. In vitro the lag time in 0.1 N HCl was longer, compared to phosphate buffer pH 7.4 because of ionisable ingredients present in the formulation (crosscarmelose sodium and sodium dodecyl sulphate). In vitro release was also longer in medium with higher ion concentration (0.9% NaCl solution compared to purified water); but independent of paddle rotation speed (50 vs.100 rpm). Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released.

However, pellets with higher coating level and correspondingly longer lag time showed decreased bioavailability of acetaminophen. This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.     

Eudragit RL and RS Pseudolatices: Properties and Performance in Pharmaceutical Coating as a Controlled Release Membrane for Theophylline Pellets

Theophylline Active pellets were coated with Eudragit RL and RS pseudolatices in a fluidized bed. The effects of polymer ratio, additional oven drying, addition of dispersed solids, and addition of water miscible organic solvents on sustained drug release through the lates film were determined by using a modified U.S.P. Paddle dissolution method.

The release rate of theophylline can be varied by changing the polymer ratio. permeability to the drug increases with an increase in the content of Eudragit RL. Additional oven drying at 60°C for 10 hours caused no significant change in the dissolution profiles. The addition of dispersed solids such as talcum and silica resulted in an increase in drug release rate. There is no significant change in dissolution profiles when 50% methanol or acetone was added to the Eudragit RS pseudolatex.     

Drug Release and Surface Morphology Studies on Salbutamol Controlled Release Pellets

The air suspension technique was employed to prepare controlled release pellets of Salbutamol (as the sulphate). The aim of the present study was to determine the influence of various film coating additives on the release characteristics and surface morphology features of salbutamol sulphate pellets coated with Eudragit^R RS30D which is the aqueous dispersion of a polymer synthesised from acrylic and methacrylic acid esters. Surface morphology features, which were examined using Scanning Electron Microscopy, revealed that triethyl citrate (plasticiser) was essential for the coalescence of polymeric membranes around the drug-loaded spheres. Higher concentrations (12.5%) of triethyl citrate displayed a more uniform and continuous polymer film resulting in a slower in vitro drug release. Micrographs of the cross-sections of pellets with higher concentrations of Eudragit^R RS30D indicated the formation of thicker polymer membranes which accounted for the slower drug release rates. Hydroxypropyl methylcellulose (HPMC) inclusion in the polymer film coating increased salbutamol release rates due to its hydrophilic nature which promoted the formation of pores and cracks on the polymer films. A slower in vitro release of salbutamol was observed with higher concentrations of the hydrophobic anti-tackiness agent, magnesium stearate. The addition of salbutamol sulphate powder to the polymer dispersion enhanced drug release rates due to increased film permeability. Polyethylene glycol 200 (PEG 200) resulted in an increased in vitro drug release due to both its water soluble nature as well as impairment of film formation attributed to too high a plasticiser content in the coating formulation. As compared to polyethylene glycol 300 (PEG 300) as a plasticiser, triethyl citrate retarded drug release to a greater extent and formed more homogeneous and compact polymer films. The moisture content of PEG 300 plasticised pellets showed a 0.6% increase in moisture content while triethyl citrate plasticised pellets displayed a loss of 0.01% moisture 8 weeks after storage at room temperature.     

The Structure Investigation of Magnesium Soap - Hydrocarbon System

The gels of Mg-stearate (2,5-20%) in apolar liquid paraffin media have been prepared with heating the binary mixture to 120-130°c, to reach the critical solution temperature (CST), and subsequently slowly (spontaneously) cooled to room temperature.

The particular components (i.e. Mg-stearate, liquid paraffin), the binary mixture (suspension) and the prepared gels and colloidal dispersions respectively were studied by means of DSC, to get the wiev into the system formation course and also to get the information about their thermal characteristics.

These results, in connection with those obtained through Theological investigation, determination of oil number and TEM micrographs, have given the following conception: on heating the metallic soap in liquid paraffin is dissolved in the range of CST and gives on cooling a gel or a colloidal dispersion (considering the Mg-stearate concentration) with spherical and planar (lamelar) structures of inverted type.

From rheological standpoint the gels represent plastic systems with well recognised yield value and thixotropy.

The rewarm of formed gels doesn't give stable ones anymore; their instability is the consequence of the lost water traces what confirms the TG curve.     

Compression Behavior of Acetylsalicylic Acid Pellets

An instrumented tablet press was used to study the compression behavior of different acetylsalicylic acid (AAS) formulations. Formulations of AAS crystals and uncoated AAS pellets have compression behavior similar to formulations of AAS pellets coated with acrylic resins (Eudragit RS) and mixed with a 20% of microcrystalline cellulose. Formulations of AAS coated pellets without any excipient exhibited a more plastic compression behavior then the other formulations. Matrix tablets of AAS were produced by compression of formulations of AAS coated pellets without any excipients.

The drug release profile of the pellets before and after compression was also studied. Microcrystalline cellulose concentrations higher than 15% w/w were required to obtain tablets of coated pellets with drug release profiles similar to the coated pellets before compression. It can be concluded from the present work that compression data of coated particles can be useful to study the possible damage of the film coat of the particles during tableting. Futhermore, instrumented tablet press data can be a good complement of in vitro drug release studies.     

The preparation of prolonged action formulations in the form of semi solid matrix into hard gelatin capsules of oxprenolol I. Thermocap method

The aim of this study was to obtain prolonged action by preparing semi-solid matrices (SSM) into hard gelatin capsules using Oxprenolol as a model drug.

SSM formulations were prepared by using different lipophilic and hydrophilic pharmaceutical excipients, polyethylene glycols as channeling agent in the semi solid mass and Gelucires. The release kinetic of drug from these formulations was determined and compared with the commercial preparation in the form of polymeric matrix of this drug.

Among the generally used excipients, we have found that Gelucires were the most appropriate excipients for preparation of SSMs and drug release from these dosage forms can be improved by the method mentioned above depending on quantity and type of channeling agent which was used.     

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid - methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.