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Properties of theophylline tablets powder-coated with methacrylate ester copolymers
J. DRUG DEL. SCI. TECH., 14 (4) 319-325 2004
Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng1*, M. Cerea1, 2, D. Sauer1, J.W. McGinity1 1 College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, United States Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi, 42 Milano 20131, Italy *Correspondence: [email protected]
2
The purpose of this paper is to characterize the physiochemical and dissolution properties of tablets coated using a novel, solvent-free powder coating process. The ammonio methacrylate copolymers, Eudragit RS PO and Eudragit RL PO (95:5), were pre-plasticized by a hot-melt extrusion process using a plasticizer and thermal lubricant, and then cryogenically ground into a fine powder. The powder coating process involved three steps including priming, powder layering and curing. The use of a solid primer at the initial stage of powder coating increased the adhesion of the pre-plasticized acrylic polymers to the substrates. At 8% w/w total weight gain, immediate release theophylline tablets that were powdercoated with Eudragit RS PO/RL PO demonstrated a 12-h sustained release profile. The theophylline release rate of powder-coated tablets was significantly influenced by the curing temperature, plasticizer concentration, coating level and particle size of the coating powder. Eudragit RS PO/RL PO powder-coated tablets demonstrated a stable drug release profile after 3-month storage at 25ºC/60% RH and 40ºC/75%RH. This novel powder coating process was demonstrated to be an efficient coating method to produce stable sustained release dosage forms. Key words: Powder coating – Eudragit RS PO/RL PO – Hot-melt extrusion – Cryogenic grinding – Tablets.
Traditionally, an organic or aqueous polymeric solution or dispersion is sprayed onto the surface of a solid substrate during a film coating process. Since the early 1970s, aqueous latex dispersions gained in popularity because latex dispersions are water-based, and the health, safety and environmental concerns that are typically associated with organic solvent-based film coating are removed [1]. However, the aqueous coating process is not problem-free. Common problems associated with the aqueous coating process include the migration of drugs into the films coating [2] and instability of drug release rate [3-7]. Powder coatings have been successfully used for decades in industrial processes for painting refrigerators, automobiles, and computers [8]. However, it was not reported in the pharmaceutical literature until the late 1990s by Obara et al. [9]. The advantages of powder coating systems include the absence of solvents, suitability for water-sensitive active ingredients and elimination of migration of highly water-soluble drugs into the polymeric film coating. Powder coating technology can also be employed to prevent the interaction between coatings and the drug present in the core pellets or tablets. Furthermore, the solid content from a powder coating process is 100% compared to 10-20% for aqueous coating processes. Therefore, a much shorter coating process can be achieved. Film formation from the application of dry powder involves a different mechanism from latex dispersions. Film formation from powder coating involves: powder deposition and packing, particle coalescence, spreading and leveling, curing and cooling [10]. Researchers have pointed out that the major driving force of coalescence is surface tension and the resisting force is the viscosity of the molten particles. In the second stage of film formation, a continuous film is formed through coalescence of
the molten particles. The irregular film is transformed into a smooth surface during the third stage. Obara et al. [9] introduced the dry coating technique, as a direct application of the polymer powder and simultaneous spraying of a liquid plasticizing agent. A hydroxypropyl methylcellulose (HPMC) solution was sprayed onto the coated substrates before the curing step [9]. More recently, Pearnchob and Bodmeier have successfully employed this technology to coat pellets with Eudragit RS PO, ethylcellulose and shellac. The plasticizer and a HPMC solution were sprayed simultaneously with the powder feed [11-12]. Higher coating levels were required for the dry coating technique to achieve a similar release profile than the dosage forms coated with aqueous dispersion. In addition, a higher plasticizer concentration was employed in the dry coating process with 40% TEC being used for the dry powder (Eudragit RS PO) compared to 15-20% for aqueous dispersions of Eudragit RS 30 D. However, the coating time was significantly reduced. In the current study, a coating process was developed without the need to spray the plasticizer or any other solution onto solid substrates. A polymer blend composed of Eudragit RS PO/RL PO (95:5) was pre-plasticized by a hot-melt extrusion process and then cryogenically ground into a fine powder. The ratio 95:5 of Eudragit RS PO/RL PO was studied since this ratio is commonly used in aqueous coating systems and the presence of the Eudragit RL PO at 5% level was sufficient to modify the permeability of the Eudragit RS PO [6, 13]. This fine powder was directly deposited onto the substrate surface and a film was formed during the curing process. The purpose of this study was to investigate the properties of theophylline tablets powder-coated with Eudragit RS PO/RL PO. 319
J. DRUG DEL. SCI. TECH., 14 (4) 319-325 2004
Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
2.3. Particle size measurement The particle size of the coating powder was determined by laser light diffraction using a Malvern Mastersizer S (Malvern Instrument Limited, Malvern, Worcestershire, UK). Dv 10, Dv 50, Dv 90, were the particle size at 10, 50 and 90 cumulative percent undersize, respectively. The measurements were performed in triplicate. The coating powder was dispersed in 0.1 N HCl to suppress the swelling of Eudragit RS PO/RL PO due to the presence of the chlorine ion in the polymer.
I. MATERIALS AND METHODS 1. Materials
Eudragit RS PO and Eudragit RL PO were donated by Röhm America L.L.C. (Parsippany, NJ, United States). Theophylline anhydrous, lactose monohydrate, magnesium stearate and cetyl alcohol were purchased from Spectrum Chemical Mfg. Corp. (Gardena, CA, New Brunswick, NJ, United States). Polyvinylpyrrolidone K-30 (PVP K-30, Kollidon 30) was supplied by BASF Corp. (Mount Olive, NJ, United States). Microcrystalline cellulose (Avicel PH-101) was donated by FMC Corp. (Newark, DE, United States); fumed silica (Cab-O-Sil, type M-5P) was provided by Cabot Corp. (Tuscala, IL, United States). Glyceryl monostearate (GMS, Inwitor 491) was supplied by Sasol Germany GmbH (Witten, Germany). Talc (Altalc 500V) was supplied by Luzenac American Inc. (Englewood, CO, United States). Triethyl Citrate, NF (TEC) was donated by Morflex, Inc (Greensoro, CA, United States).
2.4. TEC content analysis TEC content recovery in the coating powder after hot-melt extrusion and cryogenic grinding was analyzed by a Waters HPLC system with a photodiode array detector (Model 996) extracting at 210 nm. The coating powder was first dissolved in acetone and then diluted by a factor of 4 with 10 mM pH 2.5 phosphate buffer to precipitate out the polymer. All samples were filtered through 0.45 µm filters. The column used was an Alltech Inertsil ODS-3 3 µm, 150 x 4.6 mm. The mobile phase contained a mixture of 10 mM pH 2.5 phosphate buffer: acetonitrile in volume ratios of 45:55. The flow rate was 1 ml/min, and the retention time of TEC was 5.5 min. Linearity was demonstrated from 20 to 1000 µg/ml (R2 ≥ 0.9998) and injection repeatability was 1% relative standard deviation for 6 injections.
2. Methods
2.1. Tablets preparation Theophylline anhydrous (15%), microcrystalline cellulose (66.1%), lactose monohydrate (15%), and PVP K-30 (3%) were mixed in a V-shape blender (Model Yoke, Patterson-Kelley Co., East Stroudsburg, PA, United States) for 20 min, then magnesium stearate (0.5%) and amorphous fumed silica (0.4%) were added and mixed for an additional 5 min. Tablets were compressed on a rotary press (Model FJS-B2 Stokes, Bristol, PA, United States) with concave 8 mm punches. Tablets were characterized by weight (269.73 ± 1.91 mg), surface area (188.96 ± 1.36 mm2), friability (< 1%), hardness (10.30 ± 0.95 kg) and disintegration time (< 1 min).
2.5. Powder coating process The powder coating process was performed in a laboratory scale spheronizer (Model 120, G.B. Caleva, Dorset, UK) with a smooth stainless steel disc (Figure 2). The batch size for coating was 50 g of tablets. An infrared lamp (250W Infrared Red Heat Bulb, General Electric) was used as a heating source. The coating temperature was adjusted by regulating the lamp power with a variable transformer (Type PF1010, Staco Inc, Daiton, OH, United States). A digital thermoprobe (Model 600-1040, Barnant Company, Barrington, IL, United States) was used to constantly monitor the bed temperature of the tablets. In addition, an infrared thermometer (Fluke Corp. Everett, WA, United States) was used to measure the surface temperature of tablets. Talc was added to the coating powders (10% w/w based on weight of extrudate), and the coating powders were mixed in a glass mortar and pestle for 5 min. During the coating process, the mixture was continuously spread onto the cores using a single screw powder feeder, with an addition rate of 0.5 g/min. The coating parameters for each formulation are listed in Table I. Powder-coated tablets were cured in a static oven (Model 107905, Boekel Scientific Inc., Feasterville, PA, United States) on Teflon plates at 80°C for 24 h.
2.2. Hot-melt extrusion Eudragit RS PO, Eudragit RL PO (95:5), GMS (5%) and TEC (5, 10, 15% based on polymer weight) were mixed within a high shear mixer, and extruded through a single screw extruder (Randcastle Model RC 0750, Cedar Grove, NJ, United States). The extruder temperatures employed were: zone 1 = 60°C, zone 2 = 80°C, zone 3 = 90°C and die = 100°C. A cylindrical die 1.2 mm in diameter was used, and the extrudate was uniformly cut into cylindrical pellets using a Randcastle RCP-2.0 pelletizer. The pellets were cryogenically ground into fine powder (Figure 1). Powder blend
Plasticizer Pre-plasticized polymer
High-shear
Pelletize
1 2
Cylindrical pellets Temperature probe
Cylindrical extrudate
Infra-red lamp
Powder feeder
Die
Hot-melt Tablets
Coating powder
Cryogenic
Rotating disk
Figure 2 - Schematic of powder coating process.
Figure 1 - Diagram of preparation of coating powder.
320
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
coating. Thus, the time required for two particles to coalesce is proportional to the melt viscosity and particle size of the coating powder, but inversely proportional to the surface tension of the coating powder. In order to facilitate film formation from dry polymer powder, the melt viscosity and particle size of the coating powder must be decreased. In general, particles having a smaller particle size and a narrow size distribution lead to a smoother coating surface [10]. This finding may be due to the improved flow properties of smaller molten powder particles during the film formation process. Since most commercially available pharmaceutical polymers have high glass transition temperatures, the challenge was to develop a process to produce a coating powder with a suitable melt viscosity and particle size distribution. The glass transition temperatures of Eudragit RS PO and Eudragit RL PO are approximately 60ºC. Polymer melt viscosity can be decreased by increasing the temperature or the addition of a plasticizer. The hot-melt extrusion process was employed to pre-plasticize the polymer. Polymeric materials soften and become flexible primarily due to the shear effect of the rotating screw and the heat conducted from a heating device attached to the barrel [15, 16]. In addition, compression of the feedstock inside the barrel generates high pressures and forces the air out of the polymer melt. In this way, the polymer and the plasticizer can be mixed completely to form uniform mixtures. Instead of spraying the plasticizer onto the polymer powder, hot-melt extrusion provides a more efficient process to plasticize the polymer. The low glass transition temperature of the coating powder while facilitating film formation, can also present several challenges to the particle size reduction process. Due to the heat generated during the milling process, the plasticized particles became soft and formed agglomerates. A cryogenic grinding process was thus employed to maintain the temperature below the glass transition temperature of pre-plasticized polymer during the milling process, and to maintain the polymer in a glassy state. The brittle particles were ground into fine powder.
Table I - Coating parameters. Parameters
Value
Batch size Rotation speed Powder feeding rate Temperature - 0% triethyl citrate* - 5% triethyl citrate* - 10% triethyl citrate* - 15% triethyl citrate*
50 g 190 rpm 0.3-0.5 g/min 80-85°C 70-75°C 60-65°C 55-60°C
*% w/w based on the polymer weight.
2.6. Drug release properties study Dissolution testing of the theophylline powder-coated tablets (n = 6) was conducted using the USP 27 Apparatus 2 (VanKel VK 7000; Cary, NC, United States) and 900 ml of 50 mM pH 7.4 phosphate buffer at 37ºC and 50 rpm. Dissolution samples were analyzed for theophylline content according to the USP 27 method using a Waters HPLC system with a photodiode array detector (Model 996). The wavelength was 280 nm. The column was an Alltech Inertsil ODS-3 3 µm, 150 x 4.6 mm. The mobile phase contained a mixture of water: acetonitrile:glacial acetic acid in volume ratios of 845:150:5 and 1.156 g/l of sodium acetate trihydrate. The flow rate was 1.0 ml/min, and the retention time of theophylline was 3.6 min. Linearity was demonstrated from 1 to 100 µg/ml (R2 ≥ 0.9999), and injection repeatability was 1% relative standard deviation for 6 injections. 2.7. Contact angle measurement Compacts of the sample powders were prepared at a 1000 kg compression force using a Carver Laboratory Press (Model M, ISI Inc, Round Rock, TX, United States) with a flat 10 mm diameter punche. A droplet containing 3 µl purified water was placed on the surface of the compact, and the contact angle was determined by measuring the tangent to the curve of the droplets on the surface of the compact using a Goniometer (Model No. 100-00-115, Ramè-Hart Inc., Mountain Lakes, NJ, United States).
2. Powder characterizations
The TEC content of the coating powder is shown in Table II. The TEC recovery of coating powder containing 5, 10, and 15% TEC was 99.2, 94.9 and 95.9%, respectively. These results indicated that TEC was stable during the hot-melt extrusion and the small standard deviation between the samples demonstrated a uniform distribution of TEC in the acrylic polymer. The particle size distribution of the coating powder is listed in Table III. The particle size of coating powder prepared by hot-melt extrusion and cryogenic grinding process was smaller compared to the unprocessed commercial Eudragit RS PO/RL PO. The different plasticizer levels in the acrylic polymer did not significantly influence the particle size distribution of the
2.8. Scanning electron microscopy The surface and cross-sectional morphologies of the powdercoated films and tablets were observed using a scanning electron microscopy (SEM) (Model S-4500 FE, Hitachi, London UK). The samples were sputter coated for 50 s with gold:palladium (60:40; Sputter Coater Mod. K575, Emitech, Houston, TX, United States).
II. RESULTS AND DISCUSSION 1. Hot-melt extrusion and cryogenic grinding process
According to Nix and Dodge [14], the time required for two particles to coalesce can be expressed by the following equation: t=kµR/γ Eq. 1
Table II - Triethyl citrate recovery from the coating powder following hot-melt extrusion and cryogenic grinding.
where t is the time necessary for two particles to coalesce, k is a constant, µ is the viscosity of the powder coating, R is the radius of the powder particles, and γ is the surface tension of the 321
Theoretical con. (%)
Actual con. (%)
Recovery (%)
5 10 15
4.95 ± 0.01 9.49 ± 0.06 14.38 ± 0.10
99.15 94.86 95.86
J. DRUG DEL. SCI. TECH., 14 (4) 319-325 2004
Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
Table III - Particle size distribution of the coating powders following hot-melt extrusion and cryogenic grinding. Polymer
TEC%
Dv 10 (µm)
Dv 50 (µm)
Dv 90 (µm)
Span index
D [4,3] (µm)
Eudragit RS PO
0
15.17
62.63
192.76
2.835
85.70
Eudragit RL PO
0
41.53
98.97
204.41
1.646
112.28
Eudragit RS PO/ RL PO (95:5)
5
22.62
70.60
131.70
1.545
74.81
10
14.71
65.07
130.81
1.679
70.28
15
26.53
71.67
138.07
1.556
77.60
Span index: (Dv 90 - Dv 10)/Dv 50.
coating powder following hot-melt extrusion and cryogenic grinding. These results demonstrated that hot-melt extrusion and cryogenic grinding is a suitable process to produce the coating powder.
Percent theophylline released
100
3. Subcoat
A 3% weight gain of cetyl alcohol was first applied to the tablets as a primer or subcoat to increase the adhesion of the acrylic powder to the tablet surface. Preliminary studies were conducted with three primers, including the hydrophilic polymer, PEG 3350; the amphiphilic polymer, Pluronic 127; and a hydrophobic sugar alcohol, cetyl alcohol. The most successful results were obtained with cetyl alcohol, in term of adhesion and film formation. As previously discussed in the introduction section, the first stage of film formation is the deposition of polymer coating powder onto the solid substrate. The adhesion of powder onto a solid surface is a rather complex process and has been viewed as a wetting process [17]. The contact angles of the core tablets, primer, and coating powders were measured. The contact angle of core tablets was 31.33º indicating a hydrophilic surface. The Eudragit RS PO/RL PO (95:5) mixture was demonstrated to be more hydrophobic as indicated by a higher contact angle of 68.8º. The contact angle of cetyl alcohol was 63.0º, while the compact containing PEG has a lower contact angle of 16.2º. The cetyl alcohol subcoat on the core tablets modified the hydrophobicity of the surface, thereby, increasing the wetting of the coating powder on the tablet surface, to increase the adhesion of the coating powder to the tablet surface.
80 60 40 20 0 0
2
4
6
8
10
12
Time (h)
Figure 3 - Influence of the particle size on the theophylline release rate from tablets powder-coated with EudragitRS PO/RL PO (95:5) containing 10% TEC, using the USP 27 Apparatus 2 and 900 ml of 50 mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: 100-200 mesh; ■: < 300 mesh.
and thus promote film formation. For the shorter curing time, finer particles form a more complete film, resulting in a decrease in the drug release rate.
5. Curing temperature
The influence of curing temperature on the release rate of theophylline from powder coated tablets is seen in Figure 4. All powder-coated tablets were cured for 1 h at different temperatures. The uncured tablets demonstrated a rapid drug release rate. Curing at 60ºC for 1 h did not significantly change the drug release rate from powder-coated tablets. However, a significant decrease in the theophylline release rate was observed with
4. Particle size distribution
Particle size is a critical parameter to consider for powder coating. Because of the mechanism of film formation during powder coating process, the particle size of the powder coating plays an important role in determining the leveling properties of the coatings [18]. It is difficult to expect good leveling of a coating consisting of coarse large particles which have to be sintered in a uniform continuous film during curing. The influence of particle size of coating powder on the drug release rate is shown in Figure 3. Two different particle size fractions of coating powders, 100-200 mesh (75-150 µm) and < 300 mesh (45.7 µm) were employed. The mean particle size, Dv 50, of these two coating powders, as demonstrated by laser light diffraction, was 65 and 26 µm, respectively. The tablets powdercoated with the larger particles, demonstrated a faster drug release rate than the tablets coated with the smaller particles. This can be explained from the Nix and Dodge equation which indicates that smaller particles will promote the coalescence,
Percent theophylline released
100
80
60
40
20
0 0
2
4
6
8
10
12
Time (h)
Figure 4 - Influence of the curing temperature on the theophylline release rate from tablets powder-coated with 3% w/w cetyl alcohol and 5% w/w Eudragit RS/RL (95:5) containing 5% TEC, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: no curing; ■: 60°C; ▲: 80°C. 322
J. DRUG DEL. SCI. TECH., 14 (4) 319-325 2004
Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
tablets that had been cured at 80ºC for 1 h. In addition, the drug release rate decreased with increasing curing temperature. A requirement for good film formation is to maintain low polymer viscosity to promote distribution of the material over the surface of the solid substrate. For thermoplastic powders, this will depend on the molecular weight of the polymer and the curing temperature. The melt viscosity-temperature relationship for thermoplastic polymer melts can be characterized by the following Arrhenius equation: η = AeE/RT
Figure 5 - SEM micrographs of cross-section of powder-coated tablets. Left: uncoated tablet. Right: powder-coated tablet (5% TEC).
Eq. 2
where η is melt viscosity; A is a constant, characteristic for the polymer; E is activation energy for viscous flow; R is universal gas constant; and T is absolute temperature. Although the relationship between the logarithmic melt viscosity and the reciprocal temperature is linear at high temperature, the melt viscosity decreases with increasing temperature. As previously discussed, the melts viscosity is the major resisting force for film formation. Therefore, the high curing temperature decreased the melt viscosity of the coating powder and produced a better film, which resulted in a decrease in the drug release rate.
6. Influence of plasticizer concentration
The morphology of cross-sections of uncoated and powdercoated tablets is shown in Figure 5. The micrographs demonstrate a distinct coating layer on the surface of the powdercoated tablet. The influence of plasticizer level on the surface morphology is shown in Figure 6. The powder-coated tablets were cured at 80ºC for 24 h. Without plasticizer, the surface of the Eudragit RS PO/RL PO coated tablet is porous and rough, with individual or powder aggregates still visible, indicating incomplete film formation. When 5% TEC was incorporated into the acrylic polymer, the surface became continuous, however, the boundaries of coating powders still remained. The surfaces of tablets coated with Eudragit RS PO/RL PO containing either 10% or 15% TEC, were smooth, and the boundaries of coating powder became less distinct. For plasticized film-coated tablets, the surface became smoother and glossier after the curing process. All films were intact and maintained good adhesion to the tablets after curing. The influence of the plasticizer level present in the coating powder on the theophylline release rate from powder-coated tablets is seen in Figure 7. The tablets were first powder-coated with 3% w/w cetyl alcohol as a subcoat and then a second powder composed of plasticized Eudragit RS PO/RL PO (95: 5) (5% w/w) was applied to the tablets. All dissolution profiles demonstrated an initial 2 h lag time, which was followed by a sustained release phase. The drug release rate decreased with increasing levels of TEC. This is in agreement with the photographs obtained from SEM. The triethyl citrate decreased the melt viscosity of polymer particles [19], promoted film formation from the coating powders, and thus decreased the drug release rate since melt viscosity of a polymer is the major resisting force for film formation.
Figure 6 - SEM micrographs of surfaces of powder-coated tablets containing different plasticizer level. Up, left: 0% TEC. Up, right: 5% TEC. Down, left: 10% TEC. Down, right: 15% TEC.
Percent theophylline released
100
80
60
40
20
0 0
2
4
6
8
10
12
Time (h)
Figure 7 - Influence of plasticizer level on the theophylline release rate from tablets powder-coated with Eudragit RS/RL (95:5), using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: 0%. ■: 5%. ▲: 10%. ◊: 15%.
7. Coating level
The influence of coating level on the release rate of theophylline from powder-coated tablets is shown in Figure 8. The application of 3% cetyl alcohol as a subcoat did not significantly decrease the drug release rate from tablets, however, the subcoat was essential to promote adhesion of the coating powder to the surface of the tablets and to provide better film formation. The release rate of theophylline from powder-coated tablets decreased significantly with increasing coating level. With 8% total weight gain (3% w/w subcoat and 5% w/w polymer), a
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
100
100
80
80
Percent Theophylline Released
Percent theophylline released
J. DRUG DEL. SCI. TECH., 14 (4) 319-325 2004
60
40
20
0
60
40
20
0 0
2
4
6
8
10
12
0
2
4
Time (h)
Figure 8 - Influence of coating level on the theophylline release rate from tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: core tablet. ■: subcoat. ▲: 8% w/w. O: 10% w/w. ❐: 15% w/w.
8
10
12
Figure 9 - The 3-month stability of theophylline tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC at 25ºC/60% RH, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: initial. ❐: 1 month. Δ: 3 months.
sustained release profile was achieved. With 10 and 15% total weight gain, only approximately 20 and 10% of theophylline were released from powder-coated tablets after 12 h dissolution, respectively. These results indicate that powder coating is an efficient technology to control the drug release rate.
Percent theophylline released
100
8. Stability of powder-coated tablets
Stability of coated dosage forms is a primary concern since the instability of aqueous coated tablets and pellets has been previously reported [3-7]. A 3-month stability study of theophylline tablets powder-coated with Eudragit RS PO/RL PO containing 5% TEC was investigated. The coated tablets were stored at 25ºC/60% RH and 40ºC/75% RH in closed HDPE bottles. No significant difference in theophylline release rate was observed at either condition after storage, which demonstrated that powder coating can result in good physical stability of the coated dosage forms (Figures 9 and 10).
80
60
40
20
0 0
2
4
6
8
10
12
Time (h)
Figure 10 - The 3-month stability of theophylline tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC at 40ºC/75% RH, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: initial. ❐: 1 month. Δ: 3 months. 2.
*
* * Hot-melt extrusion of plasticized methacrylate ester copolymers followed by cryogenic grinding was shown to be an efficient process to produce coating powder. Powder coating, without using water or any other liquids, was demonstrated to be an effective technology to control drug release rate. Formulation and processing parameters including curing temperature, plasticizer level and particle size distribution of coating powder significantly influenced film formation and thus drug release properties of powder-coated tablets. Finally, the powder-coated dosage forms demonstrated reproducible theophylline release rates after 3 months storage at 25ºC/60% RH and 40ºC/75% RH.
3.
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16. 17.
18. 19.
McGINITY J.W., ZHANG F. - Melt-extrudated controlled-release dosage forms. -In: Pharmaceutical Extrusion Technology, I. Ghebre-Sellassie, C. Martin Eds., New York, 2003, pp. 183-208. GRUNDKE K., MICHEL S., OSTERHOLD M. - Surface tension studies of additives in acrylic resin-based powder coatings using Wilhelmy balance technique - Prog. Org. Coat., 39, 101-106, 2000. MISEV T.A. - Parameters influencing powder coating properties-In: Powder Coatings Chemistry and Technology, T.A. Misev Ed., New York, 1991, pp. 215-217. ZHU Y. - Properties of polymeric drug delivery systems prepared by hot-melt extrusion. - Dissertation, 101-102, 2002.
MANUSCRIPT Received 15 March 2004, accepted for publication 23 June 2004.
325
Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng1*, M. Cerea1, 2, D. Sauer1, J.W. McGinity1 1 College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, United States Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi, 42 Milano 20131, Italy *Correspondence: [email protected]
2
The purpose of this paper is to characterize the physiochemical and dissolution properties of tablets coated using a novel, solvent-free powder coating process. The ammonio methacrylate copolymers, Eudragit RS PO and Eudragit RL PO (95:5), were pre-plasticized by a hot-melt extrusion process using a plasticizer and thermal lubricant, and then cryogenically ground into a fine powder. The powder coating process involved three steps including priming, powder layering and curing. The use of a solid primer at the initial stage of powder coating increased the adhesion of the pre-plasticized acrylic polymers to the substrates. At 8% w/w total weight gain, immediate release theophylline tablets that were powdercoated with Eudragit RS PO/RL PO demonstrated a 12-h sustained release profile. The theophylline release rate of powder-coated tablets was significantly influenced by the curing temperature, plasticizer concentration, coating level and particle size of the coating powder. Eudragit RS PO/RL PO powder-coated tablets demonstrated a stable drug release profile after 3-month storage at 25ºC/60% RH and 40ºC/75%RH. This novel powder coating process was demonstrated to be an efficient coating method to produce stable sustained release dosage forms. Key words: Powder coating – Eudragit RS PO/RL PO – Hot-melt extrusion – Cryogenic grinding – Tablets.
Traditionally, an organic or aqueous polymeric solution or dispersion is sprayed onto the surface of a solid substrate during a film coating process. Since the early 1970s, aqueous latex dispersions gained in popularity because latex dispersions are water-based, and the health, safety and environmental concerns that are typically associated with organic solvent-based film coating are removed [1]. However, the aqueous coating process is not problem-free. Common problems associated with the aqueous coating process include the migration of drugs into the films coating [2] and instability of drug release rate [3-7]. Powder coatings have been successfully used for decades in industrial processes for painting refrigerators, automobiles, and computers [8]. However, it was not reported in the pharmaceutical literature until the late 1990s by Obara et al. [9]. The advantages of powder coating systems include the absence of solvents, suitability for water-sensitive active ingredients and elimination of migration of highly water-soluble drugs into the polymeric film coating. Powder coating technology can also be employed to prevent the interaction between coatings and the drug present in the core pellets or tablets. Furthermore, the solid content from a powder coating process is 100% compared to 10-20% for aqueous coating processes. Therefore, a much shorter coating process can be achieved. Film formation from the application of dry powder involves a different mechanism from latex dispersions. Film formation from powder coating involves: powder deposition and packing, particle coalescence, spreading and leveling, curing and cooling [10]. Researchers have pointed out that the major driving force of coalescence is surface tension and the resisting force is the viscosity of the molten particles. In the second stage of film formation, a continuous film is formed through coalescence of
the molten particles. The irregular film is transformed into a smooth surface during the third stage. Obara et al. [9] introduced the dry coating technique, as a direct application of the polymer powder and simultaneous spraying of a liquid plasticizing agent. A hydroxypropyl methylcellulose (HPMC) solution was sprayed onto the coated substrates before the curing step [9]. More recently, Pearnchob and Bodmeier have successfully employed this technology to coat pellets with Eudragit RS PO, ethylcellulose and shellac. The plasticizer and a HPMC solution were sprayed simultaneously with the powder feed [11-12]. Higher coating levels were required for the dry coating technique to achieve a similar release profile than the dosage forms coated with aqueous dispersion. In addition, a higher plasticizer concentration was employed in the dry coating process with 40% TEC being used for the dry powder (Eudragit RS PO) compared to 15-20% for aqueous dispersions of Eudragit RS 30 D. However, the coating time was significantly reduced. In the current study, a coating process was developed without the need to spray the plasticizer or any other solution onto solid substrates. A polymer blend composed of Eudragit RS PO/RL PO (95:5) was pre-plasticized by a hot-melt extrusion process and then cryogenically ground into a fine powder. The ratio 95:5 of Eudragit RS PO/RL PO was studied since this ratio is commonly used in aqueous coating systems and the presence of the Eudragit RL PO at 5% level was sufficient to modify the permeability of the Eudragit RS PO [6, 13]. This fine powder was directly deposited onto the substrate surface and a film was formed during the curing process. The purpose of this study was to investigate the properties of theophylline tablets powder-coated with Eudragit RS PO/RL PO. 319
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
2.3. Particle size measurement The particle size of the coating powder was determined by laser light diffraction using a Malvern Mastersizer S (Malvern Instrument Limited, Malvern, Worcestershire, UK). Dv 10, Dv 50, Dv 90, were the particle size at 10, 50 and 90 cumulative percent undersize, respectively. The measurements were performed in triplicate. The coating powder was dispersed in 0.1 N HCl to suppress the swelling of Eudragit RS PO/RL PO due to the presence of the chlorine ion in the polymer.
I. MATERIALS AND METHODS 1. Materials
Eudragit RS PO and Eudragit RL PO were donated by Röhm America L.L.C. (Parsippany, NJ, United States). Theophylline anhydrous, lactose monohydrate, magnesium stearate and cetyl alcohol were purchased from Spectrum Chemical Mfg. Corp. (Gardena, CA, New Brunswick, NJ, United States). Polyvinylpyrrolidone K-30 (PVP K-30, Kollidon 30) was supplied by BASF Corp. (Mount Olive, NJ, United States). Microcrystalline cellulose (Avicel PH-101) was donated by FMC Corp. (Newark, DE, United States); fumed silica (Cab-O-Sil, type M-5P) was provided by Cabot Corp. (Tuscala, IL, United States). Glyceryl monostearate (GMS, Inwitor 491) was supplied by Sasol Germany GmbH (Witten, Germany). Talc (Altalc 500V) was supplied by Luzenac American Inc. (Englewood, CO, United States). Triethyl Citrate, NF (TEC) was donated by Morflex, Inc (Greensoro, CA, United States).
2.4. TEC content analysis TEC content recovery in the coating powder after hot-melt extrusion and cryogenic grinding was analyzed by a Waters HPLC system with a photodiode array detector (Model 996) extracting at 210 nm. The coating powder was first dissolved in acetone and then diluted by a factor of 4 with 10 mM pH 2.5 phosphate buffer to precipitate out the polymer. All samples were filtered through 0.45 µm filters. The column used was an Alltech Inertsil ODS-3 3 µm, 150 x 4.6 mm. The mobile phase contained a mixture of 10 mM pH 2.5 phosphate buffer: acetonitrile in volume ratios of 45:55. The flow rate was 1 ml/min, and the retention time of TEC was 5.5 min. Linearity was demonstrated from 20 to 1000 µg/ml (R2 ≥ 0.9998) and injection repeatability was 1% relative standard deviation for 6 injections.
2. Methods
2.1. Tablets preparation Theophylline anhydrous (15%), microcrystalline cellulose (66.1%), lactose monohydrate (15%), and PVP K-30 (3%) were mixed in a V-shape blender (Model Yoke, Patterson-Kelley Co., East Stroudsburg, PA, United States) for 20 min, then magnesium stearate (0.5%) and amorphous fumed silica (0.4%) were added and mixed for an additional 5 min. Tablets were compressed on a rotary press (Model FJS-B2 Stokes, Bristol, PA, United States) with concave 8 mm punches. Tablets were characterized by weight (269.73 ± 1.91 mg), surface area (188.96 ± 1.36 mm2), friability (< 1%), hardness (10.30 ± 0.95 kg) and disintegration time (< 1 min).
2.5. Powder coating process The powder coating process was performed in a laboratory scale spheronizer (Model 120, G.B. Caleva, Dorset, UK) with a smooth stainless steel disc (Figure 2). The batch size for coating was 50 g of tablets. An infrared lamp (250W Infrared Red Heat Bulb, General Electric) was used as a heating source. The coating temperature was adjusted by regulating the lamp power with a variable transformer (Type PF1010, Staco Inc, Daiton, OH, United States). A digital thermoprobe (Model 600-1040, Barnant Company, Barrington, IL, United States) was used to constantly monitor the bed temperature of the tablets. In addition, an infrared thermometer (Fluke Corp. Everett, WA, United States) was used to measure the surface temperature of tablets. Talc was added to the coating powders (10% w/w based on weight of extrudate), and the coating powders were mixed in a glass mortar and pestle for 5 min. During the coating process, the mixture was continuously spread onto the cores using a single screw powder feeder, with an addition rate of 0.5 g/min. The coating parameters for each formulation are listed in Table I. Powder-coated tablets were cured in a static oven (Model 107905, Boekel Scientific Inc., Feasterville, PA, United States) on Teflon plates at 80°C for 24 h.
2.2. Hot-melt extrusion Eudragit RS PO, Eudragit RL PO (95:5), GMS (5%) and TEC (5, 10, 15% based on polymer weight) were mixed within a high shear mixer, and extruded through a single screw extruder (Randcastle Model RC 0750, Cedar Grove, NJ, United States). The extruder temperatures employed were: zone 1 = 60°C, zone 2 = 80°C, zone 3 = 90°C and die = 100°C. A cylindrical die 1.2 mm in diameter was used, and the extrudate was uniformly cut into cylindrical pellets using a Randcastle RCP-2.0 pelletizer. The pellets were cryogenically ground into fine powder (Figure 1). Powder blend
Plasticizer Pre-plasticized polymer
High-shear
Pelletize
1 2
Cylindrical pellets Temperature probe
Cylindrical extrudate
Infra-red lamp
Powder feeder
Die
Hot-melt Tablets
Coating powder
Cryogenic
Rotating disk
Figure 2 - Schematic of powder coating process.
Figure 1 - Diagram of preparation of coating powder.
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
coating. Thus, the time required for two particles to coalesce is proportional to the melt viscosity and particle size of the coating powder, but inversely proportional to the surface tension of the coating powder. In order to facilitate film formation from dry polymer powder, the melt viscosity and particle size of the coating powder must be decreased. In general, particles having a smaller particle size and a narrow size distribution lead to a smoother coating surface [10]. This finding may be due to the improved flow properties of smaller molten powder particles during the film formation process. Since most commercially available pharmaceutical polymers have high glass transition temperatures, the challenge was to develop a process to produce a coating powder with a suitable melt viscosity and particle size distribution. The glass transition temperatures of Eudragit RS PO and Eudragit RL PO are approximately 60ºC. Polymer melt viscosity can be decreased by increasing the temperature or the addition of a plasticizer. The hot-melt extrusion process was employed to pre-plasticize the polymer. Polymeric materials soften and become flexible primarily due to the shear effect of the rotating screw and the heat conducted from a heating device attached to the barrel [15, 16]. In addition, compression of the feedstock inside the barrel generates high pressures and forces the air out of the polymer melt. In this way, the polymer and the plasticizer can be mixed completely to form uniform mixtures. Instead of spraying the plasticizer onto the polymer powder, hot-melt extrusion provides a more efficient process to plasticize the polymer. The low glass transition temperature of the coating powder while facilitating film formation, can also present several challenges to the particle size reduction process. Due to the heat generated during the milling process, the plasticized particles became soft and formed agglomerates. A cryogenic grinding process was thus employed to maintain the temperature below the glass transition temperature of pre-plasticized polymer during the milling process, and to maintain the polymer in a glassy state. The brittle particles were ground into fine powder.
Table I - Coating parameters. Parameters
Value
Batch size Rotation speed Powder feeding rate Temperature - 0% triethyl citrate* - 5% triethyl citrate* - 10% triethyl citrate* - 15% triethyl citrate*
50 g 190 rpm 0.3-0.5 g/min 80-85°C 70-75°C 60-65°C 55-60°C
*% w/w based on the polymer weight.
2.6. Drug release properties study Dissolution testing of the theophylline powder-coated tablets (n = 6) was conducted using the USP 27 Apparatus 2 (VanKel VK 7000; Cary, NC, United States) and 900 ml of 50 mM pH 7.4 phosphate buffer at 37ºC and 50 rpm. Dissolution samples were analyzed for theophylline content according to the USP 27 method using a Waters HPLC system with a photodiode array detector (Model 996). The wavelength was 280 nm. The column was an Alltech Inertsil ODS-3 3 µm, 150 x 4.6 mm. The mobile phase contained a mixture of water: acetonitrile:glacial acetic acid in volume ratios of 845:150:5 and 1.156 g/l of sodium acetate trihydrate. The flow rate was 1.0 ml/min, and the retention time of theophylline was 3.6 min. Linearity was demonstrated from 1 to 100 µg/ml (R2 ≥ 0.9999), and injection repeatability was 1% relative standard deviation for 6 injections. 2.7. Contact angle measurement Compacts of the sample powders were prepared at a 1000 kg compression force using a Carver Laboratory Press (Model M, ISI Inc, Round Rock, TX, United States) with a flat 10 mm diameter punche. A droplet containing 3 µl purified water was placed on the surface of the compact, and the contact angle was determined by measuring the tangent to the curve of the droplets on the surface of the compact using a Goniometer (Model No. 100-00-115, Ramè-Hart Inc., Mountain Lakes, NJ, United States).
2. Powder characterizations
The TEC content of the coating powder is shown in Table II. The TEC recovery of coating powder containing 5, 10, and 15% TEC was 99.2, 94.9 and 95.9%, respectively. These results indicated that TEC was stable during the hot-melt extrusion and the small standard deviation between the samples demonstrated a uniform distribution of TEC in the acrylic polymer. The particle size distribution of the coating powder is listed in Table III. The particle size of coating powder prepared by hot-melt extrusion and cryogenic grinding process was smaller compared to the unprocessed commercial Eudragit RS PO/RL PO. The different plasticizer levels in the acrylic polymer did not significantly influence the particle size distribution of the
2.8. Scanning electron microscopy The surface and cross-sectional morphologies of the powdercoated films and tablets were observed using a scanning electron microscopy (SEM) (Model S-4500 FE, Hitachi, London UK). The samples were sputter coated for 50 s with gold:palladium (60:40; Sputter Coater Mod. K575, Emitech, Houston, TX, United States).
II. RESULTS AND DISCUSSION 1. Hot-melt extrusion and cryogenic grinding process
According to Nix and Dodge [14], the time required for two particles to coalesce can be expressed by the following equation: t=kµR/γ Eq. 1
Table II - Triethyl citrate recovery from the coating powder following hot-melt extrusion and cryogenic grinding.
where t is the time necessary for two particles to coalesce, k is a constant, µ is the viscosity of the powder coating, R is the radius of the powder particles, and γ is the surface tension of the 321
Theoretical con. (%)
Actual con. (%)
Recovery (%)
5 10 15
4.95 ± 0.01 9.49 ± 0.06 14.38 ± 0.10
99.15 94.86 95.86
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
Table III - Particle size distribution of the coating powders following hot-melt extrusion and cryogenic grinding. Polymer
TEC%
Dv 10 (µm)
Dv 50 (µm)
Dv 90 (µm)
Span index
D [4,3] (µm)
Eudragit RS PO
0
15.17
62.63
192.76
2.835
85.70
Eudragit RL PO
0
41.53
98.97
204.41
1.646
112.28
Eudragit RS PO/ RL PO (95:5)
5
22.62
70.60
131.70
1.545
74.81
10
14.71
65.07
130.81
1.679
70.28
15
26.53
71.67
138.07
1.556
77.60
Span index: (Dv 90 - Dv 10)/Dv 50.
coating powder following hot-melt extrusion and cryogenic grinding. These results demonstrated that hot-melt extrusion and cryogenic grinding is a suitable process to produce the coating powder.
Percent theophylline released
100
3. Subcoat
A 3% weight gain of cetyl alcohol was first applied to the tablets as a primer or subcoat to increase the adhesion of the acrylic powder to the tablet surface. Preliminary studies were conducted with three primers, including the hydrophilic polymer, PEG 3350; the amphiphilic polymer, Pluronic 127; and a hydrophobic sugar alcohol, cetyl alcohol. The most successful results were obtained with cetyl alcohol, in term of adhesion and film formation. As previously discussed in the introduction section, the first stage of film formation is the deposition of polymer coating powder onto the solid substrate. The adhesion of powder onto a solid surface is a rather complex process and has been viewed as a wetting process [17]. The contact angles of the core tablets, primer, and coating powders were measured. The contact angle of core tablets was 31.33º indicating a hydrophilic surface. The Eudragit RS PO/RL PO (95:5) mixture was demonstrated to be more hydrophobic as indicated by a higher contact angle of 68.8º. The contact angle of cetyl alcohol was 63.0º, while the compact containing PEG has a lower contact angle of 16.2º. The cetyl alcohol subcoat on the core tablets modified the hydrophobicity of the surface, thereby, increasing the wetting of the coating powder on the tablet surface, to increase the adhesion of the coating powder to the tablet surface.
80 60 40 20 0 0
2
4
6
8
10
12
Time (h)
Figure 3 - Influence of the particle size on the theophylline release rate from tablets powder-coated with EudragitRS PO/RL PO (95:5) containing 10% TEC, using the USP 27 Apparatus 2 and 900 ml of 50 mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: 100-200 mesh; ■: < 300 mesh.
and thus promote film formation. For the shorter curing time, finer particles form a more complete film, resulting in a decrease in the drug release rate.
5. Curing temperature
The influence of curing temperature on the release rate of theophylline from powder coated tablets is seen in Figure 4. All powder-coated tablets were cured for 1 h at different temperatures. The uncured tablets demonstrated a rapid drug release rate. Curing at 60ºC for 1 h did not significantly change the drug release rate from powder-coated tablets. However, a significant decrease in the theophylline release rate was observed with
4. Particle size distribution
Particle size is a critical parameter to consider for powder coating. Because of the mechanism of film formation during powder coating process, the particle size of the powder coating plays an important role in determining the leveling properties of the coatings [18]. It is difficult to expect good leveling of a coating consisting of coarse large particles which have to be sintered in a uniform continuous film during curing. The influence of particle size of coating powder on the drug release rate is shown in Figure 3. Two different particle size fractions of coating powders, 100-200 mesh (75-150 µm) and < 300 mesh (45.7 µm) were employed. The mean particle size, Dv 50, of these two coating powders, as demonstrated by laser light diffraction, was 65 and 26 µm, respectively. The tablets powdercoated with the larger particles, demonstrated a faster drug release rate than the tablets coated with the smaller particles. This can be explained from the Nix and Dodge equation which indicates that smaller particles will promote the coalescence,
Percent theophylline released
100
80
60
40
20
0 0
2
4
6
8
10
12
Time (h)
Figure 4 - Influence of the curing temperature on the theophylline release rate from tablets powder-coated with 3% w/w cetyl alcohol and 5% w/w Eudragit RS/RL (95:5) containing 5% TEC, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: no curing; ■: 60°C; ▲: 80°C. 322
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
tablets that had been cured at 80ºC for 1 h. In addition, the drug release rate decreased with increasing curing temperature. A requirement for good film formation is to maintain low polymer viscosity to promote distribution of the material over the surface of the solid substrate. For thermoplastic powders, this will depend on the molecular weight of the polymer and the curing temperature. The melt viscosity-temperature relationship for thermoplastic polymer melts can be characterized by the following Arrhenius equation: η = AeE/RT
Figure 5 - SEM micrographs of cross-section of powder-coated tablets. Left: uncoated tablet. Right: powder-coated tablet (5% TEC).
Eq. 2
where η is melt viscosity; A is a constant, characteristic for the polymer; E is activation energy for viscous flow; R is universal gas constant; and T is absolute temperature. Although the relationship between the logarithmic melt viscosity and the reciprocal temperature is linear at high temperature, the melt viscosity decreases with increasing temperature. As previously discussed, the melts viscosity is the major resisting force for film formation. Therefore, the high curing temperature decreased the melt viscosity of the coating powder and produced a better film, which resulted in a decrease in the drug release rate.
6. Influence of plasticizer concentration
The morphology of cross-sections of uncoated and powdercoated tablets is shown in Figure 5. The micrographs demonstrate a distinct coating layer on the surface of the powdercoated tablet. The influence of plasticizer level on the surface morphology is shown in Figure 6. The powder-coated tablets were cured at 80ºC for 24 h. Without plasticizer, the surface of the Eudragit RS PO/RL PO coated tablet is porous and rough, with individual or powder aggregates still visible, indicating incomplete film formation. When 5% TEC was incorporated into the acrylic polymer, the surface became continuous, however, the boundaries of coating powders still remained. The surfaces of tablets coated with Eudragit RS PO/RL PO containing either 10% or 15% TEC, were smooth, and the boundaries of coating powder became less distinct. For plasticized film-coated tablets, the surface became smoother and glossier after the curing process. All films were intact and maintained good adhesion to the tablets after curing. The influence of the plasticizer level present in the coating powder on the theophylline release rate from powder-coated tablets is seen in Figure 7. The tablets were first powder-coated with 3% w/w cetyl alcohol as a subcoat and then a second powder composed of plasticized Eudragit RS PO/RL PO (95: 5) (5% w/w) was applied to the tablets. All dissolution profiles demonstrated an initial 2 h lag time, which was followed by a sustained release phase. The drug release rate decreased with increasing levels of TEC. This is in agreement with the photographs obtained from SEM. The triethyl citrate decreased the melt viscosity of polymer particles [19], promoted film formation from the coating powders, and thus decreased the drug release rate since melt viscosity of a polymer is the major resisting force for film formation.
Figure 6 - SEM micrographs of surfaces of powder-coated tablets containing different plasticizer level. Up, left: 0% TEC. Up, right: 5% TEC. Down, left: 10% TEC. Down, right: 15% TEC.
Percent theophylline released
100
80
60
40
20
0 0
2
4
6
8
10
12
Time (h)
Figure 7 - Influence of plasticizer level on the theophylline release rate from tablets powder-coated with Eudragit RS/RL (95:5), using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: 0%. ■: 5%. ▲: 10%. ◊: 15%.
7. Coating level
The influence of coating level on the release rate of theophylline from powder-coated tablets is shown in Figure 8. The application of 3% cetyl alcohol as a subcoat did not significantly decrease the drug release rate from tablets, however, the subcoat was essential to promote adhesion of the coating powder to the surface of the tablets and to provide better film formation. The release rate of theophylline from powder-coated tablets decreased significantly with increasing coating level. With 8% total weight gain (3% w/w subcoat and 5% w/w polymer), a
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
100
100
80
80
Percent Theophylline Released
Percent theophylline released
J. DRUG DEL. SCI. TECH., 14 (4) 319-325 2004
60
40
20
0
60
40
20
0 0
2
4
6
8
10
12
0
2
4
Time (h)
Figure 8 - Influence of coating level on the theophylline release rate from tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: core tablet. ■: subcoat. ▲: 8% w/w. O: 10% w/w. ❐: 15% w/w.
8
10
12
Figure 9 - The 3-month stability of theophylline tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC at 25ºC/60% RH, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: initial. ❐: 1 month. Δ: 3 months.
sustained release profile was achieved. With 10 and 15% total weight gain, only approximately 20 and 10% of theophylline were released from powder-coated tablets after 12 h dissolution, respectively. These results indicate that powder coating is an efficient technology to control the drug release rate.
Percent theophylline released
100
8. Stability of powder-coated tablets
Stability of coated dosage forms is a primary concern since the instability of aqueous coated tablets and pellets has been previously reported [3-7]. A 3-month stability study of theophylline tablets powder-coated with Eudragit RS PO/RL PO containing 5% TEC was investigated. The coated tablets were stored at 25ºC/60% RH and 40ºC/75% RH in closed HDPE bottles. No significant difference in theophylline release rate was observed at either condition after storage, which demonstrated that powder coating can result in good physical stability of the coated dosage forms (Figures 9 and 10).
80
60
40
20
0 0
2
4
6
8
10
12
Time (h)
Figure 10 - The 3-month stability of theophylline tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC at 40ºC/75% RH, using the USP 27 Apparatus 2 and 900 ml of 50mM pH 7.4 phosphate buffer at 37°C and 50 rpm. ◆: initial. ❐: 1 month. Δ: 3 months. 2.
*
* * Hot-melt extrusion of plasticized methacrylate ester copolymers followed by cryogenic grinding was shown to be an efficient process to produce coating powder. Powder coating, without using water or any other liquids, was demonstrated to be an effective technology to control drug release rate. Formulation and processing parameters including curing temperature, plasticizer level and particle size distribution of coating powder significantly influenced film formation and thus drug release properties of powder-coated tablets. Finally, the powder-coated dosage forms demonstrated reproducible theophylline release rates after 3 months storage at 25ºC/60% RH and 40ºC/75% RH.
3.
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Properties of theophylline tablets powder-coated with methacrylate ester copolymers W. Zheng, M. Cerea, D. Sauer, J.W. McGinity
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MANUSCRIPT Received 15 March 2004, accepted for publication 23 June 2004.
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