Powder Technology 141 (2004) 203 209 www.elsevier.

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Application of hot-melt coating for controlled release of propranolol hydrochloride pellets

Nuttanan Sinchaipanid *, Varaporn Junyaprasert, Ampol Mitrevej
Department of Industrial Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand Accepted 15 February 2004 Available online 2 April 2004

Abstract Waxes are available in various lyophilicity, and they can be used to regulate the release from multiunit-controlled release pellets. In this study, the application of saturated polyglycolysed glyceride (GelucireR 50/02) and glycerol palmitostearate (PrecirolR ATO5) as drug release regulators for propranolol pellets and the kinetics of release were investigated. Propranolol pellets containing 60% microcrystalline cellulose (AvicelR PH101) were prepared by using direct pelletization technique in a fluidized-bed rotary granulator (Glatt GPCG1). The pellets of 16:18 mesh size were collected and coated with the molten wax(es) at various ratios and thicknesses in a fluidized-bed top spray coater (Glatt GPCG1). The dissolution was determined using test method for Propranolol Extended Release Capsules USP 24 and was found to be very rapid with the uncoated pellets. The dissolution of coated pellet was decreased with the increases in Precirol ATO5 proportion and coating thickness. Plot of log % drug release vs. reciprocal of time showed a good linear relationship. The k value derived from the slope of the plot and designated as a diffusive resistance constant linearly increased with the coating level. The findings indicated that drug release could be adjusted by varying the ratio of PrecirolR ATO5 to GelucireR 50/02 as well as the thickness of the coat. D 2004 Elsevier B.V. All rights reserved.
Keywords: Pellets; Controlled release dosage form; Hot-melt coating

1. Introduction Multiunit dosage forms, e.g., pellets and granules, are less affected by variation in the gastric emptying rate and overall gastrointestinal transit time compared to a single unit such as tablets. The advantages of multiple-unit dosage forms over the single-unit ones have been demonstrated by several investigators [1 4]. The multiunit controlled release dosage forms are usually manufactured by coating the drug-loaded pellets or granules with gastrointestinal fluid-insoluble polymers. The drug release is controlled by diffusion through the pores of polymer film. The coating of particulates such as powders, granules, pellets and tablets to produce controlled release dosage form is becoming increasingly popular, mainly due to the advances in fluidized-bed process as well as availability of new coating materials [5].
* Corresponding author. Tel./fax: +66-2-6448702. E-mail address: pynsc@mahidol.ac.th (N. Sinchaipanid). 0032-5910/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2004.02.008

Film-coating processes often require solvent, i.e., water, organic solvents or mixture. The use of organic solvents may lead to environmental problems, solvent residues and excessive costs of recovery. The aqueous solvent generally prolongs the duration of the coating process. The hot-melt coating techniques have been shown to avoid the use of solvents and show promising for taste masking, gastric resistance, acid resistance, sustained release or bioavailability enhancement, based upon type of coating polymer [6]. Gelucires are saturated polyglycolized glycerides; they are characterized by their melting points and HLB values [7]. PrecirolR ATO5 is glyceryl palmitostearate; it has been used in oral solid dosage forms as a lubricant [8 10] and lipophilic matrix for sustained release tablet and capsule formulations [10,11,12,13]. Sustained release tablet formulations containing PrecirolR ATO5 may be prepared either by granulation or by the hot-melt technique. The main objective of this study was to investigate possibility of using waxes (PrecirolR ATO5 and GelucireR 50/02) as coating films on propranolol hydrochloride pellets using

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hot-melt coating technique in a fluidized-bed processor and to evaluate their release characteristics.

2. Materials Saturated polyglycolysed glycerides (GelucireR 50/02, lot number 14547, Gattefosse, France) and glycerol palmitostearate (PrecirolR ATO5, lot number A16141, Gattefosse) were used as coating waxes. Propranolol hydrochloride (PPNL), (lot number 940926, Marsing, Denmark) and microcrystalline cellulose (AvicelR PH101, lot number 1592, Asahi Chemical, Japan) were used as a model drug and a spheronization enhancer, respectively. All other chemicals were of laboratory or reagent grade.

3. Method 3.1. Preparation of PPNL pellets PPNL pellets were prepared in a rotary fluidized-bed granulator (Glatt GPCG1). A 1-kg batch consisting of 400 g of PPNL and 600 g of AvicelR PH101 was loaded into the rotary granulator equipped with a grooved plate. Distilled water was sprayed into the powder bed to enhance agglomeration of the powder. The pellets were allowed to grow to the desired size and subsequently predried and then dried at the temperature of 40 45 jC. The pellets were coated with molten wax in a top spray fluidized-bed coater (Glatt GPCG1). The coating wax systems used in this study were Precirol ATO5 (ATO) and the mixtures of ATO and Gelucire 50/02 (G) at the

Fig. 2. Scanning electron photomicrographs of uncoated pellets.

ratios of 9.5:0.5 and 7:3. A 700-g batch of 16:18 mesh pellets was loaded into the top spray coater and coated with each coating formulation to 35%, 40% and 50% weight increases. 3.2. Evaluations of PPNL pellets 3.2.1. Physical characteristics Size determination was carried out using sieve analysis method. Approximately 200 g of pellets was placed into a sieve shaker equipped with 8-, 12-, 16-, 18-, 20-, 30- and 40-mesh US standard sieves (RetschR Model AS200 Digit, Germany) and shaken for 20 min. Each weight fraction was recorded. The mean size and size distribution were determined. Shape, surface morphology and cross-sectional view of the gold-treated pellets were photographed using a scanning electron microscope (Jeol Model JSM-35CF, Japan). 3.2.2. Determination of PPNL content An accurately weighed portion of pellets, equivalent to about 80 mg of PPNL, was dissolved in absolute methanol, filtered and adjusted to the desired concentration. The UV absorbance of the solution was determined at 289 nm. The percent drug content was calculated.

Fig. 1. Size distribution of uncoated pellets.

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3.2.3. Determination of drug release from the pellets An automated dissolution setup comprised a dissolution apparatus, a six-channel peristaltic pump, a UV/visible spectrophotometer equipped with six 1-cm quartz flow cells. For both uncoated and coated pellets, the dissolution test method followed that of PPNL Extended Release Capsules USP 24. 3.3. Differential scanning calorimetric study Differential scanning calorimetric (DSC) study was conducted for PPNL, ATO, G, melted mixtures of ATO and G at the ratios of 7:3 and 9.5:0.5 and the mixtures of PPNL and each wax at the ratio of 1:1, using Perkin-Elmer DSC 7 instrument calibrated with indium. Nitrogen was used as a carrier gas at a flow rate of 50 ml/min. The heating rate was set at 10 jC/min. Peak temperatures were determined. The thermograms of samples were recorded.

4. Results and discussion 4.1. Preparation of PPNL pellets Hot-melt coating has been adopted because it is faster and cheaper than the conventional coating techniques where

Fig. 4. Scanning electron photomicrographs of surface of PPNL pellets. Key: (A) uncoated; (B) 10% coated; (C) 35% coated.

Fig. 3. Scanning electron photomicrographs of hot-melt-coated pellets.

evaporation and/or recovery of solvent can be expensive, tedious and time consuming. The top spray fluidized-bed coater is recommended for this purpose because of its ability to operate at the production temperature close to the congealing temperature of the molten mass, which is essential for producing a continuous coating on the particles. In addition, this coating technique enhances stability and provides taste masking and sustained release characteristics to the pellets [14]. In this study, pellets containing PPNL, a highly watersoluble drug, were prepared by direct pelletization using a rotary fluidized-bed granulator equipped with grooved disc. Microcrystalline cellulose was used as filler because of its spheronization-enhancing property [15]. Both core and hotmelt-coated pellets were successfully prepared.

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Fig. 5. Cross-section of hot-melt-coated pellets.

4.2. Evaluation of PPNL pellets 4.2.1. Physical characteristics The size distribution of the uncoated pellets is shown in Fig. 1. Sieve analysis revealed that 86% of the pellets was in a size range of 1000 1680 Am, with the highest proportion of 56% in a range of 1000 1190 Am. The average diameter of the core pellets was approximately 1 mm. The uncoated pellet as shown in Fig. 2 appeared to possess spherical shape and smooth surface. Fig. 3 shows the shape and surface of the coated pellets. It could be seen that the coated pellets were not so spherical as the uncoated ones. It could be due to premature solidification of some molten wax droplets and nonuniform coating pattern of top spray coater [5]. However, the surface roughness appeared to diminish with the application of coating wax (Fig. 4). Cross-sectional view of the pellets is shown in Fig. 5. 4.2.2. Determination of PPNL contents PPNL contents in uncoated and coated pellets were determined by using UV spectrophotometer. Table 1 shows that the content in any preparation was in a range of 99.1%
Table 1 Contents of PPNL in uncoated and coated pellets % wax coat Uncoated ATO 35 (33.0) 40 (40.6) 45 (45.3) ATO/G (9.5:0.5) 35 (32.9) 40 (38.0) 45 (45.7) ATO/G (7:3) 35 (32.2) 40 (38.1) 45 (44.8) Pellet weight (mg) 200.0 270.0 280.0 290.0 270.0 280.0 290.0 270.0 280.0 290.0 Drug content of pellet (mg) 79.6 80.8 79.3 79.4 80.9 80.1 79.2 81.3 80.7 79.7 % labeled amount 99.5 101.0 99.1 99.3 101.1 100.9 99.0 101.6 100.9 99.6

Fig. 6. Dissolution profiles of PPNL from pellets coated with ATO.

and 101.6%. The results implied that direct pelletization could produce the pellets with good reproducibility of drug content. 4.2.3. Dissolution of PPNL pellets The release of PPNL from the uncoated PPNL pellets was quite rapid. More than 90% of drug release was achieved at 20 min, and the drug release was markedly decreased with the increase in the amount of lipophilic coat, ATO (Fig. 6). With 45% ATO, only 25% drug release was obtained at 12 h. The results indicated that ATO could significantly retard the release of water-soluble drug. The addition of G, which is a hydrophilic carrier to ATO could increase the drug release at any coat thickness (Fig. 7). Since G can disperse in water, small pores would be created as G dispersed or dissolved away from the pellets, the drug release would be enhanced with the increase in G proportion.

% Wax coat in parentheses represents the actual percentage of wax coat.

Fig. 7. Dissolution profiles of PPNL from pellets coated with ATO/G at 9.5:0.5 (open) and 7:3 (closed).

N. Sinchaipanid et al. / Powder Technology 141 (2004) 203209 Table 2 Coefficients of determination of linear regression analyses of various mathematical models % wax coat Zero order ATO 35 0.8234 40 0.8205 45 0.8459 ATO/G (9.5:0.5) 35 0.7251 40 0.6451 45 0.7293 ATO/G (7:3) 35 0.5138 40 0.6596 45 0.6403 First order Higuchi Hixson Crowell Weibull ln(m/m0)= k(tti) [17] 0.9466 0.8707 0.8446 0.8640 0.7326 0.7333 0.7962 0.9032 0.7742 0.9392 0.8677 0.8676 0.8774 0.7319 0.7899 0.6875 0.8054 0.7296

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0.6551 0.9393 0.5844 0.9209 0.5844 0.9359 0.5406 0.8815 0.4354 0.8230 0.4431 0.8721 0.4779 0.7368 0.6420 0.8515 0.5186 0.8250

0.9049 0.8525 0.8605 0.8290 0.7026 0.7698 0.6264 0.7577 0.6995

The dissolution profiles of all coated pellets prepared under these experimental conditions indicated that the drug release did not follow neither one of the conventional proposed models, e.g., first order, zero order and Higuchis model. The initial fast release could be due to both dissolution and diffusion from the surface and outer zone of the pellets. As the drug in the outer zone was depleted, the drug particles in the inner area diffused through the coated film at slower rate. In an attempt to describe the kinetics of drug release, several mathematical models were used to express the drug release [16]. Neither one of the conventional model could provide good coefficient of determination of linear regression analysis. Table 2 illustrates the coefficients of determination obtained from various mathematical analyses. However, the plots of log of % PPNL dissolved vs. the reciprocal of time yielded straight

Fig. 9. Log of % dissolved from pellets coated with ATO/G (9.5:0.5).

lines as shown in Figs. 8 10. From the plots, a general form of equation could be written as follows: D t D a e k = t 1 where Dt and Da are concentrations of drug dissolved at time t and at infinity, respectively, and k is a constant. k 2 ln Dt ln Da t or k 3 logDt logDa 2:303t The linear regression analysis of these lines gave the parameters shown in Table 3. It is of interest to note that the

Fig. 8. Log of % dissolved from pellets coated with ATO vs. the reciprocal of time.

Fig. 10. Log of % dissolved from pellets coated with ATO/G (7:3) vs. the reciprocal of time.

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Table 3 Linear regression analysis of log (% drug dissolved of coated pellets) vs. reciprocal of time % wax coat ATO 35 40 45 ATO/G (9.5:0.5) 35 40 45 ATO/G (7:3) 35 40 45 Intercept 1.968 1.818 1.512 1.979 1.910 1.844 1.972 1.901 1.819 Slope 0.7953 1.0524 1.1458 0.6742 0.7679 1.0058 0.3418 0.4329 0.5423 R2 0.9995 0.9950 0.9864 0.9907 0.9718 0.9776 0.9659 0.9875 0.9715 k 1.83 2.42 2.64 1.55 1.77 2.32 0.79 1.00 1.25

pellets coated with 35% ATO gave the best straight line (R2=0.9995), and these pellets exhibited the dissolution profile similar to the USP requirements for extended propranolol hydrochloride pellets. By using Eq. (3), k for each coated pellet preparation could be calculated and found to be 1.83, 2.42 and 2.64 h for ATO coated to the desired levels of 35%, 40% and 45%, respectively. The k value could be designated as a diffusive resistance constant, which implied that the larger the k value, the less drug release resulted. To illustrate a relation between the k values and the amount of coat, the actual amount of coating material used was determined for each coating condition. The actual amount of coating material could be calculated from the following equation: % wax coat Wb Da =Wa Db 1 100 4

Fig. 12. DSC thermograms of PPNL, ATO, G and the mixtures of PPNL and waxes at 1:1 ratio. Key: (A) PPNL; (B) ATO; (C) G; (D) ATO/G (7:3); (E) PPNL-ATO/G (7:3); (F) PPNL-ATO/G (9.5:0.5).

the labeled amount. All these numbers are given in Table 1. It was found that k linearly increased with the amount of coat (Fig. 11). The findings indicated that the thicker the wax coat, the larger was the k value, resulting in the decrease in the drug release. 4.3. Differential scanning calorimetric study The DSC thermograms of the single materials and mixtures are shown in Fig. 12. The melting points of PPNL, ATO and G were found to be about 162, 53 and 50 jC, respectively. Similar scans were conducted for the mixture of PPNL with ATO and G. It could be seen that no interaction between drug and wax existed.

where Wa and Wb are theoretical weights of core and coated pellets containing the desired amount of drug, respectively, and Da and Db are percentages of the drug with respect to

5. Conclusions Propranolol pellets were successfully prepared by direct pelletization process using a fluidized-bed rotogranulator equipped with grooved plate. The pellets prepared by this mean were spherical in shape and had relatively smooth surface. A narrow particle size distribution was achieved. The propranolol pellets were coated with wax using hot-melt coating technique in a fluidized-bed top spray coater and proven to be successful. Hot-melt coating technique presents a faster and cheaper alternative compared to conventional coating methods where solvent evaporation and recovery could become very expensive and time consuming.

Fig. 11. Relationship between k and % actual coating level.

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Dissolution study on the coated propranolol pellets showed that the release rate could be controlled using appropriate coating materials, i.e., PrecirolR ATO5 and GelucrieR 50/02. The dissolution rate can be regulated by varying the composition of the waxes as well as the thickness of the coat. Linear relationship was obtained with a semilog plot of % PPNL dissolved and reciprocal of time. The k value derived from the slope of this plot was linearly increased with the coating level.

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