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Granulation and tabletization of pharmaceutical lactose granules prepared by a top-sprayed fluidized bed granulator
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Journal of Industrial and Engineering Chemistry 14 (2008) 661–666 www.elsevier.com/locate/jiec
Granulation and tabletization of pharmaceutical lactose granules prepared by a top-sprayed fluidized bed granulator Tawatchai Charinpanitkul a,*, Wiwut Tanthapanichakoon b , Poj Kulvanich c, Kyo-Seon Kim d a
Center of Excellence in Particle Technology, Department of Chemical Engineering, Faculty of Engineering, Chulalongkorn University, Bangkok 10330, Thailand b National Nanotechnology Center, National Science and Technology Development Agency, Klong Luang, Phathumthani 12120, Thailand c Department of Industrial Pharmacy, Faculty of Pharmacy, Chulalongkorn University, Bangkok 10330, Thailand d Department of Chemical Engineering, Faculty of Engineering, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea Received 12 January 2008; accepted 25 March 2008
Abstract Influence of fluidizing air velocity, temperature and atomizing air pressure, as well as types of raw materials on the size distribution, shape and flow properties of pharmaceutical granules, which were tabletized using a single punch tableting machine, was experimentally investigated. The granules prepared at the fluidizing air velocity of 0.8 m/s had average particle size larger than those obtained at higher air velocity. Meanwhile the fluidizing air temperature had moderate effect on the average particle size of the granules. However, an increase in the atomizing air pressure resulted in an increase in amount of fine particles, leading to the smaller mean particle size. From microscopic analysis, a primary lactose particle wetted by binder had several contact points with other particles inside the prepared granules. Based on granule morphology, it can be implied that the granules are formed by the so-called snowballing mechanism, leading to the relatively spherical structure. In tabletization, the granules with higher average particle size provided tablets with the less weight variation and friability. Meanwhile, the tablets produced from lactose–corn starch mixture had shorter disintegration time than those of lactose powder only. # 2008 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved. Keywords: Fluidized bed; Lactose; Granule; Tablet; Pharmaceutical
1. Introduction Fluidized bed is important equipment employed in very wide ranges of applications in biochemical, chemical, electronic and pharmaceutical industries [1–3,6–8]. Advantages of this technique are providing good heat and mass transfer as well as good mixing. Especially for powder handling and pharmaceutical processes, fluidization plays a crucial role in granulation or particle size enlargement. Generally, small particles have low flowability and low bulk density then they become easy to disperse [4,5]. To improve such flow properties of fine powder by increasing its size is known as granulation process. Granulation is classified into dry and wet processes. For dry granulation, the particles are agglomerated using compressing
* Corresponding author. Fax: +66 2 218 6499. E-mail address: [email protected] (T. Charinpanitkul).
force. On the other hand, in wet granulation bonding force owing to some certain binders holds the particles together. Then successful wet granulation cannot be achieved without good mixing of particles and binder solution. The granulation process applying fluidized bed technology is recognized as the fluidized bed granulation. Scott et al. [11] is among the first pioneer studying and developing a fluidized bed granulator using modification of a fluidized bed dryer [11]. They reported that in this granulation technique there are many parameters affecting properties of granules produced. Rankell et al. investigated the effects of process variables of batch and continuous fluidized bed granulators (i.e. powder feed rate, binder feed rate, inlet air temperature and nozzle position) on physical properties of granules produced [10]. Accordingly the operating parameters of fluidized bed granulation parameters could be classified into apparatus parameters, process parameters and product parameters [7]. Aulton and Banks [2] reported influence of atomizing air pressure, nozzle type and position of nozzle on physical properties of granules [2]. They
1226-086X/$ – see front matter # 2008 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jiec.2008.03.005
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found that using higher feed rate of liquid binder would result in the larger average size of granules. In 1994, Merkku et al. studied the effect of granulation process parameters on physical properties of tablets prepared from granules [9]. It was found that binder-atomizing pressure had a significant effect of the friability and dissociation rate of the tablets produced. Wan et al. [15] examined the influence of types of polyvinylpyrrolidine (PVP K25, K29-32 and K90) on properties of granules produced by fluidized bed granulator [15]. They reported that applying the binder with higher viscosity would provide the granules of larger average size. However, the relationship among the granule and tablets prepared from the granules has not been clearly reported. In this work, we set our objective to examine the influences of operating parameters which are fluidizing air velocity, fluidizing air temperature, atomizing air pressure and type of raw-material on physical properties of granules produced. Then the granules were tabletized, and examined their physical properties by investigating the tablet disintegration performance. 2. Design and experimental procedures General design procedure for a fluidized bed granulator as suggested by Kunii and Levenspiel was employed [8]. To avoid the elutriation of fine particles smaller than 50 mm, a taper shaped column was developed to reduce the superficial velocity at the upper zone. Fluidizing air supplied from a blower was heated by a set of controlled electrical heater before entering the column. A two-fluid spray nozzle was employed for atomizing liquid binder solution using compressed air. The set of top-sprayed fluidized bed granulator developed in this work is schematically illustrated in Fig. 1. In general, lactose and lactose with corn starch are used for pharmaceutical applications. Accordingly, raw materials used to prepare the granules in this work were lactose monohydrate with nominal size of 200 mesh (Wyndale, New Zealand) and corn starch (Amylum, Netherlands). Binder was polyvinyl-
pyrrolidine (PVP) type K30, and anti-cohesive material was Cab–O–Sil (colloidal silicon dioxide), while magnesium stearate (C36H70MgO4) and talc were used as lubricant in tablet preparation. Formulations of raw powder employed for batch granulation operations were as follows; Formula 1, lactose 500 g with Cab–O–Sil 2.5 g; Formula 2, lactose 350 g with corn starch 150 g and Cab–O–Sil 2.5 g. Granulation was regularly performed using 500 g of the lactose powder or lactose–corn starch powder mixture. Cab–O–Sil 0.5% (w/w) as well as magnesium stearate and talc was added and mixed using a micro-V-shaped mixer (Tsutsui Scientific Instruments, Japan) for 10 min. The process parameters accounted in this work were as follows, fluidizing air velocity: 0.8–1.2 m/s, fluidizing air temperature: 70 and 80 8C and atomizing air pressure: 0.5 and 1.0 bar. A binder solution of 5% concentration (w/w) with a fixed volume of 100 ml was atomized into a bed of lactose or lactose– corn starch powder in the fluidized bed granulator. The binder solution prepared freshly in every experiment was sprayed for 10 s and then the spraying was stopped for 20 s. The spraying was repeated until the binder was completely used. The granules were fluidized further for drying for 10 min before taken to examine their properties as follows: (a) Granule size analysis: Average size and size distribution of granules were determined using the sieve shaker (Tsutsui scientific instruments, Japan) with standard sieve series of 53, 106, 250, 500 and 1000 mm. In each batch, 100 g of the granules were sifted for 10 min. To determine the granule size distribution, log–normal plot with weight basis was carried out and then evaluation of the geometric mean of the particle size of the granules as well as its variance was performed. (b) Morphology: Morphology of the granules sampled from each cut size was examined using scanning electron microphotography (SEM, JEOL JSM 5800). (c) Flowability and floodability evaluation: Physical properties of granules, which are angle of repose, aerated bulk density, packed bulk density, compressibility, dispersibility, flowability index and floodability index, were analyzed using Powder Characteristic Tester (Hozokawa Micron, Japan). Each sample was screened by a sieve to the size smaller than 1000 mm before the examination. 3. Tabletization process Three hundred grams of the prepared granules was mixed with magnesium stearate 3% (w/w) and Talc 1% (w/w) using a V-shaped mixer. Then the granulated mixture was compressed into tablet form by a single punch-tableting machine developed by Faculty of Pharmacy, Chulalongkorn University. The tablets produced were taken to examine as follows:
Fig. 1. Schematic diagram of the fluidized bed granulator developed in this work: (1) Blower, (2) Orifice plate, (3) Manometer, (4) Heater, (5) Distributor plate, (6) Binary nozzle, (7) Peristaltic pump, (8) Air compressor, (9) Bag filter, (10) Ball valve, and (11) Fluidized bed chamber.
(a) Weight variation: Twenty tablets were sampled and weighed using an electrical balance with accuracy of 1 mg. The data was analyzed statistically for determining the average, maximum and minimum weights of the tablets.
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Table 1 Size distribution of lactose granules. Ug (m/s)/T (8C)/P (bar)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
Percent retain on screen
Geometric mean
26.5 mm
79.5 mm
178 mm
375 mm
750 mm
Size (mm)
40.76 46.92 49.72 44.48 49.77 52.34 47.06 49.35 56.48
10.53 10.77 11.82 12.37 11.36 11.35 16.24 17.14 18.43
24.36 21.01 17.20 21.19 17.33 14.84 23.66 21.04 12.32
16.72 14.20 14.54 14.14 14.01 14.17 7.03 6.67 7.37
7.62 7.10 6.72 7.83 7.53 7.31 6.00 5.79 5.41
95.1 82.2 77.1 85.9 77.9 74.0 73.2 69.2 59.8
(b) Hardness: Twenty tablets were randomly sampled from each production batch and taken to measure the hardness using a hardness tester (THB 30, ERWEKA, USA). (c) Friability: Similarly, 20 tablets from each batch were sampled and cleaned using a brush. The tablets were taken to spin for 4 min using a tablet shaker (Erweka TAP, ERWEKA, USA), which was vibrated with a constant frequency of 25 rpm. Weight of each tablet before and after spinning was recorded for analysis of the friability (wt.% loss). (d) Disintegration time: Six tablets were sampled from each batch and then loaded into a disintegration time tester (Erweka ZT31, ERWEKA, USA) for determining the disintegration time. The arithmetic mean represents the characteristic disintegration times of tablets of each batch. 4. Results and discussion 4.1. Effect of fluidizing air on the size distribution of the granules produced Size distribution of each batch of lactose as well as lactose– corn starch granules is summarized in Tables 1 and 2. An increase in fluidizing air velocity results in the increasing amount of fine particles, leading to the smaller average particle size. This is attributed to two factors: first, the increasing evaporation rate of binder droplets and secondly the promoted attrition of granules due to turbulence induced by higher airflow rate. Considering the granule formation, the binder droplets come to contact with small seed particles and then hold them to
form granules. Therefore the droplet with smaller size could collect less small particles, resulting in the smaller granules produced. Also from experiments, it could be clearly observed that the most rigorous dispersion of fluidized granules took place at the air velocity of 1.2 m/s. After the completion of each batch, it was found that there were many fine particles remaining at the column wall and the bag filter. Aulton and Banks [2] also reported the similar trend of reduction of granules’ size with the increasing air velocity [2]. The experimental results also reveal that fluidizing air temperature moderately exerted an effect on the size and moisture of the granules produced. At low air temperature (60 8C or lower) the granules exhibited larger average size, leading to the caking of fine particles on the column wall and the formation of particle lump above the distributor. This phenomenon results in the failure of fluidization. On the other hand, it was also found that the fluidizing air temperature of 80 8C resulted in the particle clogging in the column due to fast drying of particle agglomerates [2]. 4.2. Effect on the size distribution of the granules produced It was found that atomizing air pressure exerted a remarkable influence on the droplet size. The increasing atomizing pressure leaded to a decrease in the droplet size, resulting in the decreasing granules size since the rapid reduction of droplet-particle collision [6]. It should be noted that the higher atomizing pressure would disturb the fluidized particle bed, leading to the more rigorous drifting of fine
Table 2 Size distribution of lactose–corn starch granules. Ug (m/s)/T (8C)/P (bar)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
Percent retain on screen
Geometric mean
26.5 mm
79.5 mm
178 mm
375 mm
750 mm
Size (mm)
33.72 50.85 54.53 43.07 50.71 54.67 41.09 51.65 57.16
18.45 14.78 15.27 17.20 17.00 18.78 26.56 20.45 19.09
29.90 20.27 16.21 23.96 19.31 16.92 21.41 17.09 14.73
11.34 8.58 7.81 9.20 7.15 5.28 6.25 5.83 5.02
6.59 5.52 6.17 6.58 5.83 4.35 4.69 4.99 4.01
96.6 69.2 64.5 80.3 67.8 59.8 73.6 63.3 56.5
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Fig. 2. Morphology of lactose granules: (a) 0–53 mm (1700), (b) 106–250 mm (400), (c) 250–500 mm (170), and (d) 850–1000 mm (65).
particles. Its effect was similar to the increasing in fluidizing air velocity. The granules produced had a wider size distribution, which consisted of a larger fraction of fine seed particles of lactose or corn starch. 4.3. Effect on the granule morphology So far, there are several models of granulation mechanisms employed for explaining the formation of granules [1,7–12].
First, the primary particles (nuclei) come to contact with the binder droplet and then collide with other wetted particles to form granules with increasing size. This mechanism will lead to a comparatively low rate of granule growth. The granules produced by this mechanism usually have comparatively round morphology due to the random collision of seed particles. On the other hand, the agglomeration of small granules themselves would result in very fast growing granules to form larger granules with highly irregular shape. With this mechanism, a control of
Fig. 3. Morphology of lactose–corn starch granules: (a) 106–250 mm (600), (b) 180–250 mm (330), (c) 355–500 mm (130), and (d) 850–1000 mm (60).
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Table 3 Physical properties of lactose granules. Ug (m/s)/T (8C)/P (bar)
Angle of repose (8)
Packed bulk density (kg/dm3)
Compressibility (%)
Dispersibility (%)
Flowability index
Floodability index
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
38.5 40.3 43.3 40.3 41.2 42.9 43.1 43.1 43.4
0.877 0.894 0.908 0.873 0.901 0.914 0.906 0.905 0.916
24.6 27.9 31.0 24.8 29.5 31.8 30.4 32.6 34.0
24.6 38.9 42.0 26.3 53.4 55.7 48.0 57.7 55.4
52.0 48.5 45.0 51.5 48.0 44.5 50.0 47.0 47.0
75.5 83.0 84.0 75.0 85.0 87.5 86.0 89.0 89.0
Table 4 Physical properties of lactose–corn starch granules. Ug (m/s)/T (8C)/P (bar)
Angle of repose (8)
Packed bulk density (kg/dm3)
Compressibility (%)
Dispersibility (%)
Flowability index
Floodability index
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
39.2 40.7 43.5 39.8 42.4 44.4 40.7 42.5 44.5
0.872 0.880 0.907 0.871 0.881 0.912 0.877 0.900 0.917
28.1 29.2 32.1 28.4 29.6 32.3 30.5 32.6 35.7
63.2 65.4 72.6 63.4 66.5 77.6 65.3 76.5 75.2
51.5 48.0 45.0 51.0 47.0 44.5 48.0 44.5 42.0
90.0 91.0 89.0 91.0 91.0 91.5 91.0 91.5 90.0
fluidizing air velocity will play a crucial role in determining the granule size. As shown in Figs. 2 and 3, the morphology of granules produced from lactose seed particles is remarkably different from that of lactose–corn starch powder. The granules produced from mixed powder of lactose and corn starch have relatively round morphology in comparison with those of the pure lactose granules. It could clearly be observed that a primary lactose particle wetted by binder had several contact points with other particles inside the prepared granules. Especially in Fig. 3, there were many smaller corn starch particles filling up the outer vacancy among coarse lactose particles, resulting in the comparatively spherical granules. Additionally, closer consideration of the morphology of all granules shown in either Figs. 2 and 3, it is reasonably implied that the granules are formed by accumulation of primary particles which are rolled and blended by the fluidizing air within the column. Formation of prepared granule is known as the so-called snowballing mechanism, attributed to the relatively spherical structure [7–9]. 4.4. Effect on the granule flow behavior In order to investigate effect of operating conditions on the granule flow behavior, particle flowability and floodability are employed. Carr has proposed the concept of flowability and floodability of particulate materials using various experimental parameters including angle of repose, aerated and packed bulk densities, and uniformity [12]. With high flowability, particles tend to flow without formation of arc bridging while high floodability, which is related to other parameters (angle of
collapse and dispersibility), would provide information of particle flushing tendency. Particles with sufficiently high flowability and floodability would be easy to handle, resulting in uniform bulk properties. Based on our experimental results, the flow properties of the lactose and lactose–corn starch granules produced are summarized in Tables 3 and 4. The increasing air velocity led to an increase in angle of repose, packed bulk density, compressibility and dispersibility, resulting in the decreasing flowability of the granules. It should be noted that the flowability depends on the particle size, its distribution and morphology [12–14]. The granules with highly irregular morphology as shown in Fig. 2 could easily undergo interlocking among particles. The elevated fluidizing air velocity was accounted for the increasing fraction of small granules and irregularity of the granules. Therefore, it was found that the flowability of the granules decreased with the increasing air velocity. However, because of the increasing fine fraction, the granules became more floodable, which could be seen from the increasing floodability index. It was also found that the increasing air temperature and atomizing air pressure had the similar influence on the flow behavior of the granules prepared from either lactose or lactose–corn starch powder. 4.5. Tabletization results Physical properties of tablets produced from the granules are concluded in Tables 5 and 6. The experimental results reveal that the tablets can be compressed to gain high hardness without capping. Weight variation of tablets depended on the
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Table 5 Physical properties of lactose tablets. Ug (m/s)/T (8C)/P (bar)
Hardness (kp)
Weight of tablets (mg)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
7.99 8.05 8.45 7.99 8.05 8.39 7.31 8.10 8.61
331.05 343.65 332.80 312.05 344.55 337.90 331.8 381.8 347.3
Weight variation 2.43 2.70 4.85 5.34 5.95 6.97 2.90 3.68 5.09 5.35 6.78 4.47 2.95 4.88 5.72 5.02 5.27 5.67
Friability (%)
Disintegration time (s)
0.42 0.49 0.46 0.47 0.48 0.59 0.67 0.59 0.41
380 412 190 351 342 168 170 336 758
Friability (%)
Disintegration time (s)
0.32 0.50 0.57 0.41 0.48 0.43 0.54 0.55 0.64
91 73 60 86 81 74 80 79 81
Table 6 Physical properties of lactose–corn starch tablets. Ug (m/s)/T (8C)/P (bar)
Hardness (kp)
Weight of tablets (mg)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
8.64 8.16 7.97 8.56 8.14 8.22 8.66 8.16 7.69
346.55 354.85 362.95 339.55 355.50 356.10 350.65 372.85 358.90
flowability of the granules. The tablets had low weight variation when the granules exerted good flow behavior or high flowability index. Lactose–corn starch tablets had remarkably higher weight variation than that of lactose tablets because the lactose–corn starch granules contained higher quantity of small particle as shown in Fig. 3. The small particles could stick on surface of die in tabletization process [15]. Friability and disintegration time of tablets were found to rely on the hardness of tablets. Accordingly, tablets prepared from lactose–corn starch powder had 2.5–9 times shorter disintegration time than that of lactose tablets. This is attributed to the hardness of the tablets and a fact that corn starch itself is disintegrate material. 5. Conclusion The fluidized bed granulator developed could be employed to produce granules of lactose and lactose–corn starch powder with controllable bulk density and improved flowability. The fluidizing air velocity and atomizing air pressure could remarkably affect the physical properties of the granules produced while the fluidizing air temperature has less effect. The experimental results reveal that the granules prepared at the fluidizing air velocity of 0.8 m/s had the highest average particle size. Addition of corn starch could lead to the remarkable decrease in the granule average size and flowability. The pharmaceutical tablets produced from the lactose granules had sufficiently high hardness without capping. The weight variation of the tablets relied strongly upon the size distribution and flowability of the granules. Tablet friability and disintegration time depended on its hardness as well as particulate constituent. The lactose–corn starch tablets had 2.5–9 times shorter disintegration time than that of lactose tablets.
Weight variation 5.06 3.59 6.16 5.68 6.60 6.63 5.76 5.43 6.33 2.67 6.21 7.27 5.89 5.80 6.40 4.87 6.10 3.65
Acknowledgements This work is supported by the Silver Jubilee Foundation of Chulalongkorn University. K. Phattanathong is gratefully acknowledged for his experimental support. K.S.K. also acknowledges support from the Ministry of Education and Human Resources Development (MOE) and the Ministry of Commerce, Industry and Energy (MOCIE) through the fostering project of the Industrial-Academic Cooperation Centered University.
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M.H. Alkan, A. Yuksel, Drug Dev. Ind. Pharm. 12 (10) (1986) 1529. M.E. Aulton, M. Banks, Int. J. Pharm. Tech. Prod. Manuf. 2 (4) (1981) 50. W.L. Davies, W.T. Gloor Jr., J. Pharm. Sci. 61 (4) (1972) 618. E.H. Hwang, Y.S. Ko, J.K. Jeon, J. Ind. Eng. Chem. 13 (3) (2007) 387. L. Juslin, J. Ylirusi, STP Pharma Sci. 6 (5) (1996) 328. L. Kangwen, E.P. Gernet, Drug Dev. Ind. Pharm. 21 (4) (1995) 447. H. Kokubo, S. Nakamura, H. Sanada, Chem. Pharm. Bull. 43 (8) (1995) 1402. D. Kunii, O. Levenspiel, Fluidization Engineering, Butterworth, Boston, 1991. P. Merkku, A.S. Lindqvist, K. Leiviska, J. Yliruusi, Int. J. Pharm. 102 (1994) 117. A.S. Rankell, M.W. Scott, H.A. Lieberman, F.S. Chow, J.V. Battista, J. Pharm. Sci. 53 (3) (1964) 320. M.W. Scott, H.A. Lieberman, A.S. Rankell, J.V. Battista, J. Pharm. Sci. 53 (3) (1964) 314. R.L. Carr, Chem. Eng. 72 (1965) 163. H. See, J. Ind. Eng. Chem. 10 (2004) 1132. J.H. Sung, D.P. Park, B.J. Park, H.J. Choi, J. Ind. Eng. Chem. 12 (20) (2006) 301. L.S.C. Wan, P.W.S. Heng, B.L. Ling, Int. J. Pharm. 141 (1996) 161.
Journal of Industrial and Engineering Chemistry 14 (2008) 661–666 www.elsevier.com/locate/jiec
Granulation and tabletization of pharmaceutical lactose granules prepared by a top-sprayed fluidized bed granulator Tawatchai Charinpanitkul a,*, Wiwut Tanthapanichakoon b , Poj Kulvanich c, Kyo-Seon Kim d a
Center of Excellence in Particle Technology, Department of Chemical Engineering, Faculty of Engineering, Chulalongkorn University, Bangkok 10330, Thailand b National Nanotechnology Center, National Science and Technology Development Agency, Klong Luang, Phathumthani 12120, Thailand c Department of Industrial Pharmacy, Faculty of Pharmacy, Chulalongkorn University, Bangkok 10330, Thailand d Department of Chemical Engineering, Faculty of Engineering, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea Received 12 January 2008; accepted 25 March 2008
Abstract Influence of fluidizing air velocity, temperature and atomizing air pressure, as well as types of raw materials on the size distribution, shape and flow properties of pharmaceutical granules, which were tabletized using a single punch tableting machine, was experimentally investigated. The granules prepared at the fluidizing air velocity of 0.8 m/s had average particle size larger than those obtained at higher air velocity. Meanwhile the fluidizing air temperature had moderate effect on the average particle size of the granules. However, an increase in the atomizing air pressure resulted in an increase in amount of fine particles, leading to the smaller mean particle size. From microscopic analysis, a primary lactose particle wetted by binder had several contact points with other particles inside the prepared granules. Based on granule morphology, it can be implied that the granules are formed by the so-called snowballing mechanism, leading to the relatively spherical structure. In tabletization, the granules with higher average particle size provided tablets with the less weight variation and friability. Meanwhile, the tablets produced from lactose–corn starch mixture had shorter disintegration time than those of lactose powder only. # 2008 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved. Keywords: Fluidized bed; Lactose; Granule; Tablet; Pharmaceutical
1. Introduction Fluidized bed is important equipment employed in very wide ranges of applications in biochemical, chemical, electronic and pharmaceutical industries [1–3,6–8]. Advantages of this technique are providing good heat and mass transfer as well as good mixing. Especially for powder handling and pharmaceutical processes, fluidization plays a crucial role in granulation or particle size enlargement. Generally, small particles have low flowability and low bulk density then they become easy to disperse [4,5]. To improve such flow properties of fine powder by increasing its size is known as granulation process. Granulation is classified into dry and wet processes. For dry granulation, the particles are agglomerated using compressing
* Corresponding author. Fax: +66 2 218 6499. E-mail address: [email protected] (T. Charinpanitkul).
force. On the other hand, in wet granulation bonding force owing to some certain binders holds the particles together. Then successful wet granulation cannot be achieved without good mixing of particles and binder solution. The granulation process applying fluidized bed technology is recognized as the fluidized bed granulation. Scott et al. [11] is among the first pioneer studying and developing a fluidized bed granulator using modification of a fluidized bed dryer [11]. They reported that in this granulation technique there are many parameters affecting properties of granules produced. Rankell et al. investigated the effects of process variables of batch and continuous fluidized bed granulators (i.e. powder feed rate, binder feed rate, inlet air temperature and nozzle position) on physical properties of granules produced [10]. Accordingly the operating parameters of fluidized bed granulation parameters could be classified into apparatus parameters, process parameters and product parameters [7]. Aulton and Banks [2] reported influence of atomizing air pressure, nozzle type and position of nozzle on physical properties of granules [2]. They
1226-086X/$ – see front matter # 2008 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jiec.2008.03.005
662
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found that using higher feed rate of liquid binder would result in the larger average size of granules. In 1994, Merkku et al. studied the effect of granulation process parameters on physical properties of tablets prepared from granules [9]. It was found that binder-atomizing pressure had a significant effect of the friability and dissociation rate of the tablets produced. Wan et al. [15] examined the influence of types of polyvinylpyrrolidine (PVP K25, K29-32 and K90) on properties of granules produced by fluidized bed granulator [15]. They reported that applying the binder with higher viscosity would provide the granules of larger average size. However, the relationship among the granule and tablets prepared from the granules has not been clearly reported. In this work, we set our objective to examine the influences of operating parameters which are fluidizing air velocity, fluidizing air temperature, atomizing air pressure and type of raw-material on physical properties of granules produced. Then the granules were tabletized, and examined their physical properties by investigating the tablet disintegration performance. 2. Design and experimental procedures General design procedure for a fluidized bed granulator as suggested by Kunii and Levenspiel was employed [8]. To avoid the elutriation of fine particles smaller than 50 mm, a taper shaped column was developed to reduce the superficial velocity at the upper zone. Fluidizing air supplied from a blower was heated by a set of controlled electrical heater before entering the column. A two-fluid spray nozzle was employed for atomizing liquid binder solution using compressed air. The set of top-sprayed fluidized bed granulator developed in this work is schematically illustrated in Fig. 1. In general, lactose and lactose with corn starch are used for pharmaceutical applications. Accordingly, raw materials used to prepare the granules in this work were lactose monohydrate with nominal size of 200 mesh (Wyndale, New Zealand) and corn starch (Amylum, Netherlands). Binder was polyvinyl-
pyrrolidine (PVP) type K30, and anti-cohesive material was Cab–O–Sil (colloidal silicon dioxide), while magnesium stearate (C36H70MgO4) and talc were used as lubricant in tablet preparation. Formulations of raw powder employed for batch granulation operations were as follows; Formula 1, lactose 500 g with Cab–O–Sil 2.5 g; Formula 2, lactose 350 g with corn starch 150 g and Cab–O–Sil 2.5 g. Granulation was regularly performed using 500 g of the lactose powder or lactose–corn starch powder mixture. Cab–O–Sil 0.5% (w/w) as well as magnesium stearate and talc was added and mixed using a micro-V-shaped mixer (Tsutsui Scientific Instruments, Japan) for 10 min. The process parameters accounted in this work were as follows, fluidizing air velocity: 0.8–1.2 m/s, fluidizing air temperature: 70 and 80 8C and atomizing air pressure: 0.5 and 1.0 bar. A binder solution of 5% concentration (w/w) with a fixed volume of 100 ml was atomized into a bed of lactose or lactose– corn starch powder in the fluidized bed granulator. The binder solution prepared freshly in every experiment was sprayed for 10 s and then the spraying was stopped for 20 s. The spraying was repeated until the binder was completely used. The granules were fluidized further for drying for 10 min before taken to examine their properties as follows: (a) Granule size analysis: Average size and size distribution of granules were determined using the sieve shaker (Tsutsui scientific instruments, Japan) with standard sieve series of 53, 106, 250, 500 and 1000 mm. In each batch, 100 g of the granules were sifted for 10 min. To determine the granule size distribution, log–normal plot with weight basis was carried out and then evaluation of the geometric mean of the particle size of the granules as well as its variance was performed. (b) Morphology: Morphology of the granules sampled from each cut size was examined using scanning electron microphotography (SEM, JEOL JSM 5800). (c) Flowability and floodability evaluation: Physical properties of granules, which are angle of repose, aerated bulk density, packed bulk density, compressibility, dispersibility, flowability index and floodability index, were analyzed using Powder Characteristic Tester (Hozokawa Micron, Japan). Each sample was screened by a sieve to the size smaller than 1000 mm before the examination. 3. Tabletization process Three hundred grams of the prepared granules was mixed with magnesium stearate 3% (w/w) and Talc 1% (w/w) using a V-shaped mixer. Then the granulated mixture was compressed into tablet form by a single punch-tableting machine developed by Faculty of Pharmacy, Chulalongkorn University. The tablets produced were taken to examine as follows:
Fig. 1. Schematic diagram of the fluidized bed granulator developed in this work: (1) Blower, (2) Orifice plate, (3) Manometer, (4) Heater, (5) Distributor plate, (6) Binary nozzle, (7) Peristaltic pump, (8) Air compressor, (9) Bag filter, (10) Ball valve, and (11) Fluidized bed chamber.
(a) Weight variation: Twenty tablets were sampled and weighed using an electrical balance with accuracy of 1 mg. The data was analyzed statistically for determining the average, maximum and minimum weights of the tablets.
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Table 1 Size distribution of lactose granules. Ug (m/s)/T (8C)/P (bar)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
Percent retain on screen
Geometric mean
26.5 mm
79.5 mm
178 mm
375 mm
750 mm
Size (mm)
40.76 46.92 49.72 44.48 49.77 52.34 47.06 49.35 56.48
10.53 10.77 11.82 12.37 11.36 11.35 16.24 17.14 18.43
24.36 21.01 17.20 21.19 17.33 14.84 23.66 21.04 12.32
16.72 14.20 14.54 14.14 14.01 14.17 7.03 6.67 7.37
7.62 7.10 6.72 7.83 7.53 7.31 6.00 5.79 5.41
95.1 82.2 77.1 85.9 77.9 74.0 73.2 69.2 59.8
(b) Hardness: Twenty tablets were randomly sampled from each production batch and taken to measure the hardness using a hardness tester (THB 30, ERWEKA, USA). (c) Friability: Similarly, 20 tablets from each batch were sampled and cleaned using a brush. The tablets were taken to spin for 4 min using a tablet shaker (Erweka TAP, ERWEKA, USA), which was vibrated with a constant frequency of 25 rpm. Weight of each tablet before and after spinning was recorded for analysis of the friability (wt.% loss). (d) Disintegration time: Six tablets were sampled from each batch and then loaded into a disintegration time tester (Erweka ZT31, ERWEKA, USA) for determining the disintegration time. The arithmetic mean represents the characteristic disintegration times of tablets of each batch. 4. Results and discussion 4.1. Effect of fluidizing air on the size distribution of the granules produced Size distribution of each batch of lactose as well as lactose– corn starch granules is summarized in Tables 1 and 2. An increase in fluidizing air velocity results in the increasing amount of fine particles, leading to the smaller average particle size. This is attributed to two factors: first, the increasing evaporation rate of binder droplets and secondly the promoted attrition of granules due to turbulence induced by higher airflow rate. Considering the granule formation, the binder droplets come to contact with small seed particles and then hold them to
form granules. Therefore the droplet with smaller size could collect less small particles, resulting in the smaller granules produced. Also from experiments, it could be clearly observed that the most rigorous dispersion of fluidized granules took place at the air velocity of 1.2 m/s. After the completion of each batch, it was found that there were many fine particles remaining at the column wall and the bag filter. Aulton and Banks [2] also reported the similar trend of reduction of granules’ size with the increasing air velocity [2]. The experimental results also reveal that fluidizing air temperature moderately exerted an effect on the size and moisture of the granules produced. At low air temperature (60 8C or lower) the granules exhibited larger average size, leading to the caking of fine particles on the column wall and the formation of particle lump above the distributor. This phenomenon results in the failure of fluidization. On the other hand, it was also found that the fluidizing air temperature of 80 8C resulted in the particle clogging in the column due to fast drying of particle agglomerates [2]. 4.2. Effect on the size distribution of the granules produced It was found that atomizing air pressure exerted a remarkable influence on the droplet size. The increasing atomizing pressure leaded to a decrease in the droplet size, resulting in the decreasing granules size since the rapid reduction of droplet-particle collision [6]. It should be noted that the higher atomizing pressure would disturb the fluidized particle bed, leading to the more rigorous drifting of fine
Table 2 Size distribution of lactose–corn starch granules. Ug (m/s)/T (8C)/P (bar)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
Percent retain on screen
Geometric mean
26.5 mm
79.5 mm
178 mm
375 mm
750 mm
Size (mm)
33.72 50.85 54.53 43.07 50.71 54.67 41.09 51.65 57.16
18.45 14.78 15.27 17.20 17.00 18.78 26.56 20.45 19.09
29.90 20.27 16.21 23.96 19.31 16.92 21.41 17.09 14.73
11.34 8.58 7.81 9.20 7.15 5.28 6.25 5.83 5.02
6.59 5.52 6.17 6.58 5.83 4.35 4.69 4.99 4.01
96.6 69.2 64.5 80.3 67.8 59.8 73.6 63.3 56.5
664
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Fig. 2. Morphology of lactose granules: (a) 0–53 mm (1700), (b) 106–250 mm (400), (c) 250–500 mm (170), and (d) 850–1000 mm (65).
particles. Its effect was similar to the increasing in fluidizing air velocity. The granules produced had a wider size distribution, which consisted of a larger fraction of fine seed particles of lactose or corn starch. 4.3. Effect on the granule morphology So far, there are several models of granulation mechanisms employed for explaining the formation of granules [1,7–12].
First, the primary particles (nuclei) come to contact with the binder droplet and then collide with other wetted particles to form granules with increasing size. This mechanism will lead to a comparatively low rate of granule growth. The granules produced by this mechanism usually have comparatively round morphology due to the random collision of seed particles. On the other hand, the agglomeration of small granules themselves would result in very fast growing granules to form larger granules with highly irregular shape. With this mechanism, a control of
Fig. 3. Morphology of lactose–corn starch granules: (a) 106–250 mm (600), (b) 180–250 mm (330), (c) 355–500 mm (130), and (d) 850–1000 mm (60).
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Table 3 Physical properties of lactose granules. Ug (m/s)/T (8C)/P (bar)
Angle of repose (8)
Packed bulk density (kg/dm3)
Compressibility (%)
Dispersibility (%)
Flowability index
Floodability index
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
38.5 40.3 43.3 40.3 41.2 42.9 43.1 43.1 43.4
0.877 0.894 0.908 0.873 0.901 0.914 0.906 0.905 0.916
24.6 27.9 31.0 24.8 29.5 31.8 30.4 32.6 34.0
24.6 38.9 42.0 26.3 53.4 55.7 48.0 57.7 55.4
52.0 48.5 45.0 51.5 48.0 44.5 50.0 47.0 47.0
75.5 83.0 84.0 75.0 85.0 87.5 86.0 89.0 89.0
Table 4 Physical properties of lactose–corn starch granules. Ug (m/s)/T (8C)/P (bar)
Angle of repose (8)
Packed bulk density (kg/dm3)
Compressibility (%)
Dispersibility (%)
Flowability index
Floodability index
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
39.2 40.7 43.5 39.8 42.4 44.4 40.7 42.5 44.5
0.872 0.880 0.907 0.871 0.881 0.912 0.877 0.900 0.917
28.1 29.2 32.1 28.4 29.6 32.3 30.5 32.6 35.7
63.2 65.4 72.6 63.4 66.5 77.6 65.3 76.5 75.2
51.5 48.0 45.0 51.0 47.0 44.5 48.0 44.5 42.0
90.0 91.0 89.0 91.0 91.0 91.5 91.0 91.5 90.0
fluidizing air velocity will play a crucial role in determining the granule size. As shown in Figs. 2 and 3, the morphology of granules produced from lactose seed particles is remarkably different from that of lactose–corn starch powder. The granules produced from mixed powder of lactose and corn starch have relatively round morphology in comparison with those of the pure lactose granules. It could clearly be observed that a primary lactose particle wetted by binder had several contact points with other particles inside the prepared granules. Especially in Fig. 3, there were many smaller corn starch particles filling up the outer vacancy among coarse lactose particles, resulting in the comparatively spherical granules. Additionally, closer consideration of the morphology of all granules shown in either Figs. 2 and 3, it is reasonably implied that the granules are formed by accumulation of primary particles which are rolled and blended by the fluidizing air within the column. Formation of prepared granule is known as the so-called snowballing mechanism, attributed to the relatively spherical structure [7–9]. 4.4. Effect on the granule flow behavior In order to investigate effect of operating conditions on the granule flow behavior, particle flowability and floodability are employed. Carr has proposed the concept of flowability and floodability of particulate materials using various experimental parameters including angle of repose, aerated and packed bulk densities, and uniformity [12]. With high flowability, particles tend to flow without formation of arc bridging while high floodability, which is related to other parameters (angle of
collapse and dispersibility), would provide information of particle flushing tendency. Particles with sufficiently high flowability and floodability would be easy to handle, resulting in uniform bulk properties. Based on our experimental results, the flow properties of the lactose and lactose–corn starch granules produced are summarized in Tables 3 and 4. The increasing air velocity led to an increase in angle of repose, packed bulk density, compressibility and dispersibility, resulting in the decreasing flowability of the granules. It should be noted that the flowability depends on the particle size, its distribution and morphology [12–14]. The granules with highly irregular morphology as shown in Fig. 2 could easily undergo interlocking among particles. The elevated fluidizing air velocity was accounted for the increasing fraction of small granules and irregularity of the granules. Therefore, it was found that the flowability of the granules decreased with the increasing air velocity. However, because of the increasing fine fraction, the granules became more floodable, which could be seen from the increasing floodability index. It was also found that the increasing air temperature and atomizing air pressure had the similar influence on the flow behavior of the granules prepared from either lactose or lactose–corn starch powder. 4.5. Tabletization results Physical properties of tablets produced from the granules are concluded in Tables 5 and 6. The experimental results reveal that the tablets can be compressed to gain high hardness without capping. Weight variation of tablets depended on the
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Table 5 Physical properties of lactose tablets. Ug (m/s)/T (8C)/P (bar)
Hardness (kp)
Weight of tablets (mg)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
7.99 8.05 8.45 7.99 8.05 8.39 7.31 8.10 8.61
331.05 343.65 332.80 312.05 344.55 337.90 331.8 381.8 347.3
Weight variation 2.43 2.70 4.85 5.34 5.95 6.97 2.90 3.68 5.09 5.35 6.78 4.47 2.95 4.88 5.72 5.02 5.27 5.67
Friability (%)
Disintegration time (s)
0.42 0.49 0.46 0.47 0.48 0.59 0.67 0.59 0.41
380 412 190 351 342 168 170 336 758
Friability (%)
Disintegration time (s)
0.32 0.50 0.57 0.41 0.48 0.43 0.54 0.55 0.64
91 73 60 86 81 74 80 79 81
Table 6 Physical properties of lactose–corn starch tablets. Ug (m/s)/T (8C)/P (bar)
Hardness (kp)
Weight of tablets (mg)
0.8/70/0.5 1.0/70/0.5 1.2/70/0.5 0.8/80/0.5 1.0/80/0.5 1.2/80/0.5 0.8/80/1.0 1.0/80/1.0 1.2/80/1.0
8.64 8.16 7.97 8.56 8.14 8.22 8.66 8.16 7.69
346.55 354.85 362.95 339.55 355.50 356.10 350.65 372.85 358.90
flowability of the granules. The tablets had low weight variation when the granules exerted good flow behavior or high flowability index. Lactose–corn starch tablets had remarkably higher weight variation than that of lactose tablets because the lactose–corn starch granules contained higher quantity of small particle as shown in Fig. 3. The small particles could stick on surface of die in tabletization process [15]. Friability and disintegration time of tablets were found to rely on the hardness of tablets. Accordingly, tablets prepared from lactose–corn starch powder had 2.5–9 times shorter disintegration time than that of lactose tablets. This is attributed to the hardness of the tablets and a fact that corn starch itself is disintegrate material. 5. Conclusion The fluidized bed granulator developed could be employed to produce granules of lactose and lactose–corn starch powder with controllable bulk density and improved flowability. The fluidizing air velocity and atomizing air pressure could remarkably affect the physical properties of the granules produced while the fluidizing air temperature has less effect. The experimental results reveal that the granules prepared at the fluidizing air velocity of 0.8 m/s had the highest average particle size. Addition of corn starch could lead to the remarkable decrease in the granule average size and flowability. The pharmaceutical tablets produced from the lactose granules had sufficiently high hardness without capping. The weight variation of the tablets relied strongly upon the size distribution and flowability of the granules. Tablet friability and disintegration time depended on its hardness as well as particulate constituent. The lactose–corn starch tablets had 2.5–9 times shorter disintegration time than that of lactose tablets.
Weight variation 5.06 3.59 6.16 5.68 6.60 6.63 5.76 5.43 6.33 2.67 6.21 7.27 5.89 5.80 6.40 4.87 6.10 3.65
Acknowledgements This work is supported by the Silver Jubilee Foundation of Chulalongkorn University. K. Phattanathong is gratefully acknowledged for his experimental support. K.S.K. also acknowledges support from the Ministry of Education and Human Resources Development (MOE) and the Ministry of Commerce, Industry and Energy (MOCIE) through the fostering project of the Industrial-Academic Cooperation Centered University.
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