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Binderless granulation of pharmaceutical fine powders with coarse lactose for dry powder inhalation
Powder Technology 131 (2003) 129 – 138 www.elsevier.com/locate/powtec
Binderless granulation of pharmaceutical fine powders with coarse lactose for dry powder inhalation Katsura Takano a,*, Kazuo Nishii a, Masayuki Horio b a
b
Fuji Paudal Co. Ltd., 2-2-30 Chuoh, Joto-ku, Osaka 536-0005, Japan Department of Chemical Engineering, BASE, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan Received 22 March 2002; received in revised form 22 November 2002; accepted 22 November 2002
Abstract With the Pressure Swing Granulation (PSG), a fluidized bed binderless granulation method, jet-milled fine model drug powders of roughly 2 Am in diameter were mixed with lactose and successfully agglomerated into spherical soft granules to demonstrate that PSG is an effective granulation method for dry powder inhalation. The effects of both lactose particle size, which is supposed to be of either carriers or excipients for inhalants, and granule formulations on the product properties and their dispersion characteristics were investigated. To strengthen the granule-forming tendency without decreasing the carrier particle size, lactose particles’ surface morphology was modified before granulation in a ball-milling pot with balls having their lowest milling size larger than the lactose particle size. By this modification, lactose particles of about 8.8 Am in mean diameter were successfully agglomerated without binders over the full range of mixing ratio with the model drug particles. An excellent dispersion property for inhalation was obtained with the PSG granules produced from the surface modified lactose and the PSG method is expected to add a new freedom in producing dry powder for inhalation. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Fluidized bed; Pressure swing granulation; Binderless granules; Dry powder inhalation; Lactose
1. Introduction Pharmaceutical aerosol inhalation has been used as a method for delivering drugs to treat pulmonary diseases such as asthma. This route has several advantages: medicine can be directly delivered to affected parts of the lungs allowing for rapid actions; the ‘‘first-pass effect,’’ i.e., the drug metabolism in the liver, can be avoided; and unwanted systemic side effects can be avoided [1]. Pharmaceutical aerosol inhalation is also promising as an alternative delivering method for systemic medications, e.g., peptides and proteins. There are three major delivery systems available, namely, (1) nebulizer that produces a mist to be inhaled through a mouthpiece or mask, (2) pressurized metered-dose inhaler (MDI), and (3) dry powder inhaler (DPI). DPI is now recognized to be in an advantageous position than others because the nebulizer is expensive and inconvenient to carry * Corresponding author. Tel.: +81-42-388-7067; fax: +81-42-3863303. E-mail address: [email protected] (K. Takano).
and because MDI requires chlorofluorocarbon (CFC) propellants whose utilization has to be stopped due to their ozone layer depletion nature. Alternative propellants economically feasible and acceptable from the standpoints of health and environment are not yet fully developed. However, there are still some important issues to be solved for making DPI a reliable method. Particularly, particle cohesiveness control is a key factor in DPI because it is needed to deagglomerate powders into aerosol particles that can reach bronchi or alveoli having the size range of 1– 7 Am [1 – 3] first by separating them from their container, e.g., a capsule or device, and then by dispersing them against their essential cohesiveness. Here, binderless granulation, such as granulation by a drum granulator or just a mixer, has been a fundamental way to avoid their cohesion onto the container as well as to make soft agglomerates to achieve the above-mentioned dispersibility. In this work, the potential of Pressure Swing Granulation (PSG), an advanced method of binderless granulation, is examined for its application to DPI, particularly for the carrier method. As in other binderless granulation methods, PSG utilizes the spontaneously agglomerating nature of fine
0032-5910/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0032-5910(02)00346-7
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cohesive powders [4]. In PSG, agglomeration proceeds with cyclic fluidization and compaction by reciprocal upward and downward airflows that accompany with strong attrition atmosphere for nonspherical and weaker granules. The attrited fines are captured by bag filters, returned to the bed and recaptured by larger granules. This is the mechanism of making granules of high content uniformity in PSG as discussed by Horio [5]. In addition to this content uniformity, the strength of product granules, which is not as widely scattered as other binderless granulation methods, is the special advantage of PSG method from the viewpoint of its application to DPI. The applicability of PSG to pharmaceutical powders has already been demonstrated in our previous publication [6], where jet-milled fine lactose particles of size less than roughly 5 Am were successfully agglomerated into granules of rather spherical shape, and uniform diameter and with weak strength. Fig. 1 shows a microphotograph and a SEM image of PSG granules. Concerning the strength, those granules applicable to DPI have to be sufficiently weak for easy disintegration and dispersion to form aerosols for inhalation but sufficiently strong to maintain their shape in the container until its use under practical condition. Nishii [7] demonstrated the strength of PSG granules by dropping them from a flask to the floor 0.50 m below. He found even five times falling did not change their median diameter very much although larger granules were broken as shown in Fig. 2. Their collapsing strength was about 30 kPa.
Fig. 2. Change in size distribution of PSG granules after several falling tests (original size range 500 – 710 Am) Nishii [7].
The major formulation of DPI medication includes coarse excipient particles such as lactose, first to dilute the drug and second to separate fine drug particles from them to generate dispersible and flowable drug particles. In making PSG granules from fine drug powders and coarse lactose particles, a difficulty can be foreseen because of the reduction of cohesiveness due to the introduction of coarse excipient particles into PSG. In addition, unless the property of granules with lactose particles was not known precisely, their good shape conservation characteristics as well as high dispersibility would not be achieved. In this paper, the effects of lactose particle size and its content on the properties of PSG granules are investigated.
2. Experimental procedures 2.1. Sample materials and primary particle preparations
Fig. 1. Microphotograph and SEM image of PSG lactose granules (jetmilled lactose, primary particles dp,50 = 3 Am).
A typical organic drug powder, ethenzamide (Junsei Pharmaceutical, mean diameter 18.4 Am) treated once by a jet-mill (Fuji Paudal, JM-1) was adopted as a model drug powder. Carrier materials of three kinds of lactose monohydrate, 325M (DMV, PharmatoseR325M), which is supplied for inhalation, 450M (DMV, PharmatoseR450M), which has the smallest mean particle diameter as supplied, and 450M-JB (surface modified 450M) were tested in the present work. 450M-JB was prepared from lactose 450M by jet-mill. The part over 30 Am was cut off and the rest was treated in a ball mill (balls: 18, ball size: 20 mm, mill inner diameter: 120 mm) to modify their surface roughness without decreasing their mean diameter. During the above pretreatments for ethenzamide and 450M-JB the temperature was maintained at 22 F 1 jC and the relative humidity at 60 F 2%. After preparation, these micronized powders
K. Takano et al. / Powder Technology 131 (2003) 129–138
were kept in a desiccator until they were used for the granulation. The temperature in the desiccator was maintained in the above range and the relative humidity at 22 F 1%. The primary particle diameter, dp, was determined with a laser diffraction particle size analyzer (Shimadzu, SALD1100 Ver.2.10), and the specific surface area Sw,BET was measured with a BET (Yuasa Ionics, QUANTASORB Jr.). For primary particle size determination, sample particles were suspended in a liquid that did not dissolve them, i.e., distilled water for ethenzamide and 2-Metyle-1-propanol for lactose. The suspension of an appropriate concentration was circulated through the flow-cell during the measurement. Data were analyzed by Mie’s scattering theory. The single-point BET method was adopted for measurement of Sw,BET. The sample material in the sample container was pretreated to remove gases and vapors physically adsorbed onto the sample surface by outgassing the sample under a reduced pressure with vacuum pump for 2 h by maintaining temperature at 50 jC. After the pretreatment, nitrogen was adsorbed on the powder sample in the container, which was chilled by liquid nitrogen. The pressure was decreased until adsorption reached to a new equilibrium. The volume of gas adsorbed in a monolayer was calculated from the volume of gas adsorbed at equilibrium under a partial pressure of 0.30. 2.2. Preparation of powder mixtures and granulation To obtain primary mixtures of lactose and ethenzamide, a powder mixing apparatus shown in Fig. 3 was used. The apparatus had two ejectors (Pisco, VRL 50-080801) facing each other. Premixed powders were made by putting predetermined amount of the two powders into a plastic bag of roughly 1 10 3 m3 and shaking for 300 times. Then the
Fig. 3. Schematic diagram of the mixing apparatus.
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Table 1 Mixing ratio of lactose carrier vs. ethenzamide Mixing ratio (lactose: ethenzamide, mass %) Lactose 325M: ethenzamide Lactose 450M: ethenzamide Lactose 450M-JB: ethenzamide
0:100, 25:75, 37.5:62.5, 100 25:75, 50:50, 75:25, 100 25:75, 50:50, 75:25, 87.5:12.5, 90:10, 92.5:75, 95:5, 97.5:2.5, 100:0
mixture was fed to both of the two ejectors simultaneously. Table 1 shows the mixing ratios of lactose and ethenzamide. Fig. 4 shows a schematic of the PSG granulator. Dry compressed air was adopted for the PSG for both fluidization and compaction. The compressed air was dried by an air dryer (Iwata, Air receiver SAT-400-120) and then filtered by three mist-separators in series (SMC, Mist-separator AM350, Super Mist-separator AME350 and Odour removal filter AMF350) to separate the entrained mists (water/oil). The air was further dried by a membrane dryer (Ube, DMNB5) before introduced into the PSG granulator. The fluidized bed column was made of PMMA resin. In each granulation run, 120 g of powder mixture was fed into the column. The feeding was done through a 32-mesh sieve (0.5 mm opening) to adjust initial agglomerate sizes by disintegrating large agglomerates. Air velocity was 0.425 m/s and compaction pressure was 30 kPaG. Total granulation time was 1 h. During the fluidization period, the distributor plate was vibrated at 40 Hz to assist fluidization. 2.3. Characterization of PSG granules The size distribution of product granules was determined by standard sieves. The compression strength of granules was measured by a micro-compression testing machine (Shimadzu, MCTE-200) for granules in the size range of 32 + 42 mesh (0.5 –0.35 mm). From the fracture force Ff,
Fig. 4. Schematic diagram of the PSG granulator.
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Fig. 5. Schematic diagram of dispersion system for PSG granules, equivalent aerodynamic diameters, and structure of E-halerR.
the tensile strength r can be calculated by the following equation of Hiramatsu and Oka [8]: r¼
2:8Ff pda2
ð1Þ
where da is agglomerate diameter. Recently, Shipway and Hutchings [9] used coefficient 1.6 instead of 2.8 in Eq. (1) for brittle spheres. Since PSG granules are not brittle, the tensile strength was determined by Hiramatsu equation for relative evaluation although some data in this study were beyond its applicable limit. The content uniformity of drug in product granules was examined by analyzing the quantity of ethenzamide in the sampled granules (about 2 mg) from lactose 450M-JB blends in the size range of 32 + 42 mesh (0.5 – 0.35 mm). Each sampled granule was placed in a 50-ml volumetric flask and filled up to 50 ml with ethanol. The amount of ethenzamide in each solution was determined quantitatively by a spectrophotometer (Hitachi, U-2010). The absorbances at a wavelength of 290 nm, which corresponds to ethenzamide, were used to determine its concentration. A cell with a path length of 1 cm was used for the measurement.
in Fig. 5 [10]. The cascade impactor used in the present study is designed so that impaction stages 2 – 5 among its eight stages correspond to the aerodynamic diameter range of 7.0 – 1.1 Am at an operating airflow rate of 28.3 l/min. The equivalent aerodynamic diameter range on each stage of the cascade impactor is also shown in Fig. 5. A ball mill-like inhaler of IntalR (Fujisawa Pharmaceutical, EhalerR) was connected to the cascade impactor with a throat, a 90j elbow of 20 mm in diameter, and connected to a vacuum pump. Twenty milligrams of product PSG granules (size 0.5– 0.35 mm) was fed into a No. 2 HPMC capsule (Shionogi Qualicaps) and then inserted into the end of the E-halerR opposite the mouthpiece. The structure of the E-halerR, a multiple unit dose inhaler designed for capsuled drugs, is shown in Fig. 5. As can be seen it has a plastic ball of 6 mm in diameter for disintegrating agglomerates. The top of an inserted capsule is cut off by rotating the cutter mounted on the rear part of the inhaler to feed drugs into the inhaler. The ball in the inhaler rotates in accordance with the swirling air with inhalation and
2.4. Evaluation of inhalation property of the PSG granules The inhalation property of PSG granules were evaluated with a cascade impactor (Tokyo Dylec, AN-200) as shown Table 2 Characteristics of the primary particles
Ethenzamide Milled ethenzamide 325M 450M 450M-JB
dp,10 (Am)
dp,50 (Am)
dp,90 (Am)
1.24 0.79
18.4 1.94
35.4 3.94
– –
4.81 102 1.71 103
1.96 2.72 2.18
15.4 11.1 8.82
36.4 25.6 19.5
19.0 13.7 10.9
3.30 102 8.57 102 7.18 102
dp,ae (Am)
Sw,BET (m2/kg)
Fig. 6. Size distributions of primary particles.
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Fig. 7. SEM images of primary particles: (a) milled ethenzamide, (b) lactose 325M, (c) lactose 450M, and (d) milled lactose 450M-JB.
Fig. 8. Atomic force microscope images and near surface cross-sections of primary particles: (a) lactose 450M and (b) milled lactose 450M-JB.
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Fig. 9. Microphotographs of PSG granules.
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crushes agglomerates to produce fines. Dry aerosol particles were emitted from the E-halerR for 5 s under the specified airflow rate of 28.3 l/min for the cascade impactor. Afterwards, the capsule, the inside of the inhaler, throat, and each stage of the cascade impactor were rinsed with ethanol and analyzed with a spectrophotometer (Hitachi, U-2010) to determine the quantity of ethenzamide in each part. The respiratory fraction was calculated from the amount of drug collected in each part as a percentage of the amount loaded into the capsule.
3. Results and discussion 3.1. Characterization of primary particles Table 2 shows the properties of primary particles tested in the present experiment. Fig. 6 shows primary particle size
Fig. 11. Compression strength of product PSG granules: (a) ethenzamide with 325M, (b) 450M, and (c) 450M-JB. Each value represents the mean F S.D. (n = 10).
Fig. 10. Size distributions of product PSG granules: (a) ethenzamide with 325M, 450M, and (b) ethenzamide with 450M-JB.
Fig. 12. Content uniformity of ethenzamide of product PSG granules with lactose 450M-JB (n = 10).
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distributions of ethenzamide and lactose from which the mean primary particle diameter dp,50 was determined. As shown in Table 2, dp,50 of 450M-JB is smaller than that of 450M. Nevertheless, Sw,BET of 450M-JB is smaller than that of 450M. Sw,BET of 450M-JB increased with increasing the ball-milling time. When 450M-JB was further ball-milled to make its Sw,BET larger, Sw,BET decreased and became smaller than that of 450M. It seems that the reduction of Sw,BET of 450M-JB took place beyond the grinding limit. Equivalent aerodynamic diameter [11], dp,ae, an equivalent diameter of a sphere with a reference density q0 = 1000 kg/m3 that has the same terminal velocity as
the tested particles, can be calculated by the following equation: qp 0:5 ðArB18; dp [mean free pathÞ dp;ae ¼ dp q0 / ð2Þ where Ar is Archimedes number (Ar u dp3qfluid(qparticle qfluid)g/l2) and / is the particle shape factor, assumed to be unity in the present work [12]. Fig. 7 shows the SEM images of primary particles of as received ethenzamide and lactose 325M, 450M and 450M-
Fig. 13. Dispersion characteristics of product PSG granules: (a) ethenzamide with 325M, (b) 450M, and (c) 450M-JB.
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JB after the surface treatment defined above. Ethenzamide powder was in the form of agglomerates, but most of lactose powders were individual particles on which crystal face can be observed. The surface structure of primary particles of 450M and 450M-JB was observed for further details by an atomic force microscope AFM (Shimadzu, SPM-9500J3). Fig. 8 shows the AFM images and near surface cross-sections along lines indicated on the images of the primary particles of 450M and 450M-JB. The surface of 450M-JB is rather rough than that of 450M. 3.2. Effective concentration of coarse lactose to produce PSG granules Fig. 9 shows microphotographs of PSG granules. From 325M or 450M powder, no good agglomerates were obtained when no drug powder was added. The maximum lactose content in powders allowable to obtain PSG granules were 37.5% for 325M and 75% for 450M, respectively. For lactose 450M-JB, however, good agglomerates were obtained regardless of its content in the mixture. In other words, the surface modification, 450M-JB attained a level of cohesiveness sufficient to make agglomerates by PSG without size reduction. 3.3. Characterization of PSG granules Fig. 10 shows the size distribution of product granules. When lactose concentration was increased, the product granule diameter increased and their size distribution became wider. However, concerning granules from a mixture of 450M-JB and ethenzamide, product granule diameters and size distributions were not influenced by lactose concentration when lactose content was higher than 75%. Fig. 11 shows the effect of lactose content on the tensile strength r. The temperature during the compression strength testing was maintained at 22 F 1 jC and the relative humidity at 60 F 2%. Mean value of r decreased as lactose concentration increased. However, for the granules made of a mixture of 450M-JB and ethenzamide, the tensile strength r decreased with lactose content until it reached 87.5%, but increased again above 97.5%. Fig. 12 shows the experimentally determined ethenzamide content of product PSG granules. The drug content percentages of product granules sampled for the case with lactose 450M-JB (ethenzamide concentration 2.5 – 75%) were within F 15% of bulk values except for those 450M-JB 92.5% ( F 20%).
Fig. 14. Relationship between respirable fraction of ethenzamide and compression strength for the PSG granules mixed with 450M-JB.
contained in the capsule. In addition, the total percentages of the deposition on stages of respirable size range from stage 1.1 – 2.1 to stage 4.7 –7 Am were shown in Fig. 13. The respiratory fraction for PSG granules from pure drug was 8.4%, and granules from mixtures with lactose 325M or 450M contributed to 10% of the total mass. There was a little effect of lactose content on the drug dispersion. On the other hand, for granules obtained from mixtures with 450M-JB the respirable fraction was largely improved up to 20– 50%. As can be found in Fig. 14, there is a correlation between respirable fraction and compression strength for granules made with 450M-JB.
4. Conclusions To demonstrate that the Pressure Swing Granulation (PSG) can be applied as a new granulation method to produce medicaments for dry powder inhalation, fine-milled ethenzamide powder, as a model drug, was granulated with coarse lactose particles, lactose 325M, 450M, and the 450M-JB (surface modified 450M) by PSG and the properties of product granules were investigated. By the surface modification of lactose 450M of 8.8 Am in mean diameter, which is larger than the respirable limit, successful PSG agglomeration experiment was conducted. The maximum lactose contents in powders allowable to obtain PSG granules were 37.5% for lactose 325M, 75% for lactose 450M and 100% for the surface modified lactose 450M-JB. The respiratory fractions were improved largely by applying the surface modified lactose. Furthermore, there was a correlation between the strength and the respiratory fraction for granules obtained from the surface modified lactose.
3.4. Inhalation property of PSG granules Fig. 13 shows the results of dispersion experiments of PSG granules where the mass fraction of ethenzamide deposited on the capsule, the device, the throat, and each stage of the cascade impactor are shown as a percentage of drug initially
References [1] M.P. Timsina, G.P. Martin, C. Marriott, D. Ganderton, M. Yianneskis, Drug delivery to the respiratory tract using dry powder inhalers, Int. J. Pharm. 101 (1994) 1.
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[2] S.P. Newman, A. Hollingworth, A.R. Clark, Effect of different modes of inhalation on drug delivery from a dry powder inhaler, Int. J. Pharm. 102 (1994) 127. [3] P.J. Davies, G.W. Hanlon, A.J. Molyneux, An investigation into the deposition of inhalation aerosol particles as a function of air flow rate in a modified ‘Kirk Lung’, J. Pharm. Pharmacol. 28 (1976) 908. [4] K. Nishii, Y. Itoh, N. Kawakami, M. Horio, Pressure swing granulation, a novel binderless granulation by cyclic fluidization and gas flow compaction, Powder Technol. 74 (1993) 1. [5] M. Horio, New developments through microscopic reconstruction of the nature of fluidized suspensions, AIChE PTF Award Lecture, Annual Meeting, Reno, 2001. [6] K. Takano, K. Nishii, A. Mukoyama, Y. Iwadate, H. Kamiya, M. Horio, Binderless granulation of pharmaceutical lactose powders, Powder Technol. 122 (2002) 212.
[7] K. Nishii, ‘‘Pressure swing fluidization of cohesive fine powders for binderless granulation,’’ PhD Dissertation, TUAT (1994). [8] Y. Hiramatsu, Y. Oka, Determination of the tensile strength of rock by a compression test of an irregular test piece, Int. J. Rock Mech. Sci. 3 (1966) 89. [9] P.H. Shipway, I.M. Hutchings, Attrition of brittle spheres by fracture under compression and impact loading, Powder Technol. 76 (1993) 23. [10] U.S. Pharmacopeia XXIV—US Pharmacopeia Convention, Rockville, h601i Aerosols/physical tests, Particle Size, pp. 1900 – 1910 (1994). [11] O.G. Raabe, Aerosol aerodynamic size conventions for inertial sampler calibration, J. Air Pollut. Control Assoc. 26 (1976) 856. [12] W.H. Finlay, The Mechanics of Inhaled Pharmaceutical Aerosols. An Introduction, Academic Press, London, 2001, p. 32.
Binderless granulation of pharmaceutical fine powders with coarse lactose for dry powder inhalation Katsura Takano a,*, Kazuo Nishii a, Masayuki Horio b a
b
Fuji Paudal Co. Ltd., 2-2-30 Chuoh, Joto-ku, Osaka 536-0005, Japan Department of Chemical Engineering, BASE, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan Received 22 March 2002; received in revised form 22 November 2002; accepted 22 November 2002
Abstract With the Pressure Swing Granulation (PSG), a fluidized bed binderless granulation method, jet-milled fine model drug powders of roughly 2 Am in diameter were mixed with lactose and successfully agglomerated into spherical soft granules to demonstrate that PSG is an effective granulation method for dry powder inhalation. The effects of both lactose particle size, which is supposed to be of either carriers or excipients for inhalants, and granule formulations on the product properties and their dispersion characteristics were investigated. To strengthen the granule-forming tendency without decreasing the carrier particle size, lactose particles’ surface morphology was modified before granulation in a ball-milling pot with balls having their lowest milling size larger than the lactose particle size. By this modification, lactose particles of about 8.8 Am in mean diameter were successfully agglomerated without binders over the full range of mixing ratio with the model drug particles. An excellent dispersion property for inhalation was obtained with the PSG granules produced from the surface modified lactose and the PSG method is expected to add a new freedom in producing dry powder for inhalation. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Fluidized bed; Pressure swing granulation; Binderless granules; Dry powder inhalation; Lactose
1. Introduction Pharmaceutical aerosol inhalation has been used as a method for delivering drugs to treat pulmonary diseases such as asthma. This route has several advantages: medicine can be directly delivered to affected parts of the lungs allowing for rapid actions; the ‘‘first-pass effect,’’ i.e., the drug metabolism in the liver, can be avoided; and unwanted systemic side effects can be avoided [1]. Pharmaceutical aerosol inhalation is also promising as an alternative delivering method for systemic medications, e.g., peptides and proteins. There are three major delivery systems available, namely, (1) nebulizer that produces a mist to be inhaled through a mouthpiece or mask, (2) pressurized metered-dose inhaler (MDI), and (3) dry powder inhaler (DPI). DPI is now recognized to be in an advantageous position than others because the nebulizer is expensive and inconvenient to carry * Corresponding author. Tel.: +81-42-388-7067; fax: +81-42-3863303. E-mail address: [email protected] (K. Takano).
and because MDI requires chlorofluorocarbon (CFC) propellants whose utilization has to be stopped due to their ozone layer depletion nature. Alternative propellants economically feasible and acceptable from the standpoints of health and environment are not yet fully developed. However, there are still some important issues to be solved for making DPI a reliable method. Particularly, particle cohesiveness control is a key factor in DPI because it is needed to deagglomerate powders into aerosol particles that can reach bronchi or alveoli having the size range of 1– 7 Am [1 – 3] first by separating them from their container, e.g., a capsule or device, and then by dispersing them against their essential cohesiveness. Here, binderless granulation, such as granulation by a drum granulator or just a mixer, has been a fundamental way to avoid their cohesion onto the container as well as to make soft agglomerates to achieve the above-mentioned dispersibility. In this work, the potential of Pressure Swing Granulation (PSG), an advanced method of binderless granulation, is examined for its application to DPI, particularly for the carrier method. As in other binderless granulation methods, PSG utilizes the spontaneously agglomerating nature of fine
0032-5910/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0032-5910(02)00346-7
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K. Takano et al. / Powder Technology 131 (2003) 129–138
cohesive powders [4]. In PSG, agglomeration proceeds with cyclic fluidization and compaction by reciprocal upward and downward airflows that accompany with strong attrition atmosphere for nonspherical and weaker granules. The attrited fines are captured by bag filters, returned to the bed and recaptured by larger granules. This is the mechanism of making granules of high content uniformity in PSG as discussed by Horio [5]. In addition to this content uniformity, the strength of product granules, which is not as widely scattered as other binderless granulation methods, is the special advantage of PSG method from the viewpoint of its application to DPI. The applicability of PSG to pharmaceutical powders has already been demonstrated in our previous publication [6], where jet-milled fine lactose particles of size less than roughly 5 Am were successfully agglomerated into granules of rather spherical shape, and uniform diameter and with weak strength. Fig. 1 shows a microphotograph and a SEM image of PSG granules. Concerning the strength, those granules applicable to DPI have to be sufficiently weak for easy disintegration and dispersion to form aerosols for inhalation but sufficiently strong to maintain their shape in the container until its use under practical condition. Nishii [7] demonstrated the strength of PSG granules by dropping them from a flask to the floor 0.50 m below. He found even five times falling did not change their median diameter very much although larger granules were broken as shown in Fig. 2. Their collapsing strength was about 30 kPa.
Fig. 2. Change in size distribution of PSG granules after several falling tests (original size range 500 – 710 Am) Nishii [7].
The major formulation of DPI medication includes coarse excipient particles such as lactose, first to dilute the drug and second to separate fine drug particles from them to generate dispersible and flowable drug particles. In making PSG granules from fine drug powders and coarse lactose particles, a difficulty can be foreseen because of the reduction of cohesiveness due to the introduction of coarse excipient particles into PSG. In addition, unless the property of granules with lactose particles was not known precisely, their good shape conservation characteristics as well as high dispersibility would not be achieved. In this paper, the effects of lactose particle size and its content on the properties of PSG granules are investigated.
2. Experimental procedures 2.1. Sample materials and primary particle preparations
Fig. 1. Microphotograph and SEM image of PSG lactose granules (jetmilled lactose, primary particles dp,50 = 3 Am).
A typical organic drug powder, ethenzamide (Junsei Pharmaceutical, mean diameter 18.4 Am) treated once by a jet-mill (Fuji Paudal, JM-1) was adopted as a model drug powder. Carrier materials of three kinds of lactose monohydrate, 325M (DMV, PharmatoseR325M), which is supplied for inhalation, 450M (DMV, PharmatoseR450M), which has the smallest mean particle diameter as supplied, and 450M-JB (surface modified 450M) were tested in the present work. 450M-JB was prepared from lactose 450M by jet-mill. The part over 30 Am was cut off and the rest was treated in a ball mill (balls: 18, ball size: 20 mm, mill inner diameter: 120 mm) to modify their surface roughness without decreasing their mean diameter. During the above pretreatments for ethenzamide and 450M-JB the temperature was maintained at 22 F 1 jC and the relative humidity at 60 F 2%. After preparation, these micronized powders
K. Takano et al. / Powder Technology 131 (2003) 129–138
were kept in a desiccator until they were used for the granulation. The temperature in the desiccator was maintained in the above range and the relative humidity at 22 F 1%. The primary particle diameter, dp, was determined with a laser diffraction particle size analyzer (Shimadzu, SALD1100 Ver.2.10), and the specific surface area Sw,BET was measured with a BET (Yuasa Ionics, QUANTASORB Jr.). For primary particle size determination, sample particles were suspended in a liquid that did not dissolve them, i.e., distilled water for ethenzamide and 2-Metyle-1-propanol for lactose. The suspension of an appropriate concentration was circulated through the flow-cell during the measurement. Data were analyzed by Mie’s scattering theory. The single-point BET method was adopted for measurement of Sw,BET. The sample material in the sample container was pretreated to remove gases and vapors physically adsorbed onto the sample surface by outgassing the sample under a reduced pressure with vacuum pump for 2 h by maintaining temperature at 50 jC. After the pretreatment, nitrogen was adsorbed on the powder sample in the container, which was chilled by liquid nitrogen. The pressure was decreased until adsorption reached to a new equilibrium. The volume of gas adsorbed in a monolayer was calculated from the volume of gas adsorbed at equilibrium under a partial pressure of 0.30. 2.2. Preparation of powder mixtures and granulation To obtain primary mixtures of lactose and ethenzamide, a powder mixing apparatus shown in Fig. 3 was used. The apparatus had two ejectors (Pisco, VRL 50-080801) facing each other. Premixed powders were made by putting predetermined amount of the two powders into a plastic bag of roughly 1 10 3 m3 and shaking for 300 times. Then the
Fig. 3. Schematic diagram of the mixing apparatus.
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Table 1 Mixing ratio of lactose carrier vs. ethenzamide Mixing ratio (lactose: ethenzamide, mass %) Lactose 325M: ethenzamide Lactose 450M: ethenzamide Lactose 450M-JB: ethenzamide
0:100, 25:75, 37.5:62.5, 100 25:75, 50:50, 75:25, 100 25:75, 50:50, 75:25, 87.5:12.5, 90:10, 92.5:75, 95:5, 97.5:2.5, 100:0
mixture was fed to both of the two ejectors simultaneously. Table 1 shows the mixing ratios of lactose and ethenzamide. Fig. 4 shows a schematic of the PSG granulator. Dry compressed air was adopted for the PSG for both fluidization and compaction. The compressed air was dried by an air dryer (Iwata, Air receiver SAT-400-120) and then filtered by three mist-separators in series (SMC, Mist-separator AM350, Super Mist-separator AME350 and Odour removal filter AMF350) to separate the entrained mists (water/oil). The air was further dried by a membrane dryer (Ube, DMNB5) before introduced into the PSG granulator. The fluidized bed column was made of PMMA resin. In each granulation run, 120 g of powder mixture was fed into the column. The feeding was done through a 32-mesh sieve (0.5 mm opening) to adjust initial agglomerate sizes by disintegrating large agglomerates. Air velocity was 0.425 m/s and compaction pressure was 30 kPaG. Total granulation time was 1 h. During the fluidization period, the distributor plate was vibrated at 40 Hz to assist fluidization. 2.3. Characterization of PSG granules The size distribution of product granules was determined by standard sieves. The compression strength of granules was measured by a micro-compression testing machine (Shimadzu, MCTE-200) for granules in the size range of 32 + 42 mesh (0.5 –0.35 mm). From the fracture force Ff,
Fig. 4. Schematic diagram of the PSG granulator.
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Fig. 5. Schematic diagram of dispersion system for PSG granules, equivalent aerodynamic diameters, and structure of E-halerR.
the tensile strength r can be calculated by the following equation of Hiramatsu and Oka [8]: r¼
2:8Ff pda2
ð1Þ
where da is agglomerate diameter. Recently, Shipway and Hutchings [9] used coefficient 1.6 instead of 2.8 in Eq. (1) for brittle spheres. Since PSG granules are not brittle, the tensile strength was determined by Hiramatsu equation for relative evaluation although some data in this study were beyond its applicable limit. The content uniformity of drug in product granules was examined by analyzing the quantity of ethenzamide in the sampled granules (about 2 mg) from lactose 450M-JB blends in the size range of 32 + 42 mesh (0.5 – 0.35 mm). Each sampled granule was placed in a 50-ml volumetric flask and filled up to 50 ml with ethanol. The amount of ethenzamide in each solution was determined quantitatively by a spectrophotometer (Hitachi, U-2010). The absorbances at a wavelength of 290 nm, which corresponds to ethenzamide, were used to determine its concentration. A cell with a path length of 1 cm was used for the measurement.
in Fig. 5 [10]. The cascade impactor used in the present study is designed so that impaction stages 2 – 5 among its eight stages correspond to the aerodynamic diameter range of 7.0 – 1.1 Am at an operating airflow rate of 28.3 l/min. The equivalent aerodynamic diameter range on each stage of the cascade impactor is also shown in Fig. 5. A ball mill-like inhaler of IntalR (Fujisawa Pharmaceutical, EhalerR) was connected to the cascade impactor with a throat, a 90j elbow of 20 mm in diameter, and connected to a vacuum pump. Twenty milligrams of product PSG granules (size 0.5– 0.35 mm) was fed into a No. 2 HPMC capsule (Shionogi Qualicaps) and then inserted into the end of the E-halerR opposite the mouthpiece. The structure of the E-halerR, a multiple unit dose inhaler designed for capsuled drugs, is shown in Fig. 5. As can be seen it has a plastic ball of 6 mm in diameter for disintegrating agglomerates. The top of an inserted capsule is cut off by rotating the cutter mounted on the rear part of the inhaler to feed drugs into the inhaler. The ball in the inhaler rotates in accordance with the swirling air with inhalation and
2.4. Evaluation of inhalation property of the PSG granules The inhalation property of PSG granules were evaluated with a cascade impactor (Tokyo Dylec, AN-200) as shown Table 2 Characteristics of the primary particles
Ethenzamide Milled ethenzamide 325M 450M 450M-JB
dp,10 (Am)
dp,50 (Am)
dp,90 (Am)
1.24 0.79
18.4 1.94
35.4 3.94
– –
4.81 102 1.71 103
1.96 2.72 2.18
15.4 11.1 8.82
36.4 25.6 19.5
19.0 13.7 10.9
3.30 102 8.57 102 7.18 102
dp,ae (Am)
Sw,BET (m2/kg)
Fig. 6. Size distributions of primary particles.
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Fig. 7. SEM images of primary particles: (a) milled ethenzamide, (b) lactose 325M, (c) lactose 450M, and (d) milled lactose 450M-JB.
Fig. 8. Atomic force microscope images and near surface cross-sections of primary particles: (a) lactose 450M and (b) milled lactose 450M-JB.
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Fig. 9. Microphotographs of PSG granules.
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crushes agglomerates to produce fines. Dry aerosol particles were emitted from the E-halerR for 5 s under the specified airflow rate of 28.3 l/min for the cascade impactor. Afterwards, the capsule, the inside of the inhaler, throat, and each stage of the cascade impactor were rinsed with ethanol and analyzed with a spectrophotometer (Hitachi, U-2010) to determine the quantity of ethenzamide in each part. The respiratory fraction was calculated from the amount of drug collected in each part as a percentage of the amount loaded into the capsule.
3. Results and discussion 3.1. Characterization of primary particles Table 2 shows the properties of primary particles tested in the present experiment. Fig. 6 shows primary particle size
Fig. 11. Compression strength of product PSG granules: (a) ethenzamide with 325M, (b) 450M, and (c) 450M-JB. Each value represents the mean F S.D. (n = 10).
Fig. 10. Size distributions of product PSG granules: (a) ethenzamide with 325M, 450M, and (b) ethenzamide with 450M-JB.
Fig. 12. Content uniformity of ethenzamide of product PSG granules with lactose 450M-JB (n = 10).
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distributions of ethenzamide and lactose from which the mean primary particle diameter dp,50 was determined. As shown in Table 2, dp,50 of 450M-JB is smaller than that of 450M. Nevertheless, Sw,BET of 450M-JB is smaller than that of 450M. Sw,BET of 450M-JB increased with increasing the ball-milling time. When 450M-JB was further ball-milled to make its Sw,BET larger, Sw,BET decreased and became smaller than that of 450M. It seems that the reduction of Sw,BET of 450M-JB took place beyond the grinding limit. Equivalent aerodynamic diameter [11], dp,ae, an equivalent diameter of a sphere with a reference density q0 = 1000 kg/m3 that has the same terminal velocity as
the tested particles, can be calculated by the following equation: qp 0:5 ðArB18; dp [mean free pathÞ dp;ae ¼ dp q0 / ð2Þ where Ar is Archimedes number (Ar u dp3qfluid(qparticle qfluid)g/l2) and / is the particle shape factor, assumed to be unity in the present work [12]. Fig. 7 shows the SEM images of primary particles of as received ethenzamide and lactose 325M, 450M and 450M-
Fig. 13. Dispersion characteristics of product PSG granules: (a) ethenzamide with 325M, (b) 450M, and (c) 450M-JB.
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JB after the surface treatment defined above. Ethenzamide powder was in the form of agglomerates, but most of lactose powders were individual particles on which crystal face can be observed. The surface structure of primary particles of 450M and 450M-JB was observed for further details by an atomic force microscope AFM (Shimadzu, SPM-9500J3). Fig. 8 shows the AFM images and near surface cross-sections along lines indicated on the images of the primary particles of 450M and 450M-JB. The surface of 450M-JB is rather rough than that of 450M. 3.2. Effective concentration of coarse lactose to produce PSG granules Fig. 9 shows microphotographs of PSG granules. From 325M or 450M powder, no good agglomerates were obtained when no drug powder was added. The maximum lactose content in powders allowable to obtain PSG granules were 37.5% for 325M and 75% for 450M, respectively. For lactose 450M-JB, however, good agglomerates were obtained regardless of its content in the mixture. In other words, the surface modification, 450M-JB attained a level of cohesiveness sufficient to make agglomerates by PSG without size reduction. 3.3. Characterization of PSG granules Fig. 10 shows the size distribution of product granules. When lactose concentration was increased, the product granule diameter increased and their size distribution became wider. However, concerning granules from a mixture of 450M-JB and ethenzamide, product granule diameters and size distributions were not influenced by lactose concentration when lactose content was higher than 75%. Fig. 11 shows the effect of lactose content on the tensile strength r. The temperature during the compression strength testing was maintained at 22 F 1 jC and the relative humidity at 60 F 2%. Mean value of r decreased as lactose concentration increased. However, for the granules made of a mixture of 450M-JB and ethenzamide, the tensile strength r decreased with lactose content until it reached 87.5%, but increased again above 97.5%. Fig. 12 shows the experimentally determined ethenzamide content of product PSG granules. The drug content percentages of product granules sampled for the case with lactose 450M-JB (ethenzamide concentration 2.5 – 75%) were within F 15% of bulk values except for those 450M-JB 92.5% ( F 20%).
Fig. 14. Relationship between respirable fraction of ethenzamide and compression strength for the PSG granules mixed with 450M-JB.
contained in the capsule. In addition, the total percentages of the deposition on stages of respirable size range from stage 1.1 – 2.1 to stage 4.7 –7 Am were shown in Fig. 13. The respiratory fraction for PSG granules from pure drug was 8.4%, and granules from mixtures with lactose 325M or 450M contributed to 10% of the total mass. There was a little effect of lactose content on the drug dispersion. On the other hand, for granules obtained from mixtures with 450M-JB the respirable fraction was largely improved up to 20– 50%. As can be found in Fig. 14, there is a correlation between respirable fraction and compression strength for granules made with 450M-JB.
4. Conclusions To demonstrate that the Pressure Swing Granulation (PSG) can be applied as a new granulation method to produce medicaments for dry powder inhalation, fine-milled ethenzamide powder, as a model drug, was granulated with coarse lactose particles, lactose 325M, 450M, and the 450M-JB (surface modified 450M) by PSG and the properties of product granules were investigated. By the surface modification of lactose 450M of 8.8 Am in mean diameter, which is larger than the respirable limit, successful PSG agglomeration experiment was conducted. The maximum lactose contents in powders allowable to obtain PSG granules were 37.5% for lactose 325M, 75% for lactose 450M and 100% for the surface modified lactose 450M-JB. The respiratory fractions were improved largely by applying the surface modified lactose. Furthermore, there was a correlation between the strength and the respiratory fraction for granules obtained from the surface modified lactose.
3.4. Inhalation property of PSG granules Fig. 13 shows the results of dispersion experiments of PSG granules where the mass fraction of ethenzamide deposited on the capsule, the device, the throat, and each stage of the cascade impactor are shown as a percentage of drug initially
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[7] K. Nishii, ‘‘Pressure swing fluidization of cohesive fine powders for binderless granulation,’’ PhD Dissertation, TUAT (1994). [8] Y. Hiramatsu, Y. Oka, Determination of the tensile strength of rock by a compression test of an irregular test piece, Int. J. Rock Mech. Sci. 3 (1966) 89. [9] P.H. Shipway, I.M. Hutchings, Attrition of brittle spheres by fracture under compression and impact loading, Powder Technol. 76 (1993) 23. [10] U.S. Pharmacopeia XXIV—US Pharmacopeia Convention, Rockville, h601i Aerosols/physical tests, Particle Size, pp. 1900 – 1910 (1994). [11] O.G. Raabe, Aerosol aerodynamic size conventions for inertial sampler calibration, J. Air Pollut. Control Assoc. 26 (1976) 856. [12] W.H. Finlay, The Mechanics of Inhaled Pharmaceutical Aerosols. An Introduction, Academic Press, London, 2001, p. 32.