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Micromeritic characteristics and agglomeration mechanisms in the spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent diffusion methods
Powder Technology, 76 (1993) 57-64
57
Micromeritic characteristics and agglomeration mechanisms spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent diffusion methods Kenji Morishima*
in the
and Yoichi Kawashima
Santen Pharmaceutical Co., Ltd., 9-19 Shimoshbjo
Yoshiaki Kawashima,
3-chome, Higashjodogawa-ku,
Osaka 533 (Japan)
Hirofumi Takeuchi, Toshiyuki Niwa and Tomoaki Hino
Gifu Pharmaceutical University, 5-6-l Mitahora-Higashi, Gifi 502 (Japan) (Received
February
3, 1992, in revised form January
19, 1993)
Abstract The physical properties of bucillamine were modified by the application of two spherical crystallization techniques - the spherical agglomeration and emulsion solvent diflirsion methods. The mechanisms of spherical agglomeration and crystallization were investigated. In the spherical agglomeration method, the microcrystalline drug precipitates were aggregated via liquid bridges of dichloromethane liberated from the crystallization solvent system. The growth rates were mainly determined by the amount of dichloromethane formulated. In the emulsion solvent diffusion method, the drug was precipitated within finely dispersed ethanol drops and these quasi-emulsion droplets were transformed into rigid spherical agglomerates. The mechanism determining the structure of the resultant agglomerates was clarified by measuring their mechanical strength. The crystal binding points within agglomerates produced by the spherical agglomeration method were distributed uniformly through the entire cross-section, whereas in the agglomerates prepared by the emulsion solvent diffusion method, they were localized in the agglomerate surface crust.
Introduction Particle design for solid dosage forms of pharmaceuticals involves improving the efficiency of the manufacturing processes and giving a high degree of functionality to the particles. It is difficult simultaneously to design multiple particle functions, so particle design is usually conducted in several steps. The compressibility, solubility and bioavailability of pharmaceuticals can be improved by the mechanical micronization of crystals [l-9]. This, however, leads to a decrease in flowability, packability and so on, even though the compressibility, solubility and bioavailability may be improved [lo, 111. It becomes necessary, therefore, to process microcrystals through a series of additional steps, e.g. mixing with fillers and granulation, for ease of handling. It would be more efficient to transform the microcrystalline drug itself into an agglomerated form during the crystallization process. With this in mind, the authors developed the spherical crystallization technique, combining the
processes of crystallization and agglomeration to directly produce spherically agglomerated crystals with improved physical properties, without any further processing step, such as granulation [4, 5, 12-171. In our previous study [18], we examined particle design techniques for bucillamine - an antirheumatic drug with poor packability, flowability and compressibility characteristics - using two spherical crystallization systems, i.e. spherical agglomeration and emulsion solvent diffusion. It was found that the spherically agglomerated crystals were suitable for direct compression and coating. However, the agglomeration mechanisms involved were not established. The aims of the present study were to interpret the agglomeration mechanisms of the two spherical crystallization methods, and to propose physical models of the agglomeration processes which would be able to account for the different micromeritic characteristics of agglomerated crystals produced by the two methods. Experimental
*All correspondence and proofs should be addressed to: Kenji Morishima, Central Research Laboratories, Santen Pharmaceutical Co., Ltd., 9-19 Shimoshinjo 3-chome, Higashiyodogawaku, Osaka 533, Japan.
0032-5910/93/$6.00
Preparation of spherically agglomerated crystals Particle design of bucillamine by the spherical crystallization technique was investigated by using a spher-
0 1993 - Elsevier
Sequoia. All rights reserved
58
ical agglomeration (SA) method and an emulsion solvent diffusion (ESD) method. The apparatus is shown in Fig. 1.
(Gasukuro detector.
Kogyo Inc., Japan) and a flame-ionization
Measurement of micromeritic properties SA method
Bucillamine (20 g) was dissolved in a mixture of ethanol (16 ml) and dichloromethane (12 to 14 ml), thermally controlled at 35 “C. This was poured into 300 ml of water at 5 “C, with stirring at 1000 rpm. After sufficient agitation of the system, the resultant agglomerates were collected by filtration, washed with water and dried in an oven at 40 “C for 5 h. ESD method
Bucillamine (20 g) was dissolved in ethanol (16 ml) thermally controlled at 60 “C, and the solution was poured into 300 ml of water containing hydroxypropylmethylcellulose (HPMC, TC-SRW, Shin-Etsu Chemical Co., Ltd., Japan; 0.1 to 2.0%, w/v) at 5 “C, with stirring at 200 to 500 rpm. After sufficient agitation of the system, the resultant agglomerates were filtered, washed with water and dried in an oven at 40 “C for 5 h. Di@ion of ethanol into the dispersion medium in the ESD method
The diffusion of ethanol into the dispersion medium in the ESD method was studied by measuring the ethanol concentration in the dispersion medium. A one milliliter sample of dispersion medium was collected and passed through a fine filter (Fine filter F, Toyama Sangyo, Japan) at various times. The amount of ethanol in the dispersion medium was measured by using a gas chromatograph (GC-14A, Shimadzu, Japan) fitted with a 2 m X 3 mm glass column packed with Gasukuropack55
(b)
‘n’
The mechanical strength of the resultant agglomerates was evaluated by means of a friability test and a sizestrength test. Three grams (IV,; particle size: 350-500 pm) of agglomerate was loaded onto a sieve (sieve size 250 pm) and repeatedly tapped by a ro-tap sieving machine (ES-65, Iida Manufacturing Co., Japan) at 50 t-pm for a suitable period. The weight (IV’)of the material which did not pass through the sieve was determined, and the friability (X) was calculated by using eqn. (2) below.
K-W
.__ _ mla, :t
(4
The shape and surface topography of the conventional crystals and the agglomerates were observed through a scanning electron microscope (JSM-T330A, Nihon Denshi, Japan). The shape characteristic was represented by a shape factor defined as 4 rr (area/perimeter’) with an image analyzer (GALA1 cis-1, Galai Production Ltd., Israel). The particle sizes and their distributions were measured by a sieving method. The apparent density (pap) of the agglomerates in the 350-500 pm fraction was determined by substituting the particle diameter (d), obtained as the circle equivalent diameter (Heywood diameter) with a particle size analyzer (TGZ3, Carl Zeiss, Germany), and the weight (IV) into eqn. (I).
x=
(2)
wo
84mm Y:
‘I
04
llmm w
90mm
‘E’ 1Omm
, _Y_.
_1_
(f)
MD
@I
+37mm
*
(cl
0
4 __.
1Omm
: IF.
Fig. 1. Apparatus for spherical crystallization baffle plate; (e) water bath; (f) regulator.
+ of bucillamine:
(a) cylindrical vessel (500 ml); (b) motor; (c) propeller
agitator;
(d)
59
The crushing strength of the agglomerates was measured with a compression test apparatus (Autograph 50OOD, Shimadzu, Japan). The agglomerates were fractionated into 350-500, 500-710, 710-840, 840-l 000, 1000-l 410 and 1410-2 000 pm fractions, which were compressed at 0.2 mm min-‘. The load at failure was taken as the crushing strength of the agglomerate fraction. The diameter of the agglomerates was determined as the average of the upper and lower screen mesh diameters of each fraction.
Results and discussion Aggomera tion process The agglomeration process is represented
by plotting the median diameter of the agglomerates versus the agitation time in Figs. 2(a) and 2(b). In the SA method, the median diameter of the agglomerates with 12 ml of dichloromethane was independent of the agglomeration time, while median diameter with 13 and 14 ml of dichloromethane increased with the agitation time. The growth rate drastically increased with the amount of dichloromethane added to the crystallization system. In contrast, in the case of the ESD method,
no change was observed in the median diameter of the agglomerates. Changes in the size distribution of the agglomerates in accord with the agitation time are shown in Figs. 3(a) and 3(b). In the SA method, the agglomerates had a wide distribution of size at the initial stage. Small agglomerates predominated initially, and eventually the size distribution approached a lognormal form. Finally, the agglomerates grew while maintaining constant geometrical standard deviation. On the other hand, in the case of the ESD method, no change in the size distribution of the agglomerates was observed over the entire period. These findings indicated that the agglomerates in the SA method grew by coalescence, while those in the ESD method formed without undergoing any growth process. Agglomeration mechanism
In the SA method, when the ethanol-dichloromethane mixture was poured into water, a small amount of dichloromethane was liberated from the system. The hypothesis that the precipitated crystals were held together by liquid bridges of dichloromethane liberated from the system is supported by the result that the
25001
01 0
30
60
90
120
(4
Particle Size (urn)
Agitation Time (mid
(a)
250 t
OL 0
10
20
30
40
50
60
0’) @)
Agitation Time (mid
Fig. 2. Growth process of agglomerates: (a) SA method. Amount of dichloromethane: 0, 12 ml; A, 13 ml; 0, 14 ml. (b) ESD method. Agitation speed: 250 rpm; dispersion medium: 1% HPMC solution.
Particle Size (pm)
Fig. 3. Size distribution of agglomerates: (a) SA method. Amount of dichloromethane: 13 ml; agitation time: 0, 10 min; 0, 30 min; I, 60 min; 0, 80 min; A, 100 min. (b) ESD method. Agitation speed: 250 rpm; dispersion medium: 1% HPMC solution; agitation time: 0, 5 min; A, 30 min; Cl, 60 min.
60
growth rate was affected by the amount of dichloromethane added to the system. For an understanding of the growth mechanism in coalescence agglomeration based on liquid bridges, it is important to analyze the process of compaction. As shown in Fig. 4, the apparent density of the agglomerates increased with the agitation time and the rate of compaction changed at 60 min, at which time the growth rate changed drastically. These findings can be explained as follows. The precipitated microcrystals may initially form loose agglomerates held together by discrete bridges of liberated dichloromethane. These loose agglomerates in the funicular state could coalesce with small particles and individual crystals. However, they would not be able to coalesce with other large agglomerates because they have no excess bridging liquid on their surface. On further agitation, the filling ratio of dichloromethane in the agglomerates would increase under the shear force, and finally the agglomerates would reach a capillary state. These agglomerates could coalesce into large agglomerates with a slight increase in the apparent density. On the other hand, in the case of the ESD method, the agitation time had no effect on the median diameter and its distribution. When the ethanol solution of the drug was poured into water containing HPMC, quasiemulsion droplets formed immediately. These findings suggested that the agglomerates were produced by solidification of the quasi-emulsion droplets, and that the solidified particles did not aggregate with each other. This explanation is supported by the fact that the diameter of the agglomerates decreased with increase in the agitation speed, which expects the alteration of the quasi-emulsion droplet size, as shown in Fig. 5. This procedure was reexamined by dropping the ethanol with the drug into water containing HPMC. As shown in Fig. 6, at the initial stage, the ethanol containing the drug formed droplets (Fig. 6(A)) and the outer surface of the droplets crystallized (Fig. 6(B)). Subsequently, crystals grew in the droplet and the
a
I
01
0
I
30
I
t
60 Agitation
I
90 Time
120 (min)
Fig. 4. Relationship between agitation time and apparent density in the SA method. Amount of dichloromethane: 13 ml; agitation time: 30 min.
1000 c
OO200
Agitation
Speed
(rpm)
Fig. 5. Effect of agitation speed on median diameter method. Agitation time: 5 min; dispersion medium: solution.
in the ESD 1% HPMC
droplet solidified without any change in size (Fig. 6(C)). In addition, in order to investigate the diffusion process of ethanol from the quasi-emulsion droplets, the ethanol concentration in the dispersion medium was measured. The diffusion of ethanol in the presence of the drug was delayed as compared to that without the drug, as shown in Fig. 7. These observations suggested that cooling of the solvent and instant local mixing of ethanol and water at the interface of the droplet induced precipitation of the drug, thus forming a shell, and then counter diffusions of ethanol and water through the shell promoted further crystallization of the drug in the droplet. In addition, in order to investigate the contribution of HPMC in the ESD method, the agglomerates were prepared with various HPMC concentrations in the dispersion medium. With no addition of HPMC, only an irregular mass of the drug was obtained. The presence of HPMC was indispensable to yield spherical agglomerates. The effects of HPMC concentration on the median diameter and the shape are shown in Figs. 8 and 9, respectively. The size of the agglomerates was decreased and the spheric&y of agglomerates was improved by increasing the HPMC concentration in the dispersion medium. The large-size region of the agglomerates was decreased by increasing the HPMC concentration as shown in Fig. 10. In the absence of HPMC, crystallization occurred without the stable formation of ethanol droplets and the ethanol droplets collided and adhered. On the basis of these findings, it was considered that HPMC in the dispersion medium acted as a protector against coalescence at the initial stage. As shown in Fig. 8, the effect of HPMC concentration on the coalescence decreased with increasing the agitation speed, because the size of the quasi-emulsion droplets decreased with increasing the agitation speed and the small quasi-emulsion droplets consolidated rapidly due to large specific surface.
Fig. 6. Crystallization process in the ESD method. Changes of quasi-emulsion droplets of an ethanolic into 1% HPMC solution in a glass dish. (A) 0.5 min, (B) 1 min, (C) 2 min.
solution of bucillamine
dropped
1.0 -
l-
8 0.9. z IL” g 0 f
0.8. 00 0.7.
I J.
01 0
2
1 Agitation
3
5
0
Time (mid
0.5 HPMC
Fig. 7. Diffusion process of ethanol from quasi-emulsion droplets. Ethanol with drug (0) or without drug (0) was poured into 1% HPMC solution stirred at 250 rpm.
1.5
1.0
Concentration
2.0
t%)
Fig. 9. Effect of HPMC concentration in dispersion medium on shape factor in the ESD method. Agitation speed: 250 ‘pm.
1
3 8
1250 Z .? 1000 b 5 E, 750 b55
10
z
500
5 0
50
z ._ z 5 E
90
6
s 250
0
0
0.5
1.0 HPMC
1.5
Concentration
2.0
(%I
Fig. 8. Effect of HPMC concentration in dispersion medium on median diameter in the ESD method. Agitation speed: 0, 200 ‘pm; A, 250 rpm; El, 400 rpm.
On the basis of the above results, we propose the models shown in Fig. 11 for the spherical crystallization processes in the SA and ESD methods.
Particle
Size
(pm)
Fig. 10. Effect of HPMC concentration on size distribution in the ESD method. Agitation speed: 250 rpm; HPMC concentration: 0, 0.1%; A, 0.2%; W, 0.5%; 0, l.O%, A, 2.0%.
Micromeritic characteristics of the agglomerates The micromeritic characteristics of the resultant agglomerates were affected by the agglomeration process. The shape and surface topography of conventional crystals (Fig. 12(A)) and the agglomerates (Fig. 12(BI), (B-2) (C-l) and (C-2)) were investigated with a
62
SA method
0
63o-
coalescence
compaction
Ql
Preoipitated crystals
Funicular state
!!iz$ -
COalesCeflM
@ Capillary state
Spherical agglomerate
and liberated CH2CI 2
ESD method
0
n
dlXlOl
L-J
+
0 Formation of emulsion Fig. 11. Schematic
processes
z*
water
*-
Counter diffusions of ethanol and water of spherical
Crystallization
crystallization.
1 OOpm
1OOpm
2Opm Fig. 12. Scanning electron micrographs of conventional crystals and agglomerates. by SA method, (C) agglomerate obtained by ESD method.
(A) conventional
crystals, (B) agglomerate
obtained
63
scanning electron microscope. The agglomerates obtained by the SA method were formed by coalescence of microcrystalline precipitates, so the resultant agglomerates had a rough surface covered with numerous plate-shaped crystals (Fig. 12(B-2)). On the other hand, with the ESD method, emulsion droplets crystallized instantaneously from their surface inward, so the resultant agglomerates were very dense in texture (Fig. 12(C-2)). To investigate the differences in the structures of the agglomerates obtained by the SA and ESD methods, they were subjected to the size-strength test and friability test. As shown in Fig. 13, linear relationships between the logarithmic diameter and the logarithmic crushing strength were obtained. Capes [19] and Kawashima et al. [20] established a general relationship between crushing strength (F) and agglomerate diameter (0) as shown by eqn. (3) F=KLY’
TABLE
1. Parameters
Agglomeration method
Agitation time (min)
Parameters n
K
SA method
30 60 120 5
1.97 1.84 1.89 1.27
12.7 28.0 53.3 22.9
ESD method “F=KD”,
where F and D are crushing strength size (mm), respectively.
(g) and particle
0.6
(3)
where K and n are constants. When n has a value of 2, the binding points are considered to be located uniformly over the entire cross-section. On the other hand, when most of the binding points are localized at the surface crust, the binding cross-section is directly related to the particle circumference, and n has a value close to 1. The least-squares values for parameters n and K are listed in Table 1. The agglomerates prepared by the SA method showed n close to 2 and the strength factor, K, increased with the agitation time. In contrast, the n value of the agglomerates prepared by the ESD method approached unity. On the basis of these findings, it is apparent that the crystal binding points within the agglomerates prepared by the SA method were located uniformly over the entire cross-section because the agglomerates grew by coalescence. On the other hand, the crystal binding points within the agglomerates pre-
I
4
0
2
4
1
*
1
.
0.5 Particle
*
*
*
’
.““....lcLL
1
2
Size (mm)
Fig. 13. Relationship between particle size and crushing strength. SA method: amount of dichloromethane: 13 ml; agitation time: 0, 30 min; a, 60 min; Cl, 120 min. ESD method: agitation time: 0, 5 min.
8
Fig. 14. Friability of agglomerates (X: pulverized fraction). SA method: amount of dichloromethane: 13 ml; agitation time: 0, 30 min; A, 60 min; 0, 120 min. ESD method: agitation time: 0, 5 min.
pared by the ESD method were localized at the surface crust because the quasi-emulsion droplets crystallized instantaneously at their surface and crystallization then proceeded inwards. These conclusions were also supported by the friability test results. The relationship between friability (X) and time (t) was treated by means of eqn. (4) [21], I-
5
t aP
0.3
6 Time (h)
(14y3=
I
in eqn. (3)”
0
(4)
where K is the abrasion rate constant, X0 is the diameter of the agglomerates prior to the test, pap is the apparent density of the agglomerates, and 4 is the shape factor. As shown in Fig. 14, the agglomerates obtained by the SA method showed friability in accordance with eqn. (4). It suggested that the damage to the agglomerates prepared by the SA method proceeded from their surfaces inward, and that the cohesive force worked between constitutive crystals uniformly within the agglomerates. On the other hand, the agglomerates prepared by the ESD method were not easily pulverized because the crystals’ binding points within the agglomerates were localized at their surface crusts.
64
Conclusions It was found that agglomerates in the SA method grew by coalescence based via bridges of a binding liquid, while agglomerates in the ESD method formed by crystallization of quasi-emulsion droplets from their surface inwards. As a result, the agglomerates prepared by the two methods have quite different micromeritic characteristics because of the difference in the distributions of crystal binding points within the agglomerates.
References N. Kaneniwa, K. Imagawa and J. Ichikawa, Chem. Pharm. Bull., 26 (1988) 2531. M. Hasegawa, A. Otuka and F. Higashide, J. Pharm. Sci. Technol. Jpn., 46 (1986) 50. A. McKenna and D. F. McCafferty, J. Pharm. Pharmacol., 34 (1982) 347. Y. Kawashima, T. Handa, H. Takeuchi, M. Okumura, H. Katou and 0. Nagata, Chem. Phorm. BUN., 34 (1986) 659. A. Sano, T. Kuriki, Y. Kawashima, H. Takeuchi, T. Hino and T. Niwa, Chem. Pharm. Bull., 38 (1990) 733.
6 J. H. Fincher, J. G. Adams and H. Beal, J. Pharm. Sci., 54 (1965) 704. 7 L. F. Prescott, R. F. Steel and W. R. Ferrier, Clin. Pharmacol. Ther., II (1970) 496. 8 N. Kaneniwa and N. Watari, Chem. Pharm. Bull., 26 (1978) 813. 9 Y. Hirakawa and K. Harada, J. Phann. Sot. Jpn., 103 (1983) 1190. 10 R. Carr, Chem. Eng., 67 (1960) 121. 11 J. T. Carstensen and P. C. Chan, J. Pharm. Sci., 66 (1977) 1235. 12 Y. Kawashima, M. Okumura and H. Takenaka, Science, 216 (1982) 1127. 13 Y. Kawashima, M. Okumura, H. Takenaka and A. Kojima, J. Pharm. Sci, 73 (1984) 1535. 14 Y. Kawashima, T. Handa, H. Takeuchi and M. Okumura, J. Sot. Powder Technol., Jpn., 20 (1983) 759. 15 Y. Kawashima, H. Takeuchi, T. Niwa, T. Hino, M. Yamakoshi and K. Kihara, J. Sot. Powder TechnoL, Jpn., 26 (1989) 34. 16 Y. Kawashima, Proc. Second World Gong., Particle Technology Part III, Kyoto, 1990, p. 307. 17 Y. Kawashima, H. Takeuchi, T. Niwa, T. Hino, Y. Ito and S. Furuyama, ICHEME 5th Int. Symp. Agglomeration, Brighton, 1989, p. 145. 18 Y. Kawashima, K. Morishima, H. Takeuchi, T. Niwa, T. Hino and Y. Kawashima, AIChE J. Symp. Ser., 87 (1991) 26. 19 C. E. Capes, Powder TechnoL, 4 (1970/1971) 77. 20 Y. Kawashima, H. Takagi and H. Takenaka, Chem. Phnrm. Bull., 29 (1981) 1403. 21 I. Sekiguchi, Pharm. Fact., Jpn., 3 (1983) 19.
57
Micromeritic characteristics and agglomeration mechanisms spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent diffusion methods Kenji Morishima*
in the
and Yoichi Kawashima
Santen Pharmaceutical Co., Ltd., 9-19 Shimoshbjo
Yoshiaki Kawashima,
3-chome, Higashjodogawa-ku,
Osaka 533 (Japan)
Hirofumi Takeuchi, Toshiyuki Niwa and Tomoaki Hino
Gifu Pharmaceutical University, 5-6-l Mitahora-Higashi, Gifi 502 (Japan) (Received
February
3, 1992, in revised form January
19, 1993)
Abstract The physical properties of bucillamine were modified by the application of two spherical crystallization techniques - the spherical agglomeration and emulsion solvent diflirsion methods. The mechanisms of spherical agglomeration and crystallization were investigated. In the spherical agglomeration method, the microcrystalline drug precipitates were aggregated via liquid bridges of dichloromethane liberated from the crystallization solvent system. The growth rates were mainly determined by the amount of dichloromethane formulated. In the emulsion solvent diffusion method, the drug was precipitated within finely dispersed ethanol drops and these quasi-emulsion droplets were transformed into rigid spherical agglomerates. The mechanism determining the structure of the resultant agglomerates was clarified by measuring their mechanical strength. The crystal binding points within agglomerates produced by the spherical agglomeration method were distributed uniformly through the entire cross-section, whereas in the agglomerates prepared by the emulsion solvent diffusion method, they were localized in the agglomerate surface crust.
Introduction Particle design for solid dosage forms of pharmaceuticals involves improving the efficiency of the manufacturing processes and giving a high degree of functionality to the particles. It is difficult simultaneously to design multiple particle functions, so particle design is usually conducted in several steps. The compressibility, solubility and bioavailability of pharmaceuticals can be improved by the mechanical micronization of crystals [l-9]. This, however, leads to a decrease in flowability, packability and so on, even though the compressibility, solubility and bioavailability may be improved [lo, 111. It becomes necessary, therefore, to process microcrystals through a series of additional steps, e.g. mixing with fillers and granulation, for ease of handling. It would be more efficient to transform the microcrystalline drug itself into an agglomerated form during the crystallization process. With this in mind, the authors developed the spherical crystallization technique, combining the
processes of crystallization and agglomeration to directly produce spherically agglomerated crystals with improved physical properties, without any further processing step, such as granulation [4, 5, 12-171. In our previous study [18], we examined particle design techniques for bucillamine - an antirheumatic drug with poor packability, flowability and compressibility characteristics - using two spherical crystallization systems, i.e. spherical agglomeration and emulsion solvent diffusion. It was found that the spherically agglomerated crystals were suitable for direct compression and coating. However, the agglomeration mechanisms involved were not established. The aims of the present study were to interpret the agglomeration mechanisms of the two spherical crystallization methods, and to propose physical models of the agglomeration processes which would be able to account for the different micromeritic characteristics of agglomerated crystals produced by the two methods. Experimental
*All correspondence and proofs should be addressed to: Kenji Morishima, Central Research Laboratories, Santen Pharmaceutical Co., Ltd., 9-19 Shimoshinjo 3-chome, Higashiyodogawaku, Osaka 533, Japan.
0032-5910/93/$6.00
Preparation of spherically agglomerated crystals Particle design of bucillamine by the spherical crystallization technique was investigated by using a spher-
0 1993 - Elsevier
Sequoia. All rights reserved
58
ical agglomeration (SA) method and an emulsion solvent diffusion (ESD) method. The apparatus is shown in Fig. 1.
(Gasukuro detector.
Kogyo Inc., Japan) and a flame-ionization
Measurement of micromeritic properties SA method
Bucillamine (20 g) was dissolved in a mixture of ethanol (16 ml) and dichloromethane (12 to 14 ml), thermally controlled at 35 “C. This was poured into 300 ml of water at 5 “C, with stirring at 1000 rpm. After sufficient agitation of the system, the resultant agglomerates were collected by filtration, washed with water and dried in an oven at 40 “C for 5 h. ESD method
Bucillamine (20 g) was dissolved in ethanol (16 ml) thermally controlled at 60 “C, and the solution was poured into 300 ml of water containing hydroxypropylmethylcellulose (HPMC, TC-SRW, Shin-Etsu Chemical Co., Ltd., Japan; 0.1 to 2.0%, w/v) at 5 “C, with stirring at 200 to 500 rpm. After sufficient agitation of the system, the resultant agglomerates were filtered, washed with water and dried in an oven at 40 “C for 5 h. Di@ion of ethanol into the dispersion medium in the ESD method
The diffusion of ethanol into the dispersion medium in the ESD method was studied by measuring the ethanol concentration in the dispersion medium. A one milliliter sample of dispersion medium was collected and passed through a fine filter (Fine filter F, Toyama Sangyo, Japan) at various times. The amount of ethanol in the dispersion medium was measured by using a gas chromatograph (GC-14A, Shimadzu, Japan) fitted with a 2 m X 3 mm glass column packed with Gasukuropack55
(b)
‘n’
The mechanical strength of the resultant agglomerates was evaluated by means of a friability test and a sizestrength test. Three grams (IV,; particle size: 350-500 pm) of agglomerate was loaded onto a sieve (sieve size 250 pm) and repeatedly tapped by a ro-tap sieving machine (ES-65, Iida Manufacturing Co., Japan) at 50 t-pm for a suitable period. The weight (IV’)of the material which did not pass through the sieve was determined, and the friability (X) was calculated by using eqn. (2) below.
K-W
.__ _ mla, :t
(4
The shape and surface topography of the conventional crystals and the agglomerates were observed through a scanning electron microscope (JSM-T330A, Nihon Denshi, Japan). The shape characteristic was represented by a shape factor defined as 4 rr (area/perimeter’) with an image analyzer (GALA1 cis-1, Galai Production Ltd., Israel). The particle sizes and their distributions were measured by a sieving method. The apparent density (pap) of the agglomerates in the 350-500 pm fraction was determined by substituting the particle diameter (d), obtained as the circle equivalent diameter (Heywood diameter) with a particle size analyzer (TGZ3, Carl Zeiss, Germany), and the weight (IV) into eqn. (I).
x=
(2)
wo
84mm Y:
‘I
04
llmm w
90mm
‘E’ 1Omm
, _Y_.
_1_
(f)
MD
@I
+37mm
*
(cl
0
4 __.
1Omm
: IF.
Fig. 1. Apparatus for spherical crystallization baffle plate; (e) water bath; (f) regulator.
+ of bucillamine:
(a) cylindrical vessel (500 ml); (b) motor; (c) propeller
agitator;
(d)
59
The crushing strength of the agglomerates was measured with a compression test apparatus (Autograph 50OOD, Shimadzu, Japan). The agglomerates were fractionated into 350-500, 500-710, 710-840, 840-l 000, 1000-l 410 and 1410-2 000 pm fractions, which were compressed at 0.2 mm min-‘. The load at failure was taken as the crushing strength of the agglomerate fraction. The diameter of the agglomerates was determined as the average of the upper and lower screen mesh diameters of each fraction.
Results and discussion Aggomera tion process The agglomeration process is represented
by plotting the median diameter of the agglomerates versus the agitation time in Figs. 2(a) and 2(b). In the SA method, the median diameter of the agglomerates with 12 ml of dichloromethane was independent of the agglomeration time, while median diameter with 13 and 14 ml of dichloromethane increased with the agitation time. The growth rate drastically increased with the amount of dichloromethane added to the crystallization system. In contrast, in the case of the ESD method,
no change was observed in the median diameter of the agglomerates. Changes in the size distribution of the agglomerates in accord with the agitation time are shown in Figs. 3(a) and 3(b). In the SA method, the agglomerates had a wide distribution of size at the initial stage. Small agglomerates predominated initially, and eventually the size distribution approached a lognormal form. Finally, the agglomerates grew while maintaining constant geometrical standard deviation. On the other hand, in the case of the ESD method, no change in the size distribution of the agglomerates was observed over the entire period. These findings indicated that the agglomerates in the SA method grew by coalescence, while those in the ESD method formed without undergoing any growth process. Agglomeration mechanism
In the SA method, when the ethanol-dichloromethane mixture was poured into water, a small amount of dichloromethane was liberated from the system. The hypothesis that the precipitated crystals were held together by liquid bridges of dichloromethane liberated from the system is supported by the result that the
25001
01 0
30
60
90
120
(4
Particle Size (urn)
Agitation Time (mid
(a)
250 t
OL 0
10
20
30
40
50
60
0’) @)
Agitation Time (mid
Fig. 2. Growth process of agglomerates: (a) SA method. Amount of dichloromethane: 0, 12 ml; A, 13 ml; 0, 14 ml. (b) ESD method. Agitation speed: 250 rpm; dispersion medium: 1% HPMC solution.
Particle Size (pm)
Fig. 3. Size distribution of agglomerates: (a) SA method. Amount of dichloromethane: 13 ml; agitation time: 0, 10 min; 0, 30 min; I, 60 min; 0, 80 min; A, 100 min. (b) ESD method. Agitation speed: 250 rpm; dispersion medium: 1% HPMC solution; agitation time: 0, 5 min; A, 30 min; Cl, 60 min.
60
growth rate was affected by the amount of dichloromethane added to the system. For an understanding of the growth mechanism in coalescence agglomeration based on liquid bridges, it is important to analyze the process of compaction. As shown in Fig. 4, the apparent density of the agglomerates increased with the agitation time and the rate of compaction changed at 60 min, at which time the growth rate changed drastically. These findings can be explained as follows. The precipitated microcrystals may initially form loose agglomerates held together by discrete bridges of liberated dichloromethane. These loose agglomerates in the funicular state could coalesce with small particles and individual crystals. However, they would not be able to coalesce with other large agglomerates because they have no excess bridging liquid on their surface. On further agitation, the filling ratio of dichloromethane in the agglomerates would increase under the shear force, and finally the agglomerates would reach a capillary state. These agglomerates could coalesce into large agglomerates with a slight increase in the apparent density. On the other hand, in the case of the ESD method, the agitation time had no effect on the median diameter and its distribution. When the ethanol solution of the drug was poured into water containing HPMC, quasiemulsion droplets formed immediately. These findings suggested that the agglomerates were produced by solidification of the quasi-emulsion droplets, and that the solidified particles did not aggregate with each other. This explanation is supported by the fact that the diameter of the agglomerates decreased with increase in the agitation speed, which expects the alteration of the quasi-emulsion droplet size, as shown in Fig. 5. This procedure was reexamined by dropping the ethanol with the drug into water containing HPMC. As shown in Fig. 6, at the initial stage, the ethanol containing the drug formed droplets (Fig. 6(A)) and the outer surface of the droplets crystallized (Fig. 6(B)). Subsequently, crystals grew in the droplet and the
a
I
01
0
I
30
I
t
60 Agitation
I
90 Time
120 (min)
Fig. 4. Relationship between agitation time and apparent density in the SA method. Amount of dichloromethane: 13 ml; agitation time: 30 min.
1000 c
OO200
Agitation
Speed
(rpm)
Fig. 5. Effect of agitation speed on median diameter method. Agitation time: 5 min; dispersion medium: solution.
in the ESD 1% HPMC
droplet solidified without any change in size (Fig. 6(C)). In addition, in order to investigate the diffusion process of ethanol from the quasi-emulsion droplets, the ethanol concentration in the dispersion medium was measured. The diffusion of ethanol in the presence of the drug was delayed as compared to that without the drug, as shown in Fig. 7. These observations suggested that cooling of the solvent and instant local mixing of ethanol and water at the interface of the droplet induced precipitation of the drug, thus forming a shell, and then counter diffusions of ethanol and water through the shell promoted further crystallization of the drug in the droplet. In addition, in order to investigate the contribution of HPMC in the ESD method, the agglomerates were prepared with various HPMC concentrations in the dispersion medium. With no addition of HPMC, only an irregular mass of the drug was obtained. The presence of HPMC was indispensable to yield spherical agglomerates. The effects of HPMC concentration on the median diameter and the shape are shown in Figs. 8 and 9, respectively. The size of the agglomerates was decreased and the spheric&y of agglomerates was improved by increasing the HPMC concentration in the dispersion medium. The large-size region of the agglomerates was decreased by increasing the HPMC concentration as shown in Fig. 10. In the absence of HPMC, crystallization occurred without the stable formation of ethanol droplets and the ethanol droplets collided and adhered. On the basis of these findings, it was considered that HPMC in the dispersion medium acted as a protector against coalescence at the initial stage. As shown in Fig. 8, the effect of HPMC concentration on the coalescence decreased with increasing the agitation speed, because the size of the quasi-emulsion droplets decreased with increasing the agitation speed and the small quasi-emulsion droplets consolidated rapidly due to large specific surface.
Fig. 6. Crystallization process in the ESD method. Changes of quasi-emulsion droplets of an ethanolic into 1% HPMC solution in a glass dish. (A) 0.5 min, (B) 1 min, (C) 2 min.
solution of bucillamine
dropped
1.0 -
l-
8 0.9. z IL” g 0 f
0.8. 00 0.7.
I J.
01 0
2
1 Agitation
3
5
0
Time (mid
0.5 HPMC
Fig. 7. Diffusion process of ethanol from quasi-emulsion droplets. Ethanol with drug (0) or without drug (0) was poured into 1% HPMC solution stirred at 250 rpm.
1.5
1.0
Concentration
2.0
t%)
Fig. 9. Effect of HPMC concentration in dispersion medium on shape factor in the ESD method. Agitation speed: 250 ‘pm.
1
3 8
1250 Z .? 1000 b 5 E, 750 b55
10
z
500
5 0
50
z ._ z 5 E
90
6
s 250
0
0
0.5
1.0 HPMC
1.5
Concentration
2.0
(%I
Fig. 8. Effect of HPMC concentration in dispersion medium on median diameter in the ESD method. Agitation speed: 0, 200 ‘pm; A, 250 rpm; El, 400 rpm.
On the basis of the above results, we propose the models shown in Fig. 11 for the spherical crystallization processes in the SA and ESD methods.
Particle
Size
(pm)
Fig. 10. Effect of HPMC concentration on size distribution in the ESD method. Agitation speed: 250 rpm; HPMC concentration: 0, 0.1%; A, 0.2%; W, 0.5%; 0, l.O%, A, 2.0%.
Micromeritic characteristics of the agglomerates The micromeritic characteristics of the resultant agglomerates were affected by the agglomeration process. The shape and surface topography of conventional crystals (Fig. 12(A)) and the agglomerates (Fig. 12(BI), (B-2) (C-l) and (C-2)) were investigated with a
62
SA method
0
63o-
coalescence
compaction
Ql
Preoipitated crystals
Funicular state
!!iz$ -
COalesCeflM
@ Capillary state
Spherical agglomerate
and liberated CH2CI 2
ESD method
0
n
dlXlOl
L-J
+
0 Formation of emulsion Fig. 11. Schematic
processes
z*
water
*-
Counter diffusions of ethanol and water of spherical
Crystallization
crystallization.
1 OOpm
1OOpm
2Opm Fig. 12. Scanning electron micrographs of conventional crystals and agglomerates. by SA method, (C) agglomerate obtained by ESD method.
(A) conventional
crystals, (B) agglomerate
obtained
63
scanning electron microscope. The agglomerates obtained by the SA method were formed by coalescence of microcrystalline precipitates, so the resultant agglomerates had a rough surface covered with numerous plate-shaped crystals (Fig. 12(B-2)). On the other hand, with the ESD method, emulsion droplets crystallized instantaneously from their surface inward, so the resultant agglomerates were very dense in texture (Fig. 12(C-2)). To investigate the differences in the structures of the agglomerates obtained by the SA and ESD methods, they were subjected to the size-strength test and friability test. As shown in Fig. 13, linear relationships between the logarithmic diameter and the logarithmic crushing strength were obtained. Capes [19] and Kawashima et al. [20] established a general relationship between crushing strength (F) and agglomerate diameter (0) as shown by eqn. (3) F=KLY’
TABLE
1. Parameters
Agglomeration method
Agitation time (min)
Parameters n
K
SA method
30 60 120 5
1.97 1.84 1.89 1.27
12.7 28.0 53.3 22.9
ESD method “F=KD”,
where F and D are crushing strength size (mm), respectively.
(g) and particle
0.6
(3)
where K and n are constants. When n has a value of 2, the binding points are considered to be located uniformly over the entire cross-section. On the other hand, when most of the binding points are localized at the surface crust, the binding cross-section is directly related to the particle circumference, and n has a value close to 1. The least-squares values for parameters n and K are listed in Table 1. The agglomerates prepared by the SA method showed n close to 2 and the strength factor, K, increased with the agitation time. In contrast, the n value of the agglomerates prepared by the ESD method approached unity. On the basis of these findings, it is apparent that the crystal binding points within the agglomerates prepared by the SA method were located uniformly over the entire cross-section because the agglomerates grew by coalescence. On the other hand, the crystal binding points within the agglomerates pre-
I
4
0
2
4
1
*
1
.
0.5 Particle
*
*
*
’
.““....lcLL
1
2
Size (mm)
Fig. 13. Relationship between particle size and crushing strength. SA method: amount of dichloromethane: 13 ml; agitation time: 0, 30 min; a, 60 min; Cl, 120 min. ESD method: agitation time: 0, 5 min.
8
Fig. 14. Friability of agglomerates (X: pulverized fraction). SA method: amount of dichloromethane: 13 ml; agitation time: 0, 30 min; A, 60 min; 0, 120 min. ESD method: agitation time: 0, 5 min.
pared by the ESD method were localized at the surface crust because the quasi-emulsion droplets crystallized instantaneously at their surface and crystallization then proceeded inwards. These conclusions were also supported by the friability test results. The relationship between friability (X) and time (t) was treated by means of eqn. (4) [21], I-
5
t aP
0.3
6 Time (h)
(14y3=
I
in eqn. (3)”
0
(4)
where K is the abrasion rate constant, X0 is the diameter of the agglomerates prior to the test, pap is the apparent density of the agglomerates, and 4 is the shape factor. As shown in Fig. 14, the agglomerates obtained by the SA method showed friability in accordance with eqn. (4). It suggested that the damage to the agglomerates prepared by the SA method proceeded from their surfaces inward, and that the cohesive force worked between constitutive crystals uniformly within the agglomerates. On the other hand, the agglomerates prepared by the ESD method were not easily pulverized because the crystals’ binding points within the agglomerates were localized at their surface crusts.
64
Conclusions It was found that agglomerates in the SA method grew by coalescence based via bridges of a binding liquid, while agglomerates in the ESD method formed by crystallization of quasi-emulsion droplets from their surface inwards. As a result, the agglomerates prepared by the two methods have quite different micromeritic characteristics because of the difference in the distributions of crystal binding points within the agglomerates.
References N. Kaneniwa, K. Imagawa and J. Ichikawa, Chem. Pharm. Bull., 26 (1988) 2531. M. Hasegawa, A. Otuka and F. Higashide, J. Pharm. Sci. Technol. Jpn., 46 (1986) 50. A. McKenna and D. F. McCafferty, J. Pharm. Pharmacol., 34 (1982) 347. Y. Kawashima, T. Handa, H. Takeuchi, M. Okumura, H. Katou and 0. Nagata, Chem. Phorm. BUN., 34 (1986) 659. A. Sano, T. Kuriki, Y. Kawashima, H. Takeuchi, T. Hino and T. Niwa, Chem. Pharm. Bull., 38 (1990) 733.
6 J. H. Fincher, J. G. Adams and H. Beal, J. Pharm. Sci., 54 (1965) 704. 7 L. F. Prescott, R. F. Steel and W. R. Ferrier, Clin. Pharmacol. Ther., II (1970) 496. 8 N. Kaneniwa and N. Watari, Chem. Pharm. Bull., 26 (1978) 813. 9 Y. Hirakawa and K. Harada, J. Phann. Sot. Jpn., 103 (1983) 1190. 10 R. Carr, Chem. Eng., 67 (1960) 121. 11 J. T. Carstensen and P. C. Chan, J. Pharm. Sci., 66 (1977) 1235. 12 Y. Kawashima, M. Okumura and H. Takenaka, Science, 216 (1982) 1127. 13 Y. Kawashima, M. Okumura, H. Takenaka and A. Kojima, J. Pharm. Sci, 73 (1984) 1535. 14 Y. Kawashima, T. Handa, H. Takeuchi and M. Okumura, J. Sot. Powder Technol., Jpn., 20 (1983) 759. 15 Y. Kawashima, H. Takeuchi, T. Niwa, T. Hino, M. Yamakoshi and K. Kihara, J. Sot. Powder TechnoL, Jpn., 26 (1989) 34. 16 Y. Kawashima, Proc. Second World Gong., Particle Technology Part III, Kyoto, 1990, p. 307. 17 Y. Kawashima, H. Takeuchi, T. Niwa, T. Hino, Y. Ito and S. Furuyama, ICHEME 5th Int. Symp. Agglomeration, Brighton, 1989, p. 145. 18 Y. Kawashima, K. Morishima, H. Takeuchi, T. Niwa, T. Hino and Y. Kawashima, AIChE J. Symp. Ser., 87 (1991) 26. 19 C. E. Capes, Powder TechnoL, 4 (1970/1971) 77. 20 Y. Kawashima, H. Takagi and H. Takenaka, Chem. Phnrm. Bull., 29 (1981) 1403. 21 I. Sekiguchi, Pharm. Fact., Jpn., 3 (1983) 19.