Ordered powder mixing of coarse and fine particulate systems

Powder Technology. 22 (1979) 127 - 131 0 Elsevier Sequoia S-A., Lausanne -Printed

127 in the Netherlands

I Ordered Powder Mixing of Coarse and I& CHARLES School

C. YEUNG

of Pharmaceutics,

JOHN k Institute

Particulate Systems

Victorian

College of Pharmacy

Ltd., Parkuille, Victoria,

3052

(Australia)

HERSEY of Drug Technology

(Received

July 25,1978;

Ltd., Parkuille. Victoria.

3052

(Australia)

in revised form August 29, 1978)

SUMMARY

Ordered powder mixtures have been produced using comparatively fine powder systems. Such mixtures have been produced in a ball mill and a cube mixer. The preparation of ordered mixtures in a cube mixer is slow due to the low energy input of the internal agitator. The higher energy input of the grinding media in the ball mill accounts for the more rapid mixing in this system. The ordered mixtures produced have a higher degree of homogeneity than those hitherto prepared.

INTRODUCTION

Ordered powder mixtures [l] are formed when a fine component has sufficient intrinsic cohesiveness, due to electrostatic, van der Waals or surface tensional forces, to adhere to the surface of a more coarse component [2 - 4]_ In these cases it is believed that the more coarse component assists in the mixing process by breaking down aggregates of the fine powder, thus allowing the adhesion of single cohesive particles to the surfaces of the more coarse constituents. The formation of ordered powder mixtures of this type in tumbling mixers, which give the coarse particles sufficient inertia to break down the agglomerates of fine powder, is evidence for the occurrence of this phenomena. It would be of considerable interest to observe the mixing of two fine powders, since such a system is capable of achieving values of homogeneity higher than in a system where one of the powders being mixed is more coarse [ 53 _ The theoretical problems that exist when considering the mixing of two fine powders is that they will each form agglomerates prior to mixing. These agglomerates will then mix ran-

domly with agglomerates of the other constituent just as two more coarse powders would mix, resulting in a considerably lower value of homogeneity than that theoretically possible if the fine powders are considered as individual particles. Alternatively the agglomerates of each of the individual particles must be broken down, using high energy input, and the single particlesallowed to rebuild agglomerates consisting of both components of the mixture. This paper describes the mixing of microfine salicylic acid particles with two size grades of sucrose powder (granular and icing sugar). Mixing in two different systems was observed. A Revolvo-Cube tumbling mixer fitted with internal agitators has been compared with a ball mill, nr,rmally used for the comrninution of coarse particulate solids. Mills of this type are frequently used in powder mix-kg practice, although they have not been widely evaluated for this purpose. The difference between the two mixing systems is largely confined to the energy input. In the cube mixer there is a gravitational tumbling action of the powders themselves together with the gentle motion of the internal agitator_ In the ball mill, the gravitational tumbling action is exaggerated by the high inertia of the ball mill media. The energy input ln both systems is responsible for the breakdown of the agglomerates in the fine powders. Excess energy input may cause particle size reduction, especially where coarse powders are being mixed [S] .

EXPERIMENTAL Two grades of sucrose were used. Crystalline sucrose was the sieve fraction obtained when C.S.R. brand 1A granulated sugar was

128

sieved above 630 pm sieve using a Laboratory test sieve (Endecott’s). The fine sucrose consisted of Havelock brand of icing sugar. It contained no additives, according to the manufacturer, and was ground from sugar of the same quality as the crystalline sucrose. The icing sugar was not further processed_ The particle size of the fine icing sugar was determined using the Andreasen column with chloroform as the sedimentation fluid. Microfine salicylic acid was chosen as the other constituent in the binary system_ The densities of sucrose and salicylic acid were determined using a Beckman air comparison pycnometer (Model 940). One part of salicylic acid was mixed with 999 parts of sucrose in each experiment. Mixing was carried out in a stainless steel RevolvoCube mixer (capacity 7.5 kg) revolving at 17 rev/mm. The internal agitator operated at 37 revfmin. The mixer was half-filled with 3.6 kg sucrose (or 3.3 kg of icing sugar) before operating. Alternatively, the mixing was carried out in a 8 $ in. (21.6 cm) external diameter ball mill half-filled with ceramic balls of two sizes,$in. (1 kg) andsin. (2.3 kg). 1.5 kg of sucrose (or 1.3 kg of icing sugar) was used for each mix. The different quantities used in each mixer were chosen due to the differences in bulk densities of the two varieties of sucrose. As particle size is reduced

during mixing in the ball mill, samples of crystalline sucrose powder were removed during the milling operation and sized using a nest of sieves and a test-sieve shaker (ACCheers). During mixing, twenty samples were removed at preselected time intervals using a concentric cylindrical sampling thief from random positions selected using a table of random numbers. Where the effect of sample size was to be ascertained, twenty samples of several different sample weights, between 100 mg and 4 g, were collected using avariety of sampling thieves. The samples were dissolved in 50% ethanol/ water cosolvent system and the content of salicylic acid was assayed by measuring the absorbance at 300 nm using a Varian Techtron auto-sampling unit connected to a spectrophotometer (Model 634). The blank consisted of 50% ethanol with an equivalent amount of sucrose. The standard deviation of sample concentration was calculated from the individual results.

RESULTS

The density of sucrose was found to be 1.59 g cmM3 and that of salicylic acid 1.44 g cm -3_ The particle size of the crystalline sucrose was calculated as 750 pm (ie. using

TABLE 1 Particle size distribution in the ball mill Particle size (m) 1003 853 710 600 500 425 355 250 180 150 75 0

Zfw

of crystalline sucrose at various times of milling

Wt. fraction undersize after time (min) 0

4 1 0.886 0.348 0.048 0.003

448.79

40

160

320

1

1

1

1

0.387 0.135 0.064 0.049 0.036 0.022 0.014 0.011 0.004 0

0.892 0.751 0.614 0.548 0.471 0.359 0.270 0.245 0.152 0

0.983 0.955 0.920 O-900 0.868 0.794 0.695 0.650 0.438 0

0.991 0.977 0.953 0.931 0.890 0.784 0.661 0.622 0.459 0

421.06

127.79

27.96

20.04

I.I~

Equivalent particle wt The equivalent particle weight, Zfw, is 0.000296 M, assuming monosized

of microfine particles.

salicylic acid (3.4 J&II)

129

: T

x !x

4% ------

la

EC

r I

%

95

I I

SE I I 20

. 40

.I.

mm

zzo

Fig. 1_ Size distribution of icing sugar. Y-axis - cumulative percentage undersize, X-axis - particle size (m).

sieve analysis [see Table l] ). Figure 1 shows the particle size of the icing sugar as determined by the sedimentation method. The mean diameter was 74 pm. The particle size of crystalline sucrose at various tunes of milling in the ball mill is shown in Table 1. The size reduction effect of the ball mill on icing sugar was taken as being negligible. For example, particles of 74 pm on grinding were reduced to 72 pm after two hours of milling. This difference is well within the experimental error of the sizing method (Andreasen sedimentation). The microfine salicylic acid had a particle size of 3.4 Mm determined by airpermeability technique. The values of the theoretical stanaarci ueviation of the completely randon-Used mixture ((T& were calculated using th.c above particle size data in the formula of Poole ef al. [7] :

where X, y are the proportions of the two ingredients, W is the sample weight and Z fw is the effective mean weight of the particles of the powder denoted by the suffix. The value of aa for microfine saiicylic acid and icing sugar was calculated from the equations by Crooks and Ho [9], as icing sugar has a size distribution which approached log-normal. The mixing of crystalline sucrose with the microfine salicylic acid is shown in Fig. 2, where the standard deviation of sample concentration (s) is plotted at different times (t) as mixing proceeds, in the cube mixer and the

Fig. 2. Mixing (111000) of microfine salicylic acid (3.4 pm) with crystalline sucrose (750 pm) in a Revolve-Cube mixer and a ball mill; nominal sample size of 250 mg. Y-axis -standard deviation of sample concentration; X-axis - time in minutes.- A - A -, results obtained from ball mill; - 0 - 0 -, results from Revolve-Cube mixer. A, B, C and D are the theoretical values of the standard deviation of an equivalent system assumed to be completely randomised (see text): A = 2.26 X 10-5, B = 1.06 X lo-“, C = 8.95 X lo+, D = 4.24 X lo-‘.

! E

lX104

.

124

x3204083160m

Fig_ 3. Mixing (lr1000) of microfine salicylic acid (3.4 /&II) with fine icing sugar (74 pm) in a RevolvoCube mixer and a ball mill; nominal sample size of 250 mg. Y-axis -standard deviation of sample concentration; X-axis -time in minutes. - I - n -, results obtained from Revolve-Cube mixer; - 4 - 4 -, results from ball mill. E is the theoretical value of the standard deviation of an equivalent system assumed to be completely randomised (see text): E = 1.07 X 10-5.

ball mill. Figure 3 shows the mixing of the fine icing sugar with the microfine salicylic acid in the same two mixers. During the mixing operation in the ball mill there is considerable particle size reduction, thus increasing the number of particles in the samples taken_ Whilst the premise of random

130

mixing is unacceptable in this exercise since there is either a very large particle size difference or the particles are of such size that they are extremely cohesive, the value of the theoretical standard deviation of the completely randomised system is also shown in these figures_ The effect of sample size on the standard deviations of sample concentration after mixinginaballmillfor2horinacubemtier for 320 min is shown in Figs. 4 and 5. In these two diagrams, error bars are used to show the 95% confidence limits for 20 samples.

l*eOi

Fig. 5. Standard deviation of different samp!e sizes of salicylic acid (3.4 m) and icing sugar (74 J&A) mixture after mixing in a cube mixer for 320 min. Error bars represent 95% confidence limits of the individual resil1t.s. Broken line (- - - - -) represents e, the theoretical standard deviation of the mixture, assuming complete randomisation occurs. Y-axis - standard deviation of sample concentration; X-axis - sample size, g.

01

02

05

1

2

4

Fig. 4. Standard deviation of different sampie sizes of salicylic acid (3.4.,um) and icing sugar (74 run) mixture after milling and mixing in ball mill for 3 h. Error bars represent 95% confidence limits of the individual results. Broken line (- - - - -) represents a~, the theoretical standard deviation of the mixture, assuming complete randomisation occurs. Y-axis -standard deviation of sample concentration; X-axis - sample size, g.

DISCUSSION

The mixing of coarse sucrose with the microfine salicylic acid proceeds rapidly and to the same extent in both the cube mixer and the ball mill (Fig. 2). With the cube mixer, there is little increase in homogeneity obtained after some ten minutes mixing. At t& point the mixture appears to be ordered, since it has a homogeneity better than that of the theoretically completely random&d system (OR)indicated by the point D on the graph. Whilst the ball mill shows an equally rapid mixing operation, the effect of the particle size reduction is to increase the number of particles taken in the nominal sample size

(250 mg), thus decreasing the value of ua for this system. The points A, B and C in Fig. 2 are the values of a= calculated from the different particle size data (Table 1) at each of these times of milling and mixing (40,160 and 320 min respectively). It cannot,, therefore, be assumed that an ordered mixture has been formed, since it is theoretically possible to produce a random mixture of greater homogeneity than that attained in practice. However, the presence of such fine particles would itself prevent randomisation due to the highly cohesive nature of the system. It is therefore probable that an ordered mixture, as in the cube mixer, has been produced in the ball mill. Mixing icing sugar with microfine salicylic acid presents a different problem (Fig. 3). Here there are no coarse particles in the cube mixer to break up the aggregates of fine powder, thus mixing is relatively slow. The internal agitator is likely to be of considerable benefit to the mixing process in this particular application. A much more rapid mixing is achieved using the ball mill for this particular system (Fig. 3). The high energy input of the cascading ball media can break down aggregates of fine powder. The value of CR (E in Fig. 3) has been calculated from the particle size data, which do not alter to any meas.&able extent during the

131

mixing operation in either apparatus. Whilst the degree of homogeneity actualiy attained in practice with both mixers can be said to be of the same magnitude as OR, it is unlikely that a random mixture will result for such highly cohesive powders. To investigate the question of the formation of ordered uersuS random mixture further, different sample sizes were removed after mixing icing sugar with salicylic acid in the ball mill for 2 h and in a cube mixer for 320 min. The calculated standard deviation of sample concentration for these differently sized samples is plotted in Figs. 4 and 5 respectively together with the line representing the completely randomised mixture. It is apparent that the standard deviation obtained is not affected by the sample size as would be the case in a random mixture. It can, therefore, be assumed that an ordered mixture of fine particles has been produced_ Since the homogeneity, Hi, [S] of such a system depends on the carrier particle size, W1 [5], then, for the icing sugar system: Hi=-log

=--og-

WI XP 6p

= -log

i

(74 x 10_4)3

x 1.59

= +6.47 where p is density of icing sugar. This level of homogeneity is considerable higher than that previously obtained in ordered powder mixtures [ 53 _

ACKNOWLEDGEMENTS

We wish to acknowledge the financial support of the Pharmaceutical Society of Victoria which enabled this work to be undertaken. We also wish to acknowledge the financial support of A.R.C.C. through the purchase of the Varian Techtron auto-sampling 634 spectrophotometer. The sahcylic acid used in this investigation was kindly made available to us by the Pharmacy Department, Western Australian Institute of Technology. Finally we wish to acknowledge the help and advice of our colleagues, particularly Dr. W. J_ Thiel. REFERENCES J. A_ Hersey, Ordered powder mixing: a new concept in powder mixing practice, Powder Technol., 11(1975) 41- 44. C. W. Yip and J. A. Hersey, Ordered powder mixing, Nature, London, 262 (1976) 202 - 203. C. W. Yip and J_ A_ Hersey, Powder mixing in a Revoho-Cube mixer, Au& J. Pharm. Sci., 6 (1977) 49 - 52. J. A. Hersey, Prepartion and properties of ordered mixtures, Aust. J. Pharm. Sci., 6 (1977) 29 - 31. C. W. Yip and J. A_ Hersey, Perfect powder mixtures, Powder Technol., 16 (1977) 189 - 192. C. W. Yip and J. A. Hersey, Ordered or random mixing: choice of system and mixer, Drug Dev. Ind. Pharm., 3 (1977) 429 - 438. K. R. Poole, R. F. Taylor and G. P. Wail, Mixing powders to- finescale homogeneity: studies of batch mixing. Trans. Inst. Chem. Eng., 41(1964) T305 - T315: D. Bus&k, A proposed universal homogeneity and mixing index, Powder Technol., 7 (1973) 111 - 116. M. J. Crooks and R. Ho, Direct compression in tableting. I_ Prediction of uniformity of drug-vehicle mixtures, Aust. J. Pharm. Sci., NS4 (1975) 85 - 87_