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Micronization of pharmaceutical substances in a spiral jet mill
Powder Technology 104 Ž1999. 113–120 www.elsevier.comrlocaterpowtec
Micronization of pharmaceutical substances in a spiral jet mill N. Midoux a , P. Hosek ˇ b
b,)
, L. Pailleres b, J.R. Authelin
b
a Ecole Nationale Superieure des Industries Chimiques, I.N.P.L, Nancy, France ´ Rhone-Poulenc Rorer, Process Chemistry, Centre de Recherche de Vitry, AlfortÕille, France ˆ
Received 1 September 1998; received in revised form 12 January 1999; accepted 12 January 1999
Abstract Many studies have been conducted to help understand the effects of the variables involved in jet milling. The first part of this work is an attempt to summarise the results published in the literature concerning horizontal and vertical jet mills. This focuses on the research of the optimal design of the mills and on the improvement of their performance. Several publications have been found, concerning mineral grinding. It seemed more interesting to present results on organic crystals’ jet milling in the second part of this paper. The experiments concern three organic substances, and were run on three different spiral jet mills: Chrispro-Jetmill 50 and 100 and MicronMills 8Y. The results are presented in terms of specific energy consumption with an adaptation of the correlation proposed by Sarma. These representations show that, within the operating energy range and above a critical energy value, the creation of specific surface area corresponds to an increase of fine particles production. q 1999 Elsevier Science S.A. All rights reserved. Keywords: Spiral jet mill; Micronization; Pharmaceutical substances
1. Introduction First invented at the end of the last century, fluid jet mills have been developed since the 1960s. These machines are often employed in the industry to achieve ultra fine grinding of minerals, pigments or metal oxides. They present various advantages such as the obtention of micron-sized particles with narrow size distributions, the absence of contamination and the ability of grinding heat-sensitive materials. These mills are particularly useful in the pharmaceutical industry, where micronization is used to raise drug activity by increasing particle specific surface, or by allowing active substances to reach their site of action by reducing particle size. There are various kinds of devices: spiral or loop jet mills, impact and counter flow jet mills. All these mills operate on the same principle: use of fluid energy to achieve grinding and the impact breakage mechanism. The literature presents many studies about micronization. One type is concerned with mathematical modelling of jetmilling by determination of breakage and selection functions w1–3x. This paper will focus on another type, )
Corresponding author. Tel.: q33-55-71-85-57; Fax: q33-55-71-8432; E-mail: [email protected] ŽP. Hosek ˇ .
which presents parametric studies, and tries to understand the various features which affect grinding in fluid jet mills. After a survey concerning mainly micronization in spiral jet mills, results of drug substances micronization trials, performed at Rhone-Poulenc Rorer, are presented ŽFig. 1.. ˆ
2. Micronization survey The main features affecting the grinding ratio in spiral jet mills, can be classified into two types: Ø geometrical parameters which concern the mill design such as diameter of the grinding chamber, shape, number and angle of grinding nozzles. Ø operational conditions e.g., solid feed rate, grinding pressure, injector pressure and, of course, material to grind. 2.1. Mill design The diameter of the grinding chamber conditions the capacity of the mill Žsee Table 1.. The relation between these two parameters is given by scale-up studies. In fact, for the scale-up of a fluid jet mill, three parameters are taken into account: the volumetric flow rate Vn , the solid feed rate Q and the diameter of the
0032-5910r99r$ - see front matter q 1999 Elsevier Science S.A. All rights reserved. PII: S 0 0 3 2 - 5 9 1 0 Ž 9 9 . 0 0 0 5 2 - 2
N. Midoux et al.r Powder Technology 104 (1999) 113–120
114
Fig. 1. Scheme of a spiral jet mill.
mill chamber D. In agreement with Rumpf’s statement w4x, the main manufacturers follow the relation: Vn A D 2
Ž 1.
The volumetric flow rate and the feed rate are linked according to Ito w5x: Q A Vn1.4 " 0 .1
Ž 2.
Finally, relation Ž1. and Ž2. lead us to relation Ž3. which gives the capacity of a mill with a chamber diameter D: Q A D 2.8 " 0.2
Ž 3.
This result is rather close to the relation deduced from manufacturers product information, which is Q proportional to D 2.3 " 0.3, and to Smit’s work w6x on waxes which lead us to Q proportional to D 2.5 " 0.2 . Furthermore, the exponent seems to depend on the kind of material ground. Two alternative types of nozzle are used in jet milling w7x ŽFig. 2.. The most common one is the abrupt type which provides sonic velocity at the throat. The exit pressure is about 50% of the initial fluid pressure. The final expansion takes place beyond the nozzle throat, creating a suction which entraps particles from the mill, thereby circulating gas and promoting particle collision. The second type is the Laval shaped nozzle. In this one, the gas expands in the divergent section, leading to supersonic velocities which increase the jet’s action and also the velocity of the circulating gas stream, thereby allowing greater production rate and fineness of the grind.
The number of nozzles is an important feature for jet mill design. Skelton et al. w8x experimented with three alternative configurations, with 3, 6 and 12 nozzles, keeping constant the total section of the nozzles, and so the grinding gas rate, with varied solid feed rates. The result was that the device of 12 nozzles gave the best grinding ratio. Furthermore, the improvement in the grinding ratio was better when feed rates were high. These results were explained by the fact that a greater number of grinding nozzles created a more regular pitch-circle and, moreover, a thinner jet leads to a minor perturbation of the spiral flow in the chamber. As mentioned, the jets form a circle separating the grinding and classification zones so it appears obvious that the angle of the nozzles determines the size of both areas and, therefore, the grinding ratio of the product. Furthermore, as this angle affects the penetration of the nozzle jets in the gas stream, it may be considered that the relative velocity of gas flowing at the intersection determines the kinetic energy transmitted to the particles and thereby the intensity of the collisions. Smit w6x and Skelton et al. w8x showed that an optimum value appears at high feed rates. Their values are quite similar. If we consider the angle to the tangent, Smit’s optimum is equal to 588 and Skelton’s one is between 52 and 608. 2.2. Working conditions As stated by Albus w7x, an optimum feed rate exists. This was found by Mohanty and Narasimhan w9x on a loop mill and depends greatly on the type of material ground. To our knowledge, this optimum feed rate has not yet been
Table 1 Examples of operating parameters range in a spiral jet mill Grinding chamber diameter Žmm.
Solid feed rate Žkgrh.
Volumetric flow rate ŽNm3 rh.
100 200 500
0.5–25 1.5–50 40–300
50–125 80–250 700–1400 Fig. 2. The two types of nozzle: 1. abrupt nozzle, 2. Laval shaped nozzle.
N. Midoux et al.r Powder Technology 104 (1999) 113–120
115
Table 2 Working conditions described in the literature Authors
Mill type
Mill diameter Žmm.
Material
Grinding pressure range ŽbarG.
Solid range Žkgrh.
Smit Mohanty et al.
Spiral Loop
100 ?
7 ?
0.4 to 2 f 1 to 40
Gommeren et al. Skelton et al. Ahmad Khan et al. Ramanujam et al. Schurr et al.
Spiral Spiral Spiral Loop Spiral
250 200 60 20 Žpipe. 200
Waxes Sand Chromite Lime stone Graphite Blue dust ? Lime stone Calcite Calcite Sand
? ? ? 3 to 6 f5
Muller ¨ et al.
Spiral
170
Calcite
2 to 8
8.8 to 30 7 to 40 ? 0.3 to 9 0.3 to 100 Ždepending on gases used. 2 to 8
mentioned for a spiral jet mill. Above this optimum, which is rather low, an increase of the feed rate leads to a coarser product and the variation of the size of the product can be expressed in terms of the feed rate by a power law. In fact, according to Ramanujam and Venkateswarlu w10x, there is a transition feed rate, above which the exponent changes. Gommeren et al. w11x defines a maximum rate which leads to choking conditions in the mill. These conditions correspond to instabilities of the solid–fluid flow in the chamber with discontinuous discharge of the mill and, consequently, larger particle size distributions. Another major parameter in jet milling is grinding pressure, which conditions the gas mass flow rate input. Assuming that the nozzles are isentropic, according to the ‘Barre´ de Saint Venan’ equation, the initial grinding pressure P and the pressure at the nozzle throat Pt are related by: P Pt
ž
s 1q
ky1 2
k
Mt2
/
ky 1
Ž 4.
where Mt is the Mach number at the throat and k is the ratio of specific heats of the gas. This leads us to define a critical pressure Pc : Pc Pt
s
ž
kq1 2
ky1
Table 3 Results obtained by Ramanujam and Venkateswarlu, on calcite with a 20 mm diameter loop mill
Region below transition Region above transition
Mw k RT
ž
2 kq1
kq 1
/
ky1
Ž 6.
and is directly proportional to the grinding pressure, the throat section and the molecular weight of the fluid employed for grinding. The grinding power supplied as gas kinetic energy for sonic nozzles can be expressed by: E˙k s
1 2
Mg ns2
Ž 7.
Thus, the grinding pressure is directly correlated to the kinetic energy of the gas and thereby to the energy transmitted to particles for grinding. In order to include, in the same parameter, both grinding pressure and solid feed rate, many authors w12–14x use the notion of Specific Energy Consumption Ž Esp .. According to Schurr and Zhao w15x this is calculated by: E˙k
Ž 8.
Q
Ž 5.
which corresponds to the minimum of pressure necessary to get a sonic flow at the nozzle throat.
K
)
Mg s PA
Esp s
k
/
Above this value the gas mass flow rate can be expressed by:
p
q
Mean relative deviation
0.039
0.278
0.417
"7.3
3.46
0.053
0.079
"2.7
This compares different mills, or working conditions Žtype of gas, temperature, pressure. on the same system. In
Table 4 Results obtained by Sarma and Ahmad Khan, on calcite with a 60 mm diameter spiral jet mill K Sarma’s results Ahmad Kahn’s results Data of both studies treated by least squares method
y7
7=10 4.54=10y2 0.2=10y2
p
q
s
0.6 0.4 0.59
1.5 1.2 1.04
0.6 0.7 0.72
N. Midoux et al.r Powder Technology 104 (1999) 113–120
116 Table 5 Properties of products A, B and C
Product A Product B Product C
Density Žgrcm3 .
SSA Žm2 rg.
1.12 1.25 1.28
0.14 0.4 0.67
a spiral jet mill, the specific surface area of the product is related to Esp by a power function: SSA A Espx
Ž 9.
Schurr and Zhao have shown that a critical value of the specific energy can be defined. Above this value, the size distribution of the particles are narrower, and the relationship between the specific surface area of the product and energy changes, such that the exponent of the power function is greatly diminished. This critical value is independent of the nature of the gas used for grinding, but to our knowledge, no studies have been conducted on various mills. For sand, the critical energy equals 3600 kJrkg according to Schurr et al., Muller et al. found the same ¨ value for calcite, but with a different mill Žsee Table 2.. The injector pressure is generally fixed to 0.5 or 1 bar above the grinding pressure to avoid back flow at the venturi. For Sommer w16x, the flow coming from the venturi can disturb the spiral stream in the chamber when the injector pressure is too high. This disturbance leads to a coarser product at the exit of the mill. This is why he recommends working with a minimal pressure at the injector. Moreover, Ramanujam and Venkateswarlu w10x defined a minimal injector pressure to avoid choking conditions in the loop mill. In fact, we can say that the importance of the injector pressure depends upon the design of the mill, and must be chosen according to the grinding pressure. 2.3. Dimensional analysis of fluid jet mills We have seen that the influence of the different parameters is well known, but in view of the complexity of jet
Fig. 3. Correlation SSA Malvern vs. SSA Blaine.
Fig. 4. Correlation 6rd50 vs. SSA Blaine.
milling, some authors have tried to find correlations using dimensional analysis. Ramanujam and Venkateswarlu w10x have proposed the following relation: R G s exp K Ž R d0.2 . Ž R wp Re gq .
Ž 10 .
Where: R G s ŽSSA product .rŽSSA feed ., R d s Ž d feed .r Ž Dmill ., R w s Ž Mg .rŽ Q ., Re g s Ž d N rg ns .rŽ mg . Their study was made on calcite with a vertical mill of 20 mm pipe diameter. A transition was found, and the results gave two correlations with different constants: K and exponents p and q Žsee Table 3.. Hence, these results seem to confirm the fact that there are critical conditions above which the increase of grinding ratio with energy input in the system is less important. Khan and Ramanujam w17x also reportŽs. a correlation proposed by Sarma for a horizontal jet mill. He uses the same type of variables, but the expression is simpler than the former. Moreover, it takes into account the volumetric rate of fluid passing through the venturi, whilst this is neglected in the earlier study. The coefficients calculated by these authors are presented in Table 4. q
p
R G s K Ž Re g . Ž R Wt . Ž R d .
s
Ž 11 .
Where: R Wt s Ž Mg q Mi .rŽ Q . These authors didn’t find a ‘transition zone’ but, in view of the absence of further information about the trials
Fig. 5. Product A: Esp vs. DSSA.
N. Midoux et al.r Powder Technology 104 (1999) 113–120
117
Fig. 8. Particle size distribution of product C for low energy trials. Fig. 6. Product B: Esp vs. DSSA.
conditions Žpressure and solid feed rate., this particularity doesn’t seem really noticeable.
3. Experimental Three types of organic crystals were micronized: products A, B and C. Their basic properties are given in Table 5. Experimental runs were achieved with spiral jet mills: Chrispro-Jetmill 100 Žsee Fig. 1. and MicronMills 8Y for product A, Chrispro-Jetmill 100 for product C and Chrispro-Jetmill 50 for product B, all equipped with abrupt nozzles. The solid was delivered at a constant feed rate by a screw feeder. It was dropped into the injector cone then accelerated through a venturi before its introduction to the mill chamber. The gas used for grinding was pressurised nitrogen, to avoid risks of dust explosion. The specific surface area of ground products have been evaluated by different methods depending on the substance: Blaine’s permeameter, porosimetry, BET method. In order to compare the values obtained, all the results are presented in terms of Blaine’s specific surface area. Blaine’s specific surface areas are measured according to the ‘norme AFNOR’ w18x. Particle size distributions of products A and C were determined by laser granulometry with a Malvern Master-
Fig. 7. Product C: Esp vs. DSSA.
sizer S which allows to determine sizes of particles from to 0.05 to 900 mm. All the values were very well correlated. It is notable that in the case of product C, for example, although the population is bimodal ŽFigs. 8 and 9., the Blaine surface is as well correlated with 6rd50 Žsurface of a sphere equal to the median of the mass distribution, Fig. 3. as with the surface measured by the apparatus ŽSSA Malvern., from the diameter of Sauter ŽFig. 4.. The gas mass flow rates, and the kinetic energies, were calculated assuming that the abrupt nozzles were sonic. 4. Results 4.1. Specific energy consumption As seen before, the newly created surface depends mainly on two features: nozzle grinding pressure and solid feed rate. The product specific surface increases with the pressure, and with a decrease of the solid feed rate. These two operational parameters are included in the notion of Specific Energy Consumption. Effectively, as defined in first part, the Specific Energy Consumption is equal to the power supplied by the kinetic energy of the grinding fluid divided by the solid feed rate. E k is directly proportional to the grinding pressure under the present operating conditions. Hence, the representation of the product specific surface area versus Specific Energy provides a physical understanding of the influence of grinding pressure and solid feed rate on the grinding ratio. Moreover, by notion of Specific Energy Consumption, it is interesting to compare the grinding efficiency of different mills or grinding fluids ŽFigs. 5–7..
Fig. 9. Particle size distribution of product C for high energy trials.
N. Midoux et al.r Powder Technology 104 (1999) 113–120
118 Table 6 Description of the jet mills employed for trials Parameters
Mill diameter
Nozzles number
Nozzles angle
Nozzle diameter
Nozzle type
Chrispro-Jetmill 50 Chrispro-Jetmill 100 Y MicronMills 8
50 mm 100 mm 200 mm
6 6 12
638 638 678
0.85 mm 1.25 mm 1 mm
abrupt abrupt abrupt
If we look at the results concerning product A ŽFig. 5., they obey the same trend in two mills. But this type of representation shows differences between the efficiency of both devices. The MicronMills jet mill gives a better grinding ratio, which is in agreement with the scale-up laws found in the literature Žsee paragraph ‘Scale-up’.. The specific energy required to obtain a certain grinding ratio diminishes with the mill diameter. The transition found by Schurr and Zhao wasn’t found for product B ŽFig. 6.. In fact, the product specific area required was rather high, and so the trials were achieved with high energy input. But the results obtained for low energy trials with product A seem to indicate that the ‘critical’ Esp is between 400 and 800 kJrkg. However, the runs performed with product C clearly demonstrate a transition around 400 kJrkg. Below the critical energy, the newly created surface seems proportional to the energy: the exponent x equals 1.1. This implies that results obtained in this range of energies obey Rittinger’s empirical breakage law. Above this value, the exponent is greatly diminished and the relationship between energy and created surface is no longer linear. The particles size distributions of product C, show two populations of particles, even in the feed. A first population, corresponding to very fine particles, and a second of coarser product. For low energy trials Žsee Fig. 8., up to a critical value of specific energy, the coarser particles are well ground and the mode of this population diminishes. Above the transition Žsee Fig. 9., the mode is kept constant and only fine particles are produced. So, it appears that the rise of specific surface area observed above the energy critical value corresponds to the production of fine particles. It seems that a grinding limit is reached for transition
value. Hence, grinding above critical conditions is no longer interesting. For each product, trials with helium have been undertaken. This gas permits reaching higher mill velocities. By comparison with nitrogen, the energies obtained under the same conditions of pressure and solid feed rate are higher and, moreover, the grinding appears more efficient with helium. Nevertheless, this conclusion has to be confirmed by other trials. The presentation of trials results in terms of specific energy permits a comparison of the ‘grindability’ of materials. For similar values of energy, the grinding ratio of product B is greater than for products A and C. Consequently, the expression of results in terms of Specific Energy Consumption allows comparison between different operating conditions and mills. However, the prevision of results obtained during trials can also be made by empirical correlations.
Fig. 10. Product C: SSA calculated by correlation vs. Esp.
Fig. 11. Product A: SSAest vs. SSAexp.
4.2. Correlation application An attempt to use the correlation proposed by Sarma on an horizontal jet mill is made for the three products. However, the correlation for product A concerns only the results obtained on the Chrispro 100 because of the difference in design between this mill and the MicronMills 8X which can’t be taken into account by the correlation used. In view of the absence of experimental runs with varying sizes of feed, and sizes of mill, this relation will be simplified by: q
R G s K Ž Re b . Ž R MT .
p
Ž 12 .
The coefficients of the correlation shown in Table 6. are determined by the least squares method. The comparison
N. Midoux et al.r Powder Technology 104 (1999) 113–120
119
Fig. 14. Product A: SSA vs. Pg. Fig. 12. Product B: SSAest vs. SSAexp.
4.3. Scale-up
Fig. 13. Product C: SSAexp vs. SSAest.
between the experimental specific surfaces and the calculated ones is presented in Figs. 10–13. Transitions were found for products A and C. The regions of transition correspond to the value of ‘critical Esp ’ described in the preceding paragraph. In Fig. 10, the SSA calculated with the empirical correlation versus Esp present the same transition as the experimental values. This correlation, specific to the nature of the ground material, can be employed to foresee the conditions necessary to reach the specific surface expected for organic crystals. The results obtained on product B with helium ŽFig. 12. fit very well with the correlation calculated with nitrogen. So this correlation seems to truly take into account the nature of grinding gas used. A comparison of the values calculated for products A and B confirms the conclusion about the difference of grindability of both products ŽTable 7..
The trials achieved with product A on the MC100 and the MicronMills 8Y have lead to a scale-up relationship between these two micronizers. Fig. 14 shows that the specific surface area obtained using both devices at various grinding pressure, and at constant solid feed rate, are identical. However, this represents a situation of perfect scale-up, such that the following relationship is deduced: Q A D 2.8. This expression is in agreement with those found in the literature. The fairly high exponent may be explained by the difference of geometry between each mill. As aforementioned, the MicronMills has 12 grinding nozzles whilst Chrispro 100 has only 6, and this difference seems to explain the improvement of performance with the former.
5. Conclusion Publication of several micronization studies since the 1960s has enabled the optimal design for a jetmill in terms of geometrical parameters and scale-up. A product’s ability to be ground by this type of device seems difficult. This paper presents two methods applied to organic crystals. The first method, applied to evaluate the energy input to the system, permits a comparison of different grinding devices and a physical understanding of the influence of the operating features. The second refers to an empirical correlation.
Table 7 Results obtained with Sarma’s correlation Product
Below transition K
p
q
K
p
q
A B C
5.95 = 10y8 a
0.25a
1.7 a
0.0627
0.385
0.273
0.020 0.104 0.836 a
0.043 0.14 0.037 a
0.54 0.35 0.112 a
a
Above transition
Mean relative deviation
These coefficients are calculated with very few points, so that they must be considered as a ‘trend’.
6.5% 8.6% 3.7%
N. Midoux et al.r Powder Technology 104 (1999) 113–120
120
A transition zone has been determined. It corresponds to the ‘critical’ value of SEC defined by Schurr and Zhao. This value seems dependent on the product, and lower for organic crystals than minerals. It appears that above the transition, grinding is no longer interesting because the supplementary energy furnished leads to attrition, and thereby, ‘fine particles’ production.
6. Nomenclature A Cp Cv D df dN E˙k Esp k Mg Mi Mw Pc Pg Pt Q R Rd Re g RG RW R Wt SSA SSAest SSAexp T Vn Õs DSSA mg rg
Acknowledgements The authors thank Dr. F. Leveiller, Dr. M. Sautel, Dr. M. Ubogi for analytical assistance, Mr. M. Nakach for helpful suggestions and Micron Mills for the trials conducted in their establishment. A special thank is addressed to Prof. N. Midoux for his scientific advice during the redaction of this paper. References
2.
Grinding nozzles total area Žm Gas heat capacity at constant pressure Gas heat capacity at constant volume Mill chamber diameter Žm. Mean diameter of the feed Žmm. Grinding nozzle diameter Žm. Kinetic energy of grinding gas ŽW. Specific Energy Consumption ŽkJrkg. CprC v Grinding gas mass flow rate Žkgrh. Injector gas mass flow rate Žkgrh. Molar weight Critical pressure Žbar. Initial grinding pressure Žbar. Nozzle throat pressure Žbar. Solid feed rate Žkgrh. Gas constants 8.314 Pa m3 Ky1 moly1 Ratio of feed mean diameter to chamber mill diameter: d frD Number of Reynold in the grinding nozzle: d N rg nsrmg Grinding ratio: SSA productrSSA feed Ratio of grinding gas mass flow rate to solid feed rate: MgrQ Ratio of total gas mass flow rate to solid feed rate: Ž Mg q Mi .rQ Specific surface measured by Blaine method Žm2rg. Specific surface calculated by means of correlation Žm2rg. Experimental specific surface Žm2rg. Gas temperature ŽK. Volumetric flow rate ŽNm3rs. Sonic velocity Žmrs. SSA product y SSA feed Viscosity of grinding gas ŽPa s. Volumic weight of grinding gas Žkgrm3 .
w1x R. Hendry, A mathematical model for fluid energy mills, Dechema Monographein 57 Ž2. Ž1967. 695–727. w2x H. Berthiaux, J. Dodds. Investigation on breakage and classification in a fluidized bed opposed jet mill, First International Particle Technology Forum Ž1994., 241–246. w3x I.N. Dorokhov, S.Yu. Arutyunov, D.I. Eskin, Mathematical description of the jet grinding process, Teoreticheskie Osnovy Khimicheskoi Technologii 27 Ž1993. 514–517. w4x H. Rumpf, Prinzipien der Prallzerkleinerung und ihre Anwendung bei der Strahlmahlung, Chem. Ingr. Tech. 32 Ž1960. 129. w5x H. Ito, Scale-up theory of single track jet mill, The second KoreanJapan Powder Technology Seminar, Pusan, Korea, August 18–19, 1987. w6x W.A.J. Smit, Jetmilling of heat sensitive materials, World Congress Particle Technology, Part II, 345–357. w7x F.E. Albus, The modern fluid energy mill, J. Chem. Eng. Prog. 60 Ž1964. 102–106. w8x R. Skelton, A.N. Khayyat, R.G. Temple, Fluid energy milling. An investigation of micronizer performance, Fine Particles Processing 1 Ž1980. 113–125. w9x B. Mohanty, K.S. Narasimhan, Fluid energy grinding, Powder Technology 33 Ž1982. 135–141. w10x M. Ramanujam, D. Venkateswarlu, Studies in fluid energy grinding, Powder Technology 3 Ž1970. 92–101. w11x J.C. Gommeren, H.J.M. Heitzmann, B. Scarlett, Dynamic modelling of a closed loop jet mill, First International Particle Technology Forum Ž1994., 197–202. w12x G.A. Schurr, Q.Q. Zhao, Fluid mechanic considerations for fine grinding in a fluid energy mill. 8th European Symposium on Comminution, Stockholm, Sweden, May 17–19, 1994. w13x C.J. Stairmand, Energy efficiency of milling processes. A review of some fundamental investigations and their application to mill design, Dechema Monographein for European Symposium on Comminution, 4th: Zerkleinern, Germany, 79 1549–1588 Ž1975., 1–17. w14x F. Kaiser, R. Nied, Modern jet pulverizers, Aufbereitungs Technik 10 Ž1980. 507–514. w15x J.M. Dotson, Extending the range of jet mills, Industrial and Engineering Chemistry 54 Ž2. Ž1962. 62–65. w16x K. Sommer Expose´ du 21 mars 1989 au Centre de Recherche .. d’Aubervilliers, ŽInternal document, Rhone-Poulenc ˆ w17x A. Khan, M. Ramanujam, Improved correlations for superfine grinding in a condux air jet mill, Ind. Chem. Eng. 20 Ž4. Ž1978. 49–51. w18x Norme AFNOR, Mesure de la surface specifique par le ´ permeabilimetre ´ ` de Blaine, NF P 15-442, 1st edn. 3–67.
Micronization of pharmaceutical substances in a spiral jet mill N. Midoux a , P. Hosek ˇ b
b,)
, L. Pailleres b, J.R. Authelin
b
a Ecole Nationale Superieure des Industries Chimiques, I.N.P.L, Nancy, France ´ Rhone-Poulenc Rorer, Process Chemistry, Centre de Recherche de Vitry, AlfortÕille, France ˆ
Received 1 September 1998; received in revised form 12 January 1999; accepted 12 January 1999
Abstract Many studies have been conducted to help understand the effects of the variables involved in jet milling. The first part of this work is an attempt to summarise the results published in the literature concerning horizontal and vertical jet mills. This focuses on the research of the optimal design of the mills and on the improvement of their performance. Several publications have been found, concerning mineral grinding. It seemed more interesting to present results on organic crystals’ jet milling in the second part of this paper. The experiments concern three organic substances, and were run on three different spiral jet mills: Chrispro-Jetmill 50 and 100 and MicronMills 8Y. The results are presented in terms of specific energy consumption with an adaptation of the correlation proposed by Sarma. These representations show that, within the operating energy range and above a critical energy value, the creation of specific surface area corresponds to an increase of fine particles production. q 1999 Elsevier Science S.A. All rights reserved. Keywords: Spiral jet mill; Micronization; Pharmaceutical substances
1. Introduction First invented at the end of the last century, fluid jet mills have been developed since the 1960s. These machines are often employed in the industry to achieve ultra fine grinding of minerals, pigments or metal oxides. They present various advantages such as the obtention of micron-sized particles with narrow size distributions, the absence of contamination and the ability of grinding heat-sensitive materials. These mills are particularly useful in the pharmaceutical industry, where micronization is used to raise drug activity by increasing particle specific surface, or by allowing active substances to reach their site of action by reducing particle size. There are various kinds of devices: spiral or loop jet mills, impact and counter flow jet mills. All these mills operate on the same principle: use of fluid energy to achieve grinding and the impact breakage mechanism. The literature presents many studies about micronization. One type is concerned with mathematical modelling of jetmilling by determination of breakage and selection functions w1–3x. This paper will focus on another type, )
Corresponding author. Tel.: q33-55-71-85-57; Fax: q33-55-71-8432; E-mail: [email protected] ŽP. Hosek ˇ .
which presents parametric studies, and tries to understand the various features which affect grinding in fluid jet mills. After a survey concerning mainly micronization in spiral jet mills, results of drug substances micronization trials, performed at Rhone-Poulenc Rorer, are presented ŽFig. 1.. ˆ
2. Micronization survey The main features affecting the grinding ratio in spiral jet mills, can be classified into two types: Ø geometrical parameters which concern the mill design such as diameter of the grinding chamber, shape, number and angle of grinding nozzles. Ø operational conditions e.g., solid feed rate, grinding pressure, injector pressure and, of course, material to grind. 2.1. Mill design The diameter of the grinding chamber conditions the capacity of the mill Žsee Table 1.. The relation between these two parameters is given by scale-up studies. In fact, for the scale-up of a fluid jet mill, three parameters are taken into account: the volumetric flow rate Vn , the solid feed rate Q and the diameter of the
0032-5910r99r$ - see front matter q 1999 Elsevier Science S.A. All rights reserved. PII: S 0 0 3 2 - 5 9 1 0 Ž 9 9 . 0 0 0 5 2 - 2
N. Midoux et al.r Powder Technology 104 (1999) 113–120
114
Fig. 1. Scheme of a spiral jet mill.
mill chamber D. In agreement with Rumpf’s statement w4x, the main manufacturers follow the relation: Vn A D 2
Ž 1.
The volumetric flow rate and the feed rate are linked according to Ito w5x: Q A Vn1.4 " 0 .1
Ž 2.
Finally, relation Ž1. and Ž2. lead us to relation Ž3. which gives the capacity of a mill with a chamber diameter D: Q A D 2.8 " 0.2
Ž 3.
This result is rather close to the relation deduced from manufacturers product information, which is Q proportional to D 2.3 " 0.3, and to Smit’s work w6x on waxes which lead us to Q proportional to D 2.5 " 0.2 . Furthermore, the exponent seems to depend on the kind of material ground. Two alternative types of nozzle are used in jet milling w7x ŽFig. 2.. The most common one is the abrupt type which provides sonic velocity at the throat. The exit pressure is about 50% of the initial fluid pressure. The final expansion takes place beyond the nozzle throat, creating a suction which entraps particles from the mill, thereby circulating gas and promoting particle collision. The second type is the Laval shaped nozzle. In this one, the gas expands in the divergent section, leading to supersonic velocities which increase the jet’s action and also the velocity of the circulating gas stream, thereby allowing greater production rate and fineness of the grind.
The number of nozzles is an important feature for jet mill design. Skelton et al. w8x experimented with three alternative configurations, with 3, 6 and 12 nozzles, keeping constant the total section of the nozzles, and so the grinding gas rate, with varied solid feed rates. The result was that the device of 12 nozzles gave the best grinding ratio. Furthermore, the improvement in the grinding ratio was better when feed rates were high. These results were explained by the fact that a greater number of grinding nozzles created a more regular pitch-circle and, moreover, a thinner jet leads to a minor perturbation of the spiral flow in the chamber. As mentioned, the jets form a circle separating the grinding and classification zones so it appears obvious that the angle of the nozzles determines the size of both areas and, therefore, the grinding ratio of the product. Furthermore, as this angle affects the penetration of the nozzle jets in the gas stream, it may be considered that the relative velocity of gas flowing at the intersection determines the kinetic energy transmitted to the particles and thereby the intensity of the collisions. Smit w6x and Skelton et al. w8x showed that an optimum value appears at high feed rates. Their values are quite similar. If we consider the angle to the tangent, Smit’s optimum is equal to 588 and Skelton’s one is between 52 and 608. 2.2. Working conditions As stated by Albus w7x, an optimum feed rate exists. This was found by Mohanty and Narasimhan w9x on a loop mill and depends greatly on the type of material ground. To our knowledge, this optimum feed rate has not yet been
Table 1 Examples of operating parameters range in a spiral jet mill Grinding chamber diameter Žmm.
Solid feed rate Žkgrh.
Volumetric flow rate ŽNm3 rh.
100 200 500
0.5–25 1.5–50 40–300
50–125 80–250 700–1400 Fig. 2. The two types of nozzle: 1. abrupt nozzle, 2. Laval shaped nozzle.
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115
Table 2 Working conditions described in the literature Authors
Mill type
Mill diameter Žmm.
Material
Grinding pressure range ŽbarG.
Solid range Žkgrh.
Smit Mohanty et al.
Spiral Loop
100 ?
7 ?
0.4 to 2 f 1 to 40
Gommeren et al. Skelton et al. Ahmad Khan et al. Ramanujam et al. Schurr et al.
Spiral Spiral Spiral Loop Spiral
250 200 60 20 Žpipe. 200
Waxes Sand Chromite Lime stone Graphite Blue dust ? Lime stone Calcite Calcite Sand
? ? ? 3 to 6 f5
Muller ¨ et al.
Spiral
170
Calcite
2 to 8
8.8 to 30 7 to 40 ? 0.3 to 9 0.3 to 100 Ždepending on gases used. 2 to 8
mentioned for a spiral jet mill. Above this optimum, which is rather low, an increase of the feed rate leads to a coarser product and the variation of the size of the product can be expressed in terms of the feed rate by a power law. In fact, according to Ramanujam and Venkateswarlu w10x, there is a transition feed rate, above which the exponent changes. Gommeren et al. w11x defines a maximum rate which leads to choking conditions in the mill. These conditions correspond to instabilities of the solid–fluid flow in the chamber with discontinuous discharge of the mill and, consequently, larger particle size distributions. Another major parameter in jet milling is grinding pressure, which conditions the gas mass flow rate input. Assuming that the nozzles are isentropic, according to the ‘Barre´ de Saint Venan’ equation, the initial grinding pressure P and the pressure at the nozzle throat Pt are related by: P Pt
ž
s 1q
ky1 2
k
Mt2
/
ky 1
Ž 4.
where Mt is the Mach number at the throat and k is the ratio of specific heats of the gas. This leads us to define a critical pressure Pc : Pc Pt
s
ž
kq1 2
ky1
Table 3 Results obtained by Ramanujam and Venkateswarlu, on calcite with a 20 mm diameter loop mill
Region below transition Region above transition
Mw k RT
ž
2 kq1
kq 1
/
ky1
Ž 6.
and is directly proportional to the grinding pressure, the throat section and the molecular weight of the fluid employed for grinding. The grinding power supplied as gas kinetic energy for sonic nozzles can be expressed by: E˙k s
1 2
Mg ns2
Ž 7.
Thus, the grinding pressure is directly correlated to the kinetic energy of the gas and thereby to the energy transmitted to particles for grinding. In order to include, in the same parameter, both grinding pressure and solid feed rate, many authors w12–14x use the notion of Specific Energy Consumption Ž Esp .. According to Schurr and Zhao w15x this is calculated by: E˙k
Ž 8.
Q
Ž 5.
which corresponds to the minimum of pressure necessary to get a sonic flow at the nozzle throat.
K
)
Mg s PA
Esp s
k
/
Above this value the gas mass flow rate can be expressed by:
p
q
Mean relative deviation
0.039
0.278
0.417
"7.3
3.46
0.053
0.079
"2.7
This compares different mills, or working conditions Žtype of gas, temperature, pressure. on the same system. In
Table 4 Results obtained by Sarma and Ahmad Khan, on calcite with a 60 mm diameter spiral jet mill K Sarma’s results Ahmad Kahn’s results Data of both studies treated by least squares method
y7
7=10 4.54=10y2 0.2=10y2
p
q
s
0.6 0.4 0.59
1.5 1.2 1.04
0.6 0.7 0.72
N. Midoux et al.r Powder Technology 104 (1999) 113–120
116 Table 5 Properties of products A, B and C
Product A Product B Product C
Density Žgrcm3 .
SSA Žm2 rg.
1.12 1.25 1.28
0.14 0.4 0.67
a spiral jet mill, the specific surface area of the product is related to Esp by a power function: SSA A Espx
Ž 9.
Schurr and Zhao have shown that a critical value of the specific energy can be defined. Above this value, the size distribution of the particles are narrower, and the relationship between the specific surface area of the product and energy changes, such that the exponent of the power function is greatly diminished. This critical value is independent of the nature of the gas used for grinding, but to our knowledge, no studies have been conducted on various mills. For sand, the critical energy equals 3600 kJrkg according to Schurr et al., Muller et al. found the same ¨ value for calcite, but with a different mill Žsee Table 2.. The injector pressure is generally fixed to 0.5 or 1 bar above the grinding pressure to avoid back flow at the venturi. For Sommer w16x, the flow coming from the venturi can disturb the spiral stream in the chamber when the injector pressure is too high. This disturbance leads to a coarser product at the exit of the mill. This is why he recommends working with a minimal pressure at the injector. Moreover, Ramanujam and Venkateswarlu w10x defined a minimal injector pressure to avoid choking conditions in the loop mill. In fact, we can say that the importance of the injector pressure depends upon the design of the mill, and must be chosen according to the grinding pressure. 2.3. Dimensional analysis of fluid jet mills We have seen that the influence of the different parameters is well known, but in view of the complexity of jet
Fig. 3. Correlation SSA Malvern vs. SSA Blaine.
Fig. 4. Correlation 6rd50 vs. SSA Blaine.
milling, some authors have tried to find correlations using dimensional analysis. Ramanujam and Venkateswarlu w10x have proposed the following relation: R G s exp K Ž R d0.2 . Ž R wp Re gq .
Ž 10 .
Where: R G s ŽSSA product .rŽSSA feed ., R d s Ž d feed .r Ž Dmill ., R w s Ž Mg .rŽ Q ., Re g s Ž d N rg ns .rŽ mg . Their study was made on calcite with a vertical mill of 20 mm pipe diameter. A transition was found, and the results gave two correlations with different constants: K and exponents p and q Žsee Table 3.. Hence, these results seem to confirm the fact that there are critical conditions above which the increase of grinding ratio with energy input in the system is less important. Khan and Ramanujam w17x also reportŽs. a correlation proposed by Sarma for a horizontal jet mill. He uses the same type of variables, but the expression is simpler than the former. Moreover, it takes into account the volumetric rate of fluid passing through the venturi, whilst this is neglected in the earlier study. The coefficients calculated by these authors are presented in Table 4. q
p
R G s K Ž Re g . Ž R Wt . Ž R d .
s
Ž 11 .
Where: R Wt s Ž Mg q Mi .rŽ Q . These authors didn’t find a ‘transition zone’ but, in view of the absence of further information about the trials
Fig. 5. Product A: Esp vs. DSSA.
N. Midoux et al.r Powder Technology 104 (1999) 113–120
117
Fig. 8. Particle size distribution of product C for low energy trials. Fig. 6. Product B: Esp vs. DSSA.
conditions Žpressure and solid feed rate., this particularity doesn’t seem really noticeable.
3. Experimental Three types of organic crystals were micronized: products A, B and C. Their basic properties are given in Table 5. Experimental runs were achieved with spiral jet mills: Chrispro-Jetmill 100 Žsee Fig. 1. and MicronMills 8Y for product A, Chrispro-Jetmill 100 for product C and Chrispro-Jetmill 50 for product B, all equipped with abrupt nozzles. The solid was delivered at a constant feed rate by a screw feeder. It was dropped into the injector cone then accelerated through a venturi before its introduction to the mill chamber. The gas used for grinding was pressurised nitrogen, to avoid risks of dust explosion. The specific surface area of ground products have been evaluated by different methods depending on the substance: Blaine’s permeameter, porosimetry, BET method. In order to compare the values obtained, all the results are presented in terms of Blaine’s specific surface area. Blaine’s specific surface areas are measured according to the ‘norme AFNOR’ w18x. Particle size distributions of products A and C were determined by laser granulometry with a Malvern Master-
Fig. 7. Product C: Esp vs. DSSA.
sizer S which allows to determine sizes of particles from to 0.05 to 900 mm. All the values were very well correlated. It is notable that in the case of product C, for example, although the population is bimodal ŽFigs. 8 and 9., the Blaine surface is as well correlated with 6rd50 Žsurface of a sphere equal to the median of the mass distribution, Fig. 3. as with the surface measured by the apparatus ŽSSA Malvern., from the diameter of Sauter ŽFig. 4.. The gas mass flow rates, and the kinetic energies, were calculated assuming that the abrupt nozzles were sonic. 4. Results 4.1. Specific energy consumption As seen before, the newly created surface depends mainly on two features: nozzle grinding pressure and solid feed rate. The product specific surface increases with the pressure, and with a decrease of the solid feed rate. These two operational parameters are included in the notion of Specific Energy Consumption. Effectively, as defined in first part, the Specific Energy Consumption is equal to the power supplied by the kinetic energy of the grinding fluid divided by the solid feed rate. E k is directly proportional to the grinding pressure under the present operating conditions. Hence, the representation of the product specific surface area versus Specific Energy provides a physical understanding of the influence of grinding pressure and solid feed rate on the grinding ratio. Moreover, by notion of Specific Energy Consumption, it is interesting to compare the grinding efficiency of different mills or grinding fluids ŽFigs. 5–7..
Fig. 9. Particle size distribution of product C for high energy trials.
N. Midoux et al.r Powder Technology 104 (1999) 113–120
118 Table 6 Description of the jet mills employed for trials Parameters
Mill diameter
Nozzles number
Nozzles angle
Nozzle diameter
Nozzle type
Chrispro-Jetmill 50 Chrispro-Jetmill 100 Y MicronMills 8
50 mm 100 mm 200 mm
6 6 12
638 638 678
0.85 mm 1.25 mm 1 mm
abrupt abrupt abrupt
If we look at the results concerning product A ŽFig. 5., they obey the same trend in two mills. But this type of representation shows differences between the efficiency of both devices. The MicronMills jet mill gives a better grinding ratio, which is in agreement with the scale-up laws found in the literature Žsee paragraph ‘Scale-up’.. The specific energy required to obtain a certain grinding ratio diminishes with the mill diameter. The transition found by Schurr and Zhao wasn’t found for product B ŽFig. 6.. In fact, the product specific area required was rather high, and so the trials were achieved with high energy input. But the results obtained for low energy trials with product A seem to indicate that the ‘critical’ Esp is between 400 and 800 kJrkg. However, the runs performed with product C clearly demonstrate a transition around 400 kJrkg. Below the critical energy, the newly created surface seems proportional to the energy: the exponent x equals 1.1. This implies that results obtained in this range of energies obey Rittinger’s empirical breakage law. Above this value, the exponent is greatly diminished and the relationship between energy and created surface is no longer linear. The particles size distributions of product C, show two populations of particles, even in the feed. A first population, corresponding to very fine particles, and a second of coarser product. For low energy trials Žsee Fig. 8., up to a critical value of specific energy, the coarser particles are well ground and the mode of this population diminishes. Above the transition Žsee Fig. 9., the mode is kept constant and only fine particles are produced. So, it appears that the rise of specific surface area observed above the energy critical value corresponds to the production of fine particles. It seems that a grinding limit is reached for transition
value. Hence, grinding above critical conditions is no longer interesting. For each product, trials with helium have been undertaken. This gas permits reaching higher mill velocities. By comparison with nitrogen, the energies obtained under the same conditions of pressure and solid feed rate are higher and, moreover, the grinding appears more efficient with helium. Nevertheless, this conclusion has to be confirmed by other trials. The presentation of trials results in terms of specific energy permits a comparison of the ‘grindability’ of materials. For similar values of energy, the grinding ratio of product B is greater than for products A and C. Consequently, the expression of results in terms of Specific Energy Consumption allows comparison between different operating conditions and mills. However, the prevision of results obtained during trials can also be made by empirical correlations.
Fig. 10. Product C: SSA calculated by correlation vs. Esp.
Fig. 11. Product A: SSAest vs. SSAexp.
4.2. Correlation application An attempt to use the correlation proposed by Sarma on an horizontal jet mill is made for the three products. However, the correlation for product A concerns only the results obtained on the Chrispro 100 because of the difference in design between this mill and the MicronMills 8X which can’t be taken into account by the correlation used. In view of the absence of experimental runs with varying sizes of feed, and sizes of mill, this relation will be simplified by: q
R G s K Ž Re b . Ž R MT .
p
Ž 12 .
The coefficients of the correlation shown in Table 6. are determined by the least squares method. The comparison
N. Midoux et al.r Powder Technology 104 (1999) 113–120
119
Fig. 14. Product A: SSA vs. Pg. Fig. 12. Product B: SSAest vs. SSAexp.
4.3. Scale-up
Fig. 13. Product C: SSAexp vs. SSAest.
between the experimental specific surfaces and the calculated ones is presented in Figs. 10–13. Transitions were found for products A and C. The regions of transition correspond to the value of ‘critical Esp ’ described in the preceding paragraph. In Fig. 10, the SSA calculated with the empirical correlation versus Esp present the same transition as the experimental values. This correlation, specific to the nature of the ground material, can be employed to foresee the conditions necessary to reach the specific surface expected for organic crystals. The results obtained on product B with helium ŽFig. 12. fit very well with the correlation calculated with nitrogen. So this correlation seems to truly take into account the nature of grinding gas used. A comparison of the values calculated for products A and B confirms the conclusion about the difference of grindability of both products ŽTable 7..
The trials achieved with product A on the MC100 and the MicronMills 8Y have lead to a scale-up relationship between these two micronizers. Fig. 14 shows that the specific surface area obtained using both devices at various grinding pressure, and at constant solid feed rate, are identical. However, this represents a situation of perfect scale-up, such that the following relationship is deduced: Q A D 2.8. This expression is in agreement with those found in the literature. The fairly high exponent may be explained by the difference of geometry between each mill. As aforementioned, the MicronMills has 12 grinding nozzles whilst Chrispro 100 has only 6, and this difference seems to explain the improvement of performance with the former.
5. Conclusion Publication of several micronization studies since the 1960s has enabled the optimal design for a jetmill in terms of geometrical parameters and scale-up. A product’s ability to be ground by this type of device seems difficult. This paper presents two methods applied to organic crystals. The first method, applied to evaluate the energy input to the system, permits a comparison of different grinding devices and a physical understanding of the influence of the operating features. The second refers to an empirical correlation.
Table 7 Results obtained with Sarma’s correlation Product
Below transition K
p
q
K
p
q
A B C
5.95 = 10y8 a
0.25a
1.7 a
0.0627
0.385
0.273
0.020 0.104 0.836 a
0.043 0.14 0.037 a
0.54 0.35 0.112 a
a
Above transition
Mean relative deviation
These coefficients are calculated with very few points, so that they must be considered as a ‘trend’.
6.5% 8.6% 3.7%
N. Midoux et al.r Powder Technology 104 (1999) 113–120
120
A transition zone has been determined. It corresponds to the ‘critical’ value of SEC defined by Schurr and Zhao. This value seems dependent on the product, and lower for organic crystals than minerals. It appears that above the transition, grinding is no longer interesting because the supplementary energy furnished leads to attrition, and thereby, ‘fine particles’ production.
6. Nomenclature A Cp Cv D df dN E˙k Esp k Mg Mi Mw Pc Pg Pt Q R Rd Re g RG RW R Wt SSA SSAest SSAexp T Vn Õs DSSA mg rg
Acknowledgements The authors thank Dr. F. Leveiller, Dr. M. Sautel, Dr. M. Ubogi for analytical assistance, Mr. M. Nakach for helpful suggestions and Micron Mills for the trials conducted in their establishment. A special thank is addressed to Prof. N. Midoux for his scientific advice during the redaction of this paper. References
2.
Grinding nozzles total area Žm Gas heat capacity at constant pressure Gas heat capacity at constant volume Mill chamber diameter Žm. Mean diameter of the feed Žmm. Grinding nozzle diameter Žm. Kinetic energy of grinding gas ŽW. Specific Energy Consumption ŽkJrkg. CprC v Grinding gas mass flow rate Žkgrh. Injector gas mass flow rate Žkgrh. Molar weight Critical pressure Žbar. Initial grinding pressure Žbar. Nozzle throat pressure Žbar. Solid feed rate Žkgrh. Gas constants 8.314 Pa m3 Ky1 moly1 Ratio of feed mean diameter to chamber mill diameter: d frD Number of Reynold in the grinding nozzle: d N rg nsrmg Grinding ratio: SSA productrSSA feed Ratio of grinding gas mass flow rate to solid feed rate: MgrQ Ratio of total gas mass flow rate to solid feed rate: Ž Mg q Mi .rQ Specific surface measured by Blaine method Žm2rg. Specific surface calculated by means of correlation Žm2rg. Experimental specific surface Žm2rg. Gas temperature ŽK. Volumetric flow rate ŽNm3rs. Sonic velocity Žmrs. SSA product y SSA feed Viscosity of grinding gas ŽPa s. Volumic weight of grinding gas Žkgrm3 .
w1x R. Hendry, A mathematical model for fluid energy mills, Dechema Monographein 57 Ž2. Ž1967. 695–727. w2x H. Berthiaux, J. Dodds. Investigation on breakage and classification in a fluidized bed opposed jet mill, First International Particle Technology Forum Ž1994., 241–246. w3x I.N. Dorokhov, S.Yu. Arutyunov, D.I. Eskin, Mathematical description of the jet grinding process, Teoreticheskie Osnovy Khimicheskoi Technologii 27 Ž1993. 514–517. w4x H. Rumpf, Prinzipien der Prallzerkleinerung und ihre Anwendung bei der Strahlmahlung, Chem. Ingr. Tech. 32 Ž1960. 129. w5x H. Ito, Scale-up theory of single track jet mill, The second KoreanJapan Powder Technology Seminar, Pusan, Korea, August 18–19, 1987. w6x W.A.J. Smit, Jetmilling of heat sensitive materials, World Congress Particle Technology, Part II, 345–357. w7x F.E. Albus, The modern fluid energy mill, J. Chem. Eng. Prog. 60 Ž1964. 102–106. w8x R. Skelton, A.N. Khayyat, R.G. Temple, Fluid energy milling. An investigation of micronizer performance, Fine Particles Processing 1 Ž1980. 113–125. w9x B. Mohanty, K.S. Narasimhan, Fluid energy grinding, Powder Technology 33 Ž1982. 135–141. w10x M. Ramanujam, D. Venkateswarlu, Studies in fluid energy grinding, Powder Technology 3 Ž1970. 92–101. w11x J.C. Gommeren, H.J.M. Heitzmann, B. Scarlett, Dynamic modelling of a closed loop jet mill, First International Particle Technology Forum Ž1994., 197–202. w12x G.A. Schurr, Q.Q. Zhao, Fluid mechanic considerations for fine grinding in a fluid energy mill. 8th European Symposium on Comminution, Stockholm, Sweden, May 17–19, 1994. w13x C.J. Stairmand, Energy efficiency of milling processes. A review of some fundamental investigations and their application to mill design, Dechema Monographein for European Symposium on Comminution, 4th: Zerkleinern, Germany, 79 1549–1588 Ž1975., 1–17. w14x F. Kaiser, R. Nied, Modern jet pulverizers, Aufbereitungs Technik 10 Ž1980. 507–514. w15x J.M. Dotson, Extending the range of jet mills, Industrial and Engineering Chemistry 54 Ž2. Ž1962. 62–65. w16x K. Sommer Expose´ du 21 mars 1989 au Centre de Recherche .. d’Aubervilliers, ŽInternal document, Rhone-Poulenc ˆ w17x A. Khan, M. Ramanujam, Improved correlations for superfine grinding in a condux air jet mill, Ind. Chem. Eng. 20 Ž4. Ž1978. 49–51. w18x Norme AFNOR, Mesure de la surface specifique par le ´ permeabilimetre ´ ` de Blaine, NF P 15-442, 1st edn. 3–67.