Powder Technology 179 (2007) 95 – 99

www.elsevier.com/locate/powtec

Use of milling and wet sieving to produce narrow particle size distributions
of lactose monohydrate in the sub-sieve range
Handoko Adi, Ian Larson, Peter Stewart ⁎
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Pde, Parkville, Victoria 3052, Australia
Available online 27 January 2007

Abstract

Fluid energy milling and wet sieving were used to produce narrow particle size distributions (PSD) of fine lactose in the size range size
b 40 μm. Fluid energy milling (K-tron Soder, USA) occurred at milling pressures of 552 and 690 kPa and feed rates of 400 to 1600 rpm. Wet
sieving used 1-butanol pre-saturated with lactose to classify lactose into fractions of nominally b 5 μm, 5–10 μm, 10–20 μm and 20–45 μm. The
sonicator was positioned 3 mm above the surface of the sieve during wet sieving. PSD of the lactose fractions were measured by laser diffraction
(Malvern MasterSizer S, Malvern Instrument Ltd., U.K.). Fluid energy milling produced a range of mono-modal distributions of lactose with
VMD from 2.9 μm to 41.7 μm. The distributions of milled lactose (VMD of 5.5, 20.2 and 31.1 μm) were broad with spans ranging from 1.6 to
12.4. Wet sieving required the use of sonication to achieve classification. Wet sieving removed fine particles b 5 μm in the milled lactose fractions
of 5.5 μm and 20.2 μm and 31.1 μm by 60.2%, 90.6% and 95% respectively after 15 repeat wet sieved cycles giving narrow distributions with
spans in the range of 0.9–1.6. DSC and PXRD results for both milled and wet sieved lactose were consistent with those of α-lactose monohydrate
and β-lactose was not detected.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Fluid energy milling; Wet sieving; Particle size distributions; Lactose monohydrate

1. Introduction forensic soil identification [4,5], ceramics [6] and cracking

Production of fine powders by the size reduction of coarse
materials is of considerable importance in many industries,
where it is essential that the product should have a controlled
size distribution. In particular, the production and fractionation
of very fine and micronised powders is important, but
sometimes difficult. Normally, fluid energy milling has been
used for such purposes, where it offers an effective means of
reducing the particle size of powders to the sub-sieve range with
narrow particle distributions [1]. However, the main disadvan-
tage of high fluid energy milling is the high amount of energy
required for the grinding operation [2], and the inability to
control the milling conditions to produce specific micronised
powder fractions.
Wet sieving of fine powder has been used to fractionate
powder samples because it is simple, reproducible and fairly
inexpensive [3]. This method has been used previously for
⁎ Corresponding author. Tel.: +61 3 99039517; fax: +61 3 99039583.
E-mail address: peter.stewart@vcp.monash.edu.au (P. Stewart).
0032-5910/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.powtec.2007.01.020
catalysts for the petroleum industry [7]. However this method
has not been significantly applied in the pharmaceutical
industry. Dispersion of the fine particles in liquids is easier to
use than dry sieving techniques, because electrostatic and other
agglomerating forces can be reduced [3].
The behaviour and the properties of particulate materials in
pharmaceutical formulations are to a large degree dependent on
their particle size and size distribution. Indeed particle size is
one of the crucial factors in the optimization of respiratory drug
delivery from powder mixtures for inhalation. Previous studies
have reported improved dispersion of drugs delivered from a
powder mixtures for inhalation by adding fine lactose to the
formulations [8,9]. Furthermore, the primary powder polydis-
persity would affect the amount of the fine particles deposited in
the lower respiratory tract (FPF) generated in the aerosol clouds
[10]. Powders with higher polydispersity (i.e. broad distribu-
tions) have produced lower FPF, higher impaction loss and
higher capsule and device retention. Therefore, control of the
particle size distribution of drugs and excipients is important in
designing formulations for respiratory delivery. In order to
96 H. Adi et al. / Powder Technology 179 (2007) 95–99

5.5 μm, 20.2 μm and 31.1 μm) into several fractions: b 5 μm, 5–
10 μm, 10–20 μm and 20–40 μm respectively, using test sieves
(CSIRO, Victoria). Approximately 5 g of lactose was dispersed
in the 1-butanol, with the aid of sonication for 5 min to make a
homogeneous suspension. Serial sieves were set with the
sonicator (5 μm, 10 μm, 20 μm and 45 μm), positioned 3 mm
above the surface of the sieve. The supernatant liquid was
removed and replaced by fresh 1-butanol, and vigorously
mixed. The process was repeated 15 times to obtain narrow
particle size distributions.

2.4. Particle size analysis method

The particle size distribution of powders was measured by

laser diffraction (Malvern Mastersizer S, Malvern Instruments
Ltd., U.K.) using the 300 RF lens and the small volume sample
presentation unit (capacity 150 ml). Approximately 500 mg of
lactose powder was dispersed in 5 ml of propan-2-ol with the
aid of sonication in a water bath for 3 min. Particle size analysis

Fig. 1. Particle size distribution of micronised lactose milled using 690 kPa (A)
and 552 kPa (B) with feed rates from 400 rpm to 1600 using a fluid energy mill
(K-tron Soder, USA).

further study the influence of fine lactose on the respiratory

delivery of drugs, specific, narrow particle size fractions of
lactose were required in particle size from about 2.5 to 40 μm.
The objective of this study was to use fluid energy milling
and wet sieving in the production of narrow particle size
distributions (PSD) of fine lactose in the size range of b 40 μm.

2. Experimental

2.1. Materials

Lactose Edible 90 (Lactose New Zealand, New Zealand) and

propan-2-ol (Merck, Australia). All solvents and materials were
used as supplied.

2.2. Milling of lactose

Milling of Lactose Edible 90 was conducted using a fluid

energy mill (K-tron Soder, USA). An injector pressure of
862 kPa and grinding pressure of 552 and 690 kPa were
employed at different feed rates (400, 600, 800, 1200 and
1600 rpm) to produce different size fractions of milled lactose.

2.3. Wet sieving technique

Fig. 2. Comparison on the particle size distribution of fluid energy milled and
wet sieved fractions of lactose in the size ranges of (A) 5–10 μm, (B) 10–20 μm
The wet sieving technique used 1-butanol pre-saturated with and (C) 20–45 μm determined by laser diffraction using propan-2-ol as a
lactose to classify the milled lactose fractions (VMD 2.5 μm, dispersant.
 H. Adi et al. / Powder Technology 179 (2007) 95–99
Fig. 3. Scanning electron micrograph of wet sieved lactose fraction in size range of (A) b5 μm, (B) 5–10 μm, (C) 10–20 μm and (D) 20–45 μm.
of each sample was performed using 2000 sweeps and analysed
with the reference refractive index of lactose (1.533) and
propan-2-ol (1.378) and an estimated imaginary refractive index
of lactose of 0.1. The average particle size distribution was
determined from 5 replicates of each sample. The polydispersity
of the powder was expressed by the span.
½Dðv; 90Þ−Dðv; 10Þ
Span ¼
Dðv; 50Þ
where D(v,90), D(v,10) and D(v,50) are the equivalent volume
diameters at 90, 10 and 50% cumulative volume, respectively.
The particle size of the primary powders was described by the
volume mean diameter (VMD). The residual value was always
below 1%.
2.5. Scanning electron microscopy
Powder samples were mounted on metal sample plates. The
samples were gold coated with a sputter coater (BAL-TEC SCD
005, Japan) using 2.0 kV and 25 mA for 3 min. The particles
97
were examined at several magnifications under a Hitachi S-570
scanning electron microscope (Tokyo, Japan) operating at
10 kV.
2.6. Powder X-ray diffraction (PXRD)
The crystalline properties of milled and wet sieved lactose
ð1Þ were investigated using an X-ray diffractometer (Model PAD V,
Scintag Inc., USA). Samples of 2–5 mg were placed into a
quartz holder. The samples were scanned in the range of 2–100°
using Cu Kα radiation.
2.7. Differential scanning calorimetry (DSC)
Thermal properties of milled and wet sieved lactose were
analysed using a differential scanning calorimetry (DSC; Model
DSC7, Perkin Elmer, USA). The DSC was calibrated with
indium (melting point of 159.2 °C) under a nitrogen gas purge.
A sample (3–5 mg) was crimp-sealed in 50 μL aluminium pans
with pierced lids and analysed in the range between 50–300 °C
with a baseline correction using a heating rate of 10 °C/min. The
98 H. Adi et al. / Powder Technology 179 (2007) 95–99
Fig. 4. Powder X-ray diffraction of lactose. (A) Milled lactose, and (B) wet
sieved lactose.
highest peak temperature, onset temperature and heat of
enthalpy (DH ) for each peak were determined using Pyris
Manager Software V3.8 from the normalised DSC thermogram.
2.8. Statistical analysis
Volume mean diameters of particle fractions were compared
using One Way Analysis of Variance (ANOVA) (SPSS, USA),
with probability values of less than 0.05 considered as
statistically significant.
3. Results and discussions
3.1. Production of fine lactose fractions using fluid energy
milling
In order to obtain several fractions of fine lactose, Edible
Lactose 90 was processed through the fluid energy mill.
Different mill pressures (690 and 552 kPa) were applied to the
milling chamber at a range of feed rates (400 to 1600 rpm) to
produce different fractions of lactose (Fig. 1). The use of higher
milling energies produced higher air speeds in the turbulent gas
flow, and resulted in the higher impact energy between particles
in the mill. A sequential series of impacts and size reduction
occurred until the particles of the desired size were achieved.
Milling energy of 690 kPa produced smaller fraction sizes of
lactose than 552 kPa milling pressure (Fig. 1).
The lower feed rate (400 rpm) produced lactose with smaller
particle fractions in both 690 and 552 kPa with VMD of 2.9 μm
and 4.3 μm, respectively, compared with higher feed rates
(1600 rpm) where the VMD were 31.1 μm and 41.7 μm. Lower
feed flow rate resulted in higher particle impact velocity and
greater opportunity for particle interactions.
The limitation of high fluid energy milling was the broad
particle distributions, especially for the large particle size
fractions (Fig. 1). For particle fractions with VMD of 11.3 μm
and 41.7 μm, 90% of the particle distributions were less than
25.1 μm and 146.6 μm, respectively. The production of narrow
size distributions required the selective removal of lactose at the
extremes of the distributions.
3.2. Production of particle size fractions of fine lactose using
wet sieving technique
In order to produce narrow particle size fractions of fine
lactose, a wet sieving technique was employed. Sonication
energy was used to de-agglomerate fine lactose particles during
wet sieving. Specific milled lactose fractions with the VMD of
2.5, 5.5, 20.2 and 31.1 μm were chosen for classification into
fractions of b 5, 5–10, 10–20, 20–45 μm by the wet sieving
technique.
Wet sieving significantly decreased the percentage of fine
lactose b 5 μm in the milled lactose fractions of 5.5 and 20.2 μm
and 31.1 μm by 60.2%, 90.6% and 95%, respectively, after 15
repeat wet sieving cycles (Fig. 2). For example, after wet
sieving treatment, the percentage of fine lactose b5 μm
remaining in the original milled fraction of VMD of 20.2 μm
was 0.8%, with a sharper distribution compared with that of the
milled lactose (Fig. 2B). The Scanning Electron Micrograph
(SEM) of wet sieved fractions are shown in Fig. 3 and
confirmed the removal of fine lactose from the 5–10 μm to 20–
45 μm lactose fractions; for the larger size fractions, this was
evident by the relative absence of very fine particles adhered on
the surface of the particle.
Wet sieving significantly improved the volume of particles in
the targeted size fraction in comparison to milled lactose. For
example, an 85% improvement in the percentage by volume
occurred in both size fractions of 10–20 μm and 20–45 μm and
Fig. 5. Differential scanning calorimeter thermograms of milled and wet sieved
lactose NZ.
 H. Adi et al. / Powder Technology 179 (2007) 95–99
a 50% by volume improvement was achieved in the size
fraction of 5–10 μm. In terms of the width of particle size
distribution, the span of the size fraction of 5–10 μm, 10–20 μm
and 20–45 μm were significantly reduced by 40.8%, 46.3% and
92.9% respectively (P b 0.05).
It was difficult to remove the fine particle below 5 μm for
particle fractions b10 μm, for example, after wet sieving, the
volume of fine lactose below 5 μm in the milled lactose
fractions of 5.5 μm was 25.6%. The scanning electron
micrograph of the wet sieved fraction (5–10 μm) confirmed
that the wet sieving technique was useful in removing particles
above 10 μm (Fig. 3). Particles b 10 μm possessed strong inter-
particulate forces and were very cohesive. The agglomerated
particles were difficult to disperse and separate using very small
sieve apertures (e.g. 5 μm sieve).
3.3. Solid state characterization of lactose
All milled and wet sieved samples were highly crystalline. In
the X-ray diffractogram, the major peaks of both milled and wet
sieved lactose were consistent with those of α-lactose
monohydrate and the presence of β-lactose was not detected.
The profile of the crystallinity data showed specific diffraction
peaks at 12.5–12.5°, 16.38–17.89° and 19.10–19.99° two-theta
values. The highest intensity value (100) for milled lactose and
wet sieved lactose samples was observed at two-theta values of
19.85 and 19.99 respectively (Fig. 4 A and B). Slight variations
in peak intensity observed between samples were considered to
be due to preferred orientation and minor differences in
crystallinity.
The DSC thermograms of both milled and wet sieved
lactose crystals further confirmed the presence of α-lactose
monohydrate. The DSC curve showed an endothermic peak
starting at 137–138 °C, when scanned with a heating rate of
10 °C/ min, corresponding to the loss of water of crystal-
lisation while the endothermic peak of 211.8–212 °C
represents the melting of α-lactose monohydrate [11–13].
The presence of β-lactose was not observed by DSC as there
was no endothermic peak at 224 °C [11]. No significant
change of crystallinity was observed in both milled and wet
sieved lactose due to their similarity in both endothermic
peaks of releasing water and melting of α-lactose monohy-
drate (Fig. 5). A slightly higher peak of dehydration was
observed in milled lactose compared with the wet sieved
lactose, the reason for which was not clear.
4. Conclusion
The present study proposed a method for producing narrow
particle size distributions using a combination of fluid energy
99
milling and wet sieving using sonication. In comparison to
milling, wet sieving is preferable when material with relatively
narrow PSD in the particle size range below 20 μm is required.
Both wet sieving and milling did not alter the crystallinity of the
lactose.
Acknowledgments
Handoko Adi was supported by a Departmental Scholarship,
Department of Pharmaceutics, Monash University. We would
like to extend our thanks to Micro-powders Ltd. for the
micronised lactose.
References
[1] N. Midoux, P. Hosek, L. Pailleres, J.R. Authelin, Micronisation of
pharmaceutical substances in a spiral jet mill, Powder Technology 104
(1999) 113–120.
[2] H.J.C. Gommeren, D.A. Heitzmann, J.A.C. Moolenaar, B. Scarlett,
Modelling and control of a jet mill plant, Powder Technology 108
(2000) 147–154.
[3] J. Hidaka, S. Miwa, Fractionation and particle size analysis of fine powders
by micro sieve, Powder Technology 24 (1979) 159–166.
[4] J. Robertson, C.J. Thomas, B. Caddy, A.J.M. Lewis, Particle size analysis
of soils — a comparison of dry and wet sieving techniques, Forensic
Science International 24 (1984) 209–217.
[5] R. Sugita, Y. Marumo, Screening of soil evidence by a combination of
simple techniques: validity of particle size distribution, Forensic Science
International 122 (2001) 155–158.
[6] K. Nakahira, T. Hotta, M. Naito, N. Shinohara, Y. Cho, S. Katori, H.
Emoto, T. Yamada, T. Takahashi, M. Okumiya, C. Kumagai, K. Uematsu,
Characterisation of coarse particles in alumina powders by a wet sieving
method, Journal of the European Ceramic Society 23 (2003) 1661–1666.
[7] H.W. Daeschner, Wet sieving with precision electroformed sieves, Powder
Technology 2 (1969) 349–355.
[8] M.D. Louey, P.J. Stewart, Particle interaction involved in aerosol
dispersion of ternary interactive mixtures, Pharmaceutical Research 19
(2002) 1524–1531.
[9] X.M. Zeng, G.P. Martin, S.K. Tee, C. Marriott, The role of fine particle
lactose on the dispersion and deaggregation of salbutamol sulphate in an
air stream in vitro, International Journal of Pharmaceutics 176 (1998)
99–110.
[10] N.Y.K. Chew, H.K. Chan, Effect of powder polydispersity on aerosol
generation, Journal of Pharmacy and Pharmaceutical Sciences 5 (2002)
162–168.
[11] A. Gombas, P. Scabo-Revesz, M. Kata, G. Regdon Jr, I. Eros, Quantitative
determination of crystallinity of α-lactose monohydrate by DSC, Journal
of Thermal Analysis and Calorimetry 68 (2002) 503–510.
[12] C.F. Lerk, A.C. Andreae, A.H. de Boer, Alterations of α-lactose during
differential scanning calorimetry, Journal of Pharmaceutical Sciences 73
(6) (1984) 856–857.
[13] M.D. Louey, S. Razia, P.J. Stewart, Influence of physico-chemical carrier
properties on the in vitro aerosol deposition from interactive mixtures,
International Journal of Pharmaceutics 252 (2003) 87–98.