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I
n the July 2001 Pharmaceutical Technology article about
particle-size determination, the question of what constitutes
a correct method for the determination of particle-size dis-
tributions was addressed (1). A correct method was defined as
one whose sample was obtained by an appropriate sampling pro-
cedure, in which the sample was prepared properly and intro-
duced into the instrument, and in which all instrumental para-
meters were used correctly for the analysis. It also was pointed
out that all of the correct (but differing) particle-size results ob-
tained through various methodologies are equally accurate, but
each method simply might be expressing its correct results in
different terms. When viewed in this light, the decision about
Particle-size determinations are undertaken which particle-size methodology is most appropriate for a given
to obtain information about the size situation can be seen as a simple matter of accuracy versus pre-
characteristics of an ensemble of particles. cision. If absolute accuracy is most important, then one must
Because the particles being studied are not conduct rigorous research to verify that the method finally
adopted does indeed yield particle-size results that are absolutely
usually the exact same size, information is indicative of the characteristics of the bulk material. If, however,
required regarding the average particle size one is more interested in developing profiles of lot-to-lot vari-
and the distribution of sizes about this ability, then the use of any of the available methods that yields
average. However, the concept of particle correct results is appropriate.
size is irrevocably derived from aspects of The next several articles in the Pharmaceutical Physics col-
particle shape and morphology because the umn series will examine a variety of correct methodologies that
can be used to deduce information about the shape and size
idea of a particle diameter proceeds from distribution of particles. However, one cannot begin to address
preconceived shape factors. those topics without a prior exposition of what is meant by the
shape and size of the particles that consitute a powdered solid.
Particle shape
It is not possible to discuss rationally the size of a particle or
any distribution associated with the sizes of an ensemble of par-
ticles without first considering the three-dimensional charac-
teristics of the particle itself. This is because the size of a parti-
Harry G. Brittain, PhD, is the director of
cle is expressed either in terms of linear dimension characteristics
the Center for Pharmaceutical Physics, 10
Charles Road, Milford, NJ 08848, tel. 908. derived from its shape or in terms of its projected surface or
996.3509, fax 908.996.3560, hbrittain@ volume. As will be shown, some methods of expressing parti-
earthlink.net. He is a member of Pharma- cle size discard any concept of particle shape and instead ex-
ceutical Technologys Editorial Advisory press the size in terms of some type of equivalent spherical size.
Board.
An appropriate starting place for a discussion of particle shape
can be found in USP General Test ^776& (see Figure 1) (2). In the
shape performance aspect of this particular test procedure, USP
38 Pharmaceutical Technology DECEMBER 2001 www.phar mtech.com
requires that for irregularly shaped particles, characterization plate: flat particle of similar length and width but with greater
of particle size must also include information on particle shape. thickness than flakes
The general method defines several descriptors of particle shape lath: long, thin, blade-like particle
(see Figure 2). The USP definitions of these shape parameters are equant: particles of similar length, width, and thickness; both
acicular: slender, needle-like particle of similar width and cubical and spherical particles are included.
thickness In ordinary practice, one rarely observes discrete particles but
columnar: long, thin particle with a width and thickness that typically is confronted with particles that have aggregated or ag-
are greater than those of an acicular particle glomerated into more-complex structures. USP provides sev-
flake: thin, flat particle of similar length and width eral terms that describe any degree of association:
lamellar: stacked plates
Isometric
Tetragonal
0001
Hexagonal
1011 0111
Figure 2: Growth along certain crystal directions can profoundly alter the characteristic habit of various crystals.
40 Pharmaceutical Technology DECEMBER 2001 www.phar mtech.com
(a) (b) (c) which is the distance between imaginary parallel lines tan-
Feret's diameter gent to a randomly oriented particle and perpendicular to
th
ng the ocular scale, and Martins diameter, which is the diam-
Le
eter of the particle at the point that divides a randomly ori-
Projected ented particle into two equal projected areas (see Figure
Martin's area
diameter diameter 3b).
W
Cumulative distribution
100 then one calculates the percentage of par-
Number frequency
Number frequency
0 0
0 10 20 30 40 50 60 70 In the example shown in Table I, one cal-
10 100
Particle size (mm) culates that dav 5 30.2 mm and that s =
Particle size (mm)
1.1.
The most commonly occurring value
Figure 5: Particle-size representations for a hypothetical log-normal distribution, plotted on a (a) in the distribution is the mode, which is
linear scale and on a (b) logarithmic scale. the value at which the frequency repre-
sentation is a maximum value. The me-
dian divides the frequency curve into two equal parts and equals
Table I: Particle composition of a hypothetical sample the particle size at which the cumulative representation equals
exhibiting a normal distribution. 50%. In a rigorous normal distribution, the mean, mode, and
Size Number Number Percent Percent median have the same value. For a slightly skewed distribution,
(mm) in Band Frequency Less Than Greater Than however, the following approximate relationship holds:
5 50 1.67 1.67 98.33
10 90 3.00 4.67 95.33 [5]
15 110 3.67 8.33 91.67
20 280 9.33 17.67 82.33 It would be highly advantageous if powder distributions could
25 580 19.33 37.00 63.00 be described by the normal distribution function because all of
30 600 20.00 57.00 43.00 the statistical procedures developed for Gaussian distributions
35 540 18.00 75.00 25.00 could be used to describe the properties of the sample. How-
40 360 12.00 87.00 13.00 ever, unless the range of particle sizes is extremely narrow, most
45 170 5.67 92.67 7.33 powder samples cannot be described adequately by the normal
50 120 4.00 96.67 3.33 distribution function. The size distribution of the majority of
55 60 2.00 98.67 1.33 real powder samples usually is skewed toward the larger end of
60 40 1.33 100.00 0.00 the particle-size scale. Such powders are better described by the
Total 3000 100 log-normal distribution type. This terminology arose because
when the particle distribution is plotted by means of the loga-
distribution. Samples that conform to the characteristics of a rithm of the particle size, the skewed curve is transformed into
normal distribution are described fully by a mean particle size one closely resembling a normal distribution (see Figure 5).
and the standard deviation. Table I shows an example of a sam- The distribution in a log-normal representation can be com-
ple exhibiting a normal distribution in which 3000 particles pletely specified by two parameters: the geometric median par-
have been sorted according to an undefined determiner of their ticle size (dg) and the standard deviation in the geometric mean
size. In the usual data representation, the number of particles
Pharmaceutical Technology DECEMBER 2001 43
in which n is the number of particles hav-
(a) 30 (b) ing particle size equal to di. Two samples
% mass
100 having identical dg and sg values can be
frequency 80 said to have been drawn from the same
% in bond
20
% finer
% number
frequency 60 Cumulative total population and exhibit properties
% mass of characteristics of the total population.
10 40
Cumulative
20 % number In many applications, particle-size re-
0 0 sults are processed by plotting the cu-
0 15 30 45 60 75 mulative frequency data on a logarith-
Size (mm) Size (mm) mic scale. If a straight line is obtained,
the particle-size distribution is said to
obey the log-normal function. The value
Figure 6: Particle-size representations for a hypothetical log-normal distribution. Shown are (a) of dg is equal to the 50% value of the cu-
the frequency distribution and (b) the cumulative distribution. Each contains the difference mulative distribution. The value of sg
obtained when processing the data in terms of either particle number or particle mass. is obtained by dividing the 84.1% value
of the distribution by the 50% value.
Although the distribution in the log-
normal representation is specified completely by the geomet-
(a) US M
ric median particle size and the geometric mean standard de-
standard s M Ms viation, a number of other average values have been derived to
10 2,000
Mesh (US standard sieve series)
12 1,500 define useful properties. These values are especially useful when
16
1,000 the physical significance of the geometric median particle size
20
is not clear. The arithmetic mean (dav) particle size is defined
30
40
500 as the sum of all particle diameters divided by the total num-
400
50 300 ber of particles and is calculated using Equation 3. The surface
70 200 mean (ds) particle size is defined as the diameter of a hypo-
100 150
thetical particle having an average surface area and is calculated
140 100
200
using
270 50
325
0.5 1 2 5 10 20 30 40 50 60 70 80 90 95 98 99 99.5 [7]
Cumulative percentage of undersize particles
(b) US M
standard s M Ms The volume mean (dv) particle size is the diameter of a hypo-
10 2,000
thetical particle having an average volume and is obtained from
Mesh (US standard sieve series)
12 1,500
16
1,000
20
[8]
30
500
40 400
50 300
70 200
The volume-surface mean (dvs) particle size is the average size
100 150 based on the specific surface per unit volume and is calculated
140 100 using
200
270 50
325
0.5 1 2 5 10 20 30 40 50 60 70 80 90 95 98 99 99.5 [9]
Cumulative percentage of undersize particles
Figure 7: Particle-size representations plotted in a log-probability For the distribution plotted in Figure 5, one can calculate that
format for (a) a single hypothetical log-normal distribution and for dg 5 32.91 mm, dav 5 34.42 mm, ds 5 35.93 mm, dv 5 37.43 mm,
(b) a hypothetical sample containing two log-normal distributions and dvs 5 40.62 mm.
whose average particle size differs by ;50%. Various types of physical significance have been attached to
the various expressions of particle size. For chemical reactions,
the surface mean is important, although for pigments the vol-
(sg). The geometric median is the particle size pertaining to the ume mean value is the appropriate parameter. Deposition of
50% value in the cumulative distribution and is calculated using particles in the respiratory tract is related to the weight mean
diameter, and the dissolution of particulate matter is related to
[6] the volume-surface mean.
Particle-size distributions can be sorted according to the mass
(or volume) of the particles contained within a given size band
44 Pharmaceutical Technology DECEMBER 2001 www.phar mtech.com
Recommended reading
or to the number of particles contained in the same size R.R.Irani and C.F.Callis, Particle Size: Measurement, Interpretation, and Application (John
band. With substances having real density values, the dis- Wiley & Sons,New York,1963).
tribution of the same ensemble of particles can look quite Z.K.Jelinek,Particle Size Analysis (Ellis Horwood Ltd.,Chichester,1970).
different depending on how the data are plotted. Figure J.D.Stockham and E.G.Fochtman, Particle Size Analysis (Ann Arbor Science Publishers,
6 shows the frequency and cumulative distribution plots Ann Arbor,MI,1977).
for the same sample, but the data have been separately B.H.Kaye,Direct Characterization of Fine Particles (John Wiley & Sons,New York,1981).
processed in terms of the mass and particle numbers. H.G.Barth,Modern Methods of Particle Size Analysis (John Wiley & Sons,New York,1984).
Unfortunately not every powdered sample is charac- T.Allen,Particle Size Measurement, 5th ed.(Chapman and Hall,London,1997).
Circle/eINFO 25
Pharmaceutical Technology DECEMBER 2001 45