HO

C2H5 O HH C2 H 5 O C2 H5

Pharmaceutical Physics H H H H
O HO O HO H O C2 H5 O n2 CH2

H H O

C2 H5 O CH2

C 2 H5 O

H OH

HO H

Particle-Size Distribution, Part I

Representations of Particle Shape, Size, and Distribution

Harry G. Brittain

I
Particle-size determinations are undertaken to obtain information about the size characteristics of an ensemble of particles. Because the particles being studied are not usually the exact same size, information is required regarding the average particle size and the distribution of sizes about this average. However, the concept of particle size is irrevocably derived from aspects of particle shape and morphology because the idea of a particle diameter proceeds from preconceived shape factors.

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 distributions was addressed (1). A correct method was defined as one whose sample was obtained by an appropriate sampling procedure, in which the sample was prepared properly and introduced into the instrument, and in which all instrumental parameters were used correctly for the analysis. It also was pointed out that all of the correct (but differing) particle-size results obtained 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 which particle-size methodology is most appropriate for a given situation can be seen as a simple matter of accuracy versus precision. If absolute accuracy is most important, then one must conduct rigorous research to verify that the method finally adopted does indeed yield particle-size results that are absolutely indicative of the characteristics of the bulk material. If, however, one is more interested in developing profiles of lot-to-lot variability, then the use of any of the available methods that yields correct results is appropriate. The next several articles in the Pharmaceutical Physics column series will examine a variety of correct methodologies that can be used to deduce information about the shape and size distribution of particles. However, one cannot begin to address 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 particles without first considering the three-dimensional characteristics of the particle itself. This is because the size of a particle is expressed either in terms of linear dimension characteristics derived from its shape or in terms of its projected surface or volume. As will be shown, some methods of expressing particle size discard any concept of particle shape and instead express the size in terms of some type of equivalent spherical size. 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

Harry G. Brittain, PhD, is the director of the Center for Pharmaceutical Physics, 10 Charles Road, Milford, NJ 08848, tel. 908. 996.3509, fax 908.996.3560, hbrittain@ earthlink.net. He is a member of Pharmaceutical Technologys Editorial Advisory Board.

www.phar mtech.com

requires that for irregularly shaped particles, characterization of particle size must also include information on particle shape. The general method defines several descriptors of particle shape (see Figure 2). The USP definitions of these shape parameters are acicular: slender, needle-like particle of similar width and thickness columnar: long, thin particle with a width and thickness that are greater than those of an acicular particle flake: thin, flat particle of similar length and width

Plate

Tabular

Equant

Columnar

Blade

Acicular

Figure 1: Description of particle shape as defined by USP.

plate: flat particle of similar length and width but with greater thickness than flakes lath: long, thin, blade-like particle equant: particles of similar length, width, and thickness; both cubical and spherical particles are included. In ordinary practice, one rarely observes discrete particles but typically is confronted with particles that have aggregated or agglomerated into more-complex structures. USP provides several terms that describe any degree of association: lamellar: stacked plates aggregate: mass of adhered particles agglomerate: fused or cemented particles conglomerate: mixture of two or more types of particles spherulite: radial cluster drusy: particle covered with tiny particles (2). The particle condition also can be described by another series of terms: edges: angular, rounded, smooth, sharp, fractured optical: color, transparent, translucent, opaque defects: occlusions, inclusions. Furthermore, surface characteristics can be described as cracked: partial split, break, or fissure smooth: free of irregularities, roughness, or projections porous: having openings or passageways rough: bumpy, uneven, not smooth pitted: small indentations. The pharmaceutical descriptors of particle shape are derived from the general concept of crystallographic habit. The exact shape acquired by a crystal will depend on various factors such as the temperature, pressure, and composition of the crystallizing solution. Nevertheless, precipitation of a given compound generally creates a characteristic shape or outline. Because the faces of a crystal must reflect the internal structure of the solid,

Lamellar

Tabular

Equant

Columnar

Acicular

Isometric Tetragonal

0001 Hexagonal

1011

0111

Figure 2: Growth along certain crystal directions can profoundly alter the characteristic habit of various crystals.

(a)
Le ng th

(b)
Feret's diameter

(c)

Martin's diameter

Projected area diameter

Figure 3: Some commonly used descriptors of particle size.

the angles between any two faces of a crystal will remain the same even if the crystal growth is accelerated or retarded in one direction or another (see Figure 2). Optical crystallographers usually will catalogue the various crystal faces and document the angles between them as they identify the crystal system to which the given particle belongs. When the particle is particularly well formed, a description of symmetry elements also is compiled. For many individuals, however, the concept of qualitative shape descriptors has proven inadequate, and this deficiency has necessitated the definition of more quantitatively defined shape coefficients (3). For instance, Heywood describes the elongation ratio, n, as

nL B
and the flakiness ratio, m, as

[1]

mB T

[2]

in which T is the particle thickness (the minimum distance between two parallel planes that are tangential to opposite surfaces of the particle), B is the breadth of the particle (the minimum distance between two parallel planes that are perpendicular to the planes defining the thickness), and L is the particle length (the distance between two parallel planes that are perpendicular to the planes defining thickness and breadth) (4).

Particle size
It really is not possible to continue a discussion of particle shape or size without first developing definitions of particle diameter. This step is, of course, rather trivial for a spherical particle because its size is uniquely determined by its diameter. For irregular particles, however, the concept of size requires definition by one or more parameters. It often is most convenient to discuss particle size in terms of derived diameters such as a spherical diameter that is in some way equivalent to some size property of the particle. These latter properties are calculated by measuring a size-dependent property of the particle and relating it to a linear dimension. Certainly the most commonly used measurements of particle sizes are the length (the longest dimension from edge to edge of a particle oriented parallel to the ocular scale) and the width (the longest dimension of the particle measured at right angles to the length). Intuitive as these properties may be, their definition still is best shown in Figure 3a. Closely related to these properties are two other descriptors of particle size: Ferets diameter, which is the

distance between imaginary parallel lines tangent to a randomly oriented particle and perpendicular to the ocular scale, and Martins diameter, which is the diameter of the particle at the point that divides a randomly oriented particle into two equal projected areas (see Figure 3b). The coordinate system associated with the measurement is implicit in the definitions of length, width, Ferets diameter, and Martins diameter because the magnitude of these quantities requires some reference point. As such, these descriptors are most useful when discussing particle size as measured by microscopy because the particles are immobile. Defining spatial descriptors for freely tumbling particles is considerably more difficult and hence requires the definition of a series of derived particle descriptors. However, given the popularity of techniques such as electrozone sensing or laser light scattering, derived statements of particle diameter are extremely useful. All of the derived descriptors for particle size begin with the homogenization of the length and width descriptors into either a circular or spherical equivalent and make use of the ordinary geometrical equations associated with the derived equivalent. For instance, the perimeter diameter is defined as the diameter of a circle having the same perimeter as the projected outline of the particle. The surface diameter is the diameter of a sphere having the same surface area as the particle, and the volume diameter is defined as the diameter of a sphere having the same volume as the particle. One of the most widely used derived descriptors is the projected area diameter, which is the diameter of a circle having the same area as the projected area of the particle resting in a stable position. The concept of projected area diameter is illustrated in Figure 3c. Several other derived descriptors of particle diameter have been used for various applications. For instance, the sieve diameter is the width of the minimum square aperture through which the particle will pass. Other descriptors that have been used are the drag diameter, which is the diameter of a sphere having the same resistance to motion as the particle in a fluid of the same viscosity and at the same velocity; the free-falling diameter, which is the diameter of a sphere having the same density and the same free-falling speed as the particle in a fluid of the same density and viscosity; and the Stokes diameter, which is the freefalling diameter of a particle in the laminar-flow region.

id t W h

Distribution of particle sizes

All analysts know that the particles that constitute real samples of powdered substances do not consist of any single type but instead will generally exhibit a range of shapes and sizes. Particle-size determinations therefore are undertaken to obtain information about the size characteristics of an ensemble of particles. Furthermore, because the particles being studied are not the exact same size, information is required about the average particle size and the distribution of sizes about that average. One could imagine the situation in which a bell-shaped curve is found to describe the distribution of particle sizes in a hypothetical sample; this type of system is known as the normal distribution. Samples that conform to the characteristics of a normal distribution are described fully by a mean particle size

(a) Number frequency 20 15 10 5 0 Particle size (m)

(b) Cumulative distribution 100 80 60 40 20 0 0 10 20 30 40 50 60 Particle size (m)

yields the particle size histogram (see Figure 4a). The number frequency ordinarily is used to construct a cumulative distribution, which can be ascending or descending depending on the nature of the study and what information is required (see Figure 4b). The arithmetic mean of the ensemble of particle diameters is calculated using the relation

Figure 4: Particle-size representations for a hypothetical normal distribution. Shown are (a) the frequency distribution and (b) the cumulative distribution.

d av

ndi n

[3]

(a) Number frequency

Number frequency

20 15 10 5

(b)

in which n is the number of particles having a diameter equal to di. The standard deviation in the distribution then is calculated using
20 15 10 5

d av d i n

1 2 2

[4]

In the example shown in Table I, one calculates that dav 30.2 m and that = 1.1. 0 0 The most commonly occurring value 0 10 20 30 40 50 60 70 10 100 in the distribution is the mode, which is Particle size (m) Particle size (m) the value at which the frequency representation is a maximum value. The meFigure 5: Particle-size representations for a hypothetical log-normal distribution, plotted on a (a) dian divides the frequency curve into two linear scale and on a (b) logarithmic scale. equal parts and equals the particle size at which the cumulative representation equals 50%. In a rigorous normal distribution, the mean, mode, Table I: Particle composition of a hypothetical sample and median have the same value. For a slightly skewed distribexhibiting a normal distribution. ution, however, the following approximate relationship holds:
Size (m) 5 10 15 20 25 30 35 40 45 50 55 60 Total Number in Band 50 90 110 280 580 600 540 360 170 120 60 40 3000 Number Frequency 1.67 3.00 3.67 9.33 19.33 20.00 18.00 12.00 5.67 4.00 2.00 1.33 100 Percent Less Than 1.67 4.67 8.33 17.67 37.00 57.00 75.00 87.00 92.67 96.67 98.67 100.00 Percent Greater Than 98.33 95.33 91.67 82.33 63.00 43.00 25.00 13.00 7.33 3.33 1.33 0.00

mean mode 3 mean median

[5]

and the standard deviation. Table I shows an example of a sample exhibiting a normal distribution in which 3000 particles have been sorted according to an undefined determiner of their size. In the usual data representation, the number of particles in each size fraction is identified, and then one calculates the percentage of particles in each size fraction. This calculation

It would be highly advantageous if powder distributions could be described by the normal distribution function because all of the statistical procedures developed for Gaussian distributions could be used to describe the properties of the sample. However, unless the range of particle sizes is extremely narrow, most powder samples cannot be described adequately by the normal distribution function. The size distribution of the majority of real powder samples usually is skewed toward the larger end of the particle-size scale. Such powders are better described by the log-normal distribution type. This terminology arose because when the particle distribution is plotted by means of the logarithm of the particle size, the skewed curve is transformed into one closely resembling a normal distribution (see Figure 5). The distribution in a log-normal representation can be completely specified by two parameters: the geometric median particle size (dg) and the standard deviation in the geometric mean (g). The geometric median is the particle size pertaining to the 50% value in the cumulative distribution and is calculated using

Mesh (US standard sieve series)

to di. Two samples having identical dg and values can be said to have been drawn (b) (a) 30 g 100 from the same total population and ex% mass frequency 80 hibit properties of characteristics of the 20 % number 60 total population. frequency Cumulative % mass In many applications, particle-size re40 10 Cumulative sults are processed by plotting the cu20 % number mulative frequency data on a logarith0 0 mic scale. If a straight line is obtained, 0 15 30 45 60 75 the particle-size distribution is said to Size (m) Size (m) obey the log-normal function. The value of dg is equal to the 50% value of the cumulative distribution. The value of g Figure 6: Particle-size representations for a hypothetical log-normal distribution. Shown are (a) is obtained by dividing the 84.1% value the frequency distribution and (b) the cumulative distribution. Each contains the difference of the distribution by the 50% value. obtained when processing the data in terms of either particle number or particle mass. Although the distribution in the lognormal representation is specified completely by the geometric median particle size and the geometric mean standard deviation, a number of other average values have (a) US M M M standard been derived to define useful properties. These values are espe2,000 10 cially useful when the physical significance of the geometric me12 1,500 16 dian particle size is not clear. The arithmetic mean (dav) particle 1,000 20 size is defined as the sum of all particle diameters divided by the 30 500 total number of particles and is calculated using Equation 3. The 40 400 surface mean (ds) particle size is defined as the diameter of a hy50 300 70 pothetical particle having an average surface area and is calcu200 150 100 lated using
% in bond
140 200 270 325 0.5 1 2 5 10 50 20 30 40 50 60 70 80 90 95 98 99 99.5

% finer

100

nd i ds n

1 2 2

[7]

Cumulative percentage of undersize particles

(b) US
standard

M
2,000 1,500 1,000 500 400 300 200 150 100

The volume mean (dv) particle size is the diameter of a hypothetical particle having an average volume and is obtained from

Mesh (US standard sieve series)

10 12 16 20 30 40 50 70 100 140 200 270 325 0.5 1 2 5 10

nd i dv n

1 3 3

[8]

The volume-surface mean (dvs) particle size is the average size based on the specific surface per unit volume and is calculated using

50 20 30 40 50 60 70 80 90 95 98 99 99.5

d vs

nd i nd i

3 2

[9]

Cumulative percentage of undersize particles

Figure 7: Particle-size representations plotted in a log-probability format for (a) a single hypothetical log-normal distribution and for (b) a hypothetical sample containing two log-normal distributions whose average particle size differs by 50%.

d g antilog

n logd i n

[6]

in which n is the number of particles having particle size equal

For the distribution plotted in Figure 5, one can calculate that dg 32.91 m, dav 34.42 m, ds 35.93 m, dv 37.43 m, and dvs 40.62 m. 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 volume mean value is the appropriate parameter. Deposition of particles in the respiratory tract is related to the weight mean diameter, and the dissolution of particulate matter is related to 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 or to the number of particles contained in the same size band.

Recommended reading
With substances having real density values, the distrib- R.R.Irani and C.F.Callis, Particle Size: Measurement, Interpretation, and Application (John ution of the same ensemble of particles can look quite Wiley & Sons,New York,1963). different depending on how the data are plotted. Figure Z.K.Jelinek, Particle Size Analysis (Ellis Horwood Ltd.,Chichester,1970). 6 shows the frequency and cumulative distribution plots J.D.Stockham and E.G.Fochtman, Particle Size Analysis (Ann Arbor Science Publishers, for the same sample, but the data have been separately Ann Arbor,MI,1977). 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). terized by the existence of a single distribution, and the character of real samples can be quite complicated. Recognizing the existence of multimodal distributions is not always recommended references to additional information (see Reca straightforward process, but their existence often can be de- ommended reading sidebar). Most highly recommended are tected by plotting the data on log-probability paper. The exis- the various editions of Particle Size Measurement by Allen betence of more than one particle population is indicated by a cause they contain some of the most detailed and informative change in the slope of the line. Figure 7 shows a single log-nor- expositions available about these topics. However, the scope of mal distribution and a multimodal sample consisting of two the discussion in this opening article provides a sufficient basis populations whose mean differed by approximately 50%. The for the expositions of the various methodologies that will folbreak in the log plot is clearly evident, but if one were to simply low in subsequent installments of this column. plot the latter sample in either a frequency or cumulative view, one would not have been able to detect the existence of two par- References 1. H.G. Brittain, What is the Correct Method to Use for Particle-Size ticle-size populations in the sample.

Summary
This rather simplified discussion of particle shape, size, and distribution represents only an introduction to the topic. Interested readers should consult the primary sources in the list of

Determination? Pharm. Technol. 25 (7), 9698 (2001). 2. Optical Microscopy, General Test 776, USP 24 (The United States Pharmacopoeial Convention, Rockville, MD, 2000), pp. 19651967. 3. T. Allen, Particle Size Measurement (Chapman and Hall, London, 3rd ed.,1981) pp. 107120. T 4. H. Heywood, J. Pharm. Pharmacol. (S15) 56T, (1963). P

Reprinted from

AN

ADVANSTAR PUBLICATION
Printed in U.S.A.

December 2001

Copyright Notice Copyright by Advanstar Communications Inc. Advanstar Communications Inc. retains all rights to this article. This article may only be viewed or printed (1) for personal use. User may not actively save any text or graphics/photos to local hard drives or duplicate this article in whole or in part, in any medium. Advanstar Communications Inc. home page is located at http://www.advanstar.com.