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					         REVIEW ARTICLE

A Brief Review on Particle Size Distribution, Particle Size
Analysis and its Characterization in Pharmaceutical Dosage
        Lay Desai1*, Dhaval Mistry1, Vihang Panchal1, Jemin Shah1
        Abstracts: The concepts of particle engineering and dosage form design have become dominant themes in pharmaceutical
        manufacturing. The need for particle size control of pharmaceuticals is becoming more important as the industry attempts to
        formulate active pharmaceutical ingredients (API’s) with poor aqueous solubility, which constitutes up to 40% of new chemical
        entities. The fundamental issue with particle size analysis is the variety of equivalent particle diameters generated by different
        methods, which is largely ascribable to the particle shape and particle dispersion mechanism involved. Thus, to enable selection
        of the most appropriate or optimal sizing technique, cross-correlation between different techniques may be required.

INTRODUCTION                                                             that the force overcomes viscous resistance to particle
The particle size distribution of active ingredients and                 movement in the field. While some drug product
excipients is an important physical characteristic of the                formulations can be diluted without significant change to
materials used to create pharmaceutical products. The size,              the particle size distribution (allowing appropriate sample
distribution and shape of the particles can affect bulk                  concentrations and viscosities for the aforementioned
properties, product performance, process ability, stability              methods) for the development of highly viscous gel-based
and appearance of the end product. The link between                      products, whose API particle size distribution may be
particle size and product performance is well documented                 affected by significant sample dilution, standard methods
with regards to dissolution, absorption rates and content                may not be not appropriate. The method of particle size
uniformity. Reducing particle size can aid the formulation               distribution determination by optical microscopy and
of NCE’s with poor water solubility. Proper matching of                  image analysis is a technology-intensive method requiring
active ingredient and excipients particle size is important              the capacity to automatically acquire and analyze a large
for several process steps. Particle size analysis is an                  number of photomicrographs (2).
integral component of the effort to formulate and
manufacture many pharmaceutical dosage forms. Particle                   Correlation of Laser Diffraction Method with Light
Size is Potentially Critical for Dissolution, Bioavailability,           Scattering Microscopy
Solubility, Stability, Processability, Appearance and Safety.            Ideally, the ultimate verification of any analytical
                                                                         techniques involved in particle size analysis would be the
Particle Size Distribution                                               exact agreement with another technique. To this end, the
Comparison of Methods to Measure Particle Size                           two techniques discussed here were used to examine
Distribution                                                             samples of a polydisperse particle size standard suspended
Particle sizing of dispersion can be accomplished using                  in water. Presented in Figure below are overlaid
laser scattering or diffraction techniques or by disc                    microscopic particle size distribution and laser diffraction
centrifuge techniques if high resolution of the size                     particle size distribution of the 1 to 10 micrometer
distribution is required. Laser scattering requires very low             polydisperse standards (PS192). The laser diffraction data
particle concentrations, usually requiring significant                   are the average of 5 distribution measurements (3). The
sample dilution (Figure 1).                                              distribution results from each method agree well with the
    The particles in the sample must be below 1 micrometer               95% confidence intervals provided with the certified
in size and free to undergo Brownian motion. For laser                   standard values (Figure 2). The results of similar
diffraction methods, dilution is again often required to                 determinations performed with the HEC gel showed an
optimize the intensity of diffracted light at the detectors,             upward shift (~2 micrometers) in the particle size
though dilution requirements are not as stringent as for                 distribution on estimation by microscopy. Optical
scattering techniques. These methods give weight-average                 microscopy is able to be validated, robust, and reliable as
particle size, and although these can be mathematically                  can be seen by the establishment of linearity, precision, and
converted to number-weighted distributions, the                          accuracy, with minimal sample preparation. In addition,
conversions can produce misleading artifact (1). Disc                    because only very small volumes of gel are required,
centrifuge methods rely on the ability of the particles to               microscopy presents no challenge when only small
move through the sample under the influence of a                         volumes of sample are available (4)
centripetal force generated in a spinning disc containing
the sample; so the sample viscosity must be low enough                   Scanning Electron Microscopy
                                                                          When a second test is needed to confirm an observation
                                                                         made by light microscopy, or when a particle is opaque, the
1Department of Quality Assurance, I S F College of Pharmacy, Moga,
                                                                         particle can be imaged and analyzed using electrons
Punjab, India.
                                                                         instead of light. The immediate difference is that the images
*Corresponding author                                                    produced by the SEM are gray scale with no color (unless

Inventi Rapid: Pharm Tech Vol. 2012, Issue 4                         1                       2012 ppt 587, CCC: $10 © Inventi Journals (P) Ltd
[ISSN 0976-3783]                                                                               Published on Web 19/09/2012,

Figure 1: Particle size distribution (4)                         Figure 2: Cumulative particle size distribution (4)

Figure 3: Curvve of zeta potential vs particle size (6)          Figure 4: 400X magnification by optical microscopy (9)

they are falsely colored at a later time). The images reveal a       Zeta Potential Analysis
depth of field and detail that is superior to light microscopy        Almost all particulate or macroscopic materials in contact
with an added bonus that as electrons are bombarding the             with a liquid acquire an electronic charge on their surfaces.
sample, x-rays are produced that are representative of the           Zeta potential is an important and useful indicator of this
elements present in the sample.                                      charge which can be used to predict and control the
                                                                     stability of colloidal suspensions or emulsions, for example.
Transmission Electron Microscopy                                     The greater the zeta potential the more likely the
Particles too small to be analyzed and imaged by light               suspension is to be stable because the charged particles
microscopy or scanning electron microscopy must be                   repel one another and thus overcome the natural tendency
observed and analyzed in the transmission electron                   to aggregate. The measurement of zeta potential is often
microscope. For thin samples or samples that can be made             the key to understanding dispersion and aggregation
thin, TEM imaging techniques can reveal the crystalline              processes in applications as diverse as water purification,
structure of the particle as well as its elemental                   ceramic slip casting and the formulation of paints, inks and
composition (EDS). Clays, pigment particles, thin films and          cosmetics. Zeta potential can also be a controlling
other nanometer-sized particles can be analyzed and                  parameter in processes such as adhesion, surface coating,
identified in the TEM.                                               filtration, lubrication and corrosion. Consequently, the
                                                                     presence or absence of charged groups on the surface of
Micro-Fourier Transform Infrared Spectroscopy (FTIR)                 macroscopic materials such as hair, glass fiber, paper pulp,
Particles that are plastic (easily deformed) can be                  plastic films and refractories, as revealed by their zeta
characterized using a microscope that uses reflected and             potentials can directly affect their performance and
transmitted infrared light. Polymeric materials that need to         processing characteristics (Figure 3) (6).
be characterized and identified can be prepared for FTIR.
The resulting infrared spectrum can be compared to                   PARTICLE SIZE CHARECTERIZATION
thousands of reference spectra to determine the type of              Image Analysis
polymer (5).                                                         An automated image analysis which complements the
                                                                     methods of microscopy and laser diffraction for particle
PARTICLE SIZE ANALYSIS                                               characterization, can be routinely used for the

Inventi Rapid: Pharm Tech Vol. 2012, Issue 4                     2                       2012 ppt 587, CCC: $10 © Inventi Journals (P) Ltd
[ISSN 0976-3783]                                                                           Published on Web 19/09/2012,

measurement of both size and shape parameters. In                         The Coulter Counter technique uses samples suspended
contrast to manual microscopy, image analysis generates               in an electrolytic solution. As the particle is drawn through
statistically relevant data with no subjective bias, such as          an aperture, the change in conductance gives a measure of
the operator, and can therefore be used to systematically             particle size. The important parameter is the settling
study shape and its effects. Another area of great                    velocity of the particles in the liquid phase, which depends
importance (and often overlooked) is sample preparation.              on both density and diameter. Particles having a density of
Unlike laser diffraction, image analysis generates number-            several g/cm3 can be determined with this technique.
based distributions meaning that data is generated on each            However, Coulter counter impedance measurements are
individual particle rather than the sample as a whole. The            only suitable for particles that are complete electrical
net result is the provision of high sensitivity and resolution,       isolators in the fluid. Moreover, the difference in density
particularly to the presence of fines or small numbers of             between particles and fluid must not be too large; when
foreign particles (Figure-4). Individual particle images are          this difference becomes too large, it is necessary to apply
also recorded, providing further visual verification, of              some measures such as increase of liquid density and
agglomerates or contaminants, the size of a particle is               stirring before during analysis (10).
generally related to either its geometric dimensions or its
physical behavior, and is typically described in terms of             Cascade Impaction
meters (nm or μm). Here, the geometric dimensions of a                x Material: particles of all kind.
particle refer to its linear dimensions (e.g., length or              x Size range: 0.1 – 20 and 0.5 – 80 microns.
breath), its surface area and/or its volume. Alternatively,              Cascade impactors can be used to obtain the size
the physical behavior of a particle during measurement                distribution of an aerosol (or a dust cloud). Air samples are
gives rise to for instance the Stokes diameter or the                 withdrawn through a device, which consists of several
aerodynamic particle size (7). From a geometric point of              stages on which particles are deposited on e.g. glass or
view, spherical particles are unique, since their size                glass fiber. Particles will impact on a certain stage
remains the same, regardless of how it is defined. In other           depending on their size. The cut-off size can be calculated
words, once one dimension of a sphere is known, its other             from the jet velocities at each stage by weighing each stage
dimensions are automatically available. Alternatively,                before and after sampling and the MMAD derived from
while the size of non-spherical particles varies depending            these calculations. Despite the limitations in this method,
on the applied definition of their size, equivalent sphere            namely particles bouncing off, overloading and fluctuation
theory treats them as if they were spherical. Therefore,              in flow rate etc, it is a well established technique to
the use of this approach may lead to biased findings,                 measure the airborne size distribution of an aerosol.
which are far removed from the idealized geometry. The
most straightforward concept to characterize the size of a            Rotating Drum Method
number of particles is to analyze them one-by-one for                 x Material: dry powders/ granulates/friable products.
their relevant geometric dimension(s) prior to                        x Size range: 0.5 – 10,000 microns.
classification in predefined size bins (8). Accordingly, so-             This method, currently undergoing inter- laboratory
called counting techniques typically lead to a number (N)             testing, is based on size selective sampling of an airborne
distribution. Static image analysis (SIA) is known as a true          dust cloud produced by the repeated lifting and dropping of
or absolute sizing technique since based on the maximum               a material in a rotating drum. Air drawn from the drum
projected area of each particle their linear dimensions can           passes through a specially designed outlet and a 3-stage
directly be measured. Consequently, their performance in              fractionating system consisting of two porous polyurethane
the accurate measurement of the geometric dimensions of               foams and a membrane filter. The mass of dust collected on
non-spherical particles can be limited. From a number                 each collection stage is determined gravimetrically to give a
distribution point of view, the accuracy of the PSD profile           direct measure of the biologically relevant size fractions
is negatively impacted as soon as the size of the particles           (the inhalable, thoracic and respirable fractions) as defined
is weighted by either their surface area (A) or volume (V) .          by ISO/CEN conventions. This method simulates a wide
This can readily be understood since for non-spherical                range of material handling processes in industry and
particles equivalent sphere theory only leads to an                   determines the biologically relevant size fractions of a
estimate of the surface area or volume. In other words,               material in the airborne state. Full size distribution can be
from a PSD point of view, the accuracy of the                         obtained by analyzing the contents on the dust collection
measurement may be reduced as soon as the analysis                    stages (11)
result is plotted as an area or volume distribution. An
exception to the rule is the Electrical Sensing Zone (ESZ)            CONCLUSION
detection principle since for each particle; a physical               Need for highly reproducible particle size assessment
response is measured that relates to the volume of the                techniques has grown significantly in the past decade. The
particles (9).                                                        interest in particle size measurements will remain high,
                                                                      particularly in view of FDA trends toward recommending
Electrical Sensing Zone (e.g. Coulter) Method                         more thorough descriptions of particle size distributions
x Material: dry powders/ granulates.                                  in submissions in which the emphasis of a drug product
x Size range: 1 – 1000 microns.                                       claim is based in a tightly controlled particle size. The

Inventi Rapid: Pharm Tech Vol. 2012, Issue 4                      3                      2012 ppt 587, CCC: $10 © Inventi Journals (P) Ltd
[ISSN 0976-3783]                                                                           Published on Web 19/09/2012,

improvement of currently accepted methods for particle                   6. T Allen, Particle Size Measurement (Chapman and Hall,
size analysis of pharmaceutical products will require                        London, UK, vol. 1, 5th ed., 38, 1997.
ongoing participation by those involved with this activity.              7. ISO13320-1, Particle Size Analysis—Laser Diffraction
Appropriate sampling procedures should be selected in                        Methods, Part 1 General Principles (ISO Standards Authority,
                                                                             1999), available at
order to prepare specimens really representative of the                  8. US FDA - Guidance for Industry (draft) Analytical Procedures
material under test. It is also important to note that the                   & Methods Validation: Chemistry, Manufacturing, and Controls
original particle size distribution is highly dependent on                   and documentation; 2000.
the industrial processing methods used and can also be                   9. Desai M P, Labhasetwar V, Walter E, Levy R J, Amidon G L, The
affected by subsequent environmental or human                                mechanism of uptake of biodegradable micro particles in
transformations. These methods do not provide a                              Caco-2 cells is size dependent. Pharm Res - 14:1568-73, 1997.
measure for risk exposure during handling of the                         10. Kroll R A, Pagel M A, Muldoon L L, Roman-Goldstein S,
chemical.                                                                    Fiamengo S A, Neuwelt E A. Improving drug delivery to
                                                                             intracerebral tumor and surrounding brain in a rodent model:
                                                                             a comparison of osmotic versus bradykinin modification of the
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Inventi Rapid: Pharm Tech Vol. 2012, Issue 4                         4                        2012 ppt 587, CCC: $10 © Inventi Journals (P) Ltd
[ISSN 0976-3783]                                                                                Published on Web 19/09/2012,

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