Micromeritics

Micromeritics involve the study of the science and technology of small particles, and of the
order of a few micrometers size.

Particle size is normally denoted in micrometers (formerly called as microns, µ) µm. One
micrometer is equal to 10 -3 mm (millimeters) or 10-6 m. The term 'milli micrometer' is
presently called nanometer (nm) and equal to 10-9 meters or 10-6 millimeter or 10-3 µm
(micrometer).

The study involves the characterization of individual particles and powders.

Particles are characterized by the following properties.

Applications

All dosage forms (starting from tablets to parenteral) at some point involve the use of
particle technology in their manufacture.

Release and dissolution: Particle size and surface area influence the release of drug from a
dosage form that is administered orally, rectally. parenterally and topically. Higher surface
area brings about intimate contact of the drug with the dissolution fluids in vivo and
increases the drug solubility and dissolution. In general, higher the surface area, the faster is
the dissolution and release.

Absorption and drug action: Particle size and surface area influence the drug absorption and
subsequently the therapeutic action. Higher the dissolution, faster the absorption. Hence,
quicker and greater is the drug action.

Physical stability: Particle size influences the physical stability of suspensions and
emulsions. Smaller the size of particles, better the physical stability of the dosage form
owing to Brownian movement of the particles in the dispersion. Small particle size also
promotes aggregation of particles. Hence, these opposing processes are balanced.

Dose uniformity: Good flow properties of granules and powders are important in the
manufacture of tablets and capsules. The distribution of particles should be uniform in terms
of its number and weight. At the same time, the flow of granules should be uniform in order
to ensure precise weight of the tablet and drug content. The filling of granules in the tablet
machine or into the empty capsule shell is based on volume of powder. Therefore, there is a
need to establish a relationship between volume and weight of the material filling.

Particles characteristics

According to USP, particle is defined as the smallest discrete unit.

Particle characteristics influence the dissolution rate, absorption rate, content uniformity,
taste, texture, color and stability.) Each particle can be characterized and expressed by the
following properties.

 size
 shape

Some of these are described in the following sections.

Particle Size

A particle size is expressed by radius or diameter.

The shape of particles present in a powder is normally not spherical, but asymmetrical
(uneven). Therefore, it is difficult to express the size as a meaningful diameter. However,
particle size is expressed as the diameter which is related to an equivalent spherical diameter.
It is based on geometry (projected) or some physical property (sedimentation or surface area)
Size of the particles may be expressed as follows:

(i) Surface diameter, ds is the diameter of a sphere having the same surface area as that of the
asymmetric particle.

(ii) Volume diameter, dv is the diameter of a sphere having same volume as that of the
asymmetric particle.
(iii) Projected diameter, dp is the diameter of a sphere having the same area of the
asymmetric particle as observed under a micro- scope.

(iv) Stokes' diameter, dst is the diameter of an equivalent sphere undergoing sedimentation at
the same rate as the asymmetric particle.

(v) Sieve diameter, dsieve is the diameter of a sphere that passes through the same sieve
aperture as the asymmetric particle.

(vi) Volume-surface diameter, dvs is the diameter of a sphere that has same volume to
surface area ratio as the asymmetric particle.

vii) Aerodynamic diameter (aerosolized system): is the diameter of the sphere having density
equal to one and having the same settling velocity (Stokes' law) as the asymmetric particle

Particle Shape

Particle shape is related to geometric shape and surface regularity (rugosity) (Figure 6-1).
Particle shape will influence the surface area, flow of particles, packing and compaction
properties of the particles. The surface area per unit weight and unit volume are important in
the studies of adsorption and dissolution. Spherical particle exhibit better flow than
irregularly shaped particles, because surface roughness interlock with each other, resulting in
poor flow and bridging with hopper. Irregular shaped particles have higher inter-particle
contacts. During compression, the corners and edges can undergo greater deformation
(tendency to fragment) and promote higher bond strength. Better tablets can be produced
compared to spherical particles.
Quantitative Shape Factor

Shape factor is a numerical value expressed to describe quantitatively the shape of a irregular
particle. Shape cannot be described adequately for a irregularly shaped particle. Therefore,
these properties can be compared for spheres and asymmetric (consider projected diameter,
do) particles, in order to decide the shape. The following expression can be obtained.

whereαs and αv are the surface area factor and the volume factor, respectively, for the
asymmetric particle, Solving for αs and αv, by equating the appropriate properties (surface
area and volume) provides:

The minimum possible value for shape factor is 6, which represents a sphere. If the ratio
exceeds this factor 6, the particle is considered as asymmetric.

POWDER-CHARACTERISTICS

Powder is a non-homogeneous collection of discrete solid particles of different sizes and

shapes inter-dispersed with the gas phase.

Like solids, powder can exhibit elastic recovery and brittle fracture. Unlike solids, powders
can expand or contract when stress is applied.

Like fluids, powders can flow. Unlike liquids, powders do not flow, if stresses are too small.
Thus, powder is characterized and expressed by the following properties.

 powder size
 particle number
 surface area
 volume
 flow properties
 density

Powder size

Powder is considered as a collection of particles. If the powder contains particles of one size,
the powder is termed monosize or monodisperse. Uniform size particles are normally
obtained by passing the powder through the sieves of the desired aperture. Mon size particles
are important in pharmacy in the following areas.

(a) Standardization of instruments, particle size Analyzer.

(b) Accurate determination of pore size in case of filters.

(c) For effective immunization, normally, antigens are made to adsorb on uniform sized
particles.

(d) For diagnostic purposes.

Most of the pharmaceutical powders are polydisperse, i.e., contain particles of different
sizes. Powders can be described by arithmetic mean, geometric mean and harmonic mean.

Arithmetic mean:

Arithmetic mean of a powder is defined as the sum of the particle sizes divided by the
number of particles. The powder, though polydisperse, can be expressed as its arithmetic
mean.

Types of Arithmetic Mean Sizes

1) In general terms, the numerical mean diameter based on length may be expressed as:
 Where n is the number of particles with equivalent diameter, d. This mean is
satisfactory, if the size range is narrow and distribution is normal.

2) In many pharmaceutical applications, the surface area of particles is important. So,

surface mean diameter can be employed. This is defined as:

3) If the weight of each fraction is known, then the weight-mean diameter is obtained.

4) If the particle size do not vary much, then this quantity is identical to the volume mean
diameter.
5) It is possible to express the mean diameter of powder as surface number mean, dsn.
The following expression is used for the calculation.

The latter quantity is termed the mean weight diameter which is expressed as:

This quantity is used when one is concerned with the number of particles per gram of the
material.

This refers to particles having average surface area.

The mean size values for the same powder differs from one another depending on the
method of calculation.
Geometric mean:

When working with log-normal distribution, geometric mean is more appropriate. Geometric
mean is calculated by:

di = average diameter of an interval; ni = number of particles in range

Harmonic mean:

When specific surface per unit weight is considered, harmonic mean is preferred. Harmonic
mean is calculated by:
Particle Number
The number of particles present in a dosage form should remain constant in order to maintain
dose uniformity. Larger the number of drug particles, smaller is the error. Errors are large,
when the number of drug particles are small. Particle number is more important in case of
low dose drugs or potent drugs.

The number of particles per unit weight, N, is expressed in terms of volume-number mean
diameter, dvn. Assuming that the particles are spheres, the following relationships may be
obtained.

POWDERS-PARTICLE SIZE DISTRIBUTION

In powders, particle size distribution is the number of particles present in each size range in a
given weight of powder. It is necessary because powders are polydisperse.

It helps in comparing the powder obtained from one batch with another. Thus, it is an
important quality control tool in order to obtain powders with reproducible physical,
chemical and pharmacological properties.

Particle size and size distribution are not only essential for drugs, but also for excipients such
as fillers, disintegrating agents, lubricants etc.

Particle size distribution is expressed as the number or weight of the particles lying within a
certain size range.

Data on the size distribution of a powder are given in Table 6-1.

The weight of the drug particles and its distribution should be same in each tablet to
reproduce same therapeutic action. Secondly, for a given weight of a tablet or capsule,
number of particles and their distribution should also remain same.

For these reasons, size distribution analysis in terms of weight and number is important in
pharmacy. Considerable differences in these forms are observed. Many very fine particles
make very little contribution in terms of weight. On the other hand, heavier weight of large
particles will make a small contribution in terms of percentage number.
POWDER-DISTRIBUTION CURVES-ANALYSIS OF DATA

Two powder samples may have the same mean size, but may be different in the distribution
of sizes above and below the mean. Such differences can be seen readily, if results are
presented in the form of frequency curves. Statistical methods are used to summarize the
particles that constitute the powder. Distribution curves are normally represented in the
following ways.

In a powder, a set range of particles are grouped together and spaced in equally intervals and
expressed as histograms. Many modern computer aided plots give histograms. The only
problem is that a skewed distribution may appear as symmetrical, if intervals are not selected
properly.

Frequency Distribution Curve

In this type, number or weight of particles lying within a particular size range is plotted
against the mean particle size. In general, the normal distribution curve is expected to be
symmetrical (bell shaped) around the mean, (Figure 6-2). Normal distribution is usually not
found in pharmaceutical powders because of uneven size reduction processes.

The distribution of particles in a powder is termed as unsymmetric or skewed, i.e., uneven

around the mean (Figure 6-3).
If frequency curve is elongated towards higher size range, the pattern is known as positive
skewness.

If frequency curve is elongated towards lower size range, the pattern is known as negative
skewness. It normally shows a long tail of larger particle size.

Log-Normal Distribution Curve

In this type, frequency on y axis is plotted against log mean particle size on x axis (Figure
6.4 x axis column 2; y axis column 3 and column 5 of Table 6-2. Advantage of this curve is
that the distribution pattern is made symmetrical (Figure 6-4), when compared to normal
distribution curve (Figure 6-3). Powders obtained by crystallization and milling methods
exhibit log-normal distribution. Powder blend obtained from granulation may have different
type of distribution.
Cumulative Frequency Distribution Curve

In this plot, cumulative percentage oversize (or undersize) is drawn against particle size

Size distribution data are recorded in Table 6-2 (x axis column 1; y axis column 4 and
column 6). If summation of frequencies is carried out from the bottom upward (i.e., from
higher size to lower size), the result is expressed as the percentage particles oversize.

Summation downwards gives percentage undersize (column 6 in Table 6-2).

Data yield a sigmoid curve with the mode, i.e., particle size at the greatest slope (Figure 6-5).

The advantage of this plot is that one can directly read the percentage within any given size
range without any difficulty. The disadvantage is that scattering of points cannot be
identified.
Log-Probability Plot

A plot is drawn by taking log particle size on x axis and cumulative percent frequency
of the probability scale on y axis (Figure 6-6).
In this plot, the cumulative curve is converted into a straight line. A straight line is
completely defined by one point and the slope.
Probability plot is necessary when certain data points are not well defined. For
example, in the sieve analysis, how much material has passed through the top sieve is
known. For this data point, we have to identify the midpoint interval (mid sieve
diameter) of the top (largest sieve), which is not known.
The advantages of probability graph are:
(i) Error of data points are averages by taking a best fit line.
(ii) Linearity or lack of linearity can be identified.

Interconversion of Distribution Data

Number or weight distribution of a powder can be obtained independently by selecting
an appropriate method. For example, number distribution is obtained by microscopy,
while weight distribution is obtained by sedimentation or sieve method. Sometimes it
may be necessary to convert one distribution data at hand into another. A simple
conversion method which involves only a calculation, is more useful than conducting
a separate experiment (Table 6-3).
Number distribution can be converted to weight distribution using the following
relationship.