Physical Pharmaceutics II –

BP403T
Dr. Asim Kumar Samanta
Assistant Professor
Dr. Vishwanath Karad MIT World Peace University,
School of Health Science and Technology,
Kothrud, Pune, Maharashtra 411038
Micromeritics
Unit IV

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Syllabus
• Particle size and distribution, mean particle size, number and weight
distribution, particle number
• Methods for determining particle size by different methods, counting
and separation method
• Particle shape, specific surface, methods for determining surface
area, permeability, adsorption
• Derived properties of powders, porosity, packing arrangement,
densities, bulkiness & flow properties.

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Micromeritics
• Micromeritics is science of small particles and the study of particle size
distribution.
• Micromeritics is the study of a number of characteristics, including
• particle size and distribution,
• shape
• angle of repose
• porosity
• true volume and bulk volume
• apparent density and bulkiness
• Unit of particle size used most frequently is
• Micrometer, µm or micron and is equal to 10-6 m or 10-3 mm
• nanometer, nm and is equal to 10-9 m or 10-6 mm
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Importance of Micromeritics
• Knowledge and control of the size and size range of particles are of
profound importance in pharmacy.
• Particle size can affect the release of a drug from dosage forms administered orally,
parenterally, rectally, and topically.
• The formulation of suspensions, emulsions, and tablets, both in terms of physical
stability and pharmacologic response, depends on the particle size achieved in the
product.
• In tablet and capsule manufacture, control of particle size is essential for achieving
the necessary flow properties and proper mixing of granules and powders.
• A pharmacist today must possess a sound knowledge of micromeritics to
ensure the successful formulation and administration of pharmaceutical
products.
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Particle size
• Size of a sphere is easily expressed in terms of its diameter.
• Asymmetry of particles increases, expressing size becomes
challenging → No unique diameter for a particle
• Equivalent spherical diameter is used.
• Types of Equivalent Spherical Diameter
• Surface Diameter (ds): Diameter of a sphere with the same surface area.
• Volume Diameter (dv): Diameter of a sphere with the same volume.
• Projected Diameter (dp): Diameter of a sphere with the same observed area.
• Stokes Diameter (dst): Diameter of a sphere undergoing sedimentation at the
same rate.
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Particle size
• Type of diameter used reflects the method employed to obtain the
diameter
• Projected diameter: Microscopic techniques.
• Stokes diameter: Sedimentation studies on suspended particles.
• Particle-Size Distribution
• Collection of particles usually polydisperse.
• Need to know size range and number/weight fraction of each size.
• Calculate average particle size from distribution.
• Uniform Size Particles
• Monodisperse particles used in science, medicine, and technology.
• Example: Latex particles with uniform size.
• Applications: Diagnostic tests, particle size standards for particle analyzers, pore size
determination, immunization.

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Average Particle Size
• Comparison with another batch often requires computing an average
or mean diameter.
• Edmundson's Equation
1ൗ
σ 𝑛𝑑𝑝+𝑓 𝑝
𝑑𝑚𝑒𝑎𝑛 =
σ 𝑛𝑑 𝑓
• n: Number of particles in a size range with midpoint d.
• p: Index related to particle size (1 for length, 2 for surface, 3 for volume).
• p determines mean type: arithmetic (p > 0), geometric (p = 0), or harmonic (p
< 0).
• Frequency of particle occurrence in a size range is expressed by 𝑛𝑑 𝑓 .
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Particle-Size Distribution
• When the number, or weight of particles lying within
a certain size range is plotted against the size range
or mean particle size, a frequency distribution curve
can be obtained
• Such plots give a visual representation of the
distribution that an average diameter cannot achieve
• Two samples with the same average diameter can
have different distributions.
• The mode, or most frequent particle size, is
immediately apparent from a frequency distribution
curve.
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 Particle-Size Distribution

Frequency distribution plot

A size–frequency distribution. The data are plotted as a bar graph or histogram,
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Particle-Size Distribution
• An alternative method of representing
the data is to plot the cumulative
percentage over or under a particular
size versus particle size.
• A sigmoidal curve results, with the
mode being that particle size at the
greatest slope.

The cumulative percent undersize plot.

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Difference between Mean and Median
• The mean (average) of a data set is found by adding all numbers in
the data set and then dividing by the number of values in the set.
• The median is the middle value when a data set is ordered from least
to greatest.
• The mode is the number that occurs most often in a data set.
Symmetric data: Data sets whose
values are spread around the
center
Skewed data: Data sets that are
not symmetric
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Understanding Normal and Log-Normal
Distributions
• The normal distribution is symmetric around the
mean, which is also the mode.
• The standard deviation (σ) indicates the distribution
about the mean.
• In a normal distribution, 68% of the population lies
within ±1 σ, 95.5% within ±2 σ, and 99.7% within ±3
σ.
• Pharmaceutical powders typically have a skewed,
nonsymmetric distribution.
• This skewed distribution is often depicted as a bell-
shaped curve when plotted against the logarithm of
the particle diameter.
• This bell-shaped curve is characteristic of a log-
normal distribution, contrasting with the symmetric
normal distribution.
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Properties of powder
• Fundamental properties :-These • Derived properties :-They are
properties relate to the dependent on fundamental
individual particle. properties & define the factors
• Particle size and size distribution relating to their measurement.
• Particle shape • Density of powders
• Particle surface area • Bulk density
• Particle weight • Tapped density
• Granular density
• True density
• Flow properties of powders
• Porosity
• Bulkiness

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Number and Weight Distributions
• Number distribution collected by a counting technique
such as microscopy.
• Weight Distributions achieved by sedimentation or
sieving, it will be more convenient.
• More interest in weight, rather than a number
distribution.
• Conversion of number to weight distribution and vice
versa can be done using two approaches -
• First approach:
• Estimate of weight distribution can be calculated based on
nd3 values particles assuming that shape and density of the
particles are independent of the size range
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Number and Weight Distributions
• Significant difference in the two distributions are
apparent, even though they relate to the same
sample (Example - 12% of sample by number >
11 μm, but 42% of total weight).
• Second approach:
• Use equations by Hatch and Choate.
• Convert number to weight distributions with minimal
calculation.
• Compute specific averages using relevant equation.

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Hatch-Coate Equations

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Particle Number
• Particle Number in particle technology is the number of particles per
unit weight, N, which is expressed in terms of dvn.
• The number of particles per unit weight is obtained as follows –
• Assume that the particles are spheres, the volume of a single particle is
3
𝜋𝑑𝑣𝑛 𝜋𝑑 3 𝜌
ൗ6, and the mass (volume × density) is ( 𝑣𝑛 ൗ6) g per particle.
• The number of particles per gram is then obtained from the
proportion-

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Particle size determination
• Methods
• Optical microscopy (1 – 1000 μm)
• Sieving (10 μm – 1 cm)
• Sedimentation (1 μm – 1mm)
• Particle Volume Measurement (1 μm – 1mm)
• None of the measurement are truly direct methods. Although,
microscope allows to view the actual particles.
• Selection of a particular method largely depends upon the desired
application → Sedimentation methods yield a particle size relative to
the rate at which particles settle through a suspending medium, →
important in the development of emulsions and suspensions
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Approximate size ranges of methods used for
particle-size analysis.

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Optical Microscopy
• Particle-size measurement in the range of 0.2 to about 100 μm.
• This method provides number distribution data which can be
converted to weight distribution.
• Optical microscope has limited resolving power
• Advanced microscope has better resolving power and can measure
size in nano range.
• Ultra microscope
• Electron microscope – SEM, TEM

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Optical Microscopy
• Procedure
• Eye piece of the microscope is fitted with a
micrometer.
• This eye-piece micrometer is calibrated using a
standard stage micrometer.
• The powder sample is dispersed in a suitable vehicle
in which it does not dissolve and its properties are
not altered. (eg. water, paraffin oil.)
• This sample is mounted on a slide and placed on the
stage under the objective of microscope.
• 300 to 500 particles should be counted for every
sample to get statistically valid results
• From the obtained data the size frequency
distribution curves, cumulative frequency curves are
plotted.
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Optical Microscopy

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Optical Microscopy

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Projected diameter
• In optical microscopy, particles are measured along an
arbitrarily chosen fixed line (generally made
horizontally across the center of the particle) →
particle size is expressed as dp projected diameter.
• Popular measurements are –
• Martin’s diameter: Length of a line that bisects the particle
image. The line can be drawn in any direction but must be
in the same direction for all particles measured → Line 1
• Feret’s diameter: Distance between two tangents on
opposite sides of the particle parallel to some fixed
direction → Line 2
• Projected area diameter: Diameter of a circle with the
same area as that of the particle observed perpendicular to
the surface on which the particle rests
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Optical Microscopy
• Advantages
• Microscopy method allows the direct observation (shape and size) of particles
• The field can be projected and a photograph can be taken.
• Aggregation of particles can be easily detected.
• Provides accurate results and reproducibility.
• Simple and economic.
• Easy to handle.
• Disadvantages
• Diameter is obtained from only two dimensions of the particle i.e., length and
breadth. No estimation of depth (thickness) of particle.
• The method is slow and tedious, because the number of particles that must be
counted (300-500) to obtain a good estimation of the distribution.
• Time consuming method.
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Optical Microscopy
• Application
• Particle size analysis in suspension, in aerosol or in emulsion (droplet size)

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Sieving method
• Generally used for the particles having size range
between 50 to 1500 µm.
• Consists of a series of standard sieves calibrated by the
N.B.S. [National Bureau of Standards].
• This method directly gives weight distribution.
• Useful in the development of some dosage forms like
tablets and capsules
• Sieves for pharmaceutical testing are constructed from
wire cloth with square meshes.
• The sieves are arranged in a nest of about five with the
coarsest at top and a collector at the bottom
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Sieving method
• Procedure
• A mass of sample is placed on the proper sieve in a mechanical shaker.
• The powder is shaken for a definite period of time,
• The material that passes through one sieve and is retained on the next finer
sieve is collected and weighed.
• Data obtained will be analyzed for normal, log-normal, cumulative percent
frequency distribution.
• Errors
• Sieving errors can be arise from many variables including sieve loading,
duration and intensity of agitation.
• Care must be taken to get reproducible results.
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Sieving method
• Advantages
• It is simple for handling.
• It is inexpensive and rapid.
• Provides reproducible results.
• Specially useful for weight distribution.
• It can be used for very small particles having particle diameter up to 5 µm.
• Disadvantages
• It cannot used for very small particles is below 5 µm.
• The powder sample should be dried every time, otherwise it may clog with particles,
resulting improper sieving.
• During shaking, attrition of particles may cause reduction of particle size. This may
leads to errors in estimation.
• Time consuming method.
• Approximate results can be obtained.
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Sedimentation method
• Application: The sedimentation method can be used for formulation
and evaluation of suspensions and emulsions
• The particle size obtained by gravity sedimentation and is expressed
as stokes' diameter, dst' in Stokes' law.

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Sedimentation method
• Stoke’s equation applies precisely to spheres falling freely at a constant rate
unhindered.
• This law extends to irregularly shaped particles of diverse sizes.
• Particles must not aggregate or clump in suspension, as clumps may fall
faster than individual particles.
• Incorporating a deflocculating agent prevents aggregation and maintains
suspension stability.
• Diluting the suspension to 1-2% is recommended for optimal flow, ensuring
laminar flow without turbulence.
• The Reynolds number (Re) determines flow characteristics, with values
greater than 0.2 indicating turbulent flow where Stokes' law cannot be
applied.

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Sedimentation method
• Reynolds number, Re, which is defined as

• Rearranging Stoke’s and Reynold number equations gives

• Under a given set of density and viscosity conditions, above equation

allows calculation of the maximum particle diameter whose sedimentation
will be governed by Stokes's law, that is, when Re does not exceed 0.2.
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Sedimentation method
• Commonly used sedimentation-based methods
• Pipette method,
• Balance method,
• and hydrometer method.
• The pipette method is preferred due to its ease of
analysis, accuracy, and cost-effectiveness.
• Description of Andreasen Apparatus:
• The Andreasen apparatus comprises a 550ml vessel with a
sealed 10ml pipette inserted into a ground glass stopper.
• The lower tip of the pipette is positioned 20cm below the
suspension's surface when in place. Andreasen apparatus for determining particle
size by the gravity sedimentation method.
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Sedimentation method
• Procedure:
• Prepare a 1 or 2% suspension of powder in a suitable medium and add a
deflocculating agent.
• Transfer the suspension to the Andreasen vessel and shake to distribute particles
uniformly.
• Place the vessel in a constant temperature bath.
• Withdraw 10ml samples at various time intervals using a two-way stopcock.
• Evaporate or analyze the samples, correcting for the deflocculating agent added.
• Measurement and Analysis:
• The weight or amount of particles obtained in each time interval is known as weight
undersize.
• Weight undersize values are converted into cumulative weight undersize for analysis.

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Particle Volume Measurement
• Principle of Operation:
• The Coulter counter measures particle volume by detecting changes in
electric resistance when particles pass through a small orifice in a conducting
liquid.
• A known volume of dilute suspension is pumped through the orifice, allowing
particles to pass through individually.
• A constant voltage applied across the electrodes produces a current. As
particles pass through the orifice, they displace electrolyte volume, increasing
resistance.
• The change in resistance, proportional to particle volume, generates a voltage
pulse, which is amplified and analyzed by a pulse-height analyzer calibrated in
particle size.
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Coulter counter

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Coulter counter
• Data Collection and Analysis:
• The instrument electronically records particles producing pulses within preset
threshold values.
• By varying threshold settings and counting particles in a constant sample size,
particle-size distribution is obtained.
• Data Interpretation:
• Obtained data can be easily converted from a volume distribution to a weight
distribution for analysis and interpretation.

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Coulter counter
• Advantages
• It gives very fast results [approximately 4000 particles per second].
• Short period of time is required for size distribution analysis.
• It provides accurate results.
• It can be used to measure particulate contamination in parenteral solutions.
• Submicron particle sizing instrument, the coulter Model N4 has been developed for
analyzing particles in the range of 0.003 to 0.3 µm.
• It is used in the study of the clustering process and the packing of the mineral
components of renal stones.
• It is also useful in quality control of large volume parenteral [LVP] solutions.
• Disadvantages
• It is not suitable for polar and highly water soluble materials due to solvation.
• It is expensive method.

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Particle Shape and Surface Area
• Importance of Particle Shape and Surface Area:
• Particle shape influences powder flow, packing properties, and surface area,
impacting processes like adsorption and dissolution rate studies.
• Understanding particle shape aids in characterizing powder behavior and
performance.
• Relationship between Shape and Surface Area:
• Spherical particles have minimum surface area per unit volume, while asymmetric
particles have greater surface area.
• Asymmetry complicates diameter assignment, requiring equivalent spherical
diameters for meaningful analysis.
• Surface area and volume of spherical particles are proportional to the square and
cube of the diameter, respectively.

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Particle Shape and Surface Area
• Estimation of Surface Area and Volume for Non-Spherical Particles:
• For non-spherical particles, a characteristic diameter is chosen and related to
surface area or volume through correction factors.
• Surface area and volume factors (αs and αv) represent the ratio of one
diameter to another, enabling estimation based on observed dimensions.

• Characterization of Particle Shape:

• Shape factors, such as αs/αv, indicate particle asymmetry.
• A spherical particle has αs/αv = 6.0, with higher ratios indicating increased
asymmetry.
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Specific Surface
• The specific surface is the surface area per unit volume (Sv) or per unit
weight (Sw)

where n is the number of particles. The surface area per unit weight is therefore

where ρ is the true density of the particles.

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Specific Surface
• Substituting previous equations leads to the general equation

• where the dimension is now defined as dvs, the volume–surface diameter

characteristic of specific surface.
• When the particles are spherical (or nearly so), equation simplifies to

• because αs/αv = 6.0 for a sphere

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Methods for Determining Surface Area
• Surface area of a powder sample can be computed from knowledge
of the particle-size distribution previously discussed.
• Two methods are commonly available that permit direct calculation
of surface area.:
• Adsorption Method:
• Air permeability Method: Rate at which a gas or liquid permeates a bed of
powder is related to the surface area exposed to the permeant

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Adsorption Method
• Amount of a gas or liquid solute that is adsorbed
onto the sample of powder to form a monolayer
is a direct function of the surface area of the
sample → This principle is used to estimate the
specific surface and is also used to estimate
surface diameter, ds.
• At low pressure → Monolayer of adsorbed gas
• At high pressure → Multilayer of adsorbed gas
• Volume of gas (cc) adsorbed per gram of
adsorbent can be plotted against the pressure of
the gas at constant temperature to give a Volume of N2 adsorbed on a powder at
increasing pressure ratio.
isotherms STP = standard temperature and
• Point B represents completion of a monolayer of pressure.
N2.
47
Adsorption Method
• The volume of nitrogen gas, Vm (cm3) that 1 g of the powder can
adsorb when the monolayer is complete → given by using the
Brunaver, Emmett, and Teller (BET) equation

• where V is the volume of gas in cm3 adsorbed per gram of powder at pressure
p,
• p0 is the saturation vapor pressure of nitrogen at the temperature of the
experiment,
• b is a constant (difference between the heat of adsorption and heat of
liquefaction of the adsorbate (nitrogen)
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Adsorption Method
• A plot of p/V(p0 - p) against p/p0 is
ordinarily used to obtain a straight line,
the slope and intercept of which yield the
values b and Vm.

A linear plot of the BET equation for the

adsorption of nitrogen on a powder.
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Air permeability Method
• This method can be used in powder manufacturing in controlling
batch to batch variations.
• The resistance to the flow of a fluid, such as air, through a plug of
compacted powder is the surface area of the powder.
• The resistance to flow is greater if surface area per gram of powder,
Sw' is greater.
• According to Poiseuille's equation.

50
Air permeability Method
• From the Poiseuille equation, the Kozeny-Carman equation is derived
and is used to estimate surface area.

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Fisher subsieve sizer
• Commercially available and official in
I.P.
• Utilizes a sample tube connected to
an air pump via a constant pressure
regulator.
• The opposite end is linked to a
calibrated manometer to measure
airflow.
• Air is dried to eliminate moisture
before passing through the sample
tube.
• Manometer readings vary with
particle size, allowing determination
of average particle diameter.
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Advantages of Fisher subsieve sizer
• Simplicity and Speed: Instrumentation is straightforward, enabling rapid
measurements. Widely adopted in pharmaceuticals for specific surface
determinations.
• Standardization: Several pharmaceutical compounds are standardized
using this method.
• Activity Correlation: Activity of certain drugs, such as anthelmintics,
correlates with specific surface area. Lower surface area diminishes drug
activity.
• Pharmacopoeial Usage: Officially recognized in pharmacopoeias (e.g., U.S.
Pharmacopoeia) for specific surface area determination of substances like
Griseofulvin.
• Non-Pharmaceutical Applications: Extends to industries beyond
pharmaceuticals, such as determining the fineness of Portland cement.
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Derived Properties of Powders
• Size distribution and surface area of powders are two fundamental
properties. Derived properties are based on fundamental properties.
• Porosity:
• Porosity (ε) is the ratio of void volume to bulk volume (Vb) of the packing.
• Suppose a powder is placed in a graduated cylinder and total volume noted. The
volume occupied known as bulk volume, Vb.
• If a powder is nonporous, its bulk volume (Vb) consists of the true volume of solid
particles (Vp) and the volume of spaces between particles (void volume, v).
• Void volume (v) = Vb – Vp
𝑉𝑏 − 𝑉𝑝 𝑉𝑏
𝜀= =1−
𝑉𝑏 𝑉𝑝
• Porosity is often expressed in percent, ε × 100
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Calculate Porosity
• A sample of calcium oxide powder with a true density of 3.203 and
weighing 131.3 g was found to have a bulk volume of 82.0 cm3 when
placed in a 100 mL graduated cylinder. Calculate the porosity.

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Packing Arrangements
• Packing Arrangements of Spherical Particles
• Powder beds of uniform-sized spheres can exhibit two
ideal packing arrangements:
• Closest or rhombohedral packing
• Most open, loosest, or cubic packing (a) closest packing and (b) loosest packet.
The dashed circle in (a) shows the position
• Theoretical Porosity taken by a particle in a plan above that of
the other three particles.
• Closest packing: 26%
• Loosest packing: 48%

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Packing Arrangements
• Real World Considerations
• Real powders contain non-spherical and non-uniform particles.
• Porosities typically fall between 30% and 50%.
• Particle arrangement can vary between closest and loosest packing.
• Presence of flocculates or aggregates can affect porosity, leading to values
beyond theoretical limits.
• Crystalline materials under high compression can have porosities <1%.
• Implications
• Understanding packing arrangements and porosity is crucial for powder
characterization and processing.

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Densities of Particles
• Density is universally defined as weight per unit volume.
• Challenges in determining density for particles with microscopic features
like cracks, pores, and capillary spaces.
• Types of Densities
• True Density:
• Excludes voids and intraparticle pores larger than molecular dimensions.
• Determined by displacement in helium or non-penetrating liquids.
• Granule Density:
• Determined by mercury displacement.
• Reflects volume including void spaces but not intraparticle pores.
• Bulk Density:
• Mass of powder divided by bulk volume.
• Bulk density as determined from the bulk volume and the weight of a dry powder in a
graduated cylinder. 58
Densities of Particles
• Water or mercury surrounds such a particle and
rests only in the surface irregularities such as
regions A and B.
• Helium molecules may enter deep into the cracks
at points C, allowing calculation of true rather
than granule density.

Pores and crevices of a pharmaceutical granule.

59
Densities of Particles

60
Densities of Particles
• Different densities, the interparticle, intraparticle and total porosity
can be computed.
• The intraparticle porosity of granule may be determined from the
knowledge of true and granule density.

where Vp is the true volume of the solid particles and Vg is the volume of the particles
together with the intraparticle pores.
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Densities of Particles
• Similarly interparticle or interspace or void porosity of a powder can
be computed.

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Densities of Particles
• Total porosity of a porous powder is made up of voids between the
particles as well as pores within the particles. The total porosity is
defined as

63
Bulkiness
• Specific bulk volume, the reciprocal of bulk density, is often called
bulkiness or bulk.
• It is an important consideration in the packaging of powders.
• Effect of Particle Size:
• Bulkiness increases with a decrease in particle size.
• Smaller particles tend to fill gaps between larger ones, reducing overall
bulkiness in mixtures of materials with different sizes.

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Flow Properties
• Importance in Tablet/Capsule Manufacturing
• Crucial for maintaining uniformity in tablet weight.
• Poor flow leads to weight variation due to irregular powder flow.
• Factors Affecting Flow Properties
• Particle size, shape, porosity, density, and surface texture influence flow.
• Moisture content, excess small particles, and surface roughness hinder flow
due to friction and cohesiveness.
• Improving Flow
• Addition of fines and lubricants enhances flow rate.
• Glidants like Magnesium Stearate, starch, and talc commonly used.
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Flow Properties
• Measurement
• Angle of Repose: Maximum angle between the
surface of powder pile and horizontal plane.
• Indicates powder flow characteristics.
• Rougher, irregular particles result in higher angles
of repose.
• Angle of repose is related to the coefficient of
interparticle friction µ.
ℎ
tan 𝜙 = = 𝜇
𝑟
Where, h = height of pile, r = radius of the base
of the pile, φ angle of repose.
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End

67
Hatch-Coate Equations

68