Guided By: Satyabrata Jena M.Pharm (PH.D) Department of Pharmaceutics Presented By: Ushasri.K Deptartment of Pharmaceutics

GUIDED BY: PRESENTED BY:
SATYABRATA JENA USHASRI.K

M.Pharm (Ph.D) DEPTARTMENT OF
DEPARTMENT OF PHARMACEUTICS
PHARMACEUTICS
NALANDA COLLEGE OF PHARMACY, CHERLAPALLY, NALGONDA
TOTAL NO. OF SLIDES: 36

USHASRI.K, PHARMACEUTICS
22/12/2010 1

INTRODUCTION

EFFECT OF PARTICLE SIZE ON VARIOUS
PHYSICOCHEMICAL PROPERTIES

IMPORTANCE OF PARTICLE SIZE ANALYSIS

PARTICLE SIZE DETERMINATION
METHODS

CONCLUSION

REFERENCES
22/12/2010 2

Prior to the development of dosage form with a
new drug candidate, it is essential that certain
fundamental, physical, chemical and other derived
properties have to be determined. A thorough
understanding of these properties may ultimately
provide a rationale for formulation design, or
support the need for molecular modification.
22/12/2010 3

The preformulation investigations confirm that
there are no significant barriers to the compounds
development.

Quantitation of physical & chemical properties
that will assist in developing:
Stable, safe, effective formulation with maximum
bioavailability.
22/12/2010 4

To establish the identity & physicochemical
parameters.

To establish its kinetic rate profile.

Providing a scientific data to support the dosage
form design & evaluation of the product efficacy,
stability & bioavailability.

To establish its compatibility with common
excipients.

To establish its physical characteristics.
22/12/2010 5

A newly synthesized drug shows sufficient
pharmacologic promise in animal models to
warrant evaluation in man.

Preformulation activities are usually performed
during the preclinical stage although those may
extend to phase1 and 2.

When formulation and dosage form changes are
required.
22/12/2010 6

Study of physico chemical properties of the
drug, along with excipients in order to
develop a stable, safe, efficacious dosage
form.
22/12/2010 7
MAJOR AREAS OF PREFORMULATION RESEARCH:
1. Bulk characterization
a. Crystallinity & polymorphism
b. Hygroscopy
c. Fine particle characterization
d. Powder flow properties
2. Solubility analysis
a. Ionization constant pka
b. PH solubility profile
c. Common ion effect Ksp
d. Thermal effects
e. Solubilization
f. Partition coefficient
g. Dissolution
3. Stability analysis
a. Stability in toxicology formulation
b. Solution stability – PH stability profile
c. Solid state stability –USHASRI.K,
Bulk stability compatibility
PHARMACEUTICS
22/12/2010 8

Gives direction for development of formulation
in choice of drug from excipients, composition,
physical structure.

Helps in adjustment of pharmacokinetic and
biopharmaceutical properties.

Support for process development of drug
substance.

Support for process analytical technology.

Produce necessary and useful data for
development of analytical methods.
22/12/2010 9

According to U.S.P, a particle is defined as
the smallest discrete unit, & collections of
particles can be described by their degree of
association such as aggregates,
agglomerates etc.

A particle is any unit of matter having
defined physical dimensions.
22/12/2010 10
PARTICLE SIZE :
22/12/2010 11

Is to obtain quantitative data on the size,
distribution, & shapes of drug & other components
to be used in pharmaceutical formulations.

Particle size shows effect on various physical &
chemical properties like drug dissolution rate,
absorption, bioavailability, content uniformity, flow
properties, compressibility, stability, sedimentation
rate, taste, texture, color.

The particle size characterstics should be evaluated
to ensure the development of formulations with
acceptable or reproducible bioavailability, stability,
& ease of manufacture.
22/12/2010 12

Particle size of drugs may affect formulation &
product efficacy.

Most drug dosage forms are solids, solids are not
static systems, the physical state of particles can be
altered by physical manipulation & particle
characterstics can alter therapeutic effectiveness.

In some instances, particle size show effect on
biopharmaceutical behavior of dosage form.

Eg: Bioavailability of griseofulvin & phenacetin is
directly related to the particle size distributions of
these drugs.
22/12/2010 13

ON DRUG DISSOLUTION RATE

MODIFIED NOYES WHITNEY EQUATION:

dc/dt= DAKW/O(CS-Cb)/Vh

D = Diffusion coefficient of the drug

A = Surface area of the dissolving solid

Kw/o = Water/oil partition coefficient of the drug
considering the fact that dissolution body fluids are
aqueous

= Intrinsic dissolution rate constant

V = Volume of dissolution medium

h = Thickness of stagnant layer

(Cs -Cb) = Concentration gradient for diffusion of drug
22/12/2010 14

ON BIOAVAILABILITY:

ON FLOW PROPERTIES:

ON CONTENT UNIFORMITY
22/12/2010 15

Particle size measurements provide the
evaluation of possible particle aggregation
or crystal growth & particle size distribution
data are often employed as fundamental
quality control standards for
pharmaceutical disperse systems.
22/12/2010 16

The various techniques involved in
determination of particle size include:

Optical microscopy

Sieving

Sedimentation rate method

Coulter counter and electrical sensing devices

Light scattering

Hydrodynamic chromatography

Laser particle size analysis
22/12/2010 17
ADVANTAGES:

Useful to obtain information about the
particle shape & presence of particle
aggregations.

Eg. Degree & character of aggregations.
DISADVANTAGES:

The diameter is obtained only from the
two dimensions of the particle.

Slow & tedious process, 300 -500
particles has to be counted.

22/12/2010 18

It is based on either vibratory or suction
principle. Uses a series of standard sieves
caliberated by the NATIONAL BUREAU OF
STANDARDS.
22/12/2010 19
davg = ∑(%retained)×average size/100

ADVANTAGES:

Simplicity both in equipment & technique.

DISADVANTAGES:

Sieving errors can arise from number of
variables, including sieve loading & duration &
intensity of agitation.

It can also causes attrition & thus, size
reduction of granular pharmaceutical matter.

Binding or clogging of screens, can occur.

Large sample requirement.
22/12/2010 20
 Several methods are there based on sedimentation rate
Andreasen pipette apparatus, Cahn sedimentation balance

method, & Hydrometer method.
22/12/2010 21
 DISADVANTAGES:
 Tedious method.
 Proper dispersion, consistent sampling, temperature control.
 Must be carefully controlled to obtain consistent & reliable results.
22/12/2010 22

It determine the number of particles in a known volume of an
electrolyte solution.

The device employs the electrolyte displacement method &
measures the equivalent spherical volume diameter, dv.

This type of equipment is used primarily to obtain the particle size
distribution of the sample.

It measures the change in an electrical sensing zone that occurs
when a particle passes through an orifice positioned between two
electrodes.

Electronic pulse counters are also useful in studying particle
growth, dissolution & particulate contamination.
22/12/2010 23
22/12/2010 24

ADVANTAGES:

Both units electronically size, count & tabulate the individual
particles that pass through sensing zone data in a short time with
reasonable accuracy.

Thousands of particles can be counted in seconds & used to
determine the size distribution curve.

They are powerful tools & can be used for evaluation of
parameters as crystal growth in suspension formulation.

22/12/2010 25
 The quasi elastic light scattering technique (QUELS) also
called photon correlation spectroscopy (PCS), is based on the

principle diameter & size distribution.
 Light scattering depends on the Faraday tyndall effect and is
used widely in the determination of molecular weight, size, &

shape of colloidal particles.
 Scattering may be described in terms of turbidity, T, the
fractional decrease in intensity due to scattering as the

incident light passes through a solution.
22/12/2010 26
 ADVANTAGES:
 When the particle is asymmetrical, the intensity of scattered light
varies with the angle of observation, permitting an estimation of the
shape & size of particle’
 light scattering has been used to study proteins, synthetic polymers,
association colloids & lyophobic sols.
 this method is applicable for measuring the particle size ranging
from 5nm to approx 3µm.
 DISADVANTAGES:
 PCs however cannot characterize systems having broadly
distributed particles. this problem has been overcome by combining
sedimentation field flow fractionation & QELS, which presents a
detailed record of the particle size at each size interval.

22/12/2010 27
 This method is used particularly for colloids. A colloidal
dispersion is forced through a long column packed with

nonporous beads with an approximate radius of 10µm.
Particles of different particle size travel with different speeds
around the beads & are thus collected in size fractions.
22/12/2010 28
Laser Particle Size Analysis consists in
measuring the size of particles (powders,
suspensions and emulsions) using the
diffraction and diffusion of a laser beam.
During the laser diffraction measurement,
particles are passed through a focused laser
Malvern particle size
beam. These particles scatter light at analyzer
22/12/2010 29
These particles scatter light at an
angle that is inversely proportional to
their size. The angular intensity of the
scattered light is then measured by a
series of photosensitive detectors.
The map of scattering intensity
versus angle is the primary source of
information used to calculate the
particle size.
22/12/2010 30
22/12/2010 31

Leon Lachman, Herbert A. Libermann, The Theory And
Practice of Industrial Pharmacy, Varghese publishing
house, Bombay, Third edition, 1991, page no. 171-176.

Mark Gibson, Pharmaceutical Preformulations and
Formulations, page no. 41-49

Gilbert S. Banker, Christopher T. Rhodes, Modern
Pharmaceutics, Marcell Dekker, fourth edition, revised &
expanded, 2005, page no. 273-275.

MARTIN’S Physical Pharmacy and Pharmaceutical
sciences, Lippincott William & Wilkins publications, USA,
fifth edition, 2006, page no. 533-546.

Larry L. Augusburger, Stephen W. Hoag, Pharmaceutical
Dosage Forms : Tablets, Informa health care, volume 1,
2008.
22/12/2010 32

Loyd V. Allen, Jr. Nicholas G. Popovich, Howard C. Ansel;
Ansel’s pharmaceutical dosage forms and drug delivery
systems, Lippincott William & Wilkins publications,
eighth edition, 2008, page no. 187-190.

M.E.Aulton; Pharmaceutics: The Science of Dosage form
and Design, Churchill Livingstone, second edition, page
no. 152-174.

D.M. Brahmankar, Sunil B Jaiswal, Biopharmaceutics And
Pharmacokinetics A Treatise, Vallabh prakashan, New
Delhi.

http://tetra.simtech.a-star.edu.sg/afbsUpload/FactSheet
/ICES/Malvern%20Particle%20Size%20Analyzer%20M
S2000.pdf
, 19.12.2010
22/12/2010 33

Guided By: Satyabrata Jena M.Pharm (PH.D) Department of Pharmaceutics Presented By: Ushasri.K Deptartment of Pharmaceutics

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Guided By: Satyabrata Jena M.Pharm (PH.D) Department of Pharmaceutics Presented By: Ushasri.K Deptartment of Pharmaceutics

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Copyright:

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GUIDED BY: PRESENTED BY:

SATYABRATA JENA USHASRI.K

NALANDA COLLEGE OF PHARMACY, CHERLAPALLY, NALGONDA

TOTAL NO. OF SLIDES: 36

Andreasen pipette apparatus, Cahn sedimentation balance

called photon correlation spectroscopy (PCS), is based on the

used widely in the determination of molecular weight, size, &

fractional decrease in intensity due to scattering as the

dispersion is forced through a long column packed with

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