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GUIDED BY:

SATYABRATA JENA

M.Pharm (Ph.D)

DEPARTMENT OFPHARMACEUTICS

PRESENTED BY:

USHASRI.K

DEPTARTMENT OF

PHARMACEUTICS

NALANDA COLLEGE OF PHARMACY, CHERLAPALLY, NALGONDA

TOTAL NO. OF SLIDES: 3622/12/2010 1USHASRI.K, PHARMACEUTICS


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INTRODUCTION

EFFECT OF PARTICLE SIZE ON VARIOUS

PHYSICOCHEMICAL PROPERTIES

IMPORTANCE OF PARTICLE SIZE ANALYSIS

PARTICLE SIZE DETERMINATION

METHODS

CONCLUSION

REFERENCES

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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 thoroughunderstanding of these properties may ultimately

provide a rationale for formulation design, or

support the need for molecular modification.

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The preformulation investigations confirm thatthere are no significant barriers to the compounds

development.

Quantitation of physical & chemical properties

that will assist in developing:

Stable, safe, effective formulation with maximumbioavailability.

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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 commonexcipients.

To establish its physical characteristics.

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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 phase and .

When formulation and dosage form changes

are required.

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Study of physico chemical properties of the

drug, along with excipients in order to

develop a stable, safe, efficacious dosageform.

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MAJOR AREAS OF PREFORMULATION RESEARCH:

1. Bulk characterization

a. Crystallinity & polymorphism

b. Hygroscopyc. 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 coefficientg. Dissolution

3. Stability analysis

a. Stability in toxicology formulation

b. Solution stability PH stability profile

c. Solid state stability Bulk stability compatibility


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Gives direction for development of formulationin choice of drug from excipients, composition,physical structure.

Helps in adjustment of pharmacokinetic andbiopharmaceutical properties.

Support for process development of drugsubstance.

Support for process analytical technology. Produce necessary and useful data for

development of analytical methods.

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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.

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PARTICLE SIZE :


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Is to obtain quantitative data on the size,distribution, & shapes of drug & other componentsto be used in pharmaceutical formulations.

Particle size shows effect on various physical &chemical properties like drug dissolution rate,absorption, bioavailability, content uniformity, flowproperties, compressibility, stability, sedimentationrate, taste, texture, color.

The particle size characterstics should be evaluatedto ensure the development of formulations withacceptable or reproducible bioavailability, stability,& ease of manufacture.

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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 bealtered by physical manipulation & particlecharacterstics can alter therapeutic effectiveness.

In some instances, particle size show effect onbiopharmaceutical behavior of dosage form.

Eg: Bioavailability of griseofulvin & phenacetin isdirectly related to the particle size distributions ofthese drugs.


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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 drugconsidering the fact that dissolution body fluids areaqueous

= Intrinsic dissolution rate constant

V = Volume of dissolution medium

h = Thickness of stagnant layer

(Cs -Cb) = Concentration gradient for diffusion of drug

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ON BIOAVAILABILITY:

ON FLOW PROPERTIES:

ON CONTENT UNIFORMITY

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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.

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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


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ADVANTAGES:

Useful to obtain information about theparticle shape & presence of particleaggregations.

Eg. Degree & character of aggregations.

DISADVANTAGES:

The diameter is obtained only from thetwo dimensions of the particle.

Slow & tedious process, 300 - 00particles has to be counted.

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It is based on either vibratory or suction

principle. Uses a series of standard sieves

caliberated by the NATIONAL BUREAU OF

STANDARDS.

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ADVANTAGES:

Simplicity both in equipment & technique.

DISADVANTAGES:

Sieving errors can arise from number ofvariables, 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.

davg = (%retained)average size/100


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Several methods are there based on sedimentation

rate Andreasen pipette apparatus, Cahn

sedimentation balance method, & Hydrometer

method.

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DISADVANTAGES:

Tedious method.

Proper dispersion, consistent sampling, temperature

control.

Must be carefully controlled to obtain consistent & reliable

results.


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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.

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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 ofparameters as crystal growth in suspension formulation.


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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 tyndalleffect 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.

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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 3m.

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.


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This method is used particularly for colloids. A

colloidal dispersion is forced through a long columnpacked with nonporous beads with an approximate

radius of10m. Particles of different particle size

travel with different speeds around the beads & are

thus collected in size fractions.



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Laser article 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 laserbeam. These particles scatter light atMalvern particle size

analyzer


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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.


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Leon Lachman, Herbert A. Libermann, The Theory AndPractice of Industrial Pharmacy, Varghese publishinghouse, Bombay, Third edition, 1991, page no. 171-176.

Mark Gibson, Pharmaceutical Preformulations andFormulations, page no. 41-49

Gilbert S. Banker, Christopher T. Rhodes, ModernPharmaceutics, Marcell Dekker, fourth edition, revised &expanded, 2005, page no. 273-275.

MARTINS Physical Pharmacy and Pharmaceuticalsciences, 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.



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Loyd V. Allen, Jr. Nicholas G. Popovich, Howard C. Ansel;Ansels pharmaceutical dosage forms and drug deliverysystems, Lippincott William & Wilkins publications,eighth edition, 2008, page no. 187-190.

M.E.Aulton; Pharmaceutics: The Science of Dosage formand Design, Churchill Livingstone, second edition, pageno. 152-174.

D.M. Brahmankar, Sunil B Jaiswal, Biopharmaceutics AndPharmacokinetics A Treatise, Vallabh prakashan, NewDelhi.

http://tetra.simtech.a-star.edu.sg/afbsUpload/FactSheet/ICES/Malvern%20Particle%20Size%20Analyzer%20MS2000.pdf, 19.12.2010

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