Physical Analysis1

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P N . S U R Y A T I B T S Y A F R I

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PHYSICAL ANALYSIS


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METHODS OF PHYSICAL ANALYSIS

1. MELTING POINT

2. BOILING POINT

3. DENSITY

4. REFRACTIVE INDEX

5. VISCOSITY

6. OPTICAL ROTATION

7. DISINTEGRATION

8. DISSOLUTION

9. PARTICLE SIZE ANALYSIS

10. UNIFORMITY OF TABLET WEIGHT


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MELTING POINT

The temperature rangeat which the substance melts,

when it changes from a solid state to a liquid state.

Measurement : A Kofler bench is a metal strip with atemperature gradient (range room temperature to

300C).


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BOILING POINT

The temperature at which the substance boils, when it

changes from a liquid state to a gaseous state.


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DENSITY

The volume which is occupied by a specific mass of a material

Usually given in units of grams per cubic centimeters or grams

per milliliter.

The density of a liquid can be determined by weighing a

exact volume and calculating density using the equationbelow :

20 = 998.2 (M1 + A)

M2 + A

Unit : kg/m3 or g/ml

M1 = weight in air of substance

M2 = weight in air of water

A = correction factor (0.0012 M2)

998.2 = the density water at 200 in kg/m3


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Relative density (d20)

The ratio of the mass of a given

volume of the substance to the mass of

an equal volume of water, both

weighed at 200C

Measurement :

Pycnometer

Hydrostatic balance or hydrometer

The relationship density and relativedensity:

20

= 998.202 x d20


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Viscosity7

Viscosity is the

measure of a liquids

resistance to flowing.

as "thickness", orresistance to flow

water is "thin",

having a lower

viscosity, whilevegetable oil is

"thick" having a

higher viscosity
http://en.wikipedia.org/wiki/Waterhttp://en.wikipedia.org/wiki/Vegetable_oilhttp://en.wikipedia.org/wiki/Vegetable_oilhttp://en.wikipedia.org/wiki/Vegetable_oilhttp://en.wikipedia.org/wiki/Vegetable_oilhttp://en.wikipedia.org/wiki/Water


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Viscosity8

Substances composed of small, nonpolar

molecules (such as gasoline and benzene)

have low viscosities. Polar molecules (such as glycerol) and

molecules composed of long chains of atoms

(such as oil and grease) have higher

viscosities.

The viscosity of a liquid decreases at higher

temperatures.


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APPLICATION IN PHARMACEUTICALS

Determination viscosity of :Gels

Emulsions (creams)Aerosols (nasal sprays)


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Viscosity Measurement

1. Capillary viscometer

2. Falling-ball viscometer3. Rotating viscometer


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Capillary viscometer

Principle : The time taken for the liquid to pass between

two marks as it flows by gravity through avertical capillary

The time of flow of the liquid under test iscompared with the time required for a liquidof known viscosity (usually water) to passbetween to marks

The rate of flow of the fluid through thecapillary is measured under the influence ofgravity or an externally applied pressure at

variety temperature Ubbelohde Viscometers

Ostwald viscometers


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Falling-ball viscometer

Hoeppler Viscometer

Principle :Based on the measurement of the rate of flow of a ball

through a viscous medium in tube at constant temperatureIt can be measured by the time it takes to pass two marks

on the tube


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ROTATING VISCOMETER

PRINCIPLE :determines the

required torque for

rotating a disk or bob in

a fluid at known speed

Brookfield-type viscometer


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Stormer viscometer

Rotating viscometer

PRINCIPLE : These instrument rely on the viscous

drag exerted on a body when it isrotated in the fluid to determine theviscosity of the fluid.

Viscosity determined by rate ofrotation of paddle-type rotor perminute (rpm)


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Refraction is the bending of light when the lightpasses from one medium to another.

REFRACTIVE INDEX

air

glass

normal

angle of

refraction

angle of

incidence


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REFRACTIVE INDEX

Refractive index measures how fast lightpropagates through a medium.

Such media must be poor conductors and are

usually called dielectric media.

The refractive index of a dielectric medium is

where c is the speed of light in vacuum, and v is thespeed in the medium. Note that > 1.

v

c


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REFRACTIVE INDEX

Measurement : RefractometerMajor component : PrismUnless otherwise specified

measured at the wavelength of thesodium D-line (589.3 nm) at

temperature of 200

C in a layer 1dm thick --- nD20

APPLICATIONTo identify subsantce

In quality control in the foodindustry substance such asidentified sugar

To measure purityTo determine the concentration of

substance


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OPTICAL ROTATION

The optical rotation of substance is the angle throughwhich plane of polarizations is rotated when polarizedlight passes through the substance if a liquid or asolution of the substance if solid.

Example : When a beam of plane polarized light is passed

through a solution of a chiral compound such as (S)-alanine, the plane of polarization of the light thatemerges is rotated relative to the original plane. ----optical activity

compounds that rotate the plane of polarized light aresaid to be optically active


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OPTICAL ROTATION MEASUREMENT

Measurement :POLARIMETER

Construct with a sodium

or mercury vapour lamp. Must be giving reading

to the nearest 0.010

Application :

To check the identityand purity product(based on specificrotation values)


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observed rotation: , degrees a

compound rotates polarized light

- dextrorotatory (+) right

- levorotatory (-) left

Tspecific rotation []D=

(observed, deg.)

l(dm) [ g/ mL]d

Unless otherwise specified measured at the wavelength of the sodium

D-line (589.3 nm) at temperature of 200

C in a layer 1 dm thick



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Optical purity (%) = 100 [a]mixture

[a]pure sample



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Example: 0.5g (-)-epinephrine-HCl in 10mL H2O

measured in 20 cm cell (25o/D) obs = -5.0o, []D =?25o

(obs)l(dm) [ g/ mL]

[] D =25o

obs)

(2dm) [ 0 .05 g/ mL]

[] D =25o

[

] D =

25o

-50o

OH

OH

C OHC

HN

HH

HH

CH3

Cl

R-enantiomer is (-); R or S above?

[] = deg (cm2

g-1

)


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Example

Given that (S)-bromobutane has a specificrotation of +23.1o and (R)-bromobutane has aspecific rotation of -23.1o, what is the opticalpurity whose specific rotation was found to be+18.4o?

. Optical purity, % = 100 [a]mixture / [a]pure

sample= 100 (-18.4) / +23.1o= 80%


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DISSOLUTION TEST

Dissolution testing is used to evaluate the release ofdrug substance from dosage form

Physical

Test

Analytical

Test

Dissolution is a physical test

to characterize how drug is

released from a dosage form.

We employ analytical

measurements and a clock todetermine rates of release.

Filter


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DISSOLUTION APPARATUS


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Dissolution test for tablets and capsules

Determine the dissolution rate of theactive ingredients of solid dosage form

Inert apparatus, not adsorb, react orinterfere with the preparation beingexamined


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Dissolution test for transdermal patches

Determine the dissolution rate of the active ingredients

of the transdermal patches


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METHOD OF MEASURING DISSOLUTION

Beaker method

Flask-stirrer method

Rotating basket method

Paddle method Rotating and static disc method


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METHOD OF MEASURING DISSOLUTION


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Beaker method

Beaker 400 ml containing 250 ml dissolution medium,agitated by means of a 3-bladed polyethylene stirrer;diam: 50 mm

The stirrer was immersed to a depth of 27 mm into the

dissolution medium and rotated at 60 rpm Tablets were dropped into the beaker and samples of

the liquid were removed at known times, filtered andassayed


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Flask stirrer method

Similar to beaker method except a round

bottomed flask is used- helps to avoid the problems

that may arise from the formation of mounds of

particles in different positions on the flat bottom(beaker)


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Rotating basket method

Tablets/capsules placed inside a stainless steel wire

basket, rotated at a fixed speed while immersed in

dissolution medium which is contained in a wide-

mouthed cylindrical vessel, bottom either flat or

spherical

Samples of the dissolution medium removed at

specified times, filtered and assayed


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Paddle method

Cylindrical vessel with spherical bottom

Agitation is provided by a rotating paddle and the

dosage form is allowed to sink to the bottom of the

dissolution vessel before agitation is commenced


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Rotating and static disc method

Compounds to determine its rate dissolution is

compressed into a non- disintegrating disc which is

mounted in holder so that only one face is exposed

Holder & disc are immersed in dissolution medium andeither held in a fixed position (static disc method) or

rotated at a given speed (rotating disc method)

Samples of dissolution medium are removed after

known times, filtered and assayed


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DISINTEGRATION

Breaking up of a tablet in water or in simulatedgastric and/or simulated intestinal fluid to thepoint that the particles pass through a fine screen,

Determines whether tablets/capsules/suppositoriesdisintegrate within the prescribed time whenplaced in a liquid medium In the experimentalcondition prescribed below


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TABLET DISINTEGRATOR


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DISINTEGRATION

Disintegration is considered to be achieved when:

a) No residue

b) If there Is a residue, it consists of a soft mass

a) Only fragments of coating (tablets) or onlyfragments of shell (capsules) remain on the

screen; if a disc has been used (capsules),fragments of shell may adhere to the lowersurface of the disc


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PARTICLE SIZE ANALYSIS

METHOD ANALYSIS

Sieve Methods

Mikroscope Methods

Electrical stream sensing zone (Coulter counter

Methods)

Laser light scattering methods (Kaedah

penyerakan cahaya laser Sedimentation Methods


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Sieve method- non-automated analysis

An inexpensive and reliable method for classifying largerparticles based on size and mass.

Range of analysis:

The International Standards organization (ISO) sets a

lowest sieve diameter of 45 m and since powders areusually defined as having a maximum diameter of 1000m, this could be considered to be the upper limit.

In practice sieves can be obtained for size analysis over arange from 5 to 125 000 m


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SIEVE METHODS

Sample preparation and analysis

condition

Usually carried out using dry

powder


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SIEVE METHOD

Principle of measurement1. Sieve analysis utilizes a woven, punched or

electroformed mesh often in brass, bronze or stainlesssteel with known aperture (hole) diameters which form

a physical barrier to particles.2. Stack or nest of sieves (Stack 6-8 sieves)3. Smallest mesh above a collector tray4. Coarser meshes towards the top of series

5. Powder is loaded on to the coarsest sieve at the top ofassembled stack and the nest is subjected to mechanicalvibration.


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After this time , the particles are considered to be retained

on the sieve mesh with an aperture corresponding to theminimum or sieve diameter.

A sieving time of 20 minutes is arbitrary and BS 1796recommends sieving to be continued until less than 0.2%

material passes a given sieve aperture in any 5 minutesinterval

Advantages:

1. This method is very simple.

2. Not expensive3. Easy to operate

Disadvantages:

1. Not too much precise method.

2. Not applicable for all disperse systems.

SIEVE METHOD


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Instruments;

Light microscope

Electron microscope

Size range- 0.001-1000m

MICROSCOPE METHOD


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Advantages

Simple and intuitiveGive shape informationReasonable amount of sample

Disadvantages

Statistic relevance tedious if image analyse can not beused

Risk for bias interpretation

Difficult for high concentrations

Sample preparation might be difficult

MICROSCOPE METHOD


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Microscope method

Sample preparation Specimens prepared for light microscopy must be adequately

dispersed on a microscope slide to avoid analysis ofagglomerated particles.

Specimens for scanning electron microscopy are prepared byfixing to aluminium stubs before sputter coating with a film ofgold a few nanometers in thickness.


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SEDIMENTATION METHOD

Sedimentation Methods also an ordinary and simplemethod

It is widely used as a method for the particle sizeanalysis

Range of analysis


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Sample preparation and analysis conditionsIn this method particle size can be determined by examining the

powder as it sediments out.

(a). In cases where the powder is not uniformly dispersed in afluid it can be introduced as a thin layer on the surface of theliquid.

(b). If the powder is lyophobic, e.g. hydrophobic in water , itmay be necessary to add dispersing agent to aid wetting ofthe powder.

In case where the powder is soluble in water it will benecessary to use non- aqueous liquids or carry out theanalysis in a gas.



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Principle of Measurement

Particle size analysis by sedimentation method canbe divided into two main categories according to

the method of measurement used.

1. One of the type is based on measurement ofparticle in a retention zone.

2. Another type uses a non-retention measurementzone.



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An example of a non-retention zone measurementis known as the pipette method.

In this method , known volumes of suspension are

drawn off and the concentration differences aremeasured with respect to time.

One of the most popular of the pipette methodswas that developed by Andreasen and Lundberg

and commonly called the Andreasen pipette



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10 ml sampling reservoir

3-way tap

Upper set limit

Lower set limit

pipette


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Coulter counter methods

Coulter Counter Method (Electrical stream sensingzone method) is a sophisticated method.

It is a precise and accurate method.

Range of analysis


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Sample preparation and analysis conditions

1. Powder samples are dispersed in an electrolyte to

form a very dilute suspension.

2.The suspension is usually subjected to ultrasonic agitation for a period to break up any particle

agglomerates.

3. A dispersant may also be added to aid particle deagglomeration.



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Cell counter

vacuum

orifice


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Principle of Measurement1. The particle suspension is drawn through an aperture

accurately drilled through a sapphire crystal set into thewall of a hollow glass tube.

2. Electrodes, situated on either side of the aperture andsurrounded by an electrolyte solution.

3. Monitor the change in electrical signal which occurs when

aparticle momentarily occupies the orifice and displaces itsown volume of electrolyte..



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4. The volume of suspension drawn through the orifice isdetermined by the suction potential created by a mercurythread rebalancing in a convoluted U tube.

5. The volume of electrolyte fluid which is displaced in the

orifice by the presence of a particle causes a change inelectrical resistance between the electrodes which isproportional to the volume of the particle.

6. The change in resistance is converted between into a

voltage pulse which is amplified and processedelectronically .

7. Pulses falling within pre-calibrated limits or thresholdsare used to split the particle size distribution into many

different size range



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Advantages:

1. It is one of the precise and accurate method.

2. Analysis range is wide.

Disadvantages:

1. It is a sophisticated method.

2. It is a expensive method



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ACTIVITIES

Refer to :Michael Aulton (2007), Aultons Pharmaceutics. The Design &

Manufacture of Medicines, 3rd edition

Partilcle size analysis

Sample preparation, Principle of measurement, Instrument,Advantages & Disadvantages

Sieve Methods

Mikroscope Methods

Electrical stream sensing zone (Coulter counter Methods)

Laser light scattering methods (Kaedah penyerakan cahaya laser Sedimentation Methods

Uniformity of tablet weight


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