Transcript physical_testing_1.pps

Physical Testing
1.Solutions
2.Disperse systems
3.Aerosols
4.Powders
5.Tablets
6.Sustained release products
7.Coated tablets
8.Hard & soft shell capsules
9.Microcapsules
Solutions
Parenteral
-Appearance
-Precipitation
-Swirly precipitates
-Whiskers
-Clouds
-Sterility
-Volume
-Dielectric constant
-pH
Oral
-Appearance
-Precipitation
-Organoleptic properties
-Loss of dye
-Bacterial growth
-Volume
-Dielectric constant
-pH
Appearance in solutions
Discoloration could be due to
Oxidation
Photodegradation
Appearance in solutions
Discoloration could be
Analytically
detectable
Log A
•Loss of dye could be treated
Slope = - Ea / 2.303 R
like a drug substance.
Log k
•Arrhenius plotting can be
used for prediction
1000
T
Analytically NOT
detectable
Appearance in solutions
Discoloration can be detected by
Color standards
(Roche color standard)
Dubosque colorimetry
Standard
Test
a
b
-Length of the light bath in tube b is changed.
1
2
3
4
-This length indicates concentration
-Measure intensity of discoloration
-Numbers obey Beer’s Law & are
-Results are difficult to analyze
logarithmically proportional to conc.
Swirly precipitates in solutions
Most common in
Due to interaction with container
Can be detected by
Visually by a
parenteral
inspector
Mechanical counting
(Coulter Counter)
Determining number
of positive vials/box
Swirly precipitates in solutions
Due to interaction with container
Most common in
Can be solved by
Lyophilization
Change of
container
Establishing %
probability of
finding vials
with swirls
Re-formulation
Whiskers in solutions
Most common in
Due to pinholes
Whiskers in solutions
Due to pinholes
Most common in
Ampoule was tight at time of
manufacture and the strain
caused crack during storage
(improper anealling)
Hole was present but nondetectable at time of manufacture
(too small to detect)
Sealing Verification
(Leaker testing)
Rapid heat sealing line
Incorrect flame temperature
Clouds in solutions
Precipitation can be induced by
Chemical change
(hydrolysis)
Change in drug form
(polymorph)
Exceeding drug
solubility or forming a
product with limited
solubility
Clouds in solutions
Cloud time (t*) is the time at which the solubility is exceeded
A + H2O → B
S
Clouds in solutions
Cloud times
time (t*)
Canisbe
theplotted
time atbywhich
Arrhenius
the solubility
plotting is exceeded
t*
Ln t*
25o
40o
50o
60o
70o
90o
2.7 2.8
2.9
3.0 3.1
1000/T
3.355
Clouds in solutions
Precipitation can be inhibited by
Precipitation is tied
into solubility
Co-solvents
Complexation
Viscosity testing
Precipitation is a
nucleation and crystal
growth phenomenon
Micellar
solubilization
Inhibitors
(viscosity inducers)
Organoleptic properties
Taste
Flavor
Type
Level
Sensory panel test
-Human tester
-Scale from 1 to 5 for example
-measures should be taken to minimize bias in evaluation
-Not recommended to use elevated temperatures
Organoleptic properties
Measures to minimize bias in evaluation
-Determination of organoleptic capacity of the tester
-Ability to describe the flavor well
-Ability to duplicate results
-Ability to remember results
-Ability to detect new flavors (eg. due to interaction with
container.)
Organoleptic properties
Electronic tongue is an instrument that measures and
compares tastes.
Disperse systems
Suspensions
Liquid
Emulsions
Semi-solid
-Appearance
-Organoleptic Properties
-Ease of re-dispersion
-Sedimentation volumeOintment
-Sedimentation rates
-Particle size
-Zeta potential
- Rheological properties
-Dissolution
-polymorphism
-Preservation stability
-Accelerated testing
Liquid
Suppository
Semi-solid
(ointment)
Suspensions
Deflocculated
Flocculated
Rheology
Suspensions
Deflocculated
Zeta Potential
Flocculated
zeta potential 
It is the difference in potential between surface of the
tightly bound layer (shear plane) and electro neutral
region of the solution.
Suspensions
Deflocculated
Flocculated
Potential energy
20
1ry
minimum
2ry minimum
10
0
-10
-20
0
6
12
Distance
18
24
Potential energy diagram for two particles
Liquid Suspensions
Deflocculated
Ease of re-dispersion
(Shaking test)
Subjective
Flocculated
Quantitative
Drug in supernatant
To rotate the bottle under
reproducible conditions for x
rotations
6
12
18
Number of rotations
Liquid Suspensions
Deflocculated
Sedimentation volumeFlocculated
Dosage level (g/cm3)
Density (g/cm3)
1
2
3
4
Liquid Suspensions
Deflocculated
Sedimentation volumeFlocculated
There are suspensions that do not settle, When the YIELD VALUE of the
suspension is so larger than the gravitational force.
Yield value
Viscosity
Solid content
Complete rheological profile should be carried at different
time intervals during stability study to ensure that the yield
value did not change
Liquid Suspensions
Sedimentation rate
Re-flocculation
On shaking
Deflocculated
Flocculated
Settling towards equilibrium volume
Equilibrium follicle
Two phasic
curve
Liquid Suspensions
Log x-Height
Sedimentation rate
Time
Settling time measurements
Deflocculated
Flocculated
Liquid Suspensions
Flocculated
Drug Dissolved
Cubic root of
Undissolved drug
Dissolution
Deflocculated
Time
Time
Hixon-Crowel
Liquid Suspensions
Drug Dissolved
In [% not dissolved-10]
Dissolution
Time
Deflocculated
Flocculated
Time
First order
(Sigma minus)
Liquid Suspensions
Deflocculated
Preservation stability Flocculated
Chemical assay of the used preservatives & their
decomposition products
Methyl, ethyl, propyl, and butyl esters of 4-hydroxybenzoic acid
Liquid Suspensions
Accelerated testing
Shaking at 37oC Centrifugation
Deflocculated
Flocculated
Freeze-thaw
cycle
Temperature
testing
Liquid Suspensions
Accelerated testing
Shaking at 37oC Centrifugation
Deflocculated
Flocculated
Freeze-thaw
cycle
Temperature
testing
To judge qualitatively if caking will take place
It accelerate settling by making particles move more
rapidly and allowing fine particles to slip into the
interstices of larger ones
Liquid Suspensions
Accelerated testing
Shaking at 37oC Centrifugation
Deflocculated
Flocculated
Freeze-thaw
cycle
Temperature
testing
It accelerates only the initial settling rate
Can’t predict well further settling nor caking
Liquid Suspensions
Accelerated testing
Shaking at 37oC Centrifugation
Deflocculated
Flocculated
Freeze-thaw
cycle
Temperature
testing
To alternate storage temperature every 24h (eg. 25oC to -5oC)
To predict crystal growth that could happen under
normal conditions of shipping and use
Liquid Suspensions
Deflocculated
Accelerated testing
Shaking at 37oC Centrifugation
Flocculated
Freeze-thaw
cycle
Temperature
testing
Temperatures shouldn’t exceed the temperature at which
suspended drug is soluble
Disperse systems
Suspensions
Liquid
Emulsions
Semi-solid
-Appearance
-Organoleptic Properties
-Ease of re-dispersion
Suppository
-Sedimentation volumeOintment
-Sedimentation rates -Consistency, shape
-Particle size
-Polymorphism
-Zeta potential
- Rheological properties
- Rheological properties
-Release rate
-Dissolution
-Migration of drug
-Polymorphism
-Preservation stability -Stability with container
-Accelerated testing
Liquid
Semi-solid
(ointment)
Semi-solid Suspensions
Migration of drug
Deflocculated
Flocculated
Migration of the dispersed drug within a semi-solid product is
quite possible when another phase is present.
Aluminum wrap with
polyethylene lining
Rate of drug disappearance will follow first order reaction
Rate is proportional to Sp - Ss
Disperse systems
Suspensions
Liquid
Emulsions
Liquid
Semi-solid
-Appearance
(ointment)
-Appearance
-Organoleptic Properties
-Organoleptic Properties
-Globule size & viscosity
-Ease of re-dispersion Ointment
Suppository
-Sedimentation volume-Consistency
-Electrical conductivity
-Sedimentation rates -Polymorphism
-Dissolution
-Particle size
- Rheological properties -Rheological properties
-Zeta potential
-Release rate
-Emulsion type
- Rheological properties-Migration of drug
-Stability of emulsifier
-Dissolution
-Stability with container
-Preservation stability
-Accelerated testing
-Accelerated testing
Semi-solid
Liquid Emulsions
Emulsions are meta stable systems
Thermodynamically, emulsions are more energetic than
the ground state system which is simply the totality of
the two phases separated.
There is always potential for oil droplet re-merging
Liquid Emulsions
Creaming: Droplets move upwards ( droplets density<
Droplets of continuous phase)
Sedimentation: Droplets move downwards ( droplets
density> droplets of continuous phase)
Flocculation: >2 droplets stick together and form aggregate
Coalescence: >2 droplets merge together and form single
large droplets
Phase inversion: o/w emulsion changes to w/o emulsion or
vice versa.
Liquid Emulsions
Creaming and coalescence
Breaking can be manifested in:
1. Separation of oil particles on the surface (oiling)
2. Different colors on dipping finger in the emulsion (creaming)
3. Change in draining off the skin (creaming)
4. Separation into two phases (coalescence)
Liquid Emulsions
Breaking and coalescence
Reasons for emulsion breaking:
1. Chemical instability between the emulsifier
and any other ingredient
2. Improper choice of the emulsifier (HLB)
3. High electrolyte concentration
4. Instability of an emulsifier
5. Too low viscosity
6. Temperature
Liquid Emulsions
Stability of the emulsifier/protective colloid system
Chemical instability
Change
of
Hydrolysis
particle size
Change of with
emulsion
Interaction
other
characteristics
emulsion
components
Liquid Emulsions
Emulsion type
Phase inversion affects emulsion use, appearance and stability
It is associated with creaming (a distinct difference in appearances
in various regions of the emulsion ), separation and graininess of
feel.
Liquid Emulsions
Electrical conductivity
This indicate the state of dispersion of an emulsion system
If significant changes were recorded over short periods of
time, then the emulsion system is not satisfactory
Liquid Emulsions
Appearance
Correlation between globule size and appearance of emulsions
Globule size (µm)
<0.005
0.005-0.1
0.1-1
Appearance
Transluscent (transparent)
Semi-transparent, grey
Bluish white emulsion
>1
Milky white emulsion
Liquid Emulsions
Globule size and viscosity
Globules collide and hence coalesce leading to increased viscosity.
Thus checking emulsion viscosity is a prime indicator of potential for
progressing creaming and breaking.
Viscosity is a function of droplet size and phase ratio
viscosity
large droplet size
Small droplet size
Volume fraction of oil
Liquid Emulsions
Globule size and viscosity
1. Microscopy (for large size)
2. Electronic counters (Coulter counter)
3. Photon correlation spectroscopy (for very small size)
Complete rheograms using
multiple point viscometers
(cone and plate viscometer)
4. Diffuse reflectance spectroscopy
The proper method should be chosen for each system
It is recommended to use more than one method for confirmation
especially in parenteral emulsions
Liquid Emulsions
Globule size and viscosity
8
7
7
6
6
5
5
4
4
3
3
2
2
1
1
0
0
1
2
3
4
1=Coulter counter before (intermediate particle size)
2= Photon correlation spectroscopy before (small P.S.)
3=Coulter counter (after)
4= Photon correlation spectroscopy after
1
2
3
4
1, 3= Microscopy before (large P.S.)
2, 4= Microscopy after
Liquid Emulsions
Rheological properties
Factors affecting rheological properties:
1. Globule size
2. The viscosity of the internal phase
3. The viscosity of the external phase
4. Phase volume ratio
5. Type and amount of emulsifier
6. Particle size distribution
Liquid Emulsions
Accelerated testing
Shaking
Centrifugation
Freeze-thaw
cycle
Temperature
testing
If the preparation fails the accelerated tests it may be all right,
but if it passes the test it should be all right.
If done on storage, results could differ due to other factors such
as chemical decomposition of the emulsifier
Liquid Emulsions
Accelerated testing
Shaking
Centrifugation
Freeze-thaw
cycle
Temperature
testing
It is done at 2-3 hertz
It increases the intensity and frequency of
collisions between globules which could happen
during transport in real use
Liquid Emulsions
Accelerated testing
Shaking
Centrifugation
Freeze-thaw
cycle
Temperature
testing
Often the centrifugation stresses leads to coalescence
which would not occur during normal collision stress
Liquid Emulsions
Accelerated testing
Shaking
Centrifugation
Freeze-thaw
cycle
Temperature
testing
Phase separation could be measured at different
centrifugational gs (coalescence pressure)
Liquid Emulsions
Accelerated testing
Shaking
Centrifugation
Freeze-thaw
cycle
Temperature
testing
Temperatures between -5 and 5oC being the most used
Liquid Emulsions
Accelerated testing
Shaking
Centrifugation
Freeze-thaw
cycle
Temperature
testing
Testing temperature should not exceed the inversion
temperature of the emulsion
Semi-solid Emulsions
Properties important in stability programs:
1. Particle size
2. Polymorphism
3. Sedimentation/creaming
4. Caking/coalescence
5. consistency
6. Drug release
7. Viscosity: Visoelastic properties not just simple
continuous shear measurements (dynamic viscosity and
storage modulus)
Powders
1. Appearance
2. Organoleptic properties
3. Ease of reconstitution
Reasons of changing dissolution time with time
Cohesion
Crystal growth
Moisture sorption
Powders
1. Appearance
2. Organoleptic properties
3. Ease of reconstitution
Reasons of changing dissolution time with time
Cohesion
Crystal growth
Moisture sorption
Problems due to cohesion are predominant with fine powders and
increase with vibration of the powder
Cohesional forces are inversely proportional to the square of the
distance between the particles
It leads to lumpy powder
Powders
1. Appearance
2. Organoleptic properties
3. Ease of reconstitution
Reasons of changing dissolution time with time
Cohesion
Crystal growth
Polymorphism
Amorphous to Meta-stable to
crystalline
stable
Moisture sorption
Moisture
-Vapor pressure inside container > vapor
pressure of saturated solution
-drug dissolves in moisture
-drug precipitate with temperature
fluctuations
Hydrate
formation
Powders
1. Appearance
2. Organoleptic properties
3. Ease of reconstitution
Reasons of changing dissolution time with time
Cohesion
Crystal growth
It gives Coarser product
Moisture sorption
Powders
1. Appearance
2. Organoleptic properties
3. Ease of reconstitution
Reasons of changing dissolution time with time
Cohesion
Crystal growth
Moisture sorption
Leads to dissolution of the drug
and bridge forming that simulate
wet granulation
Powders
How to test ease of reconstitution
The test is subjective & done by a tester who records the length of
time required for reconstitution.
Measures to minimize bias in evaluation
Screening of operators for reconstitution testing in a blind
manner
Reconstitution time (min)
Powders
Time (month)
Change in reconstitution time of a powder on storage
Powders
Moisture is essential in changing the time required
for reconstitution & thus moisture content should be
determined during stability test of pharmaceutical
powders
Aerosols
Aerosols are solutions, primary emulsions or suspensions of active
principle in chlorinated hydrocarbons contained in a pressure can
Physical instabilities of aerosols can lead to changes in:
1. Total drug delivered per dose
2. Total number of doses that may be obtained from the container
3. Delivery to their target in body
Aerosols
Testing:
1. Unit spray content
2. Color and odor
3. Rate of leakage
4. Moisture and trace catalytical substances
5. Particle size distribution
6. Spray characteristics
7. pH
8. Delivery rate
9. Microbial limit tests
10.Container compatibility