UNIT - III

PHARMACEUTICA
L PACKAGING
 PHARMACEUTICAL PACKAGING
• Packaging processes for pharmaceutical preparations.
• Impact on stability of the pharmaceutical drug product.
CHARACTERISTICS
• Protect drug from environmental conditions.
• Compatible and should not interact with the dosage.
• Non toxic and FDA approved.
Packaging is a process by which
the pharmaceuticals are suitably
packed so that they should retain
their therapeutic effectiveness
from the time of packaging till
they are consumed
COMPOSITION OF PACKAGE
I. Container
II. Closure
III. Carton or Outer
IV. Box
A container :
a) Should not absorb the medicament
b) Should not alter the stability
c) Should withstand sterilization procedure
d) Should facilitate easy handling and withdrawal
Selection of a packaging material depends on
- Dosage form
- Route of administration
- Chemical nature of Active Pharmaceutical Ingredient

TYPES OF PACKAGING

PRIMARY SECONDARY TERTIARY

PRIMARY
SECONDARY

TERTIARY
 CONTAINERS Are devices that
hold the formulation
and it may or may
not be in direct
contact with the
formulation

GLASS PLASTICS
 GLASS
• Most commonly used, FDA approved, of high strength
• Ability to modify into different shapes
• Resistivity towards various chemicals
• Should be sufficiently strong to tolerate high pressure and
protect degradation from UV rays.
• 4 Types –
- type 1 – borosilicate glass
- type 2 – treated soda lime glass
- type 3 – soda lime glass
- type 4 – NP glass
 INTERNAL WATER
POWDERED
BURSTING ATTACK
GLASS TEST
PRESSURE TEST TEST

SURFACE
LIGHT
TREATMENT
TRANSMISSION
QUALITY TEST
CONTROL
OF GLASS
ARSENIC
LEAKAGE TEST
TEST

HYDROLYTIC
RESISTANCE
THERMAL
TEST ATTACK TEST
1. HYDROLYTIC RESISTANCE TEST - TEST A
Wash the containers with distilled water for the prevention of
entry of air bubbles and then dried properly

Fill containers with CO2 free water and wrap

with aluminum foil •evaluate
quality of outer
Place containers in the autoclave and close the container surface of the
container
Displace air by passage of steam of air for 10 minutes. Raise •Under
the temperature from 100-121°C over 20 mints, maintain the controlled
temperature of 121°C for 60mints, and reduce the temperature
conditions with
from 121-100°C over 40mints, vent to prevent vacuum
help of
autoclave and
Remove containers from auto clave and cool them in a
bath of running tap water. Conduct a titration using HCl in thermocouples
burette and compare the endpoint with CO2 free water as
blank using methyl red as indicator.
 Volume of 0.01M
Capacity of container corresponding
Hcl/100ml
to 90% of average overflow
volume (ml) Type I/ II Type III

Not More Than (NMT) 1 2.0 20.0

More than 1 but NMT 2 1.8 17.6
More than 2 but NMT 5 1.3 13.2
More than 5 but NMT 10 1.0 10.2
More than 10 but NMT 20 0.8 8.1
More than 20 but NMT 50 0.6 6.1
More than 50 but NMT 100 0.5 4.8
More than 100 but NMT 200 0.4 3.8
More than 200 but NMT 500 0.3 2.9
More than 500 0.2 2.2
 2. POWDERED GLASS TEST - TEST B
Take three containers, rinse and dry
Limits are
same as
Crush it into coarse fragments. Pass through 725μm and TEST A
425μm sieve.

Glass fragments on 425μm are checked for metal

impurities and if present they are removed.

The glass pieces are kept in conical flask, containing

CO2 free water

Conduct a titration using HCl in burette and compare the

endpoint with CO2 free water as blank using methyl red as
indicator.
3. SURFACE TREATMENT TEST - TEST C
Select and rinse containers with distilled water, •Test whether
hydrofluoric acid and hydrochloric acid in ratio 1:9 surface of glass is
treated
•Differentiates
Wash containers with water several times Type II and III
glass

Conduct a titration using HCl in burette and compare

the endpoint with CO2 free water as blank using
methyl red as indicator.

If the limits exceeds the values of TEST A –

TREATED GLASS
 4. WATER ATTACK TEST
Fill containers with purified CO2 free
water and seal with aluminum foils.
Autoclave for 60 minutes at 120°C.
100ml of the content is taken into
250ml conical flask. Add methyl red
solution as indicator
Conduct a titration using 0.02N
Sulphuric Acid and observe the
endpoint
Done to determine the alkali
leached from the surface is under
specified limits or not.
Test is used only for glass treated
with sulphur dioxide fumes under
controlled conditions.
The amount of acid required to
neutralize the alkali released from
the surface is estimated
Volume limits of 0.02 H2SO4 for
type II glass should not exceed
0.7ml
 5. INTERNAL BURSTING PRESSURE TEST
Fill containers with purified CO2 free water and place in the
testing chamber.

A scaling head is placed an the internal pressure is increased in

increments each of which is held for specific time

Container is checked for predetermined pressure level and the test

continues till the container bursts.
 6. THERMAL ATTACK TEST

Place samples in upright position in a tray

Immerse the tray into hot water for given time and
transfer to cold water bath

Examine the cracks or breaks before and after the test

“ Small bottle withstands the temperature different of 60 to

80°c and a pint bottle 30 to 40°c”
 7. LEAKAGE TEST TEST

Drug filled container is placed in a container filed with

coloured solution.

Coloured solution is at high pressure than the pressure inside

the glass container.

Coloured solution enters the glass container if any

breakage or crack is present.
 8. ARSENIC TEST
Wash inner and outer side of container 5 times Absorbance of
Prepare test solution. the test solution
does not exceed
Pipette out 10 ml solution from the combined
contents the absorbance
obtained by
Add 10 ml nitric acid, evaporated to dryness
repeating the
Dry the residue at 130°c for 30 minute and cool
determination
Add 10 ml of Hydrogen molybdate reagent using 0.1 ml
arsenic standard
solution
Heat on water bath and reflux for 25 minute
Cool and determine absorbance at 840 nm
Prepare blank with 10 ml Hydrogen molybdate
 9. LIGHT TRANSMISSION TEST
 Break the glass container
 Select section suitable for mounting in a spectrophotometer
 Place the specimen in the spectrophotometer
ABSORBANCE MAXIMUM % OF LIGHT TRANSMISSION AT ANY
WAVELENGTH BETWEEN 290 TO 450 nm
FLAME SEALED CONTAINER WITH
CONTAINERS CLOSURE
Upto 1 50 25
Above 1 and upto 2 45 20
Above 2 and upto 5 40 15
Above 5 and upto 10 35 13
Above 10 and upto 20 30 12
Above 20 15 10
 PLASTIC
• Cross linking of synthetic or semi synthetic long chain polymer
• Addictives are added to improve physicochemical property.
• Addictives – antistatic agents
- fillers
- antioxidants
- antimicrobial agents
• Antistatic agents – plastic develop static charge on surface
responsible for the attraction of dust particles on the surface,
which males it dull and contaminated. This can be avoided by
adding antistatic agents like phosphate esters.
• Fillers – increase the bulk quantity and the strength of the
plastic.
• Antioxidants – plastics tend to permeate oxygen by breaking
the long chain polymer structure leading to oxidation.
Antioxidants like phenolic compounds can be used to prevent
oxidation.
• Antimicrobial agents- to prevent microbial attack.
 ADVANTAGES DISADVANTAGES
• Lighter than glass • Absorption of moisture
• Flexible • Thermostatic change
• Variety of sizes and shapes
• Chemically inert, strong,
Types of plastic materials
rigid
A.Thermosetting
• Extremely resistant to B.Thermoplastic
breakage.
PLASTIC MATERIALS
• POLYETHYLENE – excellent barrier to moisture, resistance to attack of acids and
alkali.
• NYLON – resistance to strong acid and alkali, strong barrier to oxygen and moisture,
not preferred to long term use due to interaction
• POLYVINYLCHLORIDE – construction of plastic bottles and lamination of inner
side of the glass bottle.
 PROPERTIES OF PLASTIC TO BE CONSIDERED
• SORPTION
• PHOTO DEGRADATION
• DESORPTION / LEACHING
• PERMEATION
• CHEMICAL REACTIVITY
SORPTION
• Loss of formulation constituents due to the interaction with
packaging materials.
• Significant decrease in the drug content, and the therapeutic
efficacy.
• Diazepam showed significant sorption of drugs when stored
at room temp. in the dark in a PVC bag whereas no sorption
was observed when stored in glass containers.
 DESORPTION / LEACHING
• One or more addictives are added in the plastic materials when
they are needed to impart specific properties to the plastic.
• Migration of the contents from the plastic into the formulation –
desorption or leaching
• Can occur due to the effect of change in pH, temp., solvent type
and type of plastic and additive present.
PERMEATION
• Plastic can permeate gases or vapours or water vapour –
this leads to instability of the formulation.
• Oxygen permeation can lead to oxidation of the product
• Water vapour permeation can lead to hydrolysis
• Storage conditions, type of plastic material or addictive,
method of manufacture can be the causes of permeation.
PHOTODEGRADATION
• Formulation ingredients when exposed to UV light can lead to
photo degradation.
• Also some functional groups of the polymers present in the plastic
are prone to absorb UV radiation and hence transmits UV rays
through the plastic container.
• Change in the physical or chemical properties of plastic.
• Subsequently affect the stability of the drugs
• Opacifying agents can be used prevent photo degradation.
CHEMICAL REACTIVITY
• Incompatibility between the ingredient and the plastic material.
• Leads to modification of the drug product.
• Which makes the drug improper for consumption.
 QUALITY
CONTROL OF PLASTIC
CONTAINERS
 LEAKAGE
TEST

TRANSPARENCY COLLAPSIBILITY
TEST

QC TEST
OF
WATER VAPOUR PLASTIC CLARITY
PERMEABILITY TEST

NON
BACTERIOLOGICAL
VOLATILE
TEST
RESIDUE
1. LEAKAGE TEST
Fill 10 containers with distilled water and fit
closures

Keep inverted at room temperature for 24

hours

No sign of leakage should be there

2. COLLAPSIBILITY TEST
Take containers with
required contents.
Indicates the
squeezing property of
Squeeze the contents with the container
optimum force.

90% of the content should be

extruded at an optimum force and
temperature.
3. CLARITY TEST
Cut several strips of 20cmsq. area from both sided from
container to be tested.

Strips taken from area of container that is unlabelled,

unmarked and non laminated.

Select 60-65 strips, wash and transfer to the 250ml

conical flask. Add water and autoclave for 121℃ for
30mints.

Carry out same procedure with blank

Cool the strips, and compare the aqueous extract of the

test and the blank for clarity
4. NON VOLATILE RESIDUE TEST
100ml of the extract from clarity test taken

Heated to dryness till constant weight

Residue should not be more than 12.5mg

5. TRANSPARENCY TEST
• Fill test containers with diluted suspensions of a sample
• Fill standard containers with distilled water
• The cloudiness of the diluted suspension should be
observed with in the container to prove the transparency
of the plastic material
 6a. BIOLOGICAL TEST
Inject sample and blank in 5 mice
each. Animal taken –
Albino Mice
Observe the animals immediately,
after 4hour, and then at 24, 48, and 72
hours.

If animals show abnormal behaviour like

convulsions or body weight loss is greater
than 2gm, the sample does not meet the
requirements.
 6b. INTRACUTANEOUS TEST
Take 3 rabbits for each sample. Remove
hairs from surface to be examined and Animal taken –
clean with dilute ethanol. Rabbit

Inject sample and blank at two

different sites on same animal

Observe and compare the local area for

edema, erythema and necrosis
 6c. EYE IRRITATION TEST
Inject 100 μl of sterile WFI in one
eye as the blank. Inject the sample in Animal taken –
another eye RABBIT

Observe the animals immediately, 24,

48, and 72 hours.

Inspect for eye irritation and compare the

sample and test.
7. WATER VAPOUR PERMEABILITY TEST

Fill 5 containers with water and seal. Weigh

each container and note down the weight.

Allow to stand for 14 days @ relative

humidity of 60±5 and temperature of 20-25℃

Reweigh each of the containers and the loss of

weight should not be more than 0.2%
 CLOSURES
• Packaging component which is in direct contact with the
drug.
• Provides a barrier to dirt, oxygen, moisture, etc
• Retains the contents.
• Keeps the product secure from undesired and premature
opening.
• Minimises the effect of change in humidity, temp. or
pressure.
• Assists in dispensing and using of product.
 CAP TYPE

PLUG TYPE

CROWN TYPE OVER CAP TYPE

ROLL ON TYPE
MATERIALS USED FOR CLOSURES
• METAL
• RUBBER
• PLASTIC
• GLASS
 RUBBER CLOSURES
• Made from materials obtained by vulcanisation of
elastomers with appropriate addictives.
• Do not pose a problem and can be used in contact with
large number of drug preparations.
• Types of rubber used – butyl rubber, nitrile rubber,
neoprene rubber, silicon rubber
CHARACTERISTICS
• Should not become sticky upon storage
• Should not become hard on exposure to atmosphere
• Should not become dark on exposure to air and light.
• Ease of penetrability and elasticity in case of vials.
• Ease in sterilisation. Must withstand at least about 120℃
• Should not allow permeation of water vapour and air. Free from leaching and
sorption.
 LIGHT
ABSORPTION
TEST
PERMEABILITY
RESIDUE ON
EVAPOURATION

SELF
REDUCING QC OF SEALABILITY
SUBSTANCE RUBBER
TEST CLOSURES

FRAGMENTATION
STERILITY
& pH
VOLATILE
SULPHIDE PENETRABILITY
TEST
PREPARATION OF A SAMPLE
• Closures are washed in 0.2% w/v surface active agents
for 5 mints.
• Rinse 5 times with distilled water and 200ml water is
added.
• Autoclave at 119-123℃ for 20-30mints covering with
aluminium foil.
• Cooled and solution is separated from closures –
Solution A
1. RESIDUE ON EVAPOURATION
• 50ml of Solution A is evaporated to dryness on a water bath and dried at 105℃.
• Residue weight should not be more than 4mg.

2. pH of AQEOUS EXTRACT
• 20ml of Solution A + 0.1ml bromothymol blue solution
• Not more than 0.3ml 0.01M NaOH or 0.8ml of 0.01M HCl is
required to change the colour of the solution to blue or yellow
respectively.
3. STERILITY TEST
• Closures are subjected for sterilization, by autoclaving at 64-66℃ and pressure
0.7kPa
• Closures should not soften or tacky
• No visual change in the closure.

4. LIGHT ABSORPTION TEST

• Must be done within 4hr of preparing sample solution
• Filtered and absorbance is measured at 220-360nm.
• Absorbance should not be more than 2.0
 5. REDUCING SUBSTANCE
• 20ml of Solution A + 1ml of sulphuric acid + 20ml of
0.002M potassium permagnate –> boil for 3mints
• Cool, add 1gm of potassium iodide
• Titrate immediately with 0.01M sodium thiosulphate using
0.25ml starch solution. As indicator added towards the end of
titration.
• Repeat the operation using blank
• Difference between the titration volume should NMT 7.0ml
 6. VOLATILE SULPHIDES TEST
• Place closure of surface area 20cmsq. in a 100ml conical flask
• Add 50ml of 2% w/v citric acid solution.
• Place a piece of lead acetate paper over the mouth of the flask. Maintain
the paper in position by placing an inverted weighing bottle.
• Heat in autoclave for 121℃ for 30 mints
• Any black stain on the paper
• The stain should not be more intense than that of the standard using
0.154mg sodium sulphide and 50ml of 2% w/v citric acid solution.
7. SELF SEALABILITY TEST
Fill 10suitable vials with water to the volume, close the
vials with closures and secure with a cap.

Using a hypodermic needle with external diameter of 0.8mm

and pierce the closure 10 times at different sites.

Immerse the vials upright in a solution of methylene blue

with an atmospheric pressure and leave for 30 mints.

None of the vials contain any trace of coloured

solution
8. FRAGMENATION TEST
9. PENETRABILITY
• Measures the force required to make a hypodermic
needle penetrate easily through a closure
• Measured by using a piercing machine
• Piercing force should not exceed the standard value
• Hypodermic needle can get damage as a result of
undesirable hardness of closure.
10. PERMEABILITY TO WATER
Put calcium chloride in vial and close with rubber
closure and seal it with aluminium seal

Weigh the seal. Place it for a limited time period.

Weigh the vial again.

If the weight difference is more than the initial weight, the

rubber closures fail the test as the weight is increased due to
absorption of water vapours.
 SECONDARY PACKING
• Secondary packaging is out side the primary packaging - used to group
primary packages together.
• Designates the packaging used to group pre-packed products together.
• Not in direct contact with actual product.
• Two central functions - Branding and logistics.
• Branding – marketing strategy surrounding the display.
• Logistics – grouping of products for ease of handling transport and storage.
DIFFERENT TYPES OF SECONDARY
PACKING
• Paper and boards.
• Cartons
• Corrugated fibreboard
IDEAL PROPERTIES
• Dimensions should be appropriate to withstand the stress during
transportation.
• Should not affect the primary packaging
• Should have sufficient strength to hold material
• Thickness should be appropriate to have mechanical strength.
 TESTING OF PAPER AND BOARD

The physical dimensions of the given paper board is taken and recorded
Dimensions

A test piece of suitable size

(10cm×10cm) is cut and weighed.
The grammage of the sample is determined by
Grammage = (104×w) / (a×b)
Grammage
w - weight in grams
a - length
b- breadth
 Cut 1gm of paper and place in a 100ml flask, fitted with a condenser. Add 20
ml of boiling distilled water in small portions till the paper is wet.
pH after Add 50 ml of distilled water. Reflux and digest with occasional shaking
extraction at 95- 1000c for 1 hr. Cool to 40-450c, remove the condenser and shake,
cool in water bath. Determine the pH of the supernatant with pH meter.

• Acidity in paper may be caused by the presence of residual chemical

left in the pulp.
Surface pH • Adrop of distilled water is placed on the top of the test piece and the
electrode of pH meter is placed in the drop touching the paper.
• Thereading is taken after 2 min.
 Conditioned specimen is weighed and heated to a constant weight to
expel the moisture. The difference of the two weights gives the
moisture content of the paper.
Moisture Content Percentage moisture = 100(A-B) / B
A- Originalweight
B- Weight afterdrying.

Take about 1g of specimen and make it in to shreds and place in a previously weighed
crucible (C). Heat carefully over a burner till completely charred. Transfer the
crucible in to a muffle furnace at 8000C. until all the carbonaceous matter are burnt
Ash off. Cool in dessicator, weighand repeat the experiment to a constant
Content weight (D)
%Ash= 100(C-D)/D
 Place about 5g (w) of accurately weighed sample, cut into pieces in a stoppered
flask containing 250 ml of 0.02N HCl. Allow to stand for 1 hr with occasional
shaking. Decant and titrate a measured quantity (v) against 0.1 N NaOH using
methyl orange asindicator. Carry out blank (B).
Alkalinity
% alkalinity= {1250 (B-A) * N} / (V* W)
A- Samplereading
N- Normality ofNaOH

This measures the mass of water absorbed by 1cm2 of the test piece in a specified time
under a head of 1 cm of water. It is determined by weighing before and after exposure
Cobb
to the water, and usually quoted in g/m2
Test
Folding endurance Fold the test piece back and forth until rupture occurs.
Tensile strength The maximum tensile force per unit width that a paper or
board will withstand breaking
Wet tensile strength Tensile strength determination when immersed in water.
Burst strength The maximum uniformly distributed pressure, applied at
right angle to surface that at test piece of paper and board
will stand under condition of test
Wet burst strength Determine bursting strength when immersed in water.
Tear strength Mean force required to continue the tearing of an initial cut
in a single paper.
Density For measuring the rigidity.
Rub resistance Resistance of printed test piece to with stand rubbing against
another test piece.
Puncture resistance Energy required to make initial puncture.
Pick test A specified amount of oil is added to the printing system and
printed on the test piece. The surface is then examined for signs of
pick.
Roughness/ Ensures the printability on a paper and board.
smoothness
Air permeability Light weighted uncoated paper on machine having vacuum pick up
system.
Creasability Determine creasing quality of board.
Stiffness of board Degree of resistance offered by paper or board when it is bent.
Ink absorbancy Determine the absorbing power of ink.
 QUALITY CONTROL TESTS OF CARTON
Compression Assess the strength of an erected package.
Carton opening force To hold the carton flat as delivered, and open its creases between
thumb and first finger press.

Coefficient of friction Both static and kinetic coefficients of friction are determined by
sliding the specimen over itself under specific test conditions.

Crease stiffness Test a carton board piece, fold it through 90⁰. It will then try to
recover to its original after the bending force is removed.

Joint shear strength Test the glued lap seam on the side of a carton for the strength of
the adhesive using tensile testing machine.
THANK YOU