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Manufacturing and Evaluation


Manufacture of pharmaceutical aerosols

Pressure filling apparatus


Figure 5. Pressure burettes for laboratory filling of aerosol 2


• It consists of a pressure burette which helps in metered filling
of liquefied gas in to the aerosol container under pressure, an
inlet valve is present at the bottom of the pressure burette,
which incorporates the propellant into the container and
flows with its own vapour pressure in the container.

• The trapped air escapes out from the top valve.
• The propellant which are having low pressure stop flowing as

the pressure of burette and container becomes equal.
• If further propellant is to be added, a hose(rubber pipe)

leading to the nitrogen cylinder is attached to the upper valve
and the added nitrogen pressure causes the flow of the
propellant into the container. 3


• Otherwise compressed air is provided on the upper

wall of the container for further addition of propellant.

another device which consists of piston arrangement

can also be used for pressure filling.

• This device helps in always maintaining positive

pressure. This type of device cannot be used for filling

inhalation aerosols which have metered valves. 4



• It is a slow method compared to cold filling method.

But with the latest developments, the production rate

has been greatly increased. This method involves filling

of the concentrate into the container at the room

temperature. Then the valve is placed in the container

and crimped. Through the opening of the valve the

propellant are added. 5


• Since the opening of the valve are smaller in size
ranging from 0.018-0.030 inches, it limits the
production and the process becomes slow.

• But with the use of rotary filling machines and new
filling heads where the propellants are filled through
valve stem, the production rate is increased.

• The trapped air in the container and air present in head
space is removed before filling the propellant.

• This is done so as to protect the products from getting
adversely affected. 6


Cold filling apparatus:

Fig 6. Apparatus for cold filling process 7


Cold filling apparatus

• simpler compared to pressure filling apparatus.

• consist of an insulated box in which copper tubings are


• The tubings are coiled to increase the area for cooling.

Before operating , the insulated box should be filled with

dry ice or acetone.

• The apparatus can be operated with or without metered

valves. 8


• Hydrocarbon propellant cannot be filled using this

apparatus because large amount of propellant

escapes out and vaporizes. This may lead to

formation of an explosive mixture at the floor level.

• Fluorocarbons do not form any explosive mixture

although their vapours are heavier than air. 9


Non aqueous products and products which can

withstand low temperature that is -40ºF are used in
this method.

The product concentrate are chilled to a temperature
of -40ºF and filled into already chilled container.

Then the chilled propellant is added completely in 1-2

The filling of propellant depends upon the amount of
propellant is used. 10


• Another method is to chill both the product concentrate and

propellant in a separate pressure vessel and then filling them into

the container.

• The valve is placed and crimped on the container. Then test for

leakage and strength of container is carried out by passing

container into a heated water bath, where the contents of the

container get heated to 130ºF. After this, they are air dried, and the

caps are placed on the container and labeled. 11


Cold filling method v/s Pressure filling method




• some suspension, emulsion and solutions Cannot be chilled
•Propellant loss
•Pressure fill method is preferred to cold method because less
danger contamination of product with moisture, high production
speeds can be achieved now a days, less propellant is lost, method is
not limited except for some metered valve 12


Compressed gas filling
• The filling of compressed gas does not require any large

equipments and can be easily done in the lab.

• To reduce the pressure of compressed gas (high pressure), a

pressure reducing valve is required.

• The apparatus consists of delivery gauge.

• A flexible hose pipe which can withstand high gauge pressure

that is 150 pounds per square inch is attached to the delivery

gauge along with the filling head.

• A flow indicator is also present in specialized equipments. 13


Compressed gas filling
• Since the compressed gases are under high pressure, pressure

reducing valve is required.

• To use this equipment for filling aerosol with compressed
gases, the concentrate is placed in container, the valve is
crimped in place, and the air is evacuated by mean of vacuum

• The filling head is inserted into the valve opening, the valve is
depressed, and the gas is allowed to flow into container.

• When pressure within container is equal to delivery pressure,
the gases stop flowing.

• To obtain maximum solubility in gas product, the container is
shaken manually during and after the filling operation. 14


Evaluation of components



• Vapour pressure is determined and compared to specifications.


• Density


• Gas chromatography – for identification of the propellants and when
the blend of the propellants is used, to determine the composition.


• Purity and acceptability propellant is determined by moisture,
halogen and non volatile residue determination. 15




• Valves are sampled according to standard procedure.

• The following three test solutions were proposed to rule out
variation in the valve delivery brought about by different

Test solution A

% w/w

Isopropyl myristate 0.10

Dichlorodifluoromethane 49.95

Dichlorotetrafluoroethane 49.95

Specific gravity at 25˚C = 1.384 16



Test solution B

% w/w

Isopropyl myristate 0.10

Alcohol USP 49.9

Dichlorodifluoromethane 25.00

Dichlorotetrafluoroethane 25.00

Specific gravity at 25˚C = 1.092

Test solution C

% w/w

Isopropyl myristate 0.10

Trichloromonofluoromethane 24.9

Dichlorodifluoromethane 50.25

Dichlorotetrafluoroethane 24.75

Specific gravity at 25˚C = 1.388 17


Testing Procedure for valve acceptance:
25 valves are selected and placed on containers which are

previously filled with test solution.
Containers are allowed to attain temp. of 25 0C
Valves are actuated to the fullest extent for 2 sec. following

complete dispensing of single delivery.
Procedure is repeated for 10 times.
Test unit is weighed.
Then valve is actuated to the fullest extent for 2sec. following

complete dispensing of single delivery.
The test unit is reweighed.
Difference between weights represents the delivery amount.
The test procedure is repeated for a total of two individual

deliveries for each of the 25 test units.
Valve delivery per actuation = individual delivery weight /

specific gravity 18


• Valve acceptance:

For valve delivering

• 54 µL or less, the limit are ±15%

• 55 to 200 µL, the limit are ±10%

1. Of the 50 individual deliveries, if four or more are outside the limit
for the specified valve delivery, the valve is rejected.

2. If three individual deliveries are outside the limits another 25
valves are sampled, and the test is repeated. The lot is rejected if
more than one delivery is outside the specifications.

3. If two deliveries from the valve are beyond the limits, another 25
valve should be taken. The lot is accepted if NMT one delivery is
outside the specification 19



Coated and uncoated containers must be examined for lining.

Degree of conductivity of electric current as a measure of exposed


Glass containers examined for flaws

Weight of the bottle also determined

Dimensions of neck and other parts are checked to determine

conformity to specifications. 20


• Weight checking
Tared container is filled on filling line to determine

weight of propellant added.
This also give the accuracy of filling operation.
• Leak testing
Measure crimp dimensions and ensure that they

meet specifications.
Leak and efficiency of valves is measured by

transferring containers in water bath and temp.
of bath are recorded. 21


• Spray testing

Aerosols are tested for spray to clear the dip

tube of pure propellant and to check for

defects in the valve and the spray pattern. 22


Evaluation of formulation

• A. Flammability and combustibility

a) Flash point

b) Flame extension



• B. Physicochemical characteristic

a) Vapour pressure

b) Density

c) Moisture content

d) Identification of propellant
e) Concentrate-propellant ratio 23


• Performance
a) Aerosol valve discharge rate
b) Spray pattern
c) Dosage with metered valve
d) Net content
e) Particle size determination
f) Leakage
g) Foam stability

• D. Biological tests 24


A. Flammability and combustibility
Flame Projection

This test indicates the effect of an aerosol formulation on the

extension of an open flame.

Product is sprayed for 4 sec. into flame.

Depending on the nature of formulation, the flame is

extended, and exact length was measured with ruler. 25


Flash point
• Determined by using standard Tag Open Cup Apparatus.
Step involves are 
• Aerosol product is chilled to temperature of – 25 0F and
transferred to the test apparatus.
• Temperature of test liquid increased slowly and the
temperature at which the vapors ignite is taken a flash point.
• Results are of limited value because flash obtained is
calculated for most flammable component, which in case of
topical hydrocarbons. 26


Vapor pressure

•To determine pressure variation from container to


•Determined by pressure gauge

•Variation in pressure indicates the presence of air in


•A can punctuating device is available for accurately

measuring vapor pressure. 27


Determined by hydrometer or a pycnometer.
This method is used for non aerosol, modified to
accommodate liquefied gas preparation.
Step involved are 
•A pressure tube is fitted with metal fingers and hoke
valve, which allow for the introduction of liquids
under pressure.
•The hydrometer is placed in to the glass pressure
•Sufficient sample is introduced through the valve to
cause the hydrometer to rise half way up the length of
the tube.
•The density can be read directly. 28


Moisture content

Method used — Karl Fischer method

G. C has also been used

Identification of propellants


 I.R spectrophotometry used to identify propellants. 29


• Aerosol valve discharge rate
Determined by taking an aerosol of known weight and
discharging the contents for given time using standard
By reweighing the container after time limit has expired,
the change in weight per time dispensed is discharge rate,
expressed as gram per seconds. 30


Spray pattern
• The method is based on the impingement of spray on piece of

paper that has treated with Dye-Talc mixture.

• Depending upon nature of aerosol, an oil soluble
or water soluble dye is used.

• The particles that strikes to paper cause dye to go
into solution and to be absorbed onto the paper.

• This gives record of spray. 31


Dosage with metered valves
Points considered are –
Reproducibility of dosage each time the valve is
Amt. of medication actually received by the patient.
Reproducibility has been determined by assay
Another method is involves accurate weighing of
filled container followed by dispensing of several
doses, container can reweighed, and difference in
weight divided by No. of dose, gives the average
dosage. 32


Net contents

•Weight method

Weight of empty container =W1 gm

Weight of the filled container = W2gm

Difference in the weight = W2-W1gm, gives net content.

Destructive method: weight the full filled container,

dispensing the content and then contents are weighed. 33


• Foam stability

• The life of foam can range from a few seconds to one
hour or more depending on the formulation

• Foam stability determined by

• Visual evaluation

• Time for a given mass to penetrate the foam

• Times for given rod that is inserted into the
foam to fall

• The use of rotational viscometers 34


Particle size determination
Cascade impactor
Light scatter decay method
Cascade impactor
•Operates on the principle that if a
stream of particles projected through a
series of nozzles and glass slides at
high velocity, larger particles became
impacted first on the lower velocity
stages and the smaller particles pass on
and are collected at higher velocity
•Particle size = 0.1 to 30 µ. Useful for
sampling of aerosols used in
respiratory tract.
Modification made to improve efficacy 35


Porush, Thiel and Young used light scattering method to

determine particle size.

As aerosols settle in turbulent condition , the change in light

intensity of Tyndall beam is measured


Sciarra and Cutie developed method based on practical

size distribution. 36


Biological tests
• Include a consideration of therapeutic activity and toxicity.

• Therapeutic activity:

• Therapeutic activity is determined by procedures similar to non

aerosols with exception of consideration given to aerosol


• The dosage of the product has to be determined for inhalation

aerosols and this must be related to the particle size distribution.

• Topical preparations are applied to the test areas and adsorption

of the therapeutic ingredients can be determined 37


• Toxicity:
• Should be studied for both topical and inhalation aerosols
• Aerosol applied topically may be irritating to the affected

area and or may cause chilling effect depending upon type
and amount of propellant present.

• When the skin is sprayed with an aerosol for a given period
of time, the change in the skin temperature was observed .

• This change in temperature is mainly determined by the
use of thermistor probes attached to recording

• Inhalation toxicity can also be determined by exposing the
test animals to vapors sprayed from an aerosol container. 38


Marketed Preparations:



Glaxo Smithkline 39


• Attention and research has been devoted to drug delivery via lungs

• Tremendous mass transfer

• Oral dosage forms are preferred but lack bioavailability

• Parenteral products are least preferred by patients but have highest


• Aerosol delivery of drug via lung can provide benefits of both without

• Research efforts continue to provide opportunities for new patient friendly
treatments using MDI’s despite challenges 40


Spray patterns:

• The method is based on the impingement of the spray
on a piece of paper that has been treated with a dye-
talc mixture.

• An oil soluble or water soluble dye is used depending
on the nature of the aerosol.

• The particles that strike the paper cause the dye to go
into the solution and to be absorbed onto the paper.

• This gives a record of the spray, which can be used for
the comparison purposes.

• To control the amount of material coming into contact
with the paper, the paper is attached to a rotating disk
that has an adjustable slit. 41


Spray Pattern:


Figure 15. Spray pattern testing 42


Cascade Impactor :


Figure 1w6w. wC.DauslocMadixe.c oimmpactor 43


Remaining points.

• Recent advances,
• objectives of therapeutic aerosols, 44