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Pharma Tech V:

Chapter 5
Aerosols

Syllabus: Pharmaceutical Aerosols:

Definition, propellants, general formulation,
manufacturing and packaging methods,
pharmaceutical applications.

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Defination:
1) An aerosol is defined as a colloidal system of solid or liquid particles in a gas.
2) A system that depends on the power of a compressed or liquefied gas to expel the
contents from the container.
3) An aerosol is a pressurized dosage form containing one or more therapeutic active
ingredients which upon actuation emit a fine dispersion of liquid and/or solid
materials in a gaseous medium of size smaller than 50 μm.
Advantages of aerosols:
1) Stability can be enhanced for those substances adversely affected by atmospheric oxygen
or moisture.
2) A specific amount of dose or drug can be removed from the container without
contamination of remaining contents.
3) The onset of action is faster compared to other dosage forms because the medicament is
directly applied to the affected area part.
4) Required quantity of contents can be easily withdrawn from the package without
contamination or exposure of the remaining material.
5) Irritation can be reduced by application of topical aerosol medication in a uniform thin
layer to the skin without touching the affected area.
6) Sterility can be for sterile product, because no microorganism can enter even when the
valve is opened.
Disadvantages of aerosols:
 If the drug is not soluble in the propellant, aerosol the formulation is difficult.
 Sometimes propellants may cause toxic reactions, if therapy is continued for a long
period of time.
 High cost
 Aerosol packs must away from temperature and fire, because it may develop high
pressure inside the container leads to explosion.
 Components of Aerosol packaging:
1) Propellant
2) Product Concentrates

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3) Container
4) Valve and Actuator

1) Propellants:
Propellants are responsible for developing the pressure in the aerosol container and also it expel
the product from the container when the valve is opened and helps in expels the product.
Types of propellant:
 Depending on use of propellants, the propellant can be classified as
1) For oral and inhalation (Fluorinated hydrocarbons), Examples
Tri-chloro-mono-flouro methane (propellant 11)
Di-chloro di-fluro methane (propellant 12)
Di-chloro tetra-fluro ethane (propellant 114)
2) Topical Pharmaceutical aerosols (Hydrocarbon propellants), Examples
Propane
Butane
Isobutane
 Depending on Physical Nature of propellants, the propellant can be classified as
I) Liquified Gas Propellants, Example,
Tri-chloro-mono-flouro methane (propellant 11)
Di-chloro di-fluro methane (propellant 12)
Di-chloro tetra-fluro ethane (propellant 114)
II) Compressed Gas Propellants. Example,
Nitrogen
Carbon dioxide
Nitrous oxide
CHLOROFLUOROCARBON (CFC) PROPELLANTS
The CFCs are gases at room temperature that can be liquefied by cooling them below their
boiling point or by compressing them at room temperature. For example,
dichlorodifluoromethane (P-12) will form a liquid (when cooled to - 21.6ºF or compressed to
84.9 psia at 70ºF) (psia = pounds per square inch).

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The basic characteristics of propellants are chemically inert, free from toxicity, inflammability
and explosiveness. Due to these characteristics, the chlorofluorocarbon (CFC) propellants P-11,
P-12 and P-114 etc., are using in aerosol products from several years. Now-a-days their usage is
reduced, as they cause the depletion of ozone layer. They are still use in small quantities in the
treatment of asthma and chronic obstructive pulmonary disease (COPD). P-11, P-12 and P-114
etc. are the CFCs suitable for oral, nasal and inhalation aerosols. P-134a and P-227 are now been
developed and are being incorporated in aerosol formulations in place of P-12.
NOMENCLATURE OF PROPELLANTS:
The numerical designations for fluorinated hydrocarbons propellants have been designed so the
chemical structure of the compound can be determined from the number given to the propellant.
The system consists of three digits. For Example: Propellant 114.
 The digit at the complete right (i.e. 4 in example propellant 114) refers to the number of
fluorine atoms in the molecule.
 The second digit from the right (i.e. the middle one, as 1 in example propellant 114), represents
one greater in the number of hydrogen atoms (means, 1 + 1 = 2 hydrogen atoms) in the
molecule.
 The third digit from the right indicates the type of propellant.
For 0 it is methane i.e. 1 carbon atom
For 1 it is ethane i.e. 2 carbon atoms
For 2 it is propane i.e. 3 carbon atoms
For 3 it is butane i.e. 4 carbon atoms
For 4 it is pentane i.e. 5 carbon atoms
For 5 it is hexane i.e. 6 carbon atoms and so on
 The number of chlorine atoms in a molecule determined by subtracting the total number of
hydrogen and fluorine atoms from the total number of atoms required to saturate the
compound.
Hence, the propellant 114 has
4 fluorine atoms, (1 + 1 more as per above rule) 2 hydrogen atoms, 2 carbon atoms, is of
ethane category, and have (8-6 =2) 2 chlorine atoms.

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Hence propellant 114 is named as, dichlorotetrafluoroethane.

Propellant 12, has only 2 digits. In order to make it 3 digits number, we can call propellant 12 as
propellant 012. Now it has three digits
Propellant 012, as per above nomenclature rules,
Has 2 fluorine atoms, (1 + 1 more as per above rule) i.e. 2 hydrogen atoms, 0 means is of
methane category means have 1 carbon atom, and have (5-3 = 2) 2 chlorine atoms.
Hence its name is dichlorodifluoromethane.

APPLICATIONS OF PHYSICAL GAS LAWS:

Gas molecules follow in random paths and collide with each other and the walls of the container.
These collisions of gas molecules exert a pressure per unit area.
If more than one propellant is mixed in a single container, then total vapour pressure of mixtures
of propellants can be calculated according to "Dalton's Law" and "Raoult's Law".

Dalton's Law: Total vapour pressure in any system is equal to the sum of the individual
pressures of the various components.
P = P1 + P2 + P3

Raoults Law:
Pa = (Na / Na + Nb) PAo
Pb = (Nb / Nb + Na) PBo
Where: Pa = partial vapour pressure of propellant A
PAo = vapour pressure of pure propellant A
Na = moles of propellant A
Nb = moles of propellant B
Pb = partial vapour pressure of propellant B
PBo = vapour pressure of pure propellant B

Total pressure is calculated as sum of their partial pressures

P = Pa + Pb

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Numerical:
Calculate the Total Vapour pressure of combination of propellant 12 and propellant 11, given in
ratio of 30:70 respectively. Given that molecular weight of propellant 12 is 120.93 and propellant
11 is 137.38. It is also given that partial vapor pressure of pure propellant 12 and 11 are 84.9 and
13.4 respectively.
Solution:

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2) Product Concentrate:
The product concentrate is the active ingredient of the aerosol which is combined with the
required adjuncts like,

 The Active drug (for therapeutic activity)

 Propellant/s (to expel the contents from the container)

 Antioxidants (to prevent degradation of product)

 Surface active agents/ Surfactants (to Increase Miscibility)

 Solvents (to prepare a stable and efficacious product and to retard the evaporation of the
propellant)

 Other important excipients like Vehicles, suspending agents etc.

3) Aerosol Containers:
They must withstand at pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at
1300 F. The glass or metal containers are generally used. Choice of the material for aerosol
container depends upon
 Pressure of the system,
 Nature of product i.e. aqueous or not,
 pH of the product,
 Physicochemical properties of preparation.

Different types of materials for aerosol containers are:

1) Metals
- Tin plated steel (Side-seam or Three, Two piece or Drawn, Tin-free steel)
- Aluminum
- Stainless steel
2) Glass
- Uncoated glass
- Plastic coated glass
3) Plastics

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1) Metals
 Tinplated steel:
It is used for most aerosols as it is light inexpensive and durable. It is steel that has been plated
on both sides with tin.

Tin plated steel containers are of two types-

(a) Two pieces container body.
(b) Three piece container body.
Oleoresin, phenolic, vinyl, or epoxy coatings are used as the coating materials in order to prevent
from corrosion. The tin plated steel containers are used in topical aerosols.
Advantages:

 The aerosol cylinders provide a sealed unit.

 Special protective coatings are applied within the container to prevent corrosion and
interaction between the container and formulation if necessary.
Disadvantage:

 For small sized container only.

 Leak of container due to flaws in the seam or welding.

 Corrosion within some preparations.

 Aluminium:
The aluminium containers are light weight and are less prone to corrosion than other metals.
Aluminium is used in most metered dose inhalers (MDIs) and many topical aerosols. Epoxy,
vinyl, or phenolic resins coatings are done on aluminium containers to reduce the interaction
between the aluminium and the formulation. The container made up from aluminium available in
different sizes ranging from 10 ml to 1,000 ml.
Advantages:

 These are manufactured by extrusion or by any other methods that make them flawless.

 Against leakage the seam type of container is of greater safety.

 No incompatibility.

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 No corrosion
Disadvantages:

 High cost.

 Stainless steel:
Advantages:

 It is resistant to corrosion.

 No coating is required.

 It can withstand high pressure.

Disadvantages:

 Expensive.

 Which restricts its sizes to small sized containers

2) Glass:
One of the materials is glass, limited usage because of its brittleness (Easy to break). Glass
disadvantage is brittleness (easy to break), so restricted usage of glass. However, if the pressure
is less than 25 psig and propellant content is less than 15% then glass can be used. If pressure
further increased, then in order to maintain the glass stable at that pressure, It should be coated
with plastic coating in two layers if pressure is less than or equal to 33 psig. For linings Epoxy
resins can be used, as they are resistant to steam. They are mainly used for some topical and MDI
(metered dose inhalers) aerosols.
Advantages:

 Glass has less chemical compatibility than metal containers.

 No corrosion.

 Glass can be molded to different design.

Disadvantages:

 More chances for accidental breakage.

 Not suitable for photosensitive preparations.

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3) Plastic:
Plastics are more permeable to vapours and atmospheric air (like oxygen), so it may interact with
the formulation and also may lead to oxidative degradation of the formulation. Polyethylene tetra
phthalate (PET) container as used for some non pharmaceutical products.
Advantages:

 Cheap.

 Malleable and ductile.

 Easy to mold.
Disadvantages:

 Incompatibility between drug- plastic and may lose its efficiency and potency.

Container Material Max. Pressure (psig) Temperature (0F)

Tin plated steel 180 130
Aluminum 180 130
Stainless steel 180 130
Un Coated glass <18 70
Coated glass <25 70
Plastic <25 70

4) VALVE AND ACTUATORS:

VALVES:
Valves deliver the drug in desired form and regulate the flow of product concentrate from the
container. The valve should be able to withstand the pressure encountered by product concentrate
and the container, should also be corrosion resistant.
There are two types of valves are available a) Continuous spray valve and b) Metering valve.
a) Continuous spray valves: To deliver the contents in spray or foam or solid stream
continuously with or without measuring its amount. These types of valves are used for all types
of pharmaceutical aerosols.
b) Metering valves: For potent medication where exact amount of medicament will be
dispensed at one time application, metering valves are used.

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Valve Assembly:

Valve Assembly and its components:

1. Actuator
2. Valve stem
3. Gasket
4. Valve Spring
5. Ferrule/Mounting cup/Valve cup
6. Valve Body/ Housing
7. Dip tube

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1. Actuators:
 It ensures that aerosol product is delivered in the proper and desired form.
 It allows easy opening and closing the valve.
 The actuator which is fitted to the aerosol valve stem is a device which on depression opens
the valve and directs the spray to the desired area.
 A proportion of the active ingredient is usually deposited on the inner surface of the actuator
and the amount available is less than the amount released by actuation of the valve.
 Following types of actuators available.
a) Spray actuators: These are having capable of dispersing the stream of product concentrate
and propellant into relatively small particles by allowing the stream to pass through various
openings 0.016 to 0.040 inches. It breaks stream into fine particles. These actuators used for
topical use such as spray-on bandages, antiseptics, local anesthetics and foot preparations.
b) Foam actuators: It consists of relatively large orifices ranges from 0.070 to 0.125 inches.
c) Solid steam actuators: Similar to foam type of actuators. Used for semisolid products like
ointments.
d) Special/ Mist actuators: These are designed for special purpose, to deliver the contents of
medicaments at site of action like throat, eye or vaginal tract.

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2. Valve Stem: The actuator is supported by the stem and the formulation is delivered in the
proper form to the chamber of the actuator by the stem. It is made up of Nylon, Delrin,
Brass and Stainless steel.
3. Gasket: The stem and valve are placed tightly in their place with the help of gasket and
the leakage of the formulation is prevented by using gasket. It is made up of Buna N and
Neoprene rubber.
4. Spring: The gasket of aerosol container is held in its place by the spring and also helps to
keep the valve in closed position when the pressure is released upon actuation of the
formulation.
5. Mounting Cup or Ferrule: The Mounting cup or Ferrule is generally made up of
aluminum which serves to place the valve in its position and then attached to the aerosol
container. So the underside of the mounting cup/ Ferrule is exposed to the contents of the
container. So it is to be compatible with the contents to prevent interactions. It may be
coated with an inert material such as vinyl coating as it prevents any interaction,
corrosion of aluminum can also be prevented by coating.
6. Housing or Valve body: The Housing or Valve body located directly below the
Mounting cup or Ferrule is made up of Nylon or Delrin, which uses to connect dip tube,
stem and actuator of aerosol container. The size of orifice will determine the rate of
delivery of product and the desired form in which the product is to be emitted. (Size is
0.013 to 0.080 inches).
7. Dip Tube: The dip tube is made up of polyethylene or polypropylene extends from the
housing body or valve body down into the product concentrate works to bring the
formulation from the container to the valve. The inner diameter of the dip tube depends
on the viscosity and the desired rate of delivery of the product. The inner diameter of the
dip tube increases with an increase in the viscosity of the formulation. For less viscous
solutions the inner diameter ranges from 0.12 inch to 0.125 inch. For viscous solutions
the inner diameter is 0.195 inch.
Generally the actuator, stem, housing and dip tube are made up of plastic. The mounting cup and
spring made up of metal. The gasket made up of rubber or plastic resistant to the formulation.

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FORMULATION OF AEROSOLS:
Different types of aerosols are available in market. Depending upon the type of aerosols its
formulation and ingredient used vary. Let us discuss different types of aerosols and their
formulations.

Types of Aerosol System

1) Solution system / Two Phase system

2) Water based system / Two components or Three components system
3) Suspension / Dispersion system
4) Foam system / Emulsion systems
5) Aqueous stable foams
6) Non-Aqueous stable foams
7) Quick Breaking foams
8) Thermal Foams
9) Intra Nasal Aerosols
10) Compressed Gas Systems

1) Solution system / Two Phase system: (Vapour + Liquid phase)

The two phase / solution system is comprised of the liquid phase containing the liquefied
propellant/s, product concentrate and the vapour phase.
 This type of system employed when the product is soluble in the propellant or no other solvent
required to dissolve the solid or liquid which using for formulation.
 Depending upon type of spray required, the propellant may consists of propellant 12 or A-70
(for very fine particles).
 Reduced vapor pressure can also be produced through the addition of less volatile solvents
such as ethyl alcohol, propylene glycol, ethyl acetate glycerin and acetone.
 The amount of propellant may vary from 5% to 95% depending upon use of aerosols.
 Containers- Metal for Oral /inhalation aerosols, Stainless steel, Aluminum, Glass for
Inhalation or Local activity and Plastic coated glass bottle for Topical aerosols.

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2) Water based system / Two or Three components system:

(Propellant + Water + Vapour phase)
 This system is composed of a layer of water immiscible liquid propellant, highly aqueous
product concentrate and the vapor phase. This type of system employed when the product is
immiscible with the propellant.
 This system emits the contents as spray or foam. Spray is dispersion of active ingredient and
other solvents in an emulsion system, in this emulsion system propellant as external phase.
 Due to immiscibility of the water and propellant, it forms a three phase aerosol.
 Ethanol used as a cosolvent to solubilize propellant in the water.
 Ester forms between the glycol, glycerol and poly hydroxylic acids can be used as surfactants.
The surfactants composition can be between 0.5 - 2.0.
 The recent advancement in water based system is the aquasol valve. In aquasol valve the drug
is dissolved in the water or the mixture of water and alcohol. The propellant layer is exists on
the top water layer. The solubility of the propellant is increases as the amount of alcohol
increases and it will become completely soluble (if only alcohol is present).

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3) Suspension / Dispersion system:

 In dispersion system, in the propellant or the mixture of propellants, the drug particles are
suspended.
 When the substances are immiscible.
 To reduce settling rate surfactants, suspending agents and lubricants added in 0.01 - 1%
concentration.
 Sometimes for certain substances agglomerates may form, if the number of agglomerates
increases leads to caking.
 As the temperature increases caking will increase. At extreme conditions, the particles will get
attached to the walls of container.
Hence, to increase the physical stability of aerosol dispersion and to get rid of all above
problems:
 1. Moisture content must be controlled.
 2. The particles should have less solubility with propellant.
 3. Use of Dispersing/ suspending agents.
 4. By decreasing the density difference between propellant and suspending agent.
 5. The particle size should be maintained less than 5 μm.

Example:

Ingredients Concentration (% W/W)

Epinephrine bitartrate 0.50
Sorbitan trioleate 0.50
Propellant 114 49.50
Propellant 12 49.50

4) Foam system / Emulsion systems:

 Emulsion or foam aerosols consist of Active ingredient + Aqueous or Non aqueous vehicle +
Surfactant + and propellant (Hydrocarbon or compressed gases).
 Here the propellant which is present in the liquid acts as internal phase.
 They are further divided into two types:

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A) Aqueous stable foams:

 This system consists of propellant in the range of 8 to 10% v/v.
 Both Hydrocarbon and Compressed gases used as propellants.
 This is generally used for steroids and antibiotics.
 As the concentration of A-70, A-46 propellant increases, it results drier spray. And as the
concentration of propellant decreases, wetter spray is produced.

B) Non-Aqueous stable foams:

 These non-aqueous stable foams of aerosols are formulated with the use of different glycols
like PEG and esters of glycols (propylene glycol monostearate) as emulsifying agents. No use
of water here.

5) Quick Breaking foams:

 Here propellant is the external phase.
 These can be applied to small area or larger surface topical medication without mechanical
application.
 Here Cationic or anionic or non-ionic types of surfactants are used in the formulation. It
should soluble in both alcohol and water.
 This is pressurized by mixing of 90% concentrate and 10% propellant.

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6) Thermal Foams:
 Generally thermal foams used when the warmness is required.
 To produce warm foam for shaving.
 Not readily accepted by the consumer, so discontinued due to expense and lack of
effectiveness.
7) Intra Nasal Aerosols:
 Drug delivery systems intended for medication into nasal pathways for effectiveness to
produce therapeutic effects.
 The design of the adaptor varies from the inhalation aerosols. To produce smaller particles, the
adaptors will be of less height and narrow.
 These are free from contamination, very less quantity of drug moves into the lungs, the
mucosal irritation will be reduced.

 Manufacturing of Aerosols:
Manufacturing of aerosols are done at two stages.

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The manufactured aerosols can be filled in to the containers, can be done by following methods:

a) Cold filling Apparatus

b) Pressure filling apparatus

c) Compressed gas filling apparatus

d) Rotary filling machine

a) Cold filling apparatus: Cold filling apparatus consists of an insulated box which fitted with
copper tubing’s and filled with dry ice or acetone. The fitted copper tubings increase the surface
area and cause faster cooling. The hydrocarbon propellant is not to be stored in the copper
tubings as it might cause explosion.

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b) Pressure filling apparatus:: Pressure filling apparatus consists of a metering burette capable
of measuring the amount of propellant to be filled to the container. The propellants are added
through the inlet valve present to the bottom of the valve under its own vapour pressure. A
cylinder of nitrogen or compressed gas is attached to the top of the valve and the pressure of
nitrogen causes the propellant to flow to the container through the metering burette. The
propellant flows to the container stops when the pressure of the flowing propellant becomes
equal to the pressure of the container.

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c) Compressed gas filling apparatus: Here compressed gas is used. As the compressed gas is
under high pressure, so the pressure is reduced by pressure reducing valve. A pressure of 150
pounds per square inch gauge (psig) is required to fill the compressed gas propellant in the
aerosol container. Here, when the compressed gases are used as the propellant in aerosol
systems, the compressed gas is transferred from large steel cylinders into the aerosol containers.
Before filling, the product concentrate is placed in the container, then the valve assembly is
moved into place and the air is removed from the container by a vacuum pump.

The compressed gas is then passed into the container through a pressure reducing valve attached
to the gas cylinder; when the pressure within the aerosol container is equal to the predetermined
value, then it stops gas flow and the aerosol valve is restored to the closed position. Some gases
like carbon dioxide and nitrous oxide (which are slightly soluble in the product concentrate) can
be used. The container is manually or mechanically shaken during the filling operation to
achieve the desired pressure in the head space of the aerosol container.

For large scale of production Concentrate filler, Valve placer, Purger and vacuum crimper,
Pressure filler, Leak test tank equipments are used.

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d) Cold filling method: The aerosol product is filled into the container is by two methods:
 In the first method, the product concentrates are chilled to a temperature of - 30 to - 400 F. The
chilled product concentrates are added to the chilled aerosol container. The chilled propellant
is added through an inlet valve present under side of the valve of the aerosol container.
 In the second method, both the product concentrate and the propellant are chilled from- 30 to
-40 0F. Then the mixture is added to the chilled container.
In both the above methods, after the aerosol containers are filled, the valves are set in its place
and the filled aerosol containers are passed through a water bath in which the contents of the
containers are heated to 130 0F to test for leaks and strength. After checking the containers, apply
air drying, cap it and label it.
The pressure filling method is more prominent than cold filling method as most of the
formulations cannot be cooled to very low temperatures.

Advantages of the pressure filling methods compared with cold filling method:

 The emulsions or suspensions are unstable at very low temperature. At that time the pressure
filling method is the preferred method then that of cold filling method.
 Here the absence of moisture reduces the chance of contamination.
 The rate of production is high.

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 Propellant loss is low.

Rotary filling machine: The pressure filling method is first slower than cold filling method.
With the development of newer technique the speed of pressure filling method was increased.
The concentrate is added to the container at room temperature, and the valve is moved in place.
The propellant is added through the valve. Since the vacuum contains extremely small openings
(0.018 to 0.030 inches), this step is slow and limits production.

Packaging, Labeling and Storage of Aerosols:

 A unique aspect of pharmaceutical aerosols compared to other dosage forms is that the product
is actually packaged as part of the manufacturing process.
 Most aerosol products have a protective cap or cover that fits tightly over the valve and
mounting cup. This mounting cap protects the valve against contamination with dust and dirt.
The mounting cap, which is generally made of plastic or metal and also serves for decorative
function.
 Aerosols containers should be maintained with the protective caps in place to prevent
accidental activation of the valve assembly or contamination by dust and other foreign
contents or atmospheric contents.
 Therapeutic aerosols that are to be dispensed only with prescription and generally labeled by
the manufacturer with plastic peel-away labels or easily removed paper labels, so that the
pharmacist easily replace the manufacturer's label.
 Safety and precaution labels must warn users not to puncture pressurized containers and not to
use or store them near heat/temperature or an open flame and not to incinerate them.

 Exposure to temperatures above 49ºC (120ºF) may burst an aerosol container.

 Storage: Aerosol products are generally recommended for storage between 15ºC and 30ºC
(59ºF and 86ºF).

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 Page 24 of 32

Typical label of Aerosols Contains the following information:

LABEL INFORMATION COMMENT

AIR FRESHENER 300ML

This tells you what the product is, and how much
OR
is in the container.
PRODUCT 'X' 200ml

This tells you that this section of the label

SAFETY INFORMATION
contains the safety information.

This is because the product may taint food, might

Do not spray or use directly onto food
stain fabrics, or may affect the appearance of
preparation surfaces, fabrics, or polished surfaces
polished surfaces.

Do not spray on or near naked flames, including This will reflect that the product has a
cooker pilot lights and fires 'flammable' classification.

Don't use on floors, the inside of baths or shower This is often seen on aerosol polishes, and is a
trays, as the high gloss could be dangerous good example of safety information.

This section contains statutory and other

CAUTION
recommended wording.

Use formulation only as directed. Intentional

This is a BAMA recommendation, and has been
misuse by inhaling the contents can be harmful
superseded by:-
or fatal.

This is a statutory requirement.

This tells you that the contents of the container
Pressurized container
are under pressure, and the aerosol is different
from other packages.

This is a statutory requirement. During manu-

Protect from sun light and do not expose to
facture aerosols are tested at 50degC, however if
temperatures exceeding 50degC. Do not pierce or
exposed to higher temperatures there is a risk that
burn after use.
the container may eventually burst.

Don't use spray on a naked flame, onto or near This is a legal requirement.
fire, or any incandescent material.

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 Page 25 of 32

Keep away from sources of ignition - No

smoking

Flammable or
Extremely flammable or together with a flame This is a legal requirement, and reflects the
symbol or flammability classification of the product.
X% by mass of the contents are flammable

KEEP OUT OF REACH OF CHILDREN A legal requirement.

 Evaluation of Aerosols:
1) Flammability and Combustibility
A) Flame Projection and flash back
B) Flash Point
2) Physico - Chemical Characteristics
A) Vapour Pressure
B) Density
C) Moisture Content
D) Identification of Propellant
E) Concentrate - Propellant ratio
3) Performance Test
A) Aerosol Valve Discharge Rate
B) Spray Patterns
C) Dose Uniformity / Dosage Testing with Metered valves
D) Net Contents
E) Foam stability
F) Particle Size determination
G) Leakage Test
4) Biological Testing
A) Therapeutic Activity
B) Toxicity
C) Extractable substances

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 Page 26 of 32

1) Flammability and Combustibility

A) Flame Projection and flash back:
 Flame test indicates the effect of an aerosol formulation on the extension of an open flame.
 Aerosol product is sprayed for 4 sec. into open flame.
 Depending on the nature and type of formulation, the flame is extended to some length and
exact length was measured with ruler.
B) Flash Point:
"Standard Tag Open Cap Apparatus" is used for determination of flash point. For this,
formulation is chilled to temperature of -25 0F and transferred to the test apparatus. The
temperature of test sample liquid increase slowly, and the temperature at which the vapors of
propellant catch fire is taken a "flash point".

2) Physico - Chemical Characteristics

A) Vapour Pressure:
Vapour pressure is determined by pressure gauges or elaborately through use of a water bath, test
gauges and other special equipments. Variation in pressure indicates the presence of air in
headscape. For accurate measurement of vapour pressure in aerosol container can punctuating
device used.
B) Density of aerosol system:
 It is determined by hydrometer or a pycnometer.
 This method is useful for non aerosols modification to accommodate the liquefied gas
preparation.
 The hydrometer is kept in to the glass pressure tube. Some sufficient amount of sample is
added through the valve to cause the hydrometer to rise half way up the length of the tube. The
density can be read directly from the apparatus.
C) Moisture Content:
Karl Fischer method or Gas chromatography method used.
D) Identification of Propellant/s:
Gas chromatography or I.R spectrophotometry methods are used for identification of propellants
and also to indicate the proportion of the each component in a blend.

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 Page 27 of 32

E) Product Concentrate - Propellant ratio:

The proportion of the each component in a blend can be determined by Gas chromatography or
I.R spectro-photometry methods are used.

Summary of physicochemical characteristics of Aerosols:

Physico-Chemical Characteristics Equipments for measurement
Can Punching device
Vapour pressure
Pressure Gauge

Hydrometer
Density
Pycnometer

Karl Fischer method

Moisture content
Gas Chromatography

Gas Chromatography
Identification of propellant/s
IR Spectrometry

Gas Chromatography
Product concentrate and propellant ratio
IR Spectrometry

3) Performance Test
A) Aerosol Valve Discharge Rate:
It is determined by taking an aerosol with known weight and discharging the contents for given
time using standard apparatus. Again reweigh the container after discharging, the difference in
weights per time release or dispensed is discharge rate. It is expressed as gram per seconds.

B) Spray Patterns:
For this, the method involves the impingement of sprays on a piece of paper, which is treated
with dye - talc mixture. Based on the nature and type of the aerosol, an oil soluble dye or water

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 Page 28 of 32

soluble dye is used. When the particles reach the paper it causes the dye to go into solution and
to be absorbed onto the paper. It gives a record of the spray pattern.

C) Dose Uniformity / Dosage Testing with Metered valves:

It is used to determine amount of medication actually received by the patient.

It can be determined by assay technique from which amount of active ingredient can be
determined. Another method for determination of active ingredient is accurately weighing of
filled container then remove all contents by dispersing and reweigh the container can. The
difference in weight divided by Number of doses, gives the average dosage.

D) Net Contents:
It can be determined by using Destructive method and consists of weighing of a full container,
and dispensing the contents. The contents are then reweighed. The difference in weight gives the
amount of contents present in the container.

E) Foam stability:
The life of a foam ranges from a few seconds (for quick breaking foam) to one hour or more
depending on the formulation and type of foam. Foam stability is determined by using Visual
evaluation. Visual evaluation is the time for a given mass to penetrate the foam, time for given
rod that is inserted into the foam to fall.

F) Particle Size determination:

Particle size can be determined by Cascade impactor and Light scattering decay methods.

Cascade impactor:
Cascade impactor works on the projections through a series of nozzle at high velocity. First the
larger particles become impacted on the lower velocity stages and then the smaller particles
impacted at high velocity stages. The size ranges from 0.1 to 30 μm (microns).

Light scattering decay: The aerosol product settles in turbulent condition. Here, the particle size
is measured by the change in light intensity of Tyndall beam.

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 Page 29 of 32

G) Leakage Test:
Leak test is done by checking the crimping of the valve. This is accomplished by measuring the
crimp's dimension and ensuring that they meet the required specifications. Final testing of valve
closure is done by passing filled containers through water bath.

4) Biological Testing
A) Therapeutic Activity:
For Inhalation Aerosols: Therapeutic activity depends on the particle size.
For Topical Aerosols: It is determined by applying the active ingredients topically to test areas
and the amount of therapeutic active ingredients absorbed is determined.
B) Toxicity:
For Inhalation Aerosols: Inhalation toxicity is studied by exposing test animals to vapor sprayed
from Aerosol container.
For Topical Aerosols: Irritation on the skin & chilling effects are checked. When aerosol is
topically applied, thermostat is used to determine the change in skin temperature for a given
period of time.
Quality control of Pharmaceutical Aerosols:
Quality control of pharmaceutical aerosols include the testing of Testing of Propellant, Testing of
Valves, Actuators and Dip tubes, Testing of Containers, Weight checking, Leakage Test and
Spray Testing/ Spray Pattern.

1) Testing of Propellant/s:
A sample is removed from the container and vapour pressure is determined which then is
compared to specifications. The density is also checked when necessary.

Other tests include -

 Identification of two or more mixture of propellants by Gas chromatography.

 For propellant purity is checked by moisture, halogen and non-volatile residue determinations.
2) Testing of Valves, Actuators and Dip tubes:
They are sampled according to the standard procedures as found in "Military Standard Mil -
STD-105D".

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Testing procedure:
 Take 25 valves are selected and placed on suitable containers.
 The containers fill with specific test solution.
 A button actuator with 0.02 inches or larger unrestricted orifice is attached to the valves.
 The filled containers are place in a suitable atmosphere at a temperature of 25 ±1 0C.
 When the products reach the temperature of 25 ± 1 0C, the filled containers are actuated to full
extent for 2 seconds for complete dispensing of contents in a single delivery.
 This procedure is repeated for a total of 2 delivered from each 25 test units.
𝐈𝐧𝐝𝐢𝐯𝐢𝐝𝐮𝐚𝐥 𝐯𝐚𝐥𝐯𝐞 𝐩𝐫𝐨𝐝𝐮𝐜𝐭 𝐝𝐞𝐥𝐢𝐯𝐞𝐫𝐲 𝐰𝐞𝐢𝐠𝐡𝐭 (𝐢𝐧 𝐦𝐠)
Content delivery in μL = 𝐒𝐩𝐞𝐜𝐢𝐟𝐢𝐜 𝐠𝐫𝐚𝐯𝐢𝐭𝐲 𝐨𝐟 𝐓𝐞𝐬𝐭 𝐬𝐨𝐥𝐮𝐭𝐢𝐨𝐧

Delivers Limits
If 54 μL or less ±15%

If 55 μL to 200 μL ± 10%

The limits for valve acceptance:

For 50 deliveries:
 If Four or more deliveries are outside limits, then valves are rejected.
 If Three or more deliveries are outside limits and then another 25 valves are tested.
 If more than 1 delivery is outside specification, the lot is rejected.
 If Two deliveries from 1 valve are beyond limits and then another 25 valves are tested.
 The lot is accepted if not more than 1 delivery is outside specifications.

3) Testing of Containers:
 Metal containers are examined for defects in linings. Several Quality Control aspects include
specifications for degree of conductivity of electric current as measure of exposed metals.
 For Glass containers examined for Flaws.

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 Page 31 of 32

4) Weight checking:
Weight checking is done by periodically adding tared to the filling lines with tared empty aerosol
containers. This will check after filling with product concentrate are removed & re weighed.
Same procedure is used for checking weight of Propellants. It ensures proper blend of the
propellants.

8.5) Leakage Test:

Leak test is done by checking the crimping of the valve must be available to prevent defective
containers. This is accomplished by measuring the crimp's dimension and ensuring that they
meet specifications. Final testing of valve closure is done by passing filled containers through
water bath.

8.6) Spray Testing/ Spray Pattern:

It is to clear dip tube of pure propellant & pure concentrate and to check for defects in valves &
spray pattern. For metered valves, it serves to prime the valve so that it is ready for use by the
consumer.

Testing the Filled Containers:

 After filling by either of method, the aerosol container is tested under different environmental
conditions for leaks or weakness in the valve assembly or container.
 Proper functionof the valve should be tested for filled aerosol containers.
 The valve discharge rate is determined by discharging a portion of the contents of a
previously weighed aerosol during a filling period and calculating by the difference in weight
in grams of contents discharged per unit of time.
 Aerosols tested for their spray patterns for particle size distribution of the spray and for
accuracy and reproducibility of dosage when using metered valves.

Pharmaceutical Applications of aerosols:

1) Less dose required so less systemic exposure so less toxic.

2) Fast action, no decomposition of drug.

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 Page 32 of 32

3) Aerosol doses are generally smaller than systemic doses; for example: oral
albuterol is 2 to 4 mg; inhaled albuterol is 0.2 mg.
4) Systemic side effects are less frequent and less severe by inhalation route as
compared to systemic delivery (injection, oral).
5) Onset of effect with inhaled drugs is faster than with oral dosing; eg, oral
albuterol is ≤ 30 min; inhaled albuterol is ~ 5 min.
6) Since the drugs are absorbed directly into the blood stream via the lungs, there is
no decomposition or loss of drug in the gastrointestinal tract such as occurs when
the drug is administered orally.
7) Since the medication is sealed in a container, there is no danger of contamination
of the product with foreign materials.
8) Drug is delivered directly to the target organ (lung). Hence, reduced side effects
to other organs.

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