UNIT-5 INDUSTRIAL PHARMACY-I PART-2

PHARMACEUTICAL AEROSOLS

Aerosol or pressurized packages are defined as system that depends upon the power of
compressed or liquefied gas to expand the content from the container.
or
Pharmaceutical aerosols are products that contain therapeutically active ingredients which
are packed under pressure and are released upon activation of an appropriate actuator and
valve system. The term ―aerosols‖ was originally accustomed to describe a liquid or solid
fine mists particles with a specific size range. The term ―aerosols‖ now refers to pressurized
packed products that contain the active ingredient(s) and excipients that are dispersed in a
liquefied or compressed gas known as the propellant. Aerosols dosage forms can
be topically, orally, nasally, and systemically inhaled.
Advantages of Pharmaceutical aerosol over other doses form:
1) Dose removal without contamination of remaining material is possible.
2) Enhance stability of substances which adversely affected by Oxygen and moisture.
3) Maintenance of sterility of product during dispensing dose.
4) Directly delivery of Medicament to the affected area in a desired form with minimum
or no irritation
5) Rapid onset of action
6) Circumvention of first pass metabolism
7) Aerosols are temper proof system so no adulteration is possible
8) Aerosol product can be applied in a thin layer
9) Irritation Produced by the mechanical application of topical medication is reduced or
eliminated.
Disadvantage of aerosols:
1) Their limitations are mostly related to the propellants used.
2) The propellants used are highly inflammable.
3) Empty aerosol containers may contain propellant residues, thus should be carefully
disposed. *
4) In MDIs, a proper coordination is required between the valve actuation and inhalation.
5) If used inaccurately, pharyngeal deposition increases; and in case of inhaled
corticosteroid, oral candidiasis, hoarseness, and increased blood absorption occurs.
6) Topical application leads to sudden coo ling, which may cause further damage to the
injured skin.

COMPONENTS OF AEROSOL PACKAGES

Aerosol packages consist of various components including
1) Propellant
2) Containers
3) Valve and actuator
4) Product concentration

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

1. PROPELLANT USED FOR PHARMACEUTICAL AEROSOLS

Propellant
A propellant develops pressure within the aerosol container, and forces out the product in the
desired physical form (spray, mist, or foam) with the help of other components.
Propellants are classified into:
A. Liquefied gases.
B. Compressed gases.

A) Liquefied Gases
Liquefied gases are preferred as propellants for most of the aerosols. They exist in gaseous or
vapour state at room temperature and atmospheric pressure. They can get liquefied easily by
either lowering the temperature below its boiling point or by increasing the pressure. The
boiling points of compounds selected as liquefied gases are usually below 70ºF (21ºC) and
the exerted vapour pressure is between 14 -85 psig at 70ºF (21ºC).

Liquefied gases are inert and non-toxic.

Chlorofluorocarbons (CFCs) and hydrofluorocarbons are the two types of liquefied gases.
Initially, pharmaceutical aerosols were prepared using CFCs -11, -12 and -114; but these
propellants have an ozone depleting effect and the current global regulations demand the use
of non -ozone depleting propellants in pharmaceutical aerosols. Therefore, they are not used
in pharmaceutical aerosols, except in MDIs.

The alternatives to CFC propellants should be non -toxic and non -flammable.
Trichloromonofluoromethane (propellant-11), dichlorodifluoromethane (propellant- 12),
and dichlorotetrafluoroethane (propellant-114) are the fluorocarbon propellants used in
aerosols nowadays. The two or three digit number helps in identifying the propellant. The
first digit is one less than the number of carbon atoms in the compound; the second digit is
one more than the number of hydrogen atoms in the compound; and the third digit is the
number of fluorine atoms in the compound. If the first digit is zero, it can be represented by
only two digits. The remaining carbon valency is satisfied by chlorine atom; for example,
Propellant 11 is CFCl3, Propellant 12 is CF2Cl2, and Propellant 114 is C2F4Cl2.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

The liquefied gas propellants are discussed below:

1) Chlorofluorocarbons: These propellants, e.g. trichloromonofluoromethane (propellant
11), dichlorodifluoromethane (propellant -12), and
dichlorotetrafluoromethane (propellant 114), are used for oral and inhalation.
Advantages
i. They are chemically inert.
ii. They are non-toxic.
iii. They are non-flammable.
iv. They are non-explosive.
Disadvantages
i. They are expensive.
ii. They are ozone-depleting by nature.

2) Hydrocarbons: These propellants, e.g., propane (propellant A-108), isobutane (propellant

A-31), and butane (propellant A-17), are used for water aerosols and topical use.
Advantages
i. They are inexpensive.
ii. They are excellent solvents.
iii. They are not ozone-depleting by nature.
Disadvantages
i. They are inflammable.
ii. They are capable of producing unknown toxicity.

B) Compressed Gases
Compressed gases, e.g., nitrogen, nitrous oxide, and carbon dioxide, are extensively used as
propellants in pharmaceutical aerosols. The gas is compressed in the container and occupies
the headspace above the liquid. On pressing the valve, the gas pressure (dependant on the
propellant concentration) acts as a piston on the contents and pushes the liquid out of the
container. The amount of gas in the headspace remains unchanged, but it expands to occupy
more volume. Thus, the pressure drops throughout the life of container.

Compressed gases are used to dispense the product either in the form of a solid stream, wet
spray, or foam. The form in which the product will be dispensed depends on the nature of
formulation and the type of compressed gas used. A considerably high initial pressure of 90-
100 psig at 70ºF is required for dispensing semisolids so that most of the product is
dispensed from the container. The product viscosity should be adjusted as per the desired
dispensing characteristics. The product viscosity also regulates the amount of residual
product in the container.

Soluble compressed gases, e.g., nitrous oxide and carbon dioxide, are used for dispensing
the product as foams. When the system is used, the gas dissolved in the product concentrate
(emulsion form) evolves and whips the emulsion into foam. By shaking the container prior to
use, some of the gas disperses throughout the product concentrate and facilitates foam
formation.

Compressed gases and a mechanical breakup actuator are required for dispensing the
product as a wet spray. Solutions of medicinal agents in aqueous solvents are generally
dispensed in this form. Contact lens saline aerosols are formulated with compressed nitrogen
gas as propellant and sterilised using γ-radiations.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

2. CONTAINER USED FOR AEROSOLS

There are containers in which the product concentrate is filled.
Container for aerosol must withstand pressure as high as 140 to 180 psig (pound per sq. inch
gauge) at 130 degrees Fahrenheit including metal and glass containers. The metal container
includes tin-plated Steel, aluminium and stainless steel whereas the glass
container includes uncoated glass and plastic coated glass.
A) Metal
i. Tin-plated steel,
ii. Tin-free steel,
iii. Aluminium, and
iv. Stainless steel.
B) Glass
i. Uncoated glass, and
ii. Plastic-coated glass.

A) Metal
i) Tin plated steel containers
Consists of a sheet of steel plate that has been electroplated on both side with tin.
Tin-plated metal containers are suitable for non-aqueous product alcohol base
Pharmaceuticals
If Aqueous product with a low pH, the tin-plated container must be subject to the organic
lining of epoxy and or Vinyl resin to avoid incompatibility or any corrosion.

ii) Tin-Free Steel Containers

TFS, also termed electrolytic chromium/chromium oxide coated steel, consists of mild
steel base coated with chromium-chromium oxide. This coating provides protection to the
steel base from corrosion before fabrication.
TFS containers can be made resistant to corrosion by applying additional protective coatings
(like enamels and lacquers) to their inside as well as outside. TFS is used for making the
bottoms and tops of aerosol containers.

iii) Aluminium containers:

Aluminium containers are seamless, resistant to corrosion and exhibit lesser
incompatibility problem.
Precautions: anhydrous ethanol is extremely corrosive to aluminium. This can be prevented
by anodizing the aluminium and adding water (2 to 3%) to the formula.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

iv) Stainless steel containers

Stainless steel containers are extremely strong and resistance to most materials but they
are costly. These containers are used for inhalation aerosol packaging.

B) Glass Containers
Glass containers can also be used for aerosol packaging. They either have or do not have a
plastic coating, which may be totally adhered or non -adhered and vented. Plastic coating
provides greater resistance to breakage, aids in identification, provides UV protection, and
absorbs shock from production operations like crimping. These containers show less
compatibility problems, and have nil corrosion problems. Glass containers provide easy
visual inspection of the content level. Glass is used for products having lower pressures and
for lower percentage of propellants. Glass also enables easy designing of containers.
Glass containers are used for small volume solution aerosols, which operate at low pressure.
Maybe uncoated or plastic coated. Glass containers are flexible in design. Absence of
corrosion problems in glass containers. Highly compatible with Pharmaceutical preparation.

Types:
i) Uncoated glass container: Less cost and high clarity and contents can be viewed at
all times.

ii) Plastic coated glass containers: These are protected by plastic coating that prevents
the glass from shattering in the event of breakage.

Limitation of the Glass container

 Brittleness and breakage problem with glass containers.
 Not bear a high pressure, so pressure should be below 25 psig.
 The plastic coating is done to increase withstand more pressure up to 33 psig.

3. VALVE & ACTUATOR

 The aerosol valve is a very important part of an aerosol container; it is a vital part
responsible for expelling and dispensing the desired dose of the aerosol contents in
the desired controlled rate. Valves account for delivering the product concentrate in
the preferred form and controlling the flow rate of contents from the container.

 An aerosol valve is a unique feature of this dosage which is a vital part for effective
expelling and dispensing the desired dose of the aerosol contents in the controlled
rate. Various types of aerosol valves are used depending on the physical form
dispensed and how the aerosol to be used.

The types of the valves are variable; mainly two types are applicable—either a continuous
spray valve or a metering valve.
i) Continuous spray valves
To deliver the product contents constantly in the form of a spray or solid foam stream with or
without amount determination. These kinds of valves are the main type used for all categories
of pharmaceutical aerosols.
ii) Metering valves
To deliver the contents for potent medication, they are dispensing the exact amount of
medicament upon each time of activation during application.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Pharmaceutical aerosol maybe dispense with required doses as in the form of

 Spray
 Foam
 Solid stream

The aerosol valve assembly consists of many different parts as follow shown in figure

Actuator:
Actuators are buttons specially designed for easy opening and closing of the valve. Actuator
is fitted to the valve stem. The types of product discharge (whether in spray or foam or solid
stream form) depend on the propellant type and quantity, and also on the actuator design and
dimension. In pharmaceutical and medicinal aerosols, special actuators are used to dispense
products into the mouth, nose, throat, vagina, or eye.

TYPES OF ACTUATORS:

1) Spray Actuators: These actuators can dispense the product concentrate and
propellant in a stream of small particles. The stream is passed through one or three
orifices. Propellant vaporisation, actuator orifice, and internal channels work together
to deliver the spray in desired range of particle size.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

2) Non-Mechanical Break Up Actuators: In these actuators, the propellant

concentration should be high so that the product can be dispensed in spray form.
3) Mechanical Break up Actuators: In these actuators, the propellant concentration
should be less than 50% that mechanically break up the stream into spray by swirling
through various channels in the actuator.
4) Foam Actuators: These actuators consist of large orifices of size ranging from 0.070-
0.125 inch and greater. The product enters a large chamber by passing through the
orifices; in the chamber the product is expanded and dispensed through a large orifice.
5) Solid Stream Actuators: These actuators are similar to foam actuators. It has an
orifice which is large so that semi-solid products (like ointments) can be dispensed.
6) Special Actuators: These actuators are specially designed for delivering the
medicament to target sites (like throat, nose, eyes, or vaginal tract).

Ferrule or Mounting Cup

Mounting cup is intended for holding the valve parts together and attaching the valve to the
container. It is made up of tin -plated steel or aluminium. Its base should be applied with
single or double coatings of epoxy or vinyl to provide protection against corrosion by the
aerosol contents. Mounting cup is made up of softer metals (e.g., aluminium or brass) with
glass containers and small aluminium tubes. The cup is attached to the container either by
clinching the metal under the lip or by rolling the end under the lip of the bottle.

Stem: Stem is a part of the valve assembly meant for controlling the product flow. It has one
to four orifices of size ranging from 1 × 0.010 inch to 4 × 0.027 × 0.045 inch. Stem is made
up of nylon, delrin, brass, and stainless steel.

Stem Gasket
Stem gasket forms a covering around the stem orifice. It simply acts as an ―on -off‖ switch. It
is made up of buna -N, neoprene, butyl, or viton. Stem gasket should undergo some necessary
tests because the rubber on coming in contact with different formulations may either shrink or
swell. A suitable stem gasket should be selected to prevent the product loss due to leakage.

Spring
Spring closes the valve after the actuator has been released. It also holds the actuator in its
place. The aerosol products mostly are equipped with stainless steel valves.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Housing
Housing (or valve body) made up of nylon or delrin, enfolds the stem, spring, and gasket. It
has an opening (ranging between 0.013 -0.080 inches depending on the type of product to be
dispensed) at the attachment point of the dip tube. It acts as a secondary metering orifice.
This opening ejects a dry and warmer spray, thus the chilling effect of some products felt on
skin, is reduced. An additional opening (called vapour tap) may also be present at the side or
bottom of the housing. This opening permits the escape of vaporised propellant and the liquid
product. The vapour tap also produces fine particles, prevents value clogging, allows the
product to dispense in an inverted position, and reduces flame extension (in case of
hydrocarbon propellants)

Dip Tube
Dip tube is meant for drawing up the product into the valve and help in delivering it. It is
made up of polyethylene or polypropylene. The diameter of dip tube depends on the product
viscosity and delivery rate. The dip tubes are notched at the bottom to prevent closing off at the bottom of
the can. The usual diameter of dip tube ranges from:
 Standard: 1/8" (0.122") inside diameter,
 Large: 3/16" (0.190") inside diameter,
 Jumbo: over 1/4" (0.260") inside diameter, and
 Capillary: < 0.060" inside diameter.

4. PRODUCT CONCENTRATE
Concentrate is either the active ingredient or is a mixture of active ingredients and other
required agents (like solvents, antioxidants, and surfactants). Propellants and the active
ingredients can be combined in many ways to obtain products having variable characteristics.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Mechanism of Aerosol Operation

 Liquefied gases have been mostly used as propellants for aerosols.
 The liquefied gas in a sealed container (such as an aerosol can), exists in liquid and
gas (or vapour) phases, thus behaving as a two-phase system.
 The molecules in the vapour phase exert pressure on the contents with increased
number of molecules in the vapour phase; the vapour pressure of the propellant also
increases.
 Pressure attained at equilibrium is the vapour pressure, which is unique for a
particular propellant at a given time.
 This vapour pressure is equally exerted in all the directions and does not depend on
the quantity present.
 When valve is actuated, gas exerts a vapour pressure on the liquid phase, which
further exerts pressure on the product and pushes it upward (liquid state) through the
dip tube.
 If no dip tube is present (as in MDIs), the container is used in inverted position.
 With the opening of valve, the liquid phase is expelled with sudden volume of
expansion and comes in contact with the atmospheric temperature.
 The propellant having boiling point much less than the room temperature immediately
turns into vapour.
 The pressure drop within the container is restored as more of the liquid propellant
vaporises into the headspace.
 As compared to compressed gases, the advantage of these propellants is that the
pressure drop within the container does not occur while using the product.
 The pressure exerted does not depend on the propellant concentration in the container.
 Due to its large volume expansion ratio, the spray performance is maintained constant
throughout the shelf -life of the aerosol until the last dose of drug is left in it.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Types of Aerosol Systems

The aerosol systems are of the following types:
1. Solution system.
2. Water based system.
3. Suspension or dispersion system.
4. Foam systems:
i. Aqueous stable foams,
ii. Non-aqueous stable foams,
iii. Quick breaking foams, and
iv. Thermal foams
5. Intranasal aerosols.

Solution System
Solution system is also referred to as the two -phase system, i.e., a liquid and a vapour phase.
This system is easy to formulate and consists of either a solution of active ingredients in pure
propellant or a mixture of propellant and solvents. In case the active ingredients are soluble in
the propellant, no other solvent is required. The propellant used depends on the type of
desirable spray. Propellant-12 or A-70, or a mixture of propellant-12 and other propellants
produces fine particles. Larger particles can be produced by reducing the pressure of the
system; this is done by adding to the above mixture, the propellants having vapour pressure
lower than that of propellant -12. Vapour pressure can be reduced by adding less volatile
solvents (e.g., ethyl alcohol, propylene glycol, ethyl acetate, glycerine, and acetone). These
types of sprays produce wetness and are suitable for topical aerosols wherein a film of
medicament forms on the surface.

The system can be exemplified by the following general formula:

The ratio of propellant -12 and -11 or propellant -12 with any other propellant (such as
propellant-114) can be used for oral inhalation also. As the pressure increases, the choice of
container also needs to be changed. Hydrocarbons in topical aerosol pharmaceutical
preparations are used as follows:

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Water Based System

A water-based aerosol is dispensed as spray or foam depending on the formulation. This
aerosol system consists of an emulsion of active ingredients and other solvents. When the
product is dispensed, the propellant turns into vapour and disperses the active ingredients into
minute particles, forming three phase, i.e., liquid propellant, product concentrate, and
vaporize propellant. A three-phase water-based system.

Ethanol is used as a co -solvent in water -based system to solubilise some of the propellants
in water. The surfactants (0.5-2.0%) that are highly soluble in non-aqueous solvents are used
to produce a homogenous dispersion. The propellant should be used in 25-60%
concentration; however, the content can be as low as 5% depending on the product nature. If
a fine particle spray is desired, the propellant concentration should be low, the water content
should be high, and a mechanical breakup actuator along with a vapour tap should be used.

The aquasol system is an example where the propellant content is less than that of water.
The product from this system is dispensed as a fine mist or spray. Since the propellant is
present in a small amount, it does not produce any chilling effect. The aquasol system is a
three-phase system; however, unlike the other three -phase systems it uses large quantities of
water in the formulation. Also, hydrocarbon propellant is used in low concentration.
The resulting spray from aquasol system is non -flammable and the product is also
economical.

Suspension or Dispersion System

In the suspension or dispersion system, the active ingredients are dispersed in a mixture of
propellants. The suspending agents or surfactants are added to decrease the settling rate of
dispersed particle s. This system is used for oral inhalation aerosols. The stability problems of
disperse systems (such as caking, agglomeration, and particle size growth) are also observed
in this system. In some cases, the particles adhere to the container walls. Agglomeration of
particles clogs the valve, and thus leads to inaccurate dosing.

These problems can be overcome by the following steps:

1) Lubricants, e.g., isopropyl myristate and oleic acid, should be added as they provide
slippage between the particles and also lubricate the valve components.
2) Surfactants should be added to disperse the particles.
3) Dispersing agents, e.g., oleic acid and lecithin should be added as they prevent the
agglomeration of suspended particles.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

 UNIT-5 INDUSTRIAL PHARMACY-I PART-2

4) The particle size for metered-dose inhalant should lie between 2-8m, while that for
topical aerosol should lie between 50-100m to prevent the aerosol valves from getting
blocked.
5) The moisture content of propellant and suspension should be below 300ppm because
higher moisture levels cause particle agglomeration.
6) The initial particle size should be reduced to less than 5 to overcome the particle size
growth during the product shelf-life.
7) The density of propellant and suspension should be equalised.
8) Vapour tap valves should be used to reduce valve clogging. The escaping of propellant as
vapour helps in clearing the valve of solid particles.

An example of a formulation for steroid-containing oral inhalation is given below:

In the above formulation, oleic acid is added as a dispersing agent for the steroid. It reduces
the growth and agglomeration of particles. It also acts as a valve lubricant and prevents the
sticking of metered valves in the open position.

Foam System
In the foam system, the liquefied propellant is emulsified. This system comprises of aqueous
or non-aqueous vehicles, propellants, and surfactants. Foam system is classified as:
i. Aqueous Stable Foam: This system consists of propellant in 3 -4% concentration. The
added propellant produces a dry spray. On increasing the concentration of propellant,
more contents can be delivered in dried form. As the propellant is present in the internal
phase, the concentration of propellant is less. This system is used in steroid antibiotics.
ii. Non-Aqueous Stable Foam: This system consists of glycol as the emulsion base and is
used as the emulsifying agent.
iii. Quick Breaking Foam: This system consists of propellant (the external phase), and
cationic, anionic or non -anionic surfactants. The product comes out in the form of foam
which amalgamates to form liquid. This system is used topically and can be applied to
small area or larger surface.
iv. Thermal Foam: In this system, aerosol is delivered in the form of foam on the application
of heat. This system is used in shaving creams.

Intranasal Aerosols
Intranasal aerosols deposit the medication into nasal passages to provide local and systemic
effects.
Advantages
1) They deliver a measured dose of drug.
2) They require lower doses compared to other systemic products.
3) They provide an excellent depth of penetration into the nasal passage way.
4) They decrease the mucosal irritability.
5) They maintain sterility from dose to dose.
6) They provide greater flexibility in the product formulation.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Manufacture of Aerosols
Pharmaceutical aerosols are prepared and packaged successfully only with special
knowledge, skills, and equipment. Aerosols should be manufactured under strict supervision
and adherence to rig id quality controls. Since the propellant is added to the concentrate
during the packaging operation, the quality control system should be modified to account for
this difference.

Apart from the equipment used for compounding of liquids, suspensions, emulsions, creams,
and ointments, some specialised equipment that can handle and package materials at
relatively low temperatures (about -40°F) or under high pressure should be available. These
equipments are used only for aerosol or pressurised packaging, and not for other
pharmaceutical operations. The following apparatus are used for manufacturing aerosols:
1) Cold filling apparatus,
2) Pressure filling apparatus, and
3) Compressed gas filling apparatus.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

1. Cold Filling Apparatus

Cold filling apparatus is a simple apparatus that comprises of an insulated box fitted with
coiled copper tubing to increase the area exposed to cooling. This system can be used with
metered and non -metered valves. Hydrocarbon aerosols cannot be filled using this system
since an excessive amount of propellant escapes and vaporises from it that may form an
explosive mixture at the floor level. However, the fluorocarbon vapours are heavier than air
and thus do not form explosive or flammable mixtures.

Fig: Apparatus for Cold Filling

Procedure
1) This method is used to fill non-aqueous products and products that can withstand low
temperatures (–40ºF).
2) The product concentrate is chilled to –40ºF temperature and filled in already chilled
container.
3) This chilled propellant is completely added in 1 or 2 stages depending on its amount.
4) In another method, the product concentrate and propellant are chilled in a separate pressure
vessel to –40ºF and then filled into a container.
5) The valve is placed and crimped over the container.
6) The leakage and strength of container can be tested by passing it into a heated water bath,
where the container contents are heated at 130ºF temperature.
7) Then the containers are dried, capped, and labelled.

Advantage
It is an easy process.

Disadvantage
Aqueous products, emulsions, and products that get adversely affected by cold temperature
are not filled by this method.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

2. Pressure Filling Apparatus

Pressure filling apparatus comprises of a pressure burette capable of metering small volumes
of liquefied gas under pressure into an aerosol container. Propellant is added into the burette
through the inlet valve located at its bottom or top. Trapped air is allowed to escape through
the upper valve. The propellant under its own vapour pressure is allowed to flow in desired
amount into the container through the aerosol valve.
When the pressure between the burette and the container equalises (this happens when low-
pressure propellants are used), the propellant stops flowing. Additional propellant is added by
attaching a hose leading to a cylinder of nitrogen or compressed air to the upper valve. This
added nitrogen pressure causes the propellant to flow. In another pressure filling apparatus, a
piston arrangement is used to maintain a positive pressure.
Procedure
1) This method is used to fill the concentrate into the container at room temperature.
2) The valve is placed in the container and crimped.
3) The propellant is added either through the valve opening or ―under the cap‖.
4) The valve opening is smaller in size (0.018 -0.030 inches), thus the product ion is limited
and the process is slow.
5) The production rate can be increased by using rotary filling machines and newer filling
heads where the propellants are filled through valve stem.
6) The air entrapped in the container and the air in head space is removed before the
propellant is filled to protect the products from getting affected.

Advantages
1) This method does not involve chilling, thus is used for filling solutions, emulsions, and
suspensions.
2) Contamination due to moisture is less in this method.
3) High production speed can be achieved in this method.
4) This method involves less propellant loss.

Disadvantages
1) Certain types of metering valves cannot be handled by pressure filling method, but only by
the cold filling method or by using an under the cap filler and valve crimper.
2) This method is slow.

3. Compressed Gas Filling Apparatus

Handling of compressed gases in the laboratory does not require any specialised equipment
and is easy.
Aerosol containers are made up of aluminium, tin plated steel, stainless steel, uncoated or
plastic coated glass and synthetic resins, or plastics.
Valve mechanism is the most essential part of an aerosol as it regulates the package
performance and the form in which the product will be dispensed.
An aerosol valve comprises of actuator, valve stem, valve housing, sealing gasket, mounting
cap, spring or toggle return action, and dip tube.
The aerosol valve stem is fitted with an actuator. On pressing the actuator, the valve opens
and directs the spray outside.
Metered valves dispense a measured quantity of spray at each actuation. These valves are
used to dispense potent medicaments, and to minimise wastage and errors of overdosing.
Time measurement of a dose in metered valves is also not a problem, which is however
difficult to control in other valve systems.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Aerosols are packaged either by cold filling method in which the propellant and the product
concentrate are filled at low temperatures ( –30 to 40°F and below 0°, respectively) or
pressure filling process method in which the aerosol products are filled under pressure.
Procedure
1) In this method, the product concentrate is filled in the container.
2) Valve is placed and crimped on the container.
3) Vacuum is applied to remove the air from the container.
4) Filling head is put in the valve opening and gas is allowed to flow into the container.
5) The valve is depressed and gas is allowed to flow into the container.
6) When the delivery pressure and the pressure within the container equalises, the gas stops
flowing.
7) If more amount of gas is required, carbon dioxide and nitrous oxide is used.
8) By shaking the container either manually or with mechanical shakers, high solubility of the
gas in the product can be achieved.

Evaluation of Aerosols
Pharmaceutical aerosols are evaluated for the following parameters:
1) Flammability and combustibility:
i) Flame extension or projection test, and
ii) Flash point test.
2) Physicochemical characteristics:
i) Vapour pressure,
ii) Density,
iii) Moisture content, and
iv) Qualitative and quantitative tests for propellants.
3) Performance characteristics:
i) Aerosol valve discharge rate,
ii) Spray pattern,
iii) Dosage with metered valves,
iv) Net contents,
v) Foam stability,
vi) Particle size determination, and
vii) Leakage.
4) Biological testing:
i) Therapeutic efficiency, and
ii) Toxicity.

1) Evaluation of Aerosols for Flammability and Combustibility

The effect of an aerosol on extension of an open flame can be evaluated by the following
two tests:
i) Flame Extension Test: In this test, the aerosol product is sprayed for 4 seconds into the
flame. Depending on the formulation nature, the flame extends and its length is measured
with ruler.
ii) Flash Point Test: In this test, the aerosol product is chilled to −25ºF temperature and
transferred to a standard tag open cap apparatus. The temperature of test liquid is gradually
increased, and the temperature at which the vapours ignite is considered as the flash point.
The flammable component is calculated in case of topical hydrocarbons.

2) Physicochemical Characteristics
The following physicochemical characteristics of aerosols are tested as follows:

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

i) Vapour Pressure: A pressure gauge is used to determine the vapour pressure of aerosol
product. Presence of air in the headspace is confirmed when excessive variations occur in
the pressure from container to container. Pressure is accurately determined using can
puncturing equipment available for metal as well as glass containers.
ii) Density: A hydrometer or a pycnometer is modified and used to determine the density of
aerosol product and the liquefied gas propellants.
iii) Moisture Content: Karl Fischer apparatus or gas chromatography is used to determine
the moisture content of aerosol product.
iv) Qualitative and Quantitative Test s for Propellants: IR spectroscopy and gas
chromatography are used for the qualitative and quantitative tests for propellants; these
methods also indicate the proportion of each propellant in the blend.

3) Performance Characteristics
The container and valve design influences the dosing, performance, and clinical efficacy of
aerosol products (especially a MDI). The following tests are performed to determine the
efficiency and performance of the valve:

i) Aerosol Valve Discharge Rate: In this test, a standard apparatus is used to discharge the
contents of an aerosol product of known weight for a given time period. After the specified
time limit, the container is re -weighed and the change in weight per unit time dispensed is
considered as the discharge rate (grams/second).

ii) Spray Patterns: In this test, the spray patterns obtained from different batches of material
or through the use of different valves are compared. The spray is impinged on a paper, treated
with a mixture of dye and talc. An oil -soluble or water –soluble dye is used depending on the
aerosol nature. The particles striking the paper cause the dye to move into the solution and to
get absorbed on the paper, thus giving a pattern of the spray which is used for making
comparison. The amount of material coming into contact with the paper can be controlled by
attaching the paper to a rotating disk with an adjustable slit.

iii) Dose Uniformity Test: This test determines that whether or not the patient receives the
same dose of medicament each time the valve is depressed. The dose uniformity test is
performed by the following two ways:
a) One or two doses are dispensed into a solvent or onto a material that absorbs the active
ingredient, and then the amount of active ingredient is dispersed in the solvent or sample.
b) A filled container is weighed. Several doses of the product dispensed in it and the
container is re -weighed. The average dose is determined by dividing the difference in weight
by the number of doses dispensed.

iv) Net Contents: This test determines that whether or not sufficient product has been placed
into each container. The tarred cans placed onto the filling line are re –weighed and the
difference in weight is considered as the net content. In destructive method, a full container is
weighed and then the contents are dispensed. The contents are then weighed, with provision
made for the amount retained in the container. In other modifications, as much product as
possible is removed from the container. These tests do not determine the actual net weight of
each container as related to the amount that can be dispensed. The National Bureau of
Standards has issued methods for determining the net contents of foam type, low -viscosity,
high -viscosity, and food aerosols. These methods standardise the manner in which the
containers are to be dispensed.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

v) Foam Stability: The foams either break down rapidly or remain stable for an hour or more
depending on the formulation. Foam stability can be determined by visual examination, by
determining the time taken for a given mass to penetrate the foam, time taken for a given rod
that has been inserted into the foam to fall, or by using rotational viscometers.

vi) Particle Size Determination: The aerosol particle size can be determined using the
following tests:
a) Microscopy: In this test, the aerosol is actuated on a glass slide after priming the valve and
washing the slide with carbon tetrachloride (avoiding loss of any particulate matter). The
slide is dried and examined microscopically.
b) Cascade Impaction: A cascade impactor is used to measure particles of size ranging
between 0.2 -20µm. The aerosol passes through a series of nozzles of decreasing diameter
under vacuum. After each stage, a glass slide coated with viscous fluid is placed. The largest
particle entraps in the first glass slide, the smaller one flows around the glass slide and passes
through the second nozzle, and so on. The remaining particles pass through another nozzle.
Then the size distribution of aerosol is determined.
c) Light Scattering Methods: These methods are used to measure the particles of size
ranging between 0.1 -20 µm using either white light or laser light. In these methods, the
particles suspended in air cause a scattering of light that is monitored by a photo detector.

vii) Leakage: This test determines that whether or not the valve crimping is free from any
leakage. In this test, the dimensions of the crimp in metal containers are determined to make
sure they fulfil the required standards. The aerosol-filled containers are carried by a
magnetised chain and submerged into heated water baths. The containers travel in the water
bath and by the time they are emerged out, the product temperature should reach 130 ºF. The
container should not show any signs of leakage or distortion.

4) Biological Testing
These tests are similar to those performed on non -aerosol preparations. The biological tests
for aerosols involve determining the following parameters:
i) Therapeutic Efficacy: The inhalation aerosols or MDIs are tested for their dose uniformity
and particle size distribution along with their pharmacokinetic and pharmacodynamics
studies. Topical aerosols are applied to the test area and absorption of therapeutic ingredients
is determined.
ii) Toxicity: The topical as well as inhalation aerosol products are tested for toxicity. The
topical aerosols can irritate the affected area and/or may produce a chilling effect. When an
aerosol is sprayed on the skin for a given time period, the change in skin temperature is
determined using thermistor probes attached to recording thermometers. The toxicity of
inhalation aerosols is determined by exposing the test animals to the sprayed vapours.

Quality Control
Quality control of pharmaceutical aerosol includes the following tests:
1) Propellant: A sample of propellant is taken to determine its vapour pressure and density,
which are compared to the specified standards. Other tests include:
i) Identifying two or more blends of propellant by gas chromatography.
ii) Checking the purity of propellant by determining moisture, halogen, and non - volatile
residue.
2) Valves, Actuators, and Dip Tubes: These components are determined by physical and
chemical examinations. They are sampled as per the standard procedures in ―Military
Standard Mil -STD-105D‖. Aerosol Specifications Committee, Industrial Pharmaceutical

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

Technology section, Academy of Pharmaceutical Sciences developed a test method for

metered dose pharmaceutical aerosols to determine the magnitude of valve delivery and
degree of uniformity between individual valves.

Composition of the test solution is given in table:

Table: Ingredients Used in the Preparation of Test Solutions

Testing Procedure
25 valves are placed on suitable containers filled with specific test solutions.
The valves are attached with button actuators with 0.02 inch orifice.
The filled containers are placed in a suitable atmosphere at 25±1 ºC temperature.
When the products have attained this temperature, the filled containers are actuated to fullest
extent for 2 seconds.
This procedure is repeated for a total of 2 deliveries from each 25 test units.

Specific Gravity of Test Solution

The valve delivery per actuation in l =
Individual Delivery Weight in Mg

The limits for acceptance out of 50 deliveries are as follows:

i) If 4 or more deliveries are outside limits, the valves are rejected.
ii) If 3 or more deliveries are outside limits, another 25 valves are tested.
iii) If more than 1 delivery is outside limits, the lot is rejected.
iv) If 2 deliveries from 1 valve are outside limits, another 25 valves are tested.
v) If more than 1 delivery is outside limits, the lot is rejected.
3) Containers: These are examined for defects in linings. Quality control aspects include
conductivity degree of electric current as a measure of exposed metals. Glass containers are
examined for flaws.
4) Weight Checking: It is done by adding empty tarred containers periodically into filling
lines. After filling with the product concentrate the containers are removed and re-weighed.
The same procedure is used for checking the propellant weight.
5) Leak Test: In this test, the crimp’s valve dimension is measured and compared with the
standard value. The final testing of valve enclosure involves passing the filled containers
through water bath.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.

UNIT-5 INDUSTRIAL PHARMACY-I PART-2

6) Spray Testing: In this test, the dip tube of pure propellant and concentrate is cleared and
any defects in the valve and the spray pattern are checked.

Stability Studies
An entire aerosol package is made up of the product and the container. Therefore, the product
effect on the container and vice versa should be studied while studying the stability aspects of
aerosols.
Since various materials are used for making an aerosol valve and container, the effect of each
material on the product should be studied separately as well as collectively. Several container
coatings and valves with different sub -components should be studied to detect any reaction
between the component and the product.* *

The pharmaceutical aerosols are tested for their stability based on the following components:
1) The product concentrates including the propellant,
2) The container, and
3) The valve assembly.

The stability testing of product concentrate involves determining the physicochemical

parameters (such as vapour pressure, spray rate of the valve , pH, density or specific gravity,
refractive index, viscosity, total weight, assay of active ingredients, chromatography curves,
colour, and odour). Compatibility between the product and the container is determined by
keeping the contents and the different container parts in close contact.

The stability testing of container involves chilling the container to 0 ºF or less temperature
and then examining the insides of container (after emptying them) for any signs of corrosion.
The containers lacquered on the insides are examined for the softening of lacquer, and the
plastic containers are checked for leaching or sorption.

The stability testing of valve assembly involves checking for any evidence of corrosion in
the valve components, especially the mounting cup. The other valve components are checked
for softening, cracking, elongation, or distortion. Since these problems lead to improper
functioning of the valve, they should be overcome in the initial stage only.

Mr. VIVEKANAND PRAJAPATI, ASST. PROFESSOR, HCOP, LUCKNOW.