Pharmaceutical Aerosols

Introduction
1. Aerosol is pressurized dosage form in which
therapeutically active drug is dissolved or dispersed
or suspended under compressed or liquified gas to
expel the content from the container in the form of
spray.
2. Aerosol mainly used for the treatment of Asthma.
3. Aerosols are used for either topical, oral or nasal
administration in the form fine particles or mist or
fog.
4. Aerosols are depends on the power of compressed
or liquefied gas to expel the contents from
containers.
 Definition of Aerosol
• An Aerosol is defined as "An aerosol is a disperse phase system, in which
very fine solid drug particles or liquid droplets get dispersed in the
propellants (gas), which acts as continuous phase". Or "An Aerosol
system which expels the contents from the container that depends on the
pressure development by compressed or liquefied gas" Or "An aerosol is a
pressurized dosage forms containing one or more therapeutic active
ingredients which upon actuation emit a fine dispersion of liquid and/or
solid materials in a gaseous medium contain smaller than 50 um".

• (Dispersed Phase -Solid / Liquid and Continuous phase - Gas /Propellants)

• An Aerosol also called as Pressurized Packages, Pressure Package or

Pressurized dosage forms.

• The term pressurized package is generally used when referring to the

aerosol container or completed product. Pressure is developed to the
aerosol system through the use of one or more liquefied or gaseous
propellants.
 Advantages
1. A dose can be removed with out contamination of
materials.
2. The medication can be delivered directly to the affected
area in a desired form, such as spray, steam, quick
breaking foam or stable foam.
3. Irritation produced by the mechanical application of
topical medication is reduced or eliminated.
4. Ease of convenience of application.
5. Application of medication in thin layer
6. Produced rapid action
7. It is suitable for when the degrade in GI tract.
8. It can avoid the hepatic metabolism of drugs.
9. It Prevents Oxidation of drugs
10.It can be maintain sterility & easy to portable
• specific amount of dose or drug can be removed from the
container without contamination of remaining contents.
• Stability can be enhanced for those substances adversely
affected by atmospheric oxygen or moisture. (Hydrolysis of
medicament can be prevented since propellants do not
contain any water. Oxidation is prevented as no air is present
in the container)
• Sterility can be for sterile product, because no microorganism
can enter even when the valve is opened.
• Metered valve can release the contents in Controlled and
Uniformly.
• The aerosol containers protect the photosensitive
medicaments. (Except clear glass containers)
• For Inhalation purpose a fine mist of the drug is produced.
• The rapid volatilization of the propellant provides a cooling,
refreshing effect.
Disadvantages
 Aerosols are costly dosage form ,which has high prices
 Disposal of empty aerosol containers are difficult.
 Due to volatility of the propellant/s can irritate the injured skin.
 Some persons may be sensitive to the propellant/s and persons
who uses an inhalation aerosol/s, the fluorinated hydrocarbons
may cause carcinotoxic effects on rapid and repeated use of the
aerosol product.
 Aerosol packs must keep away from temperature and fire,
because it may develop high pressure inside the container leads
to explosion.
 If the drug is not soluble in the propellant, aerosol the
formulation is difficult.
COMPONENTS OF AEROSOLS

Aerosols consist of

1. Propellant
2. Container
3. Valve and Actuator
4. Product concentrate container

Product concentrate consists

of API, Additives like
suspending agent, antioxidant,
aqueous and non aqueous solvents,
co solvent ,emulsifying agents etc…
Propellant
It is responsible for developing the pressure with in
the container and also expel the product, when the
valve is opened, in the form of atomization or
foam. It is classified in to mainly two types
1. Liquified gas system
a) Flourinated hydrocarbon(FHC)
b) Chloro fluro carbon (CFC)
C) Hydrocarbons (HC)
2.Compressed gas system
3. Hydrofluoroalkanes
 LIQUIFIED GAS SYSTEM
These compounds are gases
at room temperature and atmospheric pressure.
1. However they can be liquefied easily by lowering the
temperature (below the boiling point or by
increasing pressure )
2. These compounds are chosen generally have Boiling point
below 70F and vapour pressure between 14 and 85 psia
3. When it is placed into container it immediately separates
into a liquid and a vapour phase.
4. Some of the propellant molecule will leave from the liquid st
ate to vapor state. The pressure at this point is called vapour
pressure.
5. It is denoted by the symbol Psia. Psia means = pounds
per square inch absolute
6. As molecule enter the vapor state a pressure gradually devel
ops, number of molecules in vapor state = vapor pressure
Propellant
FLUORINATED HYDROCARBONS
It is Used for oral and inhalation aerosol preparation

Chemical Name Numerical Designation

Trichloromonoflouromethane Propellant 11
Dichlorodifluromethane Propellant 12
Dichlorotetrafluromethane Propellant 114
Chloropentaflouroethane Propellant 115

The term psig ( pounds per square inch gauge)

CHLORO FLURO CARBON (CFC)
Advantages
1. Low inhalation toxicity
2. High chemical stability
3. High purity
4. CFC-11 is a good solvent
Disadvantages
1. Destructive to atmospheric Ozone
2. Contribute to “greenhouse effect”
3. High cost
eg.1. Hydrochlorocarbon
2. Hydroflurocarbon
3. Hydrochloroflurocarbon
HYDROCARBONS

Chemical Name Numerical Designation

Butane A-17
Isobutane A-31
Propane A-108

It is mainly used for the preparation of topical preparation

1. Chemically stable
2. No hydrolysis
3. Inflammable
4. Low toxicity
5. They are lighter than water
 COMPRESSED GAS SYSTEM
Eg.. Co2 , No,N2

Advantages
1. Low inhalation toxicity
2. High chemical stability
3. High purity
4. Inexpensive–No environmental problem

Disadvantages
1. Require use of a nonvolatile co-solvent
2. Produce course droplet sprays
3. Pressure falls during use
PHYSIOCHEMICAL PROPERTIES OF PROPELLANTS

1. Vapor pressure

2. Boiling points

3. Liquid density

Vapor pressure of mixture of propellants is calculated by Dalton’s law

which states that total Pressure in any system is equal to the sum
of individual or partial pressure of various compounds
Raoult’s law
Regards lowering of the vapor pressure of a liquid by the addition
of another substance, States that the dispersion of the vapor
pressure of solvent upon the addition of solute is proportional to
the mole fraction of solute molecules in solution.
COMPONENT OF AEROSOLS

1. Actuator
2. Ferrule or mount cup
3. Valve body or housing
4. Stem
5. Gasket
6. Spring
7. Dip tube
 TYPES OF AEROSOLS DELIVERY

Nebulizers
Used to administer medication to people in the form of a mist
inhaled into the lungs.

Meter dose Inhaler (MDI)

It pressurized, hand-held devices that use propellants to deliver
doses of medication to the lungs of a patient with the help of
Propellant driven aqueous pump sprays

Dry powder inhaler (DPI)

Delivers medication to the lungs in the form of a dry powder.
 NEBULISER
It is a device used to converting a liquid drug (Solution
/suspension) into a fine mist which can then be inhaled
easily
Two types:
1. Jet Nebuliser( air jet /air blast)
2. Ultrasonic Nebuliser
3. Drugs are not conveniently prepared by MDI/ D
PI
 JET NEBULIZERS
It is powered by high pressure air. Nebuliser commonly used in
hospital and home for drug administration have small
medication reservoirs(<10ml)
ULTRSONIC NEBULIZER
METERED DOSE INHALER(MDI)
METERED DOSE INHALER(MDI)
 METERED DOSE INHALER(MDI)
1. Metered-dose inhalers (MDIs), introduced in the mid-1950.
2. In MDIs, drug is either dissolved or suspended in a liquid
propellant mixture together with other excipients, including
surfactants, and presented in a pressurized canister fitted with a
metering valve
3. A Predetermined dose is release when up on actuation.
4. When released from the canister the formulation undergoes volum
e expansion in the passage within the valve and forms mixture of
gas.
5. The high speed of gas flow break the liquid into fine droplets
6. MDI are Generally Packed In aluminum steel canister with
a capacity of 20 -30 ml.
7. Aluminum is inert material. So either coated with epoxy material.
8. CFC used as a propellant in MDI Preparation along with surfactan
t and lubricant. eg. CFC -11, CFC -12, CFC-14
9. Alternative for propellant CFC –HFA-134,127
 The metering valve is place in inverted position.

 Depression of the valve stem allows the content of the metering

chamber refill with liquid from the bulk is ready to dispense next dose

ADVANTAGES OF MDI

 Portable

 Low cost

 Disposability

 Hermatically sealed container to prevent oxidation of formulation.

 It cause valve clogging due to large p.size.

 MANUFACTURING OF
PHARMACEUTICAL AEROSOLS

Apparatus

1. Cold filling process

2. Pressure filling process

3. Compressed gas filling process

 COLD FILLING APPARATUS
1. The principle of cold filling method requires the chilling of all
components including concentrate and propellant to a
temperature of -30 to -40 ºF.
2. This temperature is necessary to liquefy the propellant gas .
3. The cooling system may be a mixture of dry ice and acetone or
refrigeration system.
4. First, the product concentrate is chilled and filled into already
chilled container followed by the chilled liquefied propellant
5. The heavy vapour of the cold liquid propellant generally
displace the air in the container
6. Single head or multiple head rotary unit capable of vacuum
crimping up to 120 can / min are available.
7. The rotary unit requires air pressure (90 to 120 lbs / inch) and
vacuum.
8. A valve is placed either manually or automatically depending on
the production rate required.
The cold filling aerosol line consists of:

1.Un-scrambler
2.Air-cleaner
3.Concentrate filler (capable of being chilled)
4.Propellant filler
5.Valve placer
6.Vaccum purger
7.Valve crimper
8.Heated water-bath
9.Labeler
10.Coder and packaging table
 PRESSURE FILLING
1. Pressure filling is carried out at R.T. under high pressure.
2. The apparatus consists of a pressure burette capable of
metering small volumes of liquefied gas under pressure
into an aerosol container.
3. The propellant is added through the inlet valve located at
the bottom or top of the burette.
4. The desired amount of propellant is allowed to flow
through the aerosol valve into the container under its own
vapor pressure. When the pressure is equalized between
the burette and the container, the propellant stops flowing.
5. To help in adding additional propellant, a hose leading to a
cylinder of nitrogen or compressed is attached to the upper
valve and the added nitrogen pressure causes the
propellant to flow.
 COMPRESSED FILLING
Compressed gases are present under high pressure in cylinders.
These cylinders are fitted with a pressure reducing valve and a
delivery gauge.

1.The concentrate is placed in the container

2.The valve is crimped in place
3.Air is evacuated by means of vacuum pump
4.The filling head is inserted into the valve opening, valve
depressed and gas is allowed to flow into the container.

For those products requiring an increased amount of gas or

those in which the solubility of gas in the product is necessary,
carbon dioxide and nitrous oxide can be used.
To obtain maximum solubility of the gas in the product, the
container is shaken manually during and after the filling
operation by mechanical shakers
Quality control for pharmaceutical aerosols

1. Propellants
2. Valves, actuator and dip tubes
3. Testing procedure
4. Valve acceptance
5. Containers
6. Weight checking
7. Leak testing
8. Spray testing
Evaluation parameters of pharmaceutical aerosols
A. Flammability and combustibility
1. Flash point
2. Flame extension, including flashback
B. Physiochemical characteristics
 Vapor pressure
 Density
 Moisture content
 Identification of propellant (s)
 Concentrate-propellant ratio
C. Performance
1. Aerosol valve discharge rate
2. Spray pattern
3. Dosage with metered valves
4. Net contents
5. Foam stability
6. Particle size determination
7. Leakage
D. Biologic characteristics
E. Therapeutic activity
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.
Flash point

• Determined by using standard Tag Open Cap Apparatus.

Step involves are 
Aerosol product is chilled to temperature of - 25 0 F 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.
Calculated for flammable component, which in case of topical
hydrocarbons.
Vapor pressure

Determined by pressure gauge

Variation in pressure indicates the presence of air in

headspace.

A can punctuating device is available for accurately measuring

vapor pressure.
Density
Determined by hydrometer or a pycnometer.
Step involves 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

tube.

•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.

Moisture content
Method used — Karl Fischer method
 G. C also can be use
Identification of propellants
 G.C,
 I.R spectrophotometry
Aerosol valve discharge rate
Determined by taking an aerosol known weight and discharging the
contents for given time using standard apparatus.
By reweighing the container after time limit has expired, the change
in weight per time dispensed is discharge rate,
Expressed as gram per seconds.
Dosage with metered valves

Amt. of medication actually received by the patient.

Reproducibility has been determined by assay

technique.

Another method is that, involves accurate weighing of

filled container fallowed by dispersing of several doses,
container can reweighed, and difference in weight
divided by No. of dose, gives the average dosage.

Reproducibility of dosage each time the valve is

dispersed
Net contents
•Weight method
•Filled full container, and dispensing the contents

Foam stability
• 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
 PARTICLE SIZE DETERMINATION

1. Cascade impactor
2. Light scatter decay method

Cascade impactor
Operates on the projected through a series of nozzle
and glass slides at high viscosity, the large particles
become impacted first on the lower velocity stages, and
the smaller particals pass on and are collected at high
velocity stages.
These practical ranging from 0.1 to 30 micron and
retaining on RTI. Modification made to improve efficacy
Cascade impactor
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