Aerosol

Definition

Pharmaceutical aerosol is the packaging of therapeutic active ingredients in a pressurized system.

It can be defined as, ‘A substance, such as a drug containing therapeutically active ingredients,
packaged under pressure with a gaseous propellant for release as a spray of fine particles’’.

Aerosol or pressurized package is a system that depends on the power of compressed or liquefied
gas to expel the contents from containers.

Aerosols are used for topical, oral or nasal administration in the form fine particles or mist or
fog.

History:

Aerosol industry begin in 1942, aerosol insecticide developed by Good hue and Sullivan of the
US department of agriculture.

The principle of aerosol technology was applied to the development of pharmaceutical aerosols
in the early 1950s. In 1950s aerosols were intended for topical administration. In 1955, it was
intended for local activity in the respiratory tract.

Types of pharmaceutical aerosols

There are three types of aerosol spray, depending on spray-

1. Space sprays:
These products are delivered as a fine mist is called space spray. It contains not more
than 50µm of particle. So it can retain in air.eg. Room sprays
2. Surface coating spray
Aerosols intended for carrying active ingredients to surface are termed as surface sprays
or surface coating spray.eg. Topical aerosol
3. Foam spray
These may be produced by creating an emulsion system in the product. As the propellant
evaporates, bubbles stabilized by surfactants are formed. Spermicidal preparations and
some rectal dosage forms are formulated as aerosol foams.
Depending on drug delivery system, there are three types of aerosols-

a. Nebulizers

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

b. Meter dose Inhaler (MDI)

–are pressurized, hand-held devices that use propellants to deliver doses medication to the
lungs of a patient.

–Propellant driven.

–Aqueous pump sprays.

c. Dry powder inhaler (DPI)

-delivers medication to the lungs in the form of a dry powder.

Components of Aerosols

The aerosol product consists of the following components:

A. Propellant
B. Container
C. Valve and Actuator and
D. concentrate

Propellant:

In aerosol technology, propellants are chemical substances that propel the content of the
container. It is regarded as the heart of the aerosol package that-

 Supply necessary force within the container to expel the product as droplets.
 Acts as a solvent and diluents.
 Aids in atomization or foam production.

It can be classified mainly into two types-

 I. Liquefied gases
II. Compressed gases

Liquefied gases:

Liquefied gas propellants are gases at room temperature and atmosphere pressure. In aerosols,
they are present as liquids under their own vapor pressure. These compounds chosen has a boilng
point of below 70°F and vapour pressure between 14 to 85.When it is placed into sealed
container it immediately separate into a liquid and a vapor phase Liquefied gases are –

I. Fluorinated hydrocarbons:

Fluorinated hydrocarbons are gases at room temperature. They may be liquefied by cooling
below their boiling point or by compressing the gas at room temperature. For e.g.
Dichlorodifluoromethane gas will form a liquid when cooled to -22°F or when compressed to 70
Psig at 70°F. Prior to 1978, fluorinated hydrocarbons were used almost exclusively as the
propellant of all types of pharmaceutical aerosols. Their chemical inertness, lack of toxicity, lack
of flammability and explosiveness, and their safe record of use made them main candidates for
use. The publication of “ozone depletion theory” in the mid 70s, and the implication of the fluoro
carbons in depleting the ozone levels in the atmosphere, led to the phasing out and ban of the use
of fluoro carbon propellant in aerosols.

It is used in oral and inhalation aerosol therapy. Different fluorinated hydrocarbons are-

Chemical name Chemical formula Numerical formula

Trichloromonoflouromethane CCl3F 11
Dichlorodifluoromethane CCl2F2 12
Dichlorotetrafluroethane CClF2CClF2 114
Chloropentaflouroethane CClF2CF3 115
Monochlorodifluroethane CH3CClF2 142b
Difluroethane CH3CHF2 152b
Octaflurocyclobutane CF2CF2CF2CFM2 12 C318

II. Chlorofluorocarbon:

For many years, the liquefied gas propellants most used in aerosol products were the
chlorofluorocarbons. These propellants has being phased out and will be prohibited for
nonessential use due to the scientific recognition that they reduce the amount of ozone in the
stratosphere, which results in increase in the amount of ultraviolet radiation reaching the earth
and increase in the incidence of skin cancer, and other adverse environmental
effects.eg.Hydrochlorocarbon,
Hydroflurocarbon,

Hydrochloro flurocarbon

III. Hydrocarbons:

It is mainly used for the preparation of topical products. It is

- Chemically stable

- No hydrolysis

- Inflammable

-Low toxicity

- Lighter than water.

- Minimum ozone depletion

- Negligible green house effect.

Various hydrocarbons are-

Chemical name Designation

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

Compressed gas:

In certain aerosol system, non-liquefied compressed gases are used such as, carbon dioxide,
nitrogen, nitrous oxide and argon as propellants but in limited amount. They have-

 Low inhalation toxicity

  High chemical stability
 High purity
 Inexpensive
 Nitrogen and argon are water insoluble and nitrous oxide and carbon dioxide are water-
soluble

Hydrofluoro alkane:

In order to overcome the effect of chlorofluorocarbons on the ozone layer, the hydro fluoro
alkanes are being used as propellant such as HFA 21 in pulmonary systems. The advantages are-

 Low inhalation toxicity

 High chemical stability
 High purity
 Not ozone depleting.

Container:

Different materials are used for the manufacture of aerosol containers. The materials must be
inert, non-toxic and must withstand pressure as high as 140 to 180 psig at 130ºF.

On the basis of materials, three types of materials are used-

1.Metal container: a. Tin plated steel – side-seam

- tin-free steel

b. Aluminium container- one piece

- Two piece

c. Stainless steel

2. Glass container: a. uncoated glass

b. plastic coated glass

3. Plastic containers.

Tin plated container:

The tin-plated steel containers consist of a sheet of steel plate which has been coated on both
sides with tin. The thickness of the tin coating is described in terms of its weight such as #25,
#50 and #100. The size of the container is indicated by a standard system, which is a measure of
the diameter and height of the container.

Tin-plated steel is obtained in thin sheets and when required coated with an organic material. The
sheet is cut into pieces to make a body, a top and a bottom. The body is shaped into a cylinder
and soldered. The top and bottom are attached to the body and a side seam stripe is added to the
side seam area. The formation of cylinder shaped body is performed by soldering.

Advantages:

 Light in weight
 Inexpensive

Disadvantages:

 Very corrosive
 Very reactive
 Chance of contamination is very high.

Aluminium containers:

Aluminum is used to manufacture extruded or seamless aerosol containers. Many of the

pharmaceuticals are packaged in aluminum containers because of the lessened danger of in-
compatibility due to its seamless nature and greater resistance to corrosion. However, aluminum
can be corroded by pure water and pure ethanol. The combination of ethanol and propellant II in
an aluminum container has been shown to produce hydrogen, acetyl chloride, aluminum
chloride, propellant 21 and corrosive products. They are produced from a single slug of
aluminium by an impact extrusion method. The container is seamless, bottom is demeshaped. It
is suitable for nonpolar solvent and can withstand high pressure.

Disadvantages:

 Anhydrous alcohol is extremely corrosive to Al and reacts according to the following

equation-
 2Al + 6CH3CH2OH 2(CH3CH2O)3 + 3H2
 This H2 increases the pressure in the container may result in rupture of the container.
 Combination of ethanol and propellant 11 in an Al container may produce various
corrosive products.

Stainless steel container:

Stainless steel containers are limited to small size because of production problems and cost. They
are extremely strong and resistant to most materials. No internal organic coating is necessary.
These containers have been used for inhalation aerosol. But it is difficult to mould.

Glass container:

Glass containers have been used for a large number of aerosol pharmaceuticals available with or
without plastic coatings. Advantages are elimination of compatibility problems, degree of
flexibility in design. The organic coatings provide added protection to the glass container.

Advantages:

 Non reactive with active ingredients.

 Free from corrosive and deterioration.
 Used for packaging of perfumes, cosmetics, and pharmaceuticals.
 Greater patient acceptance.

Disadvantages:

 Limited to products having lower pressure and lower percentage of propellant.

 Potential hazard due to dropping and subsequent bfeakage.
 Preparation of glass is tedious.

Valve and actuator:

Valve must be multifunctional in that it is capable of being easily opened and easily closed and
capable of delivering the contents in the desired form. Also in case of metered dose inhaler
aerosol, the valve is expected to deliver a given amount of medication. Thus there are mainly two
types of valves:

i. Continuous spray valves mainly used in topical products and non pharmaceutical products.
ii. Metering valves used in MDIs.

The function of valve assembly is to permit the expulsion of the contents of the can in the desired
form, at the desired rate, and , in the case of metered valves, in the proper amount or dose. The
materials used in the manufacture of valves must be inert toward the formulations and must be
approves by the food and drug administration. Among the material s used in the manufacture of
the various valve parts are plastic, rubber, aluminium and stainless steel.

Continuous Spray valve

It consists of different parts which are assembled together using high speed production
technique. Typical aerosol valve assembly consists of-

a. Ferrule or Mounting cup:

The ferrule or mounting cup is used to attach the value proper to the container. It is
generally made from tin-plate steel or aluminum depending on the dimension of the
opening of the container. The underside of the valve cup is exposed to the contents of the
container and to the effects of oxygen trapped in the head space. To increase the
resistance to corrosion a single or double epoxy or vinyl coating is added to the underside
of the mounting cup. Ferrules that are used with small aluminum tubes or with glass
bottles are made from softer metal such as aluminum or brass. The ferrule is attached to
the container either by rolling the end under the lip of the bottle or by clinching the metal
under the lip.
b. Valve Body or Housing:
The valve body or housing is generally manufactured from nylon or Delrin. The housing
has the dip tube attached at its bottom. It serves as the link between the dip tube and the
stem and actuator. With the stem, its orifice helps to determine the delivery rate and the
form in which the product is delivered. The housing may or may not contain another
opening referred to as the Vapor Tap. It allows the escape of vaporized propellant along
with the liquid product. It produces a fine particle size, prevents valve clogging with
products containing insoluble materials, and allows for the product to be satisfactorily
dispensed with the container in the inverted position.
c. Stem
Stem is made from nylon or Delrin, but metals such as stainless steel can be utilized. One
or more orifice is set into the stem; they range from one orifice at about 0.013 inch to
0.030 inch, to three orifices of 0.040 inch each. The stem supports the actuator and
delivers the formulation in the proper form to the chamber of the actuator.
d. Gasket
Gasket is made from Buna-N and Neoprene rubber as they are compatible with most
pharmaceutical formulations. The gasket, placed snugly with the stem, serves to prevent
leakage of the formulation when the valve is in the closed position.
e. Spring
Spring serves to hold the gasket in place and is made of stainless steel. When the actuator
is depressed and released, it returns the valve to its closed position.
f. Dip tube
Dip tube is made of polyethylene or polypropylene. Both materials are acceptable for use
although the polypropylene tube is usually more rigid. The inside diameter varies from
0.120 inch to 0.125 inch. The dip tube, which extends from the housing down into the
product, serves to bring the formulation from the container to the valve.The viscosity of
the product and its intended delivery rate dictate to a large extend the inner dimensions of
the deep tube and the housing for a particular product.
g. Actuators
The actuator is a specially designed button which delivers the product in a proper and a
desired form. It is fitted to the valve stem. It allows easy opening and closing of the valve
and is an integral part of every aerosol package. It serves to aid in producing the required
 type of product discharge. There are many types of actuators. They produce different
forms of final product and include
1. Spray actuator
2. Foam actuator.
3. Solid stream.
4. Special actuator.

Spray Actuators Are capable of dispersing the stream of product concentrate and
propellant into relatively small particles by allowing the stream to pass through various
openings (of which there may be one to three on the order of 0.016 inch to 0.040 inch in
diameter). If the percentage of propellant 12 is more, larger openings can be used. Thus
combination of propellant vaporization, orifices in the actuator and the internal channels
can deliver the spray in the desired particle size. Uses

1. Oral and Inhalation products

2. Topical use spray on bandages, local anesthetics, antiseptics and food preparation.

When the concentration of propellant is less the product is dispensed as a stream since the
propellant is not sufficient to dispense the product fully. Such cases mechanical breaking
a stream into fine particles by causing the stream to swirl through various channels will
help in obtaining a fine dispersion.
Foam Actuators Consist of large orifices ranging from 0.070 to 0.128 inches. The
product is dispensed into a relatively large chamber where it can expand and is then
dispersed through the large orifices. The product contains a small concentration of
propellant of low vapor pressure which further aids in foam production.
Solid Stream These actuators are mainly used for ointments. They are similar to foam
type. The product expands and dispersed through a large orifice. Special Actuators are
designed to deliver the medication to the appropriate site of action – throat, eye, and nose.
Special actuator: many of the pharmaceutical and medicinal aerosols require a specially
designed actuator to accomplish specific purpose.thy are designed to delivery medication
to the appropriate site of action- Throat, nose, eye, or vaginal tract.

Metering valves

Metering valves are modification of the continuous spray valve that has been explained above in
detail. It is designed to deliver specific quantity of a product each time. They operate on the
principle of a chamber size whose size determines the amount of medicament to be delivered.
Although these have been used to a great extent for aerosol products, they are limited in both size
and accuracy of dosage. Approximately 50 to 150 mg ± 10 % of liquid material can be dispensed
at one time with the use of such valves.

Product concentrate:
The product concentrate is the active ingredient of the aerosol combined with the required
adjuncts, such as antioxidants, surface active agents and solvent to prepare the stable and
efficacious product.

The principle of aerosols, or

How an Aerosol Can Works

Aerosols rely on a basic principle of physics, a gas under enough pressure will turn into a liquid,
and when that pressure is relieved will expand and turn back into a gas. That process is called
vaporization. An aerosol can is kept closed by the stem gasket, which seals the opening under the
button. This gasket is kept in place by a spring inside the housing. When the button is pressed, it
pushes the valve stem down against the spring, relieving the pressure that keeps the gasket
sealed. When the seal opens, the higher pressure inside the can pushes the product up through the
dip tube and out the valve. A controlled amount of propellant in the product vaporizes as it
leaves the can, creating a spray or foam. A small amount of liquefied gas propellant still in the
container also vaporizes, keeping the pressure constant. The combination of product and
propellant is finely tuned to produce just the right concentration, spray pattern and particle size to
make the product most effective.

Aerosol Cap:

Most aerosol products have the protective cap or cover that fits snugly over the valve and
mounting cup. This protects the valve against the contamination from dist and dirt. The cap,
which is generally made of plastic and metal, also serves a decorative function. The cap is
configured such that it does not protrude beyond an extension of the cylindrical surface defined
by the aerosol can.

Aerosol Closures

Aerosol products are exempted when the method of packaging is the only method available for
correct delivery of a drug. There are overcaps for aerosols that require a coin, knife, or other
device to pry the lid from the can. The design relies on a reclosable locking mechanism and will
reengage if the cap is replaced on the aerosol properly.

Storage
Aerosol cans are pressurized containers and should be stored at temperatures below 50°C. They
should be kept in a cool, dry place, away from direct sunlight, radiators, etc.

In the event of a fire in an area associated with the storage of aerosol cans, it is most important
that fire fighters and emergency services are informed, due to the explosive hazards of
overheating pressurized containers.