AEROSOLS

Aerosols
O Pressurized dosage forms that

upon actuation emit a fine

dispersion of liquid and/or solid
materials containing one or more
active ingredients in a gaseous
medium.

Aerosols
O Similarity with other dosage forms
Require the same types of considerations with

respect to formulation, product stability, and

therapeutic efficacy
O Differences from other dosage forms
Depends upon the function of the container, its valve

assembly, and an added component (propellant) for

the physical delivery of the medication in proper form
The product is actually packaged as part of the
manufacturing process

Pressurized package
O Refers to the aerosol container or

completed product
O Pressure is applied to the aerosol

system through the use of one or more

liquefied gaseous propellants to force the
contents of the package out through the
opening of the valve

O The physical form in which the

contents are emitted depends on the:

Formulation of the product
Type of valve
O Aerosol products may be designed to

expel their contents as:

Fine mist
Coarse, wet or dry spray
Steady stream
Stable or a fast-breaking foam

O The physical form selected for a given

aerosol is based on intended use.

For the treatment of asthma or

emphysema
An aerosol for inhalation therapy must

present particles in the form of a fine liquid

mist or as finely divided solid particles.
Particles
o (less than 6 um) will reach the respiratory

bronchioles
o (less than 2 um) will reach the alveolar ducts
and alveoli

Dermatologic spray for deposition on

the skin
The particle size is coarser and generally less

critical to the therapeutic efficacy of the product

Space sprays
O Aerosols that are used to provide an airborne mist
O Characterized by room disinfectants, room

deodorizers, and space insecticides

O Particle size of the released product
Generally quite small, usually below 50 um
Carefully controlled so the dispersed droplets or

particles remain airborne for a long time

O A 1-second burst from a typical aerosol space spray will

produce 120 million particles, which will remain

suspended in the air for an hour.

Space sprays

Surface sprays
O Surface coatings

O Aerosols that are intended to carry the

active ingredient to a surface

O Included in this group are
O Dermatological aerosols
O Cosmetic and household products
O Veterinary & pet products
O Food products

Surface sprays

ADVANTAGES OF
THE AEROSOL
DOSAGE FORMS

ADVANTAGES OF THE
AEROSOL DOSAGE FORMS
1.

A portion of medication may be easily

withdrawn from the package without
contamination or exposure to the remaining
material

1.

Aerosol container
O (Hermetic character)- protects medicinal agents

adversely affected by atmospheric oxygen and

moisture
O (Opaque)- protects drugs adversely affected by light.

ADVANTAGES OF THE
AEROSOL DOSAGE FORMS
3. Topical medication may be applied in a uniform thin
layer to the skin without anything else touching the
affected area
O

The rapid volatilization of the propellant provides a cooling,

refreshing effect

4. By proper formulation and valve control, the physical

form and the particle size of the emitted product may

be controlled, which may contribute to the efficacy of the
drug.
O

Dosage may be controlled through the use of metered

valves

5. Aerosol application is a clean process, requiring little or

no washup by the user.

Aerosols
O An aerosol formulation consists of 2 component parts:
Product concentrate
Propellant

O Product concentrate

Active ingredient of the aerosol combined with the required

adjuncts (antioxidants, surface-active agents and solvents)
to prepare a stable and efficacious product.

O Propellant

Liquefied gas/mixture of liquefied gases serves the dual

role of propellant and solvent/vehicle for the product
concentrate
Compressed gases (carbon dioxide, nitrogen and nitrous
oxide) are employed as the propellant in certain aerosol
systems.

O Chlorofluorocarbons (CFCs)
Mostly used liquefied gas propellants in aerosol

products for many years

CFCs used as propellants in pharmaceuticals
Dichlorofluoromethane
Dichlorotetrafluoroethane
Trichloromonofluoromethane

Currently being phased out and prohibited for

nonessential use under federal regulations

Negative effects
Increase in the amount of ultraviolet radiation

reaching the earth

Increase in the incidence of skin cancer
Adverse environmental effects

O Exemption from prohibition specific

products is given by the FDA when there

is evidence showing that:
O There are no technically feasible

alternatives to the use of CFC propellant

in the product
O The product provides a substantial
health or other public benefit
unobtainable without the use of the CFC
O The use does not involve a significant
release of CFCs into the atmosphere, or
the release is warranted by the benefit
conveyed

O Fluorinated hydrocarbons
Gases at room temperature
May be liquefied by:
Cooling below their melting point
Compression at room temperature

(Dichlorodifluoromethane)
Liquefy
when cooled to -30C or
when compressed to 70 psig at 21C

Equilibrium is quickly established between the liquid and vapor portions

of the propellant when the liquefied gas propellant is sealed within an
aerosol container.

The vapor phase exerts the pressure in all directions

O The pressure forces the liquid phase up the dip tube and out of the
orifice of the valve into the atmosphere upon actuation of the aerosol
valve
O

When released in the air, the propellant expands and evaporates-leaving the product concentrate as airborne liquid droplets or dry
particles

O During expulsion of the product:

O

The pressure within remains virtually constant

O The product may be continuously released at an even rate and
with the same propulsion
O When the liquid reservoir is depleted
O

The pressure may not be maintained

O The gas may be expelled from the container with diminishing
pressure until it is exhausted

Aerosol systems
O Aerosol systems
O Two-phase systems
O Three-phase systems
O Compressed gas systems
O The pressure of an aerosol is critical to its performance
O It can be controlled by:
O The type and amount of propellant
O The nature and amount of product concentrate

Specific amount of propellant in aerosol

products
O Space sprays

Generally contain a greater proportion of propellant than the

aerosols intended for surface coating
Are released with greater pressure and the resultant particles are
projected more violently from the valve
Usually operate at 30-40 psig at 21 degrees C
May contain as much as 85% propellant

O Surface aerosols

Commonly contain 30% to 70% propellant with pressures between

25 and 55 psig at 21 degrees C

O Foam aerosols

Usually operate between 35 and 55 psig at 21 degrees C

May contain only 6% to 10% propellant

FOAM AEROSOLS
May be considered to be emulsions, because the liquefied

propellant is partially emulsified with the product concentrate

rather than being dissolved in it
The liquefied propellant does not dissolve in the aqueous

formulation because the fluorinated hydrocarbons are

nonpolar organic solvents having no affinity for water
The use of surfactants or emulsifiers in the formulation
Encourages the mixing of the 2 components to

enhance the emulsion

Shaking of the package prior to use further mixes the

propellant throughout the product concentrate

When released to the air, the propellant globules vaporize

rapidly, leaving the active ingredient in the form of a foam

FOAM AEROSOLS

O Blends of the various liquefied gas propellants are generally

used in pharmaceutical aerosols

To achieve the desired vapor pressure

To provide the proper solvent features for a given product
O Some propellants are eliminated from use in certain products

because of their:

Reactivity with other formulative materials, or

Reactivity with the proposed container or valve components
(Trichloromonofluoromethane)

Tends to form free HCl acid when formulated with systems containing water
or ethyl alcohol
The free HCl acid affects the efficacy of the product and corrodes some
container components

O The physiologic effects of the propellant must also be

considered in formulating an aerosol to ensure safety of the

product

O The use of the combination of propellant/propellant blend

and the active ingredient in aerosol form may have

undesirable features
When an active ingredient ordinarily used in a nasal or oral

spray is placed in a fine aerosol mist

It may reach deeper into the respiratory tract than desired, and result

in irritation
With dermatologic, vaginal, and rectal aerosol products
The absorption pattern of the drug may change because of an

increased rate of solubility of the fine particles usually produced in

aerosol products
Fluorinated hydrocarbons as propellant agent in inhalation

aerosols
May exhibit cardiotoxic effects following rapid and repeated use in

some patients

TWO-PHASE SYSTEMS
O

consists of the:
liquid phase (liquid propellant and product
concentrate)
vapor phase

THREE-PHASE SYSTEMS
O

consists of
a layer of water-immiscible liquid propellant
a layer of highly aqueous product
concentrate
vapor phase

THREE-PHASE SYSTEM
O The liquefied propellant generally resides at the bottom of the

container with the aqueous phase floating above it.

O The pressure of the vapor phase causes the liquid phase to rise

in the dip tube and be expelled from the container

O The dip tube must extend only within the aqueous product to

avoid the expulsion of the reservoir of the liquefied propellant.

O The aqueous product is broken up into a spray by the

mechanical action of the valve

O If the container is shaken immediately prior to use,
O some liquefied propellant may be mixed with the aqueous

phase and be expelled through the valve to facilitate the

dispersion of the exited product or the production of foam

COMPRESSED GAS SYSTEMS

O Compressed gases may be used to prepare aerosols
O The pressure of the compressed gas in the head space of

the aerosol container forces the product concentrate up to

the dip tube and out of the valve
O

The use of gases that are insoluble in the product concentrate

(nitrogen)
Will result in emission of a product in the same form as it was
placed in the container

Advantages of nitrogen as a propellant

O Its inert behavior toward other formulative components
O Its protective influence on products subject to oxidation
O Odorless and tasteless gas; does not contribute adversely
to the smell or taste of a product

COMPRESSED GAS SYSTEMS

O Other gases (carbon dioxide and nitrous oxide), which are

slightly soluble in the liquid phase of aerosol products, may

be employed
when their expulsion with the product concentrate is
desired to achieve spraying or foaming
O Compressed gas filled aerosols differ from liquefied gas

propellants by means of having no reservoir of propellant

Higher gas pressure are required in these systems
The pressure in these aerosols diminishes as the product
is used

AEROSOL CONTAINER AND VALVE ASSEMBLY

O

The effectiveness of a pharmaceutical aerosol depends on:

O Achieving the proper combination of formulation, container and
valve assembly.

The formulation must not chemically interact with the container or

valve components so as to interfere with the:
O Stability of the formulation
O Integrity and operation of the container and valve assembly

The container and valve must be capable of withstanding the

pressure required by the product, and must resist corrosion.

The valve must contribute to the form of the product to be emitted

CONTAINERS
O Various materials have been used in the manufacture of

aerosol containers
Glass, uncoated or plastic coated
Metal, including tin-plated steel, aluminum, and stainless

steel
Plastics
O The selection of the container for an aerosol product is

based on its:
O Adaptability to production methods
O Compatibility with formulation components
O Ability to sustain the pressure intended for the product
O Interest in design and aesthetic appeal on the part of the

manufacturer
O Cost

GLASS CONTAINERS
O

Disadvantages:
Brittleness and danger of breakage
It must be precisely engineered to provide to provide the maximum in

pressure safety and impact resistance

O

Advantages
Presents fewer problems with respect to chemical compatibility with the

formula than do metal containers

Not subject to corrosion
O

Plastic coating are applied to the outer and inner surface of glass
containers
To render them more resistant to accidental breakage
To prevent the scattering of glass fragments in the event of
breaking
To render them more chemically resistant to formulation materials

Glass containers are considered quite safe

O When the total pressure of an aerosol system is below 25 psig, and
O When no more than 50% propellant is used

TIN-PLATED STEEL CONTAINERS

O

The most widely used metal containers for aerosols

The completed aerosol cylinders are seamed and soldered to
provide a sealed unit, because the starting material is in sheets

Special protective coatings are employed within the container when

required
To prevent corrosion and interaction between the container and
formulation

The container must be carefully examined prior to filling

To ensure that there are no flaws in the seam or in the protective
coating that would render the container weak or subject to
corrosion

O ALUMINUM CONTAINERS

Most are manufactured:

By extrusion
By other methods that make them seamless
Advantages over the seam type of container:
Greater safety against leakage, incompatibility and corrosion

O STAINLESS STEEL CONTAINERS

Employed to produce containers for certain small-volume

aerosols in which a great deal of chemical resistance is required
Main limitation is their high cost

O PLASTIC CONTAINERS

Have met with varying success in the packaging of aerosols

because of their inherent problem of being permeated by the
vapor within the container
Disadvantages:
Certain drug-plastic interactions
Affect the release of drug from the container
Reduce the efficacy of the product

VALVE ASSEMBLY
O

Function of the valve assembly:

O To permit the expulsion of the contents of the can:
O in the desired form at the desired rate
O in the proper amount or dose in metered valves

The materials used in the manufacture of valves:

O Must be inert to the formulations
O Must be approved by the FDA

Actuator, stem, housing and dip tube- generally made of plastic

O Mounting cup and spring- made of metal
O Gasket- made of rubber or plastic resistant to the formulation

PARTS OF THE VALVE ASSEMBLY

1. Actuator

The button that the user presses to activate the

valve assembly for emission of the product
Permits easy opening and closing of the valve

2. Stem

Supports the actuator and delivers the formulation

in the proper form to the chamber of the actuator

3. Gasket

Prevents leakage of the formulation

when the valve is closed

4. Spring

Holds the gasket in place

The mechanism by which the actuator retracts when pressure is
releasedreturning the valve to the closed position

PARTS OF THE VALVE ASSEMBLY

5. Mounting cup
O

Holds the valve in place

O May be coated with an inert material (epoxy resin or
vinyl)
if necessary
To prevent an undesired interaction

6. Housing

Links 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 emitted

7. Dip tube

Extends from the housing down into the product

Brings the formulation from the container to the valve

Inner dimensions are dictated by:

The viscosity of the product,

The intended delivery rate

METERED DOSE INHALERS

O

employed when the formulation is a potent

medication, as in inhalation therapy

the amount of material discharged is regulated by

an auxiliary valve chamber by virtue of its
capacity or dimensions

The integrity of the chamber is controlled by a

dual valve mechanism

When the actuator valve is closed

the chamber is sealed from the atmosphere and

is permitted to fill with the contents of the
container

Depression of the actuator causes a

simultaneous reversal of positions:

The chamber becomes open to the atmosphere,

releasing its contents, and at the same time
becoming sealed from the contents of the
container

METERED DOSE INHALERS

O

The USP contains a test to determine

quantitatively the amount of medication from a
metered valve

The effectiveness of delivering medication to the

lower reaches
of the lungs for local or systemic effects depends on
the:
O Particle size of the inhaled drug
O Breathing patterns
O Depth of respiration
O

Areas of research in developing aerosol

products for optimal oral inhalation therapy:
O Analysis of dose uniformity
O Particle size distribution patterns
O Respirable fractions of aerosol-delivered
particles

Nitrolingual Spray

A unique translingual aerosol formulation of

nitroglycerin that permits a patient to spray
droplets of nitroglycerin onto or under the tongue:
For acute relief of an attack, or

For prophylaxis of angina pectoris due to coronary

artery disease

Not to be inhaled
Two metered spray emissions, each containing

0.4 mg of nitroglycerin, are administered at the

onset of an attack

Contains:
200 doses of nitroglycerin in a propellant
mixture of dichlorodifluoromethane and
dichlorotetrafluoroethane.

FILLING OPERATIONS
O Filling operations:
O Cold Filling
O Pressure filling

O In filling the aerosol containers, the propellant is

either liquefied:
O By cooling below their boiling point
O By compressing the gas at room temperature

Cold Filling

Both the product concentrate and the propellant must be cooled to -34.5 to 40 degrees C to liquefy the propellant

The cooling system may be:

a mixture of dry ice and acetone, or
a more elaborate refrigeration system

The liquefied gas is added after the chilled product concentrate has been
quantitatively metered into an equally cold aerosol container

When sufficient propellant has been added, the valve assembly is inserted
and crimped into place

Disadvantages:
Some of the propellant vapors are lost
The aqueous systems cannot be filled by this process because water
turns to ice due to the low temperatures required
For nonaqueous systems, some moisture usually appears in the final
product due to condensation of atmospheric moisture within the cold
containers.

PRESSURE FILLING

used for most pharmaceutical aerosols

Advantages over cold filling
Less danger of moisture contamination of the product
Less propellant is lost in the process

By the pressure method:

1.
2.
3.

The product concentrate is quantitatively placed in the aerosol container

The valve assembly is inserted and crimped into place
The liquefied gas, under pressure, is metered into the valve stem from a pressure
burette

O Additional propellant may be added by increasing the pressure in

the filling apparatus through the use of a compressed air or

nitrogen gas
O The valve actuator is tested for proper function, after the

container is filled with the sufficient propellant

Spray testing- rids the dip tube of pure propellant prior to consumer use

PRESSURE FILLING
O When compressed gases are employed as the

propellant in aerosol systems

The product concentrate is placed in the container
The valve assembly is crimped into place
The air is evacuated from the container by a vacuum pump
The gas is transferred from large steel cylinders into aerosol

containers
passed into the container through a pressure-reducing valve
attached to the gas cylinder
O For

gases (carbon dioxide and nitrous oxide) which are

slightly soluble in the product concentrate
The container is manually or mechanically shaken during the filling

operation to achieve the desired pressure in the head space of the

container

TESTING THE FILLED CONTAINER

O The aerosol container is tested under various environmental

conditions for:
O

leaks or weakness in the valve assembly or container,

O proper function of the valve
O Valve discharge rate

Determined by discharging a portion of the contents of a previously

weighed aerosol and calculating the grams of contents discharged
per unit of time by the difference in weight

O Aerosol may be tested as desired:

O

For their spray patterns

O For particle size distribution of the spray
O For accuracy and reproducibility of dosage when using metered
valves

PACKAGING, LABELING, AND STORAGE

O

Most aerosol containers have a protective cap or cover

O

Prevents accidental activation of the valve assembly

O Protects the valve against contamination with dust and dirt
O Serves a decorative function
O

Medicinal aerosols that are to be dispensed upon prescription are

labeled by the manufacturer with plastic peel-away labels or
easily removed paper labels
O

Replaced with label containing the directions for use specified by

the prescribing practitioner

Other types of aerosols have manufacturers label printed directly

on the container or on the firmly affixed paper

Most medications in aerosol containers are intended for use at

ambient room temperatures
O When canisters are cold, less than the usual spray may result
O Important to users of metered-dose inhalation sprays

PACKAGING, LABELING, AND STORAGE

O

Aerosols have special requirements for use and storage:

Labels must warn users:
Not to puncture pressurized containers
Not to use or store them near heat or an open flame
Not to incinerate them

Storage:
Exposure to temperatures above 49 degrees C may burst an aerosol

container
Metered-dose inhalation sprays are generally recommended for
storage between 15-30 degrees C
O

Inhaler devices have special detailed instructions

Pharmaceutical aerosols are labeled with regard to:

O Shaking before use
O Holding at the proper angle and distance from the target

PROPER ADMINISTRATION AND USE OF

PHARMACEUTICAL AEROSOLS:
O

The pharmacist
should educate the patient about aerosol dosage forms
should provide the patient with the written instructions
should demonstrate how the inhaler is assembled, stored, and cleaned

using the oral metered dose aerosols as a model.

should share ways to assess how much medication is left in the canister
to ensure continuity of therapy
O

The patient
should be instructed whether the inhaler requires shaking before use

and how to hold it between the index finger and thumb so that the
aerosol canister is upside down
should be instructed to

hold the breath for several seconds or as long as possible to gain the
maximum benefit from the medication,
then remove the inhaler from the mouth
and exhale slowly through pursed lips

PROPER ADMINISTRATION AND USE OF

PHARMACEUTICAL AEROSOLS:
O

For inhalation aerosols, the inhaled particles must be just a few microns
in size for the drug substance or solution to reach the bronchial tree

For topical administration of aerosol dosage forms:

The patient
should first clean the affected area gently and pat it dry
should press down the button to deliver enough medication to cover

the area by holding the canister with the nozzle pointing toward the
body area and about 6-8 inches away
should allow the spray to dry and not cover the area with bandage or
dressing unless instructed by the physician.
Should avoid accidentally spraying the product into the eyes or mouth
If it is necessary to apply the product to a facial area,
The patient should spray the product into the palm of the hand, and

apply it by this means.

PROPER ADMINISTRATION AND USE OF

PHARMACEUTICAL AEROSOLS:
O

The pharmacist may recommend to the patient the use of an

extender device with the inhaler if the patient cannot properly
use the inhaler

Extender devices, or spacers

Advantages of extender devices:

Considered as an important therapeutic aid because they can

effectively assist the delivery of medication despite improper
patient inhalation technique

The patient is permitted to separate activation of the aerosol

from inhalation by up to 3 to 5 seconds
Aerosol velocity is reduced and the droplet size is decreased
because there is time for evaporation of the fluorohydrocarbon
propellant
Cause less deposition of medication in the oropharynx

Extender devices can be used with most pressurized

canisters:
O Brethancer Inhaler (Novartis)
O InspirEase (Key)

O Examples of oral inhalation

aerosols

Asmanex Twisthaler

Ventavis

Pulmicort Flexhaler

Brovana

Atrovent

EXAMPLES OF INHALATION
AEROSOLS

PHARMACEUTICAL AEROSOLS

TOPICAL AEROSOLS
O

Convenient aerosol packages

for use on the skin include:
Anti-infective agents
Povidone iodine
Tolnaftate
Thimerosal
Adrenocortical steroids
Betamethasone
dipropionate and
valerate
Dexamethasone
Triamcinolone
acetonide
Local anesthetic
Dibucaine
hydrochloride

O Advantage:

May be applied to the

desired surface area
without the use of
fingertips, making the
procedure less messy
than with most other types
of topical preparations.

O Disadvantages:

Difficulty in applying the

medication to a small area
Greater expense
associated with the
aerosol package

VAGINAL AND RECTAL AEROSOLS:

O

Aerosol foams containing estrogenic

substances and contraceptive agents are
commercially available

The foams are used intravaginally in the

same manner as for creams
contains an inserter that is filled with
foam and the contents placed in the
vagina through activation of the plunger

The foams are generally oil in water

emulsions, resembling light creams-- water
miscible and nongreasy

Some commercial rectal foams use inserters

O ProctoFoam (Schwartz)
O Contains pramoxine hydrochloride to

relieve inflammatory anorectal disorders