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Pharmaceutical Aerosols

Syllabus

Definition
Propellants
general formulation
manufacturing and
packaging methods
pharmaceutical applications.

Introduction
Packaging of therapeutic active
ingredients in a pressurized system.
A system that depends on the power of a
compressed or liquefied gas to expel the
contents from the container..

HISTORY

In1941 the aerosol spray can was first put to good use by Americans Lyle
Goodhue and William Sullivan, who are credited as the inventors of the modern spray
can was funded by the government to kill malaria-carrying bugs in
WWII for those in service.
Their invention paved the way for hair spray and spray paint to come
into existence.
Pressurized aerosol form was developed in early 1950 and was introduced as
Medihaler Epi by Ricker Laboratories.

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Concept of Pharmaceutical
Aerosols
Pressurized dosage forms containing one or more active
ingredients which upon actuation emit a fine dispersion
of liquid and/or solid materials (smaller than 50
um) in a gaseous medium.

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Definition
Aerosol is pressurized dosage form in which
therapeutically active drug is dissolved or
dispersed or suspended in compressed or
liquefied gas to expel the content from the
container in the form of spray upon activation
of an appropriate valve system.

USE
INTENDED
for topical administration,
for administration into one of the
body cavities (ear, rectum and
vagina) or
intended for administration orally or
nasally as fine solid particles or
liquid mists through the pulmonary
airways, nasal passages or oral
cavity.

ADVANTAGES
Convenient, easy, portable and maintenance of sterility
and stability.
Prevents degradation of drugs by oxidation/
Hydrolysis /hepatic metabolism/GI tract.
Directly delivered to the affected area in a desired form,
such as spray, steam, quick breaking foam or stable foam.
Rapid response.

ADVANTAGES
Removal of dose without contamination.
Controlled and uniform dosage by metered valves.
Minimized manual contact with drug.
No manual contact with patient.
Irritation produced by the mechanical
application of topical medication is reduced or
eliminated.
Application of medication in thin layer.

DISADVANTAGES
Costly.
Limited safety hazard (Flammable Nature) thus Cannot be subjected to heat.
Difficulty in disposal (empty aerosol containers ) .
Difficulty in formulation.
Q.C testing is complicated.
Chance for continuous deposition of particle in upper respiratory tract .
The propellant may cause chillness to the skin or can irritate the injured skin due

to volatility .

persons who using an inhalation aerosol/s, the fluorinated


hydrocarbons may cause carcinotoxic effects on rapid and
repeated use of the aerosol product
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2) SURFACE COATING SPRAY:


1) SPACE SPRAY:
Aerosols intended for carrying
) Its products are delivered in a
active ingredients to surface
fine mist
are termed as surface sprays
orsurface coating spray.
) It contains 85% propellant
and it is pressurized at 3040psi and 70 F
) It contains not more than
It contains 30 70%
50m of
propellant operates between
particle. So it can be
2255 psig at 70F.
retaining in air.
E.g.TopicalAerosol
) Example: Room Sprays
3) FOAM SPRAY:
Foam aerosols
(emulsion) usually
operate between 35 and
55 psi at 21c and
contains only 6-10%

Working Principle

They depend upon the function of


the container, its valve assembly,
and an added component--the
propellant--for the physical delivery
of the medication in proper form

An equilibrium is quickly established


between that portion of propellant
which remains liquefied and that which
vaporizes
The vapor phase exerts pressure in all
directions--against the walls of the
container, the valve assembly, and the
surface of the liquid phase
It is this pressure that upon actuation of
the aerosol valve forces the liquid phase

As the propellant meets the air, it


immediately evaporates due to the
drop in pressure, leaving the product
concentrate as airborne liquid droplets
or dry particles, depending upon the
formulation.
As the liquid phase is removed from
the container, equilibrium between the
propellant remaining liquefied and that

Thus even during expulsion of the


product from the aerosol package, the
pressure within remains virtually
constant, and the product may be
continuously released at an even rate
and with the same propulsion.
However, when the liquid reservoir is
depleted, the pressure may not be
maintained, and the gas may be expelled

APPLICATIONS OF PHYSICAL
GAS LAWS
Vapour pressure of mixtures of propellants can
be calculated according to "Dalton's Law" and
"Rault's Law".
Dalton's Law:Total vapour pressure in any
system is equal to the sum of the individual or
partial pressures of the various components.
P = p1+ p2+ p3
Rault's Law:It is regards lowering of the
vapour pressure of a liquid by the addition of
another substance.

Aerosols: Components
These are products that are packaged under pressure and
contain therapeutically active ingredients that are released
upon activation of an appropriate valve system.
The basic components of an aerosol system are
The propellant,
The Product concentrate containing the active ingredient(s),
The container,
The valve, and
The actuator.
Product concentrate consists of API, Additives like suspending agent,
antioxidant, aqueous and non aqueous solvents, co solvent,
emulsifying agents etc

Components of
aerosols :
Valve and actuator
Container
Propellant
container

Product concentrate
19

Propellant

These are the materials which expel the contents of the


container through the valves by applying force.
A propellant is a chemical with a vapor pressure
greater than atmospheric pressure at 40C
(105F).
Responsible for developing pressure.
Expel the product when the valve is opened.
Aids in atomization or foam production of product.
When the propellant(s) is a liquefied gas or a
mixture of liquefied gases, it frequently serves the
propellant and solvent or vehicle for the product
concentrate.

Types:
1. Compressed Gas

Propellants

Inert gases

Hydrocarbons(HC)
2. Liquefied gas
propellants

Chloroflourocarbon
(CFC)

Fluorinated
hydrocarbons(FHC)
Ethers

Carbon Dioxide
Nitrous Oxide
Nitrogen
Liquefied Petroleum
Gases(Propane,
Isobutane, n-Butane)
Isopentane, n-Pentane.
Trichloro-mono-flouro
methane (11), Di-chlorodiflouro-methane (12) ,
Di-chloro-tetra-flouromethane (114)
1,1 Diflouroethane
(152a)
Dimethyl ether

CLASSIFICATION OF PROPELLANTS
(a) Liquefied gases Propellants
(b) Compressed gases Propellants
Depending on the route of administration and use, the
propellant can be classified as
I)Type-I Propellant: Liquefied gases:
1. Halogenated hydrocarbons : For oral and inhalation
Ex: Fluorinated chlorinated hydrocarbons
Trichloro monofluoro methane
Dichloro difluoro methane
2. Hydrocarbon : Topical Pharmaceuticalaerosols
Ex: Propane. Butane, Isobutane

II)Type-II Propellant : Compressed gases:


1. Soluble gases:
Ex: Carbon dioxide, Nitrous oxide
2. Insoluble gases:
Ex: Nitrogen

LIQUEFIED GAS PROPELLANTS


Liquefied propellants are
gases that exist as liquids under
pressure.
Because the aerosol is under
pressure
propellant
exists
mainly as a liquid, but it will
also be in the head space as a
gas.
The product is used up as the
valve is opened, some of the
liquid propellant turns to gas
and keeps the head space full
of gas.
In this way the B.Revathi
pressure
in the
, MR college of pharmacy

23

CHLORO FLUORO CARBONS


Propellant of choice for oral and inhalation .
Advantages
Disadvantages
Chemical inertness
High cost
Lack of toxicity
It depletes the ozone
Non flammability.
layer
Lack of
explosiveness.
Examples: Trichloromonofluoromethane Propellant 11
Dichlorodifluoromethane
Propellant 12
Dichlorotetrafluoroethane
Propellant 114
B.Revathi , MR college of pharmacy

24

HYDROFLUORO CARBONS AND


HYDRO CHLORO FLUORO CARBONS
These compounds break down in the
atmosphere at faster rate than CFCs.
Lower ozone destroying effect.
Advantages
Low inhalation toxicity Disadvantages

High chemical stability Poor solvent


High cost
High purity
Not ozone depleting
Examples: Heptafluoro propane (HFA-227)
Tetrafluoroethane (HFA-134a)
Difluoroethane - Propellant 152a
Chlorodifluoromethane - Propellant 22
Chlorodifluoroethane - Propellant 142 b
B.Revathi , MR college of pharmacy

25

HYDROCARBONS
Can be used for water based aerosols and
topical use.
Advantages
Disadvantages
Inexpensive
Inflammable
No hydrolysis
Unknown toxicity
Chemically stable
produced
Excellent solvents
It does not cause ozone
depletion
Low order of toxicity
Ex: Propane
- Propellant A-108
Isobutane
- Propellant A-31
Butane
- Propellant A-17
B.Revathi , MR college of pharmacy

26

COMPRESSED GAS PROPELLANTS


Compressed gas propellants
occupy the head space above
the liquid in the can.
When the aerosol valve is
opened the gas 'pushes' the
liquid out of the can.
The amount of gas in the
headspace remains the same
but it has more space, and as
a result the pressure will drop
during the life of the can.
Examples: Carbon

Spray
performance
is
dioxide, Nitrous
maintained
however
by oxide and Nitrogen
careful choice ofB.Revathi
the, MRaerosol
college of pharmacy
27

Compressed Gas
Insoluble gases in liquid phase of aerosol;
e.g., Nitrogen
It is odourless, tasteless and inert towards the other
components of aerosol and protects the product from
oxidation.

Slightly soluble gases in liquid phase of aerosol;


E.g., Carbon dioxide and nitrous oxide used in dispensing
foam product.

Use
Widely used in dispensing food and non-food products
in original form i.e., semisolid.
Used as propellants in dental creams, hair preparations,
ointments, antiseptics, germicide aerosols

Compressed gas propellants


Advantages

Low inhalation toxicity

Low expansion power and has no chilling effect.

High chemical stability

High purity

Inexpensive

No environmental problem
Disadvantages

Require use of a nonvolatile co-solvent

Foams produced by them are less stable when compare with


liquefied gas foams.

Produce course droplet sprays

Pressure falls during use

Difference between Liquefied Propellant


and Compressed Gas Propellant

Difference between Liquefied Propellant


and Compressed Gas Propellant
Liquefied Propellant

As the vapor phase leaves the


container, the space above
the surface of the liquid
increases causing a slight
depression in the pressure and
at this moment some liquid
propellant passes from the
solution to the vapor phase to
compensate this drop in the
pressure and restoring the
equilibrium between the vapor
and liquid phases.
The product will have a
constant pressure as long as
there is some liquid propellant
in pressurized package.

Compressed Gas
Propellant
Unlike aerosols prepared with
liquefied gas propellant,
compressed gas filled aerosols
have no reservoir of propellant.
Thus higher gas pressures are
required in these systems.

where the pressure in these


aerosols diminishes as the
product is used.

Liquefied gases are preferred


comparing to compressed gases
Compressed gases

Among the CFCs used as propellants in pharmaceuticals


were;
dichlorteterafluoroethane (Freon 114 or propellant 114)
trichloromonofluoromethane (Freon 011)
dichlorofluoromethane (Freon 012).
N.B the numerical designation system (XYZ);
X = number of carbon atoms +1
Y = number of hydrogen atoms - 1
Z = number of fluorine atoms
E.g., propellant 113 has 2 C + no H + 3 F
Fluorinated hydrocarbons are gases at room temperature.
They may be liquefied by cooling below their boiling point or
by compression at room temperature.

How to determine the vapor pressure


of a certain mixture?

35

How to determine the vapor pressure of a certain mixture?

Example 1:What is a vapor pressure of a 60:40


mixture of propane and isobutane. Information on two
propellants is as follows:
Property

propane

isobutane

Molecular formula

C3H8

C4H10

Molecular weight

44.1

58.1

Boiling point( )

-43.7

10.9

Vapor pressure(psig@70 )

110

30.4

Liquid density(g/ml @70 )

0.50

0.56

Flash point( )

-156

-117

Assume an ideal solution.


For Raoults law, we need to determine the number
of moles of each propellants:

n propane
n isobu tan e

60

1.36
44.1
40

0.69
58.1

From Raoults law, the partial pressure exerted by


the propane is:

Ppropane

n propane
n propane n isobu tan e

P propane

1.36

110 72.98 psi


1.36 0.69

The partial pressure exerted by the isobutane is:

Pisobu tan e

n isobu tan e

Pisobu tan e
n propane n isobu tan e

0.69

30.4 10.23 psi


1.36 0.69

The vapor pressure exerted by both gases, P T, is:


Daltons
law

PT=72.98+10.23=83.21psi at 70

The vapor pressure required for a specific


application can be calculated in a similar
manner and different ratios of propellants
may be used to obtain that pressure.

Calculations of the vapor pressure:


Raoult`s law: Total vapour pressure in a container =
(sum of) [Mole fraction X vapor pressure] for each
component.
Ex: Mix of Propellant 12/11 in 70/30 ratio where:
MW 11 = 137.38
Vp 11= 13.4 psig
MW 12 = 120.93
Vp 12 = 84.9 psig
Calculate total vapor pressure?

Calculations of the vapor pressure:

1- no of moles of p11= 30/137.38 = 0.218


2- no of moles of p12 = 70/120.93= 0.579
Ptotal= (0.218/0.218+0.579) X13.4 + (0.579/0.218+0.579)X84.9 =
3.67+ 61.68= 65.35 psig.
psia= psig+14.7
1 atm = 14.696 psi

PHYSIOCHEMICAL PROPERTIES OF PROPELLANTS


1.

Vapor pressure

2.

Boiling points

3.

Liquid density

Vapor pressure of mixture of propellants is calculated by Daltons law which states that total
Pressure in any system is equal to the sum of individual or partial pressure of various
compounds
Raoults law
Regards lowering of the vapor pressure of a liquid by the addition of another substance,
States that the depression of the vapor pressure of solvent upon the addition of a solute
is proportional to the mole fraction of solute molecules in solution.

Components of Aerosols: Container/Canister

Aerosols Containers
They must be stand at pressure as high as 140 to 180 psig (pounds per
sq. inch gauge) at 1300 F.
A. Metals
B. Glass

Types of CONTAINERS
A. Metals
1. Tinplated steel
(a) Side-seam (three pieces)
(b) Two-piece or drawn
(c) Tin free steel
2. Aluminum
(a) Two-piece
(b) One-piece (extruded or drawn)
3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic coated glass
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46

3-piece cans consisting of three components of


(1) a bottom lid,
(2) a cylindrical body and
(3) a top lid (a lid with a lip [an opening] for a beverage can), and
2-piece cans consisting of two components of
(3) a body integrated with a bottom lid and
(4) a lid with a lip (an opening).
A technique called double seaming is used to attach the can body and can
lids (top and bottom) and the contents are protected from external
contamination.
3-piece cans are made of a rectangular sheet rolled into a cylindrical body and
there are two seaming methods of soldering and electric welding.

Welded cans dominate the market while soldered cans have


almost all disappeared from the market.
2-piece cans are further classified depending on their body
processing method; drawn cans (drawn cans, draw and redraw
cans [DRD cans]), DWI cans (draw and wall ironing cans)
and TULC (stretch-draw-ironing cans).

Metal Containers
1.Tin plated steel containers
It consist of a sheet of steel plate, this sheet is coated with tin by
electrolytic process
The coated sheet is cut into three desired fabricated pieces
The top and bottom attach to the body by soldering
Recent developments in welding include
Soudronic system- copper wire as electrode
Conoweld system two rotating electrode rings.
Saves considerable mfg time
Better appreciation of quality control aspects
Non aqueous product can be filled
Alcohol based pharmaceuticals
e.g. spray on bandages

Advantages:
Special protective coatings are applied within the
container to prevent corrosion and interaction
between the container and formulation if
necessary.
Disadvantage:
The main disadvantage of stainless steel
containers is high cost.
For small sized container only.
Leak of container due to flaws in the seam or
welding.
Corrosion with some preparations.

2.Aluminum Containers
Many pharmaceutical aerosols are packed in Al
containers.
The seamless aerosol containers manufactured by
an impact extrusion process have no leakage,
incompatibility and corrosion.
Light weight, less fragile.
Epoxy, vinyl, or phenolic resins coatings are done
on aluminium containers to reduce the interaction
between the aluminium and the formulation.
Used for inhalation and topical aerosols
Polar solvents corrosion to Al containers
Non polar solvents are used in Al containers

Aluminium

Aluminium is used in most metered


dose inhalers (MDIs) and many
topical aerosols.
Creams and ointments N2/HC-Propellant.
Anhydrous ethanol corrosion to Al,
produces H2 gas, this can be overcome by
anodizing Al or addition of 2-3% water
The container themselves available
in different sizes ranging from 10 ml
to over 1,000 ml.

Advantages:
These are manufactured by extrusion or
by any other methods that make them
seamless.
No leakage compared to the seam type of
container thus is of greater safety.
No incompatibility and corrosion.
Disadvantages:
High cost.

3. Stainless Steel Containers


Limited for smaller size
Extremely strong and resistant to corrosion
Withstand pressure

Reduce corrosion problems


Used for inhalation aerosols
No need for internal coating
Costly

Stainless steel

Advantages:
It is resistant to corrosion.
No coating is required.
It can withstand high pressure.

Disadvantages:
Expensive.
Which restricts its sizes to small sized
containers.

4.Glass Containers
Available with plastic or without plastic coating
Compatible with many additives thus Compatible with most
formulations.
Allows for greater degree of freedom in container design as Can
have various shape because of molding
resistant to corrosion, low cost.
Plastic coated glass containers can be filled to a pressure of
33psig
Can be safely used
Limited to use, Fragile its brittleness and breakage.
Not for light sensitive drugs

4 GLASS

One of the materials is glass, limited


usage because of its brittleness.
So glass containers are used in lower
pressure and when low amount of
propellant are in use such as if the
pressure is less than 25psig and
propellant content is less than 15%.
In order to protect the glass containers
against breakage due to high pressure,
it is to be coated with plastic coating in
two layers.

Epoxy and vinyl resins can be


used as linings.
Vinyl resins are not resistant to
high temperature of the steam about
200F.
But epoxy resins are resistant to
steam.
These coatings are suitable for low
pH water based products.
Used for some topical and Metered

Advantages:
Glass has less chemical incompatibility than
metal containers.
No corrosion.
Glass can be molded to different design.
Glass containers preferred for aerosols.
Disadvantages:
Glass containers must be precise to provide
the maximum in pressure safety and impact
resistance.
More chances for accidental breakage.
Not suitable for photosensitive preparations.

5.Plastic Containers
Made with acetyl resins or poly propylene
Can withstand high pressure

PLASTIC

Plastics are more permeable to


vapors and atmospheric air (like
oxygen), so it may interact with the
formulation and also may lead to
oxidative degradation of the
formulation.
Polyethylene tetra phthalate (PET)
container as used for some non
pharmaceutical products.

Advantages:
Cheap.
Malleable and ductile.
Easy to mold.
Disadvantages:
Incompatibility between drug- plastic
and may lose its efficiency and
potency.

ACTUATOR and Valve Assembly and its components

Actuator
Valve Assmbly
stem
Valve Seat
Gasket
Valve Spring
Ferrule/Mounting cup/Valve
cup
Valve Body/ Housing
Dip tube

TYPES OF ACTUATOR
Actuators:
Specially designed button placed on the valve system,
Helps in easy opening and closing of the valve.
Directs the spray to the desired area.

It helps in deliver the product in the desired


form

68

Actuator
To ensure that aerosol product is delivered
in the proper and desired form.

Different types of actuators


Spray actuators
Foam actuators
Solid steam actuators
Special actuators

69

SPRAY ACTUATOR
1. The stream of product concentrate and propellant are dispensed in the form
of small particle through orifices 0.016-0.040inch.
2. Large orifice are used when high pressure of propellant 12
FOAM ACTUATOR
They contain large orifice diameter 0.070-0.125 inch
SEMISOLID STREAM ACTUATOR
It is used for dispensing semisolid dosage form
SPECIAL ACTUATOR
They are specially designed to deliver the medicament on the specific sites like
nose , throat etc.

TYPESOFAEROSOLVALVES
Regulate the flow of product and discharge the content
Valve is associated with the help of actuautor (if the foam
present in the container)
to emitted the product as wet or spray
1.Continuous spray valve
Mounting Cup / Ferrule
Valve seal
Valve body or Housing
Stem
Gasket
Spring
Dip Tube
2. Metering valve

1.Continuous spray valve

Ferrule/ mounting cup


Attach the valve in proper position in container.
Coated with epoxy resin.
Valve body / housing
Made of nylon/ delrin
Connect dip tube, stem & actuator
Determines rate of delivery
Stem
It is made of nylon /delrin /s.steel
One or more orifice (0.013 to 0.030 inch)
74

Gasket
It is made of Buna N, Neoprene rubber

Spring
Hold the gasket in its place

when actuator is depressed it returns the valve in closed position


Made of stainless steel
Dip tube
Made of poly propylene material / poly ethylene
Inner diameter 0.120 0.125 inch for less viscous
Viscous product - 0.195 inch.

Pea
Most aerosol paints also have a metal, glass or plastic ball
called a pea inside of the can, which. is used to mix the paint
when the can is shaken.
75

the link between the


hold thethe
valve
in place
supports
actuator
dip tube and the stem
and
delivers
theby which
theand
mechanism
actuator
formulation
the when
the
actuator in
retracts
proper
to the
pressureform
is released,
chamber
of the actuator
thereby returning
the
valve
to the
the formulation
closed
bring
position
from the container to the
valve

the button that the


user presses to activate
leakage of
theprevent
valve assembly
for
formulation
thethe
emission
of the
when the valve is in
product
the closed position.

Product concentrate
Simply the product concentrate is the active
ingredient of the aerosol is combined with the
required adjuncts,
The Active drug (for therapeutic activity)
Propellant/s (to expel the contents from the
container)
Antioxidants (to prevent degradation of product)
Surface active agents/ Surfactants (to Increase
Miscibility)
Solvent/s (to prepare a stable and efficacious
product and to retard the evaporation of the
propellant)
Otherexcipientslike Vehicles, suspending
agents etc.

Formulation of pharmaceutical aerosols


Contains two essential components
Product concentrate
Propellant
1. Product concentrate
Product concentrate contains ingredients or mixture of active
ingredients and other such as solvents, antioxidants and surfactants.

78

Formulation of Pharmaceutical Aerosols


2. Propellant
May be single or blend of various propellants
Blends of propellant used in a pharmaceutical formulation to
achieve desired solubility characteristics or various surfactants are
mixed to give the proper HLB value for emulsion system.
To give the desired vapor pressure, solubility & particle size.
Pharmaceutical aerosol may be dispensed as fine mist, wet
spray, quick breaking foam, stable foam, semi solid etc.
Type of system selected depends on
physical, chemical and pharmacological properties of drug,
Site of application

Parameters consideration

Physical, chemical and pharmaceutical


properties of active ingredients.
Site of application

80

Formulation
Depending on the type of aerosol system utilized, the pharmaceutical
aerosol may be dispensed as a fine mist, wet spray, quick-breaking foam ,
stable foam, semisolid or solid.

Type of systems are


1. Solution system :

Consist of a solution of active ingredients in pure propellant or a


mixture of propellant and solvents.
Easy to formulate, provided that the ingredients are soluble in the
propellant
Aerosol solutions have been used
To make foot preparations
Local anesthetics
Spray on protective films
Anti-inflammatory preparations and
Aerosols for oral and nasal applications

2. Suspension or Dispersion systems


Active ingredients are suspended or dispersed throughout the propellant or
propellant and solvent phase.

Anti-asthmatic drugs, steroids, and antibiotics are delivered as suspension


aerosols. When the valve is actuated, the suspension formulation is emitted
as an aerosol and the propellant rapidly vaporizes and leaves a fine
dispersion of the product concentrate.
There are some problem arise for suspension aerosols that are include
agglomeration, particle size growth, valve clogging, moisture content, and
particle size of the dispersed aerosolized particles.

To overcome these problems:

lubricants:
isopropyl myristate , oleic acid

Provide slippage between particles

Lubricate components parts of the valve

Surfactants: to disperse particles

3. Water based system ( Emulsion, dispersion ):


. Relatively large amounts of water can be used to replace all part or part of
the non aqueous solvents used in aerosol. These products are generally
referred to as water-based aerosols and depending on the formulation are
emitted as a spray or foam.
. To produce a spray the formulation must consist of a dispersion of active
ingredients and the solvents in an emulsion system in which the
propellants is external phase.
. In this way when the product is dispensed, the propellants vaporizes and
disperses the active ingredients into many particles. Since propellant and
water are not miscible a three phase forms (propellants phase, water
phase and vapor phase) are used. To increase the solubility of propellants
in water, ethyl alcohol can be added to the system. Ethanol has been used
as a co solvent to solubilize some of the propellant in the water.

4. Foam system:

Foams are produced when the product concentrate is dispersed


throughout the propellant and the propellant is in the internal phase; i.e.,
the emulsion behaves like o/w emulsion.
Aqueous stable foams-The techniques used in preparing an aerosol
emulsion are the same as those used for non aerosol emulsions. This is
generally used for steroid antibiotics.

Non-aqueous stable foams-Various medicinal agents can be formulated by


this way.

Quick breaking foams-These type of system is specially applicable to


medication, which can be applied to limited or to large areas without the
use of mechanical force to dispense the active ingredients. Quick
breaking foams aerosol may be formulated by ethyl alcohol, surfactant,
water and hydrocarbon propellant.

Thermal foams - These are used when the warmness is required.

5. Intranasal aerosol:

Drug delivery systems intended for the deposition of the


medication into the nasal passageways has long been used as a
most effective, means of administering drugs intended to produce
either a local action of systemic effect.
The Intranasal aerosol offers numerous advantage including the
delivery of a measured dose of drug , excellent depth of
penetration into the nasal passageways with minimal intervertent
penetration into lungs, reduce droplet of particle size , lower
dosage than a comparable system preparation maintenance of
sterility from dose to dose.
The modes of administering of intranasal preparations have been
limited to nasal drops, non-pressurized nasal sprays (mist),
inhalants, intranasal gel, creams, ointments.

TYPES OF AEROSOL
SYSTEM
Five types :
1. Solution system / Two phase system
2. Water based system / Three phase system
3. Suspension or Dispersion system
4. Foam system
Aqueous stable foam
Non-Aqueous stable foam
Quick Breaking Foam
Thermal foam
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86

Solution system / Two phase system


It consists of a solution of active ingredients in
liquefied propellant or in the vaporized propellant.
The solvent is composed of the propellant or a
mixture of the propellant.

Contains

both vapor & liquid.

Drug

soluble in propellant no co-solvent.


Co-solvents such as alcohol, propylene glycol, and
polyethylene glycols, which are often used to
enhance the solubility of the active ingredients.
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87

Solution system / Two phase system


Propellant
In

12 single or mixture.

mixture propellant with vapor pressure less than

propellant 12 , bigger sized aerosol particles due to vapor


pressure reduction.
Propellant

has high pressure hence propellant114 is added

to reduce its vapour pressure .


E.g.

propellant 12/11(30:70), propellant 12/114(45:55).

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88

Types of Systems
SOLUTION SYSTEM
Large no of aerosol products can be formulated.
Solution aerosols produce a fine to coarse spray.
No solvent is required, if active ingredient is soluble in propellant.
Depending on the type of spray, propellant 12 or A-70 (very fine
particles) or mixture of propellant 12 and other propellants.
If low VP propellants are added to P-12, large particle size
The vapor pressure of system is reduced addition of less volatile solvents
such as ethanol, propylene glycol, glycerin, ethyl acetate.
Propellant from 5% (for foams) to 95% (for inhalations).

General formula
Active drug -10-15%
Propellant 12/11 (50:50) to 100%

Inhalation aerosol
Isoproterenol Hcl 0.25%W/V
Ascorbic acid 0.1
Ethanol 35.75
Propellant 12 63.9
Packed in S.S, Al container of 15 -30 ml
Hydrocarbons in Topical
Ethanol - 10-15
Water 10-15
HC propellant A-46 55-70
Depending on water content the final product may be solution or
three phase system.
Hydrocarbon propellant A-70 produces drier particles, while A17 and A-31 tend to produce a wetter spray.
These are useful for topical preparations. Plastic coated glass
containers.

Water based system / Three phase system

It consist of a suspension or emulsion of the active ingredient(s)in


addition to the vaporized propellants.
suspension consists of the active ingredient's that may be dispersed
in the propellant system with the aid of suitable excipients such as
wetting agents and/or solid carriers such as talc or colloidal silica.

Contains

water phase, vapor phase and the propellant.

Propellant
Water

content varies from 25 -60%.

immiscible with propellant solubility increased by adding,


. Co solvent (ethanol)
. Surfactants (0.5% - 2.0%) non polar ( esters of oleic acid,

palmitic acid, stearic acid)


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91

WATER BASED SYSTEM (Water based aerosols)


Large amounts of water can be used to replace all or part of the non aqueous
solvents used in aerosols.
Produce spray or foam.
To produce spray formulation must consist of dispersion of active ingredients
and other solvents in emulsion system in which the propellant is in the external
phase.
Since propellant and water are not miscible, a three phase aerosol forms
(propellant, water and vapor phases).
Ethanol can be used as cosolvent to solubilize propellant in water.
Low water soluble Surfactants and high solubility in nonpolar solvents will be
useful eg: glycol, glycerol and sorbitan esters of oleic, stearic, palmitic and
lauric acids (Conc. 0.5 to 2%)
Propellant concentration varies from about 25 to 60%.
Aquasol system (Aquasol valve) dispensing fine mist or spray of active
ingredient dissolved in water (No chilling effect, since only active ingredient
and water are dispensed, propellant is in vapor state).

Differences between aquasol system and three phase system are


Aquasol dispenses fairly dry spray, very small particles, non
flammability of the product
Fine and dry spray with 6 parts of water with 1 part of HC
propellant, even it extinguishes fire.
Alcohol use results in the two phase system
In Aquasol system vapor phase of Propellant and product enter
actuator through separate ducts moving at high velocity product
and vapor mixed with voilent force results in uniform fine spray
Fine dry spray or coarse wet spray is obtained

Based on material to be
Two
phase
propelled
Three
phase
Product is solid and
system
system
insoluble in
propellant
Or it is solid or
liquid which
dissolves in it
If a product is
insoluble solid than
it can be suitably
suspended and
system will have
one liquid phase

Product is
immiscible with
propellant and
dissolved in liquid
which also does
not mix with
propellant
Gas
Product and
Liquid propellant

Suspension system
Using
Oral

suspending agent.

inhalation aerosols.

Active ingredients dispersed in propellant or mixture

Physical

stability

by,

- Control of moisture content


- Active ingredients with minimum solubility.
- Initial particle size < 5 microns
- Propellant density
- Suspending agents

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95

SUSPENSION SYSTEM
It is prepared by dispersion active ingredients in mixture propellant
and by using suspending agent
The physical stability of suspension can be increased by use minimum
solubility of API.
Eg. Ephedrine bi tartarate is less soluble than Hcl
By Use of surfactant to reduce the agglomeration
Eg. Sorbitan monolaurate ,sorbitan monooleate sorbitan trioleate,
isopropyl myristae.

SUSPENSION OR DISPERSION SYSTEM


To overcome complications of cosolvents the disperse system was
developed which involves dispersion of active ingredient in the
propellant or mixture of propellants.
To decrease the rate of settling of dispersed particles, surfactants or
suspending agents can be added.
Primarily used for inhalation aerosols.
Epinephrine bitartrate (1-5 Microns) minimum solubility in propellant
Sorbitan trioleate
P-114
P-12
Isoproterenol sulfate
Oleyl alcohol
Myristyl alcohol
P-12
P-114

Steroid
Oleic acid
P-11
P-12 Oleic acid is dispersing agent, aids in reduction of particle

growth, valve lubricant avoids sticking.


Agglomeration results in valve clogging, inaccuracy of dosage, damage
to liner or container.
Physical stability increased by
Control of moisture content (300 ppm)
Reduction of initial particle size to less than 5 m for inhalation.
Adjustment of density of propellant and suspensoid to equal
Use of dispersing agents
Use of derivatives of derivatives of drug with minimum solubility in
propellant (epinephrine)
Isopropyl myristate and mineral oil are used to reduce agglomeration.
Surfactants of HLB less than 10 are useful (sorbitan monooleate,
monolaurate, trioleate, sesquioleate. (Conc. 0.01 to 1 %)

Foam system
Consists

of aq. or non aq. vehicles, propellant &

surfactants.
Four

types ,

. Aqueous stable foams


. Non aqueous stable forms
. Quick breaking forms
. Thermal forms

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99

. Aqueous stable foams


. Propellant 3-4%
. Dry spray is produced
. Propellant internal phase
. Steroidal antibiotics
. Non aqueous stable foams
. Emulsifying agent - glycol
. Quick breaking foams
. Propellant external phase
. Topical application
. Cationic, anionic, non ionic surfactants
. Thermal foams
. Delivered as foam on application of heat
. Shaving creams
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10

FOAM SYSTEMS
Emulsion aerosols consist of active ingredient, Aq. or non aq. vehicle,
surfactant, Propellant.
Liquefied propellant is emulsified and generally in internal phase.
AQUEOUS STABLE FOAM
Active drug
Oil
o/w surfactant
Water,
HC Propellant (3 -5%)
Hydrocarbon propellant (3 to 5% W/W or 8-10% V/V usually).
As the amount of propellant increases a stiffer and dryer foam is
produced.
Lower propellant concentrations yield wetter foams.
HC and compressed gas propellants are used.
NON AQUEOUS STABLE FOAM
Glycols such as poly ethylene glycols used.
Emulsifying agent is propylene glycol monostearate. PEG Esters

QUICK BREAKING FOAM


Propellants

are external phase

The product is dispensed a s a foam which then collapsed in to liquid


Useful for topical medication
Especially applicable to topical medications
Ethyl alcohol
Surfactant
Water
HC Propellant
Surfactant should soluble in alcohol and water.
adaptor

FOAM SYSTEM

THERMAL FOAM
To produce warm foam for shaving
Used to hair colors and dyes were unsuccessful.

INTRANASAL AEROSOLS
To deliver measured dose of drug, lower doses compared to
systemic products
Excellent penetration into the nasal passage way
Decreased mucosal irritability
Maintenance of sterility from dose to dose
Difference from inhalation aerosol is the design of

FILLING OPERATIONS

Manufacturing
In general Manufacturing
of aerosols takes place in
two stages

Manufacturi
ng of
concentrate

Addition of
propellant

This manufacturing procedure is quite


different from non aerosol pharmaceuticals
product

This require Q.C measures during filling


operation to ensure both concentrate and
propellant are brought together in the
proper proportion

The aerosol concentrate is prepared and


sample is tested (early detection prevents
loss of other components)
Once the propellant is added product is

FILLING OF AEROSOLS
The manufactured aerosols can be
filled in to the containers can be
done by following methods and
apparatus used.
a) Cold filling Apparatus
b) Pressure filling apparatus
c) Compressed gas filling apparatus
d) Rotary filling machine

Methods
1.cold filling
method
This method
requires chilling of
all components
including
concentrate and
propellant to
temperature
-30f
The
type of product
or -40 f

2.pressure filling
method
This
method is carried
out at room
temperature
utilizing pressure
equipments

and size of
container usually influence method
to be used

cold filling
method
product
concentrate is
chilled to -40
F

added to the
chilled
container
Than the
chilled
propellant is
added

Alternate
method is
to chill
both
concentra
te and
propellant
in a
pressure
vessel to
a-4
n0
d F
then
added
mixture
to
aerosol
containe

A valve is then crimped


then the container passed through a heated
water bath in which content are heated to 130 F
This is To test for leak and strength of
container
Container is air dried and
spray tested if necessary

Drawbacks..
This method is restricted to non aqueous
products
And those products not adversely affected by low
temperatures in the range of -40 F

COLD FILLING PROCESS


THE VALVE ASSEBLY IS INSERTED AND CRIMPED INTO PLACE

PRODUCT CONCENTRATE +PROPELLLENT INTO EQUALLY COLD AEROSOLE CONTAINER

ALTERNATIVE METHOD

CHILL BOTH CONCENTRATE + PROPELLENT IN A PRESSURE VES

COLD FILLING APPARATUS


Consist

of an
insulated box fitted
with coiled copper
tubing to inc the
area exposed to
cooling.

The

insulated box
should be pre filled
with acetone or
dry ice, that
functions as a
refrigerating
system.

AEROSOL FILLING

PRESSURE FILLING

Pressure filling method


When first developed its slower than cold
filling method
With development of new techniques speed
of this method has been greatly increased

Valve is
crimped

concentrate added to
container at room
temperature

Then the
propellant is
added through
the value /under

PRESSURE FILLING

PROCESS
Through the opening of valve propellant is added.

Since the valve contain extremely small


opening (0.018 to 0.030 inch)
This step is slow and limits production
With development of rotary filling
machines which allow propellant to be
added around and through the valve
stem
the speed has been increased
For those products adversely
affected by air the air in headspace is
evacuated prior to adding of propellant
i.e., Trapped air should be removed

Pressure method is preferred to


the cold
method
1. As some solutions, emulsions,
suspensions and other preparations cant
be chilled
2. There is less danger of contamination
of the
product with moisture
3. High production speed can be achieved
4. Less propellant is lost
5. And the method is not limited

PRESSURE BURRETTE

pre

Pressure burette for laboratory


filling of aerosols

TESTING

ROTATORY FILLING

COMPRESSED GAS FILLING

Compressed gases are present under high pressure in cylind

PROCESS
Gas stop flowing when pressure become equal.

ADVANTAGES
Less
It
No
isrefrigeration
the
propellant
preferred
isislost.
method
required,
forcan
solutions,
be carried
emulsions
out at room
and
suspension
temperature.

DISADVANTAGES
Slower process
Certain
metering
than
valves
coldcannot
filling
handled due to pressure

Filling machine

PACKAGING OF AEROSOLS

A unique aspect of pharmaceutical aerosols as compared


to other dosage forms is that the product is actually
packaged as part of the manufacturing process.
Most aerosols have a protective cap that fits snugly over
the valve & mounting cap.
this protect the valve against contamination with dust &
dirt
The cap which is generally made up of plastic or metal
also serves a decorative function .

STORAGE
Expose

to temp.
above 49 C (120 F)
may burst an aerosol
container.
When the containers
are cold less than the
usual spray may
result.
These products are
generally
recommended for
storage between
15C - 30C (59F &
86F)

LABELING
Medicinal

aerosols are labeled by the


manufacturer with plastic peel-away labels
or easily removed paper labels.

Aerosols

have

special
requirements for
use & storage:
For safety, labels
must warn users
not to use or store
them near heat or
an open flame.
Aerosols are
labeled with
regard to shaking
before use &
holding at the
proper angle.

Pharmaceutical Aerosol Stability


Any unwanted reaction(s) between
the following is individually checked
with different materials for aerosol
product stability:
Product concentrate and the
propellant.
Container.
Valve
140

QUALITY CONTROL TESTS


It includes the testing of
1.
2.
3.
4.
5.
6.

Propellants
Valves, Actuators and Dip Tubes
Containers
Weight Checking
Leak Testing
Spray Testing

141

ADDITIONAL TESTS
1.
2.
3.

Moisture content.
Particle size determination.
Microbial limits.

Purpose of Quality
control of aerosols
1.
2.
3.
4.
5.
6.

Propellant : tested for vapor pressure, identity,


purity and acceptability.
Valves, actuators and dip tubes : valve
acceptance, delivery rate.
Containers : dimensions, defects in lining,
weight of container.
Weight checking
Leak checking : checking of crimp dimension,
leaked tank testing.
Spray testing : to check valve and spray
pattern.

1. PROPELLANTS :

Vapor pressure and density of the propellant are


determined and compared with specification sheet.

Parameter

Tested
By

Identification

Purity and
acceptability

Gas
Chromatography
IR
Spectroscopy
Moisture, Halogen,
Non-Volatile
144
Residue

2. VALVES , ACTUATORS AND DIP TUBES :


Sampling is done according to standard procedures as
found in Military Standards MIL-STD-105D.
For metered dose aerosol valves ,test methods were
developed by
Aerosol Specifications Committee
Industrial Pharmaceutical Technology Section
Academy Of Pharmaceutical Sciences.
The objective of this test is to determine magnitude
of valve delivery & degree of uniformity between
individual valves.
Standard test solutions were proposed to rule out
variation in valve delivery.
145

TEST SOLUTIONS
Ingredients
% w/w

Test
Solutions A

Test
Solutions B

Test
Solutions C

Iso Propyl Myristate

0.10%

0.10%

0.10%

Dichloro Difluoro
methane

49.95%

25.0%

50.25%

Dichloro tetrafluoro
ethane

49.95%

25.0%

24.75%

Trichloro monofluoro
methane

Alcohol USP

Specific Gravity @
25c

1.384

24.9%

49.9%

1.092

1.388

146

Testing Procedure:
Take 25 valves and placed on containers filled with
specific test solution.
Actuator with 0.020 inch orifice is attached.
Temperature -251C.
Valve is actuated to fullest extent for 2 sec and weighed.
Again the valve is actuated for 2 sec and weighed.
Difference between them represents delivery in mg.
Repeat this for a total of 2 individual deliveries from
each of 25 test units.
Individual delivery wt in mg.
Valve delivery per actuation in L =
Specific gravity of test solution
Valve Acceptance:
54L or less 15%
55 to 200 L 10%

Deliveries

Limits

147

Of the 50 individual deliveries,

If 4 or more are outside the limits : valves are


rejected

If 3 deliveries are outside limits : another 25


valves are tested.
Lot is rejected if more than 1 delivery is
outside the specifications.
If 2 deliveries from 1 valve are beyond limits :
another 25 valves are tested.
Lot is rejected if more than1 delivery is outside
specification.
148

3. CONTAINERS :
Containers are examined for defects in lining.
Quality control aspects includes degree of
conductivity of
electric current as measure of
exposed metals.
Glass containers examined for Flaws.

4. WEIGHT CHECKING :
Is done by periodically adding to the filling line
tared empty aerosol containers, which after
filling with concentrate are removed & weighed.
Same procedure is used for checking weight of
Propellants being added.
149

5. LEAK TESTING :
It is a means of checking crimping of the valve
and detect the defective containers due to
leakage.
Is done by measuring the Crimps dimension &
comparing.
Final testing of valve closure is done by
passing the filled containers through water
bath.
6. SPRAY TESTING :
Most pharmaceutical aerosols are 100% spray
tested.
This serves to clear the dip tube of pure
propellant and pure concentrate.
150

EVALUATION TESTS
A.
B.
C.
D.

Flammability and combustibility :


Physicochemical characteristics :
Performance:
Biological testing :

151

EVALUATION TESTS
A. Flammability and combustibility :
1. Flash point
2. Flame Projection

B. Physicochemical characteristics :
1.
2.
3.
4.

Vapor pressure
Density
Moisture content
Identification of Propellants

152

C. Performance:
1.
2.
3.
4.
5.
6.

Aerosol valve discharge rate


Spray pattern
Dosage with metered valves
Net contents
Foam stability
Particle size determination

D. Biological testing :
1. Therapeutic activity
2. Toxicity studies

153

A. Flammability and combustibility


1. Flash point:
Apparatus : Tag Open Cup Apparatus
Product is chilled to 25F and test liquid
temperature is allowed to increase slowly and the
temperature at which vapors ignite is called as
Flash Point .

2. Flame Projection:
Product is sprayed for 4 sec
into a flame and the flame is
extended ,exact length is
measured with a ruler.
Flame test indicates the effect of an aerosol
formulation on the extension of an open flame.

154

B. Physicochemical characteristics:

Property
1. Vapor Pressure

Method
Pressure gauge

Can Puncturing
Device.
2. Density

Hydrometer,
Pycnometer.

3. Moisture

Karl Fisher Method,


Gas Chromatography.

4. Identification of
propellants

Gas Chromatography,
IR Spectroscopy.
157

C. Performance:

1. Aerosol valve discharge rate :


Contents of the aerosol product of known weight is
discharged for specific period of time.
By reweighing the container after the time limit, the
change in the weight per time dispensed gives the
discharge rate ( g/sec).

2. Spray pattern :
The method is based on the
impingement of spray on piece of
paper that has been treated with
Dye-Talc mixture.
The particles that strike the paper
cause the dye to go into solution and to be adsorbed onto
paper giving a record of spray for comparison purpose.
161

Spray pattern

162

3. Dosage with metered valves :


Reproducibility of dosage can be determined by:
Assay techniques
Accurate weighing of filled container followed by dispensing
of
several doses . Containers are then reweighed and difference
in
weight divided by number of doses dispensed gives average
dose.

4. Net Contents :
Tarred cans that have been placed onto the filling lines are
reweighed and the difference in weight is equal to the net
contents.
Wtotal - Wcontainer
In Destructive method : weighing a full container and then
dispensing as much of the content as possible . The contents
are then weighed . This gives the net content.
163

5. Foam stability :
Methods : Visual Evaluation,
Time for given mass to
penetrate the foam,
Time for given rod that is inserted
into the
foam to fall ,
Rotational Viscometer.
6. Particle Size Determination :
Methods : - Cascade Impactor : 0.1
to 30 microns
- Light scatter decay:

164

a). Cascade Impactor :


Principle :
Stream of particles projected
through a series of nozzles and
glass slides at high velocity,
larger particle are impacted first
on lower velocity stage and
smaller particles are collected
at higher velocity stage.
b). Light Scattering Decay :
Principle :
As aerosol settles under turbulent
conditions, the change in the light
intensity of a Tyndall beam is
measured.
Sciarra and Cutie developed method based on practical size distribution.
165

D. Biological testing:

1.Therapeutic Activity :
For Inhalation Aerosols : dosage of the product is
determined and is related to the particle size
distribution.
For Topical Aerosols : is applied to test areas and
adsorption of therapeutic ingredient is determined.

2.Toxicity :
For Inhalation Aerosols : exposing test animals to
vapors
sprayed from aerosol container.
For Topical Aerosols
: Irritation and Chilling effects
are
determined.
166

Applications:
1.Aerosols are used for oral or topical administration.
2.They exhibit systemic effect.
3.These preparations are easy to carry.
4.They are uniformly applied without touching the affected area.

Wherever the medicament is needed, there the


product can be delivered in the required form like
foam, spray etc.
It have rapid onset of action. It will act on targeted
area without any contamination.
Aerosol dosage form is a dosage form with an easy
administration. Its main advantage is it requires
lesser amount of active ingredients or medicaments.

CONCLUSION
At present there is much interest in
developing MDIs for conditions including
asthma,
COPD,
Chronic
bronchitis
,emphysema and other respiratory diseases
etc.
Many of compounds have been developed
using biotechnology process and their
delivery to the respiratory system via MDI in
an extremely challenging undertaking.
As Chlorofluorocarbon (CFC) propellants
cause ozone depletion , they are being
replaced with acceptable
169

2. METERING VALVE
It delivers only a specified quantity of product
It is most critical component of MDI
It crimped on to the container.
The volume of valve ranges from 25100l for inhalation
and up to 5ml for topical use.
Such valve consist of two valve chambers both are
connected to actuator button

Metered Dose Inhalers


OBJECTIVES
To minimize the number of administrations.
To improve the drug delivery into the nasal passage ways
and respiratory air ways.

Advantages of MDI
It delivers specified amount of dose
Small size and convenience
Usually inexpensive
Quick to use
Multi dose capability more than 100 doses available
Disadvantages of MDI
Difficult to deliver high doses
Most products have low lung deposition
Drug delivery highly dependent on good inhaler technology

Uniformity of dosage units


The test is required for aerosols fitted with dose-metered
valves, metered dose inhaler and dry powder inhalers.
The drug content of atleast 9 of the 10 doses collected from
one inhaler, are between 75% and 125% of label claim, and
none is outside the range of 65% to 135% of the label claim.
If the contents of not more than 3 doses are outside the range
of 75% to 125%, but within the range of 65% to 135% of label
claim, select 2 additional inhalers and follow the procedure for
analyzing 10 doses from each.
The requirements are met if not more than 3 results, out of the
30 values, lie outside the range of 75% to 125% of label claim
and none is outside the range of 65%to 135% of label claim.

175