Professional Documents
Culture Documents
Pharmaceutical Aerosols
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.
11/26/15
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 .
10
Working Principle
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
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
23
24
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
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.
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
High purity
Inexpensive
No environmental problem
Disadvantages
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.
35
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
0.50
0.56
Flash point( )
-156
-117
n propane
n isobu tan e
60
1.36
44.1
40
0.69
58.1
Ppropane
n propane
n propane n isobu tan e
P propane
1.36
Pisobu tan e
n isobu tan e
Pisobu tan e
n propane n isobu tan e
0.69
PT=72.98+10.23=83.21psi at 70
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.
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
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
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.
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
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
Advantages:
Cheap.
Malleable and ductile.
Easy to mold.
Disadvantages:
Incompatibility between drug- plastic
and may lose its efficiency and
potency.
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.
68
Actuator
To ensure that aerosol product is delivered
in the proper and desired form.
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
Gasket
It is made of Buna N, Neoprene rubber
Spring
Hold the gasket in its place
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
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.
78
Parameters consideration
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.
lubricants:
isopropyl myristate , oleic acid
4. Foam system:
5. Intranasal aerosol:
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
11/26/15
86
Contains
Drug
87
12 single or mixture.
11/26/15
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.
Contains
Propellant
Water
91
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.
Physical
stability
by,
11/26/15
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.
Steroid
Oleic acid
P-11
P-12 Oleic acid is dispersing agent, aids in reduction of particle
Foam system
Consists
surfactants.
Four
types ,
11/26/15
99
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
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
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
Drawbacks..
This method is restricted to non aqueous
products
And those products not adversely affected by low
temperatures in the range of -40 F
ALTERNATIVE METHOD
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
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.
PRESSURE BURRETTE
pre
TESTING
ROTATORY FILLING
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
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
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.
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.
1. PROPELLANTS :
Parameter
Tested
By
Identification
Purity and
acceptability
Gas
Chromatography
IR
Spectroscopy
Moisture, Halogen,
Non-Volatile
144
Residue
TEST SOLUTIONS
Ingredients
% w/w
Test
Solutions A
Test
Solutions B
Test
Solutions C
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
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.
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.
D. Biological testing :
1. Therapeutic activity
2. Toxicity studies
153
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
4. Identification of
propellants
Gas Chromatography,
IR Spectroscopy.
157
C. Performance:
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
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
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.
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
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
175