AEROSOLS
AEROSOLS
“A system that depends on the power of a compressed gas or liquefied gas to
expel the contents from the container.”
“Pharmaceutical aerosols are dosage systems containing one or more active ingredient which
upon actuation emit a fine dispersion of liquid/solid materials in a gaseous medium.”
‘’Pharmaceutical Aerosol is defined as aerosol product containing active ingredients
dissolved ,suspended or emulsified in a propellant or a mixture of solvent and
propellant and intended for oral or topical administration or for administration into
the eye, nose ,ear, rectum and vagina.’’
• In 1942 - First aerosol was developed. (insecticide)
• In1950 - Pharmaceutical aerosol for topical administration was developed.
• In 1955 - Aerosol for the local activity in the respiratory tract was developed
(Epinephrine).
AEROSOLS
Advantages of aerosols:
➢Removal of single dose without contaminating the remaining contents of the system
➢Stability of contents with respect to air, moisture etc.
➢No chance of backflow
➢No rubbing is required
➢Medicaments can be easily spread in most of the effected layer.
➢Convenience ,speed and ease of application.
➢Immediate local application and effect
➢No first pass effect
AEROSOLS
Disadvantages of Aerosols:
➢High cost because all parts of the package are expensive.
➢Disposal of exhausted aerosols packs may be difficult.
➢Protection from heat is necessary otherwise bursting may occur.
➢Toxicity of propellant may cause problems
➢Testing of formulation against all parts is necessary
TYPES OF AEROSOL SYSTEM
1. Pressurized packages
2. Space sprays
3. Surface coating
COMPONENTS OF AEROSOL SYSTEM
1. Propellant
2. Container
3. Valve assembly
4. Product concentrate
PROPELLANTS
“Driving force of an aerosol”
An additive which expels the contents of the container
Two types of propellant
Compressed gases
Liquefied gases
Compressed gases are of two types
Insoluble gases e.g. Nitrogen, Argon
Soluble Gases e.g. CO2, Nitrous Oxide
PROPELLANT
Liquefied Gases
They are gases at room temperature and may be liquefied by cooling
below their boiling point or by compressing them at room temperature
include
A)Flourinated Hydrocarbons (chloroflourocarbons)
❑Trichlomonoflouro methane (Propellant 11)
❑Dichlorodiflouro methane (propellant 12)
❑ Dichlorotetraflouroethane(propellant 114)
❑Theses are propellant of choice in inhalation and oral aerosols .
❑Theses liquefied gas propellants reduce the amount of ozone in the stratosphere
which results in increased reaching of UV rays to earth and increases skin cancers.
PROPELLANT
Liquefied Gases
A)evidence showing exempt from FDA jurisdiction
❑There are no technically feasible alternative to the use of CFC propellant in
theproduct
❑The product provides substantial health or public health benefit , unobtainable with
other propellants
❑The use does not involve a significant release of CFC in the atmosphere or if it does
the release will warranty benefit over harm.
PROPELLANTS
B)Hydrocarbons e.g.
Propane( Propellant A-108),
IsoButane( propellant A-31)
Butane (propellant A-17)
Propellants for water based topical aerosols(sprays).
These are inexpensive, inflammable non toxic propellants.
Propellants may be used individually or in combination.
NOMENCLATURE OF PROPELLANT
a. All propellants are designated by 3 digits (000)
b. When the 1st digit is zero ,the propellant is known by last two digits e.g.
propellant 011 is propellant 11
c. The 1st digit is one less than the no of carbon atoms present.
d. When there are only two digits 1st digit is understood to be 0 and indicates a
methane derivative. when 1st digit is 1 indicates ethane derivative and so on.
e. The 2nd digit is one more than no. of hydrogen atoms in the compound.
f. The last digit represents no of fluorine atoms.
g. In case of isomers, symmetrical isomers presented by only numbers whereas in
asymmetrical isomers letter( i.e a,b,c ) follows the numbers.
HOW PROPELLANT WORKS????
❑Propellant is sealed in container with product concentrate an equilibrium is
established b/w propellant in liquid phase and gaseous phase
❑Vapors occupy the upper portion of the container
❑Vapors exert pressure in all directions
❑Upon actuation, this pressure forces the liquid phase up in the dip tube and
out of the valve
❑As the propellant meets the air, it evaporates leaving the product concentrate
as airborne liquid droplets or dry powders.
❑In the container equilibrium is regained.
CONTAINERS
Should be non reactive with formulation components
Should be able to withstand high pressure as high as 140 to 180 psig(per square
inch gauge) at 130o F.
Containers may be of:
1. Metal
2. Glass
3. Plastic
METALS
▪Tin plated container
▪Aluminum
▪stainless steel
Tin plated steel containers are usually 3 piece
a. Cylindrical body
b. Top
c. Bottom
Aluminum containers may be of one pieced or two pieced
➢ can withstand higher pressure
➢Light in weight, fragile, compatible
➢ should be used with caution with ethanol and water containing formulations .
➢Used for inhalation and topical aerosols
Stain less steel containers are available in small size and used for inhalation
aerosols.
GLASS AND PLASTIC CONTAINERS
Glass
a. Plastic coated
b. Uncoated
Plastic coated glass containers when breaks causes no explosion and permit slow release of propellant
Preferred because of its esthetic appeal and incompatible nature
Limited to products having a lower vapor pressure (33psig) and low %age of propellant
Used for topical and metered dosed inhalation aerosols.
Plastic
Pure plastic containers can not be used due to:
a. Sorption of substance into container walls
b. Leaching of substances from container walls
c. Low pressure withstand properties
VALVE ASSEMBLY
▪Capable of delivering contents of container in desired form, at
desired rate, in proper amount or dose e.g. spray , foam
▪To regulate the flow of medicament and propellant from the
container
▪Materials used to manufacture valves should be inert
▪May be manufactured by plastic, aluminum or stain less steel
▪May be
a. Continuous spray vale : for external use only
b. Metered dose valve: deliver accurate dose
VALVE ASSEMBLY
Following components
➢ Actuator : button pressed by the user to activate the valve
assembly for emission of product
➢ Permits easy opening and closing of the valve assembly
➢ Product discharges through the orifice of actuator
➢ Design of inner chamber and size of emission orifice decides
the physical form of product
➢Spray actuators
➢Foam actuators
➢Solid stream actuators
➢ Type and quantity of propellant used and actuator design and
dimension control the particle size of the emitted product
➢ Larger orifices and less propellant is used for foam sprays than
sprays or mists
VALVE ASSEMBLY
➢ Stem: which supports the actuator delivers the formulation in the
proper form to the chamber of actuator
➢ Gasket : prevents leakage of formulation when the valve is
closed
➢ Spring: holds the gasket in place and bounces back the
actuator when the pressure is released ,returning the valve to
closed position
➢ Mounting cup : attaches the valve to container, holds the valve
in place. underside of it is exposed to formulation , it must meet
the compatibility criterion and if needed should be coated with
inert materials i.e. epoxy resins
VALVE ASSEMBLY
➢ Housing: located below the mounting cap links the dip tube, stem and
actuator. with the stem, its orifice determines the delivery rate and form
of the product to be emitted
➢ Dip Tube: Extends from the housing down into product brings product up
to the valve. Viscosity of the product and intended delivery rate
determines the dimensions of the dip tube and housing
➢ Actuator, stem, housing and dip tube are made up of plastic.
➢ Mounting cup, spring of metal
➢ Gesket of rubber or plastic resistant to the formulation
METERED DOSE INHALERS
➢ Metering valves : used when the formulation is potent
➢ In these metered valve systems, amount of material discharged is
regulated by an auxiliary valve chamber with specific capacity and
dimension
➢ Depression of actuator causes evacuation of this chamber and deliver
its contents
➢ Integrity of chamber is controlled by dual valve mechanism
➢ When actuator valve is closed, chamber is sealed from atmosphere
➢ In this position , chamber is permitted to refill its contents from
container
➢ Effectiveness of delivering drug to the depth of lungs depends upon
the
➢ Particle size
➢ Breathing pattern
➢ Depth of respiration
➢Trans lingual nitroglycerin aerosol
permits a patient to spray droplets of
nitroglycerine onto or under the tongue for
acute relief of angina pectoris
product is not to be inhaled
at the onset of attack, two metered spray of
emissions, each containing 0.4 mg of drug
are administered
AEROSOL SYSTEM
Aerosol formulation consists of two parts
a. Product concentrate
b. Propellant
Product concentrate Consists of
i. Active ingredient
ii. Solvent system
iii. Preservative
iv. Surfactants
v. Antioxidants
AEROSOL SYSTEMS
➢Pressure of an aerosol is critical to its performance
➢It can be controlled by
i. The nature and amount of the product concentrate
ii. The type and amount of the propellant
➢Each formulation is specific, so, a specific amount of propellant can not be employed
➢But a general statement may be made as
➢space sprays :
➢contain a greater amount of propellant than surface coatings so are released with greater
pressure , resultant particles are ejected more violently
➢Space sprays operate at 30 – 40 psig at 21 C
➢Contains as much as 85% of propellant
AEROSOL SYSTEMS
➢Surface aerosols :
➢Surface sprays operate at 25 – 55psig at 21 C
➢Contains as much as 30-70 % of propellant
➢Foam aerosols :
➢Surface sprays operate at 35 – 55psig at 21 C
➢Contains as much as 6-10 % of propellant
➢May be considered to be emulsions
➢Liquefied propellant is partially emulsified with product concentrate rather than
being dissolved because flourinated hydrocarbons are non polar and water insoluble
➢Shaking of the package prior to use further mixes the propellant throughout the
product concenterate
AEROSOL SYSTEMS
Following are the aerosol systems
i. Two phase system
ii. Three phase
iii. Pre-val system
Selection of the system depends upon the
a. site of application
b. physical, chemical properties of the active ingredient
TWO PHASE SYSTEM
Two phase system consists of liquid and vapor phase
Active ingredient is soluble in propellant , which is the liquid
phase
The vapor pressure of the system can be reduced by addition
of less volatile solvents i.e. ethanol, acetone etc.
THREE PHASE SYSTEM
Active ingredient is not soluble in propellant
Three phase system
(water immiscible liquid propellant /highly aqueous product concenterate /vapor )
Water is used to solubilize the A.I
Emulsion type formulation in which propellant is in external phase
Surfactants are used to reduce the surface tension in 0.5- 2 %.
Propellant concentration is 25-60%
If propellant is heavier than water, it is present below the water layer and dip tube must be out of propellant
and in the water to avoid expulsion of the reservoir of liquid propellant.
If propellant is lighter than water it will be present above aqueous layer and dip tube must be reaching the
bottom i.e. in aqueous phase.
Produce foam or spray
COMPRESSED GAS SYSTEM
➢Compressed gas rather than liquefied gas is used
➢Compressed gas filled aerosols have no reservoir of propellants
➢Higher gas pressure are required in these systems
➢Pressure in theses aerosols diminishes as product is used
➢Insoluble gases as nitrogen
➢is used as compressed gas will result in emission of contents in essentially the same form as they
were placed in container
➢ advantage of nitrogen being inert and protectant against oxidation
➢Nitrogen is an odorless, tasteless gas thus cause no effect on formulation taste or smell
➢Soluble gases as carbon dioxide and nitrous oxide
➢ Used when expulsion of propellant along with product concentrate is desired for spraying
or foaming
FOAM SYSTEM
➢Consists of emulsion of propellant + water + drug +emulsifier
➢Three phase system
➢Propellant concentration is 6-10%
➢Rapid vaporization of propellant from formulation gives rise to foam formation.
➢Stable foams: propellant conc. 3-5%
➢Increase in propellant conc. : stiffer and dryer foam is produces
➢Decrease in propellant conc. : Wetter foam is produced
➢Non aqueous foams: formed by use of various glycols e.g. polyethylene glycol
➢Quick breaking Foams: propellant is in the external phase
➢When dispensed, product is emitted as foam and collapses into liquid
➢Thermal foams: are dispensed warm from the container.oxidation reduction exothermic reaction occurs
➢E.g. in shaving creams
PRE-VAL SYSTEM
❑When propellant and product concentrate are
incompatible to each other and required to be separated
during storage
❑Consists of aluminum cartridge containing propellant and
valve fitting on container having product
❑When actuator is pressed, propellant vaporizes, escapes
from the propellant chamber and draws product up
through dip tube
❑Propellant and product mixed for a very short duration
FILLING OF AEROSOLS
AEROSOL FILLING
Two methods
Pressure filling method
Cold filing method
COLD FILLING METHOD
It consists of an insulated box fitted with copper tubing's and tubing's are coiled to increase
the area for cooling
The insulated box should be filled with alcohol or acetone prior to use.
Non aqueous or products which can withstand low temperature can be used in this method.
The product concentrate is chilled to -40oF and filled into a pre chilled container.
Chilled propellant is added completely in 1 or 2 stages depending on the quantity of
propellant.
Limitations
a. Only for non aqueous systems
b. Ice can collapse the efficiency of system
c. Denaturation of protein at low temp.
PRESSURE FILLING METHOD
Product concentrate is placed quantitatively in container,
then valve assembly is inserted and crimped into the place
then liquefied gas under pressure is metered into the valve system by depressing it
from a pressure burette.
Advantages over cold filling:
High speed
Less loss of propellant
Low risk of moisture contamination
PRESSURE FILLING EQUIPMENT
PACKAGING
➢Packaged as part of manufacturing process
➢Have a protective cap over the valve and mounting cup
➢Cap Protects valve against contamination
➢Caps are made up of plastic or metal
➢Serves as decorative purpose
LABELING
➢Pharmaceutical aerosols are usually dispensed with peel away
labels which can be replaced by pharmacist
➢Manufacturer’s preprinted lables
➢Special labeling requirements for aerosols
➢Not to puncture pressurized container
➢Not to use or store them near heat
➢Not to incinerate
STORAGE
➢Pharmaceutical aerosols are intended to use at room temperature
➢When stored in cold place , less spray is produced
➢Aerosols are generally recommended to store at 15- 30ºC
➢If stored above 49ºC may cause bursting
➢Aerosols should be maintained with protective caps to avoid
accidental activation of valve assembly
PROPER ADMINISTRATION OF PHARMACEUTICAL
AEROSOLS
PROPER ADMINISTRATION OF PHARMACEUTICAL
AEROSOLS
QUALITY CONTROL TESTS
It includes the testing of
1. Propellants
2. Valves, Actuators and Dip Tubes
3. Containers
4. Weight Checking
5. Leak Testing
6. Spray Testing
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1. PROPELLANTS :
Vapor pressure and density of the propellant are
determined and compared with specification sheet.
Parameter Tested By
Identification Gas Chromatography
IR Spectroscopy
Purity and acceptability Moisture, Halogen,
Non-Volatile Residue
determinations
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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.
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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.
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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 Crimp’s 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.
To check for defects in valves and spray pattern.
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. 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. 48
3. Dosage with metered valves :
Reproducibility of dosage can be determined by:
»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 :
Tared cans that have been placed onto the filling lines are
reweighed and the difference in weight is equal to the net
contents.
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.
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