Aerosols

-- Dr. J
Raju
 INTRODUCTION

• Aerosols - A system that depends on the power of a

compressed gas or liquefied gas to expel the
contents from the container with special valve
system.

• 1942 - First aerosol

• In 1950--- Pharmaceutical aerosol intended for

topical administration

• In 1955 - Developed for the administration into the

respiratory tract
Advantages
• Easy and convenient application
• Can be delivered directly to the affected area
• Rapid response to the medicament
• Reduced irritation
• Dose can be delivered without contamination
• Protect unstable drugs
• Portable

Disadvantages
• Expensive
• Propellants are toxic
• Highly inflammable
 Classification of aerosols
According to administration route
– Inhalation aerosols
– Non-inhalation aerosols
– Topical aerosols

According to the working way of valve

– Metered dose aerosols
– Non-metered dose aerosols

According to dispersion system

– Solution aerosols
– Emulsion aerosols
– Suspension aerosols

According to the number of phases

– Two phases aerosols
– Three phases aerosols
 Components of Aerosols

• Propellants
• Containers
• Valves and actuators
• Product concentrate
 Propellants

Responsible for developing proper pressure within the

container.

Provide driving force to expel the product from the

container.

Types of propellants
(a) Liquefied gases (b) Compressed gases
LIQUIFIED GAS

FLUORINATED HYDROCARBONS

Almost all types of pharmaceuticals, Inhalation and oral

Advantages
– Chemical inertness
– Lack of toxicity
– Non flammability & explosiveness

Disadvantages
– High cost
– It depletes the ozone layer
– Damage Global Warming Potential
HYDROCARBONS
– Can be used for water based aerosols, topical use

Advantages
– Inexpensive
– Excellent solvents
– It does not cause ozone depletion
Disadvantages
– Flammable
– Unknown toxicity produced
e.g. propane , butane , isobutane
Recently HFA propellants are used instead of CFC
propellants.
COMPRESSED GASES

- Used when the aqueous phase need not be miscible

with the propellant
- Do not have chilling effect, for topical preparation

Advantages
– Inexpensive
– Non flammable
– No environmental problems

Disadvantages
– Pressure falls during use
– Produce coarse droplet spray
– Require use of non volatile co-solvent
e.g. CO2, N2O, N2
Containers

• Containers must withstand pressure 140-180 psig

at 130°F
Types of Containers
• Metal containers
– Tin Plated Steel (140 - 180 psig)
– Aluminum (180 psig)
– Stainless Steel (180 psig)
• Glass containers
- Uncoated glass
- Plastic coated glass
- Plastic Containers
Metal Containers
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 body attach by soldering
Recent developments in welding include
Soudronic system- copper wire as electrode
Conoweld system – two rotating electrode rings.
• Corrosion minimized,
• Decrease product and container interaction
• Saves considerable mfg time
• Better appreciation of quality control aspects
• Non aqueous product can be filled
• Alcohol based pharmaceuticals e.g. spray on bandages
Aluminum Containers
• Many pharmaceutical aerosols are packed in Al
containers
• Light weight, less fragile, Less incompatibility due to its
seamless nature, Greater resistance to corrosion
• Used for inhalation and topical aerosols
• Polar solvents corrosion to Al containers
• Anhydrous ethanol corrosion to Al, produces H2 gas,
this can be overcome by anodizing Al or addition of 2-
3% water
• Non polar solvents are used in Al containers
Stainless Steel Containers
• Small size containers
• Strong
• Reduce corrosion problems
• Used for inhalation aerosols
• No need for internal coating
• Costly
Glass Containers
• Compatible with most formulations
• Allows for greater degree of freedom in container design
resistant to corrosion, low cost.
• 25 psig pressure can be filled or 15% propellant conc.
• Available with or without plastic coating
• Plastic coated glass containers can be filled to a pressure of 33
psig
• Can be safely used
• Limited to use – its brittleness and breakage
Plastic Containers
• Made with acetyl resins or poly propylene
• Can withstand high pressure
 Valves

Easy to open and close

Capable of delivering the content in the desired form
such as spray, foam, solid stream etc.
It can deliver a given amount of medicament
Types
• Continuous spray valves
• Metered valves
CONTINUOUS SPRAY VALVES
Used for topical aerosols
Valves assembles consist of following parts
Ferrule or mounting cup - Attach valve to container
Tin plated steel, Al , Brass (glass bottles), Under side of the valve cup
is coated with single or double epoxy or vinyl resins
Valve body or housing - Made up of nylon or derlin (0.013 to 0.080
inch)
Housing may or may not contain opening called VAPORTAP
This allows escape of vaporized propellant with liquid product
Fine particle, avoids clogging, inverted position, reduce flame
extension and chilling - FCIFC
Stem - Nylon or derlin , Gasket - Buna –N and neoprene rubber
Spring - Stainless steel , to hold gasket in place,
Dip tube - Poly ethylene or poly propylene , i. d- 0.120 – 0.125
inch,
Capillary dip tube – 0.050 inch
High viscous – 0.195 inches

METERING VALVE

• Used for all inhalations and some topical aerosols.

• Applicable to potent medication.
• It has defined volume of reservoir.
• It can be deliver desired volume of medicament by
depressing actuator.
 ACTUATORS
• It is a specially designed button which is fitted to the valve.
• It delivers the product in a desired form.
• It discharges the product as spray, foam, solid stream.
Spray actuators
• It can be used for topical preparation, such as antiseptics,
local anesthetics and foot preparation
• It allows the stream of product concentrate and propellant
to pass through various openings and dispense as spray
• The product is dispensed as a stream rather than as a spray
by the actuator when the propellant conc. is low (50%or
less)
• Mechanical break up actuators
FOAM ACTUATORS
• It consist of large orifice
• Ranges from 0.070—0.0125inch

SOLID STREAM ACTUATORS

• These actuators are required for semi solid products such as
ointments

SPECIAL ACTUATORS
• These are used for a specific purpose
• It delivers the medicament to the appropriate site of action
such as throat, nose, dental and eyes etc.
 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
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 25—100µl for inhalation
and up to 5ml for topical use.
• Such valve consist of two valved chambers both are
connected to actuator button
 Formulation
Consist of two essential components
Product concentrate – Active ingredient or mixture of active
ingredient, other solvents, anti oxidants, and surfactants.
Propellant - single or blend, is used to give desired vapor
pressure, solubility and 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
 Types of Systems
SOLUTION SYSTEM
• Large no of aerosol products can be formulated.
• Solution aerosols produce a fine to coarse spray.
• Two phase system consisting of Vapor and Liquid phase.
• 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
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 (drier particles) while A-17 and A-31 tend
to produce a wetter spray.
• These are useful for topical preparations. Plastic coated glass containers.
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
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 µm 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 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/Vusually).
• 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.
QUICK BREAKING FOAM
• Propellants are external phase
• Especially applicable to topical medications
Ethyl alcohol
Surfactant
Water
HC Propellant
Surfactant should soluble in alcohol and water.
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 adaptor
 Manufacturing of Pharmaceutical Aerosols
PRESSURE FILLING
• Process carried out at room temp
• HC and FHC prop can be filled by this process
• Less propellant loss
• Product is filled in to the container
• Low pressure prop is introduced into the container through the valve
• The container is then removed and filled high pressure prop up to
head of the container
• Then the container is removed and shake
• It is not used for inhalation aerosols
• Most preferable because some solution , emulsion , suspension , and
other preparation which cannot be chilled.
• Not used for metered dose inhaler
COLD FILLING
• In this method the propellants are refrigerated to a temperature at
least 5°F below their boiling points.
e.g. Propellant 12: BP (-30°F), refrigerate it to -35°F
• The chilled product and propellant filled into container, Valve
crimped and passed into a water bath.
• Used for inhalation aerosols
• Used with metered valves and non metered valves
• Should not use to fill HC propellants
 Testing of Pharmaceutical Aerosols

FLAMMABILITY AND COMBUSTIBILITY

• Flame projection: Extension of an open flame by spraying aerosol
for about 4 sec into the flame.
• Flash point: Tag open cup apparatus
Product is chilled (-25°F). Allowed to increase the temperature
and temperature at which vapors ignite is taken as flash point.

PHYSICOCHEMICAL CHARACTERISTICS
• Vapor pressure: pressure gauge
• Density: Hydrometer or Pycnometer
• Moisture content: Karl Fischer, GC
• Identification of propellants: GC, IR
PERFORMANCE
• Aerosol valve discharge rate: Change in weight per time
dispensed.
• Spray pattern
• Dosage with metered valves
- Reproducibility of dosage, each time valve is depressed
- Amount of medication actually received by patient.
• Net contents: Wtotal - Wcontainer
• Foam stability
- Visual inspection with time.
- Time for a given mass to penetrate the foam.
- Rotational viscometers
PARTICLE SIZE DETERMINATION
- Cascade Impactor: 0.1 to 30 microns
- Light scatter decay: Tyndall beam

BIOLOGICAL CHARACTERISTICS
- Therapeutic activity
- Toxicity: Topical effects – irritating, chilling
effect
Inhalation effects (even intended
for topical
preparations)
Thank U