Aerosols

AerosolsAerosolsAerosols are defined as pressurized system in Aerosols are defined as pressurized system in

which therapeutically active drug is which therapeutically active drug is dissolved,suspended,dispersed in compressed or dissolved,suspended,dispersed in compressed or

liquefied gas to expel the contents from container liquefied gas to expel the contents from container in the form of spray.in the form of spray.

components of aerosol packagecomponents of aerosol package

PropellantPropellant ContainerContainer Valve and actuatorValve and actuator Product concentrateProduct concentrate

propellantpropellant

Responsible for developing pressure.Responsible for developing pressure. To expel the product when the valve is To expel the product when the valve is

opened.opened. Aids in atomization or foam production of Aids in atomization or foam production of

productproduct

Types of propellantsTypes of propellants

1.1. Liquefied gases :Liquefied gases : Fluorinated hydro carbonsFluorinated hydro carbons Cholofluorocarbons(CFC)Cholofluorocarbons(CFC) Hydro fluorocarbons Hydro fluorocarbons Hydrochlorofluorocarbon Hydrochlorofluorocarbon HydrocarbonsHydrocarbons Hydrocarbon ethersHydrocarbon ethers

2.2. Compressed gasesCompressed gases

ChlorofluorocarbonChlorofluorocarbon

Chemically inert,non-inflammable,non-toxic.Chemically inert,non-inflammable,non-toxic. Expensive when copared with HC’s.Expensive when copared with HC’s. Immiscible with water(etahnol (only used co solvent for MDI),2-propanol,DMEor Immiscible with water(etahnol (only used co solvent for MDI),2-propanol,DMEor

acetone are used as co solvents to make FHC miscible with water) and miscible acetone are used as co solvents to make FHC miscible with water) and miscible with polar solvents.with polar solvents.

Large expansion ratio.Large expansion ratio. Deplete ozone layer.Deplete ozone layer. Addition of fluorine to carbon increases stability but also increases the risk of Addition of fluorine to carbon increases stability but also increases the risk of

hydrolysis.hydrolysis. Ex: propellant 11 may undergo hydrolysis and form HCl,hence not used for Ex: propellant 11 may undergo hydrolysis and form HCl,hence not used for

aqueous products. instead 114 is used.aqueous products. instead 114 is used. Propellants 134a,227 have similar properties of propellant 12.Propellants 134a,227 have similar properties of propellant 12. Hydrocholorocarbons,hydrofluorocarbons or hydrochlorofluorocarbon are used for Hydrocholorocarbons,hydrofluorocarbons or hydrochlorofluorocarbon are used for

as propellants for topical and cosmetic aerosols.as propellants for topical and cosmetic aerosols. Inhalational aerosols have been exempted form FDA ban and the fluorocarbons Inhalational aerosols have been exempted form FDA ban and the fluorocarbons

namely propellant 12,12/11,12/114 are still used.namely propellant 12,12/11,12/114 are still used.

Hydrocarbon(HC)Hydrocarbon(HC)

Chemically stable, no hydrolysis, inflammable, low order of toxicity.Chemically stable, no hydrolysis, inflammable, low order of toxicity. Less expensiveLess expensive Wide range of solubilty,immiscible with water hence used to make 3phase Wide range of solubilty,immiscible with water hence used to make 3phase

aerosol system.aerosol system. Low expansion ratioLow expansion ratio Environmentally acceptable.Environmentally acceptable. density<1density<1 They are lighter than water hence hey remain on the top of aqueous layer They are lighter than water hence hey remain on the top of aqueous layer

and serves to push the contents out of container.and serves to push the contents out of container. Blending of HC is based upon on the final pressure desired and not on the Blending of HC is based upon on the final pressure desired and not on the

basis of a stayed proportion of individual component.basis of a stayed proportion of individual component. Used with foams and water based aerosols.Used with foams and water based aerosols.

Compressed gasesCompressed gases

Low expansion power and has no chilling Low expansion power and has no chilling effect.effect.

Foams produced by them are less stable when Foams produced by them are less stable when compare with liquefied gas foamscompare with liquefied gas foams

Widely used in dispensing food and non-food Widely used in dispensing food and non-food products in original form i.e., semisolid.products in original form i.e., semisolid.

Used as propellants in dental creams, hair Used as propellants in dental creams, hair preparations,ointments,antiseptics,germiciadal preparations,ointments,antiseptics,germiciadal aerosolsaerosols

ContainersContainers MetalMetal1.1. Tinplate steelTinplate steela.a. side-seam (three piece)side-seam (three piece)b.b. Two-piece or drawnTwo-piece or drawnc.c. Tin-free steelTin-free steel2. Aluminum2. Aluminuma.a. Two pieceTwo pieceb.b. One-piece (extruded or drawn)One-piece (extruded or drawn)3.stainless steel3.stainless steel GlassGlassa.a. UncoatedUncoatedb.b. Plastic-coated glassPlastic-coated glass

Tin-plate steelTin-plate steel Materials used for the manufacture of aerosol container must withstand Materials used for the manufacture of aerosol container must withstand

pressure as 140 to 180 psig at 130pressure as 140 to 180 psig at 13000 F. F. These containers consist of steel plate that has been electroplated on both These containers consist of steel plate that has been electroplated on both

sides with tin.sides with tin. The thickness of tin is described in weight .ex.:#25,#50 etc.The thickness of tin is described in weight .ex.:#25,#50 etc. Size of container is measure of diameter and height.Size of container is measure of diameter and height. Recent development in theses container is welded side-seam which Recent development in theses container is welded side-seam which

eliminates soldering operation, saves manufacturing time and decreases the eliminates soldering operation, saves manufacturing time and decreases the possibility of product/container interaction.possibility of product/container interaction.

Ex: soudronic system and conweld systemEx: soudronic system and conweld system

Aluminum containers:Aluminum containers: Used to manufacture extruded (seamless) containers.Used to manufacture extruded (seamless) containers. Less danger of incompatibility due to its seamless nature and grater Less danger of incompatibility due to its seamless nature and grater

resistance to corrosion.resistance to corrosion. Inside aluminum containers are coated with organis\c materials like Inside aluminum containers are coated with organis\c materials like

epoxy,vinyl,phenolic or polyamide resins to provide additional resistance.epoxy,vinyl,phenolic or polyamide resins to provide additional resistance. Aluminum containers get corroded by pure water and ethanol.Aluminum containers get corroded by pure water and ethanol.

Stainless steel containers:Stainless steel containers: Limited to small size due to production problems and cost.Limited to small size due to production problems and cost. They are extremely strong and resistant to most materials.They are extremely strong and resistant to most materials. In most cases no internal coating is used.In most cases no internal coating is used.

Glass containerGlass container Limited to those products having lower pressure and lower percentage of Limited to those products having lower pressure and lower percentage of

propellant.propellant. Stronger than metallic containerStronger than metallic container Use of glass allows greater degree of freedom in design of container.Use of glass allows greater degree of freedom in design of container. They are of two types namelyThey are of two types namelya.a. Plastic coated glass: these containers are protected by plastic coating that prevents Plastic coated glass: these containers are protected by plastic coating that prevents

the glass from shattering in the event of breakage.the glass from shattering in the event of breakage.b.b. Uncoated glass: low cost and provide clarity by which all the contents of the Uncoated glass: low cost and provide clarity by which all the contents of the

container can be viewed.container can be viewed. Coatings :Coatings : Epoxy or vinyl coating are generally used.Epoxy or vinyl coating are generally used. Vinyl resin forms tough coating but is poorly resistant to steam about 200Vinyl resin forms tough coating but is poorly resistant to steam about 20000 c). c). Epoxy coatings has greater degree or heat stability hence mixture of above two Epoxy coatings has greater degree or heat stability hence mixture of above two

coating are used.coating are used.

ValvesValves Regulate the flow of product and discharge the content.Regulate the flow of product and discharge the content. They prevent the loss of product when the container is not in They prevent the loss of product when the container is not in

use.use. With the help of actuators, the foam present in the container With the help of actuators, the foam present in the container

can be dispensed as spray or wet-stream.can be dispensed as spray or wet-stream.Continuous spray valve: it consists of following parts.Continuous spray valve: it consists of following parts.1.1. Mounting cap or ferrule.Mounting cap or ferrule.2.2. Valve bodyValve body3.3. StemStem4.4. GasketGasket5.5. SpringSpring6.6. Dip tubeDip tube

FerruleFerrule Used to attach the valve proper to the containerUsed to attach the valve proper to the container1.1. For 1 inch container: tin-plate steel,aluminium.For 1 inch container: tin-plate steel,aluminium.2.2. For glass bottles or small aluminum tubes:aluminium,brassFor glass bottles or small aluminum tubes:aluminium,brass Valve body or housingValve body or housing:: It is generally manufactured from nylon or delrin and contains opening It is generally manufactured from nylon or delrin and contains opening

at the point of attachment of dip tube which ranges from 0.013 to 0.080 at the point of attachment of dip tube which ranges from 0.013 to 0.080 inch.inch.

Housing may or may not contain vapor tap which further produces fine Housing may or may not contain vapor tap which further produces fine particle size, prevents clogging, reduces chilling effect on the skin, particle size, prevents clogging, reduces chilling effect on the skin, decreases flame extension in case of hydrocarbons.decreases flame extension in case of hydrocarbons.

Stem:Stem: It is made of nylon or delrin but metals such as brass and stainless steel It is made of nylon or delrin but metals such as brass and stainless steel

can also be used.can also be used. One or more orifices are set into the stem; they range from one orifice of One or more orifices are set into the stem; they range from one orifice of

about 0.013 inch to 0.030 inch, to three orifices of 0.040 inch each.about 0.013 inch to 0.030 inch, to three orifices of 0.040 inch each.

Gasket: Gasket: It is made with Buna-N and Neoprene rubberIt is made with Buna-N and Neoprene rubber..

Spring:Spring: It is used to hold the he gasket in place and when actuator is depressed and It is used to hold the he gasket in place and when actuator is depressed and

released, it returns the valve to its closed position.released, it returns the valve to its closed position. Usually made with stainless steel.Usually made with stainless steel.

Dip tube:Dip tube: Made up of polypropylene (more rigid) or polyethylene .Made up of polypropylene (more rigid) or polyethylene . Inside diameter:0.120-0.125 inch, for capillary tube-0.050 inch and for Inside diameter:0.120-0.125 inch, for capillary tube-0.050 inch and for

viscous products-0.195 inch.viscous products-0.195 inch. Viscosity and delivery rate are important in selection of dip tube.Viscosity and delivery rate are important in selection of dip tube.

ActuatorsActuators These are specially designed button placed on the valve These are specially designed button placed on the valve

system which helps in easy opening and closing of the system which helps in easy opening and closing of the valve.valve.

It helps in delivering the product in the desired form i.e., It helps in delivering the product in the desired form i.e., spray, wet stream or solid stream.spray, wet stream or solid stream.

Different types of actuators:Different types of actuators:

1.1. Spray actuatorsSpray actuators

2.2. Foam actuatorsFoam actuators

3.3. Solid-stream actuatorsSolid-stream actuators

4.4. Special actuatorsSpecial actuators

5.5. Metered-dose inhalersMetered-dose inhalers

Spray actuatorsSpray actuators The stream of product concentrate and propellant are dispensed in the form of small The stream of product concentrate and propellant are dispensed in the form of small

particles through various openings or orifices.(0.016-0.040 inch).particles through various openings or orifices.(0.016-0.040 inch). Large orifices are used in case of high propellant blend which contain propellant 12 Large orifices are used in case of high propellant blend which contain propellant 12

or propane or low boiling propellant.or propane or low boiling propellant. A mechanical break up actuator is used for products containing low amount of A mechanical break up actuator is used for products containing low amount of

propellants(50% or less).propellants(50% or less). These actuators are capable of breaking the stream into fine particles.These actuators are capable of breaking the stream into fine particles. Foam actuatorsFoam actuators They contain relatively larger orifices of diameter 0.070-0.125 inch.They contain relatively larger orifices of diameter 0.070-0.125 inch. Orifices allow the passage passage of product into large chamber, where they Orifices allow the passage passage of product into large chamber, where they

expand and dispensed as foam through larger orifice.expand and dispensed as foam through larger orifice. Solid steam actuators: Solid steam actuators: used to dispense semi solid type of preparation such as ointments etc.used to dispense semi solid type of preparation such as ointments etc. Special actuators:Special actuators: They are specially designed to deliver the medicament on specific sites like They are specially designed to deliver the medicament on specific sites like

throat,nose,eye etc.throat,nose,eye etc.

Metered dose inhalersMetered dose inhalers Metering valve with 20-mm ferule is used foe all metered-dose inhalers Metering valve with 20-mm ferule is used foe all metered-dose inhalers

and nasal aerosols.and nasal aerosols. There are two types of valves namelyThere are two types of valves namely

1.1. Inverted use-do not contain dip tube -for suspension or dispersion type Inverted use-do not contain dip tube -for suspension or dispersion type system.system.

2.2. Upright use-contains capillary dip tube-used for solution type system.Upright use-contains capillary dip tube-used for solution type system. Integral part of these valves is metering chamber is metering chamber Integral part of these valves is metering chamber is metering chamber

that is directly responsible for the delivery of the desired amount of that is directly responsible for the delivery of the desired amount of therapeutic agent.therapeutic agent.

It consists of stem gasket which allows the contents to be dispensed It consists of stem gasket which allows the contents to be dispensed during actuation and metering gasket which will seal off additional during actuation and metering gasket which will seal off additional contents from entering into chamber.contents from entering into chamber.

A tube-spacers or spacers are used to reduce the fraction that is being A tube-spacers or spacers are used to reduce the fraction that is being lost due to deposition in oropharynx and swallowing.lost due to deposition in oropharynx and swallowing.

Types of systemsTypes of systems Solution type:Solution type: It is known as two-phase system since it consists of product concentrate and It is known as two-phase system since it consists of product concentrate and

propellant.propellant. The amount of propellant varies 5%(foams) to 95%(for inhalation purpose).The amount of propellant varies 5%(foams) to 95%(for inhalation purpose). They are useful for inhalational preparationThey are useful for inhalational preparation %weight%weight active ingredient 10-15%active ingredient 10-15% propellant 12/11 (50:50) or (30:70) 85-90%propellant 12/11 (50:50) or (30:70) 85-90% propellant 12/114 (45:55) or (55:45) 85-90%propellant 12/114 (45:55) or (55:45) 85-90% Propellant 12 has very high vapor pressure, hence propellant 114 is added to reduce Propellant 12 has very high vapor pressure, hence propellant 114 is added to reduce

its vapor pressure.its vapor pressure. Hydrocarbons can also be packed in plastic-coated glass provided its % does not Hydrocarbons can also be packed in plastic-coated glass provided its % does not

exceed 15% of total product.exceed 15% of total product. A-70 produces dry particles whereas A-17,A-131 produces wetter spray.A-70 produces dry particles whereas A-17,A-131 produces wetter spray.

Water based systems:Water based systems: It is a three phase system containing propellant phase, water phase and vapor phase.It is a three phase system containing propellant phase, water phase and vapor phase. Ethanol is used as co solvent to solubilize propellant in water.Ethanol is used as co solvent to solubilize propellant in water. Long chain fatty acid esters of polyhydroxylic compounds including glycerol, Long chain fatty acid esters of polyhydroxylic compounds including glycerol,

glycol, and sorbitol esters of oleic , stearic, palmitic and lauric acids (0.5-2%) are glycol, and sorbitol esters of oleic , stearic, palmitic and lauric acids (0.5-2%) are used as surfactantsused as surfactants

Propellant content varies from 25-60% and vapor tap valve may be used to produce Propellant content varies from 25-60% and vapor tap valve may be used to produce fine particles.fine particles.

Aqua sol system utilizes aqua sol valve which dispenses vaporized propellant and Aqua sol system utilizes aqua sol valve which dispenses vaporized propellant and also contributes to the no inflammability of product being dispensed.also contributes to the no inflammability of product being dispensed.

In Aqua sol system there is a mixing chamber of the actuator in which product and In Aqua sol system there is a mixing chamber of the actuator in which product and propellant are mixed with violent force resulting in uniform finely, dispersed spray.propellant are mixed with violent force resulting in uniform finely, dispersed spray.

Suspension or dispersion system:Suspension or dispersion system: Active ingredients are dispersed in propellant or mixture of propellant.Active ingredients are dispersed in propellant or mixture of propellant. The physical stability of dispersion type can be increased byThe physical stability of dispersion type can be increased by

1.1. Control of moisture content: less than 300 ppm.Control of moisture content: less than 300 ppm.

2.2. Use of derivatives of active ingredient with minimum solubility:eg Use of derivatives of active ingredient with minimum solubility:eg epinephrine bitratrate is less soluble than sulfate or HCl salt.epinephrine bitratrate is less soluble than sulfate or HCl salt.

3.3. Reduction of particle size : 1-5 micronsReduction of particle size : 1-5 microns

4.4. Adjustment of density:Adjustment of density:

5.5. Use of surfactants: reduce agglomeration and acts as lubricantsUse of surfactants: reduce agglomeration and acts as lubricants Ex : sorbitan monolaurate , sorbitan monooleate and sorbitan Ex : sorbitan monolaurate , sorbitan monooleate and sorbitan

sesquioleate, sorbitan tri oleate,isopropyl myristate. (001 to 1%)sesquioleate, sorbitan tri oleate,isopropyl myristate. (001 to 1%)

6.6. Using vapor tap valves.Using vapor tap valves.

Foam systems:Foam systems: They contain AI,aqueous vehicle, surfactant and propellant.They contain AI,aqueous vehicle, surfactant and propellant. Liquefied propellants exist as internal phase.Liquefied propellants exist as internal phase.

1.1. Aqueous stable foams:Aqueous stable foams:

active ingredients 95-96%active ingredients 95-96%

oil-waxesoil-waxes

o/w surfactantso/w surfactants

waterwater

Hydrocarbon propellant 3.5-5%Hydrocarbon propellant 3.5-5% Antibiotics, steriods,and other agents are dispersed by this manner.Antibiotics, steriods,and other agents are dispersed by this manner.

Non aqueous stable forms:Non aqueous stable forms: They are formulated by using glycols.ex PEGThey are formulated by using glycols.ex PEG Emulsifying agents used in this type belong to glycol esters.ex Emulsifying agents used in this type belong to glycol esters.ex

propylene glycol esters.propylene glycol esters.

Quick breaking foamsQuick breaking foams Product is dispensed as foam which then collapses into liquid.Product is dispensed as foam which then collapses into liquid. Useful for topical medication.Useful for topical medication. Pressure should be below 25 psig and are packed in glass containersPressure should be below 25 psig and are packed in glass containers .. Manufacture of pharmaceutical aerosols:Manufacture of pharmaceutical aerosols:

1.1. Pressure filling process:Pressure filling process: In this liquefied gas under pressure is filled into an aerosol container. then the In this liquefied gas under pressure is filled into an aerosol container. then the

propellant is added through the inlet valve.propellant is added through the inlet valve. Ti is not suitable fr filling inhalational aerosolsTi is not suitable fr filling inhalational aerosols ..

2.2. Cold filling process:Cold filling process: It involves chilling of product concentrate alone or wit propellant to a It involves chilling of product concentrate alone or wit propellant to a

temperature of -30 to -40temperature of -30 to -4000 F. F. Faster process than pressure filling technique.Faster process than pressure filling technique. Cannot be used for some solutions,emulsions,suspensions and other Cannot be used for some solutions,emulsions,suspensions and other

preparations.preparations. Pressure filling process is preferred over cold filling process because of less Pressure filling process is preferred over cold filling process because of less

danger of contamination of product with moisture, high production speeds and danger of contamination of product with moisture, high production speeds and lees propellant loss with the former.lees propellant loss with the former.

Quality control of aerosolsQuality control of aerosols

1.1. Propellant : tested for vapor pressure, identity, purity and Propellant : tested for vapor pressure, identity, purity and acceptability.acceptability.

2.2. Valves, actuators and dip tubes : valve acceptance, delivery Valves, actuators and dip tubes : valve acceptance, delivery rate.rate.

3.3. Containers : dimensions, defects in lining, weight of Containers : dimensions, defects in lining, weight of container.container.

4.4. Weight checking :Weight checking :

5.5. Leak checking : checking of crimp dimension, leaked tank Leak checking : checking of crimp dimension, leaked tank testing.testing.

6.6. Spray testing : to check valve and spray pattern.Spray testing : to check valve and spray pattern.

Evaluation of aerosolsEvaluation of aerosols Aerosol discharge rateAerosol discharge rate : : aerosol of known weight is taken and contents are discharged for given period aerosol of known weight is taken and contents are discharged for given period

of time using standard apparatus. The change in weight per time dispensed is of time using standard apparatus. The change in weight per time dispensed is known as discharge rate which is expressed as grams per second.known as discharge rate which is expressed as grams per second.

Flame projection testFlame projection test : : The product is sprayed for about 4 sec into a flame and the exact length of The product is sprayed for about 4 sec into a flame and the exact length of

flame extended is measured.flame extended is measured. Flash point testFlash point test : : This is done in Tag-Open Cup apparatus.This is done in Tag-Open Cup apparatus. Product is chilled to -250 F and transferred to test apparatus where the Product is chilled to -250 F and transferred to test apparatus where the

temperature is gradually increased and the temperature at which the vapors temperature is gradually increased and the temperature at which the vapors ignited is taken as flash point.ignited is taken as flash point.

Vapor pressure :Vapor pressure : It is determined by using pressure gauge and pressure variations from container It is determined by using pressure gauge and pressure variations from container

to container indicate presence of air in head space.to container indicate presence of air in head space.

Density : Density : pycnometepycnometerr MoistureMoisture : :measured by using Karl-Fischer method and gas measured by using Karl-Fischer method and gas

chromatography.chromatography. Identification of propellants : gas chromatography and IR spectroscopyIdentification of propellants : gas chromatography and IR spectroscopy ..

Spray patterns :Spray patterns : It is based upon impingement of spray on a paper containing dye (water or oil It is based upon impingement of spray on a paper containing dye (water or oil

soluble dye).soluble dye).

Dosage with metered valves:Dosage with metered valves: It is determined by assaying or by an artificial respiratory systemIt is determined by assaying or by an artificial respiratory system Another method involves weighing the filled container followed by dispensing of Another method involves weighing the filled container followed by dispensing of

several doses and the difference is weight divided by the number of dose dispensed several doses and the difference is weight divided by the number of dose dispensed gives the average dose.gives the average dose.

Net contents : Net contents : to determine the amount areosol placed in container.to determine the amount areosol placed in container.

Foam stability :Foam stability : It involves either time required for a mass to penetrate foam or time for a It involves either time required for a mass to penetrate foam or time for a

given rod that is inserted into foam to fall or by using rotational given rod that is inserted into foam to fall or by using rotational viscometer.viscometer.

Particle size determination:Particle size determination: Determined by using cascade impactor or light scattering decay methods.Determined by using cascade impactor or light scattering decay methods. Biologic testing: to evaluate therapeutic efficacy and toxicity of Biologic testing: to evaluate therapeutic efficacy and toxicity of

formulation.formulation.

Therapeutic activityTherapeutic activity::

Toxicity testing:Toxicity testing: Includes topical and inhalational effects.Includes topical and inhalational effects. Thermistor probes are used to detect temparature changes in skin when Thermistor probes are used to detect temparature changes in skin when

tested for topical effect.tested for topical effect. Inhalational toxicity involves exposure of test animals to vapors sprayed Inhalational toxicity involves exposure of test animals to vapors sprayed

form aerosols.form aerosols.