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PHARMACEUTICAL AEROSOL

Vikrant SalujaFaculty of Pharmaceutical Sciences

PCTE Group of Institutes, LudhianaPunjab, India

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PHARMACEUTICAL AEROSOL

Aerosols are pressurized dosage forms containing one or more

active drug dissolved, suspended, or emulsified in a propellant or

a mixture of solvent and propellant, which is released on actuation

of the valve as a fine dispersion of liquid or solid in a gaseous

medium.

Used for either topical, oral or nasal administration in the form

fine particles or mist or fog.

Mainly used for the treatment of Asthma and COPD disease

Designed to expel their contents as a fine mist, a coarse wet or

dry spray, a steady stream or a stable or fast breaking foam.

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ADVANTAGES

A dose can be removed without contaminationof remaining material.

Prevents Oxidation of drugs

Maintain sterility

Direct application to the affected area.

Irritation produced by the mechanicalapplication of topical medication is reduced oreliminated.

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TYPES OF AEROSOL SPRAY

There are three types of aerosol spray.

1. Space sprays

These products are delivered as a fine mist.

It contains not more than 50 m of particle.

eg. Room sprays

2. Surface coating spray

Aerosols intended for carrying active ingredients to surface are

termed as surface sprays or surface coating spray.

eg. Topical Aerosol

3. Foam spray

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COMPONENT OF AEROSOL

Aerosol consist of

1. Product concentrate

2. Propellant

Productconcentrateconsist of API, additives like suspending

agent , emulsifying agent,antioxidant, aqeous and non aqueous

sovents, cosolvent etc

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PROPELLANT

It is responsible for developing the vapour pressure

with in the container and also expel the product when

the valve is opened and aids in the atomization or foam

production of the product.

It is classified in to mainly two types

1. Liquified gas system

a) Flourinated hydrocarbon(FHC)

b) Hydrocarbons (HC)

2.Compressed gas system eg CO2 , NO, N2

FHC find widespread use in aerosols for oral and inhalation use. HC and compressed gas find widespread use in aerosols for topical

use.

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Liquified gas system

These compounds are gases at room temperature and atmospheric pressure

.However they can be liquified easily by lowering the temperature (below theboiling point or by increasing pressure )

These compounds are chosen generally have B.Pt below 70o F and vapour

pressure between 14 and 85 psia at 70o F.

When it is placed into sealed container it immediately separartesinto a liquid and a vapour phase

Chemical Name Numerical Designation Vapour Pressure (psia)at

70oF

Trichloromonofluoromethane 11 13.4Dichlorodifluoromethane 12 84.9

Dichlorotetrafluoroethane 114 27.6

Butane A-17 31.6

Isobutane A-31 45.8

Propane A- 108 122.8

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CHLORO FLURO

CARBON( CFC)

Advantages

Low inhalation toxicity

High chemical stability

High purity

Disadvantages

Destructive to

atmospheric Ozone

High cost

HYDROCARBONS

Chemically stable

Inflammable

Low toxicity They are lighter than

water

COMPRESSED GAS

SYSTEM

High chemical stability

High purity

Inexpensive

No environmental

problems

Produce course droplet

sprays

Pressure falls during use

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Aerosol PrincipleLiquifiedgas propellant

+

Product concentrate

Equilibriumestablished

(b/w portion of liqified propllent and which

vaporizes and occupies the upper portion

of aerosol container)

The vapour phase exerts pressure and

this pressure upon actuation of the

areosol valve forces the liquid phase

up the diptube and out of the orifice of

the valve into the atmosphere

Propllent meets the air , it expands and

evaporates because of drop in

preassure , leaving the product

concentrate as airborne liquid droplets

ordry partticles

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AEROSOL CONTAINERContainers must withstand pressure as high as 140 to 180 psig

A. Metals

1. Tinplated steel(a) Side-seam (three pieces)

(b) Two-piece or drawn

(c) Tin free steel

2. Aluminium

(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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AEROSOL CONTAINERTypes of containers:

1. Tin platecontainers

Sheet of steel plate that has been electroplated on both sides with tin.

Welded side seam are done using 2 processes: Soudoronicand Conoweld

2. Aluminumcontainers

Greater resistance to corrosion

Light weight, not fragile

Good for light sensitive drugs

3. Stainless steelcontainer

Limited for smaller size

Extremely strong and resistant to most materials

4. Glass containers

Available with plastic or without plastic coating

Compatible with many additives

No corrosion problems

Can have various shape because of molding

Fragile Not for light sensitive drugs

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COMPONENT OF AEROSOLS

Actuator Ferrule or mounting cup

Valve body or housing

Stem

Gasket

Spring

Dip tube

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TYPES OF ACTUATOR

Actuators:

These are specially designed button placed onthe valve system which helps in easy opening andclosing of the valve.

It helps in deliver the product in the desired form.

There are different type of actuators are used ,

Spray Actuators Foam Actuators Solid Stream Actuators Special Actuators

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FERRULE/ mounting cup It is used to attach the valve in proper position to the container.

Made from tin-plate steel although aluminium also can be used.

To increase resistance to corrosion a single or double epoxy orvinyl coating can be added.

Valve body / housing T

he part of the valve which holds the stem, gasket and spring inplace and to which the dip tube is attached.

It is made ofnylon/delrin and contains an opening at the point

of attachment of the diptube which ranges from 0.013 to 0.080

inch.

The housing may or may not contain another opening vapourtap

Produce fine particle size

Prevents valve clogging with products containing insoluble

materials

Reduce the chilling effect of propllent on skin

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Stem: It is made of nylon /delrin/s.steel. It contains one or more orifice (0.013 to 0.030)

Gasket : It is made of Buna N, Neoprene rubber

Spring:

It is used to hold the gasket in a place and when actuator isdepressed and released, it returns the valve to its closed position

It is made of stainless steel

Dip tube: It is made up of poly propylene material / poly ethylene

Inside diameter (0.120 0.125 inch) for capillary tubes -0.050

inch and Viscous product - 0.195

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TYPES OF AEROSOL SYSTEM

Solution system / Two phase system

Water based system / Three phase system

Suspension or Dispersion system

Foam system

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Solution system / Two phase system Consists of two phases:

Liquid phase Liquified propellent + Product concentrateVapor phase

Active ingredients soluble in the propllent no other solventrequired.

Generally used propellent may consist of:Propellent 12 Fine sprayMixture of propellent 12 and other propellent Coarse spray

As the amount of propellent 12 is increased, the pressureincreases. The preassure of these system necessitatespakaging the contents in a metal container.

Active ingredients to 10 -15 %

Propellent 12/11(50:50) to 100%

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Waterbased system/ Three phase system

Consist of large amount of water, usually to replace all ora portion of nonaqueous solvents.

Three phase system consists of:A layer of water- immisible liquid propellent

A layer of highly aqueous product concentrateA vapour phase

The formulatio must consist of a dispersion of activeingredients and other solvents in an emulsion system inwhich the propellent is in the external phase.

Ethanol is used as cosolvent in these systems.

Surfactants (0.5-2%) are added for homogenousdispersion.

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Suspensionor Dispersion system

It is prepared by dispersion active ingredients in the

propellent or a mixture of propellants by using suspendingagent.

Developed primarily for oral inhalation aerosols.

Eg. Ephedrine bitartarate aerosol

The physical stability of suspension can be increased by:

Control of moisture content- must be below 300ppm

Use of derivatives of AI having minimum solubility in propellent. Reduction of initial particle size to less than 5microns Adustment of density difference Use of surfactants (HLB < 10; 0.01 1 %)

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Foam system

Consist of AIs, aqueous or non aqueous vehicle, surfactant

and propellant. Dispensed as a stable or quick-breaking foam.

Stable foam

Liquified propellent is emulsified and is found in internalphase Both hydrocarbons and compressed gas propellents may

be used.

Quick breaking foam

Liquified propellent is in the external phase

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MANUFACTURING OF PHARMACEUTICAL AEROSOL

Apparatus

Cold filling apparatus

Pressure filling apparatus

Compressed gas filling apparatus

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PRESSURE FILLING

Pressure filling is carried out at R.T. under high pressure.

The apparatus consists of a pressure burette capable of metering smallvolumes of liquefied gas under pressure into an aerosol container.

The propellant is added through the inlet valve located at thebottom or top of the burette.

The desired amount of propellant is allowed to flow through theaerosol valve into the container under its own vapor pressure.

When the pressure is equalized between the burette and the

container (thus happens with low pressure propellant), thepropellant stops flowing.

To help in adding additional propellant, a hose leading to acylinder of nitrogen or compressed is attached to the upper valveand the added nitrogen pressure causes the propellant to flow.

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Pressure filling apparatus

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ADVANTAGES

It is the preferred method for solutions, emulsions and

suspension.

Less chances for contamination of product

with the moisture.

Less propellant is lost

No refrigeration is required, can be carried out at RT

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COLD FILLING PROCESS

The principle of cold filling method requires the chilling

of all components including concentrate and propellantto a temperature of -30 to -40 F.

This temprature is necessary to liquify the propellant

gas.

The cooling system may be a mixture of dry ice and

acetone or refergiration system.

First, the product concentrate is chilled and filled into

already chilled container followed by the chilled liquefied

propellant.

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Cold filling apparatus

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Advantages

Easy process

Disadvantages

Aqueous products, emulsions and those products

adversely affected by cold temperature cannot be filledby this method.

For nonaqueous systems, some moisture usually

appear in the final product due to condensation of

atmospheric presure

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COMPRESSED FILLING

Compressed gases are present under high pressure in

cylinders. These cylinders are fitted with a pressure reducing

valve and a delivery gauge. T he concentrate is placed in the container

The valve is crimped in place

Air is evacuated by means of vacuum pump

The filling head is inserted into the valve opening, valve

depressed and gas is allowed to flow into the container

For those products requiring an increased amount of gas or

those in which the solubility of gas in the product is necessary,carbon dioxide and nitrous oxide can be used.

To obtain maximum solubility of the gas in the product, the

container is shaken manually during and after the filling

operation by mechanical shakers.

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Evaluationofpharmaceuticalaerosols

A.Flammabilityandcombustibility

Flame extension

Flash point

B. Physiochemicalcharacteristics

Vapour pressure

Density

Moisture content Identification of propellant(s)

C. Performance

Aerosol valve discharge rate

Spray pattern

Dosage with metered valves Net contents

Foam stability

Particle size determination

D.BiologiccharacteristicsE. Therapeuticactivity

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FLAME PROJECTION TEST

This test indicates the effect of

an aerosol formulation on theextension of an open flame.

Product is sprayed for 4 sec.

into flame.

Depending on the nature of

formulation, the flame is extended,

and exact length was measured

with ruler.

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FLASH POINT

Determined by using standard Tag Open Cap Apparatus.

PROCEDURE:

Aerosol product is chilled to temperature of - 25 0 F and

transferred to the test apparatus.

Temperature of test liquid increased slowly, and the

temperature at which the vapors ignite is taken a flash point.

Calculated for flammable component, which in case of

topical hydrocarbons.

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MEASUREMENT VAPOR PRESSURE

To determine pressure variation from container to

container.

Determined by pressure gauge or Can puncturing

device.

Variation in pressure indicates the presence of air in

headspace.

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MEASUREMENT OF DENSITY

Determined by Hydrometerora Pycnometer

Procedure:

A pressure tube is fitted with metal fingers and

hoke valve, which allow for the introduction of

liquids under pressure.

The hydrometer is placed in to the glass

pressure tube.

Sufficient sample is introduced through the

valve to cause the hydrometer to rise half way upthe length of the tube.

The density can be read directly.

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MOISTURE CONTENT

KarlFischermethod Gas Chromatography

IDENTIFICATION OF PROPELLANTS

Gas Chromatography

I.R spectrophotometry

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AEROSOL VALVE DISCHARGE RATE

Expressed as gram per seconds.

Determined by taking an aerosol known weight and discharging

the contents for given time using standard apparatus.

By reweighing the container after time limit has expired, the

change in weight per time dispensed is discharge rate.

Spray pattern

Spray the product on the coated (dye +talc ) paper.

Depending upon the nature of aerosol water /oil soluble dye is

used.

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Dosage with metered valves

Reproducibilityofdosageeach timethevalveis depressed.

Amountofmedicationactually receivedbythe patient.

NET CONTENT

Weight of empty container = gm

Weight of the filled container = gm

net content

FOAM STABILITY:

Visual evaluation

Time for a given mass to penetrate the foam

Rotational viscometer

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Particle size

cascade impactor

Operates on the principle that in a stream of particles

projected through a series of nozzles and glass slides at high

velocity, larger particles became impacted first on the lower

stages and the smaller particles pass on and are collected at

higher stages