PHARMACEUTICAL AEROSOL

K.Senthil kumar M.Pharm

Asst.Prof
QIS college of Pharmacy,Ongole .Andhra pradesh
 INTRODUCTION

Aerosol is pressurized dosage form in which therapeutically active
drug is dissolved or dispersed or suspended in compressed or
liquified gas to expel the content from the conatiner in the form of
spray

Aerosol mainly used for the treatment of Asthma and COPD

disease etc….

Aerosols are used for either topical , oral or nasal administration

in the form fine particles or mist or fog.

In mid 1950 the pharmaceutical aerosol introduced in market.

DRUGS USE IN AEROSOLS
 ADVANTAGES
It produce Rapid action.

It is suitable for when the degrade in GI tract.

It Directly applied to the affected area.

It Prevents to Oxidation of drugs

It can avoid the hepatic metabolism of drugs.

It can be maintain sterility& easy to portable

It produce local & systemic effect( due to large surface area of
lung and blood capillary )
 DISADVANTAGES

Limited safety hazard (Flammable Nature)

It is a Costly Preparation

It is a chance for continuous deposition of particle in upper

respiratory tract

The propellant may cause chillness to the skin

 TYPES OF AEROSOL SPRAY

There are three types of aerosol spray.

1. Space sprays

2. Surface coating spray

3. Foam spray
 SPACE SPRAY
 These products are delivered as a fine mist is called space spray .It
contains 85% propellant and it is pressurized at 700F with 30-40
psig.
 It contains not more than 50 µm of particle. So it can be retain in air.

eg. Room sprays

 SURFACE & FOAM SPRAY

Aerosols intended for carrying active ingredients to surface are
termed as surface sprays or surface coating spray.

It contains 30 –70% propellant operate between 22–55 psig at 700F.

Eg. Topical Aerosol

Foam aerosols(emulsion ) usually operate between 35 and 55 psig at

21°c and contains only 6-10% propellant.
PHYSIOLOGY OF RESPIRATORY TRACT

The main function of respiratory tract is transfer of O2 from
inspired air to blood and removal of Co2 from the blood.

Respiratory tract divided in to two parts

1.Upper respiratory tract

{ Nose ,throat , pharynx and larynx }

2. Lower respiratory tract

{Trachea, bronchi, bronchioles ,and alveoli }
DIAGRAM OF HUMAN AIRWAYS
PARTICLE DEPOSITION IN RPT

If Particles size >100 µm in diameter may deposit in the
oropharyngeal cavity.

If Particles between 10 to 60µm will be deposited on the

epithelium of the bronchial tract.

If Particles Size is < 2 µm in diameter can reach the alveoli.

AEROSOL CONTAINER
MECHANISM OF PARTICLE DEPOSITION IN
RPT
 There are four mechanisms to operate aerosols
1. Interfacial interception

2. Brownian diffusion

3. Gravitational sedimentation

4. Electrostatic precipitation
 INERTIAL IMPACTION
 Inertial impaction occurs because a particle traveling in an air
stream has its own momentum (the product of its mass and
velocity)
 As the direction of the airflow changes due to a bend or obstacle,
the particle will continue in its original direction for a certain
distance because of its inertia.
 Impaction of particles entering the mouth with a high velocity
occurs either at the back of the mouth or at the bend where the
pharynx leads to the trachea. Only a small fraction of particles
greater than 15 µ m will reach the trachea following mouth
breathing.
 CONTIN……
Deposition by impaction will also occur as the trachea splits
into the left and right bronchus.
GRAVITATIONAL SEDIMENTATION(GS)

GS is the downward movement of particle under the action of

gravity .
 CONTIN….

If particle size is less than 5µm deposition in bronchioles and
alveoli.

 Particles settle by gravitation onto the airway walls.

It was explained by stokes Law

V= 2r2 (d1-d2)g
9ŋ
 BROWNIAN DIFFUSION

Collison and bombardment of small particle by the molecule in
the respiratory tract to produce Brownian motion.
 CONTIN…..
 Brownian motion or diffusion is a mechanism which significantly
affects only particles less than 0.5 µ m in diameter

 These particles are subjected to bombardment by surrounding gas

molecules causing random movement of the particles. In this
situation, the diffusivity of a particle is inversely proportional to its
diameter.
 INTERCEPTION

If the particles contact the airway surface because of
their larger dimension of particle
 ELECTROSTATIC PRECIPITATION

The charge on the surface of the particle may affect
the resultant deposition
i.e. Surface of charged particle( + ve ) interact with a site within
the respiratory tract that posses on opposite charge (-ve).

Unipolar charged aerosols with high number concentrations

repel each other and drive particles towards the walls.
 BREATHING PATTERN

Breathing pattern ,lung physiology will affect the deposition of
particle.

Breath holding after inhalation enhances the deposition of particle

by sedimentation and diffusion.
COMPONENT OF AEROSOL

Aerosol consist of
1. Product concentrate
2. Propellant

Product concentrate consist of API, Additives like

suspending agent , emulsifying agent , antioxidant,
aqeous and non aqueous ,cosolvent etc…
 PROPELLANT
It is responsible for developing the vapour pressure with in the
container and also expel the product when the valve is opened and
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) Chloro fluro carbon (CFC)
C) Hydrocarbons (HC)
2. Compressed gas system
3.Hydrofluoroalkanes
 LIQUIFIED GAS SYSTEM

These compounds are gases at room temperature and atmospheric
pressure .However they can be liquified easily by lowering the
temperature (below the boiling point or by increasing pressure )

These compounds are chosen generally have B.Pt below 700F and
vapour pressure between 14 and 85 psia at 700 F

When it is placed into sealed container it immediately separartes

into a liquid and a vapour phase
 CONTIN…..

Some o f the propellant molecule will leave from the liquid state
to vapor state.The pressure at this point is called vapour pressure

It is denoted by the symbol Psia

As molecule enter the vapor state a pressure gradually develops

no .of molecule in v.state = vapor pressure

FLUORINATED HYDROCARBONS
It is Used for oral and inhalation aerosol preparation.

Chemical Name Chemical Formula Numerical

Designation
Trichloromonoflouromethane CCl3F 11
Dichlorodifluoromethane CCl2F2 12
Dichlorotetrafluroethane CClF2CClF2 114
Chloropentaflouroethane CClF2CF3 115
Monochlorodifluroethane CH3CClF2 142b
Difluroethane CH3CHF2 152 b
Octaflurocyclobutane CF2CF2CF2CFM2 12 C318
 CONTIN……

Psia means = pounds per square inch absolute

The term psig ( pounds per square inch inch gauge)

0 Psig = 14.7 Psia

Eg. Flourinated hydro carbon

CHLORO FLURO CARBON( CFC)
 Advantages
Low inhalation toxicity
High chemical stability
High purity
CFC-11 is a good solvent
 Disadvantages
Destructive to atmospheric Ozone
Contribute to “greenhouse effect”
High cost

eg. 1.Hydrochlorocarbon
2.Hydroflurocarbon
3. Hydrochloro flurocarbon
 HYDROCARBONS

Chemical Name Numerical

Designation
Butane A-17

Isobutane A-31

Propane A-108

It is mainly used for for the preparation of topical preparation

 CONTIN……..

Chemically stable

No hydrolysis

Inflammable

Low toxicity

They are lighter than water
COMPRESSED GAS SYSTEM
Advantages
Low inhalation toxicity
High chemical stability
High purity
Inexpensive
– No environmental problems
 Disadvantages
Require use of a nonvolatile co-solvent
Produce course droplet sprays
Pressure falls during use
Eg.. Co2 , No,N2
 HYDROFLUOROALKANES
 Advantages
Low inhalation toxicity
High chemical stability
High purity
Not ozone depleting
 Disadvantages
Poor solvents
Minor “greenhouse effect”
 High cost
– e.g. 1,1,1,2,3,3,3 – Heptafluoropropane (HFA-227), 1,1,1,2 –
Tetrafluoroethane (HFA-134a)
 PHYSIOCHEMICAL PROPERTIES OF
PROPELLANTS

Vapor pressure

Boiling points

Liquid density
 Vapor pressure of mixture of propellants is calculated by Doltan’s
law which states that total Pressure in any system is equal to the
sum of individual or partial pressure of various compounds

 Raoult’s low regards lowering of the vapor pressure of a liquid by

the addition of another substance, States that the dispersion of the
vapor pressure of solvent upon the addition of solute is proportion
to the mole fraction of solute molecules in solution.

 The relationship can be shown mathematically :

na
pa = ------------ pAo =NApAo ----------(1)
na + nb
 AEROSOL CONTAINER
 They must be stand at pressure as high as 140 to 180 psig
(pounds per sq. inch gauge) at 1300 F.
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
 AEROSOL CONTAINERS

 Containers must withstand pressure as high as 140 to 180 psig

 Types of containers:
1. Tin plate containers
consists of sheet of steel plate that has been electroplated on
both sides with tin
2. Aluminum containers
 greater resistance to corrosion
 Light weight, not fragile
 Good for light sensitive drugs
Stainless steel container
Limited for smaller size
Extremely strong and resistant to most materials
Pressure stand
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
COMPONENT OF AEROSOLS

Actuator

Ferrule or mount cap

Valve body or housing

Stem

Gasket

Spring

Dip tube
 TYPES OF ACTUATOR
Actuators:

These are specially designed button placed on
the valve system which helps in easy opening and
closing 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
CONTIN…..
Spray actuator
 The stream of product concentrate and propellant are dispensed in the form of small

particle through orifices 0.016- 0.040inch.

 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
TYPES OF AEROSOL VALVES

1.Continuous spray valve

Mounting Cup / Ferrule

Valve body or Housing

Stem valve

Gasket

Spring

Dip Tube
2. Metering valve
 VALVE
 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

 continuous spray valve

FERRULE/ mounting cup
 It is used to attach the valve in proper position in container.it
is necessary coated with epoxy resin.

 Valve body / housing :

 It is made of nylon/delrin and contains at the opening point of

diptube(0.013 to 0.080 inch)
 It prevents clogging of p.size,reduce chilling effect of the skin
 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 is
depressed it returns the valve in 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) for c.tube ( 0.050 inch and
Viscous product 0.195)
 TYPES OF AEROSOL
SYSTEM
There are five types of aerosol system

Solution system / Two phase system

Water based system / Three phase system

Suspension or Dispersion system

Foam system
Aqueous stable foam
Non-Aqueous stable foam
Quick Breaking Foam
Thermal foam

Intranasal foam
 SOLUTION SYSTEM

which consists of two phases: a vapor phase and a

liquid phase

Propellant has high pressure hence propellant
114 is added to reduce its vapour pressure .
 WATER BASED SYSTEM

It is three phase system containing vapour phase,
propellant , water.

Ethanol used as a cosolvent to solubilize the propellant
in water

Propellant content varies from 25 -60%
 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 bitartarate is less soluble than Hcl

By Use of surfactant to reduce the agglomeration

Eg. Sorbitan monolaurate ,sorbitan monooleate sorbitan
trioleate, isopropyl myristae.
 FOAM SYSTEM
 They contain Dispersion of AI,A.Vehicle, surfactant and propellant
 Liquified propellant used as internal phase
 Aqueous stable foam :
A. Ingredients( antiseptic )
oil waxes
O/W surfactant
Water
Hydrocarbon
Non aqueous stable foam :
These are prepared by using Glycols
Emulsifying agent used this type PEG Esters
Quick breaking foam :
the product is dispensed a s a foam which then collapsed in to liquid
Useful foor topical medication
 TYPES OF AEROSOLS DELIVERY
Nebulizers

Used to administer medication to people in the form of a mist

inhaled into the lungs.

Meter dose Inhaler (MDI)

It pressurized, hand-held devices that use propellants to deliver

doses of medication to the lungs of a patient Propellant driven
aqueous pump sprays

Dry powder inhaler (DPI)

Delivers medication to the lungs in the form of a dry powder.

NEBULISER

It is a device used to converting a liquid drug(

Solution /suspension) into a fine mist which can
then be inhaled easily

Two types:
• Jet Nebuliser( air jet /air blast)
• Ultrasonic Nebuliser

• Drugs are not conveniently prepared by MDI/ DPI

NEBULIZERS
 JET NEBULIZERS

It is powered by high pressure air

Nebuliser commonly used in hospital and home

for drug administration have small medication
reservoirs(<10ml)
JET NEBULIZER
ULTRSONIC NEBULIZER
METERED DOSE INHALER(MDI)
 METERED DOSE INHALER

Metered-dose inhalers (MDIs), introduced in the mid-
1950.

In MDIs, drug is either dissolved or suspended in a
liquid propellant mixture together with other excipients,
including surfactants,and presented in a pressurized
canister fitted with a metering valve .

A Predetermined dose is release when up on
actuation
 CONTIN….

When released from the canister the formulation undergoes volume
expansion in the passage within the valve and forms mixture of gas.

The high speed of gas flow break the liquid into fine droplets

MDI are Generally Packed In aluminum steel canister with a capacity

of 20 -30 ml.

Aluminium is inert material . So either coated with epoxy material.

CFC used as a propellant in MDI Preparation along with surfactant

and lubricant.
eg. CFC -11, CFC -12, CFC-14

Alternative for propellant CFC – HFA-134,127
MDI
METERING VALVE
 CONTIN……

The metering valve is place in inverted

position.

Depression of the valve stem allows the
content of the metering chamber refill with
liquid from the bulk is ready to dispense
next dose
 ADVANTAGES OF MDI

 Portable
 Low cost
 Disposability
 Hermatically sealed container to prevent
oxidation of formulation.

 It cause valve clogging due to large p.size.

DRY POWDER INHALER(DPI)
 ADVANTAGES

In DPI the drug is inhaled as a cloud of fine particle .
The drug is either preloaded in the inhaled device or
filled in hard gelatin capsule .

DPI are propellant free.

No additive except carrier like lactose .
 It can deliver large dose than MDI

DISADVANTAGES
It chances for spilling of powder from device.
 FORMULATION OF DPI
 Preferable p.size range less than 5µm

 The particle may chance to adhere with mucus. Due to flow

properties .so overcome it is mixed with carriers (30-60 µm)
lactose . ( act as a carrier)

 The large particle will deposit in the throat and smaller particle will
reach into deeper respiratory tract.
SPINHALER (SINGLE DOSE DPI)

The first DPI in the Market( sodium cromoglycate)

MULTIPLE DOSE DEVICE DPI
MANUFACTURING OF PHARMACEUTICAL AEROSOL

Apparatus

Cold filling process

Pressure filling process

Compressed gas filling process

 Preparation of product concentrate

 The aerosol concentrate consists of drug or combination of drugs,

solvents, antioxidants and surfactants formulated as solution,
suspension .

 The aerosol concentrate is first prepared and filled into the container.

 The propellant is then filled into the container. Therefore, part of

the manufacturing operation takes place during the filling operation
measures to ensure that both concentrate and propellant are brought
together in the proper proportion.
COLD FILLING APPARATUS
 COLD FILLING PROCESS
 The principle of cold filling method requires the chilling of all
components including concentrate and propellant to a temperature of -
30 to -40 º 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.
 The heavy vapour of the cold liquid propellant generally
displace the air in the container
 Contin…

 Single head or multiple head rotary unit capable of

vacuum crimping up to 120 can / min are available.
 The rotary unit requires air pressure (90 to 120 lbs /
inch) and vacuum.
 A valve is placed either manually or
automatically depending on the production rate
required.
 CONTIN……..

The valve is crimped in place by using

valve crimper.
 Advantages

 Easy process

Disadvantages
Chilling of the product, container and propellant is required.
Aqueous products, emulsions and those products adversely
affected by cold temperature cannot be filled by this
method.
The cold filling aerosol line consists of:
1.Un-scrambler
2.Air-cleaner
3.Concentrate filler (capable of being chilled)
4.Propellant filler
5.Valve placer
6.Vaccum purger
7.Valve crimper
8.Heated water-bath
9.Labeler
10.Coder and packaging table
VALVE CRIMPER
TESTING OF FILLED CONTAINER

The container passes through a heated water bath in

which the contents of the container are heated to 130 º
F to test for leaks and strength of the container.

The container is air dried, spray – tested, capped and

labeled.
 PRESSURE FILLING
 Pressure filling is carried out at R.T. under high pressure.
 The apparatus consists of a pressure burette capable of metering
small volumes of liquefied gas under pressure into an aerosol
container.
 The propellant is added through the inlet valve located at the
bottom or top of the burette.
 The desired amount of propellant is allowed to flow through the
aerosol 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), the
propellant stops flowing.
 To help in adding additional propellant, a hose leading to a
cylinder of nitrogen or compressed is attached to the upper valve
and the added nitrogen pressure causes the propellant to flow.
 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
 COMPRESSED FILLING
 Compressed gases are present under high pressure in
cylinders. These cylinders are fitted with a pressure
reducing valve and a delivery gauge.
 1.The concentrate is placed in the container
 2.The valve is crimped in place
 3.Air is evacuated by means of vacuum pump
 4.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.
Evaluation of pharmaceutical aerosols
A. Flammability and combustibility
Flame extension
Flash point
B. Physiochemical characteristics
Vapor 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
Leakage
D. Biologic characteristics
E. Therapeutic activity
 FLAME PROJECTION TEST

This test indicates the effect of an aerosol formulation on the

extension 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.
 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.
MEASUREMENT VAPOR
PRESSURE

Determined by pressure gauge

Variation in pressure indicates the presence

of air in headspace.
 MEASUREMENT OF DENSITY

Determined by Hydrometer or a 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.
3. Sufficient sample is introduced through the valve to cause
the hydrometer to rise half way up the length of the tube.
4. The density can be read directly.
 MOISTURE CONTENT
Method used — Karl Fischer method

- G. C has also been used

IDENTIFICATION OF PROPELLANTS
1. G.C,
2 .I.R spectrophotometry
AEROSOL VALVE DISCHARGE RATE

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. It is
Expressed as gram per seconds.
 Spray pattern

 Spray the product on the coated (dye +talc )

Paper. Depending upon the nature of aerosol
water /oil soluble dye is used.
 NET CONTENT

 Weight of empty container = gm

 Weight of the filled container = gm

net content
FOAM STABILITY:
Visual evaluation
Particle size( cascade impactor)