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 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.

INERTIAL IMPACTION

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…

PROPELLANTIt 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.

C318CF2CF

2CF

2CFM

212Octaflurocyclobutane

152 bCH3CHF

2Difluroethane

142bCH3CClF

2Monochlorodifluroethane

115CClF2CF

3Chloropentaflouroethane

114CClF2CClF

2Dichlorotetrafluroethane

12CCl2F

2Dichlorodifluoromethane

11CCl3FTrichloromonoflouromethane

Numerical

Designation

Chemical FormulaChemical Name

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

A-108Propane

A-31Isobutane

A-17Butane

Numerical Designation

Chemical Name

HYDROCARBONS

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

�Actuator

�Ferrule or mount cap

� Valve body or housing

� Stem

� Gasket

� Spring

� Dip tube

COMPONENT OF AEROSOLS

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.itis 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 sorbitantrioleate, 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

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.

TYPES OF AEROSOLS DELIVERY

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

Apparatus

�Cold filling process

�Pressure filling process

� Compressed gas filling process

MANUFACTURING OF PHARMACEUTICAL AEROSOL

� 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.

Preparation of product concentrate

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 characteristicsVapor 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

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.

FLAME PROJECTION TEST

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)