Download - Pharmaceutical Aerosol (PPT)
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PHARMACEUTICAL AEROSOL
K.Senthil kumar M.Pharm
Asst.Prof
QIS college of Pharmacy,Ongole .Andhra pradesh
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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.
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DRUGS USE IN AEROSOLS
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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 )
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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
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TYPES OF AEROSOL SPRAY
� There are three types of aerosol spray.
1. Space sprays
2. Surface coating spray
3. Foam spray
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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
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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.
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PHYSIOLOGY OF RESPIRATORY TRACT
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� 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 }
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DIAGRAM OF HUMAN AIRWAYS
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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.
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AEROSOL CONTAINER
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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
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� 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
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CONTIN……
Deposition by impaction will also occur as the trachea splits
into the left and right bronchus.
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GRAVITATIONAL SEDIMENTATION(GS)
� GS is the downward movement of particle under the action of
gravity .
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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
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BROWNIAN DIFFUSION
� Collison and bombardment of small particle by the molecule in
the respiratory tract to produce Brownian motion.
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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.
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INTERCEPTION
� If the particles contact the airway surface because of
their larger dimension of particle
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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.
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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.
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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…
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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
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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 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
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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
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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
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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
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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
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A-108Propane
A-31Isobutane
A-17Butane
Numerical Designation
Chemical Name
HYDROCARBONS
It is mainly used for for the preparation of topical preparation
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CONTIN……..
� Chemically stable
� No hydrolysis
� Inflammable
� Low toxicity
� They are lighter than water
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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
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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)
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PHYSIOCHEMICAL PROPERTIES OF
PROPELLANTS
� Vapor pressure
� Boiling points
� Liquid density
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� 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
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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
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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
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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
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�Actuator
�Ferrule or mount cap
� Valve body or housing
� Stem
� Gasket
� Spring
� Dip tube
COMPONENT OF AEROSOLS
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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
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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
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TYPES OF AEROSOL VALVES
1.Continuous spray valve
� Mounting Cup / Ferrule
� Valve body or Housing
� Stem valve
� Gasket
� Spring
� Dip Tube
2. Metering valve
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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
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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
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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 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)
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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
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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 .
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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%
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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.
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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
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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
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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
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NEBULIZERS
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JET NEBULIZERS
� It is powered by high pressure air
� Nebuliser commonly used in hospital and home
for drug administration have small medication
reservoirs(<10ml)
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JET NEBULIZER
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ULTRSONIC NEBULIZER
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METERED DOSE INHALER(MDI)
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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
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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
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MDI
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METERING VALVE
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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
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ADVANTAGES OF MDI
�Portable
�Low cost
�Disposability
�Hermatically sealed container to prevent
oxidation of formulation.
�It cause valve clogging due to large p.size.
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DRY POWDER INHALER(DPI)
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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.
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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.
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SPINHALER (SINGLE DOSE DPI)
The first DPI in the Market( sodium cromoglycate)
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MULTIPLE DOSE DEVICE DPI
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Apparatus
�Cold filling process
�Pressure filling process
� Compressed gas filling process
MANUFACTURING OF PHARMACEUTICAL AEROSOL
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� 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
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COLD FILLING APPARATUS
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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
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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.
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CONTIN……..
�The valve is crimped in place by using
valve crimper.
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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.
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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
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VALVE CRIMPER
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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.
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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
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.
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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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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
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� 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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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
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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
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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
�Determined by pressure gauge
�Variation in pressure indicates the presence
of air in headspace.
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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.
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MOISTURE CONTENT
Method used — Karl Fischer method
- G. C has also been used
IDENTIFICATION OF PROPELLANTS
1. G.C,
2 .I.R spectrophotometry
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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.
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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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NET CONTENT
�Weight of empty container = gm
�Weight of the filled container = gm
net content
FOAM STABILITY:
Visual evaluation
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Particle size( cascade impactor)
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