pharmaceutical aerosols
DESCRIPTION
B.Pharm Pharmaceutical AerosolsTRANSCRIPT
Pharmaceutical Aerosols
Syllabus
• Definition • Propellants• general formulation• manufacturing and• packaging methods • pharmaceutical applications.
Introduction Packaging of therapeutic active ingredients in a pressurized system. ‘A system that depends on the power of a compressed or liquefied gas to expel the contents from the container.’.
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HISTORY•In1941 the aerosol spray can was first put to good use by Americans Lyle
Goodhue and William Sullivan, who are credited as the inventors of the modern spray
can was funded by the government to kill malaria-carrying bugs in WWII for those in
service.
•Their invention paved the way for hair spray and spray paint to come into existence.
•Pressurized aerosol form was developed in early 1950 and was introduced as
Medihaler Epi by Ricker Laboratories.
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Concept of Pharmaceutical Aerosols
‘Pressurized dosage forms containing one or more active
ingredients which upon actuation emit a fine dispersion
of liquid and/or solid materials (smaller than 50 um) in a
gaseous medium.’
Definition• Aerosol is pressurized dosage form in which
therapeutically active drug is dissolved or dispersed or suspended in compressed or liquefied gas to expel the content from the container in the form of spray upon activation of an appropriate valve system.
USE
INTENDED • for topical administration, • for administration into one of the body
cavities (ear, rectum and vagina) or • intended for administration orally or nasally
as fine solid particles or • liquid mists through the pulmonary airways,
nasal passages or oral cavity.
ADVANTAGES• Convenient, easy, portable and maintenance of sterility
and stability.
• Prevents degradation of drugs by oxidation/ Hydrolysis
/hepatic metabolism/GI tract.
• Directly delivered to the affected area in a desired form,
such as spray, steam, quick breaking foam or stable foam.
• Rapid response.
ADVANTAGES• Removal of dose without contamination.
• Controlled and uniform dosage by metered valves.
• Minimized manual contact with drug.
• No manual contact with patient.
• Irritation produced by the mechanical application of
topical medication is reduced or eliminated.
• Application of medication in thin layer.
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DISADVANTAGES• Costly.
• Limited safety hazard (Flammable Nature) thus Cannot be subjected to heat.
• Difficulty in disposal (empty aerosol containers ) .
• Difficulty in formulation.
• Q.C testing is complicated.
• Chance for continuous deposition of particle in upper respiratory tract .
• The propellant may cause chillness to the skin or can irritate the injured skin due to
volatility .
• persons who using an inhalation aerosol/s, the fluorinated hydrocarbons may
cause carcinotoxic effects on rapid and repeated use of the aerosol product
1) SPACE SPRAY:• Its products are delivered in a fine
mist
• It contains 85% propellant and it is pressurized at 30-40psi and 70 °F
• It contains not more than 50µm of particle. So it can be retaining in air.• Example: Room Sprays
2) SURFACE COATING SPRAY:• Aerosols intended for carrying active ingredients to surface are termed as surface sprays or surface coating spray.
• It contains 30 –70% propellant operates between 22–55 psig at 70F. • E.g. Topical Aerosol
3) FOAM SPRAY:
Foam aerosols (emulsion) usually operate between 35 and 55 psi at 21°c and contains only 6-10% propellant
Working Principle
• They depend upon the function of the container, its valve assembly, and an added component--the propellant--for the physical delivery of the medication in proper form
An equilibrium is quickly established between that
portion of propellant which remains liquefied and that
which vaporizes
The vapor phase exerts pressure in all directions--
against the walls of the container, the valve assembly,
and the surface of the liquid phase
It is this pressure that upon actuation of the aerosol
valve forces the liquid phase up the dip tube and out of
the orifice of the valve into the atmosphere.
As the propellant meets the air, it immediately
evaporates due to the drop in pressure, leaving the
product concentrate as airborne liquid droplets or dry
particles, depending upon the formulation.
As the liquid phase is removed from the container,
equilibrium between the propellant remaining
liquefied and that in the vapor state is reestablished.
Thus even during expulsion of the product from the
aerosol package, the pressure within remains virtually
constant, and the product may be continuously released
at an even rate and with the same propulsion.
However, when the liquid reservoir is depleted, the
pressure may not be maintained, and the gas may be
expelled from the container with diminishing pressure
until it is exhausted.
APPLICATIONS OF PHYSICAL GAS LAWS
• Vapour pressure of mixtures of propellants can be calculated according to "Dalton's Law" and "Rault's Law".
• Dalton's Law: Total vapour pressure in any system is equal to the sum of the individual or partial pressures of the various components.
• P = p1 + p2 + p3
• Rault's Law: It is regards lowering of the vapour pressure of a liquid by the addition of another substance.
Aerosols: ComponentsThese are products that are packaged under pressure and contain therapeutically active ingredients that are released upon activation of an appropriate valve system.
The basic components of an aerosol system are •The propellant, •The Product concentrate containing the active ingredient(s),•The container, •The valve, and •The actuator.
Product concentrate consists of API, Additives like suspending agent, antioxidant, aqueous and non aqueous solvents, co solvent, emulsifying agents etc
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Components of aerosols :
Valve and actuator
Container
Propellant Product concentrate container
Propellant • These are the materials which expel the contents of the
container through the valves by applying force.• A propellant is a chemical with a vapor pressure greater than
atmospheric pressure at 40°C (105°F). • Responsible for developing pressure.• Expel the product when the valve is opened.• Aids in atomization or foam production of product.• When the propellant(s) is a liquefied gas or a mixture of
liquefied gases, it frequently serves the propellant and solvent or vehicle for the product concentrate.
Types:1. Compressed Gas Propellants Inert gases
Carbon DioxideNitrous OxideNitrogen
2. Liquefied gas propellants
Hydrocarbons(HC)
Liquefied Petroleum Gases(Propane, Isobutane, n-Butane) Isopentane, n-Pentane.
Chloroflourocarbon (CFC)
Trichloro-mono-flouromethane (11), Di-chloro-diflouro-methane (12) , Di-chloro-tetra-flouro-methane (114)
Fluorinated hydrocarbons(FHC)
1,1 Diflouroethane (152a)
Ethers Dimethyl ether
CLASSIFICATION OF PROPELLANTS(a) Liquefied gases Propellants(b) Compressed gases PropellantsDepending on the route of administration and use, the propellant can be
classified asI) Type-I Propellant: Liquefied gases: 1. Halogenated hydrocarbons : For oral and inhalation Ex: Fluorinated chlorinated hydrocarbons Trichloro monofluoro methane Dichloro difluoro methane 2. Hydrocarbon : Topical Pharmaceutical aerosols Ex: Propane. Butane, Isobutane
II) Type-II Propellant : Compressed gases: 1. Soluble gases: Ex: Carbon dioxide, Nitrous oxide 2. Insoluble gases: Ex: Nitrogen
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LIQUEFIED GAS PROPELLANTS• Liquefied propellants are gases that exist as liquids under pressure. • Because the aerosol is under pressure propellant exists mainly as a liquid, but it will also be in the head space as a gas. • The product is used up as the valve is opened, some of the liquid propellant turns to gas and keeps the head space full of gas. • In this way the pressure in the can remains essentially constant and the spray performance is maintained throughout the life of the aerosol.
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CHLORO FLUORO CARBONS
Advantages • Chemical inertness • Lack of toxicity • Non flammability. • Lack of explosiveness.
• Propellant of choice for oral and inhalation .
Disadvantages • High cost • It depletes the ozone layer
Examples: Trichloromonofluoromethane - Propellant 11 Dichlorodifluoromethane - Propellant 12 Dichlorotetrafluoroethane - Propellant 114
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HYDROFLUORO CARBONS AND HYDRO CHLORO FLUORO CARBONS
•These compounds break down in the atmosphere at faster rate than CFCs.• Lower ozone destroying effect. Advantages • Low inhalation toxicity • High chemical stability • High purity • Not ozone depleting
Disadvantages • Poor solvent • High cost
Examples: Heptafluoro propane (HFA-227)Tetrafluoroethane (HFA-134a) Difluoroethane - Propellant 152a
Chlorodifluoromethane - Propellant 22 Chlorodifluoroethane - Propellant 142 b
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HYDROCARBONS
• Can be used for water based aerosols and topical use. Advantages • Inexpensive • No hydrolysis• Chemically stable• Excellent solvents • It does not cause ozone depletion• Low order of toxicity
Disadvantages • Inflammable • Unknown toxicity produced
Ex: Propane - Propellant A-108 Isobutane - Propellant A-31 Butane - Propellant A-17
B.Revathi , MR college of pharmacy 27
COMPRESSED GAS PROPELLANTS• Compressed gas propellants occupy the head space above the liquid in the can. • When the aerosol valve is opened the gas 'pushes' the liquid out of the can. • The amount of gas in the headspace remains the same but it has more space, and as a result the pressure will drop during the life of the can. • Spray performance is maintained however by careful choice of the aerosol valve and actuator.
Examples: Carbon dioxide, Nitrous oxide and Nitrogen
Compressed Gas– Insoluble gases in liquid phase of aerosol;
• e.g., Nitrogen • It is odourless, tasteless and inert towards the other
components of aerosol and protects the product from oxidation. – Slightly soluble gases in liquid phase of aerosol;
• E.g., Carbon dioxide and nitrous oxide used in dispensing foam product.
Use• Widely used in dispensing food and non-food products in
original form i.e., semisolid.• Used as propellants in dental creams, hair preparations,
ointments, antiseptics, germicide aerosols
Compressed gas propellantsAdvantages Low inhalation toxicity Low expansion power and has no chilling effect. High chemical stability High purity Inexpensive No environmental problem
Disadvantages Require use of a nonvolatile co-solvent Foams produced by them are less stable when compare with
liquefied gas foams. Produce course droplet sprays Pressure falls during use
Difference between Liquefied Propellant and Compressed Gas Propellant
Difference between Liquefied Propellant and Compressed Gas Propellant
• Liquefied Propellant• As the vapor phase leaves the
container, the space above the surface of the liquid increases causing a slight depression in the pressure and at this moment some liquid propellant passes from the solution to the vapor phase to compensate this drop in the pressure and restoring the equilibrium between the vapor and liquid phases.
• The product will have a constant pressure as long as there is some liquid propellant in pressurized package.
• Compressed Gas Propellant• Unlike aerosols prepared with
liquefied gas propellant, compressed gas filled aerosols have no reservoir of propellant. Thus higher gas pressures are required in these systems.
• where the pressure in these aerosols diminishes as the product is used.
Liquefied gases are preferred comparing to compressed gases
Compressed gases Liquefied gases
Among the CFCs used as propellants in pharmaceuticals were; dichlorteterafluoroethane (Freon 114 or propellant 114) trichloromonofluoromethane (Freon 011) dichlorofluoromethane (Freon 012).
N.B the numerical designation system (XYZ); X = number of carbon atoms +1 Y = number of hydrogen atoms - 1 Z = number of fluorine atoms E.g., propellant 113 has 2 C + no H + 3 F
Fluorinated hydrocarbons are gases at room temperature. They may be liquefied by cooling below their boiling point or by compression at room temperature.
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How to determine the vapor pressure of a certain
mixture?
How to determine the vapor pressure of a certain mixture?
Example 1:What is a vapor pressure of a 60:40 mixture of propane and isobutane. Information on two propellants is as follows:
Property propane isobutaneMolecular formula C3H8 C4H10
Molecular weight 44.1 58.1
Boiling point(℉ ) -43.7 10.9
Vapor pressure(psig@70℉ ) 110 30.4
Liquid density(g/ml @70℉ ) 0.50 0.56
Flash point(℉ ) -156 -117
Assume an ideal solution.
For Raoult’s law, we need to determine the number
of moles of each propellants:
36.11.44
60propanen
69.01.58
40tan eisobun
From Raoult’s law, the partial pressure exerted by
the propane is:
psi
Pnn
nP
propaneeisobupropane
propanepropane
98.7211069.036.1
36.1tan
The partial pressure exerted by the isobutane is:
psi
Pnn
nPeisobu
eisobupropane
eisobueisobu
23.104.3069.036.1
69.0
tantan
tantan
The vapor pressure exerted by both gases, PT, is:
PT=72.98+10.23=83.21psi at 70℉
The vapor pressure required for a specific
application can be calculated in a similar
manner and different ratios of propellants
may be used to obtain that pressure.
Dalton’s law
Calculations of the vapor pressure:
Raoult`s law: Total vapour pressure in a container =Σ (sum of) [Mole fraction X vapor pressure] for each
component.Ex: Mix of Propellant 12/11 in 70/30 ratio where:MW 11 = 137.38 Vp 11= 13.4 psigMW 12 = 120.93 Vp 12 = 84.9 psigCalculate total vapor pressure?
Calculations of the vapor pressure:
1- no of moles of p11= 30/137.38 = 0.2182- no of moles of p12 = 70/120.93= 0.579 Ptotal= (0.218/0.218+0.579) X13.4 + (0.579/0.218+0.579)X84.9
= 3.67+ 61.68= 65.35 psig.psia= psig+14.71 atm = 14.696 psi
PHYSIOCHEMICAL PROPERTIES OF PROPELLANTS
1. Vapor pressure
2. Boiling points
3. Liquid density
Vapor pressure of mixture of propellants is calculated by Dalton’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 law
Regards lowering of the vapor pressure of a liquid by the addition of another substance, States that the depression of the vapor pressure of solvent upon the addition of a solute is proportional to the mole fraction of solute molecules in solution.
Components of Aerosols: Container/Canister
Aerosols ContainersThey must be stand at pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at 1300 F.
A. MetalsB. Glass
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Types of CONTAINERS A. Metals
1. Tinplated steel
(a) Side-seam (three pieces)
(b) Two-piece or drawn
(c) Tin free steel
2. Aluminum
(a) Two-piece
(b) One-piece (extruded or drawn)
3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic coated glass
3-piece cans consisting of three components of (1) a bottom lid, (2) a cylindrical body and(3) a top lid (a lid with a lip [an opening] for a beverage can), and 2-piece cans consisting of two components of (3) a body integrated with a bottom lid and (4) a lid with a lip (an opening).
A technique called double seaming is used to attach the can body and can lids (top and bottom) and the contents are protected from external contamination.
3-piece cans are made of a rectangular sheet rolled into a cylindrical body and there are two seaming methods of soldering and electric welding.
Welded cans dominate the market while soldered cans have almost all disappeared from the market. 2-piece cans are further classified depending on their body processing method; drawn cans (drawn cans, draw and redraw cans [DRD cans]), DWI cans (draw and wall ironing cans) and TULC (stretch-draw-ironing cans).
Metal Containers1.Tin plated steel containers• It consist of a sheet of steel plate, this sheet is coated with tin by
electrolytic process• The coated sheet is cut into three desired fabricated pieces • The top and bottom attach to the body by soldering Recent developments in welding includeSoudronic system- copper wire as electrodeConoweld system – two rotating electrode rings.• Saves considerable mfg time • Better appreciation of quality control aspects• Non aqueous product can be filled • Alcohol based pharmaceuticals
e.g. spray on bandages
• Advantages:• Special protective coatings are applied within
the container to prevent corrosion and interaction between the container and formulation if necessary.
• Disadvantage:• The main disadvantage of stainless steel
containers is high cost.• For small sized container only.• Leak of container due to flaws in the seam or
welding.• Corrosion with some preparations.
2.Aluminum Containers• Many pharmaceutical aerosols are packed in Al
containers.• The seamless aerosol containers manufactured by
an impact extrusion process have no leakage, incompatibility and corrosion.
• Light weight, less fragile.• Epoxy, vinyl, or phenolic resins coatings are done
on aluminium containers to reduce the interaction between the aluminium and the formulation.
• Used for inhalation and topical aerosols• Polar solvents corrosion to Al containers • Non polar solvents are used in Al containers
Aluminium
• Aluminium is used in most metered dose inhalers (MDIs) and many topical aerosols.
• Creams and ointments –N2/HC-Propellant.• Anhydrous ethanol corrosion to Al,
produces H2 gas, this can be overcome by anodizing Al or addition of 2-3% water
• The container themselves available in different sizes ranging from 10 ml to over 1,000 ml.
• Advantages:• These are manufactured by extrusion or
by any other methods that make them seamless.
• No leakage compared to the seam type of container thus is of greater safety.
• No incompatibility and corrosion.
• Disadvantages:• High cost.
3. Stainless Steel Containers• Limited for smaller size • Extremely strong and resistant to corrosion• Withstand pressure • Reduce corrosion problems • Used for inhalation aerosols • No need for internal coating • Costly
Stainless steel• Advantages:• It is resistant to corrosion.• No coating is required.• It can withstand high pressure.
• Disadvantages:• Expensive.• Which restricts its sizes to small sized
containers.
4.Glass Containers• Available with plastic or without plastic coating• Compatible with many additives thus Compatible with most
formulations.• Allows for greater degree of freedom in container design as Can
have various shape because of molding• resistant to corrosion, low cost.• Plastic coated glass containers can be filled to a pressure of
33psig • Can be safely used • Limited to use, Fragile – its brittleness and breakage.• Not for light sensitive drugs
4 GLASS
• One of the materials is glass, limited usage because of its brittleness.
• So glass containers are used in lower pressure and when low amount of propellant are in use such as if the pressure is less than 25psig and propellant content is less than 15%.
• In order to protect the glass containers against breakage due to high pressure, it is to be coated with plastic coating in two layers.
• Epoxy and vinyl resins can be used as linings.
• Vinyl resins are not resistant to high temperature of the steam about 200 F.
• But epoxy resins are resistant to steam.
• These coatings are suitable for low pH water based products.
• Used for some topical and Metered dose inhalers aerosols.
• Advantages:• Glass has less chemical incompatibility than metal
containers.• No corrosion.• Glass can be molded to different design.• Glass containers preferred for aerosols.• Disadvantages:• Glass containers must be precise to provide the
maximum in pressure safety and impact resistance.• More chances for accidental breakage.• Not suitable for photosensitive preparations.
5.Plastic Containers• Made with acetyl resins or poly propylene• Can withstand high pressure
PLASTIC
• Plastics are more permeable to vapors and atmospheric air (like oxygen), so it may interact with the formulation and also may lead to oxidative degradation of the formulation.
• Polyethylene tetra phthalate (PET) container as used for some non pharmaceutical products.
• Advantages:• Cheap.• Malleable and ductile.• Easy to mold.• Disadvantages:• Incompatibility between drug- plastic and may
lose its efficiency and potency.
ACTUATOR and Valve Assembly and its components
• Actuator• Valve Assmbly stemValve SeatGasketValve SpringFerrule/Mounting cup/Valve cupValve Body/ HousingDip tube
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TYPES OF ACTUATOR
Actuators:
• Specially designed button placed on the valve system,
• Helps in easy opening and closing of the valve.
• Directs the spray to the desired area.
• It helps in deliver the product in the desired form .
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ActuatorTo ensure that aerosol product is delivered in the proper and desired form.
Different types of actuators
Spray actuators Foam actuators Solid steam actuators Special actuators
SPRAY ACTUATOR1. The stream of product concentrate and propellant are dispensed in the form
of small particle through orifices 0.016-0.040inch.
2. Large orifice are used when high pressure of propellant 12FOAM ACTUATOR
They contain large orifice diameter 0.070-0.125 inch
SEMISOLID STREAM ACTUATORIt is used for dispensing semisolid dosage form
SPECIAL ACTUATORThey are specially designed to deliver the medicament on the specific sites like nose , throat etc.
TYPES OF AEROSOL VALVES
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
1.Continuous spray valve Mounting Cup / Ferrule Valve seal Valve body or Housing Stem Gasket Spring Dip Tube2. Metering valve
1.Continuous spray valve
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Ferrule/ mounting cup • Attach the valve in proper position in container.
• Coated with epoxy resin.
Valve body / housing• Made of nylon/ delrin
• Connect dip tube, stem & actuator
• Determines rate of delivery
Stem• It is made of nylon /delrin /s.steel
• One or more orifice (0.013 to 0.030 inch)
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Gasket
• It is made of Buna –N, Neoprene rubber
Spring• Hold the gasket in its place
• when actuator is depressed it returns the valve in closed position
• Made of stainless steel
Dip tube
• Made of poly propylene material / poly ethylene
• Inner diameter 0.120 –0.125 inch for less viscous
• Viscous product - 0.195 inch.Pea• Most aerosol paints also have a metal, glass or plastic ball called a pea
inside of the can, which. is used to mix the paint when the can is shaken.
the button that the user presses to activate the valve assembly for the emission of the product
supports the actuator and delivers the formulation in the proper form to the chamber of the actuator
prevent leakage of the formulation when the valve is in the closed position.
the mechanism by which the actuator retracts when pressure is released, thereby returning the valve to the closed position
hold the valve in place the link between the dip tube and the stem and actuator
bring the formulation from the container to the valve
Product concentrate• Simply the product concentrate is the active ingredient
of the aerosol is combined with the required adjuncts,• The Active drug (for therapeutic activity)• Propellant/s (to expel the contents from the container)• Antioxidants (to prevent degradation of product)• Surface active agents/ Surfactants (to Increase
Miscibility)• Solvent/s (to prepare a stable and efficacious product
and to retard the evaporation of the propellant)• Other excipients like Vehicles, suspending agents etc.
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Formulation of pharmaceutical aerosolsContains two essential components
• Product concentrate• Propellant
1. Product concentrate
Product concentrate contains ingredients or mixture of active ingredients and other such as solvents, antioxidants and surfactants.
2. Propellant• May be single or blend of various propellants Blends of propellant used in a pharmaceutical formulation to
achieve desired solubility characteristics or various surfactants are mixed to give the proper HLB value for emulsion system.
To give the desired vapor pressure, solubility & particle size.
• Pharmaceutical aerosol may be dispensed as fine mist, wet
spray, quick breaking foam, stable foam, semi solid etc.
• Type of system selected depends on
physical, chemical and pharmacological properties of drug,
Site of application
Formulation of Pharmaceutical Aerosols
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Parameters consideration
Physical, chemical and pharmaceutical properties of active ingredients.
Site of application
Formulation Depending on the type of aerosol system utilized, the pharmaceutical aerosol
may be dispensed as a fine mist, wet spray, quick-breaking foam , stable foam, semisolid or solid.
Type of systems are 1. Solution system : Consist of a solution of active ingredients in pure propellant or a
mixture of propellant and solvents. Easy to formulate, provided that the ingredients are soluble in the
propellantAerosol solutions have been used To make foot preparations Local anesthetics Spray on protective films Anti-inflammatory preparations and Aerosols for oral and nasal applications
2. Suspension or Dispersion systems Active ingredients are suspended or dispersed throughout the propellant or
propellant and solvent phase. Anti-asthmatic drugs, steroids, and antibiotics are delivered as suspension
aerosols. When the valve is actuated, the suspension formulation is emitted as an aerosol and the propellant rapidly vaporizes and leaves a fine dispersion of the product concentrate.
There are some problem arise for suspension aerosols that are include agglomeration, particle size growth, valve clogging, moisture content, and particle size of the dispersed aerosolized particles.
To overcome these problems: lubricants: isopropyl myristate , oleic acid Provide slippage between particles Lubricate components parts of the valve Surfactants: to disperse particles
3. Water based system ( Emulsion, dispersion ):
Relatively large amounts of water can be used to replace all part or part of the non aqueous solvents used in aerosol. These products are generally referred to as water-based aerosols and depending on the formulation are emitted as a spray or foam.
To produce a spray the formulation must consist of a dispersion of active ingredients and the solvents in an emulsion system in which the propellants is external phase.
In this way when the product is dispensed, the propellants vaporizes and disperses the active ingredients into many particles. Since propellant and water are not miscible a three phase forms (propellants phase, water phase and vapor phase) are used. To increase the solubility of propellants in water, ethyl alcohol can be added to the system. Ethanol has been used as a co solvent to solubilize some of the propellant in the water.
4. Foam system: Foams are produced when the product concentrate is dispersed
throughout the propellant and the propellant is in the internal phase; i.e., the emulsion behaves like o/w emulsion.
Aqueous stable foams-The techniques used in preparing an aerosol emulsion are the same as those used for non aerosol emulsions. This is generally used for steroid antibiotics.
Non-aqueous stable foams-Various medicinal agents can be formulated by this way.
Quick breaking foams-These type of system is specially applicable to medication, which can be applied to limited or to large areas without the use of mechanical force to dispense the active ingredients. Quick breaking foams aerosol may be formulated by ethyl alcohol, surfactant, water and hydrocarbon propellant.
Thermal foams - These are used when the warmness is required.
5. Intranasal aerosol: Drug delivery systems intended for the deposition of the
medication into the nasal passageways has long been used as a most effective, means of administering drugs intended to produce either a local action of systemic effect.
The Intranasal aerosol offers numerous advantage including the delivery of a measured dose of drug , excellent depth of penetration into the nasal passageways with minimal intervertent penetration into lungs, reduce droplet of particle size , lower dosage than a comparable system preparation maintenance of sterility from dose to dose.
The modes of administering of intranasal preparations have been limited to nasal drops, non-pressurized nasal sprays (mist), inhalants, intranasal gel, creams, ointments.
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TYPES OF AEROSOL SYSTEM Five types :
1. Solution system / Two phase system
2. Water based system / Three phase system
3. Suspension or Dispersion system
4. Foam system
Aqueous stable foam
Non-Aqueous stable foam
Quick Breaking Foam
Thermal foam
5. Intranasal aerosols
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Solution system / Two phase system
It consists of a solution of active ingredients in liquefied propellant or in the vaporized propellant.
The solvent is composed of the propellant or a mixture of the propellant.
Contains both vapor & liquid.
Drug soluble in propellant – no co-solvent. Co-solvents such as alcohol, propylene glycol, and
polyethylene glycols, which are often used to enhance the solubility of the active ingredients.
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Solution system / Two phase system
Propellant 12 – single or mixture.
In mixture – propellant with vapor pressure less than
propellant 12 , bigger sized aerosol particles due to vapor
pressure reduction.
Propellant has high pressure hence propellant114 is added
to reduce its vapour pressure .
E.g. propellant 12/11(30:70), propellant 12/114(45:55).
SOLUTION SYSTEM • Large no of aerosol products can be formulated. • Solution aerosols produce a fine to coarse spray.• No solvent is required, if active ingredient is soluble in propellant.• Depending on the type of spray, propellant 12 or A-70 (very fine
particles) or mixture of propellant 12 and other propellants. • If low VP propellants are added to P-12, large particle size• The vapor pressure of system is reduced addition of less volatile solvents
such as ethanol, propylene glycol, glycerin, ethyl acetate.• Propellant from 5% (for foams) to 95% (for inhalations).General formulaActive drug -10-15%Propellant 12/11 (50:50) to 100%
Types of Systems
Inhalation aerosolIsoproterenol Hcl – 0.25%W/VAscorbic acid – 0.1Ethanol – 35.75Propellant 12 – 63.9Packed in S.S, Al container of 15 -30 mlHydrocarbons in TopicalEthanol - 10-15Water – 10-15HC propellant A-46 – 55-70Depending on water content the final product may be solution or
three phase system.• Hydrocarbon propellant A-70 produces drier particles, while A-
17 and A-31 tend to produce a wetter spray.• These are useful for topical preparations. Plastic coated glass
containers.
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Water based system / Three phase system
It consist of a suspension or emulsion of the active ingredient(s)in addition to the vaporized propellants.
suspension consists of the active ingredient's that may be dispersed in the propellant system with the aid of suitable excipients such as wetting agents and/or solid carriers such as talc or colloidal silica.
Contains water phase, vapor phase and the propellant.
Propellant content varies from 25 -60%.
Water immiscible with propellant – solubility increased by adding,
- Co – solvent (ethanol)
- Surfactants (0.5% - 2.0%) – non polar ( esters of oleic
acid, palmitic acid, stearic acid)
WATER BASED SYSTEM (Water based aerosols)• Large amounts of water can be used to replace all or part of the non aqueous
solvents used in aerosols.• Produce spray or foam.• To produce spray formulation must consist of dispersion of active ingredients
and other solvents in emulsion system in which the propellant is in the external phase.
• Since propellant and water are not miscible, a three phase aerosol forms (propellant, water and vapor phases).
• Ethanol can be used as cosolvent to solubilize propellant in water.• Low water soluble Surfactants and high solubility in nonpolar solvents will be
useful eg: glycol, glycerol and sorbitan esters of oleic, stearic, palmitic and lauric acids (Conc. 0.5 to 2%)
• Propellant concentration varies from about 25 to 60%.• Aquasol system (Aquasol valve) – dispensing fine mist or spray of active
ingredient dissolved in water (No chilling effect, since only active ingredient and water are dispensed, propellant is in vapor state).
• Differences between aquasol system and three phase system are
• Aquasol dispenses fairly dry spray, very small particles, non
flammability of the product
• Fine and dry spray with 6 parts of water with 1 part of HC
propellant, even it extinguishes fire.
• Alcohol use results in the two phase system
• In Aquasol system vapor phase of Propellant and product enter
actuator through separate ducts moving at high velocity product
and vapor mixed with voilent force results in uniform fine spray
• Fine dry spray or coarse wet spray is obtained
Based on material to be propelled
Two phase system• Product is solid and
insoluble in propellant• Or it is solid or liquid
which dissolves in it • If a product is insoluble
solid than it can be suitably suspended and system will have one liquid phase and a gaseous phase
Three phase system
• Product is immiscible with propellant and dissolved in liquid which also does not mix with propellant
• Gas• Product and• Liquid propellant
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Suspension system Using suspending agent.
Oral inhalation aerosols.
Active ingredients dispersed in propellant or mixture
Physical stability by,
- Control of moisture content
- Active ingredients with minimum solubility.
- Initial particle size < 5 microns
- Propellant density
- Suspending agents
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 bi tartarate is less soluble than Hcl
By Use of surfactant to reduce the agglomeration Eg. Sorbitan monolaurate ,sorbitan monooleate sorbitan trioleate, isopropyl myristae.
SUSPENSION OR DISPERSION SYSTEM • To overcome complications of cosolvents the disperse system was
developed which involves dispersion of active ingredient in the propellant or mixture of propellants.
• To decrease the rate of settling of dispersed particles, surfactants or suspending agents can be added.
• Primarily used for inhalation aerosols.Epinephrine bitartrate (1-5 Microns) minimum solubility in propellantSorbitan trioleateP-114P-12Isoproterenol sulfateOleyl alcoholMyristyl alcoholP-12P-114
SteroidOleic acidP-11P-12 Oleic acid is dispersing agent, aids in reduction of particle
growth, valve lubricant avoids sticking.Agglomeration results in valve clogging, inaccuracy of dosage, damage
to liner or container.• Physical stability increased by
– Control of moisture content (300 ppm)– Reduction of initial particle size to less than 5 µm for inhalation.– Adjustment of density of propellant and suspensoid to equal – Use of dispersing agents– Use of derivatives of derivatives of drug with minimum solubility in
propellant (epinephrine)Isopropyl myristate and mineral oil are used to reduce agglomeration.Surfactants of HLB less than 10 are useful (sorbitan monooleate,
monolaurate, trioleate, sesquioleate. (Conc. 0.01 to 1 %)
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Foam systemConsists of aq. or non aq. vehicles, propellant &
surfactants.
Four types ,
Aqueous stable foams
Non aqueous stable forms
Quick breaking forms
Thermal forms
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Aqueous stable foams- Propellant 3-4%- Dry spray is produced- Propellant – internal phase- Steroidal antibiotics
Non aqueous stable foams- Emulsifying agent - glycol
Quick breaking foams- Propellant – external phase- Topical application- Cationic, anionic, non ionic surfactants
Thermal foams- Delivered as foam on application of heat- Shaving creams
FOAM SYSTEMS Emulsion aerosols consist of active ingredient, Aq. or non aq. vehicle,
surfactant, Propellant.Liquefied propellant is emulsified and generally in internal phase. AQUEOUS STABLE FOAM Active drugOilo/w surfactantWater,HC Propellant (3 -5%)
• Hydrocarbon propellant (3 to 5% W/W or 8-10% V/V usually).• As the amount of propellant increases a stiffer and dryer foam is
produced.• Lower propellant concentrations yield wetter foams.
HC and compressed gas propellants are used.NON AQUEOUS STABLE FOAM
Glycols such as poly ethylene glycols used.Emulsifying agent is propylene glycol monostearate. PEG Esters
QUICK BREAKING FOAM
• Propellants are external phase•The product is dispensed a s a foam which then collapsed in to liquid
Useful for topical medication• Especially applicable to topical medications
Ethyl alcohol
Surfactant
Water
HC Propellant
Surfactant should soluble in alcohol and water.adaptor
FOAM SYSTEM
THERMAL FOAM • To produce warm foam for shaving • Used to hair colors and dyes were unsuccessful.
INTRANASAL AEROSOLS• To deliver measured dose of drug, lower doses compared to systemic products • Excellent penetration into the nasal passage way• Decreased mucosal irritability • Maintenance of sterility from dose to dose• Difference from inhalation aerosol is the design of
FILLING OPERATIONS
Manufacturing
Manufacturing of concentrate
• Addition of propellant
In general Manufacturing of aerosols takes place in two stages
• This manufacturing procedure is quite different from non aerosol pharmaceuticals product
• This require Q.C measures during filling operation to ensure both concentrate and propellant are brought together in the proper proportion
• The aerosol concentrate is prepared and sample is tested (early detection prevents loss of other components)
• Once the propellant is added product is sealed in to a container with a valve
FILLING OF AEROSOLS• The manufactured aerosols can be filled in to
the containers can be done by following methods and apparatus used.
a) Cold filling Apparatusb) Pressure filling apparatusc) Compressed gas filling apparatusd) Rotary filling machine
Methods • 1.cold filling method• This method requires
chilling of all components including concentrate and propellant to temperature -30f or -40 f
2.pressure filling method This method
is carried out at room temperature utilizing pressure equipments
The type of product and size of container usually influence method to be used
product concentrate is chilled to -40 F
added to the chilled container
Than the chilled propellant is added
Alternate method is to chill both concentrate and propellant in a pressure vessel to -40 F
and then added mixture to aerosol container
cold filling method
• A valve is then crimped • then the container passed through a heated
water bath in which content are heated to 130 F This is To test for leak and strength of
container Container is air dried and spray tested if necessary
Drawbacks..• This method is restricted to non aqueous
products • And those products not adversely affected by low
temperatures in the range of -40 F
COLD FILLING PROCESS
PRODUCT CONCENTRATE +PROPELLLENT INTO EQUALLY
COLD AEROSOLE CONTAINER
Propellant is
Chilled to a temp
of 30-40F
Product Concentrate Chilled To a Temp of 30-40F
THE VALVE ASSEBLY IS
INSERTED AND CRIMPED INTO
PLACE
DISPLACEMENT OF
INSIDE AIR OF THE
CONTAINER BY
PROPELLENT VAPOURS
ALTERNATIVE METHOD
CHILL BOTH CONCENTRATE + PROPELLENT IN A PRESSURE VESSEL TO -40F
ADD MIXTURE TO AEROSOLE
CONTAINER
THE VALVE IS PLACED AND
CRIMPED ON TO THE CONTAINER
COLD FILLING APPARATUSConsist of an
insulated box fitted with coiled copper tubing to inc the area exposed to cooling.
The insulated box should be pre filled with acetone or dry ice, that functions as a refrigerating system.
AEROSOL FILLING
PRESSURE FILLING
Pressure filling method• When first developed its slower than cold filling method• With development of new techniques speed of this
method has been greatly increased•
concentrate added to container at room
temperatureThen the propellant is
added through the value /under the cap
Valve is crimped
PRESSURE FILLING•It consists of a pressure burette capable of metering small volume of liquefied gas in to aerosol container under pressure.•Propellant is added from inlet.
•The propellant is allowed to flow with its own vapor pressure in the container through aerosol valve.•The trapped air escapes out from the upper valve
•Propellant stop flowing when the pressure of burette and container becomes equal.•Additional propellant may be added by increasing the pressure in the filling apparatus through the use of compressed gas or nitrogen gas
PROCESS
Through the opening of valve
propellant is added.The trapped air in the container is removed before
adding the propellant.
Valve is placed in
the container
and crimped
Filling of concentrate at room temperatu
re
• Since the valve contain extremely small opening (0.018 to 0.030 inch)
• This step is slow and limits production • With development of rotary filling machines which
allow propellant to be added around and through the valve stem
the speed has been increased For those products adversely affected by air
the air in headspace is evacuated prior to adding of propellant i.e., Trapped air should be removed
1. As some solutions, emulsions, suspensions and other preparations cant be chilled
2. There is less danger of contamination of the product with moisture
3. High production speed can be achieved 4. Less propellant is lost 5. And the method is not limited
Pressure method is preferred to the cold method
prePRESSURE BURRETTE
Pressure burette for laboratory filling of aerosols
TESTINGPASSING
THE CONTAINER
INTO
HEATED WATER BATH
HEAT THE
CONTENTS UPTO 130 C
IF NO BUBBLE FORMATION, AEROSOLE
CONTDRIEDAINER
S ARE, CAPPED AND DISPENSED
ROTATORY FILLING
COMPRESSED GAS FILLING
Compressed gases are present under high
pressure in cylinders.
These cylinders are fitted with a pressure reducing
valve and a delivery gauge
A flow indicator is also present
PROCESS
Gas stop flowing when pressure become equal.
Nitrous oxide and carbon dioxide is used if more gas
is required.
Air is removed with the help
of vacuum pump. Gas is
allowed to flow from
filling head.
The concentrate is placed in
the container. Valve is
placed in the container
ADVANTAGES
DISADVANTAGES
Certain metering valves cannot handled due to pressure
Slower process than cold filling
Filling machine
PACKAGING OF AEROSOLS A unique aspect of pharmaceutical aerosols as compared
to other dosage forms is that the product is actually packaged as part of the manufacturing process.
Most aerosols have a protective cap that fits snugly over the valve & mounting cap.
this protect the valve against contamination with dust & dirt
The cap which is generally made up of plastic or metal also serves a decorative function .
STORAGEExpose to temp.
above 49 C (120 F) may burst an aerosol container.
When the containers are cold less than the usual spray may result.
These products are generally recommended for storage between 15C - 30C (59F & 86F)
LABELING Medicinal aerosols are labeled by the
manufacturer with plastic peel-away labels or easily removed paper labels.
Aerosols have special requirements for use & storage:
For safety, labels must warn users not to use or store them near heat or an open flame.
Aerosols are labeled with regard to shaking before use & holding at the proper angle.
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• Any unwanted reaction(s) between the following is individually checked with different materials for aerosol product stability:
• Product concentrate and the propellant.• Container.• Valve
Pharmaceutical Aerosol Stability
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QUALITY CONTROL TESTS
It includes the testing of
1. Propellants 2. Valves, Actuators and Dip Tubes 3. Containers 4. Weight Checking 5. Leak Testing 6. Spray Testing
1. Moisture content.2. Particle size determination.3. Microbial limits.
ADDITIONAL TESTS
Purpose of Quality control of aerosols1. Propellant : tested for vapor pressure, identity,
purity and acceptability.2. Valves, actuators and dip tubes : valve
acceptance, delivery rate.3. Containers : dimensions, defects in lining,
weight of container.4. Weight checking 5. Leak checking : checking of crimp dimension,
leaked tank testing.6. Spray testing : to check valve and spray
pattern.
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1. PROPELLANTS :
• Vapor pressure and density of the propellant are determined and compared with specification sheet.
Parameter Tested By
Identification
Purity and acceptability
Gas Chromatography IR Spectroscopy
Moisture, Halogen, Non-Volatile Residue determinations
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2. VALVES , ACTUATORS AND DIP TUBES :
• Sampling is done according to standard procedures as found in Military Standards “MIL-STD-105D”.
• For metered dose aerosol valves ,test methods were developed by ‘Aerosol Specifications Committee’
‘Industrial Pharmaceutical Technology Section ‘Academy Of Pharmaceutical Sciences.
• The objective of this test is to determine magnitude of valve delivery & degree of uniformity between individual valves.
• Standard test solutions were proposed to rule out variation in valve delivery.
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TEST SOLUTIONSIngredients% w/w
Test Solutions ‘A’
Test Solutions ‘B’
Test Solutions ‘C’
Iso Propyl Myristate 0.10% 0.10% 0.10%
Dichloro Difluoro methane
49.95% 25.0% 50.25%
Dichloro tetrafluoro ethane
49.95% 25.0% 24.75%
Trichloro monofluoro methane
- - 24.9%
Alcohol USP - 49.9% -
Specific Gravity @ 25°c
1.384 1.092 1.388
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Testing Procedure:
• Take 25 valves and placed on containers filled with specific test solution.
• Actuator with 0.020 inch orifice is attached.• Temperature -25±1°C.• Valve is actuated to fullest extent for 2 sec and
weighed.• Again the valve is actuated for 2 sec and weighed.• Difference between them represents delivery in mg.• Repeat this for a total of 2 individual deliveries from
each of 25 test units. Individual delivery wt in mg.Valve delivery per actuation in µL = Specific gravity of test solution
Valve Acceptance: Deliveries Limit’s54µL or less ± 15%55 to 200 µL ± 10%
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Of the 50 individual deliveries,
• If 4 or more are outside the limits : valves are rejected
• If 3 deliveries are outside limits : another 25 valves are tested.
Lot is rejected if more than 1 delivery is outside the specifications.
• If 2 deliveries from 1 valve are beyond limits : another 25 valves are tested.
Lot is rejected if more than1 delivery is outside specification.
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3. CONTAINERS :• Containers are examined for defects in lining.• Quality control aspects includes degree of conductivity of electric current as measure of exposed metals.• Glass containers examined for Flaws.
4. WEIGHT CHECKING :• Is done by periodically adding to the filling line tared empty aerosol containers, which after filling with concentrate are removed & weighed.• Same procedure is used for checking weight of Propellants being added.
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5. LEAK TESTING :• It is a means of checking crimping of the valve
and detect the defective containers due to leakage.
• Is done by measuring the Crimp’s dimension & comparing.
• Final testing of valve closure is done by passing the filled containers through water bath.
6. SPRAY TESTING :• Most pharmaceutical aerosols are 100% spray
tested.• This serves to clear the dip tube of pure
propellant and pure concentrate.• To check for defects in valves and spray
pattern.
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EVALUATION TESTS
A. Flammability and combustibility :B. Physicochemical characteristics :C. Performance:D. Biological testing :
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EVALUATION TESTS
A. Flammability and combustibility :1. Flash point2. Flame Projection
B. Physicochemical characteristics :1. Vapor pressure2. Density3. Moisture content4. Identification of Propellants
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C. Performance:
1. Aerosol valve discharge rate 2. Spray pattern 3. Dosage with metered valves 4. Net contents 5. Foam stability 6. Particle size determination
D. Biological testing : 1. Therapeutic activity 2. Toxicity studies
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A. Flammability and combustibility
1. Flash point: Apparatus : Tag Open Cup Apparatus Product is chilled to – 25°F and test liquid temperature is allowed to increase slowly and the
temperature at which vapors ignite is called as Flash Point .
2. Flame Projection: Product is sprayed for 4 sec into a flame and the flame is extended ,exact length is measured with a ruler.Flame test indicates the effect of an aerosol formulation on the
extension of an open flame.
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B. Physicochemical characteristics:
Property Method1. Vapor Pressure » Pressure gauge
» Can Puncturing Device.
2. Density » Hydrometer,» Pycnometer.
3. Moisture » Karl Fisher Method,» Gas Chromatography.
4. Identification of propellants
» Gas Chromatography,» IR Spectroscopy.
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C. Performance:
1. Aerosol valve discharge rate :• Contents of the aerosol product of known weight is
discharged for specific period of time.• By reweighing the container after the time limit, the
change in the weight per time dispensed gives the discharge rate ( g/sec).
2. Spray pattern :• The method is based on the impingement of spray on piece of paper that has been treated with Dye-Talc mixture.• The particles that strike the paper cause the dye to go into solution and to be adsorbed onto
paper giving a record of spray for comparison purpose.
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Spray pattern
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3. Dosage with metered valves :• Reproducibility of dosage can be determined by: »Assay techniques »Accurate weighing of filled container followed by dispensing
of several doses . Containers are then reweighed and difference
inweight divided by number of doses dispensed gives average
dose. 4. Net Contents :• Tarred cans that have been placed onto the filling lines are
reweighed and the difference in weight is equal to the net contents.
• Wtotal - Wcontainer
• In Destructive method : weighing a full container and then dispensing as much of the content as possible . The contents are then weighed . This gives the net content.
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5. Foam stability : Methods : » Visual Evaluation, » Time for given mass to
penetrate the foam, » Time for given rod that is
inserted into the foam to fall ,
» Rotational Viscometer. 6. Particle Size Determination :
Methods : »- Cascade Impactor : 0.1 to 30
microns
- Light scatter decay: Tyndall beam
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a). Cascade Impactor :Principle : Stream of particles projected through a series of nozzles and glass slides at high velocity, larger particle are impacted first on lower velocity stage and smaller particles are collected at higher velocity stage. b). Light Scattering Decay :Principle : As aerosol settles under turbulentconditions, the change in the light intensity of a Tyndall beam is measured.
• Sciarra and Cutie developed method based on practical size distribution.
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D. Biological testing:
1.Therapeutic Activity : » For Inhalation Aerosols : dosage of the product is
determined and is related to the particle size distribution.
» For Topical Aerosols : is applied to test areas and adsorption of therapeutic ingredient is determined.
2.Toxicity : » For Inhalation Aerosols : exposing test animals to
vapors sprayed from aerosol container.
» For Topical Aerosols : Irritation and Chilling effects are determined.
Applications:
1.Aerosols are used for oral or topical administration.
2.They exhibit systemic effect.
3.These preparations are easy to carry.
4.They are uniformly applied without touching the affected area.
Wherever the medicament is needed, there the product can be delivered in the required form like foam, spray etc.
It have rapid onset of action. It will act on targeted area without any contamination.
Aerosol dosage form is a dosage form with an easy administration. It’s main advantage is it requires lesser amount of active ingredients or medicaments.
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• At present there is much interest in developing MDIs for conditions including asthma, COPD, Chronic bronchitis ,emphysema and other respiratory diseases etc. • Many of compounds have been developed using biotechnology process and their delivery to the respiratory system via MDI in an extremely challenging undertaking. • As Chlorofluorocarbon (CFC) propellants cause ozone depletion , they are being replaced with acceptable Hydro fluoro carbons (HFC) propellants.
CONCLUSION
2. METERING VALVE
• It delivers only a specified quantity of product
• It is most critical component of MDI
• It crimped on to the container.
• The volume of valve ranges from 25—100µl for inhalation
and up to 5ml for topical use.
• Such valve consist of two valve chambers both are
connected to actuator button
OBJECTIVES– To minimize the number of administrations. – To improve the drug delivery into the nasal passage ways
and respiratory air ways.
Metered Dose Inhalers
Advantages of MDI
• It delivers specified amount of dose
• Small size and convenience
• Usually inexpensive
• Quick to use
• Multi dose capability more than 100 doses available
Disadvantages of MDI
• Difficult to deliver high doses
• Most products have low lung deposition
• Drug delivery highly dependent on good inhaler technology
• Uniformity of dosage units• The test is required for aerosols fitted with dose-metered
valves, metered dose inhaler and dry powder inhalers.• The drug content of atleast 9 of the 10 doses collected from
one inhaler, are between 75% and 125% of label claim, and none is outside the range of 65% to 135% of the label claim.
• If the contents of not more than 3 doses are outside the range of 75% to 125%, but within the range of 65% to 135% of label claim, select 2 additional inhalers and follow the procedure for analyzing 10 doses from each.
• The requirements are met if not more than 3 results, out of the 30 values, lie outside the range of 75% to 125% of label claim and none is outside the range of 65%to 135% of label claim.
•
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