- 1. PHARMACEUTICAL AEROSOLS
2. AEROSOLSAerosols - A system that depends on the power of a
compressed gas or liquefied gas to expel the contents from the
container with special valve system. 1942 - First aerosol Good Hue
& Sullivan 3. AEROSOLS PRINCIPLE When a liquefied gas
propellant or propellant mixture is sealed within an aerosol
container with the product concentrate, equilibrium is quickly
established between the portion of propellant that remains
liquefied and that which vaporizes and occupies the upper portion
of the aerosol container The vapor phase exerts pressure in all
directionsagainst the walls of the container, the valve assembly,
and the surface of the liquid phase, which is composed of the
liquefied gas and the product concentrate. 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 expands and evaporates because
of the drop in pressure, leaving the product concentrate as
airborne liquid droplets or dry particles, depending upon the
formulation. 4. 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. 5. Advantages Easy and
convenient application Can be delivered directly to the affected
area It prevents oxidation of drugs Rapid response to the
medicament It can avoid first pass effect Reduced irritation Dose
can be delivered without contamination Protect unstable drugs
Portable It can maintain sterility It can produce local and
systemic effectsDisadvantages Expensive Propellants are toxic
Highly inflammable Propellants can cause chilling effect to skin 6.
Types of drug delivery systems Nebulizers used to administer
medication to people in the form of a mist inhaled into the lungs.
Meter dose Inhaler (MDI) are 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.
7. Classification of aerosols According to administration route
Inhalation aerosols Non-inhalation aerosols Topical aerosols
According to the working way of valve Metered dose aerosols
Non-metered dose aerosols According to dispersion system Solution
aerosols Emulsion aerosols Suspension aerosols According to the
number of phases Two phases aerosols Three phases aerosols 8.
Components of Aerosols Propellants Containers Valves and actuators
Product concentratePropellants Responsible for developing proper
pressure within the container. Provide driving force to expel the
product from the container. Types of propellants (a) Liquefied
gases (b) Compressed gases 9. LIQUIFIED GAS FLUORINATED
HYDROCARBONS Used in almost all types pharmaceuticals, Inhalation
and oral use Advantages Chemical inertness Lack of toxicity Non
flammability & explosiveness Disadvantages High cost It
depletes the ozone layer Damage Global Warming Potential 10.
NOMENCLATURE OF FLORINATED AEROSOLS EXTREME RIGHT DIGIT INDICATES
NUMBER OF FLORINE ATOMS IN THE MOLECULE THE SECOND DIGIT IN RIGHT
INDICATES ONE GREATER THAN NUMBER OF HYDROGEN ATOMS IN A MOLECULE
THE THIRD DIGIT FROM RIGHT IS ONE LESS THAN THE NUMBER OF CARBON
ATOMS If this number is zero it is omitted and two digit number is
given 11. HYDROCARBONS Can be used for water based aerosols,
topical use Advantages Inexpensive Excellent solvents It does not
cause ozone depletion Disadvantages Flammable Unknown toxicity
produced e.g. propane , butane , isobutane 12. Recently HFA
propellants are used instead of CFC propellants. Hydrofluoroalkanes
Advantages Low inhalation toxicity High chemical stability High
purity Not ozone depleting Disadvantages Poor solvents High cost
Minor green house effect Examples 1,1,1,2,3,3,3-Heptafluoropropane
1,1,1,2-Tetrafluoroethane 13. COMPRESSED GASES - Used when the
aqueous phase need not be miscible with the propellant - Do not
have chilling effect, for topical preparation Advantages
Inexpensive Non flammable No environmental problems Disadvantages
Pressure falls during use Produce coarse droplet spray Require use
of non volatile co solvent e.g. CO2, N2O, N2 14.
ContainersContainers must withstand pressure 140-180 psig at 130F
Types of Containers Metal containers Tin Plated Steel Aluminum
Stainless Steel Glass containers - Uncoated glass - Plastic coated
glass Plastic Containers 15. Metal Containers Tin plated steel
containers It consist of a sheet of steel plate, which is coated on
both sides with tin by electrolytic process The coated sheet is cut
into three sizes and these sizes are desired fabricated in to body
, top , bottom The body is shaped in to cylinder The top and bottom
are attach to the body by soldering If internal organic coating is
required it is given Disadvantage: This process is slow and
expensive Recent developments in welding include Soudronic system-
The round bodies are welded with copper wire electrode and they are
sent to conventional line where the bottom and top are attached
Conoweld system The round body is passed through two rotating
electrode rings and they are sent to conventional line where the
bottom and top are attached 16. Aluminum Containers Many
pharmaceutical aerosols are packed in Aluminum containers Light
weight, Less incompatibility due to its seamless nature, Greater
resistance to corrosion Used for inhalation and topical aerosols
Solvents (Pure Water and ethanol) corrode Al containers The
combination of Anhydrous ethanol and propellant 11 corrode Al,
produces H2 gas, acetyl chloride , aluminum chloride and propellant
21 This can be overcome by anodizing Al or addition of 2-3% water
Non polar solvents are used in Al containers Creams and ointments
17. Advantages with welding method Corrosion minimized Decrease
product and container interaction Saves considerable mfg time Non
aqueous product can be filled Alcohol based pharmaceuticals can be
filled Stainless Steel Containers We are going to prepare only
Small size containers because of its cost Strong Reduce corrosion
problems Used for inhalation aerosols No need for internal coating
18. Glass Containers Compatible with most formulations Allows for
greater degree of freedom in container design resistant to
corrosion, low cost. Available with or without plastic coating
Limited to use its brittleness and breakage Plastic Containers Made
with acetyl resins or poly propylene Can withstand high pressure
19. Types of Containers METAL CONTAINERSmaximum pressure
(psig)Temperature (F)Tin Plated Steelupto
140130Aluminumupto180130Stainless Steelupto181130less than
1870Plastic coated glassless than 2570PLASTIC CONTAINERSless than
2670GLASS CONTAINERS Uncoated glass 20. Valves It is
multifunctional Easy to open and close Capable of delivering the
content in the desired form(spray, foam and solidstream)It can
deliver a given amount of medicament Materials used in construction
of valves should by approved by FDA Types Continuous spray valves
Metered valves 21. Continuous spray valves In this type of aerosols
the product is released as long as the pressure is maintained in
the actuator The valve consists of many different parts and is
assembled using high speed production techniques Ferrule or
mounting cup Valve body or housing Stem Gasket Spring Dip tube 22.
Ferrule or mounting cup Used to attach valve to container It is
made up of Tin plated steel, Al , Brass (glass bottles), Under side
of the valve cup is coated with single or double epoxy or vinyl
resins (To avoid the effects of oxygen trapped in head space) They
are used with glass bottles and small aluminum tubes It is attached
to the bottle by either rolling or clinching method Valve body or
housing Made up of nylon or derlin and contains an opening at the
point of attachment of dip tube (0.013 to 0.080 inch) Housing may
or may not contain another opening called VAPORTAP (0.013 to 0.080
inch)allows escape of vaporized propellant with liquid product Fine
particle avoids clogging, inverted position reduce flame extension
and chilling Stem Nylon or derlin , metals like brass steel can
also be used Gasket Buna N and neoprene rubber They are compatible
with most of the materials 23. Spring Stainless steel to hold
gasket in place, Dip tube Poly ethylene or poly propylene ( more
rigid) , I. D- 0.120 0.125 inch, Capillary dip tube 0.050 inch Dip
tube for Highly viscous products 0.195 inches METERING VALVE It has
defined volume of reservoir It can deliver desired volume of
medicament by depressing actuator. Used for all inhalations and
some topical aerosols. Applicable to potent medication. 24.
ACTUATORS It is a specially designed button which is fitted to the
valve and allows for easy opening and closing of valve It delivers
the product in a desired form. It discharges the product as spray,
foam, solid stream.Types of actuators Spray actuators It allows the
stream of product concentrate and propellant to pass through
various openings ( 0.016 inches to 0.040 inches ) and dispense as
very fine spray The product is dispensed as a stream rather than as
a spray by the actuator when the propellant conc. is low (50%or
less) so for these case Mechanical break up actuators are used ,
which are capable of breaking the stream into fine particles It can
be used for topical preparation, such as antiseptics, local
anesthetics and foot preparation 25. FOAM ACTUATORS It consist of
large orifice (0.0700.0125inch) SOLID STREAM ACTUATORS these
actuators are required for dispensing of semi solid products such
as ointments SPECIAL ACTUATORS These are used for a specific
purpose It delivers the medicament to the appropriate site of
action such as throat, nose, dental and eyes etc. 26. Formulation
Formulation of aerosols consist of two essential components Product
concentrate Active ingredient or mixture of active ingredient,
solvents, anti oxidants, surfactants. Propellant single or blend,
is used to give desired vapor pressure, solubility and 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 27. Types of Systems
SOLUTION SYSTEM Large no of aerosol products are formulated.
Solution aerosols produce a fine to coarse spray. It is also called
as Two phase system because it consists of Vapor and Liquid phase.
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 formula Active drug -10-15% Propellant 12/11
(50:50) to 100% 28. Types of Systems SOLUTION SYSTEM Large no of
aerosol products are formulated. Solution aerosols produce a fine
to coarse spray. It is also called as Two phase system because it
consists of Vapor and Liquid phase. 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 by addition of less volatile solvents such as ethanol,
propylene glycol, glycerin, ethyl acetate. The concentration of
Propellant used is from 5% (for foams) to 95% (for inhalations).
General formula Active drug -10-15% Propellant 12/11 (50:50) to
100% 29. Depending on water content the final product may be
solution or Three phase system. Hydrocarbon propellantsA-70 (drier
particles)e A-17 and A-31 (wetter spray).These are useful for
topical and preparations and in Plastic coated glass containers
when the amount of flamable propellant donot exceed 15 % of total
product weight and the volume capacity of the containers do not
exceed 5 fluid ouncesAlso usefully in inhalation aerosols 30. Water
based system Here the non-aqueous solvents are partly or completely
replaced with water so the name water based system Depending on
formulation they emit spray or foam Also called as three phase
system( water , vapour and propellant phases The formulation is
dispersed in an emulsion system where the propellant is in external
phase Ethanol: Cosolvent and in production of small particles
Surfactants: low water soluble and high non polar soluble (0.5-2%)
Examples: long chain fatty acid esters of polyhyroxylic compounds
Concentration of propellant: 25-60% To achieve the desired fine
particle size with product containing large amounts of water and
low portion of propellant , a mechanical break up actuator is used
along with the vapour tap valve 31. Recent development is use of
aquasol valves Fine mist No chilling effect Designed to dispense
the product efficiently and effectively using small amounts of
propellantsIn aquasol valve the vapour phase of propellant and
product enter the mixing chamber of the actuator separately through
seperate ducts The vapour phase of propellant enters into actuator
with high velocity and the product is also forced into actuator
with the pressure of propellant At this point the product and
vapour are mixed thoroughly and results in uniform , finely
suspended spray 32. Suspension or Dispersed system Here the active
ingredient is dispersed in propellant or mixture of propellant This
system is primarily used with oral inhalation aerosols Physical
stability increased by Control of moisture content (300 ppm)
Moisture content of both suspensoid and propellant should be
controlled because high moisture content results in particle
agglomeration DRYINGUse of derivatives of derivatives of drug with
minimum solubility in propellant When the drug is having partial
solubility it shows signs of particle growthReduction of initial
particle size to less than 5 m for inhalation. GRINDING EQUIPMENT
33. Adjustment of density of propellant and suspensoid to equal by
adjusting the density , the rate of settling of the suspensoid can
be decreased The density can be adjusted by addition of a compound
of higher or lower density so that density of suspensoid and
propellant are made equalUse of dispersing agents 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 %) oleic
acid Dispersing agent Prevention of particle growth Valve lubricant
34. FOAM SYSTEMS Emulsion and foam aerosols consist of active
ingredient, Aq. or non aq. vehicle, surfactant, Propellant. These
systems dispense the product as stable or quick-breaking foams
Liquefied propellant is emulsified and generally in internal phase.
Stable foams AQUEOUS STABLE FOAM NON AQUEOUS STABLE FOAM 35.
AQUEOUS STABLE FOAM Active drug Oil o/w surfactant Water( 95-96.5)
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 produced. Lower propellant concentrations yield wetter foams.
HC and compressed gas propellants are used. NON- AQUEOUS STABLE
FOAMWater is replaced with glycols such as polyethylene glycolsfoam
is 36. QUICK BREAKING FOAM Propellants are external phase
Especially applicable to topical medications It dispenses the
product as foam , which collapses into liquid Ethyl alcohol (
46-66%) Surfactant ( 0.5-5%) Water ( 28-42%) HC Propellant (3-15%)
Surfactant should soluble in alcohol and water. THERMAL FOAM To
produce warm foam for shaving Used for hair colors and dyes . They
are not readily accepted by consumer 37. Manufacturing of
Pharmaceutical Aerosols PRESSURE FILLING Process carried out at
room tempHC and FHC prop can be filled by this processLess
propellant lossLess moisture contamination of the productMost
preferable because some solution , emulsion , suspension , and
other preparation which cannot be chilled.Not used for metered dose
inhalerIt is not used for inhalation aerosols 38. Method in
pressure filling: The product concentrate is quantitatively placed
in the aerosol Containers The valve assembly is inserted and
crimped into place The liquified gas under pressure is metered into
the valve stem from pressure burrete The desired amount of
propellant is allowed to enter the container under its own vapor
pressure When the pressure in the container equals to that in the
burette , propellant stops flowing. Additional amount of propellant
can be added by increasing the pressure in the filling apparatus
through the use of compressed air of nitrogen gas 39. COLD FILLING
In this method the product concentrate and propellants are
refrigerated to a temperature at least 5F below their boiling
points.(30-40C)The cooling system may be mixture of dry ice or
acetone or refrigiration systemThe chilled product concentrate is
quantitaively metered into cold aerosol containerThen liquified gas
is addedWhen sufficient propellant is added , the valve assembly is
inserted and crimped into placeUsed for inhalation aerosolsUsed
with metered valves and non metered valvesShould not use to fill HC
propellants 40. Quality Control of Aerosols Propellants: All the
propellants are shipped to the user along with a specification
sheets. Before propellant is used it is subjected to some tests A
sample of it is sent to laboratory , where its density , vapour
pressure are determined and compared with the specification sheet
And also tests for identification of propellants and if a mixture
of propellants are used their composition is determined by gas
chromatography The for purity point of view , the moisture content
, halogens , non volatile residual contents are determined and are
compared with the specification sheet These tests are preformed to
ensure that the propellants have not been contaminated during
shipment 41. Valves , actuators and dip tubes These parts are
subjected to both physical and chemical inspection Metered dose
valves: Valve Delivery rate: Test procedure: 25 valves are selected
, and placed on the containers , into which the test solutions are
filled. A button type actuator with 0.02 inch or larger orifice is
attached The containers are placed a temperature of 25 10 C The
valve is actuated to fullest extent for atlest 2 seconds following
complete dispensing of single delivery. This procedure is repeated
for 10 times The test unit is weighed and the valve is actuated to
fullest extent for atlest 2 seconds following complete dispensing
of single delivery. Again it is weighed and the difference between
this weight and previous weight is determined it gives the delivery
of the valve 42. The test procedure is repeated for a total of two
individual deliveries from 25 containers The individual delivery
weights are divided by specific gravity of test solution to obtain
the valve delivery per actuation Valve acceptance The test
procedure is applicable to two categories of metered aerosol valves
having the following limits For valves delivering 54l or less , the
limits are 15% 55 t0 200l , the limits are 10% 1.Of the 50
individual deliveries , if four or more are out side the limits for
the specified valve delivery , the valves are delivery 2.If three
individual deliveries are outside the limits another 25 valves are
Samples and test is repeated. The lot is rejected if more than one
is out side the specifications 3. If two deliveries from one valve
are beyond the limits , another 25 valves Should be taken. The lot
is accepted if not more than one delivery is out side the limits
43. Containers: Weight checking Leak testing 44. Testing of
Pharmaceutical Aerosols FLAMMABILITY AND COMBUSTIBILITY Flame
projection: Extension of an open flame by spraying aerosol for
about 4 sec into the flame.Flash point: Tag open cup apparatus
Product is chilled (-25F). Allowed to increase the temperature and
temperature at which vapors ignite is taken as flash
point.PHYSICOCHEMICAL CHARACTERISTICS Vapor pressure: pressure
gauge , water bath , test gaugesDensity: Modified Hydrometer or
PycnometerMoisture content: Karl Fischer, GCIdentification of
propellants: GC, IRConcentration of propellant ratio: GC,
IRSpecific gravity:High pressure cylinder of 500m capacity 45.
PERFORMANCE Aerosol valve discharge rate: Take an aerosol ,
determine its weight and discharge the contents for specified
period of time , reweigh the container , Discharge rate :Change in
weight per time dispensed.Spray pattern Take a paper , treat the
paper with dye-talc mixture The dye may be oil soluble or water
soluble Impinge the spray on the paper attached to rotating disk ,
the particles that strike the paper causes the dye to go into the
solution and gets absorbed on the paper 46. Dosage with metered
valves - Reproducibility of dosage, each time valve is depressed
Determined by assay techniques where one or two doses are dispensed
in a solvent or any material that absorbs active ingredient Or
Weigh a container , dispense several doses and once again determine
the Weight . The difference in weight / no doses gives the average
dose. This is repeated and is compared - Amount of medication
actually received by patient. Net contents: Wtotal - Wcontainer
Foam stability - Visual inspection with time. - Time for a given
mass to penetrate the foam. - Time for the rod inserted in the foam
to fall - Rotational viscometers 47. PARTICLE SIZE DETERMINATION -
Cascade Impactor: 0.1 to 30 microns - Light scatter decay: Tyndall
beam BIOLOGICAL CHARACTERISTICS - Therapeutic activity - Toxicity:
Topical effects irritating, chilling effect Inhalation effects
(even intended for topical preparations) 48. Thank U
