aerosol formulations

1. Pharmaceutical Aerosols
 A System that depends on the power of a compressed
or liquefied gas to expel the contents from the
container.
 1942- Goodhue & Sullivan.
 1950- Topical Pharmaceutical Aerosol.
 1955- Epinephrine aerosol for local action.
 Aerosol products containing therapeutically active
ingredients dissolved, suspended or emulsified in a
propellant or a mixture of solvent and propellant and
intended for topical administration, administration in
to body cavities, or for administration orally or
nasally as fine solid particles or liquid mists through
pulmonary airways, nasal passage or oral cavity.
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2. Advantages of Aerosol dosage forms.
a. Ease & convenience for application.
b. Dose is administered with out
contaminating remaining product.
c. Stability is enhanced for materials affected
by oxygen or moisture.
d. Sterility of the product is maintained when
dose is administered.
e. The medication is delivered directly to the
affected area in the desired foam.
f. Irritation caused by mechanical application
or topical medication can be reduced or
eliminated.
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3. g. Rapid onset of action.
h. Avoid degradation of drug at GIT or
through first pass effect.
i. Lower dose of drug can be used which
minimizes possible adverse effects.
j. Application of medication as thin layer or
film.
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4. Components of Aerosol Package.
1. Propellant.
2. Container.
3. Valve and actuator.
4. Product concentrate.
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5. 1. Propellant
• Helps in Atomization or foam product.
Fluorinated hydrocarbons
 Oral & Inhalation use
Trichloromonofluoromethane (Propellant 11)
Dichlorodifluoromethane (Propellant 12)
Dichlorotetrafluoroethane (Propellant 114)
Hydrocarbons
 Topical pharmaceutical aerosols.
Propane, Butane, Isobutane etc.
Compressed gas
 Topical pharmaceutical aerosols.
Nitrogen, Carbon dioxide, Nitrous oxide etc.
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6. • Blends of propellants are preferred.
• With in limits of individual propellant vapor
pressure.
• Purity effects vapor pressure of propellant.
Daltons law
 Total pressure of any system is equal to the
sum of the individual or partial pressure of
the various components.
P = pa + pb
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7. pa na pA
o NA pA
o
na + nb
pa = Partial vapor pressure of propellant A
pA
o = Vapor pressure of pure propellant A
na = Moles of propellant A
NA = Mole fraction of component A
pb nb pB
o NB pB
o
nb + na
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8. 8
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9. Liquefied gas Vs Compressed gas
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10. 2. Containers
◦ 140-180 Psig at 130o F
A. Metal
1. Tin plated Steel
Side seam (Three piece)
Two piece or drawn
Tin Free Steel
2. Aluminum
Two piece
One piece (Extruded or drawn)
3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic coated glass
C. Plastic
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11. 1. Tin plated containers
 Electroplated on both side by tin.
 Thickness in terms of weight: # 25, # 50, # 100.
 Size indicated by diameter x height.
22/16 x 214/16 or 202x214)
 Tin plated steel are obtained as thin sheet and
may be coated with organic materials.
 Body-Top-Bottom.
 Flanging- Soldering- Welding.
 Coating on finished container is efficient & defect
free but time consuming.
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12. 2. Aluminum containers
 Lesser incompatibility & corrosion free.
 Ethanol-Propellant 11 produce hydrogen, acetyl
chloride, aluminum chloride, propellant 21 & other
corrosive products.
 6Al + 6C2H5OH(Anhydrous) 2(C2H5O)3 Al + 3H2
3. Stainless steel containers
• Stronger, resistance to corrosion.
 No organic coating needed.
 Inhalation aerosols.
 Limited usage, cost, production problems.
4. Glass containers
 With or with out plastic coating.
 Greater design options
 No incompatibility & Its use is limited for products
having lower pressure and lower percentage of
propellant.
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13. Why curved bottom???
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1-The shape strengthens the structure of the
can.
A curved bottom has greater structural integrity.
2-The shape makes it easier to use up all the
product.

14. Valves
 Multifunctional & USFDA
approved.
 Consists of different parts,
Ferrule or Mounting cup
Valve body or Housing
Stem
Gasket
Spring
Dip tube
Metering valves
Actuators
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15. 1. Ferrule or Mounting cup
 Attach the valve assembly to the container.
 Made up of tin platted steel or aluminum.
 Ferrule for glass bottle or small aluminum
tubes are made up of softer aluminum or
brass.
 Underside of valve cup is coated with epoxy
or vinyl coating.
 Attached to container by rolling the end
under the lip of the bottle or clinching the
metal under the bottle lip.
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16. 2. Valve body or Housing
 Nylon or Delrin.
 Opening at the area of attachment with dip
tube ( 0.013-0.080 inches).
 Vapor tap allows the escape of vaporised
propellant along with liquid product.
 Vapor tap produces finer particles, prevents
clogging of insoluble materials& allows
satisfactory removal of product from
container.
 Vapor tap avoids chilling effect and reduce
flame extension in case of HC propellants.
 Vapor tap ranges between 0.013-0.080
inches.aerosol- scs
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17. 3. Stem
 Nylon,Delrin,Stainless steel or Brass.
 One or more orifice ranging between 0.013-
0.030 inches. (Three orifice of 0.040 inches
each).
4. Gasket
 Buna-N & Neoprene rubber.
 Compatible with formulations.
5. Spring
 Stainless steel.
 Holds the gasket in place.
 Helps the functioning of valve assembly.aerosol- scs
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18. 6. Dip tube
 Polyethylene or Polypropylene (Rigid).
 Viscosity & delivery rates plays the role in
selection.
 Inside diameter 0.120-0.125 inches.
 0.050 inches capillary tubes & 0.195 inches
wider tubes available.
7. Metering valves
 Potent medication.
 Chamber size fixes the medication.
 Limitations of size& dosage accuracy.
 50- 150 mg ±10% liquid materials dispensed at
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19. 8. Actuator
 Ensure delivery in proper & desired form.
 Easy opening & closing of valve assembly.
Different types of Actuators
◦ Spray actuator
◦ Foam actuator
◦ Solid stream actuator
◦ Special applications
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20. a) Spray actuator
• Disperse stream of product concentrate &
propellant in to smaller particles by passing
through various openings (0.016-0.040 inches).
• Large % of propellant mixture with sufficient
quantity of low boiling propellant (propellant 12 or
propane) large orifice actuators used.
• Combination of propellant vaporization, actuator
orifice & internal channels may deliver spray in
desired particle size.
• Used as topical sprays ie., bandages, antiseptics,
local anesthetics & foot care preparations.
• Products with low % of propellants (50% or<),
dispersed as stream than a spray. Mechanical
break up actuators as used in this case.
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21. b) Foam actuator
 Large orifice (0.070-0.125 inches or >)
 Product reaches in large chamber then
expand before dispensed through the
orifice.
c) Solid stream actuator
 Semi-solid products.
 Similar to Foam type actuators.
d) Special actuator
 Used for special purposes.
 To deliver into throat, nose,eye & vaginal
tract.
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22. Metered Dose Inhalers (MDI)
 Modifications made to reduce existing errors.
 Tube spacers, Breath actuator, Portable plastic
reservoirs & Propellant free metered pumps.
 Deliver drug at Nasal, Intra-nasal pathways&
Respiratory pathways.
 Deliver only 10-15% actuated dose of drug.
10% lost at inner surface of adaptor.
80% inertial impact/deposit at oropharynx.
 Altered geometry/ shape/size tube spacers used
to reduce the 80% fraction loss.
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23. Tobin et. al, Reservoir Aerosol Delivery System(RADS).
Consists of 700 ml capacity collapsible plastic bag in to
which aerosol is injected.(InspireEase by Key
Pharmaceutical Inc).
 Provided with special mouth piece.
 Warning alarm beep system.
Propellant free intra-nasal pump- Flunisolide-
Seasonal& allergic rhinitis.
 Reduce irritation & smarting at nasal mucosa.
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24. Metered Dose Inhaler
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26. Formulation of Pharmaceutical Aerosol
 Product concentrate & Propellant.
 AI, Solvents,Antioxidents,Surfactants.
 Propellants for desired vapor pressure.
Factors for selection of systems
 Physical,Chemical,Pharmacological
properties of AI.
 Site of application.
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27. Solution system
 Two phase system (V&L).
 No solvent required when AI is soluble in
Propellant.
 Propellant-12/A-70 or mixture of propellant-12.
 Lower vapor pressure than propellant-12 produces
larger particles.
 Low volatile solvents: Ethyl alcohol, Acetone,
Propylene glycol, Ethyl acetate, Glycerin can
produce low VP.
 5%- Foam type--------------------95%- Inhalation type.
 Larger particle size sprays used as topical
formulations.
 System avoids inhalation of airborne particles.
 Chilling effect: Depending up on BP of solventaerosol- scs
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28.  Active Ingredients : 10-15%
Propellant 12/11 : up to 100%
 For oral inhalation aerosols, FDA exempted contraceptives.
Propellant 12/11 (30:70)
Propellant 12/114 (45:55)/ (55:45)
 Aerosol (Inhalation type): 15-30ml SS/Al/Glass containers
Isoproterenol HCl : 0.25%
Ascorbic Acid : 0.10%
Ethanol : 35.75%
Propellant-12 : 63.90%
 Aersol (Inhalation type): Reduced vapor pressure
Octyl Nitrite : 0.1%
Ethanol : 20.0%
Propellant-114 : 49.2%
Propellant- 12 : 30.7%
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29. System with Hydrocarbon Propellant
 Depending up on water content final product may become
solution or three phase system. Concentration of ingredients
may produce finer to coarser spray.
 Propellant A-70: Dry spray.
Propellant A-17 & A-31: Wet spray.
 System can be packed in plastic coated glass container.
 Propellant content shall not exceed 15% of total product
weight.
 Volumetric capacity shall not exceed 5 fl.oz.
Topical formulation with hydrocarbon propellant
Active Ingredients : 10-15%
Solvent : 10-15%
Distilled water : 10-15%
Hydrocarbon propellant, A-46 : 55-70%aerosol- scs
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30. Testing of products made from hydrocarbon
propellants
 1/1000: Test at 250 psig with out failure.
 1/20000: Bursting point & Bursting pressure (not
less than 300psig).
 1/20000: Dropped from 4 ft with out flying glass &
Shattering effect.
 10 additional bottles tested for each failed test.
Further failure forces rejection of whole batch.
 1/1000: Heated so that pressure with in the
container is equivalent to equilibrium pressure of
contents at130o F with out evidence of any
leakage or defect.
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31. Water based system
 Non-aqueous solvents are replaced in full or partial.
 Propellant 25-60% (low as 5%)
 Formulation emitted as spray or foam.
 Spray: Dispersion of active ingredients & solvents as
emulsion with propellant as external phase. Leaves active
ingredients as minute particles.
 Propellant phase ≠ Water phase- Vapor phase.
 Ethanol (co-solvent) to solubilise some of the propellant in
water & reduce particle size.
 Surfactants: Produce homogenous dispersion. Low water
solubility & High solubility in non-polar solvents. Eg: Long
chain fatty acid esters of poly hydroxylic compounds
including glycol, glycerol, sorbitol esters of oleic, stearic,
palmitic &lauric acid. (0.5- 2.0%)
 Mechanical break up/vapor tap actuators.
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32. Aquasol system
 Three phase system, contains large quantity of water.
Aquasol valve.
 Dispensing of a fine mist or spray of active ingredient
dissolved in water. No chilling effect experienced as with
normal hydrocarbon propellant system.
 Need low concentration of propellant but effectively &
economically disperse the product.
 Fluorocarbon propellants can be used.
 Dispense dry spray with fine particles in comparison with
three phase system. Aquasol valve dispense vaporized
propellant than liquefied propellant.
 Non-flamable stream of product dispersed.
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33.  Active ingredients dissolved or suspended in water or
mixture of alcohol & water.
 Hydrocarbon propellant floats on top of aqueous layer &
exists as both liquid & vapor.
 Depending up alcohol concentration propellant-
water/alcohol layer may or may not be immiscible.
Miscibility improves with increase in alcohol concentration.
 As pure alcohol system is approached, complete miscibility
takes place. System becomes two phase system.
 Flammability increases with two phase system. Liquid
propellant is dispensed.
 Vapor phase of propellant and product concentrate enters
the actuator through separate channels at high velocity
causing mixing of vapor and product resulting in finely
dispersed spray.
 Fine dry spray & coarse wet spray depending up on valve
& actuator.
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34. Suspension or Dispersion systems
 Mainly as oral inhalations.
 Overcome the difficulties caused due to co-solvents.
 Dispersion of active ingredients in the propellant/mixture.
 Reduce settling by using surfactants or suspending agents.
Methods to improve physical stability of aerosol dispersions
 Control moisture content (< 300ppm)
 Derivatives with minimum propellant solubility.
 Reduction of initial particle size < 5µm.
 Density adjustment between propellant and/or suspensoid.
 Dispersing agents.
 Vapor tap valves reduces valve clogging complaints.
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35.  Active ingredient with minimum solubility in propellant
system.
Epinephrine bitartrate : 0.50%
Sorbitan trioleate : 0.50%
Propellant 114 : 49.50%
Propellant 12 : 49.50%
 Formulation with dispersing agent /lubricant to prevent
aggregation.
Steroid compound : 8.4 mg
Oleic acid : 0.8 mg
Propellant 11 : 4.7 gm
Propellant 12 : 12.2 gm
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36. Foam systems
 Stable or quick breaking foams.
 Emulsion or foam aerosol: Active ingredients, aqueous or non
aqueous vehicle, surfactant & propellant.
 Liquefied propellant is emulsified and used as internal phase.
 Steroids, antibiotics are dispensed using hydrocarbon or
compressed gas propellants.
 Fluorocarbons are banned except for contraceptives.
Aqueous stable foams
Active ingredients
Oil waxes
o/w surfactant : 95.0- 96.5%
Water
Hydrocarbon propellant : 3.5-5.0%
 Lower propellant yields wetter foam.
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37. Nonaqueous stable foams
 Use various glycols: PEG (91.0-92.5%)
 Emulsifiers from the class of Glycol esters, Eg: Propylene glycol
monostearate. (4.0%)
 Hydrocarbon propellants (3.5-5.0%)
Quick-Breaking foam
 Propellant is the external phase.
 Product dispensed as a foam then break down in to liquid.
 Topical application.
 Surfactant can be non-ionic, cationic or anionic but soluble in
alcohol and water.
 90% AI & 10% Propellant packaged at pressure below 25 psig.
Ethyl alcohol : 46.0- 66.0%
Surfactant : 0.5-5.0%
Water : 28.0-42.0%
Hydrocarbon propellant : 3.0-15.0%
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38. Thermal foams
 Warm shaving foams.
 Dispense hair dyes/colous.
 Inconvenience to use,expense,corrosion.
 May be useful in medicated aerosol due to heat.
Intranasal aerosols.
 Delivery of measured dose,
 Depth of penetration.
 Minimal inadvertent penetration to lungs.
 Reduced droplet or particle size.
 Lower dosage than comparable systemic preparation.
 Sterility maintained dose to dose.
 Greater patient compliance.
 Decreased mucosal irritation.
 Greater flexibility in formulation.
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39.  Basic formulation of intranasal aerosol
Active ingredients (Micronised) : up to 1.0%
Dispensing agent, additives, solvents etc : up to 1.0%
Propellant 12/11 (60:40) : up to 98.0%
 Decadron Turbinaire: Dexamethasone sodium phosphate-
Allergic or inflammatory nasal conditions.
 Beconase Vancenase: Beclomethasone dipropionate-
Seasonal and perennial rhinitis.
 Major difference from inhalation aerosol is the design of
adaptor which is considerably shorter & narrower
minimizing propellant vaporization before contacting nasal
mucosa.
 This results in desirable lower percentage of smaller
particles which reduces number of particles entering in to
respiratory airways.
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40. aerosol- scs 40

41. Manufacture of Pharmaceutical Aerosols
 Special knowledge, Skills and equipment-low temperature (-
40o F).
Pressure Filling Apparatus
 Pressure burette fills small volume of liquefied gas under
pressure in to an aerosol containers.
 Propellant is introduced through in-let valve located either at
bottom or top of the burette. Trapped air is allowed to
escape.
 Propellant is allowed to flow through the aerosol valve in to
the container under its own vapor pressure. Filling is
stopped when pressure becomes equal.
 To fill additional propellant, a hose leading to a cylinder of N2
or compressed air is attached to the upper valve causing
propellent to flow.
 Piston type filling apparatus is used but can not fill throughaerosol- scs
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42. Cold Filling Apparatus
 Similar to pressure filling apparatus.
 Coiled copper tube placed inside the insulated box filled with
dry ice/acetone.
 May be used for metered and non-metered valves.
 Should not be used for hydrocarbon propellant systems
since excessive escaping of vapor may form explosive
mixture at floor level.
 Heavier fluorocarbon do not form such mixtures.
 Restricted to non-aqueous products and those products
which are not adversely affected by low temperature.
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43. Compressed Gas Filling Apparatus
 Compressed gases are under high pressure, pressure
reducing valve is required.
 Flexible hose (150pounds/sq. inch) is fitted with filling head.
 Product concentrate is placed in the container and crimped
with valve.
 Filling head is attached to valve opening.
 Depression of valve allow the compressed gas to enter the
container.
 Pressure with in the container becomes equal to delivery
pressure, filling stops.
 For those products which needs higher amount of gas or
solubility of gas in product concentrate,CO2 or Nitrous oxide
can be used.
 Maximize the solubility of gas in product, manual or
mechanical shaking can be done during & after the filling.
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44. Large scale equipment
 GMP in filling process.
Concentrate Filler
 Single-stage single hopper to large straight line multiple
head filler or rotary type multiple head filler.
 Constant rate filling will be done in 1-2 operations.
Valve Placer
 Manually or automatically prior to crimping.
 High speed automatic valve placers.
Purger & Vacuum crimper
 Operate manually or by air pressure (80 pound/sq.inch)
crimping 10-12 cans/minute.
 Dual function: evacuation of air to about 24 inches of
mercury and seal the valve.
 Multiple head rotary unit capable of vacuum crimping up to
120 cans/ minute.
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45. Pressure Filler
 Adding propellant through valve assembly before crimping.
 Positive pressure is used.
 Single/Multiple stage process.
 Under cap filling:- A seal is made by lowering crimping bell on to
the container.
 Air is removed by vacuum, propellant is metered in to container.
 Crimps the valve to the container.
Leak Test Tank
 Large tank filled with water, heating units and magnetized chain.
 Length of the tank is such that the temperature of product
before it emerges from tank is 130o F.
 DOT: “each completed container filled for shipment must have
been heated until contents reached a minimum of 130o F, or
attained the pressure it would exert at this temperature with out
the evidence of leaking, distortion or other defects”
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46. Fully automatic filling process
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47. Testing of Pharmaceutical aerosols.
Flame Projection
 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 fame is
extended, and exact length was measured with ruler.
Flash point
 Determined by using standard Tag Open Cap Apparatus.
 Aerosol product is chilled to temperature of -25º 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, e.g. topical
hydrocarbons.
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48. Vapor pressure
 Determined by pressure gauge
 Variation in pressure indicates the presence of air in
headspace.
Density
 Determined by hydrometer or a pychnometer.
Moisture content
 By Karl Fischer method / gas chromatography.
Identification of propellants
 I.R spectrophotometry
Aerosol valve discharge rate
 Determined by taking an aerosol known weight and
discharging the contents for given time using standard
apparatus.
 By reweighing the container after time limit has expired, the
change in weight per time dispensed is discharge rate in
gram per seconds.aerosol- scs
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49. Dose uniformity
 To determine amount of medication actually received by the
patient.
 The method involves accurate weighing of filled container
followed by dispersing of several doses.
 Container can reweighed.
 Difference in weight divided by no of dose give the average
dose.
Net contents
 Weight filled full container.
 Dispensing the contents, then reweight the container.
 The difference in weight, will be the net weight.
Leakage
 Used to estimate the weight loss over a 1-year period.
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50. Foam stability
 Visual evaluation, time for given mass to penetrate the
foam, time for given rod inserted in to foam and to fall&
using rotational viscometers.
Particle size determination
 Cascade impactor & light scatter decay.
 Stream of particles projected through series of nozzle&
glass slides at high velocity.
 Larger particles impacted first at low velocity and smaller
pass on and collected high velocity.
 Specific for aerosol containing particles targeted for RT.
Biological testing/Therapeutic activity/ Toxicity
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