Aerosol formulations

1. PHARMACEUTICAL
AEROSOL

2. 2
Definition
Packaging of therapeutic active
ingredients in a pressurized system.
Aerosols depends on the power of
compressed or liquefied gas to expel the
contents from containers.

3. 3
Advantages
• A dose can be removed with out contamination of materials.
• Stability is enhanced for these substances adversely affected
by oxygen and or moisture.
• When sterility is an important factor, it can be maintained while
a dose is being dispensed.
• The medication can be delivered directly to the affected area in
a desired form, such as spray, steam, quick breaking foam or
stable foam.
• Irritation produced by the mechanical application of topical
medication is reduced or eliminated.
• Ease of convenience of application.
• Application of medication in thin layer
Disadvantages –
1. Cost is high.
2. Irritation may occur upon topical administration of aerosols.
3. It leads to inhalation toxicity.

4. 4
Components of aerosols
 Propellant
 Container
 Valve and actuator
 Product concentrate

5. 5
Propellant (Liquefied or compressed gas)
It is responsible for developing the power pressure with in the
container and also expel the product when the valve is opened
and in the atomization or foam production of the product.
# For oral and inhalation eg.(CFC, HFC,HC)
Fluorinated hydrocarbons
Dichlorodifluromethane (propellent 12)
Dichlorotetrafluroethane (propellent 114)
# Topical preparation (HC)
Propane
Butane
Isobutane
# Compressed gases
Nitrogen, Oxygen
Carbon di oxide
Nitrous oxide

6. Properties of FC & HC
Name Designation Pressure
(psia )at 700
F
Trichloromonofluoromethane 11 13.4
Dichlorodifluoromethane 12 84.9
Dichlorotrtrafluoroethane 114 27.6
Difluoroethane 152a 76.4
Butane A-17 31.6
Isobutane A-31 45.8
Propane A-108 122.8
6
Blends
Propellant
Blend
Composition Psia at 700
F
12/11 50:50 37.4
12/11 60:40 44.1
12/114 70:30 56.1
12/114 40:60 39.8
12/114 45:55 42.8
12/114 55:45 48.4
Design
ation
Pressure
(psig)
700
F
A-108 108
A-70 70
A-52 52
A-46 46
A-40 40
A-31 31
A-24 24
A-17 17

7. 7
Physiochemical properties of propellants
o Vapor pressure
o Boiling points
o Liquid density

8. 8
Vapor pressure of mixture of propellants is calculated by
Dolton'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 solute is proportion to the mole fraction of solute molecules
in the solution.
Given ideal behavior, the vapor pressure of a mixture
consisting of two individual propellants is equal to sum of the
mole fraction of each component present multiplied by the
vapor pressure of each pure propellant at desired temperature.

9. 9
The relationship can be shown mathematically :
Propellant A na
pa = ------------ pAo =NApAo ----------(1)
na + nb
Where, pa = partial vapor pressure of propellant A, pAo = vapor
pressure of pure propellant A
na = mole of propellant A, nb = mole of propellant B
NA = mole fraction of component A
To calculate the partial pressure of propellant B :
nb
pb = ------------ pBo = NBpBo ----------(2)
nb + na
The total vapor pressure of system is then obtained as :
P = pa + pb ----------------------------------(3)
Where, P = total vapor pressure of system

10. 10
Containers
They must withstand pressure as high as 140 to 180
psig (pounds per sq. inch gauge) at 1300
F or
54.44o
C
A. Metals
1. Tinplated steel
(a) Side-seam (three pieces)
(b) Two-piece or drawn
(c) Tin free steel
2. Aluminium
(a) Two-piece
(b) One-piece (extruded or drawn)
3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic coated glass

11. 11

12. Tin Containers
12
Seaming, Flanging & Soldering operation
Recent – Welding side seam.
1.Soudronic system
2.Conoweld system
1.Electronically controlled resistance welding method that uses copper wire as an
electrode. The rounded bodies are welded & sent to conventional line.
2.Conoweld system passes the folded body through two rotating electrode rings.
The rest is same.

13. 13
Valves
 To delivered the drug in desired form.
 To give proper amount of medication.
 Not differ from valve to valve of medication in
pharmaceutical preparation.
Types
- Continuous spray valve
- High speed production technique.
- - Metering valves
Dispersing of potent medication at proper dispersion/
spray approximately 50 to 150 mg ±10 % of liquid
materials at one time use of same valve.

14. 14
Valve components
 Ferrul or mount cap
 Valve body or housing
 Stem
 Gasket
 Spring
 Dip tube

15. 15

16. 16
Metered dose inhaler
To increased interest in modifying metered dose
inhalers (MDIs) to minimize the number of
administration error and to improve the drug
delivery of aerosols particles into the drug
delivery system of the nasal passageways and
respiratory tract.
Chamber whose size determines the amount of
medicament dispensed.

17. Metered valve aerosols
• some metering type of valves have been designed
which permit only a specified amount of product to
come out at any go
• Such valves actually consist
of two valve's chambers both
of which are
connected to actuator

18. when actuator button is in
closed position upper
chamber valve is in closed
position and power
chamber valve is open
required amount of product
is filled

19. METERED DOSE INHALER
19

20. RAD / Tube Spacer
20

21. 21
Actuator
To 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

22. 22
Formulation of pharmaceutical aerosols
Contains two essential components
• Product concentrate
• Propellant
Product concentrate
Product concentrate contains ingredients or mixture of active
ingredients and other such as solvents, antioxidants and surfactants.
Propellant
May be single or blend of various propellants
 Blends of propellant used in a p’ceutical 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.

23. 23
Parameters consideration
 Physical, chemical and p’ceutical properties of
active ingredients.
 Site of application

24. 24
Types of system
Solution system or Two-Phase system
Water based system or Three-Phase system
Suspension or Dispersion systems
Foam systems
1. Aqueous stable foams
2. Nonaqueous stable foams
3. Quick-breaking foams
4. Thermal foams
Intranasal aerosols

25. Solution system or two phase
Ingredients Weights in %
Isoproterenol
Hcl
0.25
Ascorbic acid 0.10
Ethanol 35.75
Propellant 12 63.90
25
Ingredients Weights in %
Octyl nitrate 0.1
Ethanol 20
Propellant 114 49.2
Propellant 12 30.7
Propellant 5 – 95%, 5% for foam whereas 95% for fine particles
12/114 – 20:80 0r 10:90, 12/11 – 30:70 – Metal container.

26. Water based System or
26
Aquasol Dispenser System
Help of Aquasol valve, More efficient, Economical
Surfactants – 0.5 – 2.0%, Propellant 25 -60%, Co-solvents

27. Suspensions / Dispersions systems
27
Ingredients Weights in %
Epinephrine
Bitartarate
0.50
Sorbitan
Trioleate
0.50
Propellant 114 49.50
Propellant 12 49.50
Ingredients Weights
Isoproternol
Sulfate
33.3 mg
Oleyl Alcohol 33.3mg
Myristyl Alcohol 33.4mg
Propellant 114 7.0g
Propellant 12 7.0g

28. Foam Systems
• 1. Aqueous stable foams –
3-5%
• 2. Nonaqueous stable foams
• 3. Quick-breaking foams
• 4. Thermal foams
28
Ingredients Weights in %
Active Drug 2
Emulsion base 94-95
Hydrocarbon
Propellant
A-46
3-4
Ingredients Weights in %
Glycol 91-92.5
Emulsifying
agent
4
Hydrocarbon
Propellant
A-46
3-5

29. 29
Manufacturing of Pharmaceutical Aerosols
Apparatus
 Pressure filling apparatus
 Cold filling apparatus
 Compressed gas filling apparatus

30. Pressure Burette
30

31. Pressure burette for laboratory
filling of aerosols

32. Compression Filling
32

33. Filling machine

34. 34
Large scale equipment
Concentrate filler
Valve placer
Purger and crimper
Pressure filler
Leak test tank

35. 35

36. 36
Quality control for pharmaceutical
aerosols
Propellants
Valves, actuator and dip tubes
Testing procedure
Valve acceptance
Containers
Weight checking
Leak testing
Spray testing

37. 1.Propellents
• All Propellants are accompanied by Specification
sheet. Parameter Tested By Identification Purity Gas
Chromatography Moisture, Halogen,
• Non-Volatile Residue Determination

38. 2.Valves, Actuator, Dip-tubes
• This done according to standard procedure as found
in Military Standards “MIL-STD-105D”. For metered
dose aerosols test methods was developed by
‘Aerosol Specification Committee’ ‘Industrial
Pharmaceutical Technical Section ‘Academy Of
Pharmaceutical Sciences
• The object 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.

39. Test Solutions:
% w/w Test
Solutions ‘A’
Test
Solutions ‘B’
Test
Solutions ‘C’
Isopropyl myristate 0.10% 0.10% 0.10%
Dichlorodifluoro
methane
49.95% 25.0% 50.25%
Dichlorotetrafluoro
ethane
49.95% 25.0% 24.75%
Trichloromonofluoro
methane
-- -- 24.9%
Alcohol USP -- 49.9% --
Specific Gravity @
25 °C
1.384 1.092 1.388

40. Testing Procedure::
• Take 25 valves & placed on containers, Filled with
specific test solution
• Actuator with 0.020 inch orifice is attached.
• Valve is actuated to fullest extent for 2 sec. Repeat this
for total 2 individual delivery from each 25 test units.
• Individual delivery wt in mg / Specific gravity of test
=Valve delivery per actuation in µL sol n
• Valve Acceptance :
• Deliveries Limit’s 54 µL or less ± 15%
55 to 200 µL ± 10%

41. Valve acceptance
• Of 50 delivery If 4 or more are outside limits :
valves are rejected
• If 3 delivery are outside limits : another 25 valves
are tested : lot is rejected if more than 1 delivery
outside specification
• If 2 delivery from 1 valve are beyond limits :
another 25 valves are tested : lot is rejected if
more than 1 delivery outside specification

42. 3.Containers:
• Containers are examined for defects in lining.
Q.C aspects includes degree of conductivity of
electric current as measure of exposed metals.
Glass containers examined for Flaws.(defects)
4. Weight Checking
• Weight Checking Is done by periodically adding
tarred empty aerosol container to filling lines
which after filling with concentrate are removed
& weighed. Same procedure is used for
checking weight of Propellants.

43. 5.Leak Test:
• Leak Test Is done by measuring the Crimp’s
dimension & ensuring that they meet
specification
• Final testing of valve closure is done by
passing filled containers through water
bath(temp is checked repeatedly and values are
recorded)
It is done `
To clear dip tube of pure propellant &
concentrate,
To check for defects in valves & spray
pattern.
6. Spray Testing

44. 44
Evaluation parameters of pharmaceutical aerosols
A. Flammability and combustibility
1. Flash point
2. Flame extension, including flashback
B. Physiochemical characteristics
1. Vapor pressure
2. Density
3. Moisture content
4. Identification of propellant(s)
5. Concentrate-propellant ratio
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
7. Leakage
D. Biologic characteristics
E. Therapeutic activity

45. 45
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.

46. Fire Projection Test
46

47. 47
Flash point
• Determined by using standard Tag Open
Cap Apparatus.
Step involves are 
• Aerosol product is chilled to temperature of
- 25 0
F and transferred to the test
apparatus.
• Temperature of test liquid increased slowly,
and the temperature at which the vapors
ignite is taken a flash point.
• Calculated for flammable component, which
in case of topical hydrocarbons.

48. 48
Vapor pressure
Determined by pressure gauge
Variation in pressure indicates the presence of air in
headspace.
A can punctuating device is available for accurately
measuring vapor pressure.

49. 49
Density
Determined by hydrometer or a pycnometer.
This method is use for non aerosol, modification
to accommodate liquefied gas preparation.
Step involves are A pressure tube is fitted
with metal flanges and Hoke valve, which allow
for the introduction of liquids under pressure.
•The hydrometer is placed in to the glass
pressure tube.
•Sufficient sample is introduced through the
valve to cause the hydrometer to rise half
way up the length of the tube.
•The density can be read directly.

50. 50
Moisture content
Method used — Karl Fischer method
 G. C has also been used
Identification of propellants
 G.C,
 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,
Expressed as gram per seconds.

51. 51
Dosage with metered valves
Reproducibility of dosage each time the valve is
depressed
Amt. of medication actually received by the patient.
Reproducibility has been determined by assay
technique,
Another method is that, involves accurate weighing
of filled container fallowed by dispersing of several
doses, container can reweighed, and difference in
weight divided by No. of dose, gives the average
dosage.

52. Spray pattern
• Method is based on the impingement of the
spray on a piece of paper that has been treated
with a dye-talc mixture.
• Depending on the nature of the aerosol, an oil-
soluble or water-soluble dye is used.
• The particles that strike the paper cause the dye
to go into solution and to be absorbed onto the
paper.
• These gives the record of the spray, which can
then be used for comparison.
5203/24/15

53. 53
Net contents
•Weight method
•Filled full container, and dispensing the contents
Foam stability
• Visual evaluation
• Time for a given mass to penetrate the foam
• Times for given rod that is inserted into the
foam to fall
• The use of rotational viscometers

54. 54
Particle size determination
Cascade impactor
Light scatter decay method
Cascade impactor
Operates on the projected through a series of nozzle and glass
slides at high velocity, the large particles become impacted
first on the lower velocity stages, and the smaller particals
pass on and are collected at high velocity stages.
These practical ranging from 0.1 to 30 micron and retaining on
RTI.
Modification made to improve efficacy

55. Anderson Cascade Impactor
55

56. 56
Porush, Thiel and Young used light scattering
method to determine particle size.
As aerosols settle in turbulent condition , the
change in light intensity of Tyndall beam is
measured
Sciarra and Cutie developed method based on
practical size distribution.

57. Biological TestBiological Test
• Therapeutic activity
• toxicity
5703/24/15

58. Applications
• Active ingredient in dissolved, suspended or emulsified
form for Oral or topical use.
• Local action on nose, throat, eye, ear, vagina or rectum.
• Exhibits systemic action thro’ lungs into blood stream.
• Metered dose for inhalation purpose.
• Effective particle size of 3-6μm.
• Quick, rapid action.
• Easy to carry, apply without touching affected area.
• Sterility can be maintained.
• Stability is maintained.(light, air, hydrolysis etc,)
• Several agents like analgesic, antiseptics, fungicidal,
antibiotics, anti-inflammatory.
• Non-pharmaceuticals, house hold products etc. 58