Aerosol lecture.pptx

Definition of Aerosols.
Aerosols or Pressurized packages
are products which contain
therapeutic or active Ingredients
packaged in a pressurized system.
Definition:
Aerosols are products that
depend on the power of
compressed or liquefied gas to
expel the contents from
containers.

Definition of pharmaceutical Aerosols
W Kalala, MUHAS 2017 3
•Pharmaceutical Aerosol is defined as
product containing active ingredients
dissolved ,suspended or emulsified in a
propellant or a mixture of solvent and
propellant and intended for oral or topical
administration or for administration into the
eye, nose ,ear, rectum and vagina.

•In 1942 - First aerosol was developed.
(insecticide)
• In1950 - Pharmaceutical aerosol for topical
administration was developed.
• In 1955 - Aerosol for the local activity in the
respiratory tract was developed (Epinephrine).

• Ease and convenience of application.
•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, Mist, foam or stream.
(localized action)
• Irritation produced by the mechanical application of topical
medication is reduced or eliminated.
• Economical: Application of medication in thin layer and
Direct application at site of action means low dose and
Rapid response to the medicament .
• Bypasses First pass effect
ADVANTAGES OF AEROSOLS
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W Kalala, MUHAS 2017

Advantages of aerosols for inhalation therapy
For inhalation products in the treatment of
asthma, & bronchitis, (drug delivery to the
respiratory tract):.
- Smaller dose is used (compared to oral
or parenteral)
- Rapid onset of action (It is comparable
to I.V.)
- Circumvent first – pass metabolism
- Avoid g.i.t. degradation
-

Dose can be titrated to individual needs
- provide alternate route for drugs with
interact, but yet have to be
administered concurrently
- Alternate route of drugs, which exhibit
erratic plasma levels when given orally or
parenterally.

DISADVANTAGES OF AEROSOLS
• Expensive.
• Chlorofluorocarbon propellants cause
Ozone layer depletion.
• Inflammability
• Toxicity
• Explosivity
•Complicated disposal

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Components of aerosols
Propellant
Container
Valve and actuator
Product concentrate container
AActuator
Valve

Mode of action of aerosols
1. Liquefied gas systems:
At room temperature and atmospheric pressure,
propellants are gases.
By lowering temperature (L BP) or by increasing
pressure they liquefy.
When a liquefied gas is placed in a sealed
container, immediately it separates into a
liquid and vapour phase.
At equilibrium the number of moleculess
entering vapour and gas molecules entering
liquid are the same.
The vapour phase exerts a characteristic pressure
= V.P

V.P. is exerted in all directions and is
independent of the quantity present.
The pressure pushes the liquid phase up
the dip tube and against the value.
When the value is opened, the liquid phase is
emitted and comes into contact with warm air
at atmosphere pressure.
The liquid propellant immediately reverts
to the vapour state (since its BP is < Room
temp).

When the contents are expelled, the
volume of the vapour phase increases,
causing a temporary fall in pressure
according to Boyle’s law P1V1 = P2V2.
But a sufficient # of mols change to
vapour phase to restore pressure (when
compressed gas is used, there is no such
reservoir, thus there is a constant drop in
pressure at each actuation.)

Classification of Aerosols
1. Two Phase System:
– Simplest of all aerosol systems. Consists of a solution
or suspension of Active ingredient in liquid propellant.
– The characteristics of the product will depend on the
nature of propellant, its quantity and valve
mechanisms.
•
a) Space spray :
2 – 20% Active Ingredient and 80 – 98% propellant
Particle size 1 – 50 μm and Pressure is 30 – 40
p.s.i
Examples: space insecticides, Room deodorants,
vaporizer spray. W Kalala, MUHAS 2017 14

b) Surface coating spray: (Relatively wet and
coarse).
Consist of 20 –75% Active Ingredient and
25 – 80% Propellant
Particles size 50 – 200 μm
•
Examples: Hair spray, Residual
Insecticides, Perfumes, cologne, Paints,
protective coating. Pressure is generally
lower than in space sprays.

Classification …….
2. Three Phase Systems:
• Formulation of liquid
components not miscible with
propellant – e.g. water. Consider
components which are soluble in
water. (therefore insoluble in
propellant). Two systems are
possible.

• (a) Two layer system
• The Three phases include liquid propellant,
Vaporized propellant and Aqueous solution of
the active ingredient.
• The phases are immiscible therefore
separation occurs. Depending on the density,
water or propellant will float. Fluorocarbons
sink in water while Hydrocarbons float. A
mechanical action may be required to produce
spray and special valves with smaller orifices
are required. No liquefied gas propellant is
expelled.

Classification…..
• The Specific gravity of the propellant can be
adjusted by partial replacement with e.g.
butane, isobutane or propane. Upon shaking
the propellant is dispersed evenly. Varying
characteristics are given depending on the
nature of formulation.
• In order to dispense aerosols economically
and efficiently using relatively small units of
propellant, aquasol dispenser system is
utilized. A drier product is dispensed and it is
impossible to disperse pure propellant

• (b). Foam Aerosols: Liquid propellant (10%) is
emulsified with product. When propellant
gets in touch with air it reverts to vapour,
whipping product into foam.
• o/w emulsions produce lasting foam while
w/o emulsions have quick breaking foams.

2. Compressed – Gas Aerosols:
•
• Compressed gases are used to dispense the
product as solid stream, wet spray or foam.
• Inert gases are utilized: Nitrogen, Carbon
dioxide, and Nitrous oxide.
• Expansion of compressed gas pushes contents
out.
•

(a)Semi- solid dispensing: Nitrogen is used.
– The concentrate is semi solid. N2 is insoluble;
therefore the product is dispensed in its original
form.
– e.g. Dental creams, hair dressings, ointments
cosmetic creams, foods etc.
– Compressed gas systems need high pressures (90
– 100 psig)

Compressed gas systems…..
(b) Foam dispensing :-
– Soluble gases are used: CO2, N2O used.
– Examples:
• Emulsion products e.g. whipped creams and toppings
• Veterinary and Pharmaceutical products
– Shake well before dispensing to disperse gas throughout the
concentrate - May need a whipping action. (Use of mechanical break-
up actuator)
(c) Spray dispensing: Similar to liquefied gases, but compressed gases
have less dispersing power – need mechanical break up actuator.
The product is given out as wet spray.

Other systems
Semisolid products present problems of dispensing
from conventional aerosol products. Special
aerosol deliveries were designed.
(a) Bag-in Can
(b) Piston type
• Bag-in-can system consists of a collapsible plastic
bag in a can.
• The product is in the plastic, the propellant is
added through an opening at the can bottom.

• There is no contact between product and
propellant.
• The system can dispense both limpid liquid e.g.
aqueous solutions and semi solid. The
characteristics of outcome depend on valve.
• The plastic bag is accordion shaped to avoid
pinching the bag.
• By dissolving a low boiling liquid, e.g.
Isopentane, you may form a foam in a gas (when
placed on hands, the warmth vaporizes the
solvent making a foam).

1. Valve
2. Bag
3. Product
4. Propellant
5. Actuator
6. can
Advantages of Bag-on-valve:
Protection of your product against
oxygen exposure
Product emptying up to 99%
Hygienic and able to be sterilized
FDA-approved bag
Can be used in all positions
Reduced spray noise
Product dispensing without a
chilling effect
Can be used with standard
actuators and standard aerosol cans
(aluminum or steel)
Can be used with viscous liquids

Piston-type aerosol

Other systems……
CO-DISPENSING SYSTEM
• In order to produce warm foam and dispense
from a canister, an exothermic reaction used.
(Earlier, Electrical coils; Hot water coils etc were
used, but were cumbersome).
• The problems of a chemical reaction included:
– Corrosion on can
– Violent reaction
– Irritation of reactants
– Separation of reactants + proportion of the mixing

Co-dispensing system …
• In 1967, a co-dispensing system was devised with utilizes
oxidation–reduction reaction which is Exothermic.
Hydrogen peroxide (H2O2) was the most successful
Oxidizing Agent.
2 H2O2 2H2O +O2 = 22.6 Kca/mol
Reducing agents are also used (KSO3, Na2SO3)
H2O2 + SO3
- H2O + SO4
-
Depending on proportions of reactants, max temperature is
obtained in 0.5 – 1.5 min

Principle of Co-dispensing system
• Two chemicals separated by non-permeable
membrane are dispensed at the same time in a given
proportion. On mixing in the valve, heat is evolved and
warm surround media. The system has a special valve
and operates in inverted position. When the nozzle is
tilted, the outer seal opens, allows propellant soap
(with reducing agent) – simultaneously the second
orifice of the inner container opens to release oxidizer
(it is pressed by propellant). They both enter nozzle
with long passageway to ensure through mixing.
• Using this system, incompatible ingredients can be
dispensed together (eg drugs that are unstable in
solvent, effervescent preparations).

1. PROPELLANTS
• Responsible for developing proper pressure within the
container.
• Provide driving force to expel the product from the
container.
TYPES OF PROPELLANTS
(a) Liquefied gases Propellants
(b) Compressed gases Propellants
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COMPONENTS OF AEROSOLS

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. 31

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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HYDROCARBONS
• Can be used for water based aerosols and topical use.
Advantages
• Inexpensive
• Excellent solvents
• It does not cause ozone
depletion
Disadvantages
• Inflammable
• Unknown toxicity
produced
Ex: Propane - Propellant A-108
Isobutane - Propellant A-31
Butane - Propellant A-17
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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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NOMENCLATURE OF PROPELLANTS
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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
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Compressed gases…
• Can dispense stream, spray, mist, foam, depending on
formulation, valve design,
• But have no reservoir, therefore initial pressure should
be high.
• Unlike liquefied gases compressed gases have no
expansion power. Therefore they produce wetter
sprays. Foams of compressed gases are not stable.
• Compressed gases are used to dispense food + Non –
food products in their original form.
• N2 , N2O, CO2
• Chemical properties/solubility are not very important

2. CONTAINERS
They must be able to withstand pressures as high as 140
to 180 psig (pounds per sq. inch gauge) at 130 ° F.
AEROSOL CONTAINERS
A . Metals
1. Tinplated steel
2. Aluminum
3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic coated glass
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Containers
Containers must be withstand very high pressures (as high as
140 to 180 psig (pounds per sq. inch gauge) at 130̊ F.
A. Metals
1. Tinplated steel:
(a) Side-seam (three pieces)
(b) Two-piece or drawn
(c) Tin free steel
2. Aluminium
(a) Two-piece
(b) One-piece (extruded or drawn)
3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic coated glass

Three-piece aerosol container Two-piece container

TIN PLATED STEEL CONTAINERS
– light, inexpensive
It consist of a sheet of steel plate
• The coated sheet is cut into three pieces ( top , bottom and
body) .
• The top, bottom are attached to body by soldering .
• When required it is coated with organic material usually
oleoresin, phenolic , vinyl or epoxy coating .
• Welding eliminates soldering process, Saves considerable
manufacturing time and decreases the product/container
interaction.
• Recent developments in welding include Soudronic
system and Conoweld system.
41

ALUMINIUM CONTAINERS
• Used for inhalation and topical aerosols .
• Manufactured by impact extrusion process.
• Light in weight, less fragile, Less incompatibility due to
its seamless nature.
• Greater resistance to corrosion .
• Pure water and pure ethanol cause corrosion to Al
containers.
• Added resistance can be obtained by coating inside of
the container with organic coating like phenolic , vinyl or
epoxy and polyamide resins.
42

STAINLESS STEEL CONTAINERS
• Used for inhalation aerosols
Advantage :
• Extremely Strong.
• Resistant to many materials.
• No need for internal coating.
Disadvantage :
• Costly
43

GLASS CONTAINERS
• These containers are preferred because of its Aesthetic
value and absence of incompatibilities.
• These containers are limited to the products having a lower
pressure (33 psig) and lower percentage of the propellant.
• Used for topical and MDI aerosols.
Two types of glass aerosol containers
i) Uncoated glass container:
• Less cost and high clarity and contents can be viewed at all
times.
ii) Plastic coated glass containers:
• These are protected by plastic coating that prevents the
glass from shattering in the event of breakage.
44

45
Valves
To regulate the flow of product from container.
Allows discharge when needed and prevents loss at other
times
Determines characteristics of product e.g. Spray, foam
stream or solid steam
May be designed To give proper
amount of medication when needed.
A good valve must deliver
uniform dose always and
Must be easy to open and close.

Types of Valves
1. Continuous spray valve (usually Small diameter)
2. Metering valves (Discharging potent medication at
proper dispersion/ spray approximately 50 to 150 mg ±10 % of
liquid materials at one time; Also prevent discharge of large
volume of high pressure gas in
body cavities
3. Spray valve:
4. Powder valve, water based
aerosols – use vapor tab to
avoid clogging.
5. Foam Valve|: Have an expansion
chamber which serves as a delivery
nozzle or applicator, large opening.
6. Co-Dispensing valve:
can be used in Inverted or upright position

VALVE ASSEMBLY
47

CONTINUOUS SPRAY VALVE
• Used for topical aerosols .
Valves assembly consists :
• Ferrule or mounting cup
• Valve body or housing
• Stem
• Dip tube
• Gasket
• Spring
48

FERRULE OR MOUNTING CUP :
• Used to attach valve to container.
• Made from Tin plated steel, Al , Brass .
• Under side of the valve cup is coated with single or
double epoxy or vinyl resins.
VALVE BODY OR HOUSING :
• Made up of Nylon or Derlin and contains a opening at the
point of attachment of dip tube. (0.013 to 0.080 inch)
STEM :
• Made from Nylon or Derlin , brass and stainless steel can
also be used. (orifice - 0.013 to 0.030 inch).
49

GASKET :
• Made from Buna-N and neoprene rubber.
SPRING :
• Made from Stainless steel .
• Used to hold gasket in place.
DIP TUBE :
• Made from Poly ethylene or poly propylene.
• Inner diameter 0.120 – 0.125 inch.
• However for Capillary dip tube inner diameter is 0.050
inch and for highly viscous products it is 0.195 inch.
50

METERING VALVES
• Used for dispensing of potent medication.
• Operates on the principle of a chamber whose size
determines the amount of medication dispensed.
• Approximately 50 to 150 mg ±10 % of liquid materials
can be dispensed at one time with the use of such valve.
MDI
Metering valve
51

METERING VALVE MECHANISM

ACTUATORS
These are specially designed buttons which helps in
delivering the drug in desired form i.e., spray, wet stream,
foam or solid stream .
They enable rapid and convenient means of releasing
the contents from pressurized container.
May be fitted with Mechanical break – up mechanism
for three phase or compressed gas.
TYPES OF ACTUATORS :
• Spray actuators
• Foam actuators
• Solid steam actuators
• Special actuators
53

SPRAY ACTUATORS:
• It can be used for topical preparation, such as antiseptics,
local anesthetics and spray on bandages etc.
• It allows the stream of product concentrate and propellant
to pass through various openings and dispense as spray.
FOAM ACTUATORS :
• It consist of large orifice which ranges from 0.070—0.125
inch .
SOLID STREAM ACTUATORS :
• These actuators are required for dispensing 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.
54

FOAM
ACTUATORS
SPRAY
ACTUATORS
55

METERED DOSE INHALERS
• Used to minimize the number of administration errors.
• To improve the drug delivery of aerosolized particles into
the nasal passageways and respiratory tract.
Advantages of MDI:
• It delivers specified amount of dose .
• Portable and compact.
• Quick to use , no contamination of product.
• Dose-dose reproducibility is high.
Disadvantages of MDI :
• Low lung deposition ; high pharyngeal deposition .
• Coordination of MDI actuation and patient inhalation is
needed.
56

Metered Dose Inhalers (MDIs)
57

Dip tubes:
Convey the liquid from bottom to valve.
prevents propellant from escaping with
out dispensing contents package
Must result effects of products
Optimum length. Not too short or long

MARKETED PHARMACEUTICAL AEROSOL PRODUCTS
Metered Dose inhalers :
BRAND NAME DRUG USE
Flovent Diskus Fluticasone Asthma
Advair Fluticasone and
Salmeterol
Asthma
Aerobid Flunisolide Asthma
Qvar Beclomethasone Asthma
Proventil Albuterol Bronchospasm
Asthalin Salbutamol Asthma
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Formulation of aerosols
Things to be considered in FORMULATION ASPECTS
a) Particles size, shape + size distribution
– Space sprays; - Surface coating; - Inhalation therapy
b) Physical / chemical properties
– lipid solubility; - Pulmonary absorption rate; - Dissolution
characteristics
- Free base or acid are more pharmacologically active than
water soluble salts.
c) Formulation considerations:
- Solutions, Emulsion or suspensions
- For Suspensions care for agglomeration, Caking, Particle size,
valve clogging)
- can also formulate Powders and semi-solids.
d) In formulation, Administrative techniques are also considered.

FORMULATION OF AEROSOLS
• Aerosols consist of two essential components :
1. Product concentrate and
2. Propellant
Product concentrate :
Active ingredient or mixture of active ingredients and
other necessary agents such as solvents, anti oxidants
and surfactants.
Propellant :
• Single or blend of various propellants is used.
• Blend of solvents is used to achieve desired
solubility characteristics.
61

• Various surfactants are mixed to give the proper HLB
value for emulsion system.
• The propellants are selected to give the 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
1. Physical, chemical and pharmacological properties of
drug.
2. Site of application .
62

TYPES OF SYSTEMS
TYPES OF AEROSOL SYSTEMS :
• Solution system
• Water based system
• Suspension or Dispersion systems
• Foam systems
1. Aqueous stable foams
2. Non aqueous stable foams
3. Quick-breaking foams
4. Thermal foams
• Intranasal aerosols
63

SOLUTION SYSTEM
• This system is also referred to as Two phase system
consists of vapor and liquid phase.
• If active ingredient is soluble in propellant ,no other
solvent is required.
• The vapor pressure of system is reduced by the addition of
less volatile solvents such as ethanol, acetone , propylene
glycol, glycerin, ethyl acetate. This results in production of
larger particles upon spraying.
• Amount of Propellant may vary from 5% (for foams) to
95% (for inhalations).
General formula weight %
Active drug - to 10-15
Propellant 12/11 (50:50) - to 100
64

INHALATION AEROSOL :
Formulation Weight %
Isoproterenol Hcl – 0.25
Ascorbic acid – 0.1
Ethanol – 35.75
Propellant 12 – 63.9
Packed in 15 -30 ml Stainless Steel, Aluminum or glass
container.
HYDROCARBONS IN TOPICAL AEROSOL PHARMACEUTICAL
PREPARATIONS :
Formulation Weight %
Active ingredient -up to 10-15
Ethanol - up to 10-15
Water - 10-15
Hydro Carbon propellant (A-46) - 55-70
65

• Depending on water content the final product may be
solution or three phase system.
• Solution aerosols produce a fine to coarse spray.
• Hydrocarbon propellant A-70 produces drier particles
while propellants A-17 and A-31 tend to produce a wetter
spray.
• These are useful for topical preparations.
• Packaged in Plastic coated glass containers.
66

WATER BASED SYSTEM
• 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. It also reduces surface tension aiding in the
production of smaller particles .
• 0.5 to 2% of surfactant is used to produce a homogenous
dispersion.
67

• Surfactants with low water solubility and high solubility
in non polar solvents will be most useful eg: Long chain
fatty acid esters of polyhydric compounds including
glycol, glycerol and sorbitan esters of oleic, stearic,
palmitic and lauric acids .
• 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.
• Difference between aquasol system and three phase
system is aquasol dispenses fairly dry spray with very
small particles, non flammability of the product .
68

SUSPENSION SYSTEM
• It 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.
Example:
Formulation Weight%
Epinephrine bitartrate (1-5 Microns) 0.50
Sorbitan trioleate 0.50
Propellant -114 49.50
Propellant -12 49.50
Epinephrine bitartrate has minimum solubility in propellant
system but soluble in fluids in the lungs.
69

Physical stability of aerosol dispersion can be increased by:
1. Control of moisture content. (< 300 ppm)
2. Reduction of initial particle size to less than 5 µm.
3. Adjustment of density of propellant and suspensoid so
that they are equalized.
4. Use of dispersing agents.
5. Use of derivatives of active ingredients with minimum
solubility in propellant system.
70

• Physical stability of a dispersed system depends on rate of
agglomeration of the suspensoid.
• Agglomeration is accelerated at elevated temperatures and
it is also affected by particle size of drug (1-5µ , never > 50
µ).
• Agglomeration results in valve clogging , inaccuracy of
dosage and depending on the nature of active ingredients, it
may cause damage to the liner and metal container.
• Isopropyl myristate and mineral oil are used to reduce
agglomeration.
• Surfactants of HLB value less than 10 are utilized for
aerosol dispersions (sorbitan monooleate, monolaurate,
trioleate, sesquioleate).
• Surfactants are effective in a concentration of 0.01 to1 %.
71

FOAM SYSTEMS
• Emulsion and foam aerosols consist of active ingredients,
aqueous or non aqueous vehicle, surfactant, Propellant and
are dispensed as a stable or quick breaking foam depending
on the nature of the ingredients and the formulation.
AQUEOUS STABLE FOAM :
Formulation %w/w
Active ingredient
Oil waxes
o/w surfactant 95-96.5
Water
Hydrocarbon Propellant (3 -5%) 3.5-5
72

• Total propellant content is usually (3 or 5% w/w or 8-10%
v/v) .
• As the amount of propellant increases a stiffer and dryer
foam is produced.
• Lower propellant concentrations yield wetter foams.
• Hydrocarbon and compressed gas propellants are used.
NON-AQUEOUS STABLE FOAM :
Formulation %w/w
Glycol 91-92.5
Emulsifying agent 4
Hydrocarbon propellant 3.5-5
• Glycols such as poly ethylene glycols are used.
• Emulsifying agent is propylene glycol monostearate.
73

QUICK BREAKING FOAM :
• Propellant is in the external phase .
• When dispensed the product is emitted as a foam, which
then collapses into a liquid.
• Especially applicable to topical medications .
Formulation %w/w
Ethyl alcohol 46-66
Surfactant 0.5-5
Water 28-42
Hydrocarbon Propellant 3-15
• Surfactant should be soluble in both alcohol and water
and can be of non ionic or cationic or anionic type.
74

THERMAL FOAM :
• Used to produce warm foam for shaving .
• Used to dispense hair colors and dyes but were
unsuccessful due to the corrosion problems and are
expensive , inconvenient to use and lack of effectiveness.
INTRANASAL AEROSOLS :
• Intended to deposit medication into nasal passages for
local or systemic effect.
ADVANTAGES
• Deliver measured dose of drug.
• Require lower doses compared to other systemic products.
• Excellent depth of penetration into the nasal passage way.
• Decreased mucosal irritability .
• Maintenance of sterility from dose to dose.
• Greater flexibility in the product formulation.
75

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DRY POWDER INHALERS(DPIs)
• In DPI systems, drug is inhaled as a cloud of fine particles. The
drug is either preloaded in an inhalation device or filled into
hard gelatin capsule or foil blister discs which are loaded in to
a device prior to use.
• Dry powder inhalers are devices through which dry powder
formulation of an active drug is delivered for local or systemic
action via pulmonary route.
• They are bolus drug delivery systems that contain solid drug
substance that is suspended or dissolved in a non-polar
propellant that is fluidized when the patient inhales.

77
Ideal DPI
• Effective dosing
uniform dose
targeted delivery
operable at low inhalation flow rates
• Efficient device
• Easy to use

78
FORMULATION
• DPI formulations are generally engineered
composites, containing a drug material of
micron size formulated with or without a large
carrier material. The formulation is
formulated around a device that when
actuated by patient is capable of producing a
respirable aerosol cloud that penetrates the
respiratory tract and reaches the site of
action.

79
STEPS INVOLVED IN
FORMULATION
• Active Pharmaceutical Ingredient(API)
production.
• Formulation of API with or without
carriers.
• Integration of the formulation into
device.

80
DPI design issues
• Inhaler design, especially the geometry of the
mouth piece, is critical for patients to produce
an air flow sufficient to lift the drug from the
dose chamber, break up the agglomerates in
the turbulant air stream and deliver the drug
dose to the lungs as therapeutically effective
fine particles.

82
Principle of operation
• When the patient actuates the DPI and
inhales, airflow though the device creates
shear and turbulence; air is introduced in to
the powder bed and the static powder blend
is fluidized and enters the patient airways.
There the drug particles separate from the
carrier particles and are carried deep into the
lungs to exert the effects.

83
Evaluation
• Appearance
• Identity
• Microbial limits
• Water content
• Extractives
• Drug related impurities
• Particle analysis
• Drug content per unit dose/dose delivery

84
Advantages
• Propellant free design
• Less need for patient coordination
• Less potential for formulation problems
• Environmental sustainability
• Less potential for extractable from device
components

85
Disadvantages
• Dependency on patient inspiration flow rate
and profile
• Device resistance and other device issues
• More expensive than pressurized MDI
• Complex development and manufacture
• Not available world wide
• Greater potential problems in dose uniformity

Manufacture of aerosols
86

MANUFACTURE OF PHARMACEUTICAL AEROSOLS
PRESSURE FILLING APPARATUS
• It consists of a pressure burette capable of metering small
volumes of liquefied gas into the aerosol container under
pressure.
• Propellant is added through an inlet valve located at the
bottom or top of the pressure burette.
• 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.
• Pressure filling apparatus
• Cold filling apparatus
• Compressed gas filling apparatus
87

• The propellant stops flowing when the pressure of
burette and container becomes equal.
• If further propellant is to be added, a hose (rubber pipe)
leading to a cylinder of nitrogen is attached to the upper
valve, the pressure exerted by nitrogen helps in the flow
of the propellant into the container.
• Another pressure filling device makes use of piston
arrangement and is capable of maintaining positive
pressure .
• This type of device cannot be used for filling inhalation
aerosols which have metered valves.
88

PROCEDURE:
•This method involves filling of the concentrate into the
container at the room temperature.
• Then the valve is placed in the container and crimped.
• Through the opening of the valve the propellant are added
or it can be added “under the cap”.
• Since the opening of the valve are smaller in size ranging
from 0.018-0.030 inches, it limits the production and the
process becomes slow.
• But with the use of rotary filling machines and newer filling
heads where the propellants are filled through valve stem, the
production rate is increased.
• The trapped air in the container and air present in head
space is removed before filling the propellant to protect the
products from getting adversely affected.
89

• Various units used in pressure filling line are arranged
in the following order :
Unscrambler , Air cleaner , Concentrate filler , Valve placer ,
Purger ,Valve crimper , Propellant filler ,Water bath ,
Labeler , Coder and Packing table .
• Purger ,vacuum crimper and pressure filler are replaced
with a single unit if filling is carried by ‘under the cap’
method.
90

ADVANTAGES OF PRESSURE FILLING:
• Solutions, emulsions, suspensions can be filled by this
method as chilling does not occur.
• Contamination due to moisture is less.
• High production speed can be achieved.
• Loss of propellant is less.
DISADVANTAGES :
• Certain types of metering valves can be handled only by the
cold filling process or through use of an under the cap filler
and valve crimper.
• Process is slower than Cold filling method.
91

Pressure filling Equipment Pressure burette
92

COLD FILLING APPARATUS
• It consist of an insulated box fitted with copper tubings and
the tubings are coiled to increase the area exposed to cooling.
• The insulated box should be filled with dry ice or acetone
prior to use.
• The apparatus can be operated with or without metered
valves.
• Hydrocarbon propellant cannot be filled into aerosol
containers using this apparatus because large amount of
propellant escapes out and vaporizes.
• This may lead to formation of an explosive mixture .
• Fluorocarbon vapors do not form any explosive or
flammable mixture though their vapors are heavier than air.
93

PROCEDURE:
• Non aqueous products and products which can withstand
low temperatures of - 40°F are used in this method.
• The product concentrate is chilled to a temperature of -
40°F and filled into already chilled container.
• Then the chilled propellant is added completely in 1 or 2
stages, depending on the amount.
• Another method is to chill both the product concentrate and
propellant in a separate pressure vessel to - 40 °F and then
filling them into the container.
• The valve is placed and crimped on to the container.
• Then test for leakage and strength of container is carried
out by passing container into a heated water bath, where the
contents of the container are heated to 130°F. After this, the
containers are air dried , capped and labeled.
94

• Various units used in cold filling methods are :
Unscrambler, Air cleaner ,Concentrate filler ,Propellant
filler ,Valve placer ,Valve crimper ,Water bath ,Labeler,
Coder and Packing table .
• The cold filling method is no longer being used, as it has
been replaced by pressure filling method.
Advantage:
• Easy process .
Disadvantages :
• Aqueous products, emulsions and those products
adversely affected by cold temperature cannot be filled by
this method.
95

COLD FILLING APPARATUS
96

COMPRESSED GAS FILLING APPARATUS
• Compressed gases have high pressure hence a pressure
reducing valve is required.
• The apparatus consists of delivery gauge.
• A flexible hose pipe which can withstand 150 pounds per
square inch gauge pressure is attached to the delivery gauge
along with the filling head.
• A flow indicator is also present in specialized equipments.
PROCEDURE :
• The product concentrate is filled into the container.
• Valve is placed and crimped on the container.
• With the help of vacuum pump the air is removed from the
container.
97

• Filling head is put in the opening of the valve and the
valve is depressed and the gas is allowed to flow in to
container.
• The gas stops flowing if the delivery pressure and the
pressure within the container become equal.
• Carbon dioxide and nitrous oxide is used if more amount
of gas is required.
• High solubility of the gas in the product can be achieved
by shaking the container manually or with the help of
mechanical shakers.
98

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
99

100
Evaluation parameters of pharmaceutical aerosols
A. Flammability and combustibility
1. Flash point
2. Flame extension, including flashback
B. Physiochemical characteristics
1. Vapor pressure
• Density
• Moisture content
• Identification of propellant(s)
• Concentrate-propellant ratio
C. Performance
1. Aerosol valve discharge rate
1. Spray pattern
2. Dosage with metered valves
3. Net contents
4. Foam stability
5. Particle size determination
6. Leakage
D. Biologic characteristics
E. Therapeutic activity

101
To test for
(a) flammability and combustibility:
i. Flame Projection
*This test indicates the
effect of an aerosol
formulation on open flame:
The Product is sprayed for 4 sec. into flame.
Depending on the nature of formulation, the fame is extended,
and exact length is measured with ruler.
ii. (2) Flash point
• Determined by using standard Tag Open Cap Apparatus.
Steps:
• Aerosol product is chilled to - 30 0 CF and transferred to the test apparatus.
• Temperature is increased slowly, and the temperature at which the vapors
ignite is taken as the flash point.
• Determined for flammable component,
such as topical hydrocarbons

Quality Control in aerosol manufacture
• (b) Physical Chemical Characteristics:
– Vapour pressure – use pressure gauge
– Density – use hydrometer or pyenometer
– Moisture – Use Karl – Fisher method
• (c) Propellant Identification – Gas
chromatography

Quality Control in aerosol manufacture
d) Performance:
(i) Aerosol valve discharge rate (Delivery Rate).
Weigh the container, Discharge for a given time and reweigh. Then
determin the delivery rate as g/s or g/min
• (ii) Spray Pattern:
• Impactment of spray on a paper previously treated with dye-talc
mixture (dye is water or oil soluble). When particles strike, the dye
go into solution and the Pattern can be determined.
• Photographic technique is also used. The spray is allowed to
impinge on the photographic film through a shutter system similar
to that of a camera. The film is developed and the spray pattern
can be assessed.

Quality Control ….
(e) Dosage with metered valves
- Reproducibility of the dose
- Amount delivered per actuation
(f) Net contents of the package
(g) Foam stability
(h) Particle size determination (cascade impactor method,
light scatter method).
(i) Leak testing determination (cans are immersed in
warm water at 50oC. There should not be any leakage
at the seam or joinery of the top or bottom
(j) Biological Testing
(k) Therapeutic activity

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
105

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.
106

TEST SOLUTIONS
Ingredients
% 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
107

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’s
54µL or less ± 15%
55 to 200 µL ± 10%
108

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.
109

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.
110

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.
111

EVALUATION TESTS
A. Flammability and combustibility :
1. Flash point
2. Flame Projection
B. Physicochemical characteristics :
1. Vapor pressure
2. Density
3. Moisture content
4. Identification of Propellants
112

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
113

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.
114

B. Physicochemical characteristics:
Property
Method
1. Vapor
Pressure
Variation in pressure indicates the presence of air in
headspace.
Can use a pressure gauge OR A can punctuating device,
that measures vapor pressure
2. Density Use (i) Hydrometer (ii) Pycnometer.
Step involves are 
A pressure tube is fitted with metal fingers and
hoke valve, which allow for the introduction of liquids
under pressure.
The hydrometer is placed in to the glass pressure
tube.
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.
115

116
(3) Moisture content
(i) Karl Fischer method
(ii) G. C has also been used
(C) Identification of propellants
(i) G.C,
(ii) I.R spectrophotometry
(D) 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).
(E) 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.

C. Performance:
117

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 in
weight divided by number of doses dispensed gives average dose.
4. Net Contents :
• Tared cans that have been placed onto the filling lines are
reweighed and the difference in weight is equal to the net
contents.
• 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.
118

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 :
The practical particle size ranges from 0.1 to 30 micron
which are intended to be retained on RTI.
• Modification made to improve efficacy
Methods : » Cascade Impactor; Light Scattering
Decay. 119

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 turbulent
conditions, the change in the light
intensity of a Tyndall beam is
measured.
120

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.
121

• 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
122

References:
• “The Theory & Practice Of Industrial Pharmacy” by Leon Lachman
, H.A.Lieberman.
• Remington’s “The Science & Practice Of Pharmacy” 21st Edition,
Volume-I.
123

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