5.

2 Definition: Aerosols are defined as a pressurized system that depends on the power of
compressed or liquified gas to expel the contents from the container.
Components of Aerosols:
1. Propellants
2. Container
3. Valve
4. Actuator

5.2.1 Propellants :
 These are responsible for developing adequate pressure within the container.
 They provide the driving force to expel the product from the container and help in the
atomization or foam production of the product.

Examples: Fluorinated hydrocarbons like ---

Trichloromonofluoromethane (propellant 11)
Dichlorodifluoromethane (propellant 12)
 Trichlorotrifluoroethane (propellant 114)
 These fluorinated hydrocarbons are commonly used in aerosols
for oral and inhalation purposes.
 Topical pharmaceutical aerosols use hydrocarbons:
 Propane--- (Propellant A-108),
 Butane--- (Propellant A-17)
 Isobutane--- (Propellant A-31)
 Compressed gasses (nitrogen, nitrous oxide and carbon dioxide).
 According to Dalton's law, the combination of various pressures of a mixture of
propellants can be calculated.
 Dalton’s law --------→Total pressure in any system is equal to the sum of individual
or
partial pressures of various components
Raoult’s law states that the depression of a solvent's vapour pressure upon adding a solute is
proportional to the mole fraction of solute molecules in the solution.

The vapour pressure of a mixture consisting of two individual propellants is equal to the sum
of the mole fraction of each component present multiplied by the vapour pressure of each
pure propellant at the desired temperature.

The mathematical expression of this is as follows:

1. pₐ=nana+nb PAO=NAPAO

Pa = partial vapour pressure of propellant A

PA°= vapour pressure of pure propellant A
nₐ = moles of propellant A
nь= moles of propellant B
NA = mole fraction of component A
Partial vapour pressure of propellant B can be calculated

1. Pь=nьnₐ+nь PB°=NB PB°

Total vapour pressure of the system

1. P = Pₐ+Pь
5.2.2 CONTAINERS:
Aerosol containers are usually made of glass, metals and plastics.The selection of the
container for a specific aerosol product is determined by its adaptability to production
methods, compatibility with the formulation, ability to sustain the pressure necessary for the
product.
They must withstand pressures as high as 140 to 180 psig (pound per sq. inch gauge) at 130°
F.
1. Metals
1. Tinplate steel
2. Aluminum
3. Stainless steel
B.Glass
1. uncoated glass
2. plastic-coated glass
1. Tin plate steel container: Tinplate containers are lightweight and relatively
inexpensive. However, special protective coatings are applied to the tin sheets prior to
fabrication when required. The inside of the container will be protected from
corrosion and interaction between the tin and the formulation. The coating is usually
an oleoresin, phenolic, vinyl or epoxy coating. The tin-plate containers are used in
topical aerosols.
2. Aluminium: Aluminum is used for inhalation and topical aerosols. This material is
extremely lightweight and is less reactive than other metals. Aluminium containers
can be coated with epoxy, vinyl or phenolic resins. Most aluminium containers are
manufactured by an impact extrusion process that makes them seamless. Therefore,
they have a more excellent safety against leakage, incompatibility, and corrosion.
Aluminium containers are made with a 20mm neck finish that adapts to the metered
valves.
3. Stainless steel: Stainless steel is used when the container must be chemically resistant
to product concentrate. The primary limitation of these containers is their high cost,
used for aerosols inhalation.

Fig 1 Aerosols containers

B. Glass containers: Glass containers would be the preferred containers for most aerosols.
Glass presents fewer problems concerning chemical compatibility with the targeted drug
delivery system. These containers are limited to lower pressure products and a lower
percentage of the propellant.

Fig: 2 Aerosol glass containers

Two types of glass aerosols containers :
1. Uncoated glass container: Low cost and high clarity and contents can be viewed at all
times.
2. Plastic-coated glass containers: These are protected by a plastic coating that prevents
the glass from shattering in the event of breakage.

5.2.3 VALVES:
 Valves have the capacity of delivering the content in the desired form.
 Capable of quickly opening and closing.
  The Food and Drug Administration must approve materials used in constructing the
valves.
 Capable of carrying out the content in a desired length form such as spray, foam, solid
stream, etc.
 It can deliver a given amount of medication.
Different types of valves are as follow :
1. Continuous spray valves :
 An aerosol valve consists of different parts and is assembled using high production
techniques
 The valve consists of the following parts.
Ferrule or Mounting cup:
 Used to attach the valve properly to the container
 Cup is made from tin plate steel or aluminium
 The side of the valve cup is coated with single or double epoxy or vinyl resins
 The ferrule is attached to the container by rolling the end under the bottle's lip.
Valve body or Housing:
 Generally manufactured from nylon or Delrin and contains an opening at the point of
attachment of the dip tube (ranges from 0.013 inch to 0.080inch)
 The housing may or may not contain another “vapour tap” opening.
Stem :
 Made from Nylon or Delrin.
 Stainless steel and brass can also be used.
 One or more orifices (tiny holes) are present in the stem.
 One orifice ranges from about 0.013 inches to 0.030inch.
Gasket :
 Made from Buna-N and neoprene rubber are used commonly for gasket material.
Spring :
 It helps in holding the gasket to the proper place.
 It helps the valve return to its closed position when the actuator is depressed &
released.
 It can be made with stainless steel.
Dip Tube :
 It is made from polyethene or propylene.
 The internal diameter of the dip tube is about 0.120 to 0.125 inches.
 However, for the capillary dip tube, the inner diameter is 0.050 inches, and for the
highly viscous product, it is 0.19 inches.

Fig: 2 Valve assembly and its components

1. METERING VALVES:
 Applicable to the dispensing of potent medication.
 Approximately 50-150mg ± 10% of liquid materials can be dispensed at one time
using such a valve.

ACTUATORS:
 These specially designed buttons help deliver the drug in the desired form, i.e., spray,
wet stream, foam, or solid stream.

Fig : 3 Actuators
Different types of actuators :
1. Spray Actuators:-
 It can be used for topical preparation, such as antiseptics, local anaesthetics, spray-on
bandages, and foot preparations.
 It allows product concentrate and propellant to pass through various openings and
dispense as a spray.
2. Foam Actuator: -

Fig 4 Foam actuator

 It consists of large orifices ranging from approximately 0.070-0.125 inches.
 Orifices allow the product to pass into a large chamber -expand & dispensed.
1. Solid stream Actuators:-
 These actuators are required for dispensing semi-solid products such as ointments.
4. Special Actuators:-
 These are used for a specific purpose.
 It delivers the medication to the appropriate site of action such as the throat, nose,
dental and eyes etc.
5.2.4 FORMULATION OF PHARMACEUTICAL AEROSOLS :
An aerosol formulation consists of two main components :
1. Product concentrate and
2. Propellant
 Product concentrate consists of active ingredients or a mixture of active ingredients
and other necessary agents such as solvents, antioxidants, and surfactants.
 Propellant: Propellant may be a single propellant, or a blend of various propellants is
used. A blend of solvents is used to achieve desired solubility characteristics.
 Various surfactants are mixed to give the proper HLB value for the emulsion system.
 The propellants are selected to give the desired vapour pressure, solubility and
particle size.
 The pharmaceuticals aerosols may be dispensed as a fine mist, wet spray, quick-
breaking foam, stable foam, semisolid or solid spending on the type of aerosol used.
The type of aerosols system selected depends on :
1. Physical, chemical and pharmacological properties of a drug
2. Site of application
5.2.5 TYPES OF AEROSOLS SYSTEMS:
1. Solution system :
2. Water-based system
3. Suspension or dispersion systems
4. Foam systems
1. Aqueous stable foams
2. Non-aqueous stable foams
3. Quick-breaking foams
4. Thermal foams
A. Solution system :
 This system, also referred to as a two-phase system, consists of vapour and liquid
phases.
 Propellants are selected depending on the type of spray required.
E.g., Propellant 12 or A-70 → Very fine particles
Propellant 12 + other propellants
↓
The pressure of the system decreases.
 ↓
Large particles produce
 The vapour pressure of the system is reduced by the addition of less volatile solvents
such as ethanol, acetone, propylene glycol, glycerine, ethyl acetate.
 The amount of propellant used may vary from 5% ( for foams) to 95% ( for
inhalation).
 When active ingredients are soluble in the propellant, no other solvent is required.
 These sprays are also helpful for topical preparations as it helps to coat the affected
area with a film of active ingredients.
 Propellant 12/11 ( 30:70).
 Propellant 12/114 (55:45) are used for oral inhalation aerosols.
 Aerosols are used for inhalation or local activity in the respiratory.

Table: 1 Asthma formulation

 This type of formulation is packed in a 15-30ml stainless steel, aluminium or glass
container.
 As the amount of propellant is 12 ↑, the pressure ↑.
 Propellant 12 has high v.p; the propellant is added to reduce the pressure.
 E.g., Hydrocarbon is a topical aerosol.

Table: 2 Hydrocarbon in topical aerosol

 Solution aerosols produce a fine to coarse spray.
 Hydrocarbon propellant A-70 produces drier particles, while propellant A-17 and A-
31 produce a wetter spray.

Water-Based system :
 This large amount of water replaces all or part of the non-aqueous solvents used in
aerosols.
 The formulation must use active ingredients and other solvents in the emulsion system
to produce a spray. The propellant is in the external phase.
 Since propellant and water are not miscible, a three-phase aerosol forms (propellant,
water and vapour phases).
 Ethanol can be used as a cosolvent to solubilize propellants 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.
 Surfactants with low water solubility and high solubility in nonpolar. Solvents will be
most helpful, E.g. long-chain fatty acid esters of polyhydric compounds including
glycol, glycerol, and sorbitan esters of oleic, stearic, palmitic, and palmitic, lauric
acids.
 Aquasol system helps dispense fine mist or spray of active ingredients dissolved in
water.
 It is designed to dispense pressurized products efficiently and economically using a
small amount of hydrocarbon propellant.
 The difference between the aquasol system and the three-phase system is that aquasol
dispenses relatively dry spray with tiny particles, non-flammability of the product.
C. Suspension system :
 It involves the dispersion of active ingredients in the propellant or mixture of
propellants.
  To decrease the settling rate of dispersed particles, surfactants or suspending agents
can be added.
 These systems are developed primarily for oral and oral inhalation aerosols.

 Epinephrine bitartrate has minimum solubility in the propellant system. It is soluble in

fluids in the lungs and exerts a therapeutic activity.
Physical stability of aerosol dispersion can be increased by :
1.Control of moisture content (< 300ppm).
2. Reduction of initial particle size to less than 5 𝜇m.
3. Adjusting the density of propellant and suspension to equalise them.
4. Use of dispersing agents.
5. Use derivatives of active ingredients with minimum solubility in the propellant system.
 Particles of certain materials tend to aggregate immediately after suspension. Due to
solubility, moisture or particle size.
 The physical stability of a dispersed system depends on the suspension's
agglomeration rate.
 Agglomeration is accelerated at elevated temperatures, and it is also affected by the
particle size of the drug (1-5μ, never > 50μ).
 Agglomeration results in valve clogging. Inaccurate dosage and depending on the
nature of active ingredients may cause damage to the liner and metal container.
 Isopropyl myristate and mineral oil are used to reduce agglomeration.
 Surfactants having an HLB value of less than 10 are utilized for aerosol dispersions
(sorbitan monooleate, monolaurate,trioleate).
 Surfactants are effective in a concentration of 0.0q to 1%.
 Vapour tap valves are also used with dispersion aerosols to decrease valve clogging.
D. Foaming system :
 Emulsion and foam aerosols consist of active ingredients, aqueous or non-aqueous
vehicles, surfactants, and propellants. They are dispensed as stable or quick-breaking
foam depending on the nature of the ingredients and the formulation.
 The liquified propellant is emulsified & is found in the internal phase.
 Aerosol emulsions have various applications :
Decrease irritation when applied to a limited area.

Less sensitivity reactions

1. Aqueous stable foam:
Active ingredients % w/w
oil waves
o/w surfactant 95-96.5
water
Hydrocarbon propellant (3-5%) 3.5-5
propellant concentration maybe 5% (high) in some cases or about (3-5% w/w or 8-10 v/v).
As propellant increases, a stiffer and dryer foam is produced.
Lower propellant concentrations yield wetter foams.
Hydrocarbon and compressed gas propellants are used.
1. Non-Aqueous stable foam:
can be formulated using various glycols such as PEG
Formulation % w/w
Glycol 91.-92.5
Emulsifying agent 4.0
Hydrocarbon propellant 3.5-5
 3) Quick-Breaking foam :
In this, a propellant is in the external phase.
When dispensed, the product comes out as a foam then collapses into liquid.
Mainly applicable to topical medications.
Formulation % w/w
Ethyl alcohol 46.0-66.0
Surfactant 0.5-5.0
water 28.0-42.0
Hydrocarbon propellant 3.0-15.0
Surfactants can be non-ionic, cationic, or anionic type surfactants should be soluble in both
water & alcohol.
Thermal Foam :
It is used to produce warm foam for shaving.
They were discontinued soon due to
 Inconvenience of use
 Expensive
 lack of effectiveness
5.2.6 MANUFACTURE OF AEROSOLS :
Pressure filling apparatus.
Cold filling apparatus.
Compressed gas filling apparatus.
PRESSURE FILLING APPARATUS :
 It consists of a pressure burette that can meter small volumes of liquefied gas into the
aerosol container under pressure.
 Solutions, emulsions, suspension can be filled by this method as chilling does not
occur.
 The propellant is added through an inlet valve located at the bottom or top of the
pressure burette.
 Air present inside is allowed to escape through the upper valve.
 The required amount of propellant flows through the aerosol valve into the container
under its vapour pressure.
 When the pressure is required between the burette and the container (if a low-pressure
propellant is used), the propellant stops flowing.
 A nitrogen cylinder or compressed air is added to the upper valve if additional
propellant is added. The added nitrogen or compressed air helps the propellant flow.
 Another pressure filling device uses a piston to maintain the pressure.
 This device cannot be used to fill inhalation aerosols with metered valves.
 This method involves filling the concentrate into the container at room temperature;
the valve is crimped to the container.
 Through the opening of the valve, the propellant is added.
 Since the opening of the valve is smaller in size ranging from 0.018-0.030 inches, it
limits the production, and the process becomes slow.
 The trapped air in the container and the headspace are removed before filling the
propellant to protect the product from getting adversely affected.
COLD FILLING APPARATUS :
 Simpler than pressure filling apparatus.
 It consists of an insulated box fitted with copper tubing that has been coiled to
increase the area exposed to cooling.
 Before use, the insulated box should be filled with dry ice or acetone.
 This system can be used with metered valves and non metered valves.
  In this method, components used will be in chilling conditions. including propellant &
product concentrate up to -30 to 40℉
Method A
Product concentrate chilled to -30 to -40℉
↓
Chilled product added to a chilled container
↓
Chilled propellant added through inlet valve acc. to
requirement
Method B

Product concentrate and propellant chilled to -30 to -40 ℉

↓
Mixture added to a chilled container.
↓
Filled containers are passed through water contents
heated up to 130℉ & valve is crimped to container
↓
containers dried, capped and labelled
 Used for non-aqueous products & that product which is not affected by low
temperature in the range of -40℉

COMPRESSED GAS FILLING APPARATUS :

Generally, compressed gasses are under high pressure, so a pressure reducing valve is
required.
A flexible tube is attached to the delivery gauge. It can withstand about 150psig pressure &
fitted with a filling head.
Method :
Product concentrate placed in a container
↓
valve is crimped in its place
↓
A vacuum pump removes air.
↓
The filling head is inserted into the valve orifice, the valve is
depressed & the gas is allowed to flow into the container
 If the pressure inside the container is equal to the delivery pressure, the gas stops
flowing.
 If the product requires an increased amount of gas, solubility of gas CO2 and nitrous
oxide can be used.
 To increase the solubility of a gas in the product, the container is shaken manually
during & after the filling operation. Mechanical shakers are also used.

5.2.7 EVALUATION OF PHARMACEUTICAL AEROSOLS

Physical, chemical and biological tests can evaluate aerosols. These include:
A. Flammability and Combustibility
1. Flame projection/ Flame extension
2. Flashpoint
B. Physicochemical characteristics
1. Vapour pressure
 2. Density
3. Moisture content
4. Identification of propellant
5. Concentrate propellant ratio
C.Performance
1. Aerosol valve discharge rate
2. Spray pattern
3. Dosage with a metered valve
4. Net contents
5. Foam stability
6. Particle size determination
7. Leakage
D.Biological characteristics
A. Flammability and combustibility
1. Flame projection :
 It shows the effect of an aerosol formulation on the extension of an open flame.
 In this, the product is sprayed for about 4sec into a flame. The flame is extended;
depending on the nature of the formulation, the exact length is measured with a ruler.
1. Flash point :
 Standard Tag Open Cup Apparatus is used.
Product chilled to a temp. of about -25℉
↓
transferred to the test apparatus
↓
test liquid is allowed to increase slowly in temp
↓
The temp. at which the vapour ignite is considered as the flashpoint.
↓
the flashpoint obtained is generally the flashpoint of flammable

B.Physiochemical characteristic
1. Vapor pressure :
 It can be measured with a pressure gauge or through a water bath, test gauge etc.
 It is essential to determine the pressure difference from the non-biner to the container.
If the pressure difference is more, it indicates the presence of air in the headspace.
 Its puncturing device is available for accurately measuring vapour pressure.
2. Density :
 Density can be measured/determined by the hydrometer or pycnometer.
3. Moisture :
 Karl Fisher & Gas Chromatography are used.
4. Identification of propellant :
 Gas chromatography and infrared spectrophotometry are used to identify the
propellants and indicate the proportion of each component in a blend.
C. Performance
1. Aerosol valve discharge rate :
 The aerosol product of known weight is discharged using standard apparatus for a
given period.
 After the time limit expires, the container is re-evaluated; the change in the weight per
time dispensed gives the discharge rate (g/sec).
2. Spray pattern :
  The method is based on the impingement of spray on the coated (dye-Talc mixture)
paper water/oil-soluble dye, depending on the nature of the aerosol.
 The particles that strike the paper cause the dye to go into solution and be adsorbed
onto paper, giving a spray record for comparison purposes.
3. Dosage with Metered valves :
Reproductivity of dosage can be determined by :
 Weigh the filled container accurately.
 Dispense number of doses.
 Reweighed the container and calculated the weight difference.
 weight difference/ number of times dose dispensed =avrg. dose
 The time of each dose dispensed should also be noted.
 The difference in the wt. of the full container & tarred container gives the content in
the container.
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.
 The Destructive method: Weighing a full container and then dispensing as much of
the contents as possible. The contents are then weighed. This gives the net content.
5. Foam stability :
It can be determined by
 Visual evaluation,
 Time for given mass to penetrate the foam,
 Time for the given rod that is inserted into the foam to fall
 Use of rotational viscometer
 The life of foam can range from a few seconds to 1hr or more, depending on the
formulation.
6. Particle size determinations :
 Two methods are used a) Cascade impactor
b) Light scatter decay
Cascade impactor operates on the principle that :
 A particle stream is projected through a series of nozzles and glass slides at high-
velocity stages; larger globules are impacted first, and the smaller particles pass on the
lower velocity stage. Smaller particles are collected at the high-velocity stage and
used to analyse particles having a diameter range from 0.1 to 30micron.
b) Light Scattering Decay :
 An aerosol settles under turbulent conditions, the change in the light intensity of a
Tyndall beam is measured.
D.Biological testing :
 This is the final phase of evaluation, used to evaluate the efficiency of various
products, E.g., various antibacterial agents.
1. Therapeutic Activity :
 For inhalation aerosols; the 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
ingredients is determined.
2. Toxicity :
 For inhalation Aerosols; Exposing test animals to vapours sprayed from aerosol
containers.
 For Topical Aerosols, Irritation and chilling effects are determined.
5.2.8 QUALITY CONTROL TEST FOR PHARMACEUTICAL AEROSOLS :
  It includes the testing of
1. Propellant
2. Valves, Actuators and Dip Tubes
3. Containers
4. Weight Checking
5. Leak Testing
6. Spray Testing
1. Propellant :
 This test aims to identify and work out the composition of the mixture existing when
a propellant blend is applied.
 This test is carried out by performing IR spectrophotometry or gas chromatography.
 Vapour pressure to determine its moisture and density of the propellants are
determined and compared with specification sheets.
2. Valves, Actuators and Dip Tubes :
 The objective of these tests is to measure the average magnitude of valve delivery and
the degree of uniformity between discrete valves.
 Sampling is done according to standard procedures found in Military Standards
“MIL-STD-105D”.
 Twenty-five valve samples from each batch are chosen using sampling plans.
 These receptacles are full of standard test solutions, each with specific gravity
proposed to assess variation in valve delivery.
 These solutions are alcohol USP-NF, isopropyl myristate (0.1%),
Dichlorodifluoromethane (49.95%), trichloromonofluoromethane at 25℃.
 An actuator with a 0.020-inch orifice is attached.
 The actuator is mounted on each valve. Then, filled containers are located in -25± 1℃
air space to change to that temperature.
 These filled receptacles are actuated to the fullest extent for 2sec and weighed; again,
the valve is actuated for 2sec and weighed.
 The difference between them represents delivery in mg.
 This test is repeated at least twice for each unit from the 25 sample units.
 Finally, the rate of valve delivery per actuation is calculated in microliters.
 Valve delivery rate per actuation 𝜇L = Individual delivery wt/specific gravity of test
solution.
3. Containers testing :
 One of the essential criteria for selecting an aerosol container is withstood internal
created pressure as high as 140-180 psi at 130℉.
 Both the coated and uncoated containers were evaluated for defects in the inner lining.
 Quality control aspects include the degree of conductivity of electric current as
measured metals.
 Glass containers are inspected for cracks and defects.
4. weight checking :
 This assessment procedure will check the accuracy of the filling procedure and ensure
uniformity of the final total weight of the product.
 Tared empty containers are added to filling lines; they are removed and weighed.
 The same technique is usually used for checking the weight of the propellant.
5. Leak testing :
 A leak test is done by checking the crimping of the valve and detecting the defective
container due to leakage.
 This test is done by measuring the crimp’s dimension & comparing.
  Final testing of valve closure is done by passing the filled containers through a water
bath.
 The leakage test is defined as the weight change of the same container before and
after being stored in a vertical position at 25℃±2° for a minimum of 3 days.
 Aerosol dispensers are selected and weighed in mg, considered the weight before the
positioning(𝑊1).
 Allow the filled container to stand for at least 3days, and each container's weight
should be determined again, finding the weight in mg each container as (𝑊2).
 The time during which the containers were under test (T) in hours.
 Leakage rate = 365 X 24/ T X 𝑊1-𝑊2
6. Spray testing :
 The driving purpose of this test is to eliminate any pure propellant and pure
concentrate from the dip tube.
 This method encompasses the impingement of test sprays on the surface of a treated
piece of paper with a dye-talc mixture.
 Most pharmaceuticals carry on a 100% spray tested

5.2.9 STABILITY STUDIES :

CH Harmonised Tripartite Guideline, 2003. Stability Testing of New Drug Substances and
Products Q1A(R2), (Internet) Available from <http://www.emea.eu.int>.
 The international council for harmonising technical requirements for pharmaceuticals
for human use (ICH) guidelines is a worldwide nonprofit organization underneath
Swiss law with a mission to achieve better universal harmonization to guarantee
practical, high-quality, and safe therapeutic drugs.
 These tests the environmental influence on drug constituents or finished products
considering time. Ultimately, evaluating the results of stability tests and assessing
their relation to total quality will be translated as appropriate recommended storage
conditions and shelf life for the product.
 The world can be divided into four climatic zones for worldwide stability testing, as
follows :
Zone Ⅰ : Temperature
Zone Ⅱ : Subtropical, with likely high humidity,
Zone Ⅲ : Hot/dry; and
Zone Ⅳ : Hot/humid
 Four ICH topics are coded for efficacy, safety, quality, and multidisciplinary
guidelines. Each guideline focused on a particular field of test and legislation.
Efficacy guidelines specify studies to evaluate the relationship between doses,
systemically levels, and therapeutic response for developing a new drug.
 Stability evaluation of new drug substances and finished products define
recommendations on stability testing protocols for climatic Zone Ⅰ and Ⅱ, including
temperature, relative humidity, and trial duration considering the requirements for
stability testing in climatic zones Ⅲ and Ⅳ to minimize the different storage
conditions for submission of global registration.