Pharmacy and Pharmaceutics

1. Pharmaceutical Aerosol
Dr. Khaleequr Rahman
Assistant Professor
National Institute of Unani Medicine, Bengaluru

2. INTRODUCTION
 Aerosol is pressurized dosage form in which
therapeutically active drug is dissolved or
dispersed or suspended in compressed or
liquified gas to expel the content from the
conatiner in the form of spray
 Aerosol mainly used for the treatment
of Asthma and COPD or topically as
pain killer etc.
 Aerosols are also used for topical, oral or
nasal administration in the form fine
particles or mist or fog.
 Inmid 1950 the pharmaceutical aerosol
introduced in market.

3. Drugs used in aerosol form

4. ADVANTAGES
 Itproduce Rapid action.
 It directly applied to the affected area.
 It prevents to oxidation of drugs
 Drug avoid the hepatic metabolism.
 It is suitable when drug degrade in GI tract.
 Itcan be maintain sterility
 Easy to use and portable
 It produce local & systemic effect ( due to large
surface area of lung and blood capillary )

5. DISADVANTAGES
 Safety/hazard
 Cost
 Deposition of particle in upper respiratory tract
 The propellant may cause chillness to the skin

6. ➢ TYPES OF AEROSOL SPRAY
1. Space sprays
2. Surface coating spray
3. Foam spray

7. SPACE SPRAY
 Delivered as a fine mist is called space spray.
 It contains 85% propellant and it is pressurized at 21°C with 30-40
psig.
 It contains not more than 50 µm of particle. So it can be retain in air.
e.g. Room sprays

8. ➢ SURFACE and FOAM SPRAY
 Aerosols intended for carrying active ingredients to surface are
termed as surface sprays or surface coating spray.
 It contains 30 –70% propellant operate between 22–55 psig at 21°C.
e.g. topical aerosol-pain killer or antiseptic aerosols
 Foam aerosols (emulsion ) usually operate between 35 and 55 psig at
21°C and contains only 6-10% propellant.

9. Air flow and gaseous exchange in respiratory tract

10. Particle deposition
 If particles size >100 µm in diameter may deposit in the
oropharyngeal cavity.
 If Particles between 10 to 60µm will be deposited on the
epithelium of the bronchial tract.
 If Particles Size is < 2 µm in diameter can reach the alveoli.

11. Mechanism of particle deposition
1. Impaction
2. Gravitational sedimentation
3. Interfacial interception
4. Brownian diffusion
5. Electrostatic precipitation

12. Inertial impaction
 Inertial impaction occurs because a particle traveling in an air
stream has its own momentum (the product of its mass and
velocity)
 As the direction of the airflow changes due to a bend or obstacle, the
particle will continue in its original direction for a certain distance
because of its inertia.
 Impaction of particles entering the mouth with a high velocity
occurs either at the back of the mouth or at the bend where the
pharynx leads to the trachea. Only a small fraction of particles
greater than 15 µ m will reach the trachea following mouth
breathing.
 Deposition by impaction will also occur as the trachea splits into
the left and right bronchus.

13. Gravitational sedimentation
 Gravitational sedimentation is the downward movement of particle
under the action of gravity .
 If particle size is less than 5µm deposition in bronchioles and alveoli.
 Particles settle by gravitation onto the airwaywalls.

14. ➢ Brownian diffusion
 Collison and bombardment of small particle by the molecule in the
respiratory tract produce Brownian motion.
 Brownian motion or diffusion is a mechanism which significantly affects
only particles less than 0.5 µm in diameter.
 These particles are subjected to bombardment by surrounding gas
molecules causing random movement of the particles.
 In this situation, the diffusivity of a particle is inversely proportional to
its diameter.

15. Interception
If the particles contact the airway surface because of their larger
dimension of particle

16. Electrostatic precipitation
 The charge on the surface of the particle may affect the resultant
deposition, i.e. surface of charged particle (+ve ) interact with a site
within the respiratory tractthat posses on opposite charge (-ve).
 Unipolar charged aerosols with high number concentrations repel
each other and drive particles towards the walls.

17. Breathing pattern
 Breathing pattern, lung physiology will affect the deposition of
particle.
 Breath holding after inhalation enhances the deposition of
particle by sedimentation and diffusion.

18. Dispensing unit
 Content/composition of aerosol
 Aerosol container
 Aerosol container cap/valve assembly

19. Component of aerosol
Aerosol consist of
1. Product concentrate
2. Propellant
Product concentrate consist of API, excipients like suspending agent,
emulsifying agent, antioxidant, aqueous and non aqueous cosolvent etc.

20. PROPELLANT
It is responsible for developing the vapor pressure with in the container
and also expels the product when the valve is opened and in the form of
atomization or foam production of the product.
It is classified in to mainly two types
1. Chloroflurocarbon (CFC)
2. Hydrochloroflurocarbon (HCFC) and Hydroflurocarbon (HFC)
3. Hydrocarbons (HC)
4. Compressed gas system

21. Liquefied gas system
 These compounds are gases at room temperature and atmospheric
pressure.
 However they can be liquefied easily by lowering the temperature (below
the boiling point or by increasing pressure)
 These compounds are chosen generally have B.Pt below 21°C and
vapour pressure between 14 and 85 psia at 21°C
 When it is placed into sealed container it immediately separartes into a
liquid and a vapour phase.
 Some of the propellant molecule will leave from the liquid state to vapor
state.
 As molecule enter the vapor state a pressure gradually develops.

22. 1. Chloroflurocarbons (CFC)
It is used for oral and inhalation aerosol preparation.
Chemical Name Chemical
Formula
Numerical
Designation
BP
Trichloromonoflouromethane CCl3F 11 23.7°C
Dichlorodifluoromethane CCl2F2 12 -29.7°C
Dichlorotetrafluroethane CClF2ClF2 114 4.1°C

23. Chloroflurocarbon (CFC)
Advantages
 Low inhalation toxicity
 High chemical stability
 High purity
 CFC is a good solvent
Disadvantages
 Destructive to atmospheric Ozone
 Contribute to “greenhouse effect”
 High cost

24. Chlorodifluromethane CHClF2 22
Chloropentaflouroethane CClF2CF3 115
Chlorodifluroethane CH3CClF2 142b
Trifluromonofluroethane CF3CH2F 134a
Difluroethane CH3CHF2 152b
Octaflurocyclobutane CF2CF2CF2CFM2 12 C318
Heptafluropropane CF3CHFCF3 227
2. Hydrochloroflurocarbon (HCFC) and Hydroflurocarbon (HFC)

25.  The ozone layer in the stratosphere absorbs a portion
of the UV radiation from the sun.
 UV has been linked to many harmful effects, including
skin cancers, cataracts, and harm to some crops and
marine life.
 Beginning in the 1970s, scientific evidence showed
that the ozone shield was being depleted well.
 When chlorine atoms come into contact with ozone it
destroy ozone molecules.
 One chlorine atom can destroy over 100,000 ozone
molecules before it is removed from the stratosphere.
Some compounds release chlorine or bromine when
they are exposed to intense UV light. e.g. CFC, HCFC
etc.
 In the 1970s, concerns about the effects of ozone-depleting substances on the
stratospheric ozone layer prompted several countries, to ban the use of
chlorofluorocarbons (CFCs) as aerosol propellants.
 An finally under the United Nations Framework Convention on Climate Change
in 1994, the Kyoto Protocol was adopted as a concrete implement to control
greenhouse gas emissions.

26. Advantages
 Low inhalation toxicity
 High chemical stability
 High purity
 Not/minimum ozone depleting
Disadvantages
 Poor solvents
 Greenhouseeffect
 High cost

27. Chemical name Numerical
designation
Butane A-17
Isobutane A-31
Propane A-108
3. Hydrocarbons
It is mainly used for for the preparation of topical and air
freshener preparation.

28. Advantage
 Chemically stable
 No hydrolysis
 Low toxicity
 They are lighter than water
Disadvantage
 Inflammable
 Toxicity
Odorant: Ethanethiol, EN 589, tetrahydrothiophene (thiophane) or amyl mercaptan

29. 4. Compressed-gas propellants
 Gases such as nitrogen (N2), nitrous oxide (N2O), and carbon dioxide
(CO2 )
 The pressure of the compressed gas in the headspace of the aerosol
container expels the product concentrate in essentially the same form as it
was placed into the container.
 Unlike aerosols containing liquefied-gas propellants, there is no propellant
reservoir.
 As a result, higher gas pressures are required for aerosols, and the pressure
within the aerosol diminishes as the product is used.
 Substances are dispensed as fine mists, foams, or semisolids, including
food products, dental creams, hair preparations, and ointments.
 Owing to their low expansion ratio, the sprays are fairly wet, and the foams
are not as stable as those produced by liquefied gas propellants.

30. Compressed gas system
Advantages
 Very low inhalation toxicity
 High chemical stability
 High purity
 Inexpensive
 No environmental problems
Disadvantages
 Require use of a nonvolatile co-solvent
 Produce coarse droplet sprays
 Pressure falls during use

31. Types of aerosol system
There are five types of aerosol system
1. Solution system / Two phase system
2. Water based system / Three phase system
3. Suspension or Dispersion system
4. Foam system

32. 1. Solution system
 It consists of two phases
A vapour phase
and a liquid phase
 Solution system consists of product
concentrate in a propellant or mixture
of propellant and solvent with drug.
 Solvents may also be added to the
formulation to retard the evaporation of
the propellant.
 Solution aerosols can be difficult to
formulate because many propellant or
propellant-solvent mixtures are
nonpolar and are poor solvents for the
product concentrate.
 Also, there is a limited number of
solvents that can be used.

33.  Ethyl alcohol is the most commonly used solvent but propylene
glycol, dipropylene glycol, ethyl acetate, hexylene glycol, and
acetone have also been used.
 Aerosol solutions have been used to make local anaesthetics,
anti-inflammatory preparations, and aerosols for oral and
nasal applications.
 They contain 50 to 90% propellant for topical aerosols and up
to 99.5% propellant for oral and nasal aerosols.
 As the percentage of propellant increases, so does the degree of
dispersion and the finest of the spray. As the percentage of
propellant decreases, the wetness of the spray will increase.

34. 2. Water based system
 It is three phase system containing
Vapour Phase
Water
Propellant (CFC HFC, HCFC or
Hydrocarbon)
 Ethanol used as a co-solvent to solubilize the
propellant in water
 Propellant content varies from 25 -60%
 This type of system is used when the formulation
requires the presence of a liquid phase that is not
propellant miscible.
 In this formulation the dip tube must not extend
beyond the aqueous phase.

35.  If CFCs, HCFCs, and HFCs are used as the propellants, they
will reside on the bottom of the container since their density is
greater than water. The dip tube will then need to end
somewhere in the middle of the container.
 If hydrocarbons are used as the propellants, they will reside
on the aqueous layer since their density is less than water. In
this case, the dip tube can be extended through the liquid
propellant all the way down to the bottom of the container.
Thus an important characteristic of any aerosol is the density
of the propellant, propellants, or blend of propellants.
 Sometimes it is desirable to have some liquefied propellant
mixed with the aqueous phase to facilitate in the dispersion of
the spray or to create a foam. In this case, the container should
be shaken immediately prior to use.

36. 3. Suspension system
 Suspensions aerosols can be made when the product concentrate is
insoluble in the propellant or mixture of propellant and solvent, is not
desirable.
 It is prepared by dispersion of active ingredients in mixture of
propellant and by using suspending agent
 The physical stability of suspension can be increased by use minimum
solubility of API.
 Anti-asthmatic drugs, steroids, and antibiotics are delivered as suspension
aerosols.

37.  When the valve is actuated, the suspension formulation is emitted as an
aerosol and the propellant rapidly vaporizes and leaves a fine dispersion of
the product concentrate.
 Formulation considerations for suspension aerosols, not necessary with
solution aerosols, include agglomeration, particle size growth, valve
clogging, and particle size of the dispersed aerosolized particles.
 Lubricants and surfactants are used to overcome these difficulties.
 The particle size of the insoluble product concentrate ingredients should be
in the 1 to 10 µm range for inhalation aerosols and between 40 to 50 µm
for topical aerosols.

38. 4. Foam system
 Foams are produced in aerosol when the product concentrate is dispersed
throughout the propellant and the propellant is in the internal phase; i.e.,
the emulsion behaves like o/w emulsions.
 When the propellant is in the external phase (i.e., like a w/o emulsion),
foams are not created but sprays or wet streams result.
 Stable foams are produced when surfactants are used that have limited
solubility in both the organic and aqueous phases.
 Surfactants concentrate at the interface between the propellant and the
aqueous phase forming a thin film referred to as the "lamella."
 It is the specific composition of this lamella that dictates the structural
strength and general characteristics of the foam. Thick and tightly layered
lamellae produce very structured foams which are capable of supporting
their own weight.

39. Aerosol container
A. Metals
1. Tinplated steel: consists of sheet of steel plate that has been
electroplated on both sides with tin.
2. Aluminium
3. Stainless steel
 Greater resistance to corrosion
 Light weight, not fragile
 Good for light sensitive drugs
B. Glass
1. Uncoated glass
2. Plastic coated glass
C. Plastic
The selection of the container for a particular aerosol product is based on
 adaptability to production methods
 compatibility with the formulation
 ability to sustain the pressure necessary for the product
 design and aesthetic appeal, Cost.

40. Container material
Maximum
Pressure (psig)
Temperature
in oF (oC)
Tin-plated steel 180 130 (54.44)
Stainless Steel 180 130 (54.44)
Aluminum 180 130 (54.44)
Uncoated glass < 18 70 (21.1)
Coated glass < 25 70 (21.1)
Plastic < 25 70 (21.1)
Pressure limitations of aerosol containers

41. Glass containers
It is a preferred container for most aerosols.
It has good compatibility with the formulation compared to metal
containers and is not subject to corrosion.
Glass is also more adaptive to design creativity and allows the user
to view the level of contents in the container.
However, glass containers must be precisely engineered to provide
the maximum pressure safety and impact resistance.
It is used in products that have lower pressures and lower
percentages of propellants (25 psig and less than 50% propellant).
To increase the resistance to breakage, plastic coatings are
commonly applied to the outer surface of glass containers.

42. Plastic coatings serve many purposes:
1) prevent the glass from shattering into fragments if broken
2) Absorb shock from the crimping operation during
production thus decreasing the danger of breakage around
the neck.
3) Protect the contents from ultraviolet light
4) Act as a means of identification since the coatings are
available in various colors.
 Glass containers for drug products range in size from 15 to 30
mL and are used primarily with solution aerosols.
 Glass containers are generally not used with suspension
aerosols because the visibility of the suspended particles
presents an aesthetic problem.
 All commercially available containers have a 20 mm neck
finish which adapts easily to metered valves.

43. Tin-plated steel containers
 They are light weight and relatively inexpensive.
 For some products the tin provides all the necessary protection.
However when required, special protective coatings are applied
to the tin sheets prior to fabrication so that the inside of the
container will be protected from corrosion and interaction
between the tin and the formulation.
 The coating usually is an oleoresin, phenolic, vinyl, or epoxy
coating.
 The tin plated steel containers are used in topical aerosols.

44. Stainless steel containers
 SS is used when the container must be chemically resistant to
the product concentrate.
 The main limitation of these containers is their high cost.
Plastic containers
 They have had limited success because of their inherent
permeability problems to the vapour phase inside the container
and plastic charactor.
 Also, some drug-plastic interactions have limited the efficacy of
the product.

45. Aluminum container
 It is used in most MDIs and many topical aerosols.
 This material is extremely light weight and is less reactive than
other metals.
 Aluminum containers can coated with epoxy, vinyl, or
phenolic resins to decrease the interaction between the
aluminum and the formulation.
 The aluminum can also be anodized to form a stable coating of
aluminum oxide.
 Most aluminum containers are manufactured by an impact
extrusion process that make them seamless. Therefore, they
have a greater safety against leakage, incompatibility, and
corrosion.

46.  Aluminum containers are made with a 20 mm neck finish
that adapts to the metered valves.
 For special purposes and applications, containers are also
available that have neck finishes ranging from 15 to 20
mm.
 The container themselves available in sizes ranging from
10 mL to over 1,000 mL.

47. The valve assembly
The valve is the part of the aerosol package through which the
contents of the container are delivered.
Qualities of valve
 Withstand the pressure
 Corrosive resistant
 Contribute to the form of the emitted product
 Regulate the flow of product
 Regulate the amount of emitted material (metered valves)
 and be easy to turn on and off
https://pharmlabs.unc.edu/labs/aerosols/aerosolpackage.htm

48.  Actuator
 Ferrule or mount cap
 Stem
 Spring
 Gasket
 Valve body or housing
 Dip tube
Valve assembly

49. Actuator: It is the button which the user
presses to activate the valve assembly and
provides an easy mechanism of turning the
valve on and off. In some actuators,
mechanical breakup devices are also
included.
Stem: Stem supports the actuator and
delivers the formulation in the proper form
to the chamber of the actuator.
Gasket: Gasket, placed snugly with the
stem, serves to prevent leakage of the
formulation of the valve is in the closed
position.
Spring: Spring holds the gasket in place and
also is the mechanism by which the actuator
retracts when pressure is released thereby
returning the valve to the closed position.

50. Mounting Cup: Mounting cup which is attached
to the aerosol container serves to hold the valve in
place. Because the undersigned of the mounting
cup is exposed to the formulation, it may be coated
with an inert material to prevent an undesired
interaction.
Housing: The housing located directly below the
mounting cup serves as the link between the dip
tube and the stem and actuator. With the stem, its
orifice helps to determine the delivery rate and the
form in which the product is emitted.
Dip Tube: The dip tube which extends from the
housing down into the product concentrate serves
to bring the formulation from the container to the
valve. The viscosity of the product and its intended
delivery to rate dictate the inner dimensions of the
dip tube and housing for a particular product.

51. Types of valve
1. Spray valves
2. Vapor tap valves
3. Foam valves
4. Metering valves
Spray valves are used to obtain fine to coarse wet sprays.
It has an actuator with orifices of 0.016- 0.040inch.
Depending on the formulation and the design of the valve and actuator, the
particle size of the emitted spray can be varied.
The spray is produced as an aerosol solution passes through a series of small
orifices which open into chambers that allow the product concentrate to
expand into the proper particle size.

52. Vapour tap valve
It is used with powder aerosols, water based aerosols, aerosols
containing suspended materials, and other agents that would tend
to clog a standard valve.
This valve is basically a standard valve except that a small hole has
been placed into the valve housing. This allows vaporized
propellant to be emitted along with the product concentrate and
produces a spray with greater dispersion.

53. Foam valves
It has only one orifice that leads to a single expansion chamber.
The expansion chamber also serves as the delivery nozzle or
applicator.
The chamber is the appropriate volume to allow the product
concentrate to expand into a ball of foam.
Foam valves are used for viscous product concentrates such as
creams and ointments because of the large orifice and chamber.
Foam valves also are used to dispense rectal and vaginal foams.
It has an actuator with large orifice diameter 0.070-0.125 inch.
If the size of the orifice and expansion chamber are appropriately
reduced, a product concentrate that would produce a foam will be
emitted as a solid stream.

54. Metering valves
These are used to accurately deliver a dose of medication.
Metered valves are used for all oral, inhalation, and nasal aerosols.
The amount of material emitted is regulated by an dual valve mechanism
using auxiliary valve chamber of fixed capacity and dimensions.
This metering chamber volume can be varied so that specific quantity of
product concentrate is delivered per actuation.
When the actuator is closed, a seal blocks emission from the chamber to the
atmosphere. However, the chamber is open to the contents of the container
and it is filled.
When the actuator is depressed, the seals reverse function; the chamber
becomes open to the atmosphere and releases its contents and at the same
time becomes sealed from the contents of the container.
When the actuator is again closed, the system prepares for the next dose.

57. Apparatus
 Cold filling process
 Pressure filling process
 Compressed gas filling process
Manufacturing of pharmaceutical aerosol
https://pharmlabs.unc.edu/labs/aerosols/filling_pack.htm

58. Aerosol filling
The aerosol concentrate consists of drug or combination of drugs,
solvents, antioxidants and surfactants formulated as solution,
suspension.
The aerosol concentrate is first prepared and filled into the container.
The propellant is then filled into the container.

59. Cold filling apparatus

60. Cold filling process
 The principle of cold filling method requires the chilling of all
components including concentrate and propellant to a temperature of -30
to -40 ºF (-1.1 to -4.4ºC).
 This temprature is necessary to liquify the propellant gas.
 The cooling system is an insulated tank filled with a mixture of dry
ice and acetone or refrigeration system and coiled copper pipe.
 First, the product concentrate is chilled and filled into already chilled
container followed by the chilled liquefied propellant using metered or
non metered valve.
 The heavy vapour of the cold liquid propellant generally displace the
air in the container.
 A valve is placed either manually or automatically depending on the
production rate required.
 The valve is crimped in place by using valve crimper.

61. Advantages
 Easy process
Disadvantages
 Chilling of the product, container and propellant is required.
 Aqueous products, emulsions and those products adversely affected
by cold temperature cannot be filled by this method.

62. VALVE CRIMPER

63. Pressure filling
 Pressure filling is carried out at room temperature under highpressure.
 The apparatus consists of a pressure burette capable of metering small
volumes of liquefied gas under pressure into an aerosol container.
 The propellant is added through the inlet valve located at the bottom
or top of the burette.
 The desired amount of propellant is allowed to flow through the
aerosol valve into the container under its own vapor pressure.
 When the pressure is equalized between the burette / cylinder and the
 container, the propellant stops flowing.
 To help in adding additional propellant, a hose leading to a
cylinder of nitrogen or compressed is attached to the upper valve
and the added nitrogen pressure causes the propellant to flow.

65. Advantages
 It is the preferred method for solutions, emulsions and suspension.
 Less chances for contamination of product with the moisture.
 Less propellant is lost.
 No refrigeration is required, can becarried out at room temperature.

66. COMPRESSED FILLING
Compressed gases are present under high pressure in cylinders.
These cylinders are fitted with a pressure reducing valve and a
delivery gauge.
 The concentrate is placed in thecontainer
 The valve is crimped inplace
 Air is evacuated by means of vacuum pump
 The filling head is inserted into the valve opening, valve depressed and
gas is allowed to flow into the container

67. Testing of filled container
The container passes through a heated water bath in which the contents of
the container are heated to 130 ºF (54ºC) to test for leaks and strength of
the container.
The container is air dried, spray – tested, capped and labeled.

68. Evaluation of pharmaceutical aerosols
A. Flammability and combustibility
Flame extension
Flash point
B.Physiochemical characteristics
Vapor pressure
density
Moisture content
Identification of propellants
C.Performance
Aerosol valve discharge rate
Spray pattern
Dosage with metered valves
Net contents
Foam stability
Particle size determination
Leakage
D.Biologic characteristics
E.Therapeutic activity

69. Thank you