Pharmaceuticals Aerosols introduction , specialized containers, metered dose inhaler, valves and actuators, different filling processes..

1. PHARMACEUTICA
L AEROSOLS
BINDU
Dept. of pharmaceutical sciences,
MDU Rohtak

2. CONTENTS
• Containers used for aerosols
• Valves and actuators
• Filling processes

3. INTRODUCTION
❖ PHARMACEUTICAL AEROSOLS are pressurized dosage
forms containing one or more active ingredients which
upon actuation emit a fine dispersion of liquid and/or
solid materials in a gaseous medium.
❖ They depend upon the function of the container, its
valve assembly, and an added component--the
propellant--for the physical delivery of the medication
in proper form.

4. 1. CONTAINERS USED FOR AEROSOLS
• Various materials have been used for the aerosols
containers, which must withstand pressures as high
as 140 to 180 psig at 1300F.
A. Metal
1. Tinplated steel
• Side-seam (three -piece)
• Two-piece or drawn
• Tin-free steel

5. 2. Aluminium
• Two-piece
• One-piece (extruded or drawn)
3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic-coated glass

6. Selection of container for aerosols
➢its adaptability to production methods
➢compatibility with formulation components
➢ability to sustain the pressure intended for the
product
➢the interest in design
➢cost

7. TINPLATED CONTAINERS
• the tinplated steel container consists of a sheet of the
steel plate that has been electroplated on both side
with tin.
• The thickness of tin coating is describe in term of its
weight.
• The size of system is indicated by the standard
system
• Example: a container said to be 202 x 214 if, it is 22/16
inches in diameter and 214/16 inches in height.

8. Procedure:
tinplated sheets is obtained in thin sheets and when required, it
is coated with an organic material
These sheets are lithographed, after that the each piece is
fabricated into the desired shape
The body is shaped into a cylinder and seamed via a flanging
and soldering operation
The top and bottom are attached to the body and a side seam
strip is added to the inside seam area when required

9. • the organic coating also can be added to the finished
container rather than to the flat sheet but this procedure is
slower and more expensive; a more continuous and durable
coating is produced
• Development:
welded side-seam:
• welding eliminate the soldering operation
• saves mfg time and
• decrease the possibility of the product-container
interaction

10. • Two process are used
a. Soudronic system: is based on an electrically
controlled resistance welding method that uses a
copper wire as an electrode. The rounded bodies are
welded and then sent to the conventional line,
where top and bottom ends are flanged.
b. Conoweld system : passes the folded body through
2 rotating electrode rings. The rest of the container
mfg in the usual manner.

11. • Tinplated steel containers are of two types:
1. Two piece container body, consisting of drawn
cylinder, the base of the cylinder is held in place
with double seam
2. Three piece container has a side seam the base
being attached as for two piece container, the top
has a 1 inch opening and is joined to body by double
seam

13. Aluminium containers
• They are made by extrusion process and hence
have no seam
Advantages:
• lessened danger of incompatibility due to its
seamless nature
• Greater resistance to corrosion

14. Disadvantages:
• It is corroded by pure water and pure
alcohol
• In combination of ethanol and propellant 11
in an alu. Container has been shown to
produce hydrogen, acetyl chloride,
aluminium chloride, propellant 21 and other
corrosive products

15. 3. stainless steel containers
Advantages:
• Extremely strong
• Resistant to most material
• Resistant to corrosion
• Withstand with high pressure
• No internal coating is required

16. Disadvantages:
• Limited to smaller size due to production
problem
• Expensive
Uses:
• For inhalation aerosols

17. 4. Glass containers
Advantages:
• Compatible
• Corrosion problem is eliminated
• Greater degree of freedom in design of the
container
• Inert
• transparent

18. Disadvantages:
• Breakable
Plastic coated glass:
• The coating give protection from impact

19. valves
valves
continous metered dose
spray valve valve
Features of valves:
• It is capable of being easily opened and closed
• It is capable of delivering the content in the
desired form
• It is expected to deliver a given amount of
medication

20. A. Continuous spray valve
Continuous spray
valve has following
components
• Ferrule or
mounting cup
• Valve housing
• Stem
• Gasket
• Spring
• Dip tube

21. 1. Ferrule or mounting cup
• the ferrule or mounting cup is used to attach the
valve proper to the container
• The container having a 1-inch opening, the cup is
made from tinplated steel, although aluminium also
can be used
• The underside of the valve cup is exposed to the
content of the container and to the oxygen trapped
in the headspace, a single or double epoxy or vinyl
coating can be added to increase resistance to
corrosion
• The ferrule is attached to the container either by
rolling the end under the lip of the bottle or by
clinching the metal under the lip

22. 2. Valve housing or body
• The housing is generally mfg from nylon or delrin and
contains an opening at the point of the attachment of the
dip tube, which ranges from about 0.013 – 0.080 inch.
Vapour tap:
• Allow escape of vaporized propellant along with liquid
product
• Produces fine particles
• Prevent clogging of valve
• Allow product to be satisfactorily dispensed with the
container in the inverted position
• Reduce the chilling effect of the propellant on the skin
• With hydrocarbon propellant, allow for a decrease in
flame extension

23. 3. stem
• It is made from nylon or delrin but metals such as
brass and stainless steel can be used
• One or more orifices are set into the stem, they
ranges from one orifice of about 0.013- 0.030 inch to
three orifices of 0.040 inch each
• When stem is pressed the product is emitted from
the container

24. 4. Gasket
• It is used to provide a seal between the valve and
container
• Buna-N and neoprene rubber are commonly used for
the gasket material and are compatible with most
pharmaceutical formulation

25. 5. Spring
• The spring serves to hold the gasket in place and
when actuator is depressed and released, it returns
the valve to its closed position
• Stainless steel can be used with most aerosols

26. 6. Dip tube
• it is made up of polyethylene or polypropylene having
diameter between 3 to 3.2 mm. It bring formulation
from container up to valve

27. B. Metering valve
Main function:
• To reproducibly deliver
a portion of the liquid
phase of the
formulation in which
the medicament is
either dissolved or
dispersed.
• Also form the seal atop
of the canister to
prevent loss of the
pressurised content

28. The valve generally comprise at least seven
components that are constructed from a variety of
the inert materials.
• Valve body: acetal or polyester
• Valve stem: stainless steel or acetal
• Ferrule: anodised aluminium
• Seal and gasket: butyl, nitrile or neopren
These valve are essentially designed to work in the
inverted position, although, with the aid of dip tube
they can also be used in upright position.

29. Working:
• Depression of the valve stem
allows the contents of the
metering chamber to be
dispensed through the orifice
in the valve stem
• After actuation, the metering
chamber refills from the bulk
liquid formulation, once the
metering chamber is sealed
from the atmosphere and is
ready to dispersed the next
dose.
• This is essential, otherwise
continuous spray would be
achieved.

30. Typically volume that are dispensed range from 25
to 100 micro litre.
Note:
•These valve are designed to dispense
volumetrically, change in the formulation
density (by varying the propellant ratio) can
affect the amount (by weight) that is dispensed.

31. Actuators
• It allow for easy opening
and closing of the valves.
The design of actuator
determine the proper
and desired form of the
aerosol product
• Types of actuators
✓ Spray
✓ Form
✓ Solid stream
✓ Special application

32. Spray actuators
• Orifice : 1 to 3 on the order of 0.016 inch to 0.040
inch in dia.
• When these actuators are used with aerosol
products containing relatively low amounts of
propellants (50 % or less), the product is dispensed
as a stream rather than a spray.
• For these products, a mechanical breakup actuator
is usually required.
• These actuators are capable of “mechanically”
braking a stream into fine particles by causing them
to swirl through various channels built into the
container

33. • Uses:
✓ Pharmaceutically intended for topical use
such as spray on bandages, antiseptics,
local anaesthetic and foot preparation

34. Foam actuators
• Large orifice size: 0.070 – 0.125 inch & greater
• The orifice allow the passage of the product
into a relatively large chamber, where it
expand and be dispensed through the large
orifice

35. Solid stream actuators
• Relatively large orifice allow for the passage of
product through the valve stem and into the
actuator
• Uses:
✓Semi solid product (ointments)

36. Special actuators
• Designed to deliver the medication to the
appropriate site of action such as
✓Throat
✓Nose
✓Eye
✓Vaginal tract

37. Filling processes
• Cold filling
• Pressure filling
• Compressed gas filling

38. 1. Cold filling
Cold filling apparatus:
• it consists of an insulated box fitted with
copper tubing. The insulated tubing are filled
with dry ice and cause faster cooling.
• The hydrocarbon propellant is not to be
stored in the cooper tubing as it might cause
explosion.

40. Cold filling method: two methods are involved:
• In the first method,
✓ the product concentrate are chilled to a temp of
-30 to -40 F.
✓ The chilled product concentrates are added to
the chilled aerosol container.
✓ The chilled propellant is added through the inlet
valve present under side of the valve of the
chilled container.
• In the second method,
✓ Both the product concentrate and the
propellant are chilled to -30 to -40 F. Then the
mixture is added to the chilled container.

41. Advantage:
• For the filling of metering valve containing
aerosol container.
Disadvantage:
• most of the formulations cannot be cooled to
very low temp.

42. Pressure filling
Pressure filling apparatus:
✓ it consist of a metering burette capable of
measuring the amount of propellant to be filled
to the aerosol container.
✓ The propellant is added through the inlet valve
present to the bottom of the valve under its own
vapour pressure.
✓ A cylinder of nitrogen or compressed gas is
attached to the top of the valve and the pressure
of nitrogen causes the propellant to flow to the
container stops where the pressure of the
flowing propellant becomes equal to the
pressure of the container.

43. Pressure filling method:
✓The product concentrate is filled to the
aerosol container through the metering
pressure filling burette at room temp
✓The propellant is added through the inlet
valve located at the base of the valve or
under the valve after the crimping of valve
✓The flow of propellant to the aerosol
container continues till the pressure of the
filling propellant become equal to the
pressure within the container
✓The aerosol container are capped and
labelled

44. Advantages:
• The emulsion, suspensions are unstable at
very low temp so the pressure filling method
is preferred over cold filling
• The absence of moisture reduces the chance
of contamination
• The rate of production is high
• The chance of loss of propellant is low

45. Compressed gas filling
✓ The compressed gas propellant is used
✓ As the compressed gas is under high pressure, so the
pressure is reduced by pressure reducing valve
✓ A pressure of 150 psig is required to fill the compressed
gas propellant in the aerosol container.
✓ The product concentrate is placed in the pressure gauge
and the valve is crimped in its place.
✓ The air is evacuated
✓ The filling head is inserted into the valve opening
✓ Upon the depression of the valve, compressed gas
propellant is allowed to flow into the container

46. `
✓The compressed gas stop flowing when the
pressure of the compressed gas flowing to the
container from the burette become equal to
the pressure within the container
✓In case of increasing the solubility of the gas in
the product concentrate and also when an
increased amount of compressed gas is
required, CO2 and NO2 is used
✓ the container is needed to be shaken during
and after the filling operation to enhance the
solubility of the gas in the product concentrate

47. Filling machinery
• Laboratory equipment
• Stepped rotary machines
• Continuous rotary machines

48. Laboratory equipments

49. Product filler

50. Valve crimping

51. Propellant filler

53. Stepped rotary machines
• The maximum output
is directly related to
the types of valves
used.
• In this, the
concentrate filling,
crimping, and
propellant charging
done on the same
indexing unit

54. Continuous rotary machines
• In this, all operations
in the aerosol
packaging process is
carried out on a
different continuous
rotary station.
Advantages:
• High production
output
capacity(100-200
containers/min)

55. Advancement in aerosol technology

56. Metered dose inhalers (MDIs)
Essentially comprises 4
separate components
• The base formulation
• The container
• The metering valve
• The actuators

57. Actuators tor MDIs:
• Constructed from the material like
polyethylene and polypropylene by injection
moulding method
• The common design of actuator is classic L
shape.
Advantages :
• Portability
• Low cost
• Disposability
• Reproducibility
• Less contamination

58. Disadvantages:
• Inefficient at drug delivery
• Incorrect use by the patients such as
o Failure to remove the protective cap
covering the mouthpiece, the inhaler
being used inverted
o Failure to shake canister
o Failure to inhale slowly and deeply
o Inadequate breath holding
o Poor inhalation/actuation
synchronisation

59. Spacers and breath actuated MDIs:
Overcome the coordination problem by using
extension devices or ‘spacers’ positioned
between MDI and patient.

60. Nebuhaler spacer
device:
• The dose from the
MDI is discharged
directly into the
reservior prior to
inhalation.
• This reduces the initial
doplet velocity, permit
efficient propellant
evaporation and
remove the need for
actuation/inhalation
coordination.

61. Azmacort:
• Extended mouth piece
device
• Allowing greater
evaporation time for the
less volatile propellant, plus
large particle
sedimentation in airways
resulting in reduction in
orophrangeal impaction.
Inspirease (key
pharmaceuticals):
• Has an audible signal that
indicate when the patient’s
inspiration rate is correct.

62. Some other
example of
spacers:
• Fisonair (rhone-
poulenc rorer)
• Volumatic (GSK)
• Syncroner (rhone-
poulenc rorer)
• Space inhalers
(astra zeneca)

63. Breath actuated
devices:
Autohaler:
• In this device, a vane
is used as release
mechanism, firing the
MDI when a certain
threshold inspiration
flow rate is reached.

64. Nebulizers
Types of nebulizer system:
• Jet
• Ultrasonic
Advantages:
• Deliver large volume of drug solution and
suspension
• Suited for the drug that can not be conventionally
formulated into MDIs and DPIs
• Drug inhaled during normal tidal breathing through
a mouthpiece or face mask (patient compliance
increase in elderly and children)
Disadvantages:
• Wastage of medicament into environment

65. Jet nebulizer:
• It use compressed gas(air or
oxygen) from a compressed gas
cylinder, hospital air line or
electrical compressor to convert a
liquid into a spray.
• The jet of high velocity gas is
passed either tangentially or
coaxially through a narrow venturi
nozzle, typically 0.3-0.7 mm in dia.
• An area of negative pressure
where the air jet emerges, causes
liquid to be drawn up a feed tube
from a fluid reservior by the
Bernouli effect
• Liquid emerges as fine filaments,
which collapse into droplets owing
to surface tension.

66. Pari LC nebulizer:
• Have been developed in
which the patient’s own
breath boosts nebulizer
performance, with aerosol
production matching the
patient’s tidal volume.
• On exhalation, the aerosol
being produced is
generated only from the
compressor gas source,
thereby minimizing drug
wastage.

67. Ultrasonic nebulizers:
• In these the energy necessary
to atomize liquid comes from
a piezoelectric crystal
vibrating at high frequency.
• At sufficiently high ultrasonic
intensities a fountain of liquid
is formed in the nebulizer
chamber.
• Larger droplets are emitted
from the apex and a fog of
small droplets is emitted
from the lower part.

68. Dry powder inhalers (DPIs)
Two types of DPIs
1. Unit dose devices (spinhaler and rotahaler)
2. Multiple dose devices (turbohaler and diskhaler)
Advantages:
• Do not require CFC propellant to dispense the drug
• Ozone friendly delivery system
• Do overcome the need for coordination of actuation and
inspiration b/c they are essentially breath actuated

69. Drawbacks:
• Require inspiratory flow rate of 60 L/min to effectively
deaggregate the powder (not achieved in asthmatic
patients and infants)
• Higher dose is required for DPIs than MDIs to achieve
a comparable clinical effect
• Possibilities of fragments of gelatin being
administered to patients
• Cumbersome nature of loading (during asthmatic
attack)
• Delivery of medicament by DPIs in the incidence of
cough
• Taste of medicament

70. Unit dose devices
Spinhalers:
• The drug mixture, which
often includes a bulk
carrier to aid powder
flow, is prefilled into a
hard gelatin capsule and
loaded into device.
• After activation of the
device, which pierces the
capsule, the patient inhale
the dose, which is
dispensed from the
vibrating capsule by
means of inspired air

71. Rotahaler: (by glaxo)
• Has developed for the
delivery of salbutamol and
beclomethasone
dipropionate powders.
• Here, the drug mixture is
again filled in hard gelatin
capsule, and the capsule is
inserted into the device;
however the capsule is
broken open in the device
and the powder is inhaled
through the screened tube.

72. Berotec (Boehringer
gelheim):
• Used for fenoterol
(loaded in hard gelatin
capsule) delivery
Cyclohaler (pharmtiba)

73. Multi dose devices
Turbohaler: (a division of astra)
• This device is contained
within a storage reservior
and can be dispensed into
the dosing chamber by a
simple back and forth
twisting action on the base
of the unit.
• The device is capable of
working at low flow rate and
also delivers carrier free
particles.
• Respiration flow rate
required- 28.3 L/min

74. Diskhaler (glaxo):
• This device has a circular
disk that contain eight
powder charges.
• These are maintain in
separate aluminium
blister reservior until just
before inspiration.
• On priming the device the
aluminium blister is
pierced and the contents
of the pouch are dropped
into the dosing chamber.

75. Accuhaler (GSK):
• In this drug/carrier mix is
preloaded into the device in
foil-covered blister pockets
containing 60 doses.
• The foil lid is peeled off the
drug-containing pockets as
each dose is advanced with
the blisters and the lids
being round up separately
within the device, which is
discarded at the end of
operation.

76. Clickhaler (innovata biomed):
• In this, a drug blend is stored
in a reservoir.
• Metering cup is filled by
gravity from this reservoir
and delivered to an
inhalation passage, from
which it is inhaled.
• The device is capable of
holding up to 200 doses and
incorporates a dose counter,
which informs patients
when the device is nearly
empty after use.

77. Exubera (pfizer):
• it is a prescription
medicine that
contains an insulin
powder that you
breathe in (inhale)
through your mouth
using the EXUBERA ®
Inhaler. It is used to
treat adults with
diabetes. It helps to
control high blood
sugar.

78. AERX (Aradigm):
• The patient needs only
to load the AERx Strip
dosage packet into the
Essence device, press
the activator button
while inhaling through
the mouthpiece at a
normal rate, and remove
the spent dosage packet.

79. Bag on valve
• which comprises an outer container and an inner
container inserted into the outer container, and
which has a first space being an inside of the inner
container and a second space surrounding the
first space and independent from the first space,
and in which different contents are charged in the
first space and the second space.
• wherein the inner container is formed of one or
more than two flexible laminated sheets having a
metal foil layer and a synthetic resin layer

80. US patent 8361970
Multi-chamber material dispensing system and method for
making same
• This approach includes a collapsible container
surrounded by an elastomeric band.
• A normally closed valve and an actuator assembly are
affixed to the container. When the container is initially
filled with product, it expands along with the surrounding
elastomeric band.
• Potential energy is generated as the elastomeric band
stretches. And when the actuator is operated to open the
valve, the potential energy is converted to kinetic energy
to dispense product out of the container until the
actuator is disengaged

81. US patent 8590755
Pressure regulated flow valve with gas-piston
• An object of the present invention is to provide a valve
which has a primary flow path through the valve and has
an internal movable member which is regulated by the
internal pressure of the pressurized container as well as
the internal pressure of a gas piston so that as the
internal pressure of the pressurized container falls below
a threshold value, the gas piston biases the movable
member in a manner which controls the expansion of the
product flow path so that a desired sustained volumetric
flow rate of product can continue to be emitted from the
pressurized container despite the loss of internal pressure
in the container.

82. US patent 8578934
Indicating device with warning dosage indicator
• An indicating device suitable for indicating the number of dosages of a
substance that have been dispensed from or remain in a container
includes at least one first indicator member incrementally moveable to
a plurality of positions and a second indicator member moveable in
response to a predetermined number of movements of the at least one
first indicator member.
• The at least one first indicator member includes primary dosage indicia
adapted to indicate the number of dosages of substance that have
been dispensed from or remain in the container.
• The second indicator member includes secondary dosage indicia
adapted to indicate that less than a minimum predetermined number
of dosages of substance remain in the container.
• In one preferred embodiment, the primary dosage indicia are
configured as numerical indicia and the secondary dosage indicia are
configured as color indicia.

83. US patent 8523023
Aerosol container resuscitator
• A aerosol container resuscitator restores functionality to a damaged or otherwise
compromised aerosol container by being attachable to the annular container rim
adjacent the container outlet, and by opening the valve of the compromised outlet
and subsequently directing the aerosol container's product as purposed.
• The aerosol container resuscitator comprises an annular fitting assembly and a
driver assembly. The fitting assembly comprises a fitting structure and a clamping
structure.
• The fitting assembly aligns, secures, and interfaces the driver assembly to the
container, which driver assembly comprises gasket structures, spring structures, a
sleeve structure and a driver structure. The sleeve structure comprises
communicating cavities in which the driver structure is received.
• The gaskets seal and prevent discharged aerosol container's product from
circumventing the driver structure of the driver assembly. The springs allow relative
translation between the fitting assembly and the driver assembly and between the
sleeve structure and the driver structure