PHAR 323

Aerosol Delivery Systems and

Inhalation Therapy
March 1
1, 2010

Urs Hafeli

1
 Learning Objectives
1. Discuss the advantages and problems associated with
aerosol delivery systems
2. Explain the relationship between vapor pressure of a
liquefied gas propellant and the production of an aerosol
spray
3. Draw the basic components of a pharmaceutical aerosol
system
4
4. Discuss the principles of formulation of solution
solution,
suspension and emulsion aerosols and be able to
explain how the problems associated with the physical
stability of these formulations are overcome

Pharmaceutical Aerosol
Definition
An aerosol is a pressurized delivery system that
upon actuation emits a fine dispersion of liquid
and/or solid materials containing one or more
active ingredients in a gaseous medium.

Product dispensed as
- fine or wet spray 2-Phase system of
sufficiently small size
- foam to show stability as a
- semisolid suspension

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 Advantages of Aerosols
1. Contents of the aerosol container are sealed off
from the atmosphere
• No contamination
N t i ti off theth contents
t t
• Unstable drugs protected
2. Easy and clean application
• Topical drugs can be applied to the skin without
touching and irritation
3 Regulating the formulation and the valve
3.
assembly can produce aerosols with
• metered dosing
• controlled particle size range
• varied physical form (i.e. fine spray, foam etc)

Problems Related to Aerosol Use

• Aerosol containers
– Explosion potential
– Clogged
Cl d valves,
l rendering
d i product
d t useless
l
• Abuse of aerosol propellants
Inhalant abuse, commonly called huffing, is the
purposeful inhalation of chemical vapors to achieve a
euphoric effect. Abusers inhale vapors from a wide
range of substances, including solvents (paint thinner,
nail polish remover) and gases (propellants
(propellants, propane
propane,
butane, gasoline).
– Sniffing: inhaling substance from a container
– Huffing: inhaling fumes from rags soaked in substance
– Bagging: fumes inhaled from an aerosol sprayed into a bag

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Problems Related to Aerosol Use
• Aerosol propellant toxicities
– Numerous: neuropathies, ataxia, renal toxicity,
h
hepatic
ti ttoxicity,
i it b bone marrow suppression
i
– High doses: loss of consciousness, convulsions,
coma
– Sudden sniffing death syndrome: more common in
abuse of propellants and butane gases. Fatal cardiac
arrhythmias.

Application Product Formulation Features

Topical Betadine Povidone
• Dermal Iodine
Solarcaine Triclosan /
benzocaine
• Vaginal Delfen Nonoxynol-9 Applicator
Contraceptive Applicator,
Foam isobutane,
• Rectal Proctofoam- Pramoxine, propane
HC hydrocortisone propellants
Oral g
Nitrolingual 0.4 mgg Rapid
p
PumpSpray  nitroglycerin in absorption via
aromatized oily buccal cavity
solution No loss of
(alcohol, volatile drug
glycerides, Metered dose
peppermint oil

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Application Product Formulation Features
Intranasal Rivanase Beclomethasone Rapid local
AQ (suspension in effect
aqueous vehicle, Metered dose
polysorbate, Pump sprays
cellulose, NaCMC)

Nasacort Triamcinolone
AQ
Intrapulmonary Airomir Salbutamol See later
QVAR Beclomethasone notes
Flovent Fluticasone

Aerosol Propellants
Liquefied Gas Propellants (LGP's)
• LGP's are ggases at room temperature
p and normal p
pressure
• They can be
liquefied by
lowering T and/or
increasing P
• LGP's generally
have boiling
points at or
below room
temperatures
and high vapour
pressures

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 Production of Spray
• LGP in sealed container separates into liquid and vapour
– Equilibrium vapour pressure
• VP exerted on surface of liquid
q forces LGP ((containing
g drug)
g)
up the diptube or standpipe
– Product cannot exit because the valve is closed
• When the valve is opened (actuated)
– LGP + drug are emitted
• LGP boils and vaporizes almost instantaneously in the air
( t atmospheric
(at t h i temperature
t t
and pressure)

Production of Spray
• Vaporization and rapid expansion of LGP cause the stream
of liquid to be broken up into tiny droplets
– Fine mist or spray
– Note: the liquid propellant can expand up to 250x its
volume as it converts to the vapour phase.
• Valve is closed and the LGP re-establishes the equilibrium
VP within the container almost immediately
– Therefore, there is always a constant VP maintained in the aerosol
canister
– No matter how much of the contents are used,
the VP is always constant provided there is
some liquid propellant in the canister
– Therefore, the spray characteristics
remain constant throughout use of
the aerosol.

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Physicochemical Properties of LGP's

• Halocarbon numbering system

– 1st digit: C - 1
– 2nd digit: H + 1
– 3rd digit: # F atoms
– All remaining atoms are assumed Cl atoms
– If 1st digit = 0,
0 eliminate from propellant
number

• Examples: 11, 12, 114, 134a, 227

CFC's HFA's

Tetrafluoroethane: HFA 134a

CH2F-CF3
• Boiling
B ili point: 26 C
i t -26 C
• Vapour pressure: 87 psi, 6.7 bar (at 25 C)
• Nontoxic, non-flammable
• Extremely poor solvent and will not dissolve
many formulation excipients such as surfactants
(see later notes)
• International nonproprietary name: Norflurane
When there are two or more carbon atoms present, isomers are possible and
these may have identical halocarbon numbers. For ethane derivatives, a lower
case letter is added.

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Heptafluoropropane: HFA 227ea

• Boiling point: -16 C

• Vapour pressure: 56 psi, 4.5 bar (at 25 C)
• Nontoxic, non-flammable
• Slightly better solvent than HFA 134a
• International nonproprietary name: Apaflurane

CF3-CHF-CF3

Butane Propane

Isobutane: bp = -11.7 °C

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 Principles of Formulation of
LGP Aerosols
Solutions
• Solution of active ingredients in pure LGP
or
Mixture of LGP and solvent or cosolvent
• LGP's: Propane / butane / HFA's
• LGP's
LGP' are frequently
f tl poor
solvents for drugs as they
are relatively non-polar

Effect of VP / Boiling Point of

LGP's on Spray Characteristics
• A decrease in the boiling point translates
to an increased VP
• Higher VP produces higher velocity liquid
stream
• Droplets are smaller and spray is "less
less
wet"

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• Cosolvent/solvent needs to be miscible
with the LGP. Most commonly used is
ethanol. Propylene glycol and isopropyl
alcohol may also be used.
– Note that the addition of cosolvents will
change the VP of the LGP/cosolvent blend
and change the spray characteristics
Total Vapour Pressure = PA + PB
= xA P0A + xB P0B
Raoult’s Law !

• Antioxidants may be required

– E.g., ascorbic acid

Principles of Formulation of
LGP Aerosols
Suspensions
• Active ingredients are suspended throughout the
LGP. Useful for poorly soluble compounds.
• LGP plus suspended drug is emitted, LGP
immediately vaporizes and drug particles form a
fine spray
• Formulation is difficult due to
problems with caking,
aggregation, particle size
changes, valve clogging

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Factors Affecting Suspension Formulation
1. Moisture content: Should be kept as low as possible
(between 100 to 300 ppm or less) to minimize
problems due to crystal growth and particle size
changes
2. Use of wetting agents/dispersing agents: Promotes
wetting of particles by LGP and prevents aggregation.
Agents such as sorbitan trioleate (Spans), oleic acid,
lecithins have been used.
3. Density y of p
propellant:
p If densityy of LGP can be
adjusted close to that of the drug, the sedimentation
rate can be minimized and caking can be prevented.
Blending of LGP’s is a useful strategy.
4. Use of lubricants: Can be used to prevent valve
clogging e.g. isopropyl myristate or light mineral oil.

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 Principles of Formulation of
LGP Aerosols
Emulsions
• Emitted as a foam
• Pharmaceutical foams are formulated as an
emulsion of LGP (internal phase) in aqueous
phase
• Active ingredient(s) are dissolved in the aqueous
phase
• Emulsifying agent is needed to emulsify the
droplets of LGP, e.g., polysorbates,
triethanolamine stearate
• LGP usually constitutes about 3-10% of formulation

Polysorbate, Tween 20

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 ProctoFoam HC
• 1% hydrocortisone acetate: topical corticosteroid
• 1% pramoxine
i hhydrochloride:
d hl id surface f or llocall
anesthetic
• Mucoadhesive base containing
– Cetyl alcohol
– Propylene glycol
– Triethanolamine
T i th l i stearate
t t
– Emulsifying wax
– Parabens
• LGP: Isobutane / propane

ProctoFoam HC
• 1% hydrocortisone acetate: topical
corticosteroid
ti t id O

CH3 OH
OH

HO

CH3 H
Solubility: 1 mg/100 ml
H H

• 1% pramoxine hydrochloride: surface or

local anesthetic Cl -
O
+H
O N

H3C O
soluble

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 In Summary
1. Discuss the advantages and problems associated with
aerosol delivery systems
2. Explain the relationship between vapor pressure of a
liquefied gas propellant and the production of an aerosol
spray
3. Draw the basic components of a pharmaceutical aerosol
system
4
4. Discuss the principles of formulation of solution
solution,
suspension and emulsion aerosols and be able to
explain how the problems associated with the physical
stability of these formulations are overcome

14