Pharmaceutical Aerosols
Pharmaceutical
Aerosols
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Pharmaceutical
Aerosols
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Aerosols
 Aerosols may be defined as dispersion phase system, in
which very fine solid particles or liquid droplet get
dispersed in the gas which act as continues phase.
 Achievedby use of pressurized containers with liquefied or
gaseous propellants
 Also called pressurized dosage form
 When pressure is applied to valve, contents expelled
 Delivered form depends on formulation and valve type

Pharmaceutical
Aerosols
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Pharmaceutical Aerosols
 T
o deliver active drugs for inhalation, nasal, buccal, and
sublingual administration
 Are also available for topical, rectal, and vaginal
administration
 Emit liquid/solid materials in gaseous medium when actuated
Inhalation Aerosols
 Contain active drug(s) in:
 A liquefied propellant,
 A mixture of solvents with a propellant or
 A mixture of other additives and a propellant

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Aerosols
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Pharmaceutical…
Advantages:
 Dose can be removed without contamination of the remaining
 Hermetic character  protects drug from oxygen and
moisture
 Medication can be delivered to affected area in desired form
 Usual containers protect drug from light
 Sterility may also be maintained if packed in aseptic condition
 Limit the potential for overuse of product compared to lotions

Pharmaceutical…
Advantages…
 Irritation caused by mechanical application
medication is reduced or eliminated
 Application of medication in a uniform manner.
of topical
 Convenience of application  Easy
requiring little or no wash-up by the user
Disadvantages:
 Expensive
 Discomfort on injured skin
 Limited safety (inflammable, pressurized)
and clean process,
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Aerosols
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Aerosols
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Drug delivery to the Respiratory Tract
Mainly for treatment of local disorders, e.g.,asthma
 Rapid onset of activity (e.g., bronchodilation in asthma)
 Smaller doses can be administered
 Reduced adverse effects
Useful for delivery of drugs for which oral absorption is
inappropriate
Drug is poorly absorbed (e.g., sodium cromoglycate)
Drug is rapidly metabolized (E.g., isoprenaline)
 Bypassing liver first pass metabolism

Drug delivery…
sodium cromoglycate
Lung may be used to deliver drugs for systemic effect due to:
 Large surface area of alveoli
 Abundance of capillaries (high perfusion)
Example: Delivery of ergotamine for migraine
Delivery of proteins and peptides (E.g., insulin)
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Aerosols
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Aerosols
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Drug delivery…
However, efficiency of inhalation therapy is not high
because of the difficulty in targeting particles to the sites of
maximal absorption
Example: ~8% of the inhaled dose of sodium cromoglycate
administered from a Spinhaler device reaches the alveoli

The Respiratory Tract
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Deposition of particles and droplets
 Respiratory dosage forms deliver drugs to the respiratory tract
as either particles or droplets
 Particles/droplets should be deposited to the required site of
pharmacological action
 For an optimum effect, the pharmaceutical scientist must fully
understand and embrace the factors that affect deposition:
1.Physicochemical properties of the drug
2.The formulation
3.The delivery/liberating device and
4.The patient
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Deposition…
Most important physical property of an aerosol for inhalation is
particle size
To penetrate to the peripheral regions, aerosols require a size
less than about 5 or 6 μm, with
Less than 2 μm being preferable for alveolar deposition
Larger particles or droplets are deposited in
respiratory region
Rapidly cleared by mucociliary action
Drug becomes available for systemic absorption
May potentially cause adverse effects
the upper
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Effect of Particle size on Deposition
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Aerosols
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Aerosols
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Mechanisms of Particle Deposition
 Particle size affects the mechanisms
 Four main mechanisms:
1. Inertial impaction:
 When bifurcation occurs,
 Particles > 5 μm & particularly >10 μm,
 Common in the upper airways
2. Gravitational sedimentation:
 Particles in the size range 0.5-3 μm,
 In the small airways and alveoli,
 For particles that have escaped impaction
3. Brownian diffusion: for particles < 0.5μm)
4. Electrostatic precipitation

Mechanisms….
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Aerosols
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Aerosols
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Effect of breathing patterns on deposition
 Large inhaled volume  greater peripheral distribution
 Increasing inhalation flow rate enhances deposition in
the
larger airways by inertial impaction
 Breath-holding after inhalation  deposition of particles
by sedimentation and diffusion
 Optimal deposition increases with duration of
breath holding and depth of breathing!

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Aerosols
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Aerosol Formulation
 Aerosol formulation consists of two components:
1. Product concentrate
2. Propellant
 Product concentrate = API + antioxidants + surface
active agents + solvents/co-solvents  stable and
efficacious product.
 Concentrate can be a solution, suspension, emulsion,
semisolid.

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Aerosols
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Aerosol Formulation…
Propellant
 Liquefied gas or mixture of liquefied gases; or
compressed gases
 Provides the force that expels the product concentrate
from the container in desired form
 Dual role: as propellant and solvent/vehicle for the
product concentrate (liquefied gases)

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Aerosols
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Propellants
1.Chemicals with vapor pressure greater than atmospheric
pressure (Liquefied propellants) or
2.Compressed gases
They are:
Responsible for developing pressure within the
container and
T
o expel the product when the valve is opened and in
the atomization or foam production of the product.

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Aerosols
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Liquefied Propellants
At room temperature and pressure these are gases
 Readily liquefy by decreasing T0 or increasing P0
Head space filled with propellant vapour,  saturation
vapour pressure at that temperature.
 Traditionally used in aerosol products were the
chlorofluorocarbons (CFCs)
 Hydrofluoroalkanes (HFAs) are increasingly in use.

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Aerosols
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Liquefied Propellants…
 The CFCs currently employed in MDI formulations are
CFC-11, CFC-12 and CFC-114
 Formulations generally comprise blends of CFC-11 and
CFC-12 or CFC-11, CFC-12, and CFC-114
CFCs:
 Chemical inertness
 Lack of toxicity
 Non flammability & low explosiveness
Propellant of choice for oral and inhalation

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Aerosols
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Liquefied Propellants…
 Reaction of CFCs with the ozone and their contribution
to global warming is major environmental concern
 Production of CFCs in developed countries was phased
out in 1996
 However, pharmaceutical aerosols are currently
exempted

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Aerosols
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Liquefied Propellants…
 In household & cosmetic aerosols  CFCs replaced by
hydrocarbons (HCs) such as propane and butane
HCs are not appropriate alternatives to for inhalation
 Alternatively, compressed gases such as N2, N2O and CO2
may be used
Do not maintain constant pressure in canister duringuse
 Non-ozone depleting alternatives to CFCs  HFAs (HFCs) 
break down faster in the atmosphere

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Aerosols
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Liquefied Propellants…
 HFA-134a and HFA-227 are non-ozone depleting, non-
flammable HFAs  widely investigated
 However, these gases contribute to global warming
 Have some physical properties which are similar to those of
CFC-12 and, to a lesser extent, CFC-114
 HFA-134a & HFA-227 are poor solvents for surfactants
 Ethanol used to allow dissolution of surfactants in MDI
 Ethanol has low volatility and hence may increase droplet
size of emitted aerosol

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Aerosols
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Liquefied Propellants…
Hydrocarbons:
 Used in topical aerosols  environmental acceptance
and non reactivity (non ozone depleting)
 Make three phase (two layers) aerosols because of their
immiscibility with water
 Propane, butane, and isobutane are the most commonly
used
 Used alone or blended

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Aerosols
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Compressed Gases
1. Gases insoluble in the product concentrate (e.g., N2):
Result in emission of product in essentially the same form
as it was placed in the container
2. Slightly soluble gases (e.g., CO2 & N2O), expulsion with
concentrate to achieve spraying or foaming
Pressure diminishes as the product is used
Higher gas pressures are required in these systems

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Aerosols
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Aerosol Systems
 Based on product concentrate:
1. Two phase systems
2. Three phase systems
3. Suspension or Dispersion systems

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Aerosols
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Two Phase Systems
 Consist of liquid phase containing liquefied propellant and
product concentrate, and vapor phase
 Are solution forms
 However, propellants are poor solvents for most drugs
 Cosolvents used: ethanol, propylene glycol, glycerin,
acetone, ethyl acetate or isopropanol
 Amount of propellant may vary from depends on types
formulation

Three-Phase Systems
 Large volume of water replaces all or part of non aqueous
solvent
 Water-based systems
 Layer of water-immiscible liquid propellant, a layer of highly
aqueous product concentrate, and the vapor phase
 Alcohol may be added to increase miscibility of water and
propellant
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Aerosols
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Aerosols
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Suspension/Dispersion Systems
 Used to overcome difficulties of using cosolvents
 Dispersion of APIs in propellant or mixture of propellants
 Surfactants and suspending agents to reduce settling
 Particle size control: caking, agglomeration, particle growth
etc. must be considered (< 5 μm)
 Dispersing agents (oleic acid)  reduce agglomeration,
lubricate the valve

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Aerosols
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Aerosol Container & Valve
 Formulation
components
must not interact with container and valve
 Valve and container must withstand pressure of formulation
 Valve and container must resist corrosion
 Must contribute to the form of the product to be emitted

Aerosol Containers (Reading)
 Different materials:
1. Glass (coated, uncoated)
2. Metal (tin-plated steel, aluminum, stainless steel)
3. Plastics
 Selection of container depends on:
 Adaptability to production methods
 Compatibility with formulation
 Ability to sustain the pressure of product
 Design aesthetic appeal and cost
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Aerosols
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Valve Assembly
 Permit expulsion of contents in a desired form, rate, and
amount or dose (metered valves)
 Materials must be inert to the formulations
 Materials used: plastic, rubber, aluminum, and stainless steel
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Aerosols
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Parts of the Valve
1.Actuator:
 The button patient presses for emission of product
 Permits easy opening and closing of the valve
 Product delivered through the orifice in the actuator
 Actuator design together with type and amount of
propellant used affects particle size of emitted product
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Aerosols
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Parts of the Valve…
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Aerosols
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Aerosols
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Parts of the Valve…
2. Stem:
 Supports actuator & transfers formulation into its chamber
 Made from Nylon, brass or stainless steel
 Orifice: 0.013-0.030 inch
3. Gasket:
 Placed snugly with the stem  prevents leakage when
valve is closed
 Made from rubber

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Aerosols
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Parts of the Valve…
4. Spring:
 Holds the stem in place
 Retracts actuator when pressure is released (valve closed)
 Made from stainless steel
5. Housing:
 Links dip tube with stem and actuator (nylon)
 Has orifice at point of attachment to dip tube  determine
delivery rate & the form in which product is emitted

Parts of the Valve…
6. Mounting cup (Ferrule):
 Holds the valve in place (attach valve to container)
 Made from stainless steel, aluminum, brass
 May be coated with inert material (e.g., an epoxy resin or
vinyl) to prevent an undesired interaction
7. Dip tube:
 Brings formulation from container to valve
 Dimensions of dip tube and housing dictated by viscosity of
product and desired delivery rate
 Made of poly ethylene or poly propylene
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Aerosols
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The Valve Assembly
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Aerosols
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Aerosol Filling Operations
A. Cold filling apparatus
B. Pressure filling apparatus
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Aerosols
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Aerosols
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Cold Filling
 Both product concentrate & propellant cooled to −34.5 to −40°C
 Chilled product concentrate quantitatively metered into an
equally cold aerosol container
 Liquefied gas is added  vapors of liquefied propellant
displace air in the container
 Valve assembly is inserted and crimped into place
 Alternatively, both product concentrate and propellant chilled in
a vessel  filled into a chilled container  valve placed and
crimped  tested for leakage

Cold Filling…
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Cold Filling…
 Aqueous systems cannot be filled by this process??
 Not suitable for formulations unstable in cold temperature
 HC propellants cannot be filled by this method.
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Aerosols
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Aerosols
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Pressure Filling
 Product concentrate is quantitatively placed in aerosol
container at room temperature
 Valve assembly is inserted and crimped into place
 Liquefied gas, under pressure, is metered into the valve stem
from a pressure burette
 Propellant may also be filled by ‘under-the-cup’ method
 Advantages over cold filling:
 Less danger of moisture contamination of product
 Less propellant is lost in the process

Pressure Filling…
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Aerosols
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Aerosols
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….
Large scale aerosol filling equipments are
composed of:
 Concentrate filler
 Valve placer
 Purger and Vacuum Crimper
 Pressure Filler
 Leak test tank

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Aerosols
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Delivering Inhalation Aerosols
 Currently three main types of aerosol generating devices for
use in inhaled drug therapy:
1.Metered-dose inhalers (MDIs)
2.Dry powder inhalers (DPIs); and
3.Nebulizers

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Aerosols
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Metered Dose Inhalers (MDIs)
 It is most commonly used inhalation drug delivery devices
 Drug either dissolved or suspended in a liquid propellant
mixture with other excipients, including surfactants
 Employed when the formulation is a potent medication
 Amount of material discharged is regulated by an
auxiliary valve chamber

MDIs…
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Aerosols
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MDIs…
Effectiveness of delivering medication to
reaches of the lungs depends on:
 Particle size of inhaled drug
 Breathing patterns and depth of respiration
the lower
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Aerosols
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Aerosols
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Advantages of MDIs
 Portable and compact
 Many doses (~ 200) are stored in the small canister
 Dose delivery is reproducible
 Protect drug from oxidative degradation and
microbiological contamination

Disadvantages of MDIs
Inefficient drug delivery (high pharyngeal deposition)
 The first droplets exit at a high velocity (> 30m/s)
Much drug lost through impaction of droplets in the
oropharyngeal areas
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Aerosols
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Their incorrect use by patients
Droplet size emitted may be
deposition.
large for deep lung

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Aerosols
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Proper Administration and Use
Ideally, MDIs should be actuated during a course of slow,
deep inhalation,  breath-holding  exhale slowly
Coordinate inhalation (after exhaling as completely as
possible) and pressing down of the inhaler
Use of an extender device (spacer) with the inhaler for
patients who cannot properly use inhalers
Effectively assist the delivery of medication despite improper
patient inhalation technique
Patient is permitted to separate activation of the aerosol from
inhalation by up to 3 to 5 seconds

Proper administration…
 Spacer (extender) reduces aerosol velocity and
 Droplet size is decreased because there is time for
vaporization of the propellant (s)
cause less deposition of medication in the oropharynx
 But, they may be cumbersome
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Aerosols
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Dry Powder Inhalers (DPIs)
 Drug inhaled as cloud of fine particles
 Powder either preloaded in device or filled into hard
gelatin capsules or foil blister discs  loaded into
device prior to use
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Aerosols
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Aerosols
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DPIs…
 Drug powders are usually micronized (<5μm)
 Mixed with larger 'carrier' particles (usually 30-60μm) inert
excipient, usually lactose
improves liberation of drug, uniformity of capsule or device
filling
 Air flow should be sufficient for deaggregation of drug/carrier
aggregates  larger carrier particles impact in the throat and
smaller drug particles are carried

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Aerosols
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DPIs…
 Success of DPI formulations depends on:
 Adhesion of drug and carrier
 Ability of drug to desorb from carrier during inhalation
 Adhesion and desorption depends on the morphology of
particle surfaces and surface energies
 Performance of DPIs is thus strongly dependent on
formulation factors, and on the construction of the delivery
device and inhalation technique

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Aerosols
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DPIs…
Advantages over MDIs
 Propellant free and
except carrier (solid)
 Breath actuated 
do not contain any excipient
avoid problems of inhalation-
actuation coordination
 Dose counters are available in new designs

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Aerosols
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DPIs…
Disadvantages
 Liberation of powders & deaggregation of particles are
limited by patient's ability to inhale
 An increase in turbulent air flow increases the potential for
inertial impaction in the upper airways and throat

Types of DPIs
1. Unit-dose devices with drug in hard gelatin capsules
2. Multidose devices with drug in foil blisters
3. Multidose devices with drug preloaded in inhaler
Figure:
Spinhaler
vid
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Aerosols
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Aerosols
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Nebulizers
 Deliver relatively large volumes of drug solutions and
suspensions
 Used for drugs that cannot be conveniently formulated into
MDIs or DPIs
 Drug may be inhaled during normal tidal breathing through
a mouthpiece or face-mask
 Useful for children, elderly and patients with arthritis
 For acute conditions, hospitalized patients

Nebulizers…
1.Jet nebulizers
 Use compressed gas (air or O2) from cylinder, hospital air-
line …to convert a liquid into a spray
 Jet of high-velocity gas is passed either tangentially or
coaxially through narrow nozzle
 Negative pressure (where the air jet emerges) causes liquid
to be drawn up a feed tube from a reservoir vid
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Aerosols
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Jet nebulizers…
 Rate of gas flow driving atomization is major
determinant of aerosol droplet size and rate of drug
delivery
 Patient coordination not required
 Lack of portability
 Pressurized gas source required
 Lengthy treatment time ,,,,
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Aerosols
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Nebulizers...
2. Ultrasonic wave nebulizers
 Energy necessary to atomize liquids comes
piezoelectric crystal vibrating at high frequency
At high ultrasonic
intensities a fountain of
liquid is formed in
the nebulizer chamber
from
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Aerosols
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Evaluation of Pharmaceutical Aerosols
A. Flammability and combustibility
1.Flame Projection
 Effect of an aerosol formulation on extension of an open
flame
 Product is sprayed for 4 seconds into a flame
 Exact length measured with ruler
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Aerosols
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Evaluation of Pharmaceutical Aerosols….
2. Flash point
 Using standard Tag Open Cap Apparatus
 Product chilled to temperature of -25ºF and transferred
to the test apparatus
 Temperature increased slowly  temperature at which
the vapor ignites taken as flash point
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Aerosols
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Aerosols
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Evaluation of Pharmaceutical Aerosols….
B. Physiochemical characteristics
1.Vapor pressure
 Determined by pressure gauge
 Variation in pressure from container to
indicates the presence of air in headspace
2. Moisture content
 By Karl Fischer method or gas chromatography
3. Identity test
container

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Aerosols
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Evaluation of Pharmaceutical Aerosols….
C. Performance
1.Aerosol valve discharge rate
 Determined by taking an aerosol of known weight and
discharging the contents for given time
 By reweighing the container after time limit, change in
weight per time (g/sec) dispensed is discharge rate

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Aerosols
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Evaluation of Pharmaceutical Aerosols….
2. Dose uniformity
 Reproducibility of doses delivered each time the valve
is depressed
 Accurate weighing of filled container followed by
dispensing of several doses
 Container can be reweighed
 Difference in weight divided by No. of doses, gives the
average dosage
 Assay of the contents delivered is another method

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Aerosols
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Evaluation of Pharmaceutical Aerosols….
3. Leakage
 Used to estimate the weight loss
4. Net contents
 To check whether sufficient product has been placed in
container
 T
arred cans are filled and reweighed  difference
calculated or
 Weigh filled container, dispensing the contents, then
weigh the container

Evaluation of Pharmaceutical Aerosols….
5. Particle size distribution
 By using Cascade Impactor
 Carrying particles in a stream of air through a series of
smaller jet openings
 The heavier and larger diameter particles are impacted
on a slide under the larger opening
 As the openings get smaller, the next larger particles are
deposited on the next slides
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Aerosols
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Evaluation of Pharmaceutical Aerosols….
6. Spray patterns
 Based on the impingement of the spray on a piece of
paper that has been treated with a dye (oil or water
soluble)
 Particles that strike the paper cause the dye to dissolve
and absorbed onto the paper
 This can be used for comparison of spray pattern
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Aerosols
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