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Aerosols

Definition

According to the British Pharmacopoeia (B.P.), aerosols are defined as

preparations which are packaged under pressure and contain one or more
active ingredients that are released upon actuation of an appropriate valve
system as a fine mist of liquid or solid particles in a gaseous medium.

The Aerosol Principle

An aerosol formulation has two parts: the product concentrate and the
propellant.

When a liquefied gas propellant or a mixture of them is sealed in an aerosol

container with the product concentrate, it quickly forms an equilibrium
between the liquid propellant and the vapor that fills the upper part of the
container.

The vapor phase creates pressure in all directions against the container
walls, the valve assembly, and the surface of the liquid phase, which includes
the liquefied gas and the product concentrate.
When the aerosol valve is activated, this pressure forces the liquid up the
dip tube and out of the valve into the air.
As the propellant hits the air, it expands and evaporates due to the drop in
pressure, leaving the product concentrate as airborne liquid droplets or dry
particles, depending on the formulation.

As the liquid phase is used up, the equilibrium between the remaining liquid
propellant and the vapor is reestablished.

This keeps the pressure inside the container nearly constant, allowing the
product to be released at a steady rate with consistent force.
However, when the liquid is all used up, the pressure may drop, and the gas
will be expelled with decreasing force until it runs out.

Components of pharmaceutical aerosols

The components of pharmaceutical aerosols generally include the following:

A. Product concentrate

 Active Pharmaceutical Ingredient (API):

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The medication intended to exert a therapeutic effect. Examples include

albuterol, fluticasone, and budesonide.
 Solvent (if applicable):
A liquid used to dissolve or suspend the API, aiding in the formulation of
the aerosol. Common solvents include ethanol, water, or glycerin.
 Surfactants or Dispersing Agents:
These agents help to stabilize the dispersion of solid particles or liquid
droplets within the propellant. Examples include lecithin and oleic acid.
 Stabilizers and Preservatives:
Compounds added to maintain the stability and shelf life of the aerosol
formulation. These can include antioxidants like butyrate hydroxytoluene
(BHT) and antimicrobial preservatives like benzalkonium chloride.

B. Propellant:

A propellant is the pressurized gas or liquefied gas used in an aerosol

system to expel the product from the container when the valve is opened. It
provides the driving force that pushes the formulation (drug, cosmetic, paint,
etc.) out of the can and helps in forming the desired spray or foam.

Types of Propellants Used in Aerosols:

1. Liquefied Gases:
a) Chlorofluorocarbons (CFCs)
Example: Trichloromonofluoromethane (CFC11), Dichlorodifluoromethane
(CFC12).
Mostly phased out due to their ozone depleting effects,
b) Hydrofluoroalkanes (HFAs)
HFAs are the replacement for CFCs in many pharmaceutical aerosols and
environmentally friendly compared to CFCs, and safe for inhalation. They do
not deplete the ozone layer and have similar properties to CFCs.
Examples: HFA134a (Tetrafluoroethane), HFA227 (Heptafluoropropane).
Use: Commonly used in MDIs for respiratory conditions like asthma and
COPD.
.
(c) Hydrocarbons
Hydrocarbons like propane, butane, and isobutane are commonly used in
topical aerosols due to their good propellant properties and low cost.
Examples: Propane, Butane, Isobutane.
Benefits: Inexpensive and effective, though they are flammable and pose
some safety concerns.
2. Compressed Gases:

a. Nitrogen (N₂):
Usage: Nitrogen is an inert gas used as a propellant in aerosol formulations
for its stability and nonreactive properties.
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b. Carbon Dioxide (CO₂):

Usage: Carbon dioxide is used for its solubility in water and other solvents,
making it suitable for certain aerosol formulations.

c. Nitrous Oxide (N₂O):

Usage: Nitrous oxide is sometimes used in medical aerosol applications due
to its solubility and relatively nonreactive nature.

3. Dimethyl Ether (DME)

Description: DME is a versatile propellant with good solvency properties,
used in both pharmaceutical and cosmetic aerosols.

C. Container:

The container of an aerosol is typically referred to as an aerosol can

or aerosol container. It is a pressurized vessel designed to hold a
product (like a liquid or solid
Aersols container withstand with high pressure as high as 140-180
psig at 130 F.
Main Components of an Aerosol Container:

1. Container Body: Usually made of metal (aluminum or tin-plated steel)

and plastic.

Strong, corrosion-resistant,
Tin-plated steel or can withstand internal
Metal container
aluminum pressure. Most commonly
used.
Lightweight, corrosion-
Plastic High-density polyethylene
resistant, used for non-
container(less (HDPE) or polyethylene
pressurized or low-pressure
common) terephthalate (PET)
products.

2. Valve assembly

Actuator:
This is the button or lever that the user presses to activate the valve and
release the product.
Stem:
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The stem is the central component that controls the flow of product. When
not actuated, the stem seals with the stem gasket to prevent product
release.
Stem Gasket:
The stem gasket provides a seal between the stem and the housing,
preventing product leakage when the valve is closed.
Spring:
The spring helps to return the stem to its closed position after the actuator
is released, closing the valve.
Body Housing:
The body housing encloses the spring and stem, providing structural
support and also playing a role in controlling the flow of product.
Dip Tube:
The dip tube extends into the product concentrate within the aerosol
container and draws it up towards the valve for release.
Mounting Cup and Gasket:
The mounting cup attaches the valve assembly to the aerosol can, and the
gasket provides a seal between the can and the valve to prevent leaks.

There are two forms of valves

 Continuous spray valve

 Metering valve

Continuous spray valve: It is

used mainly tropical aerosols.

Metering valves: It is used for

dispensing of potent medication.
Actuators:
These are specially designed
buttons which helps in delivering
the drug in desired form. Types of
actuators :
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1. Spray actuators : Topical preparation

2. Foam actuators: consists of

large orifice 0.0700.125 inch .

3. Solidstream actuator: used

for semi solid preparation.
4. Special actuator : It delivers
the medicaments appropriate site
of action such as throat, nose ,
eye etc.

Advantages of aerosoles
 It has rapid onset of action
which is particularly beneficial
for conditions like asthma and chronic obstructive pulmonary disease
(COPD)=
 Provide targeted drug delivery for example aerosolized drugs act directly
on the respiratory tract, reducing systemic exposure and side effects.
 Aerosols provide a noninvasive route of administration, avoiding the need
for injections.
 These devices deliver a precise dose of medication with each actuation,
ensuring consistent dosing. MDIs

Disadvantages

 Effective use of inhalers requires proper technique, which some patients,

especially the elderly and children, may find challenging.
 Devices can malfunction or deliver inconsistent doses if not used properly.
 Some aerosols use chlorofluorocarbons (CFCs) as propellants, which have
environmental impacts, such as contributing to ozone layer depletion
(CFCs)
 Aerosol formulations and delivery devices can be more expensive to
produce compared to other dosage forms like tablets and capsules.

Classification of aerosols

A. Based on Route of Administration

1. Inhalation Aerosols
2. Nasal Aerosols:
3. Topical Aerosols:
4. Oral aerosols
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1. Inhalation Aerosols: This type of aerosols deliver the drugs directly to

lungs. Types
(a) Metered Dose Inhalers (MDIs): Deliver a precise dose of medication
to the lungs. They use propellants to disperse the drug.
(b) Dry Powder Inhalers (DPIs): Contain medication in a dry powder form
that is inhaled directly into the lungs without the need for propellants.

(c) Nebulizers: Convert liquid medication into a fine mist for inhalation,
often used in clinical settings or for patients who have difficulty using MDIs or
DPIs.

2. Nasal Aerosols:
Administer medication through the nasal passages. These are typically
used for conditions such as allergic rhinitis or nasal congestion.

3. Topical Aerosols:
Apply medication to the skin or mucous membranes. Commonly used for
dermatological conditions or localized pain relief.

4. Oral Aerosols:
Administer medication via the mouth but target areas other than the lungs,
such as the oropharynx.

B. Based on physical form and dispersion

1. Space Aerosols:

Space aerosols are particles suspended in the air that is disperse liquid or
solid particles into the atmosphere.
Application: These are commonly used for air fresheners, Insecticides,
disinfectants
2. Surface Aerosols:

Surface aerosols are designed to deposit active ingredients directly onto

surfaces rather than remain airborne.
Aplication: These are used for cleaning, disinfecting, or coating surfaces.
Examples include surface cleaners, polish sprays, and disinfectant sprays.

3. Foam Aerosols:
Foam aerosols produce a foamy substance upon dispensing, which can be
applied to surfaces or used for specific applications.
Applications: These include shaving foams, fire extinguishing foams, hair
styling foams, and certain types of cleaning products.
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4. Stream Aerosols:
Stream aerosols release their contents in a concentrated stream or jet rather
than a fine mist or spray.
Applications: Used where precision application is needed, such as
insecticide sprays or medical sprays like nasal sprays.

Filling methods of aerosols

Cold Filling Method

This method is typically used for filling products with fluorocarbons as
propellants because less denser than air and forming no explosive or
flammable mixture.
Hydrocarbon can not be used because of formation of explosive mixture in
the space. It consists Of insulated box with copper tubing inside to increase
the surface area for long exposure to cold temperature. The box is filled dry
ice or acetone
Process:
 In the cold fill process, both
the product concentrate and
the propellant must be cooled
to temperatures between -
30°F ( °C) to --40°F where
they will remain liquefied.
 The chilled product
concentrate is quantitatively
added to the equally cold
aerosol container
 Liquefied gas is added.
 Sufficient time is allowed for
the propellent to parcially
vaporize in order to expel the
air present inside the
container.
 When filling is complete, the valve assembly is inserted into the
container and crimped into place.
 The container is then passed through a water bath of about (130 F)
55°C to check for leaks or distortion in the container.

Advantages:

 The product and propellant can be mixed before being added to the
container, ensuring uniformity.
 Particularly useful for filling containers with fluorocarbons as the
propellant.
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 Simple process

Disadvantage

 Requires significant energy to cool the product and propellant.

 Condensation of water vapor may occur, leading to potential
contamination.
 The low temperatures may damage or alter the properties of some
products.

Pressure Filling Method

This is one of the most common methods used for filling aerosol containers,
especially when dealing aqueous products with liquefied gases like propane,
butane, or dimethyl ether. It consist of pressure burette capable of metering
small amount of liquefied gas propellent into aerosol conatainer. Propellent is
added through an inlet volve located at the bottom ot the top of pressure
burette
Process:
 Pressure filling is carried out essentially at room temperature.
 The product concentrate is placed in the container,
 The valve assembly is inserted and crimped into place,
 lLiquefied gas, under pressure, is added through the valve.
 The entrapped air in the package might be ignored if it does not
interfere with the stability of the product, or it may be evacuated prior
to or during filling.
 After the filling operation is complete, place the container in water
bath of temperature 55 C to check the valve for proper function or
leaks.
 Pressure filling is used for most pharmaceutical aerosols on large scale.

Advantages:
 Aquous and emulsion product can not be filled by cold filling because
of freezing while tthis method overcome such problems.
 Unlike some other methods, precooling of the container isn’t required.
 Economic bcause less propellent is use
 It has the advantage that there is less danger of moisture
contamination of the product and also
Disadvantages:
 Requires specialized equipment that can handle high pressure
conditions.
 Not suitable for products that require nonliquefied gases.

UnderCup Filling Method (BagonValve)

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This modern method is used when the product needs to be separated from
the propellant, as in medical sprays, food products, or personal care items.

Process:
The product is filled into a bag or an inner container, which is then inserted
into the main container.
The propellant is filled into the space between the bag and the outer
container.
When the valve is pressed, the propellant compresses the bag, forcing the
product out.

Tests of aerosols

Quality control tests for pharmaceutical aerosols are essential to ensure that
these products meet the necessary standards for safety, efficacy, and
stability. These tests can be categorized into several key areas:

1. Physical Tests

Leak Test:
Ensures that the aerosol container is sealed properly, preventing the leakage
of the product.
Crimping Dimensions:
The crimping of the valve to the container should be within specified
dimensions to ensure proper sealing.

Spray Pattern:
This test examines the shape and distribution of the aerosol plume to ensure
it delivers the medication uniformly.

Particle Size Distribution:

The size of the particles in the aerosol affects deposition in the respiratory
tract, with an optimal range typically between 15 microns for pulmonary
delivery.
Pressure Tests:
Ensures the propellant pressure within the container is within the specified
range.
Weight Check:
Verifies the amount of product in the container.

2. Chemical Tests
Assay of Active Ingredient:
The concentration of the active pharmaceutical ingredient (API) must be
within specified limits.
Content Uniformity:
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Ensures that each dose delivered contains a consistent amount of the

active

3. Performance Tests
Dose Delivery Per Actuation:
Measures the amount of drug released per actuation to ensure consistent
dosing.
Spray Duration:
The time it takes to deliver a single dose.

4. Microbiological Tests
Sterility Test:
For products that require sterility (e.g., inhalation aerosols), sterility tests
ensure no microbial contamination.

5. Stability Tests
Storage Stability:
Aerosols are tested under different conditions (e.g., temperature,
humidity) to ensure they remain stable over their shelf life.

Packaging, Labeling, and Storage

Most aerosol products have a protective cap or cover that fits snugly over
the valve and mounting cup. This protects the valve against contamination
with dust and dirt. The cap, which is generally made of plastic or metal, also
serves a decorative function. Most other types of aerosols have the
manufacturer’s label printed directly on the container or on firmly affixed
paper. In addition to the usual labeling requirements for pharmaceutical
products, aerosols have special requirements for use and storage. For
example, for safety, labels must warn users not to puncture pressurized
containers

Inhalation Solutions

Inhalations are sterile drugs or sterile solutions of drugs administered by the

nasal or oral respiratory route for local or systemic effct in the form of
vapours. The drugs may be administered for local action on the bronchial
tree or for systemic effects through absorption from the lungs. Certain gases,
such as oxygen and ether, are administered by inhalation.

Inhalants:
Inhalants are drugs or combinations of drugs that are released upan
actuation, where they exert their effect. Certain nasal decongestants are in
the form of inhalants. For instance, propylhexedrine is a liquid that volatilizes
slowly a troom temperature. This quality makes it effective as an inhalant.
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Inhaler:
The device that holds the drug from which they are administered is an
inhaler.

Vehicles
Sterile Water for Inhalation, USP, and Sodium Chloride Inhalation, USP, may
be used as vehicles for inhalation solutions..

Examples of Medicated Solutions

Amyl Nitrite Inhalant

Amyl nitrite is a clear yellowish volatile liquid that acts as a vasodilator when
inhaled. It is prepared in sealed glass vials that are covered with a protective
gauze cloth. Upon use, the glass vial is broken in the finger tips,and the cloth
soaks up the liquid, from which the vapors are inhaled. The vials generally
contain 0.3 mL of the drug substance. The effects of the drug are rapid and
are used in the treatment of anginal pain.

Propylhexedrine Inhalant
Propylhexedrine (Benzedrex, VF Ascher) is a liquid adrenergic
(vasoconstrictor) agent that volatilizes slowly at room temperature. The
official inhalant consists of cylindrical rolls of suitable fibrous material
impregnated with propylhexedrine, usually aromatized to mask its amine-like
odor and contained in a suitable inhaler. The vapor of the drug is inhaled into
the nostrils when needed to relieve nasal congestion due to colds and hay
fever. It may also be employed to relieve ear block and pressure pain in air
travelers.

Preparation and packaging of propyl hexidrin inhalers

Ingredients:

1. Propylhexedrine: The active ingredient, typically in the form of

propylhexedrine base.
2. Menthol: Often used to provide a cooling effect and enhance the nasal
decongestant effect.
3. Lavender Oil: Sometimes included for its aromatic properties and
potential soothing effects.
4. Inactive Ingredients: These might include substances like camphor or
other essential oils to enhance the effect or stability of the product.

General Preparation Steps:

Formulation of the Solution:

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1. Measure the active ingredient (Propylhexedrine) and dissolve it in

a suitable solvent. This solvent could be ethanol or another alcohol-
based solution.
2. Add Menthol and other essential oils (like lavender oil) to the
solution. The menthol can be dissolved by gentle heating if needed.
3. Mix the solution thoroughly until all components are fully dissolved
and the solution is homogeneous.

4. Soak the Wick:

 A cotton or polyester wick is used to absorb the solution.
 Immerse the wick in the prepared solution until it is fully
saturated.
 Remove excess solution from the wick by gently pressing or
spinning it.

5. Assembly:
 Insert the soaked wick into the inhaler body (a small tube,
usually made of plastic).
 Secure the wick inside the inhaler by attaching the inhaler cap or
sealing it in a way that prevents leakage but allows the vapors to
be inhaled.

6. Packaging:
 After assembly, the inhaler is typically placed in protective
packaging to ensure its integrity and shelf life.
 Labeling includes the dosage, ingredients, and usage
instructions.

Sprays
A liquid or semi-solid preparation dispensed as small droplets or particles onto a
surface.
Usually in a pump bottle (manual pressure)

Types of Sprays

Sprays are classified based on where and how they are used:

1. Nasal Sprays
 Used for delivering drugs into the nasal cavity.
 Example: Oxymetazoline spray for nasal congestion.
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2. Throat Sprays
 Applied directly into the throat.
 Example: Antiseptic throat sprays for sore throat.
3. Topical Sprays (Skin Sprays)
 Applied onto skin for local action.
 Example: Silver sulfadiazine spray for burns.
4. Oral Sprays
 Sprayed inside the mouth (but not for inhalation).
 Example: Nicotine oral spray for smoking cessation.

1 Difference between Pharmaceutical Spray, Aerosol, and Inhalation

Solutions

Feature Spray Aerosol Inhalation Solution

Definitio A liquid or semi-solid A pressurized dosage A sterile solution in the
n preparation dispensed form that delivers form of vapours meant
as small droplets or drug in fine particles to be inhaled through
particles onto a surface.
(gas or mist) when a nebulizers to reach the
valve is activated. lungs.
Containe Usually in a pump bottle Pressurized container Solution stored in
r (manual pressure). with a propellant gas ampoules or vials (non-
inside. pressurized).

Mechanis Mechanical spraying, no Propellant-driven Nebulized into mist by a

m propellant gas. spray (under machine (nebulizer)
pressure). without pressure.
Particle Larger droplets (good Fine mist, small Very fine mist (small
Size for skin, nose, throat). particles (good for particle size to deeply
lungs, skin, nose). reach lungs).
Examples Nasal sprays, throat Asthma inhalers, Salbutamol nebulizer
sprays, skin antiseptic spray deodorants, solution, ipratropium
sprays. topical sprays. bromide solution.