8.1 Define: Pharmaceutical aerosols.

Explain the role of propellants in an aerosol

system. Classify propellants and describe liquefied gas propellants in brief.

Pharmaceutical aerosols are pressurized dosage forms containing one or more active
ingredients that, upon actuation of an appropriate valve system, release the contents as
a fine dispersion of liquid and/or solid materials in a gaseous medium.

Propellants serve multiple critical roles in aerosol systems:

• Provide pressure to expel the product from the container

• Determine the spray characteristics (pattern, droplet size)

• Act as a vehicle/solvent for the formulation

• Control the rate of delivery

• Influence product stability

Propellants are classified into two main categories:

1. Compressed gases: Nitrogen, carbon dioxide, nitrous oxide

o Remain in gaseous state at room temperature and pressure

o Provide high initial pressure that decreases during use

2. Liquefied gases: Hydrofluorocarbons (HFAs), hydrocarbons, DME

o Exist as liquids under pressure but vaporize upon release

o Maintain consistent pressure throughout product life

o Most commonly used in pharmaceutical aerosols

Liquefied gas propellants (e.g., HFA-134a, HFA-227) have specific vapor pressure,
density, and solubility characteristics that determine their suitability for different
formulations. They provide constant pressure as the container empties because the
liquid propellant continues to vaporize, maintaining equilibrium.
8.2 Draw well labeled diagram for aerosol packs. Explain the different parts of it.

An aerosol pack consists of four main components working together as a delivery system:

1. Container: Houses the formulation and propellant

o Made of tin-plated steel, aluminum, or reinforced glass

o Must withstand internal pressure (typically 30-100 psig)

o May have internal coating for chemical resistance

o Provides structural integrity and product protection

2. Valve assembly:

o Mounting cup: Crimped to container, holds valve components

o Valve stem: Product flow path during actuation

o Valve body: Houses internal components and gaskets

o Spring: Controls opening/closing mechanism

o Gaskets: Provide sealing to prevent leakage

o Dip tube: Extends to container bottom for product delivery

3. Actuator (button):

o Controls product release when pressed

o Determines spray pattern through orifice design

o May include specialized features (directional spouts, foam expansion

chamber)

o User interface for product dispensing

4. Product concentrate:

o Active ingredient(s) and formulation excipients

o Dissolved or suspended in propellant system

o May form solution, suspension, or emulsion with propellant

The system functions when the actuator depresses the valve stem, allowing the
pressurized contents to flow through the valve and be dispensed through the actuator
orifice in the desired form.
8.3 Draw a well labelled diagram: Components of aerosol container.

The aerosol container system comprises several interdependent components:

Container body:

• Cylindrical metal (tin-plated steel/aluminum) or reinforced glass

• Designed to withstand internal pressure (typically 2-10 atmospheres)

• May include internal protective coating (epoxy, vinyl)

• Bottom may be flat, concave, or convex for structural strength

Valve assembly components:

• Mounting cup: Crimped to container opening, provides platform for valve

• Valve stem: Hollow tube that product travels through when actuated

• Valve body: Houses internal components

• Spring: Maintains closed position when not actuated

• Gaskets: Provide sealing between components (typically elastomers)

• Dip tube: Polyethylene or polypropylene tube extending to container bottom

Actuator (delivery system):

• Plastic button/head with specifically designed orifice

• Mechanical break-up features for spray pattern control

• Ergonomic design for user operation

• May include specialized applicators or extensions

Additional features:

• Vapor phase tap (in some designs)

• Metering chamber (for precise dose delivery)

• Protective cap to prevent accidental discharge

• Crimp seal securing valve assembly to container

This integrated system maintains product under pressure until actuation, whereupon the
formulation is expelled in the desired form (spray, foam, or stream).
8.4 Explain the parts of Aerosol.

An aerosol system consists of four essential parts that work together to deliver the
product:

1. Container: The pressure vessel that houses the formulation and propellant.
Materials include tin-plated steel (most common), aluminum (lightweight,
corrosion-resistant), or glass with protective coating (for visibility). The container
must withstand internal pressure, resist product interaction, and maintain
integrity throughout the product's life. Internal coatings (epoxy, vinyl) may be
applied to prevent metal-product interaction.

2. Valve system: The controlling mechanism for product release consisting of: •
Valve stem: Product flow channel during actuation • Valve body: Houses gaskets,
spring, and internal components • Mounting cup: Secures valve to container via
crimping • Dip tube: Delivers product from container bottom to valve • Gaskets:
Provides sealing to prevent leakage • Spring: Returns valve to closed position after
actuation

3. Actuator: The external button/mechanism pressed by the user, designed with

specific orifice dimensions to control spray characteristics. May include
specialized features like foam expansion chambers or directional spouts.

4. Propellant-concentrate mixture: The formulation consisting of active ingredients,

excipients, and propellant system that provides pressure and delivery mechanism
for the product.
8.5 Enlist various container uses for Aerosol. Explain various types of actuator and
valve used in aerosol.

Container types for aerosols include:

• Tin-plated steel: Economical, strong, commonly used

• Aluminum: Lightweight, corrosion-resistant, suitable for higher pressures

• Glass with protective coating: For products requiring visibility

• Plastic-coated glass: Combines transparency with safety

• Plastic containers: Limited applications due to permeability

Actuator types:

1. Mechanical break-up actuators: Most common, with internal channels to create

turbulence

2. Foam actuators: Contain expansion chambers for foam formation

3. Spray actuators: Designed for specific spray patterns (fine, coarse, stream)

4. Metered-dose actuators: Deliver precise amounts per actuation

5. Specialized applicators: Directional spouts, vaginal/rectal applicators

Valve systems:

1. Continuous spray valves: Standard for most products, release product as long as
depressed

2. Metered valves: Deliver precise dose regardless of actuation duration

3. Vapor-tap valves: Direct propellant vapor through product for finer sprays

4. Foam valves: Special design with larger orifices for foam formation

5. Upright/inverted valves: Function regardless of orientation

6. Tilt-action valves: Activated by tilting rather than direct depression

Each component is selected based on formulation properties, delivery requirements,

and intended use of the aerosol product.
8.6 Discuss in detail: Propellants in Aerosol.

Propellants are the driving force behind aerosol systems, providing pressure to expel the
product and often serving as the vehicle for the formulation. Their selection critically
impacts product performance, stability, and safety.

Types of propellants:

1. Compressed gases: • Nitrogen, carbon dioxide, nitrous oxide • Remain gaseous

within the container • Pressure decreases during use as gas volume expands •
Non-flammable but limited to certain formulations

2. Liquefied gases: • Hydrofluorocarbons (HFA-134a, HFA-227) • Hydrocarbons

(propane, butane, isobutane) • Exist as liquid/vapor equilibrium in container •
Maintain constant pressure until product is depleted • Most widely used in
pharmaceutical aerosols

Critical propellant properties include: • Vapor pressure: Determines internal pressure

(30-70 psig typical for topicals) • Density: Affects product layering in container • Solubility
parameters: Compatibility with formulation components • Toxicity profile: Safety for
intended route of administration • Flammability: Safety during manufacturing and use •
Environmental impact: Ozone depletion/global warming potential

Propellants often used in combination to achieve desired pressure, solvent

characteristics, and spray properties. Selection must balance technical requirements
with safety, environmental, and regulatory considerations.
8.7 Role and properties of propellants. Discuss.

Propellants serve multiple essential functions in aerosol systems while exhibiting

specific physical and chemical properties that determine their suitability.

Roles of propellants:

• Provide internal pressure for product expulsion

• Determine spray characteristics (droplet size, pattern)

• Serve as vehicle/solvent for active ingredients

• Influence product stability and compatibility

• Control delivery rate and product form (spray, foam, stream)

Key physical properties:

• Vapor pressure: Critical for internal pressure (2-10 atmospheres)

• Density: Affects product layering in container

• Boiling point: Determines evaporation rate after dispensing

• Solubility parameters: Compatibility with formulation components

• Particle size (for solid propellants): Affects suspension stability

Chemical properties:

• Chemical stability with formulation components

• Reactivity with container materials

• Potential for oxidation/hydrolysis

• Compatibility with valve components

Selection considerations include:

• Route of administration (topical, oral, inhalation)

• Formulation requirements (solution, suspension, emulsion)

• Safety profile for intended use

• Environmental impact (GWP, flammability)

• Regulatory status and regional restrictions

The ideal propellant maintains appropriate pressure throughout product life, exhibits
compatibility with all formulation components, provides desired spray characteristics,
and meets safety and environmental requirements.
8.8 Classify the propellants used to prepare aerosol products with suitable
examples.

Propellants for pharmaceutical aerosols can be classified based on their physical state
and chemical composition:

I. Based on Physical State: A. Compressed Gas Propellants • Remain in gaseous state

within container • Examples: Nitrogen (N₂), carbon dioxide (CO₂), nitrous oxide (N₂O) •
Properties: Pressure decreases during use, non-flammable, limited solvent capacity •
Applications: Simple spray products, foam-based systems

B. Liquefied Gas Propellants • Exist in liquid-vapor equilibrium under pressure •

Examples: HFA-134a (tetrafluoroethane), HFA-227 (heptafluoropropane) • Properties:
Constant pressure, good solvent properties, controlled delivery • Applications: MDIs,
topical sprays, foams

II. Based on Chemical Composition: A. Chlorofluorocarbons (CFCs) • Examples: CFC-

11, CFC-12, CFC-114 (historical use only) • Phased out due to ozone depletion potential

B. Hydrofluoroalkanes (HFAs) • Examples: HFA-134a, HFA-227ea • Properties: Non-

flammable, low toxicity, zero ozone depletion • Applications: Medical aerosols, MDIs

C. Hydrocarbons • Examples: Propane, n-butane, isobutane, mixtures (A-46, A-70) •

Properties: Highly flammable, good solvent properties, cost-effective • Applications:
Topical products, non-medical aerosols

D. Dimethyl Ether (DME) • Properties: Flammable, good solvent for both polar/non-polar
substances • Applications: Specialized pharmaceutical aerosols

Selection depends on formulation requirements, safety profile, and regulatory

constraints.
8.9 Classify filling methods for aerosols. Describe the manufacturing of aerosols by
cold filling and pressure filling method.

Aerosol filling methods are classified into three main categories:

1. Cold Filling Method: This method involves chilling the propellant to approximately
-40°C, where it becomes a low-pressure liquid. The process includes: • Cooling
the propellant in refrigerated storage tanks • Preparing the concentrate separately
• Chilling the empty containers • Adding the concentrate to containers •
Dispensing the cold liquefied propellant into the container • Quickly crimping the
valve assembly • Allowing the system to warm to room temperature Advantages
include suitability for heat-sensitive products and thermolabile drugs.

2. Pressure Filling Method: This is the most common method, involving: • Filling the
container with product concentrate (50-80% capacity) • Crimping the valve
assembly • Injecting propellant under pressure through the valve • Using
specialized pressure filling equipment to force propellant through the valve stem
• Final quality checks and testing Advantages include efficiency, versatility, and
suitability for most formulations.

3. Compressed Gas Filling: Used specifically for compressed gas propellants,

involving: • Adding the liquid concentrate to the container • Crimping the valve •
Injecting compressed gas through the valve under pressure

Each method has specific applications based on formulation properties, propellant type,
and manufacturing capabilities.
8.10 Describe filling techniques of aerosols.

Aerosol filling involves specialized techniques to safely combine the concentrate and
propellant within a pressurized container. The three main techniques are:

Pressure Filling:

• Most widely used industrial method

• Container filled with product concentrate (75-85% of capacity)

• Valve crimped onto container

• Propellant forced through the valve under pressure (40-60 psig)

• Utilizes specialized pressure filling machines with head adaptors for different
valve types

• Advantages: Efficiency, minimal propellant loss, suitable for most formulations

• Applications: Most commercial aerosols

Cold Filling:

• Propellant chilled to approximately -40°C to liquefy at atmospheric pressure

• Product concentrate added to container

• Cold propellant poured in as a liquid

• Valve quickly crimped before significant warming occurs

• Advantages: Suitable for heat-sensitive products, simpler equipment

• Limitations: Condensation issues, worker exposure to cold, time constraints

• Applications: Smaller production runs, thermolabile formulations

Compressed Gas Filling:

• Container filled with liquid concentrate

• Valve crimped

• Compressed gas (N₂, CO₂) introduced through valve

• Requires precise volume calculation to achieve target pressure

• Applications: Non-liquefied propellant systems

• Advantages: Simpler process for gaseous propellants

Each technique requires specific safety measures, specialized equipment, and quality
control procedures to ensure product consistency and safety.
8.11 Enlist the filling methods for aerosols and describe pressure filling method in
brief.

Aerosol filling methods include:

1. Pressure filling method

2. Cold filling method

3. Compressed gas filling method

4. Under-the-cap filling method (specialized)

The pressure filling method is the most widely used technique in commercial aerosol
production and involves the following steps:

1. Concentrate loading: The product concentrate (active ingredients and

formulation components) is accurately metered into the container, typically filling
50-80% of the available volume.

2. Valve placement: The valve assembly is positioned on the container opening.

3. Crimping: A crimping machine securely fastens the valve to the container, creating
a pressure-tight seal.

4. Propellant addition: Liquefied propellant is injected through the valve under

pressure (typically 40-60 psig) using specialized filling equipment.

5. Propellant measurement: The precise amount is controlled either volumetrically

or by weight to ensure consistent pressure.

6. Equilibration: Filled containers are allowed to equilibrate to ensure proper mixing

and pressure stabilization.

7. Testing: Filled units undergo leak testing, weight checks, and spray testing.

Advantages of pressure filling include efficiency for large-scale production, minimal

propellant loss, and suitability for most formulation types. The method requires
specialized equipment with safety features to handle pressurized components.
8.12 How will you evaluate aerosols?

Evaluation of pharmaceutical aerosols involves a comprehensive battery of tests

assessing physical, chemical, and performance characteristics:

Physical Testing:

• Leak testing: Water bath immersion to detect bubbles

• Pressure testing: Gauge measurement at specified temperatures

• Net weight/fill weight determination

• Spray pattern assessment: Visual or automated analysis

• Particle/droplet size distribution: Laser diffraction, cascade impaction

• Density determination of concentrate and final product

Chemical Testing:

• Assay of active ingredients: HPLC, GC, or other appropriate methods

• Propellant composition analysis: Gas chromatography

• pH of concentrate (where applicable)

• Moisture content determination

• Related substances/degradation products

• Concentrate-propellant compatibility

Performance Testing:

• Delivery rate: Weight loss per actuation

• Dose uniformity: Consistency throughout container life

• Spray characteristics: Pattern, angle, distance

• Foam stability (for foam products): Volume, drainage time

• Discharge rate: Amount delivered per time unit

• Evacuation efficiency: Percentage of product delivered

Stability Studies:

• Accelerated and long-term stability at various temperatures

• Altitude testing for pressure variations

• Cycling conditions to simulate temperature fluctuations

• Storage orientation effects (upright, inverted, horizontal)

Product-specific tests may include specific performance criteria based on therapeutic
application and route of administration.
8.13 Describe in detail quality control for pharmaceutical aerosol products.

Quality control for pharmaceutical aerosols encompasses comprehensive testing

regimens to ensure safety, efficacy, and consistency:

Physical Parameters: • Container testing: Integrity, deformation resistance, corrosion

resistance • Pressure testing: Initial pressure measurement (typically 40-70 psig for
topicals) • Leak detection: Water bath immersion at elevated temperatures • Weight
variation: Fill weight consistency within ±3-5% • Valve functionality: Actuation force,
delivery consistency • Actuator performance: Spray pattern uniformity

Chemical Testing: • Active ingredient assay: Typically 90-110% of label claim • Propellant
composition: Gas chromatographic analysis • Moisture content: Karl Fischer titration
(typically <0.2%) • Related substances/impurities: Product-specific limits • pH of
concentrate (where applicable) • Preservative content: For multiple-use formulations

Performance Evaluation: • Delivery rate: Weight/volume delivered per actuation • Spray

characteristics: Droplet size distribution using laser diffraction • Particle size analysis:
Cascade impaction for inhalation products • Content uniformity: Throughout container
life (first to last spray) • Dose accuracy: For metered-dose products (±15-20% typical
limits) • Evacuation efficiency: Percentage of labeled contents delivered

Stability Assessment: • Accelerated conditions: 40°C/75% RH • Long-term conditions:

25°C/60% RH • Temperature cycling: To simulate real-world conditions • Multiple
orientations: Upright, inverted, horizontal storage

Product-specific testing depends on route of administration and therapeutic purpose.

8.14 Explain quality control tests for pharmaceutical aerosols.

Quality control of pharmaceutical aerosols involves specific tests addressing the unique
characteristics of pressurized systems:

Leak testing: Containers are immersed in a water bath (50-55°C) and examined for air
bubbles indicating propellant leakage. Automated systems may use pressure decay or
vacuum testing methods.

Pressure testing: Internal pressure is measured using specialized gauges at 25°C (room
temperature) and 45-50°C (elevated temperature) to evaluate pressure-temperature
relationship and safety margin.

Spray delivery: Evaluated through several tests:

• Delivery rate: Weight loss per actuation (±15% of target)

• Spray pattern: Visual assessment or automated imaging systems

• Particle/droplet size: Laser diffraction or cascade impaction analysis

Content uniformity: Analysis of multiple actuations throughout container life to ensure

consistent drug delivery. Typically requires 9 of 10 samples within 85-115% of label claim.

Propellant analysis: Gas chromatography to verify propellant composition and ratio in

propellant blends.

Valve function: Actuation force measurement (typically 2-5 kg force) and delivery
consistency over multiple actuations.

Container testing: Corrosion resistance, deformation resistance under pressure, and

compatibility with formulation.

Product-specific tests include:

• MDIs: Fine particle fraction, emitted dose uniformity

• Topical foams: Foam stability, expansion ratio

• Nasal sprays: Spray geometry, plume characteristics

These tests ensure consistent performance, safety, and therapeutic efficacy throughout
product shelf life.
8.15 Comment: Metered dose inhalers (MDI) are preferred for pulmonary aerosol
drug delivery system.

Metered dose inhalers (MDIs) are indeed preferred for pulmonary drug delivery due to
several significant advantages:

Precise dosing: MDIs deliver exact, reproducible doses (typically 50-250 μg) with each
actuation through metering valve technology, ensuring therapeutic consistency critical
for respiratory conditions like asthma and COPD.

Portability and convenience: Compact, lightweight design allows easy carrying and quick
administration, improving patient compliance compared to nebulizers or dry powder
inhalers that may require more complex handling.

Versatility: MDIs can deliver various drug classes (bronchodilators, corticosteroids,

combination therapies) efficiently to the respiratory tract.

Cost-effectiveness: Generally more economical than alternatives, containing 100-200

doses per canister with relatively simple manufacturing processes.

Stability: Propellant-based systems provide excellent protection against moisture and

oxidation, resulting in longer shelf life (typically 2-3 years).

However, limitations include coordination challenges for some patients (often addressed
with spacer devices), relatively low lung deposition (10-20% of emitted dose), and
environmental concerns with propellants. Despite these drawbacks, MDIs remain the
most prescribed inhalation delivery system globally due to their reliability, convenience,
and proven clinical efficacy.