Pharmaceutical Aerosols & Sprays

(Pressurized Packages)

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• An aerosol or pressurized package may be

defined as " a system that depends on the

power of a compressed or liquefied gas to

expel the contents from the container".

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Pharmaceutical Aerosols & Sprays

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Advantages over other dosage forms:

1. A dose can be removed without contamination of

remaining material.

2. Greater stability for substances senstive to oxygen

and / or moisture.

3. The medication can be delivered directly on the

affected area in a desired form

4. Irritation produced by the mechanical application of

topical medication is reduced or eliminated.

5. Ease and convenience of application of medication

in a thin layer.

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Disadvantages of Pressurized Delivery Systems

1.Expensive

2. Limited safety hazard

• Flammable

• Pressurized

Precautions: DO NOT

• Spray on a naked flame (protect from sunlight).

• Inhale (except those intended for medical purposes).

• Pierce or burn.

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Aerosol

Space

sprays.

Coating

sprays.Foams. Streams

1- Space sprays : dispense the products as finely

divided sprays in which the particles are less

than 50 microns in diameter.

• It is intended that the particles remain

suspended in air for a time.

• Examples: insecticides and room deodorants.

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2- Surface – coating aerosols:

• The intention is to deposit the

particles directly on a surface rather

than in the air.

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• Produce sprays with particles somewhat larger

than those produced by space aerosols.

Examples: residual insecticides, paints.

3- Foam aerosols

The product is delivered from the valve of the pressurized package in the form of foam aerosols are used principally for personal products as shaving creams, and lotion.

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4- stream aerosolsThe product is expelled form the

pressurized package in the form of a

simple stream. Examples: hand lotions.

Mode of Operation

Liquefied gassystem

(Propellants)

Two phase system

Three phase system

Compressed gas

system

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When a liquefied gas propellant

is sealed with an aerosol

container, a portion of it

vaporizes and the remainder

exists as liquid.

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1- Liquefied Gas Systems:

A-Two phase system

The liquid phase may be

composed of :

1. solution of AC:

• in propellant or

• in mixture of propellant

and a solvent if a solvent

is necessary.

2. Suspension of AC in

propellant ᴉ3. Emulsion (foam).

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B- Three – Phase systems

• The aqueous product is not miscible with the propellants, it forms a separate layer.

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2- Compressed Gas – Systems

• It is a pressure of the gas in the head space of theaerosol which expels the product from the package.

• Pressure in these aerosols decreases as the productsare dispensed.

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Propellants

• Responsible for developing the pressure within the

container

• Expel the product when the valve is opened.

• Serve as solvents, suspending agents or diluents.

• Affects the properties of the product as it leaves the

package.

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Propellants

1- Liquefied Gas Propellants• Liquid gas propellants, mostly chlorinated, fluorinated

hydrocarbons, have been used in refrigeration units for a

number of years. They are well suited as propellants and as

refrigerants due to their low BP and low vapor pressures.

• Each propellant has a definite vapor pressure at a given

temp., therefore we can select a propellant to give the

desired pressure in an aerosol.

• If a single propellant does not give the desired pressure,

two propellants can be blended to obtain a mixture which

will produce the desired pressure at a given temp.

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PropellantsHydrocarbons Chlorofluorocarbons Hydrofluroalkanes

(HFA)

1. Cost Low High High

2. Ozone depletion Minimal Destructive to

atmospheric Ozone

No ozone depletion

3. Green house effect Negligible Contribute to

“greenhouse effect”

-

4. Toxicity Highly Toxic Low Low

5.Chemical stability High High

6. Solvent effect Excellent CFC-11 is a good

solvent

Poor

Most common

But Flammable

Used only in

inhalation aerosols

-

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18

19

XYZ

11CCl3F

12CCl2F2

114CClF2CClF2

115CClF2CF3

C318CF2CF2CF2CF2

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•All propellants are designated by

three digits. XYZ

X = Number of carbon atoms – 1

Y = Number of hydrogen atoms + 1

Z = Number of fluorine atoms

•if X is zero, it is omitted and a two

digit number is used.

•A capital C before a number

indicates the cyclic nature of a

compound.

* psia = pounds per square inch absolute (psig + 14.7)

• Propellant 11 cannot be used in packaging

products that contain H2O or Ethanol

because free HCL may form, causing

corrosion of metal containers.

• Propellant 12 and 114 are relatively stable

in the presence of water and alcohol.

• propellant C318 posses extreme chemical

stability with these liquids.

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The vapor pressure of pure propellant 11 (MW

137.4) is 13.4 psi and that of propellant 12 (MW

120.9) is 84.9 psi. Calculate the total pressure

in (psi and psig) of 100 g mixture from these 2

propellants with 1:1 ratio

The total pressure = partial pressure of A + partial pressure of B

• Partial pressure = mole fraction x vapor pressure

MW

gmweigtmoleofNo

moleofNomoleNo

moleofNofractionmole

BA

AA

)( .

. .

.

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Aerosols and Rault's law

psixpressurep

psixpressurep

fractionp

fractionp

molesp

molesp

2.459.84532.0

27.64.13468.0

532.0414.0364.0

414.0

468.0414.0364.0

364.0

414.09.120

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364.04.137

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12

11

12

11

12

11

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• Total vapor pressure of the mixture =

6.27 + 45.2 = 51.5 psi

To convert to psig we have to subtract

the atmospheric pressure of 14.7 psi.

51.5 – 14.7 = 36.8 psig

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II- Compressed Gas Propellants:DisadvantagesAdvantages

•Require use of a

nonvolatile co-solvent

•Produce coarse droplet

sprays

•Pressure falls during use

•Low inhalation toxicity

•High chemical stability

•High purity

•Inexpensive

•No environmental problems

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Compressed Gas - Physical Properties

N2ONitrogenCO2Property

NoneNoneNoneFlammability

limits in air

slightlyInsolubleslightlyAqueous

solubility

Depends on

fill

Depends

on fill

Depends on

fill

Vapor pressure

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Compressed gas

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Nitrogen (Insoluble):-The dispensed product have the same consistency as

before packaging.

-Must be packaged at higher pressure than aerosols

prepared with liquefied gas because of the pressure

drop during use (Nitrous oxide and Carbon dioxide are

the same but to lesser extent)

-Nitrogen is the best choice for products liable to

oxidation.

Containers

They must withstand pressure in the range of

140 – 180 psig.

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• Can Base

The curved shape of the can’s base

1. counters the pressure of the

propellant inside.

2. creates a “valley” so that all

product can be reached by the

dip tube.

ContainersMetal Glass Plastic

Examples Tin plated steel

Aluminium

stainless steal

Acetal resin

(Delrin),

polymeric amides

(Nylon), and

acetyl copolymer.

Advantage Strong so they can

withstand high

pressure

•One can see the product inside•Easily shaped•Does not interact with the ingredients•Not subjected to corrosion.

Unbreakable

Disadvantage • One can not see

the product inside

• Can interact with

some ingredients

It is easily breakable.

therefore, glass can be

protected by using

metal shell or plastic

coating

•May interact

with some

ingredients.

•May permeate

some fluids 29

• Plastic coating of glass containers serve

as:

-- cushion impacts if the bottles are dropped.

-- container for the broken glass and the

aerosol content if the impact was hard.

In this case, the gas causes the plastic to

balloon.

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Valves

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Valve

Continuous Spray Valve

Metering Valves

Continuous Spray Valve-1

• An aerosol valve consists of many

different parts, these parts are:

I- Mounting Cup:

The mounting cup is used to attach the

valve to the container.

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• II- Housing and stem:

• It is manufactured

from Nylon or Delrin.

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• III- Gasket (ring):

• It is manufactured from Buna-N

or Neoprene rubber. The gasket

serves to seal the stem

openings when the valve is

closed.

• IV- Spring:

• The spring serves to hold the

gasket in place and when

actuator is depressed and

released, the gasket will return

the valve to its closed position.

• Springs are commonly

manufactured from stainless

steal.36

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• V- Dip Tube:

• It is made ofpolyethylene orpolypropylene

• Larger diameter of diptube is used for moreviscous preparations.

• Its length is veryimportant especiallyin 3-phase aerosolsystem.

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• The length of the dip

tube is such that the

tube dips into the

aqueous product

and not the

propellant.

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2- Metering Valves

• Metered valves are applicable to the

dispensing of potent medications.

These valves deliver measured amount

of aerosol mixture with each actuation.

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2- Metering ValvesSteal Ball

A) The dip tube may contain a steel ballwhich operate between a lower stopand a ball valve seat at the upper level.

B) When the valve is actuated, the fastflowing stream of product carries theball up in the dip tube until the ballseats in the upper valve seat.

C) When the actuator is released the ballreturns to its lower positioning the diptube.

D) The volume between the lower stopand the upper ball valve determines thequantity of spray per dose.41

Actuators• The actuator allows for easy opening and closing of the

valve.

• It also serves to aid in producing the required type of

product discharge.

• There are different types of actuators.

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Actuators 1- Spray Actuators

• Actuators for spray aerosols are capable of dispersing thestream of product concentrate and propellant inrelatively small particles by allowing the stream to passthrough various openings.

2- Foam Actuators: consist of large orifices.

3- Stream actuators: have relatively large orifices similar tothat of foam actuators.

4- Special actuators:

• Specially designed to deliver the medication to theappropriate site of action (throat or nose).43

Protective caps

• Protective caps are necessary to protect the

valve and actuator during storage and

transportation.

• They are made of metal or polyethylene.

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Filling Operations1- Cold Filling:

For liquefied gas propellants.

• First cool the container.

• Cool the drug concentrate and the propellant till liquefied

till –40 0C by using dry ice (solid CO2).

• Fill the drug concentrate quantitatively

• Fill the liquefied gas quantitatively

• Immediately fix the valve and seal it

Advantages:

Economic

No air entrapment within package

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Disadvantages:•Not for aqueous preparations (will freeze)

.Pressure Filling Method2

• For liquefied gas Propellants

1- Fill the drug concentrate

2- Fix the valve.

3- Fill the gas or the liquefied propellant using

pressure by pumping.

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Formulation of aerosols

• Drug concentrate: Solution or suspension.

• Propellant: Liquefied or compressed gas

• Valve and actuator: modified to change

droplet size.

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• 1- Solutions:

• Product concentrate is a solution of active ingredient in

single propellant, propellant blend or propellant and

other solvent.

• Propellant 12 has very high V.P:

needs metal container.

If used alone very fine spray product.

If mixed with other propellants or non volatile solvents,

coarser droplets and lower V.P

no need for metal containers.

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Water Based System

• If the propellant is immiscible with water, so 3-

phase system will appear.

Conversion into 2-phase system:

• Make emulsion of the propellant with water.

• Make the propellant miscible by

1- Co-solvency (ethyl alcohol)

2- Surfactant (Spans: 0.5- 2.0%)

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2- Suspensions

• Suspend the drug in a propellant and

SAA or Suspending agent.

• In this case, no need for cosolvents

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Formulation of Foam System

1- Stable Foam:

• The foam system is an emulsion.

• Use liquefied system (8-10%) propellant in

the internal phase.

Increase propellant 12 ratio gives stiff foam.

2- Quick breaking foam:

• Use liquefied propellant in the external phase

of the emulsion.

• Mainly for topical preparations.51

Inhalation Aerosols

Three main types of aerosol generating device

for use in inhaled drug therapy:

1. Metered-dose inhalers (MDIs).

2. Dry powder inhalers (DPIs)

3. Nebulizers.

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Metered-dose inhalers (MDIs).

• Metered-dose inhalers (MDIs), introduced in the mid-1950s

• drug is either dissolved or suspended in a liquid propellant mixture.

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• There is no dip tube (metered dose inhalers MDIs) the

container is used in the inverted position so that the

liquid phase is in direct with the valve.

Advantages of MDIs

1. Their portability

2. low cost

3. dose delivery is reproducible.

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Incorrect use by patients as:

• Failure to remove the protective cap covering the mouthpiece.

• Failure to shake the canister

• Failure to inhale slowly and deeply.

• Poor inhalation/actuation synchronization.

• Inadequate breath-holding.

Disadvantages of MDIs:

How to overcome the synchronization

problem?

• Spacer :

• It is a cylinder that has a mouth piece at one end and a fitting at the other end.

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Advantages:

1. Reduce the need for optimal coordination thusimproving delivery of drugs to the lungs.

2. Useful for young children, children unable to useMDI and patients with coordination problems.

Dry powder inhaler (DPI)

The drug is either:

1. preloaded in an inhalation device (Turbohaler)

2. or filled into Hard gelatin capsules (cap. inhaler)

3. or foil blister discs (Discus)

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Disadvantages:

1. Liberation of powders from the device and is

limited by the patient's ability to inhale, which in

the case of respiratory disease may be impaired.

2. Elevated humidity cause powders to clump.

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Advantages:

1. DPI formulations are propellant free.

2. do not contain any excipients, other than a carrierwhich is almost lactose.

3. They are breath actuated, avoiding the problems of inhalation/actuation coordination encountered with MDIs,

4. useful for young children

Aerolizer (Capsule Inhaler)

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Turbuhaler

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Diskus inhaler

Diskus inhaler

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inhalerDiskus

Nebulizers

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A nebulizer makes an aerosol by blowing air or oxygen through adrug solution e.g. albuterol, beclomethasone, and cromolynsodium.The aerosol is delivered through a face mask or a mouthpiece.

Advantages:

1. Nebulization is effective because it allows highdoses of drugs to be inhaled without any specialeffort to coordinate breathing.

2. Nebulized bronchodilators are particularly helpfulin the acutely breathless patient both at home andin hospital, young children and patients onventilators.

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Evaluation parameters of pharmaceutical aerosolsA. Flammability and combustibility

1. Flash point.

2. Flame extension.

B. Physiochemical characteristics

1. Vapor pressure

2. Density

3. Moisture content

C. Performance

1. Aerosol valve discharge rate

2. Spray pattern

3. Dosage with metered valves

4. Net contents

5. Foam stability

6. Particle size determination.

Quality Control

1. Flame Extension

Done by spraying the product for 4 seconds into a flame.

The flame will be extended.

The exact length of the extended flame is measured by a ruler.

2-Flash point

Determined by chilling the product to a temperature of -25°F

and transfer the product to the test apparatus, then increase the

temperature slowly.

The temperature at which the vapor ignites is taken as the

flash point.

Measured with a pressure gauge

Excessive variation in pressure indicates

the presence of air in the head space.

2. Density: Determined by the use of a

hydrometer or a pycnometer

3. Moisture content: measured by Karl

Fishcer method or gas

chromatography.

1. Vapor pressure:

1. Aerosol valve discharge rate

Discharging the contents for a given period of time using a

standard apparatus.

By reweighing the container, the change in weight per time is

the discharge rate (gram/second or gram/minute).

Example:

Initial weight = 100 gm.

after 10 minutes of discharge → weight = 80 gm.

discharge rate = (100 - 80) / 10 = 2 gm/minute

2. Spray pattern Spray pattern is based on spraying the aerosol on a piece of paper

coated with a dye-talc mixture.

The dye goes into solution and is absorbed onto the paper This

will give a record of the spray (finger print) which can be used for

comparison purposes.

3. Dosage with metered valves

a. Assay technique: where one or two doses are dispensed

into a solvent and the solution is assayed to determine

the drug content.

b. Another method:

Dispensing several doses.

The container is then reweighed

The difference in weight is divided by the number of doses

dispensed to give the average dose.

4. Net contents

A full container is weighed and then all its contents are

dispensed & reweighed.

5. Foam stability

1. Visual evaluation

2. Time for a given rod that’s inserted into the foam to fall.

3. By the use of a rotational viscometer.

6. particle size determination:

Cascade impactorA series of nozzles and glassslides.The large particles becomeimpacted first.The smaller particles pass on andare collected at high velocitystages.

Thank You

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