Chapter 7

Aerosols, Sprays and Inhalations

Section1: Pharmaceutical Aerosols PHARMACEUTICAL AEROSOLS are pressurized

dosage forms containing one or more active ingredients

which upon actuation emit a fine dispersion of liquid

and/or solid materials in a gaseous medium.

They depend upon the function of the container, its

valve assembly, and an added component--the

propellant--for the physical delivery of the medication

in proper form.

Ⅰ Definition

An equilibrium is quickly established between that

portion of propellant which remains liquefied and that

which vaporizes

The vapor phase exerts pressure in all directions--

against the walls of the container, the valve assembly,

and the surface of the liquid phase

It is this pressure that upon actuation of the aerosol

valve forces the liquid phase up the dip tube and out

of the orifice of the valve into the atmosphere.

As the propellant meets the air, it immediately

evaporates due to the drop in pressure, leaving the

product concentrate as airborne liquid droplets or

dry particles, depending upon the formulation.

As the liquid phase is removed from the container,

equilibrium between the propellant remaining

liquefied and that in the vapor state is reestablished.

Thus even during expulsion of the product from the

aerosol package, the pressure within remains virtually

constant, and the product may be continuously released

at an even rate and with the same propulsion.

However, when the liquid reservoir is depleted, the

pressure may not be maintained, and the gas may be

expelled from the container with diminishing pressure

until it is exhausted.

Ⅱ Features of the Aerosol Dosage Form

Some features of pharmaceutical aerosols that may be

considered advantages over other types of dosage

forms are as follows:

1. A portion of medication maybe easily withdrawn

from the package without contamination or

exposure to the remaining material.

2. By virtue of its hermetic character, the aerosol

container protects medicinal agents adversely affected

by atmospheric oxygen and moisture.

Being opaque, the usual aerosol container also protects

drugs adversely affected by light.

If the product is packaged under sterile conditions,

sterility may also be maintained during the shelf-life of

the product.

3. Topical medication may be applied in a uniform, thin

layer to the skin, without touching the affected area.

Reduce the irritation

The rapid volatilization of the propellant also

provides a cooling, refreshing effect.

4. By proper formulation and valve control, the physical

form and the particle size of the emitted product may

be controlled which may contribute to the efficacy of a

drug.

Through the use of metered valves, dosage may be

controlled. 5. Aerosol application is a "clean" process, requiring

little or no "wash-up" by the user.

6. Have a immediate effect and can distributing the

medicaments to the certain tissues of the region.

Bigger absorption area; abundant blood

circulation; smaller resistance of penetration.

7. Drug can avoid to be destroyed or inactivated by

the pH or enzymatic activity of the stomach or

intestines, also can avoid the first pass effect.

The influencing factors of absorption

The air current of breath: the amount of inspiration

and frequency of breath.

Particle size: most 5μm, must be smaller than 10μm.

The features of drug: solubility; molecular weight,

oil-solubility (Ko/w), moisture absorption.

Disadvantages of the pharmaceutical aerosol:

High cost.

Because of the volatility, the propellants has the

refrigeration effect which can irritate the skin.

To certain individuals, who may be sensitive to the

propellant agent and who utilize an inhalation

aerosol, the fluorinated hydrocarbons may exhibit

cardiotoxic effects following rapid and repeated use

of the aerosol product.

Ⅲ Aerosol Systems

TWO-PHASE SYSTEMS

This system is comprised of the liquid phase,

containing the liquefied propellant and product

concentrate, and the vapor phase.

THREE-PHASE SYSTEMS

This system is comprised of a layer of water-

immiscible liquid propellant, a layer of highly

aqueous product concentrate, and the vapor phase.

Emulsion or suspension

Ⅳ The Aerosol principle

An aerosol formulation consists of two component

parts, the product concentrate and the propellant.

1 The product concentrate is the active ingredient of

the aerosol combined with the required adjuncts,

such as antioxidants, surface-active agents, and

solvents, to prepare a stable and efficacious product.

2 the propellant

When the propellant is a liquefied gas or a mixture

of liquefied gases, it frequently serves the dual role

of propellant and solvent or vehicle for the product

concentrate.

In certain aerosol systems, no liquefied compressed

gases, as carbon dioxide, nitrogen, and nitrous

oxide, are employed as the propellant.

Chlorofluorocarbons (CFCs).

The most used propellant in aerosol products

However these propellants are being phased out and

will be prohibited due to scientific recognition that

they reduce the amount of ozone in the stratosphere,

which results in an increase in the amount of

ultraviolet radiation reaching the earth, an increase

in the incidence of skin cancer, and other adverse

environmental effects.

Among the chlorofluorocarbons used as propellants

in pharmaceuticals are

dichlorodifluoromethane,

dichlorotetrafluoroethane,

trichloromonofluoromethane.

How to determine the vapor pressure of a

certain mixture?

Example 1:What is a vapor pressure of a 60:40 mixture of propane and isobutane. Information on two propellants is as follows:

Property propane isobutane

Molecular formula C3H8 C4H10

Molecular weight 44.1 58.1

Boiling point(℉ ) -43.7 10.9

Vapor pressure(psig@70℉ ) 110 30.4

Liquid density(g/ml @70℉ ) 0.50 0.56

Flash point(℉ ) -156 -117

Assume an ideal solution.

For Raoult’s law, we need to determine the number

of moles of each propellants:

36.11.44

60propanen

69.01.58

40tan eisobun

From Raoult’s law, the partial pressure exerted by

the propane is:

psi

Pnn

nP

propane

eisobupropane

propanepropane

98.7211069.036.1

36.1

tan

The partial pressure exerted by the isobutane is:

psi

Pnn

nP

eisobu

eisobupropane

eisobueisobu

23.104.3069.036.1

69.0

tan

tan

tantan

The vapor pressure exerted by both gases, PT,

is: PT=72.98+10.23=83.21psi at 70℉

The vapor pressure required for a specific

application can be calculated in a similar

manner and different ratios of propellants

may be used to obtain that pressure.

Dalton’s law

Ⅴ Pressurized containers

Various materials have been used in the

manufacture of aerosol containers, including

(1)glass, uncoated or plastic coated;

(2)metal, including tin-plated steel, aluminum, and

stainless steel;

(3)plastics

The selection of the container for an aerosol product is

based on

its adaptability to production methods

compatibility with formulation components

ability to sustain the pressure intended for the product

the interest in design

aesthetic appeal on the part of the manufacturer

cost

Ⅵ Valve assembly

The function of the valve assembly is to permit the

expulsion of the contents of the can in the desired

form, at the desired rate, and, in the case of metered

valves, in the proper amount or dose.

Among the materials used in the manufacture of the

various valve parts are plastic, rubber, aluminum,

and stainless steel.

the button that the user presses to activate the valve assembly for the emission of the product

supports the actuator and delivers the formulation in the proper form to the chamber of the actuator

prevent leakage of the formulation when the valve is in the closed position.

the mechanism by which the actuator retracts when pressure is released, thereby returning the valve to the closed position

hold the valve in place

the link between the dip tube and the stem and actuator

bring the formulation from the container to the valve

Metered Dose Inhalers (MDIs)

Ⅶ Filling Operations

COLD FILLING

PRESSURE

FILLING

COLD FILLING

both the product concentrate and the propellant

must be cooled to temperatures of -30℉to -40℉

the chilled product concentrate is quantitatively

metered into an equally cold aerosol container

the liquefied gas is added, the heavy vapors of the

cold liquid propellant generally displace the air

present in the container

When sufficient propellant has been added, the valve

assembly is immediately inserted and crimped into

place

Notice:

because of the low temperatures required, aqueous

systems cannot be filled by this process, since the

water turns to ice.

in the process, some of the propellant vapors are also

lost

PRESSURE FILLING

the product concentrate is quantitatively placed in

the aerosol container

the valve assembly is inserted and crimped into

place

the liquefied gas, under pressure, is metered into

the valve stem from a pressure burette

Pressure filling is used for most pharmaceutical

aerosols.

It has the advantage over the cold filling

method in that there is less danger of moisture

contamination of the product, and also less

propellant is lost in the process.

Ⅷ Testing the Filled Containers

The aerosol container is tested under various

environmental conditions for leaks or weakness in

the valve assembly or container.

The valve discharge rate is determined by

discharging a portion of the contents of a previously

weighed aerosol during a given period of time, and

calculating.

Aerosols may be tested:

for their spray patterns

for particle size distribution of the spray: most

5μm, must be smaller than 10μm.

for accuracy and reproducibility of dosage when

using metered valves.

Section 2: Sprays

Sprays may be defined as aqueous or oleaginous

solutions in the form of coarse droplets or as finely

divided solids to be applied topically, most usually to

the nasal-pharyngeal tract or to the skin.

For example: medicinal atomizers, which are

employed for the issuance of a medicated solution to

the patient in the form of fine droplets

Section 3: Inhalations Inhalations are drugs or solutions of drugs

administered by the nasal or oral respiratory route.

The drugs may be administered for their local action

on the bronchial tree or for their systemic effects

through absorption from the lungs.

A unique form of powder administration involves the

inhalation of a micronized powder directly into the

lungs using a special breath-activated device

1 Capsule: drug depository

2 Spring stem

3 Fanlike propellant

4 Inhalant

5 Stainless steel spring section

Glossary

Aerosols; sprays; inhalations;

Pressurized container, valve assembly; propellant;

Two-phase systems; three-phase systems;

Ingredient; solvent or vehicle ;

Chlorofluorocarbons (CFCs);

Metered dose inhalers ;

Cold filling ; pressure filling

Problems:

1 What is aerosols, sprays and inhalations?

2 Please briefly describe the influencing factors of aerosols absorption.

3 Please briefly describe the advantages and disadvantages of aerosols.

4 Which are the constituents of aerosols?

5 Please briefly describe the quality request of aerosols.

6 What is the function of propellants?