PROPELLANTSPROPELLANTS

BYBYMADHU BURRA

(M PHARM II- SEM)(M PHARM II- SEM)

DEPARTMENT OF INDUSTRIAL PHARMACYDEPARTMENT OF INDUSTRIAL PHARMACYUNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCESUNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES

KAKATIYA UNIVERSITY,KAKATIYA UNIVERSITY,WARANGAL - 506009WARANGAL - 506009

CONTENTSCONTENTS

INTRODUCTIONINTRODUCTION CLASSIFICATIONCLASSIFICATION

– LIQUEFIED GASESLIQUEFIED GASES– COMPRESSED GASESCOMPRESSED GASES

NOMECLATURENOMECLATURE DESTRUCTION OF OZONEDESTRUCTION OF OZONE CONCLUSIONCONCLUSION REFERENCESREFERENCES

Pharmaceutical aerosols are defined as “ products containing therapeutically active ingredients dissolved, suspended, or emulsified in a propellant or a mixture of solvent and propellant, intended for

topical administration, for administration into the body cavities, intended for administration orally or nasally as fine solid particles or liquid mists via the respiratory system”.

INTRODUCTION

Components of an AerosolComponents of an Aerosol

PropellantPropellant ContainerContainer Valve and actuatorValve and actuator Product concentrateProduct concentrate

PROPELLANTS

The propellant is generally regarded as The propellant is generally regarded as the heart of the aerosol package. It is the heart of the aerosol package. It is responsible for development of responsible for development of pressure within the container, supplying pressure within the container, supplying the necessary force to expel the product the necessary force to expel the product

when the valve is openedwhen the valve is opened. . The propellant also acts as a The propellant also acts as a solventsolvent and and

as a as a diluentdiluent and has much to do with and has much to do with determing the characteristics of the determing the characteristics of the product as it leaves the container.product as it leaves the container.

CLASSIFICATIONCLASSIFICATION

Liquefied gasesLiquefied gases Chlorofluorocarbons (CFC’s)Chlorofluorocarbons (CFC’s) Hydro chlorofluorocarbons (HCFC’s)Hydro chlorofluorocarbons (HCFC’s) Hydro fluorocarbons (HFC’s)Hydro fluorocarbons (HFC’s) HydrocarbonsHydrocarbons

Compressed gasesCompressed gases Nitrogen (NNitrogen (N22)) Nitrous oxide (NNitrous oxide (N22O)O) Carbon dioxide (COCarbon dioxide (CO22))

Liquefied - gasesLiquefied - gases

Liquefied gases have been widely used as propellants for most aerosol products.Since they are gases at room temperature and atmospheric pressure. However, they can liquefied easily by lowering the temperature or by increasing the pressure.When a liquefied gas propellant is placed into a sealed container, it immediately separates into a liquid and a vapor phase.The pressure exerted against the liquid phase is sufficient to push the latter up a dip tube and against the valve.When the valve is opened, the liquid phase is emitted i.e., the pressure with in the container is decreased. Immediately a sufficient number of molecules change from liquid state to the vapor state and restore the original pressure

CHLOROFLUOROCARBONS CHLOROFLUOROCARBONS (CFC’S)(CFC’S) chlorofluorocarbons (CFC’s) are

inert, non toxic, non-inflammable used for oral and inhalation aerosols.

Among the Chlorofluorocarbons trichlorofluoromethane (Propellant 11), dichlorodifluoromethane (Propellant 12) and dichlorotetrafluoroethane (Propellant 114) were initially widely used in pharmaceutical aerosols.

Liquefied gases provide a nearly constant pressure during packaging operation and have large expansion ratio.

Conti….Conti….

Several of the fluorinated hydrocarbons have an expansion ratio of about 240 , that is 1 ml of liquefied gas will occupy a volume of app. 240 ml if allowed to vaporize.

These compounds have been implicated in causing a depletion of the ozone layer and for responsibility for the global warming effect .

In 1974, the EPA, FDA, and CPSC announced a ban on the use of CFCs, namely propellants 11, 12, and 114, in most aerosol products. Certain pharmaceutical aerosols for inhalation use (MDIs) were exempted from this ban.

NOMENCLATURENOMENCLATURE

To refer easily to the Fluorinated hydrocarbons a relatively simple system of nomenclature was developed by the “American Society of Refrigerating Engineers” in 1957.

According to this all propellants are designated by three digits(000).

The first digit is one less than the number of carbon atoms in the compound (C-1).

The second digit is one more than the number of hydrogen atoms in the compound (H+1).

The last digit represents the number of fluorine atoms (F).

Conti….Conti….

The number of chlorine atoms (for CFC’S) in the compound is found by subtracting the sum of the fluorine and the hydrogen atoms from the total number of atoms that can be added to saturate the carbon chain.

In the case of isomers , the letter a,b,c ,etc follows the number.Examples :

PHYSICAL PROPERTIESPHYSICAL PROPERTIES

Solubility- Non polar Boiling point- below 240C Density - >1 Vapor pressure

VAPOR PRESSUREVAPOR PRESSURE

It is defined as the pressure exerted by a liquid in equilibrium with its vapor.

It is dependent on temperature and is independent of quantity. i.e. the vapor pressure of a pure material is the same for 1 g or 1 ton of the compound.

The vapor pressure ranges from about 13.4 psia for propellant 11 to about 85 psia for propellant 12.

Vapor pressure between these values may be obtained by blending propellant 11 with propellant 12 and propellant 12 with propellant 114.

Conti…Conti…

The vapor pressure of a mixture of propellants can be calculated by using Raoult’s law.

Pa = [na/na+nb] POa

Pb =[nb/na+nb] Pob

Where Pa and Pb are partial pressures of components a and b,

na and nb are mole fraction of a and b,

POa and Pob are the vapor pressure of pure

compound

BLENDS OF CHLOROFLUOROCARBON BLENDS OF CHLOROFLUOROCARBON PROPELLANTSPROPELLANTS

PROPELLANT BLEND

COMPOSITION

VAPOR PRESSURE(psig) 700F

DENSITY(g/ml)700F

12/1112/11

12/1112/11

12/11412/114

12/11412/114

12/11412/114

12/11412/114

50:5050:50

60:4060:40

70:3070:30

40:6040:60

45:5545:55

55:4555:45

37.437.4

44.144.1

56.156.1

39.839.8

42.842.8

48.448.4

1.4121.412

1.3961.396

1.3681.368

1.4121.412

1.4051.405

1.3901.390

PROPERTIES OF PROPERTIES OF CHLOROFLUOROCARBONS (CFC’S)CHLOROFLUOROCARBONS (CFC’S)

PROPERTY TRICHLORO MONOFLUORO METHANE

DICHLORO DIFLUORO METHANE

DICHLORO TETRA FLUORO METHANE

Molecular formulaNumerical designationMolecular weightBoiling point(1atm)Vapor pressure(psia)Liquid density (gm/ml)

Solubility in water (wt %)

0F0C700F1300C700C1300F770F

CCl3F

11

137.2874.723.713.439.01.4851.4030.11

CCl2F2

12

120.93-21.6-29.884.9196.01.3251.1910.028

CClF2CClF2

114

170.9338.393.5527.673.51.4681.3600.013

CHEMICAL PROPERTIESCHEMICAL PROPERTIES

HydrolysisHydrolysis Reaction with alcohol- All Reaction with alcohol- All

propellants except propellants 11 propellants except propellants 11 are stable in presence of alcohol.are stable in presence of alcohol.

AdvantagesAdvantages

Lack of inhalation toxicityLack of inhalation toxicity Lack of flammability and Lack of flammability and

explosivenessexplosiveness High chemical stability except P- High chemical stability except P-

1111 High purityHigh purity

DisadvantagesDisadvantages

Destructive to atmospheric Destructive to atmospheric OzoneOzone

Contribute to “greenhouse effect”Contribute to “greenhouse effect” High costHigh cost

Destruction of OzoneDestruction of Ozone

Ozone can be destroyed by a number of free radical catalysts, the most important of which are the atomic chlorine (Cl·), hydroxyl radical (OH·), the nitric oxide radical (NO·) and bromine (Br·).

Chlorine is found in certain stable organic compounds, especially chlorofluorocarbons (CFCs), which may find their way to the stratosphere without being destroyed in the troposphere due to low reactivity. Once in the stratosphere, the Cl atoms are liberated from the parent compounds by the action of ultraviolet light, and can destroy ozone molecules through a variety of catalytic cycles.

Conti…Conti…

CFCl3 + hν → CFCl2 + Cl

Cl + O3 → ClO + O2

ClO + O → Cl + O2

In sum O3 + O → O2 + O2

=>Increase rate of recombination of oxygen, leading to an overall decrease in the amount of ozone.

Conti…Conti…

It is calculated that a CFC molecule It is calculated that a CFC molecule takes an average of 15 years to go takes an average of 15 years to go from the ground level up to the upper from the ground level up to the upper atmosphere, and it can stay there for atmosphere, and it can stay there for about a century, destroying up to about a century, destroying up to 100,000 ozone molecules during that 100,000 ozone molecules during that time.time.

Ozone hole in September 2006Ozone hole in September 2006

“Largest hole in the record.”~Size of North America

September 16 is "World Ozone Day"

Consequences of Ozone Consequences of Ozone depletiondepletion

Since the ozone layer absorbs Since the ozone layer absorbs UVB ultraviolet light from the Sun, UVB ultraviolet light from the Sun, ozone layer depletion is expected ozone layer depletion is expected to increase surface UVB levels.to increase surface UVB levels.

Possible linked to higher Possible linked to higher incidence of skin cancer.incidence of skin cancer.

Lead to decrease of crop yield.Lead to decrease of crop yield.

HYDROCARBONSHYDROCARBONS

These are used in topical pharmaceutical aerosols.

They are preferred for use as a propellant over the fluorinated hydrocarbon based on their environmental acceptance and their lesser cost. However , they are flammable and explosive.

Propane, butane and isobutane are generally used as propellants.

Conti…Conti…

They can be blended with one another and with the fluorocarbons to obtain the desired vapor pressure and or density.

Since they are flammable, they can be blended with propellant 22,which is not flammable, to produce a non flammable product or one with less flammability than the hydrocarbon propellants.

Propellant 142 and 152 can also be used to reduce the flammability of the overall propellant blend and the product.

FLAMMABILITY OF PROPELLANT 22 FLAMMABILITY OF PROPELLANT 22 BLENDSBLENDS

Flammable Flammable componentcomponent

Non flammable Non flammable below this below this concentration (wt concentration (wt %)%)

Propellant 142Propellant 142

Propellant 152Propellant 152

Dimethyl etherDimethyl ether

HydrocarbonsHydrocarbons

7070

2424

99

5-65-6

PROPERTIES OF HYDROCARBONS AND PROPERTIES OF HYDROCARBONS AND ETHERSETHERS

PROPERTY PROPANE ISOBUTANE

N-BUTANE

DIMEHTYL ETHER

Molecular formulaMolecular weightBoiling point(0F)Vapor pressure (psig at 700F )Liquid density (gm/ml)Flash point(0F)

C3H8

44.1

-43.7110.0

0.50

-156

C4H10

58.1

10.930.4

0.56

-117

C4H10

58.1

31.116.5

0.58

-101

CH3OCH3

46.1

-1363.0

0.66

--

AdvantagesAdvantages InexpensiveInexpensive Minimal ozone depletionMinimal ozone depletion Negligible “greenhouse effect”Negligible “greenhouse effect” Excellent solventsExcellent solvents Non toxic and non reactiveNon toxic and non reactive

DisadvantagesDisadvantages

FlammableFlammable AftertasteAftertaste Unknown toxicity following inhalationUnknown toxicity following inhalation Low liquid densityLow liquid density

HYDROCHLOROFLUOROCARBONS HYDROCHLOROFLUOROCARBONS AND HYDROFLUOROALKANESAND HYDROFLUOROALKANES

Several new liquefied gas materials have been developed to replace the CFC’S as propellants.

Propellant 134a and propellant 227 have been developed as a substitutes for propellant 12 in MDI’s and have survived many of the short and long term toxicities.

To date , no suitable replacement has been found for propellants 11 and 114. propellant 11 is used to form a slurry with the active ingredient and dispensing agent. This is impossible to accomplish with propellants 134a and P-227

Conti..Conti..

The HFC’S are extremely poor solvents and will not dissolve a sufficient amount of the currently used FDA-approved surfactants (oleic acid, sorbitan, trioleate, and Soya lecithin).

HFC propellants are not compatible with some of the currently used valves.

The gaskets and sealing compounds used in

MDI valves may present compatibility problems to the formulator.

PROPERTIES OF PROPERTIES OF HYDROFLUOROCARBONS (HFC’S)HYDROFLUOROCARBONS (HFC’S)

PROPERTY TETRAFLUORO ETHANE

HEPTAFLUORO PROPANE

Molecular formulaNumerical designationMolecular weight

Boiling point(1atm)

Vapor pressure(psia)

Liquid density (gm/ml)

Solubility in waterFlammability

0F0C700F1300C21.10

% W/W

CF3CH2F134a102

-15.0-26.271.1198.71.22

0.150Non flammable

CF3CHFCF3

227170

-3.2-16.543 at (200)---1.41

0.058Non flammable

PROPERTIES OF PROPERTIES OF HYDROCHLOROFLUOROCARBONSHYDROCHLOROFLUOROCARBONS

PROPERTY DIFLUORO ETHANE

Molecular formulaNumerical designationMolecular weightBoiling point (1 atm)

Vapor pressure (psia)

Liquid density (g/ml)

Solubility in water (wt %)

0F0C700F1300F700F

770F

CH3CHF2152a66.1-12.0-11.063.0176.30.91

<1.0

AdvantagesAdvantages

Low inhalation toxicityLow inhalation toxicity High chemical stabilityHigh chemical stability High purityHigh purity Not ozone depletingNot ozone depleting

DisadvantagesDisadvantages

Poor solventsPoor solvents Minor “greenhouse effect”Minor “greenhouse effect” High costHigh cost

COMPRESSED GASESCOMPRESSED GASES

The compressed gases such as nitrogen , nitrous oxide and carbon dioxide have been used as aerosol propellants. Depending on the nature of the formulation and the type of compressed gas used, the product can be dispensed as a fine mist, foam, or semisolid.

However , unlike the liquefied gases, the compressed gases possess little expansion ratio (3-10 times) and will produce a fairly wet spray and foams that are not as stable as liquefied gas foams.

Conti..Conti..

This system has been used for the most part to dispense food products and for nonfoods, to dispense the product in its original form as a semisolid.

Compressed gases have been used in products such as dental creams, hair preparations , ointments, and aqueous anti septic and germicidal aerosols and are extremely useful in contact lens cleaner saline solution and barrier systems.

PROPERTIES OF COMPRESSED PROPERTIES OF COMPRESSED GASESGASESPROPERTY CARBON

DIOXIDENITROUS OXIDE

NITROGEN

Molecular formulaMolecular weightBoiling point(0F)

Vapor pressure (psia, 700F)

Solubility in water, 770F

Density (gas) gm/ml

CO244

-109

852

0.7

1.53

N2O44

-127

735

0.5

1.53

N228

-320

492

0.014

0.96699

AdvantagesAdvantages

Low inhalation toxicityLow inhalation toxicity High chemical stabilityHigh chemical stability High purityHigh purity InexpensiveInexpensive No environmental problemsNo environmental problems

DisadvantagesDisadvantages

Require use of a nonvolatile co-Require use of a nonvolatile co-solventsolvent

Produce course droplet spraysProduce course droplet sprays Pressure falls during usePressure falls during use

CONCLUSIONCONCLUSION

The stage has been set so that use of the The stage has been set so that use of the fluorocarbons is severely limited and their fluorocarbons is severely limited and their use will become increasingly prohibitive.use will become increasingly prohibitive.

Hydrofluoroalkanes provide a safe Hydrofluoroalkanes provide a safe alternative to CFC’S as propellants in alternative to CFC’S as propellants in aerosols, but their physicochemical aerosols, but their physicochemical properties have required extensive properties have required extensive redevelopment of the entire product.redevelopment of the entire product.

Hydrofluoroalkanes are not environmentally Hydrofluoroalkanes are not environmentally neutral and contribute to hydrocarbon neutral and contribute to hydrocarbon emissions, global warming and acid rain.emissions, global warming and acid rain.

References

1)1) Ansel’s, “ pharmaceutical dosage forms Ansel’s, “ pharmaceutical dosage forms and drug delivery systems”, 8and drug delivery systems”, 8thth edition edition

2)2) Remington , " The science and practice of Remington , " The science and practice of pharmacy “ , 21pharmacy “ , 21stst edition edition

3)3) Leon. Lachman, “The Theory and Practice Leon. Lachman, “The Theory and Practice of Industrial Pharmacy”, 3of Industrial Pharmacy”, 3rdrd edition edition

4)4) Gilbert S.Banker, “ pharmaceutical dosage Gilbert S.Banker, “ pharmaceutical dosage forms” disperse systems; volume 2; 2forms” disperse systems; volume 2; 2ndnd editionedition

5)5) Bentley, “ Text book of pharmaceutics”, 8Bentley, “ Text book of pharmaceutics”, 8thth editionedition

6)6) ““Indian Pharmacopoeia”, 2007, Vol-2Indian Pharmacopoeia”, 2007, Vol-27) www.sciencedirectory.com8) www.wikipedia.com9)9) www.appspharmaceutica.comwww.appspharmaceutica.com