PROPELLANTS

PROPELLANTSBYMADHU BURRA(M PHARM II- SEM)

DEPARTMENT OF INDUSTRIAL PHARMACYUNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCESKAKATIYA UNIVERSITY,WARANGAL - 506009

CONTENTSINTRODUCTIONCLASSIFICATIONLIQUEFIED GASESCOMPRESSED GASESNOMECLATUREDESTRUCTION OF OZONECONCLUSIONREFERENCES

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 AerosolPropellantContainerValve and actuatorProduct concentrate

PROPELLANTSThe propellant is generally regarded as the heart of the aerosol package. It is responsible for development of pressure within the container, supplying the necessary force to expel the product when the valve is opened. The propellant also acts as a solvent and as a diluent and has much to do with determing the characteristics of the product as it leaves the container.

CLASSIFICATIONLiquefied gasesChlorofluorocarbons (CFCs)Hydro chlorofluorocarbons (HCFCs)Hydro fluorocarbons (HFCs)HydrocarbonsCompressed gasesNitrogen (N2)Nitrous oxide (N2O)Carbon dioxide (CO2)

Liquefied - gasesLiquefied 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 (CFCS)chlorofluorocarbons (CFCs) 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.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.

NOMENCLATURETo 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.The number of chlorine atoms (for CFCS) 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 PROPERTIESSolubility- Non polar Boiling point- below 240C Density - >1Vapor pressure

VAPOR 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.

ContiThe vapor pressure of a mixture of propellants can be calculated by using Raoults 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 PROPELLANTS

PROPELLANT BLENDCOMPOSITIONVAPOR PRESSURE(psig) 700FDENSITY(g/ml)700F12/1112/1112/11412/11412/11412/11450:5060:4070:3040:6045:5555:4537.444.156.139.842.848.41.4121.3961.3681.4121.4051.390

PROPERTIES OF CHLOROFLUOROCARBONS (CFCS)

PROPERTY TRICHLORO MONOFLUORO METHANEDICHLORO DIFLUORO METHANE DICHLORO TETRA FLUORO METHANEMolecular 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 PROPERTIESHydrolysisReaction with alcohol- All propellants except propellants 11 are stable in presence of alcohol.

Advantages

Lack of inhalation toxicityLack of flammability and explosivenessHigh chemical stability except P- 11High purity

Disadvantages

Destructive to atmospheric OzoneContribute to greenhouse effect High cost

Destruction 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.

ContiCFCl3 + h 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.

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

Ozone hole in September 2006Largest hole in the record.~Size of North America September 16 is "World Ozone Day"

Consequences of Ozone depletionSince the ozone layer absorbs UVB ultraviolet light from the Sun, ozone layer depletion is expected to increase surface UVB levels.Possible linked to higher incidence of skin cancer.Lead to decrease of crop yield.

HYDROCARBONSThese 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.

ContiThey 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 BLENDS

Flammable componentNon flammable below this concentration (wt %)Propellant 142Propellant 152Dimethyl etherHydrocarbons702495-6

PROPERTIES OF HYDROCARBONS AND ETHERS

PROPERTYPROPANEISOBUTANEN-BUTANEDIMEHTYL ETHERMolecular formulaMolecular weightBoiling point(0F)Vapor pressure (psig at 700F )Liquid density (gm/ml)Flash point(0F)

C3H8

44.1

-43.7110.0

0.50

-156C4H10

58.1

10.930.4

0.56

-117C4H10

58.1

31.116.5

0.58

-101CH3OCH3

46.1

-1363.0

0.66

--

Advantages Inexpensive Minimal ozone depletion Negligible greenhouse effect Excellent solvents Non toxic and non reactive

Disadvantages

Flammable

AftertasteUnknown toxicity following inhalationLow liquid density

HYDROCHLOROFLUOROCARBONS AND HYDROFLUOROALKANESSeveral new liquefied gas materials have been developed to replace the CFCS as propellants.Propellant 134a and propellant 227 have been developed as a substitutes for propellant 12 in MDIs 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..The HFCS 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 HYDROFLUOROCARBONS (HFCS)

PROPERTY TETRAFLUORO ETHANEHEPTAFLUORO PROPANEMolecular 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

CF3CHFCF3227170

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

0.058Non flammable

PROPERTIES OF HYDROCHLOROFLUOROCARBONS

PROPERTYDIFLUORO ETHANEMolecular formulaNumerical designationMolecular weightBoiling point (1 atm)

Vapor pressure (psia)

Liquid density (g/ml)

Solubility in water (wt %)

0F0C700F1300F700F

770FCH3CHF2152a66.1-12.0-11.063.0176.30.91