PROPELLANTS PROPELLANTS BY BY MADHU BURRA (M PHARM II- SEM) (M PHARM II- SEM) DEPARTMENT OF INDUSTRIAL PHARMACY DEPARTMENT OF INDUSTRIAL PHARMACY UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES KAKATIYA UNIVERSITY, KAKATIYA UNIVERSITY, WARANGAL - 506009 WARANGAL - 506009
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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
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.
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)
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
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