PROPELLANTS

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

2. CONTENTS • INTRODUCTION • CLASSIFICATION • LIQUEFIED GASES • COMPRESSED GASES • NOMECLATURE • DESTRUCTION OF OZONE • CONCLUSION • REFERENCES

3. INTRODUCTION • 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”.

4. Components of an Aerosol Propellant Container Valve and actuator Product concentrate

5. PROPELLANTS • The 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.

6. CLASSIFICATION • Liquefied gases • Chlorofluorocarbons (CFC’s) • Hydro chlorofluorocarbons (HCFC’s) • Hydro fluorocarbons (HFC’s) • Hydrocarbons • Compressed gases • Nitrogen (N2) • Nitrous oxide (N2O) • Carbon dioxide (CO2)

7. Liquefied - 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

8. CHLOROFLUOROCARBONS (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.

9. 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.

10. NOMENCLATURE • 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).

11. 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 :

12. PHYSICAL PROPERTIES • Solubility- Non polar • Boiling point- below 240C • Density - >1 • Vapor pressure

13. 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.

14. 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

15. BLENDS OF CHLOROFLUOROCARBON PROPELLANTS

16. PROPERTIES OF CHLOROFLUOROCARBONS (CFC’S)

17. CHEMICAL PROPERTIES • Hydrolysis • Reaction with alcohol- All propellants except propellants 11 are stable in presence of alcohol.

18. Advantages • Lack of inhalation toxicity • Lack of flammability and explosiveness • High chemical stability except P- 11 • High purity

19. Disadvantages • Destructive to atmospheric Ozone • Contribute to “greenhouse effect” • High cost

20. 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.

21. 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.

22. Conti… • It 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.

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

24. Consequences of Ozone depletion • Since 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.

25. HYDROCARBONS • 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.

26. 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.

27. FLAMMABILITY OF PROPELLANT 22 BLENDS

28. PROPERTIES OF HYDROCARBONS AND ETHERS

29. Advantages • Inexpensive • Minimal ozone depletion • Negligible “greenhouse effect” • Excellent solvents • Non toxic and non reactive

30. Disadvantages • Flammable • Aftertaste • Unknown toxicity following inhalation • Low liquid density

31. HYDROCHLOROFLUOROCARBONS AND 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

32. 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.

33. PROPERTIES OF HYDROFLUOROCARBONS (HFC’S)

34. PROPERTIES OF HYDROCHLOROFLUOROCARBONS

35. Advantages • Low inhalation toxicity • High chemical stability • High purity • Not ozone depleting

36. Disadvantages • Poor solvents • Minor “greenhouse effect” • High cost

37. COMPRESSED 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.

38. 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.

39. PROPERTIES OF COMPRESSED GASES

40. Advantages • Low inhalation toxicity • High chemical stability • High purity • Inexpensive • No environmental problems

41. Disadvantages • Require use of a nonvolatile co-solvent • Produce course droplet sprays • Pressure falls during use

42. CONCLUSION • The stage has been set so that use of the fluorocarbons is severely limited and their use will become increasingly prohibitive. • Hydrofluoroalkanes provide a safe alternative to CFC’S as propellants in aerosols, but their physicochemical properties have required extensive redevelopment of the entire product. • Hydrofluoroalkanes are not environmentally neutral and contribute to hydrocarbon emissions, global warming and acid rain.

43. References • Ansel’s, “ pharmaceutical dosage forms and drug delivery systems”, 8th edition • Remington , " The science and practice of pharmacy “ , 21st edition • Leon. Lachman, “The Theory and Practice of Industrial Pharmacy”, 3rd edition • Gilbert S.Banker, “ pharmaceutical dosage forms” disperse systems; volume 2; 2nd edition • Bentley, “ Text book of pharmaceutics”, 8th edition • “Indian Pharmacopoeia”, 2007, Vol-2 • www.sciencedirectory.com • www.wikipedia.com • www.appspharmaceutica.com

44. THANK YOU