Pharmaceutical Aerosols: Propellants and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Pharmaceutical Aerosols

The propellant generally is regarded as the heart of the aerosol package. In addition to supplying the necessary force to expel the product, the propellant must also act as a solvent and diluent and has much to do with determining the characteristics of the product as it leaves the container. Various chemical compounds have been used as aerosol propellants. Compounds useful as propellants can be classified as the following:

• Liquefied gases
• Chlorofluorocarbons (CFC)
• Hydrochlorofluorocarbons (HCFC)
• Hydrofluorocarbons (HFC) or Hydrofluoroalkaines (HFA)
• Hydrocarbons (HC)
• Hydrocarbon ethers
• Compressed gases

1. Liquefied gases – The liquefied-gas compounds have widespread use as propellants, since they are extremely effective in dispersing the active ingredients into a fine mist or foam, depending on the form desired. In addition, they are relatively inert and non-toxic. They have the added advantage that the pressure within the container remains constant. Two types of liquefied gases are used. The chlorofluorocarbons (CFCs) and hydrofluorocarbons (HFCs) find greater use since they are nonflammable in contrast to the flammable hydrocarbons. The hydrocarbons are advantageous since they are less expensive than any of the fluorocarbons and generally are environmentally acceptable.

2. Chlorofluorocarbons (CFCs) – These compounds have been implicated in causing a depletion of the ozone layer and for responsibility for the greenhouse or for the global warming effect (increase in earth’s temperature, rising sea levels, and altered rainfall patterns). Depletion of the ozone layer is also alleged to have resulted in an increase in the incidence of skin cancer. This is due to a greater penetration of the ozone layer by the skin cancer-causing UV radiation from the sun (the ozone layer will prevent these rays from penetrating the earth’s atmosphere).

While MDIs are currently being formulated with a HFC propellant in place of the CFC, only two drug entities have received FDA approval for marketing in the US. These include albuterol and beclomethosone propionate. In contrast to Europe and the rest of the world, almost every CFC metereddose inhaler has been replaced with a HFC propellant.

Nomenclature: To refer easily to the fluorinated hydrocarbons, a relatively simple system of nomenclature was developed some time ago by the refrigeration industry. A numerical designation is used to identify each propellant.

• All propellants are designated by three digits (000). When the first digit is zero, the propellant is designated by the last two digits, and zero is assumed to be the first digit (e.g., Propellant 011 is Propellant 11).
• The first digit is one fewer than the number of carbon atoms in the compound. When there are only two digits, (0) is understood to be the first digit and indicates a methane derivative. When this first digit is (1), the propellant is an ethane derivative; when (2), it is propane; and when (3), it is a butane derivative.
• The second digit is one more than the number of hydrogen atoms in the compound.
• The last digit represents the number of fluorine atoms.
• 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, each has the same number, and the most symmetrical one is indicated by the number alone. As the isomers become more and more asymmetrical, the letter a, b, c, etc., follows the number.
• For cyclic compounds, a C is used before the number. The use of this system can be exemplified as follows: CFC 114–Dichlorotetrafluoroethane.
• Propellant 114 is an ethane derivative, has no hydrogens, and contains 4 fluorine atoms.
• Since 6 atoms are required to saturate the carbon chain, of necessity there must be 2 chlorine atoms. These can be arranged in two different ways; however, since there is no letter following the numerical designation, the symmetrical structure refers to Propellant 114.

Physical properties:

Table 1 – Properties of fluorocarbons (CFCs)

Chemical properties: The fluorinated hydrocarbons have been widely used as aerosol propellants because they generally are considered to be chemically inert. From the standpoint of formulation, the only chemical property that need be considered is hydrolysis, in regard to Propellant 11. While addition of fluorine to a carbon atom generally increases stability, a propellant such as trichloromonofluoromethane may undergo hydrolysis with the formation of hydrochloric acid. Propellant 11 is not used with aqueous products, as hydrolysis will occur; Propellant 114 generally is used instead. For topical and cosmetic aerosols, hydrocarbons or hydrochlorofluorocarbons are used (Propellants 152b or DME). Propellants 134a and 227 have properties similar to those of P-12 except for their solubility characteristics.

3.Hydrocarbons – Hydrocarbon propellants have replaced CFCs for topical pharmaceutical aerosols. Their low-order toxicity makes them suitable, while their flammability tends to limit their use. With the development of newer types of dispensing valves, the flammability hazard has been reduced considerably. The advantage of hydrocarbons is their greater range of solubility and a lower cost than CFCs. To date they represent a readily available replacement for CFCs as propellants, provided that the flammability hazard can be reduced. The HFC propellant used for MDIs is also applicable to topical aerosol pharmaceuticals, with the added advantage of non-flammability. In addition to having the proper vapor pressure, hydrocarbons have other properties that make them useful as propellants. Their density of less than 1 and their immiscibility with water make them useful in the formulation of three-phase (two-layer) aerosols. Being lighter than water, the hydrocarbon remains on top of the aqueous layer and serves to push the contents out of the container. Not being halogenated, hydrocarbons generally possess better solubility characteristics than the fluorinated hydrocarbons.

Table 2 – Commonly used hydrocarbon blends

4.Alternative propellants (HCFCs and HFCs) – Many pharmaceutical aerosols were developed originally using chlorofluorocarbons (CFCs) 11, 12, and 114. These propellants have found widespread use because of their inertness, nonflammability, and non-toxicity. Unfortunately, the CFCs have been implicated in depleting the ozone layer, and their use as aerosol propellants has practically been eliminated, except for exempted medical uses, which included MDIs. Topical pharmaceutical aerosols have been successfully reformulated with Propellants 152a, DME, hydrocarbons, and compressed gases. Suitable valves are available that, together with modifications in formulation and propellant blends, produce topical aerosol pharmaceuticals that are satisfactory and acceptable. Several new liquefied-gas materials have been developed to replace the CFCs as refrigerants and foaming agents and in other non-pharmaceutical uses. Propellant 134a and Propellant 227 have been developed as substitutes for Propellant 12 in MDIs and have survived many of the short- and long-term toxicity studies.

5. 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 valve design, the product can be dispensed as a fine mist, foam, or semisolid. However, unlike the liquefied gases, the compressed gases possess little, if any, expansion power and will produce a fairly wet spray and foams that are not as stable as liquefied-gas foams. This system has been used for the most part to dispense food products and, for non-foods, 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 antiseptic and germicidal aerosols and are extremely useful in contact lens cleaner saline solution and barrier systems.

Multiple choice questions:

1.The propellant generally is regarded as the heart of the aerosol package.

a)true

b)false

2.Compounds useful as propellants can be classified as

a)Hydrocarbons (HC)

b)Hydrocarbon ethers

c)Compressed gases

d)All of these

3.The liquefied-gas compounds have widespread use as propellants, since they are extremely effective in dispersing the active ingredients into a fine mist or foam, depending on the form desired.

a)true

b)false

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

a)Liquefied gases

b)Chlorofluorocarbons (CFC)

c)Compressed gases

d)All of these

5.While MDIs are currently being formulated with a HFC propellant in place of the CFC, only two drug entities have received FDA approval for marketing in the US. These include

a)albuterol

b)beclomethosone propionate

c)none of these

d)a and b

6.Propellant 114 is

a)methane derivative

b)ethane derivative

c)propane derivative

d)butane derivative

7.Molecular formula of Trichloromono-fluoromethane is

a)CCl3F

b)CCl2F2

c)CClF2CClF2

d)None of these

8.Molecular formula of Dichlorodi- fluoromethane is

a)CCl3F

b)CCl2F2

c)CClF2CClF2

d)None of these

9.Molecular formula of Dichlorotetra-fluoroethane is

a)CCl3F

b)CCl2F2

c)CClF2CClF2

d)None of these

10.Numerical designation for Dichlorotetra-fluoroethane is

a)11

b)12

c)114

d)116

11.For topical and cosmetic aerosols which of the following propellants are used?

a)hydrocarbons

b)hydrochlorofluorocarbons

c)both of these

d)none of these

12.Hydrocarbon propellants have replaced ____ for topical pharmaceutical aerosols.

a)Liquefied gases

b)Chlorofluorocarbons (CFC)

c)Compressed gases

d)Hydrocarbon ethers

13.The advantage of hydrocarbons is

a)greater range of solubility

b)lower cost

c)both of these

d)none of these

14.Alternative propellants are

a)HCFCs

b)HFCs

c)CFCs

d)a and b

15.The compressed gases used as aerosol propellants are

a)nitrogen

b)nitrous oxide

c)carbon dioxide

d)all of these

Solutions:

1. a)true
2. d)All of these
3. a)true
4. b)Chlorofluorocarbons (CFC)
5. d)a and b
6. b)ethane derivative
7. a)CCl3F
8. b)CCl2F2
9. c)CClF2CClF2
10. c)114
11. c)both of these
12. b)Chlorofluorocarbons (CFC)
13. c)both of these
14. d)a and b
15. d)all of these

References:

1. Remington Essential of Pharmaceutics, 1st edition 2013, page no. 639-642.

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