Name: Chlorofluorocarbons (CFC)
CAS No: (a) Dichlorodifluoromethane [75-71-8], (b)1,2-Dichloro-1,1,2,2-tetrafluoroethane [76-14-2], Trichlorofluoromethane [75-69-4]
(a) USP-NF: Dichlorodifluoromethane (b) USP-NF: Dichlorotetrafluoroethane (c) USP-NF: Trichloromonofluoromethane
Arcton; Dymel; Freon; Frigen; Genetron; Halon; Isceon; Isotron.
(a) Dichlorodifluoromethane [75-71-8], (b)1,2-Dichloro-1,1,2,2-tetrafluoroethane [76-14-2], Trichlorofluoromethane [75-69-4]
(a) CCl2F2 120.91, (b) C2Cl2F4 170.92, (c) CCl3F 137.37,
Dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane are chlorofluorocarbon (CFC) aerosol propellants used in pharmaceutical formulations. They are no longer used in metered-dose inhaler (MDI) formulations, with few exceptions for existing MDIs; Dichlorodifluoromethane is used as an aerosol propellant in MDIs, either as the sole propellant or in combination with dichlorotetrafluoroethane, trichloromonofluoromethane, or mixtures of these chlorofluorocarbons. Dichlorodifluoromethane may also be used as a propellant in an aerosolized sterile talc used for intrapleural administration and is also used alone in some MDIs containing a steroid. Dichlorotetrafluoroethane is used in combination with dichlorodifluoromethane, and in several cases with dichlorodifluoromethane and trichloromonofluoromethane, as the propellant in metered-dose oral and nasal aerosols. Trichloromonofluoromethane is used in combination with dichlorodifluoromethane as the propellant in metered-dose inhaler aerosols. It is also used in combination with dichlorotetrafluoroethane and dichlorodifluoromethane. These three propellants have been blended to obtain suitable solubility characteristics for MDIs when formulated as solutions. They will produce suitable vapor pressures so that optimum particle-size distribution as well as suitable respiratory fractions may be achieved. Blends of trichloromonofluoromethane and dichlorodifluoromethane (propellant 11/12) or propellant 11/114/12 produce vapor pressures of 103–484 kPa (15–70 psig) at 258C, which adequately cover the range of pressures required to produce the proper particlesize distribution for satisfactory aerosol products. Trichloromonofluoromethane is unique among the chlorofluorocarbon propellants in that it is a liquid at room temperature and atmospheric pressure, and can be used to prepare a slurry with insoluble medicinal agents
Dichlorodifluoromethane is a liquefied gas and exists as a liquid at room temperature when contained under its own vapor pressure, or as a gas when exposed to room temperature and atmospheric pressure. The liquid is practically odorless and colorless. The gas in high concentrations has a faint etherlike odor. Dichlorodifluoromethane is noncorrosive, nonirritating, and nonflammable. Dichlorotetrafluoroethane is a colorless, nonflammable liquefied gas with a faint, ethereal odor. Trichloromonofluoromethane is a clear, volatile liquid at room temperature and atmospheric pressure. It has a characteristic carbon tetrachloride-like odor and is nonirritating and nonflammable.
See Table I.
See Table II for selected typical properties
Chlorofluorocarbon propellants are nonreactive and stable at temperatures up to 5508C. The liquefied gas is stable when used as a propellant and should be stored in a metal cylinder in a cool, dry place.
The presence of greater than 5% water in solutions that contain trichloromonofluoromethane may lead to hydrolysis of the propellant and the formation of traces of hydrochloric acid, which may be irritant to the skin or cause corrosion of metallic canisters. Trichloromonofluoromethane may also react with aluminum, in the presence of ethanol, to cause corrosion within a cylinder with the formation of hydrogen gas. Similarly, alcohols in the presence of trace amounts of oxygen, peroxides, or other free-radical catalysts may react with trichloromonofluoromethane to form trace quantities of hydrochloric acid. Both dichlorodifluoromethane and dichlorotetrafluoroethane are compatible with most ingredients used in pharmaceutical aerosols. Because of their poor miscibility with water, most MDIs are formulated as suspensions. However, solution MDIs can be prepared through the use of ethanol as a cosolvent for water and propellant, resulting in a clear solution (provided the water content is less than 5%).
Dichlorodifluoromethane is prepared by the reaction of hydrogen fluoride with carbon tetrachloride in the presence of a suitable catalyst, such as polyvalent antimony. The dichlorodifluoromethane formed is further purified to remove all traces of water and hydrochloric acid as well as traces of the starting and intermediate materials. Trichloromonofluoromethane is also obtained by this process. Dichlorotetrafluoroethane is prepared by the reaction of hydrogen fluoride with chlorine and perchloroethylene in the presence of a suitable catalyst such as polyvalent antimony
Dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane have been used for over 50 years as propellants in topical, oral, and nasal aerosol formulations, and are generally regarded as nontoxic and nonirritant materials when used as directed. The propellants used for metered-dose inhalant aerosol products generally vaporize quickly and most of the vapors escape and are not inhaled. However, a small amount of the propellant may be inhaled with the active ingredient and be carried to the respiratory system. These amounts of propellant do not present a toxicological problem and are quickly cleared from the lungs. Deliberate inhalation of excessive quantities of fluorocarbon propellant may result in death, and the following ‘warning’ statements must appear on the label of all aerosols: WARNING: Avoid inhalation. Keep away from eyes or other mucous membranes. (Aerosols designed specifically for oral inhalation need not contain this statement). WARNING: Do not inhale directly; deliberate inhalation of contents can cause death. or WARNING: Use only as directed; intentional misuse by deliberately concentrating and inhaling the contents can be harmful or fatal. Additionally, the label should contain the following information: WARNING: Contents under pressure. Do not puncture or incinerate container. Do not expose to heat or store at room temperature above 1208F (498C). Keep out of the reach of children In the USA, the Environmental Protection Agency (EPA) additionally requires the following information on all aerosols containing chlorofluorocarbons as the propellant: WARNING: Contains a chlorofluorocarbon that may harm the public health and environment by reducing ozone in the upper atmosphere. (Metered-dose inhalers are exempt from this regulation.)
Dichlorodifluoromethane and dichlorotetrafluoroethane are usually encountered as a liquefied gas and appropriate precautions for handling such materials should be taken. Eye protection, gloves, and protective clothing are recommended. These propellants should be handled in a well-ventilated environment. Chlorofluorocarbon vapors are heavier than air and do not support life; therefore, when cleaning large tanks that have contained chlorofluorocarbons, adequate provisions for supply of oxygen in the tanks must be made in order to protect workers cleaning the tanks. Although nonflammable, when heated to decomposition chlorofluorocarbons emit toxic fumes containing phosgene and fluorides. Although not as volatile as dichlorodifluoroethane or dichlorotetrafluoroethane, trichloromonofluoromethane should be handled as indicated above. Since it is a liquid at room temperature, caution should be exercised in handling this material to prevent spillage onto the skin. It is an irritant to the eyes. The long-term workplace exposure limit (8-hour TWA) for dichlorodifluoromethane and dichlorotetrafluoroathane is 7110 mg/m3 (1000 ppm). The short-term workplace exposure limit (15-minute) for both compounds is 8890 mg/m3 (1250 ppm).(1)
Included in the FDA Inactive Ingredients Database (aerosol formulations for inhalation, nasal, oral, and topical applications). With few exceptions for existing MDIs, the FDA and EPA have banned the use of CFCs in the USA after 31st December 2008, with all CFCs to be phased out by 2010–2015. Included in nonparenteral medicines licensed in the UK.
Fluorocarbon (FC) aerosol propellants may be identified by a standardized numbering nomenclature; for example, dichlorodifluoromethane is known as propellant 12, while dichlorotetrafluoroethane is known as propellant 114. Usually, three digits are used to describe the propellant, except when the first digit would be zero, in which case only two digits are used. The first digit is one less than the number of carbon atoms in the molecule. Thus, if the molecule is a methane derivative the first digit would be zero (1 – 1) and is ignored, so that only two digits are used in the propellant description; e.g. propellant 12. For an ethane derivative, the first digit would be a one (2 – 1); e.g. propellant 114. The second digit is one more than the number of hydrogen atoms in the molecule, while the third digit represents the number of fluorine atoms in the molecule. The difference between the sum of the fluorine and hydrogen atoms and the number of atoms required to saturate the carbon chain is the number of chlorine atoms in the molecule. Isomers of a compound have the same identifying number and an additional letter; a, b, c, and so on. Cyclic derivatives are indicated by the letter C before the identifying number. With unsaturated propellants, the number 1 is used as the fourth digit from the right to indicate an unsaturated double bond. Thus for dichlorodifluoromethane (propellant 12): First digit = 0 signifies number of C atoms = 1 Second digit = 1 signifies number of H atoms = 0 Third digit = 2 signifies number of F atoms = 2 Number of Cl atoms = 4 – (2 – 0) = 2 Although not used in new formulations, chlorofluorocarbons may still be present in some commercial products. Under the terms of the Montreal Protocol, aimed at reducing damage to the ozone layer, the use of chlorofluorocarbons, including dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane, has been prohibited from January 1996.(2–6) However, this prohibition does not apply to essential uses such as existing pharmaceutical formulations for which no alternative chlorofluorocarbon-free product is available. The EPA and FDA approved essential-use status for dichlorodifluoromethane for a sterile aerosol talc used in the treatment of malignant pleural effusion in patients with lung cancer. Essential-use allowances were allocated in the USA by the EPA following approval of the ‘Parties to the Montreal Protocol on Substances that Deplete the Ozone Layer’. These allocations are made for a specified essential use and cannot be used for other essential uses, traded, or sold. This allows for the continued sale of existing exempted MDIs and other products designated as an essential use. These allocations are granted on an annual basis. Both the EPA and the FDA have announced rules for the eventual elimination of CFC-containing MDIs by 31st December 2008.