Food additives Europe numbers: E940
Functional Category
Aerosol propellant
Applications in Pharmaceutical Formulation
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; see also Section 18. C Chlorofluorocarbons (CFC) 173 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
Description
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
Stability and Storage Conditions
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
Incompatibilities
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%)
Safety
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