Pharmaceutical aerosols can utilize virtually every standard propellant and mixture thereof. The only exception is that HFC-134a is restricted to metered dose inhalants (MDIs) and a few very low volume, rather exotic skin care products. Almost all pharmaceutical products contain either iso-butane (A-31) or mixtures of propane and isobutane, such as A-46 and A-55. If non-flammability is a major consideration, then Solstice HFO-1234ze(E) can be used. Up to about 12.5% of the hydrocarbons have been used for pharmaceutical foams and as high as 90% have been seen for fungicidal foot sprays. August 2015 Spray 17 Iso-butane produces a softer, less driving spray on the skin, important when the skin has been injured, where the spray cone is narrow or when spraying is done from a distance of only a few inches. Formulators of emulsion pharmaceuticals prefer to avoid wide spray cones because the lower edge of the cone may impact the valve cup. This can produce a peanut-shaper ball of foam, a phenomenon commonly called “bearding”. Using the ever more popular conical cup valve and a relatively small terminal orifice diameter of the MB actuator can usually eliminate this problem. Foam products can be more demanding. Emissions of very different foam volumes and delivery rates are needed, according to the product type. For instance, the amount of foam for a medicated shampoo or hair conditioner will be much more than that designed to be applied to a cut finger. All foams are meta-stable. They often include micronized solids, such as zinc oxide, magnesium sulfate, titanium dioxide hydrocortisone acetate, zinc pyrithione or selenium sulfide, held in suspension, at least temporarily, by the use of polymeric thickeners or gelling agents. They often increase or sometimes decrease foam stability. Ingredients that contain tiny tetrahedral needles of silicon dioxide often act as defoamers. One early theory was that the micro-needles punctured the typical 50 micron foam bubbles, but the actual mechanism is more complex. When solids are present, care must be taken to prevent hard pack agglomeration and the particles must be small enough to pass through the aerosol valve orifices with no chance of plugging them. Some commercial solid ingredients must by milled (micronized) into acceptably small diameters. Key physical properties of foams are density, stability and stiffness. The usual densities, achieved with about 3.5 to 6.0% propellant, are in the range of about 0.09 to 0.14g/mL. The foam density increases as products are used, since propellant leaves the emulsion to try and repressurize the expanding head space. With some modern foam products, the slow transition escapes notice by consumers. Products with foam densities as low as at least 0.025g/ mL have been formulated but are of no commercial interest. Foam products can be controllably applied into body orifices, unlike sprays. For example, Proctafoam (Reed & Carnrick) can be used to suppress internal hemorrhoids. The aerosol valve stem is connected to the end of a clear plastic syringe. By actuating the valve, a measured 5mL quantity of foam can be injected into the syringe. The piston can eject any overfill. A short cannula is then attached to the syringe and it is ready for therapeutic use. One aerosol is able to provide about nine treatments. Another example is contraceptive foam, based on about 12% nonoxynol 9. Some laboratories use a pre-weighed 30mL porcelain crucible, attaching a short extension tube to an aerosol valve actuator and filling the crucible with foam from the bottom up, eliminating any voids. The excess foam in the slightly overfilled crucible is wiped off with a spatula and the unit is reweighed to determine the foam weight. The capacity of the crucible is calculated using water, and from that, the foam density. Other containers, including syringes, can also be used. A disadvantage of iso-butane (A-31) and other low pressure pharmaceutical foam products is that they usually exhibit a secondary foam expansion. The initial foam density decreases for several seconds due to gasification of additional propellant. This can cause post shut-off oozing at foam spouts. In general, the phenomenon diminishes at A-40, is almost completely gone at A-46 and is imperceptible at A-55. A stiff foam is generally a more stable one. For emulsions based on triethanolamine fatty acids or alkyl fatty acids (shave cream types) adding a little cetyl alcohol enhances foam viscosity. For sodium lauryl sulfate (hair care) emulsions, the foams can be stiffened by adding lauryl alcohol. Disodium dimethicone copolyol sulfosuccinate rates zero on Draize skin and eye irritation assays. Both it and various amphoteric surfactants are of interest for baby products, hypoallergenic products and “leave on” emulsion products. These foams can be stiffened with disodium oleamide MEA sulfo-succinate or such thickeners as Crothix (Croda). Excessive thickening tends to inhibit dermal wetting actions. Several methods have been developed to quantify foam stiffness. In one, a Brookfield Visosimeter is used to either position or very slowly descend a slowly rotating spindle head into a large mass of the test foam. The (non- Newtonian) viscosity is read from a pointer on the instrument head. Foam stability is rarely a critical issue for pharmaceutical aerosols, since the foam is produced and then applied a few seconds later. It can be increased by including gels or comminuted solids in the formula. For special products, like antiseptic surgical hand scrub foams, quick-breaking foam structures can be produced by adding water soluble solvents (as ethanol) or even water-soluble propellants (as dimethyl ether). The ethanol type, pioneered by K. Klausner in 1954, has the typical formula: Quick-Breaking Surgical Scrub Foam Polyquaternium-8 (As Merquat, by Merck) 0.700% Emulsifying Wax, N.F. (As Polawax, N.F. by Croda) 0.925% Sodium Sequicarbonate 0.100% Sodium Benzoate 0.175% S.D. Alcohol 40-2 (Anhydrous) 53.700% Purified Water, USP 39.900% Hydrocarbon Propellant Blend A-46 4.500% Adjust to pH = 7.0 to 8.0 (25°C) if necessary. Tinactin Chill Liquid Spray helps relieve the itching, burning and cracking of athlete’s foot and ringworm.
Spray August 2015
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