AEROSOLS

Definition: Colloidal systems, consisting of very finely subdivided liquid or solid particles dispersed in and surrounded by a gas. Aerosols have been used for the symptomatic treatment of asthma as well as for the treatment of migraine. Topical aerosols have been used to treat dermatological manifestations. Advantages: 1) 2) 3) 4) 5) 6) Convenient and easy to use. There is no danger of contamination of the product with foreign materials. Protection from destructive effects of both air and moisture. Sterility is maintained throughout the life of the product. Accurate dosage form. Dispensing of the product in the most desirable form; spray, foam or semisolid preparation over an abraded area. 7) Reduction or elimination of the irritation produced by the application of topical preparation over an abraded area. 8) It can be easily applied in a thin layer with no waste Economy May result in faster absorption and more efficient use of medication. 9) The cooling effect of liquefied gas propellant may be desirable in certain skin conditions. Disadvantages: 1) 2) 3) 4) 5) 6) 7) Cost. Disposal may be difficult. Heat can develop high pressure. Difficulty in formulation of emulsion and suspension aerosols. Toxicity of propellants. Catalytic effect of trace metals. Interaction of aerosol components.

Components: 1- Propellants 4- Product concentrate I- 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. Functions: 1) Apply the necessary force to expel the product. 2) Solvent and diluents. 3) Determine the characteristics of the product as it leaves the container (in addition to the nature of formulation and the valve design). Classifications of propellants: A-Liquefied gases: abcdeFluorinated chlorinated hydrocarbons. Hydro-chloro-fluorocarbons. Hydro-chlorocarbons. Hydrocarbons. Hydrocarbon ether. 2- Containers 5- Protective caps 3- Valves and actuators

B-Compressed passes: a- Nitrogen. b- Nitrous oxide. c- Carbon dioxide. A- Liquefied gas propellants: Liquid gas propellants, mostly chlorinated, fluorinated-hydrocarbons, have been used in refrigeration units for a number of years. They are used as propellants and as refrigerants due to their low boiling points and low vapor pressures.

 Since each propellant has a definite vapor pressure at a given temperature, it may be possible to select a propellant to give the desired pressure in an aerosol. If a single propellant does not give the desired pressure, two of these propellants can be blended to obtain a mixture which will produce the desired pressure at a given temperature. One advantage of liquefied propellants is the fact that as long as there is some liquid propellant in the pressurized package, the product will have a constant pressure at a given temperature. Although the fluorinated hydrocarbons generally are considered to be nonreactive, some of them are subjected to hydrolysis and alcoholysis. Propellant 11 (Trichloro-monofluoro-methane) cannot be used in packaging products that contain water or ethyl alcohol because free hydrochloric acid may be formed causing corrosion of metal containers. Propellant 12 (Dichloro-difluoro-methane) and 114 (Dichloro-tetrafluoro-ethane) are relatively stable in the presence of water and alcohol. B- Compressed gas propellants The compressed gases that are used most frequently in preparing aerosols are N 2, CO2 and NO. Nitrogen is practically insoluble in water, whereas the other two gases are slightly soluble. Advantages of N2 1- The insolubility of N2 makes it possible to prepare aerosols so that the dispensed products have the same consistency that they had when they were placed in the package, an advantage in aerosols of vitamin syrups, tooth pastes and some lotions and ointments in which a foaming product would be objectionable. 2- Products packaged with N2 are not subject to oxidation. The gas is colorless, odorless and tasteless and is readily available at low cost. Disadvantage of N2 (as have also CO2 and NO, although to a lesser degree). Aerosols using N2 as the propellant must be packaged at a higher pressure than aerosols prepared with liquefied gases because there is a considerable pressure drop as the product is dispensed from the container.

Compressed gases, which are slightly soluble in water, have a slight reserve in pressure because of the dissolved quantity of gas. CO2, NO or mixtures of both are used to pressurize aerosols from which it is desired to dispense the product as a foam. When the product emerges from the opened valve into the atmosphere, the dissolved gases expand and produce the foamy product.

II- Containers: Different materials are used for the manufacture of aerosol containers. The materials must be inert, non-toxic and must withstand pressure as high as 140 to 180 psi at 130F. 1. Metal: A- Tin-plated steel: The tin-plated steel container, the most widely accepted of the metal containers, is fabricated from sheets of steel plates that have been coated with a layer of tin. The thickness of the tin on each side is dependent on the amount of tin used and is about 0.00006 inch on each surface. Advantages: 1) Light 2) Relatively inexpensive. 3) For certain preparations (e.g. hair lacquers) the tin affords sufficient protection. Disadvantages: Addition of water or other corrosive ingredients or other substances which will attack tin so require a container having an additional coating. This coating is usually organic in nature and may consist of an oleoresin, phenolic, vinyl or epoxy coating. B- Aluminum: It may have a protective coating of phenolic, vinyl or epoxy resin applied to the inner surface to protect them from the corrosive effect of some aerosol constituents. It is used for most oral aerosols.

Advantages: 1) Light weight. 2) Inert. 3) Can be used without internal coating. Many containers are available which have internal coating made from an epoxy-type resin. Thus an added resistance toward reactivity is obtained. 4) Seamless i.e. there is no danger of leakage. Disadvantages: It will react with certain solvents and other chemicals. For example, anhydrous ethanol is extremely corrosive to aluminum, so: Dissolving of aluminum. Liberation of hydrogen gas which results in increase of pressure and subsequent rupture of the container. This can be reduced or prevented by: a- Coating aluminum. b- Adding 2-3% water to the formula C-Glass: Advantages: 1234Excellent compatibility with pharmaceuticals View the level of the contents remaining in the container Greater freedom in design of the container. Plastic coated glass containers are employed mainly with solution aerosols. They are not recommended for suspension aerosol due to the visibility of suspended particles.

The plastic coating of glass bottles has the following functions: a- Protect from flying glass in the event of glass scattering when the container is broken.

b- The coating around the neck of the container serves to absorb some of the shock from the crimping operation and decreases the danger of breaking during this operation. c- The coating also serves as an ultraviolet light absorber. These plastic coatings are available in a clear finish or in various colors. D- Plastics: Advantages: 1) 2) 3) 4) 5) 6) Minimal breakage, Absorb shock due to crimping. Protect medicinal agents from UV lights Clarity Good chemical compatibility Excellent impact-resistance

III- Valves: The most basic part of any aerosol is the valve mechanism through which the contents of the package are emitted. The function of the aerosol valve is 1- To control the flow of the product from the container. 2- To allow the flow of the desired quantity of product from the container when in use, and prevents the flow of product, during storage. 3- The valve also affects the properties of the product as it flows from the container, although the formulation itself plays a part in these properties. The valve should be capable of being easily opened and closed, and deliver the specific amount in the desired form.

Classification of valves: 1- Continuous spray valve: A typical aerosol valve consists of the following parts: a- Mounting cup It is used to attach the valve to the container. For use with containers having a one-inch opening, the cup is made from tin plated steel or aluminum. Since the underside of the valve cup is exposed to the contents of the container and to the effects of O2 trapped in the head space, a single or double epoxy or vinyl coating can be added to increase the resistance.

 For attachment to container having an opening of less than 1 inch, the mounting cup is referred to as a ferrule and is attached to the outside of the container. This is made from a variety of different metals, one of which is brass. Since the ferrule doesn't come into contact with the formulation, there is less danger of incompatibility. b. Stem The stem supports the actuator and delivers the formulation in the proper form to the chamber of the actuator. One or more orifices are set into the stem about 0.013 inch to 0.030 inch to three orifices of 0.040 inch each. The stem is made from Nylon of Delrin, although a metal such as brass can be utilized. c. Gasket The gasket placed with the stem, serves to prevent leakage of the formulation when the valve is in closed position. d. Spring The spring holds the gasket in place and also in the mechanism by which the actuator retracts when pressure is a released, thereby returning the valve to the closed position e. Housing The housing is located below the mounting cup, serves as a link between the dip tube and the stem and actuator. The housing contains an opening at the point of attachment of the dip tube. Manufactured from Nylon or Delrin and contains an opening ranging from about 0.013 inch to 0.080 inch. f- Dip tube The dip tube extends the housing down into the product made from polyethylene or polypropylene. Both materials are acceptable for use although the polypropylene tube is generally more rigid. The inside diameter of the commonly used dip tube is about 0.120 inch to 0.125 inch, although capillary dip tubes are about 0.050 inch and dip tubes for very viscous products

may be as large as 0.195 inch. Viscosity and the desired delivery rate play an important role in the choice of a suitable dip tube. Its function is to: 1- Transport the liquid from the bottom of the container to the dispensing valve at the top. 2- Prevents the propellant from escaping without dispensing contents of the package. g- Actuators: They are buttons through which the user activates the valve assembly for the emission of the product. Functions: 1) Provide a rapid and convenient means for releasing the contents. 2) Allowing the product to be dispensed in the desired form e.g. fine mist, spray, foam or solid stream. The combination of the type and quantity of the propellant used and the actuator design and dimension control the particle size of the emitted product. Large orifices (0.07 inch to 0.125 inch and greater) and less propellants are used for products to be emitted as foams and solid streams than those intended to be sprayed for misted. 3) Special actuator allows the dispensing of the product into the mouth, nose, throat vagina, and eye. There are many different types of actuators: i- Spray actuators: Actuators for sprays are capable of dispersing the stream of product concentrate and propellant into relatively small particles by allowing the stream to pass through various openings (1 to 3 of 0.016 to 0.04 inch in diameter). Where there is a large percentage of propellant mixture containing a sufficient quantity of a low boiling propellant such as propellant 12, actuators having relatively large orifices can be used. The combination of propellant vaporization and actuator orifice and internal channels can deliver the spray in the desired particle size range.

Spray actuators can be used with pharmaceuticals intended for topical use such as spray on bandages, antiseptics, local anesthetics, and foot preparations. When these actuators are used with aerosol products containing relatively low amounts of propellants (50% or less), the product will be dispensed as a stream rather than as spray, since the propellant is not sufficient to fully disperse the product. For these products, a mechanical breakup actuator is usually required. These actuators are capable of "mechanically" breaking a stream into fine particles by causing the stream to "swirl" through various channels built into the actuator. ii- Foam actuators: These actuators consist of relatively large orifices which allow the passage of the product into a relatively large chamber, where it can expand and be dispensed through the large orifice. iii- Solid- stream actuator: Semi-solid products as ointments generally require relatively large openings similar to foam type -actuators to allow for the passage of product through the valve stem and into the actuator. iv- Special actuators: These are specially designed to deliver the medication to the appropriate site of action: throat, nose, eye or vaginal tract.

2- Metering valves: Metered valves are applicable to the dispensing of potent medication. These valves deliver a measured quantity of aerosol mixture at each actuation. Metering can be accomplished by one of two methods. The dip tube may contain a steel ball which operates between a lower stop (merely a pin through the polyethylene tubes) and a ball valve seat at the upper level. When the valve is actuated, the fast flowing product carries the steel ball up in the tube until the ball seats in the valve, at which time no more product can flow up the dip tube. When the actuator is released, the steel ball returns slowly to its lower position in the tube and is then ready to deliver another quantity

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Metering can be accomplished by the use of 2 valves separated by a metering chamber or reservoir. Product is admitted to the reservoir by opening the valve from the pressure packages and simultaneously closing the valve on the dispensing end of the reservoir. When the dose is to be taken, the dispensing valve is opened and the other valve is closed simultaneously. The valves are constructed to operate together on up and down strokes of the valves controls. The volume of the reservoir determines the quantity of spray per dose.

3- Standard valves: The type of valve used most commonly is the standard valve with an ordinary actuator button. These valves are suitable for space and surface sprays in which the liquid propellant is a part of the liquid phase. The actuator button for sprays usually has an external orifice which is about 0.02 inch in diameter. All spray valves have series of communicating passages which serve as expansion chamber, the drop in pressure is sufficient to cause the liquefied propellant to expand and boil. As the material passes through successive orifices into other passages, there are additional expansion and violent boiling which serve to break the product up into small particles as it is forced, along in the expanding gas stream.

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4- Foam valves: These valves are designed to deliver foamy or aerated products. It may have only one expansion orifice which connects directly into the actuator button without intermediary obstruction. The actuator usually has a large external orifice approximately 0.3 inch diameter. The relatively large expansion chamber of the valve and the actuator button allows the formation of foam within the button so that the product is forced out in a foamy condition.

5- Powdered valves: Standard valves can be used with many powder formulations, especially if the powder is very fine and the concentration of powder in the pressurized package is not too high. The most serious difficulty experienced in preparing powder aerosols is the accumulation of powder at the valve seat. Valves with a high seating pressure and with the valve seat located close to the orifice seem to be the most effective for powder aerosols. If the valve is operated wide open, then is less accumulation of powder at the valve than if the valve were only partially opened in operation. Wide-open operation may result in the discharge of a large plume of powder.

6- Compressed gas valves: Valves intended for use in systems that employ compressed gases may be provided with large orifices and large diameter dip tubes to permit the passage of thick, viscous preparations such as syrup and lotions.

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IV- Product concentrates: It is active ingredient of the aerosol combined with the required adjuncts, such as antioxidants surface, active agents and solvents to prepare a stable and efficacious product. V- Protective caps: Functions: 1. Protect the valve assembly during storage and transport. 2. Decorative. Protective caps are made of metal or polyethylene or some other plastic materials.

Formulation of Pharmaceutical Aerosols

An aerosol formulation consists of two essential components: 1. Product concentrate 2. Propellant. The product concentrate consists of active ingredients or a mixture of active ingredients and other necessary agents such as solvents antioxidants, and surfactants. However, since one must be familiar with the physicochemical properties of surfactants, solvents, and suspending agents, it follows that the formulator of aerosol preparations must be thoroughly familiar with propellants and the effect the propellant will have upon the finished product. Propellants can be combined with active ingredients in many different ways producing products having varying characteristics. Depending on the type of aerosol system utilized, the pharmaceutical aerosol may be dispensed as a fine mist, wet spray, quickbreaking foam, stable foam, semi-solid, or solid. The type of system selected is dependent on many factors including the following: (1) Physical, chemical, and pharmacological properties of active ingredients, and (2) Site of application.

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Types of systems: 1- Formulation for solution system (Two-Phase System): When the active ingredients are soluble in the propellant, no other solvents are required. Propellant 12 produces very fine particles. As other propellants are added to propellant 12, the pressure of the system is decreased giving larger sized particles. A lowering of vapor pressure also is produced through the addition of less volatile solvents such as ethyl alcohol, propylene glycol, ethyl acetate, glycerin, acetone, and other similar solvents. Some amount of propellant may vary from 5% to 50% of the entire formulation. These sprays are useful for inhalation and also for topical preparations, since they will tend to coat the affected area with a film of active ingredients. Example: Active ingredients up to Propellant 12/11 (50:50) up to 2- Formulation for water - based system: Relatively large amounts of water can be used to replace all or part of the non aqueous solvents. To obtain a spray, the formulation must consist of a dispersion of active ingredients and other solvents in an emulsion system in which the propellant is in the external phase. In this way, when the product is dispensed, the propellant vaporizes and disperses the active ingredients into minute particles. Since propellant and water are not miscible, a three - phase aerosol will be formed (propellant phase, water phase and vapor phase). Ethanol has been used as a cosolvent to solubilize some of the propellant in the water. 3- Formulation for suspension or dispersion systems: Such system involves a dispersion of active ingredients in propellant or a mixture of propellants. In order to decrease the rates of settling of the dispersed particles, various surfactants or suspending agents have been added to the system. 10-15 % 100%

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Example: Epinephrine bitartarate (1-5 um) Sorbitan trioleate Propellant 11 Propellant 12 0.5% 0.5% 49.5% 49.5%

The epinephrine bitartarate has a minimum solubility in the propellant system, but is sufficiently soluble in the fluids in the lungs to exert therapeutic activity. The stability of aerosol dispersion can be increased by: 1- Control of moisture content. 2- Use of derivatives of active ingredients having minimum solubility in propellant system. 3- Reduction of initial particle size to less than 50 m. 4- Adjustment of density of propellant and/or suspension so that they are equalized. 5- Use of dispersing agents. 4- Formulation for foam systems: Foam aerosols consist of active ingredients, aqueous or non aqueous vehicle, surfactant and propellant and are dispensed as stable or quick - breaking foam, depending on the nature of the ingredients and the formulation. The liquefied propellant is emulsified and is generally found in the internal phase. a) Stable foam: They can be formulated as follows: Active ingredients Oil- waxes O/W surfactant Water Propellant 12/114 (60-40) 75 95% 5-25%

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While the total propellant content may be as high as 25% in certain cases, it usually is about 8 to 10%. As the amount of propellant 12 increases, stiffer and dryer foam is produced. Lower propellant concentrates yield wetter foams. Propellant 114 is used as a replacement for propellant 11 in the presence of water since the latter will form hydrochloric acid. b) Non aqueous stable foams: Non aqueous stable foam may be formulated through the use of various glycols such as polyethylene glycol, which may be formulated according to the following: Glycol Emulsifying agent Propellant 12/114(40:60) 86% 4% 10%

The most effective emulsifying agent was formed from the class of glycol esters such as propylene glycol mono-stearate. Various medicinal agents can be incorporated into the above base. c) Quick-Breaking foams: This system finds the propellant in the external phase. When dispensed, the product is emitted as foam which then collapses into a liquid. This type of system is especially applicable to topical medication, which can be applied to limited or to large areas with the active ingredients. Quick-breaking aerosol foams may be formulated starting with: Ethyl alcohol Surfactant Water Propellant 46-66% 0.5-5% 28-42% 3 - 15%

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d) Thermal foams: Thermal foam systems operate on the principle that two chemicals, contained in the same package but separated from each other by non-permeable membranes, are dispensed at the same time and given portion. When they are mixed in the valve, an evolution of heat occurs warms the surrounding media. Greater importance than the production of warm foams is the possibility of dispensing incompatible ingredients since they need not to be mixed until just prior to use. Drugs of limited stability when mixed with water e.g. Vitamins and effervescent preparation are just a few of the new applications that may be possible.

Filling operations (packaging)

Two methods have been developed for the filling of aerosol products. The cold filling method requires the chilling of all components, including concentrate and propellant, to temperatures of -30 or 40F, while the pressure filling method is carried out at room temperature utilizing pressure equipment. The type of product and size of container generally influence the method to be used. For the most part, the pressure method is used to fill aerosol pharmaceutical products. Various factors determine the method to be used. The pressure method generally is preferred to the cold method, since: there is less danger of contamination of the product with moisture, high production speeds can be achieved, Less propellant is lost, and the method is not limited, except for certain type of metering valves which can only be handled by the cold fill process or through use of an "under the cap" filler and valve crimper. Some metered valves are now available which are pressure fill-able.

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Quality control for pharmaceutical aerosols

Basically there is no difference between methods used to produce pharmaceutical aerosols and those used to produce non pharmaceutical aerosols, but there are differences in the standards and specifications for their production. The standards of production for aerosol pharmaceuticals resemble more closely those for non-aerosol pharmaceuticals. Weight checking: This is generally accomplished by periodically adding to the filling line; tarred empty aerosol containers which, after being filled with concentrate, are removed and then accurately weighed. The same procedure is used to check the weight of the propellant that is being added. When a propellant blend is being utilized, checks must be made to ensure a proper blend of propellants. As a further check, the finished container is weighed in order to check the accuracy of the filling operation. Leak testing: A means of checking the crimping of the valve must be available in order to prevent defective containers due to leakage. For metal containers this is accomplished by measuring the "crimp" dimensions and ensuring that they meet specifications. Final testing of the efficiency of the valve closure is accomplished by passing the filled containers through the water bath. Periodic checks are made of the temperature of the water bath and these results are recorded. Spray testing: Many pharmaceutical aerosols are 100% spray tested. This serves to clear the dip tube of pure propellant (for pressure filled products) and as a check for defects in the valve and of the spray pattern. For metered valves, it serves to prime the valve so that it is ready for use by the consumer.

Testing of pharmaceutical aerosols

Aerosols are "pressurized packages" and many tests are necessary in order to ensure proper performance of the package and safety during use and storage.

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Pharmaceutical aerosols can be evaluated by a series of physical, chemical, and biological tests, including: A. Flammability and combustibility. 1. Flashpoint. 2. Flame extension.

B. Physicochemical characteristics 1. 2. 3. 4. 5. Vapor pressure. Density. Moisture content. Identification of propellant(s). Concentrate-propellant ratio.

C- Performance. 1. 2. 3. 4. 5. 6. 7. Aerosol valve discharge rate. Spray pattern. Dosage with metered valves. Net content. Foam stability. Particle size determination. Leakage.

D- Biological. 1. Therapeutic activity 2. Toxicity

1- Flame extension: This test indicates the effect of an aerosol formulation of the extension of an open flame. The product is sprayed for about four seconds into a flame. Depending on the nature of the formulation, the flame will be extended, the exact length being measured with a ruler. 2- Flash point:

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This is determined by use of the standard Tag Open Cup Apparatus. The aerosol product is chilled to a temperature of about -25F and transferred to the test apparatus. The test liquid is allowed to increase slowly in temperature, and the temperature at which the vapors ignite is taken as the flash point. 3- Vapor pressure: The pressure can be measured simply with a pressure gauge. It is important that the pressure variation from container to container be determined, since excessive variation indicates the presence of air in the head space. 4- Density: The density of an aerosol system may be accurately determined through the use of a hydrometer or a pycnometer. These methods, which have been used for the density of non-aerosols, have been modified to accommodate liquefied gas preparations. 5- Moisture: Many methods have been found useful for this purpose. The karl- Fischer method has been accepted to a great extent. 6- Identification of propellants: Gas chromatography and infrared spectrophotometry (IR) have been used to identify the propellants and also to indicate the proportion of each component in a blend. 7- Aerosol valve discharge rate: This is determined by taking an aerosol product of known weight and discharging the contents for a given period of time using standard apparatus. By reweighing the container after the time limit has expired the change in weight per time dispensed is the discharge rate which can then be expressed as grams /second or grams /minute. 8- Spray patterns: A method for comparing spray patterns obtained from different batches of material or through the use of different valves is available.

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The method is based on the spray on a piece of paper that has been treated with a dyetalc mixture. Depending on the nature of the aerosol, an oil-soluble or water-soluble dye is used. The particles that strike the paper cause the dye to go into solution and to be absorbed onto the paper. This will give record of the spray which can then be used for comparison purposes. To control the amount of material coming into contact with the paper, the paper is attached to a rotating disk 9- Dosage with metered valves: Several points must be considered: 1- Reproducibility of dosage each time a valve is depressed 2- Amount of medication actually received by patient.

Reproducibility of dosage may be determined by assay techniques whereby one or two doses are dispensed into a material that will absorb the active ingredients. These solutions can then be assayed and the amount of active ingredients determined. Another method that can be used involves accurate weighing of filled container followed by dispensing of several doses. The container can then be reweighed, and the difference in weight divided by the number of doses dispensed will give the average dose. This must then be repeated and the results compared. Determination of the dosage received by a patient is a rather difficult procedure, since all of the material dispensed is not carried to the respiratory tract. 10- Net contents: Several methods can be used to determine whether sufficient product has been placed into each container. The tared cans that have been placed onto the filling line are reweighed and the difference in weight is equal to the net contents. The other method is a destructive method and then dispensing the contents. The contents are then weighed, with provision being made for the amount retained in the container, other modifications consist of opening the container and removing as much of the product as possible. These tests are not indicated in determining the actual net weight of each container as related to the amount that can actually be dispensed.

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11- Foam stability: Various methods have been suggested for the determination of foam stability. The life of foam can range from a few seconds (for some quick-breaking foams) to one hour or more depending on the formulation. Several methods have been used which include a visual evaluation, time for a given mass to penetrate the foam, time for a given rod that is inserted into the foam to fall, and the use of rotational viscometers. 12- Therapeutic activity: Various testing procedures are available to determine the therapeutic activity of aerosols. With the exception of giving consideration to the aerosol feature of the package, these procedures are similar to existing tests used for non-aerosols. The dosage .of the product will have to be determined for inhalation aerosols and this must be related to particle size distribution. Topical preparations are applied on the test areas in the usual manner, and adsorption of therapeutic ingredients can be determined. 13- Toxicity: Toxicity testing should include both topical and inhalation effects. Aerosols applied topically may -be irritating to the affected area and/or way cause a chilling effect. The degree of chilling effect is dependent on the type and amount of propellant present. There is no really good test available at the present time, although the use of thermistor probes attached to recording thermometers have been used to indicate the change in skin temperature when sprayed with an aerosol for a given period of time. Inhalation toxicity must also be considered even though the product may be intended for topical administration. This can be done by exposing test animals to vapors sprayed from an aerosol container.

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