Aerosols PDF

AEROSOLS INTRODUCTION The search for new improved drug delivery systems has given rise to the advanced technology of the category of drugs called “inhalcables”. These are defined as respiratory and systemic therapies administered simply by inhalation. N...

AEROSOLS INTRODUCTION The search for new improved drug delivery systems has given rise to the advanced technology of the category of drugs called “inhalcables”. These are defined as respiratory and systemic therapies administered simply by inhalation. New dispersible formulations and drug aerosol delivery devices for inhaleable peptides, proteins and various small (drug) molecules have in the past decade, become of increasing interest for the treatment of systemic and respiratory diseases. Some of these conditions include the traditional therapies for asthma and chronic obstructive pulmonary disease (COPD). Advances in the use of the lungs as portals for delivery of medication to the blood stream have greatly expanded the potentials applications of pulmonary drug delivery. By facilitating the systemic delivery of large and small molecule drugs through inhalation deep into the lung, this advanced pulmonary technology provides a unique and innovative delivery alternative for therapies that must currently be administered by injection (i.v.. i.m., s.c.) or by oral delivery that causes great discomfort and adverse effects or is poorly absorbed. Indeed, a major advantage of therapy via the lungs is the potentially improved therapeutic index, which is the ratio of therapeutic benefit to adverse effects. This applies mainly to the therapy of pulmonary disease, but may also be applicable to systemic diseases due to reduced first-pass metabolism that may be associated with hepatocellular injury. Pulmonary delivery also offers the potential for better and possibly more economical treatment or prophylaxis of respiratory and systemic diseases (e.g. viral vaccines). Definitions A pharmaceutical aerosol may be defined as a formulation containing therapeutically active ingredient(s) dissolved, suspended, or emulsified in a propellant or a mixture of solvent and propellant and intended for oral or topical administration, or for administration into one of the body cavities (such as the ear, rectum, vagina, mouth and nostrils). It may also be formulated for the sterilization of the atmosphere and surfaces of objects. Aerosols are colloidal formulations of liquids or solid particles dispersed in and surrounded by a gas under high pressure. All aerosols contain a propellant which is a gas that exerts very high pressures. A propellant is a pressurized or liquefied gas in an aerosol formulation. This gas constitutes the driving force of an aerosol. In other words, it is responsible for dispensing the content of an aerosol. Compressed gas propellants in common use include carbon IV oxide CO2 (Carbon dioxide), Nitrogen N2, and Nitrous oxide N2O. Liquefied gas propellants in common use include the hydrocarbons such as propane, butane and isobutane. Another group is the chlorofluorocarbons (also called the halocarbons) such as trichloromonofluoromethane CCI3F (P11), dichlorodifluoromethane CCI2F2 I (Pi?), and dichlorotetrafluoroethane CCIF2CCIF2 (Pin). A newer class of aerosol propellants is called hydrofluorocarbons (HFC) or hydrofluoroalkanes (HFA). These differ from the CFC propellants in their polarity and solubilizing properties. They do not contain chlorine atoms and so do not tamper with the ozone layer. They are more polar, and could dissolve more hydrophilic compounds, including hydrophilic surfactants, than the CFC propellants. The most popular HFAs are HFA 134a (tetrafluoroethane) and HFA 227 (heptafluoropropane). Advantages of aerosols 1. Aerosols are convenient and easy to use. 2. Manual contact with the medication is avoided and immediate local application can be achieved easily to give high concentration of the medicament over a limited area. 3. Application without manual contact with the patient produces minimum irritation of painful areas. 4. Metered valves ensure controlled and uniform dosage in each application. 5. By changing the pressure in the aerosol pack or using special valves the spray characteristics can be altered from a Fine dry mist to a coarse wet spray. 6. A wide variety of pharmaceuticals can be formulated including insufflations of pressurized powders. 7. Formulation is easy if the active drug is soluble in the propellant. 8. Since the system is pressurized, no contamination of the drug concentrate from the environment ever occurs. 9. The sterility of sterile products is maintained since no organisms can enter the pack even with the valve open. 10. The exclusion of light by all but clear colorless glass containers protects photolabile constituents. 1 1. Absence of air in the container prevents oxidation of susceptible drugs. 12. Hydrolysis of susceptible drugs is prevented since propellants and indeed most aerosol formulations contain no water. 13. Drugs administered by oral inhalation arc less liable to first-pass degradation since they do not pass into or through the gastrointestinal tract (GIT). Positive therapeutic response is therefore almost always guaranteed. Disadvantages of aerosols 1. The formulation of aerosols is an expensive exercise. 2. Aerosol packs whether ‘‘empty” or not must not be subjected to high temperatures since high pressures may develop and lead to explosion. 3. Formulation of aerosol of drugs insoluble in the propellant usually involves expensive processes. *1. II inhalation therapy takes place over a long period of time, toxicity due to the propellants, co-solvents, or other additives may precipitate health problems, especially among patients with weak heart. 5. The refrigerant effect of highly volatile propellants may cause discomfort to injured skin. 6. Traces of metals in valve pails or container may cause catalytic oxidation of drugs such as Ascorbic acid and Epinephrine. 7. The quality assurance tests on aerosol formulations are both tedious and expensive. Classification of aerosol Aerosols are conveniently classified based on the nature of the propellant they contain as well as on the configuration of the packaging. A Liq uefied gas aerosols Liquefied gases are useful as propellants because they are gases at room temperature and atmospheric pressure. The gases are easily liquefied by lowering the temperature below its boiling point and/or by increasing the pressure on them. When a liquefied gas propellant is placed in a (sealed) container it immediately separates into a liquid phase as well as a vapor phase. Molecules of the gas escape from the liquid phase into the vapor phase: at the same time, some molecules return into the liquid phase from the vapor phase. Initially, the movement of the molecules is more from the liquid phase into the vapor phase. As this molecular migration occurs, there is pressure build up in the vapor phase. An equilibrium condition is soon attained during which the number of molecules of the propellant leaving the liquid phase equals the number returning to it. The pressure at this point is referred to as the equilibrium vapor pressure of the propellant. The vapor pressure of a propellant is characteristic of the propellant al any given temperature. The vapor pressure of a propellant is exerted in all directions, and is virtually independent of the quantity of the propellant present in the container. If a hole is made in the container the pressure generated inside it causes the propellant gas to escape into the atmosphere. If a dip tube that fits tightly to the hole is inserted into the propellant the vapor pressure is sufficient to drive the propellant up the dip tube against a valve. And if the valve is opened the propellant would escape into the atmosphere as a gas since its boiling point is significantly below room temperature. As the content of the aerosol is dispensed, the volume occupied by the vapor phase increases. This lead's to a transient fall in pressure. The fall in pressure is only transient because sufficient number of molecules of the 3 propellant would soon escape into the vapor phase in order to restore the original pressure (which is intrinsic to the propellant at the given temperature of operation). On the contrary, when a compressed gas is used as the propellant there is an obvious drop in pressure as the content of the aerosol is used up. 1. Two-phase aerosol system This is the simplest of all aerosol systems (sec Figure I). It consists of a solution ol active drug(s) in a liquid propellant, or a mixture of solvent and liquid propellant. There is a gas phase atop a liquid phase (drug solution). Opening the valve causes the solution of drug(s) in the propellant to be dispensed. Depending on the vapor pressure of the propellant used, the quantity of the propellant present, and the valve mechanism, a fine dry mist or a coarse wet spray may be dispensed. Solution Propellant Figure 2. A typical three-phase aerosol 2. Three-phase aerosol system I he three-phase system is indispensible when liquids that are not readily miscible with the propellant must be formulated together. Water, which is a good solvent of many drugs, may be formulated with liquefied gas propellants. Depending on the nature of the formulation, either of the following systems maybe employed. a. Two-layer aerosol The three phases in this system are the vaporized propellant, liquid propellant and the aqueous solution of active ingredient. There are two liquid layers of liquid propellant and water. - ’ —— Halocarbons are heavier than water and therefore settle at the bottom, while hydrocarbons are lighter than water and float on the water (see Figure 2). I he vapor layer is continuously replenished by vapor from the liquid layer of propellant. The propellant constitutes about 5 - 10% of the formulation and would generate 15-20 psig of pressure. In a recent development by Precision Valve Corporation the AQUASOL SYSTEM was developed. This system makes it possible to dispense a fine mist of active drug, dissolved in water. Only water and the active drug since propellant is in the vapor phase and present in only extremely small quantity. The problem of flammability is solved automatically. Particles as fine as 10pm are dispensed. The advantages of this new system are obvious: the chilling effect associated with evaporation of liquefied gas propellants is eliminated since only vaporized propellant is dispensed; only a small amount of propellant is required in the container; and with greater use of water as a solvent for active drugs a wider range of products can be formulated successfully. b. Foam aerosols In order to formulate a foam aerosol, liquid propellant is emulsified with the product. When the valve is opened the emulsion is forced through the nozzle and, in warm air and at atmospheric pressure, the entrapped propellant vaporizes. In the process, the emulsion is whipped into foam. A dip tube may or may not be used. When a dip tube is used, the aerosol can is held upright; in the absence of a dip tube, the can must be held upside down. Shaking the aerosol before use enhances foaming. Foam aerosols operate at a pressure of about 40 to 50psig at 28°C, and the propellant content is often not more than 10%. Shave creams, contraceptives, shampoos and various topical drug products are formulated as foam aerosols. More commonly used propellants include a blend of propane and isobutene, nitrous oxide, carbon dioxide, or a mixture of both gases. Contraceptive foam aerosols are exempted from the ban on the use of halocarbons; propellants 12 and 114 may be used. B. Compressed gas aerosols Commonly used compressed gases include nitrogen, carbon dioxide, and nitrous oxide. These gases may dispense the aerosol concentrate as a solid stream, wet spray or foam. The gas is pressurized in the container, and it is the expansion of the gas that constitutes the drivjng force which dispenses the formulation from the aerosol can. As the formulation is dispensed the volume of the gas phase increases thereby causing a drop in the internal pressure according to Boyle’s law. 5  Pk- y.... (1) ' '. P = -*K.... (2) r Al constant temperature, equation 2 becomes =.... (3) Where P equals pressure. V is volume of the gas phase and K is a constant. 1. Solid stream dispensing The aerosol formulation is semisolid and is packed with nitrogen gas, with which it is immiscible. The product is therefore dispensed in its original form. Dental creams, ointments, creams, hairdressings, foods, etc, are dispensed as solid stream. Initial gas pressures up to lOOpsig at 21°C are usually required in order to ensure dispensing of most of the content of the aerosol. a. Foam dispensing Emulsified products dissolve (soluble) propellant gases such as carbon dioxide and nitrous oxide. This system is popular with veterinary products as well as several drug products for human consumption. When the valve is opened, the dissolved gas escapes at room temperature and atmospheric pressure. In the process, the emulsion is whipped into foam. Shaking the aerosol container enhances even dispersion of the gas throughout the product. b. Spray dispensing When compressed gases are used as propellants, the force available to dispense the drug product is lower than that generated by a liquefied gas. This is because liquefied gases have a higher expansivity than compressed gases. A compressed gas propellant is used at a very high initial pressure. The product is dispensed as a coarse wet spray. Solutions of active drugs in aqueous solvents can be successfully dispensed. C. Miscellaneous systems a. Piston type aerosols This system is specially designed to completely empty the semi-solid drug formulation contained in an aerosol can. figure 3 illustrates the design of a piston type aerosol. A plastic (usually polytetrafluoroethylene PTFE) piston is fitted into an aluminum container. The product concentrate is placed into the upper chamber of the container; the lower compartment holds the propellant, which could be compressed nitrogen at about lOOpsig, or a liquefied hydrocarbon gas. The propellant exerts the force which pushes the piston up against the valve. The product is discharged when the valve is opened. The construction is such that the piston moves with very 6 close proximity against the inner wall of the container in order to dispense most of the product foi mutation. 1 his system is indispensible in packaging very viscous materials. b. Plastic bag aerosols 'Phis consists of a collapsible plastic bag. usually accordion-pleated, lilted into a metal container. The product is held in the bag, and the lower compartment holds the propellant. There is no direct contact between the product concentrate and the propellant. Limpid liquids can be dispensed as a stream or fine mist depending on the type of valve and propellant used. Semisolid formulations are dispensed as a stream as formulated. Emulsions containing low-boiling point liquids such as penlane can be dispensed as foam when the product is placed on the hands. The warmth of the hands causes vaporization of pentane in order to produce a foam. Shaving gels are so dispensed as formulated. All the viscous products to be dispensed as formulated are ideally packaged in the manner.  — Manufacture and Packaging of Aerosols Hie drug product or concentrate I ormulalion of the product concentrate is similar to the preparation of any equivalent phaimaceutical product. However, the overall process is unique, in that part of the manufacturing procedure for pressurised products takes place during packaging. I here are two modes of filling namely, the cold-filling process and the pressure-filling process. Coldfilling Low temperatures, in the range of- 34° to - 40°C, are required for the cold-filling process. This implies that this method may not be suitable for aqueous products or for preparations that are adversely affected by low temperatures. The product concentrate is chilled and added to the open container followed by the chilled propellant. Alternatively, the concentrate and propellant can be chilled together and the mixture added to the container. The temperature of the components must be carefully controlled to prevent loss due to evaporation. A valve is then crimped into place and the container passed through a healed test bath (at about 55°C) as a check for leakage and container strength. Pressure filling The pressure filling process can be used for all types of aerosols, although it can only be applied to metered-dose products if a specially designed container is used. The product concentrate is added to the container at room temperature and the valve crimped into place. The propellant is then added under pressure through the valve stem or through the actuator and around the sealing gaskets. A second technique, the “under-the-cap” method, is also used. The product concentrate is added to the container and the valve placed in position. A seal is formed around the shoulder of the container and. using a vacuum, the valve cup is raised slightly from the can and the propellant added. The valve is then crimped into place. For all pressure-filling techniques, air can be purged from the headspace before adding the propellant. This is a measure that protects products that are susceptible to oxidative degradation reactions. The completed container is passed to the test tank as in the cold-filling process. Propellants The aerosol propellant is a very essential component of the aerosol formulation; it is the dispensing force of the aerosol drug delivery system. It may also be the active drug, solvent and diluents of the formulation. It is a very important determinant of the spray characteristics of the aerosol formulation. Propellants may be liquefied gases or compressed gases. The former include chlorinated fluorinated hydrocarbons (halocarbons), hydrocarbons and the newer hydrofluoroalkanes. Commonly used compressed gas propellants include nitrogen, nitrous oxide and carbon dioxide. 8  Liquefied gas propellants I hese propellants enjoy numerous advantages over the compressed gases. The liquefied gases could serve as solvents and diluents of the product concentrate. They have characteristically high pressures and therefore are effective in dispensing the product concentrate as a fine dry mist or foam depending on the desired effect. The pressure generated is usually constant during use of (he aerosol. They arc relatively inert and non-toxic. Halocarbons have been banned as propellants because of their ozone-layer unfriendliness. Prior to the ban, halocarbons enjoyed great patronage because they arc non-inflammable in comparison with the highly flammable hydrocarbons. The latter are much less expensive than the halocarbons. Liquefied gas propellants have a large expansion ratio (i.e.. a high expansivity). For instance, several of the halocarbons have an expansion ratio of about 240 and dimethylether has an expansion ratio of over 350. On the contrary, compressed gases have expansion ratios of about 10. /. Chlorinated fluorinated hydrocarbons (Halocarbons) These gases are derived from methane, ethane and cyclobutane by replacing one or more of the hydrogen atoms with chlorine and or fluorine. Their use in pharmaceutical formulations is now limited to a few inhalational aerosols and contraceptive vaginal foam aerosols. Halocarbons are non-polar and are miscible with a number of non-polar solvents over a wide range of temperature. They are capable of dissolving many drug substances. They do not mix with water, fhe addition of fluorine to a carbon atom usually increases stability, while a propellant such as trichloromonofluoromethane undergoes hydrolysis with the formation of hydrochloric acid (HCI). Dichlorotetra fluoroethane (Propellant 114) is more stable to hydrolysis. it. Hydrocarbons These are more frequently used in pharmaceutical aerosols than the halocarbons. They have relatively low toxicity, but are highly inflammable. They are also less expensive and enjoy a w ider range of solubility than the halocarbons. By mixing various proportions of hydrocarbons, the vapor pressure of the propellant system, and hence, the spray characteristics can be adjusted to meet needs of the formulator. Hydrocarbons are indispensible in the formulation of water­ based aerosols since they are water immiscible and so cannot be hydrolyzed. They are extremely chemically stable. iii. Newer liquefied gas propellants The ozone unfriendly disposition of halocarbons has necessitated the search for safer propellants for industrial use (including the pharmaceutical industry). Newer gases arc currently being used in the pharmaceutical industry, in air-conditioning and refrigeration. The search for alternative propellant gas started with dimethyl ether. The adverse toxic effect of dimethyl ether precludes its widespread use in pMDI (pressurized melered-dose inhaler) formulations. Hydrofluoroalkane (I IFA) propellants arc the leading candidates to replace CFC propellants. 9 Compressed gas propellants The commonly used gases are nitrogen, nitrous oxide and carbon dioxide. Depending on the initial pressure of the gas propellant, the valve design, as well as the viscosity ol the product concentrate, a fine mist. foam, or solid stream may be dispensed. A high initial pressure is a necessity in order to completely dispense all the content of the aerosol container. A A5A drop in pressure usually occurs as the product concentrate is dispensed. High initial pressures up to lOOpsig and a gas phase of 15 - 25% of the container volume are not uncommon. Nitrogen gas is insoluble in the products, while nitrous oxide and carbon dioxide are soluble to some extent. The solubility of carbon dioxide in some beverage lood products may carbonate them as an advantage. Since the gases are generally inert and displace air from the headspace, the stability of the drugs may be enhanced. FACTORS AFFECTING SPRAY CHARACTERISTICS OF AEROSOLS For the production and proper use of aerosols, the various factors that affect their spray characteristics must be considered. Spray characteristics could be a fine dry mist or a coarse wet spray. Solid stream dispensing is also a possibility when the semi-solid product is dispensed as formulated. Spray characteristics affect the movement of dispensed particles and subsequently their pharmacological and therapeutic activity. These aspects will be considered later in the lecture. Viscosity Formulations of low viscosity have a tendency to be dispensed as fine dry mist with short life span. As the viscosity increases the dispensed particles become coarse; and indeed, as the viscosity increases further the product may be dispensed as a stream instead of a spray. Vapor pressure of the propellant The dispensing force generated by the propellant is a function of its vapor pressure. In other words, as the vapor pressure of the propellant increases, its intrinsic dispensing/expulsion force also increases. The aerosol concentrate is dispensed as fine particles. The converse is also the case such that as the vapor pressure of the propellant decreases, the concentrate is dispensed with a lower force. I his scenario causes the dispensed particles to be coarse and wet. Propeiiant/product ratio I his is probably the most important single factor affecting the spray characteristics of an aerosol. It is known that the greater the proportion of propellant in the concentrate, the finer and drier the spray. By careful adjustment of this ratio a product may be presented in various forms from a line dry mist to a coarse wet spray. Sometimes, a mixture of propellants may be used in one formulation. It is also known that a single propellant in an aerosol formulation that gives a 10 in tain intermediate pressure produces a finer spray than a mixture of two or more propellants Im\ ing the same vapor pressure. 1 his phenomenon defies easy explanation. Tresence of solvents (Co-solvents) 1 he solvents used occasionally in aerosol formulation affect the vapor pressure of the propellant b\ a dilution mechanism. The vapor pressure of solvents is often less than that of the propellant. 1 he life span of the dispensed particles is also affected; the life span increases as a result of the lowering of the vapor pressure of the propellant. This may be explained thus: low pressure solvents evaporate more slowly and therefore produce larger particles with longer life span than higher pressure solvents (such as the propellants). Temperature lemperature is known to increase Brownian motion in fluid molecules. Generally, the vapor pressure of propellants used in aerosol formulation increases with increase in temperature as a consequence of increased Brownian motion of its molecules. Therefore, aerosol formulation should take into consideration the temperature at which the aerosol product is likely to be used since the spray characteristics may change with change in vapor pressure. A finer drier mist is obtained as the lemperature of storage and usage of the aerosol is increased; and vice versa. Type of valve Spray characteristics are affected by the size and shape of the valve orifice, dimensions of the valve parts, variations in the design and working of the actuator button. Generally, as the orifice size increases, the spray characteristics change from a fine dry mist to a coarse wet spray. Foam dispensing aerosol containers are lilted with a wider orifice. The Pharmaceutical Importance of Size of Dispensed Particles Most pharmaceutical inhalation aerosols arc for oral inhalation. Oral inhalation aerosols are equipped with metered valves which facilitate the dispensing of accurate doses of the formulation repeatedly. Although most inhalation aerosols are formulated for local action in the respiratory tract there is also the possibility of general systemic absorption of potent drugs. Particles of different sizes tend to be retained in various regions of the respiratory tract. For instance, large particles (of about 20pm) are deposited in the upper regions of the respiratory tract, namely, the mouth, pharynx, trachea, bronchi, secondary bronchi, and tertiary bronchi. Smaller particles (of about 3 - 6pm) reach deeper into the lungs. However, these fine particles may be easily exhaled as a consequence of their small size and light weight. Consequently, the amount of drug retained becomes less than for larger particles. Increase in total retention, as well as trans-pulmonary absorption of drug occurs if the breath is held after inhalation. 'Phis is as a result of increase in the time during which the forces responsible for deposition can act. These include Inertial and Gravitational forces, as well as Brownian motion. 11  Inertial forces Large and heavy particles in an air stream continue in their original path even when the current changes direction. Deposition of particles in an inhalation aerosol is therefore more significant in the upper respiratory tract. Gravitational forces Gravitational pull causes particles to sediment. The pull is more significant in the deeper regions of the lungs where the air is more still. Brownian motion I his is responsible for the deposition of very small particles less than I pm in the alveoli. Particle size and shape play a significant role in the deposition pattern of the active drug in the respiratory tract. In the formulation of inhalation aerosols, at least 90% of the particles should lie between 0.5 and 10pm in order to maximize their delivery and deposition in the respiratory tract. Experimentation has shown that particles in the size range of 3 - 6pm are ideal and more effective in inhalational aerosols. Lhe particle size of the product dispensed is equally important in space and surface spray aerosols. Space sprays should ideally dispense very line particles such that the particles can remain in the atmosphere for very long; such aerosols include space deodorants. Insecticidal aerosols should have a wider range of particle sizes so that the insecticide effectively covers both the atmosphere and solid surfaces. Surface aerosols dispense coarse sprays, or they may dispense lhe product as formulated. Some Important Quality Control Tests on Aerosols Various quality control procedures have been developed and applied to ensure the suitability for use of aerosol formulations. The tests are usually parried out at ambient temperatures except where increasing lhe temperature marginally will accelerate the tests and facilitate obtaining the results after a short period of time. Some of these tests are discussed hereunder. i. Leakage It has been noted that the propellant generates the dispensing force of an aerosol dosage form. If the propellant in an aerosol package is lost, usually by leakage through a fault in the container, the concentrate cannot be dispensed. It therefore becomes imperative that every aerosol container must be tested for the possibility of leakage at any time during storage and use. Test for leakage is carried out by totally immersing lhe aerosol in a bath of hot water at about 40 - 55°C (This is accelerated stability testing because increase in temperature increases Brownian motion and hence, the internal pressure in the container.). In order to facilitate inspection, the bath is illuminated from within the water and covered with a reinforced grill. The points 12  |Kikd include the valve, the valve cup and lop, and the scams. Pharmaceutical aerosols >maining theimolabile drugs may not be subjected to this test at high temperatures. ii. Internal pressure By definition, every aerosol formulation is under pressure on the inside in order for the concentrate to be readily dispensed. It is also important that the pressure is sufficient to dispense all the concentrate from the aerosol can. Indeed, it may be preferable to have excess propellant left over after exhausting the can than being unable to dispense all the content from the can. When a compressed gas propellant is used, it is usual to have a high initial pressure since the pressure decreases during use of the aerosol. A specially adapted pressure gauge having an adaptor which fits the siem/tip of the dip lube is used to measure the pressure in an aerosol system. The button is removed from the tip of the dip lube, the aerosol container is shaken vigorously, and the adaptor is offered up to the dip tube. In other words, the pressure inside the aerosol container is measured with the container upside down. On depression of the valve with the gauge the pressure is read off and recorded. Il is usual to lake at least three readings at two minute intervals in order to allow for re-equilibration to room temperature. The mean pressure as well as other statistical parameters can then be computed. iii. Spray pattern I he spray pattern of an aerosol may be ordinarily examined visually when the actuator button is depressed (and the valve is opened). However, visual examination does not permit comparisons to be made between an aerosol formulation and the other. It does not allow the actual particle size and other characteristics of the dispensed particles to be quantitatively determined. Therefore, the need arises for more permanent records to be made of the spray characteristics of aerosols. Depending on the solvent in the aerosol, a water or oil soluble dye is mixed/scurried with talc and brushed on vellum paper. The aerosol is then sprayed onto the coated paper from a fixed distance for a fraction of a second. This is usually done in a closed box. The pattern that results is photographed. The photograph can be projected on a screen in order to facilitate further studies, such as particle size and particle shape analyses. Another method involves a target made from a photographic quarter plate from which the backing material and emulsion have been washed. A coating of soot is applied from burning magnesium ribbon. The coaled side becomes the target for the determination. The target is placed behind a shutter at a fixed distance from the aerosol. The shutter is released when the aerosol button is depressed so that a representative sample of spray is captured on the target through the slot of the shutter. Placing the coated face of the target downward onto photographic paper and printing makes a permanent record which can readily be subjected to comparison and other statistical studies. 13  iv. Discharge rates his test is used to determine the number of operations required to empty the aerosol container nd hence the most suitably sized container for the particular product. It is particularly useful in k determination of doses delivered by inhalational aerosols. Discharge rate is usually cxpiessed in gram/sec. and is measured thus: the container is immersed in a waler bath at room temperature until its content attains that temperature. It is then removed from the water bath, wiped dr}' and discharged for a few seconds (about 5 sec) to remove water and non- homogeneous mixtures from the valve and dip tube. The aerosol container is weighed and the valve is held open for about 10 sec. after which the container is reweighed. The discharge rate is calculated by dividing the weight loss by the time of discharge. The mean of at least three such determinations, as well as other statistical parameters (such as standard deviation and standard error) are calculated. v. Flammability (Flame extension test) I he risk of flammability is more pronounced when hydrocarbon propellants are used. Although CFC propellants are not inflammable the inclusion ofco-solvents such as ethanol may result in a flammable product, flic formulation pharmacist may reformulate the concentrate or the product mav be made to carry a danger alert on its label. The lest is carried out on aerosols to identify a product that may constitute a fire danger during storage and use. In the flame extension test the aerosol is discharged 18 cm from the flame of a standard candle for about 20 sec. I he tip of the candle flame is taken as the zero mark. A flame extension of over 20 cm indicates a combustible product, while an extension over 45 cm. indicates a flammable product. vi. Particle size analysis Particle size is of much importance for inhalational aerosols where it is essential that the panicles reach deep down into the respiratory lice and are not exhaled in the breath. Large particles are not ideal for insecticidal space sprays since they tend to fall out of the atmosphere too quickly; and too small particles may slipstream around the insect without impacting on it. Particle size may be directly measured by using the cascade impactor or by light scattering and diffraction techniques. Photographs of dyed particles can be projected onto a screen and particle size determined therefrom. Light microscopy can also be employed to determine particle size, vii. Moisture determination I he presence of moisture in the propellant and in the finished product may decrease the stability of the product, and may cause corrosion of the container especially when trichlorofluoromethane (C.CLF) is used as the propellant. Where the aerosol can be sacrificed it* is punctured to allow the volatile components to evaporate: where the aerosol is to be retained, a representative sample may be withdrawn from the container by inserting a sawn-off hypodermic needle into the valve orifice. Moisture is determined in the residue by the Karl Fischer method. (Water is 14 (iliumiiaii\( I) de lei mined by titration under anhydrous conditions by the u\t of a reagent that (oniains iodine, sulfur IVovdc, pyrid.ru and mtm.. d 71k c nd pur: may be detected wttalfy, oi preferably, by the use of the electrometric and automat taronon assembly 1 viii. Toxicity I aboratorv experimentation has shown that Cuorocafhe.? propellants caused death in mice as a result of being toxic io the heart of the m.c 1 x propellant were thought to have several negative cardioloxic effects that prc< r:f ’cd hradyanby’hnia^ tachsarrhythrmas or myocardial depression. Another group f h er' 'is f'irU t1'.-’ lo.k of* oxygen, and not cardi ic toxicity of the fluorocarbon propellants. ». s k'P ';sc IK d