20 Pharmaceutical Aerosols JOHN J. SCIARRA and ANTHONY J. CUTIE ‘The packaging of therapeutically active ingredi- ents in a pressurized system is not new to the pharmaceutical industry. According to present day usage, an aerosol or pressurized package is defined as “a system that depends on the power tents from the contamer.” Tt is in light of this definition that the terms aerosol, pressure pack- age, pressurized package, and other similar terms are used in this chapter. ‘Although pressurized. packages existed during the early 1900s, if was not until 1942, when the first aerosol insecticide was developed by Good- hue and Sullivan of the United States Depart- ment of Agriculture,’ that the aerosol industry was begun. The principles of aerosol technology were applied to the development of pharmaceu- tical aerosols in the early 1950s. These aerosol products were intended for topical administra- tion for the treatment of burns, minor cuts and bruises, infections, and various dermatologic conditions. Aerosol products intended for local activity in the respiratory tract appeared in 1955, when epinephrine was made available in a pressurized package. Based on their acceptabil- ity to both patient and physician, and their wide- spread use, pharmaceutical aerosols represent a significant dosage form and should be consid- ered along with other dosage forms, such as tab- lets, capsules, solutions, ete. An examination of the aerosol dosage form reveals the following specific advantages over other dosage forms: L lose can be removed without contamina- tion of remaining material. Stability is enhanced for those substances adversely affected by oxy- gen and/or moisture. When sterility is an impor- tant factor, it can be maintained while a dose is being dispensed. 2. ‘The medication can be delivered directly to the affected area in a desired form, such as spray, stream, quick-breaking foam, or stable foarn. 4 Inritation produced by the mechanical ap- plication of topical medication is reduced or eliminated. ‘Other advantages are ease and convenience of application and application of medication in a thin layer. Components of Aerosol Package ‘An aerosol product consists of the following ‘component parts: (1) propellant, (2) container, (3) valve and actuator, and (4) product concen trate. Propellants The propellant i responsible for develoing thé proy eee sssure within the container, and it cape the product when the valvels opened and alds in the atomization or foam production of the “product, Various types OF propellants are uti- tiredWhile the fluorinated hydrocarbons such as trichloromonofluoromethane (propellant 11), dichlorodifluoromethane (propellant 12), and dichlorotetrafluoroethane (propellant 114) find widespread use in most aerosols for oral and in- halation use, topical pharmaceutical aerosols utilize hydrocarbons (propane, butane, and iso- butane) and compressed gases such as nitrogen, citbon dioxide, and nitrous oxide. The physico- chemical properties of the propellants have been reviewed in other publications~* Listed in Table 20-1 are the commonly used propellants together with several of their physicochemical properties. Those properties of particular inter- est to the industrial pharmacist have been in- cluded. Blends of various fluorocarbon propel- lants gre generally used for pharmaceutical ere‘Taste 20-1. Physicochemical Properties of Fluorocarbon and Hydrocarbon Propellants® Vapor Liquid Pressure Boiling Density (psia) Point (aim) ‘Numerical Chemical Name Designation 70°F 10°F °F °c 70°F ‘Trichloromonofluoromethane u 134 390 m7 (37 149 Dichlorodifluoromethane 2 849 1960 “216-298 1 Dichlorotetrafluoroethane 14 278 635 38436 147 Difluoroethane 152a 74 191.0 “112-240 os1 Butane AIT 316 82.0 311-06 058 Tsobutane ASI 458 1110 109-118 056 Propane A108 1228 270.7 -37 -446 aerosols and are dicated in Table 20-2. By varying the proportion of each component, any desired vapor pressure can be achieved within the limits of the vapor pressure of the individual propellants. ‘As with the fluorocarbons, a range of pres- sures can be obtained by mixing the various hydrocarbons in varying proportions. Since the hydrocarbons are naturally occurring products, 050 however, their purity varies, and the blending is done onthe basis of the desired final pressure and not on the percentage of each component present. The pressure of each individual compo- nent varies somewhat, depending on the degree of purity. Table 20-3 illustrates some of the com- monly used blends that are commercially avail- able. . The vapor pressure of a mixture of propellants Tate 20-2. Blends of Fluorocarbon Propellants for Pharmaceutical Aerosols Vapor Pressure Density Propellant (psig) (giml) Blend* Composition 70°F 70°F rit 50: 374 1Al2 wn 60:40 441 1.396 raid 70:30 56.1 1.368 iis 40:60 398 1412 1214 45:55 428 1.405 iaiig 55:45 484 1.390 “Its generally understod that the designation “propellant 12/114 (70:20) indieates a composition of 703% by weight of propellant 12 and 30% by weight of propellant 114 Taste 20-3, Vapor Pressure of Hydrocarbons® Pressure Composition (mol 5) (psig) Designation 70F n= Butane Propane Isobutane Other 4-108: 108 + 4 traces 99 1 traces of ethane 4-70 70 +2 1 51 48 52 5222 2 28 70 AG 4622 2 20 78 A40 40+ 2 12 86 ASI 22 3 1 96 ADd M22 492 06 50 0.1 each neopentane and isopentane AlT +2 98 traces 2 traces of isopentane “Designations used by Philips Chemical Company, Barlesville, OK 590+ The Theory and Practice of Industrial Pharmacycan be calculated accordin which states thatthe tot ressue in any sys- 1S equal to the sumtof the indi Sarprestures-of ihe varous-compner oult’saw, which regards lowering of the vapor ‘pressure Of a liquid by the addition of another substance, states that the depression of the vapor pressure of a solvent upan the addition of ‘solute (something added to the solvent) is pro- portional to the mote fraction of solute molecules inthe solution Given ideal behavior, the vapor pressure of a mixture consisting of two individ- ual propellants is equal to the sum of the mole fraction of each component present multiplied by the vapor pressure of each pure propellant at the desired temperature. This relationship can be shown mathematically y+ My Ps Pao = Napao a where: p, = partial vapor pressure of propel- lant A Pao = Vapor pressure of pure propellant A = moles of propellant A ny = moles of propellant B Na = mole fraction of component A To calculate the partial vapor pressure of propel- lant B Dy, mb Dao mm +n, PO Nopso Q) ‘The total vapor pressure of the system is then obtained from: | P=p.+p > where P is the total vapor pressure of the sys- tem, When one component is present in relatively Jow concentration, ideal behavior is approached. For practical purposes, however, the calculated pressure is sufficiently accurate for most deter- minations. The application of Raoult’s law for calculation of vapor pressure can best be illus- trated by the following example. Calculate the vapor pressure at 70°F of a pro- pellant blend consisting of propellant 12/11 (80:70) (see Table 20-2), Moles of each substance: = Neigh 70 _ 9 595 moles, ; MW, 737.38 0.5095 0.5095 moles of propellant 11 weight, 30 MWi2 120.93 0.2481 moles of propellant 12 molesis = = 0.2481 From Roault’s law: 0.2481 0.2481 + 0.5095 27.80 psia partial pressure of propellant 12 Pio 84.9 = 27.80 psia Vapor pressure of propellant 12/11 (30:70) then equals 27.80 + 9.01, or 36.81 psia, Gauge pres- sure is obtained from: or: 36.8] = 14.7 = 22.11 psig A difference is noted in comparing the calcu- lated value for the vapor pressure with the ex- perimental value shown in Table 20-2. The dif- ference is due to deviation from ideal behavior. Flanner studied the effect of various polar and semipolar solvents and prepared vapor pressure curves.” A curve typical of this deviation is shown in Figure 20-1 Figure 20-2 shows the range of pressures available using various fluorinated hydrocar- bons, while Figure 20-3 illustrates these ranges for hydrocarbons. Graphs that relate vapor pres- sure to temperature are available, and these graphs can be utilized to determine the vapor pressure at the appropriate temperature. Containers Various materials as indicated in the following outline have been used for the manufacture of aerosol containers, which must withstand pres- sures as high as 140 to 180 psig at 130°F ‘The abbreviation psta is for pounds per square inch ab- solute, which can be converted to pounds per square inch gauge (psig) by subtracting atmospheric pressure (14.7) from psia, PHARMACEUTICAL AEROSOLS * 591Ea eae ‘Timplate Containers. The tinplated see! VAPOR PRESSURE || container consists of a sheét of steel plate that, COMPOSITION @ T0%F :| has been electroplated on both sides with tin. Mitre of : “HG thickness of the tin coating is described in sonetron: 32/01 i terms ofits weight, for example, #25, #50, and et #100. The size of the container is indicated by 2 HIE 8 standard system, which is a measure of the di- fe ameter and heighit of the container. A containez said to be 202 * 214 is 2%%e inches in diameter and 2g inches in height“! Brief discussion of the procedure used in the manufacture of tinplated containers might be advantageous for a better appreciation of the quality contol aspects. Jinplated_steel is ob- tained in thin sheets, and when required, itis ani 1686 sheets, boat are lithographed at this point. After the sheet is “cut ino sizes to make a body, a top-andl abot tom, each piece |s Tabricated into the- desired shape. he bodys shaped inie-a colinder and ‘famed vis-« Hanging and soldering-operaton remot fhe top and bottom are attached! tothe bady-and Tr Ba ero @ side seam stripe is added to the inside seam =] area when required. The organic coating also a can be added to the finished container rather ween PencenT proretLanr than to the flat sheets, This procedure is slower FIG. 20-1. Deviation of eapor pressure of nonideal sole. and somewhat more expensive, but a more con- tions from Roauit’s Inu. (Courtesy of Aled Chemical Cor. tinuous and durable coating is produced. The poration, Morristown, NJ.) use of sealing compounds, types of solder, and organic coatings are discussed in this chapter under the heading “Fermulation of Pharmaceu- Ao tical Aerosols.” 1. Tinplaed steel ‘A recent development in metal tinplate con- wie sears (thre-plece) tainers is the welded side-seam.'* Welding elim- b. Twoplece or draw nates the soldering operation, saves considera- ©. Tinfroe stel ble manufacturing me, and decreases the 2 Aluminum possibility of product/container interaction. In 2 Twoplece zeneral, two processes are used: the Soudronic One-piece (extruded or drawn) system (American Can Company, Crown Cork 3. Stainless steel and Seal, and the Southem Can Company) and B. Glass the Conoweld system (Continental Can’ Com- 1. Uncoated glass pany). The Soudronic system is based on an 2, Plasticcoated glass electronically controlled resistance welding method that uses a copper wire as an electrode. ‘The rounded bodies are welded and then sent to the conventional line, where the top and bottom ends are flanged as indicated previously. The Conoweld system passes the folded body through two rotating electrode rings. The rest of the container is manufactured in the usual man- ner Aluminum Containers. Aluminum is used to manufacture extruded (Seamless) aetosol containers. Many ME pharmaceuticals are = packaged in aluminum containers, probably be- FIG. 20.2. Range of pressures obtainable at 76°F with cause of the lessened danger of incompatibility ‘various fluorocarbon propellants. (Courtesy of E. duPont due to its seamless nature and greater resistance de Nemours and Co,, Inc., Wilmington, DE.) to corrosion. Aluminum can be rather unpredict- 592+ The Theory and Practice of Industrial Pharmacy‘fuvdiay prorony sdineya fo fissuna) ‘suoqioo0sphy Jo sounssoud ody “E-0% “DEL vy By ; a. eS ais 7 3 §5 ee ; — bg i” t joz g bab : ee is Br 8 oor Z pes PHARMACEUTICAL AEROSOES * 593able, however, in that it is corroded by pure water and pure ethanol. The combination of eth- “anol and propellant 11 in an aluminum con- tainer has been shown to produce hydrogen, acetyl chloride, aluminum chloride, propellant 2i, and other corrosive products Stainless Steel Containers. These con- tainers are limited to the smaller sizes, owing to production problems as well as cost. They are extremely strong and resistant to most materi- als. Stainless steel containers have been used for inhalation aerosols. In most cases, no internal organic coating is required. Glass Containers. Glass aerosol containers have been used for a large number of aerosol pharmaceuticals. Glass containers are-available ‘with or without plastic coatings. The plastic coating may be totally adhered (except for the neck ring) or nonadhered and vented. By adjust- ing the formulation and limiting the type and quantity of propellant, satisfactory aerosol prod- ucts can be formulated and packaged in glass containers. Glass aerosol containers are prefera- ble from a compatibility viewpoint, since corro- sion problems are eliminated. The use of glass also_allows for a greater degree of freedom in design of the container. Valves ‘The present-day aerosol valve is multifunc- tional in that itis capable of being easily opened and closed, and in addition, is capat liver- in he sua hago. Fate thote, especially in the case of phanmacenticals, the valve is expected to deliver a given amount cof medication. Valves for pharmaceuticals usu- “Aly do not differ from the valves used for nonpharmaceutical aerosol products, but the requirements for pharmaceuticals are usually more stringent than for most other products." The materials used in the construction of the valve must be approved by the Food and Drug Administration. Pharmaceutical aerosols may be dispensed as a spray, foam, or solid stream, and they may or may not require dosage control. The need for several different types of valves be- comes apparent. Continuous Spray Valves. An aerosol valve consists of many different parts and is assem- bled using high-speed production techniques. The valve manufacturers adhere to relatively close tolerances during manufacture and assem- bly of the valve. Various materials are used to manufacture the many components of the valve. Figures 20-4 and 20-5 illustrate typical aerosol valve assemblies for use with cans or bottles, 594+ The Theory and Practice of Industrial Pharmacy z see FIG, 20-4. A, Vapor tap body. B, Aerosol gn vatve assem: bly. (Courtesy of Precision Valve Corporation, Yonkers, NY) respectively. These valve assemblies consist of the following parts. Ferrule or Mounting Cup. The ferrule or mounting cup is used to attach of r the container. For use with containers having, a one-inch opening, the cup is made from tin- plate steel, although aluminum also can be used. Since the underside of the valve cup is exposed to the contents of the container and to the ef- fects of oxygen trapped in the head space, a sin- gle or double epoxy or vinyl coating can be added to increase resistance to corrosion. Ferrules are used with glass bottles or small alu e8 -adare usu ie froma softer metal such as aTaminum_or brass ‘The ferrule is attached to container either by rolling the end under thei. Cp A B D — CR ste = FIG. 20.5. Aerosol bottle yalve assembly: A, ferrule; B, stem: C, valve seat; D, value body, E, mounting gasket; F dip tube, (Courtesy of Risdon Manufacturing Co., Nauga- tuck, CT) lip of the bottle or by clinching the metal under the lip. Valve Body or Housing. The housing is generally manufactured from Nvlon or Delrin and contains an opening at the point of the at- tachment of the dip tube, which ranges from about_0.013 inch to 0,080 inch. The housing may-oF may not contain another opening referred to as the “vapor tap.” The vapor tap allows for the escape of vaporized propellant along with the liquid product (See The vapor tap Further produces a fine particle ven Tale are a sizé_prevents ¥ TORR Wh TUES cr taining insoluble materials, allows for the prod- ari be seustactonly dispensed with the c be satisfactorily dispensed with the con- Tamer_in the inve sition, the chilling ct of the propellant on the skin, and Are ee o roan olan or a decrease in fame extension. These vapor tap ‘Openings are available in sizes ranging from about 0.013 inch to 0.080 inch. Stem. The stem is made from Nylon or Del- in, but metals suthras-brass-and stainless steel can be utilized also. One or more orifices are set into the stem; they range from one orifice of about 0.013 inch to 0.030 inch, to three orifices of 0.040 inch each. Gasket. Buna-! Neoprene rubber are commonly used for the gasket material and are’ compatible with most pharmaceutical formula- tions, Spring. The spring serves to hold the gasket {in place, and when the actuator is depressed and released, it returns the valve to its closed posi- tion. Stainless steel can be used with most aero- sols, Dip Tube. Dip tubes are made from polyeth- ene or polfpropyiene~ Hoth materials are ac- “ceptable for use although the polypropylene tube is usually 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 highly vis- cous products may be as lange as 0.195 inch, Vis- cosity and the desired delivery rate play an im- t_tle_in the selection of the inner Hametar of the dip tube Metering Valves. Metering valves are appli- cable _to the dispensing of potent medication. ‘These operate on the principle of a chamber whose size determines the amount of medica- tion dispensed. This is shown in Figure 20-6. Although these have been used to a great extent for aerosol products, they are limited in both size and accuracy of dosage. Approximately 50 to 150 mg + 10% of liquid material can be dis- pensed at one time with the use of such valves. FIG. 20-6, Metering valve for pharmaceutical aerosols: A, mounting ferrule; B, plastic housing; C, capillary dip tube; D, outlet valve seal; E, inlet valve seal F, two-piece stain less steel stem; G, stainless steel spring; H, stainless steel ‘washer; I, sealing gasket. (Courtesy of Emson Research, Bridgeport, CT. PHARMACEUTICAL AEROSOLS *595Actuators To ensure that the aerosol product is delivered in the proper and desired form.a specially de- signed button or actuator must be fitted to the Sten The actuator allows for easy open- ng and closing of the valve and is an integral Part_of almost every aerosol package. It also ‘serves to aid in producing the required type of product discharge There are many different types of actuators, Among them are those that produce (1) ypray, (2) foam, (3) solid stream, and (4) special ppl cations ~— ~~ Spray Actuators. Figure 20-7 illustrates ac- ‘uators that are capable of dispersing the stream of product concentrate and propellant into rela- tively small particles by allowing the stream to FIG. 20-7. Actuators for pharmaceutical aerosols. A, In- hhalation spray type. (Courtesy of Riker Laboratories )B, Mechanical breakup type. (Courtesy of Risdon Manufac: turing Co., Naugatuck, CT 596 +The Theory and Practice of Industrial Pharmacy pass through various openings (of which there may be one to three on the order of 0.016 inch to 0.040 inch in diameter—see Figure 20-74). Where there is a large percentage of propellant Mixture containing a sufficient quantity of 2 low boring propellant such as propel fant TS or pro- Pane, actuators Taving relatively large orifices Srte used. The Combination of propellant va porization and actuator orifice and internal channels can deliver the spray in the desired particle size range. A spra\ actuator can be used with pharmaceuticals intended for topical ise, wach as-spray-on_bandages._aniseutics, focal _anesthetics, and foot preparations. When these actuators are used with aerosol products containing relatively low amounts of propellants (50% or less), the product is dispensed as a stream rather than as a spray, since the propel- lant present in the product is not sufficient to disperse the product fully. For these products, a mechanical breakup actuator is usually required (Fig, 20-7B). These actuators are capable of “mechanically” breaking a stream into fine par- ticles by causing the stream to “swirl” through various channels built into the actuator. Foam Actuators, These actuators consist of relatively large orifices ranging from approxi- mately 0.070 inch to 0.125 inch and greater (Fig. 20-8). The orifices allow for passage of the product into’ relatively large chamber, where it ‘can expand and be dispensed through the large orifice. — ~ Solid-Stream Actuators. The dispensing of such semisolid products as ointments generally requifes these actuators, Relatively large open- ings allow for the passage of product through the valve stem and into the actuator. These are es- sentially similar to foam type actuators. Special Actuators. Many of the pharmaceu- tical and medicinal aerosols require a specially designed actuator to accomplish a specific pur- pose. They are designed to deliver the medica- tion to the appropriate site of action—chroat, ose, eve, or vaginal tract, Several are shown in i Metered-Dose Inhalers. Over the last four to five years, there has been an inereased inter- est in modifying metered-dose inhalers (MDIs) to minimize the number of administration errors and to improve the drug delivery of aerosolized partcles tina the nasal passageways and respira- tory airways. Some of these modifications have inclided the introduction of tube spacers, breath actuators, and portable plastic reservoirs with inhalation aerosols. In the case of intra nasal preparations, new propellant-free metered pumps have been introduced to replace the tra- ditional propellant delivery system:During the fate 70s and early 80s, there were 2 number of in vivo and in vitro studies evaluat- ing the differences between the conventional adaptors and the expanded chamber adaptors, referred to as “spacets,” or “tube spacers.”"* At present, many conventional short-stem MDIs Geliver at best only 10 to 15% of the dose actu- ated into the respiratory airways. The balance of the dose is either lost to the inner surface of the adaptor (approximately 10%), or is deposited through inertial impaction in the oropharynx area (80%). ter leads to swallowing and possible systemic absorption of the therapeutic seen ise ena atFen lst fi amar and avaloted, 2 of tube spacers of various geometric shapes and Aiiensions wase consieze, since they shoul, at least in theory. minimize some of the effects produced by inertial compaction, which contrib- iites significantly to this problem. “Tobin et al, in attempting to further improve and simplify the delivery of aerosolized drag from an MDi, developed a new reservoir aerosol- type delivery system (RADS), consisting of a 700-mi collapsible plastic bag into which the aerosol can be injected.'® This unit is designed to allow patients more time to inhale the medica- tion after actuating than did the conventional MDI, and it eliminates some of the loss of medi- cation associated with too rapid propulsion or inhalation of aerosolized drugs. This unit (InspirEase by Key Pharmaceuticals, Inc.) con- sists of a collapsible reservoir bag and a special mouthpiece that is fitted with a reed that prov duces a warning sound when patients are inhal- ing too quickly. Anew metered propelantsive-intsanasal pump Has recently been introduced to deliver flunisolide, an cficcuve steroidal agent in the reef of siptoms asta sh Seana or perenni S- 1 pump permits the ad- ministration of a metered dose of steroid without utilizing propellants, which by their cooling ef- fects often cause smarting and irritation to the nasal mucosa. The metered aerosol pump also ensures accurate dosage and eliminates many of the administration problems associated with nose drops. The concept of propellant-free me- tered delivery offers a new dimension to intra- nasal delivery of potent therapeutic agents. Formulation of Pharmaceutical Aerosols An aerosol formulation consists of nwo essen- tial components: product concentrate and p pellant. The product concentiate Consists oF ae. tive ingredients, or a mixture of active ingredients, and other necessary agents such as solvents, antioxidants, and surfactants. The pro- pellant may be a single propellant or a blend of various propellants; it can be compared with other vehicles used in a pharmaceutical formu- lation. Just as a blend of solvents is used to achieve desired solubility characteristics, oxar- jous surfactants are mixed to give the proper HLS value foran emulsion sytem, (he Pel. lant is selected to give the desired vapor pres- ‘Sure, solubility. and particle “Sikce one mast be familiar with the physteo- chemical properties of surfactants, solvents, and suspending agents, it follows that the formulator of aerosol preparations must be thoroughly fa- miliar with propellants and the effect the propel- lant will have upon the finished product. Propel- Jants can be combined with active ingredients in many different ways, producing products with varying characteristics. Depending on the type of aerosol system utilized, the pharmaceutical, aerosal may be dispensed as a fine mist, wet spray, quick-breaking foam, stable foam, semi- solid, or solid. The tvpe of system selected de- pends on many factors, including the following: ay physical, chemical, and pharmacologic prop- erties of active ingredients, and ¥27 site of appli- cation. Types of Systems? Solution System. A large number of aerosol products can be formulated in this manner. This system s also referred to as a two-phase system and consists of a vapor and Tiquid phase. When the active ingredients are soh re propel- ilvent is requil pending ling on lant, no other sol ired. De] i¢ type of spray Tequired, the propellant may consist of pro -70 (which produce very fine particles), or a mixture of propellant 12. and other propellants as indicated in Tables 20-3, 90-9, and 90-3. As ater propellans with vapor pressures lower than that of propellant 12 ‘are added to propellant 12, the pressure of the “system decreases, resultin juction of larger particles, A lowering of the vapor pressure i0 is produced through the addition of less vol- aille solvents such as ethvl alcohol, propylene slycol, ethyl acetate, glycerin, and acetone. The amount of It 1%. r inhalation products) of the entire formulation. When a spray 18 pro- duced with larger particles, a decrease is noted in the number of fine particles, decreasing the danger of inhaling these materials through for- ‘mation and subsequent inhalation of airborne particles. These sprays are also useful for topical ‘HARMACEUTICAL AEROSOLS 597inhalation Inhalation Nasal Liquids, Foams Pharyngeal Nasal FIG. 20-8. Various actuators and applicators for pharmaceuticals. (Courtesy of Pechiney Ugine Kuhlman Development, Ine., Greenwich, CT.) preparations, since they tend to coat the affected area with a film of active ingredients. Depend- ing on the boiling point of the solvent used, the rate of vaporization of the propellant is’ de- creased, thereby increasing any chilling effect that may be present. This system can best be exemplified by the following general formula- tions: Weight % Active ingredients 10 10-15 Propellant 12/1 (50:50) 0 100 Propellant 12/11 (30:70), propellant 12/114 (45:55), or propellant 12/114 (65-45) also can be utilized for oral inhalation aerosols or other FDA-exempted products such as contraceptive foams. As the amount of propellant 12 is in- 598 + The Theory and Practice of Industrial Pharmacy creased, the pressure increases. With the excep- tion of propellant 12/11 (30:70), the pressure of these systems necessitates packaging the con- tents in a metal container. If the product is to be packaged in a glass container, a mixture of pro- pellant 12/114 (20:80) or (10:90) can be used. ‘Table 20-4 indicates the pressure limitations in using various aerosol containers ‘Aerosols intended for inhalation or for local activity in the respiratory system in the treat- ment of asthma may be formulated as follows: Weight % Isoproterenol HC] 025 Ascorbic acid a0 Ethanol 35.75 Propellant 12 63.90FIG. 20.8. (Continued) Nasal This type of formulation is usually packaged in a 15- to 30-ml stainless steel, aluminum, or glass container. Since propellant 12 has a rela~ tively high vapor pressure, the addition of pro- pellant 114 is recommended in order to reduce the pressure, as illustrated by the following ex- ample? Weight % Octy! nitrite a1 Ethanol 200 Propellant 114 492 Propellant 12 307 Hydrocarbons in topical aerosol pharmaceuti- cal preparations are used as follows: Weight % Active ingredients up to 10-15 Auricular Solvents such as ethanol or propylene glycol up to 10-15, Distilled wate, 10-15 Hydrocarbon propellant A-46 55-70 Depending on the amount of water present, the ‘inal product may nay be a solution or a three-phase, Solution aerosols produce a fine to “coarse spray, depending on the concentration of the ciher ingredients Hyancearbon. propellant 270 produces a drier particle, while propellants A-17 and A-31 tend to produce a wetter spray. Hydrocarbon propellants can also be used for products packaged in plastic-coated glass bot- tes, provided that the amount of flammable hydrocarbon propellant present does not exceed 15% of the total product weight and that the container has a volumetric capacity not exceed- ing 5 fluid ounces. In addition, one of every 1000 bottles must be tested to 250’psig without “allure. The manufacturer of the eros al product must {6st one bottle out of each lot of 20,000 PHARMACEUTICAL AEROSOLS +599Tante 20-4, Pressure Limitations of Nonrefilla- ble Aerosol Containers Maximum Pressure, Temperature os) 6 Tinplated Stel Tow pressure up t> 40" 130 2P ftom 140 to 160" 130 29 from 160 to 180° 80 ‘Uncoated glass Jess than 18t 70 Coated hase tess than 25 70 ‘Aton up wo 180; 180 Stainless steel up to 160 130 Plastic less than 25° 70 “Deparment of Transporation (DOT) Regulations. Consult regulations for definition of 2 P and 2 Q containers. ‘Aerosol containers with a pressure less than 25 psig 2t 70°F apd 89 psig at 130°F or a capacity of less than 4 fhuid ounces are ‘ot regulated by dhe DOT. "Exemptions can be obtained for higher pressures in these con bottles to the bursting paint, and the ursting ~presgure must not be less than 300 psig. One fully charged bottle from this lot must be dropped to an unyielding surface from a height of 4 feet without producing flying glass or a shat- tering effect. Should either of these two bottles fail, then 10 additional bottles must be tested for each failed test. Failure of any of these 10 sam- ples would cause the entire lot to be rejected. Finally, one fully charged bottle out of each 1000-bottle lot must be heated so that the pres- sure in the container is equivalent to the equilib- rium pressure of the contents at 130°P, without evidence of leakage or other defect." Water-Based System. Relatively large amounts of water can be used ‘to replace all or part_of the nonaqueous solvents used in aero- sols. These products are generally referred to as “Water-based” aerosols, and depending on the formulation, are emitted as a spray or foam. To produce a spray, the formulation must consist of a dispersion of active ingredients and other sol- plant 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 forms (propellant phase, Wmerphnse jase, and vapor hase) Eunanol has been used as-a CosONeAt to ‘Exemption DOT-E-8008 for 4-07. aerosol_bottles— Reguested and obtained by Wheaton Plasti-Cote Com- pany. 600 +The Theory and Practice of Industrial Pharmacy solubilize some of the propellant in the water. By ‘Virtue GF its surface-tension-lowering properties, ethanol also aids in the production of small par- ticles. Surfactants been used to a large extent to produce a satisfactory homogeneous disper- sion, Surfactants that possess low water solubil- fy anc high solubility in nonpolar solvents bave found to be the most useful. Long-chain Tatty acid esters of polyhydroxylic compounds including glycol, glycerol, and sorbitol esters of oleic, stearic, palmitic, and lauric acids exem- plify this series. In general, about 0.5 to 2.0% of surfactant is used. The propellant content varies from about 25 to 60%, but can be as low as 5%, depending on the nature of the product. To achieve the desired fine particle size with products containing large amounts of water and a low proportion of propellant, a mechanical breakup actuator must be used along with a “vapor tap valve.” A recent development that is useful for phar. maceutical aerosols is the Aquasgl* Valve.”* eno Aguas stem he dope Ing of a fi ist or spray of it solved in water, which is nat possible with the usual three-phase system. Since only active Ingredient and water are dispensed (propellant is in vapor state and present only in extremely small quantity), there is no chilling effect as oc- curs with the hydrocarbon propellant. The Aquasol system is illustrated in Figures 20-9 and 20-10. It is designed to dispense pres- surized products efficiently and economically using relatively small amounts of hydrocarbon propellant; however, it can also function effec- fively using fluorocarbon propellants. This sys- tem, which is essentially a “ sol, permits the use of fairly large quantities of water in the formulation. ‘The chief d deren peur the Aguasa} ss tem_and the “three-phase” system is that the former dispenses a fairl ‘spray with very. i is relative dryness and small article size are due chiefly tothe design of the valve, which dispenses vaporized propellant rather than liquefied propellant. In addition, the vaporized propellant contributes to the nonflam- mability of the stream of product as it is dis- pensed. For example, a fine, almost dry spray is obtained using six parts of water with one part of hydrocarbon propellant. Not only is the resulting spray nonflammable, but it actually extin- guishes an open flame. As can be noted from Figure 20-9, the active ‘Precision Valve Corporation, Yonkers, NY.FIG. 20-9. The Aquasol dispenser system—valve clased. (Courtesy of Precision Valve Corporation, Yonkers, NY.) ingredient is dissolved or suspended in water or in a mixture of alcohol and water. The hydroc: bon propellant floats on top of the aqueous layer and exists as both a liquid and a vapor. Depend- ing on the amount of alcohol present in the aqueous layer, the propellant and water/alcohol layer may or may not be immiscible. As the amount of alcohol increases, the miscibility of, these two layers increases. As a pure alcohol sys- tem is approached, complete miscibility occurs, at which time a two-phase system that can func tion satisfactorily is produced. Flammability is PHARMACEUTICAL AEROSOLS * 601VALVE OPEN OA LS Lae Ns Aaa ay, BEEEEZ Vy 7 FIG. 20-10. The Aquasol dispenser system—valve open. (Courtesy of Precision Valve Corporation, Yonkers, NY.) increased, however, owing to the large amount of alcohol present, as well as to the fact that liq- uid propellant is now also being dispensed. In the Aquasol system, the vapor phase of the propellant and the product enter the mixing chamber of the actuator through separate ducts or channels. Moving at tremendous velocity, the vaporized propellant enters into the actuator {802+ The Theory and Practice of Industrial Pharmacy while the product is forced into the actuator by the pressure of the propellant. At this point, product and vapor are mixed with violent force, resulting in a uniform, finely dispersed spray. Depending on the configuration of the valve and actuator, either a fine dry spray or a coarse. wet spray can be obiained. Previous studies have shown that a fine dry spray is obtainedwhen a ratio of about 6 parts of product to 1 part of propeliant is used. Up to 30 parts of product to one part of propellant has also produced a satis- factory spray, but in this case, a more coarse spray results. In the Aquasol system, itis almost impossible to dispense only the pure propellant until the package is depleted of the aqueous product, Suspension or Dispersion Systems. Vari- ous methods have been used to overcome the \_— ( ACcHs0),Al + 3H, ‘The hydrogen, which is slowly liberated, in- creases the pressure in the container. This in- crease in pressure, along with a general dissolv- ing of some of the aluminum, may result in rupture of the container. This reaction can be reduced or prevented by anodizing the alumi- num and adding water to formula. The presence of 2 to 3% water tends to inhibit the reaction. Nonpolar solvents appear to be relatively safe in aluminum containers. Polar solvents tend to be corrosive to bare aluminum, but the reaction can be controlled by the addition of water and/or other inhibitors. Other Containers. Creams and ointments ‘may be dispensed from a pressurized container by the use of an aluminum container that has been fitted with a piston and nitrogen or hydro- carbon as the propellant. When the valve is gpened, the pressure against the piston pushes, the piston, causing the product to be dispensed. The viscosity of the finished product plays din important role in the satisfactory dispensing of the product. Many attempts have been made to separate product from the propellant. One such system utilizes an_“accordion-pleated” plastic bag as shown in Figure 20-11. The product is placed inside the bag, and propellant is injected into the outer container through the rubber-plugged hole located in the bottom of the container. ‘Another development in barrier packs uses a laminated film made into a flexible bag. A perfo- tated dip tube is attached to the valve and fune- tions to prevent the bag from collapsing as the contents are used. This system, termed “Powr Flo" (American Can Company 3 Uschul Tor dis pensing pharamceutical ointments and creams. pensing pharamiceutical ointments and creams. PHARMACEUTICAL AEROSOLS + 607FIG. 20-11. Sepro container. (Courtesy of Continental Can Company, Chicago, IL.) The Preval system not only separates the pro- pellant from the product, but allows the product to be dispensed as a spray or powder. This sys- tem consists of an aluminum cartridge contain- ing propellant 12 and an aerosol valve. A dip tube extends from the propellant chamber to the bottom of the container and allows for the flow of product when the valve is opened. Around the top of the valve housing, a Vapor tap is placed, which extends into the propellant chamber. The product is added to the container (which need not be a pressure container), and then the valve with propellant cartridge is inserted. When the specially designed actuator is depressed, propel- lant vapor escapes from the propellant chamber. ‘This creates a “venturi” effect, drawing up some of the product. At this point, mixing of propel- lant vapor and product takes place. The vapor- ized propellant then aids in carrying the product through the actuator, where it is dispersed into the desired spray. Varying ratios of propellant to product can be achieved, with results ranging from a fine to a coarse spray (Fig. 20-12), ‘A nonaerosol package that is self-evacuating has been developed by Plant Industries and is known as Selvac. This system utilizes a resilient bladder, which is filled with the product. As the product is filled into the bladder, the bladder 608+ The Theory and Practice of Industrial Pharmacy stretches, thereby causing mechanical energy to squeeze Out the contents as the valve is released. Since this system does not contain a gas, there is little internal pressure. Two bladders are used, assembled one inside the other. The outer blad- der is usually made from natural rubber latex. The valve is inserted into the bladder, and this unit is then fitted into an outer nonpressurized container. The product is filled through the valve by means of a piston-type filler, which forces the product into the bladder. Valves, Actuators, and Applicators. Valves are selected on the basis of materials of cons si s orifices. Al- jough it is extremely difficult to indicate the proper valve for each product, suggested valve designs for specific applications are available. ‘Various applicators have been specially de- signed for use with aerosol pharmaceuticals. Inhalation actuators must have all the charac- teristics of spray actuators and must allow es- cape of propellant vapors so that the vapors are not inhaled in appreciable amounts by the user. ‘Throat applicators must be capable of depositing the medication directly into the throat area. Elongated tubes having small internal orifices, which permit a breakup of the spray, are gener- ally used. Nasal actuators are designed to fit into the nose and deliver the product as a fine mist. Other applicators have been designed for spe- cific uses, including vaginal application, oph- thalmic application, and others. (See Figs. 20-7 and 20-8.) Stability Testing of Pharmaceutical Aerosols One of the most important considerations in the formulation of a pharmaceutical aerosol is its stability. Those aspects directly concemed with the components used to prepare the pharmaceu- tical aerosol must be fully studied. The effect that the container has upon the product, and conversely, the effect of product upon container, must be considered The same considerations apply to the valve components. Even slight changes in the various components of the valve may result in an inop- erative package. The valve component of the aerosol package has several working parts made of different materials, such as natural or syn- thetic rubber, plastic, and stainless steel. All these materials may produce an adverse effect on the product and must be fully studied. Since a variety of different materials are used in the make-up of the container, valve, and dip tube, it is difficult to determine whether a reac-a tion takes place between the materials and the drug. Many of the components come into inti- mate contact with the medicinal agent. To deter- mine whether these reactions do occur, all mate- rials must be studied separately and collectively. Several container coatings as well as valves with different subcomponents may be studied so that any reaction between the component and the product may be detected. Samples are prepared and packaged in glass aerosol containers as con- trols. ‘The testing of these aerosols must cover three areas: (1) concentrate and propellant, (2) con- tainer, and (8) valve, Evidence of decomposition ordeterioration in any of these areas could result in an ineffective product. A more detailed dis- eussion of the testing of aerosols can be found elsewhere in the literature.” Concentrate and Propellant. Immediately after preparation, several of the important physi- cochemical constants of the product are deter- mined. These vary, depending on the nature of the product, but may well include vapor pres- sure, spray rate of valve, pH, density or specific gravity, refractive index, viscosity, total weight, assay of active ingredients, infrared, and/or gas PROPELLANT vapor D> SND PRooUeT DISPENSED 20-12, Schematic view of Preval. (Courtesy of Precision Valve Corporation, Yonkers, NY.) chromatography curves, color, and odor, These are then used for comparison during each evalu- ation of the product. ‘These samples are usually stored on their sides so that the product comes into contact with both the valve mounting cup and the container. When three-piece metal cans are used, care should be taken to ensure that some samples have liquid as well as gaseous contact with the side-seams (soldered or welded) Container. The contents of the container are removed by chilling the contents to a tempera- ture of O°F or Jess and opening the container. ‘The container is then examined for signs of cor- rosion. These changes can be detected without much difficulty, since attack upon tinplate, tin- free steel, or aluminum is generally visible to the naked eye and under a microscope. Small pi holes can easily be detected. For those con. tainers that have internal lacquering, the exami- nation must ensure that. the lacquer is not softened, dissolved, peeled, or blistered by the concentrate. Special attention should be paid to the side-seam and headspace, as there is a greater danger of attack upon these areas. When glass is used for the container, an ex- PHARMACEUTICAL AEROSOLS #608amination of the container can be omitted. Plas- tic containers may require special testing to de- termine whether leaching or sorption has taken place. Valve. The valve should be examined to en- sure that it is-functional and will satisfactorily dispense the product and be easily closed. This can readily be determined during the dispensing of the product. The valve cup should be exam- ined for evidence of corrosion. The various valve subcomponents should also be examined for evi- dence of softening, cracking, elongation, or dis- tortion. Several of these effects can result in de- fective valves that will not operate properly. Elongation and cracking of the dip tube should be noted, and if present, corrected Manufacture of Pharmaceutical Aerosols To prepare and package pharmaceutical aero- sols successfully, special knowledge, skills, and equipment are required. As with other pharma- ceutical products, these operations must be car- ried out under strict supervision and adherence to rigid quality contrals. Since part of the manu- facturing operation (addition of propellant to concentrate) is carried out during the packaging operation, the quality control system must be modified to account for this difference. In addi- tion to the equipment used for the compounding of liquids, suspensions, emulsions, creams, and ointments, specialized equipment capable of handling and packaging materials at relatively. low temperatures (about —40°F) or under high pressure. must-be-available. This equipment is ‘usually limited to aerosol or pressurized packag- ing, and in most instances, cannot be used for other pharmaceutical operations. Pressure Filling Apparatus. Pressure fill- ing apparatus consists of a pressure burette ca- pable of metering small volumes of liquefied gas under pressure into an aerosol container. The propellant is added through the inlet valve lo- cated at the bottom or top of the burette ‘Trapped air is allowed to escape through the upper valve. The desired amount of propellant is, allowed to flow through the aerosol valve into the container under its own vapor pressure. ‘When the pressure is equalized between the burette and the container (this happens with low-pressure propellants), the propellant stops flowing. To aid in adding additional propellant, a hose leading to a cylinder of nitrogen or com- pressed air is attached to the upper valve, and the added nitrogen pressure causes the propel- lant to flow. Another pressure filling device 610+ The Theory and Practice of Industrial Pharmacy makes use of a piston arrangement so that a pos- itive pressure is always maintained. Figure 20-13 illustrates typical laboratory pressure fill- ing equipment. This equipment cannot be used to fill inhalation aerosols fitted with a metered valve. Pressure filling equipment that fills through “pressure-fillable” metered valves is available Cold Filling Apparatus. Cold filling appara- tus is somewhat simpler than the pressure fill- ing apparatus. All that is needed is an insulated box fitted with copper tubing that has been coiled to increase the area exposed to cooling. Figure 20-14 illustrates such a unit, which must be filled with dry ice/acetone prior to use. This, system can be used with metered valves as well as with nonmetered valves; however, it should not be used to fill hydrocarbon aerosols since an excessive amount of propellant escaping and vaporizing may form an explosive mixture at the floor level (or lowest level). Fluorocarbon vapors, although also heavier than air, do not form ex- plosive or flammable mixtures. Compressed Gas Filling Apparatus. Com- pressed gases can be handled easily in the labo- ratory without the use of elaborate equipment. FIG. 20-13. Pressure burets for laboratory filling of aero- sols. (Courtesy of Aerosol Laboratory Equipment Corpora- tion, Walton, NY.)FIG, 20-14, Apparatus for cold filling process. (Courtesy of E. I duPont de Nemours and Co,, Inc., Wilmington, DE.) Since the compressed gases are under high pressure, a pressure-reducing valve is required Attached to the delivery gauge is a flexible hose capable of withstanding about_150 pounds per square inch gauge pressure and fitted with a fill- ing head. More elaborate units utilize a flow in- dicator between the gauge and the flexible hose. To use this equipment for filling aerosols’ with compressed gases, the concentrate is placed in the container, the valve is crimped in place, and the air is evacuated by means of a vacuum pump. The filling head is inserted into the valve opening, the valve is depressed, and the gas is allowed to flow into the container. When the pressure within the container is equal to the de- livery pressure, the gas stops flowing. For those products requiring an increased amount of gas, of for those in which solubility of the gas in the product is necessary, carbon dioxide and nitrous oxide can be used. To obtair: maximum solubil- ity of the gas in the product, the container is shaken manually during and after the filling ‘operation. Mechanical shakers are also available for this purpose. Large-Scale Equipment Good pharmaceutical manufacturing practice requires that the filling of pharmaceutical aero- sols be conducted under conditions that ensure freedom from contamination. Only equipment used specifically for aerosols is further discussed in this chapter. Concentrate Filler. This can range from a single-stage single hopper toa large straight-line multiple-head filler or a rotary type multiple- head filler. Production schedules dictate the type of filler required. Most of these fillers de- liver a constant Volume of product and they can be set to give a complete fill in one or more oper- ations. Usually, only part of the product is added at each stage, assuring a more accurate fill. Valve Placer. The valve can be placed over the container either manually or automatically. High-speed equipment utilizes the automatic valve placer. This orients the valve and places it in position prior to the crimping operation. Purger and Vacuum Crimper. Aerosols are * packaged in both metallic and glass containers, PrianMaceUnical AEROSOLS 6L1each requiring their own style of crimper. Com- bination can and bottle cappers can be used for most laboratory procedures and operate manu- ally or on air pressure (about 80 pounds per square inch). These are capable of producing more than 10 to 12 cans per minute. ‘Most crimpers serve a dual function, that is, to evacuate the air within the container to about 24 inches of mercury and then seal the valve in place. Single-head crimpers or multiple-head rotary units capable of vacuum crimping up to 120 cans per minute are available. These usu- ally require both air pressure (90 to 120 pounds per square inch) and vacuum. Pressure Filler. These units are capable of adding the propellant either through the valve stem, body, and dip tube, around the outside of the stem, or under the valve cup before crimp- ing, They are either single- or multiple-stage units arranged in a straight line or as a rotary unit. To speed production, a positive pressure is used to force the liquid propellant into the con- tainer. Evacuation of air from the container, crimp- ing the valve, and addition of the propellant can be achieved in basically one operation through the use of an “under the cap” filler. This unit operates as follows. A seal is made by lowering the crimping bell onto the container, air is re- moved by vacuum, and propellant is then me- tered into the container at room temperature and high pressure. The crimping collet expands and crimps the valve into the opening, This unit can be fitted with three to nine filling heads. Leak Test Tank. This consists of a large tank filled with water and containing heating units and a magnetized chain so that the cans or pucks for glass, aluminum, and plastic con- Cainers are carried through and submerged into the water. The length of the tankis such that the temperature of the product before it emerges from the tank is 130°F. According to DOT regulations, “each com- pleted container filled for shipment must have been heated until contents reached a minimum of 130°F, or attained the pressure it would exert at this temperature, without evidence of leaking, distortion, or other defects.” Manufacturing Procedure In general, the manufacture of aerosol prod- ucts takes place in two stages: manufacture of concentrate and addition of propellant. For this reasbn, part of the manufacturing operation takes place during the filling operation, which is quite different from nonaerosol pharmaceutical products. This necessitates special quality con- 612+ The Theory and Practice of Industrial Pharmacy trol measures during the filling operation to en- sure that both concentrate and propellant are brought together in the proper proportion. The aerosol concentrate is prepared according, to generally accepted procedures, and a sample is tested. Testing at this point can save both time and money should the concentrate prove to be unacceptable. Once the propellant is added and the product is sealed into a container with a valve, complete rejects must be discarded, obvi- ously a more costly solution. Early detection pre- vents the loss of the other components. This would also have made it possible to correct the rejected batch instead of discarding it. In many instances, this can be accomplished by making adjustments to the concentrate prior to aerosol filling. ‘Two methods have been developed for the fill. ing of aerosol products. The cold filling method requires the chilling of all components, includ- ing concentrate and propellant, to temperatures of -30 or —40*F, whereas the pressure filling method is carried out at room temperature uti- lizing pressure equipment. The type of product and size of container usually influence the method to be used. ‘The cold filling method is restricted to non- aqueous products and to those products not ad- versely affected by low temperatures in the range of 40°F. In this method, product concen- trate is chilled to ~40°F and added to the chilled container. The chilled propellant is then added in one or two stages, depending on the amount. An alternating method of cold filling is to chill both concentrate and propellant in a pressure vessel to —40°F and then add their mixture to the aerosol corftainer. A valve is then crimped in place. The container passes through a heated water bath in which the contents of the con- tainer are heated to 130°F to test for leaks and strength of container. The container is air-dried, spray-tested if necessary, capped, and labeled. (Containers may be lithographed, and as a.con- sequence, the latter step is omitted). This filing method is no longer used to any great extent and thas been replaced by the pressure filling proc- ess. Metered-dose aerosols can be filled by either process. The pressure filling method, when first devel- oped, was generally slower than the cold filling method. With the development of newer tech- nigues, the speed of this methoa has been greatly’ increased to make it comparable in rate Of production to the cold filling method. The concentrate is added to the container at room temperature, and the valve is crimped in place. The propellant is added through the valve or “under the cap.” Since the valve contains ex-tremely small openings (0,018 inch to 0.030 inch), this step is slow and limits production. With the development of rotary filling machines and newer filling heads, which allow propellant to be added around and through the valve stem, the speed has been increased. For those prod- ucts adversely affected by the air that may be trapped within the container, the air in the headspace is evacuated prior to adding the pro- pellant. Following the addition of the propellant, the method becomes similar to the cold filling method. For the most part, the pressure method is also preferred because some solutions, emulsions, suspensions, and other preparations cannot be chilled. Various factors determine the method to be used. The pressure method is usually pre- ferred to the cold method, because there is less danger of contamination’ of the product with moisture; high production speeds can be achieved: less propellant is lost; and the method 4s not limited, except for certain types of meter- ing valves that can only be handied by the cold filling process or through use of an “under the cap” filler and valve crimper. Some metered Valves that are pressure-filable are now avail able. Following the development of the aerosol product, an initial production of about 500 to 1000 units is scheduled. The initial fill is made according to the spetifications of the phar- maceutical concem. These units are used for additional stability studies, and for the deter- ‘mination of incompatibilities with various com- ponents (containers, valves, gaskets, dip tubes) ‘This run is also used to determine some of the problems that may become apparent in develop- ing the product from the laboratory to fall pro- duction, A larger run of 10,000 to 25,000 units is scheduled next. At this time, all materials are identical to those utilized for the production run, and the equipment used must be the same as the production equipment, These samples can be used for clinical studies and further testing if necessary. This test run should give the follow- {ng information: (1) suitability of scale-up opera- tion, (2) number of rejects to be expected (valve, container, and other components), (3) limita: tions of filling process (tolerances for filling, crimping, and other operations), (4) determina- tion of equipment to be used, and (5) check on effectiveness and acceptability of final product. Should satisfactory results be obtained at this point, arrangements for full-scale production can be made. ‘A typical cold filling aerosol line contains the following units arranged in the order given: un- scrambler, air cleaner, concentrate filler (capa- ble of being chilled), propellant filler (also capa- ble of being chilled), valve placer, valve crimper, water bath, labeler, coder, and packing table. The comparable pressure filling line would be identical in arrangement except that (I) no re- frigeration for chilling is required; (2) valve placer is located after “concentrate filler,” and a purger and vacuum crimper are added; and (3) this equipment is followed by a pressure filler. Where “under-the-cap” filling is used, the purger, vacuum crimper, and pressure filler are replaced with a single unit. Quality Control for Pharmaceutical Aerosols Basically, there is no difference between methods used to produce pharmaceutical aero- sols and those used to produce nonpharmaceuti- cal aerosols, but there are differences in the standards and specifications for their produc- ton. Propellants. Propellants used in medicinal and pharmaceutical aerosols require special handling, and in many instances, special test procedures. All propellants are shipped to the user with accompanying specification sheets; however, before the propellant is used (in fact, before it is even piped into a storage tank), it is subjected to the same rigid tests necessary for all other raw materials. A sample is removed and sent to the laboratory, where its vaparpressure is determined and compared to specifications. ‘When necessary, the density is also determined, and this is used as alurlher check. Gas cloma’ tography is used to determine the identity of the proj it, and when a blend of ropel its is tised,10- mie the composition. The purity ind a6 ify of the propellants i tested by moisture, halogen, and_nonvolatile le- terminations. Depending on the end use of the ‘propellants, several of these tests may be more important than others. All suppliers of propel- lants utilize the aforementioned tests in their own laboratories, and the tests that are run by the user are generally a check on these results, and more important, they ensure that the pro- pellants have not become contaminated during shipment. Monographs for propellants 11, 12, and 114 are included in USP XX/NF XV (1980), monographs for the hydrocarbons are currently being written. Valves, Actuators, and Dip Tubes. These parts are subjected to both physical and chemi- cal inspection. The problem is more complex than with nonaerosol components since a valve PHianMAceuTicaL AEnosots + 613is a multicomponent assembly consisting of var- ious parts made to close tolerances. The exami- nation at this point must determine whether the valves are fit to be used. They are sampled ac- cording to standard procedures as found in Mil tary Standard Mil-STD-105D.*° One manufac- turer of aerosols for this purpose actually assembles valves, using component parts having similar tolerances to ensure that parts having the minimum tolerance do not engage with parts approaching maximum tolerance. ‘To provide the means for determining the ac- cepiance of metered-dose aerosol vaives for pharmaceutical use, a suitable test method was developed by the Aerosol Specifications Com- mittee, Industrial Pharmaceutical Technology Section, Academy of Pharmaceutical Sciences. ‘The object of this test is to determine the magni tude of the valve delivery and the degree of uni- “formity between the individual valves as related fo the acceptance of any given lot of metered aejosal valves. The test Is not designed to deter- mine the suitability or the lack of suitability of the valves for a specific formulation and/or ap- plication. Detailed specifications for metered aerosol valves is a matter to be resolved between the pharmaceutical manufacturers and the aero- sol valve suppliers. The following three test solutions were pro- sed brought about by different formulations. These solutions were selected since they represent the range of propellants and propellant concentra- ons most offen used in pharmaceutical aero- ois -Since-a metered valve delivers a specific Tolume of liquid with each actuation, it was pro- posed that metered valve delivery be designated {in terms of valve delivery—volume expressed in microliters. In such a case, the test solutions recommended would apply to the control of valve delivery and uniformity for a great variety of formulations of different densities. The test solutions may be prepared in bulk and stored in hermetically sealed containers with suitable fitments for transferring the test solution into the test units. The transfer of the test solution should be made in such a manner that no change occurs in the proportions of the ingredients of the test solution. Test Solution A % wh Isopropyl myristate 0.10 Dichlorodifluoromethane 1 49.95 Dichlorotetrafluoroethane (¥ 49.95 Specific gravity at 25°C = 1.384 614 +The Theory and Practice of Industrial Pharmacy Test Solution B % wh Isopropyl myristate 0.10 Alcohol USP 499 Dichlorodifluoromethanet#?- 25.0 Dichlorotetraluoroethane 414 25.0 Specific gravity at 25°C = 1.092 ‘Test Solution C % wie Isopropyl myristate 0.10 Tiichloromonofluoromethane jy 24.9 Dichlorodifluoromethane yz, 50.25 Dichlorotetrafluoroethane jy 24.75 Specific gravity at 25°C = 1.388 Testing Procedure. A representative sampling of the valves from each shipment is made according t exist ing methods of sampling. Twenty-five valves are selected and placed onto suitable containers, into which has been’ placed the specified test solution. Where possible, the containers may be filled by the pressure process. A Dotion-type actuator with a 0.0204ncb or larger unre- siricted orifice is attached. This button remains in place throughout the test procedure. The containers are placed in a suitable atmosphere at a temperature of 25 1°C. When the product has attained this temperature, the valve should be actuated tothe fullest extent for atleast 2. sec following complete dispensing of a single delivery. ‘This procedure is repeated fora total often times. ‘The test unit is weighed to the nearest milligram. The valve is actuated to the fullest extent for at least 2 sec following complete dispensing of a singe delivery. The test unit is teweighed, and the difference between it and the previous weight represents the delivery in milligrams. “The test procedure is repeated fora total of two individual deliveries from each of the twepty-fve test units. The individual delivery weights in milligrams are divided by the specific gravity of the test solution to obtain the valve delivery per actuation in microliters. Valve Acceptance. The test procedure applies to two categories of metered aerosol valves having the fol lowing limits. For valves delivering: ‘54 uL or less, the limits are + 15%. 55 to 200 mL, the limits are +10%. 1. Of the 50 individual deliveries, if four or more are ‘outside the limits for the specified valve delivery, the valves are rejected. 2. If three individual deliveries are outside the limits, * another twenty-five valves are sampled, and the testis repeated. The lot is rejected if more than one delivery is outside the specifications. 3. If two deliveries from one valve are beyond the lim- its, another twenty-five valves should be taken. The lot is accepted if not more than one delivery is outside the specifications.Containers. Containers are sampled accord- ing to standard sampling procedures and in a manner similar to valves. Both uncoated and coated metal containers must be examined for defects in the lining. Several quality control as- pects include specifications for the degree of conductivity of an electric current as a measure of the exposed metal. Glass containers must be examined for flaws. The dimensions of the neck and other parts must be checked to determine conformity to specifications. The weight of the bottle also should be determined. Weight Checking. This is usually accom- plished by periodically adding to the filling line tared empty aerosol containers, which after being filled with concentrate, are removed and then accurately weighed. The same procedure is used to check the welght 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 to check the accuracy of the filling operation. Leak Testing. A means of checking the crimping of the valve must be available to pre- vent defective containers due to leakage, For metal containers, this is accomplished by meas- uring the “crimp” dimensions and ensuring that they meet specifications. Final testing of the efficiency of the valve clo- sure is accomplished by passing the filled con- tainers through the water bath. Periodic checks are made of the temperature of the water bath, and these results are recorded, Spray Testing. Many pharmaceutical aero- sols are 100% spray tested. This serves to clear the dip tube of pure propellant (for products filled by pressure through the stem, body, and dip tube), to clear the dip tube of pure concen- trate (for products filed by pressure under the cap or around the stem), and to check for defects in the valve and the spray pattern. For metered valves, it serves to prime the valve so that it is ready for use by the consumer. Several of the basic aspects of a quality control system have been included in this section. A more detailed discussion is available." Testing of Pharmaceutical Aerosols Aerosols are “pressurized packages,” and many tests are necessary to ensure proper per- formance of the package and safety during use and storage. All aerosol products that are shipped in interstate commerce are subject to the regulations of the DOT. These regulations impose limitations on the pressure within the container, flash points, flame extension, and flammability. The provisions of the Hazardous Substances Labeling Act and the Food, Drug and Cosmetic Act must be applied. In addition to these federal regulations, many local officials impose further restrictions upon aerosols. Pharmaceutical aerosols can be evaluated by a series of physical, chemical, and biologic tests, including A. Flammability and combustibility 1. Flash point 2. Flame extension, including flashback B. Physicochemical characteristics 1. Vapor pressure 2. Density 3, Moisture content 4. Identification of propellant(s) 5. Concentrate-propellant ratio ©. Performance 1. Aerosol valve discharge rate 2. Spray pattern 3. Dosage with metered valves 4. Net contents 5. Foam stability 6 Particle size determination 7. Leakage Bi D. Biologic Characteristics The flammability and combustibility of aerosol, pharmaceuticals may be determined by the fol- lowing procedures, Flame Projection. This test indicates the effect of an aerosol formulation on the extension of an open flame. The product is sprayed for about,4 seg into a flame. Depending on the na- ture of the Tomulation, the fame is extended, the exact length being measured with a ruler Flash Point. This is determined by use of the standard Tag Open Cup Apparatus.*? The easld wauce piled > See T product is chilled toa temperature 6 about ~25°F and transferred to the test appara- tus. The test liquid is allowed to increase slowly in temperature, and the temperature at which the vapors ignite is taken as the flash point. Al- though the test is still used, the results are of limited value because the flash point obtained is usually the flash point of the most flammable ‘component, which in the case of topical pharma- ceuticals is the hydrocarbon propellant. Vapor Pressure, ‘The pressure can be meas- ured simply with a pressure gauge or elaborately through use of a water bath, test gauges, and ‘Special equipment, It is important that the pres- Sure variation from container to container be determined, since excessive variation indicates the presence of air in the headspace. A can PHARMACEUTICAL AEROSOLS * 615