Aerosol Generation — an overview, ScienceDirect Topics

Aerosol Generation

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Toxicology Testing and Evaluation Exposure Atmosphere Generation

Aerosol generation methods have been extensively reviewed by others ( Medinsky et al. 1985; Tepper et al. 1989 ). Gas and vapor generation methods have been reviewed by Barrow (1989) . Only a brief summary of the methods will be given here and some of the most common methods of aerosol and vapor generation mentioned. Gas generation has frequently been done by controlled flow from bottled gases, as well as more infrequently by specific chemical reactions to produce the agent of interest. Vapor generation methods have frequently used J-tubes as well as other means to heat organic fluids and then the evolving vapor is dispersed into an airstream.

Liquid aerosols have been generated using a variety of nebulizers. A wide range of compressed air jet nebulizers have been characterized ( Lux et al. 1993; Mercer et al. 1968 ). Different units may be chosen based primarily on desired droplet particle size and concentration output. Ultrasonic nebulizers may also be used, particularly when high volumetric outputs are required. A significant concern for many nebulizers that have small liquid capacities is the increase in solute concentration that occurs over time as the reservoir volume is depleted with nebulization. This can lead to changes in concentration and particle size. This problem is often solved by using a feed system so that a constant level is maintained in the nebulizer reservoir for up to several hours of exposure.

There are a variety of dry powder aerosol generation methods that have been reviewed by others ( Grassel 1976; Moss and Cheng 1989; Phalen 1984 ). The Wright Dust Feeder (1950) has been a mainstay in inhalation toxicology efforts since its introduction in 1950. With suitable gearing, the system can be used to generate a very wide range of aerosol concentrations. The main disadvantage of the system is that if the powder is incorrectly packed, reliable aerosol generation is not attained. For low-density ‘fluffy’ powders, the packing pressure can result in congealing of the powder, and for these applications the Wright Dust Feeder is not recommended. More recently, air jet mills have proven to be highly useful in reliably generating dry powder aerosols with good particle size distributions particularly for materials that are ‘sticky’ and difficult to generate by other methods. Examples of jet mills that have been used successfully include the Jet-O-Mizer ( Cheng et al. 1985 ), the Trost jet mill ( Bernstein and Drew 1980 ), and the Microjet ( Lee et al. 1983 ). Other methods of dry powder generation include fluidized beds, brush mechanisms, venturis, and turntable designs. Sometimes, it can be useful to combine delivery devices. For instance, it has proven advantageous to produce small aerosols (MMAD 2–3 μm) at high concentrations by using a Wright Dust Feeder as a delivery mechanism for a Jet-O-Mizer ( Tielking 1993 ). Also, Bernstein et al. (1984) have described combining a brush feeder with a jet mill. An example of this approach is shown in Figure 4 . Lee et al. (2000) have described a versatile and robust approach using a reservoir with a stirring motor feeding into a Venturi T-section.

Figure 4 . Example of a rotating brush generator feeding particles through an in-line jet mill (upper portion of the picture) feeding the nose-only chamber in the background. Courtesy of ITR Laboratories.

Cheng et al. devised a simple system in which test article was fed continuously from the hopper of a screw feeder into a Venturi jet to help disperse the aggregates formed in the hopper. The Venturi jet is rather efficient in dispersing aggregates, but it may be necessary to place a vertical elutriator between the aerosol generator and the exposure chamber to maximize dispersion. This system has the capacity to produce a wide range of aerosol concentrations by varying the airflow rate and the screw feed rate.

Rotating brush aerosol generators can be used to generate aerosols over a wide range of concentrations and this has become one of the most common methods for dry powder aerosol generation in inhalation toxicology systems. Test article is packed in a reservoir that is moved slowly upward against a rotating brush, thus circulating the test article into a jet of air. The rate of aerosol generation is varied by use of reservoirs of different diameter and by employing feed rates of 1–700 mm h −1 . Care must be taken in filling the reservoirs because variation in packing density will cause variation in output. Use of small weights to tap down the test article in the reservoir can also assist in achieving reproducible test particle density.

The methods described above represent the most common generation methods generally used to produce aerosols from an available source of test chemical. Other more specific needs may require different solutions. For instance, if it is desired to conduct toxicology studies on materials as they are inhaled by people, then every effort should be made to generate representative aerosols that are as similar as possible to those actually inhaled in real life. In the case of combustion aerosols, this has involved using the sources used by people. Examples are cigarette smoke, automobile exhausts, and fires. In each case, the actual generation sources have been used, that is, burning cigarettes ( Baumgartner and Coggins 1980; Driscoll et al. 2000; Griffith and Standafer 1985 ), functioning engines ( Mokler et al. 1984; Peplko 1981; Schreck et al. 1981 ), and burning wood ( Caldwell and Alarie 1990 ) and carpet materials ( Alarie et al. 1994 ) under controlled conditions. Fibers have also been generated by dispersing the commercial materials after appropriate treatment ( Hesterberg et al. 1993 ). Such situations provide considerable challenges to produce aerosols for animal studies that will result in data that are appropriate to shed light on human exposures.

Dosage Forms

Delivery Mechanism

The aerosol generation and delivery mechanism for nebulizers differs from any other inhaler in that all elements required for function are not integral to the device. Air jet nebulizers consist of a tube that dips into the reservoir and a tube, frequently coaxial, that directs air over the liquid feed tube to create a high velocity, low pressure region that draws liquid by Venturi or Bernoulli effect. 33,34 High velocity air is supplied by a separate pump. The solution or suspension is then dispersed on the airflow as droplets. Due to the hydrogen bonding of water, the spray consists of both large and small droplets. The small droplets are suitable for lung delivery. The large droplets impinge on a baffle and return to the reservoir. This recycling mechanism requires delivery of the solution or suspension as a steady-state aerosol over a period sufficient to deliver a therapeutic dose, which is frequently 15 to 30 minutes depending on the drug employed.

Vibrating mesh nebulizers have their origins in a method of producing calibration standards that has been available for 50 years, the vibrating orifice monodisperse aerosol generator (VOAG). 35 The VOAG had a single orifice in a piezo-electrical plate with closely controlled frequency of oscillation to produce droplets in a narrow size range. The evolution of this technology to a series of orifices in the plate, now renamed a mesh, resulted in a novel method of producing high density (mass/volume of air) clouds of aerosol droplets that could be delivered on small volumes of air, thereby reducing the overall time of dosing. 36–39

History of inhaler devices

E. Callard preedy, P. Prokopovich, in Inhaler Devices , 2013

2.4.1 The fundamentals

Nebulisers are the oldest form of aerosol generation , and can be used at any age, for any disease severity ( Geller, 2005 ). Even though they have been commonly used for many years, their basic design and performance has changed little over the past 25 years ( Hess, 2000 ). Nebulisers rely upon the ability of the pharmaceutical formulator to dissolve the drug in a suitable solvent ( Clarke, 1995 ). The majority of commercial nebuliser devices were developed from more conventional nasal sprays and they utilise compressed gas to generate liquid aerosol droplets; a technique commonly known as airblast atomisation. Nevertheless, as with all airblast techniques, the droplet sizes that are generated at the atomiser head are relatively coarse, and inertial filtration is needed in order to limit the output to respirable droplet sizes ( Clarke, 1995 ).

It has been noted that the key aim of nebulised therapy is to deliver a therapeutic drug dose to the airways in a short time frame, and the effectiveness of this therapy is determined by the drug–nebuliser combination ( Nicolini et al., 2010 ). In some cases it is possible to mix more than one medication in a nebuliser and deliver them simultaneously, although this lengthens the administration time ( Geller, 2005 ). Another benefit associated with nebulisers is the ability to use high drug doses in diseases other than asthma and COPD. For example, inhalable tobramycin is a topical antibiotic for Pseudomonas endobronchial infections in cystic fibrosis. It comes as a unit dose of 300 mg, which would be impossible to deliver with an MDI ( Geller, 2005 ). The principal factors influencing nebuliser performance are initial fill volume, the efficiency of aerosol production, and residual volume.

The design of the nebuliser is also important as it governs the size of the aerosol and fluid output. The rate of gas flow driving atomisation is a major determinant of aerosol size, with an inverse relationship between droplet size and flow rate due to the increased shearing forces at higher flow rate ( McCallion et al., 1996 ). Furthermore, as droplet size is independent of the fill volume, the proportion of available drug increases with increased fill volume. This is due to part of the fluid being retained within the nebulisation chamber at the end of atomisation ( Geller, 2005 ). Changing temperatures when using the nebuliser may also affect the output as the fluid in the nebuliser decreases, resulting in the precipitation of poorly soluble drugs whilst producing a variation in the size of the droplets due to the changes in the physicochemical properties of the nebulised fluid.

Although the mean aerosol size is inversely proportional to viscosity, a high viscosity fluid produces smaller droplets but requires a longer amount of time to nebulise, and therefore is retained for a greater period ( McCallion et al., 1996 ). Another interesting point raised is that reducing the surface tension of fluids tends to produce aerosols of smaller size, therefore the size and dose inhaled by a patient is reliant on these variables ( McCallion et al., 1996 ), but the overall dose inhaled is totally reliant on the patient themselves. Figure 2.2 demonstrates the workings of a nebuliser, as adapted from Hess (2000) and Dalby and Suman (2003) .

Fig. 2.2 . Schematic diagram of a typical nebuliser.

How Aerosol Cans Work

Liquid Gas?

In the last section, we looked at the simplest aerosol-can design, which uses compressed gas as a propellant. In the more popular system, the propellant is a liquefied gas. This means that the propellant will take liquid form when it is highly compressed, even if it is kept well above its boiling point.

Since the product is liquid at room temperature, it is simply poured in before the can is sealed. The propellant, on the other hand, must be pumped in under high pressure after the can is sealed. When the propellent is kept under high enough pressure, it doesn’t have any room to expand into a gas. It stays in liquid form as long as the pressure is maintained. (This is the same principle used in a liquid propane grill.)

As you can see in the diagram below, the actual can design in this liquefied-gas system is exactly the same as in the compressed-gas system. But things work a little bit differently when you press down the button.

­ When the valve is open, the pressure on the liquid propellant is instantly reduced. With less pressure, it can begin to boil. Particles break free, forming a gas layer at the top of the can. This pressurized gas layer pushes the liquid product, as well as some of the liquid propellant, up the tube to the nozzle. Some cans, such as spray-paint cans, have a ball bearing inside. If you shake the can, the rattling ball bearing helps to mix up the propellant and the product, so the product is pushed out in a fine mist.

When the liquid flows through the nozzle, the propellant rapidly expands into gas. In some aerosol cans, this action helps to atomize the product, forming an extremely fine spray. In other designs, the evaporating propellant forms bubbles in the product, creating a foam. The consistency of the expelled product depends on several factors, including:

  • The chemical makeup of the propellant and product
  • The ratio of propellant to product
  • The pressure of the propellant
  • The size and shape of the valve system

Manufacturers are able to produce a wide variety of aerosol devices by configuring these elements in different combinations. But whether the can shoots out foamy whipped cream, thick shaving gel or a fine mist of deodorant, the basic mechanism at work is the same: One fluid pushes another.

To learn more about aerosol cans, as well as the chemicals used inside them, check out the links below.

Many propellants are flammable, so it’s dangerous to use aerosol cans around an open flame. Otherwise, you might end up with an accidental flamethrower. Another possible danger is inhalation: Some aerosol cans, such as whipped-cream containers, use nitrous oxide, which can be harmful if inhaled in mass quantities. To learn more about the propellants used in aerosol cans, check out this site.

Up until the 1980s, a lot of liquefied-gas aerosol cans used chlorofluorocarbons (CFCs) as a propellant. After scientists concluded that CFCs were harmful to the ozone layer, 70 nations signed the Montreal Protocol, an agreement to phase out CFC use over the next decade. Today, almost all aerosol cans contain alternative propellants, such as liquefied petroleum gas, which do not pose as serious a threat to the environment.

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