AEROSOLS

BY: BIBEK SINGH MAHAT M. PHARM. ( INDUSTRIAL)

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INTRODUCTION
An aerosol or pressurized packing is defined as "a system that depends on the power of a compressed or liquefied gas to expel the contents from the container.

INTRODUCTION
The term aerosol derives from the fact that : Matter "floating" in air is a suspension (a mixture in which solid or liquid or combined solid-liquid particles are suspended in a fluid). To differentiate suspensions from true solutions, the term sol evolvedoriginally meant to cover dispersions of tiny (sub-microscopic) particles in a liquid. With studies of dispersions in air, the term aerosol evolved and now embraces both: liquid droplets, solid particles, and combinations of these.
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HISTORY
The concept of aerosol probably goes as far back as 1790. The first aerosol spray can was invented in Oslo in November 23, 1927 by Erik Rotheim, a Norwegian chemical engineer. The patent was sold to a US company for 100,000 Norwegian kroner. The Norwegian Post Office celebrated the invention by issuing a stamp in 1998.
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HISTORY
In 1939, American Julian S. Kahn received a patent for a disposable spray can, but the product remained largely un-developed. In 1941 , the aerosol spray can was first put to good use by Americans Lyle Goodhue and William Sullivan, who are credited as the inventors of the modern spray can.
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HISTORY
In 1948, three companies were granted licenses by the United States government to manufacture aerosols.

Two of the three companies still manufacture aerosols to this day, Chase Products Company and Claire Manufacturing.
The "crimp-on valve", used to control the spray was developed in 1949 by Bronx machine shop proprietor Robert H. Abplanalp.
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PART-1

COMPONENTS OF AEROSOL PACKAGE

COMPONENTS OF AEROSOL PACKAGE

Following components are present in the aerosol package: a) Propellants, b) Containers, c) Valve, d) Actuator and e) Product concentrates.

COMPONENTS OF AEROSOL PACKAGE

The figure shows the working of the Aerosol

AEROSOL - PROPELLANTS
The propellant is responsible for developing the proper pressure within the container, and it expels the product when the valve is opened and aids in the atomization or foam production of the product. Since the propellant exists in liquid form in the can, it should be miscible with the payload
or dissolved in the payload

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AEROSOL - PROPELLANTS
Chlorofluorocarbons (CFCs) were once often used, but since the Montreal Protocol came into force in 1989, they have been replaced in nearly every country due to the negative effects on Earth's ozone layer.
The most common replacements are mixtures of volatile hydrocarbons, typically propane, n-butane and isobutane. Dimethyl ether (DME) and methyl ethyl ether are also used. All these have the disadvantage of being flammable.
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AEROSOL - PROPELLANTS
Nitrous oxide and carbon dioxide are also used as propellants to deliver foodstuffs (for example, whipped cream and cooking spray). Medicinal aerosols such as asthma inhalers use hydro-fluoro-alkanes (HFA): either HFA 134a (1,1,1,2,-tetrafluoroethane) or HFA 227 (1,1,1,2,3,3,3-heptafluoropropane) or combinations of the two. MANUAL PUMP SPRAYS are also used as an alternative to a stored propellant.
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AEROSOL - PROPELLANTS
A range of pressures can be obtained by mixing the various hydrocarbons in varying proportions. Since the hydrocarbons are naturally occurring products, their purity varies, The blending is done on the basis of the desired final pressure and not on the percentage of each component present. The pressure of each individual component varies somewhat, depending on the degree of purity.
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AEROSOL - PROPELLANTS
The vapor pressure of a mixture of propellants can be calculated according to Dalton's law, which states that The total pressure in any system is equal to the sum of the individual or partial pressures of the various components.

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AEROSOL - PROPELLANTS
Raoult's law, which regards lowering of the vapor pressure of a liquid by the addition of another substance, states that

the depression of vapor pressure of a solvent upon the addition of a solute (something added to the solvent) is proportional to the mole fraction of solute molecules in the solution.
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AEROSOL - PROPELLANTS
Given ideal behavior, the vapor pressure of a mixture consisting of two individual 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 as

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AEROSOL - PROPELLANTS
Pa= na na+nb (PAo) = NA PAO.(1)

Where, Pa = partial vapor pressure of propellant A PAO = vapor pressure of pure propellant A na = moles of propellant A nb= moles of propellant B NA= mole fraction of component A
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AEROSOL - PROPELLANTS
To calculate the partial vapor pressure of propellant B:
Pb= nb nb+na (PBo ) = NB PBO.(2)

The total vapor pressure of the system is then obtained from:

P = Pa + Pb . (3)
Where, P is the total vapor pressure of the system.
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CONTAINERS
Various materials as indicated in the following outline have been used for the manufacture of aerosol containers, which must withstand pressures as high as 140 to 180 psig at 130oF. The various containers used are: 1. Metal a) Tinplated steel b) Aluminum c) Stainless steel
2. Glass a) Uncoated glass b) b) Plastic-coated glass
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METAL CONTAINERS
a) Tinplate Containers: The tinplate steel container consists of a sheet of steel plate that has been electroplated on both sides with tin. The thickness of the tin coating is described in terms of its weight, for example, #25, #50, and #100. The size of the container is indicated by a standard system, which is a measure of the diameter and height of the container said to be 202 X 214 is 2 2/16 inches in diameter and 2 14/16 inches in height. Tinplated steel is obtained in thin sheets, and when required, it is coated with an organic material.
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METAL CONTAINERS
b) Aluminum Containers: Aluminum is used to manufacture extruded (seamless) aerosol containers. Many existing pharmaceuticals are packaged in aluminum containers, because of the lessened danger of incompatibility due to its seamless nature and greater resistance to corrosion.

The combination of ethanol and propellant 11 in an aluminum container has been shown to produce hydrogen acetyl chloride, aluminum chloride, propellant 21, and other corrosive products.
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METAL CONTAINERS
c) Stainless steel containers: These containers are limited to the smaller sizes. They are extremely strong and resistant to most materials. Stainless steel containers have been used for inhalation aerosols. In most cases, no internal organic is required.
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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 non-adhered and vented.

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GLASS CONTAINERS
By adjusting the formulation and limiting the type and quantity of propellant, satisfactory aerosol products can be formulated and packaged in glass containers.
Glass aerosol containers are preferable from a compatibility viewpoint, since corrosion problems are eliminated. The use of glass also allows for a greater degree of freedom in design of the container.
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AEROSOL - VALVE
The present-day aerosol valve is multifunctional in that it is capable of being easily opened and closed, and in addition, is capable of delivering the content in the desired form. Furthermore, especially in the case of pharmaceuticals, the valve is expected to deliver a given amount of medication. Valves for pharmaceuticals usually do not differ from the valves used for non-pharmaceutical aerosol products, but the requirements for pharmaceuticals are usually more stringent than for most other products.
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AEROSOL - VALVE
The materials used in the construction of the valves 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. There are two different types of valves used and they are: 1. Continuous Spray Valves, and 2. Metering Valves.
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AEROSOL - VALVE
a) Continuous Spray Valves: An aerosol valve consists of many different parts and is assembled using high-speed production techniques. Some of the parts are discussed below: 1. Ferrule or Mounting Cup: The ferrule or mounting cup is used to attach the valve proper to the container.
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AEROSOL - VALVE
2. Valve Body or Housing:
The housing is generally manufactured from Nylon or Delrin and contains an opening at the point of the attachment of the dip tube. The housing may or 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. These vapor tap openings are available in sizes ranging from about 0.03 inch to 0.080 inch
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AEROSOL - VALVE
3. Stem: The stem is made from Nylon or Delrin, but metals such as brass and stainless steel can be utilized also. 4. Gasket: Buna-N and Neoprene rubber are commonly used for the gasket material and are compatible with most pharmaceutical formulations. 5. Spring: The spring serves to hold the gasket in place. Stainless steel can be used with most aerosols. 6. Dip Tube: Dip tubes are made from polyethylene or polypropylene. The inside diameter of the commonly used dip tube is about 0.20 inch to 0.125 inch. Viscosity and the desired delivery rate play an important role in the selection of the inner diameter of the dip tube.
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AEROSOL - VALVE

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AEROSOL - VALVE
Drawing of the spray valve assembly

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AEROSOL - VALVE
b) Metering Valves: Metering valves are applicable to the dispensing of potent medication. These operate on the principle of a chamber whose size determines the amount of medication dispensed. 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 dispensed at one time with the use of such valves.
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AEROSOL - VALVE

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AEROSOL - ACTUATORS
To ensure that the aerosol product is delivered in the proper and desired form, a specially designed button or actuator must be fitted to the valve stem. The actuator allows for easy opening 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) Spray, (2) Foam, (3) Solid stream, and (4) Special applications.
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1. SPRAY- ACTUATORS
There may be one to three openings on the order of 0.016 inch to 0.040 inch in diameter.
Where there is a large percentage of propellant mixture containing a sufficient quantity of a low boiling propellant such as propellant 12 or propane, actuators having relatively large orifices can be used.

The combination of propellant vaporization and actuator orifice and internal channels can deliver the spray in the desired particles size range.
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2. OTHER - ACTUATORS
2) Foam Actuators: These actuators consist of relatively large orifices ranging from approximately 0.070 inch to 0.125 inch and greater. 3) Solid-Stream Actuators: The dispensing of such semisolid products as ointments generally requires these actuators. These are essentially similar to form type actuators. 4) Special Actuators: Many of the pharmaceuticals and medicinal aerosol require a specially designed actuator to accomplish a specific purpose. They are designed to deliver the medication to the appropriate site of action - throat, nose, eye, or vaginal tract.
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METERED DOSE INHALERS (MDI)

Pressurized MDIs have been used to deliver discrete doses of aerosol medicament to the lungs since 1955, although the use of pressurized aerosols dates back to 1943, when the US Department of Agriculture developed a portable insecticide using propellant 12.

A pharmaceutical MDI may be defined as a pressurized dosage form designed to deliver therapeutic agent to human respiratory tract. MDIs contain active substance, dissolved or suspended in a propellant system, which contains at least one liquefied gas in a pressurized container that is sealed with a metering valve.
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METERED DOSE INHALERS (MDI)

These MDIs minimize the number of administration errors and to improve the drugs delivery of aerosolized particles into the nasal passageways and respiratory airways. Some of these modifications have included the introduction of tube spacers, breath actuators, and portable plastic reservoirs with inhalation aerosols.

In the case of intranasal preparations, new propellant-free metered pumps have been introduced to replace the traditional propellant delivery systems.
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PART-2

FORMULATION OF PHARMACEUTICAL AEROSOLS

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FORMULATION OF PHARMACEUTICAL AEROSOLS

The formulation of pharmaceutical aerosols includes: 1. Selection of Systems: a. Solution System b. Water-Based System c. Suspension or Dispersion System d. Foam System 2. Selection of Components: a. Propellant b. Containers c. Valves, Actuators and Applicators

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SELECTION OF SYSTEMS
The type of system selected depends on many factors, including the following: 1. Physical, chemical, and pharmacologic properties of active ingredients, and 2. Site of application.

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SELECTION OF SYSTEMS
1. Solution System: This system is also referred to as a two-phase system and consists of a vapor and liquid phase.

When the active ingredients are soluble in the propellant, no other solvent is required.
Depending on the type of spray required, the propellant may consist of propellant 12 or A-70 (which produce very fine particles), or a mixture of propellant 12 and other propellants.
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SELECTION OF SYSTEMS
A lowering of the vapor pressure also is produced through the addition of less volatile solvents such as ethyl alcohol, propylene glycol, ethyl acetate, glycerin and acetone.

The amount of propellant used may vary from 5% (for foams) to 95% (for inhalation products) of the entire formulation.
These sprays are also useful for topical preparations, since they tend to coat the affected area with a film of active ingredients.
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SELECTION OF SYSTEMS
2. Water-Based System: Relatively large amounts of water can be used to replace all or part of the non-aqueous solvents used in aerosols. These products are generally referred to as "waterbased" 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 solvents in an "emulsion" system in which the propellant is in external phase. When the product is dispersed, the propellant vaporizes and disperses the active ingredients into minute particles.
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SELECTION OF SYSTEMS
Since propellant and water are not miscible, a threephase aerosol forms (propellant phase, water phase, and vapor phase). Ethanol has been used as a co-solvent to solubilize some of the propellant in the water. By virtue of its surface-tension-lowering properties ethanol also aids in the production of small particles. Surfactants have been used to a large extent to produce a satisfactory homogeneous dispersion.
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SELECTION OF SYSTEMS
3. Suspension or Dispersion System: Various methods have been used to overcome the difficulties encountered that are due to the use of a cosolvent. One such system involves a dispersion of active ingredients in the propellant or a mixture of propellant. To decrease the rate of settling of the dispersed particles, various surfactants or suspending agents have been added to the systems. These systems have been developed primarily for use with oral inhalation aerosols.
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SELECTION OF SYSTEMS
4. Foam System: Emulsion and foam aerosols consist of active ingredients, aqueous or non-aqueous vehicles, surfactant, and propellant, and are dispensed as stable or quick-breaking foam depending on the nature of the ingredients and the formulation. The liquefied propellant is emulsified and is generally found in the internal phase. Non-aerosol emulsion are usually in lotion or viscous liquid form, but aerosol emulsions are dispensed as foams.

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SELECTION OF COMPONENTS
For the proper selection we have to take care in each components: 1. Propellant 2. Containers 3. Valves, Actuators and Applicators

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SELECTION OF COMPONENTS
1. Propellant:
Some propellant manufactures indicated that there were other suitable replacement for propellants 11, 12, and 114, the only ones that have survived the necessary toxicity tests (long- and short-rage) are fluorocarbons 152a, 142B, and 22, which may be of limited value.
The other alternatives include hydrocarbons, compressed gases, and mechanical devices and pumps. Of these alternatives, how ever, hydrocarbons were restricted to use with foams and water-based aerosols, and compressed gases were of limited value in aqueous products where the propellant and water were not miscible.
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SELECTION OF COMPONENTS
While compressed gases overcome the immiscibility of the components, other problems such as loss of propellant, and to a lesser degree, dispersion of the spray becomes apparent. Since compressed gas systems do not have a chilling effect, they are applicable to topical preparations.
The compressed gases nitrogen, nitrous oxide, and carbon dioxide can be used but are of limited value. The pump system is used for liquid antiseptics, germicides, and nasal sprays.
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SELECTION OF COMPONENTS
2. Containers:
Both glass and metal containers have been used for pharmaceutical aerosols. Glass is preferred, but its use is limited, owing to its brittleness and the danger to breakage should the container accidentally be dropped. When the total pressure of the system is below 25 psig and there is not more than 15% propellant, glass can be safely used. Pressures up to 33 psig can be utilized in conjunction with a glass container having a double plastic outer coating.
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SELECTION OF COMPONENTS
Products having a low pH and containing water utilizes organic linings of epoxy and / or vinyl resins.
Although the vinyl resin forms a tough film, it is poorly resistant to steam and cannot be used for products that must be heat sterilized or fill hot (about 200oF). For this purpose, an epoxy resin can be used since it has a greater degree of heat stability. A commonly used organic coating consists of an undercoat of vinyl and a top coat of epoxy resin. This has been used to best advantage for those aqueous products of low pH.
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SELECTION OF COMPONENTS
3. Valves, Actuators and Applicators:
Valves are selected on the basis of materials of construction and size of various orifices. Various applicators have been specially designed for use with aerosol pharmaceuticals.
Inhalation actuators must have all the characteristics of spray actuators and allow escape of propellant vapors to that the vapors are not inhaled in appreciable amounts by the user.
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SELECTION OF COMPONENTS
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 generally used.
Nasal actuators are designed to fit into the nose and deliver the product as a fine mist. Other applicators have been designed for specific uses, including vaginal application, ophthalmic application, and others.
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PART-3

MANUFACTURE OF PHARMACEUTICAL AEROSOLS

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MANUFACTURE OF PHARMACEUTICAL AEROSOLS

To prepare and package pharmaceutical aerosols successfully, especial knowledge, skills and equipments are required. Since part of the manufacturing 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. Specialized equipment capable of handling and packing materials at relatively low temperatures (about 40 oF) or under high pressure must be available.
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MANUFACTURE OF PHARMACEUTICAL AEROSOLS

These equipment is usually limited to aerosol or pressurized packaging, and in most instances, cannot be used for other pharmaceutical operation.

1. Pressure Filling Apparatus: Pressure filling apparatus consists of a pressure burette capable of metering small volumes of liquefied gas under pressure into an aerosol container. The propellant is added through the inlet valve located at the bottom or top of the burette.
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MANUFACTURE OF PHARMACEUTICAL AEROSOLS

2. Compressed Gas Filling Apparatus: Compressed gases can be handled easily in the laboratory without the use of elaborate equipment.

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 filling head.
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PART-4

QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

1. Q. C. OF Propellants: A sample is removed and sent to the laboratory, where its vapor pressure is determined and compared to specification.
When necessary, the density is also determined, and this is used as a further check.
Gas chromatography is used to determine the identity of the propellant, and when a blend of propellants is used, to determine the composition.
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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

The purity and acceptability of the propellants is tested by moisture, halogen, and nonvolatile residue determination. All suppliers of propellants utilize the aforementioned tests in their own laboratories, they ensure that the propellants have not become contaminated during shipment.
Monographs for propellants 11, 22, and 114 are included in USP XX/NF XV (1980); monographs for the hydrocarbons are currently being written.
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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

2. Q.C. OF Valves, Actuators, and Dip Tubes : These parts are subjected to both physical and chemical inspection. The problem is more complex since a valve is a multi-component assembly consisting of various parts made to close tolerances. The examination at this point must determine whether the valves are fit to be used OR not.

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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

They are sampled according to standard procedures as found in Military Standard Mil-STD-105D. One manufacturer 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.

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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

3. Q.C. OF Container: Containers are sampled according 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 aspects include specification for the degree of conductivity of an electric current as measure of the exposed metal.
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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

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.

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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

4. Weight Checking: This is usually accomplished by periodically adding to the filling line tared empty aerosol containers, which after being filled with concentrate, are removed and then accurately weighted. The same procedure is used to check the weight of the propellant that us 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.
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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

5. Leak Testing: A means of checking the crimping of the valve must be available to prevent defective containers due to leakage. For metal containers, this is accomplished by measuring the "crimp" dimensions and ensuring that they meet specifications. Final testing of the efficiency of the valve closure is accomplished by passing the filled containers through the water bath. Periodic checks are made of the temperature of the water bath, and these results are recorded.
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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

6. Spray Testing: Many pharmaceutical aerosols are 100% spray tested.

This serves to clear the dip tube of pure propellant OR to clear the dip tube of pure concentrate and to check for defects in the value and the spray pattern.
For metered valves, it serves to prime the valve so that it is ready for use by consumer.
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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

7. 0THER SUGGESTED TESTINGS : Pharmaceutical aerosols can be evaluated by a series of physical, chemical, and biologic tests, including: Flammability and combustibility
Flash point Flame extension, including flashback

Physicochemical characteristics
Vapor pressure Density Moisture content Identification of propellant (s) Concentrate-propellant ratio

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QUALITY CONTROL OF PHARMACEUTICAL AEROSOLS

Performance
Aerosol valve discharge rate Spray pattern Dosage with metered valves Net contents Foam stability Particle size determination Leakage

Biologic Characteristics

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PARTICLE SIZE ANALYSIS IN PHARMACEUTICAL SPRAYS AND AEROSOLS

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Why measure PARTICLE SIZE ?

Nasal sprays It is critically important that the droplets are of a size that enables their deposition within the nasal passages. If they are too small (< 10 microns), particles may pass through the nasal passages and deposit in the lungs, potentially allowing deposition of drug and excipients not approved for pulmonary absorption. The spray droplet size is therefore important in defining the deposition pattern observed within the nasal cavity.
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Why measure PARTICLE SIZE ?

Nebulisers
Nebulisers provide a convenient means of delivering drugs to the respiratory tract. The device must deliver the drug quickly and efficiently to the appropriate part of the respiratory tract, whilst avoiding unnecessary waste. A key parameter in defining the efficiency of nebuliser treatments is the particle size of the aerosol cloud since this determines the deposition site within the respiratory tract: the smaller the particles, the greater the likelihood of their deposition in the lungs rather than in the mouth or throat. However, the particles must not be too fine (below 0.5 micron) because of the possible risk of exhalation.
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Why measure PARTICLE SIZE ?

Dry powder inhalers (DPI) Inhalers based on dry powders have a number of advantages over other formulations. Dose reproducibility and delivered particle size distribution are critical elements in DPI design, as particles with a size of less than 10 microns must be produced during actuation of the device if drug deposition is to occur within the respiratory tract.
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Why measure PARTICLE SIZE ?

Dry powder inhalers (DPI)

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PARTICLE SIZE USING LASER DIFFRACTION

Laser diffraction is an established technique within the pharmaceutical industry for particle size analysis.
Its use for the real-time, high-speed measurement of concentrated sprays and aerosols requires specialised instrumentation and software. Since its introduction in 1997, the Spraytec system (Malvern Instruments) has been widely adopted for these pharmaceutical applications, enabling the characterization of both pulsed and continuous spray events. 76

PARTICLE SIZE USING SPRAYTEC SYSTEM

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PARTICLE SIZE USING LASER DIFFRACTION

Fundamentals of operation
Laser diffraction for particle size determination requires the intensity of light scattered from the spray to be measured as a function of angle, using a series of photo-detectors.
Spraytec's unique optics and detector system allows the acquisition of scattering data over a wide angular range, which in turn enables the characterization of broad size distributions.
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Data obtained for the firing of a DPI device using two separate drug formulations. Formulation A contained crystalline drug material Formulation B was produced using a micronized form of the same drug.

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REFERENCES
Lachman L et al. Pharmaceutical Aerosols, The theory and practice of industrial pharmacy 1986: p. 589-618. Review article by Shoyele S. A. and Slowey A., Prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery , International Journal of Pharmaceutics 314 (2006): p.18. S.C.Porter. Aerosol, The Science and Practice of Pharmacy, Remington, 20th Edition (2000), Lippincot, Williams and Wilkins: p. 963-979. B.M.Mithal. A Textbook of Pharmaceutical Formulation1990 www.google.com www.wikipedia.com PARTICLE SIZE ANALYSIS IN PHARMACEUTICAL SPRAYS AND AEROSOLS, Malvern Instruments Ltd, Category: Pharmaceutical Aerosols | 11/12/2006 - 10:22:08 Influence of Particle Size on Systemic Effects After Breathing Potent Medicated Aerosols, E. ROBILLARD, M.D., Ch. LEPINE, M.D., Montreal, and, L. DAUTREBANDE, M.D., Ph.D., Brussels

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THANK-YOU

This is a BSM creation

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