Aerosols, Sprays and Inhalations Chapter 7 Aerosols, Sprays and Inhalations

Section1: Pharmaceutical Aerosols Ⅰ Definition PHARMACEUTICAL AEROSOLS are pressurized dosage forms containing one or more active ingredients which upon actuation emit a fine dispersion of liquid and/or solid materials in a gaseous medium. They depend upon the function of the container, its valve assembly, and an added component--the propellant--for the physical delivery of the medication in proper form.

An equilibrium is quickly established between that portion of propellant which remains liquefied and that which vaporizes The vapor phase exerts pressure in all directions--against the walls of the container, the valve assembly, and the surface of the liquid phase It is this pressure that upon actuation of the aerosol valve forces the liquid phase up the dip tube and out of the orifice of the valve into the atmosphere.

As the propellant meets the air, it immediately evaporates due to the drop in pressure, leaving the product concentrate as airborne liquid droplets or dry particles, depending upon the formulation. As the liquid phase is removed from the container, equilibrium between the propellant remaining liquefied and that in the vapor state is reestablished.

Thus even during expulsion of the product from the aerosol package, the pressure within remains virtually constant, and the product may be continuously released at an even rate and with the same propulsion. However, when the liquid reservoir is depleted, the pressure may not be maintained, and the gas may be expelled from the container with diminishing pressure until it is exhausted.

Ⅱ Features of the Aerosol Dosage Form Some features of pharmaceutical aerosols that may be considered advantages over other types of dosage forms are as follows: 1. A portion of medication maybe easily withdrawn from the package without contamination or exposure to the remaining material.

2. By virtue of its hermetic character, the aerosol container protects medicinal agents adversely affected by atmospheric oxygen and moisture. Being opaque, the usual aerosol container also protects drugs adversely affected by light. If the product is packaged under sterile conditions, sterility may also be maintained during the shelf-life of the product.

3. Topical medication may be applied in a uniform, thin layer to the skin, without touching the affected area. Reduce the irritation The rapid volatilization of the propellant also provides a cooling, refreshing effect.

4. By proper formulation and valve control, the physical form and the particle size of the emitted product may be controlled which may contribute to the efficacy of a drug. Through the use of metered valves, dosage may be controlled. 5. Aerosol application is a "clean" process, requiring little or no "wash-up" by the user.

6. Have a immediate effect and can distributing the medicaments to the certain tissues of the region. Bigger absorption area; abundant blood circulation; smaller resistance of penetration. 7. Drug can avoid to be destroyed or inactivated by the pH or enzymatic activity of the stomach or intestines, also can avoid the first pass effect.

The influencing factors of absorption The air current of breath: the amount of inspiration and frequency of breath. Particle size: most 5μm, must be smaller than 10μm. The features of drug: solubility; molecular weight, oil-solubility (Ko/w), moisture absorption.

Disadvantages of the pharmaceutical aerosol: High cost. Because of the volatility, the propellants has the refrigeration effect which can irritate the skin. To certain individuals, who may be sensitive to the propellant agent and who utilize an inhalation aerosol, the fluorinated hydrocarbons may exhibit cardiotoxic effects following rapid and repeated use of the aerosol product.

Ⅲ Aerosol Systems TWO-PHASE SYSTEMS This system is comprised of the liquid phase, containing the liquefied propellant and product concentrate, and the vapor phase.

Emulsion or suspension THREE-PHASE SYSTEMS This system is comprised of a layer of water-immiscible liquid propellant, a layer of highly aqueous product concentrate, and the vapor phase. Emulsion or suspension

Ⅳ The Aerosol principle An aerosol formulation consists of two component parts, the product concentrate and the propellant. 1 The product concentrate is the active ingredient of the aerosol combined with the required adjuncts, such as antioxidants, surface-active agents, and solvents, to prepare a stable and efficacious product.

2 the propellant When the propellant is a liquefied gas or a mixture of liquefied gases, it frequently serves the dual role of propellant and solvent or vehicle for the product concentrate. In certain aerosol systems, no liquefied compressed gases, as carbon dioxide, nitrogen, and nitrous oxide, are employed as the propellant.

Chlorofluorocarbons (CFCs). The most used propellant in aerosol products However these propellants are being phased out and will be prohibited due to scientific recognition that they reduce the amount of ozone in the stratosphere, which results in an increase in the amount of ultraviolet radiation reaching the earth, an increase in the incidence of skin cancer, and other adverse environmental effects.

Among the chlorofluorocarbons used as propellants in pharmaceuticals are dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane.

Example 1:What is a vapor pressure of a 60:40 mixture of propane and isobutane. Information on two propellants is as follows: How to determine the vapor pressure of a certain mixture? Property propane isobutane Molecular formula C3H8 C4H10 Molecular weight 44.1 58.1 Boiling point(℉ ) -43.7 10.9 Vapor pressure(psig@70℉ ) 110 30.4 Liquid density(g/ml @70℉ ) 0.50 0.56 Flash point(℉ ) -156 -117

Assume an ideal solution. For Raoult’s law, we need to determine the number of moles of each propellants:

From Raoult’s law, the partial pressure exerted by the propane is:

The partial pressure exerted by the isobutane is:

The vapor pressure exerted by both gases, PT, is: Dalton’s law PT=72.98+10.23=83.21psi at 70℉ The vapor pressure required for a specific application can be calculated in a similar manner and different ratios of propellants may be used to obtain that pressure.

Ⅴ Pressurized containers Various materials have been used in the manufacture of aerosol containers, including glass, uncoated or plastic coated; metal, including tin-plated steel, aluminum, and stainless steel; plastics

The selection of the container for an aerosol product is based on its adaptability to production methods compatibility with formulation components ability to sustain the pressure intended for the product the interest in design aesthetic appeal on the part of the manufacturer cost

Ⅵ Valve assembly The function of the valve assembly is to permit the expulsion of the contents of the can in the desired form, at the desired rate, and, in the case of metered valves, in the proper amount or dose. Among the materials used in the manufacture of the various valve parts are plastic, rubber, aluminum, and stainless steel.

the button that the user presses to activate the valve assembly for the emission of the product the link between the dip tube and the stem and actuator hold the valve in place supports the actuator and delivers the formulation in the proper form to the chamber of the actuator prevent leakage of the formulation when the valve is in the closed position. the mechanism by which the actuator retracts when pressure is released, thereby returning the valve to the closed position bring the formulation from the container to the valve

Metered Dose Inhalers (MDIs)

Ⅶ Filling Operations COLD FILLING PRESSURE FILLING

COLD FILLING both the product concentrate and the propellant must be cooled to temperatures of -30℉to -40℉ the chilled product concentrate is quantitatively metered into an equally cold aerosol container the liquefied gas is added, the heavy vapors of the cold liquid propellant generally displace the air present in the container

When sufficient propellant has been added, the valve assembly is immediately inserted and crimped into place Notice: because of the low temperatures required, aqueous systems cannot be filled by this process, since the water turns to ice. in the process, some of the propellant vapors are also lost

PRESSURE FILLING the product concentrate is quantitatively placed in the aerosol container the valve assembly is inserted and crimped into place the liquefied gas, under pressure, is metered into the valve stem from a pressure burette

Pressure filling is used for most pharmaceutical aerosols. It has the advantage over the cold filling method in that there is less danger of moisture contamination of the product, and also less propellant is lost in the process.

Ⅷ Testing the Filled Containers The aerosol container is tested under various environmental conditions for leaks or weakness in the valve assembly or container. The valve discharge rate is determined by discharging a portion of the contents of a previously weighed aerosol during a given period of time, and calculating.

Aerosols may be tested: for their spray patterns for particle size distribution of the spray: most 5μm, must be smaller than 10μm. for accuracy and reproducibility of dosage when using metered valves.

Section 2: Sprays Sprays may be defined as aqueous or oleaginous solutions in the form of coarse droplets or as finely divided solids to be applied topically, most usually to the nasal-pharyngeal tract or to the skin. For example: medicinal atomizers, which are employed for the issuance of a medicated solution to the patient in the form of fine droplets

Inhalations are drugs or solutions of drugs administered by the nasal or oral respiratory route. The drugs may be administered for their local action on the bronchial tree or for their systemic effects through absorption from the lungs. A unique form of powder administration involves the inhalation of a micronized powder directly into the lungs using a special breath-activated device Section 3: Inhalations

1 Capsule: drug depository 2 Spring stem 3 Fanlike propellant 4 Inhalant 5 Stainless steel spring section

Glossary Aerosols; sprays; inhalations; Pressurized container, valve assembly; propellant; Two-phase systems; three-phase systems; Ingredient; solvent or vehicle ; Chlorofluorocarbons (CFCs); Metered dose inhalers ; Cold filling ; pressure filling

Problems: 1 What is aerosols, sprays and inhalations? 2 Please briefly describe the influencing factors of aerosols absorption. 3 Please briefly describe the advantages and disadvantages of aerosols. 4 Which are the constituents of aerosols? 5 Please briefly describe the quality request of aerosols. 6 What is the function of propellants?