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Description about pharmaceutical aerosols


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By: ephraiem (32 month(s) ago)

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Aerosols --- Noohu.Muhammad M.Phramacy 1 st sem



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INTRODUCTION Aerosols - A system that depends on the power of a compressed gas or liquefied gas to expel the contents from the container with special valve system. 1942 - First aerosol In 1950--- Pharmaceutical aerosol intended for topical administration In 1955 - Developed for the administration into the respiratory tract

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Advantages Easy and convenient application Can be delivered directly to the affected area Rapid response to the medicament Reduced irritation Dose can be delivered without contamination Protect unstable drugs Portable Disadvantages Expensive Propellants are toxic Highly inflammable

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Classification of aerosols According to administration route Inhalation aerosols Non-inhalation aerosols Topical aerosols According to the working way of valve Metered dose aerosols Non-metered dose aerosols According to dispersion system Solution aerosols Emulsion aerosols Suspension aerosols According to the number of phases Two phases aerosols Three phases aerosols

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Components of Aerosols Propellants Containers Valves and actuators Product concentrate

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Responsible for developing proper pressure within the container. Provide driving force to expel the product from the container. Types of propellants (a) Liquefied gases (b) Compressed gases Propellants

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LIQUIFIED GAS FLUORINATED HYDROCARBONS Almost all types of pharmaceuticals, Inhalation and oral Advantages Chemical inertness Lack of toxicity Non flammability & explosiveness Disadvantages High cost It depletes the ozone layer Damage Global Warming Potential

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HYDROCARBONS Can be used for water based aerosols, topical use Advantages Inexpensive Excellent solvents It does not cause ozone depletion Disadvantages Flammable Unknown toxicity produced e.g. propane , butane , isobutane

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Recently HFA propellants are used instead of CFC propellants.

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COMPRESSED GASES - Used when the aqueous phase need not be miscible with the propellant - Do not have chilling effect, for topical preparation Advantages Inexpensive Non flammable No environmental problems Disadvantages Pressure falls during use Produce coarse droplet spray Require use of non volatile co-solvent e.g. CO 2 , N 2 O, N 2

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Containers Containers must withstand pressure 140-180 psig at 130°F Types of Containers Metal containers Tin Plated Steel (140 - 180 psig) Aluminum (180 psig) Stainless Steel (180 psig) Glass containers - Uncoated glass Plastic coated glass Plastic Containers

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Metal Containers Tin plated steel containers It consist of a sheet of steel plate, this sheet is coated with tin by electrolytic process The coated sheet is cut into three desired fabricated pieces The top and body attach by soldering Recent developments in welding include Soudronic system- copper wire as electrode Conoweld system – two rotating electrode rings. Corrosion minimized, Saves considerable mfg time Better appreciation of quality control aspects Non aqueous product can be filled Alcohol based pharmaceuticals e.g. spray on bandages

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Aluminum Containers Many pharmaceutical aerosols are packed in Al containers Light weight, less fragile, Less incompatibility due to its seamless nature, Greater resistance to corrosion Used for inhalation and topical aerosols Polar solvents corrosion to Al containers Anhydrous ethanol corrosion to Al, produces H2 gas, this can be overcome by anodizing Al or addition of 2-3% water Non polar solvents are used in Al containers

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Stainless Steel Containers Small size containers Strong Reduce corrosion problems Used for inhalation aerosols No need for internal coating Costly

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Glass Containers Compatible with most formulations Allows for greater degree of freedom in container design resistant to corrosion, low cost. 25 psig pressure can be filled or 15% propellant conc. Available with or without plastic coating Plastic coated glass containers can be filled to a pressure of 33 psig Can be safely used Limited to use – its brittleness and breakage

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Plastic Containers Made with acetyl resins or poly propylene Can withstand high pressure

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Valves Easy to open and close Capable of delivering the content in the desired form such as spray, foam, solid stream etc. It can deliver a given amount of medicament Types Continuous spray valves Metered valves

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CONTINUOUS SPRAY VALVES Used for topical aerosols Valves assembles consist of following parts Ferrule or mounting cup - Attach valve to container Tin plated steel, Al , Brass (glass bottles), Under side of the valve cup is coated with single or double epoxy or vinyl resins Valve body or housing - Made up of nylon or derlin (0.013 to 0.080 inch) Stem - Nylon or derlin (0.13-0.040 inch), Gasket - Buna –N and neoprene rubber

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Spring - Stainless steel , to hold gasket in place, Dip tube - Poly ethylene or poly propylene , i. d- 0.120 – 0.125 inch, Capillary dip tube – 0.050 inch High viscous – 0.195 inches


ACTUATORS It is a specially designed button which is fitted to the valve. It delivers the product in a desired form. It discharges the product as spray, foam, solid stream . Spray actuators It can be used for topical preparation, such as antiseptics, local anesthetics and foot preparation It allows the stream of product concentrate and propellant to pass through various openings and dispense as spray

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FOAM ACTUATORS It consist of large orifice Ranges from 0.070—0.0125inch SOLID STREAM ACTUATORS These actuators are required for semi solid products such as ointments SPECIAL ACTUATORS These are used for a specific purpose It delivers the medicament to the appropriate site of action such as throat, nose, dental and eyes etc.

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OBJECTIVES To minimize the number of administrations. To improve the drug delivery into the nasal passage ways and respiratory air ways. Metered Dose Inhalers

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Advantages of MDI It delivers specified amount of dose Small size and convenience Usually inexpensive Quick to use Multi dose capability more than 100 doses available Disadvantages of MDI Difficult to deliver high doses Most products have low lung deposition Drug delivery highly dependent on good inhaler technology

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METERING VALVE It delivers only a specified quantity of product It is most critical component of MDI It crimped on to the container. The volume of valve ranges from 25—100µl for inhalation and up to 5ml for topical use. Such valve consist of two valved chambers both are connected to actuator button

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Consist of two essential components Product concentrate – Active ingredient or mixture of active ingredient, other solvents, anti oxidants, and surfactants. Propellant - single or blend, is used to give desired vapor pressure, solubility and particle size. Pharmaceutical aerosol may be dispensed as fine mist, wet spray, quick breaking foam, stable foam, semi solid etc. Type of system selected depends on physical, chemical and pharmacological properties of drug, Site of application Formulation

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SOLUTION SYSTEM Large no of aerosol products can be formulated. Solution aerosols produce a fine to coarse spray. Two phase system consisting of Vapor and Liquid phase. No solvent is required, if active ingredient is soluble in propellant. The vapor pressure of system is reduced addition of less volatile solvents such as ethanol, propylene glycol, glycerin, ethyl acetate. Propellant from 5% (for foams) to 95% (for inhalations). General formula Active drug -10-15% Propellant 12/11 (50:50) to 100% Types of Systems

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Inhalation aerosol Isoproterenol Hcl – 0.25%W Ascorbic acid – 0.1 Ethanol – 35.75 Propellant 12 – 63.9 Packed in S.S, Al container of 15 -30 ml Hydrocarbons in Topical Ethanol - 10-15 Water – 10-15 HC propellant A-46 – 55-70 Depending on water content the final product may be solution or three phase system. Hydrocarbon propellant A-70 (drier particles) while A-17 and A-31 tend to produce a wetter spray. These are useful for topical preparations. Plastic coated glass containers.

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WATER BASED SYSTEM (Water based aerosols) Large amounts of water can be used to replace all or part of the non aqueous solvents used in aerosols. Produce spray or foam. To produce spray formulation must consist of dispersion of active ingredients and other solvents in emulsion system in which the propellant is in the external phase. Since propellant and water are not miscible, a three phase aerosol forms (propellant, water and vapor phases). Ethanol can be used as cosolvent to solubilize propellant in water. Low water soluble Surfactants and high solubility in nonpolar solvents will be useful eg: glycol, glycerol and sorbitan esters of oleic, stearic, palmitic and lauric acids (Conc. 0.5 to 2%) Propellant concentration varies from about 25 to 60%. Aquasol system (Aquasol valve) – dispensing fine mist or spray of active ingredient dissolved in water (No chilling effect, since only active ingredient and water are dispensed, propellant is in vapor state).

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Differences between aquasol system and three phase system are Aquasol dispenses fairly dry spray, very small particles, non flammability of the product Fine and dry spray with 6 parts of water with 1 part of HC propellant, even it extinguishes fire. Alcohol use results in the two phase system In Aquasol system vapor phase of Propellant and product enter actuator through separate ducts moving at high velocity product and vapor mixed with voilent force results in uniform fine spray Fine dry spray or coarse wet spray is obtained

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SUSPENSION OR DISPERSION SYSTEM To overcome complications of cosolvents the disperse system was developed which involves dispersion of active ingredient in the propellant or mixture of propellants. To decrease the rate of settling of dispersed particles, surfactants or suspending agents can be added. Primarily used for inhalation aerosols. Epinephrine bitartrate (1-5 Microns) minimum solubility in propellant Sorbitan trioleate P-114 P-12 Isoproterenol sulfate Oleyl alcohol Myristyl alcohol P-12 P-114

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Steroid Oleic acid P-11 P-12 Oleic acid is dispersing agent, aids in reduction of particle growth, valve lubricant avoids sticking. Agglomeration results in valve clogging, inaccuracy of dosage, damage to liner or container. Physical stability increased by Control of moisture content (300 ppm) Reduction of initial particle size to less than 5 µm for inhalation. Adjustment of density of propellant and suspensoid to equal Use of dispersing agents Use of derivatives of derivatives of drug with minimum solubility in propellant (epinephrine) Isopropyl myristate and mineral oil are used to reduce agglomeration. Surfactants of HLB less than 10 are useful (sorbitan monooleate, monolaurate, trioleate, sesquioleate. (Conc. 0.01 to 1 %)

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FOAM SYSTEMS Emulsion aerosols consist of active ingredient, Aq. or non aq. vehicle, surfactant, Propellant. Liquefied propellant is emulsified and generally in internal phase. AQUEOUS STABLE FOAM Active drug Oil o/w surfactant Water, HC Propellant (3 -5%) Hydrocarbon propellant (3 to 5% W/W or 8-10% V/Vusually). As the amount of propellant increases a stiffer and dryer foam is produced. Lower propellant concentrations yield wetter foams. HC and compressed gas propellants are used. NON AQUEOUS STABLE FOAM Glycols such as poly ethylene glycols used. Emulsifying agent is propylene glycol monostearate.

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QUICK BREAKING FOAM Propellants are external phase Especially applicable to topical medications Ethyl alcohol Surfactant Water HC Propellant Surfactant should soluble in alcohol and water. THERMAL FOAM To produce warm foam for shaving Used to hair colors and dyes were unsuccessful. INTRANASAL AEROSOLS To deliver measured dose of drug, lower doses compared to systemic products Excellent penetration into the nasal passage way Decreased mucosal irritability Maintenance of sterility from dose to dose Difference from inhalation aerosol is the design of adaptor

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PRESSURE FILLING Process carried out at room temp HC and FHC prop can be filled by this process Less propellant loss Product is filled in to the container Low pressure prop is introduced into the container through the valve The container is then removed and filled high pressure prop up to head of the container Then the container is removed and shake It is not used for inhalation aerosols Most preferable because some solution , emulsion , suspension , and other preparation which cannot be chilled. Not used for metered dose inhaler Manufacturing of Pharmaceutical Aerosols

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COLD FILLING In this method the propellants are refrigerated to a temperature at least 5°F below their boiling points. e.g. Propellant 12: BP ( -30°F), refrigerate it to -35°F The chilled product and propellant filled into container, Valve crimped and passed into a water bath. Used for inhalation aerosols Used with metered valves and non metered valves Should not use to fill HC propellants

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FLAMMABILITY AND COMBUSTIBILITY Flame projection : Extension of an open flame by spraying aerosol for about 4 sec into the flame. Flash point : Tag open cup apparatus Product is chilled (-25 ° F). Allowed to increase the temperature and temperature at which vapors ignite is taken as flash point. PHYSICOCHEMICAL CHARACTERISTICS Vapor pressure : pressure gauge Density: Hydrometer or Pycnometer Moisture content: Karl Fischer, GC Identification of propellants: GC, IR Testing of Pharmaceutical Aerosols

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PERFORMANCE Aerosol valve discharge rate: Change in weight per time dispensed. Spray pattern Dosage with metered valves - Reproducibility of dosage, each time valve is depressed - Amount of medication actually received by patient. Net contents : W total - W container Foam stability - Visual inspection with time. - Time for a given mass to penetrate the foam. - Rotational viscometers

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PARTICLE SIZE DETERMINATION - Cascade Impactor : 0.1 to 30 microns - Light scatter decay: Tyndall beam BIOLOGICAL CHARACTERISTICS - Therapeutic activity - Toxicity: Topical effects – irritating, chilling effect Inhalation effects (even intended for topical preparations)


CONCLUSION At present there is much interest in developing MDIs for conditions including asthma, diabetes, aids, cancer, heart disease and cystic fibrosis etc. Many of compounds have been developed using biotechnology process and their delivery to the respiratory system via MDI in an extremely challenging undertaking. As HFC propellents causing ozone depletion , they are being replaced with acceptable HFA propellants. Propellants are being used in Needle less Injection system .


REFERENCES Practice of industrial pharmacy by Leon Lachman , H.A Liberman , Joseph kanig ,3 rd edition varghase pub.. , P.505-618 Remington’s “The science &practise of pharmacy” 3 rd edition volume-1 , P.1000-1017

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