AEROSOLS

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Presentation Transcript

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PHARMACEUTICAL AEROSOLS SHUBHRAJIT MANTRY Asst.Prof Kottam Institute of Pharmacy . A.P

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SYLLABUS DEFINITION PROPELLANTS GENERAL FORMULATION MANUFACTURING & PACKAGING METHOD PHARMACEUTICAL APPLICATION & EVALUATION

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DEFINITION A pharmaceutical aerosol is defined as a colloidal system containing liquid and solid particles (active ingredients) suspended in a propellant (liquefied gas or compressed gas). The power propellants helps in expelling the contents from the container. Aerosols are meant for topical, systemic and oral administration, these are also known as Pressurized Packages .

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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. Lower dosage of drug minimize adverse side effect. Disadvantages Expensive Propellants are toxic in nature. Highly inflammable

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Components of Aerosols Propellants Containers Valves and actuators Product concentrate

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6 Components of aerosols Propellant Container Valve and actuator Product concentrate container

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PROPELLANTS It is responsible for developing the power pressure within the container and also expel the product when the valve is opened and in the atomization or foam production of the product. Types of propellants (a) Liquefied gases (b) Compressed gases

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(a) LIQUEFIED GASES Dispersing the active ingredient into a fine mist. Pressure within the container remains constant. Relatively inert and nontoxic. Types of Liquefied gases Chlorofluorohydrocarbons (CFCs) Trichloromonfluoromethane (Prop 11) Dichlorodifluoromethane (Prop 12) Dichlorotetrafluoroethane (Prop 114) Hydrocarbon Propane, Butane, and Isobutane 3.Hydrochlorofluorocarbon and Hydrofluorocarbon Monochlorodifluoroethane , Difluoromethane

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(1) Chlorofluorohydrocarbons (CFCs) Propellant of choice for oral and inhalation . Advantages Chemical inertness Lack of toxicity Non flammability. Disadvantages High cost It depletes the ozone layer Damage global warming potential

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(2) Hydrocarbon Can be used for water based aerosols and topical use. Advantages Inexpensive Excellent solvents It does not cause ozone depletion Disadvantages Inflammable Unknown toxicity produced e.g. propane , butane , isobutane

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(3) Hydrochlorofluorocarbon and Hydrofluorocarbon They may not contain chlorine and have one or more hydrogen atom. These compounds break down in the atmosphere at faster rate than CFCs- lower ozone destroying effect. Advantages Low inhalation toxicity High chemical stability High purity Not ozone depleting Disadvantages Poor solvent High cost

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(b) 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 e.g. CO 2 , N 2 O, N 2

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Containers They must be stand at pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at 130 0 F. A . Metals 1. Tinplated steel (a) Side-seam (three pieces) (b) Two-piece or drawn (c) Tin free steel 2. Aluminium (a) Two-piece (b) One-piece (extruded or drawn ) 3. Stainless steel B. Glass 1. Uncoated glass 2. Plastic coated glass

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Tinplated steel : Used in topical pharmaceutical aerosols Coating decreases the compatibility problems Light Inexpensive Aluminum: Used in oral aerosols - Metal containers may be further coated with organic coating, e.g. oleoresin, phenolic , vinyl or epoxy coating for additional protection .

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Glass containers: These containers are preferred because of its esthetic value and absence of incompatibilities. These containers are limited to the products having a lower pressure and lower percentage of the propellant. Glass is basically stronger than the metallic containers.

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Two types of glass aerosol containers i) Uncoated glass container: Decreased cost and high clarity and contents can be viewed at all times. ii) Plastic coated glass containers: These are protected by plastic coating that prevents the glass from shattering in the event of breakage. Pressures up to 33 psig can be used. Mainly used for some topical and metered dose inhaler aerosols.

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Glass Advantage: Absence of incompatibility Its use is limited for products having lower pressure and lower percentage of propellant There are two types of glass containers: Uncoated glass: Low cost - High clarity Plastic coated glass: Prevent the glass from shattering in the event of breakage Used for some topical and MDI aerosols

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Valves To delivered the drug in desired form. To give proper amount of medication. Not differ from valve to valve of medication in pharmaceutical preparation . Types - Continuous spray valve - High speed production technique. - Metering valves

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20 Valve components Ferrul or mount cap Valve body or housing Stem Gasket Spring Dip tube Gasket spring

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22 Actuator To ensure that aerosol product is delivered in the proper and desired form . These are specially designed buttons which helps in delivering the drug in desired form i.e., spray, wet stream, foam or solid stream Different types of actuators Spray actuators Foam actuators Solid steam actuators Special actuators

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FORMULATION Depending on the type of aerosol system utilized, the pharmaceutical aerosol may be dispensed as fine mist, wet spray, quick-breaking foam, stable foam, semi solid or solid. The type of system selected depends on i) physical, chemical and pharmacological properties of active ingredients ii) site of application An aerosol formulation consists of two components: i) Product concentrate ii) Propellant

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i) Product concentrate: consists of active ingredients or a mixture of active ingredients and other agents such as solvents, antioxidants and surfactants.

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ii) Propellant: .single or blend of propellants may be used. The propellant is selected to give the desired vapor pressure, solubility and particle size. Fluorinated hydrocarbons are gases at room temperature. They may be liquefied by cooling their boiling point or by compression at room temperature. Eg : Freon 12 will form a liquid when cooled to -30° C(-22° F) or when compressed to 70 psig at 21°C(70° F). Blend of solvents is used to achieve the desired solubility.

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Surfactants are mixed to give the proper HLB value for an emulsion system. Space aerosols usually operate at 30 to 40 psig at 21° C and may contain as much as 85% propellant. Surface aerosols commonly contain 30 to 70% propellant with pressures between 25 and 55 psig at 21°C(70° F). Foam aerosols usually contain only 6 to 10 % propellant and operate between 35 and 55 psig at 21°C (70° F). These aerosols can be considered to be emulsions.

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Types of system Solution system Water based system Suspension or Dispersion systems Foam systems 1. Aqueous stable foams 2. Nonaqueous stable foams 3. Quick-breaking foams 4. Thermal foams Intranasal aerosols

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Types of systems 1. Solution system •Consist of two phases liquid and vapor •If the active ingredient is soluble in propellant it has one system •The ratio of propellant and solvent could range from 5% (foaming) to 95% (inhalation). •To lower vapor pressure we can add solvents of non volatile e.g. Propylene glycol, acetone, alcohol

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2. Water based systems •Are increasing in use nowadays •Have relatively large amount of water •There is three phase system: water, propellant and vapor. •In aquasol system it has two phases i.e. water and vapor 3. Dispersed systems (suspension) •It needs surfactants •Particle size is important 4. Foam systems •Have foaming agent •Aqueous or non aqueous

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MANUFACTURING PROCEDURE FOR AEROSOLS Apparatus Pressure filling apparatus Cold filling apparatus Compressed gas filling apparatus

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Equipments used Those fill at pressurized and low temperature 1. Pressure filling (gauge-burette) 2. Cold filling (low temp.) 3. Compressed gas filling (after concentrate has been filled)

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Pressure filling apparatus It consists of a pressure burette which helps in metered filling of liquefied gas in to the aerosol container under pressure, an inlet valve is present at the bottom or top of the pressure burette, which incorporates the propellant into the container and flows with its own vapour pressure in the container. The trapped air escapes out from the top valve. The propellant which are having low pressure stop flowing as the pressure of burette and container becomes equal. If further propellant is to be added, then the aerosol container is attached to the container is attached to the nitrogen cylinder through a hose(rubber pipe), the pressure exerted by nitrogen helps in the flow of the propellant into the container. Otherwise compressed air is provided on the upper wall of the container for further addition of propellant. another device which consists of piston arrangement can also be used for pressure filling. This device helps in always maintaining positive pressure. This type of device cannot be used for filling inhalation aerosols which have metered valves.

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PROCEDURE: It is a slow method compared to cold filling method. But with the latest developments, the production rate has been greatly increased. This method involves filling of the concentrate into the container at the room temperature. Then the valve is placed in the container and crimped. Through the opening of the valve the propellant are added or it can be added “under the cap”.

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Since the opening of the valve are smaller in size ranging from 0.018-0.030 inches, it limits the production and the process becomes slow. But with the use of rotary filling machines and new filling heads where the propellants are filled through valve stem, the production rate is increased. The trapped air in the container and air present in head space is removed before filling the propellant. This is done so as to protect the products from getting adversely affected.

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Pressure filling

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ADVANTAGES: Solutions, emulsions, suspensions can be filled by this method as chilling does not occur. Contamination due to moisture is less. The production rate can be increased. Loss of propellant is less.

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Various units used in pressure filling methods are, Air cleaner Concentrate filler Valve placer Propellant filler Valve crimper Water bath Labeler Coder Packing table Vacuum crimper Pressure filler The fillers does not have the facility of refrigeration as chilling is not required. vacuum crimper and pressure filler comes under single unit if filling is carried by ‘under the cap’ method.

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Cold filling apparatus The apparatus used for cold filling purpose is simpler compared to pressure filling apparatus. It consist of an insulated box in which copper tubings are placed. The tubings are coiled to increase the area for cooling. Before operating the nit, the insulated box should be filled with dry ice or acetone. The apparatus can be operated with or without metered valves. Hydrocarbon propellant cannot be filled into aerosol containers using this apparatus because large amount of propellant escapes out and vaporizes. This may lead to formation of an explosive mixture at the floor level. Fluorocarbons do not form any explosive mixture although their vapours are heavier than air.

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PROCEDURE: non aqueous products and products which can withstand low temperature that is -40ºF are used in this method. The product concentrate are chilled to a temperature of -40ºF and filled into already chilled container. Then the chilled propellant is added completely in 1-2 stages. The filling of propellant depends upon the amount of propellant is used. Another method is to chill both the product concentrate and propellant in a separate pressure vessel and then filling them into the container. The valve is placed and crimped on the container. Then test for leakage and strength of container is carried out by passing container into a heated water bath, where the contents of the container get heated to 130ºF. After this, they are air dried, and the caps are placed on the container and labeled.

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Cold filling apparatus

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The cold filling method is no longer being used, as it has been replaced by pressure filling method. Various units used in pressure filling methods are, Air cleaner Concentrate filler Valve placer Propellant filler Valve crimper Water bath Labeler Coder Packing table the fillers are capable of refrigeration since the product concentrate and propellant are chilled.

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Compressed gas filling apparatus The filling of compressed gas does not require any large equipments and can be easily done in the lab. To reduce the pressure of compressed gas (high pressure), a pressure reducing valve is required. The apparatus consists of delivery guage. A flexible hose pipe which can withstand high guage pressure that is 150 pounds per square inch is attached to the delivery guage along with the filling head. A flow indicator is also present in specialized equipments.

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PROCEDURE: The product concentrate is filled into the container. Valve is placed and crimped on the container. With the help of vacuum pump the air is removed from the container. Filling head is put in the opening of the valve and the gas is allowed to pass. The gas stops flowing if the delivery pressure and the pressure within the container become equal. Carbon dioxide and nitrous oxide is used if more amount of gas is required or for the stability purposes. High solubility can be achieved by shaking the container manually or with the help of mechanical shakers.

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PHARMACEUTICAL APLLICATION 1. Aerosols are those preparations containing therapeutically active ingredients which either dissolved or suspended in the propellant blends and solvents. The propellants are in the form of compressed gases and liquefied gases. Aerosols are used for oral or topical administration. 2. Aerosols exhibits local action in nose, throat, lungs, eye, ear, vagina or rectum. 3. Aerosols also exhibit systemic effect when they pass from the lungs and get absorbed into the blood stream. 4. Metered dose inhalers help in administration of the liquid or solid mist or spray to the respiratory system or to the nasal passage. 5. The particle size should be below 10µm. For effective or maximum therapeutic activity, particle size should range between 3-6 µm, 6. Aerosols are used to formulate several agents which includes local analgesics, antiseptics, fungicides, antibiotics and anti-inflammatory agents.

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7. Aerosols are available in non pharmaceutical preparations like deodorants, perfumes, cosmetic air sprays, toothpastes and shaving creams . 8.They are also available as house hold products such as spray starch, waxes, polishes, cleaners and lubricants. 9. The drug administered through aerosols gives quick response and rapid action. As aerosol containers are fitted with metered valves. 10. These preparations are easy to carry. 11. They are uniformly applied without touching the affected area. 12. Sterility of the product is maintained during storage even after opening the valve(as micro organisms cannot enter the container). 13. The drug does not undergo hydrolysis as there is no water present in the propellant. 14. The drugs are well protected from light and air in aerosol formulation. 15. Patient compliance is high.

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Evaluation Of Pharmaceutical Aerosol

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A . Flammability and combustibility Flash point Flame extension, including flashback B. Physiochemical characteristics . Vapor pressure Density Moisture content Identification of propellant(s) Concentrate-propellant ratio C. Performance 1. Aerosol valve discharge rate Spray pattern Dosage with metered valves Net contents Foam stability Particle size determination Leakage Biologic characteristics E. Therapeutic activity Evaluation parameters of pharmaceutical aerosols

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Flammability and combustibility i) Flash point: It is mainly determined by the use of standard tag open cup apparatus. Aerosol product is chilled to a temperature of about -25° F and transferred to the test apparatus. The test liquid is allowed to increase slowly in temperature, and the temperature at which the vapors ignite is taken as the flash point. The flash point obtained is usually the flash point of the most flammable component (hydrocarbon propellant in case of topical aerosols).

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ii) Flame extension or 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 sec into the flame. Depending on the nature of the formulation, flame is extended, the exact length is measured with a ruler.

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B. Physicochemical characteristics: i) Vapor pressure: The pressure can be measured with a pressure gauge or through the use of a water bath and test gauges. Excessive pressure variation from container to container indicates the presence of air in the head space. A can puncturing device is available for accurately measuring vapor pressure.

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ii) Density: Hydrometer or pycnometer is mainly used to determine the density of an aerosol system. A pressure tube is fitted with metal flanges and a Holk valve, which allows for the introduction of liquids under pressure. The hydrometer is placed into the pressure tube. Sufficient sample is introduced the valve to cause the hydrometer to rise halfway up the length of the tube and the density can be read directly. Specific gravity can be determined through the use of high pressure 500 mL cylinder.

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iii) Moisture: Presence of moisture can be determined by using a) Karl Fischer b) Gas Chromatography

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iv) Identification of propellants: Identification of propellants and composition of each propellant in the blend can be done by using a) Gas chromatography b) Infrared spectrometry

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C) Performance: i) Aerosol valve discharge rate: Known weight of an aerosol product has been taken and discharging the contents for a given period of time using standard apparatus. The container is reweighed after the specified time, the change in the weight per time gives the discharge rate, expressed as grams per second .

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ii) Spray patterns: The method is based on the impingement of the spray on a piece of paper that has been treated with a dye-talc mixture. An oil soluble or water soluble dye is used depending on the nature of the aerosol. The particles that strike the paper cause the dye to go into the solution and to be absorbed onto the paper. This gives a record of the spray, which can be used for the comparison purposes. To control the amount of material coming into contact with the paper, the paper is attached to a rotating disk that has an adjustable slit.

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iii) Dosage with metered valves: Reproducibility of the dose was observed when the valve is pressed. Actual amount of medication received by the patient. Reproducibility of the dosage may be determined by assay techniques whereby one or two doses are dispensed into a solvent or onto a material that absorb the active ingredient. These solutions can be assayed and the amount of active ingredients determined. Another method involves accurate weighing of the filled container followed by dispensing of several doses. The container can be reweighed and the difference in weight divided by the number of doses dispensed gives the average dose. This test can be repeated and compared the results. Determination of dose received by a patient is rather difficult procedure, since all of the material dispensed is not carried to the respiratory tract.

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iv) Net contents: The tared cans that have been placed onto the filling line are reweighed and the difference in weight is equals to the net contents. Destructive method: weighing of full container followed by dispensing of the contents from the container. The contents are then weighed, with provision being made for the amount retained in the container. Other method is opening the container and removing as much of the product as possible. This test mainly useful for determining the actual amount that can be dispended. Weight of empty container =W1 gm Weight of the filled container = W2gm Difference in the weight = W1-W2gm net content. Distractive method: weight the filled container, dispensing the content and than contents are weigh.

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v) Foam stability: The life of foam can range from a few seconds to one hour or more depending on the formulation. Methods include: i) visual evaluation ii) time for a given mass to penetrate the foam iii) time for a given rod that is inserted into the foam to fall iv) use of rotational viscometers.

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vi) Particle size determination: Two methods are used to determine the particle size of the aerosols. 1) Cascade impactor 2) Light scattering decay

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1) Cascade impactor: This method analyses the particles having diameters ranging from 0.1 to 30μ. A series of nozzles and glass slides at high velocity are projected through a stream of particles, the larger particles become impacted first on the lower velocity stages. the smaller particles pass on and are collected at higher velocity stages

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2) Light scattering decay: Determination of particle size in epinephrine aerosols. The aerosol settles under turbulent conditions, the change in light intensity of a Tyndall beam is measured. It is noted that a) a mass median diameter of an epinephrine aerosol ranged from 2.7 to 3.5 μ b) 70% to 78% of the particles were less than 5μ c) 88% to 93% were less than 7μ d) 98% to 100% were less than 10μ

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D) Biological testing: This type of testing an aerosol should include a consideration of therapeutic activity and toxicity. Therapeutic activity: the dosage of the product has to be determined for inhalation aerosols and this must be related to the particle size distribution. Topical preparations are applied to the test areas and adsorption of the therapeutic ingredients can be determined Toxicity: Aerosol applied topically may be irritating to the affected area and or may cause chilling effect. When the skin is sprayed with an aerosol for a given period of time, the change in the skin temperature was observed .this change in temperature is mainly determined by the use of thermistor probes attached to recording thermometers. Inhalation toxicity can also be determined by exposing the test animals to vapors sprayed from an aerosol container.

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