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Aerosols
 

Aerosols

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Aerosols

Aerosols

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    Aerosols Aerosols Presentation Transcript

    • PHARMACEUTICAL AEROSOLS
    • AEROSOLS • 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 – Good Hue & Sullivan
    • AEROSOLS PRINCIPLE When a liquefied gas propellant or propellant mixture is sealed within an aerosol container with the product concentrate, equilibrium is quickly established between the portion of propellant that remains liquefied and that which vaporizes and occupies the upper portion of the aerosol container The vapor phase exerts pressure in all directions—against the walls of the container, the valve assembly, and the surface of the liquid phase, which is composed of the liquefied gas and the product concentrate. 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 expands and evaporates because of 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.
    • Advantages • • • • • • • • • • • Easy and convenient application Can be delivered directly to the affected area It prevents oxidation of drugs Rapid response to the medicament It can avoid first pass effect Reduced irritation Dose can be delivered without contamination Protect unstable drugs Portable It can maintain sterility It can produce local and systemic effects Disadvantages • • • • Expensive Propellants are toxic Highly inflammable Propellants can cause chilling effect to skin
    • Types of drug delivery systems Nebulizers used to administer medication to people in the form of a mist inhaled into the lungs. Meter dose Inhaler (MDI) are pressurized, hand-held devices that use propellants to deliver doses of medication to the lungs of a patient Propellant driven Aqueous pump sprays Dry powder inhaler (DPI) delivers medication to the lungs in the form of a dry powder.
    • 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
    • Components of Aerosols • • • • Propellants Containers Valves and actuators Product concentrate Propellants 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
    • LIQUIFIED GAS FLUORINATED HYDROCARBONS Used in almost all types pharmaceuticals, Inhalation and oral use Advantages – Chemical inertness – Lack of toxicity – Non flammability & explosiveness Disadvantages – High cost – It depletes the ozone layer – Damage Global Warming Potential
    • NOMENCLATURE OF FLORINATED AEROSOLS EXTREME RIGHT DIGIT INDICATES NUMBER OF FLORINE ATOMS IN THE MOLECULE THE SECOND DIGIT IN RIGHT INDICATES ONE GREATER THAN NUMBER OF HYDROGEN ATOMS IN A MOLECULE THE THIRD DIGIT FROM RIGHT IS ONE LESS THAN THE NUMBER OF CARBON ATOMS If this number is zero it is omitted and two digit number is given
    • 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
    • Recently HFA propellants are used instead of CFC propellants. Hydrofluoroalkanes Advantages Low inhalation toxicity High chemical stability High purity Not ozone depleting Disadvantages Poor solvents High cost Minor green house effect Examples 1,1,1,2,3,3,3-Heptafluoropropane 1,1,1,2-Tetrafluoroethane
    • 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. CO2, N2O, N2
    • Containers • Containers must withstand pressure 140-180 psig at 130°F Types of Containers • Metal containers – Tin Plated Steel – Aluminum – Stainless Steel • Glass containers - Uncoated glass - Plastic coated glass · Plastic Containers
    • Metal Containers Tin plated steel containers • It consist of a sheet of steel plate, which is coated on both sides with tin by electrolytic process • The coated sheet is cut into three sizes and these sizes are desired fabricated in to body , top , bottom • The body is shaped in to cylinder • The top and bottom are attach to the body by soldering If internal organic coating is required it is given Disadvantage: This process is slow and expensive Recent developments in welding include Soudronic system- The round bodies are welded with copper wire electrode and they are sent to conventional line where the bottom and top are attached Conoweld system – The round body is passed through two rotating electrode rings and they are sent to conventional line where the bottom and top are attached
    • Aluminum Containers • Many pharmaceutical aerosols are packed in Aluminum containers • Light weight, Less incompatibility due to its seamless nature, Greater resistance to corrosion • Used for inhalation and topical aerosols • Solvents (Pure Water and ethanol) corrode Al containers • The combination of Anhydrous ethanol and propellant 11 corrode Al, produces H2 gas, acetyl chloride , aluminum chloride and propellant 21 • • • This can be overcome by anodizing Al or addition of 2-3% water Non polar solvents are used in Al containers Creams and ointments
    • Advantages with welding method •Corrosion minimized •Decrease product and container interaction •Saves considerable mfg time •Non aqueous product can be filled •Alcohol based pharmaceuticals can be filled Stainless Steel Containers •We are going to prepare only Small size containers because of its cost •Strong •Reduce corrosion problems •Used for inhalation aerosols •No need for internal coating
    • Glass Containers Compatible with most formulations Allows for greater degree of freedom in container design resistant to corrosion, low cost. Available with or without plastic coating Limited to use – its brittleness and breakage Plastic Containers • Made with acetyl resins or poly propylene • Can withstand high pressure
    • Types of Containers METAL CONTAINERS maximum pressure (psig) Temperature (F)               Tin Plated Steel upto 140 130 Aluminum upto180 130       Stainless Steel upto181 130 less than 18 70                Plastic coated glass less than 25 70 PLASTIC CONTAINERS less than 26 70 GLASS CONTAINERS Uncoated glass
    • Valves It is multifunctional Easy to open and close Capable of delivering the content in the desired form (spray, foam and solid stream) It can deliver a given amount of medicament Materials used in construction of valves should by approved by FDA Types • Continuous spray valves • Metered valves
    • Continuous spray valves In this type of aerosols the product is released as long as the pressure is maintained in the actuator The valve consists of many different parts and is assembled using high speed production techniques Ferrule or mounting cup Valve body or housing Stem Gasket Spring Dip tube
    • Ferrule or mounting cup Used to attach valve to container It is made up of Tin plated steel, Al , Brass (glass bottles), Under side of the valve cup is coated with single or double epoxy or vinyl resins (To avoid the effects of oxygen trapped in head space) They are used with glass bottles and small aluminum tubes It is attached to the bottle by either rolling or clinching method Valve body or housing Made up of nylon or derlin and contains an opening at the point of attachment of dip tube (0.013 to 0.080 inch) Housing may or may not contain another opening called VAPORTAP (0.013 to 0.080 inch) allows escape of vaporized propellant with liquid product Fine particle avoids clogging, inverted position reduce flame extension and chilling Stem Nylon or derlin , metals like brass steel can also be used Gasket Buna –N and neoprene rubber They are compatible with most of the materials
    • Spring Stainless steel to hold gasket in place, Dip tube Poly ethylene or poly propylene ( more rigid) , I. D- 0.120 – 0.125 inch, Capillary dip tube – 0.050 inch Dip tube for Highly viscous products – 0.195 inches METERING VALVE •It has defined volume of reservoir •It can deliver desired volume of medicament by depressing actuator. •Used for all inhalations and some topical aerosols. • Applicable to potent medication.
    • ACTUATORS It is a specially designed button which is fitted to the valve and allows for easy opening and closing of valve It delivers the product in a desired form. It discharges the product as spray, foam, solid stream. Types of actuators Spray actuators It allows the stream of product concentrate and propellant to pass through various openings ( 0.016 inches to 0.040 inches ) and dispense as very fine spray The product is dispensed as a stream rather than as a spray by the actuator when the propellant conc. is low (50%or less) so for these case Mechanical break up actuators are used , which are capable of breaking the stream into fine particles It can be used for topical preparation, such as antiseptics, local anesthetics and foot preparation
    • FOAM ACTUATORS It consist of large orifice (0.070—0.0125inch) SOLID STREAM ACTUATORS these actuators are required for dispensing of 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.
    • Formulation Formulation of aerosols consist of two essential components Product concentrate Active ingredient or mixture of active ingredient, solvents, anti oxidants, 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
    • Types of Systems SOLUTION SYSTEM Large no of aerosol products are formulated. Solution aerosols produce a fine to coarse spray. It is also called as Two phase system because it consists of Vapor and Liquid phase. No solvent is required, if active ingredient is soluble in propellant. Depending on the type of spray, propellant 12 or A-70 (very fine particles) or mixture of propellant 12 and other propellants. If low VP propellants are added to P-12, large particle size 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 SOLUTION SYSTEM Large no of aerosol products are formulated. Solution aerosols produce a fine to coarse spray. It is also called as Two phase system because it consists of Vapor and Liquid phase. No solvent is required, if active ingredient is soluble in propellant. • Depending on the type of spray, propellant 12 or A-70 (very fine particles) or mixture of propellant 12 and other propellants. If low VP propellants are added to P-12, large particle size • The vapor pressure of system is reduced by addition of less volatile solvents such as ethanol, propylene glycol, glycerin, ethyl acetate. • The concentration of Propellant used is from 5% (for foams) to 95% (for inhalations). General formula Active drug -10-15% Propellant 12/11 (50:50) to 100%
    • Depending on water content the final product may be solution or Three phase system. • Hydrocarbon propellants • A-70 (drier particles) • e A-17 and A-31 (wetter spray). • These are useful for topical and preparations and in Plastic coated glass containers when the amount of flamable propellant donot exceed 15 % of total product weight and the volume capacity of the containers do not exceed 5 fluid ounces • Also usefully in inhalation aerosols
    • Water based system Here the non-aqueous solvents are partly or completely replaced with water so the name water based system Depending on formulation they emit spray or foam Also called as three phase system( water , vapour and propellant phases The formulation is dispersed in an emulsion system where the propellant is in external phase Ethanol: Cosolvent and in production of small particles Surfactants: low water soluble and high non polar soluble (0.5-2%) Examples: long chain fatty acid esters of polyhyroxylic compounds Concentration of propellant: 25-60% To achieve the desired fine particle size with product containing large amounts of water and low portion of propellant , a mechanical break up actuator is used along with the vapour tap valve
    • • • • • Recent development is use of aquasol valves Fine mist No chilling effect Designed to dispense the product efficiently and effectively using small amounts of propellants In aquasol valve the vapour phase of propellant and product enter the mixing chamber of the actuator separately through seperate ducts The vapour phase of propellant enters into actuator with high velocity and the product is also forced into actuator with the pressure of propellant At this point the product and vapour are mixed thoroughly and results in uniform , finely suspended spray
    • Suspension or Dispersed system Here the active ingredient is dispersed in propellant or mixture of propellant This system is primarily used with oral inhalation aerosols • Physical stability increased by Control of moisture content (300 ppm) – Moisture content of both suspensoid and propellant should be controlled because high moisture content results in particle agglomeration – DRYING Use of derivatives of derivatives of drug with minimum solubility in propellant – When the drug is having partial solubility it shows signs of particle growth Reduction of initial particle size to less than 5 µm for inhalation. GRINDING EQUIPMENT
    • Adjustment of density of propellant and suspensoid to equal by adjusting the density , the rate of settling of the suspensoid can be decreased The density can be adjusted by addition of a compound of higher or lower density so that density of suspensoid and propellant are made equal Use of dispersing agents 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 %) oleic acid Dispersing agent Prevention of particle growth Valve lubricant
    • FOAM SYSTEMS Emulsion and foam aerosols consist of active ingredient, Aq. or non aq. vehicle, surfactant, Propellant. These systems dispense the product as stable or quick-breaking foams Liquefied propellant is emulsified and generally in internal phase. Stable foams AQUEOUS STABLE FOAM NON AQUEOUS STABLE FOAM
    • AQUEOUS STABLE FOAM Active drug Oil o/w surfactant Water( 95-96.5) HC Propellant (3 -5%) •Hydrocarbon propellant (3 to 5% W/W or 8-10% V/V usually). •As the amount of propellant increases a stiffer and dryer produced. •Lower propellant concentrations yield wetter foams. HC and compressed gas propellants are used. NON- AQUEOUS STABLE FOAM Water is replaced with glycols such as polyethylene glycols foam is
    • QUICK BREAKING FOAM • Propellants are external phase • Especially applicable to topical medications •It dispenses the product as foam , which collapses into liquid Ethyl alcohol ( 46-66%) Surfactant ( 0.5-5%) Water ( 28-42%) HC Propellant (3-15%) Surfactant should soluble in alcohol and water. THERMAL FOAM • To produce warm foam for shaving • Used for hair colors and dyes . They are not readily accepted by consumer
    • Manufacturing of Pharmaceutical Aerosols PRESSURE FILLING • Process carried out at room temp • HC and FHC prop can be filled by this process • Less propellant loss • Less moisture contamination of the product • Most preferable because some solution , emulsion , suspension , and other preparation which cannot be chilled. • Not used for metered dose inhaler • It is not used for inhalation aerosols
    • Method in pressure filling: The product concentrate is quantitatively placed in the aerosol Containers The valve assembly is inserted and crimped into place The liquified gas under pressure is metered into the valve stem from pressure burrete The desired amount of propellant is allowed to enter the container under its own vapor pressure When the pressure in the container equals to that in the burette , propellant stops flowing. Additional amount of propellant can be added by increasing the pressure in the filling apparatus through the use of compressed air of nitrogen gas
    • COLD FILLING • In this method the product concentrate and propellants are refrigerated to a temperature at least 5°F below their boiling points.(30-40C) • The cooling system may be mixture of dry ice or acetone or refrigiration system • The chilled product concentrate is quantitaively metered into cold aerosol container • Then liquified gas is added • When sufficient propellant is added , the valve assembly is inserted and crimped into place • Used for inhalation aerosols • Used with metered valves and non metered valves • Should not use to fill HC propellants
    • Quality Control of Aerosols Propellants: All the propellants are shipped to the user along with a specification sheets. Before propellant is used it is subjected to some tests A sample of it is sent to laboratory , where its density , vapour pressure are determined and compared with the specification sheet And also tests for identification of propellants and if a mixture of propellants are used their composition is determined by gas chromatography The for purity point of view , the moisture content , halogens , non volatile residual contents are determined and are compared with the specification sheet These tests are preformed to ensure that the propellants have not been contaminated during shipment
    • Valves , actuators and dip tubes These parts are subjected to both physical and chemical inspection Metered dose valves: Valve Delivery rate: Test procedure: 25 valves are selected , and placed on the containers , into which the test solutions are filled. A button type actuator with 0.02 inch or larger orifice is attached The containers are placed a temperature of 25± 10 C The valve is actuated to fullest extent for atlest 2 seconds following complete dispensing of single delivery. This procedure is repeated for 10 times The test unit is weighed and the valve is actuated to fullest extent for atlest 2 seconds following complete dispensing of single delivery. Again it is weighed and the difference between this weight and previous weight is determined it gives the delivery of the valve
    • The test procedure is repeated for a total of two individual deliveries from 25 containers The individual delivery weights are divided by specific gravity of test solution to obtain the valve delivery per actuation Valve acceptance The test procedure is applicable to two categories of metered aerosol valves having the following limits For valves delivering 54µl or less , the limits are ± 15% 55 t0 200µl , the limits are ± 10% 1.Of the 50 individual deliveries , if four or more are out side the limits for the specified valve delivery , the valves are delivery 2.If three individual deliveries are outside the limits another 25 valves are Samples and test is repeated. The lot is rejected if more than one is out side the specifications 3. If two deliveries from one valve are beyond the limits , another 25 valves Should be taken. The lot is accepted if not more than one delivery is out side the limits
    • Containers: Weight checking Leak testing
    • Testing of Pharmaceutical Aerosols 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 , water bath , test gauges • Density: Modified Hydrometer or Pycnometer • Moisture content: Karl Fischer, GC • Identification of propellants: GC, IR • Concentration of propellant ratio: GC, IR • Specific gravity: • High pressure cylinder of 500m capacity
    • PERFORMANCE Aerosol valve discharge rate: Take an aerosol , determine its weight and discharge the contents for specified period of time , reweigh the container , Discharge rate : Change in weight per time dispensed. Spray pattern Take a paper , treat the paper with dye-talc mixture The dye may be oil soluble or water soluble Impinge the spray on the paper attached to rotating disk , the particles that strike the paper causes the dye to go into the solution and gets absorbed on the paper
    • Dosage with metered valves - Reproducibility of dosage, each time valve is depressed Determined by assay techniques where one or two doses are dispensed in a solvent or any material that absorbs active ingredient Or Weigh a container , dispense several doses and once again determine the Weight . The difference in weight / no doses gives the average dose. This is repeated and is compared - Amount of medication actually received by patient. Net contents: Wtotal - Wcontainer Foam stability - Visual inspection with time. - Time for a given mass to penetrate the foam. - Time for the rod inserted in the foam to fall - Rotational viscometers
    • 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)
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