Definition Packaging of therapeutic active ingredients in a pressurized system. Aerosols are depends on the power of compressed or liquefied gas to expel the contents from containers.Advantages _ A dose can be removed with out contamination of materials. Stability is enhanced for these substances adversely affected by oxygen and or moisture. When sterility is an important factor, it can be maintained while a dose is being dispensed. _ The medication can be delivered directly to the affected area in a desired form, such as spray, steam, quick breaking foam or stable foam. _ Irritation produced by the mechanical application of topical medication is reduced or eliminated. _ Ease of convenience of application. _ Application of medication in thin layer> Propellant > Container » Valve and actuator » Product concentrate fi — ACTUATOR PROPELLANT) VAPOUR PRODUCT AND LIQUID PROPELLANTPropellant It is responsible for developing the power pressure with in the container and also expel the product when the valve is opened and in the atomization or foam production of the product. # For oral and inhalation eg. Fluorinated hydrocarbons Dichlorodifluromethane (propellent 12) Dichlorotetrafluromethane (propellent 114) # Topical preparation Propane Butane Isobutane # Compound gases Nitrogen Carbon di oxide Nitrous oxideContainers They must be stand at pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at 130°F. A. Metals 1. Tinplated steel (a) Side-seam (three pieces) (b) Two-piece or drawn (c) Tin free steel (a) Two-piece (b) One-piece (extruded or drawn) B. Glass 1. Uncoated glass 2. Plastic coated glassoO Vapor pressure 0 Boiling points o Liquid densityVapor pressure of mixture of propellants is calculated by Doltan’s low which states that total Pressure in any system is equal to the sum of individual or partial pressure of various compounds Raoult’s low regards lowering of the vapor pressure of a liquid by the addition of another substance, States that the dispersion of the vapor pressure of solvent upon the addition of solute is proportion to the mole fraction of solute molecules in solution. The relationship can be shown mathematically : pa= Where, pa = partial vaopr pressure of propellant A, pAo = vaopr pressure of pure propellant A, na = mole of propellant A, nb = mole of propellant B NA= mole fraction of component ATo calculate the partial pressure of propellant B : nb pb= -- pBo =NBpBo - --(2) nb +na The total vapor pressure of system is then obtained as : P=pa + pb ----------------------------------(3) Where, P = total vapor pressure of systemValves Y To delivered the drug in desired form. Y To give proper amount of medication. Y Not differ from valve to valve of medication in pharmaceutical preparation. Types - Continuous spray valve - High speed production technique. -- Metering valves Dispersing of potent medication at proper dispersion/ spray approximately 50 to 150 mg +10 % of liquid materials at one time use of same valve.To ensure that aerosol product is delivered in the proper and desired form. BL ——actumrcr Different types of actuators » Spray actuators PROPELLANT > Foam actuators » Solid steam actuators > Special actuatorsMetered dose inhaler Metered Dose inhalerFormulation of pharmaceutical aerosols Contains two essential components * Product concentrate * Propellant Product concentrate Product concentrate contains ingredients or mixture of active ingredients and other such as solvents, antioxidants and surfactants. Propellant May be single or blend of various propellants ** Blends of propellant used in a p’ceutical formulation to achieve desired solubility characteristics or various surfactants are mixed to give the proper HLB value for emulsion system. ** To give the desired vapor pressure, solubility & particle size.Parameters consideration * Physical, chemical and p’ceutical properties of active ingredients. * Site of application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anufacturing of Pharmaceutical Aerosols Pressure filling apparatus Cold filling apparatus * Compressed gas filling apparatusPRESSURE FILLING Pressure filling is carried out at R.T. under high pressure. >The 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. *The desired amount of propellant is allowed to flow through the aerosol valve into the container under its own vapor pressure. *When the pressure is equalized between the burette and the container (thus happens with low pressure propellant), the propellant stops flowing. *To help in adding additional propellant, a hose leading to a cylinder of nitrogen or compressed is attached to the upper valve and the added nitrogen pressure causes the propellant to flow.ADVANTAGES > |t is the preferred method for solutions, emulsions and suspension. »Less chances for contamination of product with the moisture. > Less propellant is lost » No refrigeration is required, can be carried out at RTCOLD FILLING PROCESS »The principle of cold filling method requires the chilling of all components including concentrate and propellant to a temperature of -30 to -40 ° F. »This temprature is necessary to liquify the propellant gas. » The cooling system may be a mixture of dry ice and acetone or refergiration system. ¥ First, the product concentrate is chilled and filled into already chilled container followed by the chilled liquefied propellant.N \ \ \Advantages “*Easy process Disadvantages ** Aqueous products, emulsions and those products adversely affected by cold temperature cannot be filled by this method. “*For nonaqueous systems, some moisture usually appear in the final product due to condensation of atmospheric pressureCOMPRESSED FILLING “Compressed gases are present under high pressure in cylinders. These cylinders are fitted with a pressure reducing valve and a delivery gauge. *The concentrate is placed in the container * The valve is crimped in place * Air is evacuated by means of vacuum pump “The filling head is inserted into the valve opening, valve depressed and gas is allowed to flow into the container *For those products requiring an increased amount of gas or those in which the solubility of gas in the product is necessary, carbon dioxide and nitrous oxide can be used. *To obtain maximum solubility of the gas in the product, the container is shaken manually during and after the filling operation by mechanical shakers.Large scale equipment @ Concentrate filler ® Valve placer ® Purger and crimper ® Pressure filler ® Leak test tankQuality control for pharmaceutical aerosols Propellants ' Valves, actuator and dip tubes ' Testing procedure - Valve acceptance Containers Weight checking Leak testing | Spray testingEvaluation parameters of pharmaceutical aerosols rs - Flammability and combustibility 1. Flash point 2, Flame extension, including flashback . Physiochemical characteristics 1. Vapor pressure 2. Density 3. Moisture content 4. Identification of propellant(s) 5. Concentrate-propellant ratio . Performance 1. Aerosol valve discharge rate 2. Spray pattern 3. Dosage with metered valves 4. Net contents 5. Foam stability 6. Particle size determination 7. Leakage |. Biologic characteristics . Therapeutic activityViame Projection ** This test indicates the effect of an aerosol formulation on the extension of an open flame. ** Product is sprayed for 4 sec. into flame. ** Depending on the nature of formulation, the fame is extended, and exact length was measured with i/cr.Flash point * Determined by using standard (9 O>°) Cap Apparatus. Step involves are > * Aerosol product is chilled to temperature of - 25° F and transferred to the test apparatus. * Temperature of test liquid increased slowly, and the temperature at which the vapors ignite is taken a flash point. * Calculated for flammable component, which in case of topical hydrocarbons.-Yapor pressure Determined by pross60 couce Variation in pressure indicates the presence of air in headspace. A can punctuating device is available for accurately measuring vapor pressure.ensity Determined by /ipdrometer or a pycnomieter. This method is use for non aerosol, modification to accommodate liquefied gas preparation. Step involves are > *A pressure tube is fitted with metal fingers and hoke valve, which allow for the mtroduction of liquids under pressure. *The hydrometer is placed in to the glass pressure tube. Sufficient sample is introduced through the valve to cause the hydrometer to rise half way up the length of the tube. *The density can be read directly.Moisture content Method used — Karl Fischer method » G. C has also been used Identification of propellants * GC, » LR spectrophotometry Aerosol valve discharge rate & Determined by taking an aerosol known weight and discharging the contents for given time using standard apparatus. + By reweighing the container after time limit has expired, the change in weight per time dispensed is discharge rate, + Expressed as gram per seconds.Dosage with metered yalves Y Reproducibility of dosage each time the valve is dispersed ¥ Amt. of medication actually received by the patient. ¥ Reproducibility has been determined by assay technique, Y Another method is that, involves accurate weighing of filled container fallowed by dispersing of several doses, container can reweighed, and difference in weight divided by No. of dose, gives the average dosage.Net contents *Weight method ‘Filled full container, and dispensing the contents Foam stability * Visual evaluation ¢ Time for a given mass to penetrate the foam * Times for given rod that is inserted into the foam to fall . The use of rotational viscometersParticle size determination * Cascade impactor > Light scatter decay method Cascade impactor Operates on the projected through a series of nozzle and glass slides at high viscosity, the large particles become impacted first on the lower velocity stages, and the smaller particals pass on and are collected at high velocity stages. These practical ranging from 0.1 to 30 micron and retaining on RTI. Modification made to improve efficacyDorush, Thiel and Young used light scattering method to determine particle size. As aerosols settle in turbulent condition , the change in light intensity of Tyndall beam is measured Selarra and Cutie developed method based on practical size distribution.