Pharmaceutical Aerosols Quality Control DepartmentDr Amir Ramzy

Pharmaceutical AerosolsDefinitions: Disperse phase system in which solid particles or liquid droplets constitute the disperse phase and gas in the continuous phase System that depends on the power of compressed or liquefied gas to expel the content from container. Its a package contains the product and a propellant capable of expelling that product through an opened valve.Classification of Aerosols Space spray:Surface coat:Foams:

Dispensation as a fine sprayProduces a wet coatProduct comes out in the form of a foam/froth

Particle size 50 Particle size are 200 in diameter

Advantages:Disadvantages:

1. Dose is removed without contamination of remaining materials.2. Stability is enhanced for those substances adversely affected by oxygen and or moisture. Sterility can be maintained When it is an important factor,3. The medication can be delivered directly to the affected area in a desired form, such as spray, steam, quick breaking foam or stable foam.4. Reduce Irritation produced by the mechanical application of topical medication.5. Ease, convenience of application. (Application of medication in thin layer).1. Expensive.2. Disposal of empty aerosol containers are difficult.3. Due to volatility of the propellant/scan irritate the injured skin.4. Some persons may be sensitive to the propellant/s and persons who using an inhalation aerosol/s, The fluorinated hydrocarbons may cause carcinotoxic effects on rapid and repeated use of the aerosol product.5. Aerosol packs must away from temperature and fire, because it may develop high pressure inside the container leads to explosion.6. If the drug is not soluble in the propellant, aerosol formulation is difficult.7. Sometimes propellants may cause toxic reactions, if therapy is continued for a long period of time.

Components of aerosol package:1. Propellants: Develop pressure within container to expel product when the valve is opened. Serves as solvents, suspending agents or dileunts. These are compressed gases at 70 to 80 p.s.i.g Compressed gases such as CO2 or nitrogen Liquefied gases like halogen derivatives such as some saturated hydro carbons like methane ethane etc ... A large no of liquid propellants some of which are refrigerants gases also have been developed Eg. T.F.D.C.E ,T.C.M.F.E etc .... Liquefied gas are preferred comparing to compressed gas Compressed gas 1. Pressure are in order of 70-80 psig2. High tensile material steel and glass Liquefied gases:1. Constant pressure is maintained till last drop2. Low pressure used 30-40 psig3. Material other than steel can be used for packing.Based on material to be prepared to be propelled:Two phase system Three phase system

This system is comprised of the liquid phase, containing the liquefied propellant and product concentrate, and the vapor phase.This system is comprised of a layer of water-immiscible liquid propellant, a layer of highly aqueous product concentrate, and the vapor phase.

Product is solid and insoluble in propellantOr it is solid or liquid which dissolves in it.If a product is insoluble solid than it can be suitably suspended and system will have one liquid phase and a gaseous phase Product is immiscible with propellant and dissolved in liquid which also does not mix with propellant Gas Product and Liquid propellant

2. Containers: Container material are designed such that they withstand pressures as high as 140 to 180 p.s.i.g at 54C1. Metals such as aluminium, stain less steel and tin plated steelVery rare incompatible casesStain less steel containers are generally avoided because of high cost2. Glass uncoated or plastic coated In Glass containers practically no corrosion3. Plastics polymeric amides, acetyl co polymers3. Valves The modern day aerosol valves are Multifunctional i.e they deliver product in desired form As well as in measured quantities when ever required Components of aerosol valves:1. Gaskets: affix valve on container2. Housing3. Stem4. Dip tube5. Valve body or housing 6. Spring

Metered valve aerosols Some metering type of valves have been designed which permit only a specified amount of product to come out at any go Such valves actually consist of two valve's chambers both of which are connected to actuatorWhen actuator button is in closed position upper chamber valve is in closed position and power chamber valve is open required amount of product is filled.4. Actuator Actuators enable closing and opening of the valvesTo ensure that aerosol product is delivered in the proper and desired form.Different types of actuator:1. Spray actuator 2. Foam actuator3. Solid steam actuator 4. Special actuator

Manufacturing In general manufacturing of aerosol takes place in two stages1. Manufacturing of concentrate2. Addition of propellant This manufacturing procedure is quite different from non-aerosol pharmaceuticals product This require Q.C measures during filling operation to ensure both concentrate and propellant are brought together in the proper proportion The aerosol concentrate is prepared and sample is tested (early detection prevents loss of other components) Once the propellant is added product is sealed in to a container with a valve methods1. Cold filling method2. Pressure filling method

This method requires chilling of all components including concentrate and propellant to temperature -30f or- 40 FThis method is carried out at room temperature utilizing pressure equipments

The type of product and size of container usually influence method to be used

Cold filling method 1. Product concentrate is chilled to -40 F 2. Added to the chilled container 3. Then the chilled propellant is addedAlternate methods is to chill both concentrate and propellant in a pressure vessel to -40 F And then added mixture to aerosol containerA valve is then crimpedThen the container passed through a heated water bath in which content are heated to 130 FThis is to test for leak and strength of containerContainer is air dried and spray tested if necessary

Drawbacks This method is restricted to non aqueous products And those products not adversely affected by low temperatures in the range of -40 F Pressure filling method When first developed its slower than cold f filling method With development of new techniques speed of this method has been greatly increased.

1. Concentrate added to container at room temperature2. Valve is crimped 3. Then the propellant is added through the valve/ under the cap

Since the valve contain extremely small opening (0.018 to 0.030 inch), this step is slow and limits production With development of rotary filling machines which allow propellant to be added around and through the valve stem the speed has been increasedFor those products adversely affected by air the air in headspace is evacuated prior to adding of propellant

Pressure method is preferred to the cold method1. As some solutions, emulsions, suspensions and other preparations cant be chilled2. There is less danger of contamination of the product with moisture3. High production speed can be achieved4. Less propellant is lost5. And the method is not limited

Quality control and evaluation of pharmaceutical aerosols:Quality control tests includes:Evaluation tests:

1. Propellants2. Valves, Actuator. Dip Tubes3. Containers4. Weight Checking5. Leak Testing6. Spray Testing

A. Flammability & combustibility:a. Flash point b. Flash ProjectionB. Physicochemical characteristics:a. Vapor pressure b. Densityc. Moisture contentd. Identification of PropellantsC. Performance:a. Aerosol valve discharge rateb. Spray patternc. Dosage with metered valvesd. Net contentse. Foam stabilityf. Particle size determinationD. Biological testing:a. Therapeutic activity E. Toxicity studies

1. Propellants All Propellants are accompanied by Specification sheet. Parameter Tested By Identification Purity Gas Chromatography Moisture, Halogen, Non-Volatile Residue Determination2. Vales, Actuator, Dip-tubes This done according to standard procedure as found in Military Standards MIL-STD-105D". For metered dose aerosols test methods was developed by Aerosol Specification Committee industrial Pharmaceutical Technical Section Academy Of Pharmaceutical Sciences The object of this test is to determine magnitude of valve delivery & degree of uniformity between individual valves. Standard test solutions were proposed to rule out variation in valve delivery.3. Containers: Containers are examined for defects in lining. Q.C aspects include degree of conductivity of electric current as measure of exposed metals. Glass containers examined for flaws (defects)4. Weight Checking: Weight Checking is done by periodically adding tarred empty aerosol container to filling lines which after filling with concentrate are removed & weighed. Same procedure is used for checking weight of Propellants.Leak test:Leak test is done by measuring the Crimps dimension and ensuring that they meet specificationFinal testing of valve closure is done by passing filled containers through water bath (temp is checked repeatedly and values are recorded)

Spray testing:It is done to clear tube of pure propellant and concentrate to check for defects in valves and spray patternLeakage test:1- Weigh 10 can units and calculate the mean value =W12- Immerse the 10 can units in water bath for 15 min adjusted on temperature 50 C3- Re-weight the 10 can units after drying =W24- The test is passing if there is no visual leakage observed and the difference between the initial and final weight is less than 1.0%.

A. Flammability and combustibility 1- Flash point: Apparatus: Open Cup Tag ApparatusTest liquids temp. is allowed to increase slowly & temp. at which vapors Ignite is called as Flash Point.2- Flame Projection: Product is sprayed for 4 sec onto flame & exact length is measured with ruler.B. Physiochemical characteristics The pressure can be measured simply with a pressure gauge /through use of water bath ~test gauge and special equipments like1- Vapor Pressure Can Puncturing Device.2- Density >> Hydrometer, Pycnometer.3- Moisture Karl Fisher Method~4- Identification Gas Chromatography, >> IR Spectroscopy.C. Performance 1) Aerosol valve discharge rate: Aerosol product of known weight is discharged for specific time. By reweighing the container, the change in the wt. per time dispensed is the Discharge rate in gm/sec.2) 2. Spray pattern: The method is based on the impingement of spray on piece of paper that has treated with Dye-Talc mixture.3) 3 dosage with metered valves: Reproducibility of dosage determined by: Accurate weighing of filled container followed by dispensing several dosage. containers again reweighed & diff. in wt. divided by no of dosage dispensed gives average dose.4) Net contents:Tarred cans placed on filling lines are reweighed & thenDifference in wt is equal to net content. In Destructive method: opening the container & removing as much of product possible.

Mean volume of can concentrate and mean weight of propellant gas:1) Weigh each can unit individually 1 each initial unit weight= W12) Des-cramping the can unit to discharge the gas 1 re-weight the can with its des-cambered valve= W23) The different between W1-W2 =the propellant weight4) Repeat the last steps for 10 can units and calculate its mean value= mean weight of propellant gas5) Using measuring cylinder to measure the volume of each can concentrate solution of 10 unit6) Calculate the mean value = Mean volume of can concentrate

5. Foam stability: The life of a foam can range from few seconds to an hour Various Methods are used Visual Evaluation, Time for given mass to penetrate the foam, Time for given rod to fall which is inserted into the foam, Rotational Viscometer.[Type text]

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