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HISTORY In1941 the aerosol spray can was first put to good use by Americans Lyle Goodhue and William Sullivan, who are credited as the inventors of the modern spray can. Pressurized aerosol form was developed in early 1950 and was introduced as Medihaler Epi by Ricker Laboratories. 3/31/2014 2


DEFINITION ‘A system that depends on the power of a compressed or liquefied gas to expel the contents from the container.’ ‘Pressurized dosage forms containing one or more active ingredients which upon actuation emit a fine dispersion of liquid and/or solid materials in a gaseous medium.’ 3/31/2014 3


ADVANTAGES Removal of dose without contamination. Directly delivered to the affected area in a desired form. Minimized manual contact with drug. Rapid response. Convenient, easy. Controlled and uniform dosage by metered valves. No manual contact with patient. 3/31/2014 4


DISADVANTAGES Costly. Difficulty in disposal. Difficulty in formulation. Q.C testing is complicated. Cannot be subjected to heat. 3/31/2014 5

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COMPONENTS Aerosols consist of Propellant Container Valve and Actuator Product concentrate Product concentrate consists of API, Additives like suspending agent, antioxidant, aqueous  and non aqueous solvents, co solvent, emulsifying agents etc… container 3/31/2014 6

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PROPELLANT Develops pressure within the container. Expels the product, when the valve is opened. Aids in foam production. Vapor pressure differs. Mainly three types : Liquefied gas system a )  Fluorinated  hydrocarbon(FHC) b) Chlorofluorocarbon (CFC) c) Hydrocarbons (HC) Compressed gas system 3/31/2014 7


LIQUIFIED GAS SYSTEM Gases at room temperature and atmospheric pressure. Liquefied easily by lowering the temperature. Boiling point below 70 0 F and vapour pressure 14 - 85 psig. When placed into container, immediately separates into a liquid & a vapour phase. 3/31/2014 8

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FLUORINATED HYDROCARBONS It is used for oral and inhalation aerosol preparation Chemical Name Numerical Designation Trichloromonoflouromethane Propellant 11 Dichlorodifluromethane Propellant 12 Dichlorotetrafluromethane Propellant 114 Chloropentaflouroethane Propellant 115 3/31/2014 9

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CHLORO FLURO CARBON (CFC) Advantages Low inhalation toxicity High chemical stability High purity CFC-11 is a good solvent Disadvantages Destructive to atmospheric Ozone Contributes to “greenhouse effect” High cost eg.1 . Hydrochlorocarbon 2 . Hydroflurocarbon 3/31/2014 10

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HYDROCARBONS Chemical Name Numerical Designation Butane A-17 Isobutane A-31 Propane A-108 It is mainly used for the preparation of topical preparation Chemically stable No hydrolysis Inflammable Low toxicity Lighter than water 3/31/2014 11

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COMPRESSED GAS SYSTEM Eg.CO 2 , NO 2 Advantages Low inhalation toxicity High chemical stability High purity Inexpensive Disadvantages Require use of a nonvolatile co-solvent Produce coarse droplet sprays Pressure falls during use 3/31/2014 12

Physicochemical properties of propellants:

Physicochemical properties of propellants Vapor pressure, Boiling point & Liquid density Vapor pressure of mixture of propellants, calculated by Dalton’s law : ‘total pressure in any system is the sum of the individual partial pressures of various components.’ Raoult’s law regards lowering of the vapor pressure of a liquid by the addition of another substance, States that the depression of the vapor pressure of solvent upon the addition of solute is proportional to the mole fraction of solute molecules in solution. 3/31/2014 13

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p a = (n a / n a +n b ) p A o = N A p A o p a - partial vapor pressure of propellant A p A o - vapor pressure of pure propellant A n a - moles of propellant A n b - moles of propellant B N A - mole fraction of component A similarly, p b = (n b / n a +n b )p B o = N A p B o Total vapor pressure, P = p a + p b 3/31/2014 14

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CONTAINERS Withstand a 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. Aluminum ( a) Two-piece ( b) One-piece (extruded or drawn) 3. Stainless steel B. Glass 1 . Uncoated glass 2. Plastic coated glass 3/31/2014 15

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1.Tin plated containers Tin containers, electroplated with sheets of steel plate on both sides. 2 . Aluminum containers Greater resistance to corrosion Light weight, not fragile Good for light sensitive drugs 3/31/2014 16

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3 . Stainless steel container Limited for smaller size Extremely strong and resistant to corrosion Withstand pressure 4 . Glass containers Available with plastic or without plastic coating Compatible with many additives No corrosion problems Can have various shape because of molding Fragile Not for light sensitive drugs 3/31/2014 17

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VALVE Actuator Ferrule or mount cap Valve body or housing Stem Gasket Spring Dip tube 3/31/2014 18

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TYPES OF ACTUATOR Actuators : Specially designed button placed on the valve system, helps in easy opening and closing of the valve. Directs the spray to the desired area. Spray Actuators Foam Actuators Solid Stream Actuators Special Actuators 3/31/2014 19

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Ferrule / mounting cup Attach the valve in proper position in container. Coated with epoxy resin. Valve body / housing Made of nylon/ delrin Connect dip tube, stem & actuator Determines rate of delivery Stem It is made of nylon /delrin / s.steel One or more orifice (0.013 to 0.030 inch) 3/31/2014 20

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Gasket It is made of Buna –N, Neoprene rubber Spring Hold the gasket in its place Made of stainless steel Dip tube Made of poly propylene material / poly ethylene Inner diameter 0.120 –0.125 inch for less viscous Viscous product - 0.195 inch . 3/31/2014 21

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TYPES OF AEROSOL SYSTEM Four types : Solution system / Two phase system Water based system / Three phase system Suspension or Dispersion system Foam system Aqueous stable foam Non-Aqueous stable foam Quick Breaking Foam Thermal foam 3/31/2014 22

Two phase system:

Two phase system Contains both vapor & liquid. Drug soluble in propellant – no co-solvent. Propellant 12 – single or mixture. In mixture – propellant with vapor pressure less than propellant 12 , vapor pressure reduction, bigger sized aerosol particles. E.g. propellant 12/11(30:70), propellant 12/114(45:55). 3/31/2014 23

Three phase system:

Three phase system Contains water phase, vapor phase and the propellant. Water immiscible with propellant – solubility increased by adding, Co – solvent (ethanol) Surfactants (0.5% - 2.0%) – non polar ( esters of oleic acid, palmitic acid, stearic acid) 3/31/2014 24

Suspension system:

Suspension system Using suspending agent. Oral inhalation aerosols. Active ingredients dispersed in propellant or mixture Physical stability by, Control of moisture content Active ingredients with minimum solubility. Initial particle size < 5 microns Propellant density Suspending agents 3/31/2014 25

Foam system:

Foam system Consists of aq. or non aq. vehicles, propellant & surfactants. Four types , Aqueous stable foams Non aqueous stable forms Quick breaking forms Thermal forms 3/31/2014 26

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Aqueous stable foams Propellant 3-4% Dry spray is produced Propellant – internal phase Steroidal antibiotics Non aqueous stable foams Emulsifying agent - glycol Quick breaking foams Propellant – external phase Topical application Cationic, anionic, non ionic surfactants Thermal foams Delivered as foam on application of heat Shaving creams 3/31/2014 27

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MANUFACTURING OF PHARMACEUTICAL AEROSOLS Apparatus Cold filling apparatus Pressure filling apparatus Compressed gas filling apparatus 3/31/2014 28


COLD FILLING APPARATUS Insulated box fitted with copper tubings 3/31/2014 29


M ethods Method A Product concentrate chilled to -30 to -40 o F. Chilled product added to chilled container. Chilled propellant added through inlet valve. Method B Product concentrate and propellant chilled to -30 to -40 o F. Mixture added to chilled container. 3/31/2014 30

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The valves are set in place. Filled containers passed through water bath (contents heated to 130 o F). Containers dried, capped and labeled. Advantage Easy process Disadvantage Aqueous products, emulsions cannot be filled. For non aqueous systems, moisture appears in final product . 3/31/2014 31



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Consists of metering burette – measures the amount of propellant to be filled. Method Product concentrate is filled through the burette at room temperature. Propellant is added through the inlet valve. Flow of propellant stops when pressure of filling propellant become equal to the pressure within the container. 3/31/2014 33

Advantages :

Advantages Preferred for solutions, emulsions & suspensions. Less contamination. Less propellant is lost. No refrigeration . 3/31/2014 34


COMPRESSED GAS FILLING APPARATUS Propellant – compressed gas Pressure reduced by pressure reducing valve Pressure used – 150 psig METHOD Product concentrate placed in container Valve crimped in its place Air evacuated by vacuum pump Filling head inserted into valve opening, valve depressed & gas allowed to flow into container. Container shaken during and after filling by mechanical shakers 3/31/2014 35


QUALITY CONTROL TESTS It Includes the testing of : » Propellants » Valves , Actuator, Dip Tubes » Containers » Weight Checking » Leak Testing » Spray Testing 36

Propellants :

Propellants Vapor pressure is determined & compared to Specifications. Parameter Tested By Identification Purity Gas Chromatography Moisture, Halogen, Non-Volatile Residue Determinations 3/31/2014 37

Valves, Actuators & Dip tubes:

Valves, Actuators & Dip tubes Take 25 valves & placed on containers, Filled with specific test solution Actuator with 0.020 inch orifice is attached .( containers placed at temp. 25±1 0 C) Valve is actuated to fullest extent for 2 sec. Repeat for total of 2 individual delivery from each 25 test units. Individual delivery wt in mg. Valve delivery per actuation in µL = Specific gravity of test solution Valve Acceptance : Deliveries Limits 54µL or less ± 15% 55 to 200 µL ± 10% 3/31/2014 38

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Of 50 deliveries If 4 or more are outside limits : valves are rejected If 3 individual deliveries are outside limits : another 25 valves are tested Lot is rejected if more than 1 delivery is outside specification If 2 deliveries from 1 valve are beyond limits : another 25 valves are tested Lot is rejected if more than 1 delivery is outside specification 39


Containers Containers are examined for defects in lining. Q.C aspects includes degree of conductivity of electric current as measure of exposed metals. Glass containers examined for Flaws. Weight Checking Add tared empty aerosol container to filling lines which after filling with concentrate are removed & weighed. Same procedure is used for checking weight of Propellants . 3/31/2014 40

Leak Test:

Leak Test Done by measuring the Crimp’s dimension & comparing. Final testing of valve closure is done by passing filled containers through water bath. Spray Testing It is done »To clear dip tube of pure propellant & concentrate, » To check for defects in valves & spray pattern. 3/31/2014 41

Evaluation Tests:

Evaluation Tests A. Flammability & combustibility: 1.Flash point 2.Flame Projection B. Physicochemical characteristics : 1.Vapour pressure 2.Density 3.Moisture content 4.Identification of Propellants 3/31/2014 42

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C. Performance 1. Aerosol valve discharge rate 2. Spray pattern 3. Dosage with metered valves 4. Net contents 5. Foam stability 6. Particle size determination D. Biological testing 1.Therapeutic activity 2.Toxicity studies E. Extractable Substances 3/31/2014 43

A. Flammability & combustibility: :

A. Flammability & combustibility: Flash point: Apparatus : Open Cup Tag Apparatus Test liquids temp. is allowed to increase slowly & temp. at which vapors ignite is called as Flash Point . Flame Projection: Product is sprayed for 4 sec onto flame & exact length is measured with ruler. 3/31/2014 44

B. Physicochemical characteristics: :

B . Physicochemical characteristics: Property Method 1. Vapor Pressure » Can Puncturing Device. 2. Density » Hydrometer, » Pycnometer. 3. Moisture » Karl Fisher Method, » Gas Chromatography. 4. Identification » Gas Chromatography, » IR Spectroscopy. 3/31/2014 45

C. Performance: :

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 (g/sec). 2. Spray pattern : The method is based on the impingement of spray on piece of paper that has treated with Dye-Talc mixture. 3/31/2014 46

3. Dosage with metered valves : :

3. Dosage with metered valves : Reproducibility of dosage determined by: »Assay »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 : Tared cans placed on filling lines are reweighed & then difference in wt. is equal to net content. In Destructive method : opening the container & removing as much of product possible. 3/31/2014 47

5. Foam stability : :

5 . Foam stability : Methods : » Visual Evaluation » Time for given mass to penetrate the foam » Time for given rod to fall which is inserted into the foam » Rotational Viscometer 6.Partical Size Determination : Methods : » Cascade Impactor, » Light Scattering Decay. 3/31/2014 48

a). Cascade Impactor ::

a ). Cascade Impactor : Principle : Stream of particle projected through a series of nozzle & glass slides at high velocity, larger particle impacted on low velocity stage & smaller on higher velocity stage. b). Light Scattering Decay : Principle : As aerosol settles under turbulent condition, the changes in light intensity of a Tyndall beam is measured. 3/31/2014 49

D. Biological testing: :

D. Biological testing: 1.Therapeutic Activity : » For Inhalation Aerosols : Depends on the particle size. » For Topical Aerosols : Is applied to test areas & absorption of therapeutic ingredient is determined. 2.Toxicity : » For Inhalation Aerosols : Exposing test animals to vapor sprayed from aerosol container. » For Topical Aerosols : Irritation & chilling effects are determined . 3/31/2014 50

E. Extractable Substances:

E. Extractable Substances Leaching of extractable from plastic components into the formulation is a potential serious problem. Extractable include: antioxidants, plasticizers, monomers, nitrosamine, vulcanization accelerators, etc., should be identified and minimized. The composition and the quality of materials used in the manufacturing of the valve components must be carefully selected and controlled. Their compatibility with formulation components should be well established to minimize change in the medication delivery, leak rate, impurity profile of the drug product over time. 3/31/2014 51


Labeling Medicinal aerosols should contain at least the following: Avoid inhaling. Avoid spraying into eyes or onto other mucous membranes. Contents under pressure. Do not puncture or incinerate container. Do not expose to heat or store at temperature above 120 0 F. Use only as directed. 3/31/2014 52


REFERENCES The Theory and Practice of Industrial Pharmacy by Leon Lachman, Herbert A. Lieberman, 3 rd edition, Page: 589-618. Remington, The Science and Practice of Pharmacy, 21 st edition, Page: 1000 -1015. 3/31/2014 53

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