PHARMACEUTICAL AEROSOLS

1. PHARMACEUTICAL AEROSOLS By Ravi PatelAssistant Professor &Head Department of Pharmaceutics Smt. N M Padaliya Pharmacy college,Ahmedabad

2. Definition • Aerosol is pressurized dosage form in which therapeutically active drug is dissolved or dispersed or suspended in compressed or liquified gas to expel the content from the container in the form of spray • Aerosol mainly used for the treatment of Asthma. • Aerosols are used for either topical , oral or nasal administration in the form fine particles or mist or fog. • In mid 1950 the pharmaceutical aerosol introduced in market. • Aerosols are depends on the power of compressed or liquefied gas to expel the contents from containers.

3. Advantages • A dose can be removed with out contamination of materials. • 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 • Produced rapid action • It is suitable for when the degrade in GI tract. • It can avoid the hepatic metabolism of drugs. • It Prevents to Oxidation of drugs • It can be maintain sterility& easy to portable

4. Disadvantages • Limited safety hazard (Flammable Nature) • It is a Costly Preparation • It is a chance for continuous deposition of particle in upperrespiratorytract • The propellant may cause chillness to the skin.

5. Components Aerosols • Aerosols consist of • Propellant • Container • Valve and Actuator • Product concentrate • Product concentrate consist of API, Additives like suspending agent, antioxidant, aqeous and non aqueous solvents ,cosolvent ,emulsifying agents etc… container

6. Propellant Itis 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. It is classified in to mainly three types 1 Liquified gas system a) Flourinated hydrocarbon(FHC) b) Chloro fluro carbon (CFC) C) Hydrocarbons (HC) 2 Compressed gas system 3 Hydrofluoroalkanes

7. LIQUIFIED GAS SYSTEM • These compounds are gases at room temperature and atmospheric pressure .However they can be liquified easily by lowering the temperature (below the boiling point or by increasing pressure ) • These compounds are chosen generally have B.Pt below 70F and vapour pressure between 14 and 85 psia at 70F • When it is placed into container it immediately separates into a liquid and a vapour phase. • Some of the propellant molecule will leave from the liquid state to vapor state. The pressure at this point is called vapour pressure. • It is denoted by the symbol Psia. Psia means = pounds per square inch absolute • As molecule enter the vapor state a pressure gradually develops • no .of molecule in v.state =  vapor pressure

8. Propellant FLUORINATED HYDROCARBONS It is Used for oral and inhalation aerosol preparation Chemical Name Numerical Designation Trichloromonoflouromethane (propellent 11) Dichlorodifluromethane (propellent 12) Dichlorotetrafluromethane (propellent 114) Chloropentaflouroethane (propellent 115) The term psig ( pounds per square inch inch gauge) 0 Psig = 14.7 Psia Eg. Flourinated hydro carbon

9. CHLORO FLURO CARBON( CFC) • Advantages • Low inhalation toxicity • High chemical stability • High purity • CFC-11 is a good solvent • Disadvantages • Destructive to atmospheric Ozone • Contribute to “greenhouse effect” • High cost eg.1.Hydrochlorocarbon2.Hydroflurocarbon3. Hydrochloroflurocarbon

10. HYDROCARBONS • Chemical NameNumerical 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 • They are lighter than water

11. COMPRESSED GAS SYSTEM Eg.. Co2 , No,N2 Advantages Low inhalation toxicity High chemical stability High purity Inexpensive–No environmental problem Disadvantages Require use of a nonvolatile co-solvent Produce course droplet sprays Pressure falls during use

12. PHYSIOCHEMICAL PROPERTIES OF PROPELLANTS • Vapor pressure • Boiling points • Liquid density • Vapor pressure of mixture of propellants is calculated by Doltan’slaw 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.

13. Aerosols Containers They must be stand at pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at 1300 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

14. AEROSOL CONTAINERS • Containers must withstand pressure as high as 140 to 180 psig • Types of containers: • 1.Tin plate containers • consists of sheet of steel plate that has been electroplated on both sides with tin • 2. Aluminum containers • greater resistance to corrosion • Light weight, not fragile • Good for light sensitive drugs

15. AEROSOL CONTAINERS • 3. Stainless steel container • Limited for smaller size • Extremely strong and resistant to most materials • Pressure stand • 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

16. COMPONENT OF AEROSOLS • Actuator • Ferrule or mount cap • Valve body or housing • Stem • Gasket • Spring • Dip tube

17. TYPES OF ACTUATOR Actuators: These are specially designed button placed on the valve system which helps in easy opening and closing of the valve. It helps in deliver the product in the desired form. There are different type of actuators are used , Spray Actuators Foam Actuators Solid Stream Actuators Special Actuators

18. Spray actuator • The stream of product concentrate and propellant are dispensed in the form of small particle through orifices 0.016-0.040inch. • Large orifice are used when high pressure of propellant 12 • Foam Actuator: • They contain large orifice diameter 0.070-0.125 inch • Semisolid stream actuator: It is used for dispensing semisolid dosage form • Special actuator: They are specially designed to deliver the medicament on the specific sites like nose , throat

19. FERRULE/ Mounting cup It is used to attach the valve in proper position in container. it is necessary coated with epoxy resin. Valve body / housing : It is made of nylon/delrin and contains at the opening point of diptube(0.013 to 0.080 inch) It prevents clogging of p.size ,reduce chilling effect of the skin. Stem: it is made of nylon /delrin /s.steel It contains one or more orifice (0.013 to 0.030) Gasket : It is made of Buna –N, Neoprene rubber Spring: It is used to hold the gasket in a place and when actuator is depressed it returns the valve in closed position It is made of stainless steel Dip tube :It is made up of poly propylene material / poly ethylene Inside diameter (0.120 –0.125) for c.tube( 0.050 inch and Viscous product 0.195)

20. TYPES OF AEROSOL SYSTEM • There are five types of aerosol system • 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 • Intranasal foam

21. SOLUTION SYSTEM which consists of two phases: a vapor phase and a liquid phase Propellant has high pressure hence propellant114 is added to reduce its vapour pressure .

22. WATER BASED SYSTEM • It is three phase system containing vapour phase, propellant , water. • Ethanol used as a cosolvent to solubilize the propellant in water • Propellant content varies from 25 -60% • SUSPENSION SYSTEM • It is prepared by dispersion active ingredients in mixture propellant and by using suspending agent • The physical stability of suspension can be increased by use minimum solubility of API. • Eg. Ephedrine bi tartarate is less soluble than Hcl • By Use of surfactant to reduce the agglomeration • Eg. Sorbitan monolaurate ,sorbitan monooleate sorbitantrioleate, isopropyl myristae.

23. FOAM SYSTEM • They contain Dispersion of AI, A. Vehicle, surfactant and propellant • Liquefied propellant used as internal phase • Aqueous stable foam : • Ingredients( antiseptic ) • oil waxes • O/W surfactant • Water • Hydrocarbon • Non aqueous stable foam : • These are prepared by using Glycols Emulsifying agent used this type PEG Esters • Quick breaking foam : • the product is dispensed a s a foam which then collapsed in to liquid Useful for topical medication

24. TYPES OF AEROSOLS DELIVERY Nebulizers Used to administer medication to people in the form of a mist inhaled into the lungs. Meter dose Inhaler (MDI) It 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.

25. NEBULISER It is a device used to converting a liquid drug (Solution /suspension) into a fine mist which can then be inhaled easily Two types: •Jet Nebuliser( air jet /air blast) •Ultrasonic Nebuliser •Drugs are not conveniently prepared by MDI/ DPI

26. JET NEBULIZERS It is powered by high pressure air Nebuliser commonly used in hospital and home for drug administration have small medication reservoirs(<10ml)

27. ULTRSONIC NEBULIZER

28. METERED DOSEINHALER(MDI)

29. METERED DOSEINHALER(MDI)

30. METERED DOSEINHALER(MDI) • Metered-dose inhalers (MDIs), introduced in the mid-1950. • In MDIs, drug is either dissolved or suspended in a liquid propellant mixture together with other excipients, including surfactants, and presented in a pressurized canister fitted with a metering valve • A Predetermined dose is release when up on actuation. • When released from the canister the formulation undergoes volume expansion in the passage within the valve and forms mixture of gas. • The high speed of gas flow break the liquid into fine droplets • MDI are Generally Packed In aluminum steel canister with a capacity of 20 -30 ml. • Aluminium is inert material . So either coated with epoxy material. • CFC used as a propellant in MDI Preparation along with surfactant and lubricant. eg. CFC -11, CFC -12, CFC-14 • Alternative for propellant CFC –HFA-134,127

31. CONTIN…… • The metering valve is place in inverted position. • Depression of the valve stem allows the content of the metering chamber refill with liquid from the bulk is ready to dispense next dose • ADVANTAGES OF MDI • Portable • Low cost • Disposability • Hermatically sealed container to prevent oxidation of formulation. • It cause valve clogging due to large p.size.

32. MANUFACTURING OF PHARMACEUTICAL AEROSOL • Apparatus • Cold filling process • Pressure filling process • Compressed gas filling process

33. COLD FILLINGAPPARATUS • The principle of cold filling method requires the chilling of all components including concentrate and propellant to a temperature of -30 to -40 ºF. • This temperature is necessary to liquefy the propellant gas . • The cooling system may be a mixture of dry ice and acetone or refrigeration system. • First, the product concentrate is chilled and filled into already chilled container followed by the chilled liquefied propellant • The heavy vapour of the cold liquid propellant generally displace the air in the container • Single head or multiple head rotary unit capable of vacuum crimping up to 120 can / min are available. • The rotary unit requires air pressure (90 to 120 lbs / inch) and vacuum. • A valve is placed either manually or automatically depending on the production rate required.

34. The cold filling aerosol line consists of: 1.Un-scrambler 2.Air-cleaner 3.Concentrate filler (capable of being chilled) 4.Propellant filler 5.Valve placer 6.Vaccum purger 7.Valve crimper 8.Heated water-bath 9.Labeler 10.Coder and packaging table

35. 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.

36. COMPRESSED FILLING • Compressed gases are present under high pressure in cylinders. These cylinders are fitted with a pressure reducing valve and a delivery gauge. • 1.The concentrate is placed in the container • 2.The valve is crimped in place • 3.Air is evacuated by means of vacuum pump • 4.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

37. Quality control for pharmaceutical aerosols • Propellants • Valves, actuator and dip tubes • Testing procedure • Valve acceptance • Containers • Weight checking • Leak testing • Spray testing

38. Evaluation parameters ofpharmaceutical aerosols • 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 • Aerosol valve discharge rate • Spray pattern • Dosage with metered valves • Net contents • Foam stability • Particle size determination • Leakage • D. Biologic characteristics • E. Therapeutic activity

39. Flame 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 withruler.

40. Flash point • Determined by using standard Tag Open Cap Apparatus. • Step involves are  • Aerosol product is chilled to temperature of - 25 0 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.

41. Vapor pressure Determined by pressure gauge Variation in pressure indicates the presence of air in headspace. A can punctuating device is available for accurately measuring vapor pressure.

42. Density • Determined by hydrometer or a pycnometer. • Step involves are  • A pressure tube is fitted with metal fingers and hoke valve, which allow for the introduction 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.

43. Moisture content • Method used— Karl Fischer method • G. C has also been used • Identification of propellants • G.C, • I.R 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.

44. Dosage with metered valves • Amt. of medication actually received by the patient. • Reproducibility has been determined by assay technique. • 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. • Reproducibility of dosage each time the valve is dispersed

45. 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

46. 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

47. Cascadeimpactor

48. Porush, 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 Sciarra and Cutiedeveloped method based on practical size distribution.

49. Thank you for your patient listening