Aerosol

pharmaceutical aerosols.
targeting to lungs.
evaluation ect..

1. PRESENTED BY ARANTHA J JOSEPH FIRST YEAR MPHARM PHARMACEUTICS 1 AEROSOLS

2. PHARMACEUTICAL AEROSOLS are 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. They depend upon the function of the container, its valve assembly, and an added component  the propellant - for the physical delivery of the medication in proper form. 2

3. 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 ADVANTAGES

4. Costly. Difficulty in disposal. Difficulty in formulation. Q.C testing is complicated. Cannot be subjected to heat. 4 DISADVANTAGE

5. 5 COMPONENTS

6. Propellant Container Valve and actuator Product concentrate [ additives like Suspending agent, antioxidant, aqueous and non aqueous solvents, co solvent, emulsifying agents etc…] 6

7. PROPELLANTS Liquefied gas or a mixture of liquefied gases. Dual role of propellant and solvent or vehicle for the product concentrate. In certain aerosol systems, non liquefied compressed gases are also used as propellants [CO2, N, NO] 7

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10. Gases at room temperature and atmospheric pressure. Liquefied easily by lowering the temperature. When placed into container, immediately separates into a liquid & a vapour phase. Inert Nontoxic nonflammable LIQUIFIED GAS SYSTEM 10

11. Fluorinated hydrocarbons I t is used for oral ,inhalation topical aerosol preparation Range of pressure can be obtained by mixing various hydrocarbons with different proportions. Chemical Name Numerical Designation Trichloromonoflouromethane Propellant 11 Dichlorodifluromethane Propellant 12 Dichlorotetrafluromethane Propellant 114 Chloropentaflouroethane Propellant 115 11

12. CHLOROFLUOROCARBONS Was Commonly used [However these propellants are being phased out and will be prohibited due to scientific recognition that they reduce the amount of ozone in the stratosphere , which results in an increase in the amount of ultraviolet radiation reaching the earth, an increase in the incidence of skin cancer, and other adverse environmental effects.] 12

13. HYDROCARBONS Butane Isobutane Propane It is mainly used for topical preparation Chemically stable No hydrolysis Inflammable Low toxicity Lighter than water 13

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15. Eg.CO 2 , NO 2 Advantages Low inhalation toxicity High chemical stability High purity Inexpensive 15

16. 16 Disadvantages Require use of a nonvolatile co-solvent Produce coarse droplet sprays Pressure falls during use

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18. 18 Physiochemical properties Vapor pressure, Boiling point & Liquid density Vapor pressure of propellant calculated by Dalton’s law ‘ total pressure in any system is the sum of the individual partial pressures of various components.’ Raoult’s law - lowering of the vapor pressure of a liquid by the addition of another substance, Depression of the vapor pressure of solvent upon the addition of solute is proportional to the mole fraction of solute molecules in solution.

19. 19 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

20. MECHANISAM An equilibrium is quickly established between propellant which remains liquefied and that which vaporizes. The vapor phase exerts pressure in all directions--against the walls of the container, the valve assembly, and the surface of the liquid phase 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. 20

21. As the propellant meets the air, it immediately evaporates due to 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. 21

22. 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. However, when the liquid reservoir is depleted, the pressure may not be maintained, and the gas may be expelled from the container with diminishing pressure until it is exhausted. 22

23. 23 Containers Withstand a pressure as high as 140 to 180 psig at 130 F. Metals 1. Tinplated steel. Side-seam (three piece) ( b) Two-piece or drawn. (c) Tin free steel 2. Aluminum Two-piece. (b ) One-piece (extruded or drawn ) 3. Stainless steel

24. 24 Glass 1. Plastic Uncoated glass 2. Plastic coated glass plastic

25. Container selection is based on; Its adaptability to production methods Compatibility with formulation components Ability to sustain the pressure intended for the product Aesthetic appearance. Cost 25

26. Tin plated containers Sheet of steel plate that has been electroplated on both sides with tin. Thickness describes – weight #25,#50 Sheets are cut Fabricated into desired shape. Organic coating can be done- expensive, slower. Recent development- welded side seam - eliminates soldering operations. -saves time. 26

27. 27 Aluminum containers Greater resistance to  corrosion light weight, not fragile good for light sensitive drugs

28. 28 Stainless steel container Limited for smaller size Extremely strong and resistant to corrosion Withstand pressure

29. 29 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

30. VALVE Actuator Ferrule or mount cap Valve body or housing Stem Gasket Spring Dip tube 30

31. VALVES ASSEMBLY The function of the valve assembly is to permit the expulsion of the contents of the can in the desired form, at the desired rate. M etered valves- proper amount or dose. Materials - manufacture - valve parts - plastic, rubber, aluminum, and stainless steel. 31

32. 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. Types of actuators Spray Actuators Foam Actuators Solid Stream Actuators Special Actuators 32

33. 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) 33

34. 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. 34

35. 35 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

36. 36 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).

37. 37 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)

38. 38 Suspension system Using suspending agent. Oral inhalation aerosols. Active ingredients dispersed in propellant or mixture Physical stability can be increased by Control of moisture content Active ingredients with minimum solubility. Initial particle size < 5 microns Propellant density Suspending agents

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40. 40 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

41. 41 Aqueous stable foams Propellant 3-4% Dry spray is produced Propellant – internal phase Steroidal antibiotics Non aqueous stable foams Emulsifying agent - glycol

42. 42 Quick breaking foams Propellant – external phase Topical application Cationic, anionic, non ionic surfactants Thermal foams Delivered as foam on application of heat Shaving creams

43. 43 MANUFACURING OF PHARMACEUTICAL AEROSOLS

44. 44 Cold filling Pressure filling Compressed gas filling

45. 45 Insulated box fitted with copper tubing's.

46. 46 METHODS 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.

47. 47 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.

48. 48 Pressure filling

49. 49 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.

50. 50 Advantages Preferred for solutions, emulsions & suspensions. Less contamination. Less propellant is lost. No refrigeration .

51. Compressed gas filling Propellant – compressed gas Pressure reduced by pressure reducing valve Pressure used – 150 psig 51

52. 52 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

53. 53 Targeting to Lungs

54. 54 Anatomy of lungs Organ of external respiration. Oxygen and carbon dioxide are exchanged between blood and inhaled air. The large absorptive surface area. Good vascularization. Immense capacity for solute exchange . Facilitate systemic delivery via pulmonary. administration .

55. 55 ADVANTAGES Improve efficiency. Reduce unwanted systemic side effects. Large surface area for absorption. Thin alveolar epithelium permitting rapid absorption. Absence of first pass metabolism. Rapid onset of action .

56. 56 DISADVANTAGE Oropharyngeal deposition gives local side effect. Patient may have difficulty using the pulmonary drug devices correctly. Drug absorption may be limited by the physical barrier of the mucous layer.

57. 57 Deposition of drug or aerosol depends on 3 factors The Physico-chemical properties of the drug.  Shape size  density hygroscopic character etc.. The anatomy of the respiratory tract . Physiologic factors Air flow and breathing pattern .

58. 58 Different systems used to target lungs

59. 59 Microspheres

60. 60 Dendrimer

61. 61 Liposomes

62. 62

63. 63 Microparticles

64. 64 Micelles

65. 65 Solid Nanoparticles (SLN)

66. 66 Formulation and delivery of therapeutic inhalation aerosols

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68. DEVICES 3 MAIN TYPE Pressurized metered dose inhaler (PMDI ) Dry powder inhalers(DPI) Nebulizers 68

69. 69 Pressurized metered dose inhalers Drug is either dissolved or suspended in liquid propellants Together with other excipients and Pressurized container fitted with metering valve. The predetermined dose is released as a spray on actuation of the metering valve.

70. 70 Dry powder inhaler The drug is inhaled as a cloud of fine particles. The drug is either preloaded in an inhalation device or filled into hard gelatin capsules or foil glister disc, which are loaded into the device prior to use . Commercially available in 2 types – Unit dose -Drug filled gelatin capsules ( rotohaler ) Multidose - R eservoir ( turbuhaler )

71. 71 Unit dose Rotahaler

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73. 73 Multi dose Turbuhaler

74. 74 Formulating DPI

75. 75 Advantages Propellant free Do not contain excipients They are breath actuated avoiding the problems of inhalation Actuation coordination encountered with mdi’s .

76. 76 Disadvantages Liberation of powder from the device and the deaggregation of particles are limited . which in the case of respiratory disease maybe impaired. Dpi’s are exposed to ambient atmospheric conditions, which may reduce formulation stability . Dpi’s are generally less efficient at drug delivery than mdi’s .

77. 77 NEBULIZERS These are applied to aerosolize drug solution and suspensions. It delivers relatively large volume of drug . They are used for the drugs that cannot be formulated into pMDI’s and DPI. 3 categories Jet nebulizers Ultrasonic nebulizers Vibrating mesh nebulizers

78. 78 JET NEBULIZERS ‘Air jet’ or ‘air blast’ Nebulizers using compressed gas. Compressed gas passes through a narrow orifice creating an area of low pressure at the outlet of the adjacent liquid feed tube. This results in drug solution being drawn up from the fluid reservoir and shattered into droplets in the gas.

79. 79 Ultrasonic nebulizer

80. 80 Vibrating mesh nebulizers

81. 81 Formulation of nebulizer fluid

82. Current application of pulmonary drug delivery Pulmonary drug delivery in asthma and COPD. For patients on ventilators . Pulmonary delivery in cystic fibrosis . In migraine . Angina pectoris . Recent use in transplantation. In pulmonary arterial hypertension. In acute lung injury . 82

83. Quality control test 83

84. It Includes the testing of Propellants Valves, Actuator, Dip Tubes Containers Weight Checking Leak Testing Spray Testing 84

85. Propellant Vapor pressure is determined & compared to Specifications . 85

86. VALVES, ACTUATORS & DIP TUBES 86

87. Test procedure Take 25 valves & placed on containers. Filled with test solution Actuator with 0.020 inch orifice is attached. (containers placed at temp. 25±1 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 87

88. Out 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. 88

89. 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. 89

90. WEIGHT CHECKING Add tared empty aerosol container to filling lines which after filling with concentrate. R eweighed. Same procedure is used for checking weight of Propellants. 90

91. LEAK TEST passing filled containers through HOT water bath . 54.4˚C 91

92. SPRAY TESTING It is done To clear dip tube of pure propellant & concentrate To check for defects in valves & spray pattern. 92

93. 93 EVALUATION TESTS

94. A. Flammability & combustibility 1.Flash point 2.Flame Projection B. Physicochemical characteristics: 1.Vapour pressure 2.Density 3.Moisture content 4.Identification of Propellants 94

95. 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 95

96. 96 D. Biological testing 1.Therapeutic activity 2.Toxicity studies E. Extractable Substances

97. 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. B. Physicochemical characteristics: 97

98. 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). 98

99. 99 2. Spray pattern The method is based on the impingement of spray on piece of paper that has treated with Dye-Talc mixture Water / oil soluble dye.

100. 100 3. Dosage with metered valves Method 1 Doses are dispensed into the solvents. Assay- amount of active ingredients. Method 2 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 .

101. 4. Net Contents Method 1 Tared cans placed on filling lines are reweighed & then difference in wt. is equal to net content. Method 2 In Destructive method : opening the container & removing as much of product possible. 101

102. 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. 5. Foam stability 102

103. 103 6. Particle Size Determination Methods Cascade Impactor. Light Scattering Decay.

104. 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. D. Biological testing: 104

105. E. EXTRACTABLE SUBSTANCES Leaching of extractable from plastic components into the formulation is a potential serious problem. Extractable- 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 . 105

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107. The Theory and Practice of Industrial Pharmacy by Leon Lachman , Herbert A. Lieberman, 3 rd edition, Page: 771-803. Remington, The Science and Practice of Pharmacy, 21 st edition, Page: 1000 -1015. The Design and Manufacture of Medicines by Micheal E.Aulton,third edition,pgno-97-99,196,542-52,660. http://www.yorks.karoo.net/aerosol/link4.htm http:// resources.schoolscience.co.uk/bama/14-16/aerosch5pg1.html REFERENCES 107

108. Thankuuuuuuu …….. 108