PHARMACEUTICAL AEROSOLS

In this slide contains PHARMACEUTICAL AEROSOLS
Presented by: NARAYAN SINGH UDIT (Department of pharmaceutics).RIPER, anantapur.

1. PHARMACEUTICAL AEROSOLS A Seminar as a part of curricular requirement for I year M.Pharm II semester   Raghavendra Institute of Pharmaceutical Education and Research(RIPER)- Autonomous JNT University Anantapur Master of Pharmacy in Pharmaceutics Presented by UDIT NARAYAN SINGH (20L81S307) Under the guidance of Dr. C H Pavan Kumar Head of the Department Department of Pharmaceutics

2. 2 I got a hike of extra 80,000 I got just of 20,000 Almost 71% of total profit incurred by CIPLA Ltd. is from “AEROSOL” products.

3. Contents Background What are “Aerosols” Advantages & Disadvantages of aerosols Desired characteristics Components of aerosol Types of aerosol system Formulation of aerosols Manufacturing of aerosols Evaluation of aerosols References 3

4. 4 Background 1942 Beginning of aerosol industry 1950s Application of aerosol technology to pharmaceuticals 1955 Aerosols for local activity in respiratory tract were developed Aerosols were invented by Erik Rotheim in 1926

5. 5 What is this Aerosol ?

6. 6 Definition AEROSOLS Depend upon the power of a liquified or compressed gas To dispense the active ingredient(s) in the form of a finely dispersed mist Pharmaceutical product

7. 7 Dose removal without contamination of the bulk Enhanced stability for substances affected by oxygen and/or moisture Sterility is maintained Minimum or no irritation due to application Dose lowering in case of steroid therapy Circumvention of first pass effect Application of medication in a thin layer Tamperproof system. Advantages of using Aerosols

8. 8 Costly Difficult disposal of container due to flammable propellants Allergic in some cases Explosive Some formulations are difficult to formulate as aerosols In some cases propellants may cause toxic reactions. Disadvantages of using Aerosols

9. 9 Less explosive. Uniform and constant dose delivery. Non allergic. Economic/Low cost. Easy to handle. Non Breakable. Eco-friendly Desired characteristics

10. 10 Propellant Container Valve Actuator Product concentrate Components of Aerosol

11. 11 PROPELLANTS “Heart of Aerosol” Determine characteristics of the product Types Provide force to expel the product in desired form Act as solvent and diluent Liquified gas Hydrocarbon Compressed gases

12. 12 Widely used propellant Relatively inert, nontoxic and non flammable Immediately separate into a liquid and a vapor phase Maintain a constant pressure within the container Contains are maintained in fine mist or foam form Examples – Chlorofluorocarbons (CFCs) Hydrochlorofluorocarbons (HCFCs) Hydrofluorocarbons (HFCs) FCs are widely used in inhalational and oral aerosols. Liquified gases

13. 13 Flammable Less toxic Less dense More Soluble Chemically more stable More economic Examples – Butane Propane Earlier restricted to use with foams and water based aerosols Development of “Vapor tap” and “ Aquasol valve” extended their use. Hydrocarbons

14. 14 Have little expansion power Fairly wet spray is produced Foam is less stable as compared to liquified gases Do not have a chilling effect Used mostly in topical pharmaceutical aerosol products Examples – Nitrogen Nitrous oxide Carbon dioxide Compressed Gases

15. 15 All propellants are designated by three digits When the first digit is zero, the propellant is designated by last two digits Example – Propellant 011 is Propellant 11 The first digit is one fewer than the number of carbon atoms in the compound First digit – Zero indicates methane derivative First digit – One indicates Ethane derivative First digit – Two indicates Propane derivative The second digit is one more than the number of hydrogen atoms in the compound For cyclic compounds a “C” is used before the number Common rules of nomenclature

16. 16 Containers Must withstand pressure as high as 140 to 180 psig at 130 degree F Two types Glass Metals Tinplated Aluminium Stainless steel Uncoated Plastic coated

17. 17 Tin plated steel containers Consist of a sheet of steel plate, the sheet is coated with tin by electrolytic method Divided into three parts Top Attached to body by shouldering Bottom Body Coated Sheet If required Coated with – Organic material usually oleoresin, phenolic, vinyl or epoxy coating

18. 18 Aluminium Containers Used for inhalational and topical aerosols Manufactured by impact extrusion process Added resistance can be obtained by coating with organic coat Light in weight, Less fragile, reduced incompatibility instances, greater resistance to corrosion Pure water and ethanol cause corrosion Phenolic Vinyl Epoxy Polyamide resins

19. 19 Stainless Steel Containers Used for “Inhalational” aerosols Advantages – Extremely strong Resistant to many materials No need for internal coating Disadvantages – Costly Higher molding force needed

20. 20 Glass containers Preferred because of its aesthetic value and absence of incompatibilities Used for topical and MDI aerosols Uncoated – Less cost, High clarity Limited to products having lower pressure (33 psig ) and lower percentage of propellant Two types Plastic coated – Higher protection from shattering

21. 21 Valves Two types Delivers the drug in desired form Delivers proper amount of medication Metering valve Continuous spray valve Used for topical preparations Used to dispense potent medication

22. 22 Components of “Valve” Gasket Body / Housing Dip tube Ferrule or Mounting cup Spring Stem Attaches valve to container, Made of tin plated steel, Al, Brass. Under side is coated with epoxy or vinyl resins. Made of Nylon or Derlin , Contains a opening at attachment point of Dip tube (0.013 to 0.080 inch). Made of Nylon or Derlin , Sometimes brass and stainless steel (Orifice – 0.013 to 0.030 inch) Made of Buna-N and neoprene rubber Made of stainless steel, Used to hold gasket in place Made of Poly ethylene or poly propylene, Inner diameter – 0.120 to 0.125 inch

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24. 24 METERED DOSE VALVE Operates on the principle of dispensing medication based on the size of a “chamber” Used for dispensing “potent medication” Approx. 50 to 150 mg +/- 10% of liquid materials can be dispensed at one time with such valve

25. 25 METERED VALVE

26. 26 ACTUATORS Four types Especially designed buttons which helps in delivering drug in desired form i.e., spray, foam, solid stream, wet stream Foam actuators Spray actuators Special actuators Solid stream actuators Dispenses in the form of spray, Used for topical preparations e.g., antiseptics Required to dispense semi solid products e.g., ointments Used to deliver medicament to appropriate site e.g., throat, nose, dental, eyes, etc. Consists of a large orifice ranging from 0.070 to 0.125 inch

27. 27 What…! AEROSOLS also have systems, was the syllabus too less before…

28. 28 TYPES OF AEROSOL SYSTEM Solution system Foam system Suspension or dispersion system Water based system Non aqueous stable Aqueous stable Thermal Quick breaking Intranasal system

29. 29 Also referred as “ Two phase system ” Consists of vapor and liquid phase If active ingredient is soluble in propellant no other solvent is needed Vapor pressure of system is reduced by addition of less volatile solvents such as – Ethanol, Acetone, Propylene glycol, Glycerin Amount of propellant may vary from 5% ( for foams) to 95% ( for inhalations) General formula Weight % Active drug to 10-15 Propellant 12/11 (50:50) to 100 Solution system

30. 30 Depending on water content, final product may be solution or three phase system Solution aerosols produce a fine to coarse spray Hydrocarbon propellant A-70 produces drier particles Hydrocarbon propellant A-17 and A-31 tend to produce a wetter spray Useful for topical preparations Packaged in plastic coated glass containers Contd.

31. 31 SOLUTION SYSTEM

32. 32 Large amounts of water can be used to replace all or part of non aqueous solvent Spray or foam is produced For spray production formulation must consist of dispersion of API and other solvents in emulsion system with propellant as external phase Since propellant and water are not miscible, a three phase aerosol forms (propellant, water and vapor phases). Ethanol can be used as cosolvent to solubilize propellant in water. It also reduces surface tension aiding in the production of smaller particles . 0.5 to 2% of surfactant is used to produce a homogenous dispersion. Water based system

33. 33 Surfactants with low water solubility and high solubility in non polar solvents will be most useful e.g., Long chain fatty acid esters of polyhydric compounds including glycol, glycerol and sorbitan esters of oleic, stearic, palmitic and lauric acids Propellant concentration varies from about 25 to 60% Aquasol system ( Aquasol valve) – dispensing fine mist or spray of active ingredient dissolved in water No chilling effect, since only active ingredient and water are dispensed, propellant is in vapor state Difference between aquasol system and three phase system is aquasol dispenses fairly dry spray with very small particles, non flammability of the product . Contd.

34. 34 It involves dispersion of active ingredient in the propellant or mixture of propellants. To decrease the rate of settling of dispersed particles, surfactants or suspending agents can be added. Primarily used for inhalation aerosols. Example: Formulation Weight% Epinephrine bitartrate(1-5 Microns) 0.50 Sorbitan trioleate 0.50 Propellant -114 + Propellant -12 99 Epinephrine bitartrate has minimum solubility in propellant system but soluble in fluids in the lungs. Suspension system

35. 35 FOAM SYSTEM Total propellant content – 3-5%w/w or 8-10%v/v Aqueous stable foam Non-aqueous stable foam Quick breaking foam Thermal foam Glycols such as Polyethylene glycol are used Emulsifying agent used is Propylene glycol monostearate Propellant is in external phase Used to produce warm foam for shaving Higher propellant cause stiff and dry foam, Low conc. cause wet foam Propellant – HC & CG Product is emitted as foam when dispensed Surfactant soluble in both alcohol and water, used for topical medication Corrosion problems with hair colors and dyes Expensive, Inconvenient to use, Less effectiveness

36. 36 FOAM SYSTEM

37. 37 Physical stability of aerosol dispersion can be increased by Control of moisture content(<300ppm) Reducing rate of agglomeration Use of dispersing agents Density of propellant and suspensoid equalized Avoiding high temperatures Aqueous stable Use of Isopropyl myristate and mineral oil HLB less than 10 Conc.- 0.01-1% Particle size less than 5 micron

38. 38 Formulation & Manufacture (AEROSOLS)

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40. 40 FORMULATION OF AEROSOLS Can be dispensed as- Fine mist, Wet spray, Quick breaking foam, Stable foam, Semi solid Product concentrate Propellant API or mixture of API and other necessary ingredients – Solvents, Anti oxidants, Surfactants for proper HLB Single or blend of propellants is used based on desired vapor pressure, solubility and particle size Selection is based on – Physical, Chemical, Pharmacological properties of drug & Site of application

41. 41 MANUFACTURE OF AEROSOLS Pressure filling apparatus Compressed gas filling apparatus Cold filling apparatus Disadvantages – Certain metering valves can only be handled by cold filling, Process is slower than cold filling Advantage – Solutions, suspensions, emulsions can be filled, Contamination by moisture is less, High production speed, Loss of propellant is less Advantage – Easy process Disadvantages – Aqueous products, emulsions, and those adversely effected by cold temperature cannot be used

42. 42 VARIOUS UNITS USED IN AEROSOL FILLING LINE Unscrambler Purger , Vaccum crimper, Pressure filler are replaced with single unit filling by “under the cap method” Purger Water bath Valve placer Air cleaner Valve crimper Propellant filler Concentrate filler Labeler, Coder and Packaging table

43. 43 It consists of a pressure burette capable of metering small volumes of liquefied gas into the aerosol container under pressure Propellant is added through an inlet valve located at the bottom or top of the pressure burette The propellant is allowed to flow with its own vapor pressure in the container through aerosol valve the trapped air escapes out from the upper valve Propellant stops flowing when the pressure of burette and container becomes equal Excess of the propellant is replaced into the container by help of positive pressure exerted by nitrogen from another container This type of device cannot be used for filling inhalation aerosols which have metered valves . Pressure filling apparatus

44. 44 This method involves filling of the concentrate into the container at the room temperature Then the valve is placed in the container and crimped Through the opening of the valve the propellant are added or it can be added “under the cap” Since the opening of the valve are smaller in size ranging from 0.018-0.030 inches, it limits the production and the process becomes slow But with the use of rotary filling machines and newer filling heads where the propellants are filled through valve stem, the production rate is increased The trapped air in the container and air present in head space is removed before filling the propellant to protect the products from getting adversely affected. Procedure

45. 45 PRESSURE FILLING APPARATUS PRESSURE BURETTE

46. 46 It consist of an insulated box fitted with copper tubings and the tubings are coiled to increase the area exposed to cooling The insulated box should be filled with dry ice or acetone prior to use The apparatus can be operated with or without metered valves Hydrocarbon propellant cannot be filled into aerosol containers using this apparatus because large amount of propellant escapes out and vaporizes This may lead to formation of an explosive mixture Fluorocarbon vapors do not form any explosive or flammable mixture though their vapors are heavier than air. Cold filling apparatus

47. 47 Non aqueous products and products which can withstand low temperatures of - 40°F are used in this method The product concentrate is chilled to a temperature of - 40°F and filled into already chilled container Then the chilled propellant is added completely in 1 or 2 stages, depending on the amount Another method is to chill both the product concentrate and propellant in a separate pressure vessel to - 40 °F and then filling them into the container The valve is placed and crimped on to the container Then test for leakage and strength of container is carried out by passing container into a heated water bath, where the contents of the container are heated to 130°F. After this, the containers are air dried , capped and labeled. Procedure

48. 48 COLD FILLING APPARATUS

49. 49 Compressed gases have high pressure hence a pressure reducing valve is required. The apparatus consists of delivery gauge A flexible hose pipe which can withstand 150 pounds per square inch gauge pressure is attached to the delivery gauge along with the filling head A flow indicator is also present in specialized equipments . Compressed gas filling apparatus

50. 50 • The product concentrate is filled into the container Valve is placed and crimped on the container With the help of vacuum pump the air is removed from the container Filling head is put in the opening of the valve and the valve is depressed and the gas is allowed to flow in to container The gas stops flowing if the delivery pressure and the pressure within the container become equal Carbon dioxide and nitrous oxide is used if more amount of gas is required High solubility of the gas in the product can be achieved by shaking the container manually or with the help of mechanical shakers. Procedure

51. 51 Is your product’s quality upto the mark..?

52. 52 EVALUATION OF AEROSOLS Quality control Tests involved Propellants, Valve acceptance, Actuator, Dip tubes, Weight checking, Leak testing, Spray testing Performance – Aerosol valve discharge, Spray pattern, Dosage with metered valve, Net content, Foam stability, Particle size, Leakage Flammability and combustibility – Flash point, Flame extension Biological characteristics Physicochemical – Vapor pressure, Density, Moisture content, Identification of propellant, Concentrate propellant ratio

53. 53 PROPELLANTS Vapor pressure and density compared with specification sheet Purity and acceptability Identification Moisture, Halogen, Non-volatile residue determination Gas chromatography, IR spectroscopy

54. 54 VALVES, ACTUATORS AND DIP TUBES Objective is to minimize variation in valve delivery Sampling is done as in military standards “MIL-STD-105D” 25 Valves are placed on containers Actuator 0.02 inch orifice is placed Weight difference upon fullest actuation for 2 sec is measured Test repeated for 25 samples

55. 55 Valve acceptance 54 microliter or less - +/- 15% 55-200 microliter - +/- 10% If 3 are outside limit, another 25 valves are tested – If more than 1 fail - Rejected Out of 50 individual deliveries If 4 or more are outside the limits – valves are rejected If 2 deliveries from one valve are outside limit, another 25 valves are tested – If more than 1 fail - Rejected

56. 56 CONTAINERS Containers are examined for defects in lining Quality control aspects includes degree of conductivity of electric current as measure of exposed metals Glass containers are examined for flaws WEIGHT CHECKING Done by periodic weighing of containers in two stages – Before filling (tared weight) After filling (increased weight is checked)

57. 57 LEAK TESTING Checking crimping of valve and detect any defects (Crimp’s dimension) SPRAY TESTING Most pharmaceutical aerosols are 100% spray tested Final testing is done by passing filled containers through water bath This checks for defects in valves and spray patterns

58. 58 FLAMMABILITY & COMBUSTIBILITY Apparatus – Tag Open Cup Apparatus Flash point Product is chilled at -25 degree centigrade and test liquid temperature is allowed to rise Temperature at which vapor ignites is “Flash point” Product is sprayed for 4 sec into a flame Flame projection Exact extension in the length of the flame is measured

59. 59 PHYSICOCHEMICAL Pressure gauge, Can puncturing device Vapor Pressure Density Moisture Propellant identification Hydrometer, Pycnometer Karl Fischer method, Gas chromatography Gas chromatography, IR spectroscopy

60. 60 PERFORMANCE Contents of the aerosol product of known weight is discharged Aerosol valve discharge rate Impingement of spray on piece of paper treated with “Dye-Talc mixture” Spray pattern Change in weight per time dispensed gives the discharge rate (g/sec) Particles that strike the paper cause the dye to go into solution Particles get adsorbed on the paper giving a record for comparison purpose

61. 61 DOSAGE WITH METERED VALVES Reproducibility of dosage can be determined by - NET CONTENTS Tared cans weighed and filled in lines and reweighed for difference Assay techniques Accurate weighing of filled container followed by dispensing of several dose and subsequent weighing Destructive technique – weighing full container and then dispensing as much content as possible. Contents are weighed to get net content values

62. 62 FOAM STABILITY Methods Visual examination Time for given mass to penetrate the foam Time for given rod that is inserted into foam to fall Rotational viscometer

63. 63 PARTICLE SIZE DETERMINATION Cascade Impactor Light Scattering Decay Stream of particles projected through a series of nozzles and glass slides at high velocity As aerosol settles under turbulent conditions, the change in light intensity of a Tyndall beam is measured Larger particles are impacted first on lower velocity and smaller particles are collected later at higher velocity PARTICLE SIZE DETERMINATION

64. 64 CASCADE IMPACTOR

65. 65 Stage 0 Nozzle diameter 96 2.55 +/- 0.025 Stage 1 Nozzle diameter 96 1.89 +/- 0.025 Stage 2 Nozzle diameter 400 0.914 +/- 0.0127 Stage 3 Nozzle diameter 400 0.711 +/- 0.0127 Stage 4 Nozzle diameter 400 0.533 +/- 0.0127 Stage 5 Nozzle diameter 400 0.343 +/- 0.0127 Stage 6 Nozzle diameter 400 0.254 +/- 0.0127 Stage 7 Nozzle diameter 201 0.254 +/- 0.0127 DESCRIPTION NUMBER DIMENSION ( microm .)

66. 66 Therapeutic activity BIOLOGICAL TESTING Toxicity Determination of therapeutic activity is dependent on the particle size Activity is determined by applying the formulation and calculating amount absorbed Exposing test animals to vapors sprayed from aerosol formulation under testing Irritation and chilling effects are determined Inhalational Topical Inhalational Topical

67. 67 ED Test mandatory as per IP

68. 68 DEPOSITION OF EMITTED DOSE Measure of drug deposition during inhalation Test determines the fine particles characteristics of the aerosol clouds generated Sometimes referred as “Mass Balance” Total mass of active substance is NLT 75% and NMT 125%

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70. 70 Khar K R, Vyas S P, Ahmad J F, Jain K G. Lachman/ Leiberman’s The Theory and Practice of Industrial Pharmacy. Delhi; India: CBS Publishers & Distributors; 2017 Felton L. Remington Essentials of Pharmaceutics. New Mexico; USA: Pharmaceutical Press; 2013 References

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