PHARMACEUTICAL AEROSOL
K.Senthil kumar M.Pharm Asst.Prof QIS college of Pharmacy,Ongole .Andhra pradesh
INTRODUCTION 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 conatiner in the form of spray
Aerosol mainly used for the treatment of Asthma and COPD
disease etc….
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.
DRUGS USE IN AEROSOLS
ADVANTAGES It
produce Rapid action.
It
is suitable for when the degrade in GI tract.
It
Directly applied to the affected area.
It
Prevents to Oxidation of drugs
It
can avoid the hepatic metabolism of drugs.
It
can be maintain sterility& easy to portable
It
produce local & systemic effect( due to large surface area of lung and blood capillary )
DISADVANTAGES
Limited safety hazard (Flammable Nature)
It is a Costly Preparation
It is a chance for continuous deposition of particle in upper respiratory tract
The propellant may cause chillness to the skin
TYPES OF AEROSOL SPRAY
There are three types of aerosol spray. 1. Space sprays 2. Surface coating spray 3. Foam spray
SPACE SPRAY
These products are delivered as a fine mist is called space spray .It contains 85% propellant and it is pressurized at 700F with 30-40 psig.
It contains not more than 50 µm of particle. So it can be retain in air. eg. Room sprays
SURFACE & FOAM SPRAY
Aerosols intended for carrying active ingredients to surface are termed as surface sprays or surface coating spray.
It contains 30 –70% propellant operate between 22–55 psig at 700F. Eg. Topical Aerosol
Foam aerosols(emulsion ) usually operate between 35 and 55 psig at 21°c and contains only 6-10% propellant.
PHYSIOLOGY OF RESPIRATO RESPIRATORY RY TRACT
The main function of respiratory tract is transfer of O2 from inspired air to blood and removal of Co2 from fro m the blood.
Respiratory tract divided in to two parts 1.Upper respiratory tract { Nose ,throat , pharynx and larynx } 2. Lower respiratory tract {Trachea, bronchi, bronchioles ,and alveoli }
DIAGRAM OF HUMAN AIRWAYS
PARTICLE DEPOSITION IN RPT
If Particles size >100 µm in diameter may deposit in the
oropharyngeal cavity.
If Particles between 10 to 60 µm will be deposited on the epithelium of the bronchial tract.
If Particles Size is < 2 µm in diameter can reach the alveoli.
AEROSOL CONTAINER
MECHANISM OF PARTICLE DEPOSITION IN RPT There
are four mechanisms to operate aerosols
1. Interfacial I nterfacial interception interception 2. Brownian diffusion 3. Gravitational sedimentation 4. Electrostatic precipitat precipitation ion
INERTIAL IMPACTION
Inertial impaction occurs because a particle traveling in an air stream has its own momentum (the product of its mass and velocity)
As the direction of the airflow changes due to a bend or obstacle, the particle will continue in its original direction for a certain distance because of its inertia.
Impaction of particles entering the mouth with a high velocity occurs either at the back of the mouth or at the bend where the pharynx leads to the trachea. Only a small fraction of particles greater than 15 µ m will reach the trachea following mouth breathing.
CONTIN…… Deposition by impaction will also occur as the trachea splits into the left and right bronchus.
GRAVITATIONAL SEDIMENTATION(GS)
GS is the downward movement of particle under the action of gravity .
CONTIN….
If particle size is less than 5µm 5µ m deposition deposition in bronchioles and alveoli.
Particles settle by gravitation onto the airway walls.
It was explained by stokes Law V= 2r2 (d1-d2)g 9ŋ
BROWNIAN DIFFUSION
Collison and bombardm bombardment ent of small particle by the molecu molecule le in the respiratory tract to produce Brownian motion.
CONTIN…..
Brownian motion or diffusion is a mechanism which significantly affects only particles less than 0.5 µ m in diameter
These particles are subjected to bombardment by surrounding gas molecules causing random movement of the particles. In this situation, the diffusivity of a particle is inversely proportional to its diameter.
INTERCEPTION
If the particles contact the airway surface because of their larger dimension of particle
ELECTROSTATIC PRECIPITATION
The charge on the surface of the particle may affect
the resultant deposition i.e. Surface of charged particle( + ve ) interact with a site within the respiratory respiratory tract tract that posses on opposite charge (-ve). (-ve).
Unipolar charged aerosols with high number concentrations repel each other and drive particles towards the walls.
BREATHING PATTERN
Breathing pattern ,lung physiology will affect the deposition of particle.
Breath holding after inhalation enhances the deposition of particle by sedimentation and diffusion.
COMPONENT OF AEROSOL Aerosol consist of 1. Product concentrate 2. Propellant
Product concentrate consist of API, Additives like suspending agent , emulsifying agent , antioxidant, aqeous and non aqueous ,cosolvent etc…
PROPELLANT It is responsible for developing the vapour 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 two types
1. Li Liqu quif ifie ied d gas gas sy syst stem em a) Flourinated hydrocarbon( hydrocarbon(FHC) FHC) b) Chloro fluro carbon (CFC) C) Hydrocarbons (HC) 2. Compressed gas system 3.Hydrofluoroalkanes
LIQUIFIED GAS SYSTEM
These compounds compounds are gases at room temperature and atmospheric pressuree .However they can be liquified easily by lowering the pressur temperature (below the boiling boiling point or by increasing pressure )
These compounds are chosen generally have B.Pt below 700F and vapour pressure between 14 and 85 psia at 700 F
When it is placed into sealed container it immediately separartes into a liquid and a vapour phase
CONTIN…..
Some o f 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
As molecule enter the vapor state a pressur pressuree gradually develops
no .of mol molecu ecule le in v.st v.state ate =
vaporr pressu vapo pressure re
FLUORINATED HYDROCARBONS It is Used for oral and inhalation aerosol preparation. Chemical Name
Chemical Formula
Numerical Designation
Trichloromonoflouromethane
CCl3F
11
Dichlorodifluoromethane
CCl2F2
12
Dichlorotetrafluroethane
CClF2CClF2
114
Chloropentaflouroethane
CClF2CF3
115
Monochlorodifluroethane
CH3CClF2
142b
Difluroethane
CH3CHF2
152 b
Octaflurocyclobutane
CF2CF2CF2CFM2 12
C318
CONTIN……
Psia means = pounds per square inch absolute
The term term psig ( pounds per square inch inch gauge)
0 Psig = 14.7 Psia Eg. Flourinated hydro carbon
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.Hydrochlorocarbon 2.Hydroflurocarbon 3. Hydrochloro flurocarbon
HYDROCARBONS Chemical Name
Numerical Designation
Butane
A-17
Isobutane
A-31
Propane
A-108
It is mainly used for for the preparat preparation ion of topical preparat preparation ion
CONTIN……..
Chemically stable
No hydrolysis
Inflammable
Low toxicity
They are lighter than water
COMPRESSED GAS SYSTEM Advantages Low inhalation toxicity High chemical stability High purity Inexpensive
– No env envir iron onm men enta tall prob proble lem ms Disadvantages Require use of a nonvolatile co-solvent Produce course droplet sprays Pressure falls during use Eg.. Co2 , No,N2
HYDROFLUOROALKANES Advantages Low inhalation toxicity High chemical stability High purity Not ozone depleting
Disadvantages Poor solvents Minor “greenhouse effect” High cost – e.g e.g.. 1,1, 1,1,1,2 1,2,3, ,3,3,3 3,3 – Hep Hepta taflu fluoro oropro propan panee (HFA (HFA-22 -227), 7), 1,1 1,1,1, ,1,2 2– Tetrafluoroethane Tetrafluoroeth ane (HFA-134a)
PHYSIOCHEMICAL PROPERTIES OF PROPELLANTS
Vapor pressure
Boiling points
Liquid density
Vapor pressure of mixture of propellants is calculated by Doltan’s law 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 addition of another substance, substance, States States that the dispersion dispersion of the vapor pressure of solvent upon the addition of solute solute is proportion proportion to the mole fraction of solute molecules in solution.
The relationship can be shown mathematically : na pa = ---------------------- pAo =NApA =NApAo o ----------------(1) ---(1) na + nb
AEROSOL CONTAINER
They must be stand at pressure as high as 140 to 180 psig (pounds per sq. 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
AEROSOL CONTAINERS
Containers must withstand pressure as high as 140 to 180 psig Containers Types of containers: 1. Ti Tin n plate plate cont contain ainers ers 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
Stainless steel container Limited for smaller size
materialss Extremely strong and resistant to most material Pressure stand
4. Glass containers co ntainers 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
COMPONENT OF AEROSOLS Actuator Ferrule or mount cap Valve body or housing Stem Gasket Spring Dip tube
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
CONTIN….. 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 pr essure 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 form Special actuator: They are specially designed to deliver the medicament on the specific sites like nose , throat
TYPES OF AEROSOL VALVES 1.Continuous spray valve Mounting Cup / Ferrule Valve body or Housing Stem valve Gasket Spring Dip Tube
2. Metering valve
VALVE
Regulate the flow of product and discharge the content
Valve is associated with the help of actuautor (if the foam present in the container) to emitted the product as wet or spray
continuous spray valve
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 made of nylon/delri nylon/delrin n and contains contains at the the opening opening point of diptube(0.013 to 0.080 inch) It prevents cloggin clogging g of p.size,reduce p.size,reduce chillin chilling g effect of the skin 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 diam Inside diameter eter (0.12 (0.120 0 – 0.125 0.125)) for for c.tube c.tube ( 0.050 0.050 inch and Viscous product 0.195)
TYPES OF AEROSOL SYSTEM There are five types of aerosol system Solution system / Two phase system
s ystem 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
SOLUTION SYSTEM
which consists of two phases: a vapor phase and a liquid phase
Propellant has high pressure hence propellant 114 is added to reduce its vapour pressure p ressure .
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 suspensio suspension n can be increased by use minimum solubility of API. Eg. Ephedrine bitartarate is less soluble than Hcl
By Use of surfacta surfactant nt to reduce the agglomeration Eg. Sorbitan monolaurate ,sorbitan monooleate sorbitan trioleate, isopropyl myristae.
FOAM SYSTEM
They contain Dispersion of AI,A.Vehicle, surfactant and propellant Liquified propellant used as internal phase Aqueous stable foam : A. 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 Usef ul foor foor topi topical cal med medica ication tion
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.
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 Neb Nebul ulis iser( er( air air jet jet /ai /airr blas blast) t) • Ul Ultr tras ason onic ic Ne Nebu buli lise serr • Drug Drugss are not conv convenie enientl ntly y prep prepared ared by MDI/ DPI
NEBULIZERS
JET NEBULIZERS It
is powered by high pressure air
Nebuliser commonly used in hospital and home for drug administrati administration on have small medication medication reservoirs(<10ml)
JET NEBULIZER
ULTRSONIC NEBULIZER
METERED DOSE INHALER(MDI)
METERED DOSE INHALER
Metered-dose inhalers (MDIs), introduced in the mid1950. In MDIs, drug is either dissolved or suspended in a
liquid propellant mixture together with other o ther excipients, including surfactants,and presented in a pressurized canister fitted with a metering valve .
A Predetermined dose is release when up on
actuation
CONTIN….
When released from the canister the formulation undergoes volume expansion in the passage within the valve and forms mixture of gas. The high speed speed of gas flow break the liquid liquid into fine droplets
MDI are Generally Packed In aluminum steel canister canister with a capacity of 20 -30 ml.
Aluminium is inert inert material material . So either coated with epoxy epoxy material.
CFC used as a propellant in MDI Preparation along with surfactant and lubricant. eg. CFC -11, CFC -12, CFC-14
Alternat Alte rnative ive for propellan propellantt CFC – HFA-1 HFA-134,12 34,127 7
MDI
METERING VALVE
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.
DRY POWDER INHALER(DPI)
ADVANTAGES
In DPI the drug is inhaled as a cloud of fine particle . The drug is either preloaded in the inhaled device or filled in hard gelatin capsule .
DPI are propellant free.
No additive except carrier like lactose .
It
can deliver large dose than MDI
DISADVANTAGES It chances for spilling of powder from device.
FORMULATION OF DPI
Preferable p.size range less than 5µm
The particle may chance to adhere with mucus. Due to flow properties .so overcome overcome it is mixed with carriers (30-60 µm) µ m) lactose . ( act as a carrier)
The large particle will deposit in the throat and smaller particle will reach into deeper respiratory tract.
SPINHALER (SINGLE DOSE DPI)
The first DPI in the Market( sodium cromoglycate)
MULTIPLE DOSE DEVICE DPI
MANUFACTURING OF PHARMACEUTICAL AEROSO
Apparatus Cold filling process Pressure filling process Compressed gas filling process
Preparation of product concentrat concentratee
The aerosol concentrate consists of drug or combination of drugs, solvents, antioxidants and surfactants formulated as solution, suspension .
The aerosol concentrate is first prepared and filled into the container.
The propellant is then filled into the container. Therefore, part of the manufacturing operation takes place during the filling operation measures to ensure that both concentrate and propellant are brought together in the proper proportion.
COLD FILLING APPARATUS
COLD FILLING PROCESS
The principle of cold filling method requires the chilling of all components including including concentrate concentrate and propellant to a temperature temperature of 30 to -4 -40 0 º F.
This temp tempratu rature re is nece necessary ssary to liqu liquify ify the prope propellan llantt gas .
The cooling system may may be a mixture of dry ice and acetone or refergiration 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 propellant generally displace the air in the container
Contin… 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 12 0 lbs / inch) and vacuum.
A
valve is placed either e ither manually or automatically depending on the production rate required.
CONTIN…….. The
valve is crimped in place by using valve crimper.
Advantages Easy
process Disadvantages
Chilling of the product, container and propellant is required. Aqueous products, emulsions and those products adversely affected by cold temperature cannot be filled by this method.
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
VALVE CRIMPER
TESTING OF FILLED CONTAINER The container passes through a heated water bath in which the contents of the container are heated to 130 º F to test for leaks and strength of the container. The containe containerr is air dried, dried, spray spray – test tested, ed, capped capped and labeled.
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 propellan propellant), t), 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.
ADVANTAGES It
is the preferred method for solutions, emulsions and suspension.
Less
chances for contamination of product with the moisture
Less
propellant is lost
No refrigeration is required, can be carried out at RT
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.
Evalua Eva luatio tion n of of pha pharma rmaceu ceutica ticall aero aerosol solss A. Flammability and combustibility Flame extension Flash point
B. Physiochemical characteristics Vapor pressure Density Moisture content Identification of propellant(s)
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
FLAME PROJECTION TEST
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 flame is extended, and exact length was measured with ruler.
FLASH POINT Determined
by using standard Tag Open Cap
Apparatus. PROCEDURE: Aero Aerosol sol pro product duct is chil chilled led to tempe temperatu rature re of - 25 0 F
and transferred to the test apparatus. Temperatur Temperaturee 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.
MEASUREMENT VAPOR PRESSURE Determined
Variation
by pressure gauge
in pressure indicates the presence of air in headspace.
MEASUREMENT OF DENSITY
Determined by Hydrometer or a Pycnometer
Procedure:
A pressure tube is fitted with metal fingers and hoke valve, which allow for the introduct introduction ion of liquids under pressure. The hydrometer is placed in to the glass pressure tube. 3. Sufficient sample is introduced through the valve to cause the hydrometer to rise half way up the length of the tube. 4. The density can be read directly.
MOISTURE CONTENT Method used — Karl Fischer method - G. C has has al also so bee been n use used d IDENTIFICATION OF PROPELLANTS
1. G.C, 2 .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. It is Expressed as gram per seconds.
Spray pattern Spray
the product on the the coated (dye +talc )
Paper. Depending upon the nature of aerosol water /oil soluble dye is used.
NET CONTENT Weight
of empty container =
gm
Weight
of the filled container =
gm
net content FOAM STABILITY: Visual evaluation
Particle size( cascade impactor)