PHARMACEUTICAL AEROSOL

DEFINITION "An aerosol is a disperse phase system, in which

very fine solid drug particles or liquid droplets get dispersed in the propellants (gas), which acts as continuous phase".

OR"An Aerosol system which expels the contents

from the container that depends on the pressure development by compressed or liquefied gas"

“ An aerosol is a pressurized dosage forms containing one or more therapeutic active ingredients which upon actuation emit a fine dispersion of liquid and/or solid materials in a gaseous medium contain smaller than 50 um".

• An Aerosol also called as Pressurized Packages, Pressure Package or Pressurized dosage forms.

• The term pressurized package is generally used when referring to the aerosol container or a complete product. Pressure is developed to the aerosol system through the use of one or more liquefied or gaseous propellants.

ADVANTAGES OF AEROSOLS• Required quantity of contents can be easily

withdrawn from the package without contamination or exposure of the remaining material.

• Aerosols are easy and convenient to apply and can be administered without the help of others.

• The onset of action is faster compared to other dosage forms because the medicament is directly applied to the affected area /part.

• The dispersion of medicament is very good.• Due to closed packing of aerosols, there is no

manual/ direct contact with the medicament.

• Aerosol form can avoid decomposition or inactivation of drug by the pH or enzymatic action of the stomach or intestine and also can avoid the first pass metabolism.

• A specific amount of dose or drug can be removed from the container without contamination of remaining contents.

• Stability can be enhanced for those substances adversely affected by atmospheric oxygen or moisture. (Hydrolysis of medicament can be prevented since propellants do not contain any water. Oxidation is prevented as no air is present in the container)

• Sterility can be for sterile product, because no microorganism can enter even when the valve is opened.

• Metered valve can release the contents in Controlled and Uniform manner.

• The aerosol containers protect the photosensitive medicaments. (Except clear glass containers)

• For Inhalation purpose a fine mist of the drug is produced.

• The rapid volatilization of the propellant provides a cooling, refreshing effect.

• Formulation of aerosol and maintaining valve control, the physical form and the particle size of the emitted product may be controlled, which may provides efficacy of a drug.

• Irritation can be reduced by application of topical aerosol medication in a uniform thin layer to the skin without touching the affected area.

DISADVANTAGES OF AEROSOLS• Aerosols are cost effective.• Disposal of empty aerosol containers are

difficult.• Due to volatility of the propellant/s can irritate

the injured skin.• Some persons may be sensitive to the

propellant/s and persons who using an inhalation aerosol/s, the fluorinated hydrocarbons may cause carcinotoxic effects on rapid and repeated use of the aerosol product.

• Aerosol packs must away from temperature and fire, because it may develop high pressure inside the container leads to explosion.

• If the drug is not soluble in the propellant, aerosol the formulation is difficult.

• Sometimes propellants may cause toxic reactions, if therapy is continued for a long period of time.

Components of Aerosol Package

• The following components / parts require for aerosol product:

1) Propellant2) Product concentrate3) Container4) Valve and Actuator

Propellants• Propellants are responsible for developing the

pressure in the aerosol container and also it expel the product from the container when the valve is opened and helps in expelling the product by atomization of contents or by causing foam production of the product.

• When the propellant/s is a liquefied gas or a mixture of liquefied gases, it frequently serves the propellant and solvent or vehicle for the product concentrate.

Types of propellant• Depending on the route of administration and

use, the propellant can be classified asI) Type-I Propellant: A- Liquified GasII) Type-II Propellant B - Compressed Gas Propellants

I) Type-I Propellant

A- Liquified Gas:1) For oral and inhalation (Fluorinated

hydrocarbons):• Tri-chloro-mono-flouro methane (propellant

11)• Di-chloro di-fluro methane (propellant 12)• Di-chloro tetra-fluro ethane (propellant 114)

2) Topical Pharmaceutical aerosols (Hydrocarbons):• Propane• Butane• IsobutaneII) Type-II Propellant B - Compressed Gas Propellants3) Compound gases:• Nitrogen• Carbon di-oxide• Nitrous oxide

CHLOROFLUOROCARBON (CFC) PROPELLANTS

• The basic characteristics of propellants are chemically inert, free from toxicity, inflammability and explosiveness.

• Due to these characteristics, the chlorofluorocarbon (CFC) propellants P-11, P-12 and P-114 etc., are using in aerosol products from several years.

• Now-a-days their usage is reduced, as they cause the depletion of ozone layer.

• The CFCs are using in some aerosol products, due to their low toxicity and inflammability. They are still use in small quantities in the treatment of asthma and chronic obstructive pulmonary disease (COPD).

• P-134a and P-227 are now been developed and are being incorporated in aerosol formulations in place of P-12.

• The CFCs are gases at room temperature that can be liquefied by cooling them below their boiling point or by compressing them at room temperature.

• For example, dichlorodifluoromethane (P-12) will form a liquid (when cooled to - 21.6F or compressed to 84.9 psia at 70F) (psia = pounds per square inch).

• Some liquefied gases also have a very large expansion ratio compared to the compressed gases (e.g., nitrogen, carbon dioxide).

• The usual expansion ratio for liquefied gases is about 240 which mean that 1 ml of liquefied gas will occupy a volume of approximately 240 ml (it allowed to vaporize). Compressed gases expansion ratio is about 3 - 10.

Hydrochlorofluorocarbons (HCFC) and Hydrofluorocarbons (HFC)

• The Hydro Chlorofluorocarbons (HCFC) and Hydro Fluorocarbons (HFC) differ from CFCs. These may not contain chlorine and contains one or more hydrogen. These compounds break down in the atmosphere at a faster rate than the CFCs resulting in a lower ozone depleting effect.

HYDROCARBONS PROPELLANTS• The environmental acceptance, low toxicity and

non reactivity are the characteristics of hydrocarbons propellants allowing them to be used as the propellant.

• Hydrocarbons are used in the preparation of water based aerosols as they are stable to hydrolysis due to the absence of chlorine. Since they are immiscible with water, they retain on the top of water.

• Hydrocarbons will develop good pressure to push the contents out of the container.

• The disadvantage of Hydrocarbon propellants are flammability and explosive. So the usage is reduced as propellant.

• Hydrocarbons do not contains halogens and therefore hydrolysis does not occur making these good propellants for water based aerosols.

COMPRESSED GAS PROPELLANTS

• The use of compressed gas like Nitrogen, Nitrogen dioxide and Carbon dioxide as propellant/s, which emits contents in the form of fine mists, foams, fine mists or semisolid. It produces fairly wet sprays and the foams are not as stable as produced by the liquefied gas propellant. Unlike the aerosol prepared with liquefied gas propellant, there is no propellant reservoir.

• The compressed gas propellant is contained in the headspace of the aerosol container which forces the product concentrate to emit contents out of the container. For this higher gas pressure is require in this aerosol. This aerosol finds its application to dispense food products, dental creams, hair preparation and ointments.

Difference between Liquefied Propellant and Compressed Gas Propellant

APPLICATIONS OF PHYSICAL GAS LAWS

• Vapour pressure of mixtures of propellants can be calculated according to "Dalton's Law" and "Rault's Law".

• Dalton's Law: Total vapour pressure in any system is equal to the sum of the individual or partial pressures of the various components.

• P = p1 + p2 + p3

• Rault's Law: It is regards lowering of the vapour pressure of a liquid by the addition of another substance.

Product concentrate• Simply the product concentrate is the active ingredient

of the aerosol is combined with the required adjuncts,• The Active drug (for therapeutic activity)• Propellant/s (to expel the contents from the container)• Antioxidants (to prevent degradation of product)• Surface active agents/ Surfactants (to Increase

Miscibility)• Solvent/s (to prepare a stable and efficacious product

and to retard the evaporation of the propellant)• Other excipients like Vehicles, suspending agents etc.

AEROSOL CONTAINERS• They must be stand at pressure as high as 140 to

180 psig (pounds per sq. inch gauge) at 130 F. • The glass or metal containers are generally used.

Glass disadvantage is brittleness, so restricted usage of glass.

• If the pressure is less than 25 psig and propellant content is less than 15% then glass can be used.

• It should be coated with plastic coating in two layers if pressure is less than or equal to 33 psig. For linings Epoxy and vinyl resins can be used.

• Vinyl resins can form strong lining but it will get damaged by steam.

• But the epoxy resins can be used, as they are resistant to steam.

• The products which have less pH, vinyl coating on the epoxy coating is most suitable.

• Choice of the material is depend on- Pressure of the system, whether product is aqueous or not, pH of the product, physicochemical properties of preparation.

• Different types of materials for aerosol containers are:

1) Metals- Tin plated steel (Side-seam or Three, Two piece

or Drawn, Tin-free steel)- Aluminum- Stainless steel2) Glass- Uncoated glass- Plastic coated glass3) Plastics

1) METALS• Tinplated steel:• It is used for most aerosols as it is light, inexpensive and

durable. It is steel that has been plated on both side with tin.

• Tin plated steel containers are of two types-(a) Two pieces container body, consisting of a drawn cylinder,

the base of the container, is held in place with double seam.(b) The three piece container has aside seam the base being

attached as for two piece container, the top has a 1 inch opening and is joined to body by double seaming to protect container from corrosion and also to prevent the interaction between the tin and the formulation. Oleoresin, phenolic, vinyl, or epoxy coatings are used as the coating materials. The tin plated steel containers are used in topical aerosols.

• Advantages:• Special protective coatings are applied within the

container to prevent corrosion and interaction between the container and formulation if necessary.

• Disadvantage:• The main disadvantage of stainless steel containers

is high cost.• For small sized container only.• Leak of container due to flaws in the seam or

welding.• Corrosion with some preparations.

Aluminium

• The aluminium containers are light weight and are less prone to corrosion than other metals. Aluminium is used in most metered dose inhalers (MDIs) and many topical aerosols.

• Epoxy, vinyl, or phenolic resins coatings are done on aluminium containers to reduce the interaction between the aluminium and the formulation.

• The seamless aerosol containers manufactured by an impact extrusion process have no leakage, incompatibility and corrosion.

• The container themselves available in different sizes ranging from 10 ml to over 1,000 ml.

• Advantages:• These are manufactured by extrusion or by

any other methods that make them seamless.• Against leakage the seam type of container is

of greater safety.• No incompatibility and corrosion.• Disadvantages:• High cost.

Stainless steel• Advantages:• It is resistant to corrosion.• No coating is required.• It can withstand high pressure.• Disadvantages:• Expensive.• Which restricts its sizes to small sized

containers.

2) GLASS

• One of the materials is glass, limited usage because of its brittleness.

• So glass containers are used in lower pressure and when low amount of propellant are in use such as if the pressure is less than 25psig and propellant content is less than 15%.

• In order to protect the glass containers against breakage due to high pressure, it is to be coated with plastic coating in two layers.

• Epoxy and vinyl resins can be used as linings. Vinyl resins are not resistant to high temperature of the steam about 200 F.

• But epoxy resins are resistant to steam. These coatings are suitable for low pH water based products.

• Used for some topical and Metered dose inhalers aerosols.

• Advantages:• Glass has less chemical compatibility than metal

containers.• No corrosion.• Glass can be molded to different design.• Glass containers preferred for aerosols.• Disadvantages:• Glass containers must be precise to provide the

maximum in pressure safety and impact resistance.• More chances for accidental breakage.• Not suitable for photosensitive preparations.

PLASTIC

• Plastics are more permeable to vapors and atmospheric air (like oxygen), so it may interact with the formulation and also may lead to oxidative degradation of the formulation.

• Polyethylene tetra phthalate (PET) container as used for some non pharmaceutical products.

• Advantages:• Cheap.• Malleable and ductile.• Easy to mold.• Disadvantages:• Incompatibility between drug- plastic and may

lose its efficiency and potency.

Actuators

• It ensures that aerosol product is delivered in the proper and desired form.

• It allows easy opening and closing the valve.• The actuator or adaptor which is fitted to the

aerosol valve stem is a device which on depression or any other required movement opens the valve and directs the spray to the desired area.

• The design of the actuator which incorporates an orifice of varying size and shape and expansion chamber is very important which influences the physical characteristics of the foam or spray, particularly in the case of inhalation aerosols, where the active ingredient/s must emit in the proper particle size range.

• Some proportion of the active ingredient/s is usually deposited on the inner surface of the actuator, the amount available which is released by actuation of the valve.

• Following types of actuators available.a) Spray actuators: These are having capable of

dispersing the stream of product concentrate and propellant into relatively small particles by allowing the stream to pass through various openings 0.016 to 0.040 inches. It breaks stream into fine particles.

• These actuators used for topical use such as spray-on bandages, antiseptics, local anesthetics and foot preparations.

b) Foam actuators: It consists of relatively large orifices ranges from 0.070 to 0.125 inches.

c) Solid steam actuators: Similar to foam type of actuators. Used for semisolid products like ointments.

d) Special/ Mist actuators: These are designed for special purpose, to deliver the contents of medicaments at site of action like throat, eye or vaginal tract.

Valve and Valve Assembly

• Valves deliver the drug in desired form and regulate the flow of product concentrate from the container.

• The valve should be able to withstand the pressure encountered by product concentrate and the container, should be corrosion resistant.

• They also provide proper amount of medication. • Dispersing of potent medication at proper

dispersion/ spray approximately 50 to 150 mg± 10 % of liquid materials at one time use of same

valve.

• There are two types of valves available a) Continuous spray valve and b) Metering valve.a) Continuous spray valves: To deliver the contents

in spray or foam or solid stream continuously with or without measuring. These types of valves are used for all types of pharmaceutical aerosols.

b) Metering valves: For potent medication and exact amount of medicament will be dispensed at one time application. Approximately 50 to 150 mg +- 10% at one time application.

Valve Assembly and its components• Actuator• Valve stem• Gasket• Valve Spring• Ferrule/Mounting cup/Valve cup• Valve Body/ Housing• Dip tube

• Stem: The actuator is supported by the stem and the formulation is delivered in the proper form to the chamber of the actuator by the stem. It is made up of Nylon, Brass and Stainless steel.

• Gasket: The stem and valve are placed tightly in their place by the gasket and the leakage of the formulation is prevented by gasket. It is made up of Buna N and Neoprene rubber.

• Spring: The gasket of aerosol container is held in its place by the spring and also helps to keep the valve in closed position when the pressure is released upon actuation of the formulation.

• Mounting Cup or Ferrule: • The Mounting cup or Ferrule is generally made up

of aluminum which serves to place the valve in its position and then attached to the aerosol container.

• So the underside of the mounting cup/ Ferrule is exposed to the contents of the container.

• So it is to be compatible with the contents to prevent interaction/s.

• It may be coated with an inert material such as vinyl coating as it prevents any interaction with the contents also corrosion of aluminum is prevented.

• Housing or Valve body: • The Housing or Valve body located directly

below the Mounting cup or Ferrule is made up of Nylon or Delrin work, which uses to connect dip tube, stem and actuator of aerosol container.

• The size of orifice will determine the rate of delivery of product and the desired form in which the product is to be emitted. (Size is 0.013 to 0.080 inches)

• Dip Tube: The dip tube is made up of polyethylene or polypropylene extends from the housing body or valve body down into the product concentrate works to bring the formulation from the container to the valve.

• The inner diameter of the dip tube depends on the viscosity and the desired rate of delivery of the product.

• The inner diameter of the dip tube increases with an increase in the viscosity of the formulation.

• For less viscous solutions the inner diameter ranges from 0.12 inch to 0.125 inch.

• For viscous solutions the inner diameter is 0.195 inch.

• Generally the actuator, stem, housing and dip tube are made up of plastic.

• The mounting cup and spring made up of metal.

• The gasket made up of rubber or plastic resistant to the formulation.

Principle / Mechanism and working of Aerosols

• In Aerosol, liquefied gas propellant / propellant mixture and product concentrate is sealed within an aerosol container, equilibrium is quickly established between the portion of propellant that remains liquefied and that propellant which vaporizes and occupies the upper portion of the aerosol container.

• So, the vapour phase which develops pressure in container, against the walls of the container. at valve assembly and the surface of the liquid phase, this contains the liquefied gas and the product concentrate.

• This pressure is responsible for actuation of the aerosol valve, forces the liquid phase up to the dip tube and through the orifice of the valve contents will released into the atmosphere.

• As the propellant/s released in to the air, it expands and evaporates because of the drop down in pressure, which leaves the product concentrate as airborne liquid droplets or dry particles depending upon the formulation type at applied area.

• Upon activation of the valve assembly of the aerosol system, the pressure exerted by the propellant/s forces the contents of the package to outside through the opening of the aerosol valve.

• The physical form of the contents emitted which depends on the formulation type of the product and the type of valve used.

• Generally, aerosol products designed as to expel their contents in the form of a fine mist, a coarse, wet, or dry spray; a steady stream; or stable or fast breaking foam.

• Some portion of the liquid phase released from the container, equilibrium develops between the propellant/s of remaining contents and thus the vapour state is reestablished.

• So even during expulsion of the product from the aerosol the pressure within the container remains constant and the product may be continuously released at same rate and with the same proportion.

• When the liquid reservoir is completed, the pressure cannot be maintained, and the gas may be expelled from the container with diminishing pressure until it is exhausted.

Classification of Aerosols

• Aerosols may be classified as1) Space Sprays 2) Surface coats 3) Foam1) Space Sprays: These are finely divided sprays having particle

size up to 50 um. E.g. Insecticides, Disinfectants and Room Deodorants etc.

2) Surface Coats: These are also sprays but disperse phase

particles are coarse with sizes up to 200 um. They produce a wet coat when sprayed on a surface. E.g. Hair sprays, Powder sprays and topical medicament sprays.

3) Foam: These are produced by rapid expansion of

propellants through an emulsion. Hence product comes out in the form of a foam or froth. E.g. Shaving cream and vaginal cream.

Types of Aerosol Systems

1) Solution system / Two Phase system2) Water based system / Two components or

Three components system3) Suspension / Dispersion system4) Foam system / Emulsion systems5) Aqueous stable foams6) Non-Aqueous stable foams7) Quick Breaking foams8) Thermal Foams9) Intra Nasal Aerosols10) Compressed Gas Systems

Solution system / Two Phase system: (Vapour + Liquid phase)

• Solution Aerosols are two phase systems consisting of the product concentrate in a propellant or mixture of propellants or a mixture of propellant and solvent. Some solvents may also be added to the formulation to retard the evaporation of the propellant.

• Solution aerosols can be difficult to formulate because many propellant or propellant-solvent mixtures are non polar in nature and these are poor solvents for the aerosol product concentrate.

• Few solvents can be used. E.g.: Ethyl alcohol (most commonly used solvent), dipropylene glycol, propylene glycol, ethyl acetate, hexylene glycol and acetone.

• Solution aerosols are used to make foot protective preparations, local anesthetics, anti-inflammatory preparations, spray on protective films and for oral and nasal applications.

• They contain 50 to 90% propellant for topical aerosols and up to 99.5% propellant for oral and nasal aerosols. If the percentage of propellant increases, the degree of dispersion and spray also fine form.

• The percentage of propellant decreases, the wetness of the spray will get increases. The particle sizes of the sprays can vary from 5 to 10 mm in inhalation aerosols and 50 to 100 mm for topical sprays.

Water based system / Two components or Three components system : (Propellant + Water + Vapour phase)• Large amount of water can be used to replace all or

part of the non aqueous solvents used in aerosols.• This system is composed of a layer of water

immiscible liquid propellant, highly aqueous product concentrate and the vapour phase. This type of system employed when the product is immiscible with the propellant.

• This system emits the contents as spray or foam. Spray is dispersion of active ingredient and other solvents in an emulsion system, in this emulsion system propellant as external phase.

• In this way, when the product is dispensed, the propellant vaporizes and dispersed the active ingredient in minute particles. Due to immiscibility of the water and propellant, it forms a three phase aerosol.

• Ethanol used as a cosolvent to solubilize propellant in the water.

• Surfactant used for the preparation of homogeneous dispersion. Ester forms between the glycol, glycerol and poly hydroxylic acids (oleic, palmitic stearic acids) can be used as surfactants. The surfactants composition can be between 0.5 to 2.0 and propellant composition from 25 to 60%.

• The recent advancement in water based system is the aquasol valve.

• In aquasol valve the drug is dissolved in the water or the mixture of water and alcohol. The propellant layer is exists on the top water layer.

• The solubility of the propellant is increases as the amount of alcohol increases and it will become completely soluble (if only alcohol is present).

• In aquasol, the vaporized propellant and product concentrate will reach to different ducts finally to the actuator.

• Finally this gives an uniform spray.• Water based systems produces in dried spray.

Suspension Aerosols

• Suspension Aerosols can prepare, when the product concentrate is insoluble in the propellant or mixture of propellant and solvent or when a co-solvent is not desirable.

E.g: Anti-asthmatic drugs, steroids and antibiotics are prepared in suspension aerosols.

• When the valve is opened or actuated, the suspension formulation is emitted to atmosphere and the propellant rapidly gets vaporizes and leaves a fine dispersion of the product concentrate.

• For formulation of suspension aerosols some disadvantages occur which include agglomeration, particle size growth, moisture content, valve clogging and particle size of the dispersed aerosolized particles.

• Lubricants such as isopropyl myristate, light mineral oil and surfactants such as oleic acid, sorbitan trioleate and lecithin have been used to overcome the difficulties of particle size agglomeration and growth which are directly related to the clogging problems.

Foam system / Emulsion systems• Emulsion or foam aerosols consist of Active

ingredient + Aqueous or Non aqueous vehicle + Surfactant + and propellant (Hydrocarbon or compressed gases).

• Here the propellant which is present in the liquid acts as internal phase.

• These aerosols dispensed as stable aqueous or non aqueous or quick breaking foam aerosol.

Aqueous stable foams

• This system consists of propellant in the range of 8 to 10% v/v. As the concentration of A-70, A-46 propellant increases, it results in stiff and drier spray. And wetter spray is produced as the concentration of propellant decreases.

• Both Hydrocarbon and Compressed gases used as propellants.

• This is generally used for steroids and antibiotics.

• Non-Aqueous stable foams:• These non aqueous stable foams of aerosols are formulated

with the use of different glycols like PEG and esters of glycols (propylene glycol monostearate) as emulsifying agents.

Quick Breaking foams

• Here propellant is the external phase. When dispensed, the product will emitted as foam which soon collapses or merges in to liquid.

• Hence, this type of system can be applied to small area or larger surface topical medication without mechanical application.

• Here Cationic or anionic or non-ionic types of surfactants are used in the formulation. It should soluble in both alcohol and water.

• This is pressurized by mixing of 90% concentrate and 10% propellant.

• Thermal Foams• These are not using these days. Generally

thermal foams used when the warmness is required.

• To produce warm foam for shaving.• Not readily accepted by the consumer, so

discontinued due to expense and lack of effectiveness.

Intra Nasal Aerosols

• Drug delivery systems intended for the deposition of medication into the nasal pathways for effectiveness to produce local or systemic effect.

• Intranasal preparations are limited to nasal drops, non pressurized nasal sprays (mists), inhalants and intranasal gels (jellies), ointments and creams. A new alternative is Pressurized metered nasal aerosol.

• The design of the adaptor varies from the inhalation aerosols. To produce smaller particles, the adaptors will be of less height and narrow.

• These are free from contamination, very less quantity of drug moves into the lungs, the mucosal irritation will be reduced.

Inhalers• Inhalation dosage forms are the form of

drugs or solutions of drugs administered through the (nasal or oral) respiratory route. Inhalers used for local action on the bronchial tree or for the systemic effects through absorption from the lungs.

• Inhalation of a micronized powder directly administered into the lungs using a special breath activated device through inhalers only.

• Depending on the physical state of the dispersed phase and continuous phase, inhalation system of drug is classified into three types

A. Pressurized metered dose inhalers (pMDIs)B. Dry powder inhalers (DPIs)C. NebulizersA. Pressurized Metered dose inhaler (pMDIs) The pressurized metered dose inhalers (pMDIs)

consist of a canister, actuator and a spacer. The canister is composed of a metering dose valve with an actuating stem. The formulation (containing the active ingredient i.e. drug, a liquefied gas propellant and a stabilizer) is present in the canister. The drug may be suspended or dissolved in the liquefied gas

• propellant. Upon actuation, the metering dose valve is opened which releases a single metered dose of medication along with the liquified gas propellant to spray out of a canister. This process is called"cavitation". The liquefied gas propellant is volatile in nature, which breaks down into liquid droplets and evaporates rapidly and the dried micronized drug are inhaled to the lung.

Drawbacks of Pressurized metered dose delivery• Various chlorofluorocarbons (CFC) are used as the

propellant, it causes depletion of ozone layer. So later it was replaced with hydro fluorocarbons. Hydro fluorocarbons cause greenhouse effect.

• pMDIs are pressurized forms and it emits the dose at high velocity and gets deposited in the oropharynx.

• The mixture of propellant and the cosolvent may extract some of the organic compounds from the device components and it leads to chemical degradation.

Dry powder inhalers (DPIs)• The DPIs are very advantageous than pMDIs. Becausea) DPIs require no coordination of actuation and

inhalation. It activated by patient's inspiratory airflow.b) DPIs do not extract organic compounds from the

device components and the chances of degradation is less than pMDIs.

c) The rate of drug release / delivery is good than pMDIs.

d) These are efficient, more stable and easier to use than pMDIs.

• DPIs are composed of micronized powdered drug particles. The micronized powdered drug particles (of sizes < 5um) are mixed with much larger sugar particles (of size < 30 um) e.g. Lactose monohydrate.

• The smaller drug particles forms loose aggregate with lactose monohydrate. The micronized powdered drug particles have high cohesive force, so they have a tendency of adhering to each other. The addition of large particle sized lactose monohydrate reduces the cohesive force of the micronized drug particles and form loose agglomerate with the micronized drug particles.

• It helps in an easy deaggregation of the agglomerates, upon inhalation, the agglomerates get broken down into its constituent particles, with the help of mechanical devices such as screens, on which the particles agglomerates impact.

• It releases the smaller sized powdered drug particles into the air to be inhaled to the lung. Here the larger sized lactose monohydrates particles are retain or left behind in the device and in the mouse throat.

Nebulizers• Nebulizer is a device used to administer

medication in the form of a mist inhaled through the lungs. Nebulizers use oxygen, compressed air or ultrasonic power to break up medical solutions and suspensions into small aerosol droplets called mists that can be directly inhaled from the mouthpiece of the device. It produces a mist of drug containing water droplets for inhalation purpose. The powdered drug is present either in solution form or suspension form in the nebulizer.

Advantages of nebulizers

• Patient coordination not required.• Effective with tidal breathing.• High dose possible.• No chlorofluorocarbon (CFC) is released.• Nebulizers used with supplemental oxygen.• Can use for combination therapy if compatible.• The ultrasonic nebulizer is faster in delivery,

smaller and portable.

Disadvantages of nebulizer

• They are expensive.• Electrical power or battery sources are required.• Jet nebulizer requires pressurized form of gas.• The frequent cleaning required.• There is a chance of contamination.• The suspension of dosage cannot be properly

aerosolized.• The jet nebulizer produces large and different

sizes of particles.• The ultrasonic stimulation and rise in

temperature may cause degradation of drug.

• Nebulizers are usually of two types:i) Electronic nebulizer andii) Jet or ultrasonic nebulizer. Jet or ultrasonic nebulizer uses a source of

pressurized air to blast a stream of air through a drug containing water reservoir, producing water droplets. In contrast, electronic nebulizers develop mechanical vibration to produce water droplets. The nebulizers are generally used for the treatment of acute conditions (e.g. acute asthma, respiratory infection) or in those patients who have difficulties using other respiratory dosage forms.

FILLING OF AEROSOLS• The manufactured aerosols can be filled in to

the containers can be done by following methods and apparatus used.

a) Cold filling Apparatusb) Pressure filling apparatusc) Compressed gas filling apparatusd) Rotary filling machine

a) Cold filling apparatus• Cold filling apparatus consists of an insulated

box which fitted with copper tubings and filled with dry ice or acetone.

• The fitted copper tubings increase the surface area and cause faster cooling.

• The hydrocarbon propellant is not to be stored in the copper tubings as it might cause explosion.

Cold filling method:

• Two different methods are involved:• The aerosol product is filled into the container is by

two methods:• In the first method, the product concentrates are

chilled to a temperature of - 30 to - 40 F. The chilled product concentrates are added to the chilled aerosol container. The chilled propellant is added through an inlet valve present under side of the valve of the aerosol container.

• In the second method, both the product concentrate and the propellant are chilled to - 30 to - 400 F. Then the mixture is added to the chilled container.

• In both the above methods, after the aerosol containers are filled, the valves are set in its place and the filled aerosol containers are passed through a water bath in which the contents of the containers are heated to 130 F to test for leaks and strength. After checking the containers apply air drying, cap it and label it.

• Cold filling method is advantageous for the filling of metering valve containing aerosol container. The pressure filling method is more prominent than cold filling method as most of the formulations cannot be cooled to very low temperatures.

b) Pressure filling apparatus• Pressure filling apparatus consists of a metering burette

capable of measuring the amount of propellant to be filled to the container.

• The mixture of propellant or propellant/s are added through the inlet valve present to the bottom of the valve under its own vapour pressure.

• A cylinder of nitrogen or compressed gas is attached to the top of the valve and the pressure of nitrogen causes the propellant to flow to the container through the metering burette.

• The propellant flows to the container stops when the pressure of the flowing propellant becomes equal to the pressure of the container.

Pressure filling method

• The product concentrate is filled to the aerosol container through the metering pressure filling burette at room temperature. The propellant is added through the inlet valve located at the base of the valve or under the valve after the crimping of valve. The flow of propellant to the aerosol container continues till the pressure of the filling propellant becomes equal to the pressure within the container. The aerosol container are capped and labeled.

A. Method-1• - The product concentrate is added to

container at room temperature.• - The valve crimped into place.• - The propellant is then added under pressure

through the valve stern or through the actuator and around the sealing gaskets.

B. Method-2• - Under the cap method: product concentrate is

added to the container and valve place in a position.

• - A seal is formed around the shoulder of the container and using a vacuum, the valve cup is raised slightly from the can and propellant is added.

• - The valve is then crimped into the place.• This method is more prominent than cold filling

method as most of the formulations cannot be cooled to very low temperatures.

c) Compressed gas filling apparatus• A compressed gas propellant is used. As the

compressed gas is under high pressure, so the pressure is reduced by pressure reducing valve. A pressure of 150 pounds per square inch gauge is required to fill the compressed gas propellant in the aerosol container. The product concentrate is placed in the pressure gauge and the valve is crimped in its place. The air is evacuated. The filling head is inserted into the valve opening. Upon the depression of the valve, the compressed gas propellant is allowed to flow into the container.

• The compressed gas stops flowing when the pressure of the compressed gas flowing to the container from the burette becomes equal to the pressure within the container. In case of increasing the solubility of the gas in the product concentrate and also when an increased amount of compressed gas is required, carbon dioxide and Nitrous dioxide is used. The container is needed to be shaken during and after the filling operation to enhance the solubility of the gas in the product concentrate.

Compressed gases filling

• Here, when the compressed gases are used as the propellant in aerosol systems, the compressed gas is transferred from large steel cylinders into the aerosol containers. Before filling, the product concentrate is placed in the container, then the valve assembly is crimped into place and the air is removed from the container by a vacuum pump.

• The compressed gas is then passed into the container through a pressure reducing valve attached to the gas cylinder; when the pressure within the aerosol container is equal to the predetermined rate and set/ regulated delivery pressure, the stops gas flow and the aerosol valve is restored to the closed position. Some gases like carbon dioxide and nitrous oxide (which are slightly soluble in the product concentrate) the container is manually or mechanically shaken during the filling operation to achieve the desired pressure in the head space of the aerosol container.

Rotary filling machine

• The pressure filling method is first slower than cold filling method. With the development of newer technique the speed of pressure filling method was increased. The concentrate is added to the container at room temperature, and the valve is crimped in place. The propellant is added through the valve or "under the cap". Since the vacuum contains extremely small openings (0.018 to 0.030 inches), this step is slow and limits production. With the development of new rotary filling machines for aerosols and newer filling heads, which allows propellant to be added around and through the valve stem.

• Advantages of the pressure filling methods compared with cold filling method:

• The emulsions or suspensions are unstable at very low temperature. At that time the pressure filling method is the preferred method then that of cold filling method.

• Here the absence of moisture reduces the chance of contamination.

• The rate of production is high.• Propellant loss is low.

General Formulation and Manufacturing components of Aerosols

Evaluation of Aerosols

Pharmaceutical aerosols can be evaluated by testing physicochemical, performance and biological tests.

1) Flammability and CombustibilityA) Flame Projection and flash back B) Flash Point2) Physicochemical CharacteristicsA) Vapour Pressure B) DensityC) Moisture ContentD) Identification of PropellantE) Concentrate - Propellant ratio

3) Performance TestA) Aerosol Valve Discharge Rate B) Spray Patterns C) Dose Uniformity / Dosage Testing with

Metered valvesD) Net ContentsE) Foam stabilityF) Particle Size determinationG) Leakage Test

4) Biological TestingA) Therapeutic ActivityB) ToxicityC) Extractable substances

1) Flammability and Combustibility

A) Flame Projection and flash back:• Flame test indicates the effect of an aerosol

formulation on the extension of an open flame.

• Aerosol product is sprayed for 4 sec. into open flame.

• Depending on the nature and type of formulation, the fame is extended to some length and exact length was measured with ruler.

B) Flash Point

• "Standard Tag Open Cap Apparatus" is used for determination of flash point. For this the formulation is chilled to temperature of -25 F and transferred to the test apparatus.

• The temperature of test sample liquid increase slowly, and the temperature at which the vapors of propellant ignite is taken a "flash point".

• It is calculated for flammable component, which in case of topical hydrocarbon propellants.

2) Physicochemical Characteristics

A) Vapour Pressure:• Vapour pressure is determined by pressure

gauges or elaborately through use of a water bath, test gauges and other special equipments. Variation in pressure indicates the presence of air in headscape. Variation in pressure indicates the presence of air in the headscape. For accurate measurement of vapour pressure in aerosol container can punctuating device used.

B) Density of aerosol system:

• It is determined by hydrometer or a pycnometer.• This method is useful for non aerosols

modification to accommodate the liquefied gas preparation.

• In which a pressure tube is fitted with metal fingers and hoke valve of apparatus, which under pressure the liquids are introduced.

• The hydrometer is kept in to the glass pressure tube. Some sufficient amount of sample is added through the valve to cause the hydrometer to rise half way up the length of the tube. The density can be read directly from the apparatus.

D) Identification of Propellant/s

• Gas chromatography or I.R spectrophotometry methods are used for identification of propellants and also to indicate the proportion of the each component in a blend.

BIOLOGICAL TESTING:C) Extractable substances

• The pressurized inhalers and aerosols are normally formulated with organic solvents as the propellant or the vehicle. The leaching of extractables from the elastomeric and plastic components into the formulation is a potentially serious problem.

• So, the composition and the quality of materials used in the manufacture of the valve components (e.g., stem, gaskets, housing, container etc.) must be carefully selected and controlled.

• The container compatibility with formulation components should be thoroughly checked, so as to prevent distortion of the valve components and to minimize changes in the medication delivery, discharge rate, leaks and impurity profile of the drug product over time.

• he extractables profiles of a representative sample of each of the elastomeric and plastic components of the valve should be established under specified conditions and should be correlated to the extractable profile of the placebo or aged drug product, to ensure quality and purity of the drug product. Extractable substance which may include poly nuclear aromatics, nitrosamines, antioxidants, plasticizers, vulcanization accelerators and monomers, etc., should be identified and minimized wherever possible.

• Depends on the specifications and limits for individual components and total extractables from different valve components may require the use of different analytical methods.

Packaging, Labeling and Storage

• A unique aspect of pharmaceutical aerosols compared to other dosage forms is that the product is actually packaged as part of the manufacturing process. The product is completely manufactured before itself and then placed in the appropriate container.

• Most aerosol products have a protective cap or cover that fits snugly over the valve and mounting cup. This mounting cap protects the valve against contamination with dust and dirt. The mounting cap, which is generally made of plastic or metal and also serves a decorative function.

• Aerosols containers should be maintained with the protective caps in place to prevent accidental activation of the valve assembly or contamination by dust and other foreign contents or atmospheric contents.

• Therapeutic aerosols that are to be dispensed only with prescription and generally labeled by the manufacturer with plastic peel-away labels or easily removed paper labels, so that the pharmacist easily replace the manufacturer's label.

• Safety and precaution labels must warn users not to puncture pressurized containers and not to use or store them near heat/temperature or an open flame and not to incinerate them.

• Exposure to temperatures above49degC (120degF) may burst an aerosol container.

• When the canisters are cold (less than the usual results into spray). This may be particularly important to users of metered-dose inhalation sprays.

• For aerosol products are generally recommended for storage between 15degC and 30degC (59degF and 86degF).