PHARMACEUTICAL AEROSOLS

BINDU Dept. of pharmaceutical sciences,MDU Rohtak

CONTENTS

• Containers used for aerosols• Valves and actuators• Filling processes

INTRODUCTION

❖ 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.

1. CONTAINERS USED FOR AEROSOLS

• Various materials have been used for the aerosols containers, which must withstand pressures as high as 140 to 180 psig at 1300F.

A. Metal1. Tinplated steel• Side-seam (three -piece)• Two-piece or drawn• Tin-free steel

2. Aluminium• Two-piece• One-piece (extruded or drawn)

3. Stainless steel

B. Glass1. Uncoated glass2. Plastic-coated glass

Selection of container for aerosols

➢ its adaptability to production methods

➢ compatibility with formulation components

➢ ability to sustain the pressure intended for the product

➢ the interest in design

➢ cost

TINPLATED CONTAINERS

• the tinplated steel container consists of a sheet of the steel plate that has been electroplated on both side with tin.

• The thickness of tin coating is describe in term of its weight.

• The size of system is indicated by the standard system• Example: a container said to be 202 x 214 if, it is 22/16

inches in diameter and 214/16 inches in height.

Procedure:tinplated sheets is obtained in thin sheets and when required, it is coated with an organic material

These sheets are lithographed, after that the each piece is fabricated into the desired shape

The body is shaped into a cylinder and seamed via a flanging and soldering operation

The top and bottom are attached to the body and a side seam strip is added to the inside seam area when required

• the organic coating also can be added to the finished container rather than to the flat sheet but this procedure is slower and more expensive; a more continuous and durable coating is produced

• Development: welded side-seam:

• welding eliminate the soldering operation• saves mfg time and • decrease the possibility of the product-container

interaction

• Two process are used

a. Soudronic system: is based on an electrically controlled resistance welding method that uses a copper wire as an electrode. The rounded bodies are welded and then sent to the conventional line, where top and bottom ends are flanged.

b. Conoweld system : passes the folded body through 2 rotating electrode rings. The rest of the container mfg in the usual manner.

• Tinplated steel containers are of two types:

1. Two piece container body, consisting of drawn cylinder, the base of the cylinder is held in place with double seam

2. Three piece container has a side seam the base being attached as for two piece container, the top has a 1 inch opening and is joined to body by double seam

Aluminium containers

• They are made by extrusion process and hence have no seam

Advantages:• lessened danger of incompatibility due to its

seamless nature• Greater resistance to corrosion

Disadvantages:• It is corroded by pure water and pure

alcohol

• In combination of ethanol and propellant 11 in an alu. Container has been shown to produce hydrogen, acetyl chloride, aluminium chloride, propellant 21 and other corrosive products

3. stainless steel containers

Advantages:• Extremely strong• Resistant to most material• Resistant to corrosion• Withstand with high pressure• No internal coating is required

Disadvantages:• Limited to smaller size due to production

problem• Expensive

Uses:• For inhalation aerosols

4. Glass containers

Advantages:• Compatible• Corrosion problem is eliminated• Greater degree of freedom in design of the

container• Inert• transparent

Disadvantages:• Breakable

Plastic coated glass:• The coating give protection from impact

valves valves

continous metered dose spray valve valve

Features of valves:• It is capable of being easily opened and closed• It is capable of delivering the content in the

desired form• It is expected to deliver a given amount of

medication

A. Continuous spray valveContinuous spray valve has following components• Ferrule or

mounting cup• Valve housing• Stem• Gasket• Spring• Dip tube

1. Ferrule or mounting cup

• the ferrule or mounting cup is used to attach the valve proper to the container

• The container having a 1-inch opening, the cup is made from tinplated steel, although aluminium also can be used

• The underside of the valve cup is exposed to the content of the container and to the oxygen trapped in the headspace, a single or double epoxy or vinyl coating can be added to increase resistance to corrosion

• The ferrule is attached to the container either by rolling the end under the lip of the bottle or by clinching the metal under the lip

2. Valve housing or body• The housing is generally mfg from nylon or delrin and

contains an opening at the point of the attachment of the dip tube, which ranges from about 0.013 – 0.080 inch.

Vapour tap: • Allow escape of vaporized propellant along with liquid

product• Produces fine particles• Prevent clogging of valve• Allow product to be satisfactorily dispensed with the

container in the inverted position• Reduce the chilling effect of the propellant on the skin• With hydrocarbon propellant, allow for a decrease in

flame extension

3. stem

• It is made from nylon or delrin but metals such as brass and stainless steel can be used

• One or more orifices are set into the stem, they ranges from one orifice of about 0.013- 0.030 inch to three orifices of 0.040 inch each

• When stem is pressed the product is emitted from the container

4. Gasket • It is used to provide a seal between the valve and

container• Buna-N and neoprene rubber are commonly used for

the gasket material and are compatible with most pharmaceutical formulation

5. Spring • The spring serves to hold the gasket in place and

when actuator is depressed and released, it returns the valve to its closed position

• Stainless steel can be used with most aerosols

6. Dip tube

• it is made up of polyethylene or polypropylene having diameter between 3 to 3.2 mm. It bring formulation from container up to valve

B. Metering valveMain function:• To reproducibly deliver

a portion of the liquid phase of the formulation in which the medicament is either dissolved or dispersed.

• Also form the seal atop of the canister to prevent loss of the pressurised content

The valve generally comprise at least seven components that are constructed from a variety of the inert materials.

• Valve body: acetal or polyester• Valve stem: stainless steel or acetal• Ferrule: anodised aluminium• Seal and gasket: butyl, nitrile or neopren

These valve are essentially designed to work in the inverted position, although, with the aid of dip tube they can also be used in upright position.

Working:•Depression of the valve stem

allows the contents of the metering chamber to be dispensed through the orifice in the valve stem• After actuation, the metering

chamber refills from the bulk liquid formulation, once the metering chamber is sealed from the atmosphere and is ready to dispersed the next dose.• This is essential, otherwise

continuous spray would be achieved.

Typically volume that are dispensed range from 25 to 100 micro litre.

Note:•These valve are designed to dispense volumetrically, change in the formulation density (by varying the propellant ratio) can affect the amount (by weight) that is dispensed.

Actuators • It allow for easy opening

and closing of the valves. The design of actuator determine the proper and desired form of the aerosol product

• Types of actuators✓Spray✓Form✓Solid stream✓Special application

Spray actuators• Orifice : 1 to 3 on the order of 0.016 inch to 0.040

inch in dia.• When these actuators are used with aerosol

products containing relatively low amounts of propellants (50 % or less), the product is dispensed as a stream rather than a spray.

• For these products, a mechanical breakup actuator is usually required.

• These actuators are capable of “mechanically” braking a stream into fine particles by causing them to swirl through various channels built into the container

• Uses:✓ Pharmaceutically intended for topical use

such as spray on bandages, antiseptics, local anaesthetic and foot preparation

Foam actuators

• Large orifice size: 0.070 – 0.125 inch & greater• The orifice allow the passage of the product

into a relatively large chamber, where it expand and be dispensed through the large orifice

Solid stream actuators

• Relatively large orifice allow for the passage of product through the valve stem and into the actuator

• Uses:✓Semi solid product (ointments)

Special actuators

• Designed to deliver the medication to the appropriate site of action such as

✓Throat✓Nose✓Eye✓Vaginal tract

Filling processes

• Cold filling • Pressure filling• Compressed gas filling

1. Cold filling

Cold filling apparatus:• it consists of an insulated box fitted with

copper tubing. The insulated tubing are filled with dry ice and cause faster cooling.

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

Cold filling method: two methods are involved:• In the first method,

✓ the product concentrate are chilled to a temp of -30 to -40 F.

✓ The chilled product concentrates are added to the chilled aerosol container.

✓ The chilled propellant is added through the inlet valve present under side of the valve of the chilled container.

• In the second method,✓ Both the product concentrate and the

propellant are chilled to -30 to -40 F. Then the mixture is added to the chilled container.

Advantage:• For the filling of metering valve containing aerosol container.

Disadvantage:• most of the formulations cannot be cooled to very low temp.

Pressure filling Pressure filling apparatus:

✓ it consist of a metering burette capable of measuring the amount of propellant to be filled to the aerosol container.

✓ The propellant is 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 stops where 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 temp

✓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 become equal to the pressure within the container

✓The aerosol container are capped and labelled

Advantages:• The emulsion, suspensions are unstable at

very low temp so the pressure filling method is preferred over cold filling

• The absence of moisture reduces the chance of contamination

• The rate of production is high• The chance of loss of propellant is low

Compressed gas filling✓The 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 psig 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, compressed gas

propellant is allowed to flow into the container

`

✓The compressed gas stop flowing when the pressure of the compressed gas flowing to the container from the burette become 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, CO2 and NO2 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

Filling machinery

• Laboratory equipment• Stepped rotary machines• Continuous rotary machines

Laboratory equipments

PRODUCT FILLER CRIMPING EQUIPMENT

PROPELLANT FILLER

Product filler

Valve crimping

Propellant filler

Stepped rotary machines• The maximum output

is directly related to the types of valves used.

• In this, the concentrate filling, crimping, and propellant charging done on the same indexing unit

Continuous rotary machines• In this, all operations

in the aerosol packaging process is carried out on a different continuous rotary station.

Advantages:• High production

output capacity(100-200 containers/min)

Advancement in aerosol technology

Metered dose inhalers (MDIs)

Essentially comprises 4 separate components

• The base formulation• The container• The metering valve• The actuators

Actuators tor MDIs:• Constructed from the material like

polyethylene and polypropylene by injection moulding method

• The common design of actuator is classic L shape.

Advantages : • Portability • Low cost• Disposability• Reproducibility• Less contamination

Disadvantages:• Inefficient at drug delivery• Incorrect use by the patients such as

o Failure to remove the protective cap covering the mouthpiece, the inhaler being used inverted

o Failure to shake canistero Failure to inhale slowly and deeplyo Inadequate breath holdingo Poor inhalation/actuation

synchronisation

Spacers and breath actuated MDIs:

Overcome the coordination problem by using extension devices or ‘spacers’ positioned between MDI and patient.

Nebuhaler spacer device:• The dose from the

MDI is discharged directly into the reservior prior to inhalation.

• This reduces the initial doplet velocity, permit efficient propellant evaporation and remove the need for actuation/inhalation coordination.

Azmacort:• Extended mouth piece

device• Allowing greater

evaporation time for the less volatile propellant, plus large particle sedimentation in airways resulting in reduction in orophrangeal impaction.

Inspirease (key pharmaceuticals):• Has an audible signal that

indicate when the patient’s inspiration rate is correct.

Some other example of spacers:• Fisonair (rhone-

poulenc rorer)• Volumatic (GSK)• Syncroner (rhone-

poulenc rorer)• Space inhalers (astra

zeneca)

Breath actuated devices:

Autohaler:• In this device, a vane

is used as release mechanism, firing the MDI when a certain threshold inspiration flow rate is reached.

Nebulizers Types of nebulizer system:• Jet• Ultrasonic

Advantages:• Deliver large volume of drug solution and

suspension• Suited for the drug that can not be conventionally

formulated into MDIs and DPIs• Drug inhaled during normal tidal breathing through

a mouthpiece or face mask (patient compliance increase in elderly and children)

Disadvantages:• Wastage of medicament into environment

Jet nebulizer:• It use compressed gas(air or

oxygen) from a compressed gas cylinder, hospital air line or electrical compressor to convert a liquid into a spray.

• The jet of high velocity gas is passed either tangentially or coaxially through a narrow venturi nozzle, typically 0.3-0.7 mm in dia.

• An area of negative pressure where the air jet emerges, causes liquid to be drawn up a feed tube from a fluid reservior by the Bernouli effect

• Liquid emerges as fine filaments, which collapse into droplets owing to surface tension.

Pari LC nebulizer:• Have been developed in

which the patient’s own breath boosts nebulizer performance, with aerosol production matching the patient’s tidal volume.

• On exhalation, the aerosol being produced is generated only from the compressor gas source, thereby minimizing drug wastage.

Ultrasonic nebulizers:• In these the energy necessary

to atomize liquid comes from a piezoelectric crystal vibrating at high frequency.

• At sufficiently high ultrasonic intensities a fountain of liquid is formed in the nebulizer chamber.

• Larger droplets are emitted from the apex and a fog of small droplets is emitted from the lower part.

Dry powder inhalers (DPIs)

Two types of DPIs1. Unit dose devices (spinhaler and rotahaler)2. Multiple dose devices (turbohaler and diskhaler)

Advantages:• Do not require CFC propellant to dispense the drug• Ozone friendly delivery system• Do overcome the need for coordination of actuation and

inspiration b/c they are essentially breath actuated

Drawbacks:

• Require inspiratory flow rate of 60 L/min to effectively deaggregate the powder (not achieved in asthmatic patients and infants)

• Higher dose is required for DPIs than MDIs to achieve a comparable clinical effect

• Possibilities of fragments of gelatin being administered to patients

• Cumbersome nature of loading (during asthmatic attack)

• Delivery of medicament by DPIs in the incidence of cough

• Taste of medicament

Unit dose devicesSpinhalers: • The drug mixture, which

often includes a bulk carrier to aid powder flow, is prefilled into a hard gelatin capsule and loaded into device.

• After activation of the device, which pierces the capsule, the patient inhale the dose, which is dispensed from the vibrating capsule by means of inspired air

Rotahaler: (by glaxo)• Has developed for the

delivery of salbutamol and beclomethasone dipropionate powders.

• Here, the drug mixture is again filled in hard gelatin capsule, and the capsule is inserted into the device; however the capsule is broken open in the device and the powder is inhaled through the screened tube.

Berotec (Boehringer gelheim):• Used for fenoterol

(loaded in hard gelatin capsule) delivery

Cyclohaler (pharmtiba)

Multi dose devicesTurbohaler: (a division of astra)• This device is contained

within a storage reservior and can be dispensed into the dosing chamber by a simple back and forth twisting action on the base of the unit.

• The device is capable of working at low flow rate and also delivers carrier free particles.

• Respiration flow rate required- 28.3 L/min

Diskhaler (glaxo):• This device has a circular

disk that contain eight powder charges.

• These are maintain in separate aluminium blister reservior until just before inspiration.

• On priming the device the aluminium blister is pierced and the contents of the pouch are dropped into the dosing chamber.

Accuhaler (GSK):• In this drug/carrier mix is

preloaded into the device in foil-covered blister pockets containing 60 doses.

• The foil lid is peeled off the drug-containing pockets as each dose is advanced with the blisters and the lids being round up separately within the device, which is discarded at the end of operation.

Clickhaler (innovata biomed):• In this, a drug blend is stored

in a reservoir.• Metering cup is filled by

gravity from this reservoir and delivered to an inhalation passage, from which it is inhaled.

• The device is capable of holding up to 200 doses and incorporates a dose counter, which informs patients when the device is nearly empty after use.

Exubera (pfizer):• it is a prescription

medicine that contains an insulin powder that you breathe in (inhale) through your mouth using the EXUBERA ® Inhaler. It is used to treat adults with diabetes. It helps to control high blood sugar.

AERX (Aradigm):

• The patient needs only to load the AERx Strip dosage packet into the Essence device, press the activator button while inhaling through the mouthpiece at a normal rate, and remove the spent dosage packet.

Bag on valve

• which comprises an outer container and an inner container inserted into the outer container, and which has a first space being an inside of the inner container and a second space surrounding the first space and independent from the first space, and in which different contents are charged in the first space and the second space.

• wherein the inner container is formed of one or more than two flexible laminated sheets having a metal foil layer and a synthetic resin layer

US patent 8361970

Multi-chamber material dispensing system and method for making same

• This approach includes a collapsible container surrounded by an elastomeric band.

• A normally closed valve and an actuator assembly are affixed to the container. When the container is initially filled with product, it expands along with the surrounding elastomeric band.

• Potential energy is generated as the elastomeric band stretches. And when the actuator is operated to open the valve, the potential energy is converted to kinetic energy to dispense product out of the container until the actuator is disengaged

US patent 8590755

Pressure regulated flow valve with gas-piston

• An object of the present invention is to provide a valve which has a primary flow path through the valve and has an internal movable member which is regulated by the internal pressure of the pressurized container as well as the internal pressure of a gas piston so that as the internal pressure of the pressurized container falls below a threshold value, the gas piston biases the movable member in a manner which controls the expansion of the product flow path so that a desired sustained volumetric flow rate of product can continue to be emitted from the pressurized container despite the loss of internal pressure in the container.

US patent 8578934

Indicating device with warning dosage indicator

• An indicating device suitable for indicating the number of dosages of a substance that have been dispensed from or remain in a container includes at least one first indicator member incrementally moveable to a plurality of positions and a second indicator member moveable in response to a predetermined number of movements of the at least one first indicator member.

• The at least one first indicator member includes primary dosage indicia adapted to indicate the number of dosages of substance that have been dispensed from or remain in the container.

• The second indicator member includes secondary dosage indicia adapted to indicate that less than a minimum predetermined number of dosages of substance remain in the container.

• In one preferred embodiment, the primary dosage indicia are configured as numerical indicia and the secondary dosage indicia are configured as color indicia.

US patent 8523023

Aerosol container resuscitator • A aerosol container resuscitator restores functionality to a damaged or otherwise

compromised aerosol container by being attachable to the annular container rim adjacent the container outlet, and by opening the valve of the compromised outlet and subsequently directing the aerosol container's product as purposed.

• The aerosol container resuscitator comprises an annular fitting assembly and a driver assembly. The fitting assembly comprises a fitting structure and a clamping structure.

• The fitting assembly aligns, secures, and interfaces the driver assembly to the container, which driver assembly comprises gasket structures, spring structures, a sleeve structure and a driver structure. The sleeve structure comprises communicating cavities in which the driver structure is received.

• The gaskets seal and prevent discharged aerosol container's product from circumventing the driver structure of the driver assembly. The springs allow relative translation between the fitting assembly and the driver assembly and between the sleeve structure and the driver structure