propellents

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ADVANCES IN PROPELLANTS

Presented By SUNILBOREDDY

M.Pharmacy (Pharmaceutics)


CONTENTS History Definition Types Of Aerosols Applications And Advantages Advantages Over Other Dosage Faorms Disadvantages Of Aerosol Components Of Aerosols How An Aerosol Works Why Do We Need A Propellant Propellant Definition Propellant Examples Advances In Metered Dose Inhaler Technology Ideal Properties ReferencesCompany LogoCompany Logo


Lyle Goodhue and William Sullivan (United States Department of

Agriculture), who are credited as the inventors of the modern spray can.

In the first modern day pressurized aerosol form’s was developed in early

1950 and has introduced as Medihaler Epi by Ricker Laboratories.

HISTORY


HISTORY Pharmaceutical aerosols have been playing a crucial role in the health and well

being of millions of people throughout the world for many years. These products include pressurized metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulizers, sublinguals, skin sprays (coolants, anesthetics, etc.) and dental sprays.

Since the mid 1950s, aerosol forms of pharmaceuticals have played an important role in treating respiratory illnesses such as asthma and chronic obstructive pulmonary disease (COPD), and MDIs and DPIs have become an important part of that treatment.

Traditionally most pharmaceutical aerosols have been propelled with chlorofluorocarbons (CFCs), but current global regulations require pharmaceutical aerosols to be reformulated to contain non-ozone-depleting propellants.


Alternatives to CFC propellants must satisfy many other criteria in addition to environmental acceptability. Most importantly, they need to have acceptable toxicity profiles given their use in the delivery of medicaments. For the sake of patient safety, it is also important that they are nonflammable. Finally, their physical properties must allow workable formulations within the available technology.

The two current alternatives to CFC propellants for pharmaceutical aerosols are hydrofluorocarbon (HFC) 134a (also known as hydrofluoroalkane (HFA) 134a or 1,1,1,2- tetrafluoroethane), and HFC-227ea (HFA-227ea or 1,1,1,2,3,3,3-

heptafluoropropane)


Of the alternatives identified, the hydrofluoroalkanes (HFAs) or HFCs were targeted

for development as replacements for the CFCs in MDIs. Within this class, 134a and

227ea were adopted for inhalation toxicity testing by two consortia of pharmaceutical

companies: IPACT 1 for 134a and IPACT 2 for 227ea.

(IPACT: International Pharmaceutical Aerosol Consortium for Toxicity Testing)

These programs established the safety profile of both propellants, which has led to the

recommendation by the Committee of Proprietary Medicinal Products (CPMP) of their

suitability for use in MDIs.


NEW CFC SUBSTITUTES FOR MDIS.

The HFAs are rapidly replacing CFCs in MDIs. Numerous clinical studies

have focused on documenting efficacy and safety. Some data suggest that the

lung deposition fraction of beclomethasone dipropionate using HFA-134a

MDI is much higher than that for CFC MDI. The major reason for this

difference is the particle size of the HFA aerosol, 1.1 mm, compared to

the CFC aerosol, with a size of 3.5 mm. Evidence indicates that pulmonary

deposition can be significantly influenced by HFA chosen and by actuator

design. Lung deposition for fenoterol was significantly influenced by the

actuator nozzle designed for HFA-134a.


AEROSOL CONTAINER


DEFINITION

An aerosol can be defined as a dispersion of solid and liquid particles suspended in gas

Pharmaceutical aerosols or pressurized dosage forms is defined as “ a system that depends on the power of a compressed or liquefied gas to expel the contents from the container.”

Pharmaceutical aerosols are products that are packaged under pressure and contain therapeutically active ingredients that are released upon activation of an appropriate valve system.

They are intended for topical application to the skin as well as local application into the nose (nasal aerosols), mouth (lingual aerosols), or lungs (inhalation aerosols).


HOW AN AEROSOL WORKS

An aerosol contains two essential components:-

The product, in the form of a liquid, emulsion or suspension.

The propellant, which can be a liquefied gas, or even a compressed gas.


The way in which the liquid is turned into a spray depends on a

number of factors which include,

1. The valve specification

2. The actuator specification

3. The type and amount of propellant


TYPES OF AEROSOLS

Aerosols consist of Two-phase (gas and liquid) Three-phase (gas, liquid, and solid or liquid) systems.

The two-phase aerosol It consists of a solution of active ingredients in liquefied propellant or in the

vaporized propellant. The solvent is composed of the propellant or a mixture of the propellant. Co-solvents such as alcohol, propylene glycol, and polyethylene glycols, which are often used to enhance the solubility of the

active ingredients.

Three-phase systems It consist of a suspension or emulsion of the active ingredient(s)in addition to

the vaporized propellants. suspension consists of the active ingredient's that may be dispersed in the

propellant system with the aid of suitable excipients such as wetting agents and/or solid carriers such as talc or colloidal silica.


APPLICATIONS AND ADVANTAGES

Ease of use Protection from contamination with foreign materials since the product is

sealed inside the container. Protection from the effect of air and moisture. Regulation of dosage by the use metered dose valve. Economic usage of dosage form metered dose valves are used for

expensive topical preparations which may otherwise be formulated as ointments, creams or lotions.

The usage of these latter dosage forms will depend on the users attitude to economy and often involved some loss of the product on an applicator

Topical preparations are also well suited for presentation as aerosol or sprays. The irritation of a sore wound caused by the rubbing in of an ointment or creams is avoided and cooling effect of aerosols containing liquefied gases may be advantageous.

These aerosol products were intended for topical administration for the treatment of burns, minor cuts, and bruises, infections and various dermatologic conditions.


ADVANTAGES OVER OTHER DOSAGE FORMS

A dose can be removed without contamination of remaining material.

The medication can be delivered directly to the affected area in a desired form, such as spray, stream, quick-breaking foam or stable foam.

Irritation produced by the mechanical application of topical medication is reduced or eliminated.

Other advantages are ease and convenience of application and application of medication in a thin layer.


DISADVANTAGES OF AEROSOL

Aerosol packs are must not be subjected to heat since high pressures can develop most pharmaceuticals should not be exposed to heat in any case.

Toxicity of propellants.

Catalytic oxidation of drugs such as ascorbic acid and epinephrine has been caused by traces of metal from valve parts of container.


COMPONENTS OF AEROSOLS

Components of Aerosol Package are

1. propellant,

2. container,

3. valve, and actuator

4. product concentrate (concentrate containing the active ingredient's)

The nature of these components determines such characteristics as particle size distribution, uniformity of dose for metered valves, delivery rate, wetness and temperature of the spray, spray pattern and velocity or plume geometry, foam density, and fluid viscosity.


WHAT IS PROPELLANT

A propellant is a material that is used to move (“Propel") an object. The

material is usually expelled by gas pressure through a nozzle. The pressure may

be from a compressed gas, or a gas produced by a chemical reaction. The

exhaust material may be a gas, liquid, plasma, or, before the chemical reaction,

a solid, liquid or gelled.

The propellant supplies the necessary pressure within an aerosol system to expel

material from the container and, in combination with other components, to

convert the material into the desired physical form.


Common chemical propellants consist of a fuel; like gasoline, jet fuel, rocket fuel, and an

oxidizer.

In aerosol spray cans, the propellant is simply a pressurized gas in equilibrium with its

liquid. As some gas escapes to expel the payload, more liquid evaporates, maintaining an even

pressure.

Various types of propellants are utilized, while the fluorinated hydrocarbons such as

trichloromonofluromethane (propellant 11), dichlorodifluoromethane (propellant 12), and

dichlorotetrafluroethane (propellant 114) are found to be widespread use in most aerosols for oral

and inhalation use, topical pharmaceutical aerosols utilize hydrocarbons ( propane, butane, and

isobutene) and compressed gases such as nitrogen, carbon dioxide, and nitrous oxide.


WHY DO WE NEED A PROPELLANT

The contents of the aerosol are made up of two components:

1. The product, in the form of a liquid, emulsion or suspension.

2. The propellant, which can be a liquefied gas, or even a compressed gas.

The propellant is the driving force (or, you could say, the ‘ENGINE’), behind the

aerosol.


PROPELLANTS CLASSIFICATION

Propellants may be broadly classified LIQUEFIED GASES

COMPRESSED GASES

Propellants within this definition include various hydrocarbons, especially halogenated derivatives of methane, ethane, and propane, low molecular weight hydrocarbons such as the butanes and pentanes, and compressed gases such as carbon dioxide, nitrogen, and nitrous oxide.

Mixtures of propellants are frequently used to obtain desirable pressure, delivery, and spray characteristics.

A good propellant system should have the proper vapor pressure characteristics consistent with the other aerosol components.


Liquefied propellants are gases that exist as liquids under pressure. Because the

aerosol is under pressure the propellant exists mainly as a liquid, but it will also be in

the head space as a gas. As the product is used up as the valve is opened, some of the

liquid propellant turns to gas and keeps the head space full of gas. In this way the

pressure in the can remains essentially constant and the spray performance is

maintained throughout the life of the aerosol. The propellant is an essential element in

the formulation.

Compressed gas propellants really only occupy the head space above the liquid in the

can. When the aerosol valve is opened the gas 'pushes' the liquid out of the can. The

amount of gas in the headspace remains the same but it has more space, and as a result

the pressure will drop during the life of the can. Spray performance is maintained

however by careful choice of the aerosol valve and actuator.


In both of the examples above, you will see that the can is not full to the top with liquid. This is for safety reasons, as there must always be sufficient space for the propellant gas to occupy, under all likely storage conditions. If all the space in the can was full of liquid, there would be the possible danger of the can bursting.


LIQUEFIED PROPELLANTS

Liquefied propellants are gases that exist as liquids under pressure. Because the

aerosol is under pressure the propellant exists mainly as a liquid, but it will also be

in the head space as a vapour. As the product is used up as the valve is opened,

some of the liquid propellant turns to vapour and keeps the head space full of

vapour. In this way the pressure in the can remains essentially constant and the

spray performance is maintained throughout the life of the aerosol. The

propellant is an essential element in the formulation.


LIQUIFIED GAS

FLUORINATED HYDROCARBONS

Almost all types pharmaceuticals, Inhalation and oral use Advantages

– Chemical inertness – Lack of toxicity – Non flammability & explosiveness

Disadvantages

– High cost – It depletes the ozone layer – Damage Global Warming Potential


HYDROCARBONS

– Can be used for water based aerosols, topical use

Advantages

– Inexpensive

– Stability & Purity

– Odorless!!

– Wide range of Boiling Points

– Wide range of Vapor Pressure

– Low Toxicity

– Excellent solvents

– It does not cause ozone depletion

Disadvantages

– Flammable

– Unknown toxicity produced

e.g. propane , butane , isobutane


Recently HFA propellants are used instead of CFC

propellants.


COMPRESSED GAS PROPELLANTS

Compressed gas propellants really only occupy the head space above the liquid in

the can. When the aerosol valve is opened the gas 'pushes' the liquid out of the can.

The amount of gas in the headspace remains the same but it has more space, and as

a result the pressure will drop during the life of the can.

Unlike liquefied propellants, there is NO liquid to instantly vaporise when the

product emerges from the actuator, and only the product is sprayed out.


COMPRESSED GASES

Used when the aqueous phase need not be miscible with the propellant. Do not have chilling effect, for topical preparation .

Advantages

– Inexpensive

– Non flammable

– No environmental problems

Disadvantages

– Pressure falls during use

– Produce coarse droplet spray

– Require use of non volatile co solvent

e.g. CO2, N2O, N2


Liquefied Petroleum Gas (LPG)

Aerosol propellant grade LPG consists of high purity hydrocarbons derived directly from oil wells, and as a by-product from the petroleum industry.

They consist of a mixture of propane, isobutane and n-butane. These propellants are used in most aerosols today, and have been used for many years in household aerosol products.

These gases are flammable, and this is reflected in the classification of aerosols which contain them.

Di Methyl Ether (DME)

This is an alternative liquefied propellant, and is more common in personal care products, and some air fresheners

TYPICAL PROPELLANTS


Chlorofluorocarbons (CFCs)

These liquefied propellant gases used to be very common prior to the discovery that they

were affecting the ozone layer. They are no longer used in consumer aerosols in the western

world. They are however permitted in inhalation aerosols, as used in the treatment of asthma.

Non-soluble compressed Gasses. (e.g. Compressed Air and Nitrogen)

These are sometimes seen in consumer products, and are an environmental alternative to

LPG.

Soluble compressed Gasses (e.g. Carbon Dioxide)

This is another alternative to LPG, but has limited use, mainly with alcoholic systems,

such as air treatment products, deodorants and personal care products.


GENERAL REQUIREMENTS

1. Propellants used in aerosol products shall meet the relevant Standards of BIS

(Bureau of Indian Standards) pertaining to safety, quality and performance.

2. The manufacture must produce the consent clearance as per the provisions of

water (Prevention and Control of Pollution) act 1981 along with the

authorisation, if required under environment (Protection) Act 1986 and the

rules made thereunder to BIS while applying for Ecomark.

3. The product package shall be suitably marked that the Ecomark label is

applicable only to the propellants used in aerosol sprays, if the product package

is not separately covered under the Ecomark Scheme.


4. Product package or leaflet accompanying it may display instructions of proper use, storage and disposal so as to maximize the product performance, safety and minimize wastage.

5. The material used for product packaging shall be made from recyclable or biodegradable material.


BASIC PROPELLANT PROPERTIES



• Pressurize the aerosol package

• Influence the form in which the product is discharged:

Foam

Stream

Spray



Propellants also can act as:

• Solvent

• Diluent

• Viscosity modifier

• Freezant

• Refrigerant Refill Liquid


Chemical Name Numerical Vapour Pressure(psia) BP liquid Density(g/ml)

Designation 700 1300F 0F 0C 700F

Trichloromonofluoromethane

11 13.4 39.0 74.7 23.7 1.49

Dichlorodifluoromethane 12 84.9 196.0 -21.6 -29.8 1.33

Dichlorotetrafluroethane 114 27.6 63.5 38.4 3.6 1.47

Difluoroethane 152a 76.4 191.0 -11.2 -24.0 0.91

Butane A-17 31.6 82.0 31.1 -0.6 0.58

Isobutane A-31 45.8 111.0 10.9 -11.8 0.56

Propane A-108 122.8 270.7 -43.7 -44.6 0.50

PROPERTIES OF FLUOROCARBON AND HYDROCARBON PROPELLANTS PHYSICOCHEMICAL

PHYSICOCHEMICAL PROPERTIES OF FLUOROCARBON AND HYDROCARBON PROPELLANTS


Propellant Blend* Composition Vapour Pressure(psig) 700F Density (g/ml) 700F

12/11 50:50 37.4 1.412

12/11 60:40 44.1 1.396

12/114 70:30 56.1 1.368

12/114 40:60 39.8 1.412

12/114 45:55 42.8 1.405

12/114 55:45 48.4 1.390

Blends of Fluorocarbon Propellants for Pharmaceutical Aerosols


PROPELLANT EXAMPLES

CHLOROFLUOROCARBONS:-

propellant 12 (dichlorodifluoromethane), propellant 21 (dichlorofluoromethane),

propellant 114 (1,2-dichloro-1,1,2,2-tetrafluoroethane),

propellant 114a (1,1-dichloro-1,1,2,2-tetrafluoroethane),

propellant 142b (1-chloro-1,1-difluoroethane),

propellant 152a (1,1,-difluoroethane)


HYDRO CARBON PROPELLANTS:-

•Propane

•Isobutane

•Butane,

FLUOROCARBONS:-

• Octafluoropropane

• Octafluorocyclobutane

• Dimethyl ether

NON-CFC PROPELLANTS:-

Hydrofluoroalkanes:-

• Propellant 134a (1,1,1,2-tetrafluoroethane)

• Propellant 227 (1,1,1,2,3,3,3-heptafluoropropane).


THE MOLECULAR STRUCTURE OF PROPELLANT TO BE DERIVED FROM THE NUMERICAL DESCRIPTOR THE RULES

MAY BE LISTED AS FOLLOWS:

1. The digit on the extreme right e.g.: propellant 114 (1,2-dichloro-1,1,2,2-tetrafluoroethane) represents the number of chlorine atoms

2. The second digit from the right e.g.: propellant 114 (1,2-dichloro-1,1,2,2-tetrafluoroethane) represent one more than the number of hydrogen atoms

3. The third digit from the right propellant 114 (1,2-dichloro-1,1,2,2-tetrafluoroethane) represents one less than the number of carbon atoms.

4. The subscripted lowercase letter represent the symmetry of the molecule the earlier in the alphabet the more symmetrical the molecule being described e.g.; propellant 114a (1,1-dichloro-1,1,2,2-tetrafluoroethane)Two additional rules have not been required for pharmaceutical purposes but may be included for completeness

5. A forth number from the right indicates the number of double bonds in the

molecules.

6. A prefixed lowercase ‘c’ indicates that the molecule is cyclic


Vapor pressure of mixture of propellants is calculated by Dalton’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 law, which regards lowering of the vapor pressure of a liquid by the

addition of another substance, states that the depression of the vapor pressure of solvent

upon the addition of solute is proportion to the mole fraction of solute molecules in the

solution.


The relationship can be shown mathematically

To calculate the partial pressure of propellant A:

Pa=(na/na + nb)pA0=NApA0

Where: Pa = partial vapor pressure of propellant A, pA

o = vapor pressure of pure propellant A

na = mole of propellant A, nb = mole of propellant B NA = mole fraction of component A

To calculate the partial pressure of propellant B: Pb =(nb/nb + na)pB

0=NBpB0

The total vapor pressure of system is then obtained as : P = pa + pb

Where P = total vapor pressure of system


NONOZONE DEPLETING PROPELLANTS

The search for possible replacements for CFC for MID were defined in terms of toxicity, flammability, chemical, physical properties and environmental compatibility. The template for these properties, with the exception of environmental suitability, were the existing MDI propellants, CFC 11, 12 and 114, which had been safely and effectively for many years. The candidates that emerged were hydrofluoroalkanes (HFA) specifically, tetrafluoroethane (HFA 134a) and heptafluoropane (HFA 227) were recognized and potentially suitable MDI propellants. These were non-flammable, non-ozone depleting, and chemical stable propellants with suitable vapor pressures for MDI use.

Hydrofluoroalkanes contribute to the greenhouse effect but to a lesser extent than CFC indicated in the table. It has been estimated that HFA from MDIs will contribute less than 0.1% of total worldwide green house gas emission by 2005.(INTERNATIONAL PHARMACEUTICAL AEROSOL CONSORTIUM).


ENVIRONMENTAL IMPACT OF MDI PROPELLANTS

PROPELLANTS OZONE DEPLETION POTENTIAL

ATMOSPHERE LIFE (YEARS)

GLOBAL WARNING

POTENTIAL

CFC 11 1 60 1

CFC 12 1 125 3

CFC 114 0.7 200 3.9

HFA 134a 0 16 0.3

HFA 227 0 33 0.7


ADVANCES IN METERED DOSE INHALER TECHNOLOGY WITH THEDEVELOPMENT OF A CHLOROFLUOROCARBON-FREE DRUG

DELIVERY SYSTEM

More than 440 million MDIs are produced every year, and that number is

estimated to grow to 800 million by the year 2000. MDIs have traditionally

contained chlorofluorocarbons (CFCs) as propellants. Although safe for human

use, scientific evidence shows that chlorine atoms in CFCs deplete the earth's

stratospheric ozone layer, which filters out the sun's harmful ultraviolet

rays. Over 144 signatory countries are now complying with the protocol in

banning the production of CFCs. Production of most CFCs in developed

countries ceased in January 1996. Intensive research led to the identification of

suitable alternative propellants and, ultimately, to the selection and development

of hydrofluoroalkane (HFA) 134a as the first nonozone- depleting MDI

propellant.


ADVANCES IN MDIs TECHNOLOGY WITH CFC-FREE SYSTEMS

The standard first-line therapy for acute relief of asthma

symptoms is the use of beta-agonists, and the most widely used

compound in this class is Salbutamol (Albuterol). For this

reason, Salbutamol was the first bronchodilator considered for

reformulation in a new CFC-free system. 3M Pharmaceuticals

developed the first CFC-free MDI containing Salbutamol

sulfate in an HFA- 134a propellant system.


ADVANTAGES

1. Consistent dosing through the end of canister life

2. Consistent dosing at all storage orientations

3. Reliable dose delivery at low temperatures(This can be of

concern to patients who live or work in environments where

the temperature is considerably lower than room temperature

or to those who use their inhalers for cold-induced asthma

symptoms.)


CFC DISADVANTAGE

1. CFC products also tend to produce a cold blast

striking the back of a patient's throat, resulting in

patient discomfort and poorer drug delivery.

2. Dosing could be inconsistent toward the end of

the life of the container and was sensitive to

temperature extremes, storage time.


INTEGRATING CHEMISTRY AND PROCESS

This research program seeks to tackle HFC reformulation challenges from two aspects:

1. Characterizing the surface interaction between the formulation components, and

2. Introducing process benefits by integrating chemistry with new milling techniques to improve HFC dispersions of MDI medicaments.


ULTIMATE GOALS

The ultimate goals are:To use a fundamental understanding, rather than a trial-and-

error, reformulation approach Integrate formulation and process development, and

Accomplish HFC performance equivalent to CFC performance in MDIs Research has proceeded in two phases.

The first phase evaluates

Chemistry of formulation components with various asthma medicaments.

The second phase

Advances optimized formulations to processing in a high-pressure media mill.


FORMULATION CHEMISTRY

Experiments were conducted to understand interactions of the

basic MDI formulation

Drug active

Surfactant

Co-solvent

Propellant

In doing so, each formulation component was characterized by

certain physical properties judged to be important to the surface

interactions.


The MDI medicaments were characterized by:log POW (Octanol-water partition coefficient)DensityParticle sizeSurface energyMorphology

The propellants were characterized by:DensityDielectric constant

The surfactants were characterized by:Head/tail structureMolecular weightChemistry


PHYSICAL PROPERTIES FOR THE PROPELLANTS

HFC 134a HFC 227ea

Boiling Point °C -26.1 -15.6

Vapor Pressure @ 25°C

Bar 6.7 4.5

Liquid Density @ 25°C

g/cc 1.2 1.4

Dielectric Constant

- 9.5 4.1

Dipole Moment D 2.1 0.9

This high-pressure media milling (HPMM) process yields stable, fine particle dispersion of medicament in liquid HFC propellant. The milling is performed with the entire MDI formulation so that surfactants and cosolvents are available to the drug actives during the milling process. Milling is believed to increase dispersion stability because having the surfactant available during milling results in improved deposition or adsorption onto the surface of the medicament particles as they are milled.


A second advantage for HPMM process using HFC propellant as the medium is that, when milling is complete, it is the final formulation that is available. Conceptually, the batch in the mill can be filtered and directly packaged to the MDI container, offering a potential improvement in commercial processing productivity, cost and quality.

The HPMM process produces medicament dispersions in liquefied HFC propellant that are stable for long periods of time and that are easily re-suspended if they do settle.


IDEAL PROPERTIES

The ideal propellant for use in an MDI will exhibit the

following properties:

Non-toxic

Inert and unreactive in the formulation

Chemically stable under a range of conditions

High purity

Acceptable taste and odor


CONCLUSION HFAs provide a safe alternative to CFCs as propellants in these

devices but their physicochemical properties have required

extensive redevelopment of the entire product.

HFAs are not environmentally neutral and contribute to

hydrocarbon emissions, global warming and acid rain. Nevertheless,

the contribution of HFAs to environmental damage is considered to

be comparatively small and the health benefit of drugs formulated

using HFAs currently outweighs the environmental concerns, but

this may not continue indefinitely.

The technical challenge to reformulate MDIs has almost

been achieved and the next challenge is the transition of patients

from CFC-MDIs to the new products.


1. Leon lachmen,Herbert A.Lieberman,Joseph L. kanig “the theory and practice of Industrial pharmacy” third edtion 589-618

2. E.A.raulins “Bentley’s Text book of pharmaceutics” eighth edition 669-684

3. Gilbert S.banker,christopher T.rhodes “Modern pharmaceutics” Third edition 547-554

4. James Swerbrick,James C.Boylon “Encyclopedia of pharmaceutical technology” volume 2 second edition 1735-1752

5. M.E.Aulton “Pharmaceutics the scince of dosage form design” second edition 473-489

6. Philip d Gerbino “Remingtons The science and practice of pharmacy” volume 1 21st edition 1000-1017


INTERNET LINKShttp://en.wikipedia.org/wiki/Aerosol_sprayhttp://www.yorks.karoo.net/aerosol/link4.htmhttp://www2.dupont.com/Medical_Device_Materia/en_US/assets/downloads/metered_dose.pdfhttp://ww.aboutaerosols.com/industry.phphttp://www2.dupont.com/Medical_Device_Material/en_US/assets/downloads/metered_dose.pdfhttp://www.liebertonline.com/doi/abs/10.1089/jm.1999.12.151http://en.cnki.com.cn/Article_en/CJFDTOTALGWYZ200803012.htm http://www.docstoc.com/docs/13418747/ECOMARK-CRITERIA-

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propellents

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personal care products

remains essentially constant

soluble compressed gasses

head space full

liquid propellant turns

dosage forms

active ingredients

headspace remains