DIKTAT KULIAH

SISTEM PENGHANTARAN OBAT

BAGIAN

AEROSOL SEBAGAI SISTEM PENGHANTARAN OBAT

AEROSOL DRUG DELIVERY SYSTEM

DISUSUN OLEH :

Dr. FEBRIYENTI, M.Si.,Apt.

NIP. 19740210 200501 2001

FAKULTAS FARMASI
UNIVERSITAS ANDALAS
PADANG
2019
 KATA PENGANTAR

Berkat rahmat Allah SWT, diktat Aerosol sebagai Sistem Penghantaran Obat
yang dirancang untuk melengkapi diktat kuliah Sistem Penghantaran Obat akhirnya
dapat diselesaikan.
Aerosol adalah salah satu sistem penghantaran yang dapat menghantarkan obat
dalam bentuk dispersi padatan atau cairan dalam gas. Teori-teori tentang aerosol
diuraikan dalam diktat ini. Kemudian aplikasinya pada sistem aerosol untuk permukaan
dan untuk paru-paru juga diuraikan sebagai contoh pemakaiannya. Materi diktat dikutip
dari buku-buku teks dan aktualisasi materi diambil beberapa kutipan dari jurnal ilmiah.
Diktat ini masih jauh dari sempurna. Namun semoga ada manfaatnya, kritik yang
membangun terhadap isi diktat akan sangat dihargai.

Padang, 10 September 2019

Penyusun

Dr. Febriyenti, M.Si.,Apt.

NIP. 19740210 200501 2001
 LIST OF CONTENT

Page

CHAPTER 1 1

1.1 Aerosol 1

1.2 Aerosol Formulation 18

CHAPTER 2 20

2.1 Evaluation of Aerosol Concentrate 20

2.2 Selection of Final Aerosol Concentrate 22

2.3 Aerosol Evaluation 24

CHAPTER 3 28

REFERENCES 32
 CHAPTER 1
INTRODUCTION

1.1 AEROSOL

Aerosol dosage form for oral and topical application was developed for use in the

mid-1950s. Since that time it has found widespread acceptance because of its ease of use

and therapeutic efficacy. The first textbook devoted exclusively to the subject of aerosol

science and technology appeared in 1958 and was authored by Herzka and Pickthall

(Sciarra, 1974).

Pharmaceutical aerosols are dosage forms containing therapeutically active

ingredients intended for topical administration, introduction into body cavities or by

inhalation via the respiratory tract (Sciarra and Cutie, 1990b). The dosage form is

packaged in a metal or glass container and sealed with either a metered or continuous-

spray valve. The aerosol product itself consists of four components: concentrate

(containing the active ingredient(s), propellant(s), container and valve-actuator (Sciarra,

1976). The propellant provides the internal pressure that forces the product out of the

container when the valve is opened and delivers the product in its desired form. For

metered dose inhalers (MDIs) the product is delivered as a finely dispersed mist

(particles less than 8 µm in diameter). Topical aerosol delivers its content as a spray,

foam, or semisolid (Sciarra, 1996; Sciarra and Stoller, 1974).

Topical pharmaceutical aerosols have been accepted by both patients and

physicians because of their aesthetic properties, ease of application, maintainability of

sterility (if the package is sterile), tamperproof system, prevention of contamination of

the unused contents, and increased stability. Topical aerosols have been dispensed as

sprays, foams, and semisolids. When applied to the body they avoid or reduce pain that

normally may result from the mechanical rubbing of ointments and creams onto the skin.
Through use of a metered dose valve, an accurate amount of medication can be

dispensed each time the valve is actuated. Topical products that have been formulated as

aerosol include first-aid products containing local anaesthetics and antiseptics, adhesive

tape removers and bandage adherents, products used in athletic and sports, burn

remedies, foot preparations, germicidal and disinfectant products, spray-on bandages,

protective, topical dermatologic, including antibiotics and steroids, veterinary products,

body liniments and rubs, products for vaginal and rectal applications which include

contraceptive foams and rectal foams, edible foams and saline solutions to cleanse

contact lenses (Sciarra, 1996; Sciarra and Stoller, 1974).

1.1.1 Concentrate

The concentrate can be of the solution, dispersion, emulsion, or semisolid type.

The concentrate is made up of active ingredient(s) and may include solvent(s) and

dispersing agent. Depending on the type of product, various inert ingredient(s) are used

as additive(s) to prepare solutions, suspensions, and emulsions (Sciarra, 1996; Sciarra

and Stoller, 1974).

(a) Solution Systems

This type of aerosol system consists of two distinct phases: liquid and vapour.

The solvent is used to dissolve the active ingredient and/or to retard the evaporation

of the propellant. Solution aerosols are relatively easy to formulate, provided that the

ingredients are soluble in the propellant. However, the liquefied gas propellants are

nonpolar in nature and in most cases are poor solvents for some of the commonly

used medicinal ingredients. Through use of a solvent that is miscible with the

propellant, one can achieve varying degrees of solubility. Ethyl alcohol has found
widespread use for this purpose. Other solvents use in pharmaceuticals may also be

used with topical aerosols (Sciarra, 1996).

When the valve of a solution aerosol is depressed, a mixture of active

ingredients, solvents, and propellants which has a very high vapour pressure is

forced and emitted into the atmosphere. As the liquid propellant encounters the

surrounding atmospheric (very much lower vapour pressure) air, it tends to vaporize

and, in so doing, breaks up the active ingredients and solvents into fine particles.

Depending on their size, the particles remain suspended in air for relatively long

period of time. The particles sizes of aerosol can vary from as small as 5 to 10 µm or

less to as large as 50 to 100 µm (Sciarra and Stoller, 1974). The size of aerosol

droplets produced will depend on the nature of the propellant, the amount of

propellant, the nature of the product concentrate, and the valve design. Metered-dose

inhalers require particles of less than 8 µm whereas nasal aqueous aerosols generally

have particles in the range of 50 to 75 µm. Topical aerosols have a particle size of

about 100 µm (Sciarra, 1996).

Table 1.1: Prototype formulation for topical aerosol solutions (Sciarra and Cutie,
1990b)

Active ingredient(s) Dissolved in system

Solvents Ethyl and isopropyl alcohol
Glycols
Isopropyl esters
Surfactants
Antioxidants Ascorbic acid
Preservative Methyl and propyl parabens
Propellant(s) Isobutane
Propane/butane
Propane/isobutene
Propellant 22
Propellant 152/142
Propellant 22/142
Dimethyl ether
(b) Suspension systems

For substances that are insoluble in the propellant or the mixture of

propellant and solvent, or in cases where a cosolvent is not desirable, the active

ingredients can be suspended in the propellant vehicle. When the valve is depressed,

the suspension is emitted, followed by rapid vaporization of the propellant, leaving

behind the finely dispersed active ingredients. This system has been used

successfully to dispense anti-asthmatic aerosol as well as topical aerosol containing

antibiotics. However, the formulation of this type of aerosol is not without difficulty.

Problems involving caking, agglomeration, particle size growth and clogging of the

valve arise (Sciarra and Stoller, 1974). Salt of the active ingredient having very low

solubility or not soluble in the propellant and solvents should be selected. It is the

slight solubility of the active ingredients in the propellants and solvents that

contributes to particle size growth. This phenomenon, known as Ostwald Ripening

occurs because the small particles have higher equilibrium solubility than larger

particle of the same substance. These small particles will gradually dissolve and

deposited onto the surface of the larger particles, resulting in an increase in the

particle size of the originally micronized active drug substances. By adjusting the

density of both the propellant and/or the insoluble material so that they are

approximately equal, the rate of sedimentation can be reduced substantially. This

can be accomplished by using a mixture of different propellants of varying densities

as well as by addition of an inert powder to the active ingredients. Final

consideration should be given to the use of a surfactant or dispersing agent. Sorbitan

oleate, lecithin, oleic acid, and oleyl alcohol have been used in oral and metered-

dose inhalers; isopropyl myristate has been used primarily in topical aerosols.

Although it may be easier to formulate a solution system compared to a suspension

 system, the latter is generally preferred because one can obtain closer control over

the particle size distribution of droplets dispersed in the suspension aerosol.

Suspensions generally show greater stability of the active ingredient as compared

with solution (Sciarra, 1996; Sciarra and Stoller, 1974).

Table 1.2: Prototype formulation for topical aerosol suspensions (Sciarra and Cutie,
1990b)

Active ingredient(s) Pass through a 325 mesh screen

Dispersing agents Isopropyl myristate
Mineral oil
Sorbitan esters
Polysorbates
Glycerol ethers and derivatives
Propellant(s) 12/11; 12/114 (only if exempted)
Hydrocarbons
142, 152, 22
Dimethyl ether

(c) Emulsion systems

Water and hydrocarbon or fluorinated hydrocarbon propellants are not

miscible. In order to formulate a suitable aerosol using these materials, various

techniques can be used. An emulsion aerosol consists of active ingredient(s), aqueous

or non aqueous vehicle, surfactant and propellant. Depending on the choice of

ingredients, the product can be emitted as stable or quick-breaking foam or as a spray

(Sciarra, 1996; Sciarra and Stoller, 1974).

Table 1.3: Prototype formulation for topical aerosol emulsions/foam (Sciarra and
Cutie, 1990b)

Active ingredient(s) Solubilised in fatty acid, vegetable oil, glycol

Emulsifying agents Fatty acid soaps (triethanolamine stearate)
Polyoxyethylene Sorbitan esters
Emulsifiable waxes
Surfactants
Other modifiers Emollients
Lubricants
Presevatives
Perfumes
Propellant(s) 12/114 (only if exempted)
Hydrocarbons
22/152
22/142
152/142
Dimethyl ether

(i) Foam system

The propellant used in an emulsion is an important part of this system

and determines the type of foam produced. The propellant is generally considered

part of the immiscible phase and as such can be in the internal or external phase.

When the propellant is included in the internal phase, typical stable or quick-

breaking foam is emitted. When the propellant is in the external phase, the

product is dispensed as a spray (Sciarra, 1996; Sciarra and Stoller, 1974).

(ii) Stabilized foams

In an emulsion system where the propellant is in the internal phase

(generally part of the oil phase of the emulsion), water makes up the external or

dispersing phase. The propellant is generally used to the extent of about 7% to

10% of the total weight. When a hydrocarbon propellant is used (such as

isobutane/propane blend) as little as 3% to 4% is sufficient to produce suitable

foam. These propellants are emulsified in the aqueous or nonaqueous emulsion.

Some of the propellant will vaporize in the container and be present in the head
 space to produce the necessary vapour pressure. The pressure should be

approximately 40 psig, depending on the propellant used. When the valve is

depressed, the pressure provided by the vaporised propellant forces the emulsion

up the dip tube and out the valve. The low atmospheric pressure cause the

propellant trapped in the emulsion droplets to expand and vaporises to form

stable foam, e.g. shaving foams (Sciarra, 1996; Sciarra and Stoller, 1974).

(iii) Quick-breaking foams

These foams consist of ethyl alcohol, water, and a surfactant that is

soluble in either alcohol or water but not in both. Other miscible solvents can be

used in place of alcohol and water. The surfactant can be non-ionic, anionic, or

cationic. The product is dispensed as foam but quickly collapse, so that there is

no further injury by mechanical dispersion of the product.

Steroid, burn, and other topical preparations can be applied in this manner.

One advantage of a foam system over an aerosol system is the fact that the area

with which the product comes into contact is limited or can be controlled.

Preparations containing irritating ingredients may also be dispensed in this

manner. The incidence of airborne particles can be substantially reduced, thereby

lowering the incidence of toxicity of the sprayed products which may cause

irritation on release and may be inhaled (Sciarra, 1996; Sciarra and Stoller, 1974).

(iv) Spray emulsion

The base for this product is a water-in-oil emulsion. A fairly large amount

of propellant (about 25% to 30%) is miscible with the outer oil phase so that the

propellant remains in the external phase of the final emulsion. When this system

is dispensed, the propellant vaporizes, leaving behind droplets of water-in-oil

emulsion with no foaming. Because the propellant and concentrate phase tend to
 separate on standing, products formulated using this system must be shaken

before use. A hydrocarbon propellant or a mixed hydrocarbon/fluorocarbon

propellant is preferred for this system, because the specific gravity of the

propellant is less than 1 and the propellant will float on the aqueous layer. In

addition, such systems use a vapour tap valve, which tends to produce finely

dispersed particles (Sciarra, 1996; Sciarra and Stoller, 1974).

1.1.2 Propellants

The propellant can be either a liquefied or a compressed gas. The propellant is

responsible for developing the proper pressure within the container and for expulsion of

the product when the valve is opened. It also is responsible (together with the valve) for

dispensing the product as a spray, foam, or semisolid. Various types of propellants are

utilized. The fluorinated hydrocarbons, such as trichloromonofluoromethane (propellant

11), dichlorodifluoromethane (propellant 12), and dichlorotetrafluoro-ethane (propellant

114) found widespread use in most aerosol for oral, nasal, and inhalation use. Topical

pharmaceutical aerosols utilize hydrocarbons (propane, butane, and isobutene) a limited

number of hydrofluorocarbons and hydrochlorofluorocarbons (142b, 152a, 22), and

compressed gases such as nitrogen and carbon dioxide (Sciarra, 1996; Sanders, 1979).

(a) Chlorofluorocarbons (CFCs)

The use of chlorinated fluorocarbons for aerosols and other commercial uses

has been seriously curtailed and, in certain cases, banned. These compounds have

been implicated in causing a depletion of the ozone layer and partially responsible for

the “greenhouse” effect (increase in earth’s temperature, rising sea levels, and altered

rainfall patterns) (Sciarra, 1996).

 Prior to 1978, fluorinated hydrocarbons were used almost exclusively as the

propellants for all types of pharmaceutical aerosols. Their chemical inertness, lack of

toxicity, lack of flammability and explosiveness and their safe record of use made

them ideal candidates for use. The publication of the “ozone depletion theory” in the

mid-1970s, however, and the alleged implication of the fluorocarbons in depleting

the ozone levels in the atmosphere, led to the phasing out and ban of the use of

fluorocarbon propellants in aerosols (with few exceptions) in 1978. This ban,

promulgated by the Environmental Protection Agency (EPA), Food and Drug

Administration (FDA) and the Consumer Products Safety Commission, became fully

effective in April 1979, when manufacturers could no longer ship aerosol products

containing fluorocarbons unless the product carried a specific federal exemption.

While some propellant manufacturers indicated that there were other suitable

replacements for propellants 11, 12, and 114, the only ones that have survived the

necessary toxicity tests (long- and short-range) are fluorocarbons 152a, 142b and 22

which may be of limited value. The other alternatives include hydrocarbons,

compressed gases, and mechanical devices and pumps. Of these alternatives,

hydrocarbons were restricted to use with foams and water-based aerosols while

compressed gases were of limited value in aqueous products where the propellant

and water were not miscible. When compressed gases overcame the immiscibility of

the components, other problems such as loss of propellant and to a lesser degree the

change in the dispersion of the spray became apparent. Since compressed gas

systems do not have chilling effect, they are applicable to topical preparations. With

the development of newer valve technology (the vapour tap and the Aquasol valve),

it was found that hydrocarbon propellants, such as butane, propane, isobutene and

their mixtures could be safely used not only with aqueous products but with solvent-
 based aerosol as well. At present, hydrocarbons can be used for all types of topical

aerosols (Sciarra and Cutie, 1986).

All MDIs marketed prior to 1995 contained CFCs as a propellant. These are

also implicated in the depletion of stratospheric ozone. Except for some specific

exemptions; their production has been banned since 1996 under the terms of the

Montreal Protocol (UNEP, 2000). Hydrofluoroalkanes have been identified as

suitable alternatives for MDI propellants but their physico-chemical properties differ

significantly from CFCs and an extensive redevelopment and testing programme has

been required to demonstrate the safety, quality and efficacy of hydrofluoroalkanes

(HFAs) containing MDIs. HFAs contribute to global warming but the benefit to

human health through continued MDI availability currently outweighs the

environmental concern. Several HFA-MDIs have reached the market and the

transition to replace existing CFC-MDIs is now underway (Smyth et al., 2005;

McDonald and Martin, 2000).

(b) Hydrochlorofluorocarbons and hydrofluorocarbons

Topical pharmaceutical products must be formulated using a propellant other

than the chlorofluorocarbons. For this purpose, a series of hydrochlorofluorocarbons

and hydrofluorocarbons are available. These propellants do not present a hazard to

the environment and can be used successfully to formulate topical pharmaceuticals.

Table 1.4 illustrates these propellants along with some of their more useful

physicochemical properties. As can be seen from Table 1.4, these propellants have

suitable vapour pressures making them useful for a variety of different products.

Propellant 152a and 142b may be blended to yield a vapour pressure within the

useful range of from 35 to 50 psig. They may also be blended with propellant 22 to
 give the desired nonflammability to the final mixture as well as to obtain a higher

vapour pressure (Sciarra, 1996).

Table 1.4: Propellants useful for topical pharmaceutical aerosol

Propellant Propellant
Designation Propellant 22
142b 152a
Formula CHClF2 CH3CClF2 CH3CHF2
Molecular weight 86.5 100.5 66.1
Boiling Point, 0F (0C) -41.4(-40.8) 14.4(-9.44) -11.2(-23.0)
Vapour pressure (psig), 70 0F 121 29 62
Vapour pressure (psig), 130 0F 297 97 176
Density (g/mL), 70 0F 1.21 1.12 0.91
Solubility in water (wt.%), 70 0F 3.0 0.5 1.7
Kauri-butanol value 25 20 11
Flammability limits in air (vol.
%) Nonflammable 6.3-14.8 3.9-16.9
Flash point, 0F - - -

(c) Hydrocarbons

The hydrocarbon propellants; butane, propane, and isobutene have replaced

the chlorofluorohydrocarbons as the propellant for most consumer aerosol products

(other than MDIs). They have also been used for topical pharmaceuticals. They are

ideal for use with foams because they are nontoxic, nonreactive, and relatively

inexpensive. They yield satisfactory foam and are environmentally acceptable. The

chief drawback to their use is their flammability. However, this is of greater concern

to the manufacturer than to the consumer. The advantage of hydrocarbons is their

greater range of solubility and lower cost compared to fluorinated hydrocarbons.

Their density of less than 1 and their immiscibility with water, make them useful in

formulation of three-phase (two-layer) aerosols. Being lighter than water, the

hydrocarbon remains on top of the aqueous layer and serves to push the contents out

of the container. They are not subject to hydrolysis, making them useful with water-

based aerosols (Sciarra and Cutie, 1990a).

 Table 1.5: Selected properties of hydrocarbons and dimethyl ether

Designation Propane Isobutane n-Butane DME

Formula C3H8 i-C4H10 n-C4H10 CH3OCH3
Molecular weight 44.1 58.1 58.1 46.07
Boiling Point, 0F (0C) -43.7(-42.0) 10.9(-11.7) 31.1(-0.56) -12.7
Vapour pressure (psig), 109 31 17 63
70 0F
Vapour pressure (psig), 257 97 67 174
130 0F
Density (g/mL), 70 0F 0.50 0.56 0.58 0.66
Solubility in water 0.01 0.01 0.01 34
(wt.%), 70 0F
Kauri-butanol value 15 17 20 60
Flammability limits in 2.2-9.5 1.8-8.4 1.8-8.5 3.4-18
air (vol.%)
Flash point, 0F -156 -117 -101 -42

As can be seen in Table 1.5, they all have a density of about 0.5 to 0.6 g/mL

and therefore less is required as compared to a fluorocarbon (generally 1.2 to 1.4

g/mL). They can also be blended with each other and with hydrochlorofluorocarbons

and hydrochlorocarbons so as to obtain different vapour pressures. Recently,

dimethyl ether has been used to formulate aerosols. As can be seen in Table 1.5, its

main advantage over all other materials used in aerosol formulations is its rather high

miscibility with water (about 34%). This allows the formulator greater flexibility in

developing different types of aerosol systems (Sciarra, 1996).

(d) Compressed gases

The compressed gases nitrogen, nitrous oxide, and carbon dioxide are limited

in use. They are used in those cases where large quantity of water is present and the

product must be dispensed as a spray. Such is the case with contact lens cleaners.

Nitrogen is used because its inertness and its lack of solubility and miscibility with
water. It is used to push the contents out of the container and to dispense a fine

stream of solution that can be directed to the contact lens. Nitrous oxide and carbon

dioxide are used with products where solubility of the gas in the product is desirable.

Their main use at the present time is with foams. Table 1.6 indicates some of the

other properties of these gases. Unlike liquefied gases, there is a drop in pressure as

the contents of a product using compressed gas as propellant are dispensed (Sciarra,

1996). Since compressed gases are utilized in the gaseous state and not in the liquid

state which may act as depot for the propelling gas, a higher initial pressure is

required, as well as a relatively larger head space as in liquefied-gas aerosols. While

the pressure of a liquefied-gas aerosol remains constant during use because the

pressure is not influenced by the head space but by the mole ratio of the gas which

remain constant during use and the gas is constantly replaced by the evaporating

propellant liquid. A drop in pressure is noted during use of a compressed-gas aerosol

because the gas pressure drop as the volume of head space increase (Sciarra and

Cutie, 1990a).

Table 1.6: Properties of the compressed gases

Carbon Nitrous
Designation Nitrogen
dioxide oxide
Formula CO2 N2O N2
Molecular weight 44.0 44.0 28.0
Solubility in water (%w/w, 70 0F,
100 psig) 1.5 0.7 -
Solubility in isobutene 5.3 7.3 -
Solubility in ethyl alcohol 5.6 5.7 -
Solubility in Propellant 11 3.5 4.9 -
 For safety reasons, the package should not be filled full to the top with liquid or

concentrate. There must always be sufficient space for the propellant gas to occupy. The

actual amount of liquid or concentrate that can be filled into an aerosol container is

controlled by legislation, and there has to be a greater head space when using

compressed gas propellants.

1.1.3 Containers

The concept of an aerosol originated as early as 1790, when self-pressurized

carbonated beverages were introduced in France. In 1837, Perpigna invented a soda

siphon incorporating a valve. Metal aerosol cans on the other hand were being

introduced and tested as early as 1862. They were constructed from heavy steel and were

too bulky to be commercially successful. In 1899, inventors Helbling and Pertsch

patented aerosols pressurized by methyl and ethyl chloride as propellants. Department of

Agriculture researchers, Lyle Goodhue and William Sullivan, developed a small aerosol

can pressurized by a liquefied gas (a fluorocarbon) in 1943 (Bellis, 1997; Stoller, 1974).

In 1949, Robert H. Abplanalp’s invention of a crimp on valve enabled liquids to

be sprayed from a can under the pressure of an inert gas. In 1953, Robert H. Abplanalp

patented his crimp-on valve "for dispensing gases under pressure." In the mid-1970s,

concern over the use of fluorocarbons adversely affecting the ozone layer drove

Abplanalp back into the lab for a solution. Robert H. Abplanalp invented both the first

clog-free valve for aerosol cans and the "Aquasol" or pump aerosol, which used water-

soluble hydrocarbons as the propellant source (Bellis, 1997).

(a) Glass

Glass bottle are not recommended for suspension aerosol because of the

visibility of the suspended particles may present an aesthetic problem for the patient.
 Glass, being inert, has always been preferred for use with all types of

pharmaceuticals, but with the advent and introduction of many newer materials, glass

has been replaced by aluminium containers for most aerosols.

Glass does have several advantages (Chapman, 2004):

(i) It is inert to most medicinal products

(ii) It is impervious to air and moisture

(iii) It allows easy inspection of the container contents

(iv) It can be coloured to protect contents from harmful wavelengths of light

(v) It is easy to clean and sterilized by heat

(vi) It is available in variously shaped containers

The disadvantages of glass (Chapman, 2004) are:

(i) It is fragile: glass fragments can be released into the product during transport or

contaminants can penetrate the product by way of cracks in the container.

(ii) Certain types of glass release alkali into the container contents.

(iii) It is expensive when compared to the price of plastic.

(iv) It is heavy resulting in increased transport costs.

The chemical stability of glass for pharmaceutical use is governed by the

resistance of the release of soluble minerals into water contacting the glass. This

is known as the hydrolytic resistance. Details of four types of glass are given in

the BP (2007) and Ambrosio (2002).

(b) Aluminium

Aluminium is extremely lightweight and also is essentially inert. Aluminium

can be used without an internal organic coating for certain aerosol formulations
 (especially those that contain only active ingredient and propellant) but many are

available with an internal coating made from an epon- or expoxy-type resin (Sciarra,

1996; Sciarra and Cutie, 1986).

(c) Tin-Plated steel

These containers are used for most nonpharmaceutical aerosol and are the

least expensive and most versatile of all containers (Sciarra, 1996; Sciarra and Cutie,

1986).

(d) Other container

There are many additional container systems available that allow for special

dispensing of some product. The viscosity of the product, incompatibility of the

product concentrate and propellant and desired dispensing characteristics of the

finished product represent a few of the reasons why the typical aerosol systems may

be unsuitable (Sciarra, 1996; Sciarra and Cutie, 1986).

1.1.4 Valves

A Valve is an important component of all aerosols and is responsible together

with the propellant for the delivery of the product in the desired form whether as a spray,

foam, semisolid, or as a fine mist having particles below 8 µm that suitable for inhalation

(Sciarra, 1996; Sciarra and Cutie, 1986).

(a) Metered Valves

Metered valves, fitted with a 20 mm ferrule, are used with glass bottles and

aluminium canisters for all MDIs (Sciarra, 1996).

(b) Continuous-Spray Valves

 These valves are used primarily with topical pharmaceuticals. Table 1.7

indicates some of the commonly used materials for each of the subcomponents.

These materials must be tested with the specific formulation in order to determine its

compatibility with the formulation. Leakage and/or absorption (or adsorption) of the

active ingredient are sometimes noted with these valves and generally can be

overcome through proper selection of the material of construction (Sciarra, 1996;

Sciarra and Cutie, 1986).

Table 1.7: Materials used in valve construction

Subcomponent Material
Actuator (button, spout) Polypropylene, polyethylene
Mounting cup Tinplate, aluminium
Mounting cup gasket Flowed-in or polyethylene sleeve
Stem Nylon, delrin, acetal
Stem gasket Buna N, neoprene, butyl
Spring Stainless steel-passivated, stainless steel
Body Nylon, delrin, acetal
Dip tube Polyethylene, polypropylene

Depending on the design of the actuator or spout, the product can be

dispensed as a spray, foam, or semisolid (Sciarra, 1996; Sciarra and Cutie, 1986).

1.2 AEROSOL FORMULATION, MANUFACTURING PROCEDURE AND

QUALITY CONTROL

An aerosol formulation consists of two essential components: product concentrate

and propellant. The product concentrate consists of active ingredients, or a mixture of

active ingredients and other necessary agents such as solvents, antioxidants and

surfactants. The propellant may be a single propellant or a blend of various propellants

and is selected to give the desired vapour pressure, compatibility and dispensing

characteristics (Sciarra, 1996; Sciarra and Cutie, 1986).

Both manufacturing procedures and packaging must be considered

simultaneously, as part of the manufacturing operation takes place during the packaging

of the product. The concentrate, which contains the active ingredients, solvents and

cosolvents, other inert ingredients and may even contain a small portion of the propellant

are compounded separately and then mixed with the remainder of the propellant. Two

methods are available for use that includes a cold-fill and a pressure-fill method. Present-

day technology and the availability of good equipment give preference to the pressure

method over the cold-fill method. Less propellant may escapes into the atmosphere from

the pressure fill method thus is more environmentally friendly (Sciarra, 1996).

A quality control system for aerosol is no different from the system used for

nonaerosol pharmaceuticals except that several in-process tests are necessary in order to

ensure that the concentrate has been properly prepared. In most cases this will include an

assay to determine the level of active ingredient present. Other tests are dependent on the

nature of the product. Weights of both the concentrate and the propellant must be

checked routinely throughout the manufacturing process. Any errors and variation will

affect the strength of active ingredient present in the final product and will result in

product’s rejection. Other essential tests that must be carried out on topical aerosol

include: pressure, weight loss, delivery-amount/second, specific gravity, density,

viscosity, interaction of product with valve, interaction of product with container, aerosol

valve discharge rate, spray pattern, net contents, particle size, leakage and others

depending on nature of product (Sciarra, 1996; Sciarra and Cutie, 1986).

Aerosol to be formulated in this study is a drug delivery system which delivers

spray-bandage. Aerosol sprayed on the wound surface would release the active
ingredient and additives onto the wound and form a thin layer of bandage that would

cover and protect the wound. The aerosol to be formulated would contain the suitable

type and amount of film-forming polymer and plasticizer which could produce the

proper film for covering the wound and function as dressing.

Films prepared from pure polymers frequently are brittle and crack on drying. To

correct this deficiency, the polymer can be chemically modified or other ingredients can

be added to make the film more pliable. As a general rule, the film will become more

flexible and more resistant to mechanical stress when a plasticizer is added to a film

composition. There is an optimal concentration of plasticizer to be used for any film

composition (Seitz, 1988).

 CHAPTER 2
EVALUATION OF AEROSOL

2.1 Evaluation of aerosol concentrates

(a) Measurement of pH and density

The pH of each concentrate or dispersion was measured with a pH meter

(Corning Scientific Products, New York). The density of each concentrate or dispersion

was measured at room temperature by using a glass pycnometer (specific gravity bottle)

(BP, 2007). The density was determined by dividing the weight of the quantity of the

liquid being examined that fills a pycnometer at room temperature by the weight of water

required filling the pycnometer (BP, 2007).

(b) Determination of surface tension

The surface tension of each concentrate or dispersion was determined by using a

Du-Nouy Torsion Balance (Model OS, White Elect. Inst. Co. Ltd, England) at room

temperature (García et al., 2004; Martin et al., 2001).

(c) Evaluation of rheological properties

The rheological properties of each aerosol concentrate were determined at room

temperature by using a rheometer (Reologica Instrument AB version 5.0.40.38) equipped

with a concentric cylinder CC 25 measuring system. About 16 ml of each concentrate

sample was carefully poured into the cylinder. The flow profile and viscosity of each

aerosol concentrate was determined at the following settings: stress from 1 – 10 Pa, delay

time 5.000 s, and integration time 2.000 s.

(d) Determination of particle size distribution

The particle size distribution of each concentrate or dispersion was determined by

using a Mastersizer S V2.19 (Malvern Instruments Ltd., UK) fitted with a small sample

dispersion unit (MS1) connected to a dispersion unit controller. A beam length of 2.4

mm and 300 RF lens (range 0.05 – 900 µm) were used. Concentrates were loaded into

the small sample dispersion unit and stirred at a speed of 800 rpm until an obscuration

value between 12 - 17% was obtained. Before each sample was run, the system was

aligned and a background measurement was taken with either distilled water or ethanol

which was used as the dispersing solvent. The determination was carried out in

triplicates for each sample.

(e) Tack measurement

The method using a texture analyser type TA-XT2 (TA, England) has been

previously reported by others (Baie et al., 2004; Heng et al., 1996; Wan and Lai, 1992b,

1992a). Acrylic plastic probe of cylindrical shape with a round and flat contact surface

area (r = 10 mm) was used. Two millilitres of the sample was placed into a petri dish

with an internal diameter of 9 cm, and kept in a horizontal position with a metallic

clamp. The probe was mounted vertically on the load test shaft of the tensile tester.

During the operation of the test, the probe was lowered vertically and brought into

contact with the liquid film in the petri dish and allowed to rest against the film for 30

seconds. The probe was then raised at 5.0 mm/s rate of separation. The maximum force

generated during separation was recorded. Six replicate determinations were carried out.

The sample should be free from air bubbles.

2.2 Selection of final aerosol concentrates

(a) Compatibility study

Physical compatibility between the concentrate and the propellant is one of the

physical properties should be determined and is a first step in the rational formulation

design (Caballero et al., 2008; Gupta and Myrdal, 2005).

Aerosol containers are usually made of glass, plastic or metal. Metals commonly

used include tin-plated steel, aluminium and stainless steel. Glass is usually preferred,

but its used is limited owing to its brittleness and danger of breakage and explode should

the container accidentally be dropped. Glass is not safe for use in the existing

propellant’s pressures of 35 to 40 psig at 70 0F (Herst, 1974; Obarski, 1974). Glass is not

recommended for aerosol containing suspension formulation because of the visibility of

the suspended particles may present aesthetic problem for the patient.

To study the compatibility between the concentrate and the propellant, glass

bottles were used as containers. Only LPG and butane can be tested for their

compatibility with aerosol concentrate because of their relatively low vapour pressure

thus can be filled into a glass bottles e.g. 16.9 psig for butane (Sanders, 1979).

Nevertheless compatibility between P134a and concentrates can still be studied in the

glass bottles for short observation period because the bottles would rupture within 24

hours due to the vapour pressure of P134a of 70.9 psig which is over the mentioned limit

of 35 to 40 psig.

Twenty grams of each major ingredient of the concentrate (distilled water,

ethanol, Channa striatus extract) and aerosol were filled separately into separate glass

bottle, the valve was placed and sealed to the bottle opening before manual filling of

propellant by using aerosol filling machine. Weights of the filled propellants were 15.3
g, 15 g and 12 g for P134a, filtered LPG and butane respectively. The mixtures were

shaken to mix them properly after which they were observed visually for any change or

deviation from the initial conditions.

(b) Tin-plate Steel as container and filtered LPG as propellant

The use of chlorinated fluorocarbons (CFCs) for aerosols and other commercial

uses have been seriously curtailed and in certain cases, banned. Since 1996, CFCs have

been ban under the term of the Montreal Protocol (Smyth et al., 2005; McDonald and

Martin, 2000; Goodwin, 1998). These compounds have been implicated in causing a

depletion of the ozone layer and showing partial responsibility for the “greenhouse”

effect (increase in earth’s temperature, rising sea levels, and altered rainfall patterns).

CFCs produce HCl with ethanol by reaction: CCl3F + C2H5OH  CH3CHO + HCl

+CHCl2F. HCl can cause corrosion to the tin and is an irritant to the skin. Due to the

above reasons, filtered LPG (hydrocarbon) was used as propellant in this part of the

study. Liquefied Petroleum Gas (LPG) was filtered by activated charcoal and alkaline

alumina silicate to remove the smelly compounds (ethanetiol) in LPG.

Forty grams of E1, E2, E3, G1, G2 and G3 concentrates were separately filled

into separate tin-plated steel containers fitted with continuous-spray valves. The sealed

containers were filled with 15 g of filtered LPG using aerosol filling machine. Containers

cannot be filled with concentrate and propellant more than 85% of the internal volume of

the container (SIRIM, 1993). Containers were stored at room temperature for one

month. After one month, the containers were opened and their inside layer are examined

visually.
(c) Adhesion of the films onto the skin

The experiment was performed on living skin as this allowed the assessment of

the performance of the formed film under actual wearing condition. There is no

substitute for live human skin for investigation of the film adhesion onto the skin. The

forearm skin was defatted with ethanol and the aerosol was sprayed onto it for 5 seconds

from a distance of 15 cm. Evaluated aerosols were E1, E2, E3, G1, G2 and G3 aerosols.

After the films were formed, the films were observed visually and determined the

formula that attached onto the skin for the longest period possible (Fetisova and Tsetlin,

1976).

2.3 Aerosol Evaluations

(a) Delivery rate

The delivery rate of aerosol was evaluated according to procedure stated in

A.S.T.M (2005a), USP XXIV (2000d) and Sciarra and Cutie (1986). Six aerosol

containers of each formulation were used. The valve of each container containing the

aerosol formulation was actuated for 5 seconds at room temperature. Difference weight

before and after actuated was the amount of content that was delivered by propellant.

Test was repeated three times for each container. The average delivery rate was

calculated, in gram per second, for each container.

(b) Delivery amount

The delivery amount of aerosol was determined by using six containers of each

formulated aerosol according to the procedure stated in USP XXIV (2000d). The valves
were continuously pressed for 5 seconds each time to discharge the content until the

container is exhausted. The total weight loss was determined for each container.

(c) Pressure test

The vapour pressure in six containers of each formulated aerosols was

determined by using method in A.S.T.M (2005b), Sanders (1979), Sciarra and Cutie

(1986) and USP XXIV (2000d), at a temperature of 25 0C. Each container was inverted

and actuator was pressed to remove any liquid dispersion trapped in the dip tube. The

actuator was removed and pressure gauge was placed to the valve stem. By holding

firmly in that position, the valve was actuated to open fully and the vapour pressure was

read directly from the gauge.

(d) Minimum fills

Twelve filled containers were selected to determine the minimum fill. Containers

were weighted individually. The contents were removed from each container. Valve was

opened and any residual contents were removed with suitable solvents, and the container

then rinsed with a few portions of methanol. The container, the valve, and all associated

parts were collected and heated to dry at 100 0C for 5 minutes. Each of the containers

was then cooled, and again weighed together with their corresponding parts. The

difference between the original weight and the weight of the empty aerosol container is

the net fill weight. The product passed the test if the net weight of the contents of each of

the 10 containers is not less than the labelled amount (USP, 2000d).
(e) Leakage test

The leakage test was conducted by using the method in USP XXIV (2000d).

Twelve aerosol containers were selected for each formulation, and the date and time

recorded to nearest half hour. Each container and content was weighed to the nearest mg

and recorded as W1. The containers were allowed to stand in an upright position at room

temperature for 3 days, before the second weight was recorded as W2 and T (in hours) as

the test period. The leakage rate, in mg per year, of each container was calculated using

formula: (365)(24/T)(W1 – W2). The product passed the average leakage test if the rate

per year for the 12 containers is not more than 3.5 % of the net fill weight, and none of

the containers leak more than 5.0 % of the net fill weight per year.

(f) Flammability

The flammability of aerosol was determined based on method in A.S.T.M

(2005c), Sciarra and Stoller (1974), Sanders (1979) and Sciarra and Cutie (1986). The

sample is flammable if the flame projects more than 18 inch beyond the ignition source

with the valve fully opened or if the flame flashes back and burns at the valve with any

degree of valve opening.

(g) Spray patterns

Products were sprayed onto absorbent paper. The distance separating the

container from the target was kept constant (15 cm). This test will give a record of spray

which can then be used for comparison purposes (Sciarra and Cutie, 1986; Sanders,

1979; Sciarra and Stoller, 1974).

(h) Particles size and particles image

The aerosols were sprayed onto slides and the image of particles were photograph

by using Leica DMLB Microscope with Leica DC 300 Camera and Leica QWin

Program, Leica Microsystems DI Cambridge CB 1 3xJ Type DC 300 V2.O, equipped

with an objective lens of 20 x magnification and 10 x magnification of eye piece lens

that has been fitted with a standardised micrometer. A thousand particles were counted to

obtain the Martin’s diameter (Martin et al., 2001).

 CHAPTER 3
APPLICATION OF THE AEROSOL DRUG DELIVERY SYSTEM AS WOUND
DRESSING

Aerosol is a new dosage form for wound dressing and wound healing. The

concentrates of aerosol containing suitable polymer(s) will produce films after being

sprayed onto the skin or wound. The active ingredient(s) will be delivered to the affected

area or wound over time firstly from the moist formulation before it become dry and then

from the dry film. The dressing film can be formed onto any size of wound area

compared to the plasters which have limited size and singly packaged. Aerosol dressing

causes less suffering and pains to patients compare to conventional wound dressing.

From the preliminary formulation and evaluation of several formulated aerosol

concentrates, HPMC has been identified as the most suitable polymer to form film for

dressing the wound, while PEG 400, glycerine and propylene glycol are the candidates of

plasticizer. The films produced from several selected formula will be evaluated with the

aim of narrowing down the selection of suitable concentrates formula based on the

mechanical strength of the films produced and water vapour permeability properties.

(a) Preparation of films

Film was produced by casting technique as reported by Pongjanyakul and

Puttipipatkhachorn (2008). The films were evaluated for their physical parameters

including their thickness, mechanical properties and water vapour permeability.

(b) Measurement of films thickness

The thicknesses of the films produced from the formulated aerosol concentrates

were measured using a micrometer (Digimatic micrometer, Mitutoyo, Tokyo, Japan) as

the method reported and used by Yoo et al. (2006) and Fulzele et al. (2002). Samples
with air bubbles, nicks or tears and having mean thickness variations of greater than 10

% were excluded from analysis (Macleod et al., 1997).

(c) Mechanical properties measurements

The mechanical properties of aerosol concentrate films were evaluated by using a

texture analyser (TA.XT2, Stable Micro System, Haslemere, Surrey, UK) according to

the method reported by Khan et al. (2000), Wu et al. (2000) and Frohoff-Hulsmann

(1999). Film strip in dimension of 10 mm by 50 mm and free from air bubbles or

physical imperfections, was held between two clamps positioned at a distance 3 cm.

During measurement, the film was pulled by top clamps at a rate of 1.0 mm/s to a

distance of 5 cm before returning to the starting point. The tensile strength and

elongation at break were calculated as below:

Breaking Force (F)

Tensile strength (N/mm2) = -----------------------------------------
Cross sectional area of sample (A)

Increase in length at breaking point (L - Lo)

Elongation at break (%) = ---------------------------------------------------------- x 100 %.
Original length (Lo)

Cross section area of sample (mm2) = [width of the test film (mm)] x [thickness

of the test film (mm)]. Lo = original length (mm), L = length at breaking point (mm).

Young’s modulus (E), a measure of intrinsic film stiffness (García et al., 2009) can be

calculated by using the following equation (Martin et al., 2001):

F (L – Lo)
--- = E ------------
A Lo
Tensile Strength (N/mm2)
Young’s modulus (N/mm2) = ------------------------------------
Elongation at break

(d) Water vapour permeability of films

The rates of water vapour permeability of films were determined by using the

method described in ASTM (2005d), USP XXIV (2000b) and Fetisova and Tsetlin

(1976). Films were tied onto the mouth of twelve small glass bottles of the same size and

type (diameter = 1.6 cm) with an average volume of 25 ml ± 0.5 ml. The average area

available for vapour permeation was 2.0096 cm2. Each of the ten glass bottles was filled

with desiccant (anhydrous calcium chloride) to about two-third of the capacity of the

bottles. Each of the remaining 2 bottles used as controls, was filled with sufficient

number of glass beads to attain a weight approximately equal to that of each of the test

bottles. Weights of the individual bottles were recorded as initial weights. These bottles

were stored in a desiccators at 75 ± 3% relative humidity and room temperature

(Macleod et al., 1999). A saturated system of sodium chloride in the bottom of a

desiccators maintains the specified humidity. After 14 days, the weights of the individual

bottles were recorded in the same manner. The rate of moisture permeability was

calculated by using the equation (USP, 2000b):

1000
Rate of moisture permeability (mg/day/litre) = -------- x [(Tf – Ti) – (Cf – Ci)]
14 V

Where V is volume (ml) of the container, (Tf – Ti) is the difference (mg) between the

final and initial weights of each test container, (Cf – Ci) is the average of the difference

(mg) between final and initial weights of two containers (control).

And other equation by Fetisova and Tsetlin (1976):

 1000
Water vapour permeability (mg/cm2/day) = ------------- x [(Tf – Ti) – (Cf – Ci)]
14 A

Where A is the area of the film available for vapour permeation (cm2)
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