Yam, Kit L. (ed.). The Wiley encyclopedia of packaging technology

Подождите немного. Документ загружается.

are also summarized in the respective transmission-rate

proﬁle plots. The values k

and k

calculated from the

experimental data ranged within 4–14% of the theoretical

values given by Gavara and Hernandez (33).

PERMEABILITY MEASUREMENT METHODS OF AROMAS

AND SOLVENTS

The permeabilities of the permanent gases through dif-

ferent packaging materials are well known and deeply

described elsewhere (36). They can be summarized by the

following four major methods:

. Pressure increase method, a detailed description of

which is given in the ASTM standard method D 1434

(37).

. Concentration increase method (also known as the

isostatic method), related to the ASTM standard

method D 3985 (38).

. Volume increase method. This technique is also

described in the ASTM standard method D 1434 (39).

. Detector ﬁlm method. This is a more recent method

which requires little equipment and is both rapid and

accurate (40).

Concerning aromas and organic vapors, unfortunately, not

many data are available. Moreover, there are not accepted

standard tests for the measurement and evaluation of

aromas and organic vapors permeability. However, differ-

ent methods and procedures related to the vapor perme-

ability measurements can be recovered, including the

isostatic and quasi-isostatic methods as seen before for

the permeability studies of the permanent gases.

It is worth citing the sophisticated device developed by

Niebergall et al. (41), able to provide accurate permeabil-

ity values also at very low vapor levels. Zobel (24) built a

simple equipment characterized by a higher sensitivity

over vapor sampling methods due to the fact that the

entire permeant is supplied to a speciﬁc detector, making

it possible the measurements of permeation also at low

vapor concentration gradients (in the low parts per million

range). DeLaussus et al. (42) built an apparatus based on

the use of a spectrometer to study the permeation phe-

nomenon of aromas in polymer ﬁlms, with the possibility

to set the temperatures up to 1501C and relative humid-

ities from 0% to 100%, allowing to achieve data on the

aroma and odor permeation of materials used in retortable

pouches. Finally, a procedure able to provide quantitative

results on the aroma barrier property of different packa-

ging materials has been developed (43). In this case, a

permeation cell similar to that used for the concentration

increase method is employed.

In recent years, several studies had been performed to

develop new apparatuses for more effective and cheaper

permeation test for aromas and organic vapors, with a

wider application range than the previous ones. Al-Ati

et al (44) developed an equipment based on a commercial

TCD. The innovation involved in this new device is that it

is able to detect permeants by measuring their thermal

characteristics different with those of helium. Because

helium is characterized by a low thermal capacity, nearly

all volatile gases and vapors can be detected with this

instrument. Moreover, this instrument provides not only

permeability but also solubility and diffusion coefﬁcients.

Finally, it is claimed that this kind of apparatus can be

built with an investment 10% less than a commercial

instrument. Zhou et al. (45) constructed a system by

combining dynamic vapor sorption (DVS) with purge-

and-trap/fast gas chromatography (P&T-fGC). In particu-

lar, this apparatus can be used for simultaneous measure-

ment of permeability of multiple aroma compounds.

Simplicity, speed, and accuracy are some of the most

interesting features of this new measurement system.

Finally, a new quasi-isostatic permeation test method

has been developed for aroma barrier testing by Va

Nissi et al. (46). In this case, aroma concentrations

accumulated in the receiving cell as a function of time

are measured during permeation from the source cell

containing the model aroma solution through the tested

polymer. This system uses automatic gas sampling from

the test cells to the gas chromatography. It was success-

fully used to test different materials such as paper and

paperboard (coated and uncoated) and polymer ﬁlms. The

main advantage linked to this new solution is represented

by the absence of interfering carrier gas ﬂows in the test

cells. In fact, these ﬂows could affect the ﬁnal results,

because the carrier gas can penetrate partly to porous

materials such as ﬁber-based samples.

BIBLIOGRAPHY

1. B. R. Harte and J. R. Gray, Food Product-Package Compat-

ibility Proceedings, Technomic Publishing, Lancaster, PA,

1983.

2. M. Salame, J. Plast. Film Sheet. 2, 321 (1986).

3. E. Bagley and F. A. Long, J. Am. Chem. Soc. 77, 2172 (1958).

4. J. Fujita, Fortsch-Hochpolym-Forsch. 3, 1 (1961).

5. J. Crank, The Mathematics of Diffusion, 2nd edition, Clar-

endon Press, Oxford, UK, 1975.

6. A. R. Berens, Polymer 18, 697 (1977).

7. P. Mears, J. Appl. Polymer. Sci. 9, 917 (1965).

8. P. T. DeLassus, in Proceedings TAPPI, 1993 Polymers, Lami-

nations and Coatings Conference, Chicago, 1993, p. 263.

9. R. J. Hernandez, J. R. Giacin, K. Jayaraman, and A. Shir-

akura, in Proceedings ANTEC 90, Dallas, 1990.

10. M. Shimoda, T. Matsui, and Y. Osajima, Nippon Shokuhin

Kogyo Gakkaishi. 36(6), 402–406 (1987).

11. G. W. Halek and J. P. Luttmann, in J. H. Hotchkiss, ed., Food

Packaging Interactions, Vol. 2, ACS, Washington, DC, 1991,

pp. 212–226.

12. G. Strandburg, P. T. DeLassus, and B. A. Howell in W. J.

Koros ed., Barrier Polymer Structure, ACS, Washington, DC,

1990, pp. 333–350.

13. D. K. Arora, A. P. Hansen, and M. S. Armagost, in J. H.

Hotchkiss ed., Food Packaging Interactions, Vol. 2, ACS,

Washington, DC, 1991, pp. 203–211.

14. D. K. Arora, A. P. Hansen, and M. S. Armagost, J. Food Sci.

56(5), 1421–1423 (1991).

948 PERMEATION OF AROMAS AND SOLVENTS THROUGH POLYMERIC PACKAGING MATERIALS

15. J. P. H. Linssen, A. Verheul, J. P. Roozen, and M. A. Post-

humus, Int. Dairy J. 1(2), 33–40 (1991).

16. J. P. H. Linssen and J. P. Roozen, in M. Mathlouthi, ed., Food

Packaging and Preservation, Blackie Academic & Profes-

sional, Glasgow, UK, 1994, pp. 48–61.

17. G. Pieper and K. Petersen, J. Food Sci. 60(5), 1088–1091

(1995).

18. Z. N. Charara, J. W. Williams, R. H. Schmidt, and M. R.

Marshall, J. Food Sci. 57(4), 963–966, 972 (1992).

19. T. J. Nielsen, I. M. Jagerstad, and R. E. Oste, J. Sci. Food

Agric. 60(3), 377–381 (1992).

20. T. J. Nielsen, I. M. Jagerstad, R. E. Oste, and B. O. Wesslen,

J. Food Sci. 57(2), 490–492 (1992).

21. A. Leufven and C. Hermansson, J. Sci. Food Agric. 64(1), 101–

105 (1994).

22. P.-J. Blain, in Memoire d’Ingenieur ENS.BANA, Wageningen

Agricultural University, The Netherlands, 1994. pp. 9–11.

23. J. R. Giacin and R. J. Hernandez, in Proceedings of the Fall

1986 Meeting of Research and Development Associates for

Military Food Packaging Systems, Inc., 1987, p. 79.

24. M. G. R. Zobel, Polymer Test. 3, 133 (1982).

25. T. M. Hensley, J. R. Giacin, and R. J. Hernandez, in Proceed-

ings of IAPRI 7th World Conference on Packaging, Utrecht,

The Netherlands, 1991.

26. T. J. Nielsen and J. R. Giacin, Packag. Technol. Sci. 7, 247

(1994).

27. A. R. Berens, Polymer 18 , 697 (1977).

28. D. A. Blackadder and J. S. Keniry, J. Appl. Polym. Sci. 17, 351

(1973).

29. S. Nagaraj, The Effect of Temperature and Sorbed Water on

the Permeation of Acetone Vapor through Amorphous Poly-

amide Film, M.S. thesis, Michigan State University, East

Lansing, MI, 1991.

30. T. Sajaki and J. R. Giacin, J. Plast. Film Sheet. 9(2), 97 (1993).

31. J. J. Liu, R. J. Hernandez, and J. R. Giacin, J. Plast. Film

Sheet. 7(1), 56 (1991).

32. C. H. Lin, Permeability of Organic Vapors through a Pack-

aged Confectionery Product with a Cold Seal Closure: Theo-

retical and Practical Considerations, M.S. thesis, Michigan

State University, East Lansing, MI, 1996.

33. R. Gavara and R. J. Hernandez, J. Plast. Film Sheet. 9, 126

(1993).

34. R. S. Pasternak, J. F. Schimscheimer, and J. Heller, J. Polym.

Sci. (Part A-2) 8, 467 (1970).

35. S. J. Huang, A Comparison of the Isostatic and Quasi-Isostatic

Procedures for Evaluating the Organic Vapor Barrier Proper-

ties and Polymer Membranes, M.S. thesis, Michigan State

University, East Lansing, MI, 1996.

36. R. P. Brown, ed., Handbook of Plastics Test Methods, 2nd

edition,

George Godwin Ltd.,

Essex, England, 1981, Chapter

18.

37. ASTM D1434-82(2003). Standard Test Method for Determin-

ing Gas Permeability Characteristics of Plastic Film and

Sheeting—Procedure M.

38. ASTM D3985-05. Standard Test Method for Oxygen Gas

Transmission Rate through Plastic Film and Sheeting Using

a Coulometric Sensor.

39. ASTM D1434-82(2003). Standard Test Method for Determin-

ing Gas Permeability Characteristics of Plastic Film and

Sheeting—Procedure V.

40. R. V. Holland, M. L. Rooney, and R. A. Santangelo, Angew.

Makromol. Chem. 88, 209 (1980).

41. H. Niebergall, A. Humeid, and W. Blochl, Lebensm.-Wiss. U.

Technol. 11, 1 (1978).

42. P. T. DeLaussus, G. Strandburg, and B. A. Howell, Tappi J.

71, 177 (1988).

43. E. Hatzidimitriu, S. G. Gilbert, and G. Loukakis, J. Food Sci.

52, 472 (1987).

44. T. Al-Ati, J. Garza, and J. H. Hotchkiss, Packag. Technol. Sci.

16, 249-257 (2003).

45. Q. Zhou, B. Guthrie, and K. R. Cadwallader, Packag. Technol.

Sci. 17, 175-185 (2004).

46. M.Va

-Nissi, T. Hjelt, M. Jokio, R. Kokkonen, J. Kukkonen,

and A. Mikkelson, Packag. Technol. Sci. 21, 425–431 (2008).

DOI: 10.1002/ pts.791.

PHARMACEUTICAL PACKAGING

M. I. R. M. SANTORO

A. K. SINGH

Department of Pharmacy,

Faculty of Pharmaceutical

Sciences, University of Sa˜o

Paulo, Sa˜o Paulo, Brazil

INTRODUCTION

The packaging of a pharmaceutical product fulﬁlls as-

sorted roles, such as product presentation, identiﬁcation,

convenience, and protection until administration or use.

Selection of packaging requires a basic knowledge of

packaging materials, the environmental conditions to

which the product will be exposed, and the characteristics

of the drug formulation. Several types of packaging are

used to contain and protect the drug product, such as the

primary packaging around the product and secondary

packaging such as subsequent transit cases (1).

Packaging system development, including primary and

secondary packaging components, is as important as drug

product itself. Basically, the packaging material is used as

a barrier to protect the drug product against external

factors that can degrade them and consequently decrease

their efﬁcacy and even provoke toxic effects. The material

should be selected based on the characteristics of drug

product and type of dosage form. After the production

phase, packaging must be planned according to regulatory

requirements and its quality should be controlled accord-

ing to predeﬁned speciﬁcations.

Once the type of packaging material is selected based

on factors such as size, shape, capacity, and physicochem-

ical properties, all these data, including quality control

(QC) tests, should be included in the speciﬁcation of the

products in order to ensure the therapeutic effectiveness

during its shelf life.

Several types of materials are being used in the man-

ufacture of containers and closure systems: glass, plastics,

metals, and combinations of these materials. However,

PHARMACEUTICAL PACKAGING 949

care should be taken in the selection of appropriate

material. These materials should not present any physical

or chemical reactivity that could modify drug activity,

quality, purity, or physical characteristics of the drug

substance and drug product. Any minor modiﬁcation in

the pharmacopeial speciﬁcation is acceptable if it does not

present a threat to patient’s health.

The role of packaging in the pharmaceutical industry

has grown substantially over the past decade. The total

packaging operation is part of any drug development

program. Drug product require a standard of packaging

which is superior to that of most other products

(nonpharmaceutical) in order to support and comply

with their main requirements, such as efﬁcacy, integrity,

purity, safety, and stability. For these reasons, packaging

technology should be based on detailed information on

drug substance and drug product, including their physical

and chemical properties.

In the past, packaging concerns often arose only during

the later steps of product development. Today, packaging

is integral part of drug product development and is among

the earliest considerations of new drug product being

studied. Few examples of packaging concerns for common

classes of drug products are presented in Table 1. How-

ever, the challenge is to maintain low packaging cost that

is always integrated into the cost of the product itself.

Packaging in the post-World War II period beneﬁted

immensely from the commercialization of plastics, which

were little known or used in prior years. Since then, the

packaging industry has openly adopted plastics as a

powerful new tool in the development of new packaging

forms and functions.

Quality control of a packaging component starts at the

design stage. All aspects of package development that may

generate quality problems must be identiﬁed and mini-

mized by good design. Identifying and correcting in packa-

ging will avoid product recall and rejection of drug product

(2–4).

The aim of this article is to discuss the importance of

the packaging in the development of drug products and

pharmaceuticals.

IMPORTANCE OF PROPER PACKAGING AND LABELING

The United States’ Poison Prevention Packaging Act en-

acted in 1970 (www.cpsc.gov/businfo/pppa.html) requires

special packaging of most human oral prescription drugs,

oral controlled drugs, certain normal prescription drugs,

certain dietary supplements, and many over-the-counter

(OTC) drug preparations in order to protect the public

from personal injury or illness from misuse of these

preparations.

In many countries there are very strict regulations for

packaging of many drug substances. Various types of

child-resistant packages are covered in ASTM Interna-

tional Standard D-3475. Medication errors linked to poor

labeling and packaging can be controlled through the use

of error potential analysis. The recognition that a drug

name, label, or package may constitute a hazard to safety

typically occurs after the drug has been approved for use

and is being marketed. Numerous reports of medication

errors are being reported, some of which have resulted in

patient injury or death. In a number of these reports, a

medication was mistakenly administered either because

the drug container (bag, ampoule, preﬁlled syringe, and

bottle) was similar in appearance to the intended medica-

tion’s container or because the packages had similar

labeling. Obviously, the severity of such errors depends

largely on the medication administered. The problem

of medical errors associated with the naming, labeling,

and packaging of pharmaceuticals is being very much

discussed.

PACKAGING MATERIALS

General Considerations

Packaging refers to all the operations, including ﬁling and

labeling, through which a bulk product should pass to

become a ﬁnished product. Usually, sterile ﬁling is not

considered part of the packaging process, although the

bulk product is still in the primary container.

Table 1. Examples of Packaging Concerns for Common Classes of Drug Products (2, 4)

Degree of Concern Associated

with the Route of

Administration

Likelihood of Packaging Component–Drug Product Interaction

High Medium Low

Highest Inhalation aerosols and

solutions; injection;

injectable suspensions

Sterile powders and powders

for injections and inhalation

powders

High Ophthalmic solutions and

suspensions; transdermal

ointments and patches; nasal

aerosols and sprays

Low Topical solutions and

suspensions; topical and

lingual aerosols; oral

solutions and suspensions

Topical powders; oral powders Oral tablets and oral (hard and

soft gelatin) capsules

950 PHARMACEUTICAL PACKAGING

A packaging component means any single part of a

container closure system. Typical components are contain-

ers (e.g., ampoules, vials, bottles), container liners (e.g.,

tube liners), closures (e.g., screw caps, stoppers), closure

liners, stopper over seals, container inner seals, adminis-

tration ports [e.g., on large-volume parenterals (LVPs)],

overwraps, administration accessories, and container la-

bels (4).

A primary packaging component is one that is or may

be in direct contact with the drug product. A secondary

packaging component is one that is not and will not be in

direct contact with the drug product (4).

A container closure system refers to the sum of packa-

ging components that together contain and protect the

drug product. This includes primary packaging compo-

nents and secondary packaging components, if the latter

are intended to provide additional protection to the drug

product. A packaging system is equivalent to a container

closure system (4).

The role of packaging material on the overall perceived

and actual stability of the drug product is well established.

Packaging plays an important role in quality mainte-

nance, and the resistance of packaging materials to

moisture and light can signiﬁcantly affect the stability of

drugs and their drug products. It is crucial that stability

testing of drug products in their ﬁnal packaging be

performed. The primary role of packaging, other than its

esthetic one, is to protect the drug products from moisture

and oxygen present in the atmosphere, light, and other

types of exposure, especially if these factors affect the

overall quality of the product on long-term storage (5).

Compliance packaging such as for ﬁxed-dose-combina-

tion pills and unit-of-use packaging is a therapy-related

interventions that is designed so as to simplify medication

regimens and thus potentially improve adherence. Com-

pliance packaging can be deﬁned as a prepackaged unit

and provides one treatment cycle of the medication to both

the pharmacist and the patient in a ready-to-use package.

This innovation type of packaging is usually based on

blister packaging using unit-of-one dosing. The separate

dosage units and separate days are usually indicated on

the dosage cards to help remind the patient when and how

much of the medication to take, for example, blister-

packed oral dosage forms with drug information leaﬂets,

speciﬁcally the contraceptive pills (3, 6, 7).

The selection of packaging material for any pharma-

ceutical product is as important as proper drug product. To

guarantee the safe and adequate delivery of drug product

to the patient and improve patient compliance, the man-

ufacturer should consider the following factors:

1. Compatibility and safety concerns raised by the route

of administration of the drug product and the nature

of the dosage form (e.g., solid or liquid based)

2. Kinds of protection the container closure system

should provide to the drug product (e.g., photosensi-

tive, hygroscopic, easily oxidized drug products)

3. Potential effect of any treatment or handling that

may be unique to the drug product in the packaging

system

4. Patient compliance to the treatment and ease of

drug administration

5. Safety, efﬁcacy, and quality of drug product through-

out its shelf life

Glass as Packaging Material

A packaging system found acceptable for one drug product

is not automatically assumed to be appropriate for an-

other. Each application should contain enough informa-

tion to show that each proposed container closure system

and its components are suitable for its intended use.

Non Sterile Products.

Solids. Some topical drug products such as powders

may be considered for marketing in glass bottles with

appropriate dispenser. These topical drug products may be

sterile and could be subject to microbial limits.

The most common glass-packed solid oral dosage forms

is oral powders and granules for reconstitution. A typical

solid oral dosage forms container closure system is a glass

bottle (although plastic bottles are also used) with a screw-

on or snap-off closure. A typical closure consists of a metal

cap, often with a liner, and frequently with an inner seal.

Powders for oral administration that are reconstituted

in their market container, need not be sterile; however,

they have an additional possibility of an interaction

between the packaging components and the reconstituting

ﬂuid. Although the contact time will be relatively short

when compared to the component/dosage form contact

time for liquid-based oral dosage forms, it should still be

taken into consideration when the compatibility and

safety of the container closure system is being evaluated.

Nonsolids. For nonsterile products the preservative

provides some protection, but continual microbial chal-

lenge will diminish the efﬁcacy of the preservative, and

spoilage or disease transmission may occur (8).

Antimicrobial preservatives such as phenylmercuric

acetate are known to partition into rubbers during sto-

rage, thus reducing the formulation concentration below

effective antimicrobial levels (9). A complication of modern

packaging is the need for the application of security seals

to protect against deliberate adulteration and maintain

consumer conﬁdence.

Sterile Products. The sterile dosage forms share the

common attributes that they are generally solutions,

emulsions, or suspensions and are all required to be

sterile. Injectable dosage forms represent one of the high-

est-risk drug products (Table 1). Any contaminants pre-

sent (as a result of contact with a packaging component or

due to the packaging system’s failure to provide adequate

protection) can be rapidly and completely introduced into

the

patient’s general

circulation. Injectable drug products

may be liquids in the form of solutions, emulsions, suspen-

sions, or dry solids that are to be combined with an

appropriate vehicle to yield a solution or suspension.

Although ophthalmic drug products can be considered

topical products, they have been grouped here with

PHARMACEUTICAL PACKAGING 951

injectables because they are required to be sterile and the

descriptive, suitability, and quality control information is

typically the same as that for an injectable drug product.

The potential effects of packaging component/dosage

form interactions are numerous. Hemolytic effects may

result from a decrease in tonicity, and pyrogenic effects

may result from the presence of impurities. The potency of

the drug product or concentration of the antimicrobial

preservatives may decrease due to adsorption or

absorption.

A cosolvent system essential to the solubilization of a

poorly soluble drug can also serve as a potent extractant of

plastic additives.

A disposable syringe may be made of plastic, glass,

rubber, and metal components, and such multicomponent

construction provides a potential for interaction that is

greater than when a container consists of a single material.

Injectable drug products require protection from micro-

bial contamination (loss of sterility or added bioburden)

and may also need to be protected from light or exposure

to gases (e.g., oxygen).

Performance of a syringe is usually addressed by

establishing (a) the force to initiate and maintain plunger

movement down the barrel and (b) the capability of the

syringe to deliver the labeled amount of the drug product.

Solids. For solids that must be dissolved or dispersed in

an appropriate diluent before being injected, the diluent

may be in the same container closure system (e.g., a two-

part vial) or be part of the same market package (e.g., a kit

containing a vial of diluent).

Sterile powders or powders for injection may need to be

protected from exposure to water vapor. For elastomeric

components, data showing that a component meets the

requirements of USP Elastomeric Closures for Injections

will typically be considered sufﬁcient evidence of safety.

Nonsolids. The package must prevent the entry of

organisms; for example, packaging of sterile products

must be absolutely microorganism-proof, hence the con-

tinued use of glass ampules. Liquid injections are classi-

ﬁed as small-volume parenterals (SVPs), if they have a

solution volume of 100 mL or less, or as large-volume

parenterals (LVPs), if the solution volume exceeds

100 mL (8). Liquid-based injectables may need to be

protected from solvent loss.

A SVP may be packaged in a vial or an ampule. A LVP

may be packaged in a vial, in a glass bottle, or, in some

cases, as a disposable syringe. Packaging material for

vials and ampules are usually composed of Type I or II

glass. Stoppers and septa in cartridges and vials are

typically composed of elastomeric materials.

Pharmaceuticals may interact with packaging and

containers, resulting in the loss of drug substances by

adsorption onto and absorption into container components

and the incorporation of container components into phar-

maceuticals. Diazepam in intravenous ﬂuid containers

and administration sets exhibited a loss during storage

due to adsorption onto glass (3).

Glass surfaces are also known to adsorb drug sub-

stances. Chloroquine solutions in glass containers

decreased in concentration owing to adsorption of the

drug onto the glass (3).

Rubber closures are also known to absorb materials,

including drugs. Absorption of preservatives such as

chlorocresol into the rubber closures of injectable formula-

tions has been studied extensively (3).

Water permeability of rubber closures used in injection

vials is considered an important parameter in assessing

the closures, but quantitative prediction of water perme-

ability through rubber closures is difﬁcult because the

diffusion coefﬁcient of water is dependent on relative

humidity (3).

Liquid-based oral drug products are usually dispensed

in glass bottle (sometimes in plastic), often with a screw

cap with a liner, and possibly with a tamper-resistant seal

or an overcap that is welded to the bottle. The same cap

liners and inner seals are sometimes used with solid oral

dosage forms. A laminated material could be used to

overwrap glass bottles for extra safety.

The USP grade glass packaging components are che-

mical-resistant and could be considered sufﬁcient evi-

dence of safety and compatibility. In some cases (e.g., for

some chelating agents), a glass packaging component may

need to meet additional criteria to ensure the absence of

signiﬁcant interactions between the packaging component

and the dosage form.

Several ophthalmic preparations are commercialized in

glass containers. Although the risk factors associated with

ophthalmic preparations are generally considered to be

lower than for injectables, any potential for causing harm

to the eyes demands caution.

A large-volume intraocular solution (for irrigation) may

be packaged in a polyoleﬁn (polyethylene and/or polypro-

pylene) container.

The liquid-based oral dosage forms may be marketed in

multiple-unit bottles. The dosage form may be used as is

or admixed ﬁrst with a compatible diluent or dispersant.

Liquid-based oral drug products in glass containers must

meet the requirements of USP containers. Glass contain-

ers are accepted as sufﬁcient evidence of safety and

compatibility. Performance is typically not a factor for

liquid-based oral drug products but should be considered

while treating pressurized liquid-based oral drug products

(e.g., elixir spray).

Topical dosage forms such as unpressurized sprays,

lotions, ointments, solutions, and suspensions may be

considered

for marketing in

glass bottles with appropriate

dispensers. Some topical drug products, especially

ophthalmic, are sterile or may be subject to microbial

limits. In these cases, packaging material and its handling

should be done in the same manner as those for

injectables.

Plastic as Packaging Material

For plastic components, data from USP biological reactiv-

ity tests will typically be considered sufﬁcient evidence of

safety. Whenever possible, the extraction studies should

be performed using the drug product. If the extraction

properties of the drug product vehicle may reasonably be

expected to differ from that of water (e.g., due to high or

952 PHARMACEUTICAL PACKAGING

low pH or due to a solubilizing excipient), then drug

product should be used as the extracting medium. If the

drug substance signiﬁcantly affects extraction character-

istics, it may be necessary to perform the extractions using

the drug product vehicle. If the total of extracts signiﬁ-

cantly exceeds the amount obtained from water extrac-

tion, then an extraction proﬁle should be obtained. It may

be advisable to obtain a quantitative extraction proﬁle of

an elastomeric or plastic packaging component and to

compare this periodically to the proﬁle from a new batch

of the packaging component. Extractables should be iden-

tiﬁed whenever possible (Table 2 and 3).

Nonsterile Products.

Solids. The most common solid oral dosage forms are

capsules and tablets. A typical solid oral dosage forms

container closure system is a plastic, usually high-density

polyethylene (HDPE) bottle with a screw-on or snap-off

closure and a ﬂexible packaging system, such as a pouch

or a blister package. A typical closure consists of a cap,

often with a liner and frequently with an inner seal. If

used, ﬁllers, desiccants, and other absorbent materials are

considered primary packaging components.

A change in the selection of packaging materials com-

bined with a change in storage conditions or conditions

during administration of the drug products may provoke

stability problems.

Many studies have been conducted on predicting the

role of packaging in moisture adsorption by drug products.

Adsorption of moisture by tablets contained in polypropy-

lene ﬁlms was successfully modeled from storage tempera-

ture and the difference in water vapor pressure between

the inside and outside of the packaging (3).

Chemical and physical degradation of packaged drug

products caused by moisture adsorption has been pre-

dicted from the moisture permeability of the packaging.

For example, strength changes of lactose-corn starch

tablets in strip packaging and discoloration of sugar-

coated tablets of ascorbic acid were predicted using the

moisture permeability coefﬁcient of the packaging.

Typical ﬂexible forms of packaging containing solid oral

dosage forms are the blister package and the pouch. A

blister package usually consists of a lidding material and a

forming ﬁlm. The lidding material is usually a laminate

that includes a barrier layer (e.g., aluminum foil) with a

print primer on one side and a sealing agent (e.g., a heat-

sealing lacquer) on the other side.

The sealing agent contacts the dosage form and the

forming ﬁlm. The forming ﬁlm may be a single ﬁlm, a

coated ﬁlm, or a laminate. A pouch typically consists of

ﬁlm or laminate that is sealed at the edges by heat or

adhesive.

Solid oral dosage forms generally need to be protected

from the potential adverse affects of following:

1. Water vapor (e.g., moisture may affect the decom-

position rate of the active drug substance or the

dissolution rate of the drug product)

2. Incident light (e.g., in case of photosensitive

products)

3. Reactive gases (e.g., oxygen could provoke oxidative

reactions)

The packaging material should be carefully studied

and tailor-made to help protect the drug product. For

example, photosensitive drug product may be blister-

packed in dark polymeric ﬁlm, and the covering lid on

Table 2. Plastic Additives (6)

Type Purpose Examples

Lubricants Improves processibility Stearic acid parafﬁn waxes, PE waxes

Stablizers Retard degradation Epoxy compounds, organotins, mixed metals

Plasticizers Enhance ﬂexibility, resiliency, melt

ﬂow

Phthalates

Antioxidants Prevent oxidative degradation Hindered phenolics (BHT), aromatic amines, thioesters,

phosphites

Antistatic agents Minimize surface static charge Quaternary ammonium compounds

Slip agents Minimize coefﬁcient of friction,

especially polyoleﬁns

Dyes, pigments Color additives

Table 3. Parenteral Drug Administration Devices (6)

Sterile Device Plastic Material

Containers for blood products Polyvinyl chloride

Disposable syringes Polycarbonate, polyethylene, polypropylene

Irrigating solution containers Polyethylene, polypropylene, polyvinyl chloride

I.V. infusion ﬂuid containers Polyethylene, polypropylene, polyvinyl chloride

Administration sets Nylon (spike), polyvinyl chloride (tubing), polymethylmethacrylate (needle adapter),

polypropylene (clamp)

Catheter Teﬂon, polypropylene, thermoplastic elastomers

PHARMACEUTICAL PACKAGING 953

the opposite side may be made of aluminum to give

protection against incident light.. A blister packaging

using multilayered HDPE packaging material and selec-

tion of adequate sealing technique may help prevent

moisture access into the blister system. However, ade-

quacy of plastics and glass for packaging of solid oral

dosage forms and for powders for reconstitution should

meet the requirements of the USP containers test.

Incorporating oxygen adsorbents such as iron powder

in packaging units can reduce the effect of oxygen. Protec-

tion from light can be achieved using primary packag-

ing (packaging that is in direct contact with the dosage

forms) and secondary packaging made of light-resistant

materials.

The photochemical reaction is a very complex process;

many variables may be involved in the photolytic degra-

dation kinetics. The velocity of the photochemical reaction

may be affected not only by the light source, intensity, and

wavelength of the light, but also by the size, shape,

composition, and color of the container.

Great effort is taken to stabilize a formulation in such a

way that the shelf life becomes independent on the storage

conditions. Photostability of drugs and excipients should

be evaluated at the formulation development stage in

order to assess the effects of packaging on the stability

of the ﬁnal product. Molsidomine tablet preparations in

inadequate primary container (blister) without secondary

when exposed to irradiations may produce morpholine.

These results illustrate the importance of packaging for

the stability of molsidomine (3).

Three standard tests for water vapor permeation have

been established by the USP for use with solid oral dosage

forms.

1. Polyethylene containers (USP o 661 W ) (8)

2. Single-unit containers and unit-dose containers for

capsules and tablets (USP o 671W)

3. Multiple-unit containers for capsules and tablets

(USP o671W) (8)

The cotton and rayon used as ﬁller in solid oral dosage

forms containers may not meet pharmacopeial standards,

but through appropriate tests and acceptance criteria for

identiﬁcation and for moisture content, their adequacy

should be shown; for example, rayon has been found to be

a potential source of dissolution problems for gelatin

capsules and gelatin-coated tablets.

Desiccants are often used to eliminate moisture in

packaging when the moisture resistance of the packaging

itself is not sufﬁcient to prevent exposure. The utility of

desiccants has been assessed based on a sorption–deso-

rption moisture transfer model (3).

The desiccant or other absorbent materials are primary

packaging components. The component should differ in

shape and/or size from the tablets or capsules with which

it is packaged. Their composition should be provided, their

inertness should be proved through appropriate tests, and

acceptance criteria should be established.

A topical powder product may be marketed in a sifter-

top container made of ﬂexible plastic tubes or as a part of a

sterile dressing (e.g., antibacterial product). The topical

formulations in a collapsible tube can be constructed from

low-density polyethylene (LDPE), with or without a lami-

nated material. Normally, there is no product contact with

the cap on storage. Thus usually there is no cap liner,

especially in collapsible polypropylene screw caps. Nor-

mally, separate applicator devices are made from LDPE.

Product contact is possible if the applicator is part of the

closure, and therefore an applicator’s compatibility with

the drug product should be established, as appropriate

(e.g., vaginal applicators).

Nonsolids. Typical liquid-based oral dosage forms are

elixirs, emulsions, extracts, ﬂuid extracts, solutions, gels,

syrups, spirits, tinctures, aromatic waters, and suspen-

sions. These products are usually nonsterile but typically

need to be protected from solvent loss, microbial contam-

ination, and, sometimes, exposure to light or reactive

gases (e.g., oxygen).

The presence of a liquid phase implies a signiﬁcant

potential for the transfer of materials from a packaging

component into the dosage form.

The higher viscosity of semisolid dosage forms and

transdermal systems may cause the rate of migration of

leachable substances into these drug products to be slower

than for aqueous solutions. Due to extended contact, the

amount of leachables in these drug products may depend

more on a leachable material’s afﬁnity for the liquid–

semisolid phase than on the rate of migration.

In addition to adsorption onto and absorption into

containers, transfer of container components into phar-

maceuticals may affect the perceived stability/quality

of drug products. Adsorption of volatile components from

rubber closures onto freeze-dried parenterals during

both dosage form processing and storage brought

about haze formation upon reconstitution. Leaching of

dioctyl phthalate, a plasticizer used especially in PVC

plastics, into intravenous solutions containing surfactants

was observed. Plastics contain additives to enhance poly-

mer

performance. PVC may

contain phthalate diester

plasticizer, which can leach into infusion ﬂuids from

packaging (3).

The liquid-based oral dosage forms may be marketed in

multiple-unit bottles or in unit-dose or single-use pouches

or cups. The dosage form may be used as is or admixed

ﬁrst with a compatible diluent or dispersant. A liquid-

based oral drug pouch may be a single-layer plastic or a

laminated material. The pouches may use an overwrap,

which is usually a laminated material.

For LDPE components, data from USP container tests

are typically considered sufﬁcient evidence of compatibil-

ity. The USP general chapters do not speciﬁcally address

safety for polyethylene (HDPE or LDPE), polypropylene

(PP), or laminate components.

For liquid-based oral drug products that the patient

will continue to take for an extended period (i.e., months

or years), during which time he or she is expected to

extract greater amounts of substances from plastic packa-

ging components than water (presence of cosolvents),

additional extractable information may be needed to ad-

dress safety issues.

954 PHARMACEUTICAL PACKAGING

Topical dosage forms such as creams, emulsions, gels,

lotions, ointments, pastes, and powders may be marketed

in plastic materials. Topical dosage formulations are for

local (not systemic) effect and are generally applied to the

skin or oral mucosal surfaces. Some vaginal and rectal

creams, as well as nasal and ophthalmic solutions, may be

considered for topical drug products.

A rigid bottle, a collapsible tube, or a ﬂexible pouch

made of plastic material may be used for liquid-based

topical product. These preparations are marketed in a

single- or multiple-unit container. Dissolved drug (or any

substance, e.g., benzocaine) may diffuse in the suppository

base, and can, for instance, partition into polyethylene

linings of the suppository wrap.

Topical delivery systems are self-contained, discrete

dosage forms that are designed to deliver drug for an

extended period via intact skin or body surface (e.g.,

transdermal, ocular, and intrauterine).

These systems may be constructed of a plastic or

polymeric material loaded with active ingredients or a

coated metal. Each of these systems is generally marketed

in a single-unit soft blister pack or a preformed tray with a

preformed cover or overwrap.

Compatibility and safety for topical delivery systems

are addressed in the same manner as for topical drug

products. Performance and quality control should be

addressed for the rate-controlling membrane (Table 2

and 3).

Sterile Products.

Nonsolids. An SVP may be packaged in a disposable

cartridge, a disposable syringe, or a ﬂexible bag made of

polymeric plastic. Flexible bags are typically constructed

with multilayered plastic.

An LVP may be packaged in a vial, a ﬂexible bag, or, in

some cases, a disposable syringe. Packaging material for

cartridges, syringes, vials, and ampules are usually com-

posed of polypropylene.

Stoppers and septa in cartridges, as well as syringes,

are typically composed of elastomeric materials. An over-

wrap may be used with ﬂexible bags to retard solvent loss

and to protect the ﬂexible packaging system from rough

handling.

Diazepam in intravenous ﬂuid containers and admin-

istration sets exhibited a loss during storage due to

adsorption onto and absorption into plastics. Absorption

of clomethiazole edisylate and thiopental sodium into PVC

infusion bags was observed (3).

The pH dependence of adsorption/absorption of acidic

drug substances such as warfarin and thiopental and

basic drug substances such as chlorpromazine and diltia-

zem indicates that only the un-ionized form of the drug

substance is adsorbed onto or absorbed into PVC infusion

bags (3).

The absorption was correlated to the octanol–water

partition coefﬁcients of the drugs, suggesting that predic-

tion of absorption from partition data is possible. Polymers

such as Nylon-6 (polycaprolactam) are known to adsorb

drug substances such as benzocaine (3).

The ophthalmic drug products are usually solutions

marketed in a low-density polyethylene bottle with a

dropper built into the neck. A few solution products use

a glass container due to stability concerns regarding

plastic packaging components.

Metal as Packaging Material

Metal tubes constructed of single material are packaging

material of choice for topical dosage forms and may be

tested readily for stability with a product. Tubes with a

coating, however, present additional problems. The inert-

ness of coating material must be established through

adequate tests and guarantee that it completely covers

underlying material. The coating material must be resis-

tant to creaking, leaking, leaching and solvent erosion; for

example, frequently used aluminum tubes have demon-

strated reactivity with fatty alcohol emulsions, mercurial

compounds, and preparations with pH below 6.5 and

above 8.0. Nonreactive epoxy linings have been found to

make aluminum tubes resistant to attack (6).

The ophthalmic ointments are marketed in a metal

tube with an ophthalmic tip. Ophthalmic ointments that

are reactive toward metal may be packaged in a tube lined

with an epoxy or vinyl plastic coating.

Metal containers, pressurized or not, may also be used

for topical drug products. topical dosage forms such as

aerosols, emulsions, gels, powders, and solutions may be

marketed in metallic ﬂasks, pressurized or not. Topical

dosage formulations are for local (not systemic) effect and

are generally applied to the skin or oral mucosal surfaces.

Some preparations for topical use, such as vaginal and

rectal creams, as well as nasal and otic sprays, may be

considered for marketing in metallic containers.

A number of topical products marketed as a pressur-

ized aerosol may be dispensed in a metallic bottle with a

screw cap. Topical dosage forms in aluminum tubes

usually include a liner. A tube liner is frequently a lacquer

or shellac whose composition should be stated. A metallic

pressurized packaging system for a liquid-based topical

product may deter solvent loss and may provide protection

from light when appropriate.

The droplet size of topical aerosols spray does not need

to be carefully controlled, nor is the dose usually metered

as in case of inhalers. The spray may be used to apply

dosage form to the skin (topical aerosol) or mouth (lingual

aerosol), and functionality of the sprayer should be ad-

dressed. The drug product has no contact with cap and

short-term contact with nozzle. A topical aerosol may be

sterile or may conform to acceptance criteria for microbial

limits. However, physical stability of aerosols can lead to

changes

in total drug

delivered per dose and total number

of doses that may be obtained from the container.

QUALITY CONTROL OF PACKAGING MATERIAL

The acquisition, handling, and QC of primary and second-

ary packaging materials and of printed materials should

be accomplished in the same way as that for the raw

materials. The printed materials should be stocked in a

reserved place so the possibility of unauthorized access is

avoided. The labels and other rejected printed materials

PHARMACEUTICAL PACKAGING 955

should be stored and transported with proper identiﬁca-

tion and before adequate destruction procedure.

The identiﬁcation afﬁxed on the containers, on the

equipment, in the facilities, and on the product containers

should be clear, without ambiguity, and in a format

approved by the company and contain the necessary

data. Besides the text, differentiated colors indicating its

condition could be used (e.g., in quarantine, approved,

rejected, and cleaned).

The packaging materials should attend to the speciﬁca-

tions, giving emphasis to the compatibility of the same

with the drug product that it contains. The material

should be examined with relation to visible physical and

critical defects as well as the required speciﬁcations.

Several regulatory agencies as well as private agencies

[Food and Drug Administration (FDA), United States

Pharmacopeia (USP), World Health Organization (WHO),

British Pharmacopoeia (BP)] (4, 8–10) have issued guide-

lines on the safety evaluation of materials and container

closure systems. However, the ultimate proof of safety and

suitability of a container closure system and the packaging

process is established by full shelf life stability studies. An

important step in such evaluations is characterization of

the packaging materials and the chemicals that can mi-

grate or extract from container closure system components

to the drug product. This extractable material belongs to

diverse chemical classes that can migrate from polymeric

materials, such as antioxidants, contaminants, lubricants,

monomers, plasticizers, and preservatives. Such basic in-

formation is critical to understanding the biological safety

and suitability of a container.

Establishing the safety of container closure systems is

of key importance to the medical and pharmaceutical

industries (Table 1). It is no less important than the

contents themselves. The FDA’s document ‘‘Guidance on

Container Closure Systems for Packaging Human Drugs

and Biologics’’ makes this point clear (4).

While the tests and methods described in Table 4 allow

one to provide data that the container closure system is

suitable for its intended use, an application must also

describe the QC measures that will be used to ensure

consistency in the packaging components (11).

UPDATING ON PACKAGING MATERIALS: FUTURE

DEVELOPMENTS

Within the last 20 years, computer simulations of materi-

als have evolved from an academic curiosity to a predictive

tool for addressing structure–property–processing–perfor-

mance relations that are critical to the design of new

products and processes.

The computational prediction of physical properties is

particularly challenging for polymeric material, because

of the extremely broad spectra of length and time scales

governing structure and molecular motion in these mate-

rials. In a recent paper, Theodoro (12) discuss the funda-

mental underpinnings and presents applications of new

methods and algorithms for the hierarchical modeling of

polymers. It was discussed that quantitative relations can

be established between structure, properties, processing,

and performance of materials.

New packaging materials are being developed. A trans-

lucent PVC alloy having a satin look and soft touch was

designed for use in the cosmetic industry (13). Meneghetti

and Qutubuddin (14) studied and presented the synthesis,

thermal properties, and applications of polymer–clay na-

nocomposites, with potential applications in ﬁlm packa-

ging and gas storage.

In every aseptic ﬁlling application, the sterile transfer

of goods into the aseptic area is a challenge, and there are

many different ways to do it. Thus, different types of

sterilization of packaging materials are being studied

and published (15–17).

Photostabilization of drugs substance in drug products

without protection from packaging materials was studied

by Thoma and Klimek (18), proving that when enwrapped

by the packaging material, the drug product is normally

well protected from the inﬂuence of photodegradation.

Tveit et al. (19) presented a study in which they evaluated

Table 4. Properties of Suitability Concerns and Interactions (3, 11)

Attributes Concerns and Interactions Proposed Methods

Protection Exposure to light, moisture, microbial ingress, and

oxidation from presence of oxygen

USPo661W Light transmission and water vapor

permeation, container integrity (microbial ingress,

dye penetration, helium leak)

Compatibility Leachable induced degradation; absorption or

adsorption of drug, precipitation, change in pH,

discoloration, brittleness of packaging materials

Leachability study (migration of chemicals into drug

product) using LC/MS, GC/MS, ICP/AA, pH,

appearance of drug and container, thermal analysis

(DSC, TGA), and IR

Safety No leached harmful or undesirable amounts of

substances to expose patients treated with drug

Extraction study (USP physicochemical test—plastics),

USP elastomeric closures for injections, Toxicological

Evaluation, USP Biological Reactivity and complies

with CFR, additives and purity

Performance Container closure system functionality, drug delivery Functionality (improved patient compliance or use),

delivery (transfer dose in right amount or rate)

Abbreviations: DSC, differencial scanning calorimetry; TGA, thermal gravimetric analysis; AA, atomic absorption.

956 PHARMACEUTICAL PACKAGING

general patient tolerance to Omnipaque

350 mgI/mL

supplied in polypropylene containers compared to

that of same product supplied in routinely used glass

vials, with emphasis on allergy-like adverse events.

This kind of research proves the importance of pack-

aging material used to protect the pharmaceutical

preparations.

A simple and rapid HPLC method for determination of

di-2-ethylhexyl- phthalate (DEHP) the major plasticizer of

most PVC materials was proposed by Aignasse et al. (20).

Some practical pharmaceutical applications are presented

in order to demonstrate the reliability of the proposed

method for this determination of DEHP in PVC packa-

ging, as well as for traces of DEHP leached on infusion

bags.

During the past 20 years, research interest in the use of

natural biopolymers for the manufacture of ‘‘green’’ biode-

gradable materials, such as ﬁlms and coatings, has greatly

increased. This is to overcome environmental problems

associated with the use of synthetic petroleum polymers

(21). As new biodegradable polymers and their packaging

applications are emerging, there is a need to address their

environmental performance. In particular, there is a need

to understand the time required for their complete degra-

dation, before these materials are deployed in commercial

composting processes (22). For this reason, in some coun-

tries the substitution of plastic products with paper

products is being suggested (23).

The recycling of either model polymers or waste pro-

ducts based on low-density polyethylene (LDPE), high-

density polyethylene (HDPE), or polypropylene (PP), as

well as pyrolysis, was studied by Achilias et al. (24) using

the dissolution/reprecipitation method.

In demand for ‘‘green’’ packaging and consumer goods

applications, chemical and pharmaceutical industries

are introducing new families of all-natural colorants

and additives for use in these environmental friendly

polymers (25).

Biomimetics is a ﬁeld of science that investigates

biological structures and processes for their use as

models for the development of artiﬁcial systems. Biomi-

metic approaches have considerable potential in the

development on new high-performance materials with

low environmental impact. The cell walls of different

plant species represent complex and highly sophisticated

composite materials that can provide inspiration on

how to design and fabricate lightweight materials

with unique properties. Such materials can provide

environmentally compatible solutions in advanced

packaging, electronic devices, vehicles, and sports equip-

ment (26).

BIBLIOGRAPHY

1. J. P. Grifﬁn and J. OuGrady, ed., The Textbook of Pharmaceu-

tical Medicine, 5th edition, Blackwell Publishing Inc., Oxford,

UK, 2006, p. 880.

2. K. Harburn, Quality Control of Packaging Materials in the

Pharmaceutical Industry, Marcel Dekker, New York, 1990,

p. 196.

3. M. I. R. M. Santoro and A. K. Singh, ‘‘Packaging and Label-

ing’’ in S. C. Gad, editor-in-chief, Pharmaceutical Manufac-

turing Handbook: Production and Processes, John Wiley &

Sons, Hoboken, NJ, 2007, pp. 159–200.

4. U.S. Food and Drug Administration (FDA), Guidance on

Container Closure System for Packaging Human Drugs and

Biologics, U.S. Department of Health and Human Services,

FDA, Washington, D.C., 1999.

5. S. Yoshioka, Stability of Drugs and Dosage Forms, Kluwer

Academic Publishers, New York, NY, 2000, p. 272.

6. G. S. Banker and C. T. Rhodes, Modern Pharmaceutics, 4th

edition, Marcel Dekker, New York, 2002, p. 1222.

7. J. Connor, N. Rafter, and A. Rodgers, Bull. World Health Org.

82, 935–939 (2004).

8. United States Pharmacopeia, 31st edition, United States

Pharmacopeial Convention, Rockville, MD, Vol. 1, 2008,

pp. 248–260.

9. World Health Organization (WHO), The International

Pharmacopeia, Tests and General Requirements for Dosage

Forms: Quality Speciﬁcations for Pharmaceutical Sub-

stances and Tablets, 3rd edition, Vol. 5, WHO, Geneva,

2003, p. 371.

10. British Pharmacopoeia, Her Majesty’s Stationery Ofﬁce,

London, UK, 2002.

11. D. E. Albert, Pharm. Med. Packag. News, 3, 76–78 (2004).

12. D. N. Theodoro, Chem. Eng. Sci. 62, 5697–5714 (2007).

13. Solvay Benvic, Plastics Additives and Compounding 3,13

(2001).

14. P. Meneghetti and S. Qutubuddin, Thermochim. Acta 442,

74–77 (2006).

15. T. Sadat and T. Huber, Radiat. Phys. Chem. 63, 587–589

(2002).

16. M. Haji-Saied, M. H. O. Sampa, and A. G. Chmielewski,

Radiat. Phys. Chem. 76, 1535–1541 (2007).

17. F. Reymondon, B. Pellet and E. Marcon, Int. J. Prod. Econ.,

112, 326–335 (2008).

18. K. Thoma and R. Klimek, Int. J. Pharm. 67, 169–175 (1991).

19. K. Tveit, A. N. Dardenne, R. Svihus, J. Fairhurst, G. Jenssen,

L. Lemaitre, J. Grellet, D. Brekke, and K. Skinnningsrud,

Clin. Radiol. 50,

44–48 (1995).

20. M. F

. Aignasse, P. Prognon, M. Stachowicz, R. Gheyouche,

and D. Pradeau, Int. J. Pharm. 113, 241–246 (1995).

21. J. L. Audic, F. Fourcade, and B. Chaufer, Biodegradable

Material Obtained from Renewable Resource: Plasticized

Sodium Caseinate Films in Thermodynamics, Solubility

and Environmental Issues, Elsevier Science, The Nether-

lands, 2007, pp. 369–382.

22. G. Kale, R. Auras, S. P. Singh, and R. Narayan, Polym. Test.

26, 1049–1061 (2007).

23. C. C. Chen, Environ. Int. 32, 478–486 (2006).

24. D. S. Achilias, C. Roupakias, P. Megalokonomos, A. A. Lappas,

and E. V. Antonakou, J. Hazard. Mater. 149, 536–542 (2007).

25. Additives for Polymers; Clariant Masterbatches Division,

(2007), pp. 2–3.

26. T. T. Teeri, H. Brumer III, G. Daniel, and P. Gatenholm,

Tr. Biotech. 25, 299–306 (2007).

PHARMACEUTICAL PACKAGING 957