Pharmaceutical Development and Technology, 7(2), 227–234 (2002)

RESEARCH ARTICLE
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Use of Oxygen Scavengers to Stabilize

Solid Pharmaceutical Dosage Forms:
A Case Study
Kenneth C. Waterman* and Michael C. Roy

Pfizer Global Research and Development, Eastern Point Road, Groton,

CT 06340
For personal use only.

ABSTRACT

A case study is described where degradation of a solid pharmaceutical dosage form

susceptible to oxidation is minimized by incorporation of an oxygen scavenger as
part of the packaging. Extremely low oxygen levels are attainable within 24 hr of
packaging, even with permeable high-density polyethylene bottles commonly used in
the pharmaceutical industry. This packaging methodology allows for a practical
formulation-independent pathway for reducing or eliminating oxidative instability.
In addition, this technology provides a convenient mechanistic probe for the
degradation mechanism of solid dosage forms.

INTRODUCTION used oxygen scavenger, is shown below:

Over the last few years, oxygen scavengers have 4Fe þ 3O2 þ 6H2 O ! 4FeðOHÞ3
found an increasingly wide use in the food industry for
preservation of foods and beverages (1 –4). Mitsubishi ! 2ðFe2 O3 ·3H2 OÞ ð1Þ
Gas Corporation (Tokyo, Japan) introduced iron plus
various salt sachets as the first commercial oxygen 4FeðOHÞ2 þ O2 þ 2H2 O ! 4FeðOHÞ3
scavengers under the trade name Agelesse (5), while
similar products were introduced by Multisorb Tech- ! 2ðFe2 O3 ·3H2 OÞ ð2Þ
nologies, Inc. (formerly Multiform Desiccants, Inc.;
Buffalo, NY) under the trade name Fresh Paxe. The As can be seen, water must also be present for the
metal oxidation reaction with iron, the most commonly reaction to proceed. Water provides the activation

*Corresponding author. Fax: (860) 441-3972; E-mail: ken_waterman@groton.pfizer.com

227
Copyright q 2002 by Marcel Dekker, Inc. www.dekker.com
 228
mechanism used in most applications. Scavengers are
generally stored dry where they can be handled without
consuming oxygen. In the presence of moist foods, the
scavengers are activated and begin removing oxygen. On
the basis of the stoichiometry of the chemical reaction,
300 cm3 of oxygen are consumed per gram of iron. This
means that effectively 1500 cm 3 of air can be
deoxygenated by 1 gram of iron. Since the reaction is
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essentially irreversible, the air around these iron-based
oxygen scavengers will eventually be virtually oxygen
free.
Self-activated oxygen scavengers have been intro-
duced to provide oxygen absorption with dry food
products [see for example Refs. (6,7)]. These involve
combining moisture-holding additives to the metals,
usually iron, in sachets. Such additives include activated
carbon, silica, zeolites, molecular sieves, hydrogels, and
diatomaceous earth.
Plastics containing oxygen scavengers have also
become increasingly prevalent in the new packaging
arena. The simplest of these “stealth scavengers” use the
same metal oxidation process as above, but embed the
For personal use only.
metal in an extrudable plastic [see for example Refs.
(8,9)]. These are activated by moisture, generally by
either being in direct contact with water or having a
permeable co-extruded layer adjacent to the water.
Although these systems are relatively easy and
inexpensive to make, they suffer from relatively low
absorption capacity and high opacity. Another commer-
cial option involves the use of ultraviolet photoinitiated
oxygen-absorbing plastics (10,11). In these systems,
light in combination with a cobalt salt produces a radical
site, which has high reactivity with oxygen. Prior to
photoinitiation, the system is quite stable in air and can
be extruded to provide transparent, “active packaging.”
The plastics are reported to be capable of consuming 45 –
78 cm3 of oxygen per gram of plastic.
For pharmaceutical products, there have been only
limited reports of using oxygen absorbers to stabilize
drugs. For example, in 1984, tablets of an anti-
inflammatory drug were stabilized in large glass jars
with oxygen absorbing sachets for six months at 508C
(12). The source of the oxygen being removed was
primarily from the headspace and not from ingress since
the glass is essentially impermeable. Similarly, cold
remedy powders were stabilized in impermeable bottles
by either nitrogen purging or with oxygen scavengers in
the bottle (13). In a 1990 publication, L -cysteine in an
ophthalmic ointment was stored with an oxygen
scavenger (14). In 1993, stabilization of dopamine
formulations with oxygen scavengers (nonstandard) in
Waterman and Roy
combination with secondary packaging was reported
(15). In 1995, tonic solutions of vitamin C were
stabilized using a bottle cap having an oxygen scavenger
covered with a polyolefin (16). The use of oxygen
scavengers with parenteral drug products has also been
reported (17,18).
Oxygen induced drug degradation often limits shelf
life (expiration date) or may render a drug unmarketable.
In fact, drug candidates that are highly oxygen sensitive
are often excluded from further development. In a
number of cases, oxygen sensitivity occurs only in the
presence of certain excipients. Since oxidation kinetics
are often non-Arrhenius in behavior, there are a number
of drug candidates where the oxygen sensitivity of the
drug is not recognized in accelerated aging studies and
only becomes apparent in the later stages of drug
development. At that point, fixing the stability problem
by reformulation and addition of antioxidants can require
considerable time and money, and may not be successful.
In addition, more clinical data may be necessary with a
new formulation. Therefore, it can often be the case that
use of a packaging option without reformulation for drug
stabilization is quite appealing.
Even in early drug development, there is a need for
oxidation prevention with a new drug candidate to
provide adequate stability for initial studies without
investing significant resources prior to demonstrating a
proof of concept. Once a candidate has been selected for
further development, either use of oxygen scavengers or
more traditional stabilization methods can then be
incorporated. We have also found (as discussed below)
that oxygen scavengers are useful in mechanistic
investigations by verifying that the degradation pathway
is indeed oxidation.
We were interested in determining quantitatively the
efficacy of oxygen scavengers in standard plastic
packaging for solid dosage forms where the active
pharmaceutical ingredient (API) has a high sensitivity to
oxygen. In prior, more qualitative publications, solid
dosage forms were stored in glass bottles rather than the
highly oxygen permeable plastic packaging common in
pharmaceutical applications.
There are three major sources of oxygen in the
permeable bottles typically used in the pharmaceutical
industry: (1) oxygen in the headspace, (2) oxygen that
permeates through the walls, and (3) leakage through the
bottle caps. The amount of oxygen contributed by the
three sources will vary with the size and shape of the
bottle, the type of cap and seal, the permeability of the
bottle material, and the number of tablets in the bottle. To
eliminate oxygen ingress through the bottle cap, we
 Stabilization by Oxygen Scavengers
chose to use heat-induction seal (HIS) closures (19). We
have found that these provide essentially airtight seals in
an easy and practical manner. For these studies, round
bottles made of high-density polyethylene (HDPE) with
a labeled capacity of 60 cm3 and a wall thickness of
0.9 mm (37 mils) were used. Oxygen permeability
through HDPE is reported to be 102 cm3 mm/(m2 d atm)
in one publication (20) and 26.3 cm3 mm/(m2 d atm) in
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another (21). To assure we have adequate oxygen
scavenging capacity, we will assume the higher value.
The bottles used in this study were 4 cm in diameter and
7.3 cm in height giving an approximate surface area of
100 cm2. With a maximum driving force for oxygen
ingress (i.e., zero oxygen inside, 0.21 atm oxygen outside
the bottle), the amount of oxygen permeating into the
bottle over a one-year period can be calculated as
follows:
102 cm3 mm=ðm2 d atmÞ £ 0:21 atm £ 365 d
£ 0:01 m2 =0:9 mm
For personal use only.
¼ 87 cm3 of O2 =year
If the bottle holds 60 cm3 of air (i.e., 11 cm3 of
oxygen) and assuming no volume is occupied by tablets,
then 185 cm3 ð11 cm3 þ 2 £ 87 cm3 Þ of oxygen absorb-
ing capacity will be needed for a two-year shelf life. As
can be seen in this calculation, the initial headspace
oxygen is a minor portion of the two-year oxygen content
available for reaction in an HDPE bottle. Conversely, the
major source of oxygen is due to permeation through the
bottle walls, which is why previous studies involved the
use of glass jars. To be effective in a practical sense (i.e.,
with permeable plastic bottles), oxygen scavengers need
both to match the oxygen ingress rate and to have a
sufficient scavenging capacity to handle the entire shelf
life.
One of the key potential benefits of oxygen
scavengers is their ability to reduce oxidation in a
dosage form without the need for direct contact with the
API. Oxygen scavengers are commercially packaged as
sachets typically made from exterior materials that are
generally regarded as safe (GRAS). As such, they have
been used in a number of food products. On the basis of
their history in foods, and the fact that there is no direct
contact with the API, we anticipate that oxygen-
scavenging sachets will meet with regulatory approval
for use with pharmaceutical products.
To illustrate the effectiveness of the incorporation of
oxygen scavengers in oxygen permeable containers, a
229
drug was selected having a known oxidative degradation
pathway. The oxidative degradation pathway for the anti-
emetic drug candidate 1, as previously reported (22), is
shown in Sch. 1. Although the primary oxidative product
of 1 is the imine 2, this material hydrolyzes readily,
partly in the dosage form and partly during work-up to
give the two products 3 and 4, as shown. A second
oxidative pathway involves the formation of the peroxide
5, which decomposes slowly to the alcohol 6. There also
appears to be an oxidation process converting 1 to the
alcohol 6, which does not go through the intermediate 5.
We speculate that this latter process may be a metal-
catalyzed oxidation with trace oxygen. Metal-catalyzed
oxidations of cumenes to alcohols have been reported in
the literature (23). In conducting these studies, excipients
and processing conditions were chosen such that the drug
was very prone to oxygen-based degradation. In addition,
storage conditions were used to accelerate the degra-
dation, thereby accentuating the beneficial effects of
oxygen removal in a relatively short time. This study was
therefore carried out to determine if indeed oxygen
scavengers could match the oxygen ingress rate and
thereby adequately stabilize oxygen-sensitive formu-
lations even using oxygen permeable packaging contain-
ers common in the pharmaceutical industry.
EXPERIMENTAL
Preparation of Tablets Containing the Active
Pharmaceutical Ingredient
Tablets containing 1 as the API were prepared by first
V-blending for 15 min 162.3 g of 1 (prepared according
to Ref. (24)), 101.1 g of lactose (Fast Flo 316 available
from Foremost Corp., Baraboo, WI), 101.1 g of
microcrystalline cellulose (Avicele PH102) and 19.6 g
of sodium crosscarmelose (Ac-Di-Sole) (both available
from FMC Pharmaceuticals, Philadelphia). Magnesium
stearate (7.8 g) was then added and the mixture was
blended an additional 5 minutes. The blended material
was compressed into tablets using an F-press (Vector
Corp., Marion, IA) equipped with 3/800 SRC tooling.
Tablet weights averaged 392 mg with a hardness of
9.5 kP. Because there was no granulation process used,
there was significant segregation occurring. This resulted
in some potency variability. We therefore chose not to
use a potency analysis when looking at the relatively
small degradation changes. Instead, results are reported
as percentages of the drug peak, by HPLC analysis.
 Pharmaceutical Development and Technology Downloaded from informahealthcare.com by University of Leeds on 08/16/13
For personal use only.

230

Scheme 1.
Oxidative degradation pathways for drug candidate 1.
Waterman and Roy
 Stabilization by Oxygen Scavengers
Packaging Tablets with Oxygen Scavengers
Samples were prepared by placing the indicated
materials in round, white HDPE bottles (60-cc capacity)
and sealing with HIS closures (33/400) using a Enercon
Industries Corp. (Tulsa, OK) demonstration unit
induction sealer with a 1-sec dwell time at 80% output.
Sample-1 (Control): 45 placebo tablets plus one tablet
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containing 1 (no oxygen scavenger added)
Sample 2: 45 placebo tablets plus one tablet
containing 1 and one 100 cm 3 Agelesse sachet
(Mitsubishi Gas Chemical Company, Tokyo).
Sample 3: 45 placebo tablets plus one tablet
containing 1 and two sachets of 50D Fresh Paxe (total
of 100 cm3 oxygen absorbing capacity; Multisorb
Technologies, Inc., Buffalo, NY).
Sample 4: 45 placebo tablets plus one tablet
containing 1 and four ZPTJe sachets (total of 120 cm3
of oxygen absorbing capacity; Mitsubishi Gas Chemical
Company, Tokyo).
Stability Testing and Analysis
For personal use only.
Packaged tablets were stored 18 weeks under three
different conditions: (1) 58C/75% relative humidity (RH);
(2) 408C/75% RH; and (3) 508C/20% RH. Air in the
bottles was sampled using a gas tight syringe. A rubber
septum was placed on the HIS foil to allow for air-tight
sampling of the headspace gas. The sampled air was
analyzed using a zirconium –oxygen headspace analyzer
(PAC Check 450; available from Mocon Corp.,
Minneapolis, MN). An extraction and mobile phase
solvent for degradation analysis was prepared by first
dissolving 21.6 g of octane sulfonic acid and 6.8 g of
potassium phosphate in 1.0 L of purified water. The pH
was adjusted to 3 with phosphoric acid followed by the
addition of 818 mL of acetonitrile. Degradation products
were identified using a Hewlett-Packard 1100 series
HPLC system (Waters symmetry C8 column, 3.9 mm
ID £ 150 mm; column temperature, 408C; injection
volume, 20 mL; flow rate, 1.0 mL/min; run time, 45 min,
isocratic; ultraviolet detection at 229 nm). The degra-
dation products were analyzed by comparing three known
standards of 3, 4, and 6 with relative retention times of
0.36, 0.10, and 0.21, respectively. A peak with a relative
retention time (relative to the peak for 1) of 0.26 has been
tentatively identified as 5 based on mass spectral data.
Because of the lack of a standard for 5, the data are
reported as area percent rather than weight percent as with
the other products. For each time point, a single tablet was
analyzed due to the limited supply of tablets.
231
RESULTS AND DISCUSSION
In packaging tablets of an API with an oxygen
scavenger in common HDPE bottles with HIS closures,
we hoped to determine whether oxygen scavengers
could be a practical method for stabilizing pharmaceu-
tical formulations. Toward this end, we used three
representative oxygen scavengers, all of the self-
activating type. Each of these scavengers is designed
for optimal performance at room temperature and above.
Although oxygen scavengers that work optimally at
lower temperatures are available, for this and most
drugs, low temperature stability is adequate even
without oxygen scavenging. Samples were stored
under conditions designed to accentuate the oxidation
reaction as well as under control conditions (58C). It
should be noted that the use of the 58C samples as
controls appears justified both because of similar
impurity levels to the initial API and because of the
observed 58C stability. Tablets were removed from the
packaging and analyzed at either 7 or 18 weeks. The
results of this analysis are summarized in Table 1.
Without the presence of an oxygen scavenger, the level
of oxidative degradants increases dramatically at
elevated temperatures. The total degradant level after
seven weeks at 408C/75% RH was found to be about
1.1% above the level of degradants present either
initially in the API or under the 58C storage conditions.
With each of the oxygen scavengers, the total degradant
level above the initial degradant level for 7 or 18 weeks
at 40 and 508C is reduced with the oxygen scavengers.
The overall amount of the degradant 4 decreases with
the addition of oxygen scavengers and increasing
temperature, thus leading to an overall decrease in the
percent degradants with increased temperature. This
slow decomposition of 4 does not lead to a significant
corresponding increase in other HPLC peaks. We
assume that the primary amine 4 reacts with the lactose
present in the formulation in a Maillard type reaction to
give products not extracted in our methods (25).
Consistent with this, tablets appeared brown after
elevated temperature storage.
As part of this investigation, we also examined the
oxygen levels in the bottles. The results of these
studies are shown in Table 2. As can be seen in each
case, the level of oxygen is reduced dramatically. At
58C, the oxygen consumption rate is slowed such that
the level of oxygen in the bottles is low, but still much
higher than seen with the higher temperatures.
Commercial oxygen scavengers formulated to function
at lower temperatures are available. Fortunately, for
 232 Waterman and Roy

Table 1
3
Stability of Compound 1 Packaged in 60 cm High-Density Polyethylene Bottles with Heat-Induction Seal Closures. Weight Percents
Refer to the Percent of the Active Pharmaceutical Ingredient (API) (1). Area Percents are the Percent of the Total Area

Product

Test Condition Weeks Wt% 3 Wt% 4 Area% 5 Wt% 6 Area%a Total Area%
API Initial 0 0.000 0.300 0.03 0.027 0.01 0.20
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1-control 58C/75% RH 7 0.006 0.336 0.03 0.029 0.01 0.23

18 0.000 0.305 0.02 0.028 0.02 0.21
408C/75% RH 7 0.134 0.703 0.52 0.166 0.09 1.29
18 0.107 0.546 0.66 0.266 0.08 1.41
508C/20% RH 7 0.084 0.488 0.84 0.252 0.08 1.50
18 0.079 0.393 1.14 0.288 0.09 1.81
2-added Agelesse 58C/75% RH 7 0.011 0.329 0.03 0.032 0.01 0.23
18 0.002 0.303 0.02 0.030 0.01 0.20
408C/75% RH 7 0.000 0.246 0.02 0.046 0.01 0.18
18 0.002 0.139 0.02 0.049 0.02 0.15
508C/20% RH 7 0.000 0.141 0.03 0.047 0.00 0.13
18 0.003 0.105 0.01 0.060 0.02 0.15
3-added Fresh Paxe 58C/75% RH 7 0.006 0.330 0.03 0.032 0.01 0.22
18 0.005 0.310 0.02 0.034 0.01 0.21
408C/75% RH 7 0.004 0.250 0.02 0.047 0.01 0.19
For personal use only.

18 0.003 0.191 0.01 0.049 0.02 0.18

508C/20% RH 7 0.003 0.159 0.01 0.058 0.01 0.15
18 0.004 0.098 0.01 0.056 0.01 0.12
4-added ZPTJe 58C/75% RH 7 0.004 0.340 0.03 0.031 0.01 0.23
18 0.002 0.314 0.02 0.029 0.01 0.20
408C/75% RH 7 0.003 0.172 0.04 0.048 0.02 0.18
18 0.003 0.125 0.03 0.055 0.02 0.17
508C/20% RH 7 0.000 0.121 0.05 0.068 0.02 0.18
18 0.004 0.099 0.05 0.109 0.03 0.23
a
Unknown product with relative retention time of 0.12.

Table 2
Oxygen Levels in 60 cm3 High-Density Polyethylene Bottles with Heat-Induction Seal Closures After Storage

Test Storage Conditions Time Oxygen Level (mol%)

Control 58C/75% RH 18 wks 21.0
408C/75% RH 18 wks 19.9
508C/20% RH 18 wks 19.0
with Agelesse 58C/75% RH 7 wks 1.1
258C/40% RHa 1d 0.0
408C/75% RH 7 wks 0.0
508C/20% RH 18 wks 0.3
with Fresh Paxe 58C/75% RH 7 wks 2.2
408C/75% RH 7 wks 0.0
508C/20% RH 18 wks 0.0
with ZPTJe 58C/75% RH 7 wks 0.7
408C/75% RH 7 wks 0.0
508C/20% RH 18 wks 0.0
a
Packaged without tablets.
 Stabilization by Oxygen Scavengers
the majority of pharmaceutical products, oxidation
kinetics is also slowed at lower temperatures. In
packaging with the Fresh Paxe oxygen absorber,
oxygen levels in a bottle were measured after 24 hr
at room temperature. The oxygen level was found
to be 80 ppm, indicative of the rapid rate that the
oxygen scavenger was able to consume the headspace
oxygen.
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by University of Leeds on 08/16/13
In mechanistic investigations, it is often useful to
know whether oxygen is involved in the rate-limiting
step for degradation processes. Commonly, tests are
conducted by degassing samples in bottles fitted with
rubber septa. We have carried out a number of such
degassing experiments and have found that the level of
oxygen in bottles remains at 2 –3% after even several
hours of purging. Only with a vacuum step does the
level of oxygen drop much below 2 – 3%. In contrast,
oxygen scavengers achieve and maintain much lower
oxygen levels in a facile packaging scheme, thereby
providing an easy method for evaluating oxygen
sensitivity for drug substance, powder blends, com-
pacts, and final dosage forms. By knowing the oxygen
For personal use only.
sensitivity at an early stage of development, it may be
possible to choose appropriate salt forms, excipients,
and processing conditions to minimize instability
issues. This information can also be useful in
determining which antioxidants are appropriate for
stabilization (26).
CONCLUSIONS
Self-activated, iron-based oxygen scavengers used
widely in the food and beverage industries are quite
effective in stabilizing pharmaceutical formulations
through adaptations to common packaging systems,
provided the dosage form can tolerate relatively high
humidity. For a model drug compound, rapid oxidative
degradation is eliminated effectively by the addition of
the oxygen scavengers. These scavengers do not
involve direct contact with the dosage form, and are
expected to meet regulatory requirements for safety.
Even with the permeable HDPE packaging commonly
used in the pharmaceutical industry, the amount of
scavenger needed for multi-year shelf life is manage-
able and will generally not add significantly to the cost
of goods.
Once a package is opened, the scavenger can be
quickly consumed. Thus, a separate expiry period may be
required for opened and closed bottles. Alternatively,
blister packaging with oxygen absorption capacity could
233
be utilized such that single doses can be maintained
under anaerobic conditions.
The use of oxygen scavengers is appealing for solving
stability issues with commercial products. Additionally,
this technology can readily be implemented with early
drug development where a proof of concept for a drug
can be established without having to modify a
formulation as a solution to a stability problem. In the
event the drug progresses, it may be that a formulation
solution is still more desirable; however, the timesavings
involved in generating the proof of concept data may
justify the use of scavengers in early development stages.
ACKNOWLEDGMENTS
The authors would like to acknowledge the sugges-
tions and initial contacts for oxygen scavenger producers
from Dr. Karen Alsante and Mr. Robert Bergeson (at
Pfizer). The assistance of Mr. Nimish Shah, a summer
intern who helped with this project, was essential in
getting this work off the ground. Dr. Scott Smith and Mr.
Hai Wang (at Pfizer) provided help in identifying a drug
formulation with the requisite instability issues. Dr. Joel
Hawkins (at Pfizer) helped with rationalizing some of the
stability results. We would also like to acknowledge
Mitsubishi Gas Corp. and Multisorb Corp. for samples of
their oxygen scavengers.
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