Rapid Headspace Oxygen Analysis
for Pharmaceutical Packaging Applications
Allen C. Templeton,* Yieng-Hau R. Han, Rajiv Mahajan, Rey T. Chern, and Robert A. Reed
The accurate
determination
of headspace
oxygen levels
in common
STEVE SMITH
pharmaceutical
packaging
configurations
presents several analytical challenges in
terms of both sampling and measurement.
This article reviews headspace gas
chromatography, electrochemical analysis,
frequency-modulation spectroscopy,
fluorescence quenching, and quadrupole
mass spectrometry as methods available to
packaging R&D technologists and
laboratory analysts for rapid headspace
oxygen analysis. The article describes the
strengths and limitations of each approach.
Allen C. Templeton, PhD, is a senior
research chemist in the pharmaceutical
analysis and control department at Merck
Research Laboratories, WP78-210,
Sumneytown Pike, West Point, PA 19486,
tel. 215.652.9204, fax 215.652.2835,
allen_templeton@merck.com. Yieng-Hau
R. Han is a research associate in the
pharmaceutical analysis and control
department; Rajiv Mahajan, PhD, is a
senior research chemical engineer and Rey
T. Chern, PhD, is a senior research fellow
in the packaging systems development
department; and Robert A. Reed, PhD,
is a director in the pharmaceutical analysis
and control department, all at Merck
Research Laboratories.
*To whom all correspondence should be addressed.
44 Pharmaceutical Technology JULY 2002
O
xidative degradation of drug substances in pharma-
ceutical formulations is well documented (1). Although
exact mechanistic details about what promotes reac-
tions between drug substances (RH in the schematic
below) and molecular oxygen in pharmaceutical formulations
is not understood fully, such reactions are generally thought to
be in the category of auto-oxidation processes as described by
the following schematic (2):
Initiation RH R

Propagation R

O2 ROO

ROO

RH ROOH
R

Termination 2ROO
molecular products
Molecular oxygen is involved in the propagation step of this re-
action, and it is an integral part of the catalytic cycle that gen-
erates the oxidative degradation of drug substances in pharma-
ceutical formulations.
Oxidative degradation of the active drug substance in a for-
mulation decreases drug potency and reduces product shelf
life (2). The rate of oxidative degradate formation is propor-
tional to the structural susceptibility of the specific drug sub-
stance to auto-oxidize and to storage (reaction) conditions
such as temperature, humidity, oxygen concentration, and time.
Other deleterious effects of oxidative processes include prod-
uct discoloration, changes in dissolution rate and profile, pre-
cipitation, and the generation of foul odors and flavors (1).
Most important, oxidative degradation products generated in
the final pharmaceutical product during storage may also have
adverse pharmacological properties, including those associ-
ated with toxicity or negative side effects.
Drug oxidation can also pose significant challenges during
manufacturing processes, particularly for easily oxidized drug
substances. The effects are especially pronounced in formula-
tions that require manufacturing unit operations to be per-
formed in solutions or suspensions. In such cases, extra care
may be required to minimize or eliminate exposure to oxygen.
Inert-gas purging to lower solution oxygen levels as well as inert
blanketing of process vessels have long been used in parenteral
manufacturing processes. Besides purging at key manufactur-
ing steps — for example, during drug compounding or while
holding a drug in solution before lyophilization — packaging
with an inert blanket over the final product also protects paren-
teral formulations that are susceptible to oxidation. Removing
www.phar mtech.com
one of the two key reactants in the auto-oxidation cycle from
the package may lengthen product shelf life and ensure prod-
uct quality when it reaches the consumer. Modified atmosphere
packaging (MAP), a process used to package oxygen-sensitive
commercial products such as foodstuffs and medical devices in
an inert atmosphere, can be used to increase shelf life. Although
MAP has taken hold in the parenteral pharmaceuticals indus-
try, relatively few solid dosage forms are packaged under re-
duced oxygen levels.
Smart packaging methods such as MAP may advance the com-
mercial development of oral formulations with drug compounds
that are particularly prone to oxidation and thus make available
critical therapeutic agents in a high-quality, stable, and conve-
nient dosage form. Integrating formulation and packaging im-
provements could stabilize these compounds and shorten their
development cycle. The implementation of MAP for solid dosage
forms is clearly on the horizon.
The key components to successfully using MAP for an oxygen-
sensitive product are
● packaging that furnishes an effective barrier to oxygen per-
meation
● incorporation of an inert gas–flushing step that is compa-
tible with the speed of current product packaging lines
● selection of an appropriate inert gas (e.g., argon, nitrogen, or
carbon dioxide)
● rapid means to measure residual headspace oxygen content
in various pharmaceutical packaging configurations that range
from very low volume (tens to hundreds of microliters) to
relatively high volume (milliliters to liters).
Fast, sensitive methods for monitoring headspace oxygen
levels would greatly benefit the development and use of MAP
and facilitate its implementation in packaging R&D, manu-
facturing process development, and final product quality assur-
ance. For packaging R&D, robust oxygen measurement meth-
ods would enable real-time screening of the suitability of
packaging systems (all components of a container and closure)
for MAP packaging applications. The most obvious example
is the determination of oxygen ingress kinetics for a packag-
ing system under both realistic and accelerated storage condi-
tions. Experimental data could be used to develop predictive
models for each critical packaging system component to sup-
port future MAP development programs.
For manufacturing process development, rapid and accurate
oxygen determination in the development feedback loop would
benefit the scale-up and validation of a manufacturing process
that implements maximum package throughput per unit time
while achieving and maintaining critical threshold levels for
oxygen. Tools that provide quality assurance and quality con-
trol information at-, on-, or off-line would ensure that the oxy-
gen content of the inert atmosphere in the packaging container
headspace is below the predetermined specification for the prod-
uct. Such testing also could assess the container-closure integrity
and could augment or replace current microbial ingress mea-
surement methods that are based on sterility assessment.
The rapid and accurate determination of headspace oxygen
levels in the various packaging forms used in the pharmaceu-
tical industry poses several unique analytical challenges that
are beyond the capabilities of a single measurement technique.
This article describes various measurement options that are
available to packaging R&D technologists and laboratory an-
alysts in the context of pharmaceutical packaging applications.
The article is organized by technique, with a brief introduc-
tion to measurement principles followed by a discussion of
pharmaceutical packaging applications.
Experimental
Sample preparation. Standards that contained various concen-
trations of oxygen in nitrogen were prepared from double gravi-
metrically certified gas cylinders (Scott Specialty Gases, Plum-
steadville, PA). The concentrations were 0.00, 5.0, 10.0, 15.0,
and 20.0% oxygen in nitrogen. Vials filled with air (20.9% oxy-
gen) were substituted in some experiments for a 20.0% stan-
dard. In brief, gas from each respective cylinder was fed slowly
into a portable glove bag (Spilfyter, Thomas Scientific, Swedes-
boro, NJ) by means of a short length of Tygon tubing. After
purging for 30 min to remove residual atmosphere (longer
purge times provided no benefit), 10-mL clear glass vials (25
 54 mm Type I untreated, Kimble/Kontes, Vineland, NJ) each
were filled under a given atmosphere, and 20-mm gray rubber
stoppers (S-87J, 4405/50, West Pharmaceutical Services, Li-
onville, PA) immediately were positioned into the vials. After
nearly 50 vials were filled, they were removed from the bag,
and an aluminum flip-top cap was crimped into place on each
vial. Using an oxygen–carbon dioxide analyzer (CheckMate
9900, PBI Dansenor A/S, Ringstëd, Denmark), vials from each
prepared lot were analyzed immediately and after three months’
storage in ambient laboratory conditions (19–22 C, 45–55%
RH) for changes in relative oxygen levels. Comparisons of the
two timepoints confirmed that no oxygen had leaked into the
vials. In fact, this vial–closure combination, which is used for
commercial parenteral pharmaceutical products, has been
shown to maintain headspace integrity for at least two years.
Although the previously described sample preparation
method undoubtedly fails to produce the exact concentrations
of gases in the prepared vials as those provided in the corre-
sponding certified cylinders, the use of these vials for relative
comparisons of the capabilities of each technique should be
valid. For the purposes of the experiments, the vial contents
(vial-to-vial variability in each lot was found to be very low)
are understood to be the same as those of the respective fill
tanks. Of course, any attempt at an absolute measurement of
vial oxygen contents with any given analytical method will be
subject to the same technique biases that this report attempts
to address. To facilitate comparison, for a given concentration,
vials from the same lot of prepared samples were used for com-
parative purposes for all five measurement techniques. For ex-
ample, of the nearly 50 vials prepared at 5.0% oxygen levels,
five were reserved for measurement for all five techniques ex-
amined in the study. Measurement of relative vial-to-vial con-
tent variability using the CheckMate 9900 oxygen–carbon diox-
ide analyzer indicated excellent content uniformity (no
differences) among five randomly pulled vials.
Instrumentation. Headspace gas chromatography (GC). Headspace GC
was implemented using a GC system (HP 6890, Agilent Tech-
Pharmaceutical Technology JULY 2002 45
 surements. The instrument was allowed to equi-
librate for 30 min before taking measurements.
Soap-bubble meter The sample holder was purged constantly with
Recorder
dry nitrogen set at a flow rate of 3 standard
L/min, and measurements were acquired at a
Syringe sampling rate of 100 Hz.
Detector Fluorescence quenching. A miniature spectrom-
Flow Electrometer
Two-stage splitter or bridge eter (SF2000, Ocean Optics, Inc., Dunedin, FL)
pressure Rotometer Injector equipped with a 300-m bifurcated optical
regulator fiber and a 21-gauge, custom-designed needle
A/D probe was used for oxygen analysis. The cus-
tom needle probe consisted of a 2-mm shaft
Flow
controller opening offset by 2 mm from the pointed tip
Data of the needle. The blistal end of the aluminum-
Carrier-gas Column
system clad bifurcated optical fiber was fed into the
supply needle and exposed at the shaft opening. The
exposed optical fiber tip was coated with a fluo-
Column oven rophore sol-gel film. Fluorescence intensity as
a function of oxygen concentration was moni-
Figure 1: The components of a typical GC instrument.
tored by means of the same fiber at a charge-
coupled device 2048-element silicon detector
array.
nologies, Wilmington, DE) equipped with a thermal conduc- Quadrupole mass spectrometry. A quadrupole mass spectrometer
tivity detector. Separations were performed using an HP porous equipped with a miniature array of nine quadrupole mass ana-
layer open tubular (PLOT) Molesieve 5-Å column (30 m long lyzers (Micropole, Ferran Scientific, San Diego, CA) was used for
 530 m i.d.) with 50-m film thickness (Agilent). The thin- oxygen determination. The system’s roughing and turbomole-
film HP PLOT Molesieve 5-Å capillary column is a fused- cular pumps achieved low base vacuum pressures (<107 Torr).
silica column coated with a homogeneous layer of 50-m-thick A thoriated iridium electron source ionized the sample before
5-Å molecular-sieve zeolite stationary phase. Because of the quadrupole mass filtering. The ions formed at the source were
column’s sensitivity to moisture, a moisture trap was installed extracted and focused into the entrance apertures of the quadru-
in-line with the carrier-gas feed. Injections were performed pole array by a series of lenses. Detection was achieved at a Fara-
with a 25-L gas-tight locking syringe (Hamilton, Reno, NV) day cup positioned at the opposite end of the quadrupole array.
fitted with a 22S-gauge needle with a #2 point style. Chroma- The instrument was operated in a trend gas–only mode wherein
tographic conditions were as follows: the analysis residence time per each gas monitored was set to
● carrier gas: helium (2 mL/min) 4.5 s, and the partial pressures of each monitored gas were
● oven temperature: 26 C recorded during the course of the measurement. An analog mass
● inlet: 160 C, split mode, 10:1 split ratio, 20 mL/min split flow spectra output that allows for species identification throughout
● injector: 160 C the mass range (2–300 amu) of the detector was used.
● run time: 10 min

● TCD detector: 160 C. Headspace GC

A series of standards and system-suitability samples also was Principles of operation. When a problem arises in a pharmaceu-
analyzed. tical research laboratory that requires analysis of a headspace
Electrochemical methods. The authors used the CheckMate 9900 sample, headspace GC is probably the first method that comes
oxygen–carbon dioxide analyzer equipped with a solid-state to mind for solving the problem. This approach is reasonable
zirconia ion-selective electrode for oxygen determination and given that a vast body of knowledge, stretching back 40 years,
a nondispersive infrared spectrometer for carbon dioxide mea- describes its theory and application (3). Although headspace
surements. The instrument was warmed up for 10 min before GC is an analytical problem-solving tool with capabilities far
measurements were taken and was calibrated according to the beyond the bounds of oxygen analysis, other techniques can
vendor’s specification. The instrument was set to withdraw provide similar or better results for specific headspace analytes,
2 mL of headspace sample using a small internal-diaphragm often in a more timely and simplistic fashion. The following
pump that fed the sample into a small cell that contained the description of headspace GC is intended only as a cursory
measurement electrode. The carbon dioxide measurement mod- overview. The authors refer those who are interested to the sub-
ule was turned off during the experiments. stantive literature about the topic for greater detail (3).
Frequency modulation spectroscopy. A headspace oxygen analyzer GC is inherently a technique for the study of volatile com-
(FMS-760, Lighthouse Instruments, Charlottesville, VA) equipped pounds. Figure 1 is a schematic of the components that con-
with a tunable diode laser source (762 nm) and photodiode de- stitute a typical GC instrument that is equipped with a split
tector was used for frequency modulation spectroscopic mea- injection port and a capillary column. For headspace sampling,
46 Pharmaceutical Technology JULY 2002 www.phar mtech.com
a gaseous sample is introduced by injection into an inert mov-
ing gas stream called the mobile phase or carrier gas.
The mobile phase transports the sample onto a stationary
phase where the components of the sample are separated by
means of selective partitioning between stationary and mobile
phases. The time, referred to as retention time (tR), that elapses
between sample introduction and the point at which peaks ap-
pear at the detector is characteristic of the properties of the ana-
lyte molecules. The area of the respective peaks as they appear
in the resultant chromatogram is proportional to the analyte
concentration in the sample, as related by a measurable response
factor. As applied to the analysis of oxygen in pharmaceutical
packaging applications, a sample of headspace (tens of micro-
liters) is removed from a package by withdrawing a portion of
sample with either a gas-tight syringe or a GC autosampler to
pressurize the container with mobile phase to displace an aliquot
of sample. Performing the experiment in either manner requires
operation in what is referred to as the static mode of headspace
sampling, wherein the goal is to sample the equilibrium con-
tents of a package headspace at a given instance.
Figure 2, which shows an example chromatogram of lab air,
illustrates the determination of headspace oxygen by means of
a megabore capillary column with thermal conductivity detec-
tion. Specific experimental conditions for the analysis are de-
scribed in detail in the “Experimental” section of this article.
As in any type of chromatographic analysis, selection of the ap-
10) of oxygen for the technique was estimated at 0.25%
propriate column to achieve separation of the sample gas mix-
ture into its various components is pivotal.
To separate oxygen from argon and nitrogen in an air sample
during a 10-min analysis, the authors used a commercially avail-
able thin-film PLOT capillary column consisting of a fused-
silica capillary tube coated with a homogeneous 50-m-thick
zeolite molecular sieve (5-Å pore size) film. The mode of sepa-
ration is based on the size of the analyte molecule or atom;
retention time is as follows: nitrogen > oxygen > argon. The net
area and area percentage of oxygen are determined using the
following equations
 He   x
AreaNet, x  AreaRaw, x
 He
AreaNet, x
AreaNet, x %  100%
AreaNet, Ar
AreaNet, N
AreaNet, O
in which x is argon, nitrogen, or oxygen; AreaRaw,x is raw peak
area of x (mV s); AreaNet,x is net peak area of x after conversion;
He is the conductivity of helium (154.6 W/m K); and x is the
conductivity of argon (17.8 W/m K), nitrogen (25.9 W/m K),
or oxygen (26.2 W/m K) (4).
The authors evaluated the linearity of headspace GC for the
determination of oxygen in the range of 0.00–20.9%. A gas-
tight locking syringe was used to extract and manually inject
25 L from the contents of vials that contained 0.00, 5.0, 10.0,
or 15.0% oxygen, and lab air (see the “Experimental” section
for details about sample preparation). As previously mentioned,
48 Pharmaceutical Technology JULY 2002
for a given concentration, vials from the same lot of prepared
samples were used for comparative purposes for all five tech-
niques discussed in this report. The technique displayed good
linearity throughout the concentration range explored (r2
0.9903; data not shown), but a substantial y offset was observed
that was studied in subsequent experiments. A series of experi-
ments was performed to examine
● amount of leakage of the package during sample removal
● syringe leakage during sample transport from package to in-
strument
● septum port leakage during sample introduction.
For the type of sample studied, all three sources showed neg-
ligible amounts of sample contamination.
Another source of bias introduction that was examined was
residual air from the syringe barrel. Three sizes of syringe
needles were used, and a direct correlation between bias and
syringe-barrel volume was observed. Purging the syringe-
needle volume with carrier gas before sampling reduced bias
from 4689.9 area counts by approximately tenfold, giving 0.08%
for the 0.00% oxygen standard. Precision was evaluated by per-
forming five replicate analyses (with a 22S-gauge needle, no
purging) of 20.9% (air, high) and 0.00% standards (low); these
experiments yielded an average of 22.1% and 0.83% with a
relative standard deviation (RSD) of 1.6% and 10%, respec-
tively. The limit of quantitation (LOQ) (signal to noise [S/N]
without purge and 0.025% with purge step. However, sampling
bias must be understood for any specific system before accu-
rate data at low levels can be realized.
Applications. The use of headspace GC to analyze oxygen in
pharmaceutical packaging configurations offers several ad-
vantages such as the widespread availability of instruments and
user familiarity. For sample containers of appropriate dimen-
sions, the autosampling capability of commercial headspace
GCs makes the instrument particularly appealing for analyz-
ing samples en masse. GC autosampler vial dimensions typi-
cally are not consistent with common pharmaceutical package
sizes, thus the use of an autosampler usually is limited to
either a few samples of appropriate dimension or samples that
can be transferred to headspace autosampling vials. The latter
would defeat the purposes of many of the investigations
described in this article.
Withdrawing and injecting samples manually with a gas-tight
syringe can pose various problems. For example, when work-
ing with samples that are under vacuum, pressure equalization
with ambient air can lead to sample dilution and erroneously
large values for oxygen. Therefore, one must use a gas-tight
locking syringe and institute appropriate controls as described
in the previous discussion. Moreover, one must carefully re-
move samples from packages to avoid introducing ambient at-
mospheric leakage during the sampling process. Our experi-
ence showed that applying a self-adhesive rubber septum before
puncturing the sample usually was sufficient as a preven-
tative measure when puncturing aluminum foil (e.g., foil
induction–sealed high-density polyethylene [HDPE] bottles).
Sealing samples with rubber stoppers (e.g., lyo vials) usually
provides an adequate barrier to leakage during sampling. Sam-
www.phar mtech.com
 O2 REF
E RT ln
240 nF O2 UNK
Nitrogen
200 in which E is potential (V), R is the gas constant (J/K), T
is the temperature (K), n is the number of electrons trans-
Intensity (mV)

160
ferred, and F is the Faraday constant (J/V) (5).
120
Oxygen In practice, the measurement procedure involves punc-
turing the package and removing 2–4 mL of headspace for
80 purging and subsequent analysis in a small cell that con-
tains the electrode. The analysis is rapid, typically requir-
40 ing 5 s. The measurement is not adversely affected by hu-
Argon midity, but the sensor can be damaged if it is inadvertently
exposed to liquid samples. Some commercial instruments
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0
simultaneously measure oxygen and carbon dioxide levels
Time (min)
in headspace samples and are available with sampling acces-
sories for a variety of package containers (e.g., aluminum
Figure 2: An example chromatogram illustrating the determination of
cans, beer bottles). Other commercial electrochemical
headspace oxygen by GC with a PLOT molecular sieve column with thermal
oxygen-analysis techniques are based on the direct reduc-
conductivity detection.
tion of oxygen at a planar gold electrode (Clark techniques
or modifications thereof), but the authors found these tech-
pling errors are common to all destructive headspace oxygen niques to offer no advantage compared with those that are de-
analysis methods, and they demonstrate the difficulties of quan- scribed in this article, thus they are not discussed.
titatively measuring small amounts of an oxygen analyte with- In the present study, a single-point calibration of the instru-
out contaminating it with air. Despite problems with sample ment in laboratory air was performed (yearly calibration typi-
removal, the low absolute sample volume requirements (tens cally is advocated), followed by immediate analysis of a set of
of microliters) make static headspace GC an attractive and po- prepared standards (see the “Experimental” section). The lin-
tentially useful analysis tool for pharmaceutical packaging forms earity of the analytical method was evaluated for oxygen over
of all types and sizes. the range of 0.00–20.9%, and the technique was found to de-
In addition to sample introduction, the major limitations of liver good linearity (r2 0.9984; data not shown). The authors
this technique for the analysis of oxygen are the requirement of evaluated precision by performing five replicate analyses of
a relatively lengthy separation step (a few minutes at best) to be 20.9% (air, high) and 0.00% standards (low). These experiments
oxygen selective, the need to assess appropriate standards, and yielded an average of 20.6% and 0.11% with an RSD of 0.00%
the need to demonstrate system suitability throughout the analy- and 13%, respectively. The vendor-indicated LOQ for the par-
sis of a sample set. Although traditionally a GC instrument has ticular instrument was 0.0001% (1 ppm). As with GC, sampling
a large footprint that would make at-line work unfeasible, the errors may contribute to the observed bias, as discussed later
recent commercial development of portable GC units (some- in this article.
times termed micro-GCs) is beginning to make at-line sam- Applications. The sample-volume requirements of electro-
pling more feasible. chemical methods limit the use of this analysis approach to
large-dimension pharmaceutical packaging types with 2-mL
Electrochemical methods headspace volume such as HDPE bottles, glass vials, and blis-
Principles of operation. The use of electrochemical methods for ter packages (individual blisters) of sufficient volume. The
oxygen analysis also has long historical precedence from both rugged character of such instruments and their ease of use make
a scientific and a commercial perspective. The basis of opera- the technique particularly suited for the manufacturing setting.
tion of most commercial electrochemical headspace-oxygen
analyzers is a solid-state zirconium oxide ion-selective elec- Frequency-modulation spectroscopy (FMS)
trode (5). With this type of sensor, oxygen ions migrate into Principle of operation. Recently commercialized for package in-
defect sites in the ceramic lattice structure of zirconia at ele- spection applications, FMS is a high-sensitivity laser absorp-
vated temperatures (>400 C). As has been known since the tion technique for nondestructive monitoring of gas concen-
time of Nernst (1899), when gases of differing concentrations trations in optically transparent containers (6). Oxygen absorbs
reside on opposite sides of an electrode membrane, a measur- near-infrared (NIR) light in a band of rotational transitions
able potential (E) difference is generated. If one side of the centered at 762 nm. Oxygen absorbance measurements at this
membrane is exposed to gas of reference-oxygen concentra- wavelength with standard spectrometers that use incoherent
tion ([O2]REF), then the potential generated in the presence of white-light sources lack the sensitivity to provide a useful mea-
a gas of unknown oxygen concentration ([O2]UNK) is propor- sure of headspace oxygen levels because of low-frequency lamp
tional to the difference in oxygen concentration across the intensity fluctuations. However, the measurement of S/N can
membrane, as shown by the Nernst Equation be improved vastly (100–10,000 ) with laser-light sources and
50 Pharmaceutical Technology JULY 2002 www.phar mtech.com
 cies, c  . When the laser is scanned through
(a) the wavelength of oxygen absorbance, the amount
of light absorption, which is proportional to the
Recorder
c   c  
gas concentration, is “written” into the side-band
c c c
frequencies by recording the difference in absorp-
c
 c

tion between the two side bands. The differential
(b) absorption information is recovered by means of
Current and
Diode phase-sensitive detection techniques. Figure 4
temperature Sample Detector
controller
laser shows the demodulated absorption line shape. The
amount of light that is absorbed is directly pro-
portional to oxygen concentration. The gas den-
Mixer
Scan rf Lo RF sity, n, is related to the peak-to-peak signal am-
Amp
controller oscillator plitude, I, according to Beer’s law, which for a
IF Data weakly absorbing molecule is shown by
system
••
n cm3
A/D converter I o•S •x
Computer
in which  is the change in intensity of light after
passing through the container (W/cm2),  is the
full width at half maximum of the absorption sig-
Figure 3: a) Frequency and intensity profile of a diode laser beam, from left to right:
nal (cm1),  is a constant, Io is the incident laser
unmodulated, modulated with no absorption, and modulated with absorption by the
intensity (W/cm2), S is the integrated absorption
upper sideband. b) Schematic diagram of an instrument for frequency modulation
cross section (cm2  cm1), and x is the container
spectroscopy. The frequency modulated diode laser output is converted to an
diameter (cm). The measured density in a sample
amplitude modulation after passing through a gas sample which absorbs at a
vial is referenced to a standard and displayed as a
particular wavelength. The amplitude modulation is proportional to gas concentration
concentration in percentage.
and can be phase sensitively detected and related to oxygen concentration.
The authors investigated the capability of the
technique to measure oxygen in 10-mL clear glass vials. A
0.4 single-point calibration of a factory-supplied 20% oxygen stan-
0.2
dard was used to calibrate the instrument. The linearity of the
20% analytical approach was evaluated for oxygen over the range
Instrument response (V)

0.0
of 0.00–20.0% by analysis of 0.00, 5.0, 10.0, 15.0, and 20.0%
0.2
standards. Each sample was measured by placing a vial in a
0.4
13% small optical sample holder and collecting absorption data for
0.6
each sample for 10 s at a sampling frequency of 100 Hz. The
0.8 8%
technique displayed good linearity in the range of concentra-
1.0 4% tions examined in the study (r2 0.9948; data not shown).
1.2 2% Precision for the technique was evaluated by performing five
1.4 1%
replicate analyses of 20.0% (high) and 0.00% (low) standards.
0%
1.6
These experiments yielded an average of 19.8% and 0.19% with
Wavelength (arbitrary units)
an RSD of 0.05% and 26%, respectively. Because the instru-
Figure 4: Frequency-modulation signals from oxygen absorption. The ment is nondestructive, the precision of replicate analyses on
peak-to-peak amplitude of each spectra is proportional to oxygen the same vial also was evaluated by measuring, removing, re-
concentration (noted to the right of each scan). inserting, and remeasuring the sample. Five repeat measure-
ments on a single 20.0% and 0.00% standard indicated good
precision for the method, with an RSD of 1% and 34%, respec-
frequency modulation detection techniques. When a tunable tively. The vendor-specified quantification limits for the mea-
diode laser is modulated with a radio frequency oscillator, the surement were estimated at 0.38% oxygen with a S/N of 2 and
detection bandwidth can be shifted to high frequency at which 1.9% oxygen with a S/N of 10.
intensity fluctuations, inherent to low-frequency measurements, Applications. The application of this technique is limited to
are minimized. headspace monitoring in packages that are optically transpar-
The measurement is conducted by frequency modulating a ent (e.g., glass vials, ampuls, and bottles, including colored glass-
diode laser by superimposing a radio frequency oscillation, , ware such as amber) or translucent (low-density polyeythylene
onto the diode-injection current. The spectral output of a but not HDPE). Other containers with various optical densi-
frequency-modulated diode laser, shown at the top of Figure ties and corresponding transmittance properties also can be
3, consists of a carrier frequency,
c, and side-band frequen- sampled but must be evaluated on a case-by-case basis. Pack-
52 Pharmaceutical Technology JULY 2002 www.phar mtech.com
 Quenchers act by depleting the excited-state population (M*),
thus lowering the intensity of luminescent emission or shorten-
20 mA blue— ex 470 Bifurcated
green LED optical fiber
ing decay time. In the case of commercial oxygen sensors, M is
max 470 nm a fluorescent ruthenium dye whose fluorescence intensity is
Linear quenched by oxygen in a manner commonly referred to as dy-
CCD-array namic fluorescence quenching. In terms of the process previously
silicon detector described, a collision of an oxygen molecule (Q) with the fluo-
rophore in its excited state (M*) leads to a nonradiative energy
transfer and a loss of fluorescence intensity.
em 600 nm The amount of fluorescence-intensity quenching can be quan-
Thin sol-gel
film containing titatively related to the partial pressure of oxygen in a sample
Ru complex from the simplified Stern–Volmer equation (8)
Io
Figure 5: Schematic diagram of a headspace oxygen analyzer based
1
K pO2
I
on fluorescence quenching.
in which I is the quenched fluorescence signal intensity, Io is the
ages are inserted into a sample holder that can be customized unquenched fluorescence signal intensity, K is the quenching
for cell volumes of 1–100 mL, which typically present cell constant that relates to a particular fluorophore used as M, and
path lengths of 1–3 cm. pO2 is the oxygen partial pressure.
The method’s principal advantage is that it can nondestruc- An expanded version of the Stern–Volmer equation con-
tively analyze oxygen contents within sealed containers without taining a factorial expansion of these same terms can also be
changing the sample. Thus, a single package can be used to study used to relate Io to oxygen levels in a more exact manner. Stan-
oxygen concentration profiles at periodic intervals and in various dard operation includes, at minimum, a daily calibration at sev-
storage conditions without the need to destructively insert a probe eral oxygen concentrations at a fixed pressure and temperature
or remove the headspace contents for analysis. The value of this and use of the measured calibration coefficients to determine
advantage cannot be overstated in terms of absolute sample re- the concentration of oxygen in an unknown sample.
quirements, sample preparation time, and sample-to-sample varia- In the current study, an instrument that is based on
bility. From a quality assurance perspective, substantial cost sav- fluorescence-quenching technology was calibrated with six oxy-
ings can also be realized from a nondestructive analysis approach. gen concentrations (see “Experimental” section) before initiat-
ing analysis. Although a single-point calibration is recom-
Fluorescence-quenching methods mended, the authors have found that this practice is insufficient
Principles of operation. Oxygen-sensing technologies that are based to provide reasonable accuracy over a 0.00–20.9% oxygen con-
on luminescence quenching are also a relatively new com- centration range. Moreover, a second-order polynomial fit of
mercial development, and the scientific underpinnings for their the data is required to generate calibration coefficients across
operation are described extensively in a recent review article (7). wide ranges of sample concentrations (more than a few per-
This discussion will introduce briefly this oxygen measurement cent). Also, frequent recalibration is necessary because the sen-
technology; the reader is referred to more-specialized literature sors tend to degrade under normal operating conditions. This
for further detail. Figure 5 shows a commercial configuration in characteristic is particularly true of new sensors, which may re-
which fluorescence is used to measure the partial pressure of quire “burn in” for a few hours before stable operation is
oxygen by using a bifurcated optical fiber to transmit an excita- achieved. Analyses were accomplished by inserting a custom
tion source from a blue–green LED (max 470 nm) to a thin- needle probe (see “Experimental” section) into a 10-mL sam-
film coating applied to the tip of the fiber. A ruthenium com- ple vial and waiting 1 min for equilibration of the sensor to the
plex dispersed in the thin film is excited and produces a headspace environment. Shorter equilibration times can be used
fluorescence emission maximum at 600 nm that is collected at and are a function of the chemical composition of the protec-
the tip and carried back to a charge-coupled device detector. The tive overcoat applied to the sensor tip to exclude ambient light
intensity of fluorescence observed is inversely proportional to (a PTFE coating was used in this study).
the amount of oxygen in a liquid or gaseous sample. The linearity of the analytical approach was evaluated for
Luminescence-quenching sensors can be explained by the oxygen over a 0.00–20.9% range in the present study. The
following processes in which M represents the luminescing fluorescence-quenching technique demonstrated a linear rela-
molecule and Q is a quencher: tion between measured versus standard concentration (r2
0.9952; data not shown), but an offset in the data predicted
Photon absorption (Ia) M
h M* 0.83% oxygen for the 0.00% standard, which measured at
Luminescence (kr) M* M
h 1.6%. The accuracy of fluorescense quenching is commonly
known to be limited by resolution (random noise), deviations
Nonradiative decay (knr) M* M

from the Stern–Volmer relationship, and calibration error (8).
Dynamic quenching (kq) M*
Q M
Q* Which, if any, of these factors may have promoted inaccuracy
in the previously described experiments has yet to be experi-
54 Pharmaceutical Technology JULY 2002 www.phar mtech.com

Ion with unstable trajectory
Ion
collector
Ion with
stable trajectory
dc and rf
Ionizing voltages
electron beam
Figure 6: Block schematic of a quadrupole mass spectrometer.
mentally isolated. Measurement precision was evaluated by per-
forming five replicate analyses of 20.9% (air, high) and 0.00%
(low) standards; these experiments yielded an average of 20.3%
and 1.6% with an RSD of 1% and 17%, respectively.
Applications. Fluorescence-quenching sensors do not actually
consume headspace oxygen and thus can be miniaturized for
use on very small volume samples. Still, the technique is de-
structive because the tip of a 300-m probe must be used to
puncture the package and come in contact with the relevant
headspace, allowing an effective smallest volume of 100 L
to be probed.
Some attributes of the technique include
● rapid response times (from 5 s to 2 min) that are limited to
the time required for equilibrium to be reached between oxy-
gen in the sample headspace and the sensing film by way of
diffusion through the protective overcoat
● very low sample volume requirements (100 L) that are
limited only by the contact dimensions of the probe
● low cost and small instrument footprint.
The low sample volume requirement makes the fluorescence-
quenching sensor the only instrument besides headspace GC
that is capable of rapidly measuring oxygen levels in individual
blister cavities of typical dimensions used in pharmaceutical
packaging. In addition, the sensor’s small size and easy setup
make it very attractive from a portability perspective for achiev-
ing at-line packaging measurements. Fluorescence-quenching
instruments are also available in multichannel configurations
that allow the simultaneous measurement of several samples,
and the data-logging component of the software executes pro-
grammed measurements at fixed time intervals.
The fluorescence-quenching method does have some limita-
tions, however. Care must be taken to calibrate throughout the
intended measurement temperature range of samples because
fluorescence-quenching levels change as a function of tempera-
ture. Temperature affects the measurement by modifying fluo-
rescence decay time and the collisional frequency of oxygen with
the fluorophore. Requirements to maintain the sample at 1 C
or to concurrently measure temperature while conducting the
measurement curtail the practical utility of the method. Expe-
56 Pharmaceutical Technology JULY 2002
rience in our lab also has indicated a need to consistently use
longer signal-integration times during the life of any given probe
to achieve sufficient signal intensities (1800 counts over the mea-
surement time at zero oxygen) over background noise. The de-
creased response factor that was observed could be the result of
changes in the ruthenium dye (e.g., degradation) over time.
Higher signal intensities or lower noise levels are desirable be-
cause S/N is proportional to the square root of integration time.
Moreover, as can be seen from the Stern–Volmer equation, the
rate of change of signal intensity with quenching is highest at
lower oxygen levels. Further development of the instrumenta-
tion for oxygen-specific measurements would benefit greatly the
overall utility of the technique.
Quadrupole mass spectrometric analyzers
Principles of operation. Quadrupole mass analyzers are by far the
most common type of mass spectrometer in use today, and the
literature about this type of analyzer is extensive (8). Quadru-
pole mass analyzers often are thought of as mass filters because
they can be tuned to transmit ions of a narrow range of mass-
to-charge (m/z) ratios. Figure 6 shows a generalized block
schematic of a quadrupole mass spectrometer. A typical quadru-
pole instrument separates ions with differing masses by apply-
ing a combination of static- and radio-frequency electric fields
to four cylindrical rods. A headspace gas sample is introduced
at an inlet and fed into an ion source where electrons are emit-
ted from a filament and ionize the sample gas. The sample ions
then are accelerated in an electrical field and are injected into
the opening at the center of the rods. In the most simple sys-
tems, one pair of rods is connected and attached to the positive
terminal of a dc power source, and the other connected pair is
attached to the negative end of the same source. A variable rf
field with phase differences of 180 also is applied to each con-
nected pair of rods with an ac power supply. For an ion to travel
through the quadrupole to the detector, the ion must have a
stable trajectory in the presence of these applied voltages and
electric field, as described by the Mathieu equations of motion
for ions. The application of a particular set of voltages to the
rods allows mass filtering and the transmission of a band of ions
with a limited range of m/z values. This process usually is accom-
plished by scanning the rf voltage and dc voltages from zero to
a predetermined maximum value while maintaining a fixed ratio.
In this manner, a mass spectrum of analyte ions reaching the
detector can be recorded at a Faraday-cup detector.
The quadrupole mass analyzer used in this study comprised
a set of 16 identical cylindrical rods arranged to form nine
quadrupoles (8). The mass resolution of the quadrupole was
1 amu, and the mass range of the analyzer was 2–300 amu.
The sample was introduced to the instrument by means of a
custom-made analysis port with a toggle switch to introduce
sample from a needle used to puncture a sample package. How-
ever, other package-puncturing sampling techniques could also
be used (e.g., syringe and injection port). The linearity of the
analytical approach was demonstrated for oxygen over the range
of 0.00–20.9% (r2 0.9965; data not shown). Precision was
evaluated by performing five replicate analyses of 20.9% (air,
high) and 0.00% (low) standards; these experiments yielded an
www.phar mtech.com
 QA/QC setting other con-
Table I: Performance parameters for the oxygen-analysis methods evaluated. siderations such as long-
Standard Measured Precision Accuracy Linearity LOQ term method robustness,
Method (%)* (%)** Std. Dev.† RSD (%) Bias ‡ r2 (%) § stability, ease of calibration
Headspace GC 20.9 22.1 0.30 1.6 1.20 0.9903 0.25 and use, oxygen levels to be
0.00 0.83 0.08 10.0 0.83 routinely analyzed, and
Electrochemical 20.9 20.6 0.00 0.0 0.30 0.9984 0.0001** other practical considera-
0.00 0.11 0.01 13.0 0.11 tions will help guide tool se-
lection. The forthcoming
FMS 20.0 19.8 0.01 0.05 0.20 0.9948 1.9
discussion will examine tool
0.00 0.19 0.05 26.0 0.19
selection criteria in terms of
Fluorescence 20.9 20.3 0.20 1.0 0.6 0.9952 unknown performance considerations,
quenching 0.00 1.6 0.27 17.0 1.6 other relevant technique at-
Quadrupole MS 20.9 21.9 0.10 0.50 1.0 0.9965 sub-ppm tributes, and type of pack-
0.00 0.00 7.54  105 2.60 2.9  103 age being considered.
* Prepared as described in the “Experimental” section of this article. First, what can we learn
** Average of five different samples. about how the five tech-
†
Standard deviation. niques presented in this ar-
‡
Bias calculated as measured—theoretical. ticle performed in terms of
§
Limit of quantitation, S/N
10, all specified by instrument supplier with the exception of headspace
GC, which was measured.
measuring oxygen concen-
trations in the range of zero
to roughly ambient oxygen
average of 21.9% and 0.00% with an RSD of 0.5% and 2.6%, levels? The data shown in Table I are clarified in the following
respectively. The very small amount of offset observed for this discussion of the performance parameters that were studied.
instrument was the result of the extremely low LOQ (estimated Key points. Linearity. All five techniques that were investigated
at sub-ppm levels) of the measurement technique, limited only displayed good linearity over the measurement range
by the lower limit of vacuum achieved in the analyzer. 0.00–20.0% or 0.00–20.9%, all displaying r2 0.9903.
Applications. The application of quadrupole mass analyzers Measurement precision. The standard deviation and RSD at both
in a residual gas–analysis mode has long precedence in the high (20.0%) and low (0.00%) ends were examined for each
semiconductor industry in which residual contaminant gas technique. As the data show, the precision for the techniques at
levels in various ultrahigh vacuum chambers must be moni- low concentrations ranged from 2.6% to 26%. Note that the
tored and controlled. The principal advantage of using quadru- RSD of five replicate measurements at ambient oxygen levels
pole mass spectrometry for pharmaceutical packaging appli- were 2% for all five of the techniques.
cations is that many analytes can be monitored simultaneously Accuracy. Generally speaking, for most MAP programs the aim
and quantitated (2–300 m/z) with one injection of headspace is to reduce oxygen values from ambient to a predetermined
sample. As is the case for other destructive techniques, the specified level. Often, the measurement technique may not be
largest drawback for this instrumentation is sample introduc- required to give the absolute oxygen level in the container but
tion. Several sample-introduction strategies are being explored only to be sufficiently accurate to indicate that the oxygen con-
to improve the utility of the approach. The technique likely tent of the package is below the target threshold, thus serving
would be useful in process-monitoring applications in which as a limit test. Thus, the importance of the measurement tech-
the detailed contents of an inert gas blanket beyond that of nique to measure at low levels (e.g., 5%) is more important
simple oxygen levels is required. than capabilities at high levels. One way to interpret the per-
formance data in Table I in this context is to examine the ab-
Which technique should I use? solute differences observed between theory and experiment for
The answer to this important question depends on the type of the low-level oxygen standard. As Table I shows, the degree of
information desired, instrumentation availability, and the type deviation (from least to greatest) that was observed between
of packaging being considered. In MAP development, the stud- predicted and measured low oxygen level standards followed
ies may comprise research into the oxygen permeability prop- this trend: quadrupole MS < electrochemical < FMS < GC <
erties of various packaging systems, packaging-system selec- fluorescence quenching.
tion, process development, process implementation, and finally, LOQ. The lower LOQs shown in Table I were not measured di-
quality assurance. For the evaluation of various packaging sys- rectly as part of the study. In instances in which they are pro-
tems, the most common questions may be about understand- vided, the values are either estimated or obtained from the ven-
ing the rates of oxygen ingress (or consumption) ranging from dor. For critical absolute oxygen concentration measurements
very low levels (1% oxygen) to ambient oxygen concentra- at very low levels, the lower LOQs should be established for the
tions. The types of tools used in a research laboratory should specific system being studied. Clearly, the sampling method
be reevaluated when considering a manufacturing setting for plays a critical role in the quality of the data for oxygen levels
process development and implementation. In addition, in the 2% and limits the accuracy of the data.
58 Pharmaceutical Technology JULY 2002 www.phar mtech.com
 Table II: Some attributes of various headspace oxygen–sampling tools.
Analysis Ease of Instrument
Instrument Time Calibration/Use* Availability
GC Minutes 3 Commercial
Electrochemical Seconds 1 Commercial
Fluorescence
quenching Minutes 3 Commercial $2–5K
FMS Seconds 2 Semicommercial $35–50K
Quadrupole MS Minutes 3 Semicommercial $25–50K
* 1 easiest to calibrate and use; 2 more difficult to calibrate and use; 3 most difficult to calibrate and use.
** A sufficient sample volume must be available so that a probe can be inserted and make contact with the
sample, estimated at 100 L.
†
Instrument is nondestructive and can be used on vials through which a laser can be transmitted.
Knowing the performance limitations of a particular in-
strument is key to interpreting the results obtained from a se-
ries of measurements. Other considerations also affect tech-
nique selection. Table II summarizes some additional points
to consider when matching an analytical requirement to a head-
space oxygen–analysis tool. The table shows that analysis times
for the five techniques range from minutes (GC, fluorescence
quenching, quadrupole MS) to seconds (electrochemical meth-
ods, FMS). All the instruments are available commercially, al-
though at various stages of development, and vary in expense
from $2,000 to $50,000. FMS and quadrupole MS are the least
commercially developed of the techniques at this time, and
more work is needed before their routine use will be possible.
Ease of calibration and use, which is a highly subjective cate-
gorization, reflects the authors’ judgments about the relative
ease of training others to operate the equipment. Other fac-
tors such as versatility, portability, and suitability for use in a
manufacturing setting also are important when one is choos-
ing an instrument. For example, both headspace GC and
quadrupole MS have numerous uses beyond oxygen monitor-
ing, and one may want to acquire other information simulta-
neously (e.g., amount of moisture, carbon dioxide, or other
volatiles). FMS is the only nondestructive technique of which
the authors currently are aware, and it can be used only with
package types that allow adequate transmittance of the instru-
ment probe beam.
Package types. Identifying the type of package from which
oxygen levels must be sampled and analyzed is another con-
sideration for determining the appropriate analysis tool. Mak-
ing a decision from this angle requires information from both
Tables I and II, especially the sample-volume requirements for
each technique that are listed in the latter. For the sake of brevity,
only the three most common pharmaceutical packaging con-
figurations (plastic bottles, glass vials–ampuls, and blister pack-
ages) are discussed.
Plastic bottles with foil-induction inner seal. Plastic (e.g., HDPE) bot-
tles with foil-induction inner seals (the most common have
33-, 75-, 120-mL volumes) are used commonly to package
pharmaceutical products. For the rapid and accurate determi-
nation of headspace oxygen in a package of this type, all the
techniques discussed in this report apply, with the exception
of FMS. Based on the authors’ experience, the electrochemical
methods are best suited for large-volume (
2 mL) packages,
60 Pharmaceutical Technology JULY 2002
Required
Expense Sample Volume Destructive
$40K
10–30 L Yes
$4–10K 1–3 mL Yes
None** Yes
None† No
10–30 L Yes
and they display an unparalleled ease of use. These instruments
also tend to be among the most rugged of all the instrumen-
tation described herein and seem to be the most well suited for
use by operators with a limited amount of technical training.
Glass vials and ampuls. Glass vials and ampuls are another com-
monly used pharmaceutical packaging form, especially for paren-
teral formulations. Any of the five techniques discussed in this
report can be used to analyze headspace oxygen levels as long
as sufficient volume is available. FMS offers considerable advan-
tages for this package type because it is nondestructive. In ad-
dition, FMS can be used for vials filled with a variety of media,
including powders that may coat the walls of the container. As
long as a portion of the analysis beam is transmitted, the dif-
ferential absorptive signal processing inherent to the technique
can be used to yield oxygen concentration values.
Blister packages. The small volume of individual blister cavities
makes this type of packaging the most challenging to analyze
for headspace oxygen levels. The challenges are twofold: the ex-
tremely small volume available for sampling as well as sample
removal or introduction without contamination. All the instru-
ments that are applicable for small-volume measurements (i.e.,
headspace GC, fluorescence quenching, quadrupole MS) have
drawbacks from a sampling perspective. Although future de-
velopment in this area is needed, headspace GC seems to be
most suitable at this time because self-adhesive septa can be
placed on the package backing and a small portion of sample
can be withdrawn manually for injection. Other viable ap-
proaches, including nondestructive techniques, currently are
being investigated.
Summary
This article has provided an introduction to the principles of
five measurement techniques for analyzing the headspace oxy-
gen levels in common types of pharmaceutical packages. Vari-
ous performance criteria were applied to examine the fit of each
particular tool to typical pharmaceutical package types. Future
research about the topic is needed to better address the ro-
bustness of sample introduction techniques for small-volume
samples and perhaps to develop sensor technologies that would
allow oxygen levels to be remotely sampled and profiled for a
period of time from a small device integrated or inserted into
the package.
www.phar mtech.com
Acknowledgments
The authors thank the instrumentation vendors whose coop-
eration greatly facilitated the work described in this article.
Particularly, special thanks goes to Jim Veale and Bobby An-
derson of Lighthouse Instruments, Inc. The authors also thank
Denise Farquharson for assistance with the preparation of gas
standards.
Disclaimer
The information described in this report does not constitute
endorsement by Merck & Co., Inc. of any particular instrument
type or supplier.
References
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and Practice (Wiley & Sons, New York, NY, 1997).
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Boca Raton, FL, 72d ed., 1991), p 2040.
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R.U. Martinelli, Laser Focus World 28 (11), 133–146 (November 1992).
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7. J.N. Demas, B.A. DeGraff, and P.A. Coleman, “Oxygen Sensors Based
on Luminescence Quenching,”Anal. Chem. 71 (23), 793–801 (1999).
8. (a) M.J. Drinkwine and D. Lichtman, “Quadrupole Mass Analyzers,”
in Partial-Pressure Analyzers and Analysis, N.R. Whetten and R. Long,
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(b) R.J. Ferran and S. Boumsellek, “High-Pressure Effects in Minia-
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FYI
Postdoctoral fellowships
The College of Pharmacy at Rutgers offers postdoctoral fellowships
in partnership with various pharmaceutical companies.
The fellowships include practical industry experience; an adjunct
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must possess a PharmD from an American Council on
Pharmaceutical Education–accredited college of pharmacy and must
submit a curriculum vitae,a written career-objective statement,and
three letters of recommendation.
For more information or to apply,contact Joseph A.Barone,PhD,
Rutgers,The State University of New Jersey,College of Pharmacy,
Department of Pharmacy Practice and Administration,Attention:
Fellowship Program,160 Frelinghuysen Rd.,Piscataway,NJ 08854-
8020,tel.732.445.2675 ext.600,fax 732.445.5767,
http://pharmacy.rutgers.edu.
Pharmaceutical Technology JULY 2002 61