Note: Descriptions are shown in the official language in which they were submitted.
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TEMPER~TURE IN~NBITIVE C~LIBRATION ~YBTEM
B~C~GROUND OF 'r~lE INVENTION
1. Field of the Invention
The present invention is directed yenerally to a
multi-phase control or calibration system and, more
particularly, to such a system exhibiting relatively
constant partial pressures with respect to certain diverse
dissolved gaseous species of interest in one or more liquid
phases over a range of ambient temperatures. The preferred
fluid consists of a first non-aqueous liquid phase
containing an amount of dissolved oxygen (23 in which the
partial pressure of 2 iS relatively temperature insensitive
over an ambient temperature range of interest, a second,
aqueous phase, immiscible with the first phase and
containing an amount of dissolved carbon dioxide (CO2~ and
one or more solute species that provide temperature
stability with respect to the partial pressure of Co2 over
the ambient temperature range of interest. The llquid
phases are in equilihrium with a vapor phase.
2. De~cription of the Related Art
Relatively inert fluids which have the ability to
dissolve rather large amounts of oxygen and which are
stable and do not affect biological media, for example, are
known. The class of fluorinated organic compounds known as
perfluorocarbons are the best known examples of such
materials. Perfluorocarbon substances are completely
fluorinated organic compounds in which all the carbon-bound
hydrogen atoms are replaced with fluorine atoms. These
materials have an unique combination of properties. The
compounds are extremely non-polar and have essentially no
solvent action. They are so chemically inert and have such
high thermal stability that they can be mixed with almost
any material without fear of any adverse reactive effect
either upon other mixture components or upon the mater1al
itsel~. The compouncls also have a relatively hlgh boilLny
points and low pour po:ints yivincJ them a relatively wide
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liquid range. Many of these perfluorocarbon materials also
have a higll, relatively st~ble, oxygen solubility.
These properties have led to the use of
perfluorocarbon solutions as oxygen carriers and as
controls for oz sensors. ~queous perfluorocarbon multi-
phase emulsions have been proposed for applications which
involve the need to carry or sense oxygen in the presence
of carbon dioxide andtor where pll needs to be controlled or
sensed. These include medical related technologies
involving blood and syn-thetic blood materials and blood gas
analysis controls and calibrators. One such emulsion
system is illustrated and described in U.S. Patent
4 722 904 to Feil. Other such systems are disclosed in
Turner (U.S. Patent 4 001 142), Cormier, et al. (U~S.
Patent Nos. 4 299 728 and 4 369 127) and Sorenson, et al.
(U.S. Patent Nos~ 4 116 336 and 4 151 108).
These fluids typically comprise an aqueous emulsion of
the organic oxygen carrier. Certain of these emulsions may
contain surfactant materials, p}l buffers and preservative
materials. The aqueous phase and the perfluorocarbon phase
are chemically compatible but completely immiscible. While
the perfluorocarbon phase reversibly carries the oxygen of
interest, the aqueous phase reversibly carries other
constituents of interest such as carbon dioxide and
hydrogen ions.
The use of such materials, particularly as quality
controls Eor blood gas analyzers, for example, requires
that the control system contain a known partial pressure of
oxygen and a known partial pressure of carbon dioxide and
be oE a known pll. Accordingly, the con-trol system must be
supplied in gas-tight, sealed ampules, or the like
containing known amounts of dissolved oxygen and carbon
dioxide species so that e~uilibrium p~rtial pressures
remain constant. Such a known or control substance can
later be used to check the relative accuracy oE an
instrument utilized to measure 2 and CO2 concentratlon and
the pll of such substances ag blood.
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Although such prior approaches have been successful
with respect to achieving proper quality control of sucll
devices, the integrity of the partial pressure of the
dissolved species used in control measurements depends on
the complete isolation o~ the control system from the time
it is prepared until the time of use. In addition, because
of the variation in solubility of the gas species of
interest with temperature, the opening and use of the
control must occur at a specific temperature; and thus the
results are also quite temperature dependent.
There remains a definite need to reduce the
sensitivity of such control systems to fluctuating or
uncertain ambient temperature conditions. This would lead
to more versatile uses of the materials and to the
development of accurate devlce calibration methods without
the need for rigorous environmental control at the time of
calibration. Accordingly, it is an object of the present
invention to develop a calibration/control system which is
less temperature sensitive than known fluids of the class
including aqueous emulsions of perfluorocarbons.
~UMMARY OF THE INVENTION
In accordance with the present invention, the
temperature sensitivity of the partial pressures of
dissolved gases of interest has been greatly reduced. The
accuracy of calibration system established at a filling
temperature of 20C, for example, will not be sacrificed by
ater removal at, for example, 30~C.
In the preferred embodiment, the oxygen carrying
solution phase is a solution of oxygen in one or more
perfluorocarbon materials. The preferred perfluorocarbon
materials include FC-43, FC-75, FC-77, and others,
manufactured by and available from the 3M Company of St.
Paul, Minnesota. 'rhe aqueous solution phase contains a
specific amount of C02 complexing agerlts such as ethylene
diamine, ~ICO3-, Ca~ and 0ll~ or other compounds wh:Lch buffer
the partial pressure of carbon dioxide (C02) in the aqueous
solution to changes in temperature. ~n ,~lmount of a
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compatible pll buffer can also be employed to stabilize the
solution with respect to acidity.
The multi--p}lase control/calibration system of the
invention is prepared under tig}ltly controlled conditions
and transferred to containers designed to accommoda-te the
desired amount. The filled containers are provided with a
sealed storage atmosphere which maintains the desired
conditions in equilibrium during the shelf life of the
system. This atmosphere typically contains sufficient
oxygen and carbon dioxide in a mi~ture with one or more
other gases inert to the system to maintain the desired
amount f 2 and C02 species in the liquid phases of the
system.
The preferre~ range Of 2 (Po2) partial pressure with
respect to the system is from about 10 to about 200 mm Hg
and the preferred range of partial pressure for C0z (pC0z)
is from about 5 to lO0 mm ~Ig. The preferred temperature
range of temperature relative partial pressure
insensitivity is about 20C to about 30C. It is also
contemplated that various phase components can be used, if
desired, to expand the ambient temperature range o~
relative partial pressure insensitivity beyond the range of
20~C to 30C, if desired. The range 20 to 30C, however,
represents the normal range of temperatures for an indoor
conditioned space.
In addition, surfactants or other wettiny agents can
be added to emulsify the multiliquid phases, if desired.
It is also contempla-ted that the solution of the
calibration system of the invention consist of a sin~le
aqueous phase containing, in addition to a Co2 binding
component or components, one or more solutes which
reversibly bind 2~ such as copper ions, hemoglobin, and
transition metal macromolecular complexing agents. These
include meso-tetraphenyl porphorin complexes of Co(II),
Co~III), Mn(III) and Fe(II).
Solutions ~ormulated in accordance with the invention
should exhibit stable overall solubilities of the c3ases of
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interest over a range of ambient temperatures between about
20C and 30C. This means that calibratlon/control systems
in impermeable containers which are filled under strictly
controlled conditions at one temperature may be removed
~rom a storage atmosphere at a different -temperature and
used with complete confidence.
DETAILED DESCRIPTION
Although there are some exceptions, notably dilute
solutions of hydrogen chloride in water, the solubility of
most gases and liquids decreases with increases in
temperature. It is further well known that the equilibrium
solubility oE any volatile constituent of a solution at a
yiven temperature is rela-ted to the partial pressure of
thak constituent in the vapor pllase above the liquid at any
given temperature. It follows, then, that solutions of
critical concentrations of dissolved gaseous species and
liquids have an extreme sensitivity both to changes in the
partial pressure of each such species above the solution
and to changes in temperature of the solution. Prior to
the present invention, it has heretofore been necessary to
expose the calibration/control system to the ambient
environment at a specific temperature to preserve the
compositional integrity of the system.
This has heretofore always been the case with respect
to control solutions, including those in which oxygen is
carried by a perfluorocarbon in one phase and carbon
dioxide is carried in a second aqueous solution phase of
con-trolled p~ which are used to calibrate biological
sensors utilized to detect dissolved oxygen, carbon dioxide
and acidity. Because of the inherent properties of these
systems, it has always been assumed that the temperature
limitation with respec-t to exposure was one which had to be
accommodated and could not be overcome.
~ccordiny to the present inventlon, however, it has
been discovered that such multi-phase solution~ can,
indeed, be made less sensitive to variations in ambient
temperature over the ranye of ambienk temperatures normally
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encountered in indoor conditioned spaces, e.g., 20C to
30C.
While it has been ~ound that a variety of
perfluorocarbon substances exhibit rather stable properties
with respect to dessolving amounts of oxygen in the range
of 20C-30C and, in some instances, even beyond this range,
the same cannot be said o~ the relative concentration of
dissolved C02, which decreases with increasing temperature.
In accordance with the invention, it has further been
discovered, however, that the use of a dissolved species,
such as ethylene diamine in the aqueous phase of the multi~
phase calibration solution, can stabilize the amount of
carbon dioxide dissolved in the aqueous solution. In fact,
the overall partial pressure C02 can be substantially
linearized over a temperature ranye comparable to that of
0z in the perfluorocarbon. Compatible buffers can also be
added to the aqueous solution to control acidity at the
desired pH value.
The solutions or liquid phases in accordance with the
2Q invention are prepared under controlled conditions. Known
amounts of the dissolved gases 2 and C02 are present in the
phases as prepared. Ilowever, it may be months or even
years before the system is actually used so that long-term
stability is required. To preserve the integrity of the
system over the shelf life of the product, the calibration
system is sealed in an impermeable fluid tight container
together with an amount of storage atmosphere which
contains sufficient P02 and PC02 to maintian the amount of
dissolved species in the liquids over time.
The container may be a glass ampule, or the like, but
is preferably a polymeric envelope or laminated pouch which
may consist of several layers of metallic foil and
polymeric materials which make the pouch impervious to
atmosphere exchange with the environment.
When the seal of the encclpsulating container is
breached, of course, the protective or storaye atmosphere
is lost. The calibration system oE the present inven-tion,
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however, maintains its known PO2/ pC0z and pll ~or the
relatively shorter time required to perform the control or
calihration procedure, regardless of the ambient
temperature at which the breach occurs as long as that
temperature is in the range of relative stability for the
system, e.g., 20C-30C.
It is apparent that the calibration system of the
present invention can also function well as a control
system for analytical instruments of the class normally
employing such controls as periodic checks. Controls
generally require somewhat less precision than calibration
systems.
This invention has been described in this application
in considerable detail itl order to comply witll the Patent
Statutes and to provide those skilled in the art with the
information needed to apply the novel principles and to
construct and use such specialized components as are
required. ~lowever, it is to be further understood that the
invention can be carried out by specifically different
equipment and devices and that various modifications can be
accomplished without departing from the scope of the
invention itself.
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