EP0227815A4 - Procedes de mesure de la concentration en oxygene. - Google Patents

Procedes de mesure de la concentration en oxygene.

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Publication number
EP0227815A4
EP0227815A4 EP19860904575 EP86904575A EP0227815A4 EP 0227815 A4 EP0227815 A4 EP 0227815A4 EP 19860904575 EP19860904575 EP 19860904575 EP 86904575 A EP86904575 A EP 86904575A EP 0227815 A4 EP0227815 A4 EP 0227815A4
Authority
EP
European Patent Office
Prior art keywords
oxygen
emission
tfpp
luminescent
light
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19860904575
Other languages
German (de)
English (en)
Other versions
EP0227815A1 (fr
Inventor
Gamal-Eddin Kahil
Martin P Gouterman
Edmond Green
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
International Biomedics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by International Biomedics Inc filed Critical International Biomedics Inc
Publication of EP0227815A1 publication Critical patent/EP0227815A1/fr
Publication of EP0227815A4 publication Critical patent/EP0227815A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0015—Phosphorescence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0036—Porphyrins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6408—Fluorescence; Phosphorescence with measurement of decay time, time resolved fluorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6432—Quenching
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N2021/6484—Optical fibres
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7786—Fluorescence

Definitions

  • This invention relates generally to the measurement of oxygen concentration using the quenching of emission of a luminescent aromatic molecule embedded in a plastic medium.
  • the quenching of the luminescence of an emitter at the end of an optical fiber has been used in temperature sensors.
  • the emitters are generally solid phosphors rather than an aromatic molecule embedded in plastic, since access by molecules from the environment is notd esirable.
  • Various methods have been used to measure the amount of quenching: (i) Quick et al. in U.S. Patent No. 4,223,226 ratios the Intensity at one wavelength of the emission against another; (ii) Quick et al. also proposes determining the length of time it takes for the signal to fall from one level to another; (iii) Samulski in U.S. Patent No. 4,245,507 (reissued as Patent No. Re.
  • Oxygen concentration is determined by observing quenching of the emission from a luminescent (phosphorescent or fluorescent) molecule embedded In oxygen-permeable plastic.
  • a test fluid of unknown oxygen concentration is contacted with a plastic film containing at least one luminescent substance.
  • the film is subjected to irradiation over some period of time by light of a wavelength that is strongly absorbed by the luminescent substance, and a measure of the time dependence of luminescent emission intensity I(t) is obtained, Three modes of determining oxygen concentration from I(t) are described.
  • the sample is irradiated for some time interval (generally under 50 us) using a flash lamp or a light emitting diode.
  • Intensity segments of emission, I 1 and I 2 are determined during two time intervals defined with respect to the time of irradiation. These two intensity segments are compared to form a ratio R, and a calibration plot of R versus oxygen pressure is obtained using solutions of known oxygen concentration.
  • Three different methods for determining I 1 , I 2 , and R are presented. These methods (i-iii) of measuring quenching are insensitive to variation in plastic thickness and emitter concentration of the probe and to decomposition during operation. Methods (i ⁇ iii) also take into account the non-exponential decay of the emission, and thus extend the pressure range over which the probe is sensitive. Method (iii) requires at most one point calibration against atmospheric oxygen.
  • Pt(TFPP) platinum tetra(pentafluorophenyl)porphyrin, Pt(TFPP) serves as the luminescent oxygen quenchingsensitive molecule.
  • Pt(TFPP) has a strong absorbance in the visible region, a strong phosphorescence with lifetime of roughly 100 ⁇ s, and is photostable. Photostability is provided by the substitution of fluorine atoms in the periphery of the synthetic porphyrin ring.
  • fluorinated luminescent molecules include metallo derivatives, particularly platinum and palladium derivatives, of partially or fully fluorinated octaethylporphyrin, tetraphenylporphyrin, tetrabenzoporphyrin, or the chlorins, bacteriochlorins, or isobacteriochlorins thereof.
  • metallo derivatives particularly platinum and palladium derivatives
  • octaethylporphyrin tetraphenylporphyrin
  • tetrabenzoporphyrin tetrabenzoporphyrin
  • FIGURE 1 is a block diagram of a representative system 10 for measuring oxygen concentration by the emission lifetime method of this invention
  • FIGURE 2 is a graph showing phosphorescence emission of
  • FIGURE 3 is a graph plotting and ⁇ versus p0 2 for the decay curves shown in FIGURE 2 and the data presented in Table 1;
  • FIGURE 4 is a representative plot showing the two intensity segments I 1 and I 2 as used in Equation (9) in conjunction with system 10;
  • FIGURE 5 is a plot of R versus pO 2 for the embodiment shown in FIGURE 4;
  • FIGURE 6 is a block diagram of representative systems 10' and 10" suitable for monitoring oxygen concentration in the bloodstream
  • FIGURE 7 is a representative plot showing the two intensity segments I 1 ' and I 2 ' as used in Equation (10) in conjunction with system 10';
  • FIGURE 8 is a plot of R' versus pO 2 for the embodiment shown in FIGURE 7;
  • FIGURE 9 is a representative plot showing the two intensity segments I 1 " and I 2 ' as used in Equation (11) in conjunction with system 10";
  • FIGURE 10 is a plot of R" versus pO 2 for the embodiment shown in FIGURE 9;
  • FIGURE 11 presents Stern-Volmer plots for Pt(TFPP) in various film matrices containing various amounts of plasticizer, as described in
  • FIGURE 12 presents Stern-Volmer plots of k for films con taining various mixtures of PtCTFPP) and Pd(TFPP), as described in Example 4. Detailed Description of the Preferred Embodiment
  • the present invention addresses several previously unrecognized problems inherent in the prior art.
  • the previously unreported fluorinated derivative platinum tetra(pentafluorophenyl)porphyrln, Pt(TFPP) must be used.
  • tetra(pentafluorophenyl)porphyrin refers to the identical compoun d as the term “tetraperfluorophenylporphyrin” as stated in our referenced prior application.
  • Metastable photoexcited states are of two types: (i) those with the same spin as the ground state and (ii) those of different spin from the ground state.
  • Emission from metastable excited states of type (i) is called fluorescence and is generally accomplished in under 0.2 microseconds.
  • Emission from metastable excited states of type (ii) is called phosphorescence and is generally accomplished in times ranging from 1 microsecond to 20 seconds. Both types of emission are quenched by oxygen.
  • k nat is the natural radiative lifetime of the metastable excited state
  • k d is the rate of any intrinsic radiationless decay processes
  • k q is the quenching rate of oxygen
  • [ 0 2 ] is the oxygen concentration
  • the inverse of k is called the emission lifetime, ⁇ .
  • the amount of light emitted by a sample is called the quantum yield, ⁇ , and is defined as;
  • Equations (1) and (3) are two forms of the Stern-Volmer equation for the effect of oxygen on quantum yield. This relationship is the basis for oxygen monitors that study the intensity of emission (I), which is directly proportional to quantum yield as follows:
  • I o /I I + k q [ 0 2 ] (4) wherein I o and I are respectively the emission intensities in the absence and presence of oxygen.
  • the decay rate measurement of Equation (5) avoids difficulties caused by variability in sensor manufacture and by photodegradation.
  • the oxygen sensors of Stevens, Lubbers et al., and Peterson et al. are all based on the quenching of fluorescence, which decays generally in under 0.1 microsecond ( ⁇ s) and so requires fast electronics and fast light flashes to measure decay rate. This may account for their preferred use of the intensity ratio of Equation (4).
  • the molecule used in the preferred embodiment of our oxygen sensor has a decay time in the 100 ⁇ s time range, so that slower electronics and exciting light flashes can be used, making the study of quenching through decay rate very practical.
  • Equations (1) and (4) are generally considered to be equivalent measures of oxygen quenching, a serious problem arises in determining decay rate of aromatic molecules in plastic, since we find that such decay is generally nonexponential. That is, the decay time of luminescent aromatic molecules in plastic cannot be fit by a simple exponential but must rather be considered as a sum of two exponentials:
  • I(t) A 1 e -k 1 t + A 2 e -k 2 t (6) wherein e is the exponential function.
  • the four fitting parameters A 1 , k 1 , A 2 , k 2 can be fit if I(t) is measured at many times t following an interval of photoexcitation. This type of determination requires considerable instrumentation and software analysis that may not be practical for routine operation. Furthermore, even given the knowledge of these four parameters, it is not clear how best to employ them to determine oxygen concentration because in the absence of an exponential decay the Stern-Volmer Equations (1) and (3) no longer apply.
  • FIGURE 1 shows a representative system 10 for determining the oxygen concentration of gaseous samples by measuring the quenching of various emitting sensor compositions in plastic.
  • a flashing light source 12 e.g., Strobotac Model No. 1538A
  • time dependent light excitation indicated by dashed arrow 14
  • Film 16 is mounted inside the fluid, depicted as vapor 18 here, that is to be sampled.
  • Phosphorescent light (dashed arrow 20) emitted from film 16 impinges on a photodetector 22 (e.g., RCA 7265).
  • a housing 24 containing windows 26, 28 can be used to isolate film 16 inside the fluid 18 being monitored, which is typically not identical with the environment of the rest of system 10. Windows 26, 28 can be made of quartz or glass.
  • Filter 30 is a band-pass filter (e.g., Ealing 35-3649) that allows only shorter wavelength light 14, e.g., wavelengths in the range 480 to 600 nanometers (nm), to impinge on film 16.
  • the range of band-pass filter 30 is chosen to match the region of strong absorption by the phosphorescing compound that is sequestered in film 16.
  • Filter 32 is a cutoff filter (e.g., Corning 261) that allows only long wavelength light 20, e.g., wavelengths longer than 620 nm, to impinge on photodetector 22 and is chosen to allow the phosphorescent light 20 to reach the photodetector 22.
  • the band-pass of filter 30 and the cutoff of filter 32 are complementary such that no light 14 from flashing light source 12 reaches photodetector 22.
  • the electric output (arrow 38) of photodetector 22 passes into preamplifier, 40 of standard design.
  • the output (arrow 42) of preamplifier 40 passes into a transient recorder 44 (e.g., Biomation Model No. 805) that is capable of sampling intensity, I(t), at time intervals below a microsecond.
  • the timing of system 10 is under control of microcomputer 36.
  • microcomputer 36 puts out a trigger (arrow 46) to activate transient recorder 44 and after a slight delay on the order of 20 microseconds puts out another trigger (arrow 48) to start flash light source 12.
  • Transient recorder 44 thus collects data relating to I(t i ), the intensity I of phosphorescence at various times t i before and after the flash, which data are read (as indicated by arrow 50) into the computer 36.
  • Flash rates using system 10 are typically on the order of 100 per second.
  • the time interval between successive flashes 14 is sufficiently long that a decay time and hence oxygen concentration can be calculated after each flash 14.
  • the limiting time of response is set by the diffusion rate of oxygen into the monitor film 16, which is typically under one second. This diffusion rate becomes faster, permitting response times on the order of milliseconds, with thinner films 16 and by adding plasticizer to the carrier matrix, as described below.
  • real-time measurements of oxygen concentrations can be made by this method.
  • measurement is made of the intensity, I(t i ), of phosphorescence 20 emitted by the film 16 at a series of times, t 1 , t 2 , t 3 . . ., after the flash 14.
  • the light intensities I(t i ) at any particular time t i following several flashes can be averaged.
  • a decay rate, k, of the phosphorescence is calculated from these data by the computer 36 using various algorithms. In particular, with a full set of values I(t i ) we can fit the decay to Eq. (6) above.
  • Decay curves for Pt(TFPP) in polyvinyl chloride with plasticizer are shown in FIGURE 2, wherein t' is the period of linear decay, i.e., where ⁇ I/ ⁇ t has a constant slope at any particular oxygen pressure of interest, and wherein t" is the remaining period of the detectable emission, during which ⁇ I/ ⁇ t is not constant.
  • Representative values found for the fitting param eters A 1 , k 1 , A 2 , k 2 are listed in Table 1.
  • FIGURE 3 we plot representative and curves using the data listed In Table 1. These curves would be identical for an exponential decay.
  • FIGURE 3 sbows that gives a more linear Stern-Volmer plot; hence provides a more accurate determination of oxygen concentration at higher oxygen pressures.
  • the double exponential decay of Eq. (6) can be understood as resulting from two types of emitting molecules: Those with larger k 1 are more subject and those with smaller k 2 are less subject to quenching by oxygen.
  • the average decay time gives heavier weight to the unquenched molecules, whereas the average decay rate, gives heavier weight to the quenched population and provides a better measure of oxygen quenching.
  • the slope of the emission profile during the period of linear decay is compared with similarly obtained slopes for fluids of known oxygen concentrations. Due to the double exponential nature of the luminescent decay curve, the referenced slope values must not encompass any of the tail region (t" in Fig. 2) of the emission profile. Once this relationship is established, the time it takes for the intensity of emission to fall to any particular level within time t' can provide a convenient readout of pO 2 . Alternatively, the intensity measured with the test fluid at any particular time t less than t' can be compared with standard curves of intensity versus time (again, less than t') for a series of fluids of known oxygen concentrations.
  • I 1 and I 2 are the sums of the intensities, or total flux of luminescent light, measured by the transient recorder during two time periods that together substantially encompass the period of linear decay of the luminescent emission once the light source 12 is turned off.
  • the time intervals for I 1 and I 2 can be readily optimized for particular combinations of luminescent substance, matrix, and oxygen pressure range of interest by sampling time intervals and selecting those that provide the best resolution within the linear decay period.
  • I 1 can be the flux of phosphorescence detected over times from 0 to 10 ⁇ s
  • I 2 can be the sum of the intensities over times from 10 to 20 ⁇ s, with time zero for both measurements being the end of the period of illumination.
  • FIGURE 4 illustrates the two intensity segments I 1 and I 2 , and a corresponding plot of R versus p0 2 (oxygen pressure) is shown in FIGURE 5. It, is not necessary for the selected time intervals to encompass the entire period of linear decay. However, I 1 and I 2 preferably subdivide the period of linear decay (t' in Fig. 2) into two equal time periods.
  • the subject method can be used to measure oxygen concentration in a fluid, meaning gas and/or liquid.
  • a fluid meaning gas and/or liquid.
  • the oxygen concentration in closed and semiclosed atmospheres 18 such as aircraft and mines can be measured using a detection system similar to 10, shown in FIGURE 1.
  • Oxygen concentrations in liquids such as blood, seawater, and sewage can also be monitored by the method of this invention.
  • FIGURE 6 shows representative systems 10', 10" for monitoring oxygen in the bloodstream 18'.
  • sensing composition 16 phototube 22, filters 30,32, microcomputer 36, and preamplifier 40.
  • the film 16 containing the oxygen quenching-sensitive composition is positioned at the end of an optical pipe 56, which carries the exciting light to and the emitted light from the film 16.
  • the exciting light source 12' is a flash lamp
  • the exciting light source 12" is a light emitting diode (LED).
  • the exciting light from light source 12' or 12" passes into light pipe 55.
  • the emitted light exits through light pipe 57.
  • the light pipes 55, 56, 57 are connected by a standard three-way optical coupler 58 (e.g., GTE ATA No. OCL-0102-X).
  • a standard three-way optical coupler 58 e.g., GTE ATA No. OCL-0102-X.
  • the output 42 from the preamplifier 40 passes into a fast A/D converter 44' (e.g., the LAB-40 manufactured by Computer Continuum, Daly City, CA 94015).
  • the output from the preamplifier 40 passes into a specially designed electronic circuit 44", termed herein an integral ratio determinator, which calculates R" using Eq. (11) below.
  • oxygen quenching is measured as the intensity ratio, R', given by:
  • R' I 1 '/I 2 ', (1 0) wherein I 1 ' and I 2 ' represent the fluxes of luminescence over two time periods that substantially encompass the period of detectable luminescent emission once the light source 12' is turned off.
  • time intervals are selected from the lamp-off regions of linear t' and nonlinear t" decay to provide ratioing R values of I 1 ' and I 2 ' that give the best resolution within the oxygen pressure range of interest.
  • I 1 ' preferably encompasses the period of linear decay of the luminescent emission.
  • I 1 ' can be the sum of the intensities I(t i ) digitized by the fast A/D converter over times from 0 to about 20 ⁇ s
  • I 2 ' can be the sum of the intensities over times from 20 to 300 ⁇ s, with time zero for both measurements being the end of the period of illumination.
  • FIGURE 7 illustrates the two intensity segments I 1 ' and I 2 , and a corresponding a plot of R' versus p0 2 is shown in FIGURE 8.
  • the LED is turned on, for example, from time 0 to approximately 50 ⁇ s.
  • the measure of oxygen quenching is the intensity ratio, R", given by:
  • I 1 " preferably encompasses the entire time period during which light source 12" is turned on, and I 2 " preferably encompasses substantially the entire period of detectable luminescent emission subsequent to turning off the light source 12".
  • the light source 12" is most preferably turned on only until the detected luminescent intensity plateaus, meaning attains its maximum intensity, as shown in FIGURE 9.
  • I 1 " can be the intensity of emission gathered over the time period from 0 to 50 ⁇ s, i.e., while the LED is on
  • I 2 " can be the intensity of emission gathered from 50 u s to 300 ⁇ s, after which there is no more emitted light.
  • the signal 42 from the preamp 40 is split by two balanced synchronous demodulators into the pulse and decay (light 12" on and off) components. Circuit 44" then integrates the pulse and decay components separately, passes the signals through V/F converter channels, and respectively counts each component for the digitized equivalent.
  • FIGURE 9 illustrates the two intensity segments I 1 " and l 2 ", and a corresponding plot of R" versus p0 2 is shown in FIGURE 10.
  • each sensor should be calibrated at one pressure, preferably the oxygen pressure of air.
  • the disclosed method uses as emitters metallc-organic molecules, in particular Pt and Pd derivatives of porphyrins.
  • the organic region of these molecules is where light absorption and emission occurs, and this provides a strong absorption coefficient.
  • their natural phosphorescence decay rate, k nat has been greatly increased by the metal atom so they have a high quantum yield of phosphorescence.
  • their phosphorescence decay time is sufficiently short so that it is in a convenient range to monitor for oxygen quenching.
  • a suitable oxygen quenching-sensitive monitor 16, or sensor composition, for practicing this invention contains at least one species of phosphorescent molecule having the following properties (a) through (i):
  • the phosphorescent molecule should have a high absorption coefficient for light obtained from a convenient flashing light source.
  • the quantum yield of phosphorescence should be large so that there is sufficient light to work with, roughly ⁇ > 0.2.
  • the phosphorescence lifetime in the absence of oxygen should be in the range 50 microseconds to 5 milliseconds. With too short a lifetime, apparatus becomes more expensive. With too long a lifetime, the emission will tend to be entirely quenched in higher oxygen ranges of interest.
  • the wavelengths of strong absorption and strong emission should be well separated so that complementary filters can be obtained to isolate these spectral regions.
  • the emission should be in the red, with wavelengths longer than 600 nanometers, as this avoids competition from extraneous emission that might occur from the sample or from windows, filters, and optical pipes.
  • the phosphorescent molecule should be stable to photooxidation, since they will be used under illumination and with oxygen present.
  • the phosphorescent molecule should be insoluble in the fluid being monitored so that it does not leach out of the monitor.
  • the molecule should not be water soluble.
  • the molecule must have solubility suitable for monitor fabrication.
  • the natural and radiationl ⁇ ss decay times, k nat and k d in Eq. (1), should be insensitive to small temperature changes.
  • the emission properties should not be sensitive to common molecules, e.g., H 2 O, CO 2 , N 2 , and to other molecules likely to be present in the fluid to be monitored, e.g., halothane or N 2 O in blood.
  • the phosphorescent molecule(s) having the foregoing properties can be sequestered in a carrier matrix to form an oxygen monitor 16.
  • the following characteristics (j) through (1) apply to both the phosphorescent molecule and the carrier matrix:
  • the phosphorescent molecule(s) and the carrier matrix should be chemically stable, so that they do not deteriorate.
  • the carrier matrix which is preferably an oxygen-permeable plastic:
  • the carrier matrix should dissolve or bond with the phosphorescent molecule and be easily cast onto the substrate which holds it.
  • the carrier matrix must be porous to oxygen and should equilibrate over convenient times, since hhis equilibration rate determines the response time of the oxygen monitor. We have found that the response time can be shortened by the amount of plasticizer in a PVC carrier matrix.
  • the equilibrium oxygen concentration in the carrier matrix, [ O 2 ] mx , and the quenching constant, kq should be of size: k q [O 2 ] mx k nat + k d (9) wherein these quantities are those of Eq. (1). If the left side of Eq. (9) is much larger than the right side, then little emission is observed; if the left side is much smaller than the right side, then little quenching is observed. Thus the product k q [ O 2 ] mx must be adjusted to match the parameters k na t + k d of the phosphorescing molecule and the oxygen concentration [ O 2 ] f1 in the fluid to be monitored.
  • the carrier matrix should stick to the substrate on which it is mounted, e.g., the end of a light pipe 56 as in FIG. 6.
  • the carrier matrix should be nonvolatile and insoluble in the fluid being monitored.
  • the carrier matrix should be chemically stable with respect to the fluid being monitored, the phosphorescent molecule in its ground state, and the phosphorescent molecule in light in the presence of oxygen. (s) Finally, the carrier matrix should be transparent to the exciting light and to the phosphorescent light.
  • Suitable oxygen quenching-sensitive phosphorescent molecules for practicing this invention include porphyrins, meaning those compounds that contain the porphyrin ring structure (Monograph No. 7468, Tenth Edition of The Merck Index, Merck & Company, Inc., Rahway, NJ, 1983), chlorins, bacteriochlorins, and isobacteriochlorins.
  • the porphyrin ring structure gives rise to intense optical absorption and emission in the wavelength range of interest. The wavelengths for absorption and emission can be shifted by various chemical modifications to the porphyrin ring structure. In addition, the emission lifetimes and quantum yields are strongly dependent on any metal incorporated into the center of the ring.
  • the preferred synthetic rings for employment in the practice of this invention are tetra(pentafluorophenyl)porphyrin (TFPP), octaethylporphyrin (OEP), tetraphenylporphyrin (TPP), and tetrabenzporphyrin (TBP) compounds.
  • Preferred metals are second and third transition row metals with electron configurations d 6 or d 8 , including Ru(II), Rh(III), Pd(II), Os(II), Ir(III), Pt(II), and Au(III). All of the aforementioned metalloporphyrins show phosphorescence with moderate quantum yields and suitable lifetimes.
  • Pd(II) and Pt(II) derivatives are the most preferred since only they are free of axial ligands and/ or counter ions, which can complicate the synthesis and can introduce instabilities either during film preparation or during operation under light; moreover, they have the highest quantum yields of emission.
  • Som e other metalloporphyrins may also be suitable; for example, we have had some success using Hf(IV) octaethylporphyrin.
  • Pd(II) and Pt(II) complexes of tetra(pentafluorophenyl)porphyrin (TFPP), octaethylporphyrin (OEP), tetraphenylporphyrin (TPP), and tetrabenzporphyrin (TBP) have proven in our hands to be the best phosphorescent molecules for practicing this invention as they tend to satisfy most of the above ⁇ stated criteria (a) to (i).
  • the palladium, Pd(II), porphyrins have lifetimes in the absence of oxygen of 1-2 milliseconds and the platinum, Pt(II), porphyrins of around 100 microseconds.
  • these Pd (II) and Pt(II) porphyrins are most sensitive in different regions of oxygen concentration:
  • the palladium porphyrins are best used under 10 torr pressure, while the platinum porphyrins can best be used above 50 torr pressure.
  • a combination of different phosphorescent molecules having different phosphorescent lifetimes e.g., any of the above-stated Pd porphyrins along with any of the above-stated Pt porphyrins, a wider range of oxygen pressures can be monitored than by use of either phosphorescent molecule alone.
  • the range of sensitivity for any particular phosphorescent molecule used in the oxygen quenching-sensitive composition can be adjusted by choice of the carrier matrix and also the amount of plasticizer dissolved in the matrix.
  • Polyvinyl chloride with variable amounts of plasticizer provide suitable carrier matrices, as does polymethyl methacrylate without plasticizer.
  • Other suitable oxygen-permeable matrices can be made of cellulose acetate or silicohe-polybicarbonate copolymer (Petrarch MB).
  • Pd and Pt tetraphenylporphyrin and tetra(pentafluorophenyl)porphyrin show a specific absorption band proportional to the deterioration of the compound. This band lies in the wavelength range 550-620 nm, depending on the compound. This new band may be due to a photooxidation product. The appearance of the specific band upon prolonged irradiation can be used to provide a quality control check of photodeterioration to determine when the monitor film should be changed.
  • OEP, TBP, TFPP, and TPP are the preferred phosphorescent molecules for use in the disclosed measurement methods. All of these preferred molecules are in addition reasonably stable when freshly synthesized and over the time course of typical laboratory analyses of absorption and emission properties. However, we found that some of these eight species proved less stable than others when subjected to extended illumination and ambient oxygen. Not all of the Pd and Pt porphyrins in polyvinyl chloride containing plasticizer are sufficiently stable under extended illumination to be suitable for oxygen sensors. The OEP and TBP rings deteriorated so readily that they were entirely gone, as evidenced by lack of absorption spectrum, after fifteen hours of illumination.
  • the TPP ring proved more hardy and showed a survival of emission intensity and lifetime slightly poorer than perylene dibutyrate (PDB), the molecule of choice for a fluorescent oxygen sensor described in U.S. Patent No. 4,476,870 and in Anal.Chem. 56:62-67, 1984.
  • the TFPP ring proved more hardy than PDB under the same test conditions.
  • the survival of the emission intensity of Pd(TFPP) was comparable to that of PDB, while that of Pt(TFPP) was better.
  • the emission intensity of the Pt(TFPP) after 15 hours of illumination was 80% of its initial value while the lifetime was 95% of its initial value.
  • luminescent compounds are quite generally photooxidized in the presence of oxygen, it is critical to select a relatively photostable phosphorescent or fluorescent molecule for use in luminescent oxygen sensors.
  • the most preferred phosphorescent molecules for monitoring oxygen concentration by any of the previously reported or subject methods therefore include Pd(TFPP) and Pt(TFPP).
  • Photooxidation of aromatic molecules is one of the most important processes by which compounds are degraded and undergo permanent chemical transformations.
  • photooxidation reactions of aromatic compounds are enhanced by more extended conjugation, higher electron density, and lower oxidation potentials.
  • Porphyrin reactivity with molecular oxygen in the presence of light is influenced by the inductive effects of the functional group attached either at the periphery of the porphyrin ring or in extraplanar ligands.
  • the electron withdrawing effect of the pentafluorophenyl substituents raises the oxidation potential and reduces the electron density.
  • other aromatic molecules can be made more photostable by substituting fluorine atoms on the periphery of the synthetic ring.
  • fluorine atoms on the periphery of the synthetic ring.
  • Such complete or partial fluorine substitutions make the luminescent molecule less susceptible to photodeterioration.
  • Photodeterioration is indicated by a diminution following exposure to illumination of the molecule's absorption spectrum and/or its emission peak ratios and lifetime ratios.
  • the first step in photodeterioration probably Involves electron loss from the luminescent molecule to ambient oxygen molecules, and we believe that the fluorinated sidegroups inhibit such transfers.
  • fluorination serves to protect the Integrity of the phosphorescent molecule's emission lifetime profile more than its emission intensity.
  • these fluorinated porphyrins are particularly well-suited for monitoring oxygen concentration using the disclosed emission lifetime method.
  • Pd(TFPP) and Pt(TFPP) Closely related molecules to Pd(TFPP) and Pt(TFPP) that may retain the advantage of photostability are the reduced ring chlorin [dihydroporphyrin] , bacteriochlorin [opposite tetrahydroporphyrin] , and isbbacterioehlorin [adjacent tetrahydroporphyrin] ; described in M. Gouterman, Chapter 1, pp. 1-165, in The Porphyrins, Vol. Ill, D, Dolphin, Ed., Academic Press, N.Y. 1978, expressly incorporated herein by reference.
  • TFBP molecules are expected to prove more stable than TBP to photooxidation when exposed to light and oxygen. Partial fluorination to give compounds of formula III should also enhance photostability.
  • the Pd and Pt tetrabenzporphyrins proved unstable under extended illumination, they exhibit certain other advantages as compared with the TFPP derivatives.
  • the TBP absorption maxima are further to the red, they are more suitable for excitation by available light emitting diodes.
  • their emission is further to the red than Pt(TFPP) it is less absorbed by optical piping and is less subject to interference by extraneous emission.
  • Pd(II) and Pt(II) derivatives of the above-stated molecules II or III will provide photostability as well as a more convenient spectral range.
  • the product was chromatographed on neutral alumina column with CH 2 Cl 2 as eluant. 10 mg of the Pt(TFPP) were then dissolved in a 25 ml aliquot of a PVC stock solution made by dissolving 3 grams of polyvinyl chloride (PVC; B.F. Goodrich) in 70 ml tetrahydrofuran and 200 ul of 2-nitrophenyl-octylether (Fluka AG) as plasticizer. Samples are prepared by casting the resulting solution on a glass slide and allowing the tetrahydrofuran to evaporate. Films prepared in this manner were smooth and transparent.
  • PVC polyvinyl chloride
  • Fluka AG 2-nitrophenyl-octylether
  • One of the films was mounted inside of an aluminum sample chamber that was then evacuated.
  • the chamber consisted of 3 optical flats to allow absorption and emission data acquisition, and .had a valve assembly for controlling the pressure of ambient gases. This chamber allowed the lifetime and intensity of the emission to be monitored as functions of 0 2 pressure. Measurements were made using the system 10 shown in FIGURE 1.
  • Pd(TFPP) was synthesized following the procedure described in Inorg.Chem. 19:388, 1980. 10 mg of Pd(TFPP) was then dissolved in a 25 ml aliquot of the PVC stock solution described In Example 1. Films of Pd(TFPP) In PVC were made as in Example 1. Phosphorescence emission intensity decay curves, I(t), of the Pd(TFPP) In plasticized PVC film were determined at various molecular oxygen pressures ranging from 1 to 600 torr. Stern-Volmer plots of and were also made for this Pd(TFPP) in PVC film as a function of oxygen pressure. The data are shown in Table 3.
  • polymethyl methacrylate (PMM), cellulose acetate (CA), and silicone polymer can be used as matrices for the Pt(TFPP), Pd(TFPP), or other luminescent aromatic molecule.
  • PMM polymethyl methacrylate
  • CA cellulose acetate
  • silicone polymer can be used as matrices for the Pt(TFPP), Pd(TFPP), or other luminescent aromatic molecule.
  • these polymers are more permeable to gases than PVC and so can be used without plasticizer.
  • films of these matrices were made as described above from the following stock solutions that each contained 10 mg of Pt(TFPP):
  • FIGURE 11 Quenching plots of the Pt(TFPP) in PMM, CA, and silicone PMB films as a function of O 2 pressure are shown in FIGURE 11.
  • FIGURE 11 also shows data from two PVC films with different amounts of plasticizer, thus indicating the influence of plasticizer concentration on oxygen quenching. These films were made as described in Example 1: PVC-1 was made using 200 microliters of the plasticizer 2-nitrophenyloctaethylether, and PVC-2 was made using 500 mlcroliters of the plasticizer.
  • the metalloporphyrins and films were prepared fresh for this test and were subjected to 15 hours of illumination in the above-described setup. Absorptions, emission intensities, and emission lifetimes were measured before and after the 15 hour illumination period. The results are summarized in Table 4.
  • the absorption spectrum is a minimal test for survival of the compound. If the spectrum is gone, the compound is gone. The absorption spectra of neither the OEP nor the TBP rings survived 15 hours of illumination. The absorption spectra for Pd(TFPP), Pt(TFPP), Pd(TPP), and
  • Pt(TPP) showed growth of an impurity with an absorption at approximately 600 nm.
  • the impurity appeared slightly blue shifted from Pd to Pt (with the shift more marked for the TPP rings). This would suggest that the impurity somehow contains or is associated with the metal.
  • the emission lifetimes of the TFPP molecules provide a much more stable measure of oxygen pressure than the emission intensities of Peterson's fluorescent dye of choice.
  • PDB and other oxygen-quenchable fluorescent substances known in the art can be used with our disclosed methods, which provide measurements of oxygen quenching that are insensitive to photodeterioration of the luminescent substance during use.
  • plastic refers to a polymeric product of large molecular weight that can be shaped by flow, including principally at least one polymeric starting material and permissible amounts of plasticizer as described above.

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Abstract

Des procédés et des substances luminescentes sont utilisés pour mesurer la concentration en oxygène d'un fluide d'analyse (18). Un fluide d'analyse (18) est mis en contact avec une pellicule plastique (16) contenant une substance luminescente dont l'intensité d'émission est inhibée en présence d'oxygène. La pellicule (16) est irradiée (14) par une lumière qui est fortement absorbée par la substance luminescente, et l'on obtient une mesure de l'intensité de l'émission luminescente en fonction du temps I(t). Trois procédés de mesure de l'inhibition, et par conséquent de la concentration en oxygène, à partir d'I(t) sont décrits. Ces procédés ne sont pas affectés par des variations de l'épaisseur du plastique, de la concentration en substance luminescente et de sa décomposition et prennent en considération la décroissance non-exponentielle de l'émission, en élargissant ainsi la plage de sensibilité de la pellicule (16). Les substances luminescentes comprennent des dérivés métalliques de porphyrines fluorées entièrement ou partiellement, rendues photostables par la fluorisation de la chaîne porphyrine.
EP19860904575 1985-07-03 1986-06-27 Procedes de mesure de la concentration en oxygene. Withdrawn EP0227815A4 (fr)

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