Chemistry: electrical and wave energy – Processes and products – Electrophoresis or electro-osmosis processes and electrolyte...
Reexamination Certificate
1999-09-21
2001-09-04
Gorgos, Kathryn (Department: 1741)
Chemistry: electrical and wave energy
Processes and products
Electrophoresis or electro-osmosis processes and electrolyte...
C204S627000
Reexamination Certificate
active
06284115
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to enrichment of analytes in liquid sample analysis.
2. Description of the Related Art
In a range of multidimensional analytical techniques, the presence of non-analyte, matrix-related substances required for one analytical dimension often interfere with another dimension, and in these circumstances it is desirable to remove non-analytes from the analytical stream flowing from an upstream analytical dimension before the stream is introduced to a subsequent downstream analytical dimension in the scheme. In particular, for example, for liquid phase based separation techniques, it is desirable to remove non-analyte(s) from the analytical stream in an on-line flow-through manner without compromising the analytical procedure.
In liquid phase separation techniques, such as High Performance Liquid Chromagraphy (“HPLC”), mixtures are separated from each other spatially, volumetrically and temporally in a flowing stream. The resolution of such a system is based on the separation between the mean of the concentration profile for two peaks relative to the standard deviation of the concentration profile of each of the peaks. The separation process itself introduces an increase in the variance of the concentration profile. However, further increase in the variance (also known as band broadening, peak broadening or dispersion) is introduced as the analyte peaks pass through extra-column “dead-volume” such as connecting tubes, detector flow cells and mixing chamber. Particularly for modern miniaturized chromatography systems, this extra dispersion can be unacceptable and steps are taken to minimize it.
In mass spectrometry (“MS”) where electrospray ionization is employed, introduction of non-volatile salts into the electrospray ion source leads to diminished performance. Accordingly, contamination of a sample stream from a liquid chromatography (“LC”) column by non-volatile salts effectively precludes the use of ion exchange chromatography as a separation technique in analytical systems in which liquid chromatography is coupled with mass spectrometry (“LC/MS”).
Electrodialytic treatment may be employed for isolation and enrichment of compounds from complex solutions. Publications of interest with respect to sample treatment using electrodialysis or electrofiltration include: A. J. J. Debets et al. (1992),
Journal of Chromatography,
Vol. 600, pp. 163-173; A. J. J. Debets, et al. (1990),
Chromatographia,
Vol. 30, No. 7/8, pp. 361-366; A. J. J. Debets, et al. (1994),
Chromatographia,
Vol. 39, No. 7/8, pp. 460-468; M. W. Lada, et al. (1995),
Analytica Chemica Acta,
Vol. 307, pp. 217-225; E. Jacobs, et al. (1986),
Analytical Biochemistry,
Vol. 154, pp. 583-589; W. R. Bowen (1991), “Electrically Driven Membrane Process”, in
Chromatographic and Membrane Processes in Biotechnology,
C. A. Costa and J. S. Cabral, eds., Kluwer Academic Publishers, Dordrecht, Netherlands, pp. 207 to 221 (review); K. Takahashi et al. (1995),
Journal of Chemical Engineering of Japan,
Vol. 28, No. 2, pp. 154-158; T. -C. Huang et al. (1993),
Chemical Engineering Communications,
Vol. 122, pp. 213-225; U. Göbel et al. (1987),
Journal of Biochemical and Biophysical Methods,
Vol. 14, pp. 245-260; M. Bier et al. (1990),
Separation Science and Technology,
Vol. 25, Nos. 9/10, pp. 997-1005; E. Sommerfeld et al., German patent publication 2,340,362; N. B. Egen, et al. U.S. Pat No. 5,336,387; J. -I. Liao, et al. U.S. Pat. No. 5,480,526; S. M. Jain, U.S. Pat. No. 4,441,978; R. Oertli, U.S. Pat. No. 4,576,696; J. M. Goldstein, U.S. Pat. No. 4,614,576; W. A. McRae, U.S. Pat. No. 4,146,455 and 4,180,451; and S. B. Tuwiner, U.S. Pat. No. 3,674,669.
Additional publications and patents of interest include U.S. Pat. No. 5,082,548 and U.S. Pat. No. 5,055,399; and N. Hese et al., German patent publication 3,337,668.
All articles, references, standards, patents, patent applications and the like referred to herein are hereby incorporated herein by reference in their entirety.
SUMMARY OF THE INVENTION
The degree to which components below a molecular weight cutoff are removed from a solution by a dialysis system is based on the mixing and the residence time in the apparatus. Micro-dialysis can be employed in the stream downstream from an LC column. In an in-line, post-column micro-dialysis system, complete removal of low molecular weight salts requires a long residence time in the micro-dialysis zone, resulting in excessive dispersion. According to the invention, an electric field is applied to the micro-dialysis zone, providing for an accelerated movement of smaller charged molecules (such as non-volatile salts) across the dialysis membrane and resulting in a reduction in the residence time in dialysis. Samples can be enriched for subsequent analysis without unacceptable loss of chromatographic fidelity, and non-volatile salts can be removed from the analytical stream without introducing excessive dilution or chromatographic band broadening.
Accordingly, the invention provides methods and an apparatus for sample treatment by in-line flow-through electromicro-dialysis.
In one general aspect, the invention features an apparatus for in-line flow-through sample treatment, including a sample channel having a sample inlet and a sample outlet and being defined in part by inner surfaces of walls of a solid material and in part by an inner surface of a first membrane, and a first flushing channel having an inlet port and an outlet port and being defined in part by inner surfaces of walls of a solid material and in part by an outer surface of the first membrane, and means for applying an electric field across the first membrane in liquids carried within the sample channel and the first flushing channel.
The analytical stream flows from an upstream liquid analysis device, such as a liquid chromatographic column, into the sample inlet and through the sample channel and out from the sample outlet, and a flushing liquid flows into the inlet port and through the flushing channel and out from the outlet port. The electric field is applied, causing charged particles (such as ions of inorganic salts) in the analytical stream to move in a direction, depending upon their respective charges, generally away from or toward the membrane. Particles (including solvent molecules) sufficiently small to pass through the membrane move across the membrane from the sample channel to the flushing channel, in which they are carried away by the flushing liquid. Thus, as the analytical stream flows through the dialysis zone smaller particles are removed from the analytical stream, and smaller charged particles are removed particularly rapidly under force of the electric field, resulting in a rapid enrichment of sample analytes in the analytical stream.
In some embodiments, the sample channel is further defined in part by an inner surface of a second membrane, and the apparatus further includes a second flushing channel having an inlet port and an outlet port and being defined in part by inner surfaces of walls of a solid material and in part by an outer surface of the second membrane; and the means for applying an electric field includes means for applying the electrical field across both the first membrane and the second membrane in liquids carried within the sample channel and the flushing channels. In such embodiments, application of the electrical field results in movement of particles having one charge polarity toward the first membrane and in movement of particles having opposite charge polarity toward the second membrane.
The membrane (or, where two membranes are employed, each of them) has a molecular size-selective permeability selected according to the sizes of the particular molecules whose removal is desired, as is well understood in the dialysis art. In some embodiments, conventional dialysis membrane material suitable for electrodialysis is employed, having a nominal molecular weight cut-off, for example, about 30,000 daltons, 10,000 daltons, 5,000 daltons, 1,000 daltons,
Agilent Technologie,s Inc.
Gorgos Kathryn
Parsons Thomas H.
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