WO1999020983A2 - Systems and methods using an optical sensor for liquid metering - Google Patents

Systems and methods using an optical sensor for liquid metering Download PDF

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Publication number
WO1999020983A2
WO1999020983A2 PCT/US1998/022192 US9822192W WO9920983A2 WO 1999020983 A2 WO1999020983 A2 WO 1999020983A2 US 9822192 W US9822192 W US 9822192W WO 9920983 A2 WO9920983 A2 WO 9920983A2
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WO
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Prior art keywords
liquid
container
light
metering assembly
array
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PCT/US1998/022192
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French (fr)
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WO1999020983A3 (en )
Inventor
Steve Miller
Christopher Kilcoin
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Argonaut Technologies, Inc.
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01FMEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F23/00Indicating or measuring liquid level, or level of fluent solid material, e.g. indicating in terms of volume, indicating by means of an alarm
    • G01F23/22Indicating or measuring liquid level, or level of fluent solid material, e.g. indicating in terms of volume, indicating by means of an alarm by measurement of physical variables, other than linear dimensions, pressure or weight, dependent on the level to be measured, e.g. by difference of heat transfer of steam or water
    • G01F23/28Indicating or measuring liquid level, or level of fluent solid material, e.g. indicating in terms of volume, indicating by means of an alarm by measurement of physical variables, other than linear dimensions, pressure or weight, dependent on the level to be measured, e.g. by difference of heat transfer of steam or water by measuring the variations of parameters of electric or acoustic waves applied directly to the liquid or fluent solid material
    • G01F23/284Electromagnetic waves
    • G01F23/292Light, e.g. infra-red or ultra-violet
    • G01F23/2921Light, e.g. infra-red or ultra-violet for discrete levels
    • G01F23/2928Light, e.g. infra-red or ultra-violet for discrete levels using light reflected on the material surface
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01FMEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F23/00Indicating or measuring liquid level, or level of fluent solid material, e.g. indicating in terms of volume, indicating by means of an alarm
    • G01F23/22Indicating or measuring liquid level, or level of fluent solid material, e.g. indicating in terms of volume, indicating by means of an alarm by measurement of physical variables, other than linear dimensions, pressure or weight, dependent on the level to be measured, e.g. by difference of heat transfer of steam or water
    • G01F23/28Indicating or measuring liquid level, or level of fluent solid material, e.g. indicating in terms of volume, indicating by means of an alarm by measurement of physical variables, other than linear dimensions, pressure or weight, dependent on the level to be measured, e.g. by difference of heat transfer of steam or water by measuring the variations of parameters of electric or acoustic waves applied directly to the liquid or fluent solid material
    • G01F23/284Electromagnetic waves
    • G01F23/292Light, e.g. infra-red or ultra-violet
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00351Means for dispensing and evacuation of reagents
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00351Means for dispensing and evacuation of reagents
    • B01J2219/00389Feeding through valves
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00351Means for dispensing and evacuation of reagents
    • B01J2219/00418Means for dispensing and evacuation of reagents using pressure
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00585Parallel processes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068Means for controlling the apparatus of the process
    • B01J2219/00698Measurement and control of process parameters
    • CCHEMISTRY; METALLURGY
    • C40COMBINATORIAL CHEMISTRY
    • C40BCOMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES, IN SILICO LIBRARIES
    • C40B60/00Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Abstract

A metering assembly uses light refraction to determine the liquid level in a metering container (20). An image of a liquid-air boundary in the metering container (20) is projected onto a sensor (36) which accurately tracks the movement of the boundary. By tracking the location of this boundary, the assembly can determine when the container (20) has the desired level of liquid (6) being metered. In one embodiment, the assembly for use in a combinatorial chemistry synthesis apparatus has a generally transparent or translucent container (20) adapted to hold a liquid (6) and an optical liquid level sensor (30) coupled to the container. The sensor (30) comprises a light source (32), a photosensor (36), and a focusing device (34) positioned at a distance from the light source (32) to reproduce an image of a liquid-air boundary in the container onto the photosensor (36).

Description

SYSTEMS AND METHODS USING AN OPTICAL SENSOR FOR LIQUID METERING

CROSS-REFERENCE TO RELATED APPLICATIONS The present invention claims the benefit of and is a continuation-in-part of U.S. Provisional Patent Application No. 60/063,137, filed on October 22, 1997, the full disclosure of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention generally relates to methods and apparatus for the parallel synthesis of large numbers of molecularly diverse compounds . The present invention is particularly useful in generating combinatorial libraries of chemical compounds by simultaneously employing solid phase synthesis in a plurality of reaction vessels.

A standard method for searching for new chemical compounds employs the screening of pre-existing compounds in assays which have been designated to test particular properties of the compound being screened. Similarly, in designing compounds having desired physiochemical properties for general chemical applications, numerous compounds must be individually prepared and tested. To reduce the time and expense involved in preparing and screening a large number of compounds for biological activity or for desirable physiochemical properties, technology has been developed for providing massive numbers or libraries of compounds for the discovery of lead compounds. Current methods for generating large numbers of molecularly diverse compounds focus on the use of solid phase synthesis. The generation of combinatorial libraries of chemical compounds by employing solid phase synthesis is well known in the art. For example, Geysen et al . (Proc. Natl. Acad. Sci . USA, 3998 (1984) describe the construction of multi-amino acid peptide libraries; Houghton et al . (Nature, 354, 84 (1991) and PCT Patent Pub. No. WO 92/09300) describe the generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery; Lam et al . (Nature, 354, 82 (1991) and PCT Patent Pub. No. WO 92/00091) describe a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin. The growing importance of combinatorial chemistry as an integral component of the drug discovery process has spurred extensive technological and synthetic advances in the field (Thompson, L.A. ; Ellman, J.A. (1996) Chem . Rev. 96, 555- 600) . Founded in peptide synthesis devised by Merrifield, solid phase chemistry has emerged as the prominent method for construction of small molecule combinatorial libraries (see e.g. Merrifield, R.B. (1963) J. AM. Chem . Soc. 85, 2149-2154; (a) Terrett, N.K.; Gardner, M. ; Gordon, D.W.; Kobylecki, R.J.; Steele, J. (1995) Tetrahedron 51 (30) , 8135-8173. (b) Gordon, E.M.; Barrett, R. W. ; Dower, W.J.; Fodor, S.P.A.; Gallop, M.A. (1994) J. Med . Chem . 37, 1385-1401.).

To aid in the generation of chemical compounds in such Combinatorial chemical libraries, scientific instruments should be developed which automatically perform many or all of the steps required to generate such compounds. One factor limiting the capabilities of automated combinatorial chemistry instrumentation, is the use of conventional mechanical plungers for metering liquid to be used in the system. To provide the requisite level of accuracy, these mechanical plungers use step motors which inherently move the plunger at a slow rate to accurately draw fluid into the metering vessel. Taking in the range of minutes or more for each flushing and filling step, known metering devices are undesirably slow for the perhaps thousands of steps performed in high-volume, automated combinatorial chemistry instruments. Additionally, these plunger devices contain numerous moving parts such as plungers and 0-rings which require frequent replacement to maintain accuracy in liquid metering. Accordingly, there is a need for improved liquid metering systems and methods suitable for rapid synthesis of chemical compounds. In particular, it would be desirable to provide improved liquid metering devices and methods, where the metering device maintains levels of metering accuracy comparable to mechanical syringes, but with an increase in liquid metering speed. Preferably, the metering device will use sensors that can detect the liquid level without coming into contact with the liquid chemistries. Furthermore, the sensor accuracy should be independent of the chemicals used in the system. For example, conventional optical sensors which detect the presence of liquid by changes in light intensity have their accuracy affected by the color and opacity of the liquid being measured. To more precisely detect the liquid level, it desirable that some other sensing methodology be developed to accurately track the upper level of liquid in a container. The present invention will provide at least some of the desired improvements.

SUMMARY OF THE INVENTION

The present invention is directed to apparatus and methods for metering liquid. In particular, the present invention provides a metering apparatus using light refraction to determine the liquid level in a metering container. An image of the boundary between the upper surface of the liquid and the air above it (i.e. liquid-air boundary) is projected onto a sensor which accurately tracks the movement of this boundary. Advantageously, the use of light refraction provides a metering system which operates at speeds faster than conventional mechanical syringes since the system does not rely on accurately moving a mechanical piston. Additionally, the sensors are typically not in contact with the chemicals being metered, and" this allows the invention to be used with caustic and corrosive chemistries. As the device further relies on changes in light refraction, not light intensity, the present invention is chemistry independent since the color or opacity of the chemicals may affect the strength of light passing through the chemicals.

A liquid metering assembly of the present invention for use in a combinatorial chemistry synthesis apparatus generally comprises a generally transparent or translucent container adapted to hold a liquid and an optical liquid level sensor coupled to the container to measure the liquid level therein. The sensor has a light source, a photosensor, and a focusing device positioned at a distance from the light source to reproduce an image of a liquid-air boundary in the container onto the photosensor. By tracking the location of this boundary, the present invention can determine when the liquid has reached the desired level in the container. The assembly typically further includes a plurality of valves and tubing fluidly coupled to the container to regulate the flow of liquid into and out of the container. The assembly also typically has a controller for determining the level of said liquid in the container.

In one aspect of the present invention, the light source of the liquid metering assembly is oriented to shine light along an imaginary line through the container, and the focusing device is positioned at an angle from the imaginary line o ' f the light source. This angle is preferably between about 25 to 40 degrees. The focusing device may also comprise of an array of focusing elements and an array of photosensitive elements. These arrays facilitate the tracking of the liquid-air boundary in the container. In one embodiment, the photosensor array has at least about 200 photosensitive elements per linear inch. The present invention may also use arrays of light sources such as light emitting diodes (LEDs) or fiber optic cables/elements to project light through the container.

In a combinatorial chemistry synthesis apparatus according to the present invention, the apparatus may comprise of a source of chemicals, an optical liquid metering system fluidly coupled to the source of chemicals and a plurality of valves, and a plurality of reaction vessels fluidly coupled to the plurality of valves. Advantageously, using the optical metering system allows for a more rapid delivery of chemicals to reaction vessels in the synthesis apparatus. It may also provide certain cost efficiencies and performance benefits such as increased reliability by reducing the number of moving parts as compared to conventional metering systems .

In another aspect, a method according to the present invention for metering liquid comprises the step of shining light through a container having a curved inner surface. The container is filled with liquid, which creates a liquid-air boundary. Light is passed through the container. An image of the liquid-air boundary is focused onto a photosensor which detects the liquid-air boundary. The detecting step typically comprises scanning a plurality of photosensors to locate the liquid-air boundary. In a further aspect, the present invention may be a modular optical liquid level sensor for measuring the level of a liquid in a generally transparent or translucent container. The sensor comprises an array of light sources aligned with the container in the direction that the liquid level changes. The array of light sources are oriented to shine light along an imaginary line through the container. An array of focusing devices are at a position where they reproduce an image of the liquid-air boundary onto an array of photosensors.

A further understanding of the nature and advantages of the present invention may be realized by reference to the remaining portions of the specification and the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic of a liquid metering assembly according to the present invention that is simplified for purposes of illustration.

Fig. 2 is a top-down view of an alternative embodiment of a container according to the present invention. Figs. 3A-3B are perspective views depicting the various ways in which light can pass through a container that is empty and one that is partially filled. Figs. 4A-5B depict light refraction for various conditions as light passes through a container of Fig. 2.

Figs. 6A-6B compares the quality of a liquid-air boundary as projected onto a photosensor. Figs. 7A-7B illustrate the use of lenses to focus light according to the present invention.

Figs. 7C-7D show embodiments of a rod lens arrays according to the present invention.

Figs. 8A and 8E are side and end views of an exemplary embodiment of an optical liquid level sensor.

Figs. 8B and 8C are cross-sectional views taken along lines 8B-8B and 8C-8C of Fig. 8E.

Fig. 8D is a cross-sectional view taken along line 8D-8D of Fig. 8A. Figs. 9A-9E depict the metering of fluid using the assembly of Fig. 1.

Fig. 10 shows a container of the present invention in a horizontal orientation.

Figs. 11A-11B illustrate alternative embodiments of the present optical liquid level sensor.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention provides an assembly for metering and delivering liquid. In particular, the present invention uses an optical liquid level sensor to control the flow of liquid into and out of a metering container. For convenience, the remainder of the disclosure describes the present invention as used with an apparatus for solid phase synthesis or organic synthesis. However, it will be appreciated that the present invention can be applied equally well to liquid-liquid chemistry, or other synthesis apparatus.

The present invention may be used with systems for rapidly generating and systematically synthesizing large numbers of molecules that may vary in their chemical structure or composition. Such synthesis apparatus are useful for randomly generating a large number of candidate compounds, then later optimizing those candidate compounds exhibiting the desired properties. Because large numbers of compounds are being synthesized, assemblies which can quickly and accurately meter and deliver liquid reagents to reaction vessels in the synthesis apparatus are desirable. The present invention uses optical sensors to accurately determine the distance, preferably the height, of liquid entering into a metering container. By coupling the sensor to a valve controller, the assembly can meter liquid by detecting the level of liquid in the container and closing the valve when the desired level of liquid is in the container. The metering assembly is typically limited only by the speed by which a controller can process information from the sensor and the mechanical accuracy of the valves used to control flow of the liquid. Advantageously, both of these requirements still allow the optical sensor to operate significantly faster than conventional mechanical syringes. Further, the a liquid metering assembly does not require components such as expensive stepper motors and O-rings used on mechanical syringes which wear out often and require replacement. The involved optical sensor elements of the present invention are typically not in contact with the chemistries used during synthesis. Thus, the present invention is useful in almost all of the synthetic reactions which are know to one of skill in the art, including, for example, peptide synthesis, acylation, alkylation, condensation, cyclization, halogenation, heterogeneous catalysis, hydrolysis, metallation, nitration, nucleophilic displacement, organometallic reactions, oxidation, reduction, sulfonation, acid chloride formation, Diels-Alder reaction, Friedel-Crafts reactions, Fischer indole synthesis, Michael, reactions, and the like (see e.g., H.O. House, "Modern Synthetic Reactions", 2nd ed. (Benjamin/Cu mings, Menlo Park 1972) ; J. March, "Advanced Organic Chemistry", 3rd ed. , (John Wiley & Sons, New York, 1985) ; Fieser and Fieser, "Reagents for Organic Synthesis", Volumes 1-end (Wiley Interscience, New York)).

Likewise, the present invention has application in essentially* any synthetic reaction which may be conducted in solution or on solid phase supports, including acetal formation, alkylations, alkynation, chiral alkylation, reductive alkylation, carbanion reactions, Grignard reactions, organiocadmium/aganese reactions, organolithim reactions, organozinc reaction, carbene insertion, condensations, Claisen reactions, aldol reactions, Dieckmann cyclization, Knoevenagel condensations, mannich reactions, cycloadditions, cyclizations (in particular to form heterocyclic rings) , Friedel-Crafts reactions, halogenation, bromination, chlorination, nucleophilic addition, Michael addition, aromatic nucleophilic substitution, Finkelstein reaction, Mitsunobu reaction, palladium (0) catalyzed reactions, Stille coupling, Suzuki coupling, Heck reaction, carbamate/urea formation, oxidation of primary alcohol to aldehyde, Sharpless reaction, oxidation of secondary alcohol to ketone, oxidation of aldehyde to carboxylic acid, epoxidation, oxidation of primary chloride to aldehyde, oxidative phenol coupling, reduction of acid to alcohol, reduction of aldehyde to alcohol, reduction of alkyne to alkene, reduction of amide to amine, reduction of aryl nitro to amine, reduction of azide to amine, reduction of ester to alcohol, reduction of imine to amine, reduction of iodide to alkyl, reduction of ketone to alcohol, Witting reaction, Horner-Emmons condensation, and the like (see generally , "Solid Phase Organic Chemistry (SPOC) " and "Solid Phase Inorganic Chemistry (SPIC)", Chiron Mimotopes, pp. 1-31 (August 1995) .

As defined herein, a "combinatorial library" is a collection of compounds in which the compounds comprising the collection are composed of one or more subunits or monomeric units (i.e. synthons) . The subunits may be selected from natural or unnatural moieties including amino acids, nucleotides, sugars, lipids, carbohydrates, dienes, dienopholes, and the like. The compounds of the combinatorial library differ in one or more ways with respect to the type(s), number, order or modification of the subunits comprising the compounds.

Combinatorial libraries generated by the methods of the present invention may be screened for pharmacologically or diagnostically useful compounds, as well as for desired physical or chemical properties. It will be clear to one skilled in the art that such screening may be conducted on a library of compounds which have been separated from the polyvalent support, or may be conducted directly on the library of compounds which are still linked to the polyvalent support .

I . Overview of a Liquid Metering Assembly Fig. 1 is a broad overview of a liquid metering assembly 10 according to the present invention. Although the assembly shown in Fig. 1 has been simplified for illustrative purposes, it should be understood that the metering assembly 10 may include other components such as additional valves, chemical sources, optical sensors, or the like.

As shown in Fig. 1, liquid metering assembly 10 generally includes a transparent or translucent container 20 adapted to hold a liquid. Generally, liquid to be metered will enter this container 20, be metered, and then expelled towards a target site. In a preferred embodiment, the container 20 is a tubular structure with a cylindrical lumen 22 extending longitudinally through the tubular structure and having a generally constant inner diameter. Of course, it will be recognized that the present invention is not limited to a container 20 having a tubular configuration. For example, the container 20 may be a rectilinear member having a cylindrical lumen passing therethrough. Preferably, the container 20 is some type of elongate element of any cross- sectional shape such as triangular, hexagonal, elliptical, etc. having a lumen with a curved inner surface, passing longitudinally therethrough. Alternatively, the container 20 may also have a lumen with a flat or straight inner surface 23 with an angled, opposing surface 24 (Fig. 2) or vice versa. The container 20 is usually made of inert materials such as borosilicate glass or Teflon® which will allow the passage of light but will not react with the various chemistries used in a combinatorial synthesis apparatus. Additionally, although the container 20 is shown in Fig. 1 as having a vertical orientation, it should be understood that the container 20 is orientation independent and may be horizontally or otherwise positioned, as described further below.

To detect the liquid level in container 20, the liquid metering assembly 10 will include an optical liquid level sensor 30 generally comprising a light source 32, a focusing device 34, and a photosensor 36 in predetermined positions about the liquid container 20. In the preferred embodiment, light source 32 of sensor 30 projects light through container 20 at an angle perpendicular to a longitudinal axis length of the container (Figs. 2-3) . When the container 20 is empty, the light, after passing through the container, typically shines onto focusing device 34 and photosensor 36. As discussed below, the focusing device 34 and photosensor 36 are at specific angular positions from the light source 32 and typically the container 20 so as to receive light when the container 20 is empty and to not receive light when the container is filled with liquid. The optical liquid level sensor 30 preferably spans the longitudinal length of the container 20 to maximize the range of coverage of the liquid level sensor.

As shown in Fig. 1, the metering assembly 10 uses a plurality of fluid conduits 40 and valves 50 to introduce liquid into container 20. The valves 50 are operated by a controller 60 which controls the flow of liquids and gases from sources 70 and 80 into the container 20. The controller 60 interprets the typically electronic signals from optical liquid level sensor 30 and opens or closes the valves so that a desired amount of liquid is metered into the container 20. The controller 60 also opens and closes valves for expelling liquid from the container 20.

The assembly 10 may also have a specialized plug 90 which couples fluid conduit 40 to the container 20. The plug 90 has a tapered lumen 92 which increases in inner diameter until the lumen 92 has the same inner diameter as lumen 22 of the container 20. This tapered lumen 92 facilitates the formation of a "plug" of liquid when the container 20 is filled downward from the top, as described in further detail below. Specifically, the taper smooths the flow when the diameter changes between the fluid conduit 40 and the container 20. This smoothing advantageously increases the flow rate at which the liquid can be introduced before it begins to cavitate and distort the liquid-air surface.

The liquid source 70 and the gas source 80 used with the present liquid metering assembly 10, are preferably pressurized such that the liquid or gas from these sources 70 and 80 will enter into the container 20 upon opening of the valves 50. As shown in Fig. 1, valve 52 is coupled to a pressurized gas source 80 which is used to push liquid downward from the container 20 towards valves 55 and 56. Valve 53 is coupled to a liquid source 70 while valve 54 is opened to vent 82 which facilitates the entry of liquid into container 20 from valve 55. Valve 55, as mentioned, supplies liquid from a liquid source 70 into the container 20 while valve 56 is connected towards a target site to which the liquid in container 20 will be delivered.

The metering assembly description presented above is mainly for general illustrative purposes and should not be considered as limiting the scope of the present invention. As previously mentioned, the present invention is applicable to a Variety of synthesis apparatus such as solid phase synthesis and can be applied equally well to liquid-liquid chemistry, or other synthesis processes. Although various synthesis apparatus may use plumbing and fluid systems more complicated than the simplified system present above, the present invention nonetheless remains applicable to those systems .

II . Optical Liquid Level Sensor

The functionality of the liquid metering device 10 is due mainly in part to the accuracy of the optical liquid level sensor 30 described below. A. Light Refraction

Referring now to Figs . 2 and 3 , the general theory behind the operation of an optical liquid level sensor 30 will now be described. As shown in Fig. 2, when the container 20 is empty, light from the light source 32 passes through the container 20 and is refracted towards focusing device 34 as indicated by lines 150. The light source 32 may be filtered or otherwise adjusted to provide only one wavelength of light or only light within a certain frequency range. This prevents the need to completely shield the device from' ambient light that could interfere with measurement accuracy. The light or radiation used with the present invention is typically between the infrared and ultraviolet frequencies . Refraction occurs as a result of the index of refraction of container 20 and preferably the curvature of the inner surface of the container. As shown in Fig. 3, when the container 20 is partially filled with a liquid L, only the light above the upper surface is refracted towards the focusing device 34. The presence of liquid in the container 20 has changed the index of refraction of the container and thus the light is focused away from the focusing device 34 when the light passes through the liquid in the container 20. Controller 60 scans the photosensor 36, which preferably comprises of a linear array of a plurality of photosensitive elements 38, to locate " the break between those photosensitive elements receiving light and those that are not.

As more clearly illustrated in Figs. 4A-4C, the demarkation point is quite distinct between those photosensitive elements 38 receiving light and those that are not. Those photosensitive elements above the liquid-air boundary 160, as indicated by arrow 162 in Fig. 4A, have a light refraction pattern as indicated by Fig. 4B. Those photosensitive elements below the liquid-air boundary 160, as indicated by arrow 164, have a light refraction pattern as indicated in Fig. 4C. For those locations above the liquid- air boundary 160, light is generally evenly refracted from the* refraction created by the curved inner surface of container 20. Referring now to Fig. 4C, light passing through the liquid in container 20 is less evenly refracted and focuses away from the photosensor 36 and focusing device 34. The photosensor 36 in Fig. 4C receives almost no light, creating a distinct demarkation point between those photosensitive elements receiving light and those that are not. The area of liquid in the transition may be specific for different types of liquids and measurement accuracy may be improved by mathematical calculation of this transition.

The refraction of light passing through the container 20 is more accurately depicted in Figs. 5A and 5B .

As shown, a light source 32 is aligned to shine light along an imaginary line 170 passing through container 20. For ease of illustration, the light refraction pattern as indicated by lines 180 for Figs. 5A and 5B only originate from a single point 182 located on light source 32. As can be seen in Fig. 5A, light from point 182 is generally evenly distributed as it passes through container 20 when the container is not filled with liquid. Fig. 5B shows the light refraction pattern originating from point 182 when the container 20 is filled with liquid. When there is liquid in the container, the majority of the refracted light or light rays, as indicated by lines 180, are focused away from the photosensor 36 and focusing device 34. A "blank" zone as indicated by arrows 190, where no light reaches the photosensor 36, is created between the majority of the light rays 180 and reflected light rays 192. Line 192 results from rays intersecting the inner surface of the container 20 and being completely reflected because of the angle which line 192 intersects the inner surface. In the preferred embodiment, the focusing device 34 and the photosensor 36 are positioned within this blank zone so that either no light reaches the photosensor 36 or a substantial amount of light reaches it. The photosensor 36 is typically aligned between the range of about 25° to 40°, or more preferably about 30° to 37°, away from the imaginary line 170 as indicated by arrows 194. It should be noted that using a smaller light source, such as a fiber optic light source, will result in a larger blank zone 190. It should also be understood, that the photosensor 36 may be positioned at an angle between about 20° to 25° where the photosensor receives a reduced amount of light, instead of no light when liquid is present. Although less desirable, such a position may also be operable so long as the photosensor 36 can register the difference between the two conditions.

B . Focusing Device

Although there is a distinct change in signal strength created by the liquid-air boundary 160, the optical liquid level sensor 30 will not accurately meter liquid unless the demarkation point of this change in signal strength (between when there is air and there is liquid) is registered by the photosensor 36. Fig. 6A shows the liquid-air boundary 160 and the light pattern received by the photosensor 36. As can be seen, the light projecting onto the photosensor 36 diffuses as illustrated by lines 200. This diffusion of light blurs the originally, crisp image of the liquid-air boundary 160 into a faded, blurry area 202 on the photosensor 36. This faded area 202 masks the real location of the liquid-air boundary 160, reducing accuracy of the liquid level measurement .

The optical liquid level sensor 30 according to the present invention preferably uses a focusing device that focuses an image of the liquid-air boundary onto the photosensor 36 as shown in Fig. 6B . In essence, using a focusing device 32 allows a photosensor 36 to "see" the boundary 160 in the container 20. The focusing element eliminates light diffusion by reproducing an image of the distinct liquid-air boundary directly on the photosensor 36. Since there is almost no blurring, this ability to "see" the boundary 160 allows closely spaced photosensitive elements 38 of photosensor 36 to provide meaningful information as to the location of the liquid level or liquid-air boundary 160. The focusing device 32 reduces the signal noise created by light that is refracted and reflected, thereby increasing measurement accuracy. The focusing device 32 is also advantageous as it can be used to detect the variation in liquid-air surface due to liquid adhesion to the container 20.

The focusing element 34 is preferably placed at a distance from photosensor 36 based on the focal length of the focusing element used. This allows an image to be projected. Placing the lenses to focus light beams to a single point so as to increase the intensity of the light, as shown in Fig. 7A, does not serve the needs of the present invention. By projecting an image, as the liquid-air boundary 160 rises from line 220 to line 230, the movement of the boundary will.be projected onto the photosensor 36. When the light is focused to a single point (Fig. 7A) , movement of the liquid-air boundary 160 will not be registered as light will continue to be projected to point 232, and the movement of the liquid-air boundary 160 will not be tracked on the photosensor 36.

In the preferred embodiment, the present invention uses a plurality of linearly aligned rod lenses 250. These lenses are of a compact configuration and provided cost benefits not found in convention convex or concave lens . Additionally, the rod lenses can be placed close together, preferably in single rows or in multiple rows as shown in Fig. 7C. ^Nonetheless, it should be understood that conventional lens imay be used if desired. As seen, the rod lenses 250 can accurately project an image onto a targeted surface 260. Higher resolution and accuracy can be achieved by the photosensor 36 when an image is accurately reproduced onto a photosensor.

The rod lenses 250, as used in the present invention and shown in Fig. 7D, have a varying index of refraction within the lens material to smoothly and continually directed light rays towards a point of focus. This internal structure reduces the need for a tightly controlled tolerances during manufacture of surface curvatures as required in conventional concave or convex lenses. The rod lenses 250 of the present invention are made by NSG America, Inc., and come in a variety of sizes and focal lengths. In the preferred embodiment, the rod lens 250 has a focal length of about 18 millimeters and produces an accurate image of the liquid-air boundary 160 on the photosensor 36. It should be understood, however, rod lenses of other focal lengths may be use to accommodate containers and light sources of varying sizes.

C. Exemplary Embodiment

Referring now to Figs. 8A-8E, an exemplary embodiment of an optical liquid level sensor 30 will be described in further detail. In an exemplary embodiment, the container 20 and optical liquid level sensor 30 of the liquid metering assembly 10 are contained in a housing 100 to provide a compact and integrated configuration. The housing 100 may have viewing portals 102 which span along the length of the elongate container 20 to allow direct observation of the liquid level in the container. This view port 102 act as a visual confirmation of the operation of the liquid metering assembly 10.

Referring now to Fig. 8B, the location of light source 32, focusing device 34, and photosensor 36 are more clearly depicted in this cross-sectional view. In the exemplary embodiment, light source 32 comprises of an array of light sources such as a plurality of light emitting diodes (LED)' or alternatively a ribbon of fiber optic cables shining along the longitudinal length of the container 20. Though less cost efficient, the fiber optic ribbon creates a narrower band of light passing through the container 20. This narrower band of light, as mentioned above, provides certain performance benefits for the optical liquid level sensor 30. As shown in Fig. 8B, the focusing device 34 and the photosensor 36 are also preferably linear arrays of focusing elements and photosensitive elements. In the exemplary embodiment, the focusing device 34 comprises of a linear array of rod lenses aligned along the longitudinal length of container 20. Although conventional concave or convex lenses may also be used, the rod lenses of Fig. 7D provide a compact and cost efficient alternative to conventional lenses which require tolerance control to maintain a constant focal length from lens to lens. The photosensor 36 in the preferred embodiment has at least about 200 photosensitive elements 38 per linear inch. As a general rule, the higher the number of photosensitive elements 38, the higher the photosensor resolution, so long as the scan time of the controller 60 does not increase. In one exemplary embodiment, the controller 60 scans 1728 photosensitive elements about every 8 milliseconds. Referring now to Fig. 8D, the dotted line 110 shows the path of light from the light source 32 to the photosensor 36. As shown, light travels from the light source 32 towards the container 20 and then is refracted towards focusing device 34. As the light travels from the container 20 to the focusing device 34, the light passes through a slot 112 that minimizes the amount of ambient light reaching the focusing device 34. Light travels through the focusing device and an image unto the photosensor 36. Light is also refracted towards the view port 102 which is located perpendicular to slot 112.

III. Method of Liquid Metering

Referring now to Figs. 1 and 9A-9E, a method of the present invention using the liquid metering assembly 10 will now b'e described. As shown in Fig. 1, the container 20 is fluidly coupled to a plurality, of valves 52-56 which are in turn coupled to liquid sources 70, gas sources 80, gas vents 82, and the target site. In the preferred embodiment, the container 20 is vertically oriented with liquid to be delivered to a target site entering through a lower end 25 of the container 20 from valve 55. As the container 20 fills with the liquid L coming from valve 55, valve 54 in fluid contact with the upper end of 26 of container 20 is opened to facilitate the exit of gas to vent 82 as the container 20 begins to fill with liquid L.

As the container 20 is filled with the liquid L, as shown in Figs. 9A-B, controller 60 cycles through all 1728 photosensitive elements in the preferred embodiment of the photosensor 36 to locate the liquid level in. the container 20 As the amount of liquid in container 20 nears the desired liquid level, controller 60 will close valve 55, taking into account mechanical delays in closing valve 55 and also the amount of fluid remaining in line 40 leading towards the container 20. These constants are typically determined empirically during calibration of the liquid metering assembly 10.

The liquid metered into a container 20 can then be delivered toward the target site by opening valve 56 and valves 52 (Figs. 1 and 9C) . Valves 56 in Fig. 1 provides fluid access to the target site while valve 52 is connected to a pressurized gas source which "blows out" the metered volume of liquid from the container 20. Although not limited in this manner, in the exemplary embodiment, a chase fluid typically comprising an inert solvent will be delivered into the container 20 from valve 53 and the upper end 26 of the container. The tapered orifice 92 of the plug 90 facilitates the formation of a "plug" of chase fluid which can be metered as it fills downwardly into the container 20 as shown in Fig. 9D. The controller 60 may be calibrated to account for the change of the leading surface 300 of the plug as it is downwardly filled in the container 20. This chase fluid of solvents is blown downwardly through the container 20 toward the target site as shown in Fig. 9E . As the plug of liquid travels through container 20, it collects any droplets of desired liquid left behind by the first liquid metered in the container 20. Both the desired liquid and the solvent are then delivered toward the target site.

As described earlier, the container 20 may be positioned in a variety of configurations as long as the leading surface 300 of the liquid being metered has a consistent shape (Fig. 10) . The container 20 may be orientated in a variety of positions so long as the controller 60 can be calibrated to account for the varying shapes of the leading surfaces 300 of the liquids used in the container. In an alternative embodiment of the optical liquid level sensor, a modular optical liquid level sensor 400 as shown in Figs. 11A and 11B can be used with a variety of translucent elongate conduits or containers to measure the amounts of fluid therein. As seen in Fig. 11A, the sensor 400 has a light source 402 positioned by a support 404 attached to a housing 406. Housing 406 has slit 408 to receive transmitted light from a light source 402. The housing 406 contains a focusing device and a photosensor (not shown) which are used in a manner similar to that described above to meter the amount of liquid entering through a translucent or transparent container C. The modular sensor 400 is held in place by surface 410 and clamp 412. The modular sensor 400 may be placed on a variety of positions and moved as desired to measure liquid in a desired location.

While the above is a full description of the specific embodiments, various modifications, alternative constructions and equivalents may be used. For example, although the invention is shown in the enclosed drawings and described for use with solid-phase synthesis, it is not intended to be limited in this manner. That is, the invention can be used in a variety of synthesis processes such as organic and liquid-liquid chemistries. The present invention may also find application in other chemical, fuel, or slurry environments .

Claims

WHAT IS CLAIMED IS;
1. A liquid metering assembly for use in a combinatorial chemistry synthesis apparatus, the assembly comprising: a generally transparent or translucent container adapted to hold a liquid; an optical liquid level sensor coupled to said container to measure a level of a liquid in said container; and said optical liquid level sensor having a light source, a photosensor, and a focusing device positioned at a distance from the light source to reproduce an image of a liquid-air boundary in the container onto the photosensors.
2. A liquid metering assembly of claim 1 further comprising: a plurality of valves coupled to said container to allow liquid to enter and exit said container; and a control circuit, coupled to the photosensor, for determining the level of said liquid in the container.
3. A liquid metering assembly of claim 1 wherein said container comprises chemically inert material.
4. A liquid metering assembly of claim 1 wherein said container has a substantially curved inner surface.
5. A liquid metering assembly of claim 1 wherein said container is a tube.
6. A liquid metering assembly of claim 1 wherein said container has a wall thickness between about 0.5 mm to 2.0 mm.
7. A liquid metering assembly of claim 1 wherein the optical liquid level sensor is adapted to measure the presence of light scatter passing through the container.
8. A liquid metering assembly of claim 1 further comprising a housing surrounding the container, said housing having a viewing portal .
9. A liquid metering assembly of claim 1 wherein: said light source is oriented to shine light along an imaginary line through the container; said focusing device is positioned at an angle from the imaginary line of the light source.
10. A liquid metering assembly of claim 9 wherein said angle is between about 25 to 40 degrees.
11. A liquid metering assembly of claim 1 wherein said focusing device comprises an array of focusing elements.
12. A liquid metering assembly of claim 1 wherein said photosensor comprises an array of photosensitive elements .
13. A liquid metering assembly of claim 12 wherein said array has at least 200 photosensitive elements per linear inch.
14. A liquid metering assembly of claim 1 wherein the light source comprises an array of light sources.
15. A liquid metering assembly of claim 1 wherein said array of light sources comprises a plurality of light emitting diodes (LEDs) .
16. A liquid metering assembly of claim 1 wherein said array of light sources comprises a plurality of fiber optic elements.
17. A liquid metering assembly of claim 1 wherein said array of light sources only transmits one wavelength of light.
18. A liquid metering assembly of claim 1 wherein said container has a lumen with a flat inner surface with an angled, opposing inner surface.
19. A combinatorial chemistry synthesis apparatus comprising: a source of chemicals; an optical liquid metering system fluidly coupled to said source of chemicals; said optical liquid metering system fluidly coupled to a plurality of valves; and a plurality of reaction vessels fluidly coupled to said plurality of valves.
20. A combinatorial chemistry synthesis apparatus as in claim 19 wherein said optical liquid metering system uses an energy source that emits radiation in the range from infrared to ultraviolet radiation.
21. A method for metering liquid comprising the steps of : shining light through a container having a curved inner surface; filling said container with liquid to have a liquid- air boundary; passing light through the container; focusing an image of said liquid-air boundary onto a photosensor,- detecting said liquid-air boundary.
22. A method of claim 21 wherein the detecting step comprises scanning a plurality of photosensors to locate the liquid-air boundary.
23. A modular optical liquid level sensor for measuring the level of a liquid in a generally transparent or translucent container, said sensor comprising: an array of light sources aligned with the container in the direction that the liquid level changes; said array of light sources oriented to shine light along an imaginary line through the container; an array of focusing devices; an array of photosensors ; and said array of focusing devices at a position where the devices accurately reproduce an image of the liquid-air boundary onto an array of photosensors .
PCT/US1998/022192 1997-10-22 1998-10-21 Systems and methods using an optical sensor for liquid metering WO1999020983A3 (en)

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