Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
  • B01L3/50255—Multi-well filtration
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
  • B01J2219/00315—Microtiter plates
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
  • B01J2219/00319—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks the blocks being mounted in stacked arrangements
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00351—Means for dispensing and evacuation of reagents
  • B01J2219/00414—Means for dispensing and evacuation of reagents using suction
  • B01J2219/00416—Vacuum
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00351—Means for dispensing and evacuation of reagents
  • B01J2219/00421—Means for dispensing and evacuation of reagents using centrifugation
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00351—Means for dispensing and evacuation of reagents
  • B01J2219/00423—Means for dispensing and evacuation of reagents using filtration, e.g. through porous frits
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00495—Means for heating or cooling the reaction vessels
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
  • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Definitions

• porous PTFE polytetrafluoroethylene
• single-well glass devices containing porous PTFE frits or porous glass frits have also been used.
• Such porous materials have an unfavorable critical surface energy for many of the solvents and reaction conditions typically desirable in chemical syntheses and so do not retain these solutions.
• the present invention allows for an efficient, versatile, and tailored approach for conducting, simultaneously or otherwise, any number of chemical reactions involving single- step or multi-step syntheses and associated processes by use of a single device. Controlling the retention of the reaction mixture by tailoring the energetic interplay among the critical
• a reaction-well device and method for simultaneously conducting multiple chemical reactions in series or in-parallel, or a combination of parallel and serial manipulations, is described.
• the chemical reactions can be of synthetic origin or biochemical origin or a combination of synthetic and biochemical transformations.
• reaction-well device can vary from less than microliter( ⁇ L) to more than liter(L) volumes
• each well can be of the same or differing volumes depending upon the quantity of the reactants used or the quantity of product(s) desired.
• the nature of the chemical reactions carried out in the device can be of a homogeneous phase, e.g. a single solution or liquid phase, or a heterogeneous phase, e.g. a liquid phase and a solid phase, a liquid phase and a gas phase, two or more immiscible liquid phases, or any combination of solid, liquid and gas phases.
• the chemical reaction conditions employable with the multi-well device will depend upon the materials of construction of the device as well as the reaction conditions necessary for obtaining the desired product(s) and include but are not limited to: elevated, ambient and low temperatures and pressures; acidic, basic and neutral aqueous and organic solvents; inert and reactive gases.
• a novel feature of the device and methodology of the present invention is a selectively permeable barrier encapsulated within the reaction-well device. This acts essentially as a molecular flow control switch. Permeability through the barrier can be selected for or designed through the interplay of energetics between the critical surface
• This selectively permeable barrier "holds-up" or retains the reaction mixture in the wells of the multi-well device until such time that it is desirable to remove some or all of its components through the selective barrier. Removal of the reaction medium or components from the reaction medium is accomplished by manipulation of the effective
• Methods of manipulating the effective difference in ⁇ app and ⁇ c include changing
• reaction medium or reaction conditions.
• the present invention allows for a greater number of simultaneous chemical syntheses to be operating at any one time depending upon the array of wells in the multi-well reaction- well device, as well as operating under a wide range of chemical reaction conditions, using many of the organic solvents typically used in traditional synthetic chemistry without the need of additional filtration and isolation devices and associated processes.
• the present invention may include a means for selectively retaining desirable reaction product(s), i.e. a mechanism for further processing of chemical reactions for targeted product(s) isolation and purification.
• Such a means includes, but is not limited to, the use of additional solid media which selects for the targeted product(s) for isolation and further purification.
• the present approach also allows for the "modular" combination of one or more filter plates (for chemical reaction(s), product isolation(s) and purification) for further versatility and efficiency as well as for automation.
• the present device and methodology are readily amenable to automation by design or by utilizing commercially available instrumentation, equipment, and technology currently adopted by the chemical, pharmaceutical and biotech industries and related industries.
• the device described in the present invention is disposable, if desirable, or reusable with minimal maintenance and care.
• the present invention has applications in the areas of combinatorial chemistry, peptide and nucleotide library formation, and phage display libraries. Additionally, the present invention has applications in diagnostic or biological assays in order to identify, for qualitative or quantitative purposes, specific predetermined compounds, target molecules, and microbes (viral, bacterial and the like).
• the present invention is amenable to automation either by design or by using existing instrumentation and equipment such as that commonly used in the chemical, pharmaceutical, biotech, and related industries.
• Figure 1 is a sectional-side view of a 96-well device, i.e. a 12 x 8 array of reaction cells, used in the present invention.
• the device of the present invention includes: (1) A filter plate 10 with one or more reaction wells and a filter plate cover 12.
• the plate cover may have associated with it a mechanism and means for attachment (integral or separate to the plate cover) of the cover to the filter plate for operation of the device under a variety of reaction conditions such as elevated or lowered temperatures and pressures.
• the plate cover may have associated with it a mechanism and means of attachment of a gas manifold (integral or separate to the plate cover) for reactions operating under a variety of atmospheres (inert or reactive) such as argon and nitrogen.
• the plate cover may have attached to it (integral or separate to the cover) solid-phase synthetic supports (of a similar or differing array to that of the filter plate) that protrude into the volume of the wells of the filter plate for chemical reaction under a variety of reaction conditions.
• the manifold may also have a heat source 34 for operation at elevated temperatures and/or a heat sink 34 for operation at lower temperatures.
• the manifold may be clamps and seals for attachment of the filter plate (and cover) and collection plate for operation of the device under a variety of reaction conditions such as elevated and lower temperatures and pressures as well as a means and mechanism for agitation of the chemical reaction(s) and for device automation.
• the present invention contains a heater jacket around the reaction filter bottom plate as well as a plate seal block which is attached to the bottom of the manifold so that the whole system can be placed on a table top shaker instead of being placed into an oven or incubator.
• Materials for construction of the multi-well device will depend upon the reactants used and the conditions necessary for the formation of desired product(s) and include but are not limited to: polymeric materials (synthetic or natural), metals, ceramics, and glasses or any combination thereof.
• the reaction-well filter plate 10 contains at its base a porous material or substrate 14 having an oleophobic (or low energy) chemical surface.
• the oleophobic chemical surface is inherent in or applied to the porous
• This low energy or oleophobic surface repels many of the more commonly used solvents in synthetic chemistry, i.e. it inhibits spontaneous solvent flow or seepage through the porous substrate.
• the oleophobic chemical surface confers selective permeability to the porous substrate.
• the oleophobic surface of the porous substrate "holds-up" solvents or other solutions in the multi-well device until it is intentionally desirable to remove some or all of the contents of the multi-well device through the porous substrate.
• the critical surface energy of the porous material( ⁇ c ) is an empirical parameter
• the characteristic, in part, of the porous substrate It depends on such factors as the surface energy of the materials of construction of the porous substrate, the nature and degree of the substrate porosity, the morphology of the porous substrate, the nature and volume(V) of liquid intended for the porous substrate to hold up as well as the temperature(T) and duration(t) of liquid exposure.
• the temperature and duration of liquid exposure to the porous substrate can be selected to be typical conditions characteristic of many chemical reactions or characteristic of the reaction condition(s) of interest.
• the critical surface energy of the porous substrate can be readily determined by exposing the substrate to some fixed volume of liquid(s) or mixture of liquids of known or determined surface tension.
• Such liquids could include miscible mixtures of one or more alcohols and water of known or determined surface tension as well as homologous series of hydrocarbons (e.g. pentane, hexane, heptane, octane, etc.) or fluorocarbons, or the like with known or determined surface tension.
• hydrocarbons e.g. pentane, hexane, heptane, octane, etc.
• fluorocarbons e.g. pentane, hexane, heptane, octane, etc.
• ⁇ c may be selected for or designed by the methods described previously.
• ⁇ c e.g. porous PTFE
• Removal of all or part of the contents of the multi-well device through the porous substrate may be accomplished by the application of a pressure differential across the porous substrate or by lowering the surface tension of the reaction medium as described above.
• porous substrates synthetic or natural have characteristically unfavorable ⁇ c 's
• substrate can be accomplished by, for example: (1) lowering the effective ⁇ c of the porous
• reaction medium now becomes greater than the critical surface energy( ⁇ c ) of the porous
• reaction medium thereby inhibiting spontaneous flow or seepage of the reaction medium through the porous substrate.
• This increase in the surface tension of the reaction medium may be accomplished by changes in the reaction conditions such as temperature or by the addition of another component, preferably inert to the desired reaction, to the reaction medium that
• ⁇ app e.g. a solvent with high surface tension, an additive such as a salt or the like.
• Low surface energy may be conferred to the porous substrate by a number of different means including, but not limited to, the following: (1) Coating the substrate with oligomeric or polymeric materials with functionality such that the functionality is favorably dispositioned at the solid-liquid interface of the reaction medium and porous substrate.
• coating material(s) and associated functionality will depend upon
• Coating materials include, for example, fluorocarbons and hydrocarbons and
• oligomeric or polymeric coating may be preformed or prepared in situ.
• the coating may be cross-linked by thermal, chemical, or radiational techniques commonly practiced by those skilled in the art. Alternatively, coating materials of relatively
• high ⁇ c may be further modified and converted to lower ⁇ c by attachment of the appropriate
• sites on the porous substrate may be accomplished by treatment with the appropriate
• All or part of the reaction medium or components of the reaction medium in the reaction- well device may be drained by lowering the effective surface energy of the reaction medium below the critical surface energy of the oleophobic surface on the substrate. This can be accomplished in a number of ways, for example, by lowering the surface tension of
• the reaction-well device may be drained by employing a pressure differential across the permeable barrier either by application of a vacuum "downstream" of the porous material or by the application of pressure "upstream” of the porous material or by eliminating any net applied partial pressure, or by applying centrifugal force either by use of a centrifuge or other suitable instrumentation.
• the lowering of the surface tension of the reaction medium, ( ⁇ app ) may be
• an additive such as a salt or surfactant or the like which lowers the surface tension
• Example 1 A glass fiber filter (GF/F, Whatman, Inc.) was dipped into a Fluorad® solution (3M,
• the treated filter was incorporated into a polypropylene microplate having 96 wells of 2 mL each. A group of three wells was filled with each of twenty six solvents and the
• a glass fiber filter (GF/F, Whatman, Inc.) was dipped into mixture of 40 mL Aversin KFC ® (Henkel Performance Chemicals), 10 mL Repellan HY-N ® (Henkel Performance Chemicals), 0.5 grams citric acid, and water to 1 liter, to saturate it. Excess solution was drained. The filter was then cured for 30 minutes in an oven at a temperature of 130°C.
• Example 2 Using a 96 well plate containing a treated glass fiber filter prepared as in Example 2, 1.0 mL methylene chloride was added to each of twelve wells. No liquid drained from the wells after two hours at room temperature.
• Example 2 Using a 96 well plate containing a treated glass fiber filter prepared as in Example 2, 1.0 mL methylene chloride was added to each of twelve wells.
• Pentane (1.0 mL) was added to each of three of the wells. Dripping began within 15 seconds and all the liquid (2 mL) had drained within 75 minutes. No liquid drained from the wells containing only methylene chloride after four hours.
• Example 6 Using a 96 well plate containing a treated glass fiber filter prepared as in Example 2, methanol (1.0 mL) was added into each of 6 wells. After 70 minutes none had passed through the filter. Tetrahydrofuran (1.0 mL) was added to three of the wells, all of which began to drip within another hour. The wells containing only methanol still did not drip.
• Tetrahydrofuran (1.0 mL) was placed into a dry well and began dripping within 10 minutes. The well was completely drained within 1.5 hours.
• methanol 1.0 mL was added into each of 6 wells. After 25 minutes none had passed through the filter. Trifluoroacetic acid (0.5 mL) was added to three of the wells, all of which began dripping within fifteen minutes. The wells containing only methanol still did not drip.
• Trifluoroacetic acid (0.5 mL) was placed into a dry well and began dripping within 1 minute. The well was completely drained within 25 minutes.
• pentane 1.0 mL was added into 2 dry wells and 2 wells already containing an immiscible lower phase of 0.2 mL of water. Both wells containing only pentane began to drip within one minute and completely drained within 10 minutes. The wells containing the water barrier did not drip after 1 hour. Acetone (0.4 mL) was added to the water layer in one well and the well contents were mixed. This well began to drip within 10 minutes. The remaining well containing water and pentane was drained by vacuum.

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Analytical Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Hematology (AREA)
• Clinical Laboratory Science (AREA)
• Physical Or Chemical Processes And Apparatus (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=21839731

Family Applications (1)

Country Status (2)

Families Citing this family (55)

Family Cites Families (12)

• 1997
  • 1997-10-03 WO PCT/US1997/018046 patent/WO1998014277A1/en not_active Application Discontinuation
  • 1997-10-03 EP EP97945535A patent/EP0929361A4/de not_active Withdrawn

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events