WO2001039877A1 - Porteurs inertes - Google Patents

Porteurs inertes Download PDF

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Publication number
WO2001039877A1
WO2001039877A1 PCT/GB2000/004525 GB0004525W WO0139877A1 WO 2001039877 A1 WO2001039877 A1 WO 2001039877A1 GB 0004525 W GB0004525 W GB 0004525W WO 0139877 A1 WO0139877 A1 WO 0139877A1
Authority
WO
WIPO (PCT)
Prior art keywords
carrier
compound
adsorbed
compounds
soluble
Prior art date
Application number
PCT/GB2000/004525
Other languages
English (en)
Inventor
Nicola Colclough
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
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 Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to AU17154/01A priority Critical patent/AU1715401A/en
Priority to EP00979762A priority patent/EP1242178A1/fr
Priority to JP2001541604A priority patent/JP2003515572A/ja
Publication of WO2001039877A1 publication Critical patent/WO2001039877A1/fr

Links

Classifications

    • 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
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/262—Synthetic macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. obtained by polycondensation
    • 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
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • 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
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/24—Naturally occurring macromolecular compounds, e.g. humic acids or their derivatives
    • 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
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • 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
    • B01J4/00—Feed or outlet devices; Feed or outlet control devices
    • B01J4/02—Feed or outlet devices; Feed or outlet control devices for feeding measured, i.e. prescribed quantities of reagents
    • 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
    • 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
    • B01J2219/00497—Features relating to the solid phase supports
    • 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
    • B01J2220/00—Aspects relating to sorbent materials
    • B01J2220/40—Aspects relating to the composition of sorbent or filter aid materials
    • B01J2220/48—Sorbents characterised by the starting material used for their preparation
    • B01J2220/4812—Sorbents characterised by the starting material used for their preparation the starting material being of organic character
    • B01J2220/4825—Polysaccharides or cellulose materials, e.g. starch, chitin, sawdust, wood, straw, cotton
    • 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

  • the invention relates to adsorbing chemical samples onto carriers which are inert and soluble, to form highly stable free flowing solid powders for long term storage of compounds in, for example, a proprietary compound collection.
  • Compound collections are used in the search for agents with novel pharmaceutical, agrochemical or other fine chemical applications and are a valuable source of structural and chemical diversity used in identifying new leads as potential inhibitors of a biological target.
  • Compound collections may contain more than 100,000 different compounds and due to increasingly efficient compound acquisition, either through commercial sources, or by high throughput synthesis, compound collections with more than 1 million different compounds are now of a typical size in some research organisations.
  • High throughput multiple parallel synthesis can generate very large numbers of individual compounds, typically 100-5000 per week, but the sample size is usually small, ⁇ 100mg.
  • To try and obtain all or most of these samples as crystalline or amorphous powders using the methods normally available to chemists would increase the overall synthesis time to such an extent that the HTMPS process would be impractical.
  • compounds from HTMPS are stored sometimes as dry films or as solutions, usually in dimethyl sulphoxide (DMSO). The dispensing of compounds stored as dry films is often very difficult, and the difficulty increases significantly as the sample size decreases.
  • DMSO dimethyl sulphoxide
  • HTS high throughput screening
  • a whole compound collection of , for example, 100,000 compounds may be screened in a number of days against a new biological target, using automated or semi-automated procedures.
  • HTS high throughput screening
  • a typical sample size of compound sample needed to be dispensed for HTS may be less than 0.1 mg, but despite weight variations of ⁇ 10% being tolerated for the purposes of screening, including HTS, it is not practicable to rapidly dispense such small sample sizes.
  • the compound and carrier may be directly dispensed into the vessel in which a test is to be performed either as a liquid in which the carrier is dissolved and which also contains the compound, or as solid carrier and adsorbed compound to which is then added the liquid in which a test is to be performed.
  • the carrier is inert.
  • Additional advantages include the use of the carrier to significantly add to the mass of the compound to allow a low amount of the compound ( ⁇ lmg) to be dispensed when adsorbed onto a large excess of the carrier by automated machines which can not normally disperse such small quantities of compound.
  • Such a system lends itself to automation and hence rapid dispensing of compound samples because similar/identical weights, or volumes, of carrier with adsorbed compound can be measured in order that a similar amount, in moles, of compound sample is dispensed because variations in the molecular weight of the compound are diluted by the large excess of carrier.
  • a method of storing and dispensing a compound which comprises (1) adsorbing the compound onto a carrier (2) when required measuring an amount of the compound adsorbed onto the carrier, (3) adding the compound and carrier to a liquid in which the carrier is soluble.
  • Additional, optional, steps include either
  • the carrier is in a large excess to the compound adsorbed onto it.
  • a further feature of the invention is a carrier which is soluble and inert having adsorbed onto it a compound, characterised in that the compound is adsorbed onto a large excess of the carrier.
  • a further feature of the invention is a method of dispensing compound samples of substantially similar molar quantity which comprises (1) for each compound measuring an amount of compound which is adsorbed onto a large excess of a carrier, wherein the amount measured is substantially the same for each sample (2) adding the compounds to a liquid in which the carrier is soluble.
  • the exact ratio of carrier to adsorbed compounds is unimportant provided that there is a "large excess" of carrier, for guidance it is intended that there is at least a 10, preferably at least a 200, 500, 1000, 5,000, 10,000, 20,000, 30,000 or 40,000, depending upon the solubility of the carrier in the liquid used, fold excess of carrier, in grams, compared with adsorbed compound, in moles.
  • Preferred levels of adsorption are less than 400 ⁇ mol, preferably less than 300 ⁇ mol or less than 200 ⁇ mol, of adsorbed compound per gram of carrier.
  • the measurement used in dispensing the inert carrier plus adsorbed compound may be by weight, volume or any other means, preferably by volume.
  • Typical weights that may be measured with levels of adsorption described above include from 2 to 250mg, preferably 10 to 125mg, of carrier and adsorbed compound.
  • Typical volumes that may be measured include from 15 ⁇ l to 600 ⁇ l, preferably from 15 ⁇ l to 300 ⁇ l, depending upon the density of the inert carrier used.
  • a method of dispensing a submicrogram (preferably less than 5mg, lmg, or less than O.lmg, or even less than 0.05mg) amount of compound which comprises (1) adsorbing the compound onto a carrier, wherein the carrier is in a large excess to the compound, (2) measuring an amount of the adsorbed compound and carrier, (3) adding the compound and carrier to a liquid in which the carrier is soluble.
  • adsorption is achieved from a solution of the carrier and compound by removing the solvent, for example by evaporation.
  • Extraction of the compound from the carrier may be achieved, if necessary, by contacting the carrier with the compound adsorbed on it with a suitable solvent for the carrier, which is not a solvent for the compound, and separating the compound from the solution.
  • the compound may be separated from the solvent by using either manual techniques, such as by filtration.
  • separation of the compound from the carrier is not necessary prior to testing the compound and thus avoiding the need to separate the carrier from the compound prior to dispensing the compound.
  • the compound may be one of any number of different compounds, such as within a compound collection and as such represents a further feature of the invention.
  • Suitable carriers are those which are soluble in a wide range of solvents and are inert. Alternatively carriers may be selected which are known to be soluble in the liquid to be used and it is not necessary that the carrier is soluble in any other type of liquid for the purposes of this invention. By “soluble” we mean that the carrier will significantly (at least 50%, 75% or 95%o) dissolve in the liquid used in a subsequent test and at removable temperature ( ⁇ 60°C, ⁇ 40°C, ⁇ 30°C, ideally ambient temperature).
  • Typical solvents in which the carrier may need to be soluble in are typically either aqueous or organic; aqueous systems may include buffered solutions ; organic solvents include protic solvents, such as ethanol, and aprotic solvents, such as DMSO and acetonitrile ; alternatively the solvent may be a mixture of any of the above solvents. Additional excipients may be added to the liquid to improve the solubility of the carrier, compound or both.
  • the carrier is able to form free flowing powders by either forming an amorphous or crystalline powder after the compound has been adsorbed or by forming a solid after compound is adsorbed which is capable of being formed into a free flowing powder, such as by grinding, nibbling or such like.
  • Suitable carriers which are inert and soluble include; polysaccharides, disaccharides and monosaccharides, either natural or synthetic and in L or D or ⁇ or ⁇ forms. Specific examples are inositol, galactose, arabinose, lactose, lactulose, manitol, mannose, sorbose, turanose and platinose. Also suitable carriers include soluble polymers, such as povidone.
  • carriers not included in the present invention are cyclodextrins.
  • the carrier is conditioned or treated in a way to provide an even particle size (preferably the particle size is from 5 to 200 microns and of low particle size distribution) for ease of flowing and even adsorption.
  • the inert carrier has a porous surface (preferably greater than 3m 2 /g and ideally greater than 200m 2 /g), to maximise the amount of compound adsorbed.
  • a method for storing and dispensing a number of different compounds with different physical properties which comprises (1) adsorbing each compound onto a carrier, (2) storing the adsorbed compound until the compound is required, (3) adding the compound and carrier to a liquid in which the earner is soluble.
  • a further feature of the invention is a compound collection comprising a number of different compounds wherein each compound has been adsorbed onto an inert carrier, and preferably where each compound is adsorbed onto a large excess of carrier.
  • extended duration we mean that we have found that "significant recovery” (which means >50 %w/w, ideally >80% w/w, preferably >90%w/w recovery of the sample) of compound may be extracted from the inert carrier even after a period of storage at room temperature of at least 6 months, and in particular over a period of more than 1 year.
  • the "number" of compounds in a compound collection which may be stored by the techniques as described above is not limited by the invention, ideally the invention may be used for storage of compounds in compound collections where the number of different compounds stored may be more than 5, 50, 100, 10 3 , 10 4 or even more than 10 6 .
  • the invention may also be applied to a subset of a compound collection.
  • inert we mean that the carrier can not interfere in the test being performed on the compound, i.e. it does not chemically react with biological systems or is not able to be metabolically utilised.
  • compounds we refer to compounds which are able to be adsorbed onto carriers. The physical and chemical properties of the compounds are generally unimportant in applying the present invention. However, it will be appreciated that this method is not suited to compounds with low boiling points.
  • Preferred compounds are those stored in compound collections of pharmaceutical, biotechnology or agrochemical companies. Preferred compounds are organic molecules of molecular weight of less than 2000 Daltons, and ideally of 1000 Daltons or less.
  • the carrier adsorbed with a compound provides a powder with very similar physical properties even when compounds are adsorbed which have different physical properties.
  • the handling of samples from collections containing large numbers of compounds is greatly facilitated as all compounds can be stored as free flowing, easily measured, uniform powders. Further advantages include:
  • Carrier + compound give a free flowing powder
  • Compound can be quantitatively and reproducibly adsorbed and extracted from inert carrier
  • Adsorption onto an inert carrier produces solid powders with very similar handling characteristics
  • the compound when adsorbed onto the carrier can be directly dispensed into a vessel, such as an assay plate, without the need to extract the carrier from the compound.
  • the compound may be stored in a vessel, such as an assay plate, without loss of stability.
  • Eluents Eluent A: Water containing 50 mM ammonium acetate.
  • Eluent B Methanol containing 43.75 mM ammonium acetate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Analytical Chemistry (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)

Abstract

L'invention concerne l'adsorption d'échantillons chimiques sur des porteurs inertes et solubles, destinée à former des poudres solides très stables à écoulement libre pour le stockage à long terme de composés, par exemple dans une collection de composés exclusive.
PCT/GB2000/004525 1999-12-02 2000-11-28 Porteurs inertes WO2001039877A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU17154/01A AU1715401A (en) 1999-12-02 2000-11-28 Inert carriers
EP00979762A EP1242178A1 (fr) 1999-12-02 2000-11-28 Porteurs inertes
JP2001541604A JP2003515572A (ja) 1999-12-02 2000-11-28 不活性担体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9928370.7A GB9928370D0 (en) 1999-12-02 1999-12-02 Inert carriers
GB9928370.7 1999-12-02

Publications (1)

Publication Number Publication Date
WO2001039877A1 true WO2001039877A1 (fr) 2001-06-07

Family

ID=10865493

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/004525 WO2001039877A1 (fr) 1999-12-02 2000-11-28 Porteurs inertes

Country Status (5)

Country Link
EP (1) EP1242178A1 (fr)
JP (1) JP2003515572A (fr)
AU (1) AU1715401A (fr)
GB (1) GB9928370D0 (fr)
WO (1) WO2001039877A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140187579A1 (en) * 2010-12-03 2014-07-03 The Trustees Of The University Of Pennsylvania Tip60 inhibitors

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182612A2 (fr) * 1984-11-23 1986-05-28 Tessek Sdruzeni Praha Récipient pour échantillons à analyser
US5002695A (en) * 1987-09-30 1991-03-26 Henkel Kommanditgesellschaft Auf Aktien Foam regulators suitable for use in detergents and cleaning preparations
DE4341005A1 (de) * 1993-11-29 1995-06-01 Ljuba Dr Rer Nat Mavrina Verfahren und Vorrichtung zum selektiven Konzentrieren der Leukozyten aus einer Probe eines Blutpräparates
GB2316941A (en) * 1996-07-02 1998-03-11 Merck & Co Inc Combinatorial sythesis on soluble polyvalent supports
US5751629A (en) * 1995-04-25 1998-05-12 Irori Remotely programmable matrices with memories
WO2000006297A1 (fr) * 1998-07-28 2000-02-10 Astrazeneca Ab Stockage de composes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182612A2 (fr) * 1984-11-23 1986-05-28 Tessek Sdruzeni Praha Récipient pour échantillons à analyser
US5002695A (en) * 1987-09-30 1991-03-26 Henkel Kommanditgesellschaft Auf Aktien Foam regulators suitable for use in detergents and cleaning preparations
DE4341005A1 (de) * 1993-11-29 1995-06-01 Ljuba Dr Rer Nat Mavrina Verfahren und Vorrichtung zum selektiven Konzentrieren der Leukozyten aus einer Probe eines Blutpräparates
US5751629A (en) * 1995-04-25 1998-05-12 Irori Remotely programmable matrices with memories
GB2316941A (en) * 1996-07-02 1998-03-11 Merck & Co Inc Combinatorial sythesis on soluble polyvalent supports
WO2000006297A1 (fr) * 1998-07-28 2000-02-10 Astrazeneca Ab Stockage de composes

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140187579A1 (en) * 2010-12-03 2014-07-03 The Trustees Of The University Of Pennsylvania Tip60 inhibitors
US9701631B2 (en) * 2010-12-03 2017-07-11 The Trustees Of The University Of Pennsylvania TIP60 inhibitors

Also Published As

Publication number Publication date
AU1715401A (en) 2001-06-12
EP1242178A1 (fr) 2002-09-25
GB9928370D0 (en) 2000-01-26
JP2003515572A (ja) 2003-05-07

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