Large collections of chemical compounds are valuable assets of research organisations. 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.

The handling of samples within large compound collections for the purposes of storage, retrieval and testing presents numerous problems. In most organisations samples are obtained and stored as crystalline or amorphous powders and can be dispensed relatively easily by weighing, although this often needs to be done manually because of the varying nature of the solids. Some samples are made or obtained as glassy solids, syrups, oils or liquids and are subsequently stored in these forms. The weighing of these samples is often very time consuming and wasteful.

High throughput multiple parallel synthesis (HTMPS) 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. To avoid this problem, 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. Compounds stored as solutions can be dispensed quickly and accurately, but the manipulation and storage of the solutions subsequent to, and after, dispensing can be very problematical especially in compound handling systems designed to handle solids. In addition, some samples are unstable in solution and decompose on prolonged storage, even at low temperatures.

Increasingly the demands of a compound collection are changing. With the advent of high throughput screening (HTS) 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. Faced with the need for more rapid dispensing of compounds from the compound collection, the small sample size needed and the large numbers of different sample types existing in a compound collection, current systems of storage and dispensing are increasingly incompatible with modem needs. For example, 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.

We have found that it is possible to store and retrieve compounds, even after an extended duration of storage, by adsorbing the compound onto a carrier. Additionally we have found that when the carrier is soluble in the liquid in which the compound is to be tested then this avoids the need to perform a separation step to remove the support from the compound prior to dispensing the compound. Therefore 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. To avoid the possibility of the carrier interfering with the assay or test to which the compound is be subjected then it is important that 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.

We have found that if the same carrier is used for a number of different compounds of different molecular weight, and all compounds are adsorbed onto the carrier at approximately the same concentrations, then only a single weight or volume of compound adsorbed onto an carrier is required to be dispensed to produce a substantially similar quantity (up to +/-15%, ideally +/-10%), in moles, of compound sample, provided that the amount of carrier is in large excess to the compound sample adsorbed onto it. 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.

We present as a first feature of the invention 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 (a) preparing a further dilution of the solution; (b) adding the solution to a test; or (c) adding the components of the test to the solution.

Preferably 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 400mol, preferably less than 300tmol or less than 2001mol, 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 151 to 600p1, preferably from 15p1 to 300p1, depending upon the density of the inert carrier used.

We present as a further feature of the invention 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.

Ideally 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. However, it is the primary intention of the invention that 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%) 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. Ideally 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 a or D forms. Specific examples are inositol, galactose, arabinose, lactose, lactulose, manitol, mannose, sorbose, turanose and platinose. Also suitable carriers include soluble polymers, such as povidone.

Preferably carriers not included in the present invention are cyclodextrins.

Preferably 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. Preferably the inert carrier has a porous surface (preferably greater than 3m2/g and ideally greater than 200m2/g), to maximise the amount of compound adsorbed.

Presented as a further feature of the invention is 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 carrier 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.

By use of the term"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 5,50,100,103,10'or even more than 106. The invention may also be applied to a subset of a compound collection.

By the use of the term"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.

By the use of the term"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; Even distribution of compound on inert carrier; Compound can be quantitatively and reproducibly adsorbed and extracted from inert carrier; Storage and dispensing of compounds which exist normally as liquids, gums or glasses; Adsorption onto an inert carrier produces solid powders with very similar handling characteristics; For the reasons outlined above, robotic handling and weighing of samples is much simpler than for non-adsorbed materials, thereby enabling rapid dispensing of large numbers of compounds; and

Compounds for which only small samples are available can be dispensed far more economically.

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.

The invention is illustrated below by the following non-limiting examples Examples Sixteen compounds were selected which spread across physical property space. Parameters considered in the selection were ClogP, molecular volume, number of hydrogen bond donors, number of hydrogen bond acceptors, number of positive charges and number of negative charges. All the parameters were given an equal weighting.

Adsorption of compound onto Inert Supports 10 mM stock solutions in neat DMSO were first made for all 13 compounds. This mimics the format of the solubilised compound collection in many companies.

In order to get the maximum amount of compound dispersion onto the lactose it was first important to determine the maximum solubility of the lactose in DMSO at room temperature.

This was found to be 1 g lactose in 3 mls DMSO. Consequently lactose was added to each of the 10 mM solutions at 330 mg/ml. These solutions were then dried in an oven at 60°C over night to remove the DMSO. In all 13 cases what was left was a granular material that was easy to handle Extraction in to aqueous phosphate buffer (O. 1M phosphate) pH 7.4

Extraction was carried out by stirring the support for 72 hrs at 25°C in a vial containing 0.1 M phosphate buffer solution, pH 7.4. The aim was to generate an aqueous solution of concentration 10-5 M, typical of that used in HTS assays. In the case of the lactose this was calculated to be 1 mg of treated lactose in 3mls of buffer.

Following 72 hours of stirring the aqueous solutions were analysed using HPLC-UV. The chromatography used is outlined below.

Column: Phenomenex Columbus 3p C, 8 30 mm x 2 mm.

Eluents: Eluent A: Water containing 50 mM ammonium acetate.

(Weigh accurately 3.854 g ammonium acetate and dissolve in 1 litre of Milli-Q deionised water.) Eluent B: Methanol containing 43.75 mM ammonium acetate.

(Weigh accurately 3.372 g ammonium acetate and dissolve in 1 litre methanol (HPLC Gradient grade)).

Flow rate: 1.2 ml/min.

Temperature: 50°C.

Detection: 5 wavelengths :- 220, 230,250,270 and 320 nm.

Gradient: Time (min) % A % B 0 95 5 3 100 6. 0 O 100 6. 1 95 5 7. 75 95 5 The results from the analysis are captured in table 1. Also included in the table are the aqueous solubilities of the 13 compounds in 0.1 M phosphate buffer pH 7.4.

Table 1-Compound Extraction from Lactose following 72 hrs Stirring in Phosphate Buffer, pH 7.4 Compound Solubility Impurity Cmpd Multiple Multiple ClogP Vol H H Bond Pos Neg Lactose DMSO Number uM in DMSO Extracted peaks in peaks in Bond Accept Charge Charge Colour Sol cal. Lactose extract extract Donor Colour Solution uM 1 >9316 6. 5 2. 4 167 3 2 1 0 White off white 2 >4190 9.5-0.4 302 3 5 1 1 White white 3 330 6.0 4.0 199 2 3 0 0 White white 4 >7400 2.8 2.9 244 2 2 0 1 White white 5 270 6.6 0.6 322 3 6 0 0 White white 6 43 4.9 3.6 415 0 3 1 0 Pale off yellow white 7 6 10-30% 0.0 4.7 313 0 6 0 0 White white 8 28 10-30% 0.0 Y 5.4 236 0 2 0 0 White white impurity 9 470 0.0 2.6 149 1 3 0 1 White yellow 10 2900 0.0 Y 3.1 384 3 5 0 2 Pink off degrad? white 11 490 2.1 Y 4.0 379 4 7 2 1 Pale white degrad?yellow 12 430 0.0 1.6 156 1 4 0 1 Vivid yellow yellow 13 76 10-30% 0.0 3.4 180 1 1 0 0 White white ND = Peak not detected in buffer solution.