WO2011046915A1

WO2011046915A1 - Apparatus for crystallization and method therefor

Info

Publication number: WO2011046915A1
Application number: PCT/US2010/052285
Authority: WO
Inventors: Leandra Kindon; Stuart Anscombe
Original assignee: R.P. Scherer Technologies, Llc
Priority date: 2009-10-12
Filing date: 2010-10-12
Publication date: 2011-04-21

Abstract

The disclosure is directed to forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom. A plurality of vessels is provided, each having an upper closable open end and a lower closable open end with an up-down longitudinal axis between the ends. The plurality of vessels are supported and arranged in an array in a plane transverse to the longitudinal axis direction with each of their longitudinal axis directions being substantially parallel to each other. Also provided is a plurality of porous filters located to obstruct downward flow from the plurality of vessels, the plurality of filters being capable of allowing liquid to flow downwardly therethrough but capable of retaining formed precipitate thereon. Further provided is means to create a pressure differential across each of the plurality of filters such that there is a higher pressure above each filter which forces liquid in the vessel above the filter through the filter.

Description

APPARATUS FOR CRYSTALLIZATION AND METHOD THEREFOR

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Great Britain Provisional Application No. 0917876.5 filed October 12, 2009 and Great Britain Provisional Application No.

1002992.4 filed February 23, 2010, the contents of which are hereby incorporated by reference as if fully stated herein.

Field

[0002] The present disclosure generally relates to an apparatus for making crystals and to a process for making crystals using the apparatus.

Background

[0003] In the field of chemistry, and more particularly pharmaceutical chemistry, it is common to seek to prepare a substance, generally a chemical compound, in the form of crystals. One reason is because crystallization is a well-known method of purification in which a substance can separate from a solution while leaving impurities in the solution. Another reason is that the crystalline state is a thermodynamic ally stable state in which a substance in crystalline form can remain relatively stable.

[0004] A common research or development investigation is to identify optimum conditions for crystallization. This may involve investigation of suitable crystallization conditions such as optimum solvents or mixtures of solvents, temperatures, and/or rates of crystallization, for obtaining crystals of optimum purity, size or shape, or in the case of substances which crystallize in different crystal forms, for achieving a desired crystal form.

[0005] Many methods are known for making crystals. For example, one known method is to allow a hot saturated solution of a substance to cool so that the solubility of the substance in a cooler solvent decreases. Another known method for making crystals is to add an anti-solvent to the solution to cause precipitation of crystals. Other known methods include investigating preparative conditions, e.g., reaction temperatures, filtration temperatures, crystallization temperatures, cooling rates, and/or reagents, to achieve optimized crystal formation.

[0006] In modern chemistry, and more particularly modern pharmaceutical chemistry, it has been observed that there is a particular need to provide high throughput screening of a crystallization process, so that the above-mentioned investigations may be performed rapidly. Moreover, it has been observed that there is a need to provide such processes in a way in which the crystallization process itself, or further investigation of the crystals, can be easily automated. One example in which high throughput automation of investigation of chemical processes such as crystallization has been achieved is by performance or reactions under investigation in vessels which are arranged in an array format, and typically arranged in an 8 x 12 array. Much modern automated laboratory equipment is configured to operate with vessels configured in such an 8 x 12 array format. Such an array, e.g., a 12 x 8 array, conforms to the standard dimensions for microtiter plates as recommended by The Society of Biomolecular Screening. [0007] Various apparatuses to provide the above-described automation or to provide high throughput screening processes, e.g., by operating in an 8 x 12 array format are known. For example, WO Publication No. 2000/067872, WO Publication No. 2004/000452, and U.S. Patent No. 6,939,515 each disclose such an apparatus, capable of performing filtration among other operations.

[0008] This disclosure is to provide an improved apparatus to facilitate a high throughput investigation of chemical processes, and in particular crystallization. Advantages of this disclosure will be apparent from the following description.

SUMMARY

[0009] In an example embodiment described herein, an apparatus is provided for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom. The apparatus includes a plurality of vessels, each of the plurality of vessels having an upper closable open end and a lower closable open end with an up-down longitudinal axis between the ends. The plurality of vessels are supported and arranged in an array in a plane transverse to the longitudinal axis direction with each of their longitudinal axis directions being substantially parallel to each other. The apparatus further includes a plurality of porous filters located to obstruct a downward flow from the plurality of vessels, the plurality of filters being capable of allowing liquid to flow downwardly therethrough but capable of retaining formed precipitate thereon. The apparatus also includes means to create a pressure differential across each of the plurality of filters such that there is a higher pressure above each filter which forces liquid in the vessel above the filter through the filter.

[0010] By virtue of the foregoing arrangement, the apparatus can be used so that different crystallization conditions may be investigated in the liquid phase in different vessels. So- formed precipitate may then be collected on the filter by application of the pressure differential. The array format facilitates easy automation of the investigation by means of instrumentation adapted to handle samples in an array format. [0011] In another example embodiment, a method is provided for using an apparatus for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom. The method includes providing a plurality of vessels, each vessel having an upper closable open end and a lower open end with an up-down longitudinal axis between the ends. The vessels are supported and arranged in an array in a plane transverse to the longitudinal axis direction with their longitudinal axis directions in parallel. Each vessel has a porous filter located therein to obstruct downward flow from the vessel, where the filters are capable of allowing liquid to flow downwardly therethrough but capable of retaining formed precipitate thereon. The method further includes introducing reagents into each of the plurality of vessels via the upper ends to provide a liquid phase within each vessel. The method also includes applying a positive atmospheric pressure to liquid in each vessel above the filter to thereby create a pressure differential across the filter such that there is a higher pressure above the filter which forces liquid in the vessels above the filter through the filter.

[0012] In yet another example embodiment, a method is provided for using an apparatus for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom. The method includes providing an array of a plurality of tubular vessels with an internal cylindrical profile, each of the plurality of tubular vessels having an upper closable open end and a lower closeable open end with an up-down longitudinal axis between the ends. The method further includes positioning an array of a plurality of lower closures supported upwardly extending from a base support, each of the plurality of lower closures removeably supporting at its upper end a piston, with a filter, below the array of the plurality of tubular vessels and in register with the corresponding open end of a vessel. In addition, the method includes moving the base support with its array of lower closures and pistons, and the array of vessels longitudinally relatively together so that the pistons enter the lower open ends of the vessels and move to a suitable location within the vessels, and so that the lower closures close the lower ends of the vessels. The method also includes introducing reagents into the vessels via the upper ends to provide a liquid phase within the vessels, and moving the base support with its array of lower closures and the array of vessels longitudinally relatively apart so that the lower closures are removed from the lower open ends of the vessels, but retaining the pistons in their location within the vessels. The method further includes inserting an array of receptacles with an external cylindrical cross-section which is smaller than the internal cross-section of the lower open ends of the vessels, so that upper ends of the receptacles fit into the lower open ends of the vessels, so that the upper ends of the receptacles are brought into contact with the lower surfaces of the pistons, and so that the upper ends of the receptacles are positioned beneath the lower open ends of the vessels. Additionally, the method includes bringing the array of vessels and the array of receptacles longitudinally together so that the upper ends of the receptacles enter the lower open ends of the vessels and further longitudinal movement of the vessels and the receptacles telescopingly together causes the upper ends of the receptacles to push the pistons upwardly relative to the vessels to thereby compress liquid in the vessels above the pistons and force the liquid through the filters and into the receptacles. The method also includes collecting precipitate which has been formed on the upper surfaces of the filters as the liquid phase flows downwardly through the filters.

[0013] This brief summary has been provided so that the nature of the disclosure may be understood quickly. A more complete understanding can be obtained by reference to the following detailed description and to the attached drawings.

BRIEF DESCRIPTION OF DRAWINGS

[0014] Figures 1 to 9 are representative views which show schematically the construction and operation of an apparatus according to a first example embodiment.

[0015] Figures 10 and 11 are representative isometric views of the apparatus according to the first example embodiment.

[0016] Figures 12 to 16 are representative views which show schematically the construction and operation of an apparatus according to a second example embodiment. [0017] Figure 17 is a representative isometric view of the apparatus according to the second example embodiment.

DETAILED DESCRIPTION

[0018] In an example embodiment described herein, an apparatus is provided for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom. The apparatus includes a plurality of vessels, each of the plurality of vessels having an upper closable open end and a lower closable open end with an up-down longitudinal axis between the ends. The plurality of vessels are supported and arranged in an array in a plane transverse to the longitudinal axis direction with each of their longitudinal axis directions being substantially parallel to each other. The apparatus further includes a plurality of porous filters located to obstruct a downward flow from the plurality of vessels, the plurality of filters being capable of allowing liquid to flow downwardly therethrough but capable of retaining formed precipitate thereon. The apparatus also includes means to create a pressure differential across each of the plurality of filters such that there is a higher pressure above each filter which forces liquid in the vessel above the filter through the filter.

[0019] By virtue of the foregoing arrangement, the apparatus can be used so that different crystallization conditions may be investigated in the liquid phase in different vessels. So- formed precipitate may then be collected on the filter by application of the pressure differential. The array format facilitates easy automation of the investigation by means of instrumentation adapted to handle samples in an array format.

[0020] In an example embodiment, the array may be a rectangular array, such as an 8 x 12 array of 96 vessels.

[0021] In an example embodiment, in the array, the plurality of vessels may be supported by being mounted on a support. Such a support may comprise a support frame, typically a sheet form frame in a plane perpendicular to the longitudinal direction, with apertures therethrough through which vessels, for example, tubular vessels, may be threaded. The frame may be made of, for example, a suitably robust metal such as stainless steel or a robust plastic material.

[0022] Each of the plurality of vessels may be made of a material which is inert to the liquid phase, its vapor, any individual components of the liquid phase, and to the substance. Such suitable materials include, for example, glass, inert polymers such as polytetrafluoroethylene (PTFE), and inert metals such as stainless steel. A transparent material such as glass may be used so the contents of each vessel can be easily observed.

[0023] In an example embodiment, the vessels may be tubular. Tubular vessels are suitably cylindrical, for example, with circular open upper and lower open ends. The upper opening may be closable by means of a closure adapted for the introduction of one or more liquid or gaseous materials therethrough, e.g., a reagent in a crystal-forming process. Such a closure may be puncturable so that such material may be introduced by means of an injection needle. For example, the closure may comprise a septum cap. In addition, the closure should be robust, such that it withstands positive pressure created above the liquid in the plurality of vessels.

[0024] In an example embodiment, the filter may comprise a membrane of a porous material, for example, a matted fibrous material or a sintered material having

interconnected pores between its sinter particles. A suitable material for the filter material is, for example, a glass frit. Moreover, in this example embodiment, the filter has a porosity such that the action of gravity alone is insufficient to cause a significant flow of a liquid within the vessel above the filter to flow through the filter, so that liquid may be retained above the filter during a liquid phase experiment performed in the vessel above the filter. However, the filter also has a porosity such that on creating the pressure differential across the filter, liquid passes downwardly through the filter.

[0025] In an example embodiment, the filter may be separable from the vessel so that the precipitate retained thereon may be examined in situ on the filter. [0026] The pressure differential may be created in various ways. For example, in one embodiment, the apparatus may be constructed to apply a negative pressure to the lower surface of the filter to draw liquid above the filter through the filter.

[0027] In another example embodiment, the plurality of vessels are tubular vessels having an upper closeable open end and an open lower end, and a longitudinal up-down axis between the ends along the axis of the tubular shape. In this example embodiment, the plurality of vessels have their longitudinal up-down axes arranged in parallel, and a moveable piston having a slideable liquid-tight seal with the interior surface of the tubular vessel is located in the tubular vessel between the upper and lower ends. The piston has a longitudinal channel therethrough, and a channel of the tubular vessel is obstructed by the porous filter.

[0028] In this example embodiment, the piston carrying the filter is slideably moveable in the tubular vessel, and the filter is easily separable from the vessel by sliding the piston out of the vessel. In addition, in this example embodiment, a pressure differential can be easily created across the filter such that there is a higher pressure above the filter, which forces liquid in the vessel above the filter through the filter, by closing the upper closeable open end of the vessel and moving the piston slideably upwards to thereby compress the liquid contained in the vessel above the filter.

[0029] In an example embodiment, the piston may have a resiliently compressible perimeter and may be made of an elastically compressible material such as a polymer to facilitate a slideable liquid tight seal between the outer surface of the piston and the internal surface of the vessel. Such a piston may therefore have an outer cross-section slightly larger than the inner cross-section of the vessel. For a vessel having a cylindrical internal cross-section, e.g., a tubular vessel, the piston is cylindrical in its outer profile. The longitudinal channel through the piston may also be cylindrical, but in this example embodiment, the uppermost part of the channel may have an upwardly flaring conical profile. [0030] In an example embodiment, the open lower end of the vessel, beneath the filter, may be closed by an openable, e.g., removable lower closure, to assist in retention of liquid within the vessel above the filter. The lower closure may be openable or removable from the lower end of the vessel to allow liquid to pass downwardly through the filter. The lower closure may also be in the form of a plug which can fit closely into the lower open end of the vessel, or a cap which can fit over the lower open end of the vessel.

[0031] In this example embodiment, the lower closures may be provided and supported in an array corresponding to the arrangement of the array of the plurality of vessels. In such an example embodiment, the array may be supported upwardly extending from a base support which may be positioned beneath the open lower end of an array of the plurality of vessels, with the lower closures in register with the corresponding open end. The base support and array of vessels may be moved longitudinally relatively together so that the lower closures enter the open lower end of the vessels to close the lower end. Such a base support may be made, for example, from a suitably robust metal or a plastic material.

[0032] In an example embodiment, the lower closure and/or the base support may have an upper surface which, when the lower closure is closed or in place at the lower end of the vessel, is in contact with the lower surface of the filter. Such a lower closure may be made of, for example, a resilient material such as an elastic stopper.

[0033] The upper end of such a lower closure and/or base support may be provided in the form of a support for the above-described piston, on which the piston may be removably seated. For example, the lower surface of the piston may comprise a concavity, which may be the lower end of the channel therethrough, and the upper end of the lower closure may be correspondingly convex so as to be able to mate with the concavity. In this example embodiment, the base support may conveniently be used to locate the piston in the vessel. For example, a piston may be supported on the base support, and the base support, while supporting the piston, may be positioned beneath the open lower end of an array of the plurality of vessels, with the piston in register with the corresponding open end. In addition, the base support and array of the plurality of vessels may be moved longitudinally relatively together so that the piston enters the open lower end of the vessels and moves to a suitable location within the vessels, and the lower closure closes the lower end of the vessel.

[0034] In yet another example embodiment, the apparatus may be constructed to apply a positive atmospheric pressure to liquid in the vessel above the filter.

[0035] In this example embodiment, the plurality of vessels may be provided with a means for introduction of a pressurized gas into their internal volume above the filter, and the introduction of this gas may create an above-atmospheric pressure above liquid in the vessel. In this example, the vessels may be closed at their upper end by a closure adapted for the introduction of a gas through the closure, e.g., as mentioned above. The closure may be puncturable so that such a gas may be introduced by means of an injection needle. For example, such a closure may comprise a septum cap. The closure should be robust, such that it withstands positive pressure created above the liquid in the vessels.

[0036] In this example embodiment, the filter may be fixed in the vessel. Alternatively, the filter may be insertable into the vessel via its lower end. For example, the filter may be supported on a filter support which can be inserted into the lower open end of the vessel and which makes a liquid-tight seal with the interior surface of the vessel. In addition, a plurality of filters may be supported on a plurality of filter supports. The plurality of filter supports may themselves be supported upwardly extending from a base support which may be positioned beneath the open lower end of an array of the plurality of vessels, with the plurality of filter supports in register with the corresponding open end. In addition, the base support and array of vessels may be moved longitudinally relatively together so that the plurality of filter supports enter the open lower end of the vessels to close the lower end. The base support may be made from, for example, a suitably robust metal or plastics material. [0037] In another example embodiment, the apparatus is provided in combination with an array of receptacles correspondingly positioned beneath the filters to receive liquid after it has flowed through the filters.

[0038] The receptacles are made of, for example, a material which is inert to the liquid phase, such as an inert polymer or metal. One such example material is glass which is generally inert and is also transparent so that the contents of the receptacle can be easily observed.

[0039] In an example embodiment, the receptacles may be mounted in a support which holds them arranged in an array corresponding to the above-mentioned array of vessels. For example, glass vials may be supported in holders on the upper surface of a receptacle support.

[0040] When the vessels are the above-mentioned tubular vessels with the above- mentioned internal sliding piston with its filter, the array of such receptacles may be used to push the pistons upward relative to the vessels to thereby compress liquid in the vessels above the pistons and force the liquid through the filter and into the receptacles. For example, the receptacles may have an external cross-section which is smaller than the internal cross-section of the lower open end of the vessels so that the upper end of the receptacles may be inserted into the open lower end of the vessels. In addition, the vessels and the receptacles may be moved relatively longitudinally together so that the upper end of the receptacles can push the piston upwardly relative to the vessels. For example, when the vessels have a cylindrical internal profile, the receptacles may have a smaller cylindrical external profile, so that the receptacles can fit in a telescoping manner within the vessels. Contact between the upper end of the receptacle and the piston may be either direct or indirect, e.g., via some intermediate bearing part between the receptacle and the piston. [0041] In an example embodiment in which a positive atmospheric pressure is introduced above the filter, a receptacle may be positioned beneath the filter ready to receive liquid forced through the filter by the positive pressure.

[0042] A liquid guide, such as a funnel, may be located between the lower surface of the filter and the receptacle to guide liquid into the receptacle. This guide may be used with an example embodiment that uses the sliding piston, and an example embodiment in which a pressurized gas is introduced above the liquid in the vessel. For example, the above-mentioned filter support may comprise such a liquid guide.

[0043] In other example embodiments, a method is provided for use of an apparatus as described above for the formation of a solid precipitate in a liquid phase and the isolation thereof.

[0044] In one example embodiment, such a method includes providing a plurality of tubular vessels each having an upper closable open end and an open lower end, and a longitudinal up-down axis between the ends along the axis of the tubular shape. The plurality of vessels have their longitudinal up-down axes arranged in parallel, and each of the plurality of vessels has a moveable piston having a slideable liquid- tight seal with an interior surface of the tubular vessel located in the tubular vessel between the upper and lower ends. The piston has a longitudinal channel therethrough, in which the channel is obstructed by a porous filter. The method further includes slideably upwardly moving the piston carrying the filter in the tubular vessel to thereby compress liquid in the vessel above the piston and thereby create a pressure differential across the filter such that there is a higher pressure above the filter, and thereby to force liquid in the vessel above the filter through the filter.

[0045] In this example embodiment, the method may further include positioning beneath the array of vessels an array of plural lower closures supported upwardly extending from a base support, each lower closure removeably supporting at its upper end a piston, with its filter, below the array of tubular vessels and in register with the corresponding open end of a vessel. The method may also include moving the base support with its array of lower closures and pistons, and the array of vessels longitudinally relatively together so that the pistons enter the open lower end of the vessels and move to a suitable location within the vessel, and the lower closure closes the lower end of the vessel. In addition, the method may include introducing reagents into the vessel via the upper end to provide a liquid phase within the vessel, moving the base support with its array of lower closures and the array of vessels longitudinally relatively apart so that the lower closures are removed from the lower open ends of the vessels, but retaining the pistons in their location within the vessels, and then slideably upwardly moving the pistons carrying the filter in the tubular vessel.

[0046] In the foregoing example embodiment, the pistons may be slideably upwardly moved by inserting an array of receptacles with an external cylindrical cross-section which is smaller than the internal cross-section of the lower open end of the vessels, so that the upper end of the receptacles fits into the open lower end of the vessels, so that the upper end of the receptacles is brought into contact with the lower surface of the piston, and so that the upper end of the receptacles is positioned beneath the open lower ends of the vessels. The method further includes bringing the array of vessels and the array of receptacles longitudinally together so that the upper end of the receptacles enters the open lower end of the vessels, and further longitudinal movement of the vessels and the receptacles telescopingly together causes the upper end of the receptacles to push the pistons upwardly relatively to the vessels to thereby compress liquid in the vessels above the pistons and force the liquid through the filter and into the receptacle. The method also includes collecting precipitate which has been formed on the upper surface of the filter as the liquid phase flows downwardly through the filter.

[0047] In another example embodiment, a method includes providing a plurality of vessels, each vessel having an upper closable open end and a lower open end with an up- down longitudinal axis between the ends. The plurality of vessels are supported and arranged in an array in a plane transverse to the longitudinal axis direction with their longitudinal axis directions parallel, each vessel having a porous filter located therein to obstruct downward flow from the vessel. The filters are capable of allowing liquid to flow downwardly therethrough but capable of retaining formed precipitate thereon. The method further includes introducing reagents into each of the plurality of vessels via the upper end to provide a liquid phase within each vessel, and applying a positive atmospheric pressure to liquid in each vessel above the filter to thereby create a pressure differential across the filter such that there is a higher pressure above the filter which forces liquid in the vessels above the filter through the filter.

[0048] In the foregoing example embodiment, the positive atmospheric pressure may be applied by providing each vessel with a puncturable closure and introducing a pressurized gas into the volume of the vessel above the liquid therein via a hollow needle inserted through the closure.

[0049] In addition, in this example embodiment, an array of receptacles may be located beneath the lower end of the vessels to receive liquid which has flowed through the filter.

[0050] The liquid which has flowed through the filters may be collected in the receptacles located beneath the vessels.

[0051] Thereafter, the array of receptacles may be removed from the lower end of the vessels. The upper end of the vessels may be opened to provide access to precipitate which has collected on the filters. Pistons or filter supports with their filters carrying the collected precipitate may be removed from the vessels. Precipitate on the filter may then be examined or further processed, in situ on the filter.

[0052] Alternatively, if pistons have been pushed upwardly far enough in the tubular vessels so the collected precipitate is easily accessible via the open upper end of the tubular vessel, the precipitate may be examined or further processed in situ with the piston in place in the tubular vessel. [0053] In this process, the reagents introduced into the vessel are selected such that a solid precipitate which is crystalline is expected to form.

[0054] Additionally, in this process, respective different reagents, different

concentrations of reagents, or different quantities of reagents are introduced into respective different vessels in the array. In this way, the range of reaction conditions in each vessel can be used to map out the effectiveness of the different reaction conditions in forming the solid precipitate or in forming a desirable form of solid precipitate.

[0055] In another example embodiment, a method is provided for using an apparatus for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom. The method includes providing an array of a plurality of tubular vessels with an internal cylindrical profile, positioning an array of a plurality of lower closures supported upwardly extending from a base support, each lower closure removeably supporting at its upper end a piston, with its filter, below the array of tubular vessels and in register with the corresponding open end of a vessel. The method further includes moving the base support with its array of lower closures and pistons, and the array of vessels longitudinally relatively together so that the pistons enters the open lower end of the vessels and move to a suitable location within the vessel, and the lower closure closes the lower end of the vessel. In addition, the method includes introducing reagents into the vessel via the upper end to provide a liquid phase within the vessel, moving the base support with its array of lower closures and the array of vessels longitudinally relatively apart so that the lower closures are removed from the lower open ends of the vessels, but retaining the pistons in their location within the vessels. The method also includes inserting an array of receptacles with an external cylindrical cross-section which is smaller than the internal cross-section of the lower open end of the vessels so that the upper ends of the receptacles fit into the open lower end of the vessels, so that the upper ends of the receptacles are brought into contact with the lower surface of a piston, and so that the upper ends of the receptacles are positioned beneath the open lower ends of the vessels. In addition, the method includes bringing the array of vessels and the array of receptacles longitudinally together so that the upper ends of the receptacles enter the open lower ends of the vessels and further longitudinal movement of the vessels and the receptacles telescopingly together causes the upper end of the receptacles to push the pistons upwardly relatively to the vessels to thereby compress liquid in the vessels above the pistons and force the liquid through the filter and into the receptacle. Additionally, the method includes collecting precipitate which has been formed on the upper surface of the filter as the liquid phase flows downwardly through the filter.

[0056] The disclosure will now be described by way of example only with reference to the accompanying drawings.

[0057] As shown in Fig. 1, in a first example embodiment, an apparatus 10 comprises plural tubular glass vessels 11 with a cylindrical internal profile. Each vessel 11 has an open upper end 11 A and an open lower end 1 IB with an up-down longitudinal axis L-L between the ends 11A, 1 IB. The plural vessels 11 are supported by a support frame 12A, 12B with upper and lower sheet form components 12A, 12B, respectively, made of, for example, a plastic material, connected by rods 13. The rods 13 may be, for example, metal rods. As also shown in Fig. 1, the plural vessels 11 pass through apertures in the upper and lower components 12A, 12B. The plural vessels 11 are supported by the frame 12A, 12B in a two-dimensional array.

[0058] Fig. 2 shows a plan view of the upper open ends 11A of the plural vessels 11. In Fig. 2, the plural vessels 11 are arranged in the array, and more particularly are arranged in a 6 x 4 array. However, this example embodiment is not limited to a 6 x 4 array, and other array formats, for example, an 8 x 12 array, may be used.

[0059] As shown in Fig. 1, the open upper ends 11 A of the vessels 11 are closed by puncturable plug closures 14 which may be, for example, rubber septum caps. These plug closures 14 are covered by caps 15 provided with a central aperture 16 through which an injection needle (not shown) might be passed. [0060] Arranged beneath the apparatus 10 is a base support 17 made of, for example, a plastic material. The base support comprises plural upwardly extending support parts 18 on which are removably seated plural pistons 19. The arrangement of the parts 18 and the pistons 19 seated thereon is in register with the open ends 1 IB of corresponding vessels 11 in the array above the parts 18 and the pistons 19. Each piston 19 is cylindrical and is made of, for example, an elastically compressible material to facilitate a slideable liquid tight seal between the outer surface of the piston 19 and the internal surface of a vessel 11. The piston 19 also has an outer cross-section slightly larger than the inner cross-section of the vessel 11 to facilitate the seal. Passing longitudinally through each piston 19 is a longitudinal channel 110. As shown in Fig. 1, the

longitudinal channel 110 through the piston 19 has a cylindrical profile. The longitudinal channel 110 of each piston 19 is obstructed by a porous filter 111 being, for example, a disk-shaped borosilcate glass frit. Also located on the base support 17 and threaded around each support part 18 are lower closures 112, each in the form of a plug which can fit closely into the lower open end of a vessel 11.

[0061] Fig. 3 shows the base support 17 positioned beneath the apparatus 10, with the lower closures 112 in register with the corresponding open ends 1 IB of the vessels 11. In Fig. 3, the base support 17 and the apparatus 10 have been moved longitudinally relatively together so that the lower closures 112 enter the open lower ends 1 IB of the vessels 11, to close the lower end 1 IB. As the closures 112 enter the open lower end 1 IB of the vessels 11, the pistons 19 also enter the lower open end 1 IB and move up the interior of the vessels 11, being pushed up the vessels 11 by the support parts 18 and the closures bearing upon them. The sides of the pistons 19 make a smooth sliding seal with the interior surface of the vessels 11 until the pistons 19 are in a suitable location within the vessels 11, close to the lower open end 1 IB. The base support 17 and the apparatus 10 may then be locked together by a conventional clamping means (not shown).

[0062] Fig. 4 shows an arrangement of the apparatus 10, the base support 17 and their various sub-components in a similar arrangement as shown in Fig. 3. As shown in Fig. 4, an injection needle 41 has been inserted through the upper closure 14, through which liquid reagents 42 have been introduced into the vessel 11. In an alternative procedure, the upper closures 14 may be omitted during the steps shown in Figs. 1 to 3, and liquid and optionally solid reagents may be introduced via the open upper end 11 A of the vessels 11. Then, when the pistons 19 and closures 112 are in place as shown in Fig. 3, the upper closures 14 may be inserted into the upper open end 11A of the vessels 11. The liquid phase 42 is retained in the vessels 11 by means of the lower closures 112.

[0063] Fig. 5 shows an arrangement of the apparatus 10, the base support 17 and their various sub-components in a similar arrangement as shown in Fig. 4, except that injection needles 41 have been withdrawn, and the reagents present in liquid phase 42 within vessels 11 have reacted to form a solid phase precipitate 43 being a crystalline precipitate.

[0064] In Fig. 6, the assembly of base support 17, support parts 18 and lower closures 112 has been detached from the apparatus 10 with its pistons 19. Because the pistons 19 are removably mounted on the support parts 18 and form a tight sliding seal with the inner wall surface of vessels 11, the pistons 19 remain in place in the vessels 11. The porosity of the filters 111 is such that the liquid phase 42 in vessels 11 remains in vessels 11 above the filters 111 before an array of receptacles are positioned beneath the vessels, which is described in more detail below.

[0065] As shown in Fig. 6, an array 61 of receptacles 62 being, for example, glass vials, has been positioned beneath the assembly 60, with each receptacle 62 being in register with the open lower end 1 IB of a corresponding vessel 11. The vials may have, for example, a volume of ca. 2ml, and the vessels 11 may have a similar volume. In the array 61, the receptacles 62 are each held by a tubular holder 63, which is itself supported on the upper surface of a receptacle support 64, made from, for example, a plastics material, or alternatively made from, for example, a suitably robust metal such as stainless steel. Mounted in the upper open end of the receptacles 62 are funnels 65 to guide liquid into receptacles 62. A slot 66 (not shown) such as an air vent slot at the upper end of tubular holders 63 facilitates removal of receptacles 62 from holders 63 and allows displaced air to escape if liquid enters receptacles 62.

[0066] In Fig. 7, the array 61 and the assembly 60 have been moved relatively

longitudinally together so that the funnels 65 have entered the open lower end 1 IB of vessels 11 and have come into contact with the lower surface of pistons 19, so as to be able to bear upon the pistons 19 and push them relatively upward along vessels 11.

[0067] Fig. 8 shows an arrangement similar to the arrangement shown in Fig. 5, but the array 61 has been moved upwardly relative to the apparatus 10. The funnels 65 have caused pistons 19 to move slidingly upwardly along vessels 11. As a consequence, liquid in the interior of vessels 11 above the pistons 19 is compressed, and the pressure differential across the filters 111 has caused liquid 81 to flow through filters 111, and through funnels 65 into receptacles 62. The precipitated crystals 82 have been retained on filters 111.

[0068] Fig. 9 shows a disassembled version of the assembly shown in Fig. 8. In Fig. 9, the upper closures (not shown) have been removed from vessels 11 via the upper open end of the vessels 11, so that the crystals 82 retained on filters 111 can be examined. The array arrangement of the vessels 11 and correspondingly the filters 111 facilitates in situ examination of the crystals 82 on the filters 111. Alternatively, the pistons 19 may be removed (not shown) from the vessels 11, for example, by pushing them downwards through the vessels 11 until they emerge from the open bottom end 1 IB of the vessels 11. The pistons 19 plus filters 111 may then be received onto a transfer plate 91 which can support the pistons 19 in the same array arrangement as the vessels 11. The transfer plate 91 has cavities 92 into which pistons 19 can be fitted in an array arrangement. When supported on the support plate 91, the crystals 82 on the filters 111 can be placed directly into a Raman spectrometer or an XRPD diffractometer adapted in a standard way to handle such an array, for analysis. [0069] Fig. 10 shows an exploded perspective view of the construction of an apparatus according to the first example embodiment as shown schematically in Fig. 1. This apparatus comprises plural tubular glass vessels 11 with a cylindrical internal profile, each having an open upper end 11A and an open lower end 1 IB. The plural vessels 11 are supported by a support frame 12A, 12B with upper and lower sheet form components 12A, 12B, respectively, made of, for example, stainless steel, connected by rods 13, which are, for example, metal rods, and co-operating bolts 1001. One example two- dimensional array arrangement of vessels 11 is depicted in Fig. 10.

[0070] In Fig. 10, the open upper ends 11A (not shown in detail) of the vessels 11 are closed by puncturable septums and caps 14, 15 through which the injection needle shown in Fig. 4 might be passed. More specifically, the open upper ends 11 A of the vessels 11 are closed by puncturable plug closures 14, for example, rubber septum caps. These plug closures 14 are covered by caps 15 provided with a central aperture 16 through which the injection needle shown in Fig. 4 might be passed.

[0071] As shown in Fig. 10, arranged beneath the above-described assembly is a base support 17 made of, for example, two plastic material sub-parts. The base support 17 comprises plural upwardly extending support parts 18 on which are removably seated the plural cylindrical pistons 19, in register with the lower open ends 1 IB of corresponding vessels 11 in the array above them. Passing longitudinally through each piston 19 is a longitudinal channel 110 (not shown in detail) of a cylindrical profile. The longitudinal channel 110 of each piston 19 is obstructed by a porous filter 111 being a sintered glass disk, which is held within the channel 110 by a filter holder 1002.

[0072] Also located on the base support 17, and threaded around each support part 18, are lower closures 112, each in the form of a plug which can fit closely into the lower open end of a vessel 11.

[0073] The apparatus 10 shown in Fig. 10 may also include a jacket 1003 through which a heating or cooling fluid may be passed via connectors 1004. This can be used to control the temperature of the liquid phase inside vessels 11. Typically, the jacket 1003 can set the temperature of the vessels 11 within a range of -10 to +90°C, the feasible range being dependent upon, e.g., the freezing point and boiling point of the solvents in the vessels 11. The jacket 1003 may, for example, apply controlled heating and cooling, and temperature cycling. In a typical experiment screening crystallization conditions for the drug compound sulfathiazole, the jacket was used to temperature cycle reaction mixtures in vessels 11 from 0 to +40°C in blocks of about 1 to 1.1 hours for 24 hours.

[0074] Fig. 11 shows assembly 60 as shown in Fig. 6 positioned above array 61 as also shown in Fig. 6. Parts of the assembly 60 which have been shown in Fig. 10 are numbered as in Fig. 10. The array 61 comprises receptacles 62 which are shown in Fig. 6. Receptacles 62 may be glass vials (not shown) each held by a tubular holder 63 supported on the upper surface of the receptacle support 64 made from, for example, a plastic material. Mounted in the upper open end of the tubular holders 63 are funnels 65, made from, for example, a plastic material, to guide liquid into the receptacles. Air vent slots 66 at the upper end of tubular holders 63 facilitate removal of the receptacles 62 from holders 63, and allow displaced air to escape as liquid enters receptacles 62.

[0075] Fig. 12 shows the apparatus according to a second example embodiment, constructed to apply a positive atmospheric pressure to liquid in the vessel above the filter.

[0076] In Fig. 12, an array 120 of plural tubular glass vessels 121 with a cylindrical internal profile is shown in cross-section. Each vessel 121 has an open upper end 121A and an open lower end 12 IB with an up-down longitudinal axis between the ends 121 A, 121B. The plural vessels 121 are supported in a two-dimensional array by a support frame 122A, 122B comprising upper and lower sheet form components 122A, 122B, respectively, made of, for example, a plastic material, connected by rods 123, which are, for example, metal rods. The plural vessels 121 pass through apertures in the upper and lower components 122A, 122B, respectively, in a similar manner to the apparatus of Figs. 1 to 11 described in detail above. [0077] As shown in Fig. 12, the open upper ends 121A of the vessels 121 are closed by puncturable plug closures 124, for example, rubber septum caps, through which an injection needle (not shown) might be passed. These plug closures 124 may be covered by caps (not shown) analogous to the caps 15 of Figs. 1 to 11.

[0078] In Fig. 12, a corresponding array 125 is shown located below the array of vessels 121 over all of insertable filters 126, each being, for example, a sintered glass frit. Each filter 126 is supported on a filter support 127 which can be inserted into the lower open end 12 IB of a corresponding vessel 121, and which makes a liquid- tight seal with the interior surface of the vessel 121. Supports 127 can be made of, for example, a resilient polymer material. The plural filter supports 127 are themselves fixed in a base support 128 made from a plastic material, from which they upwardly extend with the filter supports 127 in register with the corresponding open ends 12 IB.

[0079] Fig. 13 shows the base support 128 and array 120 of vessels 121 having been moved longitudinally relatively together so that the filter supports 127 enter the open lower end 121B of the vessels 121 to close the lower end 121B.

[0080] Fig. 14 shows an array 129 of receptacles 1210, being, for example, glass vials. The receptacles 1210 are supported by a receptacle support 1211 in the form of upper and lower parts 1211 A and 121 IB, respectively, made, for example, from a plastic material, and connected by rods 1212 such as metal rods.

[0081] Fig. 15 shows the array of vessels 120 and the array of receptacles 129 having been brought together with each vessel 121 above a corresponding receptacle 1210. The lower ends 1213 of the filter supports 127 extend into the receptacles 1210 and are shaped as a liquid guide funnel to direct flow of liquid from a vessel 121 into a receptacle 1210. [0082] The operation of the apparatus of Figs. 12 to 15 according to the second example embodiment will now be described with reference to Fig. 16 which shows the sequence of operations in a single set of a vessel 121, a receptacle 1212 and a filter 126.

[0083] As shown in Fig. 16A, the arrays 120 and 129 are together, and the closure 124 is not yet in place, allowing reagents, solvent(s), etc., indicated by reference numeral 161 in Figure 16A, comprising a liquid phase to be introduced into the vessel via the open upper end 121A. Alternatively, the closure 124 may be in place and liquid reagents, solvent(s), etc., may be introduced into vessel 121 via a hollow needle passed through closure 124.

[0084] In Fig. 16B, the closure 124 has been put in place and the contents of the vessel 121 have been heated or cooled to a suitable temperature, for example, by use of a temperature control jacket such as the jacket 1003 described above in connection with Fig. 10.

[0085] In Fig. 16C, a reaction between the reagents in vessel 121 has taken place and a crystalline product 162 has formed.

[0086] In Fig. 16D, a hollow needle 163 has been passed through the puncturable closure 124. Compressed nitrogen gas has been introduced through the needle 163 to thereby generate an above atmospheric pressure in the vessel 121 above the liquid therein. The closure 124 fits in the upper open end 121A of the vessel 121 tightly so that it is not forced out of the vessel 121 by this pressure. This above atmospheric pressure in the vessel 121 has forced the liquid 161 in the vessel 121 down through the filter 126, through the guide 1213 into the receptacle 1210, leaving the crystalline product 162 on the filter 126.

[0087] Thereafter, the filters 126 may be removed from the vessels 121 while in their supports 127. Filters 126 may then be removed from supports 127 and transferred to a transfer plate (not shown) similar to plate 91 described above, e.g., provided with cavities to hold the filters 126 in an array. The crystals 162 on the filters 126 may be analyzed as described above.

[0088] The foregoing described apparatus may be used in experiments in which the influence of a range of reaction and/or crystallization and/or filtration temperatures, and/or different combinations of reagents, solvents and/or concentrations thereof in producing crystals is investigated.

[0089] Fig. 17 shows the assembly of Fig. 15 in a perspective exploded view. An array 120 of plural tubular glass vessels 121 is shown, as described in detail above. The plural vessels 121 are supported in a two-dimensional array by a support frame 122A, 122B comprising upper and lower sheet form components 122A, 122B, respectively, made of, for example, a plastic material, connected by rods 123 such as metal rods. The plural vessels 121 pass through apertures in the upper and lower components 122A, 122B.

[0090] In Fig. 17, shown located below the array of vessels 121 is a corresponding array 125 overall of insertable filters 126, each being, for example, a sintered glass frit. Each filter 126 is supported on a filter support 127 which can be inserted into the lower open end of a corresponding vessel 121. The plural filter supports 127 are themselves supported upwardly extending from a base support 128 made from, for example, a plastic material, with the filter supports 127 in register with the corresponding lower open ends of vessels 121.

[0091] Beneath the array 125 shown in Fig. 17 is an array 129 overall of receptacles 1210, being, for example, glass vials, supported by a receptacle support in the form of upper and lower parts 1211 A and 121 IB, respectively, made from, for example, a plastic material and connected by rods 1212 such as metal rods.

[0092] This disclosure has provided a detailed description with respect to particular illustrative embodiments. It is understood that the scope of the appended claims is not limited to the above-described embodiments and that various changes and modifications may be made by those skilled in the relevant art without departing from the scope of the claims.

Claims

WHAT IS CLAIMED IS:

1. An apparatus for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom, the apparatus comprising:

a plurality of vessels, each of the plurality of vessels having an upper closable open end and a lower closable open end with an up-down longitudinal axis between the ends, wherein the plurality of vessels are supported and arranged in an array in a plane transverse to the longitudinal axis direction with each of their longitudinal axis directions being substantially parallel to each other;

a plurality of porous filters located to obstruct a downward flow from the plurality of vessels, the plurality of filters being capable of allowing liquid to flow downwardly therethrough but capable of retaining formed precipitate thereon; and

means to create a pressure differential across each of the plurality of filters such that there is a higher pressure above each filter which forces liquid in the vessel above the filter through the filter.

2. The apparatus according to claim 1, wherein the array is a rectangular array.

3. The apparatus according to claim 1, wherein the plurality of vessels are provided with a means for introduction of a pressurized gas into their internal volume above the plurality of filters, such that the introduction of this gas creates an above- atmospheric pressure above liquid in the plurality of vessels.

4. The apparatus according to claim 1, wherein the plurality of vessels are tubular vessels, each having an upper closeable open end, a lower open end, and a longitudinal up-down axis between the ends along the axis of the tubular shape, wherein the plurality of vessels have their longitudinal up-down axes arranged substantially in parallel, wherein a moveable piston having a slideable liquid-tight seal with an interior surface of the tubular vessel is located in each of the tubular vessels between the upper and lower ends, and wherein the piston has a longitudinal channel therethrough, the channel being obstructed by the porous filter.

5. The apparatus according to claim 4, wherein the upper closeable open end of each of the plurality of vessels is closed by means of a closure adapted for introduction of one or more liquid or gaseous materials therethrough.

6. The apparatus according to claim 5, wherein the closure is puncturable so that the one or more liquid or gaseous materials may be introduced by means of an injection needle.

7. The apparatus according to claim 4, wherein the piston is made of an elastically compressible material.

8. The apparatus according to claim 4, wherein an uppermost part of the channel has a conical profile.

9. The apparatus according to claim 1, wherein the plurality of vessels are closed at their upper ends by a closure adapted for introduction of a gas through the closure.

10. The apparatus according to claim 9, wherein the closure is puncturable so that the gas may be introduced by means of an injection needle.

11. The apparatus according to claim 1, wherein each of the plurality of filters comprises a membrane of a porous material.

12. The apparatus according to claim 1, wherein each of the plurality of filters has a porosity such that the action of gravity alone is insufficient to cause a significant flow of a liquid within the vessel above the filter to flow through the filter, so that liquid may be retained above the filter during a liquid phase experiment performed in the vessel above the filter, but has a porosity such that on creating the pressure differential across the filter liquid passes downwardly through the filter.

13. The apparatus according to claim 1, wherein each of the plurality of filters is separable from the vessel so that the precipitate retained thereon may be examined in situ on the filter.

14. The apparatus according to claim 1, wherein each of the plurality of filters is insertable into a vessel via its lower end and is supported on a filter support which can be inserted into the lower open end of the vessel and which makes a liquid- tight seal with an interior surface of the vessel.

15. The apparatus according to claim 14, wherein the plurality of filters are supported on a plurality of filter supports which are supported upwardly extending from a base support which is positioned beneath the lower open ends of the array of the plurality of vessels, with the plurality of filter supports in register with the corresponding open ends, and the base support and the array of the plurality of vessels are moved longitudinally relatively together so that the plurality of filter supports enter the lower open ends of the vessels to close the lower ends.

16. The apparatus according to claim 1, wherein the lower open end of each of the plurality of vessels beneath a filter is closed by an openable lower closure to assist in retention of liquid within the vessel above the filter.

17. The apparatus according to claim 16, wherein the lower closure is in the form of a plug which can fit closely into the lower open end of the vessel.

18. The apparatus according to claim 17, wherein lower closures are provided supported in an array corresponding to the arrangement of the array of the plurality of vessels.

19. The apparatus according to claim 18, wherein the array of closures is supported upwardly extending from a base support which may be positioned beneath the lower open ends of the array of the plurality of vessels, with each of the lower closures in register with the corresponding open ends, and the base support and array of vessels moved longitudinally relatively together so that the lower closures enter the lower open ends of the vessels to close the lower ends.

20. The apparatus according to claim 19, wherein the lower closure and/or the base support have an upper surface which, when the lower closure is closed or in place at the lower ends of the vessel, is in contact with the lower surface of the filter.

21. The apparatus according to claim 19, wherein the upper end of the lower closure and/or base support are in the form of a support for a piston on which a piston may be removably seated.

22. The apparatus according to claim 21, wherein the lower surface of the piston comprises a concavity and the upper end of the lower closure is correspondingly convex so as to be able to mate with the concavity.

23. The apparatus according to claim 22, wherein the piston is supported on the base support, and the base support while supporting the piston is positioned beneath the lower open ends of the array of the plurality of vessels, with the piston in register with the corresponding open end, and the base support and the array of the plurality of vessels moved longitudinally relatively together so that the piston enters the lower open end of the corresponding vessel and moves to a suitable location within the vessel, and the lower closure closes the lower end of the vessel.

24. The apparatus according to claim 1, wherein an array of receptacles are correspondingly positioned beneath the filters to receive liquid after it has flowed through the filters.

25. The apparatus according to claim 24, wherein a liquid guide is located between the lower surface of the filter and the receptacle to guide liquid into the receptacle.

26. The apparatus according to claim 24, wherein the vessels are tubular vessels with internal sliding pistons with filters, and the array of receptacles is moveable to push the pistons upwardly relative to the vessels to thereby compress liquid in the vessels above the pistons and force the liquid through the filters and into the receptacles.

27. The apparatus according to claim 26, wherein each of the receptacles has an external cross-section which is smaller than the internal cross-section of the lower open end of the vessels so that the upper end of each of the receptacles may be inserted into the lower open end of each corresponding vessel, the vessels and the receptacles may then be moved relatively longitudinally together so that the upper ends of the receptacles can push the piston upwardly relative to the vessels.

28. The apparatus according to claim 27, wherein the vessels each have a cylindrical internal profile and the receptacles each have a smaller cylindrical external profile, so that the receptacles can fit in a telescoping manner within the vessels.

29. A method for using an apparatus for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom, the method comprising:

providing an array of a plurality of tubular vessels with an internal cylindrical profile, each of the plurality of tubular vessels having an upper closable open end and a lower closeable open end with an up-down longitudinal axis between the ends;

positioning an array of a plurality of lower closures supported upwardly extending from a base support, each of the plurality of lower closures removeably supporting at its upper end a piston, with a filter, below the array of the plurality of tubular vessels and in register with the corresponding open end of a vessel; moving the base support with its array of lower closures and pistons, and the array of vessels longitudinally relatively together so that the pistons enter the lower open ends of the vessels and move to a suitable location within the vessels, and so that the lower closures close the lower ends of the vessels;

introducing reagents into the vessels via the upper ends to provide a liquid phase within the vessels;

moving the base support with its array of lower closures and the array of vessels longitudinally relatively apart so that the lower closures are removed from the lower open ends of the vessels, but retaining the pistons in their location within the vessels;

inserting an array of receptacles with an external cylindrical cross-section which is smaller than the internal cross-section of the lower open ends of the vessels, so that upper ends of the receptacles fit into the lower open ends of the vessels, so that the upper ends of the receptacles are brought into contact with the lower surfaces of the pistons, and so that the upper ends of the receptacles are positioned beneath the lower open ends of the vessels;

bringing the array of vessels and the array of receptacles longitudinally together so that the upper ends of the receptacles enter the lower open ends of the vessels and further longitudinal movement of the vessels and the receptacles telescopingly together causes the upper ends of the receptacles to push the pistons upwardly relative to the vessels to thereby compress liquid in the vessels above the pistons and force the liquid through the filters and into the receptacles; and

collecting precipitate which has been formed on the upper surfaces of the filters as the liquid phase flows downwardly through the filters.

30. The method according to claim 29, wherein, after the precipitate which has been formed on the upper surfaces of the filters as the liquid phase flows downwardly through the filters has been collected, the array of receptacles is removed from the lower ends of the vessels.

31. The method according to claim 29, wherein the upper ends of the vessels are opened after the precipitate which has been formed on the upper surfaces of the filters as the liquid phase flows downwardly through the filters has been collected to provide access to the precipitate.

32. The method according to claim 29, wherein the pistons with filters carrying the collected precipitate are removed from the vessels after precipitate has been collected thereon.

33. The method according to claims 29, wherein the pistons are pushed upwardly far enough in the tubular vessels so that the precipitate may be examined or further processed in situ with the pistons in place in the tubular vessels.

34. The method according to claim 29, wherein respective different reagents, different concentrations of reagents, or different quantities of reagents are introduced into respective different vessels in the array.

35. A method for using an apparatus for forming a solid precipitate of a substance in a liquid phase and isolating the precipitate therefrom, the method

comprising:

providing a plurality of vessels, each vessel having an upper closable open end and a lower open end with an up-down longitudinal axis between the ends, the vessels being supported and arranged in an array in a plane transverse to the longitudinal axis direction with their longitudinal axis directions in parallel, wherein each vessel has a porous filter located therein to obstruct downward flow from the vessel, the filters being capable of allowing liquid to flow downwardly therethrough but capable of retaining formed precipitate thereon;

introducing reagents into each of the plurality of vessels via the upper ends to provide a liquid phase within each vessel; and

applying a positive atmospheric pressure to liquid in each vessel above the filter to thereby create a pressure differential across the filter such that there is a higher pressure above the filter which forces liquid in the vessels above the filter through the filter.

36. The method according to claim 35, wherein the positive atmospheric pressure is applied by providing each vessel with a puncturable closure and introducing a pressurized gas into the volume of the vessel above the liquid therein via a hollow needle inserted through the closure.