WO2011044582A1

WO2011044582A1 - Apparatus for making crystals

Info

Publication number: WO2011044582A1
Application number: PCT/US2010/052354
Authority: WO
Inventors: David Harlan Igo; Stephen Aaron Relayo Carino
Original assignee: R.P. Scherer Technologies, Llc
Priority date: 2009-10-09
Filing date: 2010-10-12
Publication date: 2011-04-14

Abstract

An apparatus is used to make crystals and a related process for making crystals uses the apparatus.

Description

TITLE

APPARATUS FOR MAKING CRYSTALS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61/250,179, filed October 9, 2009, the contents of which are hereby incorporated by reference as if fully stated herein.

Field of the Invention

[0002] This invention relates to an apparatus for making crystals and to a process for making crystals using the apparatus.

BACKGROUND

[0003] It is a common process in chemistry, for example, pharmaceutical chemistry, 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 solution whilst leaving impurities in solution. Another reason is that the crystalline state is a

thermodynamically stable state in which a substance in crystalline form can remain relatively stable. 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, rate of crystallization, etc. for obtaining crystals of optimum purity, size or shape, or in the case of substances which crystallize in different crystal forms, achieving a desired form. Many methods are known for making crystals. One method is to allow a hot saturated solution of the substance to cool so that the solubility of the substance in the cooler solvent becomes less. Another method is the addition of an anti- solvent to the solution to reduce the solubility of a substance and so cause precipitation of crystals. A common method is to allow solvent to evaporate from a solution of the substance, and for this method an open-topped vessel such as a crystallizing dish has been used in the past. However, the use of such vessels can leave the crystals as a crust which needs to be scraped off for further examination or experimentation. In modern chemistry, particularly pharmaceutical chemistry, there is a particular need to provide high throughput screening of crystallization process, so that the above- mentioned investigations may be performed rapidly.

[0004] There is a further need to provide such processes in a way in which the crystallization process itself or further investigation of the resulting product can be easily automated.

[0005] Various apparatus to automate crystallization processes and/or high throughput screening processes are known. For example, U.S. Patent No.

6,726,765 discloses an apparatus in which a vessel is rotated and antisolvent vapor is caused to slowly diffuse into a solution of a substance to be crystallized. U.S. Patent No. 6,939,515 and WO 2004/000452 disclose apparatus for high throughput crystallographic screening.

[0006] It is an object of this invention to provide an apparatus and a process using this apparatus for providing crystals of a substance from solution, which, in part, addresses these needs and problems. Other objects and advantages of the invention will be apparent from the following.

SUMMARY OF THE INVENTION

[0007] According to this invention, an apparatus for making crystals of a substance from a solution of the substance dissolved in a solvent comprises: at least one vessel for holding the solution of the substance, each vessel having an upper opening through which vapor of the solvent can pass, and a lower closed bottom with an up-down axis direction between the upper opening and the lower closed bottom, the upper opening obstructed by a porous membrane having a lower surface exposed to the interior of the vessel and an opposite upper surface exposed to an atmosphere outside of the vessel, the porous membrane being capable of allowing the solution to permeate the membrane from the lower toward the upper surface and to evaporate into the atmosphere therefrom; and a means to rotate the at least one vessel about a rotation axis transverse to the up- down axis direction between upright and inverted orientations of the at least one vessel, such that, in an inverted orientation of the at least one vessel, solution therein contacts and permeates the porous membrane and, when the at least one vessel subsequently returns to the upright orientation, the solution, or a portion thereof, flows back to the bottom of the at least one vessel.

[0008] The present invention also provides a method of making crystals of a substance from a solution of the substance dissolved in a solvent using such an apparatus, the method comprising the steps of: containing a solution of the substance in at least one vessel, each vessel having an upper opening, through which vapor of the solvent can pass, and a lower closed bottom with an up-down axis direction between the upper opening and the lower closed bottom, the upper opening being obstructed by a porous membrane having a lower surface exposed to the interior of the vessel and an opposite upper surface exposed to an atmosphere outside of the vessel, the porous membrane being capable of allowing the solution to permeate the membrane from the lower to the upper surface and to evaporate into the atmosphere therefrom; rotating the at least one vessel about a rotation axis transverse to the up-down axis direction between upright and inverted orientations of the vessel such that, in an inverted orientation of the at least one vessel, solution therein contacts and permeates the porous membrane and, when the at least one vessel subsequently returns to the upright orientation, a portion of the solution flows back to the bottom of the at least one vessel; and allowing the solution retained by the membrane and exposed to the atmosphere to evaporate from the upper surface into the atmosphere so that crystals of the substance are formed. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Fig. 1 shows a dissembled view of part of an apparatus of this invention.

[0010] Fig. 2 shows a schematic cross-section view through the part shown in Fig. 1.

[0011] Fig. 3 shows a perspective view of an apparatus of this invention.

[0012] Fig. 4 shows the operation of the apparatus.

[0013] Fig. 5 shows a schematic cross-section view through another form of part of the apparatus of this invention.

[0014] Fig. 6 shows an alternative form of vessels for the apparatus of this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The first embodiment of the invention is directed to an apparatus for making crystals of a substance from a solution of the substance dissolved in a solvent comprises: at least one vessel for holding the solution of the substance, each vessel having an upper opening through which vapor of the solvent can pass, and a lower closed bottom with an up-down axis direction between the upper opening and the lower closed bottom, the upper opening obstructed by a porous membrane having a lower surface exposed to the interior of the vessel and an opposite upper surface exposed to an atmosphere outside of the vessel, the porous membrane being capable of allowing the solution to permeate the membrane from the lower toward the upper surface and to evaporate into the atmosphere therefrom; and a means to rotate the at least one vessel about a rotation axis transverse to the up-down axis direction between upright and inverted orientations of the at least one vessel, such that, in an inverted orientation of the at least one vessel, solution therein contacts and permeates the porous membrane and, when the at least one vessel subsequently returns to the upright orientation, the solution, i.e., the portion of the solution that is not retained by the porous membrane, flows back to the bottom of the at least one vessel.

[0016] The related second embodiment of the present invention is directed to a method of making crystals of a substance from a solution of the substance dissolved in a solvent using such an apparatus, the method comprising the steps of: containing a solution of the substance in at least one vessel, each vessel having an upper opening, through which vapor of the solvent can pass, and a lower closed bottom with an up-down axis direction between the upper opening and the lower closed bottom, the upper opening being obstructed by a porous membrane having a lower surface exposed to the interior of the vessel and an opposite upper surface exposed to an atmosphere outside of the vessel, the porous membrane being capable of allowing the solution to permeate the membrane from the lower to the upper surface and to evaporate into the atmosphere therefrom; rotating the at least one vessel about a rotation axis transverse to the up-down axis direction between upright and inverted orientations of the vessel such that, in an inverted orientation of the at least one vessel, solution therein contacts and permeates the porous membrane and, when the at least one vessel subsequently returns to the upright orientation, a portion of the solution flows back to the bottom of the at least one vessel; and allowing the solution retained by the membrane and exposed to the atmosphere to evaporate from the upper surface into the atmosphere so that crystals of the substance are formed. As the solution permeates the membrane, it passes through to the upper surface of the membrane and evaporates from this upper surface into the atmosphere so that crystals of the substance are formed. Crystals suitably form on the upper surface of the membrane.

[0017] The rotation of the vessel can control the rate at which solution reaches this upper surface and consequently the rate at which evaporation of solvent occurs.

[0018] The at least one vessel is suitably elongate about its up-down axis direction and, for example, may be cylindrical. The at least one vessel may, for example, comprise a cavity in a block of material, for example, in a block of glass, a polymer material such as PTFE, or a metal which is inert to the solvent, substance and solution. Alternatively the at least one vessel may comprise a discrete vessel such as a glass or polymer vial. For example, a suitable volume of the vessel is about 0.5 to about 2.0 ml, more preferably, about 1 to about 1.5 ml. The upper opening of the at least one vessel may, for example, be circular and may, for example, be the same cross-section as that of a cylindrical vessel.

[0019] Suitably for high throughput, plural vessels may be used, suitably all of the same size and shape. For example, plural vessels may comprise plural cavities in a block. For example, plural vessels may comprise plural discrete vessels supported in a rack. Plural vessels are suitably arranged in a regular array, for example, in an array format corresponding to the position and spacing of arrays handled by standard liquid manipulation apparatus. Typically this may be a standard 96 well, e.g., 12 x 8 vessel rectangular array format. Suitably such an array, e.g., a 12 x 8 array may conform to the standard dimensions for microtiter plates as recommended by The Society of Biomolecular Screening.

[0020] The porous membrane may be made of any suitable material into which the solution may permeate and from which the solvent may evaporate, and which is inert to the solvent, solution and substance. Typical materials include fabric or compacted fiber materials, sintered materials such as porous polymers, and, in particular, a fine stainless steel mesh, e.g. a 2 micron steel mesh. For example, when plural vessels are used arranged in an array, a membrane support may support plural porous membranes in a corresponding array. Such a membrane support may comprise a mask of a suitable material pierced with apertures in an array corresponding to the array of vessels, and a porous membrane obstructing each aperture. Such a membrane support may be positioned adjacent the upper end of each vessel, such that its apertures are in communication with the corresponding upper open end of a vessel. Suitable dimensions, e.g., area, pore size and thickness for such a porous membrane may be determined

experimentally for any particular combination of substance and solvent.

[0021] Stainless steel provides the advantage that it is inert, "invisible", to the laser radiation used in Raman spectroscopy. Therefore, Raman spectroscopy can be used to analyze crystals in situ on such a stainless steel mesh. Furthermore, the apparatus of the invention allows the crystals formed by evaporation to accumulate on the surface of the membrane thereby improving the strength of the Raman signal relative to the background noise. [0022] Optionally, above the upper surface of the membrane may be positioned a constriction to further control the rate of evaporation of the solvent from the solution by reducing the rate at which solvent vapor can escape from the membrane. Such a constriction may comprise a mask having an aperture therethrough of smaller cross-section than the porous membrane. Such a mask may be placed adjacent to the upper surface of the membrane so that the aperture is in communication with the opening of the vessel through the membrane.

[0023] An assembly of one or plural vessels, an optional rack, a porous membrane and optional constriction may be held together for use by means of suitable clamps, etc. For example, such an assembly of one or plural vessels, an optional rack, a porous membrane and optional constriction may be supported in a frame comprising a lower base support and an upper support, with the assembly sandwiched between the base support and an upper support. Suitably this is under a suitable compression to prevent leakage of solvent. Leakage of solvent may also be prevented by means of optional compressible gaskets, "O" rings, etc. between, for example, the opening of the vessel and the porous membrane. Such an assembly may also incorporate one or more guide members to maintain components of the assembly in a suitable orientation. For example, if there are plural vessels being vials, the assembly may incorporate a vial guide to hold the vials in a suitable orientation.

[0024] The means to rotate the at least one vessel about a rotation axis transverse to the up-down axis direction between upright and inverted orientations of the vessel such that in an inverted orientation of the vessel, solution therein contacts and permeates the porous membrane, and when the vessel subsequently returns to the upright orientation, a portion of the solution flows back to the bottom of the vessel, may comprise a conventional electric motor with a drive shaft

communicating rotary force to the vessel.

[0025] Conveniently, if the vessel is supported in the above-described frame, the drive shaft of such an electric motor may communicate rotary force to the frame, so that the vessel, porous membrane, etc. rotates correspondingly.

[0026] The means to rotate the at least one vessel and/or the balance of the assembly of frame, vessel(s), etc. may be set that the default position is with the vessel(s) in the upright position. With such a setting, if the motor or electric power fails, liquid is not likely to be lost by spillage.

[0027] The apparatus may include means to control the temperature within the vessel(s), for example, a generally conventional heating jacket or, for example, an assembly of vessel(s) etc. in the above-mentioned frame may be located within a temperature controlled environment.

[0028] The apparatus may further comprise a control system constructed to rotate the vessel(s) at a suitable speed (e.g., to avoid centrifugal retention of solution against the lower surface of the membrane) and for a suitable time, and to maintain a suitable temperature. The control system may be adapted to cause the means to rotate the at least one vessel to rotate in any selected rotation mode. For example, the control system may be constructed to provide uniform continuous circular rotation or, for example, a pulsed inversion mode, in which the vessel is held for a dwell time in the inverted orientation then rotated back into the upright orientation for a dwell time in the upright configuration before rotating it into the inverted configuration, then repeating this sequence. The control system may include a timer so that a suitable time period of rotation may be set. Motors are available with a built-in programmable control system enabling suitable rotation regimes to be set without the need for an external control system.

[0029] The atmosphere outside of the vessel into which the solvent evaporates may be ambient air. Alternately the atmosphere may be an atmosphere of, for example, controlled composition such as an inert gas such as nitrogen, controlled pressure, humidity or temperature. Such an atmosphere may be maintained under the control of the control system inside a closed enclosure.

[0030] In the process of the invention, suitable solvents include any volatile solvent which can dissolve the substance to be crystallized and evaporate to deposit crystals of the substance. Suitable solvents for any particular compound will be apparent to those skilled in the art. Examples of such solvents include water, acetonitrile, 2-propanol and tetrahydrofuran. Preferably the solution of the substance in the solvent is saturated. [0031] The process may be operated at ambient temperature, or a temperature elevated, or reduced relative to ambient temperature.

[0032] The process may be operated under an ambient air atmosphere or under a protective or inert atmosphere such as nitrogen. The process may be performed under ambient humidity but is suitably operated with the apparatus inside a typical laboratory "dry box", for example, a sealed enclosure with its interior kept as water-free as possible by means of a desiccant within the enclosure. The process may be operated with a static atmosphere, but is preferably operated under an atmosphere which is flowing, to assist removal of vapor of the solvent as it evaporates.

[0033] In the process of the invention, the vessel may be rotated in various rotation modes. An example of such a mode is uniform continuous circular rotation. Another mode is pulsed inversion mode, in which the vessel is held for a dwell time in the inverted orientation then rotated back into the upright orientation for a dwell time in the upright configuration before rotating it into the inverted configuration, then repeating this sequence. Other modes of rotation may be appropriate for different solvents, substances and solutions. Such modes of rotation may be set by the control system of the apparatus. Uniform continuous circular motion may be used to achieve a relatively fast evaporation, whereas pulsed inversion mode may be used to achieve relatively slow evaporation.

[0034] In the method of the invention, after crystals have been formed on the porous membrane, the apparatus may be dissembled, and the formed crystals may be further investigated in situ on the surface of the membrane, e.g., by

microscopy, particularly polarized light microscopy, or by spectroscopy, in particular Raman spectroscopy. In the method of the invention, the use of a stainless steel porous membrane is advantageous as steel does not rotate plane- polarized light and appears black when examined using polarized light microscopy, making a contrast background for crystals, and steel exhibits negligible fluorescence background and is "invisible" to Raman spectroscopy.

[0035] The invention will now be described by way of example only with reference to the accompanying drawings. [0036] Referring to Figs. 1 and 2, an apparatus of the present invention is shown. In Fig. 2 clearances between parts are exaggerated for clarity. This comprises a plastics material rack 11 which is subdivided into plural compartments arranged in a 12 x 8 rectangular array, each compartment being able to contain and support a standard 1.2 ml glass vial, such as those shown 12, in a vertical orientation. Each vial 12 is generally cylindrical, with an open upper end 12A and a rounded lower closed end 12B.

[0037] The rack 11 is supported on a stainless steel base support 13 in the form of a stainless steel plate with a recessed mounting position 14 for the rack 11.

[0038] The apparatus further comprises a vial guide 15 in the form of a rectangular stainless steel plate pierced with apertures 16 through which the upper ends 12A of vials 12 supported in rack 11 may pass to thereby hold the vials 12 securely in an upright orientation. The vial guide 15 is provided with side flaps 17 along each of its four sides which can friction fit against corresponding sides of the rack 11 to hold the vial guide 15 securely in place on rack 11.

[0039] The apparatus further comprises a membrane support 18. This comprises a plate-form mask, pierced with an array of apertures 19. When the membrane support 18 is in place above the array of vials 12 in rack 11, each of the apertures 19 is above the open end of a corresponding vial 12. Each of the apertures 19 is obstructed by a porous membrane 21 (not shown in Fig.l) being a 2 micron pore size stainless steel frit. Each porous membrane 21 has an upper surface 21A exposed to the atmosphere outside the vial 12, and a lower surface 21B exposed to the interior of the vial 12. The membranes 21 are a friction fit in the apertures 19.

[0040] The apparatus further comprises an upper support 110, in the form of a stainless steel plate pierced with openings 111. When the upper support 110 is in place above the membrane support 18, each of the openings 111 is above an aperture 19 in the membrane support 18, and hence in communication via the porous membrane (not shown) with the open end 12A of a corresponding vial 12. The upper support 110 is provided with threaded bolts 112 extending from its lower surface 110A, which when the upper support is in place, pass through corresponding holes 113 in the base support 13 to thereby enable the assembly of rack 11, vial guide 15, membrane support 18 and upper support 110 to be fastened securely together under sufficient compression to prevent leakage of liquid from the vials 12.

[0041] A gasket (not shown) or individual "O" rings 114 are positioned between the upper end of the vials 12 and the membrane support 18 to improve the seal between the vials 12 and support 18, in a generally conventional manner. The "O" rings 114 serve as a gasket between the vials 12 and the membrane support 18.

[0042] Referring to Fig. 3, an assembly of base support 13, rack 11 including vials 12 (not shown), vial guide 15, membrane support 18 and upper support 110, held together by bolts 112 is designated generally 30 in Fig. 3. The assembly 30 is connected by conventional connector 31 to the drive shaft 32 of rotary electric motor 33 mounted on stand 34. Electric power is supplied to motor 33 and the operation of the motor 33 is controlled by a control unit (not shown). It is seen that the rotation axis of the drive shaft 32 is perpendicular to the up-down direction of the vials 12 within rack 11.

[0043] Typically the control unit can control motor 33 to run in continuous rotation mode or in pulsed inversion mode. Typically the control unit allows user to specify rotation speed and time of inversion. This can be done by selecting a desired program on the control unit, typically for evaporation conditions in both fast and slow evaporation experiments. The control unit can also control the flow of an atmosphere such as nitrogen through an enclosure enclosing the assembly 30. For example, the control system may enable the motor 33 to turn the assembly 30 through 180° from an upright to an inverted mode, to hold the assembly inverted for a set time such as between one second and twenty minutes, then return the assembly through 180° from the inverted mode to the upright mode. The control unit may enable the user to set an automatic stop time for an experiment, for example, between one second and several days, or alternatively the control unit may enable manual shut down. The control system may be set up to inform the user of the status and/or progress of an experiment and to store information about the experiment in a defined location. [0044] Referring to Figs. 4A-4C, these show schematically how the process of the invention functions. The numbering system of Fig. 2 is used, and a single vial 12 is shown. In Fig. 4A the vial 12 is shown in its upright orientation, with its open upper end 12A uppermost, its lower closed end 12B lowest, and its up-down axis vertical. The vial 12 is of ca. 1.2 ml capacity and contains a saturated solution 41 of a substance dissolved in a solvent. In Fig. 4B the vial 12 has been rotated by motor 33 into its inverted orientation, with its lower closed end 12B uppermost, its open upper end 12A lowest, and its up-down axis vertical but inverted. The solution 41 has flowed under gravity to the upper end 12A of vial 12 and has permeated the stainless steel frit 21. In Fig. 4C the vial 12 has been rotated from the orientation shown in Fig. 4B and restored back into its upright orientation, with its open upper end 12A uppermost, its lower closed end 12B lowest, and its up-down axis vertical. The saturated solution 41 which has permeated through frit 21 has evaporated from the upper surface 21 A of the frit, to leave a deposit of crystals 42 on the upper surface 21 A of the frit 21. This sequence of inversion and restoration is repeated until a sufficient amount of crystals 42 have been formed on the upper surface 21 A of frit 21. Thereafter the assembly 30 can be dissembled, and the crystals 42 can be investigated, e.g., in situ by polarized light microscopy and by Raman spectroscopy. The 12x8 array format of the frits 21 facilitates easy automated investigation by laboratory instruments adapted to work with this format.

[0045] In a preferred apparatus of this invention, parts of the apparatus have the following specifications.

[0046] "0"-rings (where used) - supplied by Anchor Rubber Products: AS568- 008 SZ485 O-Ring

[0047] Stainless steel frits - supplied by Chand Eisenmann Metallurgical, 258 Spielman Highway, Burlington, CT 06013 - provided in the form of porous disc: 0.249"+/-0.0005" OD x 0.031 +/-0.003" thick (= 6.325 mm +/-0.0127 mm OD x 0.787mm +/-0.076mm) - Porous Grade: 2 Micron Grade - Porous Material: 316L Stainless Steel

[0048] Upper & Lower Support, Vial Guide, Control System, hardware - supplied by Montec, Inc., 5241 Raynor Road, Garner, NC. [0049] Vials - supplied by VWR as KIT, ULPLATE, 1.2ML BLUE MAT Cat # 100532-832

[0050] A typical operation of the apparatus of this invention to perform the process of the invention is as follows:

[0051] Preparation of the porous membrane and support: The membrane support and porous membranes are inspected for contaminants, dust and wear. It is confirmed that the "0"-rings and frits are clean, intact and properly seated. A barcode label is affixed for subsequent identification.

[0052] Assembly: Filtered solutions are transferred to 1.2 ml glass vials. The vial rack is centered on the base support. The steel vial guide is placed on top, seating the vial lips snugly. The membrane support is gently placed on top of the vial guide. If performing slow evaporation, a constriction was positioned on top of the membrane support. The upper support is centered over the membrane support or the constriction respectively. The six bolt holes are aligned with the bolts and the bolts inserted. The bolts are made finger tight. Using a torque wrench, the bolts are tightened to no greater than 15 in-lbs, tightening in an alternating sequence to maintain the balance of stress on vials. Over tightening is avoided to avoid cracking the vials. The assembly is tested for leaks by inverting the rack for 30 seconds. The assembly is bolted to the motor and placed inside a dry box, insuring the assembly could spin freely inside the dry box. The lid of the dry box is closed.

[0053] Operation: The motor is operated to rotate the assembly in a continuous rotation mode or in a pulsed inversion mode. The control system allows the user to specify rotation speed and time of inversion. A desired program is selected on the control system and nitrogen flow is preferably established according to Table 1 below for the evaporation conditions in both fast and slow evaporation experiments.

Table 1.

Parameter Slow Fast

evaporation evaporation

Evaporation Time (d) >3 2-3 Inverted Time (s) 5 Not

applicable

Upright Time (s) 30 Not

applicable

Rotation Rate (rpm) 20 10

(continuous)

N2 flow rate (Lpm) 1 5

[0054] Disassembly and Analysis: Evaporation rates vary, based on the vapor pressure of the solvent. Typical fast evaporation times were 2-4 days. Typical slow evaporation times were 7-21 days. The upper surfaces of the frits are observed for crystals. If the desired yield had been achieved, the rotation program is stopped, and the assembly righted itself in the upright orientation. The dry box is opened and the assembly is removed. The assembly is unbolted and moved to a fume hood. The retainer bolts are unscrewed and the upper support carefully removed. In some cases, crystals may be in contact with the upper support and care should be taken to avoid cross -contamination. The membrane support is carefully removed from vial rack, and both upper and lower surfaces are inspected for crystals before handling.

[0055] Cleaning the Membrane Support and Membranes: All tapes, barcodes and other gummy substances were removed with solvent. The support and membranes are soaked in an appropriate solvent to remove most of contaminant. All frits and O-rings are removed, and frits are discarded. The "O" rings are cleaned in methanol or other appropriate solvent (DMSO, toluene and other solvents known to soften rubber are avoided). The membrane support is sonicated, and if necessary, stood in warm detergent solution or other solvent before inspection for contamination and wear and to make sure that the frit holes are not overly worn. New 2μιη frits are fitted and inspected for good fit, and clean O-rings are inserted. The membrane support was stored in a dust-free environment.

[0056] Referring to Fig. 5, this shows a cross-section through an alternative form of the assembly 30. It will be seen that the construction is identical to Fig. 2, except that adjacent to the upper surface of the membrane support 18 and its porous membranes 21 is positioned a constriction 51 to further control the rate of evaporation of the solvent from the solution by reducing the rate at which solvent vapor can escape from the membrane 21 to facilitate slow evaporation. The constriction 51 comprises a PTFE plate mask having apertures 52 therethrough of smaller cross-section than the underlying apertures 19. The constriction 51 is placed in contact with the upper surface of the membrane support 18 so that the apertures 52 are in communication with the opening of the vials through the membranes 21.

[0057] Referring to Fig. 6, this shows a cross-section through an alternative construction of vessels for the apparatus of this invention. As shown in Fig. 6, plural vessels 61 are provided as cavities in a block of a polymer material such as PTFE which is inert to the solvent, substance e and solution to be used.

EXAMPLE 1

[0058] A three-day evaporative crystallization experiment was performed with succinylsulfathiazole, a test compound with several well-documented crystalline forms and solvates. Three different solvents were used: acetonitrile, 2-propanol, and tetrahydrofuran. Raman spectroscopy of crystals formed using the process of this invention yielded good quality data that verified the successful generation of the expected succinylsulfathiazole crystal forms on the frits. Advantageously the crystals were birefringent while the steel frits were opaque, so under polarized light microscopy the crystals showed up white against a black steel background. Spectral data showed a good level of correlation between crystalline

succinylsulfathiazole grown on the frits using the process of this invention, and crystals formed using traditional evaporation.

Claims

WHAT IS CLAIMED IS:

1. An apparatus for making crystals of a substance from a solution of the substance dissolved in a solvent, comprising:

at least one vessel for holding the solution of the substance, each vessel having an upper opening through which vapor of the solvent can pass, and a lower closed bottom with an up-down axis direction between the upper opening and the lower closed bottom, the upper opening being obstructed by a porous membrane having a lower surface exposed to the interior of the vessel and an opposite upper surface exposed to an atmosphere outside of the vessel, the porous membrane being capable of allowing the solution to permeate the membrane from the lower to the upper surface and to evaporate into the atmosphere therefrom; and

a means to rotate the at least one vessel about a rotation axis transverse to the up-down axis direction between upright and inverted orientations of the at least one vessel, such that, in an inverted orientation of the at least one vessel, solution therein contacts and permeates the porous membrane and, when the at least one vessel subsequently returns to the upright orientation, a portion of the solution flows back to the bottom of the at least one vessel.

2. The apparatus according to claim 1, wherein the at least one vessel is elongate about its up-down axis direction.

3. The apparatus according to claim 2, wherein the at least one vessel is cylindrical.

4. The apparatus according to claim 1, wherein the at least one vessel comprises at least one cavity in a block of material.

5. The apparatus according to claim 1, wherein the at least one vessel comprises at least one glass or polymer vial.

6. The apparatus according to claim 5, wherein plural vials are supported in a rack.

7. The apparatus according to claim 6, wherein vials are arranged in a regular rectangular array format.

8. The apparatus according to claim 1, wherein the porous membrane comprises a stainless steel mesh.

9. The apparatus according to claim 1, wherein plural vessels are used arranged in an array, and a membrane support supports plural porous membranes in a corresponding array.

10. The apparatus according to claim 9, wherein the membrane support comprises a mask of a material pierced with apertures in an array corresponding to the array of vessels, and a porous membrane obstructs each aperture.

11. The apparatus according to claim 1, wherein adjacent to the upper surface of the membrane is positioned a constriction to control the rate of evaporation of the solvent.

12. The apparatus according to claim 11, wherein the constriction comprises a mask having an aperture therethrough of smaller cross-section than the porous membrane.

13. The apparatus according to claim 1, wherein an assembly of one or more vessels, an optional rack, a porous membrane and optional constriction is supported in a frame comprising a lower base support and an upper support, with the assembly sandwiched between the lower base support and the upper support.

14. The apparatus according to claim 13, wherein the assembly also incorporates one or more guide members to maintain components of the assembly in a suitable orientation.

15. The apparatus according to claim 14, wherein one or more guide members comprise a vial guide to hold plural vials in a suitable orientation.

16. The apparatus according to claim 1, wherein the means to rotate the vessel about a rotation axis transverse to the up-down axis direction between upright and inverted orientations of the vessel comprises an electric motor with a drive shaft communicating rotary force to the vessel.

17. The apparatus according to claim 16, wherein the drive shaft of an electric motor communicates rotary force to the frame, so that the assembly rotates correspondingly.

18. The apparatus according to claim 1, wherein the means to rotate the at least one vessel and/or the balance of the assembly is set that the default position is with the at least one vessel in the upright position.

19. The apparatus according to claim 1 further comprising including means to control the temperature within the at least one vessel.

20. The apparatus according to claim 1 further comprising a control system constructed to rotate the at least one vessel at a suitable speed and for a suitable time, and to maintain a suitable temperature.

21. The apparatus according to claim 1, wherein the control system is constructed to provide uniform continuous circular rotation and/or a pulsed inversion mode, in which the vessel is held for a dwell time in the inverted orientation then rotated back into the upright orientation for a dwell time in the upright configuration before rotating it into the inverted configuration, then repeating this sequence.

22. A method of making crystals of a substance from a solution of the substance dissolved in a solvent, the method comprising the steps of:

containing a solution of the substance in at least one vessel, each vessel having an upper opening, through which vapor of the solvent can pass, and a lower closed bottom with an up-down axis direction between the upper opening and the lower closed bottom, the upper opening obstructed by a porous membrane having a lower surface exposed to the interior of the vessel and an opposite upper surface exposed to an atmosphere outside of the vessel, the porous membrane being capable of allowing the solution to permeate the membrane from the lower to the upper surface and to evaporate into the atmosphere therefrom;

rotating the at least one vessel about a rotation axis transverse to the up- down axis direction between upright and inverted orientations of the at least one vessel, such that, in an inverted orientation of the at least one vessel, solution therein contacts and permeates the porous membrane and, when the vessel subsequently returns to the upright orientation, a portion of the solution flows back to the bottom of the vessel; and

allowing the solution retained by the membrane and exposed to the atmosphere to evaporate from the upper surface into the atmosphere so that crystals of the substance are formed.

23. The method according to claim 22, wherein the rotation of the at least one vessel is used to control the rate at which solution reaches this upper surface.

24. The method according to claim 22, wherein the solvent is a volatile solvent which can dissolve the substance and evaporate to deposit crystals of the substance.

25. The method according to claim 24, wherein the solvent is selected from water, acetonitrile, 2-propanol, tetrahydrofuran, and combinations thereof.

26. The method according to claim 22, wherein the solution of the substance in the solvent is saturated.

27. The method according to claim 22, wherein the method is performed under an atmosphere which is flowing to assist removal of vapor of the solvent as it evaporates.

28. The method according to claim 22, wherein the at least one vessel is rotated in uniform continuous circular rotation.

29. The method according to claim 22, wherein the at least one vessel is rotated in pulsed inversion mode, in which the vessel is held for a dwell time in the inverted orientation then rotated back into the upright orientation for a dwell time in the upright configuration before rotating it into the inverted configuration, then repeating this sequence.

30. The method according to claim 22, wherein, after crystals have been formed on the porous membrane, the crystals are investigated in situ on the surface of the porous membrane.