Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00281—Individual reactor vessels
  • B01J2219/00286—Reactor vessels with top and bottom openings
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
  • B01J2219/00315—Microtiter plates
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00331—Details of the reactor vessels
  • B01J2219/00333—Closures attached to the reactor vessels
  • B01J2219/00344—Caps
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00351—Means for dispensing and evacuation of reagents
  • B01J2219/00364—Pipettes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00351—Means for dispensing and evacuation of reagents
  • B01J2219/00423—Means for dispensing and evacuation of reagents using filtration, e.g. through porous frits
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00477—Means for pressurising the reaction vessels
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00495—Means for heating or cooling the reaction vessels
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00585—Parallel processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00599—Solution-phase processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00702—Processes involving means for analysing and characterising the products
  • B01J2219/00707—Processes involving means for analysing and characterising the products separated from the reactor apparatus
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/0072—Organic compounds
  • B01J2219/00725—Peptides
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/00756—Compositions, e.g. coatings, crystals, formulations

Definitions

• High-throughput screening is a technique used in a variety of fields including drug discovery. It is a process in which a large number of compounds are tested at one time for interaction with a specific target. Examples of interactions include various types of binding and biological activity against a target. Sophisticated systems can screen over 100,000 compounds per day, allowing for a fast way to eliminate compounds that are not potential drug candidates. Similar high throughput techniques are used in systems where an experimental design can be performed to evaluate the effects of the variables on one or more specific characteristics.
• polymorphism is used to refer to this phenomenon and has been found to be increasingly important in catalytic, cosmetic, pharmaceutical and other applications.
• Drug research and development greatly depends on which polymorph of a drug substance is being used in the process because polymorphs of a substance can exhibit varying physical properties. Such varying properties may include: 1. Solubility 2. Melting point 3. Dissolution rate 4. Chemical Stability 5. Physical Stability 6. Powder flowability 7. Compaction 8. Particle Morphology 9. Hygroscopic behavior
• WO 02/20538 also teaches an unexpected finding of a way to produce a polymorph with a high level of purity by controlling the amount of water in the solvent.
• WO 01/82659 specifically discloses a system and method for the high- throughput screening of polymorphs.
• the system is comprised of an X-ray source which can emit a beam.
• An automatic sample changer allows for each sample to be positioned in the path of the beam. Once the sample is irradiated, a detector is used so the sample can be analyzed further. The automatic sample changer then removes the sample and inserts a new one in the path of the beam.
• One embodiment of the present invention provides a method for screening polymorphs of a desired substance.
• the steps of this method embodiment comprise: (i) providing a plurality of enclosed spaces; (ii) transferring the dispersions of the desired substance in at least one solvent into different enclosed spaces; and (iii) applying a compressed antisolvent to the enclosed spaces to solidify the desired substance.
• Another embodiment of the present invention provides an apparatus for the screening of polymorphs of a desired substance.
• the steps of this apparatus embodiment comprise: (i) a pluraHty of enclosed spaces; (ii) a means for transferring dispersions of the desired substance in at least one solvent into different enclosed spaces; and (iii) a means for applying a compressed antisolvent to the enclosed spaces to solidify the desired substance.
• FIG.l is a schematic representation of one embodiment of the present invention.
• FIG.2 illustrates the bottom cap of the battery of enclosed spaces referred to in the present invention
• FIG.3 illustrates the same element referred to in FIG.2 with a series of enclosed spaces
• FIG.4 illustrates another embodiment of the present invention with enclosed spaces taking any shape or form
• FIG.5 illustrates an embodiment of the present invention with antisolvent directly injected into the dispersion phase
• FIG. 6 is a schematic representation of one embodiment of the polymorph screening system which uses a compressed antisolvent
• FIG. 7 is a schematic representation of one embodiment of the polymorph screening system which uses a compressed antisolvent and a co- antisolvent;
• Different crystalline or non-crystalline structures of a solid material includes the amorphous form and various solvate, hydrate forms commonly referred to as pseudo polymorphs. Different polymorphs have different free energies associated with them.
• Polymorph screening means
• the material comprised of one or more substances of interest.
• End Space means A space enclosed by a metal or any other material.
• Antisolvent means
• a fluid that acts as a nonsolvent to a substance and crystallizes the substance acts as a nonsolvent to a substance and crystallizes the substance.
• Crystal identification means means
• Crystal identification means transparent material means
• Dispersant means A homogeneous or heterogeneous mixture of the desired substance in one or more suitable solvents with or without dispersants. Description
• the present invention provides a method and apparatus for screening polymorphs of a variety of substances in a reasonably rapid way.
• screening is used herein to mean “producing” and “producing and identifying” polymorphs of a variety of substances. It uses supercritical fluid technology as the basis for screening polymorphs.
• dispersions of a desired substance in various suitable solvents at various concentrations are prepared and transferred into several enclosed spaces which are capable of holding high pressures.
• a compressed antisolvent is added to the enclosed space either directly into the dispersion phase or near the dispersion phase at a controlled rate.
• the enclosed space already contains the compressed antisolvent prior to the transfer of the dispersion of the desired substance into the enclosed space.
• solidification of the desired substance can be varied. It will be obvious to one skilled in the art that the term “solidification” includes crystallization or precipitation of the desired substance. By controlling crystallization, different polymorphs are formed.
• the temperature of the enclosed spaces can be controlled by devices including, but not limited to, electric heaters, zone heaters or magnetic heaters.
• Crystal structure identification may be performed while the dispersion is being solidified, after the dispersion is solidified, after the enclosed space is depressurized, or after the solidified desired substance is removed from the enclosed space.
• at least one side of the enclosed space is made of crystal structure identification means transparent material.
• Fig. 1 illustrates an embodiment of the present invention. For representative reasons, four enclosed spaces are illustrated. It does not signify any limitation on the present invention. It can be 4, 8, 12, 96, 384, 864, 1536, or as many spaces as possible in any design. Typically, it can be defined by the automation available in crystal structure identification means and its ability to handle as many samples in an automated fashion. Enclosed spaces 1, 2, 3, 4 are capable of holding pressures up to 30,000 psi.
• Antisolvent inlets 5, 6, 7, 8 are provided with a one way check valve to ensure no fluid is moved out of the enclosed space in those inlet lines.
• Outlets 9, 10, 11 and 12 are provided for the antisolvent/ solvent mixture to exit the enclosed space.
• Filtering element 15 provides a way to retain the crystallized material in the enclosed space.
• Fig. 2 illustrates how bottom cap 14 and enclosed space wall 13 are attached and sealed using a high pressure seal 15. A high pressure seal is optional if the bottom cap is pressure fitted to the vessel.
• Fig. 3 illustrates the same in a configuration with four enclosed spaces.
• Fig. 4 illustrates an embodiment of the present invention in which the enclosed space can be in any shape. In a preferred embodiment, it is shown to be close to a spherical or spheroidal shape 1 with two split half spheres or spheroids pressed together with an optional high pressure seal. Crystallized material can be transferred either to a well plate designed for crystal structure identification means or a well plate designed to fit in the bottom half of the spheroids. In another embodiment of the present invention, the material can be crystallized directly onto the well plate. A crystal structure identification means that is coupled to the apparatus can then be used to analyze the material. The spheroids are connected together forming a structure that can be described in layman's terms similar to a carton of eggs.
• Dispersion droplet 2 can be placed in the well plates prior to closing the spheroidal enclosed space by several dispensing means.
• Commercially available dispensers like ROBBINS® HYDRA ® dispenser from Robbins Scientific Corporation, Sunnyvale, California can be used.
• the volume of the fluid can vary from fempto liter (lxlO 15 ) quantities to mflliliter quantities based on the dispensing means used and the availability of the dispersion. Certain solutes, such as new drug candidates, are very expensive and difficult to synthesize in large quantities. As a result, very small quantities need to be used.
• a dispensing means capable of dispensing fempto liter (lxlO- 15 ), pico liter (1x10 12 ) or nanoliter (lxlO- 9 ) quantities will be chosen.
• Antisolvent inlet 3 can add antisolvent directly into the dispersion droplet or just into the enclosed space. It has a check valve to ensure no reverse flow of any fluid.
• a high pressure seal 5 seals the two spheroids or spheroids and the well plate element to ensure no fluid leaks out.
• Exit 4 is fitted with a filtering element to retain the crystallized material inside the enclosed spaces.
• Fig. 5 illustrates an embodiment similar to the one in Fig. 4 except that the compressed antisolvent is added directly into the dispersion phase.
• the enclosed spaces are closed and sealed.
• Compressed antisolvent is added at a controlled rate either into the enclosed space or directly inside the dispersion phase.
• slow additions increase the pressure inside the enclosed space slowly leading to slow saturation.
• crystallization starts and the pressure is further increased to a point where almost all the material is crystallized as per the thermodynamics and kinetics of crystallization.
• a valve in the exit line is opened and using a valve or a back pressure regulator, the pressure is maintained at the same value while antisolvent is continuously added to and removed from the enclosed spaces.
• the antisolvent extracts the solvent from the droplet while simultaneously dissolving in the droplet, thus expanding it and crystallizing the desired substance.
• the solvent/ antisolvent mixture exits the enclosed space through exit 4 while the crystallized material is retained in the enclosed spaces.
• the pressure of the enclosed spaces can be varied. The pressure can be varied before or during the application of the compressed antisolvent. Adding pressure at different times can also vary the crystallization parameters and therefore lead to obtaining different polymorphs.
• provisions are provided for introducing external agents that can enhance or induce the crystallization of the dispersion droplets in the enclosed space.
• the amount of the enhancing agent or inducing agents can be varied depending on the nature of the system.
• the rate of addition of such agents can also be varied to vary the crystallization rate and obtain different polymorphs.
• a small amount of a desired polymorph can be seeded around the time the dispersion starts crystallizing in the enclosed space.
• Such addition of a solid to a pressurized enclosed space may require some solid addition means.
• the system comprises high pressure pump 1 for pumping a compressed antisolvent.
• a plunger 3 is in fluidic communication with the compressed antisolvent.
• a pluraHty of enclosed spaces is provided in a circular carousel 2.
• the pluraHty of enclosed spaces can also be in the form of a well plate, high pressure vessels or any other from capable of enhanced throughput.
• An enclosed space 13 presented to the plunger 3 can be pushed from the carousel 2 by the plunger 3 into the chamber 4.
• the enclosed space 13 contains a filter with a check valve 5 at the inlet and another filter 6 at the outlet.
• the check valve 5 ensures no dispersion flow back into the compressed antisolvent addition line.
• each enclosed space 13 wiU be a dispersion of a desired substance dissolved in a suitable solvent at a desired concentration.
• compressed antisolvent is added to the enclosed space 13 in a controlled manner increasing the pressure in the enclosed space 13 slowly. This results in crystallization of the dispersion in the enclosed space 13.
• Experimental conditions such as dispersion concentration, pressure, temperature and compressed antisolvent addition rate will be varied in each enclosed space 13. Depending on the experimental conditions, different polymorphs can be formed.
• the compressed antisolvent with the solvent will be carried out of the chamber 4 through a back pressure regulator (BPR) 7 into a separator 8 in which the compressed antisolvent will be vented off through the top 9 and the solvent will be removed at the bottom 10.
• BPR back pressure regulator
• the enclosed space 13 that is inside of the chamber 4 wiU be returned to its designated place in the carousel 2 and the carousel 2 will then rotate so as to aUow another enclosed space 13 to be pushed into the chamber 4 by the plunger 3.
• the individual enclosed space 13 can then be removed from the carousel 2.
• the contents of enclosed space 13 can be transferred to a crystal structure identification means. Such transfer can be accomplished after all the enclosed spaces were processed in chamber 4. [0040] Another embodiment of the present invention is shown in FIG. 7.
• the system comprises high pressure pump 1 for pumping a compressed antisolvent. Another high pressure pump 11 to pump a co-antisolvent is also provided. A mixing tee 14 is provided so as to completely mix the compressed antisolvent and the co-antisolvent. A plunger 3 is in fluidic communication with the compressed antisolvent/ co-antisolvent mixture. A plurality of enclosed spaces is provided in a circular carousel 2. The plurality of enclosed spaces can also be in the form of a well plate, high pressure vessels or any other from capable of enhanced throughput. An enclosed space 13 presented to the plunger 3 can be pushed from the carousel 2 by the plunger 3 into chamber 4. The enclosed space 13 contains a filter with a check valve 5 at the inlet and another filter 6 at the outlet.
• the check valve 5 ensures no dispersion flow back into the compressed antisolvent addition line.
• Inside each enclosed space 13 will be a dispersion of a desired substance dissolved in a suitable solvent at a desired concentration.
• compressed antisolvent is added to the enclosed space 13 in a controUed manner increasing the pressure in the enclosed space 13 slowly. This results in crystaHization of the dispersion in the enclosed space 13.
• Experimental conditions such as dispersion concentration, pressure, temperature and compressed antisolvent addition rate will be varied in each enclosed space 13. Depending on the experimental conditions, different polymorphs can be formed.
• the compressed antisolvent, with the solvent and co- antisolvent wiU be carried out of the chamber 4, through a back pressure regulator (BPR) 7 into a separator 8 in which the compressed antisolvent will be vented off through the top 9 and the solvent will be removed at the bottom 10.
• BPR back pressure regulator
• the enclosed space 13 that is inside of the chamber 4 will be returned to its designated place in the carousel 2 and the carousel 2 will then rotate so as to allow another enclosed space 13 to be pushed into the chamber 4 by the plunger 3.
• the individual enclosed space 13 can then be removed from the carousel 2.
• the contents of 13 can be transferred to a crystal structure identification means. Such transfer can be accomplished after all the enclosed spaces were processed in chamber 4.
• FIG. 8 Another embodiment of the present invention is shown in FIG. 8.
• the system comprises a high pressure pump 1 for pumping a compressed antisolvent.
• a plunger 3 is in fluidic communication with the compressed antisolvent.
• An enclosed space 13 presented to the plunger 3 can be pushed from the carousel 2 by the plunger 3 into chamber 4.
• the enclosed space 13 contains a filter with a check valve 5 at the inlet and another filter 6 at the outlet.
• the check valve ensures no dispersion flow back into the compressed antisolvent addition Hne.
• a dispensing means 12 transfers the dispersion containing the desired substance in a suitable solvent directly into the enclosed space 13 which is inside chamber 4.
• Appropriate fluidic connections are provided to accompHsh this transfer.
• An optional dispersing means 16 may be provided for dispersing the dispersion into the enclosed space 13. This can be accomplished by any suitable dispersing means, including but not limited to a nozzle. This example is meant to illustrate a suitable dispersing means, but is not intended to Hmit the scope of this invention. It will be obvious to one skilled in the art that a multitude of suitable dispersing means exist and aU are encompassed by the scope of the present invention. A dispersing means is not mandatory to practice the present invention.
• Mass transfer can also be enhanced by a vibrating surface.
• This can be accomplished by any suitable means for surface vibration, including but not limited to ultrasound and magnetorestrictive means.
• the frequency of the vibrating surface includes, but is not limited to, the gigahertz range. This is meant to illustrate a suitable means for surface vibration, but is not intended to Hmit the scope of this invention. It will be obvious to one skilled in the art that a multitude of suitable surface vibration means exist and aU are encompassed by the scope of the present invention.
• the dispensing means 12 has the ability to vary properties such as dispersion concentration, dispersion addition rate and solvent type.
• the substance in the dispersion is crystallized and such crystals are retained inside the enclosed space 13 by the provided filters at the outlet end.
• the compressed antisolvent, with the solvent will be carried out of the chamber 4, through the back pressure regulator (BPR) 7 into a separator 8 in which the compressed antisolvent will be vented off through the top 9 and the solvent will be removed at the bottom 10.
• BPR back pressure regulator
• the enclosed space 13 that is inside of the chamber 4 wiU be returned to its designated place in the carousel 2 and the carousel 2 will then rotate so as to allow another enclosed space 13 to be pushed into the chamber 4 by the plunger 3.
• the individual enclosed space 13 can then be removed from the carousel 2.
• the contents of enclosed space 13 can be transferred to a crystal structure identification means.
• FIG. 9 Another embodiment of the present invention is shown in FIG. 9.
• the system comprises a high pressure pump 1 for pumping a compressed antisolvent.
• Another high pressure pump 11 for pumping a co-antisolvent is also provided.
• a mixing tee 14 is provided so as to completely mix the compressed antisolvent and the co-antisolvent.
• a plunger 3 is in fluidic communication with the compressed antisolvent/ co-antisolvent mixture.
• An enclosed space 13 presented to the plunger 3 can be pushed from the carousel 2 by the plunger 3 into chamber 4.
• the enclosed space 13 contains a filter with a check valve 5 at the inlet and another filter 6 at the outlet.
• the check valve ensures no dispersion flow back into the compressed antisolvent addition line.
• compressed antisolvent is added to the enclosed space at a constant rate and the pressure of the enclosed space 13 is maintained at a constant pressure with the use of back pressure regulator (BPR) 7.
• BPR back pressure regulator
• a dispensing means 12 transfers the dispersion containing desired substance in a suitable solvent directly into the enclosed space 13 which is inside the chamber 4.
• Appropriate fluidic connections are provided to accompHsh this transfer.
• An optional dispersing means 16 may be provided for dispersing the dispersion into the enclosed space 13. This can be accomplished by any suitable dispersing means, including but not limited to a nozzle.
• a dispersing means is not mandatory to practice the present invention. However, such dispersing means may provide for increased crystauization rate, aHowing some embodiments of the present invention to be practiced more easily.
• Mass transfer can also be enhanced by a vibrating surface. This can be accomplished by any suitable means for surface vibration, including but not Hmited to ultrasound and magnetorestrictive means. The frequency of the vibrating surface includes, but is not limited to, the gigahertz range.
• the dispensing means 12 has the abiHty to vary properties such as dispersion concentration, dispersion addition rate and solvent type.
• the substance in the dispersion is crystallized and such crystals are retained inside the enclosed space 13 by the provided filters at the outlet end.
• the compressed antisolvent with the solvent wiU be carried out of chamber 4 through back pressure regulator (BPR) 7 into a separator 8, where the compressed antisolvent will be vented off through the top 9 and the solvent will be removed at the bottom 10.
• BPR back pressure regulator
• the enclosed space 13 that is inside of the chamber 4 wiU be returned to its designated place in the carousel 2 and the carousel 2 will then rotate so as to allow another enclosed space 13 to be pushed into the chamber 4 by the plunger 3.
• the individual enclosed space 13 can then be removed from the carousel 2.
• the contents of 13 can be transferred to a crystal structure identification means. Such transfer can be accomplished after all the enclosed spaces were processed in chamber 4.
• a collecting plate 15 can be placed beneath the carousel 2 in order to coUect the polymorphs that are formed from each enclosed space 13 present in the carousel 2. Once all polymorphs are coUected on the coUecting plate 15, the collecting plate 15 can be transferred to a crystal structure identification means.
• Fig. 7 and Fig. 9 provide for co- antisolvent mixed with antisolvent. Such schemes are used when the solvent used is not directly substantially miscible with the antisolvent. For example, when water or any other polar solvents are used, a co-antisolvent such as ethanol or methanol can be used with carbon dioxide as the antisolvent.
• a co-antisolvent such as ethanol or methanol can be used with carbon dioxide as the antisolvent.
• antisolvents include, but are not Hrnited to, methanol, ethanol, dimethylsulf oxide, tetrahydrofuran, N,N dimethylformamide, toluene, dichloromethane, ethyl ether, heptane, hexane, methylethylketone, methylisobutylketone, acetone, chloroform, fluoroform, carbon tetrachloride, cyclohexane, ethyl acetate, ethyl formate, isbutyl acetate, isopropyl acetate, 2- methyl- 1 propanol, pentane, 1-pentanol, 1-propanol, and 2-propanol, ethane, propane, carbon dioxide, nitrous oxide, butane, isobutene, sulfur hexafluoride, a bydrofluorocarbon, a chlorofluorocarbon, or a combination
• Crystal structure identification means may be broadly classified into visual analysis, microscopic analysis, thermal analysis, diffraction analysis and spectroscopic analysis.
• Any one or more than one of these techniques can be used to identify a crystal structure or a lack thereof.
• Visual analysis includes, but is not limited to, observing it under different Hght sources.
• Microscopic analysis includes, but is not limited to, scanning or tunneling electron microscopy, atomic force microscopy, thermal microscopy, or optical microscopy.
• Thermal analysis includes, but is not limited to, thermo gravimetric analysis and differential scanning calorimetry.
• Diffraction analysis includes, but is not limited to, X-ray diffraction, laser diffraction or dynamic laser diffraction.
• Spectroscopic techniques include, but are not limited to, near infrared spectroscopy, fourier transform infrared spectroscopy, attenuated total reflectance fourier tranform infrared spectroscopy, and nuclear magnetic resonance spectroscopy.
• the portion of the dispersion inside the enclosed spaces can be pre-pressurized before the end anti-solvent is apphed.
• such a pre-pressurized system can be maintained at a constant pressure while the compressed anti- solvent is being added by increasing the volume simultaneously. This aUows crystallization to take place at a constant pressure.
• Various elements of the present invention can be practiced individually or in any combination thereof without any limitation.
• Example 1 Searching for and generating polymorphs of sulfathiazole. Carbon dioxide was used as the antisolvent and testing was carried out in an antisolvent system manufactured by Thar Technologies, Inc. This design of experiments utilized only one pressure, 100 bar, but pressure may be varied as a process parameter. Table 1 summarizes the temperatures and solvents used in this design of experiments. Table 1: Solvents and Temperatures Used for Sulfathiazole Polymorph Generation

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