Claims
- 1. A method for performing high throughput testing of a drug candidate or salt thereof to characterize polymorphs that form from said drug candidate or salt thereof, the method comprising:
preparing a library having a plurality of members, each said member comprising said drug candidate or salt thereof and at least one solvent; subjecting said members to at least one crystallization condition to produce at least one crystalline structure of said drug candidate or salt thereof, said at least one crystalline structure having a crystal and a supernatant; screening said crystal of each of said at least one crystalline structure to obtain data for each of said crystals; and characterizing each said crystal based on said data.
- 2. The method according to claim 1, wherein said characterizing comprises:
comparing said data of each of said crystals to data of said at least one polymorph family to obtain at least one correlation coefficient; and categorizing said data of each of said crystals to one of said at least one polymorph family based on said at least one correlation coefficient and selection criteria.
- 3. The method according to claim 2, further comprising the step, prior to said comparing step, of assigning said data associated with one of said crystals to a polymorph family.
- 4. The method according to claim 1, further comprising filtering said members to provide seedless or pure members for said subjecting.
- 5. The method according to claim 4, wherein said filtering is performed using a filtration assembly or centrifugation.
- 6. The method according to claim 1, further comprising heating said members to promote mixing of said drug candidate or salt thereof and said at least one solvent.
- 7. The method according to claim 1, further comprising:
providing a rotating magnetic field; and spinning at least one object with said rotating magnetic field to stir said drug candidate or salt thereof and said at least one solvent.
- 8. The method according to claim 1, wherein said preparing comprises dispensing said drug candidate or salt thereof and said at least one solvent into predetermined regions of a reactor assembly, wherein said predetermined regions correspond to said members according to said library.
- 9. The method according to claim 8, wherein said dispensing is substantially automated for liquid compositions of said drug candidate or salt thereof and said at least one solvent.
- 10. The method according to claim 1, further comprising extracting said supernatant to perform solubility testing on said supernatant.
- 11. The method according to claim 1, further comprising dispensing said members into a crystallization assembly.
- 12. The method according to claim 11, wherein said dispensing is substantially automated.
- 13. The method according to claim 1, wherein said screening comprises screening said members with at least two tests selected from the group consisting of solubility, log P, melting point, birefringence, hygroscopicity, infrared spectroscopy, near infrared spectroscopy, Raman spectroscopy, X-ray diffraction, UV-Vis spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography, and liquid chromatography testing.
- 14. The method according to claim 1, wherein said comparing comprises:
obtaining a best correlation coefficient from said at least one correlation coefficient; and using said best correlation coefficient to perform said categorizing.
- 15. The method according to claim 1, wherein said at least one polymorph family comprises an existing polymorph family.
- 16. The method according to claim 1, wherein said at least one polymorph family comprises a new polymorph family.
- 17. The method according to claim 1, wherein said preparing comprises:
using a software program to generate said library; and formulating said plurality of members based of said library based on said computer based library.
- 18. The method according to claim 2, wherein said selection criteria is a user-defined threshold value.
- 19. The method according to claim 1, further comprising after said preparing step:
daughtering said members to form a plurality of daughter libraries; and crystallizing said daughter libraries under different crystallization conditions.
- 20. The method according to claim 19, further comprising determining if any crystalline forms formed during said crystallizing by screening said daughter libraries.
- 21. The method according to claim 1, wherein said at least one crystallization conditions comprise conditions selected from the group consisting of temperature, pressure, time, humidity, and any combination thereof.
- 22. The method according to claim 17, wherein said using comprises providing a user with an opportunity to enter at least one parameter to generate said library.
- 23. The method according to claim 22, wherein said at least one parameter comprises at least one of:
defining said drug candidate or salt thereof; and defining a solvent library.
- 24. The method according to claim 23, wherein said solvent library comprises solvents selected from the group consisting of aromatics, water, alcohols, esters, and mixtures thereof.
- 25. A method for performing high throughput salt selection for a drug candidate, the method comprising:
preparing a library having a plurality of members, each member comprising said drug candidate, a salt reactant and at least one library solvent; reacting said drug candidate and said salt reactant under conditions to a produce drug candidate salt; adding said at least one library solvent to said drug candidate salt to form said members; subjecting said members to at least one condition to produce at least one crystalline structure of said drug candidate salt, said at least one crystalline structure having a crystal and a supernatant; screening said crystal and said supernatant to obtain data, wherein said data comprises at least two selected from the group consisting of solubility, log P, melting point, birefringence, infrared spectroscopy, near infrared spectroscopy, Raman spectroscopy, X-ray diffraction, hygroscopicity, UV-Vis spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography, and liquid chromatography testing; and selecting at least one said drug candidate salt of interest.
- 26. The method according to claim 25, further comprising isolating said drug candidate salt after said reacting.
- 27. The method according to claim 25, further comprising filtering said members after said adding.
- 28. A method for performing high throughput salt selection and polymorph characterization for a drug candidate, the method comprising:
reacting a drug candidate and a salt reactant in a plurality of regions under reacting conditions to produce a drug candidate salt in said regions; adding at least one solvent to said regions; subjecting said regions to at least one condition to produce at least one crystalline salt of said drug candidate salt, said at least one crystalline salt comprising at least a salt crystal; screening said salt crystal to obtain information; selecting one of said at least one drug candidate salts based on said information, wherein said selecting provides a selected drug candidate salt; preparing a library having a plurality of members, each member comprising said selected drug candidate salt and at least one solvent; subjecting said members to at least one crystallization condition to produce at least one crystalline structure of said selected drug candidate salt, said at least one crystalline structure having at least a crystal; screening said crystal of each of said at least one crystalline structure to obtain data for each of said crystals; and characterizing each said crystal based on said data.
- 29. The method according to claim 28, wherein said characterizing comprises
comparing said data of each of said crystals to data of said at least one polymorph family to obtain at least one correlation coefficient; and categorizing said data of each of said crystals to one of said at least one polymorph family based on said at least one correlation coefficient and selection criteria.
- 30. The method according to claim 29, wherein said at least one polymorph family is an existing polymorph family or a new polymorph family.
- 31. The method according to claim 29, further comprising assigning said data associated with one said crystals to a polymorph family prior to said comparing.
- 32. A method for obtaining solubility data from at least one crystallized structure of a drug candidate or salt thereof, said method comprising:
subjecting an array of materials to crystallization conditions to form said at least one crystalline structure, wherein said crystalline structure comprises a crystal and a supernatant; extracting said supernatant from said at least one crystalline structure such that said crystal resides on a substrate; subjecting said supernatant to solubility testing to obtain solubility data; screening said crystal to obtain crystal data; and categorizing said at least one crystalline structure into either a new polymorph family or at least one polymorph family based on said solubility data and said crystal data.
- 33. The method according to claim 32, wherein said solubility testing comprises using a testing technique selected from the group consisting of liquid chromatography, thin layer chromatography, gas chromatography, infrared, fluorescence, log P and ultra-violet absorption.
- 34. The method according to claim 32, wherein said screening comprises screening said crystal with a test selected from the group consisting of melting point, birefringence, hygroscopicity, infrared spectroscopy, near infrared spectroscopy, Raman spectroscopy, X-ray diffraction, UV-Vis spectroscopy, nuclear magnetic resonance spectroscopy and gas chromatography.
- 35. The method according to claim 32, wherein said existing polymorph family is a polymorph family in which the properties of said at least one crystalline structure have been previously discovered.
- 36. The method according to claim 32, wherein said new polymorph family is a polymorph family in which the properties of said crystalline structure have not been previously discovered.
- 37. The method according to claim 32, wherein said categorizing comprises:
comparing said crystal data of any of said at least one crystalline structure with said crystal data obtained from at least one other said crystalline structure, wherein said comparing generates a correlation coefficient; and categorizing said at least one crystalline structure into said new polymorph family or said existing polymorph family based on said correlation coefficient.
- 38. A method for testing and categorizing a plurality of crystalline structures formed from a drug candidate or salt thereof, said method comprising:
preparing said plurality of crystalline structures; screening said plurality of crystalline structures with at least two different screening techniques to obtain data on said crystalline structures; comparing said data of each of said crystalline structures to data of said at least one polymorph family to obtain at least one correlation coefficient; and categorizing said data of each of said crystalline structures to one of said at least one polymorph family based on said at least one correlation coefficient and selection criteria.
- 39. The method according to claim 38, wherein said preparing comprises:
preparing said plurality of library members, each said library member comprising said drug candidate or salt thereof; and subjecting said library members to at least one condition to produce said plurality of crystalline structures.
- 40. The method according to claim 38, wherein said screening techniques are selected from the group consisting of solubility, log P, melting point, birefringence, infrared spectroscopy, near infrared spectroscopy, Raman spectroscopy, X-ray diffraction, hygroscropicity, UV-Vis spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography, and liquid chromatography testing.
- 41. The method according to claim 38, further comprising creating a new polymorph family if said at least one crystalline structure is associated with a correlation coefficient that is below a predetermined threshold value.
- 42. The method according to claim 41, wherein said predetermined threshold value sets a threshold that determines whether said at least one crystalline structure should be clustered into one of said at least one polymorph family or said new polymorph family.
- 43. A system for performing high throughput testing of a drug candidate to characterize polymorphs that form from said drug candidate, said system comprising:
a reactor assembly configured to contain a plurality of mixtures, said reactor assembly having a plurality of regions to contain said mixtures; a crystallization assembly configured to contain said mixtures on a substrate, wherein said mixtures are subjected to crystallization conditions to provide at least one crystalline structure; a temperature controlled housing configured to house a subassembly, said housing maintains said subassembly at a predetermined thermal profile; at least two screening devices that obtain data on said at least one crystalline structure, wherein said at least two screening devices perform measurements on said at least one crystalline structure located on the same said substrate; and a computer that controls said temperature controlled housing and receives data obtained by said screening devices, wherein said computer provides crystalline structure data obtained to a polymorph grouping algorithm, said polymorph grouping algorithm further configured to:
compare said data for said at least one crystalline structure with data of at least one polymorph family to obtain a best correlation coefficient; and cluster said data associated with said at least one crystalline structure into said at least one polymorph family based on said best correlation coefficient and selection criteria.
- 44. The system according to claim 43 further comprising a filter assembly that filters said mixtures to provide substantially pure mixtures to said crystallization assembly.
- 45. The system according to claim 44, wherein said substantially pure mixtures have no nucleation sites contained therein.
- 46. The system according to claim 43, wherein said reactor assembly and said filtration assembly comprise at least one common part.
- 47. The system according to claim 46, wherein said at least one common part comprises a reactor base.
- 48. The system according to claim 43 further comprising a robotic pipette system that is controlled by said computer.
- 49. The system according to claim 48, wherein said robotic pipette system is controlled to dispense materials into said reactor assembly.
- 50. The system according to claim 48, wherein said robotic pipette system is controlled to dispense materials into said crystallization assembly.
- 51. The system according to claim 43, wherein said subassembly is said reactor assembly.
- 52. The system according to claim 43, wherein said subassembly is said crystallization assembly.
- 53. The system according to claim 43, wherein said subassembly is a filtration assembly.
- 54. The system according to claim 43, wherein said temperature controlled housing is controlled by said computer to heat said reactor assembly to said predetermined thermal profile to promote dissolution of said mixtures contained therein.
- 55. The system according to claim 43, wherein said temperature controlled housing is controlled by said computer to cool said crystallization assembly to the predetermined thermal profile to crystallize said mixtures contained therein.
- 56. The system according to claim 43 further comprising a dispensing assembly that dispenses a structure in each region of said reactor assembly to promote agitation of said mixture.
- 57. The system according to claim 43, wherein said at least two screening devices comprise two devices selected from the group consisting of solubility, log P, melting point, birefringence, infrared spectroscopy, near infrared spectroscopy, hygroscopicity, Raman spectroscopy, X-ray diffraction, UV-Vis spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography, and liquid chromatography testing device.
- 58. The system according to claim 43, wherein said computer is further configured to generate a library based on at least one parameter.
- 59. The system according to claim 43, wherein said computer is further configured to generate a solvent library, wherein said solvent library comprises at least two different groups of solvents.
- 60. The system according to claim 43, wherein said computer comprises a database for storing said data.
- 61. The system according to claim 43 further comprising a second crystallization assembly that is configured to receive an aliquot of said mixtures synthesized in said reactor assembly, wherein said second crystallization assembly is subjected to a different crystallization condition than said crystallization assembly.
- 62. The system according to claim 43, wherein said computer is configured to display the result obtained by said polymorph grouping algorithm.
- 63. The system according to claim 43, wherein said computer is configured to allow a user to interact with said polymorph grouping algorithm.
- 64. The system according to claim 43, wherein said selection criteria comprises a predetermined threshold value.
- 65. A method for categorizing a plurality of crystalline structures, said method comprising:
providing at least one polymorph family; selecting one of said plurality of crystalline structures; comparing said selected crystalline structure to each said at least one polymorph family, wherein each said comparison produces a correlation coefficient; obtaining a best correlation coefficient among each said correlation coefficient produced; categorizing said selected crystalline structure to either (a) said at least one polymorph family or to (b) a new polymorph family based on said best correlation coefficient.
- 66. The method according to claim 65, wherein said providing comprises assigning one of said plurality of crystalline structures to said at least one polymorph family.
- 67. The method according to claim 65, wherein said providing comprises obtaining said at least one polymorph family from a database.
- 68. The method according to claim 65, wherein each one of said at least one polymorph family comprises characteristics that are different than the characteristics associated with any other said at least one polymorph family.
- 69. The method according to claim 65, wherein said correlation coefficient comprises a value that indicates how similar said selected crystalline structure is to said at least one polymorph family.
- 70. The method according to claim 65, wherein said comparing comprises performing a statistical analysis to produce said correlation coefficient.
- 71. The method according to claim 65, wherein said comparing comprises comparing data associated with said selected crystalline structure with data associated with said at least one polymorph family.
- 72. The method according to claim 71, wherein said data is based on a screening test selected from the group consisting of solubility, log P, melting point, birefringence, hygroscopicity, infrared spectroscopy, near infrared spectroscopy, Raman spectroscopy, X-ray diffraction, UV-Vis spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography, and liquid chromatography.
- 73. The method according to claim 65, wherein said comparing comprises:
providing crystalline structure data based on said selected crystalline structure; providing polymorph family data; performing a point-to-point analysis of said crystalline structure data to said polymorph family data to obtain said correlation coefficient.
- 74. The method according to claim 73, wherein said crystalline structure data is Raman spectroscopy data.
- 75. The method according to claim 73, wherein said polymorph family data is Raman spectroscopy data.
- 76. The method according to claim 65, wherein said comparing comprises:
providing crystalline structure data based on said selected crystalline structure; providing polymorph family data; performing a peak-to-peak analysis of said crystalline structure data to said polymorph family data to obtain said correlation coefficient.
- 77. The method according to claim 76, wherein said crystalline structure data is X-ray diffraction spectroscopy data.
- 78. The method according to claim 76, wherein said polymorph family data is X-ray diffraction spectroscopy data.
- 79. The method according to claim 65, wherein said categorizing comprises associating said selected crystalline structure with said new polymorph family when said best correlation coefficient is below a predetermined value.
- 80. The method according to claim 65, wherein said categorizing comprises associating said selected crystalline structure with one of said at least one polymorph family when said best correlation coefficient is equal to or exceeds a predetermined value, wherein said at least one polymorph family that receives said crystalline structure is said at least one polymorph family that is associated with said best correlation coefficient.
- 81. The method according to claim 65 further comprising creating another said at least one polymorph family based on said new polymorph family.
- 82. The method according to claim 65 further comprising providing crystallization condition data to perform said categorizing.
- 83. The method according to claim 82, wherein said crystallization condition data comprises data selected from the group consisting of temperature, pressure, time, solvents, nucleation, precipitation, slurry, pH, concentration of a drug candidate, and any combination thereof.
- 84. A method for categorizing a plurality of crystalline structures in which no data has been previously obtained for any of said crystalline structures, the method comprising:
associating any one of said crystalline structures with as at least one reference polymorph family; for each of said remaining crystalline structures:
comparing said remaining crystalline structures to said at least one reference polymorph family; generating at least one correlation coefficient based on analysis between said remaining crystalline structures and said at least one reference polymorph family; categorizing said remaining crystalline structures into said at least one reference polymorph family based on said at least one correlation coefficient.
- 85. A method for performing high throughput testing of a drug candidate or salt thereof to characterize crystalline structures that form from said drug candidate or salt thereof, the method comprising:
preparing a plurality of members, each said member comprising said drug candidate or salt thereof and at least one solvent; subjecting said members to at least one crystallization condition to produce at least one crystalline structure of said drug candidate or salt thereof, said at least one crystalline structure having a crystal and a supernatant; screening said at least one crystalline structures with at least two different screening techniques to obtain at least crystallinity and identity data on said crystalline structures; and characterizing said crystalline structures.
- 86. The method according to claim 85, wherein said crystalline structures of said drug candidate or salt thereof form on a substrate.
- 87. The method according to claim 85, wherein said plurality of crystalline structures is eight or more.
- 88. The method according to claim 85, wherein said screening techniques for identity comprise at least one test selected from the group consisting of birefringence, X-ray diffractometry, Raman spectroscopy, gas chromatography, liquid chromatography, thin layer chromatography, capillary electrophoresis, Infrared spectroscopy, UV-Vis spectroscopy and near infrared spectroscopy, and wherein said screening techniques for crystallinity comprises at least one test selected from the group consisting of birefringence and X-ray diffraction.
- 89. The method according to claim 85, wherein prior to said subjecting step, each of said plurality of solutions is subjected to either (1) filtering to remove possible solids or (2) daughtering or (3) both filtering and daughtering.
- 90. A method for performing high throughput testing of a drug candidate or salt thereof to characterize crystalline structures that form from said drug candidate or salt thereof, the method comprising:
preparing a plurality of members, each said member comprising said drug candidate or salt thereof and at least one solvent; subjecting said members to at least one crystallization condition to produce at least one crystalline structure of said drug candidate or salt thereof, said at least one crystalline structure having a crystal and a supernatant; screening said at least one crystalline structure with at least two different screening techniques to obtain at least crystallinity and identity data on said crystalline structures; and characterizing said plurality of crystalline structures according to said crystallinity and identity data.
- 91. The method according to claim 90, wherein said crystalline structures of said drug candidate or salt thereof form on a substrate.
- 92. The method according to claim 90, wherein said plurality of crystalline structures is eight or more.
- 93. The method according to claim 90, wherein said screening techniques for identity comprise at least one test selected from the group consisting of birefringence, X-ray diffractometry, Raman spectroscopy, gas chromatography, liquid chromatography, thin layer chromatography, capillary electrophoresis, Infrared spectroscopy, UV-Vis spectroscopy and near infrared spectroscopy, and wherein said screening techniques for crystallinity comprises at least one test selected from the group consisting of birefringence and X-ray diffraction.
- 94. The method according to claim 90, wherein prior to said subjecting step, each of said plurality of solutions is subjected to either (1) filtering to remove possible solids or (2) daughtering or (3) both filtering and daughtering.
- 95. A system for performing a workflow, said workflow including preparing and testing a plurality of materials, said system comprising:
a work surface; at least one assembly optionally mounted to said work surface, wherein said at least one assembly comprises:
a reactor assembly; a filtration assembly; and/or a crystallization assembly; at least one thermal housing assembly mounted to said work surface, said thermal housing assembly configured to retain said at least one assembly; and a robotic material handling system mounted to said work surface, said robotic material handling system configured to (a) dispense said plurality of materials into said at least one assembly and (b) retrieve a plurality of mixtures formed from said plurality of materials from said at least one assembly, thereby preparing said plurality of materials for testing.
- 96. The system according to claim 95, wherein said robotic handling system comprises a vented needle assembly configured for maintaining a substantially constant pressure within a sealed receptacle when aspirating a liquid out of or dispensing liquid into said sealed receptacle, said vented needle assembly comprising:
a body having a main axis; at least one guide rod that slides in and out of said body along said main axis; a guide block attached to said at least one guide rod such that said guide block moves in conjunction with said at least one guide rod; a compressible spacer that provides tension between said body and said guide block; a venting needle coupled within said guide block in parallel to said main axis, said venting needle extending beyond a first side of said guide block by a fixed length, thereby providing an open passage through said guide block; and a liquid handling needle coupled to said body in parallel to said main axis, said liquid handling needle configured to pass through said guide block.
CROSS-REFERENCE TO A RELATED PATENT APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 60/311,332, filed Aug. 10, 2001, the disclosure of which is hereby incorporated by reference in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60311332 |
Aug 2001 |
US |