Solid forms of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate and methods for preparing same

Abstract

Solid state forms, pharmaceutical compositions, preparations and uses of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and / or the benefit of U.S. Provisional Patent Application No. 62 / 865,826, filed June 24, 2019, which is incorporated by reference herein in its entirety and serves as the basis for any priority and / or benefit claimed for this application. The subject matter described herein relates to solid state forms, e.g., crystalline and amorphous forms, of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate, pharmaceutical compositions thereof, methods for preparation, and uses thereof. [Background technology]

[0002] N-methyl-D-aspartate receptor (NMDA receptor) is believed to play a key role in the synaptic plasticity that underlies many higher cognitive functions, such as memory acquisition, retention and learning, as well as in certain cognitive pathways and in pain perception.NMDA receptor also appears to be involved in a wide spectrum of CNS disorders.Therefore, NMDA receptor modulators can provide pharmaceutical benefits. Tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate is disclosed in U.S. Pat. No. 9,512,134 (which is incorporated herein by reference in its entirety) as an NMDA receptor modulator that may be useful, for example, for the treatment of depression. There remains a need for stable solid state forms of Compound A that can be used in pharmaceutical compositions and their manufacture. Summary of the Invention

[0003] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope. In one embodiment, there is provided a solid form of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate (hereinafter "Compound A"). Compound A has the following structure:

[0004] [ka] has.

[0005] In some embodiments, a crystalline anhydrous form of Compound A, designated as crystalline Form I of Compound A, is disclosed herein. In some embodiments, disclosed herein is a crystalline dihydrate form of Compound A, designated as crystalline Form II of Compound A. In some embodiments, amorphous forms of Compound A are disclosed herein. In another aspect, disclosed herein is a pharmaceutical composition comprising at least one pharma- ceutically acceptable carrier and a solid form of Compound A. Disclosed herein, in some embodiments, is a pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient and crystalline Form I of Compound A. Disclosed herein, in some embodiments, is a pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient and crystalline Form II of Compound A. In some embodiments, disclosed herein is a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and an amorphous form of Compound A.

[0006] In another embodiment, a method of treating a subject identified as in need of treatment for a disease or disorder responsive to NMDA modulation, e.g., major depressive disorder, is disclosed, comprising administering to said subject in need thereof a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a pharma- ceutical acceptable excipient and a solid form of Compound A. In some embodiments, a method of treating a subject identified as in need of treatment for a disease or disorder responsive to NMDA modulation, e.g., major depressive disorder, is disclosed, comprising administering to said subject in need thereof a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a pharma- ceutical acceptable excipient and crystalline Form I of Compound A. In some embodiments, a method of treating a subject identified as in need of treatment for a disease or disorder responsive to NMDA modulation, e.g., major depressive disorder, is disclosed, comprising administering to said subject in need thereof a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a pharma- ceutical acceptable excipient and crystalline Form II of Compound A. In some embodiments, a method of treating a subject identified as in need of treatment for a disease or disorder responsive to NMDA modulation, e.g., major depressive disorder, is disclosed, comprising administering to said subject in need thereof a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a pharma- ceutical acceptable excipient and an amorphous form of Compound A.

[0007] In another embodiment, a method of preparing a solid form of Compound A is disclosed. In some embodiments, a method for preparing crystalline Form I of Compound A is disclosed. In some embodiments, a method for preparing crystalline Form II of Compound A is disclosed. In some embodiments, a method of preparing an amorphous form of Compound A is disclosed. Some non-limiting exemplary embodiments are listed below. Exemplary embodiment 1: Compound A:

[0008] [ka] 1. A process for preparing solid crystalline Form I of Dissolving compound A in ethyl acetate and heating the solution; Cooling the solution; and Add diisopropyl ether to the solution A method comprising: Exemplary embodiment 2: The method of exemplary embodiment 1, wherein the solution is heated to about 65°C to about 70°C. Exemplary embodiment 3: The method of exemplary embodiment 1, wherein the solution is cooled to about 25°C. Exemplary embodiment 4: The method of any one of exemplary embodiments 1-3, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, and 12.8. Exemplary embodiment 5: The method of exemplary embodiment 4, wherein the solid crystalline Form I of Compound A further has one or more peaks (2θ) in an X-ray powder diffraction pattern selected from those having approximately the following values: 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9. Exemplary embodiment 6: The method of any one of exemplary embodiments 1-3, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, and 13.7. Exemplary embodiment 7: The method of any one of exemplary embodiments 1-3, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, and 15.7. Exemplary embodiment 8: The method of any one of exemplary embodiments 1 to 3, having peaks (2θ) in a powder X-ray diffraction pattern selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, and 16.8. Exemplary embodiment 9: The method of any one of exemplary embodiments 1-3, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, and 17.3. Exemplary embodiment 10: The method of any one of exemplary embodiments 1-3, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, and 18.5. Exemplary embodiment 11: The method of any one of exemplary embodiments 1-3, wherein the solid crystalline Form I of Compound A has three, four or five peaks (2θ) selected from those having approximately the following values ​​in an X-ray powder diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5 and 19.9. Exemplary embodiment 12: The method of any one of exemplary embodiments 1-3, wherein the solid crystalline Form I of compound A has an XRPD pattern substantially similar to one of the XRPD patterns depicted in FIG. Exemplary embodiment 13: The method of any one of exemplary embodiments 1-12, wherein the solid crystalline form I of compound A has a DSC with an endothermic peak at about 159°C. Exemplary embodiment 14: Compound A:

[0009] [ka] A solid crystalline form of A solid crystalline form, which is crystalline form I of Compound A. Exemplary embodiment 15: The solid crystalline form of exemplary embodiment 14, having, in an X-ray powder diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, and 12.8. Exemplary embodiment 16: The solid crystalline form of exemplary embodiment 15, further having one or more peaks (2θ) in a powder X-ray diffraction pattern selected from those having approximately the following values: 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9. Exemplary embodiment 17: The solid crystalline form of exemplary embodiment 14, having, in an X-ray powder diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, and 13.7. Exemplary embodiment 18: The solid crystalline form of exemplary embodiment 14, having, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, and 15.7. Exemplary embodiment 19: The solid crystalline form of exemplary embodiment 14, having peaks (2θ) in a powder X-ray diffraction pattern selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, and 16.8. Exemplary embodiment 20: The solid crystalline form of exemplary embodiment 14, having in a powder X-ray diffraction pattern peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, and 17.3. Exemplary embodiment 21: The solid crystalline form of exemplary embodiment 14, having in an X-ray powder diffraction pattern peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, and 18.5. Exemplary embodiment 22: The solid crystalline form of exemplary embodiment 14, having 3, 4 or 5 peaks (2θ) selected from those having approximately the following values ​​in an X-ray powder diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5 and 19.9. Exemplary embodiment 23: A solid crystalline form of exemplary embodiment 14 having an XRPD pattern substantially similar to one of the XRPD patterns depicted in FIG. Exemplary embodiment 24: The solid crystalline form of any one of exemplary embodiments 14-23, having a DSC with an endothermic peak at about 159° C. Exemplary embodiment 25: A solid composition comprising the solid crystalline form of any one of exemplary embodiments 14-24, wherein the solid composition is at least 99%, at least 95%, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% by weight free of any other solid forms of Compound A. Exemplary embodiment 26: A pharmaceutical composition comprising the solid crystalline form of any one of exemplary embodiments 14-24 and a pharma- ceutically acceptable excipient. Exemplary embodiment 27: The pharmaceutical composition of exemplary embodiment 26, wherein the solid crystalline form is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition. Exemplary embodiment 28: Compound A:

[0010] [ka] A solid crystalline form of A solid crystalline form of Compound A, which is crystalline Form II. Exemplary embodiment 29: The solid crystalline form of exemplary embodiment 28, having, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 9.4, 10.8, 11.9, and 13.0. Exemplary embodiment 30: The solid crystalline form of exemplary embodiment 29, further having one or more peaks (2θ) in a powder X-ray diffraction pattern selected from those having approximately the following values: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. Exemplary embodiment 31: The solid crystalline form of exemplary embodiment 28, having, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 9.4, 10.8, 11.9, 13.0, and 13.7. Exemplary embodiment 32: The solid crystalline form of exemplary embodiment 28, having peaks (2θ) in a powder X-ray diffraction pattern selected from those having approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, and 16.0. Exemplary embodiment 33: The solid crystalline form of exemplary embodiment 28, having in an X-ray powder diffraction pattern peaks (2θ) selected from those having approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, and 20.4. Exemplary embodiment 34: The solid crystalline form of exemplary embodiment 28, having in an X-ray powder diffraction pattern peaks (2θ) selected from those having approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, and 21.3. Exemplary embodiment 35: The solid crystalline form of exemplary embodiment 28, having in an X-ray powder diffraction pattern peaks (2θ) selected from those having approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. Exemplary embodiment 36: The solid crystalline form of exemplary embodiment 28, having 3, 4 or 5 peaks (2θ) selected from those having approximately the following values ​​in an X-ray powder diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3 and 23.3. Exemplary embodiment 37: A solid crystalline form described in exemplary embodiment 28, having an XRPD pattern substantially similar to one of the two XRPD patterns depicted in FIG. Exemplary embodiment 38: The solid crystalline form of any one of exemplary embodiments 28-37, having a DSC with endothermic peaks at about 82° C. and about 159° C. Exemplary embodiment 39: The solid crystalline form of any one of exemplary embodiments 28-38, having a TGA showing dehydration above approximately 60° C. with a water loss of approximately 9.6% by weight. Exemplary embodiment 40: The solid crystalline form of any one of exemplary embodiments 28-39, having a DVS that exhibits a mass change of about 11% at 0% RH and 25° C., and no mass loss of water at or above 20% RH. Exemplary embodiment 41: A solid composition comprising the solid crystalline form of any one of exemplary embodiments 28-40, wherein the solid composition is at least 99%, at least 95%, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% by weight free of any other solid forms of Compound A. Exemplary embodiment 42: A pharmaceutical composition comprising the solid crystalline form of any one of exemplary embodiments 28-40 and a pharma- ceutically acceptable excipient. Exemplary embodiment 43: The pharmaceutical composition of exemplary embodiment 42, wherein the solid crystalline form is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition. Exemplary embodiment 44: Compound A:

[0011] [ka] A solid amorphous form of. Exemplary embodiment 45: The solid amorphous form of exemplary embodiment 44, having an amorphous halo in an X-ray powder diffraction pattern. Exemplary embodiment 46: A solid amorphous form as described in exemplary embodiment 44, having an XRPD pattern substantially similar to that in FIG. Exemplary embodiment 47: A pharmaceutical composition comprising the amorphous form of any one of exemplary embodiments 44-46 and a pharma- ceutically acceptable excipient. Exemplary embodiment 48: The pharmaceutical composition of exemplary embodiment 47, wherein the amorphous form is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition. Exemplary embodiment 49: A method of treating a subject in need of treatment for a disease or disorder responsive to NMDA modulation, comprising administering to said subject in need thereof a therapeutically effective amount of a pharmaceutical composition described in any one of exemplary embodiments 26, 27, 42, 43, 47 and 46. Exemplary embodiment 50: The disease or disorder is autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychiatric disorder, a psychotic symptom, social withdrawal, obsessive-compulsive disorder (OCD), a phobia, post-traumatic stress syndrome, a behavioral disorder, an impulse control disorder, a substance abuse disorder, 50. The method of exemplary embodiment 49, wherein the condition is selected from: chronic myocardial infarction, chronic obstructive pulmonary disease, ... Exemplary embodiment 51: The method of exemplary embodiment 50, wherein the substance abuse disorder is selected from withdrawal symptoms, opiate addiction, nicotine addiction, and ethanol addiction. Exemplary embodiment 52: The method of exemplary embodiment 50, wherein the memory impairment is selected from deficits, loss, and a reduced ability to create new memories. Exemplary embodiment 53: The method of exemplary embodiment 49, wherein the disease or disorder is major depressive disorder. Exemplary embodiment 54: orthorhombic crystal system, P212121 space group, and the following unit cell dimensions: a=5.85088(9) Å, b=11.57133(12) Å, and c=25.8340(3) Å, α=β=γ=90°, V=1749.02(4) Å 3 , a crystalline form of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate, with Z=4. Exemplary embodiment 55: orthorhombic crystal system, P212121 space group, and the following unit cell dimensions: a=8.9035(2) Å, b=10.5404(2) Å, and c=21.3018(5) Å, α=β=γ=90°, V=1999.10(8) Å 3 , a crystalline form of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate dihydrate, with Z=4. Exemplary embodiment 56: Compound A, substantially as described herein:

[0012] [ka] A solid crystalline form of. Exemplary embodiment 57: Compound A, substantially as described herein:

[0013] [ka] Solid crystalline form I of. Exemplary embodiment 58: Compound A, substantially as described herein:

[0014] [ka] Solid crystalline form II. Exemplary embodiment 59: Compound A, substantially as described herein:

[0015] [ka] A solid amorphous form of.

[0016] Additional embodiments of each of the aspects will be apparent from the following description, drawings, examples and claims. As can be understood from the above and following description, each and every feature described herein, and each and every combination of two or more of such features, are included within the scope of the present disclosure, so long as the features are included such that the combinations are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows an experimental X-ray powder diffraction (XRPD) pattern of crystalline Form I of Compound A and a calculated powder X-ray diffraction pattern from the single crystal structure of crystalline Form I of Compound A. [Diagram 2] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form I of Compound A. [Diagram 3] FIG. 3 shows the experimental X-ray powder diffraction (XRPD) pattern of crystalline Form II of Compound A and the calculated powder X-ray diffraction pattern from the single crystal structure of crystalline Form II of Compound A. [Figure 4] FIG. 4 shows the thermogravimetric analysis (TGA) curve of crystalline Form II of Compound A. [Diagram 5] FIG. 5 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form II of Compound A. [Figure 6]FIG. 6 shows the water vapor isotherm (DVS) desorption profile of crystalline Form II of Compound A at 25° C. [Figure 7] FIG. 7 shows an experimental X-ray powder diffraction (XRPD) pattern of the amorphous form of Compound A. [Figure 8] FIG. 8 shows an atomic displacement ellipsoid diagram of crystalline Form I of Compound A based on single crystal X-ray analysis. [Figure 9] FIG. 9 shows a packing diagram of crystalline Form I of Compound A viewed along the axis. [Figure 10] Figure 10 shows a molecular conformation diagram of crystalline Form II of Compound A based on single crystal X-ray analysis. Hydrogen atoms are omitted in the diagram and only heavy atoms (C, N, O) are represented. [Figure 11] FIG. 11 shows a packing diagram of crystalline Form II of Compound A viewed along the axis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] I. Definition Various aspects will now be described more fully hereinafter. However, such aspects may be embodied in many different forms and should not be construed as limiting the embodiments set forth herein, but rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art. As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to show benefit to an individual or subject, which prevents, alleviates, attenuates or otherwise reduces the severity of symptoms of a disease or disorder that responds to NMDA modulation, such as major depressive disorder. When a range of values ​​is provided, each intervening value between the upper and lower limits of that range, as well as any other stated or intervening value in that stated range, is intended to be encompassed within the disclosure. For example, if a range of 1 μm to 8 μm is stated, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are intended to be expressly disclosed, as well as ranges of values ​​equal to or greater than 1 μm and equal to or less than 8 μm. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes not only a single excipient but two or more of the same or different excipients, and the like. The term "about," particularly in reference to a given quantity, is meant to encompass a deviation of plus or minus 5%, 15% or 20%.

[0019] II. Solid State Forms of Compound A Disclosed herein are solid state forms of Compound A and methods for preparing them. A solid state form can be crystalline (the molecules of the solid form are arranged in a long-term regularly repeating crystal lattice that can be described by a unit cell) or amorphous (the molecules of the solid form are not arranged in any significantly regularly repeating manner). Furthermore, particularly with respect to crystalline forms, compound A can be present in the crystal lattice as the only component of the crystal lattice (e.g., compound A is present in the crystalline solid state as an anhydrous form or other non-solvated form). Alternatively, compound A can be present in the crystal lattice together with another molecule (e.g., water or other solvent molecule), which also forms part of the crystal lattice such that it is present in a fixed ratio overall with respect to compound A (e.g., for water, as a dihydrate of compound A). Furthermore, those skilled in the art are also aware that crystalline forms can often be incomplete, where some vacancies may be present in the crystal lattice and / or some impurities (e.g., molecules other than compound A, or stoichiometric solvent molecules) may be present in parts of the crystal lattice. However, even in such imperfect forms, the forms may still be described as being a particular crystalline form (eg, crystalline Form I or crystalline Form II as described herein).

[0020] The solid state forms described herein can be identified by any one or more solid state analytical methods.For example, the crystalline form I and / or crystalline form II of compound A described herein can be characterized by, for example, any one or more of X-ray diffraction (including powder X-ray diffraction), unit cell constant obtained from single crystal, differential scanning calorimetry and thermogravimetry.

[0021] In some embodiments, the solid-state forms described herein can be characterized according to powder X-ray diffraction (XRPD). However, it is known in the art that the intensity and / or measured peaks in the powder X-ray diffractogram of different batches of solid-state forms may vary, for example, due to different experimental conditions and / or preferred adaptations. And, due to the precision of the instrument, the measurement error of 2θ values ​​is ±0.2 2θ. However, despite principles such as experimental and machine errors and preferred adaptations, a person skilled in the art can find enough information in the XRPD data provided herein to identify crystalline Form I and crystalline Form II without having to rely on all of the XRPD provided.

[0022] Thus, "substantially similar" exists between one XRPD pattern and another XRPD pattern if a majority of the peaks (e.g., more than 80 of the peaks) in the range of 0 to 40 degrees 2θ of one XRPD can be found to have corresponding peaks in another XRPD, even if the relative intensities of the corresponding peaks differ. Unless otherwise indicated, XRPD described herein was obtained using Cu K alpha radiation at 1.54 A (λ), 40 kV and 15 mA.

[0023] A. Crystalline Form I of Compound A Provided herein is crystalline Form I of Compound A and a method for preparing same. Crystalline Form I of Compound A is believed to be an anhydrous form of Compound A. In some embodiments, the XRPD of crystalline Form I described herein has peaks (2θ) selected from those having at the following values, each of which is ±0.2 degrees 2θ: 6.9, 8.4, 10.3, and 12.8. In some embodiments, the XRPD of crystalline Form I described herein further has one or more peaks (2θ) selected from those having at the following values, each of which is ±0.2 degrees 2θ: 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9.

[0024] In some embodiments, the XRPD of crystalline Form I described herein may have peaks (2θ) selected from those having the following values: 6.9, 8.4, 10.3, 12.8, and 13.7, each of which is a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline Form I described herein may have peaks (2θ) selected from those having the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, and 15.7, each of which is a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline Form I described herein may have peaks (2θ) selected from those having the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, and 16.8, each of which is a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline Form I described herein may have peaks (2θ) selected from those having the following values, each of which is ±0.2 degrees 2θ: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, and 17.3. In some embodiments, the XRPD of crystalline Form I described herein may have peaks (2θ) selected from those having the following values, each of which is ±0.2 degrees 2θ: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, and 18.5. In some embodiments, the XRPD of crystalline Form I described herein may have 3, 4, or 5 peaks selected from those having the following values ​​of diffraction angle (2θ), each of which is ±0.2 degrees (2θ): 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9.

[0025] In some embodiments, crystalline Form I described herein may have an XRPD substantially similar to one of the XRPDs shown in FIG. In some embodiments, crystalline Form I of Compound A can be characterized according to a DSC thermogram. For example, embodiments of crystalline Form I described herein are provided having a DSC thermogram substantially similar to that shown in Figure 2. For example, embodiments of crystalline Form I described herein are also provided having a DSC with an endothermic peak at about 159°C, e.g., about 159.21°C. In some embodiments, crystalline Form I may be present in a solid composition. In some embodiments, the solid composition may be composed almost entirely of Compound A, but it may contain some additional components (e.g., a solid composition obtained from the synthesis and / or purification of Compound A, where the composition may contain some residual solvent). In such a solid composition, solid Compound A may be present almost entirely as crystalline Form I, or it may be present as a mixture of crystalline Form I and crystalline Form II and / or amorphous solid forms of Compound A. The existence and presence of crystalline Form I in a solid composition may be determined by XRPD, which shows the characteristic 2θ peaks for crystalline Form I as described herein, as well as other characterization techniques as described herein and / or as identifiable to one of skill in the art upon reading this specification.

[0026] In some embodiments, the solid composition may comprise crystalline Form I and may be substantially free of crystalline Form II and / or amorphous form of Compound A. For example, the solid composition comprising crystalline Form I may be at least 99%, at least 95%, at least 90% or at least 80% free by weight of crystalline Form II and / or amorphous form of Compound A. Further, for example, the solid composition comprising crystalline Form I may be at least 70% or at least 60% free by weight of crystalline Form II and / or amorphous form of Compound A. Further, for example, the solid composition comprising crystalline Form I may be at least 50% free by weight of crystalline Form II and / or amorphous form of Compound A. The amount of crystalline Form I relative to crystalline Form II and / or amorphous form of Compound A may be determined by methods identifiable to those skilled in the art, such as, for example, powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry and dynamic vapor sorption.

[0027] In some embodiments, a solid composition comprising crystalline Form I may be substantially free of any other solid form (crystalline or amorphous) of Compound A. For example, a solid composition comprising crystalline Form I may be at least 99%, at least 95%, at least 90% or at least 80% free by weight of any other solid form of Compound A. Further, for example, a solid composition comprising crystalline Form I may be at least 70% or at least 60% free by weight of any other solid form of Compound A. Further, for example, a solid composition comprising crystalline Form I may be at least 50% free by weight of any other solid form of Compound A. The amount of crystalline Form I relative to other forms of Compound A may be determined by methods identifiable to those skilled in the art, such as, for example, powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry and dynamic vapor sorption. In some embodiments, crystalline Form I of Compound A has an orthorhombic crystal system, a P212121 space group, and the following unit cell dimensions: a=5.85088(9) Å, b=11.57133(12) Å, and c=25.8340(3) Å, α=β=γ=90°, V=1749.02(4) Å 3 , having a crystalline form with Z=4.

[0028] A method of preparing crystalline Form I of Compound A, comprising dissolving Compound A in a first solvent (e.g., ethyl acetate) and heating the solution (e.g., to about 65-70° C.); Also provided are methods that include cooling the solution (e.g., to about 25° C.); and adding a second solvent (e.g., diisopropyl ether) to the solution. In some embodiments, the method further includes filtering and drying the collected solid. Also provided is a method for preparing crystalline Form I of Compound A, comprising heating crystalline Form II of Compound A to dehydrate it. In some embodiments, the heating is performed at about 80° C.

[0029] B. Crystalline Form II of Compound A Provided herein is crystalline Form II of Compound A and a method for preparing same. Crystalline Form II of Compound A is believed to be a hydrate form of Compound A.

[0030] In some embodiments, the XRPD of the crystalline Form II described herein has peaks (2θ) selected from those having at the following values, each of which is ±0.2 degrees 2θ: 9.4, 10.8, 11.9, and 13.0. In some embodiments, the XRPD of the crystalline Form II described herein further has one or more peaks (2θ) selected from those having at the following values, each of which is ±0.2 degrees 2θ: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3.

[0031] In some embodiments, the XRPD of the crystalline Form II described herein may have peaks (2θ) selected from those having the following values: 9.4, 10.8, 11.9, 13.0, and 13.7, each of which is a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of the crystalline Form II described herein may have peaks (2θ) selected from those having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, and 16.0, each of which is a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of the crystalline Form II described herein may have peaks (2θ) selected from those having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, and 20.4, each of which is a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of the crystalline Form II described herein may have peaks (2θ) selected from those having the following values, each of which is ±0.2 degrees 2θ: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, and 21.3. In some embodiments, the XRPD of the crystalline Form II described herein may have peaks (2θ) selected from those having the following values, each of which is ±0.2 degrees 2θ: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. In some embodiments, the XRPD of the crystalline Form II described herein may have 3, 4, or 5 peaks selected from those having the following values ​​of diffraction angle (2θ), each of which is ±0.2 degrees (2θ): 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. In some embodiments, crystalline Form II described herein may have an XRPD substantially similar to one of the two XRPDs shown in FIG.

[0032] In some embodiments, the crystalline Form II of Compound A can be characterized by thermogravimetric analysis (TGA). For example, an embodiment of the crystalline Form II described herein is provided having a TGA that shows that the crystalline Form II described herein dehydrates above approximately 60° C. with a loss of approximately 9.5% water by weight. See, for example, FIG. 4. In some embodiments, crystalline Form II of Compound A can be characterized according to a DSC thermogram. The crystalline Form II described herein has a DSC thermogram showing that Form II dehydrates at about 82°C, followed by melting at about 159°C. For example, an embodiment of the crystalline Form II described herein is provided having a DSC thermogram substantially similar to that shown in Figure 5. Upon dehydration, this form converts to crystalline Form I, which melts at about 159°C, e.g., about 159.56°C.

[0033] In some embodiments, crystalline Form II of Compound A can be characterized by DVS (dynamic vapor sorption), which shows that crystalline Form II loses about 11% water at 0% relative humidity (RH) and no water at or above 20% RH. In some embodiments, crystalline Form II may be present in the solid composition. In some embodiments, the solid composition may be composed almost entirely of Compound A, but it may contain some additional components (e.g., a solid composition resulting from the conversion of a composition containing crystalline Form I to a composition containing Form II, where the original composition containing crystalline Form I has some impurities such as residual solvent). In such a solid composition, the solid Compound A may be present almost entirely as crystalline Form II, or it may be present as a mixture of crystalline Form II and crystalline Form I and / or amorphous solid forms of Compound A. The existence and presence of crystalline Form II in the solid composition may be determined by XRPD, which shows the characteristic 2θ peaks for crystalline Form I as described herein, as well as other characterization techniques as described herein and / or as identifiable to the skilled artisan upon reading this specification.

[0034] In some embodiments, the solid composition may comprise crystalline Form II and may be substantially free of crystalline Form I and / or amorphous form of Compound A. For example, the solid composition comprising crystalline Form II may be at least 99%, at least 95%, at least 90%, or at least 80% free by weight of crystalline Form I and / or amorphous form of Compound A. Further, for example, the solid composition comprising crystalline Form II may be at least 70% or at least 60% free by weight of crystalline Form I and / or amorphous form of Compound A. Further, for example, the solid composition comprising crystalline Form II may be at least 50% free by weight of crystalline Form I and / or amorphous form of Compound A. The amount of crystalline Form II relative to crystalline Form I and / or amorphous form of Compound A can be determined by methods identifiable to those skilled in the art, such as, for example, powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor sorption.

[0035] In some embodiments, a solid composition comprising crystalline Form II may be substantially free of any other solid form (crystalline or amorphous) of Compound A. For example, a solid composition comprising crystalline Form II may be at least 99%, at least 95%, at least 90% or at least 80% free by weight of any other solid form of Compound A. Further, for example, a solid composition comprising crystalline Form II may be at least 70% or at least 60% free by weight of any other solid form of Compound A. Further, for example, a solid composition comprising crystalline Form II may be at least 50% free by weight of any other solid form of Compound A. The amount of crystalline Form II relative to other forms of Compound A can be determined by methods identifiable to those skilled in the art, such as, for example, powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry and dynamic vapor sorption.

[0036] In some embodiments, crystalline Form II of Compound A has an orthorhombic crystalline system, a P212121 space group, and the following unit cell dimensions: a=8.9035(2) Å, b=10.5404(2) Å, and c=21.3018(5) Å, V=1999.10(8) Å. 3 It has a crystalline form with

[0037] Also provided is a method of preparing crystalline Form II of Compound A, comprising mixing, e.g., slurrying, crystalline Form I of Compound A with water for a period of time (e.g., about 4 hours). In some embodiments, the method further comprises filtering and drying the solid. In some embodiments, the amount of Compound A slurried in water ranges from 0.1 to 1.0 g per milliliter of water. In other embodiments, the amount of Compound A slurried in water ranges from 0.1 to 5.0 g per milliliter of water.

[0038] C. Amorphous form of compound A Amorphous forms of Compound A and methods for preparing same are also provided. In some embodiments, the amorphous forms described herein may have an XRPD substantially similar to that shown in FIG. In some embodiments, the amorphous form of Compound A may be present in the solid composition. In some embodiments, the solid composition may be composed almost entirely of Compound A, but it may contain some additional components (e.g., a solid composition obtained from spray drying a solution of Compound A in a solvent, which may contain some residual solvent). In such a solid composition, the solid Compound A may be present almost entirely as the amorphous form of Compound A, or it may be present as a mixture of the amorphous form of Compound A and crystalline Form I and / or crystalline Form II of Compound A. The existence and presence of the amorphous form of Compound A in the solid composition can be determined by XRPD showing the appearance of that in Figure 7 (i.e., there is no indication of crystallinity), as well as other characterization techniques described herein and / or identifiable to the skilled artisan upon reading this specification.

[0039] In some embodiments, the solid composition may comprise an amorphous form of Compound A and may be substantially free of crystalline Form I and / or crystalline Form II of Compound A. For example, a solid composition comprising an amorphous form of Compound A may be at least 99%, at least 95%, at least 90%, or at least 80% free by weight of crystalline Form I and / or crystalline Form II of Compound A. Further, for example, a solid composition comprising an amorphous form of Compound A may be at least 70% or at least 60% free by weight of crystalline Form I and / or crystalline Form II of Compound A. Further, for example, a solid composition comprising an amorphous form of Compound A may be at least 50% free by weight of crystalline Form I and / or crystalline Form II of Compound A. The amount of amorphous form relative to crystalline Form I and / or crystalline Form II of Compound A can be determined by methods identifiable to those skilled in the art, such as, for example, powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor sorption.

[0040] In some embodiments, a solid composition comprising crystalline Form I may be substantially free of any other non-amorphous solid forms (e.g., crystalline solid forms) of Compound A. For example, a solid composition comprising crystalline Form I may be at least 99%, at least 95%, at least 90% or at least 80% free by weight of any other non-amorphous solid forms of Compound A. Further, for example, a solid composition comprising an amorphous form of Compound A may be at least 70% or at least 60% free by weight of any other non-amorphous solid forms of Compound A. Further, for example, a solid composition comprising an amorphous form of Compound A may be at least 50% free by weight of any other non-amorphous solid forms of Compound A. The amount of amorphous form relative to other forms of Compound A may be determined by methods identifiable to those skilled in the art, such as, for example, powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry and dynamic vapor sorption.

[0041] Also provided is a method of preparing an amorphous form of Compound A, comprising drying a solution of Compound A in a solvent. In some embodiments, the solvent is acetone. In some embodiments, the ratio of Compound A to acetone (g / mL) is in the range of 0.05 to 0.2. In some embodiments, the drying is performed in the form of spray drying.

[0042] III. Pharmaceutical Compositions and Uses Thereof A pharmaceutical composition is provided comprising crystalline Form I of Compound A and a pharma- ceutically acceptable excipient. In some embodiments, crystalline Form I of Compound A is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of Compound A in the pharmaceutical composition. A pharmaceutical composition is provided comprising crystalline Form II of Compound A and a pharma- ceutically acceptable excipient. In some embodiments, crystalline Form II of Compound A is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of Compound A in the pharmaceutical composition. A pharmaceutical composition is provided that includes an amorphous form of Compound A and a pharma- ceutically acceptable excipient. In some embodiments, the amorphous form of Compound A is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of Compound A in the pharmaceutical composition.

[0043] Representative excipients must be compatible with other components of the composition and must not be harmful to the patient's health. The excipients may be solid or liquid or both and may be formulated with Compound A, e.g., crystalline Form I, crystalline Form II and / or amorphous forms described herein, as a single dose, e.g., as a tablet or capsule, which may be prepared with 0.05% to 95% by weight of Compound A described herein. The pharmaceutical compositions described herein may be produced by known pharmaceutical methods, e.g., a method comprising mixing the ingredients with pharma- ceutically acceptable excipients. In some embodiments, representative excipients may include, but are not limited to, microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, disintegrants such as starch, cross-linked sodium carboxymethylcellulose, synthetic silicates and polyethylene glycols having high molecular weight, granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic, and lubricants such as magnesium stearate, glycerin and talc.

[0044] Also provided is a method of treating a subject in need of treatment for a disease or disorder responsive to NMDA modulation, comprising administering to said subject in need thereof a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a solid form of Compound A selected from crystalline Form I, crystalline Form II, and an amorphous form of Compound A as disclosed herein. The disease or disorder can be a psychiatric disease or disorder, a nervous system disease or disorder, or a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, psychiatric disorders, psychotic symptoms, social withdrawal, obsessive-compulsive disorder (OCD), phobias, post-traumatic stress syndrome, behavioral disorders, impulse control disorders, substance abuse disorders (e.g., withdrawal symptoms, opiate addiction, nicotine addiction, and ethanol addiction), sleep disorders, memory disorders (e.g., deficits, loss, or decreased ability to create new memories), learning disabilities, urinary incontinence, multiple systemic disorders, and the like. The disease is selected from optic atrophy, progressive supranuclear palsy, Friedreich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivopontocerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasms, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain and chronic neuropathic pain. In some embodiments, the disease or disorder is major depressive disorder. EXAMPLES

[0045] IV. Working Examples The following examples are illustrative in nature and are not intended to be limiting in any way. Unless otherwise indicated, powder X-ray diffractograms were obtained using a Rigaku MiniFlex 600 equipped with a D / tex detector by placing the sample in a zero background sample holder with radiation generated from a Cu Kα source at 15 mA and 40 kV, and the instrument was operated over the range 3–45° 2θ with a scan step of 0.02° and a scan rate of 2° / min. DSC: Thermograms were obtained using a TA Instruments DSC Q2000. Approximately 1-2 mg of sample was weighed into a Tzero aluminum pan and sealed with a Tzero sealing lid. For crystalline Form II samples, the lid was pierced with a pinhole. - DSC: Samples were scanned from 20 to 180°C at 10°C / min. TGA: Approximately 5-10 mg of sample was heated from room temperature to 250° C. at 10° C. / min. DVS: The following method was used for water vapor sorption analysis using the DVS Advantage (Surface Measurement System). - Temperature: 25℃ - RH Program: 95, 90, 80, 70, 60, 50, 40, 35, 30, 20, 10, 0% - Dm / dt(% / min):0.0005 - Minimum equilibration time: 120 minutes - Maximum equilibration time: 2000 minutes

[0046] Single crystal analysis of crystalline Form I of Compound A was performed on a Rigaku SuperNova diffractometer, single Cu Kα (λ=1.54184 Å) microfocus source, using a Pilatus 200K hybrid pixel array detector at 300 K. Refinement was performed using ShelXL. Single crystal analysis of crystalline Form II of Compound A was performed on a Bruker AXS D8 Quest CMOS diffractometer equipped with a 4-axis kappa stage using Cu Kα radiation (λ=1.54178 Å), an I-μ-S microsource X-ray tube with laterally graded multilayer optics, a Photon2 CMOS area detector, and an Oxford Cryosystems cryodevice at 150 K.

[0047] Example 1 Preparation of Form I of Compound A Crystalline Form I of Compound A was prepared according to the following scheme.

[0048] [ka]

[0049] Step 1: Synthesis of compound H A nitrogen purged reactor was charged with acetonitrile, D-proline (69.0 kg), molecular sieves and chloral hydrate (106 kg). The mixture was heated at 50° C. for 5.3 hours. Proton NMR showed complete conversion. The reaction mixture was filtered through a pad of acetonitrile-wet celite and rinsed through with acetonitrile. The filtrate was concentrated under vacuum at less than 45° C. to a total volume of 100 L. n-Butanol (140 L) was added and the mixture was concentrated under vacuum at less than 45° C. for 3.5 hours until no further distillate was observed. The mixture was kept at 20° C. overnight, then cooled to 0-5° C. and stirred. The precipitate was collected by pressure filtration and then washed with n-butanol. The resulting solid was dried under vacuum at 45° C. to give compound H (108.7 kg, 74.2% yield). 1 H-NMR (DMSO-d6) δ 1.1-1.4 (m, 1H), 1.4-1.7 (m, 1H), 1.7-2.0 (m, 1H), 2.1-2.5 (m, 1H), 3.2-3.4 (m, 1H), 3.5-3.8 (m, 1H), 4.1-4.4 (m, 1H), 5.8 (s, 1H). MS (ESI) m / z (M-H+2H2O) -277.94.

[0050] Step 2: Synthesis of compound F A nitrogen purged reactor was charged with toluene, MTBE and compound H (1 equiv). The resulting solution was cooled to -55 to -45°C. A solution of lithium diisopropylamide (LDA) (26.8%, 1.1 equiv) in THF / n-heptane / ethylbenzene was added over 1.3 hours at -50 to -44°C. The resulting solution was stirred at -45±5°C for 37 minutes and then cooled to -75 to -65°C. A solution of methyl formate (2 equiv) in MTBE was added over 45 minutes at below -60°C and then rinsed with MTBE. The mixture was stirred at -70 to -60°C for 44 minutes. A second reactor was flushed with nitrogen and charged with deionized water and citric acid monohydrate. The resulting solution was cooled to 0 to 5°C and the contents of the first reactor were added over 53 minutes at below 10°C and rinsed with MTBE. The mixture was warmed to 11° C. and the phases were separated. The aqueous layer was extracted with MTBE and then discarded. The main organic layer, followed by the MTBE wash, was washed with a solution of sodium chloride in water (57%) (1.8 vol). The combined organics were concentrated under vacuum below 50° C. Toluene (2×) was added and the mixture was concentrated after each addition until the total volume was 47 L. The mixture was cooled to 35° C. and diluted with methylene chloride to give compound F as a crude solution in 65.1% yield. Crystallization of a sample of crude compound F from MTBE / hexane provided an analytical sample. 1 H-NMR (DMSO-d6) δ 1.7-1.8 (m, 1H), 1.8-1.9 (m, 1H), 2.2-2.3 (m, 2H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 1H), 5.9 (s, 1H), 9.5 (s,1H). MS (ESI) m / z (M+H) + 272.0.

[0051] Step 3: Synthesis of compound D A nitrogen purged reactor was charged with the solution of crude compound F, methylene chloride, and compound G (1.2 equiv.). The resulting suspension was heated to 30-35° C. for 6 hours, then compound E was stirred at 20-25° C. overnight. An analytical sample of compound E was isolated via silica gel column chromatography (methylene chloride / ethyl acetate eluent) followed by crystallization from ethyl acetate / hexanes. 1 H-NMR (DMSO-d6) δ 1.2 (d, 3H, J = 8 Hz ), 1.8-1.9 (m, 2H), 2.0-2.1 (m, 1H), 2.2-2.3 (m, 1H), 3.1-3.2 (m, 1H), 3.2-3.3 (m, 1H), 3.6-3.8 (m, 2H), 4.7 (d, 2H, J = 15 Hz), 5.5 (s,1H), 7.2 (s, 1H), 7.5 (s, 1H). MS (ESI) m / z (M+H) + 372.0.

[0052] The crude compound E mixture was cooled to 20° C. and sodium triacetoxyborohydride (3.0 equiv.) was added over 1.5 h at 20-29° C., then the mixture was stirred at 30-35° C. for 5 h. Water was added over 49 min at 15-20° C. with gas evolution. The medium was stirred and then the phases were separated. The aqueous layer was extracted twice with methylene chloride (2×). The combined organics were washed with saturated aqueous sodium bicarbonate. The methylene chloride extract was assayed by HPLC as containing pure compound D in 78.9% yield. An analytical sample of compound D was crystallized from toluene / hexane and water. 1 H-NMR (DMSO-d6) δ 1.1 (d, 3H, J = 8 Hz ), 1.8-1.9 (m, 2H), 2.0-2.1 (m, 2H), 2.7-2.8 (m, 2H), 3.1-3.2 (m, 1H), 3.3-3.4 (m, 1H), 3.6-3.7 (m, 1H), 4.7 (d, 2H, J = 6 Hz), 5.6 (s,1H), 7.0 (s, 1H), 7.1 (s, 1H). MS (ESI) m / z (M+H) + 374.1.

[0053] Step 4: Synthesis of compound C The crude solution of compound D was concentrated under vacuum at less than 45° C. to a total volume of 110 L. Acetonitrile was added and the mixture was concentrated to a total volume of 110 L. Acetonitrile, water and triethylamine (6 eq.) were added and the mixture was heated to 45° C. and then stirred. The mixture was concentrated under vacuum at less than 50° C. to a total volume of less than 110 L. Acetonitrile and then isopropanol were added. The mixture was cooled to 15-20° C., MTBE was added at 15-20° C. over 1 h, the resulting slurry was stirred at 15-20° C. and the product was collected by filtration. The crude solid was slurried in methanol and stirred at 60-65° C., then the suspension was cooled slowly to 20-25° C. The product was collected by filtration, washed with methanol and the solid was dried under vacuum at 50° C. to give compound C in 72.4% yield. 1 H-NMR (MeOH-d4) δ 1.23 (3H, d, J = 6.4Hz); 1.9-2.1 (m, 3H), 2.2-2.3 (m, 1H), 2.9 (d, 1H, J = 13Hz), 3.0 (d, 1H, J = 6 Hz), 3.1 (d, 1H, J = 13Hz), 3.2-3.3 (m, 1H), 3.4-3.5 (m, 1H), 3.8 (quintet, 1H, J=6Hz). MS (ESI) m / z (M+H) + 246.2.

[0054] Step 5: Synthesis of compound B Acetone, water and compound C (1 eq.) were charged successively to a nitrogen purged reactor. Triethylamine (6 eq.) was added to the medium below 30° C. for 20 min and rinsed with acetone. A solution of di-tert-butyl dicarbonate (1.3 eq.) was added to the mixture below 30° C. and rinsed with acetone (13 L). The mixture was stirred at 20-30° C. A solution of di-tert-butyl dicarbonate (0.5 eq.) in acetone was added to the mixture. A solution of di-tert-butyl dicarbonate (0.5 eq.) in acetone was added. The mixture was concentrated at atmospheric pressure to a total volume of 65 L. Acetone, then THF, was added and the mixture was concentrated to a total volume of 65 L. The resulting suspension was cooled to 0-5° C., then the precipitate was collected by filtration, washed with THF, and dried under vacuum at 45° C. to give compound B in 90.5% yield. 1 H-NMR (DMSO-d6) δ 1.1 (d, 3H, J = 6 Hz ), 1.3 (s, 5H), 1.4 (s, 4H), 1.7-1.8 (m, 2H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.5-3.1 (m, MS (ESI) m / z (M+H) + 346.3.

[0055] Step 6: Synthesis of compound A A nitrogen purged reactor was charged with THF and compound B (1 equiv). Triethylamine (1.8 equiv) was added at 20-25° C. and rinsed with THF. A solution of diethyl chlorophosphate (1.8 equiv) in THF was added at 20-33° C. After stirring at 25-33° C., a solution of sodium chloride in water was added at 25-30° C. and the phases were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organics were concentrated under vacuum below 60° C. to a total volume of 65-70 L. Ethyl acetate was added and the mixture was concentrated to a total volume of 65-70 L. Ethyl acetate was added to the mixture followed by a solution of sodium chloride in water (60 L). Phosphoric acid was then added to adjust the pH to 2.0. The mixture was stirred at 20-25° C., the phases were separated and the aqueous was discarded. The organic layer was washed with a mixture of sodium chloride and aqueous ammonia, and the washes were back-extracted with ethyl acetate. The combined organics were mixed with activated charcoal, stirred overnight, then filtered through ethyl acetate-wet celite, rinsing through ethyl acetate. The filtrate was concentrated under vacuum at less than 60° C. to a total volume of 100 L. Ethyl acetate was added and the mixture was concentrated to 100 L after each addition. Ethyl acetate was added and the mixture was cooled to 20-25° C. The mixture was heated to 45-55° C. and the remaining solids were removed by filtration, washed with ethyl acetate, and discarded.

[0056] Step 7: Crystallization of Crystalline Form I of Compound A The filtrate was concentrated under vacuum below 60° C. to a total volume of 105 L. The mixture was heated to 65-70° C. and then cooled to 25° C. Diisopropyl ether was added and the mixture was stirred at 20-25° C. The precipitate was collected by filtration, washed with diisopropyl ether, and then dried at 50° C. to give compound A as a white crystalline powder in 62.7% yield. 1 H-NMR (DMSO-d6) δ 1.1 (m, 3H), 1.3 (s, 4H), 1.4 (s, 5H), 1.7-1.9 (m, 2H), 2.0-2.3 (m, 2H), 3.1-3.5 (m, 3H), 3.5-4.0 (m, 3H), 4.9 (m, 1H), 7.1-7.6 (m, 2H). MS (ESI) m / z (M+Na)+ 350.2. The XRPD obtained on the sample of Compound A obtained above was substantially the same as that in FIG. 1 (top panel), indicating crystalline Form I of Compound A.

[0057] The powder X-ray diffraction pattern calculated from the single crystal structure of crystalline Form I of Compound A is shown in FIG. Atomic displacement ellipsoid diagrams and packing diagrams of crystalline Form I of Compound A based on single crystal X-ray analysis are shown in Figures 8-9. Crystalline Form I of Compound A has an orthorhombic crystal system, P212121 space group, and the following unit cell dimensions: a=5.85088(9) Å, b=11.57133(12) Å, and c=25.8340(3) Å, α=β=γ=90°, V=1749.02(4) Å. 3 , Z=4. For Z=4 and a formula weight of 327.38 g / mol, the calculated density is 1.243 g / cm 3 It is. Computer programs used for single crystal analysis and calculated XRPD include ShelXL, CrysAlisPro, Olex2, ShelXT and Mercury.

[0058] Example 2 Preparation of Form II of Compound A In one experiment, about 200 mg of crystalline Form I of Compound A from Example 1 was weighed into a 4 mL scintillation vial, and 1 mL of Milli-Q water was added to the vial. The vial was rotated thoroughly at room temperature for 12 days. The residue was vacuum filtered and air-dried at room temperature for 2 days (about 22° C. and 60% RH). The dried solid was ground with a mortar and pestle, after which the XRPD shown in the top panel of FIG. 3 was obtained. The solid was also subjected to DVS measurement and lost about 11% water at 0% RH. The DVS plot is shown in Figure 6, which shows that crystalline Form II of Compound A did not lose water at or above 20% RH. In another experiment, about 2 g of crystalline Form I of Compound A from Example 1 was weighed into a 20 mL scintillation vial, and 4 mL of Milli-Q water was added to the vial. The resulting suspension was stirred with a spatula and left at room temperature for 1 day. The residue was then filtered under vacuum and dried in a vacuum oven at room temperature for about 20 hours. An XRPD was obtained after drying, and Form II was confirmed as it was substantially the same as the upper panel of Figure 3. A DSC, shown in Figure 5, was obtained after drying, and showed a possible dehydration event at about 82°C, followed by melting at about 159°C. A TGA obtained after drying, shown in Figure 4, showed a mass loss of 9.6%, consistent with that of a dihydrate. The dried sample was then dehydrated in a TGA pan at 80°C (ramp from room temperature to 80°C at 10°C / min, then isothermal for 2 minutes). XRPD and DSC were performed on the dehydrated sample and confirmed that the sample was mostly crystalline Form I with residual amorphous content and very small amounts of crystalline Form II.

[0059] The X-ray diffraction pattern calculated from the single crystal structure of crystalline Form II of Compound A is shown in the lower panel of FIG. Atomic conformation and packing diagrams of crystalline Form II of Compound A based on single crystal X-ray analysis are shown in Figures 10-11. Crystalline Form II of Compound A has an orthorhombic crystal system, P212121 space group, and the following unit cell dimensions: a=8.9035(2) Å, b=10.5404(2) Å, and c=21.3018(5) Å, α=β=γ=90°, V=1999.10(8) Å. 3 , Z=4. For Z=4 and a formula weight of 363.41, the calculated density is 1.207 g / cm 3 It is. Computer programs used for single crystal analysis and calculated XRPD include Apex3 v2017.3-0 (Bruker, 2017), SAINT V8.38A (Bruker, 2016), SHELXS97 (Sheldrick, 2008), SHELXL2018 / 3 (Sheldrick, 2015, 2018), SHELXLE Rev937 (Hubschle et al., 2011).

[0060] Example 3 Preparation of Amorphous Form of Compound A One gram of crystalline Form I of Compound A was dissolved in 10 mL of acetone. The material was spray dried using a Buchi Mini Spray Dryer B-290. The inlet temperature is 65° C. and the outlet temperature is 44° C. The spray dried material weighed 0.44 g (44% yield) and was analyzed using XRPD. The XRPD is shown in FIG. 7.

[0061] Example 4 Conversion between crystalline form I and crystalline form II Competitive slurries in mixtures of water and isopropanol show that the phase boundary between crystalline Form I and crystalline Form II is between water activities of 0.66 and 0.78 at 25° C. At water activities above 0.78, crystalline Form II is the stable form, while at water activities below 0.66, crystalline Form I is the stable form.

[0062] Throughout this specification, references are made to publications such as U.S. and foreign patent applications, journal articles, book chapters, etc. All such publications are expressly incorporated by reference in their entirety, including any supplemental / supporting information sections published with the corresponding reference, for all purposes, unless otherwise indicated.

[0063] While a number of exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain modifications, variations, additions and subcombinations thereof, and it is therefore intended that the following appended claims and the claims introduced hereinafter shall be construed to include all such modifications, variations, additions and subcombinations as are within their true spirit and scope. Preferred aspects of the present invention are as follows. [1] Compound A: TIFF0007617043000011.tif3946 1. A process for preparing solid crystalline Form I of dissolving compound A in ethyl acetate and heating the solution; cooling the solution; and adding diisopropyl ether to the solution. A method comprising: [2] The method according to [1] above, wherein the solution is heated to about 65°C to about 70°C. [3] The method according to [1], wherein the solution is cooled to about 25°C. [4] The method according to any one of [1] to [3] above, wherein the solid crystalline form I of compound A has a peak (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 6.9, 8.4, 10.3, and 12.8. [5] The method according to [4] above, wherein the solid crystalline form I of compound A further has one or more peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 13.7, 15.3, 15.7, 16.8, 17.3, 18.5 and 19.9. [6] The method according to any one of [1] to [3] above, wherein the solid crystalline form I of compound A has a peak (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 6.9, 8.4, 10.3, 12.8 and 13.7. [7] The method according to any one of [1] to [3] above, wherein the solid crystalline form I of compound A has a peak (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3 and 15.7. [8] The method according to any one of [1] to [3] above, wherein the powder X-ray diffraction pattern has peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, and 16.8. [9] The method according to any one of [1] to [3] above, wherein the solid crystalline form I of compound A has a peak (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8 and 17.3.

[10] The method according to any one of [1] to [3] above, wherein the solid crystalline form I of compound A has a peak (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3 and 18.5.

[11] The method according to any one of [1] to [3] above, wherein the solid crystalline form I of compound A has 3, 4 or 5 peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5 and 19.9.

[12] The method according to any one of [1] to [3] above, wherein the solid crystalline form I of compound A has an XRPD pattern substantially similar to one of the XRPD patterns shown in Figure 1.

[13] The method according to any one of [1] to

[12] above, wherein the solid crystalline form I of compound A has a DSC with an endothermic peak at about 159°C.

[14] Compound A: TIFF0007617043000012.tif4047 A solid crystalline form of A solid crystalline form of Compound A, which is crystalline Form II.

[15] The solid crystalline form according to

[14] above, having peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 9.4, 10.8, 11.9 and 13.0.

[16] The solid crystalline form according to

[15] , further having one or more peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3 and 23.3.

[17] The solid crystalline form according to

[14] above, having peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0 and 13.7.

[18] The solid crystalline form according to

[14] above, having peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5 and 16.0.

[19] The solid crystalline form according to

[14] above, having peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0 and 20.4.

[20] The solid crystalline form according to

[14] above, having peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4 and 21.3.

[21] The solid crystalline form according to

[14] above, having peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3 and 23.3.

[22] The solid crystalline form according to

[14] above, having 3, 4 or 5 peaks (2θ) selected from those having approximately the following values ​​in a powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3 and 23.3.

[23] The solid crystalline form according to

[14] above, having an XRPD pattern substantially similar to one of the two XRPD patterns shown in Figure 3.

[24] The solid crystalline form according to any one of

[14] to

[23] above, having a DSC with endothermic peaks at about 82°C and about 159°C.

[25] The solid crystalline form according to any one of

[14] to

[24] above, having a TGA showing dehydration above approximately 60° C. with a loss of approximately 9.6% by weight of water.

[26] The solid crystalline form according to any one of

[14] to

[25] above, having a DVS that exhibits a mass change of about 11% at 0% RH and 25°C, and mass loss of water at or above 20% RH.

[27] A solid composition comprising the solid crystalline form according to any one of

[14] to

[26] above, wherein the solid composition is free of any other solid form of Compound A at least 99%, at least 95%, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% by weight.

[28] A pharmaceutical composition comprising the solid crystalline form according to any one of

[14] to

[26] above and a pharma- ceutical acceptable excipient.

[29] The pharmaceutical composition according to

[28] , wherein the solid crystalline form is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition.

[30] Compound A: TIFF0007617043000013.tif4046 A solid amorphous form of.

[31] The solid amorphous form according to

[30] above, having an amorphous halo in a powder X-ray diffraction pattern.

[32] The solid amorphous form according to

[30] above, having an XRPD pattern substantially similar to that shown in FIG. 7.

[33] A pharmaceutical composition comprising the amorphous form according to any one of

[30] to

[32] above and a pharma- ceutical acceptable excipient.

[34] The pharmaceutical composition according to

[33] , wherein the amorphous form is at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, or at least 50% by weight of the total amount of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition.

[35] A method for treating a subject in need of treatment for a disease or disorder responsive to NMDA modulation, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition described in any one of

[28] ,

[29] ,

[33] and

[34] .

[36] The disease or disorder is selected from the group consisting of autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, psychiatric disorder, psychotic symptoms, social withdrawal, obsessive-compulsive disorder (OCD), phobia, post-traumatic stress syndrome, behavioral disorder, impulse control disorder, substance abuse disorder, sleep disorder, memory disorder, learning disorder, urinary incontinence, multiple system atrophy, progressive supranuclear palsy, Friedreich's ataxia, Down's syndrome, fragile X syndrome, and tuberous sclerosis. 36. The method according to claim 35, wherein the medical condition is selected from the group consisting of glaucoma, olivopontocerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasms, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, and chronic neuropathic pain.

[37] The method according to

[36] , wherein the substance abuse disorder is selected from withdrawal symptoms, opiate addiction, nicotine addiction and ethanol addiction.

[38] The method according to

[36] above, wherein the memory impairment is selected from deficits, loss, and a reduced ability to create new memories.

[39] The method according to

[35] above, wherein the disease or disorder is major depressive disorder.

[40] Orthorhombic system, P2 1 2 1 2 1 Space group and the following unit cell dimensions: a=8.9035(2) Å, b=10.5404(2) Å and c=21.3018(5) Å, α=β=γ=90°, V=1999.10(8) Å 3 , a crystalline form of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate dihydrate, with Z=4.

[41] Compound A, substantially as described herein: TIFF0007617043000014.tif4047 Solid crystalline form II.

[42] Compound A, substantially as described herein: TIFF0007617043000015.tif4047 A solid amorphous form of.

Claims

1. Compound A: 【Chemistry 1】 1. A method for preparing solid crystalline Form I of dissolving compound A in ethyl acetate and heating the solution; cooling the solution; and adding diisopropyl ether to the solution. A method comprising:

2. The method of claim 1, wherein the solution is heated to about 65°C to about 70°C.

3. The method of claim 1 , wherein the solution is cooled to about 25° C.

4. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, and 12.

8.

5. 5. The method of claim 4, wherein the solid crystalline Form I of Compound A further has one or more peaks (2θ) in an X-ray powder diffraction pattern selected from those having approximately the following values: 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.

9.

6. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, and 15.

7.

7. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A has, in an X-ray powder diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, and 16.

8.

8. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, and 17.

3.

9. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A has, in a powder X-ray diffraction pattern, peaks (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, and 18.

5.

10. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A has 3, 4 or 5 peaks (2θ) selected from those having approximately the following values ​​in an X-ray powder diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5 and 19.

9.

11. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A has a DSC with an endothermic peak at about 159°C.

12. The solid crystalline form I of Compound A is an orthorhombic crystal system, P2 1 2 1 2 1 Space group, and the following unit cell dimensions: a=5.85088(9) Å, b=11.57133(12) Å and c=25.8340(3) Å, α=β=γ=90°, V=1749.02(4) Å 3 2. The method of claim 1 , wherein the compound has a crystalline form with Z=4.

13. 2. The method of claim 1, wherein the solid crystalline Form I of Compound A is anhydrous.

14. Orthorhombic system, P2 1 2 1 2 1 Space group, and the following unit cell dimensions: a=5.85088(9) Å, b=11.57133(12) Å and c=25.8340(3) Å, α=β=γ=90°, V=1749.02(4) Å 3 A crystalline form of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate, having Z=4.

15. Compound A: 【Chemistry 2】 and a pharma- ceutical composition comprising crystalline Form I of Compound A and a pharma- ceutical acceptable excipient, wherein crystalline Form I of Compound A is an orthorhombic crystal, P2 1 2 1 2 1 Space group, and the following unit cell dimensions: a=5.85088(9) Å, b=11.57133(12) Å and c=25.8340(3) Å, α=β=γ=90°, V=1749.02(4) Å 3 , Z=4.

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