Crystalline compounds

Abstract

A specific polymorph of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane is required. [Solution] The present invention relates to the crystalline form of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, compositions containing the same, and methods for producing and using the same.

Description

[Technical Field]

[0001] This application claims priority based on U.S. Provisional Application No. 62 / 181,174, filed on 17 June 2015, the contents of which are incorporated herein by reference.

[0002] The present invention relates to the crystalline form of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, compositions containing the same, and methods for producing and using the same. [Background technology]

[0003] (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane, is a useful unbalanced triple reuptake inhibitor (TRI) that is most effective against norepinephrine (NE) reuptake, has one-sixth the effectiveness against dopamine (DA) reuptake, and exhibits one-fourteenth the effectiveness against serotonin (5-HT) reuptake. The compound and its usefulness are disclosed in detail in U.S. Patent Application Publication No. 2007 / 0082940, which is incorporated herein by reference. [Overview of the project] [Problems that the invention aims to solve]

[0004] Pharmaceutical active ingredients can exist in different physical forms (e.g., different crystalline, amorphous, hydrated, or solvated forms; liquid or solid), and the processability, stability, solubility, bioavailability, pharmacokinetics (absorption, distribution, metabolism, excretion, etc.), and / or bioequivalence of the pharmaceutical active ingredients and the pharmaceutical compositions containing them may differ. It is unpredictable whether a compound exists in a particular polymorph. Generating and identifying advantageous physical forms of pharmaceutical active ingredients (e.g., free bases or salts in solid, liquid, crystalline, hydrated, solvated, or amorphous forms) is important in pharmaceutical development. Therefore, a specific polymorph of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane is needed. [Means for solving the problem]

[0005] (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane ("the compound"), also known as (+)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane, is represented by the following formula I: [ka] Equation I

[0006] The inventors have identified specific polymorphs of the hydrochloride addition salt form of this compound. These specific polymorphs have different stability and solubility properties and are particularly advantageous for the production of a wide variety of galenic formulations, with crystalline form A, shown below, being particularly useful. Accordingly, in a first embodiment, the present invention provides crystalline forms of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example: 1.1 Crystalline form A of the hydrochloride addition salt form of this compound ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride). 1.2 Belongs to the P212121 space group, with the following unit cell parameters: a=5.7779(2)Å, b=8.6633(2)Å, c=25.7280(8)Å, α=β=γ=90゜ Item 1.1 is a crystal form A having the characteristics of . 1.3 Belonging to the P212121 space group, and possessing any of the following combinations of unit cell parameters: a = 5~7 Å, e.g., 6 Å, e.g., 5.6~5.9 Å, e.g., 5.7~5.8 Å, e.g., 5.8 Å, e.g., 5.78 Å, e.g., 5.778 Å; b = 8~10 Å, e.g., 9 Å, e.g., 8.5~8.8 Å, e.g., 8.6~8.7 Å, e.g., 8.7 Å, e.g., 8.66 Å, e.g., 8.663 Å; c = 25~27 Å, e.g., 26 Å, e.g., 25.6~25.9 Å, e.g., 25.7~25.8 Å, e.g., 25.7~25.8 Å, e.g., 25.73 Å, e.g., 25.728 Å; and α=β=γ=90° Item 1.1 is a crystal form A having the characteristics of . 1.4 Crystal form A is V = 1287.83(7) Å 3 Any of items 1.1 to 1.3, having the calculated volume of the following: 1.5 A crystal of crystal form A having an approximate volume of 0.38 mm × 0.30 mm × 0.18 mm, for example, a colorless plate-like crystal having an approximate volume of 0.38 mm × 0.30 mm × 0.18 mm, as described in any of items 1.1 to 1.4. 1.6 The crystal structure of crystal form A is obtained using Mo Kα radiation, for example, Mo Kα radiation at λ=0.71073 Å, according to any of sections 1.1 to 1.5. 1.7 The crystal structure of crystal form A is obtained at 150K, according to any of sections 1.1 to 1.6. 1.8 Crystal form A has a single crystal structure as shown in the ORTEP diagram in Figure 18, one of the properties of items 1.1 to 1.7. 1.9 Crystal form A has one of the calculation XRPD patterns shown in Figure 23, according to any of items 1.1 to 1.8. 1.10 The crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five 2θ(°) values ​​selected from the group consisting of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.9. 1.11 Any of items 1.1 to 1.10, where crystal form A exhibits an XRPD pattern containing 2θ(°) values ​​of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9 and 25.7, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.12 The crystal form A exhibits an XRPD pattern with characteristic 2θ(°) values ​​of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9 and 25.7, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.11. 1.13 The crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five 2θ(°) values ​​selected from the group consisting of 15.42, 16.55, 17.15, 18.50, 19.45, 20.46, 20.68, 22.90, and 25.69, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.12. 1.14 The crystal form A exhibits an XRPD pattern containing 2θ(°) values ​​of 15.42, 16.55, 17.15, 18.50, 19.45, 20.46, 20.68, 22.90 and 25.69, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, any of items 1.1 to 1.13. 1.15 Crystal form A exhibits an XRPD pattern with characteristic 2θ(°) values ​​of 15.42, 16.55, 17.15, 18.50, 19.45, 20.46, 20.68, 22.90 and 25.69, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.14. 1.16 Crystal form A is as follows (Table A): Table A [Table 1] The XRPD pattern exhibits at least three, e.g., at least five 2θ(°) values ​​selected from those shown, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.15. 1.17 Any of items 1.1 to 1.16, wherein crystal form A exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table A of item 1.16, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.18 The crystal form A exhibits an XRPD pattern with characteristic 2θ(°) values ​​shown in Table A of item 1.16, the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, or any of items 1.1 to 1.17. 1.19 The crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least ten 2θ(°) values ​​selected from the group consisting of 12.3, 13.8, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.18. 1.20 Crystal form A exhibits an XRPD pattern containing 2θ(°) values ​​of 12.3, 13.8, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.5, 20.7, 22.9 and 25.7, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.19. 1.21 Crystal form A exhibits an XRPD pattern with typical 2θ(°) values ​​of 12.3, 13.8, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.5, 20.7, 22.9 and 25.7, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.20. 1.22 The crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least ten 2θ(°) values ​​selected from the group consisting of 12.26, 13.78, 15.42, 16.55, 17.15, 18.19, 18.50, 19.45, 20.46, 20.68, 22.90, and 25.69, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.21. 1.23 Crystal form A exhibits an XRPD pattern containing 2θ(°) values ​​of 12.26, 13.78, 15.42, 16.55, 17.15, 18.19, 18.50, 19.45, 20.46, 20.68, 22.90 and 25.69, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.22. 1.24 Crystal form A exhibits an XRPD pattern with typical 2θ(°) values ​​of 12.26, 13.78, 15.42, 16.55, 17.15, 18.19, 18.50, 19.45, 20.46, 20.68, 22.90 and 25.69, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.23. 1.25 Crystal form A is shown in Table B below: Table B [Table 2] The XRPD pattern exhibits at least three, e.g., at least five, e.g., at least ten 2θ(°) values ​​selected from those shown, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.24. 1.26 Any of items 1.1 to 1.25, where crystal form A exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table B of item 1.25, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.27 Crystal form A exhibits an XRPD pattern with typical 2θ(°) values ​​shown in Table B of item 1.25, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.26. 1.28 The crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty 2θ(°) values ​​selected from the group consisting of 6.9, 12.3, 13.8, 14.5, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.1, 20.5, 20.7, 21.0, 21.5, 22.9, 24.7, 25.2, 25.4, 25.7, 26.4, 27.5, and 27.8, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty 2θ(°) values, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty 20 2θ(°) values, e.g., at least five five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty 20 2θ( 1.29 Crystal form A has the following 2θ(°) values: 6.9, 12.3, 13.8, 14.5, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.1, 20.5, 20.7, 21.0, 21.5, 22.9, 24.7, 25.2, 25.4, 25.7, 26.4, 27.5, and 27.8 The XRPD pattern includes any of items 1.1 to 1.28, where the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, and where the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.30 Crystal form A 6.87, 12.26, 13.78, 14.49, 15.42, 16.55, 17.15, 18.19, 18.50, 19.45, 20.06, 20.46, 20.68, 20.96, 21.54, 22.90, 24.69, 25.17, 25.44, 25.69, 26.36, 27.52, and 27.76 The XRPD pattern exhibits at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty 2θ(°) values ​​selected from the group consisting of the following, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.29. 1.31 Crystal form A has the following 2θ(°) values: 6.87, 12.26, 13.78, 14.49, 15.42, 16.55, 17.15, 18.19, 18.50, 19.45, 20.06, 20.46, 20.68, 20.96, 21.54, 22.90, 24.69, 25.17, 25.44, 25.69, 26.36, 27.52, and 27.76 The XRPD pattern includes any of items 1.1 to 1.30, where the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, and where the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.32 Crystal form A is shown in Table C below: Table C [Table 3] The XRPD pattern exhibits at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty 2θ(°) values ​​selected from those shown, wherein the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.31. 1.33 The crystal form A exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table C of item 1.32, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.32. 1.34 Any of items 1.1 to 1.33, wherein crystal form A exhibits an XRPD pattern containing at least three, for example, at least five d-interval (Å) values ​​selected from the group consisting of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5. 1.35 Any of items 1.1 to 1.34, wherein crystal form A exhibits an XRPD pattern with d-interval (Å) values ​​of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5. 1.36 Any of items 1.1 to 1.35, wherein crystal form A exhibits an XRPD pattern containing at least three, for example, at least five d-interval (Å) values ​​selected from the group consisting of 5.74, 5.35, 5.17, 4.79, 4.56, 4.34, 4.29, 3.88, and 3.47. 1.37 Any of items 1.1 to 1.36, in which crystal form A exhibits an XRPD pattern with d-interval (Å) values ​​of 5.74, 5.35, 5.17, 4.79, 4.56, 4.34, 4.29, 3.88, and 3.47. 1.38 Any of items 1.1 to 1.37, wherein crystal form A exhibits an XRPD pattern containing at least three, for example, at least five d-interval (Å) values ​​selected from the group consisting of 5.741, 5.352, 5.167, 4.792, 4.560, 4.338, 4.291, 3.880, and 3.466. 1.39 Any of items 1.1 to 1.38, in which crystal form A exhibits an XRPD pattern with d-interval (Å) values ​​of 5.741, 5.352, 5.167, 4.792, 4.560, 4.338, 4.291, 3.880, and 3.466. 1.40 Any of items 1.1 to 1.39, wherein crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five d-interval (Å) values ​​selected from those shown in Table A of item 1.16. 1.41 Any of items 1.1 to 1.40, wherein crystal form A exhibits an XRPD pattern containing the d-interval (Å) values ​​shown in Table A of item 1.16. 1.42 Any of items 1.1 to 1.41, wherein crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least ten d-interval (Å) values ​​selected from the group consisting of 7.2, 6.4, 5.7, 5.4, 5.2, 4.9, 4.8, 4.6, 4.3, 3.9, and 3.5. 1.43 Any of items 1.1 to 1.42, in which crystal form A exhibits an XRPD pattern with d-interval (Å) values ​​of 7.2, 6.4, 5.7, 5.4, 5.2, 4.9, 4.8, 4.6, 4.3, 3.9, and 3.5. 1.44 Any of items 1.1 to 1.43, wherein crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least ten d-interval (Å) values ​​selected from the group consisting of 7.21, 6.42, 5.74, 5.35, 5.17, 4.87, 4.79, 4.56, 4.34, 4.29, 3.88, and 3.47. 1.45 Any of items 1.1 to 1.44, in which crystal form A exhibits an XRPD pattern containing d-interval (Å) values ​​of 7.21, 6.42, 5.74, 5.35, 5.17, 4.87, 4.79, 4.56, 4.34, 4.29, 3.88, and 3.47. 1.46 Any of items 1.1 to 1.45, wherein crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least ten d-interval (Å) values ​​selected from the group consisting of 7.211, 6.421, 5.741, 5.352, 5.167, 4.873, 4.792, 4.560, 4.338, 4.291, 3.880, and 3.466. 1.47 Any of items 1.1 to 1.46, in which crystal form A exhibits an XRPD pattern containing d-interval (Å) values ​​of 7.211, 6.421, 5.741, 5.352, 5.167, 4.873, 4.792, 4.560, 4.338, 4.291, 3.880, and 3.466. 1.48 Any of items 1.1 to 1.47, wherein crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least ten d-interval (Å) values ​​selected from those shown in Table B of item 1.25. 1.49 Any of items 1.1 to 1.48, wherein crystal form A exhibits an XRPD pattern containing the d-interval (Å) values ​​shown in Table B of item 1.25. 1.50 Any of items 1.1 to 1.49, wherein crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen d-interval (Å) values ​​selected from the group consisting of 12.9, 7.2, 6.4, 6.1, 5.7, 5.4, 5.2, 4.9, 4.8, 4.6, 4.4, 4.3, 4.2, 4.1, 3.9, 3.6, 3.5, 3.4, and 3.2. 1.51 Any of items 1.1 to 1.50, in which crystal form A exhibits an XRPD pattern containing d-interval (Å) values ​​of 12.9, 7.2, 6.4, 6.1, 5.7, 5.4, 5.2, 4.9, 4.8, 4.6, 4.4, 4.3, 4.2, 4.1, 3.9, 3.6, 3.5, 3.4, and 3.2. 1.52 The crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty d-interval (Å) values ​​selected from the group consisting of 12.86, 7.21, 6.42, 6.11, 5.74, 5.35, 5.17, 4.87, 4.79, 4.56, 4.42, 4.34, 4.29, 4.24, 4.12, 3.88, 3.60, 3.54, 3.50, 3.47, 3.38, 3.24, and 3.21, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty d-interval (Å) values, e.g. 1.53 Any of items 1.1 to 1.52, in which crystal form A exhibits an XRPD pattern containing d-interval (Å) values ​​of 12.86, 7.21, 6.42, 6.11, 5.74, 5.35, 5.17, 4.87, 4.79, 4.56, 4.42, 4.34, 4.29, 4.24, 4.12, 3.88, 3.60, 3.54, 3.50, 3.47, 3.38, 3.24 and 3.21. 1.54 The crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty d-interval (Å) values ​​selected from the group consisting of 12.859, 7.211, 6.421, 6.106, 5.741, 5.352, 5.167, 4.873, 4.792, 4.560, 4.422, 4.338, 4.291, 4.236, 4.123, 3.880, 3.602, 3.535, 3.499, 3.466, 3.378, 3.239, and 3.211, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty d-interval (Å) values, e.g., any of items 1.1 to 1.53. 1.55 Any of items 1.1 to 1.54, where crystal form A exhibits an XRPD pattern containing d-interval (Å) values ​​of 12.859, 7.211, 6.421, 6.106, 5.741, 5.352, 5.167, 4.873, 4.792, 4.560, 4.422, 4.338, 4.291, 4.236, 4.123, 3.880, 3.602, 3.535, 3.499, 3.466, 3.378, 3.239, and 3.211. 1.56 Any of items 1.1 to 1.55, wherein crystal form A exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least twelve, e.g., at least fifteen, e.g., at least twenty d-interval (Å) values ​​selected from those shown in Table C of item 1.32. 1.57 Any of items 1.1 to 1.56, wherein crystal form A exhibits an XRPD pattern containing the d-interval (Å) values ​​shown in Table C of item 1.32. 1.58 Crystal form A exhibits an XRPD pattern containing characteristic peaks of the XRPD pattern shown in Figure 1, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.57. 1.59 Crystal form A exhibits an XRPD pattern containing the typical peaks of the XRPD pattern shown in Figure 1, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.58. 1.60 Crystal form A exhibits a powder X-ray diffraction (XRPD) pattern including three peaks selected from the peaks shown in Figure 1, five peaks in some specific embodiments, a powder X-ray diffraction pattern measured using an incident beam of, for example, Cu, for example, Cu Kα, a high-resolution powder X-ray diffraction pattern measured using an incident beam of, for example, Cu Kα, where the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.59. 1.61 Crystal form A exhibits an XRPD pattern including at least nine peaks selected from the peaks shown in Figure 1, e.g., at least ten peaks, e.g., at least twelve peaks, e.g., at least fifteen peaks, e.g., at least twenty peaks, e.g., an XRPD pattern measured using an incident beam of e.g., Cu line, e.g., Cu Kα line, e.g., a high-resolution XRPD pattern measured using an incident beam of e.g., Cu Kα line, e.g., the XRPD is measured using a wavelength of 1.54059 Å, any of items 1.1 to 1.60. 1.62 Crystal form A exhibits a powder X-ray diffraction (XRPD) pattern substantially as shown in Figure 1, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.61. 1.63 Crystal form A exhibits the powder X-ray diffraction (XRPD) pattern shown in Figure 1, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.62. 1.64 Crystal form A exhibits an XRPD pattern containing characteristic peaks of the XRPD pattern shown in any of Figures 1, 35, 37, and 47, e.g., Figure 1, e.g., Figure 35, e.g., Figure 37, e.g., Figure 47, and the XRPD is measured using Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.63. 1.65 Crystal form A exhibits an XRPD pattern containing typical peaks of the XRPD pattern shown in any of Figures 1, 35, 37, and 47, e.g., Figure 1, e.g., Figure 35, e.g., Figure 37, e.g., Figure 47, and the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, and the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.64. 1.66 Crystal form A exhibits an XRPD pattern having three peaks selected from any of Figures 1, 35, 37, and 47, e.g., Figure 1, e.g., Figure 35, e.g., Figure 37, e.g., Figure 47, or five peaks in some specific embodiments, an XRPD pattern measured using an incident beam of e.g., Cu lines, e.g., Cu Kα lines, a high-resolution XRPD pattern measured using an incident beam of e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.65. 1.67 Crystal form A exhibits an XRPD pattern having at least nine peaks, for example, at least ten peaks, for example, at least twelve peaks, for example, at least fifteen peaks, for example, at least twenty peaks, selected from any of Figures 1, 35, 37, and 47, for example, Figure 1, for example, Figure 35, for example, Figure 37, for example, Figure 47, an XRPD pattern measured using an incident beam of, for example, Cu lines, for example, Cu Kα lines, a high-resolution XRPD pattern measured using an incident beam of, for example, Cu Kα lines, and for example, the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.1 to 1.66. 1.68 Any of items 1.1 to 1.67, wherein crystal form A substantially exhibits the XRPD pattern shown in any of Figures 1, 35, 37, and 47, e.g., Figure 1, e.g., Figure 35, e.g., Figure 37, e.g., Figure 47, e.g., an XRPD pattern measured using an incident beam of e.g., Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.69 Crystal form A exhibits an XRPD pattern shown in any of Figures 1, 35, 37, and 47, for example, Figure 1, for example, Figure 35, for example, Figure 37, for example, Figure 47, for example, an XRPD pattern measured using an incident beam of, for example, Cu lines, for example, Cu Kα lines, for example, any of items 1.1 to 1.68, where the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.70 A differential scanning calorimetry (DSC) thermogram in which crystal form A shows an endothermic peak between 245°C and 249°C, for example between 245°C and 248°C; a differential scanning calorimetry (DSC) thermogram in which crystal form A shows multiple endothermic peaks, for example between 245°C and 249°C, for example between 245°C and 248°C; a differential scanning calorimetry (DSC) thermogram in which crystal form A starts at 245°C and shows an endothermic peak at 247°C, an endothermic shoulder peak at 248°C, and an endothermic peak at 248°C, any of items 1.1 to 1.69. 1.71 Any of items 1.1 to 1.70, where crystal form A shows an endothermic peak at 247°C, for example, a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak starting at 245°C and ending at 247°C. 1.72 Any of items 1.1 to 1.71, where crystal form A shows a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 248°C. 1.73 Crystal form A shows any of the differential scanning calorimetry (DSC) thermograms shown in Figure 2, as described in items 1.1 to 1.72. 1.74 Any of items 1.1 to 1.73, where the thermogravimetric analysis (TGA) thermogram shows a 0.4% weight loss at temperatures below 200°C for crystal form A. 1.75 Any of items 1.1 to 1.74, having a thermogravimetric analysis (TGA) thermogram that includes the decomposition initiation temperature at 276°C. 1.76 Crystal form A shows the thermogravimetric analysis (TGA) thermogram shown in Figure 2, one of items 1.1 to 1.75. 1.77 Crystal form A is shown in the dynamic vapor adsorption / desorption isotherm in Figure 3, for example, crystal form A is: 0.03% weight loss at equilibrium in 5%RH; 0.10% weight increase at 5%~95%RH; and It exhibits a dynamic vapor adsorption / desorption isotherm showing a weight loss of 0.10% at 95% to 5% RH, according to any of items 1.1 to 1.76. 1.78 Crystalline form B of the hydrochloride addition salt form of this compound ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) ("Crystalline form B") 1.79 Crystal form B belongs to the P212121 space group, and the following unit cell parameters: a=5.9055(2)Å, b=7.4645(3)Å, c=29.1139(13)Å, α=β=γ=90° Article 1.78, which includes: 1.80 Crystal form B belongs to the P212121 space group, and the following unit cell parameters: a = 5~7 Å, e.g., 6 Å, e.g., 5.7~6.1 Å, e.g., 5.8~6.0 Å, e.g., 5.9 Å, e.g., 5.91 Å, e.g., 5.906 Å; b = 6~8 Å, e.g., 7 Å, e.g., 7.3~7.7 Å, e.g., 7.4~7.6 Å, e.g., 7.5 Å, e.g., 7.46 Å, e.g., 7.465 Å; c = 28~30 Å, e.g., 29 Å, e.g., 28.9~29.3 Å, e.g., 29.0~29.2 Å, e.g., 29.1 Å, e.g., 29.11 Å, e.g., 29.114 Å; and α=β=γ=90° Item 1.78, which has any combination of the following. 1.81 Crystal form B is V = 1283.39(9) Å 3 The calculation volume is one of the following, from item 1.78 to 1.80. 1.82 A crystal of crystal form B having an approximate volume of 0.31 mm × 0.21 mm × 0.09 mm, for example, a colorless plate-like crystal having an approximate volume of 0.31 mm × 0.21 mm × 0.09 mm, as specified in items 1.78 to 1.81. 1.83 The crystal structure of crystal form B is obtained using Cu Kα lines, for example, Cu Kα lines with λ = 1.54178 Å, one of terms 1.78 to 1.82. 1.84 The crystal structure of crystal form B is obtained at 100(2)K, according to any of items 1.78 to 1.83. 1.85 Crystal form B has a single crystal structure as shown in the atomic displacement ellipsoid diagram in Figure 24, one of items 1.78 to 1.84. 1.86 Crystal form B has the calculated XRPD pattern shown in Figure 32, according to any of terms 1.78 to 1.85. 1.87 The crystal form B exhibits an XRPD pattern containing at least three 2θ(°) values ​​selected from the group consisting of 6.0, 17.4, 18.9, 19.2, and 24.4, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.86. 1.88 The crystal form B exhibits an XRPD pattern containing 2θ(°) values ​​of 6.0, 17.4, 18.9, 19.2 and 24.4, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.87. 1.89 The crystal form B exhibits an XRPD pattern with characteristic 2θ(°) values ​​of 6.0, 17.4, 18.9, 19.2 and 24.4, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.88. 1.90 The crystal form B exhibits an XRPD pattern containing at least three 2θ(°) values ​​selected from the group consisting of 6.04, 17.41, 18.94, 19.19 and 24.39, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.89. 1.91 The crystal form B exhibits an XRPD pattern containing 2θ(°) values ​​of 6.04, 17.41, 18.94, 19.19 and 24.39, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.90. 1.92 The crystal form B exhibits an XRPD pattern with characteristic 2θ(°) values ​​of 6.04, 17.41, 18.94, 19.19 and 24.39, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.91. 1.93 Crystal form B is shown in Table D below: Table D [Table 4] The XRPD pattern exhibits at least three 2θ(°) values ​​selected from those shown, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.78 to 1.92. 1.94 The crystal form B exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table D of item 1.93, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.78 to 1.93. 1.95 The crystal form B exhibits an XRPD pattern with characteristic 2θ(°) values ​​shown in Table D of item 1.93, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.78 to 1.94. 1.96 The crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five 2θ(°) values ​​selected from the group consisting of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4, and 28.2, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.95. 1.97 The crystal form B exhibits an XRPD pattern containing 2θ(°) values ​​of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4 and 28.2, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.96. 1.98 The crystal form B exhibits an XRPD pattern with typical 2θ(°) values ​​of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4 and 28.2, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.97. 1.99 The crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five 2θ(°) values ​​selected from the group consisting of 6.04, 13.21, 17.41, 18.94, 19.19, 23.59, 23.79, 24.39, and 28.15, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.98. 1.100 Crystal form B exhibits an XRPD pattern containing 2θ(°) values ​​of 6.04, 13.21, 17.41, 18.94, 19.19, 23.59, 23.79, 24.39 and 28.15, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, or e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.99. 1.101 Crystal form B exhibits an XRPD pattern with typical 2θ(°) values ​​of 6.04, 13.21, 17.41, 18.94, 19.19, 23.59, 23.79, 24.39 and 28.15, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.100. 1.102 Crystal form B is shown in Table E below: Table E [Table 5] The XRPD pattern exhibits at least three, e.g., at least five 2θ(°) values ​​selected from those shown, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.101. 1.103 The crystal form B exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table E of item 1.102, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.102. 1.104 The crystal form B exhibits an XRPD pattern with typical 2θ(°) values ​​shown in Table E of item 1.102, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.78 to 1.103. 1.105 The crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty 1.106 Crystal form B has the following 2θ(°) values: 6.0, 12.1, 13.2, 14.9, 15.1, 16.0, 16.9, 17.4, 18.2, 18.9, 19.2, 19.9, 21.1, 21.3, 21.7, 22.6, 23.6, 23.8, 24.4, 25.3, 26.1, 26.6, 27.2, 28.2, 28.7, and 29.5 The XRPD pattern includes any of items 1.78 to 1.105, where the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., where the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.107 Crystal form B is 6.04, 12.12, 13.21, 14.86, 15.13, 16.02, 16.90, 17.41, 18.23, 18.94, 19.19, 19.91, 21.05, 21.27, 21.74, 22.55, 23.59, 23.79, 24.39, 25.34, 26.06, 26.61, 27.15, 28.15, 28.66 and 29.47 The XRPD pattern exhibits at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty-five 2θ(°) values ​​selected from the group consisting of the following, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.106. 1.108 Crystal form B has the following 2θ(°) values: 6.04, 12.12, 13.21, 14.86, 15.13, 16.02, 16.90, 17.41, 18.23, 18.94, 19.19, 19.91, 21.05, 21.27, 21.74, 22.55, 23.59, 23.79, 24.39, 25.34, 26.06, 26.61, 27.15, 28.15, 28.66 and 29.47 The XRPD pattern includes any of items 1.78 to 1.107, where the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.109 Crystal form B is shown in Table F below: Table F [Table 6] The XRPD pattern exhibits at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty-five 2θ(°) values ​​selected from those shown, wherein the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.108. 1.110 The crystal form B exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table F of item 1.109, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.109. 1.111 Any of items 1.78 to 1.110, wherein crystal form B exhibits an XRPD pattern containing at least three d-interval (Å) values ​​selected from the group consisting of 14.6, 5.1, 4.7, 4.6, and 3.6. 1.112 Any of items 1.78 to 1.111, in which crystal form B exhibits an XRPD pattern with d-interval (Å) values ​​of 14.6, 5.1, 4.7, 4.6 and 3.6. 1.113 The crystal form B exhibits an XRPD pattern containing at least three d-interval (Å) values ​​selected from the group consisting of 14.62, 5.09, 4.68, 4.62, and 3.65, as specified in any of items 1.78 to 1.112. 1.114 Any of items 1.78 to 1.113, where crystal form B exhibits an XRPD pattern with d-interval (Å) values ​​of 14.62, 5.09, 4.68, 4.62, and 3.65. 1.115 The crystal form B exhibits an XRPD pattern containing at least three d-interval (Å) values ​​selected from the group consisting of 14.620, 5.089, 4.681, 4.622, and 3.646, as specified in any of items 1.78 to 1.114. 1.116 Any of items 1.78 to 1.115, where crystal form B exhibits an XRPD pattern with d-interval (Å) values ​​of 14.620, 5.089, 4.681, 4.622, and 3.646. 1.117 Any of items 1.78 to 1.116, wherein crystal form B exhibits an XRPD pattern containing at least three d-interval (Å) values ​​selected from those shown in Table D of item 1.93. 1.118 Any of items 1.78 to 1.117, wherein crystal form B exhibits an XRPD pattern containing the d-interval (Å) values ​​shown in Table D of item 1.93. 1.119 Any of items 1.78 to 1.118, wherein crystal form B exhibits an XRPD pattern containing at least three, for example, at least five d-interval (Å) values ​​selected from the group consisting of 14.6, 6.7, 5.1, 4.7, 4.6, 3.8, 3.7, 3.6, and 3.2. 1.120 Crystal form B exhibits an XRPD pattern containing d-interval (Å) values ​​of 14.6, 6.7, 5.1, 4.7, 4.6, 3.8, 3.7, 3.6, and 3.2, as described in any of items 1.78 to 1.119. 1.121 Any of items 1.78 to 1.120, wherein crystal form B exhibits an XRPD pattern containing at least three, for example, at least five d-interval (Å) values ​​selected from the group consisting of 14.62, 6.70, 5.09, 4.68, 4.62, 3.77, 3.74, 3.65, and 3.17. 1.122 Any of items 1.78 to 1.121, where crystal form B exhibits an XRPD pattern with d-interval (Å) values ​​of 14.62, 6.70, 5.09, 4.68, 4.62, 3.77, 3.74, 3.65 and 3.17. 1.123 Any of items 1.78 to 1.122, wherein crystal form B exhibits an XRPD pattern containing at least three, for example, at least five d-interval (Å) values ​​selected from the group consisting of 14.620, 6.699, 5.089, 4.681, 4.622, 3.769, 3.737, 3.646, and 3.168. 1.124 Any of items 1.78 to 1.123, where crystal form B exhibits an XRPD pattern with d-interval (Å) values ​​of 14.620, 6.699, 5.089, 4.681, 4.622, 3.769, 3.737, 3.646 and 3.168. 1.125 Any of items 1.78 to 1.124, wherein crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five d-interval (Å) values ​​selected from those shown in Table E of item 1.102. 1.126 Crystal form B exhibits an XRPD pattern containing the d-interval (Å) values ​​shown in Table E of item 1.102, one of items 1.78 to 1.125. 1.127 The crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty d-interval (Å) values ​​selected from the group consisting of 14.6, 7.3, 6.7, 6.0, 5.9, 5.5, 5.2, 5.1, 4.9, 4.7, 4.6, 4.5, 4.2, 4.1, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, and 3.0, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty d-interval (Å) values, e.g. 1.128 Any of items 1.78 to 1.127, in which crystal form B exhibits an XRPD pattern containing d-interval (Å) values ​​of 14.6, 7.3, 6.7, 6.0, 5.9, 5.5, 5.2, 5.1, 4.9, 4.7, 4.6, 4.5, 4.2, 4.1, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 and 3.0. 1.129 Any of items 1.78 to 1.128, wherein crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty d-interval (Å) values ​​selected from the group consisting of 14.62, 7.30, 6.70, 5.96, 5.85, 5.53, 5.24, 4.17, 4.09, 3.94, 3.77, 3.74, 3.65, 3.51, 3.42, 3.35, 3.28, 3.17, 3.11, and 3.03. 1.130 Any of items 1.78 to 1.129, where crystal form B exhibits an XRPD pattern containing d-interval (Å) values ​​of 14.62, 7.30, 6.70, 5.96, 5.85, 5.53, 5.24, 5.09, 4.86, 4.68, 4.62, 4.46, 4.22, 4.17, 4.09, 3.94, 3.77, 3.74, 3.65, 3.51, 3.42, 3.35, 3.28, 3.17, 3.11 and 3.03. 1.131 The crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty d-interval (Å) values ​​selected from the group consisting of 14.620, 7.296, 6.699, 5.958, 5.853, 5.529, 5.529, 5.242, 5.089, 4.861, 4.681, 4.622, 4.457, 4.217, 4.173, 4.085, 3.939, 3.769, 3.737, 3.646, 3.512, 3.416, 3.347, 3.282, 3.168, 3.112, and 3.028, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty. 1.132 Any of items 1.78 to 1.131, where crystal form B exhibits an XRPD pattern containing d-interval (Å) values ​​of 14.620, 7.296, 6.699, 5.958, 5.853, 5.529, 5.242, 5.089, 4.861, 4.681, 4.622, 4.457, 4.217, 4.173, 4.085, 3.939, 3.769, 3.737, 3.646, 3.512, 3.416, 3.347, 3.282, 3.168, 3.112 and 3.028. 1.133 The crystal form B exhibits an XRPD pattern containing at least three, e.g., at least five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty d-interval (Å) values ​​selected from those shown in Table F of item 1.109, as specified in any of items 1.78 to 1.132. 1.134 Crystal form B exhibits an XRPD pattern containing the d-interval (Å) values ​​shown in Table F of item 1.109, one of items 1.78 to 1.133. 1.135 Crystal form B exhibits a powder X-ray diffraction pattern containing characteristic peaks of the XRPD pattern shown in Figure 5, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., any of items 1.78 to 1.134, where the XRPD is measured using radiation with a wavelength of 1.541871 Å. 1.136 Crystal form B exhibits a powder X-ray diffraction pattern containing typical peaks of the XRPD pattern shown in Figure 5, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., any of items 1.78 to 1.135, where the XRPD is measured using radiation with a wavelength of 1.541871 Å. 1.137 Crystal form B exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and any of items 1.78 to 1.136, for example, XRPD measured using radiation of wavelength 1.541871 Å and including three peaks selected from the peaks shown in Figure 5, or five peaks in some specific embodiments. 1.138 Crystal form B exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation of wavelength 1.541871 Å and includes at least five peaks selected from the peaks shown in Figure 5, for example, at least nine peaks, for example at least ten peaks, for example at least fifteen peaks, for example at least twenty peaks, for example at least twenty five peaks, any of items 1.78 to 1.137. 1.139 Crystal form B exhibits a powder X-ray diffraction pattern substantially as shown in Figure 5, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.541871 Å, any of items 1.78 to 1.138. 1.140 Crystal form B exhibits the powder X-ray diffraction pattern shown in Figure 5, for example, the powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.541871 Å, any of items 1.78 to 1.139. 1.141 Crystal form B exhibits a powder X-ray diffraction pattern containing characteristic peaks in the XRPD pattern shown in Figure 7, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation at a wavelength of 1.54059 Å, e.g., the XRPD pattern also includes peaks of crystal form A (e.g., a mixture of crystal forms A and B), any of items 1.78 to 1.140. 1.142 Crystal form B exhibits a powder X-ray diffraction pattern containing typical peaks of the XRPD pattern shown in Figure 7, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation at a wavelength of 1.54059 Å, e.g., the XRPD pattern also includes peaks of crystal form A (e.g., a mixture of crystal forms A and B), any of items 1.78 to 1.141. 1.143 Crystal form B exhibits a powder X-ray diffraction pattern, for example, a high-resolution powder X-ray diffraction pattern, measured using an incident beam of Cu, for example, Cu Kα, and for example, the XRPD is measured using radiation of wavelength 1.54059 Å and includes three peaks selected from the peaks shown in Figure 7, five peaks in some specific embodiments, and for example, the XRPD pattern also includes the peaks of crystal form A (for example, a mixture of crystal forms A and B), any of items 1.78 to 1.142. 1.144 Crystal form B exhibits a powder X-ray diffraction pattern, for example, a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, the XRPD is measured using radiation of wavelength 1.54059 Å and includes at least five peaks selected from the peaks shown in Figure 7, for example, at least nine peaks, for example, at least ten peaks, for example, at least fifteen peaks, for example, at least twenty peaks, for example, at least twenty peaks, and for example, the XRPD pattern includes peaks of crystal form A (for example, a mixture of crystal forms A and B), any of items 1.78 to 1.143. 1.145 Crystal form B exhibits a powder X-ray diffraction pattern, e.g., a high-resolution powder X-ray diffraction pattern, e.g., measured using an incident beam of Cu, e.g., Cu Kα, e.g., a high-resolution powder X-ray diffraction pattern, e.g., measured using an incident beam of Cu Kα, e.g., XRPD measured using radiation at a wavelength of 1.54059 Å, substantially as shown in Figure 7, e.g., the XRPD pattern includes peaks of crystal form A (e.g., a mixture of crystal forms A and B), any of items 1.78 to 1.144. 1.146 Crystal form B exhibits a powder X-ray diffraction pattern, for example, a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, the XRPD is measured using radiation at a wavelength of 1.54059 Å, as shown in Figure 7, and for example, the XRPD pattern includes the peak of crystal form A (for example, a mixture of crystal forms A and B), any of items 1.78 to 1.145. 1.147 Crystal form B exhibits an XRPD pattern containing characteristic peaks of the XRPD pattern shown in any of Figures 7, 40, and 48, e.g., Figure 7, e.g., Figure 40, e.g., Figure 48, and the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.146. 1.148 Crystal form B exhibits an XRPD pattern containing typical peaks of the XRPD pattern shown in any of Figures 7, 40, and 48, e.g., Figure 7, e.g., Figure 40, e.g., Figure 48, and the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.78 to 1.147. 1.149 Crystal form B exhibits an XRPD pattern, a powder X-ray diffraction pattern measured using an incident beam, e.g., Cu line, e.g., Cu Kα line, e.g., a high-resolution powder X-ray diffraction pattern measured using an incident beam, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å and includes any of items 1.78 to 1.148, which include three peaks selected from the peaks shown in any of Figures 7, 40, and 48, e.g., Figure 7, e.g., Figure 40, e.g., Figure 48, and five peaks in some specific embodiments. 1.150 Crystal form B exhibits an XRPD pattern, e.g., a powder X-ray diffraction pattern measured using an incident beam of Cu, e.g., Cu Kα, e.g., a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu Kα, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å and includes at least five peaks selected from any of the peaks shown in Figures 7, 40, and 48, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty five, e.g., at least nine, e.g., at least ten, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty five, e.g., at least nine nine, e.g., at least ten ten, e.g., at least fifteen 1.151 Crystal form B exhibits an XRPD pattern, a powder X-ray diffraction pattern measured using an incident beam, e.g., Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, and substantially one of Figures 7, 40, and 48, e.g., Figure 7, e.g., Figure 40, e.g., any of items 1.78 to 1.150. 1.152 Crystal form B exhibits a powder X-ray diffraction (XRPD) pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, the XRPD is measured using radiation with a wavelength of 1.54059 Å, and is shown in any of Figures 7, 40, and 48, for example, Figure 7, for example, Figure 40, for example, Figure 48, or any of items 1.1 to 1.151. 1.153 The differential scanning calorimetry (DSC) thermogram of crystal form B shows an endothermic peak between 247°C and 248°C, as specified in items 1.78 to 1.152. 1.154 Crystal form B shows a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 247°C, as specified in items 1.78 to 1.153. 1.155 The differential scanning calorimetry (DSC) thermogram shows crystal form B including an endothermic peak at 248°C, for example, an endothermic peak at 248°C starting from 246°C, as specified in items 1.78 to 1.154. 1.156 Crystal form B shows a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 251°C, according to any of items 1.78 to 1.155. 1.157 Crystal form B shows a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 264°C, according to any of items 1.78 to 1.156. 1.158 The differential scanning calorimetry (DSC) thermogram shows crystal form B including an endothermic peak at 141°C, for example, an endothermic peak at 141°C starting from 137°C to 138°C, or an endothermic peak at 141°C starting from 137°C, for example, an endothermic peak at 141°C starting from 138°C, as specified in items 1.78 to 1.157. 1.159 Crystal form B shows any of the differential scanning calorimetry (DSC) thermograms shown in Figure 8, as described in items 1.78 to 1.158. 1.160 The thermogravimetric analysis (TGA) thermogram of crystal form B shows a 0.2% weight loss at temperatures below 200°C, as specified in items 1.78 to 1.159. 1.161 Any of items 1.78 to 1.160, where crystal form B shows a thermogravimetric analysis (TGA) thermogram including the decomposition onset temperature at 281°C. 1.162 Crystal form B shows the thermogravimetric analysis (TGA) thermogram shown in Figure 8, one of items 1.78 to 1.161. 1.163 Crystalline form C of the hydrochloride addition salt form of this compound ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride). 1.164 The crystal form C exhibits an XRPD pattern including a 2θ(°) value of 17.7, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, item 1.163. 1.165 The crystal form C exhibits an XRPD pattern with a characteristic 2θ(°) value of 17.7, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, item 1.163 or 1.164. 1.166 The crystal form C exhibits an XRPD pattern including a 2θ(°) value of 17.74, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.165. 1.167 The crystal form C exhibits an XRPD pattern with a characteristic 2θ(°) value of 17.74, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.163 to 1.166. 1.168 Crystal form C is as follows (see Table G): Table G [Table 7] The XRPD pattern includes the 2θ(°) value, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.163 to 1.167. 1.169 The crystal form C exhibits an XRPD pattern with characteristic 2θ(°) values ​​shown in Table G of item 1.168, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.163 to 1.168. 1.170 The crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five 2θ(°) values ​​selected from the group consisting of 7.0, 13.2, 14.4, 17.7, 18.0, 19.9, 21.3, 22.6, 23.7, and 26.5, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.169. 1.171 The crystal form C exhibits an XRPD pattern containing 2θ(°) values ​​of 7.0, 13.2, 14.4, 17.7, 18.0, 19.9, 21.3, 22.6, 23.7 and 26.5, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.170. 1.172 The crystal form C exhibits an XRPD pattern with typical 2θ(°) values ​​of 7.0, 13.2, 14.4, 17.7, 18.0, 19.9, 21.3, 22.6, 23.7 and 26.5, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.171. 1.173 The crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten 2θ(°) values ​​selected from the group consisting of 6.97, 13.24, 14.39, 17.74, 17.98, 18.03, 19.85, 21.32, 22.60, 23.68, and 26.52, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.172. 1.174 The crystal form C exhibits an XRPD pattern containing 2θ(°) values ​​of 6.97, 13.24, 14.39, 17.74, 17.98, 18.03, 19.85, 21.32, 22.60, 23.68 and 26.52, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.173. 1.175 The crystal form C exhibits an XRPD pattern with typical 2θ(°) values ​​of 6.97, 13.24, 14.39, 17.74, 17.98, 18.03, 19.85, 21.32, 22.60, 23.68 and 26.52, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, or e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.174. 1.176 Crystal form C is as follows (see Table H): Table H [Table 8] The XRPD pattern exhibits at least one, e.g., at least three, e.g., at least five, e.g., at least ten 2θ(°) values ​​selected from those shown, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.175. 1.177 The crystal form C exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table H of item 1.176, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.163 to 1.176. 1.178 The crystal form C exhibits an XRPD pattern with typical 2θ(°) values ​​shown in Table H of item 1.176, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.163 to 1.177. 1.179 The crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen, e.g., at least twenty 2θ(°) values ​​selected from the group consisting of 7.0, 13.2, 13.7, 14.0, 14.4, 16.3, 17.7, 18.0, 18.3, 19.9, 21.1, 21.3, 22.6, 23.4, 23.7, 23.9, 26.0, 26.5, 26.7, 26.9, 27.4, 28.0, 28.2, 29.1, and 29.5, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen, e.g., at least twenty 2θ(°) values, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen, e.g., at least twenty 20 2θ(°) values, e.g., at least three three two, e.g., at least five two, e.g., at least ten, e.g., at least ten, e.g 1.180 Crystal form C has the following 2θ(°) values: 7.0, 13.2, 13.7, 14.0, 14.4, 16.3, 17.7, 18.0, 18.3, 19.9, 21.1, 21.3, 22.6, 23.4, 23.7, 23.9, 26.0, 26.5, 26.7, 26.9, 27.4, 28.0, 28.2, 29.1 and 29.5 The XRPD pattern includes any of items 1.163 to 1.179, where the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.181 The crystal form C exhibits an XRPD pattern containing at least one, for example, at least three, for example, at least five, for example, at least ten, for example, at least eleven, for example, at least fifteen, for example, at least 20, for example, at least 25 2θ(°) values ​​selected from the group consisting of 6.97, 13.24, 13.68, 13.97, 14.39, 16.29, 17.74, 17.98, 18.03, 18.30, 19.85, 21.06, 21.32, 22.60, 23.35, 23.68, 23.94, 25.99, 26.52, 26.66, 26.90, 27.40, 27.99, 28.19, 29.06 and 29.52, and the XRPD is a Cu line, for example, Cu Measured using an incident Kα beam, for example, XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.163 to 1.180. 1.182 Crystal form C has the following 2θ(°) values: 6.97, 13.24, 13.68, 13.97, 14.39, 16.29, 17.74, 17.98, 18.03, 18.30, 19.85, 21.06, 21.32, 22.60, 23.35, 23.68, 23.94, 25.99, 26.52, 26.66, 26.90, 27.40, 27.99, 28.19, 29.06 and 29.52 The XRPD pattern includes any of items 1.163 to 1.181, where the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å. 1.183 Crystal form C is as follows (see Table I): Table I [Table 9] The XRPD pattern exhibits at least one, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty five 2θ(°) values ​​selected from those shown, and the XRPD is measured using an incident beam of Cu lines, e.g., Cu Kα lines, and the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.182. 1.184 The crystal form C exhibits an XRPD pattern containing the 2θ(°) values ​​shown in Table I of item 1.183, and the XRPD is measured using an incident beam of Cu, e.g., Cu Kα, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, one of items 1.163 to 1.183. 1.185 Crystal form C exhibits an XRPD pattern with a d-interval (Å) value of 5.0, one of items 1.163 to 1.184. 1.186 Crystal form C exhibits an XRPD pattern with a d-interval (Å) value of 4.99, one of items 1.163 to 1.185. 1.187 Crystal form C exhibits an XRPD pattern with a d-interval (Å) value of 4.994, one of items 1.163 to 1.186. 1.188 Crystal form C exhibits an XRPD pattern containing the d-interval (Å) values ​​in Table G of item 1.168, one of items 1.163 to 1.187. 1.189 Any of items 1.163 to 1.188, wherein the crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five d-interval (Å) values ​​selected from the group consisting of 12.7, 6.7, 6.2, 5.0, 4.9, 4.5, 4.2, 3.9, 3.8, and 3.4. 1.190 Any of items 1.163 to 1.189, where the crystal form C exhibits an XRPD pattern with d-interval (Å) values ​​of 12.7, 6.7, 6.2, 5.0, 4.9, 4.5, 4.2, 3.9, 3.8, and 3.4. 1.191 Any of items 1.163 to 1.190, wherein the crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten d-interval (Å) values ​​selected from the group consisting of 12.68, 6.68, 6.15, 4.99, 4.93, 4.92, 4.47, 4.16, 3.93, 3.75, and 3.36. 1.192 Any of items 1.163 to 1.191, where the crystal form C exhibits an XRPD pattern with d-interval (Å) values ​​of 12.68, 6.68, 6.15, 4.99, 4.93, 4.92, 4.47, 4.16, 3.93, 3.75, and 3.36. 1.193 Any of items 1.163 to 1.192, wherein the crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten d-interval (Å) values ​​selected from the group consisting of 12.677, 6.683, 6.150, 4.994, 4.929, 4.915, 4.470, 4.164, 3.931, 3.754, and 3.359. 1.194 Any of items 1.163 to 1.193, where the crystal form C exhibits an XRPD pattern with d-interval (Å) values ​​of 12.677, 6.683, 6.150, 4.994, 4.929, 4.915, 4.470, 4.164, 3.931, 3.754, and 3.359. 1.195 Any of items 1.163 to 1.194, wherein the crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten d-interval (Å) values ​​selected from those shown in Table H of item 1.176. 1.196 Crystal form C exhibits an XRPD pattern containing the d-interval (Å) values ​​shown in Table H of item 1.176, one of items 1.163 to 1.195. 1.197 Any of items 1.163 to 1.196, wherein the crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen d-interval (Å) values ​​selected from the group consisting of 12.7, 6.7, 6.5, 6.3, 6.2, 5.4, 4.9, 4.8, 4.5, 4.2, 3.9, 3.8, 3.7, 3.4, 3.3, 3.2, 3.1, and 3.0. 1.198 Any of items 1.163 to 1.197, in which crystal form C exhibits an XRPD pattern with d-interval (Å) values ​​of 12.7, 6.7, 6.5, 6.3, 6.2, 5.4, 5.0, 4.9, 4.8, 4.5, 4.2, 3.9, 3.8, 3.7, 3.4, 3.3, 3.2, 3.1 and 3.0. 1.199 Any of items 1.163 to 1.198, wherein the crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty five d-interval (Å) values ​​selected from the group consisting of 12.68, 6.68, 6.47, 6.33, 6.15, 5.44, 4.99, 4.93, 4.92, 4.84, 4.47, 4.21, 4.16, 3.93, 3.81, 3.75, 3.71, 3.43, 3.36, 3.34, 3.31, 3.25, 3.19, 3.16, 3.07, and 3.02. 1.200 Any of items 1.163 to 1.199, where crystal form C exhibits an XRPD pattern containing d-interval (Å) values ​​of 12.68, 6.68, 6.47, 6.33, 6.15, 5.44, 4.99, 4.93, 4.92, 4.84, 4.47, 4.21, 4.16, 3.93, 3.81, 3.75, 3.71, 3.43, 3.36, 3.34, 3.31, 3.25, 3.19, 3.16, 3.07, and 3.02. 1.201 Any of items 1.163 to 1.200, wherein the crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty, e.g., at least twenty five d-interval (Å) values ​​selected from the group consisting of 12.677, 6.683, 6.469, 6.333, 6.150, 5.435, 4.994, 4.915, 4.843, 4.470, 4.214, 4.164, 3.931, 3.806, 3.754, 3.714, 3.426, 3.359, 3.340, 3.311, 3.252, 3.185, 3.163, 3.070, and 3.024. 1.202 Any of items 1.163 to 1.201, where the crystal form C exhibits an XRPD pattern with d-interval (Å) values ​​of 12.677, 6.683, 6.469, 6.333, 6.150, 5.435, 4.994, 4.929, 4.915, 4.843, 4.470, 4.214, 4.164, 3.931, 3.806, 3.754, 3.714, 3.426, 3.359, 3.340, 3.311, 3.252, 3.185, 3.163, 3.070 and 3.024. 1.203 The crystal form C exhibits an XRPD pattern containing at least one, e.g., at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at least twenty d-interval (Å) values ​​selected from those shown in Table I of item 1.183, as specified in any of items 1.163 to 1.202. 1.204 Any of items 1.163 to 1.203 having an XRPD pattern that includes the d-interval (Å) values ​​shown in Table I of item 1.183. 1.205 The crystal form C exhibits a powder X-ray diffraction pattern containing characteristic peaks in the XRPD pattern shown in Figure 9, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, or, e.g., the XRPD is measured using radiation with a wavelength of 1.541871 Å, any of items 1.163 to 1.204. 1.206 Crystal form C exhibits a powder X-ray diffraction pattern containing typical peaks of the XRPD pattern shown in Figure 9, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, or, e.g., the XRPD is measured using radiation with a wavelength of 1.541871 Å, any of items 1.163 to 1.205. 1.207 The crystal form C shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and any of the terms 1.163 to 1.206, for example, the XRPD is measured using radiation of wavelength 1.541871 Å and includes three peaks selected from the peaks shown in Figure 9, or five peaks in some specific embodiments. 1.208 The crystal form C exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and for example, the XRPD is measured using radiation of wavelength 1.541871 Å and includes at least one peak selected from the peaks shown in Figure 9, for example, at least five peaks, for example at least eleven peaks, for example at least fifteen peaks, for example at least twenty peaks, for example at least twenty five peaks, or for example at least twenty five peaks, whichever of items 1.163 to 1.207 applies. 1.209 The crystal form C exhibits a powder X-ray diffraction pattern substantially as shown in Figure 9, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and for example, the XRPD is measured using radiation with a wavelength of 1.541871 Å, any of items 1.163 to 1.208. 1.210 Crystal form C exhibits the powder X-ray diffraction pattern shown in Figure 9, for example, the powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and XRPD is measured using radiation with a wavelength of 1.541871 Å, any of items 1.163 to 1.209. 1.211 Crystal form C exhibits a powder X-ray diffraction pattern containing characteristic peaks in the XRPD pattern shown in Figure 11, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation at a wavelength of 1.54059 Å, e.g., the XRPD pattern also includes peaks for crystal form A (e.g., a mixture of crystal forms A and C), any of items 1.163 to 1.210. 1.212 The powder X-ray diffraction pattern of crystal form C includes a typical peak in the XRPD pattern shown in Figure 11, the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation at a wavelength of 1.54059 Å, e.g., the XRPD pattern also includes a peak in crystal form A (e.g., a mixture of crystal forms A and C), any of items 1.163 to 1.211. 1.213 Crystal form C exhibits a powder X-ray diffraction pattern, for example, a high-resolution powder X-ray diffraction pattern, measured using an incident beam of Cu, for example, Cu Kα, and for example, the XRPD is measured using radiation of wavelength 1.54059 Å and includes three peaks selected from the peaks shown in Figure 11, five peaks in some specific embodiments, and for example, the XRPD pattern also includes the peaks of crystal form A (for example, a mixture of crystal forms A and C), any of items 1.163 to 1.212. 1.214 Crystal form C exhibits a powder X-ray diffraction pattern, e.g., a powder X-ray diffraction pattern measured using an incident beam of Cu, e.g., Cu Kα, e.g., a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu Kα, e.g., XRPD is measured using radiation of wavelength 1.54059 Å and includes at least one peak selected from the peaks shown in Figure 11, e.g., at least five peaks, e.g., at least eleven peaks, e.g., at least fifteen peaks, e.g., at least 20 peaks, e.g., at least 25 peaks, e.g., the XRPD pattern also includes peaks of crystal form A (e.g., a mixture of crystal forms A and C), any of items 1.163 to 1.213. 1.215 Crystal form C exhibits a powder X-ray diffraction pattern substantially as shown in Figure 11, a powder X-ray diffraction pattern measured using an incident beam of, for example, Cu, e.g., Cu Kα, e.g., a high-resolution powder X-ray diffraction pattern measured using an incident beam of, for example, Cu Kα, e.g., XRPD measured using radiation with a wavelength of 1.54059 Å, e.g., the XRPD pattern also includes the peak of crystal form A (e.g., a mixture of crystal forms A and C), any of items 1.163 to 1.214. 1.216 Crystal form C exhibits the powder X-ray diffraction pattern shown in Figure 11, e.g., a powder X-ray diffraction pattern measured using an incident beam of Cu, e.g., Cu Kα, e.g., a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu Kα, e.g., XRPD measured using radiation with a wavelength of 1.54059 Å, e.g., the XRPD pattern also includes the peak of crystal form A (e.g., a mixture of crystal forms A and C), any of items 1.163 to 1.215. 1.217 The crystal form C exhibits an XRPD pattern that includes characteristic peaks of the XRPD patterns shown in either Figure 11 or 43, e.g., Figure 11, e.g., Figure 43, and the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.216. 1.218 The crystal form C exhibits an XRPD pattern containing typical peaks of the XRPD pattern shown in either Figure 11 or 43, e.g., Figure 11, e.g., Figure 43, and the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, any of items 1.163 to 1.217. 1.219 The crystal form C exhibits an XRPD pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, for example, a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu Kα, for example, the XRPD is measured using radiation of wavelength 1.54059 Å and includes any of the items 1.163 to 1.218, which include three peaks selected from the peaks shown in either Figure 11 or 43, for example, Figure 11 or Figure 43, and five peaks in some specific embodiments. 1.220 The crystal form C exhibits an XRPD pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, for example, a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu Kα, for example, the XRPD is measured using radiation of wavelength 1.54059 Å and includes at least one peak selected from the peaks shown in either Figure 11 or 43, for example, Figure 11 or Figure 43, for example, at least five peaks, for example, at least ten peaks, for example, at least eleven peaks, for example, at least fifteen peaks, for example, at least twenty peaks, for example, at least twenty five peaks. Any of items 1.163 to 1.219. 1.221 The crystal form C exhibits an XRPD pattern, a powder X-ray diffraction pattern measured using an incident beam, e.g., Cu lines, e.g., Cu Kα lines, and e.g., the XRPD is measured using radiation with a wavelength of 1.54059 Å, and is substantially one of either Figure 11 or 43, e.g., Figure 11, e.g., Figure 43, as described in sections 1.163 to 1.220. 1.222 The crystal form C exhibits an XRPD pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and for example, the XRPD is measured using radiation with a wavelength of 1.54059 Å, as shown in either Figure 11 or 43, for example, Figure 11 or Figure 43, as per any of items 1.163 to 1.221. 1.223 A differential scanning calorimetry (DSC) thermogram showing crystal form C containing an endothermic peak between 247°C and 248°C, for example, starting at 246°C, as specified in items 1.163 to 1.222. 1.224 The differential scanning calorimetry (DSC) thermogram shows crystal form C including an endothermic peak at 247°C, for example, an endothermic peak at 247°C starting from 246°C, as specified in items 1.163 to 1.223. 1.225 The differential scanning calorimetry (DSC) thermogram shows crystal form C including an endothermic peak at 248°C, for example, an endothermic peak at 248°C starting from 246°C, as specified in items 1.163 to 1.224. 1.226 The differential scanning calorimetry (DSC) thermogram shows crystal form C including an endothermic peak at 122°C, for example, an endothermic peak at 122°C starting from 112°C, as specified in items 1.163 to 1.225. 1.227 The crystal form C shows a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 271°C, as specified in items 1.163 to 1.226. 1.228 Crystal form C shows any of items 1.163 to 1.227, with the differential scanning calorimetry (DSC) thermogram shown in Figure 12. 1.229 Any of items 1.163 to 1.228, where the crystal form C shows a thermogravimetric analysis (TGA) with a weight loss of 1.3% below 200°C. 1.230 Any of items 1.163 to 1.229, where the crystalline form C shows a thermogravimetric analysis (TGA) thermogram with a decomposition onset temperature of 266°C. 1.231 Crystal form C is one of the thermogravimetric analysis (TGA) thermograms shown in Figure 12, as specified in items 1.163 to 1.230. 1.232 The crystalline form of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride prepared as described in the above and / or any of the examples. 1.233 The crystalline form of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride having the powder X-ray diffraction and / or X-ray crystal structure shown in any of the figures. 1.234 A crystal form of any of items 1.1 to 1.233, where the XRPD pattern is measured using a copper source, e.g., a copper anode. 1.235 Any of crystal forms A to F, for example, any combination of any of items 1.1 to 1.234 and any of items 2.1 to 2.25, for example, a combination of crystal form A and crystal form B; a combination of crystal form A and crystal form C; a combination of crystal form A, crystal form B and crystal form C; a combination of crystal form B and crystal form C; a combination of crystal form B and crystal form D; a combination of crystal form E and crystal form F. 1.236 A crystalline form as described in any of items 1.1 to 1.234, for example, crystalline form A, for example, any of items 1.1 to 1.77, for example, crystalline form B, for example, any of items 1.78 to 1.162, wherein the crystalline form does not contain or substantially contains any other form, for example, less than 20% by weight of amorphous material, for example less than 15% by weight, for example less than 10% by weight, preferably less than 5% by weight, preferably less than 3% by weight, more preferably less than 2% by weight, even more preferably less than 1% by weight, even more preferably less than 0.1% by weight, and most preferably less than 0.01% by weight. 1.237 A crystal form as described in any of items 1.1 to 1.234, for example, crystal form A, for example, any of items 1.1 to 1.77, for example, crystal form B, for example, any of items 1.78 to 1.162, wherein the crystal form does not contain or substantially contains any other form, for example, any other crystal form is less than 20% by weight, for example less than 10% by weight, preferably less than 5% by weight, preferably less than 3% by weight, more preferably less than 2% by weight, even more preferably less than 1% by weight, even more preferably less than 0.1% by weight, and most preferably less than 0.01% by weight. 1.238 A crystalline form as described in any of items 1.1 to 1.234, for example, crystalline form A, for example, any of items 1.1 to 1.77, for example, crystalline form B, for example, any of items 1.78 to 1.162, wherein the crystalline form does not contain or substantially contains any other form, for example, amorphous and any other crystalline form in less than 20% by weight, for example less than 10% by weight, preferably less than 5% by weight, preferably less than 3% by weight, more preferably less than 2% by weight, even more preferably less than 1% by weight, even more preferably less than 0.1% by weight, and most preferably less than 0.01% by weight. 1.239 A crystalline form according to any of sections 1.1 to 1.238, which is produced by any of the methods described in sections 4.1 to 4.20 or in the same manner as in any of the examples, or which has a powder X-ray diffraction or X-ray crystal structure as shown in any of the figures.

[0007] In a second aspect, the present invention provides the citrate of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane.

[0008] In a third aspect, the present invention provides a phosphate of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane.

[0009] In a fourth embodiment, the present invention provides a crystalline form having powder X-ray diffraction, which is manufactured or described in any of the embodiments or shown in any of the figures, for example: 2.1 Crystal form D. 2.2 Crystal form D shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.541871 Å and includes characteristic peaks in the XRPD pattern shown in Figure 15, as in Section 2.1. 2.3 Crystal form D exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.541871 Å and includes a typical peak in the XRPD pattern shown in Figure 15, as in section 2.1 or 2.2. 2.4 Crystal form D shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and any of sections 2.1 to 2.3, for example, XRPD measured using radiation with a wavelength of 1.541871 Å and including three peaks selected from those shown in Figure 15, or five peaks in some specific embodiments. 2.5 Crystal form D shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and any of sections 2.1 to 2.4, for example, XRPD measured using radiation of wavelength 1.541871 Å and including 10 peaks selected from those shown in Figure 15, 20 peaks in some specific embodiments, and 25 peaks in some specific embodiments. 2.6 Crystal form D shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and XRPD, for example, is measured using radiation with a wavelength of 1.541871 Å and is substantially shown in Figure 15, any of sections 2.1 to 2.5. 2.7 Crystal form D shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and XRPD is measured using radiation with a wavelength of 1.541871 Å, as shown in Figure 15, any of sections 2.1 to 2.6. 2.8 Any of items 2.1 to 2.7, wherein the crystal form D is the citrate of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane. 2.9 Crystal form E. 2.10 Crystal form E shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.541871 Å and includes characteristic peaks in the XRPD pattern shown in Figure 16, as in Section 2.9. 2.11 Crystal form E exhibits a powder X-ray diffraction pattern, e.g., a powder X-ray diffraction pattern measured using an incident beam of Cu, e.g., Cu Kα, and e.g., XRPD is measured using radiation with a wavelength of 1.541871 Å and includes a typical peak in the XRPD pattern shown in Figure 16, as in Section 2.9 or 2.10. 2.12 Crystal form E exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and for example, XRPD is measured using radiation of wavelength 1.541871 Å and includes any of the three peaks selected from those shown in Figure 16, or five peaks in some specific embodiments, as specified in sections 2.9 to 2.11. 2.13 Crystal form E exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and any of sections 2.9 to 2.12, for example, XRPD measured using radiation of wavelength 1.541871 Å and including 10 peaks selected from those shown in Figure 16, 20 peaks in some specific embodiments, and 25 peaks in some specific embodiments. 2.14 Crystal form E exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and XRPD, for example, is measured using radiation with a wavelength of 1.541871 Å and is substantially shown in Figure 16, any of sections 2.9 to 2.13. 2.15 Crystal form E shows a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.541871 Å, as shown in Figure 16, any of sections 2.9 to 2.14. 2.16 Any of items 2.9 to 2.15, wherein the crystal form E is the phosphate of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane. 2.17 Crystal form F. 2.18 Crystal form F exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, XRPD is measured using radiation with a wavelength of 1.541871 Å and includes characteristic peaks in the XRPD pattern shown in Figure 17, as in Section 2.17. 2.19 The crystal form F exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and for example, the XRPD is measured using radiation with a wavelength of 1.541871 Å and includes a typical peak in the XRPD pattern shown in Figure 17, as in Section 2.17 or 2.18. 2.20 Crystal form F exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and for example, XRPD is measured using radiation of wavelength 1.541871 Å and includes any of the three peaks selected from those shown in Figure 17, or five peaks in some specific embodiments, as specified in sections 2.17 to 2.19. 2.21 The crystal form F exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu lines, for example, Cu Kα lines, and any of the terms 2.17 to 2.20, for example, the XRPD measured using radiation of wavelength 1.541871 Å and including 10 peaks selected from those shown in Figure 17, 20 peaks in some specific embodiments, and 25 peaks in some specific embodiments. 2.22 The crystal form F exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and the XRPD, for example, is measured using radiation with a wavelength of 1.541871 Å and is substantially shown in Figure 17, any of sections 2.17 to 2.21. 2.23 Crystal form F exhibits a powder X-ray diffraction pattern, for example, a powder X-ray diffraction pattern measured using an incident beam of Cu, for example, Cu Kα, and XRPD, for example, is measured using radiation with a wavelength of 1.541871 Å and is shown in Figure 17, any of sections 2.17 to 2.22. 2.24 Any of items 2.17 to 2.23, wherein the crystalline form F is the phosphate of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane. 2.25 A crystal form of any of sections 2.1 to 2.24, where the XRPD pattern is measured using a copper source, e.g., a copper anode. 2.26 Any of crystal forms A to F, for example, any combination of any of items 1.1 to 1.234 and any of items 2.1 to 2.25, for example, a combination of crystal form A and crystal form B; a combination of crystal form A and crystal form C; a combination of crystal form A, crystal form B and crystal form C; a combination of crystal form B and crystal form C; a combination of crystal form B and crystal form D; a combination of crystal form E and crystal form F. 2.27 A crystalline form as described in any of sections 2.1 to 2.25, wherein the crystalline form does not contain or substantially contain any other form, for example, less than 20% by weight of amorphous material, for example less than 15% by weight, for example less than 10% by weight, preferably less than 5% by weight, preferably less than 3% by weight, more preferably less than 2% by weight, even more preferably less than 1% by weight, even more preferably less than 0.1% by weight, and most preferably less than 0.01% by weight. 2.28 A crystalline form as described in any of sections 2.1 to 2.25, wherein the crystalline form does not contain or substantially contain any other form, for example, less than 20% by weight, for example less than 10% by weight, preferably less than 5% by weight, preferably less than 3% by weight, more preferably less than 2% by weight, even more preferably less than 1% by weight, even more preferably less than 0.1% by weight, and most preferably less than 0.01% by weight. 2.29 A crystalline form as described in any of sections 2.1 to 2.25, wherein the crystalline form does not contain or substantially contain any other form, for example, amorphous material and any other crystalline form in less than 20% by weight, for example less than 10% by weight, preferably less than 5% by weight, preferably less than 3% by weight, more preferably less than 2% by weight, even more preferably less than 1% by weight, even more preferably less than 0.1% by weight, and most preferably less than 0.01% by weight. 2.30 A crystalline form according to any of sections 2.1 to 2.29, which is manufactured by any of the methods described in sections 4.1 to 4.20 or in the same manner as any of the examples, or which has the powder X-ray diffraction or X-ray crystal structure shown in any of the figures.

[0010] Phase transitions in solids can be thermodynamically reversible or irreversible. A specific transition temperature (T t Crystal forms that can be reversibly deformed under these conditions are interdeformable polymorphs. If crystal forms cannot be interconverted under these conditions, the system is monodeformable (a single thermodynamically stable form).

[0011] Crystal forms A, B, and C are anhydrous tautomorphs of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. Crystal form C has a transition temperature of Tt,C→B is a stable solid phase below, and crystalline form B is T t,C→B and T t,B→A is a stable solid phase between, and crystalline form A is T t,B→A is a stable solid phase at temperatures above. T t,C→B is considered to be less than 2°C. T t,C→A is between 2°C and room temperature, and T t,B→A is 37 - 54°C.

[0012] Due to kinetic constraints, the thermodynamic transformation from crystalline form A to crystalline form B is hindered. Thus, surprisingly, crystalline form A seems to be kinetically stable enough for its solid state to persist under thermodynamically metastable temperature conditions.

[0013] Even when crystalline form A as a slurry is stirred in dichloromethane at room temperature for 16 days (see Example 6a), no solvent-mediated polymorphic transformation to crystalline form B, which is the more stable form at that temperature, occurs. This indicates that without seeds of the more stable polymorph, the critical free energy barrier for nucleation cannot be overcome within the evaluated time frame.

[0014] Even when exposed to accelerated harsh conditions for two weeks, crystalline forms A and B remain unchanged at 30°C / 56%RH or 40°C / 75%RH (Example 11). In contrast, crystalline form C transforms into a mixture of crystalline forms A and B within two weeks at 40°C / 75%RH (Example 11). Thus, unlike crystalline form A, crystalline form C transforms under metastable conditions.

[0015] For crystalline form A, without seeds of the more stable polymorph, the critical free energy barrier for nucleation of crystalline form B cannot be overcome within the evaluated time in solid state or solvent-mediated transformation experiments.

[0016] Thus, crystalline form A can be easily synthesized on a large scale, and even more surprisingly, its solid state persists even under thermodynamically metastable conditions.

[0017] In a fifth aspect, the present invention provides the following: 3.1. A pharmaceutical composition comprising any of the crystalline forms A to F described in any of sections 1.1 to 1.239 or 2.1 to 2.30, for example, crystalline form A, for example, any of sections 1.1 to 1.77, for example, crystalline form B, for example, any of sections 1.78 to 1.162, and a pharmaceutically acceptable diluent or carrier. 3.2. The pharmaceutical composition described in subsection 3.1, wherein the composition is sustained-release. 3.3. Any of the crystal forms A to F of the present invention, for example, any of items 1.1 to 1.239, for example crystal form A, for example any of items 1.1 to 1.77, for example crystal form B, for example any of items 1.78 to 1.162, for example any of items 2.1 to 2.30, in amounts from 1 mg to 1800 mg, for example 10 mg to 1800 mg, for example 25 mg to 1800 mg, for example 10 mg to 1600 mg, for example 10 mg to 1200 mg, for example 50 mg to 1200 mg, for example 50 mg to 1000 mg, for example 75 mg to 1000 mg, for example 75 mg to 800 mg, for example 75 mg to 500 mg, for example 100 mg to 750 mg, for example 100 mg to 500 mg, for example 100 mg to 400 mg, for example 100 mg to 300 mg, for example 100 mg to 200 mg A pharmaceutical composition as described in item 3.1 or 3.2, containing mg. 3.4. A composition according to any of items 3.1 to 3.3, comprising 75 mg to 1000 mg, for example, 100 mg to 600 mg, for example, 100 mg to 400 mg, for example, 100 mg to 200 mg, of any of the crystalline forms A to F of the present invention, for example, any of items 1.1 to 1.239, for example, crystalline form A, for example, any of items 1.1 to 1.77, for example, crystalline form B, for example, any of items 1.78 to 1.162, for example, any of items 2.1 to 2.30. 3.5. A composition according to any of items 3.1 to 3.3, comprising 50 mg to 600 mg, for example 100 mg to 600 mg, for example 100 mg to 400 mg, for example 100 mg to 200 mg, for example 100 mg to 200 mg, of any of the crystalline forms A to F of the present invention, for example any of items 1.1 to 1.239, for example crystalline form A, for example any of items 1.1 to 1.77, for example crystalline form B, for example any of items 1.78 to 1.162, for example any of items 2.1 to 2.30. 3.6. A composition according to any of items 3.1 to 3.3, comprising 5 mg to 500 mg, for example, 5 mg to 10 mg, for example, 10 mg to 25 mg, for example, 30 mg to 50 mg, for example, 10 mg to 300 mg, for example, 25 mg to 300 mg, for example, 50 mg to 100 mg, for example, 100 mg to 25 mg, for example, 250 mg to 500 mg, for example, 50 mg to 100 mg, for example, 100 mg to 250 mg, for example, 250 mg to 500 mg of any of the crystalline forms A to F of the present invention, for example, any of items 1.1 to 1.239, for example, crystalline form A, for example, any of items 1.1 to 1.77, for example, crystalline form B, for example, any of items 1.78 to 1.162, for example, any of items 2.1 to 2.30. 3.7. A composition according to any of items 3.1 to 3.3 for administering any of the crystalline forms A to F of the present invention, for example, any of items 1.1 to 1.239, for example, crystalline form A, for example, any of items 1.1 to 1.77, for example, crystalline form B, for example, any of items 1.78 to 1.162, for example, any of items 2.1 to 2.30, at a rate of 0.5 mg / kg to 20 mg / kg / day, for example, 1 mg / kg to 15 mg / kg / day, for example, 1 mg / kg to 10 mg / kg / day, for example, 2 mg / kg to 20 mg / kg / day, for example, 2 mg / kg to 10 mg / kg / day, for example, 3 mg / kg to 15 mg / kg / day. 3.8. A composition according to any of items 3.1 to 3.7, comprising less than 50% by weight of any of crystal forms A to F of the present invention, for example, any of items 1.1 to 1.239, for example crystal form A, for example any of items 1.1 to 1.77, for example crystal form B, for example any of items 1.78 to 1.162, for example any of items 2.1 to 2.30, for example, less than 40% by weight, for example less than 30% by weight, less than 20% by weight, for example 1 to 40% by weight, for example 5 to 40% by weight, for example 10 to 30% by weight, for example 15 to 25% by weight, for example 15 to 20% by weight, for example 17% by weight, for example 25% by weight. 3.9. A composition according to any of sections 3.1 to 3.8, wherein the pharmaceutically acceptable diluent or carrier contains hydroxypropyl methylcellulose. 3.10. The composition according to item 3.9, wherein the composition comprises at least 10% by weight, for example, 10-50% by weight, for example, 10-40% by weight, for example, 20-50% by weight, for example, 20-40% by weight, for example, 30-40% by weight, for example, 37% by weight of hydroxypropyl methylcellulose. 3.11. The composition of item 3.9 or 3.10, wherein the degree of methoxy substitution of hydroxypropyl methylcellulose is 19-24%. 3.12. A composition according to any of sections 3.9 to 3.11, wherein the degree of hydroxypropoxy substitution of hydroxypropyl methylcellulose is 4 to 12%. 3.13. A composition according to any of sections 3.9 to 3.12, wherein hydroxypropyl methylcellulose is hypromellose 2208. 3.14. A composition according to any of sections 3.9 to 3.13, wherein hydroxypropyl methylcellulose has a nominal viscosity of 4,000 mPA·σ. 3.15. A composition according to any of sections 3.9 to 3.13, wherein the hydroxypropyl methylcellulose has a viscosity of 2,000 to 6,000 mPA·σ, for example 2,600 to 5,000 mPA·σ, for example 2,663 to 4,970 mPA·σ. 3.16. A composition according to any of sections 3.9 to 3.15, wherein the pharmaceutically acceptable diluent or carrier contains alpha-lactose monohydrate. 3.17. The composition of item 3.16, comprising at least 10% by weight, for example 10-80% by weight, for example 20-70% by weight, for example 20-60% by weight, for example 20-50% by weight, for example 20-40% by weight, for example 20-30% by weight, for example 30-70% by weight, for example 30-60% by weight, for example 30-50% by weight, for example 30-40% by weight, for example 37% by weight. 3.18. The composition of item 3.16 or 3.17, wherein the composition comprises pulverized alpha-lactose monohydrate. 3.19. Any composition according to any of sections 3.1 to 3.18, wherein the composition comprises a co-processed mixture of hydroxypropyl methylcellulose and alpha-lactose monohydrate (e.g., Retalac®). 3.20. The composition of item 3.19, wherein the mixture comprises equal amounts of hydroxypropyl methylcellulose and alpha-lactose monohydrate. 3.21. The mixture is in the range of 100 μm to 200 μm, for example, 125 μm d 50 A composition according to item 3.19 or 3.20, comprising particles of hydroxypropyl methylcellulose and alpha-lactose monohydrate having (median diameter). 3.22. The mixture contains particles of hydroxypropyl methylcellulose and alpha-lactose monohydrate, with the following particle size distribution: <63μm ≤ 25% <100μm: 35% <250μm≧80% The composition is as described in items 3.19 to 3.21. 3.23. Any composition according to clauses 3.19 to 3.22, wherein the composition comprises at least 20% by weight of the mixture, for example, at least 30% by weight, for example at least 40% by weight, for example at least 50% by weight, for example at least 60% by weight, for example at least 70% by weight, for example at least 80% by weight, for example 20-90% by weight, for example 30-80% by weight, for example 40-80% by weight, for example 50-80% by weight, for example 60-80% by weight, for example 70-80% by weight, for example 75% by weight. 3.24. Any composition of sections 3.1 to 3.23, wherein the pharmaceutically acceptable diluent or carrier contains a lubricant, such as magnesium stearate. 3.25. The composition of item 3.24, wherein the lubricant is one or more of glyceryl behenate, magnesium stearate, talc, and sodium stearyl fumarate, for example, magnesium stearate. 3.26. The composition of item 3.24 or 3.25, wherein the composition contains a lubricant in an amount of less than 10% by weight, e.g., less than 5% by weight, less than 3% by weight, less than 1% by weight, e.g., 0.1 to 1% by weight, e.g., 0.1 to 0.8% by weight, e.g., 0.5% by weight. 3.27. A composition according to any of items 3.24 to 3.26, wherein the composition contains less than 10% by weight of magnesium stearate, for example less than 5% by weight, less than 3% by weight, less than 1% by weight, for example 0.1 to 1% by weight, for example 0.1 to 0.8% by weight, for example 0.5% by weight. 3.28. A composition according to any of sections 3.1 to 3.27, wherein the pharmaceutically acceptable diluent or carrier comprises one or more diluents, disintegrants, binders, and release regulators. 3.29. The composition of item 3.28, wherein the diluent is one or more of mannitol (e.g., Pearlitol 300 DC), microcrystalline cellulose (e.g., Avicel pH102), and pregelatinized starch (e.g., Starch 1500). 3.30. The composition of item 3.29, wherein the disintegrant is one or both of crospovidone (e.g., Polyplasdone XL-10) and sodium starch glycolate (e.g., Explotab). 3.31. The composition of item 3.28, wherein the binder is polyvinylpyrrolidone (e.g., Povidone K29 / 32). 3.32. The composition of item 3.28, wherein the release regulator is one or more of hydroxypropyl cellulose (e.g., Klucel EXF, Klucel MXF and / or Klucel HXF) and hydroxypropyl methylcellulose (e.g., Methocel K100M, Methocel K4M PREM, Methocel K15M PREM CR). 3.33. The composition according to item 3.28 or 3.32, wherein the composition contains at least 5% by weight, e.g., 5-60% by weight, e.g., 10-50% by weight, e.g., 10-40% by weight, of a release regulator. 3.34. The composition of section 3.32 or 3.33, wherein the release regulator is hydroxypropyl methylcellulose. 3.35. A method for preventing or treating a disorder and / or alleviating symptoms associated with any of the disorders, characterized by administering to a patient in need of a therapeutically effective amount of any of the crystalline forms A to F described in any of items 1.1 to 1.239, e.g., crystalline form A, e.g., any of items 1.1 to 1.77, e.g., crystalline form B, e.g., any of items 1.78 to 1.162, e.g., any of items 2.1 to 2.30, or any of items 3.1 to 3.34, wherein the crystalline form A is selected from norepinephrine and / or serotonin and / or dopamine as the crystalline form B is selected from norepinephrine and / or serotonin and / or dopamine, in a particular specific embodiment, a method for preventing or treating any of the following disorders: (i) Attention-deficit hyperactivity disorder (ADHD, both in children and adults) and related behavioral disorders, as well as forms and symptoms of alcohol abuse, substance abuse, obsessive-compulsive disorder, learning disabilities, reading comprehension, gambling addiction, manic episodes, phobias, panic attacks, oppositional defiant disorder, conduct disorder, destructive behavior disorder, school-related academic problems, smoking, abnormal behavior, schizophrenic behavior, somatization, depression (including, but not limited to, major depressive disorder, relapsing; dysthymia; unspecified depressive disorder (NOS); major depressive disorder, monoepisodic; bipolar disorder, depression associated with Alzheimer's disease, psychosis or Parkinson's disease; postpartum depression; and seasonal affective disorder), sleep disorders, generalized anxiety disorder, stuttering and tic disorders (such as Tourette's disorder); (ii) ADHD, substance abuse, depression, anxiety disorders (including, but not limited to, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety disorder), autism, traumatic brain injury, cognitive impairment, schizophrenia (especially cognitive impairment), obesity, chronic pain disorder, personality disorders, and mild cognitive impairment; (iii) Anxiety disorders, panic disorders, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorders, addiction, Parkinson's disease and chronic pain; (iv) Substance abuse disorders (including, but not limited to, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogenic drug use disorders, inhalant-related disorders, and opioid-related disorders); (v) Cognitive impairment, bipolar disorder, anorexia nervosa, bulimia nervosa, cyclothymic disorder, chronic fatigue syndrome, chronic or acute stress, fibromyalgia and other somatoform disorders (such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, somatoform NOS, etc.), incontinence (i.e., tension incontinence, true stress incontinence and mixed incontinence), inhalation disorders, mania, migraine, peripheral neuropathy; (vi) Addiction disorders (including, but not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogenic drug use disorders, inhalant-related disorders, opioid-related disorders, etc.); (vii) Fragile X syndrome-related disorders; (viii) In patients with autism spectrum disorder (ASD), such as fragile X syndrome-related disorder; (ix) ADHD in patients with Fragile X syndrome-related disorder; (x) Comorbidity of ADHD and depression; (xi) Comorbidity of ADHD and substance abuse; (xii) Comorbidity of ADHD and anxiety disorder. 3.36. A pharmaceutical composition according to any of sections 3.1 to 3.34 for use as a medicine, for example, for use in the manufacture of a medicine for the treatment or prevention of any of the disorders described in section 3.35. 3.37. Crystalline forms A to F as described in any of sections 1.1 to 1.239, for use in the prevention or treatment of any disorder described in section 3.35, or in the manufacture of a medicament for the treatment or prevention of any disorder described in section 3.35, e.g., crystalline form A, e.g., any of sections 1.1 to 1.77, e.g., crystalline form B, e.g., any of sections 1.78 to 1.162, e.g., any of sections 2.1 to 2.30.

[0018] In a sixth aspect, the present invention provides a crystalline form described in any of sections 1.1 to 1.239 or any of sections 2.1 to 2.30, which is produced by any of the following methods or similar methods: 4.1 Add water to the hydrochloride addition salt form of this compound ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride); All solids are heated and melted, and heated to an internal temperature of, for example, 30-40°C, for example, 34°C; Add an organic solvent, such as tetrahydrofuran and / or isopropyl acetate; Separate the water layer; Add a base, such as ammonia water, to the aqueous layer; Add an organic solvent, such as isopropyl acetate; For example, stir for at least 15 minutes; For example, let the layers stand for at least 30 minutes; Separate the organic layer; The organic layer is dried, for example, with magnesium sulfate; Filter; Wash the filtered cake with an organic solvent, such as isopropyl acetate; Concentrate the filtrate and washing solution; Add isopropyl alcohol; Dissolve all solids by stirring at room temperature; Add hydrochloric acid, for example HCl / isopropanol, to form a solid, for example HCl over 10 minutes, for example HCl / isopropanol over 10 minutes; Add hydrochloric acid, for example HCl / isopropanol, and add HCl over 55 minutes, for example HCl / isopropanol over 55 minutes; Stir the slurry, for example, stir the slurry for 35 minutes; Add hydrochloric acid, for example HCl / isopropanol, then add HCl over 10 minutes, then add HCl / isopropanol over 10 minutes; Stir the slurry, for example, stir the slurry for 30 minutes; Filter; Wash the filtered cake with an organic solvent, such as isopropyl alcohol; Dry the filtered cake. 4.2 Store crystal form A at 40°C / 75%RH; for example, store crystal form A at 40°C / 75%RH for 7 days; Isolate the crystals. 4.3 Prepare a solution of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example crystalline form A, with, for example, chloroform, dichloromethane, hexafluoroisopropyl alcohol, methanol and / or 2,2,2-trifluoroethanol (TFE); Ultrasonic treatment; Complete dissolution was determined by visual observation; Filter; Under ambient conditions, for example, evaporate the solvent in a container covered with aluminum foil that has small holes in it; Isolate the crystals. 4.4 Prepare solutions of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example crystalline form A, with, for example, chloroform, dichloromethane, ethanol and / or methanol; Filter; Mix with a poor solvent, such as toluene, heptane, acetonitrile, methyl ethyl ketone, acetone, hexane, tetrahydrofuran, dioxane, ethyl acetate and / or isopropyl ether; Isolate the crystals. 4.5 (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example crystalline form A, is exposed to vapor, for example, the vapor of an organic solvent, for example, the vapor of dichloromethane and / or ethanol; Isolate the crystals. 4.6 Prepare a suspension of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example crystalline form A, with, for example, dichloromethane, ethanol, isopropyl alcohol, 1-propanol and / or water; Stir at room temperature or under elevated temperature; The crystals are isolated, for example, by vacuum filtration. 4.7 Prepare a solution of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example crystalline form A, in an organic solvent, such as dichloromethane, ethanol, isopropyl alcohol and / or 1-propanol, under elevated temperature; For example, filter the contents through a 0.2 μm nylon filter into a heated container; Cool; Further cool by placing in a refrigerator and / or freezer as needed; Isolate the crystals. 4.8 Prepare a solution of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example, crystalline form A, in an organic solvent, such as dichloromethane, ethanol, isopropyl alcohol and / or 1-propanol, under elevated temperature; For example, filter it through a 0.2 μm nylon filter into a chilled container; Cool to below 0°C, for example, in a -78°C bath, for example, in an isopropyl alcohol / dry ice bath; Further cooling can be achieved by placing it in the freezer as needed; Isolate the crystals. 4.9 Prepare a solution of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example crystalline form A, with an organic solvent, for example ethanol, isopropyl alcohol, methanol, acetone, toluene, 1-propanol, water and / or dioxane; Ultrasonic treatment; Complete dissolution was determined by visual observation; For example, filter through a 0.2 μm nylon filter; Evaporate the solvent at room temperature; Isolate the crystals. 4.10 Prepare a solution or suspension of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example, crystalline form A, in an organic solvent, for example, dichloromethane, ethanol, isopropyl alcohol and / or 1-propanol; For example, cooling in a freezer; Isolate the crystals. 4.11 Prepare a solution or suspension of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example, crystalline form A, in an organic solvent, for example, hexafluoroisopropyl alcohol and / or 2,2,2-trifluoroethanol; For example, filter through a 0.2 μm nylon filter; Add a poor solvent, such as an organic poor solvent, such as isopropyl ether, tetrahydrofuran, acetonitrile, ethyl acetate and / or methyl ethyl ketone, to precipitate the precipitate; For example, crystals are isolated by vacuum filtration. 4.12 Dissolve (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane in an organic solvent, such as isopropanol; Add HCl, for example, HCl / isopropanol; Filter as needed. 4.13 Add the desired form of crystal to the solution or slurry, for example, add crystal form A to the solution or slurry, for example, while the temperature of the solution or slurry is above room temperature, for example, at 65°C. 4.14 Dissolve (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in an organic solvent, such as ethanol, while heating to, for example, 70°C; Filter as appropriate, for example, using a capsule carbon filter; Concentrate as appropriate, for example, up to five times the total volume (relative to the added (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride); Reheat as needed to remelt the solid; Cool as appropriate, for example, to 65°C; Add a seed crystal to the solution; Stir as needed to allow the seed bed to grow; Cool as appropriate; Filter as needed. 4.15 Dissolve (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in water, for example, while heating, for example 30-40°C, for example 34°C; Wash the aqueous solution; Addition of a base, such as ammonia; (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane is extracted with an organic solvent, such as isopropyl acetate; Dry as appropriate, for example, with magnesium sulfate; Concentrate as needed to obtain a solid; Add an organic solvent, such as isopropanol, as appropriate to dissolve the solid; Add HCl, for example, HCl / isopropanol; Filter as appropriate; Wash with an organic solvent, such as isopropanol, as needed. 4.16 Dissolve (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in an organic solvent, such as ethanol, while heating it to, for example, 70°C; Filter as appropriate, for example, using a capsule carbon filter; For example, concentrate to five times the total volume (relative to the added (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride); Add seed crystals before or after concentration as appropriate; Filter as needed. 4.17 Dissolve (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane in an organic solvent; Add HCl, for example, HCl / isopropanol; Filter as needed. 4.18 The method according to any of items 4.1 to 4.17, comprising isolating a crystal form, for example, any of items 1.1 to 1.239 or 2.1 to 2.30, for example crystal form A, for example any of items 1.1 to 1.77, for example crystal form B, for example any of items 1.78 to 1.162. 4.19 A crystal form described in any of sections 1.1 to 1.239 or 2.1 to 2.30, produced by any of Examples 1 to 3, for example, Example 1. 4.20 Crystalline forms according to any of sections 1.1 to 1.239 or 2.1 to 2.30, produced by any of the synthesis methods described in 4.20 Examples, for example Example 1, for example Example 3, for example any of Examples 6 to 13, for example Example 17, for example Example 18.

[0019] In a seventh embodiment, the present invention provides a method for producing crystal forms A to F described in any of sections 1.1 to 1.239 or 2.1 to 2.30, for example, crystal form A, for example, any of sections 1.1 to 1.77, or crystal form B, for example, any of sections 1.78 to 1.162, by the method described in sections 4.1 to 4.20 or in any of the examples.

[0020] In its eighth aspect, the present invention relates to a method for producing a pharmaceutical composition comprising any of the crystal forms A to F described in any of items 1.1 to 1.239 or 2.1 to 2.30, for example, crystal form A, for example, any of items 1.1 to 1.77, for example, crystal form B, for example, any of items 1.78 to 1.162, for example, a pharmaceutical composition described in any of items 3.1 to 3.34, comprising the following steps: A step of isolating any of the crystal forms A to F described in either item 1.1 to 1.239 or 2.1 to 2.30, for example, crystal form A, for example, any of items 1.1 to 1.77, for example, crystal form B, for example, any of items 1.78 to 1.162, and A step of mixing the isolated crystalline form with a pharmaceutically acceptable diluent or carrier. This provides a method that includes [something]. [Brief explanation of the drawing]

[0021] [Figure 1] Figure 1 shows the high-resolution powder X-ray diffraction (XRPD) pattern of crystal form A.

[0022] [Figure 2] Figure 2 shows the DSC and TGA thermograms of crystal form A.

[0023] [Figure 3] Figure 3 shows the dynamic vapor adsorption / desorption isotherm for crystal form A.

[0024] [Figure 4] Figure 4 shows overlays of the powder X-ray diffraction (XRPD) patterns for crystal forms A, B, and C (from top to bottom): Figure 4A shows the high-resolution powder X-ray diffraction pattern for crystal form A, Figure 4B shows the powder X-ray diffraction pattern for crystal form B, and Figure 4C shows the powder X-ray diffraction pattern for crystal form C.

[0025] [Figure 5] Figure 5 shows the powder X-ray diffraction (XRPD) pattern of crystal form B.

[0026] [Figure 6] Figure 6 shows the indexing results for crystal form B.

[0027] [Figure 7] Figure 7 shows the high-resolution powder X-ray diffraction (XRPD) pattern of crystal form B.

[0028] [Figure 8] Figure 8 shows the DSC and TGA thermograms of crystal form B.

[0029] [Figure 9] Figure 9 shows the powder X-ray diffraction (XRPD) pattern of crystalline form C.

[0030] [Figure 10] Figure 10 shows the indexing results for crystal form C.

[0031] [Figure 11] Figure 11 shows the high-resolution powder X-ray diffraction (XRPD) pattern of crystal form C.

[0032] [Figure 12] Figure 12 shows the DSC and TGA thermograms of crystal form C.

[0033] [Figure 13] Figure 13 shows overlays of powder X-ray diffraction (XRPD) patterns for crystal forms A, B, and C (top to bottom): Figure 13A shows the powder X-ray diffraction pattern of crystal form B (slow cooling in IPA, solid precipitate in a refrigerator), Figure 13B shows the powder X-ray diffraction pattern of crystal form C + crystal form B (slow crystallization cooling in IPA with seed crystal, solid precipitate in a freezer), Figure 13C shows the powder X-ray diffraction pattern of crystal form C + crystal form A (slow cooling in IPA, solid precipitate in a freezer), Figure 13D shows the powder X-ray diffraction pattern of crystal form B (slow cooling in IPA, solid precipitate in a freezer), and Figure 13E shows the powder X-ray diffraction pattern of crystal form B + crystal form A (crushed and cooled in IPA, solid precipitate in dry ice / IPA). Figure 13F shows the powder X-ray diffraction pattern of crystal form A + crystal form C (slow cooling in IPA, solid precipitate in a freezer), and Figure 13G shows the powder X-ray diffraction pattern of crystal form C (slow cooling in IPA).

[0034] [Figure 14] Figure 14 shows overlays of the powder X-ray diffraction (XRPD) patterns for crystal forms D, E, and F (from top to bottom): Figure 14D shows the powder X-ray diffraction pattern for crystal form D (stirred at 70°C for 30 minutes in pH 4.4 buffer), Figure 14E shows the powder X-ray diffraction pattern for crystal form E (slurry at 50°C in pH 6.0 buffer, including the peak of crystal form F), and Figure 14F shows the powder X-ray diffraction pattern for crystal form F (stirred at 70°C for 30 minutes in pH 8.1 buffer).

[0035] [Figure 15] Figure 15 shows the powder X-ray diffraction (XRPD) pattern of crystal form D.

[0036] [Figure 16] Figure 16 shows the powder X-ray diffraction (XRPD) pattern of crystal form E (including the peak of crystal form F).

[0037] [Figure 17] Figure 17 shows the powder X-ray diffraction (XRPD) pattern of crystal form F.

[0038] [Figure 18] Figure 18 shows the ORTEP diagram for crystal form A. Atoms are represented by anisotropic thermal vibration ellipsoids with a 50% probability.

[0039] [Figure 19] Figure 19 shows a packing diagram of crystal form A viewed from above along the a-axis of the crystal.

[0040] [Figure 20] Figure 20 shows the packing diagram of crystal form A as viewed from above along the b-axis of the crystal.

[0041] [Figure 21] Figure 21 shows a packing diagram of crystal form A viewed from above along the c-axis of the crystal.

[0042] [Figure 22] Figure 22 shows the hydrogen bonding in crystal form A.

[0043] [Figure 23] Figure 23 shows the calculated powder X-ray diffraction (XRPD) pattern of crystal form A.

[0044] [Figure 24] Figure 24 shows the atomic displacement ellipsoid diagram for crystal form B (atoms are represented by anisotropic thermal vibration ellipsoids with a 50% probability).

[0045] [Figure 25] Figure 25 shows the packing diagram of crystal form B as viewed along the a-axis of the crystal.

[0046] [Figure 26] Figure 26 shows the packing diagram of crystal form B as viewed along the b-axis of the crystal.

[0047] [Figure 27]Figure 27 shows the packing diagram of crystal form B as viewed along the c-axis of the crystal.

[0048] [Figure 28] Figure 28 shows the hydrogen bonding in the structure of crystal form B.

[0049] [Figure 29] Figure 29 shows the molecular conformations of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane, which are crystal forms A and B (left: structure of crystal form A, (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane; right: structure of crystal form B, (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane).

[0050] [Figure 30] Figure 30 shows the packing diagrams of crystal forms A and B as viewed along the a-axis of the crystal (left: packing of crystal form A; right: packing of crystal form B).

[0051] [Figure 31] Figure 31 shows the hydrogen bonds in the structures of crystal forms A and B (left: hydrogen bonds in the structure of crystal form A; right: hydrogen bonds in the structure of crystal form B).

[0052] [Figure 32] Figure 32 shows the calculated powder X-ray pattern of crystal form B.

[0053] [Figure 33] Figure 33 shows the experimental and calculated XRPD patterns of crystal form B (top: experimental XRPD pattern at room temperature; middle: calculated XRPD pattern adjusted to room temperature; bottom: calculated XRPD pattern at 100K).

[0054] [Figure 34] Figure 34 shows the experimental and calculated XRPD patterns for crystal form A (top: calculated XRPD pattern; bottom: experimental XRPD pattern at room temperature).

[0055] [Figure 35] Figure 35 shows the XRPD pattern of crystalline form A.

[0056] [Figure 36] Figure 36 shows the comparison of XRPD patterns of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride of Examples 1 and 5 (top: Example 5; bottom: Example 1) (the patterns are corrected along the y-axis for comparison).

[0057] [Figure 37] Figure 37 shows the XRPD pattern of crystalline form A collected with Cu Kα radiation.

[0058] [Figure 38] Figure 38 shows the indexing results of the XRPD pattern shown in Figure 37 collected with Cu Kα radiation.

[0059] [Figure 39] Figure 39 shows the measured peaks of the XRPD pattern shown in Figure 37 collected with Cu Kα radiation.

[0060] [Figure 40] Figure 40 shows the XRPD pattern of crystalline form B.

[0061] [Figure 41] Figure 41 shows the indexing results of the XRPD pattern shown in Figure 40 collected with Cu Kα radiation.

[0062] [Figure 42] Figure 42 shows the measured peaks of the XRPD pattern shown in Figure 40 collected with Cu Kα radiation.

[0063] [Figure 43] Figure 43 shows the XRPD pattern of crystalline form C.

[0064] [Figure 44]Figure 44 shows the indexing results of the XRPD pattern shown in Figure 43 collected using Cu Kα radiation.

[0065] [Figure 45] Figure 45 shows the measured peaks of the XRPD pattern shown in Figure 43 collected using Cu Kα radiation.

[0066] [Figure 46] Figure 46 shows the presented energy - temperature plots for crystal forms A, B, and C.

[0067] [Figure 47] Figure 47 shows the XRPD pattern of crystal form A.

[0068] [Figure 48] Figure 48 shows the XRPD pattern of crystal form B.

[0069] [Figure 49] Figure 49 shows the XRPD pattern of a mixture of crystal form A and a small amount of crystal form B.

[0070] [Figure 50] Figure 50 shows the XRPD patterns of crystal form A before and after DVS analysis (top: before, bottom: after).

[0071] [Figure 51] Figures 51 - 54 show the XRPD patterns of irregular crystal form A. [Figure 52] Figures 51 - 54 show the XRPD patterns of irregular crystal form A. [Figure 53] Figures 51 - 54 show the XRPD patterns of irregular crystal form A. [Figure 54] Figures 51 - 54 show the XRPD patterns of irregular crystal form A.

[0072] [Figure 55] Figure 55 shows the DSC thermogram of crystal form B.

[0073] [Figure 56] Figure 56 shows the XRPD pattern of a mixture of crystal forms A and B. [Modes for carrying out the invention]

[0074] In this specification, the term "this compound" refers to (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane. The term "hydrochloride addition salt form of this compound" refers to the following structure: [ka] This refers to (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride or (+)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride having the characteristic. This compound does not contain or substantially does not contain the corresponding (-)-enantiomer, for example, it contains 20% by weight or less of the free form or pharmaceutically acceptable salt form of the corresponding (-)enantiomer, for example, it contains 10% by weight or less of the free form or pharmaceutically acceptable salt form of the corresponding (-)enantiomer, for example, it contains 5% by weight or less of the free form or pharmaceutically acceptable salt form of the corresponding (-)enantiomer, for example, it contains 2% by weight or less of the free form or pharmaceutically acceptable salt form of the corresponding (-)enantiomer, for example, it contains 1% by weight or less of the free form or pharmaceutically acceptable salt form of the corresponding (-)enantiomer.

[0075] "Crystal form A" refers to the crystalline form of the hydrochloric acid addition salt of the compound as described in any of sections 1.1 to 1.77, or as characterized in the relevant sections of the following examples.

[0076] "Crystalline form B" refers to the crystalline form of the hydrochloride addition salt of the compound as described in any of sections 1.78 to 1.162, or as characterized in the relevant sections of the following examples.

[0077] "Crystal form C" refers to the crystalline form of the hydrochloride addition salt of the compound as described in any of sections 1.163 to 1.231, or as characterized in the relevant sections of the following examples.

[0078] "Crystal form D" refers to the crystalline form described in any of sections 2.1 to 2.8, or characterized in the relevant sections of the following examples.

[0079] "Crystal form E" refers to the crystalline form described in any of sections 2.9 to 2.16, or characterized in the relevant parts of the following examples.

[0080] "Crystal form F" refers to the crystalline form described in any of sections 2.17 to 2.24, or characterized in the relevant sections of the following examples.

[0081] The present invention claims crystal forms A to F and combinations thereof as described herein, for example, in any of sections 1.1 to 1.239 or in any of sections 2.1 to 2.30. These crystal forms can be manufactured and characterized as described in the following examples section. Accordingly, the present invention provides any of crystal forms A to F as shown in any of sections 1.1 to 1.239 or in any of sections 2.1 to 2.30, or as characterized in the following examples section.

[0082] The term “substantially free” of other crystalline forms means that other forms or crystalline forms, such as amorphous or other crystalline forms, are present in less than 10% by weight, less than 5% by weight in some specific embodiments, less than 2% by weight in some specific embodiments, less than 1% by weight in some further specific embodiments, less than 0.1% by weight in some further specific embodiments, and less than 0.01% by weight in some further specific embodiments.

[0083] The term "solvate" refers to a crystalline solid adduct that contains stoichiometric or non-stoichiometric amounts of solvent within its crystal structure. Therefore, in this specification, the term "nonsolvate" refers to a crystalline form of the present invention that does not contain or substantially contains solvent molecules within its crystal structure. Similarly, in this specification, the term "nonhydrate" refers to a salt crystal of the present invention that does not contain or substantially contains water molecules within its crystal structure.

[0084] The term "amorphous" refers to a solid with an irregular molecular arrangement that lacks a discernible crystalline lattice.

[0085] The term "patient" includes both human and non-human entities. In one embodiment, the patient is human. In another embodiment, the patient is non-human.

[0086] The term "poor solvent" refers to a solvent in which the compound and / or the hydrochloride addition salt form of the compound ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) are sparingly soluble or insoluble. For example, poor solvents include solvents in which the solubility of the compound and / or the hydrochloride addition salt form of the compound is less than 35 mg / ml, e.g., 10-30 mg / ml, e.g., 1-10 mg / ml, e.g., less than 1 mg / ml.

[0087] The term "XRPD" stands for powder X-ray diffraction.

[0088] It will be understood that the powder X-ray diffraction pattern of a given sample may vary (standard deviation) depending on the equipment used, the time and temperature during sample measurement, and the standard experimental error. Therefore, the 2θ values, d-interval values, height, and relative intensity of the peaks may have acceptable deviations. For example, these values ​​may have acceptable deviations of, for example, about 20%, 15%, 10%, 5%, 3%, 2%, or 1%. In certain embodiments, the 2θ(°) value or d-interval value (Å) of the XRPD pattern of the crystal form of the present invention may have an acceptable deviation of ±0.2 degrees and / or ±0.2 Å. Furthermore, the XRPD pattern of the crystal form of the present invention may be identified by characteristic peaks recognized by those skilled in the art. For example, the crystal form of the present invention may be identified by, for example, two characteristic peaks, three characteristic peaks in some cases, or five characteristic peaks in other cases. Therefore, the term “substantially” as shown in a particular table or in a particular drawing refers to any crystal having an XRPD with the main or characteristic peaks shown in the table / drawing as recognized by those skilled in the art.

[0089] It should be understood that the differential scanning calorimetry or thermogravimetric analysis thermogram of a given sample may vary (standard deviation) depending on the equipment used, the time and temperature during sample measurement, and the standard experimental error. The temperature value itself may have a deviation of ±10°C, preferably ±5°C, and preferably ±3°C from the reference temperature.

[0090] For XRPD, in most cases, select peaks within a range of approximately 30°²θ. Using a rounding algorithm, round each peak to the nearest approximation of 0.1° or 0.01°²θ, depending on the instrument used to collect the data and / or inherent peak resolution. The variability of the peak position should be within ±0.2°²θ.

[0091] In this specification, the wavelength used to calculate the d-interval (Å) value was 1.5405929 Å, Cu-K α1 This is the wavelength (Phys. Rev., A56 (6), 4554-4568 (1997)).

[0092] According to the United States Pharmacopeia guidelines, the peaks of variable hydrates and solvates may differ by more than ±0.2°²θ.

[0093] "Prominent peaks" are a subset of all observed peaks, preferably non-overlapping, and are selected from the measured peaks by identifying low-angle, high-intensity peaks.

[0094] When multiple diffraction patterns are obtained, particle statistics (PS) and / or preferred selective orientation (PO) can be evaluated. The reproducibility of XRPD patterns from multiple samples analyzed with a single diffractometer indicates appropriate particle statistics. Agreement of relative intensities between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD patterns may be compared, if possible, with calculated XRPD patterns based on the single-crystal structure. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS / PO. If the effects of PS and PO are deemed negligible, the XRPD pattern is typical of the average powder intensity of the sample, and prominent peaks may be identified as "typical peaks." Generally, the more data collected to determine typical peaks, the more reliably such peaks can be classified.

[0095] To the extent that they exist, "characteristic peaks" are a subset of typical peaks used to distinguish one crystalline polymorph from another (polymorphs that are crystalline forms with the same chemical composition). Characteristic peaks are determined by evaluating whether typical peaks, if any, are present in a particular crystalline polymorph of the compound within ±0.2°2θ of all other known crystalline polymorphs of that compound. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0096] It was observed that crystal form B may also be formed in the reaction for producing crystal form A. However, the synthesis of the product may be controlled, for example, by using crystal form A as a seed crystal.

[0097] As described herein, crystalline forms A-F, e.g., items 1.1-1.239, e.g., items 2.1-2.30, and combinations thereof, are useful as unbalanced triple reuptake inhibitors (TRIs), being most effective against norepinephrine (NE) reuptake, having one-sixth the effectiveness against dopamine (DA) reuptake, and about one-fourteenth the effectiveness against serotonin (5-HT) reuptake. Accordingly, as described herein, crystalline forms A-F, e.g., items 1.1-1.239, e.g., items 2.1-2.30, and combinations thereof, are useful for the prevention or treatment of treatable disorders and / or the alleviation of symptoms associated with any of these disorders by inhibiting the reuptake of multiple biogenic amines associated as causative factors of target central nervous system disorders, with the biogenic amines targeted for reuptake inhibition being selected from norepinephrine and / or serotonin and / or dopamine. Accordingly, the present invention provides a method for the prevention or treatment of any of the following disorders, comprising administering a therapeutically effective amount of any of the crystalline forms A to F described in any of items 1.1 to 1.239, for example, crystalline form A, for example, any of items 1.1 to 1.77, for example, crystalline form B, for example, any of items 1.78 to 1.162, for example, any of items 2.1 to 2.30, to a patient in need: Attention-deficit hyperactivity disorder (ADHD) and related behavioral disorders, as well as substance abuse (alcohol abuse, drug abuse), obsessive-compulsive behavior, learning disabilities, reading comprehension, gambling addiction, manic episodes, phobias, panic attacks, defiant attitudes, conduct disorder, school-related academic problems, smoking, abnormal behavior, schizophrenic behavior, somatization, depression, sleep disorders, generalized anxiety disorder, stuttering, and tic disorders. Further disorders are disclosed in U.S. Patent Application Publication No. 2007 / 0082940, which is incorporated herein by direct reference; • Depression, anxiety disorders, autism, traumatic brain injury, cognitive impairment and schizophrenia (especially cognitive impairment), obesity, chronic pain disorders, personality disorders and mild cognitive impairment; Panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorder, Parkinson's disease; The diseases disclosed in International Publication No. WO2013 / 019271 are incorporated herein by reference; • Fragile X syndrome-related disorders; • Fragile X syndrome-related disorder in patients who have not responded to previous treatment for Fragile X syndrome-related disorder; For example, attention deficit / hyperactivity disorder (ADHD), which is a comorbidity of one or both anxiety and / or depression (e.g., depression) in patients with fragile X syndrome-related disorders; Autism Spectrum Disorder (ASD); The details of the impairment disclosed in International Application No. PCT / US2014 / 069401 are incorporated herein by reference.

[0098] The disorders for which treatment using the crystalline form of the present invention described herein is being considered include those listed in the Quick Reference to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, Washington, DC, 1994. These target disorders include, but are not limited to, attention-deficit / hyperactivity disorder, predominantly inattentive; attention-deficit / hyperactivity disorder, predominantly hyperactive-impulsive; attention-deficit / hyperactivity disorder, mixed type; attention-deficit / hyperactivity disorder not otherwise specified (NOS); conduct disorder; oppositional defiant disorder; and disruptive behavior disorder not otherwise specified (NOS).

[0099] Examples of depressive disorders suitable for treatment and / or prevention according to the present invention include, but are not limited to, major depressive disorder, recurrent; dysthymic disorder; unspecified (NOS) depressive disorder; and major depressive disorder, single episode.

[0100] Addiction disorders suitable for treatment and / or prevention using the methods and compositions of the present invention include, but are not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogenic drug use disorders, inhalant-related disorders, and opioid-related disorders.

[0101] Preferably, the crystal form of the present invention is crystal form A.

[0102] In this specification, "therapeutically effective dose" refers to the amount that is effective in providing therapeutic benefits, such as symptom relief, when administered to humans or non-humans. The specific dose of a substance administered to obtain therapeutic benefits will, of course, be determined by specific circumstances, such as the specific substance administered, the route of administration, the disease being treated, and the individual being treated.

[0103] The dosage or method of administration of said dosage is not particularly limited. The dosage used to implement the disclosure will of course vary depending on, for example, the form of administration and the desired therapy. Generally, satisfactory results are shown to be obtained with oral administration at dosages on the order of about 0.01 to 2.0 mg / kg. The daily dose indicated for oral administration is in the range of about 0.75 mg to 200 mg, preferably administered once daily or in 2 to 4 divided doses, or in a sustained-release form. Accordingly, the oral unit dosage form may contain, for example, about 0.2 mg to 75 mg or 150 mg, for example, about 0.2 mg or 2.0 mg or 50 mg or 75 mg or 100 mg to 200 mg or 500 mg of any or a combination thereof of crystal forms A to F, preferably crystal form A, for example, any of items 1.1 to 1.77, together with a pharmaceutically acceptable diluent or carrier therefor.

[0104] The crystalline forms of the present invention may be administered by any suitable route, such as oral, parenteral, transdermal, inhalation, or sustained release, although various other known delivery routes, devices, and methods may be used. In some specific embodiments, a sustained-release pharmaceutical composition, such as a sustained-release oral pharmaceutical composition, comprising any of the crystalline forms of the present invention, e.g., crystalline form A, e.g., any of items 1.1 to 1.77, is provided for a sustained delivery period of about 6 hours or more, e.g., 8 hours or more, e.g., 12 hours or more, e.g., 18 hours or more, e.g., 24 hours or more. In some specific embodiments, an immediate-release pharmaceutical composition, such as an immediate-release oral pharmaceutical composition, is provided, comprising any of the crystalline forms of the present invention, e.g., crystalline form A, e.g., any of items 1.1 to 1.77.

[0105] Further dosages and formulations are provided in International Application Nos. PCT / US2014 / 069401 and PCT / US2014 / 069416, which are incorporated herein by reference.

[0106] The hydrochloride addition salt form of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane may be prepared as described in U.S. Patent Publication No. 2007 / 0082940 or International Publication No. WO2013 / 019271, both of which are incorporated herein by direct reference.

[0107] U.S. Patent Publication No. 2007 / 0082940 and International Publication No. WO2013 / 019271 both describe the synthesis of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, but they do not discuss any specific crystalline form of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

[0108] The following section illustrates methods for producing and characterizing crystal forms A to F of the present invention. Both thermodynamic and kinetic crystallization methods are employed. These techniques are described in more detail below.

[0109] Poor solvent precipitation: Prepare solutions with various solvents and filter them into vials through a 0.2 μm nylon filter. Then, add the poor solvent until precipitation is observed. Isolate the resulting solid by vacuum filtration and analyze it.

[0110] Crush Cool (CC): Prepare solutions with various solvents under increasing temperature, and filter them hot through a 0.2 μm nylon filter into a pre-cooled vial. Place the vial in a (dry ice + isopropanol) cooling bath. If solid precipitation is not immediately observed, place the sample in a freezer. Isolate the resulting solid by vacuum filtration and analyze it.

[0111] First Evaporation (FE): The solution is prepared with various solvents, and each addition is sonicated to aid dissolution. As soon as the dissolution of the mixture is visually confirmed to be complete, the solution is filtered through a 0.2 μm nylon filter. The filtered solution is evaporated in an open vial under ambient conditions. Unless otherwise specified, the solution is evaporated to dryness. The resulting solid is isolated and analyzed.

[0112] Freeze-drying: Prepare a solution in a 1:1 dioxane:water or water ratio, filter it through a 0.2 μm nylon filter, and freeze it in a vial or flask immersed in a bath of dry ice and isopropanol. Attach the vial or flask containing the frozen sample to a Flexi-Dry freeze-dryer and dry for a set period of time. After drying, isolate the solid and store it in a freezer with a desiccant until use.

[0113] Grinding: Place the solid sample in a stainless steel grinding jar equipped with grinding balls. Then, grind the sample in a ball mill (Retsch Mixer Mill model MM200) at 30 Hz for a set period of time. Collect the solid and analyze it.

[0114] Relative humidity stress: The solid is stored for a set period of time under controlled conditions, approximately 40°C / 75%RH, by placing it in a vial in a sealed temperature / humidity chamber. The sample is then analyzed after being removed from the stress environment.

[0115] Rotary Evaporation: Prepare an HFIPA solution of the hydrochloride addition salt form of this compound ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride). Obtain a solid by rotary evaporation of the solvent under vacuum while immersing the sample vial in a water bath heated to approximately 40°C. Then, dry the solid under vacuum at ambient temperature for approximately 10 minutes. After evaporation, store the solid in a freezer with a desiccant until use.

[0116] Slow Cooling (SC): Prepare the solution with various solvents under increasing temperature. Hot filter the solution into a warmed vial through a 0.2 μm nylon filter. Cover the vial and leave it on a hot plate. Turn off the hot plate and allow the sample to cool slowly to ambient temperature. If no solid is present after cooling to ambient temperature, place the sample in a refrigerator and / or freezer to further cool it. Collect the solid by vacuum filtration and analyze it.

[0117] Slow Evaporation (SE): The solution is prepared with various solvents and sonicated to aid dissolution. As soon as the mixture is completely dissolved, as determined by visual inspection, the solution is filtered through a 0.2 μm nylon filter. The filtered solution is allowed to evaporate the solvent at ambient temperature in a vial covered with perforated aluminum foil. Unless otherwise specified, the solution is evaporated to dryness. The resulting solid is isolated and analyzed.

[0118] Slurry method: A suspension is prepared by adding a sufficient amount of solid to a predetermined solvent, so that an excess of solid is present. The mixture is then stirred in a covered vial at ambient temperature or under elevated temperature. After a certain period of time, the solid is isolated by vacuum filtration and analyzed.

[0119] Vapor diffusion (VD): Prepare solutions with various solvents and filter them through a 0.2 μm nylon filter. Dispense the filtered solutions into one drum vial, then place them in a 20 mL vial containing a poor solvent. Leave the drum vial uncovered, and cover the 20 mL vial to allow vapor diffusion. Isolate the resulting solid and analyze it.

[0120] Vapor stress (VS): Place a solid sample in a drum vial. Then, place the drum vial into a 20 mL vial containing a solvent. Cover the 20 mL vial and leave it in the ambient environment for a set period of time. Analyze the sample after removing it from the stress environment.

[0121] XRPD overlay: The XRPD pattern overlay is generated using Pattern Match 2.3.6.

[0122] XRPD Indexing: The high-resolution XRPD patterns of the crystalline form of the present invention are indexed using X'Pert High Score Plus (X'Pert High Score Plus 2.2a (2.2.1)) or dedicated software. Indexing and structural refinement are performed by computer analysis.

[0123] Instrumental Techniques: The test substances in this study will be analyzed using the instrumental techniques described below.

[0124] Differential Scanning Calorimetry (DSC): DSC is performed using a TA Instruments differential scanning calorimeter. Temperature calibration is performed using NIST-traceable indium metal. The sample is placed in an aluminum DSC pan, covered with a lid, and its weight is accurately recorded. The aluminum pan, set as the sample pan and weighed, is placed on the reference side of the cell. Data acquisition parameters and pan configuration are shown in each thermogram image. The method code on the thermogram is an abbreviation for the start and end temperatures and heating rate; for example, -30-250-10 means "-30°C to 250°C, 10°C / min". The following table summarizes the abbreviations used in each image regarding pan configuration: Abbreviations and their meanings T0C Tzero Crimp Pan The HS lid is sealed tightly. The HSLP lid is sealed tightly and has holes made with laser pinholes. It is open C The lid is crimped. The NC lid is not crimped.

[0125] Thermogravimetric Analysis (TGA): TG analysis is performed using a thermogravimetric analyzer manufactured by TA Instruments. Temperature calibration is performed using nickel and Alumel®. Each sample is placed in an aluminum pan. The sample is sealed, a hole is made in the lid, and then it is placed in the TG furnace. The furnace is heated under nitrogen. Data acquisition parameters are shown in the image of each thermogram. The method code on the thermogram is an abbreviation for the start and end temperatures and heating rate; for example, 25-350-10 means "25°C to 350°C, 10°C / min".

[0126] Powder X-ray diffraction (XRPD): Inel XRG-300. Powder X-ray diffraction analysis is performed using an Inel XRG-3000 diffractometer equipped with a curved position detection element with a 2θ range of 120°. Real-time data is acquired using Cu Kα rays with a resolution of 0.03°2θ. Tube voltage and current are set to 40kV and 30mA, respectively. Patterns are displayed from 2.5° to 40°2θ to facilitate direct pattern comparison. Samples are prepared for analysis by packing them into thin-walled glass capillaries. Each capillary is mounted on a goniometer head with a motor to rotate the capillary during data acquisition. Instrument calibration is performed daily using a silicon reference standard. Data acquisition and processing parameters are displayed on each pattern in the data section.

[0127] Powder X-ray diffraction (XRPD): Bruker D-8 Discover diffractometer. XRPD patterns are collected using a Bruker D-8 Discover diffractometer and Bruker's General Area Diffraction Detection System (GADDS, v. 4.1.20). The Cu Kα incident beam is generated using a fine focus tube (40kV, 40mA), a Goebel mirror, and a 0.5mm two-hole collimator. The sample is packed between 3-micron thick films to form a portable disc-shaped sample. The prepared sample is loaded into a holder fixed to a translation stage and analyzed by transmission geometry. The incident beam is scanned and rasterized to optimize orientation statistics. A beam stop is used to minimize air scattering from low-angle incident beams. Diffraction patterns are collected using a Hi-Star area detector located 15cm from the sample and processed using GADDS. A silicon standard is analyzed before analysis to confirm the Si 111 peak position. Data acquisition and processing parameters are displayed on each pattern in the data section.

[0128] Powder X-ray diffraction (XRPD): PANalytical X'Pert Pro diffractometer. XRPD patterns are collected using a PANalytical X'Pert Pro diffractometer. Samples are analyzed using Cu beams prepared with an Optix long high-precision focal source. An elliptic stepwise multilayer mirror is used to focus the Cu Kα X-ray beam onto the sample and direct it towards the detector. The sample is sandwiched between 3-micron thick films and analyzed by transmission geometry, and the orientation statistics are optimized by rotating it parallel to the diffraction path. Background generated by air scattering is minimized using a beam stop, anti-scattering short extension, anti-scattering knife edge, and helium packing. A solar slit is used for the incident and diffracted beams to minimize axial divergence. Diffraction patterns are collected using a scattering position detector (X'Celerator) located 240 mm from the sample. Data acquisition parameters for each diffraction pattern are displayed on the image of each pattern in the data section. Before analysis, a silicon sample (NIST reference standard material 640d) is analyzed to confirm the position of the silicon 111 peak.

[0129] For indexing, agreement in unit cell determination is indicated by the agreement between acceptable peak positions, those marked with bars, and the measured peaks. Successful indexing of the pattern indicates that the sample consists mainly of single-crystal phases. The space groups that match the assigned extinction symbols, unit cell parameters, and derived quantities are listed below the figure. To confirm the provisional indexing results, the molecular packing motifs within the crystallographic unit cell must be determined. Molecular packing is not attempted. [Examples]

[0130] Abbreviation Acetonitrile (ACN) Birefringence (B) Saturated saline solution (saturated sodium chloride solution) Density (d) Dichloromethane (DCM) equivalent (eq) Ethanol (EtOH) Ethyl acetate (HCl) Extinction (E) Formula weight (FW) grams (g) Time (h,hrs) Hexafluoroisopropanol (HFIPA) High-performance (high-pressure) liquid chromatography (HPLC) Isopropanol (IPA) Isopropyl acetate (IPAc) Isopropyl ether (IPE) kilograms (kg) liters (L) methanol (MeOH) Methyl ethyl ketone (MEK) Minutes milliliters (mL) Molar concentration of solution (mol / L) (M) Molecular weight (MW) mole Room temperature (RT) saturation Hexamethyldisilazane sodium (NaHMDS) Starting material (SM) Tetrahydrofuran (THF) 2,2,2-Trifluoroethanol (TFE) vs Weight (wt) Example 1 - Preparation of Crystal Form A [Table 10]

[0131] Add 2-naphthylacetonitrile (1500 g, 8.97 mol, SM) to a 50 L three-necked round-bottom flask equipped with an overhead stirring bar, dropping funnel, thermocouple, cooling bath, nitrogen inlet, and drying tube. Add tetrahydrofuran (6.0 L, 4 mL / g, SM) to the reaction vessel. Stir at room temperature until all of the 2-naphthylacetonitrile is dissolved. Add (S)-(+)-epichlorohydrin (1081 g, 11.67 mol, 1.30 eq) to the reaction vessel. Cool the reaction mixture to an internal temperature of -28°C. Cool using a dry ice / acetone bath. Add dry ice intermittently to the bath and maintain the cooling bath at -35 to -25°C during the addition of sodium bis(trimethylsilyl)amide. A THF solution of sodium bis(trimethylsilyl)amide (9.0 L, 18.0 mol, 2 mol eq) is placed in a dropping funnel and added to the reaction mixture, which has been slowly cooled at a rate such that the internal temperature remains below -14°C. The addition takes 1 hour and 40 minutes. The internal temperature during addition is generally -20 to -17°C. After addition is complete, the resulting solution is stirred at -21 to -16°C for 2 hours and 30 minutes. The reaction is monitored by HPLC. The reaction mixture is kept at a temperature of -20 to -15°C, and the sample is analyzed by HPLC.

[0132] An HPLC assay at 2 hours and 30 minutes indicates that the reaction is not yet complete. Next, a THF solution of sodium bis(trimethylsilyl)amide (0.30 L, 0.60 mol, 0.067 mole eq) is added over 10 minutes using a dropping funnel, while maintaining the internal temperature of the reaction mixture below -15°C. The mixture is stirred for 15 minutes, the time at which the HPLC assay indicates the reaction is complete. Borane-dimethyl sulfide (2.25 L, 22.5 mol, 2.5 mole eq) complex is added using a dropping funnel at a rate that keeps the internal temperature of the reaction mixture below 0°C. This addition takes 40 minutes. After the addition of borane is complete, the reaction mixture is slowly heated to 40°C. Heating is stopped when the internal temperature reaches 40°C. Slow and stable exothermic reaction is observed over approximately 2 hours, reaching a maximum internal temperature of 49°C. Once the exothermic reaction stops, the internal temperature rises to 60°C. The reaction mixture is stirred overnight at 60°C. Monitor the reaction using HPLC. Maintain the temperature of the reaction mixture at 60°C and analyze the sample using HPLC.

[0133] Next, borane-dimethyl sulfide (0.35 L, 0.70 mol, 0.39 mole eq) is added to the reaction mixture using a dropping funnel. The reaction mixture is stirred at 60°C for 3 hours and 30 minutes. The reaction mixture is then cooled to room temperature.

[0134] A second 50 L three-necked round-bottom flask, equipped with an overhead stirring bar, thermocouple, cooling bath, and nitrogen inlet, is filled with 2 M HCl / water (prepared from 2.9 L of concentrated HCl and 14.4 L of water, 17.3 L of 11.5 mL / g SM). The HCl aqueous solution is cooled to 3°C. The reaction mixture at room temperature, containing cyclopropylamine, is slowly added to the cooled HCl solution at a rate such that the maximum internal temperature of the quench mixture is 23°C. Quenching takes 2 hours and 50 minutes. Once the reaction has quenched, the two-phase mixture is heated to 50°C. Stir at 50°C for 1 hour. Cool to room temperature. Add isopropyl acetate (6.0 L, 4 mL / g SM). Add water (7.5 L, 5 mL / g SM). Stir the mixture for at least 15 minutes. Stop stirring and allow the layers to stand for at least 30 minutes. Discard the organic (upper) layer. Add aqueous ammonia (2.25 L, 1.5 mL / g SM) to the aqueous layer. Add isopropyl acetate (7.5 L, 5 mL / g). Stir the mixture for at least 15 minutes. Stop stirring and let the layers stand for at least 30 minutes. Separate the layers. The product is in the organic (upper) layer. Add isopropyl acetate (7.5 L, 5 mL / g SM) to the aqueous layer. Stir the mixture for at least 15 minutes. Stop stirring and let the layers stand for at least 30 minutes. Separate the layers. The product is in the organic (upper) layer. Combine the two isopropyl acetate extracts. Add 5% dibasic sodium phosphate aqueous solution (6.0 L, 4 mL / g SM) to the combined extracts. Stir the mixture for at least 15 minutes. Stop stirring and let the layers stand for at least 30 minutes. Separate the layers and discard the aqueous (lower) layer. Add saturated saline solution (6.0 L, 4 mL / g SM) to the combined extract. Stir the mixture for at least 15 minutes. Stop stirring and allow the layers to stand for at least 30 minutes. Separate the layers and discard the aqueous (lower) layer. Concentrate the final organic layer under reduced pressure in a 20 L net Buchi flask. Obtain a total of 1967.6 g of a light orange waxy solid. Transfer the solid to a 50 L three-necked round-bottom flask equipped with an overhead stirring bar, thermocouple, heating mantle, nitrogen inlet and drying tube. Add isopropyl acetate (15 L, 10 mL / g SM). Heat the mixture to 50°C.p-toluenesulfonic acid monohydrate (1586 g, 8.34 mol, 0.93 mole eq) is added gradually over 30 minutes while maintaining the temperature below 60°C. After the addition is complete, heating is stopped and the mixture is allowed to cool to room temperature. The solid is collected by filtration. The filtration cake is washed with isopropyl acetate (3 L, 2 mL / g SM). The filtration cake is washed again with isopropyl acetate (3 L, 2 mL / g SM). The filtration cake is dried in a filter funnel to a certain weight by vacuum suction of air from the cake. After the initial drying, the filtration cake is crushed with a spatula and the cake is periodically stirred to promote drying. 2049 g of white solid is obtained. HPLC assay: 98.2% for the main peak, cis:trans ratio 98.5:1.5. [Table 11]

[0135] Note: Adding 5M NaOH to the reaction mixture is exothermic, so active cooling is necessary.

[0136] 2039.7 g (5.10 mol, 1.0 mol eq) of naphthylcyclopropylamine tosylate obtained above is packed into a 50 L three-necked round-bottom flask equipped with an overhead stirring bar, thermocouple, dropping funnel, nitrogen inlet, drying tube, and room temperature water bath. 13.2 L of isopropyl acetate (IPAc, 13.2 L, 6.5 mL / g SM) is packed into the reaction flask and stirred at room temperature to obtain a white slurry. 445 mL (6.13 mol, 1.2 mol eq) of thionyl chloride is added using a dropping funnel while maintaining the temperature below 25°C. The addition takes 1 hour and 5 minutes. The viscous slurry is stirred at room temperature for at least 2 hours. The reaction is monitored by HPLC. The reaction mixture is maintained at room temperature while the sample is analyzed by HPLC. Add 5M NaOH (6.1 L, 30.5 mol, 6.0 mol eq) using a dropping funnel, maintaining the temperature below 30°C with an ice / water bath. The addition takes 1 hour and 40 minutes. Monitor the reaction by HPLC. Maintain the reaction mixture at room temperature while analyzing the sample by HPLC. Stir the reaction mixture at 25°C for 1 hour and 5 minutes, then allow the layers to stand. Separate the layers. Wash the organic (upper) layer with 1M NaOH (2.1 L, 1 mL / g SM). Combine the two aqueous layers. Back-extract the combined aqueous layer with isopropyl acetate (7.6 L, 3.75 mL / g SM). Combine the washed organic layer with the back extract. Wash the combined organic layer with saturated brine (4.1 L, 2 mL / g SM). Dry the organic layer over granular magnesium sulfate. Remove the solid by filtration. Wash the filtration cake with isopropyl acetate (1 L, 0.5 mL / g SM). Concentrate the combined filtrate and washings to a total volume of 4.2 L in a 20 L Buchi Rotavap flask. Transfer to a 22 L three-necked round-bottom flask equipped with an overhead stirring bar, dropping funnel, thermocouple, cooling bath, nitrogen inlet, and drying tube. Dilute with isopropyl acetate (7.2 L, total solution volume = 11.4 L, 5.6 mL / g SM). Add HCl / isopropyl alcohol (5.7 M, 0.90 L, 5.13 mol, 1.0 mol eq) over 50 minutes using a dropping funnel at a rate that keeps the internal temperature below 30°C. Stir the slurry at room temperature for 45 minutes. Filter and collect the solid.The filtration cake is washed with isopropyl acetate (2.3 L, 1.13 mL / g SM). The filtration cake is washed again with isopropyl acetate (2.3 L, 1.13 mL / g SM). The filtration cake is partially dried by vacuum aspirating air from the cake. HPLC assay of the wet cake shows a 96.3 area % purity and 89.5% EE.

[0137] The wet cake from this experiment and another batch are combined in a 50 L three-necked round-bottom flask equipped with an overhead stirring bar, heating mantle, thermocouple, reflux condenser, nitrogen inlet, and drying tube. Isopropyl alcohol (34.6 L, 7.45 mL / g SM) is added. The slurry is heated and refluxed. Reflux is maintained for 3 hours. Heating is stopped and the mixture is allowed to cool to room temperature. The mixture is filtered, and the solid is collected. The filtered cake is washed with isopropyl alcohol (6.9 L, 1.5 mL / g SM). The filtered cake is washed again with isopropyl alcohol (6.9 L, 1.5 mL / g SM). The filtered cake is dried to a constant weight by vacuum, removing air from the cake. 2009 g of the product is obtained as a yellowish-brown solid. HPLC: >99.5%. Chiral HPLC: 95.4%. [Table 12]

[0138] Note: The minimum amount of ethanol necessary to completely dissolve the starting material should be used.

[0139] (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride is packed into a 50 L three-necked round-bottom flask equipped with an overhead stirring bar, thermocouple, reflux condenser, heating mantle, nitrogen inlet, and drying tube. Ethanol (20 L, mL / g SM) is added. The stirred slurry is heated to 77°C. A further 0.5 L aliquot of ethanol is added, and the mixture is refluxed again until all solids are dissolved. After adding a further 1.5 L of ethanol (total 21.5 L), dissolution is complete. Heating is stopped, and the solution is allowed to cool to room temperature. The solution is filtered, and the solid is collected. The filter cake is washed with ethanol (4.3 L, 2.14 mL / g SM). The filter cake is dried to a certain weight by vacuum suction of air from the filter cake. 1435 g of light yellowish-brown solid is obtained. Yield = 74%. HPLC: 99.5%. Chiral HPLC: 99.9%. [Table 13]

[0140] The compound in hydrochloride addition salt form ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) (1406 g, 5.72 mol, 1.0 mol eq) (compound obtained from the above step and another batch) is packed into a 22 L three-necked round-bottom flask equipped with an overhead stirring bar, heating mantle, thermocouple and nitrogen inlet. Water (14 L, 10 mL / g SM) is added. The slurry is heated to an internal temperature of 34°C to dissolve all solids. Transfer to a large separatory funnel. Tetrahydrofuran (2.8 L, 2 mL / g SM) is added. Isopropyl acetate (2.8 L, 2 mL / g SM) is added. Stirring is stopped and the layers are separated. The organic (upper) layer is discarded. The product is in the lower (aqueous) layer. Add aqueous ammonia (1.14 L, 17.1 mol, 3.0 mol eq) to the aqueous (lower) layer. Add isopropyl acetate (14.0 L, 10 mL / g SM). Stir the mixture for at least 15 minutes. Stop stirring and let the layers stand for at least 30 minutes. Separate the layers. The product is in the organic (upper) layer. Add granular magnesium sulfate to the organic layer. Filter to remove the solid. Wash the filter cake with isopropyl acetate (1 L). Wash the filter cake again with isopropyl acetate (1 L). Concentrate the recovered filtrate and washings in a 20 L Buchi rotavap flask to obtain a grayish-white solid. Pack the solid into a 22 L round-bottom flask equipped with an overhead stirring bar, thermocouple, dropping funnel, nitrogen inlet and drying tube. Add isopropyl alcohol (14 L, 10 mL / g SM). Stir at room temperature to dissolve all solids. Add 5.7 N HCl / IPA (175 mL, 1.0 mol, 0.17 mol eq) using a dropping funnel over 10 minutes to form a white solid. Stir the thin slurry at room temperature for 30 minutes. Add 5.7 N HCl / IPA (670 mL, 3.82 mol, 0.67 mol eq), followed by 5.6 N HCl / IPA (110 mL, 0.62 mol, 0.11 mol eq) using a dropping funnel over 55 minutes. Stir the slurry for 35 minutes, then check for volume loss of the mother liquor. Add 5.6 N HCl / IPA (60 mL, 0.34 mol, 0.06 mol eq) using a dropping funnel over 10 minutes.After stirring the slurry for 30 minutes, check for volume loss of the mother liquor. Filter and collect the solid. Wash the filter cake with isopropyl alcohol (2.8 L, 2 mL / g SM). Wash the filter cake again with isopropyl alcohol (2.8 L, 2 mL / g SM). Dry the filter cake to a constant weight by aspirating air from it under vacuum. Obtain 1277 g of product as a grayish-white solid. HPLC: 99.9%.

[0141] The obtained compound shows a crystalline XRPD pattern (Figure 1) and is denoted as crystal form A. The XRPD pattern is collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu-line incident beam generated using an Optix long high-precision focal source. The Cu Kα X-ray is focused on the sample using an elliptical stepwise multilayer mirror and directed towards the detector. Before analysis, a silicon sample (NIST SRM 640d) is analyzed to confirm the Si 111 peak position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for the incident and diffracted beams to minimize broadening from axial divergence. The diffraction pattern is collected using a scattering position detection element (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. The experimental XRPD pattern is collected according to the cGMP specification. The acquired XRPD pattern is shown in Figure 1 (Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, current: 40 mA, scan range: 1.01-40.00°²θ, step size: 0.017°²θ, acquisition time: 1939 s, scan speed: 1.2° / min., slit: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission).

[0142] The thermal analysis results are shown in Figure 2 (DSC, size: 1.7800 mg, method: (-30)-300-10, T0C; TGA, size: 6.8320 mg, method: 00-350-10). According to TGA, crystal form A shows a weight loss of approximately 0.4% up to 200°C. The dramatic weight change of TGA at approximately 276°C is consistent with decomposition. The DSC thermogram (Figure 2) shows multiple endothermic reactions at approximately 245-248°C, and according to TGA, dramatic weight changes occur simultaneously, indicating that overlapping events are occurring during heating.

[0143] The characteristic data of crystal form A are summarized in Table 1 below: [Table 14]

[0144] Based on the collected dynamic vapor adsorption / desorption data (Figure 3), the obtained crystalline form A is a non-hygroscopic substance. At the initial equilibrium at 5% RH, crystalline form A shows a weight loss of 0.03%, and a weight increase of 0.10% is observed between 5% and 95% RH. During the desorption process between 95% and 5% RH, crystalline form A shows a weight loss of approximately 0.10%.

[0145] According to XRPD, the substance after humidity adjustment is similar to the starting material (Figure 50).

[0146] Data acquisition parameters for dynamic vapor adsorption / desorption isotherms: [Table 15]

[0147] Example 2 - Preparation of crystals of crystal form A A solution of the hydrochloride addition salt form of the compound ((1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) was prepared using 98.5 mg of the compound from Example 1 in 2 mL of methanol and filtered through a 0.2 μm nylon filter. A 0.5 mL aliquot of the filtered solution was distributed into a 1-drum open vial, and then placed in a 20 mL vial containing 3 mL of poor solvent and ethyl acetate. The 1-drum vial was left uncovered, and the 20 mL vial was covered to allow vapor diffusion to occur. A single crystal grew in the 1-drum vial after approximately 7 days.

[0148] Data collection: Colorless plate-like object C with an approximate volume of 0.38 × 0.30 × 0.18 mm. 15 H 16 ClN [Cl, C 15 H 16 N] is mounted on the fiber in a random orientation. Preliminary tests and data acquisition are performed by Mo Kα irradiation (λ=0.71073Å) using a Nonius Kappa CCD diffractometer equipped with a graphite crystal and an incident beam monochromatic light spectrometer. Refinement is performed using SHELX97 (Sheldrick, GM Acta Cryst., 2008, A64, 112). Cell constants and orientation matrices for data acquisition are obtained from least-squares refinement using 5812 reflection setting angles in the range of 1°<θ<27°. The refinement mosaicity from DENZO / SCALEPACK is 0.38°, indicating good crystalline quality (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307). The space group is determined using the XPREP program (Bruker, XPREP in SHELXTL v. 6.12., Bruker AXS Inc., Madison, WI, USA, 2002). Based on the systematic existence of the following conditions: h00 h=2n; 0k0 k=2n; 00l l=2n, and subsequent least-squares refinement, the space group is determined to be P212121 (no. 19). Data are collected at a temperature of 150±1 K up to a maximum 2θ value of 55.71°.

[0149] Data preparation: Frames were integrated using DENZO-SMN (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307). A total of 5812 reflectors were collected, of which 2930 were unique. Lorentz and polarization corrections were applied to the data. The linear absorption coefficient was 0.273 mm for Mo Kα irradiation. -1 The empirical absorption correction using SCALEPACK (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307) is applied. The transmission coefficient is in the range of 0.953 to 0.953. The equivalent reflection intensities are averaged. The agreement factor for averaging is 2.9% based on intensity.

[0150] Structural analysis and refinement: The structure is analyzed using a direct method with SIR2004 (Burla, MC, Caliandro, R., Camalli, M,. Carrozzini, B., Cascarano, GL, De Caro, L., Giacovazzo, C., Polidori, G., and Spagna, R., J. Appl. Cryst. 2005, 38, 381). The remaining atoms are left behind by subsequent difference Fourier synthesis. Hydrogen atoms are included in the refinement process, but are constrained depending on the atoms they bond to. The structure is functional:

number

number

[0151] Computed Powder X-ray Diffraction (XRPD) Patterns: Computed XRPD patterns are generated using PowderCell 2.3 (PowderCell for Windows Version 2.3 Kraus, W.; Nolze, G. Federal Institute for Materials Research and Testing, Berlin Germany, EU, 1999) for atomic coordinates, space group, and unit cell from Cu line and single crystal data. Since the single crystal data is collected at low temperatures (150 K), peak shifts may be evident between the pattern calculated from the low-temperature data and the room-temperature experimental powder diffraction pattern, especially at high diffraction angles.

[0152] ORTEP diagrams and filling diagrams: ORTEP diagrams are prepared using the ORTEP III program (Johnson, CK ORTEPIII, Report ORNL-6895, Oak Ridge National Laboratory, TN, USA 1996. OPTEP-3 for Windows V1.05, Farrugia, LJ, J. Appl. Cryst. 1997, 30, 565) within the PLATON software package (Spek, AL PLATON. Molecular Graphics Program. Utrecht University, Utrecht, The Netherlands, 2008. Spek, A. L, J. Appl. Cryst. 2003, 36, 7). Atoms are represented by anisotropic thermal vibration ellipsoids with a 50% probability. Packing diagrams are prepared using CAMERON (Watkin, DJ; Prout, CK; Pearce, LJ CAMERON, Chemical Crystallography Laboratory, University of Oxford, Oxford, 1996) model software. Chiral centers are evaluated using the PLATON (Spek, AL PLATON. Molecular Graphics Program. Utrecht University, Utrecht, The Netherlands, 2008. Spek, A. L, J.Appl.Cryst. 2003, 36, 7) software package. Absolute configurations are evaluated using the specifications of molecular chiral laws (Cahn, RS; Ingold, C; Prelog, V. Angew. Chem. Intern. Ed. Eng., 1966, 5, 385; Prelog, VG Helmchen Angew. Chem. Intern. Ed. Eng., 1982, 21, 567).Further figures are created using the Mercury 2.4 visualization package (Macrae, CF Edgington, PR McCabe, P. Pidcock, E. Shields, GP Taylor, R. Towler M. and van de Streek, J.; J. Appl. Cryst., 2006, 39, 453-457). Hydrogen bonds are represented by dashed lines.

[0153] Results: Orthorhombic cell parameters and calculated volumes are: a=5.7779(2)Å, b=8.6633(2)Å, c=25.7280(8)Å, α=β=γ=90°, V=1287.83(7)Å 3 The formula weight of the asymmetric unit in the crystal structure is 245.75 g mol at Z=4. -1 It is 1.267 g cm -3 The computational density is as follows. The space group is determined to be P212121. An overview of the crystal data and crystallographic data acquisition parameters is shown in Table 2 below.

[0154] The R-value is 0.033 (3.3%).

[0155] The ORTEP diagram for crystal form A is shown in Figure 18.

[0156] The asymmetric unit shown in Figure 18 contains a protonated (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane molecule and a chloride counterion. The proton is located in the differential distribution and can be freely refined on nitrogen, which indicates salt formation.

[0157] The packing diagrams along the a, b, and c crystal axes are shown in Figures 19-21, respectively. Hydrogen bonding occurs between chlorine and nitrogen atoms, and the structure consists of an infinite one-dimensional hydrogen bond chain along the a crystal axis, as shown in Figure 22.

[0158] The absolute structure can be determined through the analysis of anomalous X-ray scattering by the crystal. The refinement parameter x, known as the Flack parameter (Flack, HD; Bernardinelli, G., Acta Cryst., 1999, A55, 908; Flack, HD; Bernardinelli, G., J. Appl. Cryst., 2000, 33, 1143), encodes the relative abundance of the two components in the inverse twin. The structure includes the fraction 1-x and its reciprocal x of the refined model. When low standard uncertainty is obtained, the Flack parameter should be close to 0 if the analyzed structure is accurate and close to 1 if the inverse model is accurate. The measured Flack parameter for the structure of crystal form A shown in Figure 18 is -0.02, with a standard uncertainty of 0.06.

[0159] After analyzing the structure, the quality of the data can be evaluated in terms of its inversion-distinguishing power, which is performed by testing the standard uncertainty of the Flack parameter. For crystal form A, the standard uncertainty (u) is 0.06, which indicates a strong inversion-distinguishing power. The compound is enantiopure, and its absolute structure can be directly assigned from the crystal structure.

[0160] Refinement of the Flack parameter (x) (Flack, HD Acta Cryst. 1983, A39, 876) does not provide a quantitative presentation of the assignment of absolute structure. However, an approach applying Bayesian statistics to the Bijvoet difference can provide a set of probabilities for different hypotheses of absolute structure (Hooft, RW, J. Appl. Cryst., 2008, 41, 96-103; Bijvoet, JM; Peederman, AF; van Bommel, AJ, Nature 1951, 168, 271). This analysis provides the probability of the absolute structure being correct, incorrect, or racemic twinning, as well as the Flack equivalent (Hooft) parameter. Based on the current data, the Flack equivalent (Hooft) parameter is determined to be -0.01(3), the probability that the structure is correct is 1.000, the probability that the structure is incorrect is 0.000, and the probability that the material is a racemic twin is 0.4 -59 That is the case.

[0161] The structure contains two chiral centers at C11 and C15 (see Figure 18, ORTEP diagram), which are assigned to R and S configurations, respectively.

[0162] Figure 23 shows the calculated powder X-ray diffraction pattern of crystal form A, created from single crystal data.

[0163] The experimental powder X-ray diffraction pattern for crystal form A is shown in Figure 1.

[0164] In Figure 34, the experimental XRPD for crystal form A in Figure 1 is superimposed with the calculated pattern.

[0165] The difference in intensity between the calculated and experimental powder X-ray diffraction patterns is due to selective orientation. Selective orientation is a tendency for crystals to align to an order of several degrees. This selective orientation of the sample can significantly affect the peak intensity in the experimental powder diffraction pattern, but not the peak position. Furthermore, since the experimental powder pattern is collected at room temperature and the single-crystal data is collected at 150K, some shift in peak position between the calculated and experimental powder diffraction patterns can be expected. In single-crystal analysis, lower temperatures improve structural quality, but this can reduce the size of the crystals that cause changes in unit cell parameters, which is reflected in the calculated powder diffraction pattern. Such shifts are particularly evident at high-dispersion diffraction angles.

[0166] The tables for positional parameters and their estimated standard deviation (Table 3), anisotropic temperature factor coefficients (Table 4), bond distance (Table 5), bond angle (Table 6), hydrogen bond and angle (Table 7), and torsion angle (Table 8) are as follows. Table 2. Crystal data and data collection parameters for (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride form A (crystal form A). Expression C 15 H 16 ClN Formula weight 245.75 Space group P212121(No. 19) a, Å 5.7779(2) b, Å 8.6633(2) c, Å 25.7280(8) V, Å 3 1287.83(7) Z 4 d calc , g cm -3 1.267 Crystal dimension, mm 0.38 x 0.30 x 0.18 Temperature, K 150 Irradiation (wavelength, Å) Mo Kα (0.71073) Monochromatic light spectrometer, graphite Linear absorption coefficient, mm -1 0.273 Applicable absorption correction: Empirical a Transmission factor: min, max 0.953, 0.953 Diffraction meter Nonius Kappa CCD h, k, l range -7~7 -11~11 -33~33 2θ range, degrees 1.58-55.71 Mosaicism, degree 0.38 Program used: SHELXTL F 000 520.0 weight 1 / [σ 2 (F o 2 )+(0.0384P) 2 +0.2436P](where P=(F o 2 +2F c 2 ) / 3) Collected data 5812 Unique data 2930 R int 0.029 Data used for refinement: 2930 The truncated F used in R-factor calculation o 2 >2.0σ(F o 2 ) Data for I > 2.0σ(I): 2678 Number of variables: 162 Maximum shift / esd in the final cycle: 0.00 R(F o ) 0.033 R w (F o 2 ) 0.080 Goodness of fit: 1.066 Absolute structure determination Flack parameters b (-0.02(6)) Voft parameters c (-0.01(3)) Friedel coverage 90% a Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307. b Flack, HD Acta Cryst., 1983 A39, 876. c Hooft, RWW, Straver, LH, and Spek, ALJ Appl. Cryst., 2008, 41, 96-103. Table 3. Positional parameters and their estimated standard deviations for crystal form A. atom x y z U( Å 2 ) Cl1 -0.21843(7) 1.09587(4) 0.483829(15) 0.02856(9) N13 0.2878(3) 1.04618(14) 0.53004(5) 0.0234(3) C1 0.4183(3) 0.93704(19) 0.70605(6) 0.0294(4) C2 0.2847(3) 0.88296(17) 0.66572(6) 0.0268(4) C3 0.0828(3) 0.7983(2) 0.67700(7) 0.0380(5) C4 0.0151(3) 0.7719(3) 0.72723(8) 0.0426(6) C5 0.1497(3) 0.8274(2) 0.76923(7) 0.0340(5) C6 0.0855(4) 0.8007(3) 0.82173(8) 0.0465(6) C7 0.2208(4) 0.8543(2) 0.86149(7) 0.0483(6) C8 0.4249(4) 0.9340(2) 0.85125(7) 0.0447(6) C9 0.4915(4) 0.9627(2) 0.80087(7) 0.0391(5) C10 0.3549(3) 0.9099(2) 0.75855(6) 0.0294(4) C11 0.3521(3) 0.91598(19) 0.61066(6) 0.0261(4) C12 0.2704(3) 1.06743(16) 0.58785(5) 0.0270(4) C14 0.2577(3) 0.87808(16) 0.51906(6) 0.0282(4) C15 0.3409(3) 0.7984(2) 0.56741(7) 0.0314(5) C16 0.5712(3) 0.8497(2) 0.58846(7) 0.0352(5) H131 0.436(4) 1.082(2) 0.5177(8) 0.036(5) * H132 0.168(4) 1.105(2) 0.5138(7) 0.039(5) * H1 0.555 0.993 0.699 0.035 H3 -0.008 0.759 0.649 0.046 H4 -0.123 0.716 0.734 0.051 H6 -0.052 0.745 0.829 0.056 H7 0.175 0.837 0.896 0.058 H8 0.519 0.969 0.879 0.054 H9 0.630 1.018 0.794 0.047 H15 0.285 0.692 0.575 0.038 H12A 0.109 1.089 0.598 0.032 H12B 0.370 1.154 0.600 0.032 H14A 0.351 0.847 0.489 0.034 H14B 0.093 0.853 0.512 0.034 H16A 0.659 0.776 0.610 0.042 H16B 0.667 0.918 0.566 0.042 The atoms with the star symbol are refined isotropically. U eq = (1 / 3)σ i σ j U ij a * i a * j a i .a j Hydrogen atoms are included in the structure factor calculation, but not in the refinement calculation. Table 4. Anisotropic temperature factor coefficients - U's for crystal form A name U(1,1) U(2,2) U(3,3) U(1,2) U(1,3) U(2,3) Cl1 0.02543(19) 0.02561(17) 0.03463(19) 0.00075(15) 0.00262(16) 0.00196(16) N13 0.0268(7) 0.0213(6) 0.0222(6) 0.0008(6) -0.0013(6) -0.0002(5) C1 0.0292(9) 0.0301(9) 0.0290(8) -0.0056(7) 0.0005(7) 0.0014(7) C2 0.0258(8) 0.0290(8) 0.0256(7) 0.0017(7) -0.0019(6) 0.0053(6) C3 0.0278(9) 0.0550(12) 0.0313(9) -0.0099(9) -0.0063(8) 0.0089(8) C4 0.0286(10) 0.0605(13) 0.0388(11) -0.0118(10) -0.0015(8) 0.0154(10) C5 0.0326(10) 0.0394(10) 0.0301(8) 0.0019(8) 0.0016(7) 0.0094(8) C6 0.0458(12) 0.0584(13) 0.0354(10) -0.0020(11) 0.0068(10) 0.0160(9) C7 0.0664(14) 0.0518(11) 0.0266(8) 0.0055(12) 0.0037(10) 0.0084(8) C8 0.0628(14) 0.0437(12) 0.0276(9) 0.0012(10) -0.0062(9) -0.0020(8) C9 0.0479(12) 0.0386(10) 0.0309(10) -0.0053(9) -0.0015(8) -0.0037(8) C10 0.0334(9) 0.0282(8) 0.0265(8) 0.0020(7) -0.0002(6) 0.0017(7) C11 0.0252(8) 0.0282(8) 0.0249(7) -0.0008(7) -0.0014(6) 0.0018(7) C12 0.0352(9) 0.0244(7) 0.0215(7) -0.0015(7) 0.0001(7) -0.0019(5) C14 0.0343(8) 0.0221(7) 0.0283(7) 0.0013(6) -0.0041(7) -0.0040(6) C15 0.0393(11) 0.0245(8) 0.0303(8) 0.0047(7) -0.0011(7) 0.0004(7) C16 0.0308(9) 0.0452(10) 0.0297(8) 0.0105(8) 0.0006(7) 0.0081(8) The shape of the anisotropic temperature factor: exp[-2π h 2 a *2 U(1,1) + k 2 b *2 U(2,2) + l 2 c *2 U(3,3) + 2hka * b * U(1,2) + 2hla * c * U(1,3)+ 2klb * c * U(2,3)] (where a * , b * and c * are the reciprocal lattice constants) Table 5. Bond Distances (Å) for Crystal Form A atom 1 atom 2 distance atom 1 atom 2 distance N13 C14 1.4936(18) C7 H7 0.950 N13 C12 1.5023(18) C8 C9 1.375(3) N13 H131 0.96(2) C8 H8 0.950 N13 H132 0.96(2) C9 C10 1.420(3) C1 C2 1.376(2) C9 H9 0.950 C1 C10 1.419(2) C11 C16 1.503(2) C1 H1 0.950 C11 C15 1.510(2) C2 C3 1.408(2) C11 C12 1.513(2) C2 C11 1.497(2) C12 H12A 0.990 C3 C4 1.370(3) C12 H12B 0.990 C3 H3 0.950 C14 C15 1.501(2) C4 C5 1.415(3) C14 H14A 0.990 C4 H4 0.950 C14 H14B 0.990 C5 C10 1.412(3) C15 C16 1.504(3) C5 C6 1.420(3) C15 H15 1.000 C6 C7 1.369(3) C16 H16A 0.990 C6 H6 0.950 C16 H16B 0.990 C7 C8 1.391(3) The numbers in parentheses are the estimated standard deviations at the least significant digits. Table 6. Crystalline form Aについてのbinding angle (degrees) atom 1 atom 2 atom 3 angle atom 1 atom 2 atom 3 angle C14 N13 C12 107.39(11) C5 C10 C1 119.08(16) C14 N13 H131 110.6(12) C5 C10 C9 118.71(16) C12 N13 H131 110.3(12) C1 C10 C9 122.21(17) C14 N13 H132 110.8(13) C2 C11 C16 120.40(14) C12 N13 H132 108.7(12) C2 C11 C15 123.87(14) H131 N13 H132 109.2(16) C16 C11 C15 59.90(12) C2 C1 C10 121.10(16) C2 C11 C12 116.85(14) C2 C1 H1 119.50 C16 C11 C12 116.53(15) C10 C1 H1 119.50 C15 C11 C12 106.60(13) C1 C2 C3 119.14(15) N13 C12 C11 104.89(12) C1 C2 C11 120.17(15) N13 C12 H12A 110.80 C3 C2 C11 120.69(15) C11 C12 H12A 110.80 C4 C3 C2 121.22(17) N13 C12 H12B 110.80 C4 C3 H3 119.40 C11 C12 H12B 110.80 C2 C3 H3 119.40 H12A C12 H12B 108.80 C3 C4 C5 120.43(18) N13 C14 C15 104.74(12) C3 C4 H4 119.80 N13 C14 H14A 110.80 C5 C4 H4 119.80 C15 C14 H14A 110.80 C10 C5 C4 119.01(16) N13 C14 H14B 110.80 C10 C5 C6 119.16(17) C15 C14 H14B 110.80 C4 C5 C6 121.82(18) H14A C14 H14B 108.90 C7 C6 C5 120.4(2) C14 C15 C16 116.45(15) C7 C6 H6 119.80 C14 C15 C11 108.31(14) C5 C6 H6 119.80 C16 C15 C11 59.81(11) C6 C7 C8 120.71(18) C14 C15 H15 119.20 C6 C7 H7 119.60 C16 C15 H15 119.20 C8 C7 H7 119.60 C11 C15 H15 119.20 C9 C8 C7 120.36(19) C11 C16 C15 60.29(12) C9 C8 H8 119.80 C11 C16 H16A 117.70 C7 C8 H8 119.80 C15 C16 H16A 117.70 C8 C9 C10 120.6(2) C11 C16 H16B 117.70 C8 C9 H9 119.70 C15 C16 H16B 117.70 C10 C9 H9 119.70 H16A C16 H16B 114.90 The numbers in parentheses represent the estimated standard deviation with the fewest significant figures. Table 7. Hydrogen bond distances (angstroms and angles) for crystal form A. DH A DH AH DA DHA N13 H131 Cl1 0.96(2) 2.18(2) 3.121(2) 164.1(15) N13 H132 Cl1 0.96(2) 2.36(2) 3.187(2) 144.0(15) N13 H132 Cl1 0.96(2) 2.674(18) 3.1217(19) 109.2(14) The numbers in parentheses represent the estimated standard deviation with the fewest significant figures. Table 8. Helix angle (degrees) for crystal form A. atom 1 atom 2 atom 3 atom 4 angle C14 N13 C12 C11 28.20 (0.18) C12 N13 C14 C15 -27.51 (0.18) C10 C1 C2 C3 -0.50 ( 0.25 ) C10 C1 C2 C11 178.63 (0.15) C2 C1 C10 C5 -0.71 ( 0.25 ) C2 C1 C10 C9 179.13 (0.16) C1 C2 C3 C4 1.39 (0.26) C11 C2 C3 C4 -177.73 (0.18) C1 C2 C11 C12 -85.92 (0.20) C1 C2 C11 C15 137.54 (0.17) C1 C2 C11 C16 65.41 (0.21) C3 C2 C11 C12 93.19 (0.19) C3 C2 C11 C15 -43.34 (0.24) C3 C2 C11 C16 -115.47 (0.18) C2 C3 C4 C5 -1.05 ( 0.30 ) C3 C4 C5 C6 -179.38 ( 0.20) C3 C4 C5 C10 -0.18 ( 0.30) C4 C5 C6 C7 179.21 ( 0.21) C10 C5 C6 C7 0.02 ( 0.46) C4 C5 C10 C1 1.04 ( 0.26) C4 C5 C10 C9 -178.80 ( 0.18) C6 C5 C10 C1 -179.74 ( 0.18) C6 C5 C10 C9 0.42 ( 0.27) C5 C6 C7 C8 -0.85 ( 0.33) C6 C7 C8 C9 1.25 ( 0.30) C7 C8 C9 C10 -0.80 ( 0.29) C8 C9 C10 C1 -179.87 ( 0.17) C8 C9 C10 C5 -0.03 ( 0.25) C2 C11 C12 N13 -160.97 ( 0.14) C15 C11 C12 N13 -17.56 ( 0.17) C16 C11 C12 N13 46.58 ( 0.18) C2 C11 C15 C14 141.11 ( 0.16) C2 C11 C15 C16 -108.36 ( 0.18) C12 C11 C15 C14 0.94 ( 0.18) C12 C11 C15 C16 111.47 ( 0.15) C16 C11 C15 C14 -110.53 ( 0.16) C2 C11 C16 C15 114.01 ( 0.17) C12 C11 C16 C15 -94.57 ( 0.15) N13 C14 C15 C11 16.15 ( 0.18) N13 C14 C15 C16 -48.59 (0.19) C14 C15 C16 C11 96.68 (0.16) The numbers in parentheses represent the estimated standard deviation with the fewest significant figures.

[0167] Example 3 - Preparation of Crystal Forms A to F Crystal forms A to F were prepared using crystal form A obtained in Example 1 as follows. Various crystallization techniques such as evaporation, cooling, solvent / poor solvent precipitation, slurry, vapor stress, and vapor diffusion were used. The results are shown in Table 9 below. [Table 16-1] [Table 16-2] [Table 16-3]

[0168] Crystal Form B - As outlined above, Crystal Form B is obtained by evaporation and slow cooling and crush-cooling in aqueous slurry, slurry, DCM, and 1-propanol. Furthermore, substances exhibiting the XRPD pattern of Crystal Form A along with the Crystal Form B peak are obtained by evaporation in DCM, ethanol, HFIPA, and TFE. Substances exhibiting the XRPD pattern of Crystal Form B along with weak peaks of Crystal Form A and Crystal Form C are observed from crush-cool experiments in 1-propanol.

[0169] Crystal form B is indexed from a high-resolution XRPD pattern using X'Pert High Score Plus (X'Pert High Score Plus 2.2a (2.2.1)) (Figure 6; the high-resolution XRPD pattern is also shown in Figure 7). The pattern appears to represent a mixture of crystal forms B and A. The agreement between acceptable peak positions, bar marks indicating the current morphology, and measured peaks indicates the determination of a matching unit cell. Peaks at 18.5°, 20.7°, 25.7°, and 27.5° at 2θ do not match the indexing results for crystal form B and appear to be from crystal form A. The space groups that match the assigned extinction symbols, unit cell parameters, and derived quantities are listed in the following figure. To confirm the transient indexing results, the molecular packing motifs within the crystallographic unit cell must be determined. No attempts have been made regarding molecular packing. Crystal form B is indexed to crystal form A by a similar volume per formula unit, indicating that crystal form B is a non-solvated crystalline form.

[0170] XRPD data acquisition parameters for Figures 4B and 45: INEL XRG-3000, X-ray tube: 1.54187100 Å, voltage: 40 (kV), current: 30 (mA), acquisition time: 300 sec, rotating capillary, step size: approximately 0.03°²θ.

[0171] XRPD data acquisition parameters for Figures 6 and 7: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 1939 s, Scan speed: 1.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0172] The characterization data for crystal form B is summarized in Table 10 below: [Table 17]

[0173] The thermal analysis results for crystal form B are shown in Figure 8 (DSC, size: 1.2600 mg, method: (-30)-300-10, T0C; TGA, size: 9.4320 mg, method: 00-350-10). According to the TGA, crystal form B shows a small weight loss of approximately 0.2% from room temperature to 200°C, which is probably due to trace amounts of solvent. The dramatic change in the slope of the TGA thermogram at approximately 281°C is consistent with decomposition. According to the DSC, the broad endothermic reaction observed at approximately 141°C (peak) is thought to be due to a change in solid form or the loss of volatiles during heating. Crystal form B shows endothermic reaction at approximately 248°C (peak), similar to the thermal behavior observed for crystal form A, followed by two broad endothermic reactions at approximately 251°C and 264°C. Based on the obtained data, crystal form B is a non-solvated crystalline substance.

[0174] Crystalline form C-Crystalline form C may also be prepared by slow cooling in isopropanol. Substances showing an XRPD pattern of crystalline form A along with a weak peak of crystalline form C originate from slow cooling experiments in ethanol, but an XRPD pattern of crystalline form C along with a weak peak of crystalline form A can be obtained by crush-cool experiments in ethanol and isopropanol.

[0175] Six scale-up attempts were made to prepare crystalline form C by cooling at a scale of approximately 50-150 mg in isopropanol (Table 11), and the solid was tested with XRPD. The solid precipitated at refrigeration temperature was crystalline form B. After cooling in a refrigerator (no solid was observed) and before leaving it in a freezer, seed crystals of crystalline form C were added, and an XRPD pattern of crystalline form C was obtained along with the peak of crystalline form B. Precipitation at freezing temperature yielded a solid with an XRPD pattern of crystalline form C along with the peak of crystalline form A. Crystallized form B was obtained in a solution cooled to room temperature at a low concentration (7 mg / mL compared to 10 mg / mL) and then left in a freezer. The solid produced by crush-cooling (ambient solution placed in dry ice / isopropanol) was a mixture of crystalline forms B and A. Finally, when tested at a scale of approximately 50 mg, a mixture of crystalline forms A and C was produced. The differing results of these experiments suggest that factors (e.g., concentration, temperature, cooling time, and seed crystal addition) may influence the crystallization of crystal form C on a large scale, and that competitive crystallization of crystal forms A and B, which may be more stable under the experimental conditions used, is possible. Note that crystal form C remained unchanged in XRPD even after 22 days of storage at room temperature.

[0176] XRPD data acquisition parameters in Figures 13A, C, and F: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 717 s, Scan speed: 3.3° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0177] XRPD data acquisition parameters in Figure 13B: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 720 s, Scan speed: 3.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0178] XRPD data acquisition parameters in Figure 13D: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 718 s, Scan speed: 3.3° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0179] XRPD data acquisition parameters in Figure 13E: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54060 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 720 s, Scan speed: 3.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission. [Table 18]

[0180] Crystal form C is indexed from a high-resolution XRPD pattern (Figure 10) obtained using dedicated software. The pattern appears to show a mixture of crystal forms C and A. The agreement between the allowed peak positions, the bar marks indicating the current morphology, and the measured peaks indicates the determination of the matching unit cell. Peaks at 12.3°, 15.4°, 16.6°, 20.7°, and 25.7° at 2θ do not match the indexing results for crystal form C and appear to be from crystal form A. The space groups that match the assigned extinction symbols, unit cell parameters, and derived quantities are listed in the following figure. To confirm the transient indexing results, the molecular packing motifs within the crystallographic unit cell must be determined. No attempts have been made regarding molecular packing. Crystal form C is indexed to crystal form A by a similar volume per formula unit, which indicates that crystal form C is a non-solvated crystalline form.

[0181] XRPD data acquisition parameters in Figures 4C, 9 and 13G: INEL XRG-3000, X-ray tube: 1.54187100 Å, voltage: 40 (kV), current: 30 (mA), acquisition time: 300 sec, rotating capillary, step size: approximately 0.03°²θ.

[0182] XRPD data acquisition parameters in Figures 10 and 11: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 720 s, Scan speed: 3.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0183] The characterization data for crystal form C is summarized in Table 12 below. [Table 19]

[0184] The thermal analysis results for crystalline form C are shown in Figure 12 (DSC, size: 1.0100 mg, method: (-30)-300-10, T0C; TGA, size: 2.2300 mg, method: 00-350-10). According to TGA, crystalline form C shows a weight loss of approximately 1.3% from room temperature to 200°C, which is thought to be due to the loss of volatiles during heating. The dramatic change in the slope of the TGA thermogram at approximately 266°C is consistent with decomposition. According to DSC, the broad, small endothermic reaction observed at approximately 122°C (peak) is thought to be due to a change in solid form or the loss of volatiles during heating. Crystalline form C shows endothermic reaction at approximately 248°C (peak), similar to the thermal behavior observed for crystalline form A, followed by broad endothermic reaction at approximately 271°C.

[0185] Based on the data obtained, crystalline form C is a non-solvated crystalline substance.

[0186] Crystal forms D, E, and F are dissolved in a pH-adjusted buffer medium. Any observed insoluble solids or precipitates are analyzed by XRPD. Some experiments are performed at elevated temperatures to improve solubility, and insoluble solids are also analyzed by XRPD. The resulting crystal forms D, E, and F are generated during these experiments, as outlined in Table 13 below.

[0187] XRPD data acquisition parameters in Figures 14D-F: INEL XRG-3000, X-ray tube: 1.54187100 Å, voltage: 40 (kV), current: 30 (mA), acquisition time: 300 sec, rotating capillary, step size: approximately 0.03°²θ. [Table 20] - pH 2.0 buffer (50 mM KCl / HCl): Crystal form A is recovered from the slurry at room temperature after slow cooling (approximately 70°C to room temperature). - pH 4.4 buffer (50 mM citrate / sodium citrate): Crystal form D is obtained by spontaneous precipitation at room temperature and after stirring of the suspension at approximately 70°C; crystal form B, which contains a weak peak of crystal form D in XRPD, is obtained from a room temperature slurry. - pH 6.0 buffer (50 mM Na2HPO4 / NaH2PO4): XRPD revealed that crystal form E, which also exhibits the peak seen in crystal form F, was observed in the slurry at approximately 50°C. - pH 8.1 buffer (50 mM Na2HPO4 / NaH2PO4): Crystalline form F is obtained by stirring the suspension at approximately 70°C.

[0188] Crystal forms D, E, and F are characterized by the XRPD shown in Figure 14.

[0189] Example 4 - Amorphous Attempts to prepare amorphous (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride were made by grinding, freeze-drying, and rotary evaporation (Table 14). From all attempts used in this study, a material with possible irregular crystalline form A was recovered.

[0190] XRPD data acquisition parameters in Figures 52-55: Bruker Discovery D8, X-ray tube: Cu (1.54059 Å), scan range: 2.14-37.02°²θ, step size: 0.04°²θ, acquisition time: 900 s. [Table 21]

[0191] Example 5 - Preparation of Crystal Form A [ka] Unless otherwise specified, use commercially available reagents as purchased. Reactions requiring an inert atmosphere should be carried out under nitrogen unless otherwise specified. Steps 1 and 2: [Table 22]

[0192] Dissolve 2-naphthylacetonitrile (4500 g) in THF (32 L), add 3.2 kg of (S)-(+)-epichlorohydrin, and cool the solution to -16°C. Then, while maintaining the internal temperature below -10°C, add 2.0 M sodium hexamethyldisilazane / tetrahydrofuran (THF) solution (24.7 kg). This addition takes 2 hours and 45 minutes. Next, stir the reaction mixture at approximately -15°C for a further 6 hours, and then analyze the sample by HPLC. While maintaining the internal temperature below 0°C, add borane-dimethyl sulfide (6.5 kg) over 36 minutes. After the addition of borane is complete, slowly heat the reaction mixture to 60°C to reduce the nitrile to the amine. During heating, exothermic reaction occurs, reaching 45°C. After heating at 60°C for 2 hours, analyze the reaction mixture sample by HPLC. Cool the reaction mixture to 24°C and transfer it to a 2 M HCl solution over 1 hour. The two-phase mixture is heated to 50°C, stirred at this temperature for 1 hour, and then cooled to 29°C. The pH of the quenched reaction mixture is measured and found to be 5. Further 2M HCl is added, the mixture is heated to 50°C, stirred for 1 hour, and then cooled to 25°C. The pH is measured and found to be 1. Workup of the reaction is performed by adding isopropyl acetate (IPAc), stirring, separating the layers, and discarding the organic layer. Ammonia water is added to the aqueous layer, and the pH is measured to be 8. Further ammonia is added, and the pH is remeasured to be 8.5. Next, workup is performed by extracting the aqueous layer with IPAc in a two-stage extraction. The collected organic extract is washed with 5% dibasic sodium phosphate / water, and then with saturated brine. A portion of the obtained organic layer is concentrated, azeotropically dried, and then diluted with IPAc. Then, p-toluenesulfonic acid hydrate (4.9 kg) is added gradually to precipitate the desired product as pTsOH salt, which is isolated by filtration. After washing the filtered cake with IPAc, it was dried to a certain weight to obtain 5785 g of the desired product as a white solid. Yield: 54%. HPLC: 98.2%. Steps 3 and 4: [Table 23]

[0193] Step 3: The amine-pTsOH salt (5785 g) obtained in step 2 is suspended in IPAc (176 L) to obtain a slurry. Then thionyl chloride (2.1 kg) is added over 1 hour. After the addition of thionyl chloride is complete, the reaction mixture is stirred for another hour and the sample is analyzed by HPLC. Sodium hydroxide aqueous solution (5 M, 6 mol equivalents) is added over 1 hour, followed by stirring for another 4 hours. After allowing the layers to stand, the pH of the aqueous layer is found to be 9. The layers are separated and the organic layer is washed with 1 M NaOH / water. The aqueous layers are combined and back-extracted with IPAc, and the first organic layer and back extract are combined. These combined organic layers are washed with 0.5 M HCl and (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane is extracted into the aqueous layer. The acidic aqueous layer is washed with a 1:1 mixture of IPAc and THF to remove the colorant. The aqueous layer is basicized with aqueous ammonia and then extracted with IPAc. After separating the layers, the organic layer is washed with saturated brine, dried over magnesium sulfate, and partially concentrated. After concentration, HCl / isopropyl alcohol (IPA) (1.0 mol equivalent of HCl, 0.90 L) is added to form a crude salt, which is isolated by filtration, washed with IPAc, and partially dried. The wet cake is refluxed with IPAc. The crude salt is refluxed with IPA, the solid is isolated by filtration, washed with IPA, and dried. Purity >99.5% HPLC area percent and 97.7% chiral area percent. 1759 g of the desired product.

[0194] Step 4: The crude (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (1753 g) obtained in step 3 is dissolved in 20 volumes of hot ethanol (70°C), and then filtered using an in-line filter as a final filtration. The dissolution container, in-line filter, and transfer line are then rinsed further with hot ethanol (61°C), and the wash is combined with the filtrate. The combined filtrate and wash are partially concentrated under reduced pressure to a total of approximately 11.5 volumes (relative to the crude (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride added), and the solid is reheated and redissolved. The solution is cooled to 65°C, and seed crystals are added as an ethanol slurry. After stirring at approximately 65°C to grow the seed bed, the slurry is cooled to room temperature. The obtained solid is isolated by filtration, the filtration cake is washed with ethanol, and the washed solid is dried. A total of 1064 g of yellowish-brown product was obtained. Both chiral and achiral HPLC showed >99.5%.

[0195] Step 5: The (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (1064 g) obtained in step 4 is dissolved in 10.7 L of water while heating to 35°C. Immediately after all the solid has dissolved, the aqueous solution is washed with 1:1 THF:IPAc to remove most of the colorants. After washing, ammonia water is added to the aqueous layer and (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane is extracted into IPAc. The organic layer is dried over magnesium sulfate and then concentrated under reduced pressure to obtain a grayish-white solid. The solid is dissolved in IPA and transferred to a 22 L three-necked round-bottom flask by in-line filtration. Filtered HCl / IPA is then added to reform the salt, and it is isolated by filtration. After washing the filtered cake with IPA, it was dried to obtain 926 g of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride as a grayish-white solid.

[0196] The XRPD of the product is shown in Figure 35 and matches crystal form A. The XRPD pattern is collected using a PANalytical X'Pert Pro MPD diffractometer with a Cu-line incident beam prepared using an Optix long high-precision focal source. An elliptic stepwise multilayer mirror is used to focus the Cu KαX-ray onto the sample and direct it towards the detector. Before analysis, a silicon sample (NIST SRM 640d) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for the incident and diffracted beams to minimize expansion from axial divergence. The diffraction pattern is collected using a scattering position detection element (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 717 s, Scan speed: 3.3° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0197] Figure 36 shows a superposition of the XRPD patterns from Figures 1 and 35. There is a certain degree of difference in relative peak intensity, which is thought to be due to selective orientation (PO). PO is a tendency for crystals to be packed with a certain degree of order, usually in a plate-like or needle-like structure. PO can affect the peak intensity of the XRPD pattern, but not the peak position.

[0198] The XRPD of the product after long-term storage is shown in Figure 37 and matches crystal form A. The XRPD pattern is collected using a PANalytical X'Pert Pro MPD diffractometer with a Cu-line incident beam prepared using an Optix long high-precision focal source. An elliptic stepwise multilayer mirror is used to focus the Cu KαX-ray onto the sample and direct it towards the detector. Before analysis, a silicon sample (NIST SRM 640e) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for the incident and diffracted beams to minimize expansion from axial divergence. The diffraction pattern is collected using a scattering position detection element (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 719 s, Scan speed: 3.3° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0199] One of the PANalytical patterns for crystal form A is analyzed, and the selective orientation and particle statistical effects are evaluated by comparing it with another XRPD pattern analyzed using an alternative geometry in addition to the calculated XRPD pattern from single-crystal analysis. The indexing results for the XRPD shown in Figure 37, collected with Cu Kα radiation, are shown in Figure 38. The XRPD patterns are indexed using X'Pert High Score Plus 2.2a (2.2.1). The observed peaks are shown in Figure 39 and in Table C of Section 1.32 above, typical peaks are shown in Table B of Section 1.25 above, and characteristic peaks are shown in Table A of Section 1.16 above.

[0200] Example 6 - Preparation of crystals of crystal form B Example 6a Crystal form A (558.9 mg) from Example 5 above is slurryed in dichloromethane (5 mL). The preparation is stirred at room temperature for 16 days in a sealed vial (300 RPM). The white solid is isolated by vacuum filtration, rinsed with dichloromethane (1 mL), and dried briefly under nitrogen. The product is crystal form A. The XRPD pattern of the product is shown in Figure 47. The XRPD pattern is collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu-line incident beam prepared using an Optix long high-precision focus source. An elliptical stepwise multilayer mirror is used to focus the Cu KαX-ray onto the sample and direct it towards the detector. Before analysis, a silicon sample (NIST SRM 640e) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for both the incident and diffracted beams to minimize expansion from axial divergence. The diffraction pattern is collected using a scattering position detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, current: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 720 s, scan speed: 3.2° / min., slit: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission.

[0201] Example 6b Crystal form A (34.3 mg) of Example 6a is brought into contact with water (1 mL). The sample is sonicated until the solid dissolves. The sample is covered and left at room temperature until nucleation is observed (within 1 day). The element is isolated from the bulk sample for analysis.

[0202] Data collection: Colorless plate-like object C with an approximate volume of 0.31 × 0.21 × 0.09 mm. 15 H 16 ClN [C 15 H 16 N, Cl] are mounted on nylon loops in a random orientation. Preliminary tests and data acquisition are performed using a Rigaku Rapid II diffractometer with a confocal optical system for Cu Kα lines (λ=1.54178Å). Refinement is performed using SHELX2014 (Sheldrick, GM Acta Cryst. 2015, C71, 3-8). Cell constants and orientation matrices for data acquisition are obtained from least-squares refinement using 22958 set angles of reflection in the range of 2°<θ<26°. From the systematic existence of the following conditions: h00 h=2n; 0k0 k=2n; 00l l=2n, and subsequent least-squares refinement, the space group is determined to be P212121 (no. 19). Data are collected up to the maximum diffraction angle (2θ) value of 144.79° at a temperature of 100 K.

[0203] Data preparation: Frames were integrated using HKL3000 (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307). A total of 22,958 reflectors were collected, of which 2,415 were unique. Lorentz and polarization corrections were applied to the data. The linear absorption coefficient for Cu Kα lines was 2.422 mm. -1 The empirical absorption correction using SCALEPACK (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307) is applied. The transmission coefficient is in the range of 0.753 to 0.976. Second-order extinction correction is applied (Sheldrick, GM Acta Cryst. 2015, C71, 3-8). The final coefficient refined by least squares is 0.0055(8) (in absolute units). The equivalent reflection intensities are averaged. The agreement factor for averaging is 4.95% based on intensity.

[0204] Structure analysis and refinement: The structure was analyzed by the direct method using SHELXS - 97 (Sheldrick, G. M. Acta Cryst. 2015, C71, 3 - 8). The remaining atoms were placed by subsequent difference Fourier syntheses. Hydrogen atoms were included in the refinement but were constrained depending on the bonding atoms. The structure was refined by full - matrix least - squares methods by minimizing the function: [Number] The weight w is defined as 1 / [σ (F 2 (F o 2 )+(0.0437P) 2 +(2.1802P)] (where P = (F o 2 +2F c 2 ) / 3). Scattering factors were taken from "International Tables for Crystallography" (International Tables for Crystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.1.4). Of the 2415 reflections used in the refinement, only reflections with F o 2 >2σ(F o 2 ) were used in the calculation of the goodness - of - fit R factor. All 2372 reflections were used in the calculation. The final cycle of refinement included 155 variable parameters and converged to the unweighted and weighted agreement factors of the function: [Number] The standard deviation of the observations per unit weight (goodness - of - fit) is 1.150. The highest peak in the final difference Fourier is 0.318 e / Å in height. The lowest negative peak is - 0.313 e / Å3 in height. ' 3 The lowest negative peak is - 0.313 e / Å3 in height.

[0205] Computed Powder X-ray Diffraction (XRPD) Patterns: Computed XRPD patterns are generated using Mercury (Macrae, CF; Edgington, PR; McCabe, P.; Pidcock, E.; Shields, GP; Taylor, R.; Towler, M.; and van de Streek, J., J. Appl. Cryst., 2006, 39, 453-457) for Cu lines and atomic coordinates, space group, and unit cell parameters from the single crystal structure. Since the single crystal data is collected at low temperatures (100 K), peak shifts may be evident between the pattern calculated from the low-temperature data and the room-temperature experimental powder diffraction pattern, especially at high diffraction angles. The calculated XRPD patterns are adjusted to room temperature using the unit cell parameters obtained earlier from XRPD indexing.

[0206] Atomic displacement ellipsoid diagrams and packing diagrams: Atomic displacement ellipsoid diagrams are created using Mercury (Macrae, CF; Edgington, PR; McCabe, P.; Pidcock, E.; Shields, GP; Taylor, R.; Towler, M.; and van de Streek, J., J. Appl. Cryst., 2006, 39, 453-457). Atoms are represented by 50% probability anisotropic thermal vibration ellipsoids. Packing diagrams and additional diagrams are created using Mercury. Hydrogen bonds are represented by dashed lines. Chiral center analysis is performed using PLATON (Spek, AL PLATON. Molecular Graphics Program. Utrecht University, Utrecht, The Netherlands, 2008. Spek, AL, J. Appl. Cryst. 2003, 36, 7). Absolute configuration is analyzed using specifications for molecular chirality (Cahn, RS; Ingold, C; Prelog, V. Angew. Chem. Intern. Ed. Eng., 1966, 5, 385 and Prelog, V., Helmchen, G. Angew. Chem. Intern. Ed. Eng., 1982, 21, 567).

[0207] Results: Orthorhombic cell parameters and calculated volumes are: a=5.9055(2)Å, b=7.4645(3)Å, c=29.1139(13)Å(α=β=γ=90°), V=1283.39(9)Å 3 The formula weight of the asymmetric unit in crystal form B is 245.74 g mol at Z=4. -1 The computational density is 1.272 g cm³. -3 The space group is determined to be P212121 (no. 19). A summary of the crystal data and crystallographic data acquisition parameters is shown in Table 15 below. The space group and unit cell parameters are consistent with those obtained for crystal form B by XRPD indexing.

[0208] The R-value is 0.0453 (4.53%).

[0209] The atomic displacement ellipsoid diagram for crystal form B is shown in Figure 24.

[0210] The asymmetric unit shown in Figure 24 contains one protonated (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane molecule and one chloride counterion.

[0211] Packing diagrams along the a, b, and c crystal axes are shown in Figures 25-27, respectively. Hydrogen bonds proceed from the amine to the chloride, forming helical chains with primary hydrogen bonds along the a axis, as shown in Figure 28.

[0212] The molecular conformation of the (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane molecule in the structure of crystal form B is compared with the molecular conformation observed in the structure of crystal form A in Figure 29, and the two forms of packing along the a-axis are compared in Figure 30. Hydrogen bonding in the structures of crystal forms A and B is shown in Figure 31. Adjacent molecules are linked by hydrogen bonds that form a linear chain along the a-axis through chloride ions in crystal form A. In the packing of crystal form B, the amine groups of adjacent molecules are too far apart to be linked in the same way, and instead of hydrogen bonding, a helical chain is formed in crystal form B.

[0213] The absolute structure can be determined through analysis of anomalous X-ray scattering by the crystal. The refinement parameter x, known as the Flack parameter (Flack, HD; Bernardinelli, G., Acta Cryst. 1999, A55, 908; Flack, HD, Bernardinelli, G., J. Appl. Cryst. 2000, 33, 1143, Flack, HD, Acta Cryst. 1983, A39, 876; Parsons, S.; Flack, HD; Wagner, T., Acta Cryst. 2013, B69, 249-259), encodes the relative abundance of the two components within the inverse twin. The structure includes the refined model fraction 1-x and its reciprocal x. When low standard uncertainty is obtained, the Flack parameter should be close to 0 if the analyzed structure is correct and close to 1 if the inverse model is correct. The measured Flack parameter for the crystal structure B shown in Figure 24 is 0.010, and the standard uncertainty is also 0.010, indicating a strong ability to distinguish inverted structures. The compound is enantiopure, and its absolute configuration can be directly assigned from the crystal structure.

[0214] Refining the Flack parameter (x) does not provide a quantitative indication of the assignment of absolute structure. However, an approach applying Bayesian statistics to the Bijvoet difference can provide a set of probabilities for different hypotheses of absolute structure (Hooft, RWW; Straver, LH; and Spek, AL, J. Appl. Cryst., 2008, 41, 96-103 and Bijvoet, JM; Peerdeman, AF; van Bommel, AJ, Nature, 1951, 168, 271). This analysis provides the probability of the absolute structure being correct, incorrect, or racemic twinning, in addition to the Flack equivalent (Hooft) parameter. Based on the current data, the Flack equivalent (Hooft) parameter is determined to be -0.001(7), the probability that the structure is correct is 1.000, the probability that the structure is incorrect is 0.000, and the probability that the material is a racemic twin is 0.000.

[0215] This structure contains two chiral centers at C2 and C3 (see Figure 24), which are bonded in S and R configurations, respectively.

[0216] Figure 32 shows the calculated XRPD pattern of crystal form B generated from the single crystal structure.

[0217] The experimental XRPD pattern of crystal form B shown in Figure 33 (the same as the XRPD pattern in Figure 40, Example 8) is superimposed with the calculated pattern and the calculated pattern adjusted to room temperature. All peaks in the experimental pattern are shown in the calculated XRPD pattern, indicating a single phase.

[0218] Differences in intensity between calculated and experimental powder diffraction patterns may be due to selective orientation. Selective orientation is the tendency for crystals to align to an order of several degrees. This selective orientation of the sample can significantly affect the peak intensity in the experimental powder diffraction pattern, but not the peak position. Furthermore, since the experimental powder pattern is collected at room temperature and the single-crystal data is collected at 100K, some shift in peak position between calculated and experimental powder diffraction patterns can be expected. While low temperatures improve structural quality in single-crystal analysis, they can reduce the size of crystals that cause changes in unit cell parameters, which is reflected in the calculated powder diffraction pattern. Such shifts are particularly evident at high-dispersion diffraction angles. The calculated XRPD pattern was adjusted to room temperature using the unit cell previously obtained from XRPD indexing. Table 15. Crystal data and data collection parameters for (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride crystal form B (crystal form B). Empirical formula C 15 H 16 ClN Formula weight 245.74 Temperature 100(2) K Wavelength 1.54178Å Crystal system Orthorhombic system Space group P212121 Unit cell dimensions a = 5.9055 (2) Å α = 90° b = 7.4645 (3) Å β = 90° c = 29.1139 (13) Å γ = 90° Volume 1283.39(9)Å 3 Z 4 Density (calculated) 1.272 Mg / m 3 Absorption coefficient 2.422 mm -1 F(000) 520 Crystal size: 0.310 x 0.210 x 0.090 mm 3 Theta range for data acquisition: 6.080~72.393° Index range -7<=h<=7, -8<=k<=8, -35<=l<=35 Collecting reflection 22958 Independent reflection 2415 [R(int)=0.0495] Completeness with respect to theta = 67.679° 98.5% Absorption correction: Semi-empirical analysis from equivalents Maximum and minimum transmission: 0.976 and 0.753 Refinement method F 2 Least squares of a complete matrix in Data / Suppression / Parameters 2415 / 0 / 155 F 2 Goodness of fit in: 1.150 Final R index [I>2 sigma(I)]: R1=0.0453, wR2=0.1224 R-index (all data): R1=0.0464, wR2=0.1240 Absolute structure parameter Flack parameter: 0.010 (10) Hooft parameter: -0.001(7) Extinction coefficient 0.0055(8) Maximum difference peak and hole: 0.318 and -0.313 e. Å -3

[0219] Example 7 - Preparation of Crystal Form B Crystal form A (470.9 mg) from Example 5 above is mixed with water (5 mL) in a 20 mL glass vial. The slurry is stirred with a stirring bar at room temperature for 16 days to allow conversion. The solid is recovered by vacuum filtration and short-term drying under nitrogen.

[0220] Example 8 - Preparation of Crystal Form B The product (1 g) from Example 16 below was stirred over a weekend at room temperature in 5 mL of Special Industrial 200 (denatured ethanol). The mixture was filtered and rinsed with 2 mL of Special Industrial 200 (denatured ethanol), followed by isopropyl acetate (2 x 3 mL). The solid was vacuum-dried for 2 hours, then dried at 40°C for 6 hours to obtain 0.81 g of the product.

[0221] XRPD analysis indicates that the product is crystalline form B (see the top XRPD patterns in Figures 40 and 33). The XRPD patterns are collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu-line incident beam generated using an Optix long high-precision focal source. The Cu Kα X-ray is focused on the sample and directed towards the detector using an elliptical stepwise multilayer mirror. Before analysis, a silicon sample (NIST SRM 640d) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. Solar slits are used for the incident and diffracted beams to minimize expansion from axial divergence. The diffraction patterns are collected using a scattering position detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.01-39.98°²θ, Step size: 0.017°²θ, Acquisition time: 720 s, Scan speed: 3.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0222] One of the PANalytical patterns for this material is analyzed, and the selective orientation and particle statistical effects are evaluated by comparing it with another XRPD pattern analyzed using an alternative geometry in addition to the calculated XRPD pattern from single-crystal analysis. The indexing results for the XRPD shown in Figure 40, collected with Cu Kα radiation, are shown in Figure 41. The XRPD patterns are indexed using X'Pert High Score Plus 2.2a (2.2.1). Observed peaks are shown in Figure 42 and in Table F of Section 1.109, typical peaks are shown in Table E of Section 1.102, and characteristic peaks are shown in Table D of Section 1.93.

[0223] Example 9 - Crystalline form C An opaque solution containing crystalline form A (458.2 mg) and IPA (40 mL) from Example 5 was prepared by increasing the temperature. The hot solution was filtered through a 0.2 μm nylon filter into a clean vial and placed in a freezer. After 2 days, the solid was recovered by vacuum filtration and dried briefly under nitrogen. The solid was identified as a mixture of crystalline forms A and C. A slurry was prepared with the mixture (42.2 mg) and saturated DCM solution (0.8 mL) (the saturated solution was prepared at room temperature from crystalline form A (65.4 mg) from Example 5 in 5 mL of DCM. The next day, excess solid was filtered off the solution through a 0.2 μm nylon filter). The slurry was stirred in an agate ball at 100 RPM and 2°C for 3 weeks to convert it. The solid isolated from the suspension obtained by vacuum filtration was stored at a temperature of -25 to -10°C.

[0224] The XRPD of the product is shown in Figure 43. The XRPD pattern is collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu-line incident beam generated using an Optix long high-precision focal source. The Cu Kα X-ray is focused on the sample and directed towards the detector using an elliptical stepwise multilayer mirror. Before analysis, a silicon sample (NIST SRM 640d) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for the incident and diffracted beams to minimize expansion from axial divergence. The diffraction pattern is collected using a scattering position detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 720 s, Scan speed: 3.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0225] One of the PANalytical patterns for this material is analyzed, and the selective orientation and particle statistical effects are evaluated by comparing it with another XRPD pattern analyzed using an alternative geometry. The indexing results for the XRPD pattern shown in Figure 43, collected with Cu Kα radiation, are shown in Figure 44. The XRPD pattern is indexed using dedicated software (U.S. Patent No. 8,576,985). Observed peaks are shown in Figure 45 and Table I in Section 1.183, typical peaks are shown in Table H in Section 1.176, and characteristic peaks are shown in Table G in Section 1.168.

[0226] Example 10 - Interconversion Slurry Method The energy-temperature diagram is a semi-quantitative illustration of the Gibbs-Helmholtz equation (where the enthalpy (H) and free energy (G) curves for each form are shown as functions of temperature). According to the graph, it is assumed that the free energy curves intersect at most once, and secondly, that the enthalpy curves of the polymorphs do not intersect. The melting point of a polymorph is defined as the temperature at which the free energy curve of the polymorph intersects the free energy curve of the liquid. The transition temperature is defined as the temperature at which the free energy curve of one polymorph intersects the free energy curve of a second polymorph. Therefore, T t Therefore, the free energies of both polymorphs are equal, and as a result they are in equilibrium with each other.

[0227] The presented energy - temperature diagrams for crystal forms A, B, and C shown in Figure 46. In the figure, the enthalpy (H) and free energy (G) curves for each form are shown as functions of temperature (T). The subscripts A, B, C, and L represent crystal forms A, B, C, and the liquid phase, respectively. The subscripts f, t, and m represent melting, transition point, and melting point, respectively. According to the graph, it is assumed that the free energy curves intersect at most once, and then the enthalpy curves of the polymorphs do not intersect. The melting point of a polymorph is defined as the temperature at which the free energy curve of the polymorph intersects with the free energy curve of the liquid. The transition temperature is defined as the temperature at which the free energy curve of one polymorph intersects with the free energy curve of another polymorph. Therefore, T t At T, the free energies of both polymorphs are equal, and as a result they are in equilibrium with each other. The crystalline form C is T t,C→B It is a stable solid phase below T (because the free energy of crystalline form C is lower than that of crystalline form B), and crystalline form B is T t,C→B and T t,B→A It is a stable solid phase between T t,B→A It is a stable solid phase at temperatures above a certain level. Low-energy polymorphs have low fugacity, vapor pressure, thermodynamic activity, solubility, elution rate per unit surface area, and reaction rate with other polymorphs.

[0228] Interconversion experiments are conducted to test the hypothetical thermodynamic relationships between substances as shown in the energy-temperature diagram above. Interconversion or competitive slurry methods are solution-mediated processes that provide a pathway for less soluble (more stable) crystals to grow at the expense of more soluble crystal forms (Bernstein, J. Polymorphism in Molecular Crystals. Clarendon Press, Oxford, 2006; Brittain, HG, Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999). Apart from the formation or decomposition of solvates, more thermodynamically stable polymorphs have lower energy and therefore lower solubility; thus, the more stable polymorphs obtained from interconversion experiments are independent of the solvent used. The choice of solvent affects the kinetics of polymorph transformation, but not the thermodynamic relationships between polymorphs (Gu, CH, Young, V. Jr., Grant, DJ, J. Pharm. Sci. 2001, 90 (11), 1878-1890).

[0229] The binary interconversion slurry method between crystalline forms A, B, and C in different solvent systems at temperatures of approximately 2 to 67°C is outlined in Table 16 below. After preparing a saturated solution, it is added to a mixture consisting of approximately equal amounts of the two polymorphs. The sample is slurryed overnight for 3 weeks to obtain a solid, which is analyzed by XRPD. The results of the interconversion studies show that the relative thermodynamic stability of the tautomorphic crystalline forms A, B, and C is accurately represented in the presented energy-temperature diagram. Furthermore, T t,C→B It is thought to be less than 2℃ (not yet determined), T t,C→A It is between 2°C and room temperature, T t,B→A The temperature range is between 37 and 54°C. [Table 24]

[0230] Crystal form B is shown to have lower apparent solubility than crystal form A in both methanol and water (Table 17 below). Solcal analysis was also performed to measure the heat of the solution in methanol at 25°C to confirm the stable form at this temperature (see Example 15). Based on the Solcal data, the solubility of both crystal forms A and B in methanol was an endothermic event with average heat of dissolution of 48.618 and 64.567 J / g, respectively, indicating that crystal form B is more stable than crystal form A at 25°C.

[0231] Experiment: Approximate Solubility The weighted sample is treated with aliquots of the test solvent at room temperature. The mixture is sonicated between additions to promote dissolution. Complete dissolution of the test substance is determined by visual inspection. Solubility is estimated based on the total solvent used to provide complete dissolution. Actual solubility may be greater than the calculated value due to the use of large amounts of solvent aliquots or a slow dissolution rate. [Table 25]

[0232] Example 11 - Accelerated Stress Conditions Crystal forms A, B, and C were exposed to accelerated stress conditions for two weeks (Table 18 below). Based on XRPD, crystal forms A and B remained unchanged at 30°C / 56%RH or 40°C / 75%RH within the evaluated time frame. However, crystal form C was converted to a mixture of crystal forms A and B within two weeks at 40°C / 75%RH. Crystal form C is metastable under these conditions. For crystal form A, if there is no seed crystal of a more stable polymorph, the critical free energy barrier for nucleation of crystal form B cannot be overcome in the solid state or solvent-mediated conversion experiment within the evaluated time frame. [Table 26]

[0233] T t,B→AThe temperature range is 37-54°C. A mixture of crystalline forms A and B (a mixture of quantities 1 and 2 from Example 17) is completely converted to crystalline form A when heated to 230°C (see Table 19 below). Experiment: Relative humidity stress

[0234] The following relative humidity bottles (which generate the desired relative humidity using saturated salt solutions) are used: 75% RH (NaCl) and 56% RH (NaBr) (Nyqvist, H., Int. J. Pharm. Tech.&Prod. Mfr. 1983, 4 (2), 47-48). [Table 27]

[0235] Example 12 - Preparation of Crystal Form B A portion of crystal form A from Example 5 above is slurryed with water at room temperature for 16 days. Crystal form B is isolated. The XRPD of the product is shown in Figure 48. The XRPD pattern is collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu-line incident beam generated using an Optix long high-precision focal source. The Cu Kα X-ray is focused on the sample using an elliptical stepwise multilayer mirror and directed towards the detector. Before analysis, a silicon sample (NIST SRM 640e) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for the incident and diffracted beams to minimize expansion from axial divergence. The diffraction pattern is collected using a scattering position detection element (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 716 s, Scan speed: 3.3° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0236] Example 13 - XRPD of a mixture of crystalline form A and a small amount of crystalline form B The XRPD pattern of a mixture of crystal form A and a small amount of crystal form B product is shown in Figure 49 (synthesis in Example 17). The XRPD pattern is collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu-line incident beam generated using an Optix long high-precision focal source. The Cu Kα X-ray is focused on the sample and directed towards the detector using an elliptical stepwise multilayer mirror. Before analysis, a silicon sample (NIST SRM 640e) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for the incident and diffracted beams to minimize expansion from axial divergence. The diffraction pattern is collected using a scattering position detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 720 s, Scan speed: 3.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0237] Example 14 - Solcal analysis of crystalline forms A and B Dissolution heat analysis was performed three times in methanol for each form, and the data are summarized in Table 21. Two heats of dissolution are obtained for each test—one calibrated and calculated before sample analysis, and the other calibrated and calculated before sample analysis. The average value from the two calibrations is also shown in the table. Clear dissolution is observed after each test.

[0238] The dissolution of crystalline forms A and B in methanol is an endothermic event with average heats of dissolution of 48.618 and 64.567 J / g, respectively. The standard deviations for each set are 0.457 and 0.344 J / g, respectively.

[0239] Crystal form B has a higher heat of dissolution than crystal form A, indicating that crystal form B is more stable than A at 25°C. The transition enthalpy from crystal form B to crystal form A, calculated from SolCal data, is approximately 15.9 J / g. The difference in heat of fusion during the solid state transition of crystal form B in DSC is 15.9 J / g (see Figures 8 and 55), which is in good agreement with the SolCal results.

[0240] The heat of dissolution is measured using a semi-adiabatic calorimeter, the Thermometric 2225 Precision Solution Calorimeter. Solution Calorimeter System v.1.2 software is used. The sample is weighed in a glass crushing ampoule and sealed with a silicone rubber plug and hot wax. The experiment is conducted at 25°C in 100 mL of methanol. The heat of dissolution of the sample is measured before and after calibration using an internal heater. The heat of dissolution is calculated using the dynamics of the calibration model. [Table 28]

[0241] Example 15 - High-temperature microscope (HSM) of crystal form A from Example 1 High-temperature microscopy is performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope. Samples are observed using 20x magnification objects (obj.). After placing the sample on a coverslip, a second coverslip is placed on top of it. Each sample is visually observed while the stage is heated. SPOT Insight with SPOT software v. 4.5.9 is used. TM A color digital camera is used to capture the image. The hot stage is calibrated using a USP melting point standard.

[0242] High-speed microscopy (HSM) analysis of crystal form A at 182–239°C revealed that the smallest particles evaporated, and the resulting vapor recrystallized into larger crystals. Condensation and melting were observed at 239–247°C, with the needle-like particles appearing to melt last, consistent with multiple endothermic reactions observed by DSC. Two preparations were used for analysis. The first showed discoloration (decomposition) after melting. The second showed recrystallization of the molten material due to rapid cooling.

[0243] Example 16 - Preparation of a mixture of crystalline forms A and B Unless otherwise specified, commercially available reagents should be used as received. Reactions requiring an inert atmosphere should be carried out under nitrogen unless otherwise specified. [Table 29]

[0244] Steps 1 and 2 50 kg of 2-naphthylacetonitrile is dissolved in 250 L of THF, and 32 kg of (S)-(+)-epichlorohydrin is added. The solution is cooled to -10°C. Then, while maintaining the internal temperature below -10°C, 2.0 M sodium hexamethyldisilazane / THF (299 L) is added. This addition takes 14 hours and 14 minutes to complete. The reaction mixture is then stirred for a further 4 hours at approximately -10°C, and a sample of the reaction mixture is analyzed by HPLC. 71 kg of borane dimethyl sulfide is added over 4 hours and 33 minutes while maintaining the internal temperature below 0°C. After the addition of borane is complete, the reaction mixture is slowly heated to 60°C to reduce the nitrile to the amine. During this heating, exothermic reaction occurs, reaching 45°C. After heating at 60°C for 14 hours and 46 minutes, a sample of the reaction mixture is analyzed by HPLC.

[0245] Next, the reaction mixture is cooled to 24°C and transferred to a 2M HCl solution over 2 hours and 28 minutes. The reaction vessel is rinsed with THF (22.3 kg) and the reaction mixture is transferred to the HCl containing the reaction mixture. The two-phase mixture is heated to 45°C-55°C and stirred at this temperature for 1 hour and 48 minutes, then cooled to 30°C. The pH of the reaction mixture to be stopped is measured and found to be 1. The reaction stopping treatment is performed by adding IPAc, stirring, and separating the layers. A 1M HCl solution is added to the organic layer, stirred, the layers are separated, and the organic layer is discarded. When the aqueous layer, which has been combined with ammonia water, is measured, the pH is 9. Next, the aqueous layer is stopped by extracting it twice with IPAc. The combined organic extract is then washed with a 5% sodium chloride solution. A portion of the obtained organic layer is concentrated and azeotropically dried and evaporated four times with methylene chloride, then diluted with methylene chloride. The reaction mixture is transferred to a clean, dry reaction vessel using an in-line filter and diluted with IPAc. Next, 54 kg of p-toluenesulfonic acid hydrate was added little by little to precipitate the desired product as the pTsOH salt. The reaction suspension was stirred at 10°C to 15°C for 3 hours, and the product was isolated by filtration. The filter cake was washed with 2-methyltetrahydrofuran, then with IPAc, and then dried by vacuum for 2 hours. The crude product was purified by stirring with 2-methyltetrahydrofuran at 10°C to 15°C for 11 hours and 36 minutes, and the product was isolated by filtration. The filtered solid was washed with 2-methyltetrahydrofuran and dried to a constant weight to obtain 73.8 kg of the desired product as a white solid. Yield = 73.8 kg (62%). HPLC = 96.8%. Steps 3 and 4 [Table 30]

[0246] The amine-pTsOH salt (73.8 kg) obtained in step 2 above is suspended in 2-methyltetrahydrofuran (738 L) to obtain a slurry. Then thionyl chloride (26.4 kg) is added over 3 hours. After the addition of thionyl chloride is complete, the reaction mixture is stirred for a further 3 hours. Sodium hydroxide aqueous solution (5 M, 10 mol equivalents) is added over 3 hours, followed by stirring for a further 2 hours. The layers are allowed to stand, and the pH of the aqueous layer is checked to be 9. Water (2 mL / g, SM) is added, and the reaction mixture is stirred at room temperature for a further 15 minutes. The layers are separated, and the organic layers are washed twice with water. The aqueous layers are combined and back-extracted with 2-methyltetrahydrofuran, and the first organic layers and the back extract are combined. These combined organic layers are washed with saturated brine, dried over magnesium sulfate, and partially concentrated. After concentration, hydrogen chloride / IPA (1.0 mol equivalent of HCl / IPA) is added, and the mixture is stirred for 2 hours to form a crude salt. This is isolated by filtration, washed with 2-methyltetrahydrofuran, then with IPAc, and then vacuum-dried for 2 hours.

[0247] The crude product (82.6 kg) obtained above was dissolved in 14 volumes of hot ethanol (70°C), and then filtered through a capsule carbon filter to improve the color. The dissolution container, capsule carbon filter, and transfer line were then rinsed further with hot ethanol (70°C), and the washing solution was combined with the filtrate. The combined filtrate and washing solution were partially concentrated under reduced pressure to a total volume of approximately 5 volumes (relative to the crude product added), and then stirred at 0°C for 2 hours. The resulting solid was isolated by filtration, and the filtration cake was washed with cold (0°C~5°C) ethanol, then with IPAc. The washed solid was dried to obtain the product (33.6 kg) as a grayish-white solid. Yield = 33.6 kg (73% yield). Achiral HPLC = 98%.

[0248] Next, the material is dried using a cone dryer. After drying, the material is sieved.

[0249] Next, a portion of the substance (14 kg) is dissolved in 15 volumes of hot ethanol (70°C), filtered through a capsule carbon filter, and the color is improved. The dissolution container, capsule carbon filter, and transfer line are then rinsed further with hot ethanol (70°C), and the washing solution is combined with the filtrate. The combined filtrate and washing solution are partially concentrated under reduced pressure to a total volume of approximately 8 volumes (relative to the initial 14 kg of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride), and then stirred at 18°C ​​for 2 hours. The obtained solid is isolated by filtration, the filtration cake is washed with cold (5°C~10°C) ethanol, then with IPAc, and the washed solid is dried to obtain (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (9.4 kg, yield 67.1%) as a white solid. Achiral HPLC = 98%.

[0250] The XRPD of the product is shown in Figure 56. The XRPD shows traces of low-intensity peaks at 18.9°, 19.2°, 23.6°, 23.8°, 28.2°, and 28.7°²θ, which are attributed to crystal form B, but are consistent with crystal form A. The XRPD pattern is collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu-line incident beam generated using an Optix long high-precision focus source. The Cu Kα X-ray is focused on the sample and directed towards the detector using an elliptical stepwise multilayer mirror. Before analysis, a silicon sample (NIST SRM 640e) is analyzed to confirm that the observed position of the Si 111 peak matches the NIST certified position. The sample is sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air is minimized using a beam stop, anti-scattering short extension, and anti-scattering knife edge. A solar slit is used for the incident and diffracted beams to minimize expansion from axial divergence. The diffraction pattern is collected using a scattering position detection element (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b.

[0251] XRPD data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), Voltage: 45 kV, Current: 40 mA, Scan range: 1.00-39.99°²θ, Step size: 0.017°²θ, Acquisition time: 721 s, Scan speed: 3.2° / min., Slit: DS: 1 / 2°, SS: Zero, Rotation time: 1.0 s, Mode: Transmission.

[0252] Example 17 - Preparation of a mixture of crystalline forms A and B Add 50 g of the product from Example 16 and 750 mL (15 vol) of special industrial EtOH to a 2 L three-necked round-bottom flask equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, thermocouple, and heating mantle. Heat the mixture under reflux (77°C). Dissolve the solid at 72°C to form a clear solution. Add a non-viscous dark gray slurry (5 g, 0.1 eq / 100 mL EtOH) and stir the mixture for 1 hour. Filter with hot EtOH (150 mL) and rinse. Divide the filtrate into two equal parts.

[0253] quantity 1 Concentrate to 10 volumes (250 mL) at 50°C. A small amount of solid will begin to precipitate during concentration. Transfer to a 500 mL three-neck round-bottom flask equipped with a mechanical stirrer and cool to room temperature. Stir at room temperature for 2 hours. A suspension will form. Filter and rinse with EtOH (50 mL, 2 volumes), then with IPAc (50 mL). Suction dry on the filter. Yield = 20.5 g (82%).

[0254] quantity 2 Concentrate to 7 volumes (175 mL) at 50°C. A small amount of solid begins to precipitate during concentration. Transfer to a 500 mL three-neck round-bottom flask equipped with a mechanical stirrer and cool to room temperature. Stir at room temperature for 2 hours. A suspension is formed. Filter and rinse with EtOH (50 mL, 2 volumes), then with IPAc (50 mL). Dry by suction on the filter. Yield = 19.8 g (79.2%).

[0255] The products from the two quantities were combined, and the XRPD pattern of the combined quantity is shown in Figure 49 (Example 13).

[0256] Example 18 - Preparation of Crystal Form The following crystal forms are produced using crystal form A from Example 5. [Table 31]

Claims

1. P2 1 2 1 2 1 Belonging to the space group, with the following unit cell parameters: a=5.7779(2)Å, b=8.6633(2)Å, c=25.7280(8)Å, α=β=γ=90° Crystal form A of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, which has the properties of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

2. Crystal form A according to claim 1, wherein the powder X-ray diffraction (XRPD) pattern measured using a Cu Kα incident beam includes an XRPD pattern comprising five peaks selected from the peaks shown in Figure 1.

3. Crystal form A according to claim 1 or 2, wherein the powder X-ray diffraction (XRPD) pattern measured using a Cu Kα incident beam substantially has the XRPD pattern shown in Figure 1.

4. Crystal form A according to any one of claims 1 to 3, wherein the powder X-ray diffraction (XRPD) pattern measured using a Cu Kα incident beam has the XRPD pattern shown in Figure 1.

5. Crystal form A of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride exhibits an XRPD pattern containing 2θ(°) values ​​of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, and the XRPD is measured using an incident Cu Kα beam, crystal form A of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

6. Crystal form A is shown in Table A below: Table A Table 1 Crystal form A according to any one of claims 1 to 5, wherein the XRPD pattern includes the 2θ(°) value shown, and the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

7. Crystal form A according to any one of claims 1 to 6, wherein crystal form A exhibits an XRPD pattern containing 2θ(°) values ​​of 12.3, 13.8, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, and the XRPD is measured using an incident Cu Kα beam.

8. Crystal form A is shown in Table B below: Table B Table 2 Crystal form A according to any one of claims 1 to 7, which exhibits an XRPD pattern including the 2θ(°) value shown, and the XRPD is measured by irradiation at a wavelength of 1.54059 Å.

9. Crystal form A has the following 2θ (°) values: 6.9, 12.3, 13.8, 14.5, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.1, 20.5, 20.7, 21.0, 21.5, 22.9, 24.7, 25.2, 25.4, 25.7, 26.4, 27.5, and 27.8 Crystal form A according to any one of claims 1 to 8, which exhibits an XRPD pattern including and is measured using an incident Cu Kα beam.

10. Crystal form A is shown in Table C below: Table C Table 3 Crystal form A according to any one of claims 1 to 9, wherein the XRPD pattern includes the 2θ(°) value shown, and the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

11. Crystal form A according to any one of claims 1 to 10, wherein crystal form A exhibits an XRPD pattern including d-interval (Å) values ​​of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9 and 3.

5.

12. Crystal form A is shown in Table A below: Table A Table 4 Crystal form A according to any one of claims 1 to 11, showing an XRPD pattern including the d-interval (Å) values ​​shown.

13. Crystal form A according to any one of claims 1 to 12, wherein crystal form A exhibits an XRPD pattern including d-interval (Å) values ​​of 7.2, 6.4, 5.7, 5.4, 5.2, 4.9, 4.8, 4.6, 4.3, 3.9, and 3.

5.

14. Crystal form A is shown in Table B below: Table B Table 5 Crystal form A according to any one of claims 1 to 13, showing an XRPD pattern including the d-interval (Å) values ​​shown.

15. Crystal form A according to any one of claims 1 to 14, wherein crystal form A exhibits an XRPD pattern including d-interval (Å) values ​​of 6.9, 12.3, 13.8, 14.5, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.1, 20.5, 20.7, 21.0, 21.5, 22.9, 24.7, 25.2, 25.4, 25.7, 26.4, 27.5, and 27.

8.

16. Crystal form A is shown in Table C below: Table C Table 6 Crystal form A according to any one of claims 1 to 15, which shows an XRPD pattern including the d-interval (Å) values ​​shown.

17. Crystal form A according to any one of claims 1 to 16, wherein crystal form A has a differential scanning calorimetry (DSC) thermogram or thermogravimetric analysis (TGA) thermogram shown in Figure 2.

18. Crystal form A according to any one of claims 1 to 17, wherein crystal form A exhibits substantially the XRPD pattern of any one of Figures 35, 37, and 47, as measured using irradiation at a wavelength of 1.54059 Å.

19. Crystal form A according to any one of claims 1 to 18, wherein crystal form A exhibits an XRPD pattern as shown in any of Figures 35, 37, and 47, measured using irradiation at a wavelength of 1.54059 Å.

20. P2 1 2 1 2 1 Belonging to the space group, with the following unit cell parameters: a=5.9055(2)Å, b=7.4645(3)Å, c=29.1139(13)Å, α=β=γ=90° Crystalline form B of (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, which has the following properties.

21. Crystal form B according to claim 20, wherein crystal form B exhibits an XRPD pattern including 2θ(°) values ​​of 6.0, 17.4, 18.9, 19.2 and 24.4, and the XRPD is measured using an incident Cu Kα beam.

22. Crystal form B is shown in Table D below: Table D Table 7 Crystal form B according to claim 20 or 21, wherein the XRPD pattern includes the 2θ(°) value shown, and the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

23. Crystal form B according to any one of claims 20 to 22, wherein crystal form B exhibits an XRPD pattern including 2θ(°) values ​​of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4 and 28.2, and the XRPD is measured using an incident Cu Kα beam.

24. Crystal form B is shown in Table E below: Table E Table 8 Crystal form B according to any one of claims 20 to 23, wherein the XRPD pattern includes the 2θ(°) value shown, and the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

25. Crystal form B according to any one of claims 20 to 24, wherein crystal form B exhibits an XRPD pattern including 2θ(°) values ​​of 6.0, 12.1, 13.2, 14.9, 15.1, 16.0, 16.9, 17.4, 18.2, 18.9, 19.2, 19.9, 21.1, 21.3, 21.7, 22.6, 23.6, 23.8, 24.4, 25.3, 26.1, 26.6, 27.2, 28.2, 28.7 and 29.5, and the XRPD is measured using an incident Cu Kα beam.

26. Crystal form B is shown in Table F below: Table F Table 9 Crystal form B according to any one of claims 20 to 25, wherein the XRPD pattern includes an Xθ(°) value selected from those shown, and the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

27. Crystal form B according to any one of claims 20 to 26, wherein crystal form B exhibits an XRPD pattern including d-interval (Å) values ​​of 14.6, 5.1, 4.7, 4.6 and 3.

6.

28. Crystal form B is shown in Table D below: Table D Table 10 Crystal form B according to any one of claims 20 to 27, showing an XRPD pattern including the d-interval (Å) values ​​shown.

29. Crystal form B according to any one of claims 20 to 28, wherein crystal form B exhibits an XRPD including d-interval (Å) values ​​of 14.6, 6.7, 5.1, 4.7, 4.6, 3.8, 3.7, 3.6, and 3.

2.

30. Crystal form B is shown in Table E below: Table E Table 11 Crystal form B according to any one of claims 20 to 29, showing an XRPD pattern including the d-interval (Å) values ​​shown.

31. Crystal form B according to any one of claims 20 to 30, wherein crystal form B exhibits an XRPD including d-interval (Å) values ​​of 14.6, 7.3, 6.7, 6.0, 5.9, 5.5, 5.2, 5.1, 4.9, 4.7, 4.6, 4.5, 4.2, 4.1, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 and 3.

0.

32. Crystal form B is shown in Table F below: Table F Table 12 Crystal form B according to any one of claims 20 to 31, showing an XRPD pattern including the d-interval (Å) values ​​shown.

33. Crystal form B according to any one of claims 20 to 32, wherein crystal form B exhibits a substantially XRPD pattern shown in Figure 5, as measured using irradiation at a wavelength of 1.541871 Å.

34. Crystal form B according to any one of claims 20 to 33, wherein crystal form B exhibits the XRPD pattern shown in Figure 5, measured using irradiation at a wavelength of 1.541871 Å.

35. Crystal form B according to any one of claims 20 to 34, wherein crystal form B exhibits substantially the XRPD pattern of any one of Figures 7, 40, and 48, as measured using irradiation at a wavelength of 1.54059 Å.

36. Crystal form B according to any one of claims 20 to 35, wherein crystal form B exhibits an XRPD pattern as shown in Figures 7, 40, and 48, measured using irradiation at a wavelength of 1.54059 Å.

37. A pharmaceutical composition comprising crystalline form A as described in any one of claims 1 to 19 and a pharmaceutically acceptable diluent or carrier.

38. A method for preventing or treating attention deficit hyperactivity disorder in, for example, a patient with fragile X syndrome-related disorder, characterized by administering a therapeutically effective amount of crystalline form A according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 37 to a patient who requires such an amount.

39. A method for preventing or treating substance abuse disorder, fragile X syndrome-related disorder, or autism spectrum disorder in patients who require a therapeutically effective amount of crystalline form A described in any one of claims 1 to 19 or the pharmaceutical composition described in claim 37, for example, patients with fragile X syndrome-related disorder, comorbid attention deficit hyperactivity disorder and depression, comorbid attention deficit hyperactivity disorder and substance abuse, or comorbid attention deficit hyperactivity disorder and anxiety disorder.

40. A pharmaceutical composition comprising crystalline form B as described in any one of claims 20 to 36 and a pharmaceutically acceptable diluent or carrier.

41. A method for preventing or treating attention deficit hyperactivity disorder in, for example, a patient with fragile X syndrome-related disorder, characterized by administering a therapeutically effective amount of crystalline form B according to any one of claims 20 to 36 or the pharmaceutical composition according to claim 40 to a patient who requires such an amount.

42. A method for preventing or treating substance abuse disorder, fragile X syndrome-related disorder, or autism spectrum disorder in patients who require a therapeutically effective amount of crystalline form A according to any one of claims 20 to 36 or the pharmaceutical composition according to claim 40, for example, patients with fragile X syndrome-related disorder, comorbid attention deficit hyperactivity disorder and depression, comorbid attention deficit hyperactivity disorder and substance abuse, or comorbid attention deficit hyperactivity disorder and anxiety disorder.

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