Crystalline compounds

Abstract

To provide a specific polymorph of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane.SOLUTION: The present invention relates to crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride and compositions comprising the same and methods of making and using the same.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] The present invention relates to crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride and compositions containing same, as well as methods of making and using same. [Background technology]

[0003] (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is a compound useful as an unbalanced triple reuptake inhibitor (TRI) that is most effective against norepinephrine (NE) reuptake, six times less effective against dopamine (DA) reuptake, and 14 times less effective against serotonin (5-HT) reuptake. This compound and its utility are disclosed in more detail in U.S. Patent Application Publication No. 2007 / 0082940, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention [Problem to be solved by the invention]

[0004] An active pharmaceutical ingredient may exist in different physical forms (e.g., different crystalline, amorphous, hydrated or solvated forms, liquid or solid), which may affect the processability, stability, solubility, bioavailability, pharmacokinetics (absorption, distribution, metabolism, excretion, etc.) and / or bioequivalence of the active pharmaceutical ingredient and pharmaceutical compositions containing the same. It is not possible to predict whether a compound exists in a particular polymorphic form. It is important in pharmaceutical development to generate and identify advantageous physical forms of an active pharmaceutical ingredient (e.g., free base or salt in solid, liquid, crystalline, hydrated, solvated or amorphous form). Thus, there is a need for a specific polymorph of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. [Means for solving the problem]

[0005] (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane ("the Compound"), is represented by Formula I, below: [ka] Formula I

[0006] The inventors have found that certain polymorphs of the hydrochloride addition salt form of the compound have different stability and solubility properties and are particularly advantageous for the preparation of a wide variety of galenical formulations, in particular crystalline form A shown below. Thus, in a first aspect, the present invention provides a crystalline form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, for example: 1.1 Crystalline Form A of the hydrochloride addition salt form of the Compound ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) ("Crystalline Form A"). 1.2 P2 1 2 1 2 1 It belongs 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° Item 1.1 is crystalline form A having the formula: 1.3 P2 1 2 1 2 1 Belonging to the space group, any combination of the following unit cell parameters: a=5-7 Å, for example 6 Å, for example 5.6-5.9 Å, for example 5.7-5.8 Å, for example 5.8 Å, for example 5.78, for example 5.778 Å; b=8-10 Å, for example 9 Å, for example 8.5-8.8 Å, for example 8.6-8.7 Å, for example 8.7 Å, for example 8.66 Å, for example 8.663 Å; c=25-27 Å, such as 26 Å, for example 25.6-25.9 Å, for example 25.7-25.8 Å, for example 25.7-25.8 Å, for example 25.73 Å, for example 25.728 Å; and α=β=γ=90° Item 1.1 is crystalline form A having the formula: 1.4 Crystal form A has a V=1287.83(7)Å 3 Any of items 1.1 to 1.3 having a calculated volume of 1.5 Any of items 1.1 to 1.4, wherein the crystal structure of crystalline form A is obtained as a crystal 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. 1.6 Any of items 1.1 to 1.5, in which the crystal structure of crystalline form A is obtained by Mo Kα radiation, for example Mo Kα radiation with λ=0.71073 Å. 1.7 Any of items 1.1 to 1.6, in which the crystal structure of crystalline form A is obtained at 150K. 1.8 Any of items 1.1 to 1.7, wherein crystalline form A has a single crystal structure as shown in the ORTEP diagram of FIG. 1.9 Any of paragraphs 1.1 to 1.8, wherein crystalline form A has the calculated XRPD pattern shown in Figure 23. 1.10 Any of paragraphs 1.1 to 1.9, wherein crystalline form A exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.11 Any of paragraphs 1.1 to 1.10, wherein crystalline form A exhibits an XRPD pattern comprising 2θ(°) values ​​of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, and wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.12 Any of paragraphs 1.1 to 1.11, wherein crystalline form A exhibits an XRPD pattern having characteristic 2θ (°) values ​​of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.13 Any of paragraphs 1.1 to 1.12, wherein crystalline form A exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.14 Any of paragraphs 1.1 to 1.13, wherein crystalline form A exhibits an XRPD pattern comprising 2θ(°) values ​​of 15.42, 16.55, 17.15, 18.50, 19.45, 20.46, 20.68, 22.90, and 25.69, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation. 1.15 Any of paragraphs 1.1 to 1.14, wherein crystalline form A exhibits an XRPD pattern having characteristic 2θ (°) values ​​of 15.42, 16.55, 17.15, 18.50, 19.45, 20.46, 20.68, 22.90, and 25.69, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.16 Crystalline Form A is shown in Table A below: Table A [Table 1] and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.17 Any of sections 1.1 to 1.16, wherein crystalline form A exhibits an XRPD pattern comprising the 2θ(°) values ​​set forth in Table A of section 1.16, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.18 Any of sections 1.1 to 1.17, wherein crystalline form A exhibits an XRPD pattern having characteristic 2θ (°) values ​​as set forth in Table A of section 1.16, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.19 Any of paragraphs 1.1 to 1.18, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as 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 wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.20 Any of paragraphs 1.1 to 1.19, wherein crystalline form A exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.21 Any of paragraphs 1.1 to 1.20, wherein crystalline form A exhibits an XRPD pattern having 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, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.22 Any of paragraphs 1.1 to 1.21, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as 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 wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.23 Any of paragraphs 1.1 to 1.22, wherein crystalline form A exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.24 Any of paragraphs 1.1 to 1.23, wherein crystalline form A exhibits an XRPD pattern having 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, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.25 Crystalline Form A is in accordance with Table B below: Table B [Table 2] and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.26 Any of paragraphs 1.1-1.25, wherein crystalline form A exhibits an XRPD pattern comprising 2θ(°) values ​​set forth in Table B of paragraph 1.25, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.27 Any of paragraphs 1.1 to 1.26, wherein crystalline form A exhibits an XRPD pattern having the typical 2θ(°) values ​​shown in Table B of paragraph 1.25, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.28 Any of paragraphs 1.1 to 1.27, wherein crystalline form A exhibits an XRPD pattern comprising at least 3, such as at least 5, such as at least 9, such as at least 10, such as at least 12, such as at least 15, such as at least 20 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, wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.29 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 and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.30 Crystal form A is 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 and wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.31 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 and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.32 Crystalline Form A is shown in Table C below: Table C [Table 3] and the XRPD is measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.33 Any of paragraphs 1.1-1.32, wherein crystalline form A exhibits an XRPD pattern comprising 2θ(°) values ​​set forth in Table C of paragraph 1.32, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.34 Any of paragraphs 1.1 to 1.33, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, d-spacing (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 paragraphs 1.1 to 1.34, wherein crystalline form A exhibits an XRPD pattern comprising d-spacing (Å) values ​​of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5. 1.36 Any of paragraphs 1.1 to 1.35, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, d-spacing (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 paragraphs 1.1 to 1.36, wherein crystalline form A exhibits an XRPD pattern comprising d-spacing (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 paragraphs 1.1-1.37, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, d-spacing (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 paragraphs 1.1 to 1.38, wherein crystalline form A exhibits an XRPD pattern comprising d-spacing (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 paragraphs 1.1 to 1.39, wherein crystalline form A exhibits an XRPD pattern comprising at least three, e.g., at least five, d-spacing (Å) values ​​selected from those shown in Table A in paragraph 1.16. 1.41 Any of paragraphs 1.1 to 1.40, wherein crystalline form A exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table A in paragraph 1.16. 1.42 Any of paragraphs 1.1 to 1.41, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as at least 10 d-spacing (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 paragraphs 1.1 to 1.42, wherein crystalline form A exhibits an XRPD pattern comprising d-spacing (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 paragraphs 1.1 to 1.43, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as at least 10 d-spacing (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 paragraphs 1.1 to 1.44, wherein crystalline form A exhibits an XRPD pattern comprising d-spacing (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 paragraphs 1.1 to 1.45, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as at least 10 d-spacing (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 paragraphs 1.1 to 1.46, wherein crystalline form A exhibits an XRPD pattern including d-spacing (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 paragraphs 1.1 to 1.47, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as at least 10 d-spacing (Å) values ​​selected from those shown in Table B of paragraph 1.25. 1.49 Any of paragraphs 1.1 to 1.48, wherein crystalline form A exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table B of paragraph 1.25. 1.50 Any of paragraphs 1.1 to 1.49, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as at least nine, such as at least ten, such as at least twelve, such as at least fifteen d-spacing (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 paragraphs 1.1 to 1.50, wherein crystalline form A exhibits an XRPD pattern containing d-spacing (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 Any of paragraphs 1.1 to 1.51, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, for example at least nine, such as at least ten, for example at least twelve, such as at least fifteen, for example at least twenty d-spacing (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. 1.53 Any of paragraphs 1.1 to 1.52, wherein crystalline form A exhibits an XRPD pattern including d-spacing (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 Any of paragraphs 1.1 to 1.53, wherein crystalline form A exhibits an XRPD pattern comprising at least three, such as at least five, such as at least nine, for example at least ten, such as at least twelve, for example at least fifteen, such as at least twenty d-spacing (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. 1.55 Any of paragraphs 1.1 to 1.54, wherein crystalline form A exhibits an XRPD pattern including d-spacing (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 paragraphs 1.1 to 1.55, wherein crystalline form A exhibits an XRPD pattern comprising at least 3, such as at least 5, such as at least 9, such as at least 10, such as at least 12, such as at least 15, such as at least 20 d-spacing (Å) values ​​selected from those shown in Table C of paragraph 1.32. 1.57 Any of paragraphs 1.1 to 1.56, wherein crystalline form A exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table C of paragraph 1.32. 1.58 Any of paragraphs 1.1 to 1.57, wherein crystalline form A exhibits an XRPD pattern including the characteristic peaks of the XRPD pattern shown in Figure 1, 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. 1.59 Any of paragraphs 1.1 to 1.58, wherein crystalline form A exhibits an XRPD pattern including peaks typical of the XRPD pattern shown in FIG. 1, wherein 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. 1.60 Any of paragraphs 1.1-1.59, wherein crystalline form A exhibits an X-ray powder diffraction (XRPD) pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, comprising three peaks, in some embodiments five peaks, selected from those shown in FIG. 1, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.61 Any of sections 1.1 to 1.60, wherein crystalline form A exhibits an XRPD pattern, e.g. an XRPD pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution XRPD pattern measured using an incident beam of Cu Kα radiation, comprising at least 9 peaks, such as at least 10 peaks, for example at least 12 peaks, such as at least 15 peaks, for example at least 20 peaks selected from the peaks shown in Figure 1, e.g. the XRPD is measured using a wavelength of 1.54059 Å. 1.62 Any of paragraphs 1.1 to 1.61, wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.63 Any of paragraphs 1.1 to 1.62, wherein crystalline form A exhibits the X-ray powder diffraction (XRPD) pattern shown in Figure 1, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.64 Any of paragraphs 1.1 to 1.63, wherein crystalline form A has an XRPD pattern including characteristic peaks in an 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, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.65 Any of paragraphs 1.1 to 1.64, wherein crystalline form A has an XRPD pattern including typical peaks of an 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 wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.66 Any of paragraphs 1.1-1.65, wherein crystalline form A exhibits an XRPD pattern comprising three peaks selected from those 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, in some embodiment five peaks, e.g., an XRPD pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., a high resolution XRPD pattern measured using an incident beam of Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.67 any of paragraphs 1.1 to 1.66, wherein crystalline form A exhibits an XRPD pattern, such as an XRPD pattern measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g. a high resolution XRPD pattern measured using an incident beam of Cu Kα radiation, comprising at least 9 peaks, such as at least 10 peaks, such as at least 12 peaks, such as at least 15 peaks, such as at least 20 peaks selected from those shown in any of Figures 1, 35, 37 and 47, such as Figure 1, such as Figure 35, such as Figure 37, such as Figure 47, e.g. 1.68 Any of paragraphs 1.1 to 1.67, wherein crystalline form A exhibits an XRPD pattern substantially as 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 Cu radiation, e.g. Cu Kα radiation, e.g. wherein the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.69 Any of paragraphs 1.1 to 1.68, wherein crystalline form A exhibits an XRPD pattern as 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 Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.70 Any of paragraphs 1.1 to 1.69, wherein crystalline form A exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak between 245°C and 249°C, for example between 245°C and 248°C, e.g., crystalline form A exhibits a differential scanning calorimetry (DSC) thermogram containing multiple, for example three, endotherms between 245°C and 249°C, for example between 245°C and 248°C, e.g., crystalline form A exhibits a differential scanning calorimetry (DSC) thermogram starting at 245°C and including an endothermic peak at 247°C, an endothermic shoulder peak at 248°C and an endothermic peak at 248°C. 1.71 Any of paragraphs 1.1 to 1.70, wherein crystalline form A exhibits an endothermic peak at 247°C, e.g., a differential scanning calorimetry (DSC) thermogram starting at 245°C and including an endothermic peak at 247°C. 1.72 Any of paragraphs 1.1 to 1.71, wherein crystalline form A exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 248°C. 1.73 Any of paragraphs 1.1 to 1.72, wherein crystalline form A exhibits the differential scanning calorimetry (DSC) thermogram shown in FIG. 1.74 Any of paragraphs 1.1 to 1.73, in which crystalline form A exhibits a thermogravimetric analysis (TGA) thermogram containing a weight loss of 0.4% at or below 200°C. 1.75 Any of items 1.1 to 1.74 having a thermogravimetric analysis (TGA) thermogram including a decomposition onset temperature at 276°C. 1.76 Any of paragraphs 1.1 to 1.75, wherein crystalline form A exhibits the thermogravimetric analysis (TGA) thermogram shown in FIG. 1.77 The dynamic vapor sorption / desorption isotherm of crystalline form A is shown in FIG. 3, for example, crystalline form A is: 0.03% weight loss at equilibrium at 5% RH; 0.10% weight gain from 5% to 95% RH; and Any of sections 1.1-1.76 that exhibit a dynamic vapor sorption / desorption isotherm showing a weight loss of 0.10% from 95% to 5% RH. 1.78 Crystalline Form B of the hydrochloride addition salt form of the Compound ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) ("Crystalline Form B"). 1.79 Crystal form B is P2 1 2 1 2 1 It belongs 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° With, term 1.78. 1.80 Crystal form B is P2 1 2 1 2 1 It belongs to the space group with the following unit cell parameters: a=5-7 Å, for example 6 Å, for example 5.7-6.1 Å, for example 5.8-6.0 Å, for example 5.9 Å, for example 5.91, for example 5.906 Å; b=6-8 Å, for example 7 Å, for example 7.3-7.7 Å, for example 7.4-7.6 Å, for example 7.5 Å, for example 7.46 Å, for example 7.465 Å; c=28-30 Å, such as 29 Å, for example 28.9-29.3 Å, for example 29.0-29.2 Å, for example 29.1 Å, for example 29.11 Å, for example 29.114 Å; and α=β=γ=90° Term 1.78, having any combination of 1.81 Crystal form B has a V of 1283.39(9)Å 3 Any of items 1.78 to 1.80 having a calculated volume of 1.82 Any of items 1.78 to 1.81, wherein the crystal structure of crystalline form B is obtained as a crystal 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. 1.83 Any of items 1.78 to 1.82, in which the crystal structure of crystalline form B is obtained with Cu Kα radiation, for example Cu Kα radiation having λ=1.54178 Å. 1.84 Any of items 1.78 to 1.83, in which the crystal structure of crystalline form B is obtained at 100(2)K. 1.85 Any of paragraphs 1.78 to 1.84, wherein crystalline form B has a single crystal structure as shown in the atomic displacement ellipsoid diagram of Figure 24. 1.86 Any of paragraphs 1.78 to 1.85, wherein crystalline form B has the calculated XRPD pattern shown in FIG. 32. 1.87 Any of paragraphs 1.78 to 1.86, wherein crystalline form B exhibits an XRPD pattern comprising at least three 2θ (°) values ​​selected from the group consisting of 6.0, 17.4, 18.9, 19.2, and 24.4, and wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.88 Any of paragraphs 1.78 to 1.87, wherein crystalline form B exhibits an XRPD pattern comprising 2θ(°) values ​​of 6.0, 17.4, 18.9, 19.2, and 24.4, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.89 Any of paragraphs 1.78 to 1.88, wherein crystalline form B exhibits an XRPD pattern having characteristic 2θ (°) values ​​of 6.0, 17.4, 18.9, 19.2, and 24.4, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.90 Any of paragraphs 1.78 to 1.89, wherein crystalline form B exhibits an XRPD pattern comprising at least three 2θ (°) values ​​selected from the group consisting of 6.04, 17.41, 18.94, 19.19, and 24.39, and wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.91 Any of paragraphs 1.78 to 1.90, wherein crystalline form B exhibits an XRPD pattern comprising 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 radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.92 Any of paragraphs 1.78 to 1.91, wherein crystalline form B exhibits an XRPD pattern having characteristic 2θ (°) values ​​of 6.04, 17.41, 18.94, 19.19, and 24.39, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.93 Crystalline form B is shown in Table D below: Table D [Table 4] and wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.94 Any of paragraphs 1.78 to 1.93, wherein crystalline form B exhibits an XRPD pattern comprising 2θ(°) values ​​set forth in Table D of paragraph 1.93, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.95 Any of paragraphs 1.78 to 1.94, wherein crystalline form B exhibits an XRPD pattern having characteristic 2θ (°) values ​​as set forth in Table D of paragraph 1.93, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.96 Any of paragraphs 1.78 to 1.95, wherein crystalline form B exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.97 Any of paragraphs 1.78 to 1.96, wherein crystalline form B exhibits an XRPD pattern comprising 2θ(°) values ​​of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4, and 28.2, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.98 Any of paragraphs 1.78 to 1.97, wherein crystalline form B exhibits an XRPD pattern having typical 2θ(°) values ​​of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4, and 28.2, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.99 Any of paragraphs 1.78 to 1.98, wherein crystalline form B exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.100 Any of paragraphs 1.78 to 1.99, wherein crystalline form B exhibits an XRPD pattern comprising 2θ (°) values ​​of 6.04, 13.21, 17.41, 18.94, 19.19, 23.59, 23.79, 24.39, and 28.15, and wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.101 Any of paragraphs 1.78 to 1.100, wherein crystalline form B exhibits an XRPD pattern having typical 2θ (°) values ​​of 6.04, 13.21, 17.41, 18.94, 19.19, 23.59, 23.79, 24.39, and 28.15, and wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.102 Crystalline form B is shown in Table E below: Table E [Table 5] and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.103 Any of paragraphs 1.78 to 1.102, wherein crystalline form B exhibits an XRPD pattern comprising the 2θ(°) values ​​set forth in Table E of paragraph 1.102, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.104 Any of paragraphs 1.78 to 1.103, wherein crystalline form B exhibits an XRPD pattern having the typical 2θ(°) values ​​shown in Table E of paragraph 1.102, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.105 Any of paragraphs 1.78 to 1.104, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, such as at least nine, such as at least ten, such as at least fifteen, such as at least twenty, such as at least twenty-five 2θ(°) values ​​selected from the group consisting 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, wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.106 Crystalline 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 and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.107 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 and wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.108 Crystalline 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 and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.109 Crystalline form B is shown in Table F below: Table F [Table 6] and wherein the XRPD is measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.110 Any of paragraphs 1.78 to 1.109, wherein crystalline form B exhibits an XRPD pattern comprising 2θ(°) values ​​set forth in Table F of paragraph 1.109, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.111 Any of paragraphs 1.78 to 1.110, wherein crystalline form B exhibits an XRPD pattern containing at least three d-spacing (Å) values ​​selected from the group consisting of 14.6, 5.1, 4.7, 4.6, and 3.6. 1.112 Any of paragraphs 1.78 to 1.111, wherein crystalline form B exhibits an XRPD pattern containing d-spacing (Å) values ​​of 14.6, 5.1, 4.7, 4.6, and 3.6. 1.113 Any of paragraphs 1.78 to 1.112, wherein crystalline form B exhibits an XRPD pattern containing at least three d-spacing (Å) values ​​selected from the group consisting of 14.62, 5.09, 4.68, 4.62, and 3.65. 1.114 Any of paragraphs 1.78 to 1.113, wherein crystalline form B exhibits an XRPD pattern containing d-spacing (Å) values ​​of 14.62, 5.09, 4.68, 4.62, and 3.65. 1.115 Any of paragraphs 1.78 to 1.114, wherein crystalline form B exhibits an XRPD pattern containing at least three d-spacing (Å) values ​​selected from the group consisting of 14.620, 5.089, 4.681, 4.622, and 3.646. 1.116 Any of paragraphs 1.78 to 1.115, wherein crystalline form B exhibits an XRPD pattern containing d-spacing (Å) values ​​of 14.620, 5.089, 4.681, 4.622, and 3.646. 1.117 Any of paragraphs 1.78 to 1.116, wherein crystalline form B exhibits an XRPD pattern containing at least three d-spacing (Å) values ​​selected from those shown in Table D of paragraph 1.93. 1.118 Any of paragraphs 1.78 to 1.117, wherein crystalline form B exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table D of paragraph 1.93. 1.119 Any of paragraphs 1.78 to 1.118, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, d-spacing (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 Any of paragraphs 1.78 to 1.119, wherein crystalline form B exhibits an XRPD pattern containing d-spacing (Å) values ​​of 14.6, 6.7, 5.1, 4.7, 4.6, 3.8, 3.7, 3.6, and 3.2. 1.121 Any of paragraphs 1.78 to 1.120, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, d-spacing (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 paragraphs 1.78 to 1.121, wherein crystalline form B exhibits an XRPD pattern containing d-spacing (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 paragraphs 1.78 to 1.122, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, d-spacing (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 paragraphs 1.78 to 1.123, wherein crystalline form B exhibits an XRPD pattern containing d-spacing (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 paragraphs 1.78 to 1.124, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, d-spacing (Å) values ​​selected from those shown in Table E of paragraph 1.102. 1.126 Any of paragraphs 1.78 to 1.125, wherein crystalline form B exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table E of paragraph 1.102. 1.127 Any of paragraphs 1.78 to 1.126, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, such as at least nine, such as at least ten, such as at least fifteen, such as at least twenty d-spacing (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. 1.128 Any of paragraphs 1.78 to 1.127, wherein crystalline form B exhibits an XRPD pattern comprising d-spacing (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 paragraphs 1.78 to 1.128, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, for example at least nine, such as at least ten, for example at least fifteen, such as at least twenty, for example at least twenty-five d-spacing (Å) values ​​selected from the group consisting 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. 1.130 Any of terms 1.78 to 1.129, wherein crystalline form B exhibits an XRPD pattern including d-spacing (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 Any of paragraphs 1.78 to 1.130, wherein crystalline form B exhibits an XRPD pattern comprising at least three, such as at least five, such as at least nine, for example at least ten, such as at least fifteen, for example at least twenty, for example at least twenty-five d-spacing (Å) values ​​selected from the group consisting 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. 1.132 Any of terms 1.78 to 1.131, wherein crystalline form B exhibits an XRPD pattern including d-spacing (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 Any of paragraphs 1.78 to 1.132, wherein crystalline form B exhibits an XRPD pattern comprising at least 3, such as at least 5, for example at least 9, such as at least 10, for example at least 15, such as at least 20, for example at least 25 d-spacing (Å) values ​​selected from those shown in Table F of paragraph 1.109. 1.134 Any of paragraphs 1.78 to 1.133, wherein crystalline form B exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table F of paragraph 1.109. 1.135 Any of paragraphs 1.78 to 1.134, wherein crystalline form B exhibits an X-ray powder diffraction pattern including the characteristic peaks of the XRPD pattern shown in FIG. 5, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å. 1.136 Any of paragraphs 1.78 to 1.135, wherein crystalline form B exhibits an X-ray powder diffraction pattern including peaks typical of the XRPD pattern shown in FIG. 5, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å. 1.137 Any of paragraphs 1.78 to 1.136, wherein crystalline form B exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes three peaks, and in some embodiment five peaks, selected from the peaks shown in FIG. 5. 1.138 Any of paragraphs 1.78 to 1.137, wherein crystalline form B exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. an XRPD measured using radiation of wavelength 1.541871 Å, which comprises at least 5 peaks, such as at least 9 peaks, for example at least 10 peaks, such as at least 15 peaks, for example at least 20 peaks, for example at least 25 peaks selected from the peaks shown in Figure 5. 1.139 Any of paragraphs 1.78 to 1.138, wherein crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG. 5, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å. 1.140 Any of paragraphs 1.78 to 1.139, wherein crystalline form B has an X-ray powder diffraction pattern as shown in FIG. 5, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å. 1.141 Crystalline form B exhibits an X-ray powder diffraction pattern including the characteristic peaks of the XRPD pattern shown in Figure 7, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 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 paragraphs 1.78 to 1.140. 1.142 Crystalline form B exhibits an X-ray powder diffraction pattern including peaks typical of the XRPD pattern shown in FIG. 7, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 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 paragraphs 1.78 to 1.141. 1.143 Any of paragraphs 1.78 to 1.142, wherein crystalline form B exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. an XRPD measured using radiation of wavelength 1.54059 Å, which comprises three peaks, in some embodiments five peaks selected from the peaks shown in FIG. 7, e.g. an XRPD pattern which also comprises peaks for crystalline form A (e.g. a mixture of crystalline forms A and B). 1.144 Crystalline form B exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å and comprises at least 5 peaks, such as at least 9 peaks, for example at least 10 peaks, such as at least 15 peaks, for example at least 20 peaks, for example at least 25 peaks selected from the peaks shown in Figure 7, e.g. the XRPD pattern comprises peaks for crystalline form A (e.g. a mixture of crystalline forms A and B), any of paragraphs 1.78 to 1.143. 1.145 Crystalline form B exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. an XRPD measured using radiation of wavelength 1.54059 Å, substantially as shown in FIG. 7, e.g. the XRPD pattern includes peaks for crystal form A (e.g. a mixture of crystal forms A and B), any of paragraphs 1.78 to 1.144. 1.146 Crystalline form B exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. an XRPD measured using radiation of wavelength 1.54059 Å and shown in FIG. 7, e.g. an XRPD pattern which includes peaks for crystal form A (e.g. a mixture of crystal forms A and B), any of paragraphs 1.78 to 1.145. 1.147 Any of paragraphs 1.78 to 1.146, wherein crystalline form B has an XRPD pattern including the 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, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.148 Any of paragraphs 1.78 to 1.147, wherein crystalline form B has an XRPD pattern including typical peaks of an XRPD pattern shown in any of Figures 7, 40 and 48, e.g., Figure 7, e.g., Figure 40, e.g., Figure 48, and wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.149 Any of paragraphs 1.78 to 1.148, wherein crystalline form B exhibits an XRPD pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. the XRPD is measured using radiation of a wavelength of 1.54059 Å, and comprises three peaks, in some embodiment five 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. 1.150 any of paragraphs 1.78 to 1.149, wherein crystalline form B exhibits an XRPD pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. the XRPD is measured using radiation of a wavelength of 1.54059 Å and comprises at least 5, such as at least 9, for example at least 10, such as at least 15, for example at least 20, for example at least 25 peaks selected from those shown in any of Figures 7, 40 and 48, e.g. Figure 7, e.g. Figure 40, e.g. Figure 48. 1.151 Crystalline form B has an XRPD pattern, e.g. a powder X-ray diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å, substantially as shown in any of Figures 7, 40 and 48, e.g. Figure 7, e.g. Figure 40, e.g. Figure 48, any of paragraphs 1.78 to 1.150. 1.152 any of paragraphs 1.1 to 1.151, wherein crystalline form B exhibits an X-ray powder diffraction (XRPD) pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å, and is shown in any of Figures 7, 40 and 48, e.g. Figure 7, e.g. Figure 40, e.g. Figure 48. 1.153 Any of paragraphs 1.78 to 1.152, wherein crystalline form B exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak between 247°C and 248°C. 1.154 Any of paragraphs 1.78 to 1.153, wherein crystalline form B exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 247°C. 1.155 Any of paragraphs 1.78 to 1.154, wherein crystalline form B exhibits a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak at 248°C, e.g., an endothermic peak at 248°C beginning at 246°C. 1.156 Any of paragraphs 1.78 to 1.155, wherein crystalline form B exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 251°C. 1.157 Any of paragraphs 1.78 to 1.156, wherein crystalline form B exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 264°C. 1.158 Any of paragraphs 1.78 to 1.157, wherein crystalline form B exhibits a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 141°C, e.g., an endothermic peak at 141°C starting from 137°C to 138°C, an endothermic peak at 141°C starting from 137°C, e.g., an endothermic peak at 141°C starting from 138°C. 1.159 Any of paragraphs 1.78 to 1.158, wherein crystalline form B exhibits the differential scanning calorimetry (DSC) thermogram shown in FIG. 1.160 Any of items 1.78 to 1.159, in which crystalline form B exhibits a thermogravimetric analysis (TGA) thermogram that includes a weight loss of 0.2% at or below 200°C. 1.161 Any of paragraphs 1.78 to 1.160, wherein crystalline form B exhibits a thermogravimetric analysis (TGA) thermogram that includes an onset decomposition temperature at 281°C. 1.162 Any of paragraphs 1.78 to 1.161, wherein crystalline form B exhibits the thermogravimetric analysis (TGA) thermogram shown in FIG. 8. 1.163 The hydrochloride addition salt form of the compound ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) in crystalline form C ("crystalline form C"). 1.164. Item 1.163, wherein crystalline form C exhibits an XRPD pattern comprising a 2θ(°) value of 17.7, and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.165. Crystalline form C exhibits an XRPD pattern having a characteristic 2θ(°) value of 17.7, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å, paragraph 1.163 or 1.164. 1.166 Any of paragraphs 1.163 to 1.165, wherein crystalline form C exhibits an XRPD pattern comprising a 2θ(°) value of 17.74, and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.167 Any of paragraphs 1.163 to 1.166, wherein crystalline form C exhibits an XRPD pattern having a characteristic 2θ(°) value of 17.74, and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.168 Crystalline form C is shown in Table G below: Table G [Table 7] Any of paragraphs 1.163 to 1.167, wherein the XRPD pattern comprises 2θ (°) values ​​of 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 ...1, 1.2, 1.3, 1.4, 1.5, 1.5, 1.6, 1.7, 1.8, 1.1, 1.1 1.169 Any of paragraphs 1.163 to 1.168, wherein crystalline form C exhibits an XRPD pattern having characteristic 2θ (°) values ​​as set forth in Table G of paragraph 1.168, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.170 Any of paragraphs 1.163 to 1.169, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as 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 wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.171 Any of paragraphs 1.163 to 1.170, wherein crystalline form C exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.172 Any of paragraphs 1.163 to 1.171, wherein crystalline form C exhibits an XRPD pattern having 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.173 Any of paragraphs 1.163 to 1.172, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as 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 wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.174 Any of paragraphs 1.163 to 1.173, wherein crystalline form C exhibits an XRPD pattern comprising 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.175 Any of paragraphs 1.163 to 1.174, wherein crystalline form C exhibits an XRPD pattern having 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 wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.176 Crystalline form C is listed in Table H below: Table H [Table 8] and the XRPD is measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.177 Any of paragraphs 1.163 to 1.176, wherein crystalline form C exhibits an XRPD pattern comprising 2θ(°) values ​​set forth in Table H of paragraph 1.176, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.178 Any of paragraphs 1.163 to 1.177, wherein crystalline form C exhibits an XRPD pattern having the typical 2θ(°) values ​​shown in Table H of paragraph 1.176, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.179 Any of paragraphs 1.163 to 1.178, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least ten, such as at least 11, such as at least 15, such as at least 20 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, wherein the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.180 Crystalline 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 and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.181 Crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least ten, such as at least eleven, such as at least fifteen, such as at least twenty, such as at least twenty-five 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 shows Cu lines, such as Cu Any of items 1.163 to 1.180, measured using an incident beam of Kα radiation, e.g., XRPD measured using radiation with a wavelength of 1.54059 Å. 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 and the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation having a wavelength of 1.54059 Å. 1.183 Crystalline form C is shown in Table I below: Table I [Table 9] and the XRPD is measured using an incident beam of Cu radiation, such as Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 1.184 Any of paragraphs 1.163 to 1.183, wherein crystalline form C exhibits an XRPD pattern comprising 2θ(°) values ​​set forth in Table I of paragraph 1.183, wherein the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.185 Any of paragraphs 1.163 to 1.184, in which crystalline form C exhibits an XRPD pattern containing a d-spacing (Å) value of 5.0. 1.186 Any of paragraphs 1.163 to 1.185, in which crystalline form C exhibits an XRPD pattern containing a d-spacing (Å) value of 4.99. 1.187 Any of paragraphs 1.163 to 1.186, in which crystalline form C exhibits an XRPD pattern containing a d-spacing (Å) value of 4.994. 1.188 Any of paragraphs 1.163 to 1.187, wherein crystalline form C exhibits an XRPD pattern containing the d-spacing (Å) values ​​in Table G of paragraph 1.168. 1.189 Any of paragraphs 1.163 to 1.188, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five d-spacing (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 paragraphs 1.163 to 1.189, wherein crystalline form C exhibits an XRPD pattern containing d-spacing (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 paragraphs 1.163 to 1.190, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least 10 d-spacing (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 paragraphs 1.163 to 1.191, wherein crystalline form C exhibits an XRPD pattern containing d-spacing (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 paragraphs 1.163 to 1.192, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least 10 d-spacing (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 paragraphs 1.163 to 1.193, wherein crystalline form C exhibits an XRPD pattern containing d-spacing (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 paragraphs 1.163 to 1.194, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least 10 d-spacing (Å) values ​​selected from those shown in Table H of paragraph 1.176. 1.196 Any of paragraphs 1.163 to 1.195, wherein crystalline form C exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table H of paragraph 1.176. 1.197 Any of paragraphs 1.163 to 1.196, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least ten, such as at least 11, such as at least 15 d-spacing (Å) values ​​selected from the group consisting 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. 1.198 Any of paragraphs 1.163 to 1.197, wherein crystalline form C exhibits an XRPD pattern comprising d-spacing (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 paragraphs 1.163 to 1.198, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, for example at least five, such as at least ten, for example at least eleven, such as at least fifteen, for example at least twenty, for example at least twenty-five d-spacing (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 terms 1.163 to 1.199, wherein crystalline form C exhibits an XRPD pattern including d-spacing (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 paragraphs 1.163 to 1.200, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least ten, for example at least eleven, such as at least fifteen, for example at least twenty, for example at least twenty-five d-spacing (Å) values ​​selected from the group consisting 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. 1.202 Any of paragraphs 1.163 to 1.201, wherein crystalline form C exhibits an XRPD pattern including d-spacing (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 Any of paragraphs 1.163 to 1.202, wherein crystalline form C exhibits an XRPD pattern comprising at least one, such as at least three, such as at least five, such as at least ten, such as at least 11, such as at least 15, such as at least 20, such as at least 25 d-spacing (Å) values ​​selected from those shown in Table I of paragraph 1.183. 1.204 Any of paragraphs 1.163 to 1.203 having an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table I of paragraph 1.183. 1.205 Any of paragraphs 1.163 to 1.204, wherein crystalline form C has an X-ray powder diffraction pattern including the characteristic peaks of the XRPD pattern shown in Figure 9, and the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å. 1.206 Any of paragraphs 1.163 to 1.205, wherein crystalline form C has an X-ray powder diffraction pattern including peaks typical of the XRPD pattern shown in FIG. 9, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation with a wavelength of 1.541871 Å. 1.207 Any of paragraphs 1.163 to 1.206, wherein crystalline form C exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes three peaks, and in some embodiment five peaks, selected from the peaks shown in FIG. 9. 1.208 Any of paragraphs 1.163 to 1.207, wherein crystalline form C exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.541871 Å and comprises at least one peak selected from the peaks shown in Figure 9, such as at least five peaks, for example at least 11 peaks, such as at least 15 peaks, for example at least 20 peaks, for example at least 25 peaks. 1.209 Any of paragraphs 1.163 to 1.208, wherein crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG. 9, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å. 1.210 Any of paragraphs 1.163 to 1.209, wherein crystalline form C has an X-ray powder diffraction pattern as shown in FIG. 9, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å. 1.211 Crystalline form C has an X-ray powder diffraction pattern including the characteristic peaks of the XRPD pattern shown in Figure 11, where the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å, e.g., the XRPD pattern also includes peaks of crystal form A (e.g., a mixture of crystal forms A and C), any of paragraphs 1.163 to 1.210. 1.212 Crystalline form C has an X-ray powder diffraction pattern including peaks typical of the XRPD pattern shown in FIG. 11, wherein the XRPD is measured using Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å, e.g., the XRPD pattern also includes peaks of crystal form A (e.g., a mixture of crystal forms A and C), any of paragraphs 1.163 to 1.211. 1.213 Any of paragraphs 1.163 to 1.212, wherein crystalline form C exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. an XRPD measured using radiation of wavelength 1.54059 Å, which comprises three peaks, in some embodiments five peaks selected from the peaks shown in FIG. 11, e.g. an XRPD pattern which also comprises peaks for crystalline form A (e.g. a mixture of crystalline forms A and C). 1.214 Any of paragraphs 1.163 to 1.213, wherein crystalline form C exhibits an X-ray powder diffraction pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. the XRPD comprises at least one peak, such as at least 5 peaks, such as at least 11 peaks, for example at least 15 peaks, such as at least 20 peaks, for example at least 25 peaks selected from the peaks shown in Figure 11 measured using radiation of wavelength 1.54059 Å, e.g. the XRPD pattern also comprises peaks of crystalline form A (e.g. a mixture of crystalline forms A and C). 1.215 Crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG. 11, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. the XRPD is measured using radiation of a wavelength of 1.54059 Å, e.g. the XRPD pattern also contains peaks for crystal form A (e.g. a mixture of crystal forms A and C), any of paragraphs 1.163 to 1.214. 1.216 Crystalline form C exhibits the powder X-ray diffraction pattern shown in FIG. 11, e.g. a powder X-ray diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high-resolution powder X-ray diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å, e.g. the XRPD pattern also contains peaks for crystal form A (e.g. a mixture of crystal forms A and C), any of paragraphs 1.163 to 1.215. 1.217 Any of paragraphs 1.163 to 1.216, wherein crystalline form C has an XRPD pattern including the characteristic peaks of the XRPD pattern shown in any of Figures 11 and 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 of a wavelength of 1.54059 Å. 1.218 Any of paragraphs 1.163 to 1.217, wherein crystalline form C has an XRPD pattern including peaks typical of the XRPD pattern shown in any of Figures 11 and 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 of wavelength 1.54059 Å. 1.219 Any of paragraphs 1.163 to 1.218, wherein crystalline form C exhibits an XRPD pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å, and comprises three peaks, in some embodiment five peaks selected from the peaks shown in any of Figures 11 and 43, e.g., Figure 11, e.g., Figure 43. 1.220 Any of paragraphs 1.163 to 1.219, wherein crystalline form C exhibits an XRPD pattern, e.g. an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. a high resolution X-ray powder diffraction pattern measured using an incident beam of Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å and comprises at least one peak, such as at least 5 peaks, for example at least 10 peaks, such as at least 11 peaks, for example at least 15 peaks, such as at least 20 peaks, for example at least 25 peaks, selected from the peaks shown in any of Figures 11 and 43, e.g. Figure 11, e.g. Figure 43. 1.221 Any of paragraphs 1.163 to 1.220, wherein crystalline form C has an XRPD pattern, e.g. a powder X-ray diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å, substantially as shown in any of Figures 11 and 43, e.g. Figure 11, e.g. Figure 43. 1.222 Crystalline form C has an XRPD pattern, e.g. a powder X-ray diffraction pattern measured using an incident beam of Cu radiation, e.g. Cu Kα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å, and is shown in any of Figures 11 and 43, e.g. Figure 11, e.g. Figure 43, any of paragraphs 1.163 to 1.221. 1.223 Any of paragraphs 1.163 to 1.222, wherein crystalline form C exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak between 247°C and 248°C, e.g., starting at 246°C, between 247°C and 248°C. 1.224 Any of paragraphs 1.163 to 1.223, wherein crystalline form C exhibits a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak at 247°C, e.g., an endothermic peak at 247°C beginning at 246°C. 1.225 Any of paragraphs 1.163 to 1.224, wherein crystalline form C exhibits a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak at 248°C, e.g., an endothermic peak at 248°C beginning at 246°C. 1.226 Any of paragraphs 1.163 to 1.225, wherein crystalline form C exhibits a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak at 122°C, e.g., an endothermic peak at 122°C beginning at 112°C. 1.227 Any of paragraphs 1.163 to 1.226, wherein crystalline form C exhibits a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at 271°C. 1.228 Any of paragraphs 1.163 to 1.227, wherein crystalline form C exhibits the differential scanning calorimetry (DSC) thermogram shown in FIG. 1.229 Any of items 1.163 to 1.228 in which crystalline form C exhibits a thermogravimetric analysis (TGA) that includes a weight loss of 1.3% at or below 200°C. 1.230 Any of paragraphs 1.163 to 1.229 in which crystalline form C exhibits a thermogravimetric analysis (TGA) thermogram with an onset decomposition temperature of 266°C. 1.231 Any of paragraphs 1.163 to 1.230, wherein crystalline form C exhibits the thermogravimetric analysis (TGA) thermogram shown in FIG. 1.232 A crystalline form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride prepared as described above and / or any of the Examples. 1.233 A crystalline form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride having the X-ray powder diffraction and / or X-ray crystal structure depicted in any of the figures. 1.234 Any of the crystalline forms of paragraphs 1.1 to 1.233, wherein the XRPD pattern is measured using a copper source, e.g., a copper anode. 1.235 Any of crystalline forms A to F, for example any of the combinations of items 1.1 to 1.234 and any of items 2.1 to 2.25, for example a combination of crystalline form A and crystalline form B; a combination of crystalline form A and crystalline form C; a combination of crystalline form A, crystalline form B and crystalline form C; a combination of crystalline form B and crystalline form C; a combination of crystalline form B and crystalline form D; a combination of crystalline form E and crystalline form F. 1.236 A crystalline form according to any of paragraphs 1.1 to 1.234, such as crystalline form A, such as any of paragraphs 1.1 to 1.77, such as crystalline form B, such as any of paragraphs 1.78 to 1.162, wherein the crystalline form is free or substantially free of any other form, for example having less than 20% by weight of amorphous matter, such as 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, most preferably less than 0.01% by weight. 1.237 A crystalline form according to any of paragraphs 1.1 to 1.234, such as crystalline form A, such as any of paragraphs 1.1 to 1.77, such as crystalline form B, such as any of paragraphs 1.78 to 1.162, wherein the crystalline form is free or substantially free of any other form, such as having less than 20% by weight, such as 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, most preferably less than 0.01% by weight of any other crystalline form. 1.238 A crystalline form according to any of paragraphs 1.1 to 1.234, such as crystalline form A, such as any of paragraphs 1.1 to 1.77, such as crystalline form B, such as any of paragraphs 1.78 to 1.162, wherein the crystalline form is free or substantially free of any other forms, such as having less than 20% by weight, such as 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, most preferably less than 0.01% by weight. 1.239 A crystalline form according to any of paragraphs 1.1 to 1.238, prepared by any of the methods described in paragraphs 4.1 to 4.20 or analogously to any of the Examples, or having the powder X-ray diffraction or X-ray crystal structure set forth in any of the Figures.

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

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

[0009] In a fourth aspect, the present invention provides a crystalline form as prepared or described in any Example or shown in any Figure, having an X-ray powder diffraction pattern, for example: 2.1 Crystal form D. 2.2 Section 2.1, wherein crystalline form D exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, which includes the characteristic peaks of the XRPD pattern shown in FIG. 15. 2.3 Sections 2.1 or 2.2, wherein crystalline form D exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å and includes typical peaks of the XRPD pattern shown in FIG. 15. 2.4 Any of paragraphs 2.1-2.3, wherein crystalline form D exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, comprising three peaks, and in some embodiments five peaks, selected from those shown in FIG. 15. 2.5 Any of paragraphs 2.1-2.4, wherein crystalline form D exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes 10 peaks, in some embodiments 20 peaks, and in some embodiments 25 peaks selected from those shown in FIG. 15. 2.6 Any of paragraphs 2.1 to 2.5, wherein crystalline form D has an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, substantially as shown in FIG. 15. 2.7 Any of sections 2.1 to 2.6, wherein crystalline form D exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, as shown in FIG. 15. 2.8 Any of paragraphs 2.1 to 2.7, wherein crystalline form D is the citrate salt of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. 2.9 Crystal form E. 2.10. Section 2.9, wherein crystalline form E exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes the characteristic peaks in the XRPD pattern shown in FIG. 16. 2.11 Sections 2.9 or 2.10, wherein crystalline form E exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å and includes typical peaks of the XRPD pattern shown in FIG. 16. 2.12 Any of paragraphs 2.9-2.11, wherein crystalline form E exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, comprising three peaks, and in some embodiments five peaks, selected from those shown in FIG. 16. 2.13 Any of sections 2.9-2.12, wherein crystalline form E exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes 10 peaks, in some embodiments 20 peaks, and in some embodiments 25 peaks selected from those shown in FIG. 16. 2.14 Any of paragraphs 2.9 to 2.13, wherein crystalline form E has an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, substantially as shown in FIG. 16. 2.15 Any of paragraphs 2.9 to 2.14, wherein crystalline form E exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, as shown in FIG. 16. 2.16 Any of paragraphs 2.9 to 2.15, wherein crystalline form E is the phosphate salt of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. 2.17 Crystal form F. 2.18. Section 2.17, wherein crystalline form F exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes the characteristic peaks in the XRPD pattern shown in FIG. 17. 2.19 Section 2.17 or 2.18, wherein crystalline form F exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., the XRPD is measured using radiation of wavelength 1.541871 Å and includes typical peaks of the XRPD pattern shown in Figure 17. 2.20 Any of paragraphs 2.17-2.19, wherein crystalline form F exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes three peaks, and in some embodiments five peaks, selected from those shown in FIG. 17. 2.21 Any of paragraphs 2.17-2.20, wherein crystalline form F exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, that includes 10 peaks, in some embodiments 20 peaks, and in some embodiments 25 peaks selected from those shown in FIG. 17. 2.22 Any of paragraphs 2.17 to 2.21, wherein crystalline form F exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, substantially as shown in FIG. 17. 2.23 Any of paragraphs 2.17 to 2.22, wherein crystalline form F exhibits an X-ray powder diffraction pattern, e.g., an X-ray powder diffraction pattern measured using an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., an XRPD measured using radiation of wavelength 1.541871 Å, and shown in FIG. 17. 2.24 Any of paragraphs 2.17 to 2.23, wherein crystalline form F is the phosphate salt of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. 2.25 Any of the crystalline forms of paragraphs 2.1 to 2.24, wherein the XRPD pattern is measured using a copper source, e.g., a copper anode. 2.26 Any of crystalline forms A to F, for example any combination of any of items 1.1 to 1.234 and any combination of items 2.1 to 2.25, for example a combination of crystalline form A and crystalline form B; a combination of crystalline form A and crystalline form C; a combination of crystalline form A, crystalline form B and crystalline form C; a combination of crystalline form B and crystalline form C; a combination of crystalline form B and crystalline form D; a combination of crystalline form E and crystalline form F. 2.27 A crystalline form according to any of paragraphs 2.1 to 2.25, wherein the crystalline form is free or substantially free of any other form, for example having less than 20% by weight amorphous form, such as 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, most preferably less than 0.01% by weight. 2.28 A crystalline form according to any of paragraphs 2.1 to 2.25, wherein the crystalline form is free or substantially free of any other form, for example having less than 20% by weight of any other crystalline form, such as 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, most preferably less than 0.01% by weight. 2.29 A crystalline form according to any of paragraphs 2.1 to 2.25, wherein the crystalline form is free or substantially free of any other forms, e.g. the amorphous form and any other crystalline form are 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, most preferably less than 0.01% by weight. 2.30 A crystalline form according to any of paragraphs 2.1 to 2.29, prepared by any of the methods described in paragraphs 4.1 to 4.20 or analogously to any of the Examples, or having the X-ray powder diffraction or X-ray crystal structure set forth in any of the Figures.

[0010] Phase transitions in solids can be thermodynamically reversible or irreversible. t ) are tautotropic polymorphs. If the crystalline forms cannot interconvert under these conditions, the system is monotropic (one thermodynamically stable form).

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

[0012] Kinetic constraints prevent the thermodynamic transformation of form A to form B. Surprisingly, form A therefore appears to be kinetically stable enough to persist in the solid state under thermodynamically metastable temperature conditions.

[0013] Stirring crystalline form A as a slurry in dichloromethane at ambient temperature for 16 days (see Example 6a) does not result in solvent-mediated form conversion to the more stable form at that temperature, crystalline form B. This indicates that in the absence of a seed of the more stable polymorph, the critical free energy barrier for nucleation cannot be overcome within the time frame evaluated.

[0014] Upon exposure to accelerated aging conditions for 2 weeks, forms A and B remain unchanged at 30°C / 56% RH or 40°C / 75% RH (Example 11). In contrast, form C transforms into a mixture of forms A and B within 2 weeks at 40°C / 75% RH (Example 11). Thus, unlike form A, form C transforms under metastable conditions.

[0015] For Form A, in the absence of the seed of the more stable polymorph, the critical free energy barrier for nucleation of Form B is not surmountable in solid-state or solvent-mediated transformation experiments within the time periods evaluated.

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

[0017] In a fifth aspect, the present invention provides: 3.1. A pharmaceutical composition comprising any of crystalline forms A to F according to any of paragraphs 1.1 to 1.239 or 2.1 to 2.30, such as crystalline form A, such as any of paragraphs 1.1 to 1.77, such as crystalline form B, such as any of paragraphs 1.78 to 1.162, and a pharma- ceutically acceptable diluent or carrier. 3.2. The pharmaceutical composition according to paragraph 3.1, wherein the composition is a sustained release composition. 3.3. Any of the crystalline forms A to F of the present invention, for example, any of the items 1.1 to 1.239, for example, crystalline form A, for example, any of the items 1.1 to 1.77, for example, crystalline form B, for example, any of the items 1.78 to 1.162, for example, any of the items 2.1 to 2.30, is administered in an amount of 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. The pharmaceutical composition according to Item 3.1 or 3.2, comprising: 3.4. The 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 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. The 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 of any of 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. The 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 250 mg, for example 250 mg to 500 mg of any of 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. The composition according to any of items 3.1 to 3.3 for administering 0.5 mg / kg to 20 mg / kg / day, such as 1 mg / kg to 15 mg / kg / day, such as 1 mg / kg to 10 mg / kg / day, such as 2 mg / kg to 20 mg / kg / day, such as 2 mg / kg to 10 mg / kg / day, such as 3 mg / kg to 15 mg / kg / day, of any of crystalline forms A to F of the present invention, such as any of items 1.1 to 1.239, such as crystalline form A, such as any of items 1.1 to 1.77, such as crystalline form B, such as any of items 1.78 to 1.162, such as any of items 2.1 to 2.30. 3.8. The composition according to any one of items 3.1 to 3.7, comprising less than 50% by weight of any one of crystalline forms A to F of the present invention, for example any one of items 1.1 to 1.239, for example crystalline form A, for example any one of items 1.1 to 1.77, for example crystalline form B, for example any one of items 1.78 to 1.162, for example any one 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. Any of the compositions of paragraphs 3.1 to 3.8, wherein the pharma- ceutically acceptable diluent or carrier comprises hydroxypropyl methylcellulose. 3.10. The composition of item 3.9, wherein the composition comprises at least 10% by weight, such as 10 to 50% by weight, such as 10 to 40% by weight, such as 20 to 50% by weight, such as 20 to 40% by weight, such as 30 to 40% by weight, such as 37% by weight of hydroxypropyl methylcellulose. 3.11. The composition of item 3.9 or 3.10, wherein the methoxy substitution degree of hydroxypropyl methylcellulose is 19 to 24%. 3.12. Any of the compositions according to items 3.9 to 3.11, wherein the hydroxypropoxy substitution degree of the hydroxypropyl methylcellulose is 4 to 12%. 3.13. Any of the compositions of paragraphs 3.9 to 3.12, wherein the hydroxypropyl methylcellulose is hypromellose 2208. 3.14. Any of the compositions of paragraphs 3.9 to 3.13, wherein the hydroxypropyl methylcellulose has a nominal viscosity of 4,000 mPA·σ. 3.15. Any of the compositions of paragraphs 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. Any of the compositions of paragraphs 3.9 to 3.15, wherein the pharma- ceutically acceptable diluent or carrier comprises alpha-lactose monohydrate. 3.17. The composition according to paragraph 3.16, wherein the composition comprises at least 10% by weight of alpha-lactose monohydrate, such as 10-80% by weight, for example 20-70% by weight, such as 20-60% by weight, for example 20-50% by weight, such as 20-40% by weight, for example 20-30% by weight, such as 30-70% by weight, for example 30-60% by weight, such as 30-50% by weight, for example 30-40% by weight, for example 37% by weight. 3.18. The composition of paragraph 3.16 or 3.17, wherein the composition comprises milled alpha-lactose monohydrate. 3.19. Any of the compositions of paragraphs 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 paragraph 3.19, wherein the mixture comprises equal amounts of hydroxypropyl methylcellulose and alpha-lactose monohydrate. 3.21. If the mixture has a d in the range of 100 μm to 200 μm, e.g. 125 μm 50 The composition of claim 3.19 or 3.20, comprising particles of hydroxypropyl methylcellulose and alpha-lactose monohydrate having a median diameter of 100 nm to 150 nm. 3.22. A mixture having particles of hydroxypropyl methylcellulose and alpha-lactose monohydrate with a particle size distribution of: <63μm≦25% <100μm: 35% <250μm≧80% The composition according to any one of items 3.19 to 3.21, wherein 3.23. Any of the compositions of paragraphs 3.19 to 3.22, wherein the composition comprises at least 20% by weight of the mixture, such as at least 30% by weight, for example at least 40% by weight, such as at least 50% by weight, for example at least 60% by weight, such as at least 70% by weight, for example at least 80% by weight, such as 20-90% by weight, for example 30-80% by weight, such as 40-80% by weight, for example 50-80% by weight, such as 60-80% by weight, for example 70-80% by weight, for example 75% by weight. 3.24. Any of the compositions of paragraphs 3.1 to 3.23, wherein the pharma- ceutically acceptable diluent or carrier comprises a lubricant, e.g., magnesium stearate. 3.25. The composition of paragraph 3.24, wherein the lubricant is one or more of glyceryl behenate, magnesium stearate, talc, and sodium stearyl fumarate, e.g., magnesium stearate. 3.26. The composition of paragraph 3.24 or 3.25, wherein the composition comprises less than 10% by weight of a lubricant, such as less than 5% by weight, less than 3% by weight, less than 1% by weight, such as 0.1 to 1% by weight, such as 0.1 to 0.8% by weight, for example 0.5% by weight. 3.27. The composition of any of paragraphs 3.24 to 3.26, wherein the composition contains less than 10% by weight of magnesium stearate, such as less than 5% by weight, less than 3% by weight, less than 1% by weight, such as 0.1 to 1% by weight, such as 0.1 to 0.8% by weight, for example 0.5% by weight. 3.28. The composition of any of paragraphs 3.1 to 3.27, wherein the pharma- ceutically acceptable diluent or carrier comprises one or more of a diluent, disintegrant, binder, and release modifier. 3.29. The composition of paragraph 3.28, wherein the diluent is one or more of mannitol (e.g., Pearlitol 300 DC), microcrystalline cellulose (e.g., Avicel pH 102), and pregelatinized starch (e.g., Starch 1500). 3.30. The composition of paragraph 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 paragraph 3.28, wherein the binder is a polyvinylpyrrolidone (e.g., Povidone K29 / 32). 3.32. The composition of paragraph 3.28, wherein the release modifier is one or more of hydroxypropylcellulose (e.g., Klucel EXF, Klucel MXF, and / or Klucel HXF) and hydroxypropylmethylcellulose (e.g., Methocel K100M, Methocel K4M PREM, Methocel K15M PREM CR). 3.33. The composition of paragraph 3.28 or 3.32, wherein the composition comprises at least 5% by weight of the release modifier, such as 5-60% by weight, such as 10-50% by weight, such as 10-40% by weight. 3.34. The composition of paragraphs 3.32 or 3.33, wherein the release modifier is hydroxypropyl methylcellulose. 3.35. A method for preventing or treating a disorder treatable by inhibiting the reuptake of a number of biogenic amines causally associated with a target central nervous system disorder and / or alleviating symptoms associated with any disorder, characterized in that a therapeutically effective amount of any of the crystalline forms A to F as described in any of sections 1.1 to 1.239, such as crystalline form A, such as any of sections 1.1 to 1.77, such as crystalline form B, such as any of sections 1.78 to 1.162, such as any of sections 2.1 to 2.30, or any of sections 3.1 to 3.34 is administered to a patient in need thereof, wherein the biogenic amines targeted for reuptake inhibition are selected from norepinephrine and / or serotonin and / or dopamine, in a particular embodiment, a method for preventing or treating any of the following disorders: (i) Attention Deficit Hyperactivity Disorder (ADHD, both children and adults) and related behavioral disorders, as well as forms and symptoms of alcohol abuse, drug abuse, obsessive-compulsive disorder, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, oppositional defiant disorder, conduct disorder, disruptive behavior disorders, academic problems at school, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression (such as, but not limited to, major depressive disorder, recurrent; dysthymic disorder; depressive disorder not otherwise specified (NOS); major depressive disorder, single episode; 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 tics (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 phobia), autism, traumatic brain injury, cognitive impairment, schizophrenia (particularly regarding cognition), obesity, chronic pain disorder, personality disorder 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 (such as, but not limited to, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-related disorders, inhalant-related disorders, and opioid-related disorders); (v) cognitive disorders, 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), incontinence (i.e. stress 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, Hallucinogen Use Disorders, Inhalant-Related Disorders, and Opioid-Related Disorders); (vii) fragile X syndrome-related disorders; (viii) Autism spectrum disorder (ASD), e.g., in individuals with fragile X syndrome-related disorders; (ix) ADHD in patients with fragile X syndrome-related disorders; (x) comorbidity of ADHD and depression; (xi) comorbidity of ADHD and substance abuse; (xii) comorbidity of ADHD and anxiety disorders. 3.36. A pharmaceutical composition according to any of sections 3.1 to 3.34 for use as a medicament, for example for use in the manufacture of a medicament for the treatment or prevention of any of the disorders according to section 3.35. 3.37. Crystalline form A to F according to any of paragraphs 1.1 to 1.239, such as crystal form A, for example any of paragraphs 1.1 to 1.77, such as crystal form B, for example any of paragraphs 1.78 to 1.162, such as any of paragraphs 2.1 to 2.30, for use in the prevention or treatment of any of the disorders according to paragraph 3.35 or for use in the manufacture of a medicament for the treatment or prevention of any of the disorders according to paragraph 3.35.

[0018] In a sixth aspect, the present invention provides a crystalline form according to any of paragraphs 1.1 to 1.239 or any of paragraphs 2.1 to 2.30, prepared by any of the methods described below or methods similar thereto: 4.1 Add water to the hydrochloric acid addition salt form of the compound ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride); Heat to dissolve all solids, e.g., to an internal temperature of 30-40°C, e.g., 34°C; adding an organic solvent, such as tetrahydrofuran and / or isopropyl acetate; Separate the aqueous layer; Add a base, e.g. aqueous ammonia, to the aqueous layer; Add an organic solvent, such as isopropyl acetate; Stir for at least 15 minutes; Allow the layers to settle, e.g., for at least 30 minutes; Separate the organic layer; The organic layer is dried, for example with magnesium sulfate; Filter; Washing the filter cake with an organic solvent, such as isopropyl acetate; Concentrate the filtrate and washings; Add isopropyl alcohol; Stir at room temperature to dissolve all solids; Add hydrochloric acid, e.g., HCl / isopropanol, to form a solid, e.g., add HCl over 10 minutes, e.g., add HCl / isopropanol over 10 minutes; adding more hydrochloric acid, e.g. HCl / isopropanol, e.g. adding more HCl over 55 minutes, e.g. adding HCl / isopropanol over 55 minutes; Agitating the slurry, e.g., agitating the slurry for 35 minutes; adding more hydrochloric acid, e.g. HCl / isopropanol, e.g. adding more HCl over 10 minutes, e.g. adding more HCl / isopropanol over 10 minutes; Agitating the slurry, e.g., agitating the slurry for 30 minutes; Filter; Washing the filter cake with an organic solvent, e.g., isopropyl alcohol; The filter cake is dried. 4.2 Storing crystalline form A at 40°C / 75%RH, for example storing crystalline form A at 40°C / 75%RH for 7 days; The crystals are isolated. 4.3 Preparing a solution of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, in, e.g., chloroform, dichloromethane, hexafluoroisopropyl alcohol, methanol and / or 2,2,2-trifluoroethanol (TFE); Sonicate; Complete dissolution is achieved as determined by visual observation; Filter; Allow the solvent to evaporate at ambient conditions, e.g. in a container covered with aluminum foil with small holes; The crystals are isolated. 4.4 Preparing a solution of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, e.g., in chloroform, dichloromethane, ethanol and / or methanol; Filter; Mixing with a poor solvent, such as toluene, heptane, acetonitrile, methyl ethyl ketone, acetone, hexane, tetrahydrofuran, dioxane, ethyl acetate and / or isopropyl ether; The crystals are isolated. 4.5 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, is exposed to steam, e.g., steam of an organic solvent, e.g., steam of dichloromethane and / or ethanol; The crystals are isolated. 4.6 Preparing a suspension of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, in, e.g., dichloromethane, ethanol, isopropyl alcohol, 1-propanol and / or water; Stir at room temperature or elevated temperature; The crystals are isolated, for example, by vacuum filtration. 4.7 A solution of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, in an organic solvent, e.g., dichloromethane, ethanol, isopropyl alcohol, and / or 1-propanol, is prepared at an elevated temperature; Filter through, for example, a 0.2 μm nylon filter into a warmed container; Cool; If appropriate, further cool by placing in a refrigerator and / or freezer; The crystals are isolated. 4.8 A solution of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, in an organic solvent, e.g., dichloromethane, ethanol, isopropyl alcohol, and / or 1-propanol, is prepared at an elevated temperature; Filter, for example through a 0.2 μm nylon filter, into a chilled container; Cool below 0°C, e.g. by placing in a -78°C bath, e.g. an isopropyl alcohol / dry ice bath; If appropriate, further cool by placing in a freezer; The crystals are isolated. 4.9 Preparing a solution of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, in an organic solvent, e.g., ethanol, isopropyl alcohol, methanol, acetone, toluene, 1-propanol, water and / or dioxane; Sonicate; Complete dissolution is achieved as determined by visual observation; For example, filtered through a 0.2 μm nylon filter; Evaporate the solvent at room temperature; The crystals are isolated. 4.10 Preparing a solution or suspension of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, in an organic solvent, e.g., dichloromethane, ethanol, isopropyl alcohol and / or 1-propanol; Cooling, e.g. in a freezer; The crystals are isolated. 4.11 Preparing a solution or suspension of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, e.g., crystalline form A, in an organic solvent, e.g., hexafluoroisopropyl alcohol and / or 2,2,2-trifluoroethanol; For example, filtered through a 0.2 μm nylon filter; Precipitation by adding a poor solvent, such as an organic poor solvent, such as isopropyl ether, tetrahydrofuran, acetonitrile, ethyl acetate and / or methyl ethyl ketone; The crystals are isolated, for example by vacuum filtration. 4.12 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is dissolved in an organic solvent, such as isopropanol; Add HCl, e.g. HCl / isopropanol; Filter appropriately. 4.13 Add crystals of the desired form to the solution or slurry, e.g., add crystalline form A to the solution or slurry, e.g., while the temperature of the solution or slurry is above room temperature, e.g., at 65°C. 4.14 Dissolving (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in an organic solvent, e.g., ethanol, with heating, e.g., to 70°C; Optionally, filter, for example with a capsule carbon filter; Concentrate as appropriate, for example to 5 total volumes (relative to the (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride added); Reheat as needed to redissolve solids; Cool as appropriate, for example to 65°C; Seed the solution; Grow the seed bed with adequate stirring; Cool appropriately; Filter appropriately. 4.15 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride is dissolved in water, e.g., by heating, e.g., to an internal temperature of 30-40°C, e.g., 34°C; Washing the aqueous solution; adding a base, e.g. ammonia; (1R,5S)-1-(naphthalen-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 accordingly to obtain a solid; Optionally, an organic solvent, such as isopropanol, is added to dissolve the solids; Add HCl, e.g. HCl / isopropanol; Filter accordingly; If appropriate, washing is performed with an organic solvent, such as isopropanol. 4.16 Dissolving (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in an organic solvent, e.g., ethanol, by heating, e.g., to 70°C; Optionally, filter, for example with a capsule carbon filter; Concentrate, for example, to a total of 5 volumes (relative to the (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride added); Seed before or after concentration as appropriate; Filter appropriately. 4.17 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is dissolved in an organic solvent; Add HCl, e.g. HCl / isopropanol; Filter appropriately. 4.18 A method according to any of paragraphs 4.1 to 4.17 comprising isolating a crystalline form, such as any of paragraphs 1.1 to 1.239 or 2.1 to 2.30, such as crystalline form A, such as any of paragraphs 1.1 to 1.77, such as crystalline form B, such as any of paragraphs 1.78 to 1.162. 4.19 A crystalline form according to any of paragraphs 1.1 to 1.239 or 2.1 to 2.30, prepared according to any of Examples 1 to 3, e.g., Example 1. 4.20 A crystalline form according to any of paragraphs 1.1 to 1.239 or 2.1 to 2.30, prepared by any of the synthetic methods described in an Example, such as Example 1, such as Example 3, such as any of Examples 6 to 13, such as Example 17, such as Example 18.

[0019] In a seventh aspect, the present invention provides a process for preparing crystalline form A to F according to any of sections 1.1 to 1.239 or 2.1 to 2.30, such as crystalline form A, such as any of sections 1.1 to 1.77, such as crystalline form B, such as any of sections 1.78 to 1.162, by the method described in any of sections 4.1 to 4.20 or the Examples.

[0020] In an eighth aspect, the present invention provides a method for producing a pharmaceutical composition comprising any of crystalline forms A to F according to any of items 1.1 to 1.239 or 2.1 to 2.30, such as crystalline form A, such as any of items 1.1 to 1.77, such as crystalline form B, such as any of items 1.78 to 1.162, such as a pharmaceutical composition according to any of items 3.1 to 3.34, comprising the steps of: isolating any of crystalline forms A to F according to any of sections 1.1 to 1.239 or 2.1 to 2.30, such as crystalline form A, such as any of sections 1.1 to 1.77, such as crystalline form B, such as any of sections 1.78 to 1.162; and mixing the isolated crystalline form with a pharma- ceutically acceptable diluent or carrier; The present invention provides a method comprising: [Brief description of the drawings]

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

[0022] [Diagram 2] FIG. 2 shows the DSC and TGA thermograms of crystalline form A.

[0023] [Diagram 3] FIG. 3 shows the dynamic vapor sorption / desorption isotherm of crystalline form A.

[0024] [Figure 4] FIG. 4 shows an overlay of X-ray powder diffraction (XRPD) patterns of crystalline form A, crystalline form B and crystalline form C (top to bottom): FIG. 4A shows the high resolution X-ray powder diffraction pattern of crystalline form A, FIG. 4B shows the X-ray powder diffraction pattern of crystalline form B, and FIG. 4C shows the X-ray powder diffraction pattern of crystalline form C.

[0025] [Diagram 5] FIG. 5 shows the X-ray powder diffraction (XRPD) pattern of crystalline form B.

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

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

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

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

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

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

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

[0033] [Figure 13] FIG. 13 shows an overlay of powder X-ray diffraction (XRPD) patterns of form A, form B and form C (top to bottom): FIG. 13A shows the powder X-ray diffraction pattern of form B (slow cooling in IPA, solid precipitate in refrigerator); FIG. 13B shows the powder X-ray diffraction pattern of form C + form B (slow cooling in IPA with seed crystals, solid precipitate in freezer); FIG. 13C shows the powder X-ray diffraction pattern of form C + form A (slow cooling in IPA, solid precipitate in freezer); FIG. 13D shows the powder X-ray diffraction pattern of form B (slow cooling in IPA, solid precipitate in freezer); and FIG. 13E shows the powder X-ray diffraction pattern of form B + form A (crash-cooled in IPA, solid precipitate in dry ice / IPA). FIG. 13F shows the powder X-ray diffraction pattern of Form A+Form C (slow cooling in IPA, solid precipitate in freezer), and FIG. 13G shows the powder X-ray diffraction pattern of Form C (slow cooling in IPA).

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

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

[0036] [Figure 16] FIG. 16 shows the X-ray powder diffraction (XRPD) pattern of Form E (including peaks for Form F).

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

[0038] [Figure 18] Figure 18 shows the ORTEP diagram of crystalline form A. Atoms are shown as 50% probability anisotropic thermal ellipsoids.

[0039] [Figure 19] FIG. 19 shows the packing diagram of Form A looking down the a-axis of the crystal.

[0040] [Figure 20] FIG. 20 shows the packing diagram of Form A viewed down the b-axis of the crystal.

[0041] [Figure 21] FIG. 21 shows the packing diagram of Form A viewed down the c-axis of the crystal.

[0042] [Figure 22] FIG. 22 shows the hydrogen bonds in crystalline form A.

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

[0044] [Figure 24] FIG. 24 shows an atomic displacement ellipsoid diagram for crystalline form B (atoms are shown with 50% probability anisotropic thermal ellipsoids).

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

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

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

[0048] [Figure 28] FIG. 28 shows the hydrogen bonds in the structure of crystalline form B.

[0049] [Figure 29] FIG. 29 shows the molecular conformation of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, which is the structure of crystalline forms A and B (left: (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, which is the structure of crystalline form A; right: (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, which is the structure of crystalline form B).

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

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

[0052] [Diagram 32] FIG. 32 shows the calculated powder X-ray pattern of crystalline form B.

[0053] [Diagram 33] FIG. 33 shows the experimental and calculated XRPD patterns of crystalline form B (Top: experimental XRPD pattern at room temperature; Middle: calculated XRPD pattern adjusted to room temperature; Bottom: calculated XRPD pattern at 100K).

[0054] [Diagram 34] FIG. 34 shows the experimental and calculated XRPD patterns of crystalline form A (top: calculated XRPD pattern; bottom: experimental XRPD pattern at room temperature).

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

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

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

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

[0059] [Figure 39] FIG. 39 shows the observed peaks for the XRPD pattern shown in FIG. 37 collected with Cu Kα radiation.

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

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

[0062] [Diagram 42] FIG. 42 shows the observed peaks for the XRPD pattern shown in FIG. 40 collected with Cu Kα radiation.

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

[0064] [Diagram 44]FIG. 44 shows the indexing results of the XRPD pattern shown in FIG. 43 collected with Cu Kα radiation.

[0065] [Diagram 45] FIG. 45 shows the observed peaks for the XRPD pattern shown in FIG. 43 collected with Cu Kα radiation.

[0066] [Figure 46] FIG. 46 shows the proposed energy-temperature plots of crystalline forms A, B and C.

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

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

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

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

[0071] [Figure 51] 51-54 show the XRPD pattern of the disordered crystalline form A. [Figure 52] 51-54 show the XRPD pattern of the disordered crystalline form A. [Figure 53] 51-54 show the XRPD pattern of the disordered crystalline form A. [Figure 54] 51-54 show the XRPD pattern of the disordered crystalline form A.

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

[0073] [Figure 56] FIG. 56 shows the XRPD pattern of a mixture of crystalline forms A and B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] As used herein, the term "the compound" refers to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. The term "the hydrochloride addition salt form of the compound" refers to the compound having the following structure: [ka] This refers to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride or (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, The compound is free or substantially free of the corresponding (-)-enantiomer, for example it contains not more than 20% by weight of the corresponding (-) enantiomer in free form or in a pharma- ceutically acceptable salt form, for example it contains not more than 10% by weight of the corresponding (-) enantiomer in free form or in a pharma- ceutically acceptable salt form, for example it contains not more than 5% by weight of the corresponding (-) enantiomer in free form or in a pharma- ceutically acceptable salt form, for example it contains not more than 2% by weight of the corresponding (-) enantiomer in free form or in a pharma- ceutically acceptable salt form, for example it contains not more than 1% by weight of the corresponding (-) enantiomer in free form or in a pharma- ceutically acceptable salt form.

[0075] "Form A" refers to a crystalline form of the hydrochloride addition salt of the Compound as described in any one of Sections 1.1 to 1.77 or as characterized in the relevant part of the Examples below.

[0076] "Crystalline Form B" refers to the crystalline form of the hydrochloride addition salt of the Compound as described in any one of Sections 1.78 to 1.162 or as characterized in the relevant part of the Examples below.

[0077] "Crystalline Form C" refers to the crystalline form of the hydrochloride addition salt of the Compound as described in any one of Sections 1.163-1.231 or as characterized in the relevant part of the Examples below.

[0078] "Form D" refers to the crystalline form described in any of Sections 2.1 to 2.8 or characterized in the relevant part of the Examples below.

[0079] "Form E" refers to the crystalline form described in any of Sections 2.9 to 2.16 or characterized in the relevant part of the Examples below.

[0080] "Form F" refers to the crystalline form described in any one of Sections 2.17 to 2.24 or characterized in the relevant part of the Examples below.

[0081] The present invention claims crystalline forms A to F and combinations thereof as described herein, for example in any of Sections 1.1 to 1.239 or any of Sections 2.1 to 2.30. These crystalline forms can be prepared and characterized as described in the Examples section below. Thus, the present invention provides any of crystalline forms A to F as described in any of Sections 1.1 to 1.239 or any of Sections 2.1 to 2.30 or as characterized in the Examples section below.

[0082] The term "substantially free" of other crystalline forms refers to less than 10% by weight, in some embodiments less than 5% by weight, in some embodiments less than 2% by weight, in some embodiments less than 1% by weight, in some embodiments less than 0.1% by weight, and in some embodiments less than 0.01% by weight of other forms or crystalline forms, such as amorphous or other crystalline forms.

[0083] The term "solvate" refers to a crystalline solid adduct that includes a stoichiometric or non-stoichiometric amount of a solvent within the crystal structure. Thus, the term "non-solvate" form herein refers to a crystalline form of the present invention that is free or substantially free of solvent molecules within the crystal structure. Similarly, the term "non-hydrate" form herein refers to a salt crystal of the present invention that is free or substantially free of water molecules within the crystal structure.

[0084] The term "amorphous" refers to a solid with a disordered arrangement of molecules and lacking a discernible crystal lattice.

[0085] The term "patient" includes humans and non-humans. In some embodiments, the patient is a human. In other embodiments, the patient is a 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-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) is poorly 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, such as 10 to 30 mg / ml, such as 1 to 10 mg / ml, such as less than 1 mg / ml.

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

[0088] It will be understood that the powder X-ray diffraction pattern of a given sample may vary (standard deviation) depending on the instrument used, the time and temperature when the sample is measured, and standard experimental error. Thus, the 2θ values, d-spacing values, heights, and relative intensities of the peaks 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 (°) values ​​or d-spacing values ​​(Å) of the XRPD pattern of the crystalline forms of the invention may have acceptable deviations of ±0.2 degrees and / or ±0.2 Å. Furthermore, the XRPD pattern of the crystalline forms of the invention may be identified by characteristic peaks that are recognized by those of skill in the art. For example, the crystalline forms of the invention may be identified by, for example, two characteristic peaks, in some cases three characteristic peaks, and in other cases five characteristic peaks. Thus, the term "substantially" as shown in a particular table or as shown in a particular drawing refers to any crystal having an XRPD with the main or characteristic peaks shown in that table / drawing as recognized by those of skill in the art.

[0089] It will be understood that the differential scanning calorimetry or thermogravimetry thermogram of a given sample may vary depending on the equipment used, the time and temperature at which the sample is measured, and standard experimental error (standard deviation). The temperature values ​​themselves may vary by ±10°C, preferably ±5°C, preferably ±3°C of the reference temperature.

[0090] For XRPD, peaks are selected in most cases within a range of up to about 30° 2θ. A rounding algorithm is used to round each peak to the nearest 0.1° or 0.01° 2θ depending on the instrument used to collect the data and / or the inherent peak resolution. Variability in peak positions is allowed within ±0.2° 2θ.

[0091] The wavelengths used to calculate the d-spacing (Å) values ​​herein are 1.5405929 Å, Cu-K α1 is the wavelength (Phys. Rev., A56 (6), 4554-4568 (1997)).

[0092] Per US Pharmacopeia guidelines, variable hydrate and solvate peaks may differ by more than ±0.2° 2θ.

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

[0094] When multiple diffraction patterns are obtained, particle statistics (PS) and / or preferred orientation (PO) can be assessed. Reproducibility between XRPD patterns of multiple samples analyzed on one diffractometer indicates good particle statistics. Agreement of relative intensities between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, observed XRPD patterns may be compared to calculated XRPD patterns based on single crystal structures, if available. Two-dimensional scattering patterns using an area detector may also be used to assess PS / PO. If the contributions of PS and PO are determined to be negligible, the XRPD pattern is representative of the powder average intensities for that sample, and prominent peaks may be identified as "typical peaks". In general, the more data collected to determine typical peaks, the more confidently such peaks can be classified.

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

[0096] It has been observed that in the reaction to prepare crystalline form A, crystalline form B may also be formed. However, the synthesis of the product may be controlled, for example by seeding with crystalline form A.

[0097] As described herein, crystalline forms A-F, e.g., sections 1.1-1.239, e.g., sections 2.1-2.30, and combinations thereof, are useful as unbalanced triple reuptake inhibitors (TRIs), being most effective against norepinephrine (NE) reuptake, six times less effective against dopamine (DA) reuptake, and about fourteen times less effective against serotonin (5-HT) reuptake. Thus, as described herein, crystalline forms A-F, e.g., sections 1.1-1.239, e.g., sections 2.1-2.30, and combinations thereof, are useful for preventing or treating disorders treatable by inhibiting the reuptake of multiple biogenic amines causally associated with a target central nervous system disorder and / or alleviating symptoms associated with any disorder, wherein the biogenic amines targeted for reuptake inhibition are 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 to a patient in need thereof a therapeutically effective amount of any of crystalline forms A to F as described in any of paragraphs 1.1 to 1.239, such as crystalline form A, such as any of paragraphs 1.1 to 1.77, such as crystalline form B, such as any of paragraphs 1.78 to 1.162, such as any of paragraphs 2.1 to 2.30: Attention Deficit Hyperactivity Disorder (ADHD) and related behavioral disorders, as well as types and symptoms of substance abuse (alcohol abuse, drug abuse), obsessive-compulsive behavior, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, oppositional attitudes, conduct disorders, academic problems in school, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression, sleep disorders, generalized anxiety disorder, stuttering, and tic disorders. Additional disorders are disclosed in U.S. Patent Application Publication No. 2007 / 0082940, the contents of which are incorporated herein by reference in their entirety; Depression, anxiety, autism, traumatic brain injury, cognitive disorders and schizophrenia (especially cognitive disorders), 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 disorders, Parkinson's disease; Diseases disclosed in International Publication No. WO2013 / 019271, the contents of which are incorporated herein by reference in their entirety; · Fragile X syndrome-related disorders; Fragile X syndrome-related disorder in which the patient has failed a prior Fragile X syndrome-related disorder treatment; · Attention-deficit / hyperactivity disorder (ADHD), which is comorbid with anxiety and / or depression (e.g., depression) in patients with fragile X syndrome-related disorders; · Autism Spectrum Disorder (ASD); Disorders disclosed in International Application No. PCT / US2014 / 069401, the contents of which are incorporated herein by reference in their entirety.

[0098] Disorders contemplated for treatment with the crystalline forms of the invention described herein include those described in the Quick Reference to Diagnostic Criteria of DSM-IV (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 Type; Attention Deficit / Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type; Attention Deficit / Hyperactivity Disorder, Combined Type; Attention Deficit / Hyperactivity Disorder Not Otherwise Specified (NOS); Conduct Disorder; Oppositional Defiant Disorder; and Disruptive Behavior Disorder Not Otherwise Specified (NOS).

[0099] 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; depressive disorder not otherwise specified (NOS); and major depressive disorder, single episode.

[0100] Addiction disorders suitable for treatment and / or prevention using the methods and compositions of the 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, hallucinogen use disorders, inhalant-related disorders, and opioid-related disorders.

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

[0102] As used herein, a "therapeutically effective amount" refers to an amount effective to provide a therapeutic benefit, such as alleviation of symptoms, when administered to a human or non-human. The specific dose of an agent administered to provide a therapeutic benefit will, of course, be determined by the particular circumstances, including, for example, the specific agent administered, the route of administration, the condition being treated, and the individual being treated.

[0103] The dosage of the present disclosure or the method of administration of said dosage is not particularly limited. The dosage used in carrying out the present disclosure will of course vary depending, for example, on the form of administration and the desired therapy. In general, it has been shown that satisfactory results can be obtained with oral administration at dosages of the order of about 0.01-2.0 mg / kg. The daily dosage indicated for oral administration ranges from about 0.75 mg to 200 mg, suitably administered once or in 2-4 divided doses per day, or in sustained release form. Thus, a unit dosage form for oral administration 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 of crystalline forms A to F or a combination thereof, preferably crystalline 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, sustained release pharmaceutical compositions, e.g. sustained release oral pharmaceutical compositions, comprising any of the crystalline forms of the present invention, e.g. crystalline form A, e.g. any of sections 1.1-1.77, are 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, immediate release pharmaceutical compositions, e.g. immediate release oral pharmaceutical compositions, comprising any of the crystalline forms of the present invention, e.g. crystalline form A, e.g. any of sections 1.1-1.77, are provided.

[0105] Further dosages and formulations are provided in International Application No. PCT / US2014 / 069401 and International Application No. PCT / US2014 / 069416, the contents of each of which are incorporated herein by reference in their entireties.

[0106] The hydrochloride acid addition salt form of (1R,5S)-1-(naphthalen-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 reference in their entireties.

[0107] Both U.S. Patent Publication No. 2007 / 0082940 and International Publication No. WO2013 / 019271 describe the synthesis of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, but no specific crystalline form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride is discussed.

[0108] The following sections illustrate methods for preparing and characterizing crystalline forms A-F of the present invention, using both thermodynamic and kinetic crystallization techniques. These techniques are described in more detail below.

[0109] Anti-solvent precipitation: Solutions are prepared in various solvents and filtered through a 0.2 μm nylon filter into a vial. Anti-solvent is then added until precipitation is observed. The resulting solids are isolated by vacuum filtration and analyzed.

[0110] Crash-cool (CC): Solutions are prepared in various solvents at elevated temperatures and hot filtered through 0.2 μm nylon filters into pre-chilled vials. The vials are placed in a (dry ice + isopropanol) cooling bath. If no immediate precipitation of solids is observed, the samples are placed in a freezer. The resulting solids are isolated by vacuum filtration and analyzed.

[0111] First Evaporation (FE): Solutions are prepared in various solvents and sonicated after each addition in portions to aid dissolution. As soon as dissolution of the mixture is complete as judged by visual observation, filter the solutions through a 0.2 μm nylon filter. Allow the filtered solutions to evaporate at ambient conditions in open vials. If not specified as partial evaporation, evaporate the solutions to dryness. Isolate and analyze any solids that form.

[0112] Freeze-drying (lyophilization): Solutions are prepared in 1:1 dioxane:water or water, filtered through a 0.2 μm nylon filter, and frozen in a vial or flask immersed in a bath of dry ice and isopropanol. The vial or flask containing the frozen sample is placed in a Flexi-Dry freeze dryer and allowed to dry for a period of time. After drying, the solid is isolated and stored in a freezer with desiccant until use.

[0113] Grinding: The solid sample is placed in a stainless steel grinding jar equipped with grinding balls. The sample is then ground in a ball mill (Retsch Mixer Mill model MM200) at 30 Hz for a period of time. The solid is collected and analyzed.

[0114] Relative Humidity Stress: Solids are stored under controlled conditions by placing them in vials in a capped temperature / humidity chamber for a period of time at approximately 40°C / 75% RH conditions. Samples are analyzed after removal from the stressed environment.

[0115] Rotary Evaporation: A solution of the hydrochloride addition salt form of the compound ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) in HFIPA is prepared. The solid is obtained by rotary evaporation of the solvent under vacuum while the sample vial is immersed in a heated water bath at approximately 40°C. The solid is then further dried under vacuum at ambient temperature for approximately 10 minutes. After evaporation, the solid is stored in a freezer with desiccant until use.

[0116] Slow Cooling (SC): Solutions are prepared in various solvents at elevated temperatures. The solutions are hot filtered through 0.2 μm nylon filters into warmed vials. The vials are capped and placed on a hot plate, the hot plate is turned off and the samples are allowed to cool slowly to ambient temperature. If no solids are present upon cooling to ambient temperature, the samples are placed in a refrigerator and / or freezer for further cooling. Solids are collected by vacuum filtration and analyzed.

[0117] Slow Evaporation (SE): Solutions are prepared in various solvents and sonicated to aid dissolution. Once the mixture is completely dissolved as judged by visual observation, the solutions are filtered through a 0.2 μm nylon filter. The filtered solutions are evaporated at ambient temperature in vials covered with aluminum foil with small holes punctured. If not specified as partial evaporation, the solutions are evaporated to dryness. The solids that form are isolated and analyzed.

[0118] Slurry method: Enough solids are added to a given solvent so that there is excess solids to create a suspension. The mixture is then stirred in a capped vial at ambient or elevated temperature. After a period of time, the solids are isolated by vacuum filtration and analyzed.

[0119] Vapor Diffusion (VD): Solutions are prepared in various solvents and filtered through 0.2 μm nylon filters. The filtered solutions are distributed into 1-dram vials, which are then placed into 20 mL vials containing antisolvent. The 1-dram vials are left uncapped, while the 20 mL vials are capped and allowed to vapor diffuse. The resulting solids are isolated and analyzed.

[0120] Vapor Stress (VS): A solid sample is placed in a 1-dram vial. The 1-dram vial is then placed in a 20 mL vial containing a solvent. The 20 mL vial is capped and placed in an ambient environment for a period of time. The sample is analyzed after removal from the stress environment.

[0121] XRPD Overlays: Overlays of XRPD patterns are generated using Pattern Match 2.3.6.

[0122] XRPD Indexing: High resolution XRPD patterns of the crystalline forms of the invention are indexed using X'Pert High Score Plus (X'Pert High Score Plus 2.2a (2.2.1)) or proprietary software. Indexing and structure refinement are computational.

[0123] Instrumental Techniques: 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. Samples are placed in aluminum DSC pans, covered with lids, and weights are accurately recorded. A pre-weighed aluminum pan, designated as the sample pan, is placed on the reference side of the cell. Data acquisition parameters and pan configuration are displayed on each thermogram image. Method codes on the thermograms are abbreviations for start and end temperatures and heating rates, e.g. -30-250-10 means "-30°C to 250°C, 10°C / min". The following table summarizes the abbreviations used in each image for pan configuration: Abbreviation Meaning T0C Tzero Crimp Pan HS lid is hermetically sealed The HSLP lid is hermetically sealed and a hole is made with a laser pinhole. It is open C The lid is crimped NC Lid not crimped

[0125] Thermogravimetric Analysis (TGA): TG analysis is performed using a TA Instruments Thermogravimetric Analyzer. Temperature calibration is performed using nickel and Alumel™. Each sample is placed in an aluminum pan. The sample is sealed and the lid is pierced before being inserted into the TG furnace. The furnace is heated under nitrogen. Data acquisition parameters are displayed on the image of each thermogram. Method codes on the thermograms are abbreviations for the start and end temperatures and heating rate, e.g., 25-350-10 means "25°C to 350°C, 10°C / min."

[0126] X-ray Powder Diffraction (XRPD): Inel XRG-300. X-ray powder diffraction analysis is performed on an Inel XRG-3000 diffractometer equipped with a curved position sensitive detector with a 2θ range of 120°. Real-time data is collected using Cu Kα radiation at a resolution of 0.03° 2θ. Tube voltage and current are set at 40 kV and 30 mA, respectively. Patterns are displayed from 2.5 to 40° 2θ to facilitate direct pattern comparison. Samples are prepared for analysis by packing into thin-walled glass capillaries. Each capillary is mounted on a goniometer head equipped 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 shown in the data section.

[0127] X-ray Powder 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 incident beam of Cu Kα radiation is generated using a fine focus tube (40 kV, 40 mA), a Goebel mirror, and a 0.5 mm two-hole collimator. Samples are packed between 3 micron thick films to form a portable disk-shaped specimen. Prepared samples are loaded into a holder fixed to a translation stage and analyzed in transmission geometry. The incident beam is scanned and rastered to optimize orientation statistics. A beam stop is used to minimize air scattering from the low angle incident beam. Diffraction patterns are collected using a Hi-Star area detector positioned 15 cm from the sample and processed using GADDS. A silicon standard is run prior to analysis to confirm the Si 111 peak position. Data acquisition and processing parameters are displayed on each pattern seen 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 radiation generated using an Optix long fine focus source. An elliptical stepped multilayer mirror is used to focus the Cu Kα X-rays onto the sample and onto the detector. Samples are sandwiched between 3 micron thick films, analyzed in transmission geometry, and rotated parallel to the diffraction path to optimize orientation statistics. A beam stop, anti-scatter short extension, anti-scatter knife edge, and helium filling are used to minimize background generated by air scattering. Soller slits are used on the incident and diffracted beams to minimize axial divergence. Diffraction patterns are collected using a scatter position sensitive 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. Prior to analysis, a silicon sample (NIST reference standard 640d) is analyzed to confirm the location of the silicon 111 peak.

[0129] For indexing purposes, agreement between accepted peak positions, those marked with bars, and observed peaks indicates agreement with the unit cell determination. Successful indexing of the pattern indicates that the sample consists primarily of a single crystalline phase. The assigned extinction symbols, unit cell parameters, and space groups that correspond to the derived quantities are listed below the figure. To confirm the tentative 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 salt solution (saturated sodium chloride solution) Density (d) Dichloromethane (DCM) equivalent (eq) Ethanol (EtOH) Ethyl acetate (EtOAc) 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) Kilogram (kg) Litres (L) Methanol (MeOH) Methyl ethyl ketone (MEK) Minutes Milliliters (mL) Molarity of the solution (mol / L) (M) Molecular weight (MW) Mole Room temperature (RT) saturation Sodium hexamethyldisilazane (NaHMDS) Starting material (SM) Tetrahydrofuran (THF) 2,2,2-Trifluoroethanol (TFE) vs Weight (wt) Example 1 - Preparation of Crystalline Form A [Table 10]

[0131] Add 2-naphthylacetonitrile (1500 g, 8.97 mol, SM) to a 50 L three-neck round bottom flask equipped with an overhead stir 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. Dry ice is added intermittently to the bath to maintain the cooling bath at -35 to -25 °C during the addition of sodium bis(trimethylsilyl)amide. A solution of sodium bis(trimethylsilyl)amide in THF (9.0 L, 18.0 mol, 2 mol eq) is charged to the dropping funnel and slowly added to the cooled reaction mixture at such a rate that the internal temperature is less than -14°C. The addition takes 1 hour 40 minutes. The internal temperature during the addition is typically -20 to -17°C. After the addition is complete, the resulting solution is stirred at -21 to -16°C for 2 hours 30 minutes. The reaction is monitored by HPLC. The reaction mixture is kept at a temperature of -20 to -15°C and a sample is analyzed by HPLC.

[0132] An HPLC assay at 2 hours 30 minutes indicates that the reaction is not complete. An additional solution of sodium bis(trimethylsilyl)amide in THF (0.30 L, 0.60 mol, 0.067 mole eq) is added via addition funnel over 10 minutes while maintaining the internal temperature of the reaction mixture below -15°C. Stir for 15 minutes, at which point the reaction is complete by HPLC assay. Borane-dimethylsulfide complex (2.25 L, 22.5 mol, 2.5 mole eq) is added via addition funnel at such a rate that the internal temperature of the reaction mixture is below 0°C. The addition takes 40 minutes. After the addition of borane is complete, the reaction mixture is slowly heated to 40°C. When the internal temperature is 40°C, heating is stopped. A slow and steady exotherm is observed over approximately 2 hours, with a maximum internal temperature of 49°C. When the exotherm ceases, the internal temperature rises to 60°C. The reaction mixture is stirred at 60°C overnight. The reaction is monitored by HPLC: the temperature of the reaction mixture is kept at 60° C. and a sample is analyzed by HPLC.

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

[0134] Charge a second 50 L three-neck round bottom flask equipped with an overhead stir bar, thermocouple, cooling bath, and nitrogen inlet with 2M HCl / water (17.3 L, 11.5 mL / g SM, prepared from 2.9 L concentrated HCl and 14.4 L water). Cool the aqueous HCl solution to 3° C. Slowly add the room temperature reaction mixture containing cyclopropylamine to the cooled HCl solution at a rate such that the maximum internal temperature of the quench mixture is 23° C. The quench takes 2 hours 50 minutes. Upon completion of the reaction quench, heat the biphasic mixture 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 a minimum of 15 minutes. Stop stirring and allow the layers to settle for a minimum of 30 minutes. Discard the organic (top) 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 a minimum of 15 minutes. Stop stirring and allow the layers to settle for a minimum of 30 minutes. Separate the layers. The product is in the organic (top) layer. Add isopropyl acetate (7.5 L, 5 mL / g SM) to the aqueous layer. Stir the mixture for a minimum of 15 minutes. Stop stirring and allow the layers to settle for a minimum of 30 minutes. Separate the layers. The product is in the organic (top) layer. Combine the two isopropyl acetate extracts. Add 5% aqueous sodium phosphate dibasic solution (6.0 L, 4 mL / g SM) to the combined extracts. Stir the mixture for a minimum of 15 minutes. Stop stirring and allow the layers to settle for a minimum of 30 minutes. Separate the layers and discard the aqueous (bottom) layer. Saturated brine (6.0 L, 4 mL / g SM) is added to the combined extracts. The mixture is stirred for a minimum of 15 minutes. Stirring is stopped and the layers are allowed to settle for a minimum of 30 minutes. The layers are separated and the aqueous (lower) layer is discarded. The final organic layer is concentrated under reduced pressure into a tared 20 L Büchi flask. A total of 1967.6 g of a light orange waxy solid is obtained. The solid is transferred to a 50 L three-neck round bottom flask equipped with an overhead stirrer, thermocouple, heating mantle, nitrogen inlet and drying tube. Isopropyl acetate (15 L, 10 mL / g SM) is added. The mixture is heated to 50°C.p-Toluenesulfonic acid monohydrate (1586 g, 8.34 mol, 0.93 mole eq) is added in portions over 30 min, keeping the temperature below 60°C. Upon complete addition, the heat is removed and the mixture is allowed to cool to room temperature. The solid is collected by filtration. The filter cake is washed with isopropyl acetate (3 L, 2 mL / g SM). The filter cake is washed once more with isopropyl acetate (3 L, 2 mL / g SM). The filter cake is dried to constant weight in the filter funnel by drawing air through the cake under vacuum. After initial drying, the filter cake is crushed with a spatula and the cake is periodically stirred to aid drying. 2049 g of a white solid is obtained. HPLC assay: 98.2% for main peak, cis:trans ratio 98.5:1.5. [Table 11]

[0135] NOTE: The addition of 5 M NaOH to the reaction mixture is exothermic and therefore requires aggressive cooling.

[0136] 2039.7 g (5.10 mol, 1.0 mol eq) of naphthylcyclopropylamine tosylate obtained above is charged to a 50 L three-necked round bottom flask equipped with an overhead stirrer, 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 charged to 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 via 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 a minimum of 2 hours. The reaction is monitored by HPLC. The reaction mixture is maintained at room temperature while a sample is analyzed by HPLC. Add 5M NaOH (6.1 L, 30.5 mol, 6.0 mol eq) via addition funnel, keeping the temperature below 30°C using an ice / water bath. The addition takes 1 h 40 min. Monitor the reaction by HPLC. Keep the reaction mixture at ambient temperature while a sample is analyzed by HPLC. Stir the reaction mixture at 25°C for 1 h 5 min and then allow the layers to settle. 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 layers with saturated brine (4.1 L, 2 mL / g SM). Dry the organic layer over granular magnesium sulfate. Remove the solids by filtration. Wash the filter cake with isopropyl acetate (1 L, 0.5 mL / g SM). Concentrate the combined filtrate and washes to a total volume of 4.2 L in a 20 L Buchi Rotavap flask. Transfer to a 22 L three-neck round bottom flask equipped with an overhead stirrer, addition 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) via addition funnel over 50 min at such a rate that the internal temperature is below 30° C. Stir the slurry at room temperature for 45 min. Filter and collect the solid.The filter cake is washed with isopropyl acetate (2.3 L, 1.13 mL / g SM). The filter cake is washed once more with isopropyl acetate (2.3 L, 1.13 mL / g SM). The filter cake is partially dried by drawing air through the cake with a vacuum. HPLC assay of the wet cake shows 96.3 area % purity and 89.5% EE.

[0137] The wet cakes from this experiment and another batch are combined in a 50 L three-neck round bottom flask equipped with an overhead stirrer, heating mantle, thermocouple, reflux condenser, nitrogen inlet, and drying tube. Add isopropyl alcohol (34.6 L, 7.45 mL / g SM). Heat the slurry to reflux. Maintain reflux for 3 h. Remove heat and allow to cool to room temperature. Filter and collect the solids. Wash the filter cake with isopropyl alcohol (6.9 L, 1.5 mL / g SM). Wash the filter cake once more with isopropyl alcohol (6.9 L, 1.5 mL / g SM). Dry the filter cake to constant weight by pulling air through the cake under vacuum. Obtain 2009 g of product as a tan 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] Charge (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride to a 50 L three-neck round bottom flask equipped with an overhead stirrer, thermocouple, reflux condenser, heating mantle, nitrogen inlet, and drying tube. Add ethanol (20 L, mL / g SM). Heat the stirred slurry to 77° C. Add an additional 0.5 L aliquot of ethanol and reflux the mixture again until all solids are dissolved. Dissolution is complete after an additional 1.5 L of ethanol is added (total 21.5 L). Stop heating and allow the solution to cool to room temperature. Filter and collect the solid. Wash the filter cake with ethanol (4.3 L, 2.14 mL / g SM). Dry the filter cake to constant weight by pulling air through the filter cake under vacuum. Obtain 1435 g of light tan solid. Yield=74%. HPLC: 99.5%. Chiral HPLC: 99.9%. [Table 13]

[0140] Charge the hydrochloride addition salt form of compound ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) (1406 g, 5.72 mol, 1.0 mol eq) (compound obtained from above step and from another batch) to a 22 L three-neck round bottom flask equipped with an overhead stirrer, heating mantle, thermocouple and nitrogen inlet. Add water (14 L, 10 mL / g SM). Heat the slurry to an internal temperature of 34° C. to dissolve all solids. Transfer to a large separatory funnel. Add tetrahydrofuran (2.8 L, 2 mL / g SM). Add isopropyl acetate (2.8 L, 2 mL / g SM). Stop stirring and separate the layers. Discard the organic (top) layer. The product is in the bottom (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 a minimum of 15 minutes. Stop stirring and allow the layers to settle for a minimum of 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 solids. Wash the filter cake with isopropyl acetate (1 L). Wash the filter cake once more with isopropyl acetate (1 L). Concentrate the combined filtrate and washes and concentrate in a 20 L Buchi rotavap flask to obtain an off-white solid. Charge the solids to a 22 L round bottom flask equipped with an overhead stirrer, thermocouple, addition 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) via addition funnel over 10 min until a white solid forms. Stir the thin slurry at room temperature for 30 min. 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) via addition funnel over 55 min. Stir the slurry for 35 min and note the loss of mother liquor. Add 5.6 N HCl / IPA (60 mL, 0.34 mol, 0.06 mol eq) via addition funnel over 10 min.Stir the slurry for 30 minutes and then check for loss of 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 once more with isopropyl alcohol (2.8 L, 2 mL / g SM). Dry the filter cake to constant weight by pulling air through the filter cake under vacuum. Obtain 1277 g of product as an off-white solid. HPLC: 99.9%.

[0141] The resulting compound exhibits a crystalline XRPD pattern (Figure 1) and is designated crystalline form A. XRPD patterns are collected on a PANalytical X'Pert PRO MPD diffractometer using a Cu radiation incident beam generated using an Optix long fine focus source. Cu Kα X-rays are focused onto the sample using an elliptical stepped multilayer mirror and directed to the detector. Prior to analysis, a silicon sample (NIST SRM 640d) is analyzed to confirm the Si 111 peak position. Sample specimens are sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extension, and anti-scatter knife edge are used to minimize background generated by air. Soller slits are used on the incident and diffracted beams to minimize spread from axial divergence. Diffraction patterns are collected using a scatter position detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Experimental XRPD patterns are collected according to cGMP specifications. The collected 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, collection time: 1939 s, scan speed: 1.2° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission).

[0142] 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). Form A exhibits a weight loss of about 0.4% up to 200 °C by TGA. The dramatic weight change in the TGA at about 276 °C is consistent with decomposition. The DSC thermogram (Figure 2) shows multiple endotherms from about 245 to 248 °C, and the dramatic weight changes by TGA are occurring simultaneously, indicating overlapping events occurring during heating.

[0143] The characterizing data for crystalline form A are summarized in Table 1 below: [Table 14]

[0144] Based on the collected dynamic vapor sorption / desorption data (Figure 3), the obtained crystalline form A is a non-hygroscopic material. At initial equilibration at 5% RH, crystalline form A exhibits a weight loss of 0.03%, and a weight gain of 0.10% is observed from 5% to 95% RH. During the desorption process from 95% to 5% RH, crystalline form A exhibits a weight loss of about 0.10%.

[0145] The humidity adjusted material is similar to the starting material by XRPD (Figure 50).

[0146] Dynamic vapor sorption / desorption isotherm data acquisition parameters: [Table 15]

[0147] Example 2 - Preparation of Crystals of Crystalline Form A A solution of the hydrochloride addition salt form of the compound ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) is prepared in 2 mL of methanol using 98.5 mg of the compound of Example 1 and filtered through a 0.2 μm nylon filter. A 0.5 mL aliquot of the filtered solution is dispensed into a 1-dram open vial and then placed into a 20 mL vial containing 3 mL of antisolvent, ethyl acetate. The 1-dram vial is left uncapped and the 20 mL vial is capped and allowed to undergo vapor diffusion. Single crystals grow in the 1-dram vial after approximately 7 days.

[0148] Data collection: Colorless plate C with 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 random orientation. Preliminary testing and data collection are performed with graphite crystals, Mo Kα radiation (λ=0.71073 Å) on a Nonius Kappa CCD diffractometer equipped with an incident beam monochromator. Refinement is performed using SHELX97 (Sheldrick, GM Acta Cryst., 2008, A64, 112). The cell constant and orientation matrix for data collection are obtained from a least-squares refinement using set angles of 5812 reflections in the range 1°<θ<27°. The refined mosaicism from DENZO / SCALEPACK is 0.38° indicating good crystalline quality (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307). The space group was determined by the program XPREP (Bruker, XPREP in SHELXTL v. 6.12., Bruker AXS Inc., Madison, WI, USA, 2002). 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 was determined to be P2. 1 2 1 2 1 (no. 19). Data are collected at a temperature of 150±1 K up to a maximum 2θ value of 55.71°.

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

[0150] Structure analysis and refinement: The structure is solved by a direct method using 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 placed by subsequent difference Fourier synthesis. Hydrogen atoms are included in the refinement, but are constrained depending on the atoms to which they are bonded. The structure is determined by the functions:

number

number

[0151] Calculated X-ray powder diffraction (XRPD) patterns: Calculated XRPD patterns are generated for atomic coordinates, space group, and unit cell from Cu radiation and single crystal data 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). Because the single crystal data is collected at low temperature (150 K), peak shifts may be evident between the patterns calculated from the low temperature data and the room temperature experimental powder diffraction patterns, especially at high diffraction angles.

[0152] ORTEP and packing diagrams: ORTEP diagrams are prepared using the ORTEP III (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) program in 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. Atoms are represented by 50% probability anisotropic thermal ellipsoids. Packing diagrams are prepared using the CAMERON (Watkin, DJ; Prout, CK; Pearce, LJ CAMERON, Chemical Crystallography Laboratory, University of Oxford, Oxford, 1996) model software. Chiral centers are evaluated with 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 molecular chiral rules specification (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 diagrams will be generated with the Mercury 2.4 (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) visualization package. 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 and 1.267 g cm -3 The calculated density is: 1 2 1 2 1 A summary of the crystallographic data and crystallographic data collection parameters is given in Table 2 below.

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

[0155] The ORTEP diagram of crystalline form A is shown in FIG.

[0156] The asymmetric unit shown in Figure 18 contains a protonated (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane molecule and a chloride counterion. The protons are located in the difference diagram and are free to refine onto the nitrogen, indicating salt formation.

[0157] 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, H.D.; Bernardinelli, G., Acta Cryst., 1999, A55, 908; Flack, H.D.; Bernardinelli, G., J. Appl. Cryst., 2000, 33, 1143), encodes the relative abundance of the two components in the inverse twin. The structure contains the fraction 1-x of the refined model and its reciprocal x. If low standard uncertainties are obtained, the Flack parameter should be close to 0 if the solved structure is accurate and close to 1 if the inverse model is accurate. The measured Flack parameter for the structure of crystalline form A shown in FIG. 18 is −0.02 with a standard uncertainty of 0.06.

[0159] After solving the structure, the quality of the data can be assessed for its inversion-distinguishing power by examining the standard uncertainty of the Flack parameter. For crystalline form A, the standard uncertainty (u) is 0.06, indicating a strong inversion-distinguishing power. The compound is enantiopure and the absolute structure can be assigned directly from the crystal structure.

[0160] Refinement of the Flack parameter (x) (Flack, HD Acta Cryst. 1983, A39, 876) does not provide a quantitative indication of the assignment of the absolute structure. However, an approach applying Bayesian statistics to the Bijvoet difference can provide a range of probabilities for different hypotheses of the 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 Flack equivalent (Hooft) parameters as well as the probability that the absolute structure is correct, incorrect, or racemic twinned. For the current data, the Flack equivalent (Hooft) parameter was 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 racemic twinned is 0.4. -59 It is.

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

[0162] FIG. 23 shows the calculated powder X-ray diffraction pattern of Form A generated from the single crystal data.

[0163] The experimental X-ray powder diffraction pattern of crystalline form A is shown in FIG.

[0164] In FIG. 34, the experimental XRPD of Form A in FIG. 1 is overlaid with the calculated pattern.

[0165] The difference in intensity between the calculated and experimental powder X-ray diffraction patterns is due to preferred orientation. Preferred orientation is the tendency of crystals to align on the order of a few degrees. The preferred orientation of the sample can significantly affect the peak intensities in the experimental powder diffraction pattern, but not the peak positions. Furthermore, because the experimental powder pattern was collected at room temperature and the single crystal data was collected at 150K, some shifts in peak positions between the calculated and experimental powder diffraction patterns can be expected. Although low temperatures are used in single crystal analysis to improve the quality of the structure, they can shrink the crystals resulting in changes in the unit cell parameters, which are reflected in the calculated powder diffraction pattern. Such shifts are especially evident at high dispersion diffraction angles.

[0166] The positional parameters and their estimated standard deviations (Table 3), anisotropic temperature factor coefficients (Table 4), bond lengths (Table 5), bond angles (Table 6), hydrogen bonds and angles (Table 7) and torsion angles (Table 8) are tabulated below. Table 2. Crystallographic data and data collection parameters for (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride form A (crystalline form A). Expression C 15 H 16 ClN Formula weight 245.75 space group P2 1 2 1 2 1 (No. 19) a,Å 5.7779(2) b,Å 8.6633(2) c,Å 25.7280(8) V,Å 3 1287.83(7) Z4 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) Monochromator Graphite Linear absorption coefficient, mm -1 0.273 Applied absorption correction: empirical a Transmission factor: min, max 0.953, 0.953 Nonius Kappa CCD Diffractometer h, k, l range -7~7 -11~11 -33~33 2θ range, deg. 1.58-55.71 Mosaic 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 cutoff value used in the R-factor calculation is F. o 2 >2.0σ(F o 2 ) Data for I>2.0σ(I) 2678 Number of variables: 162 Maximum shift / esd in last 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)) Hooft 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. Position parameters and their estimated standard deviations for crystalline 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 Atoms marked with an asterisk 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 calculation of structure factors but not in the refinement. 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)] (In the formula, a * , b * and c * is the mutual lattice constant) Table 5. Bond distances (Angstroms) for crystalline 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) Numbers in parentheses are estimated standard deviations to the least significant figure. Table 6. Bond angles (degrees) for crystal form A 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 Numbers in parentheses are estimated standard deviations to the least significant figure. Table 7. Hydrogen bond distances (Angstroms and angles) for crystalline form A. D H A DH AH D.A. 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) Numbers in parentheses are estimated standard deviations to the least significant figure. Table 8. Torsion angles (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) Numbers in parentheses are estimated standard deviations to the least significant figure.

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

[0168] Form B - As outlined above, Form B is obtained from evaporation and slurry in water, slurry, slow cooling and crash-cooling in DCM and slow cooling in 1-propanol. Additionally, material showing the XRPD pattern of Form A with Form B peaks is obtained from evaporation in DCM, ethanol, HFIPA and TFE. Material showing the XRPD pattern of Form B with weak Form A and Form C peaks is observed from crash-cool experiments in 1-propanol.

[0169] Form B is indexed from the 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 show a mixture of forms B and A. The agreement between the accepted peak positions, those marked with bars for the current form, and the observed peaks indicates the determination of a consistent unit cell. The peaks at 18.5°, 20.7°, 25.7° and 27.5° 2θ are inconsistent with the indexing results for form B and appear to be from form A. The assigned extinction symbols, unit cell parameters and space group consistent with the derivatives are tabulated in the figure below. To confirm the tentative indexing results, the molecular packing motifs within the crystallographic unit cell must be determined. No attempt at molecular packing has been made. Form B indexes with a similar volume per formula unit to Form A, indicating that Form B is a non-solvated crystalline form.

[0170] XRPD data acquisition parameters for Figures 4B and 5: 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, collection time: 1939 s, scan speed: 1.2° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission.

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

[0173] Thermal analysis results for crystalline form B are shown in FIG. 8 (DSC, size: 1.2600 mg, method: (-30)-300-10, T0C; TGA, size: 9.4320 mg, method: 00-350-10). By TGA, crystalline form B exhibits a small weight loss of about 0.2% from ambient to 200° C., likely due to traces of solvent. The dramatic change in slope of the TGA thermogram at about 281° C. is consistent with decomposition. By DSC, the broad endotherm observed at about 141° C. (peak) is likely due to a solid form change or loss of volatiles upon heating. Crystal form B exhibits an endotherm at about 248° C. (peak) followed by two broad endotherms at about 251 and 264° C., similar to the thermal behavior observed for crystalline form A. Based on the data obtained, crystalline form B is a nonsolvated crystalline material.

[0174] Form C - Form C may be prepared by slow cooling in isopropanol. Material showing the XRPD pattern of form A with weak peaks of form C comes from slow cooling experiments in ethanol, while crash-cool experiments in ethanol and isopropanol give the XRPD pattern of form C with weak peaks of form A.

[0175] In six scale-up runs, form C is prepared by cooling in isopropanol on a ca. 50-150 mg scale (Table 11) and the solids are examined by XRPD. The solid precipitated at refrigeration temperature is form B. Seeds of form C are added after cooling in the refrigerator (no solids observed) and before placing in the freezer, giving the XRPD pattern of form C with peaks of form B. Precipitation at freezer temperature gives a solid with the XRPD pattern of form C with peaks of form A. At lower concentrations (7 mg / mL vs. 10 mg / mL) solutions cooled to room temperature and then placed in the freezer give form B. The solids produced by crash-cooling (ambient solution placed in dry ice / isopropanol) are a mixture of forms B and A. Finally, a run on a ca. 50 mg scale gives a mixture of forms A and C. The differing results of these experiments suggest factors (e.g. concentration, temperature, cooling time and seeding) that may influence the crystallization of form C on a large scale, as well as competitive crystallization of forms A and B, which may be more stable under the experimental conditions used. Note that form C remains unchanged by XRPD after 22 days of storage at room temperature.

[0176] XRPD data acquisition parameters for 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, collection time: 717 s, scan speed: 3.3° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission.

[0177] XRPD data acquisition parameters for FIG. 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, collection time: 720 s, scan speed: 3.2° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission.

[0178] XRPD data acquisition parameters for FIG. 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, collection time: 718 s, scan speed: 3.3° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission.

[0179] XRPD data acquisition parameters for FIG. 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, collection time: 720 s, scan speed: 3.2° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission. [Table 18]

[0180] Form C is indexed from the high resolution XRPD pattern (Figure 10) using dedicated software. The pattern appears to represent a mixture of forms C and A. The agreement between the accepted peak positions, those marked with a bar for the current form, and the observed peaks indicates the assignment of a consistent unit cell. The peaks at 12.3°, 15.4°, 16.6°, 20.7° and 25.7° 2θ are inconsistent with the indexing results for form C and appear to be from form A. The assigned extinction symbols, unit cell parameters and space groups consistent with the derivatives are tabulated in the figure below. To confirm the tentative indexing results, the molecular packing motifs within the crystallographic unit cell must be determined. No attempt at molecular packing has been made. Form C is indexed with a similar volume per formula unit to form A, indicating that form C is a nonsolvated crystalline form.

[0181] XRPD data acquisition parameters for 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 for 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, collection time: 720 s, scan speed: 3.2° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission.

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

[0184] Thermal analysis results for Form C are shown in FIG. 12 (DSC, size: 1.0100 mg, method: (-30)-300-10, T0C; TGA, size: 2.2300 mg, method: 00-350-10). By TGA, Form C exhibits a weight loss of about 1.3% from ambient to 200° C., likely due to loss of volatiles upon heating. The dramatic change in slope of the TGA thermogram at about 266° C. is consistent with decomposition. By DSC, a broad, minor endotherm observed at about 122° C. (peak) is likely due to a solid state morphology change or loss of volatiles upon heating. Form C exhibits an endotherm at about 248° C. (peak) followed by a broad endotherm at about 271° C., similar to the thermal behavior observed for Form A.

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

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

[0187] XRPD data acquisition parameters for 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): Crystalline 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 citric acid / sodium citrate): Form D is obtained by spontaneous precipitation at room temperature and after stirring the suspension at about 70°C; room temperature slurry gives Form B which contains a weak peak of Form D in XRPD. - pH6.0 buffer (50 mM Na 2 HPO 4 / NaH 2 PO 4 ): Form E is observed from a slurry at about 50° C., with peaks also seen in Form F by XRPD. - pH8.1 buffer (50mM Na 2 HPO 4 / NaH 2 PO 4 ): Crystalline form F is obtained by stirring the suspension at about 70°C.

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

[0189] Example 4 - Amorphous Attempts to prepare amorphous (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride were made by grinding, lyophilization, and rotary evaporation (Table 14). All attempts used in this study recovered material that was likely irregular crystalline form A.

[0190] XRPD data acquisition parameters for 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 Crystalline Form A [ka] Commercially available reagents are used as purchased unless otherwise specified. Reactions requiring an inert atmosphere are carried out under nitrogen unless otherwise specified. Steps 1 and 2: [Table 22]

[0192] 2-Naphthylacetonitrile (4500 g) is dissolved in THF (32 L) and 3.2 kg of (S)-(+)-epichlorohydrin is added and the solution is cooled to -16°C. A 2.0 M solution of sodium hexamethyldisilazane / tetrahydrofuran (THF) (24.7 kg) is then added while maintaining the internal temperature below -10°C. This addition takes 2 hours 45 minutes to complete. The reaction mixture is then stirred at about -15°C for an additional 6 hours after which a sample is analyzed by HPLC. Borane-dimethylsulfide (6.5 kg) is added over 36 minutes while maintaining the internal temperature below 0°C. After the borane addition is complete, the reaction mixture is slowly heated to 60°C to reduce the nitrile to the amine. An exotherm is observed during heating, indicating 45°C. After heating at 60°C for 2 hours, a sample of the reaction mixture is analyzed by HPLC. The reaction mixture is cooled to 24°C and transferred to a solution of 2M HCl over 1 hour. The biphasic mixture is heated to 50° C. and stirred at this temperature for 1 hour before being cooled to 29° C. The pH of the quenched reaction mixture is measured and found to be 5. Further 2M HCl is added and the mixture is heated to 50° C. and stirred for 1 hour before being cooled to 25° C. The pH is measured and found to be 1. The reaction is worked up by adding isopropyl acetate (IPAc), stirring, separating the layers and discarding the organic layer. Aqueous ammonia is added to the aqueous layer and the pH is measured, which shows a pH of 8. Further ammonia is added and the pH is measured again and found to be 8.5. The work up is then carried out by extracting the aqueous layer with IPAc in a two-stage extraction. The combined organic extracts are washed with 5% sodium phosphate dibasic / water and then with saturated brine. The resulting organic layer is partially concentrated, azeotropically dried and then diluted with IPAc. p-Toluenesulfonic acid hydrate (4.9 kg) is then added in portions to precipitate the desired product as the pTsOH salt, which is isolated by filtration. The filter cake is washed with IPAc and then dried to constant weight to give 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 from step 2 (5785 g) is suspended in IPAc (176 L) to give a slurry. Thionyl chloride (2.1 kg) is then added over 1 h. After the addition of thionyl chloride is complete, the reaction mixture is stirred for an additional hour and a sample is analyzed by HPLC. Aqueous sodium hydroxide (5M, 6 mol equiv.) is added over 1 h and then stirred for an additional 4 h. The layers are allowed to settle and the pH of the aqueous layer is found to be 9. The layers are separated and the organic layer is washed with 1M 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 0.5M HCl to extract (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane into the aqueous layer. The acidic aqueous layer is washed with a 1:1 mixture of IPAc and THF to remove color. The aqueous layer is basified with aqueous ammonia and then extracted with IPAc. After separation of 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 equivalents of HCl, 0.90 L) is added to form the crude salt, which is isolated by filtration, washed with IPAc, and then partially dried. The wet cake is refluxed with IPAc. The crude salt is refluxed with IPA and the solid is isolated by filtration, washed with IPA, and then dried. >99.5 HPLC area percent and 97.7% chiral area percent purity. 1759 g of desired product.

[0194] Step 4: The crude (1R,5S)-1-(naphthalen-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 through an in-line filter as a polishing filtration. The dissolution vessel, in-line filter, and transfer line are then rinsed with additional hot ethanol (61°C) and the washes are combined with the filtrate. The combined filtrate and washes are partially concentrated under reduced pressure to a total of about 11.5 volumes (relative to the crude (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride charged), and the solids are reheated to redissolve. The solution is cooled to 65°C and seed crystals are added as a slurry in ethanol. After stirring at about 65°C to grow the seed bed, the slurry is cooled to room temperature. The resulting solids are isolated by filtration, the filter cake is washed with ethanol, and the washed solids are dried. A total of 1064 g of tan product is obtained. >99.5% by both chiral and achiral HPLC.

[0195] Step 5: (1R,5S)-1-(naphthalen-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. Once all solids have dissolved, the aqueous solution is washed with 1:1 THF:IPAc to remove most of the colored material. After washing, aqueous ammonia is added to the aqueous layer and (1R,5S)-1-(naphthalen-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 an off-white solid. The solid is dissolved in IPA and transferred to a 22 L three-neck round-bottom flask by in-line filtration. Filtered HCl / IPA is then added to reform the salt, which is isolated by filtration. The filter cake is washed with IPA and then dried to give 926 g of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride as an off-white solid.

[0196] The XRPD of the product is shown in Figure 35 and is consistent with crystalline form A. XRPD patterns are collected using a PANalytical X'Pert Pro MPD diffractometer with a Cu radiation incident beam generated using an Optix long fine focus source. An elliptical stepped multilayer mirror is used to focus the Cu Kα X-rays onto the sample and onto the detector. A silicon sample (NIST SRM 640d) is analyzed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. Sample specimens are sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extensions, and anti-scatter knife edges are used to minimize background generated by air. Soller slits are used on the incident and diffracted beams to minimize the extension from axial divergence. Diffraction patterns are collected using a scatter position detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters were: 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, collection time: 717 s, scan speed: 3.3° / min., slits: DS:1 / 2°, SS:zero, rotation time: 1.0 s, mode: transmission.

[0197] Figure 36 is an overlay of the XRPD patterns of Figures 1 and 35. There is some difference in relative peak intensities that may be due to preferred orientation (PO). PO is the tendency of crystals, usually plates or needles, to pack together with some degree of order. PO can affect the peak intensities in the XRPD pattern, but not the peak positions.

[0198] The XRPD of the product after long term storage is shown in Figure 37 and is consistent with crystalline form A. XRPD patterns are collected using a PANalytical X'Pert Pro MPD diffractometer with a Cu radiation incident beam generated using an Optix long fine focus source. An elliptical stepped multilayer mirror is used to focus the Cu Kα X-rays onto the sample and direct them to the detector. A silicon sample (NIST SRM 640e) is analyzed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. Sample specimens are sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extensions, and anti-scatter knife edges are used to minimize background generated by air. Soller slits are used on the incident and diffracted beams to minimize the extension from axial divergence. Diffraction patterns are collected using a scatter position detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters were: 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, collection time: 719 s, scan speed: 3.3° / min., slits: DS:1 / 2°, SS:zero, rotation time: 1.0 s, mode: transmission.

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

[0200] Example 6 - Preparation of Crystals of Crystalline Form B Example 6a Form A (558.9 mg) from Example 5 above is slurried in dichloromethane (5 mL). The preparation is stirred (300 RPM) at ambient temperature for 16 days in a sealed vial. The white solid is isolated by vacuum filtration, rinsed with dichloromethane (1 mL) and dried briefly under nitrogen. The product is Form A. The XRPD pattern of the product is shown in FIG. 47. The XRPD pattern is collected using a PANalytical X'Pert PRO MPD diffractometer with a Cu radiation incident beam generated using an Optix long fine focus source. An elliptical stepped multilayer mirror is used to focus the Cu Kα X-rays onto the sample and direct them to the detector. A silicon sample (NIST SRM 640e) is analyzed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. The sample specimen is sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extension, and anti-scatter knife edge are used to minimize background generated by air. Soller slits are used on the incident and diffracted beams to minimize the broadening from axial divergence. Diffraction patterns are collected using a scattering position sensitive 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, collection time: 720 s, scan speed: 3.2° / min., slits: DS: 1 / 2°, SS: zero, rotation time: 1.0 s, mode: transmission.

[0201] Example 6b Form A of Example 6a (34.3 mg) is contacted with water (1 mL). The sample is sonicated until the solids dissolve. The sample is capped and left at room temperature until nucleation is observed (within 1 day). The monomer is isolated from the bulk sample for analysis.

[0202] Data collection: Colorless plate C with an approximate volume of 0.31 x 0.21 x 0.09 mm 15 H 16 ClN[C 15 H 16 The nuclei are mounted on nylon loops in random orientation. Preliminary examination and data collection are performed on a Rigaku Rapid II diffractometer equipped with confocal optics using Cu Kα radiation (λ=1.54178 Å). Refinement is performed using SHELX2014 (Sheldrick, GM Acta Cryst. 2015, C71, 3-8). The cell constants and orientation matrix for data collection are obtained from a least-squares refinement using set angles of 22958 reflections in the range 2°<θ<26°. The systematic presence of the following conditions: h00 h=2n; 0k0 k=2n; 00l l=2n and subsequent least-squares refinement determined the space group to be P2. 1 2 1 2 1 (no. 19). Data are collected at a temperature of 100 K up to a maximum diffraction angle (2θ) value of 144.79°.

[0203] Data reduction: Frames are integrated with HKL3000 (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307). A total of 22958 reflections are collected, of which 2415 are unique. Lorentzian and polarization corrections are applied to the data. The linear absorption coefficient is 2.422 mm for Cu Kα radiation. -1 An empirical absorption correction using SCALEPACK (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307) is applied. Transmission coefficients range from 0.753 to 0.976. A quadratic 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 intensities of equivalent reflections are averaged. The agreement factor for averaging is 4.95% based on the intensity.

[0204] Structure analysis and refinement: The structure is solved by direct methods using SHELXS-97 (Sheldrick, GM Acta Cryst. 2015, C71, 3-8). The remaining atoms are placed by subsequent difference Fourier synthesis. Hydrogen atoms are included in the refinement, but are constrained depending on the atoms to which they are bonded. The structure is determined by the functions:

number

number

[0205] Calculated X-ray Powder Diffraction (XRPD) Patterns: Calculated XRPD patterns are generated for the atomic coordinates, space group, and unit cell parameters from the Cu radiation and single crystal structure 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). Because the single crystal data is collected at low temperature (100 K), peak shifts may be evident between the patterns calculated from the low temperature data and the room temperature experimental powder diffraction patterns, especially at high diffraction angles. The calculated XRPD patterns are adjusted to room temperature using the unit cell parameters previously obtained from XRPD indexing.

[0206] Atomic displacement ellipsoid diagrams and packing diagrams: Atomic displacement ellipsoid diagrams 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). Atoms are represented by 50% probability anisotropic thermal ellipsoids. Packing diagrams and additional diagrams are generated using Mercury. Hydrogen bonds are represented by dashed lines. Analysis of chiral centers is performed with PLATON (Spek, AL PLATON. Molecular Graphics Program. Utrecht University, Utrecht, The Netherlands, 2008. Spek, AL, J. Appl. Cryst. 2003, 36, 7). The absolute configuration is analyzed using the specifications of the rules of 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 for Z=4. -1 and the calculated density is 1.272 g cm -3 The space group is P2 1 2 1 2 1 (no. 19). A summary of the crystallographic data and crystallographic data collection parameters is given below in Table 15. The space group and unit cell parameters are consistent with those obtained for crystalline form B by XRPD indexing.

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

[0209] The atomic displacement ellipsoid diagram for crystalline form B is shown in FIG.

[0210] The asymmetric unit shown in Figure 24 contains one protonated (1R,5S)-1-(naphthalen-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 run from the amine to the chloride, forming a primary hydrogen-bonded helix along the a axis, shown in Figure 28.

[0212] The molecular conformation of the (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane molecules in the structure of crystalline form B is compared to that observed in the structure of crystalline form A in Figure 29, and the packing of the two forms along the a-axis is compared in Figure 30. The hydrogen bonds in the structures of crystalline forms A and B are shown in Figure 31. Adjacent molecules are connected by hydrogen bonds forming linear chains along the a-axis through the chloride ions in crystalline form A. In crystalline form B packing, the amine groups of adjacent molecules are too far apart to be similarly connected, and instead of hydrogen bonds they form helical chains in crystalline form B.

[0213] The absolute structure can be determined through the analysis of anomalous X-ray scattering from 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 in the inverse twin. The structure contains the fraction 1-x of the refined model and its reciprocal x. For low standard uncertainties, the Flack parameter should be close to 0 if the solved structure is correct and close to 1 if the inverse model is correct. The Flack parameter measured for the structure of crystalline form B shown in Figure 24 is 0.010 with a standard uncertainty of 0.010, indicating strong discrimination between inverted structures. The compound is enantiopure and the absolute configuration can be assigned directly from the crystal structure.

[0214] Refinement of the Flack parameter (x) does not provide a quantitative indication of the assignment of the absolute structure. However, an approach that applies Bayesian statistics to the Bijvoet difference can provide a range of probabilities for different hypotheses of the 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 Flack equivalent (Hooft) parameter as well as the probability that the absolute structure is correct, incorrect, or racemic twinned. For 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 racemic twinned is 0.000.

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

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

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

[0218] The difference in intensity between the calculated and experimental powder diffraction patterns may be due to preferred orientation. Preferred orientation is the tendency of crystals to align on the order of a few degrees. The preferred orientation of the sample may significantly affect the peak intensities in the experimental powder diffraction pattern, but not the peak positions. Furthermore, since the experimental powder pattern was collected at room temperature and the single crystal data was collected at 100K, some shift in peak positions between the calculated and experimental powder diffraction patterns may be expected. Although low temperatures are used in single crystal analysis to improve the quality of the structure, they may shrink the crystals resulting in changes in the unit cell parameters, which are reflected in the calculated powder diffraction patterns. Such shifts are especially evident at high dispersion diffraction angles. The calculated XRPD patterns were adjusted to room temperature using the unit cell previously obtained from XRPD indexing. Table 15. Crystallographic data and data collection parameters of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride crystalline form B (crystalline 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 P2 1 2 1 2 1 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 Z4 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 collection: 6.080~72.393° Index range: -7<=h<=7, -8<=k<=8, -35<=l<=35 Collection Reflection 22958 Independent reflection 2415 [R(int)=0.0495] Perfectness for theta = 67.679° 98.5% Absorption correction: semi-empirical from equivalents Maximum and minimum transmission 0.976 and 0.753 Refinement method F 2 Full matrix least squares 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 structural parameters 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 Crystalline Form B 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 stir bar at room temperature for 16 days to allow conversion. The solid is collected by vacuum filtration and briefly dried under nitrogen.

[0220] Example 8 - Preparation of Crystalline Form B The product of Example 16 below (1 g) is stirred in 5 mL of Special Industrial Grade 200 (denatured ethanol) at room temperature over the weekend. The mixture is filtered and rinsed with 2 mL of Special Industrial Grade 200 (denatured ethanol) and then with isopropyl acetate (2 x 3 mL). The solid is sucked dry for 2 hours and then dried at 40°C for 6 hours to give 0.81 g of product.

[0221] XRPD indicates that the product is crystalline form B (see Figure 40 and top XRPD pattern in Figure 33). XRPD patterns are collected on a PANalytical X'Pert PRO MPD diffractometer using a Cu radiation incident beam generated using an Optix long fine focus source. Cu Kα X-rays are focused onto the sample and directed to the detector using an elliptical stepped multilayer mirror. A silicon sample (NIST SRM 640d) is analyzed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. Sample specimens are sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extensions, and anti-scatter knife edges are used to minimize background generated by air. Soller slits are used on the incident and diffracted beams to minimize extension from axial divergence. Diffraction patterns are collected using a scatter position detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters were: 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, collection time: 720 s, scan speed: 3.2° / min., slits: DS:1 / 2°, SS:zero, rotation time: 1.0 s, mode: transmission.

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

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

[0224] The XRPD of the product is shown in Figure 43. XRPD patterns are collected on a PANalytical X'Pert PRO MPD diffractometer using a Cu radiation incident beam generated using an Optix long fine focus source. An elliptical stepped multilayer mirror is used to focus the Cu Kα X-rays onto the sample and direct them to the detector. A silicon sample (NIST SRM 640d) is analyzed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. Sample specimens are sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extensions, and anti-scatter knife edges are used to minimize air-generated background. Soller slits are used on the incident and diffracted beams to minimize the extension from axial divergence. Diffraction patterns are collected using a scatter position detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters were: 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, collection time: 720 s, scan speed: 3.2° / min., slits: DS:1 / 2°, SS:zero, rotation time: 1.0 s, mode: transmission.

[0225] One of the PANalytical patterns for this material is analyzed to assess preferred orientation and particle statistical effects in comparison to 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 patterns are indexed using dedicated software (U.S. Patent No. 8,576,985). The observed peaks are shown in Figure 45 and are listed in Table I in section 1.183, typical peaks in Table H in section 1.176, and characteristic peaks 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 a function of temperature. According to the graph, it is assumed that the free energy curves cross at most once and, secondly, the enthalpy curves of the polymorphs do not cross. The melting point of a polymorph is defined as the temperature where the free energy curve of the polymorph crosses the free energy curve of the liquid. The transition temperature is defined as the temperature where the free energy curve of one polymorph crosses the free energy curve of a second polymorph. Thus, T t At , the free energies of both polymorphs are equal and therefore in equilibrium with each other.

[0227] Presented energy-temperature diagram for crystalline forms A, B and C shown in Figure 46. In the diagram, the enthalpy (H) and free energy (G) curves for each form are shown as a function of temperature (T). The subscripts A, B, C and L refer to crystalline forms A, B, C and the liquid phase, respectively. The subscripts f, t and m refer to the melting, transition and melting points, respectively. According to the graph, it is assumed that the free energy curves cross at most once and then the enthalpy curves of the polymorphs do not cross. The melting point of a polymorph is defined as the temperature at which the free energy curve of the polymorph crosses the free energy curve of the liquid. The transition temperature is defined as the temperature at which the free energy curve of one polymorph crosses the free energy curve of another polymorph. Thus, T t At T the free energies of both polymorphs are equal and therefore in equilibrium with each other. t,C→B (Because the free energy of crystalline form C is lower than that of crystalline form B), crystalline form B is a stable solid phase below T t,C→B and T t,B→A Form A is a stable solid phase between T t,B→A Low energy polymorphs have lower fugacity, vapor pressure, thermodynamic activity, solubility, dissolution rate per unit surface area, and reaction rate relative to other polymorphs.

[0228] Interconversion experiments are performed to test the hypothetical thermodynamic relationship between substances as shown by the energy-temperature diagram above. Interconversion or competitive slurry methods are solution-mediated processes that provide a route for less soluble (more stable) crystals to grow at the expense of more soluble crystalline 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, the more stable polymorphs obtained from interconversion experiments are independent of the solvent used, since the more thermodynamically stable polymorphs are less soluble due to their lower energy. The choice of solvent affects the kinetics of polymorphic transformation but does not affect the thermodynamic relationships between the polymorphs (Gu, CH, Young, V. Jr., Grant, DJ, J. Pharm. Sci. 2001, 90 (11), 1878-1890).

[0229] The binary interconversion slurry process between crystalline forms A, B and C in different solvent systems at temperatures between about 2 and 67°C is outlined in Table 16 below. A saturated solution is generated and then added to a mixture of approximately equal amounts of the two polymorphs. Samples are slurried overnight to 3 weeks to obtain solids that are analyzed by XRPD. The results of the interconversion studies indicate that the relative thermodynamic stabilities of the enantiotropic crystalline forms A, B and C are accurately represented in the presented energy-temperature diagram. Furthermore, the T t,C→B is thought to be less than 2°C (not determined), and T t,C→A is between 2℃ and room temperature, and T t,B→A is between 37 and 54 degrees Celsius. [Table 24]

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

[0231] Experiment: Approximate solubility Weighed samples are treated with aliquots of test solvent at room temperature. The mixture is sonicated between additions to facilitate 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 calculated due to the use of large solvent aliquots or slow dissolution rates. [Table 25]

[0232] Example 11 - Accelerated Stress Conditions Forms A, B, and C are exposed to accelerated stress conditions for two weeks (Table 18 below). Based on XRPD, forms A and B remain unchanged at 30° C. / 56% RH or 40° C. / 75% RH within the time frame evaluated. However, form C converts to a mixture of forms A and B within two weeks at 40° C. / 75% RH. Form C is metastable under these conditions. For form A, in the absence of seeds of the more stable polymorph, the critical free energy barrier for nucleation of form B is not surmountable in the solid-state or solvent-mediated conversion experiments within the time frame evaluated. [Table 26]

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

[0234] The following relative humidity bottles (using saturated salt solutions to generate the desired relative humidity) 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 Crystalline Form B A portion of crystalline form A from Example 5 above is slurried in water at ambient temperature for 16 days. Crystalline form B is isolated. The XRPD of the product is shown in Figure 48. XRPD patterns are collected on a PANalytical X'Pert PRO MPD diffractometer using a Cu radiation incident beam generated using an Optix long fine focus source. The Cu Kα X-rays are focused onto the sample using an elliptical stepped multilayer mirror and directed to the detector. A silicon sample (NIST SRM 640e) is analyzed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. Sample specimens are sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extensions, and anti-scatter knife edges are used to minimize background generated by air. Soller slits are used on the incident and diffracted beams to minimize the extension from axial divergence. Diffraction patterns are collected using a scatter position sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters were: 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, collection time: 716 s, scan speed: 3.3° / min., slits: DS:1 / 2°, SS:zero, rotation time: 1.0 s, mode: transmission.

[0236] Example 13 - XRPD of a mixture of Form A and a small amount of Form B The XRPD pattern of the mixture of Form A and a small amount of Form B product is shown in Figure 49 (synthesis in Example 17). XRPD patterns are collected on a PANalytical X'Pert PRO MPD diffractometer using a Cu radiation incident beam generated using an Optix long fine focus source. The Cu Kα X-rays are focused onto the sample and directed to the detector using an elliptical stepped multilayer mirror. A silicon sample (NIST SRM 640e) is analyzed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. Sample specimens are sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, anti-scatter short extensions, and anti-scatter knife edges are used to minimize background generated by air. Soller slits are used on the incident and diffracted beams to minimize the extension from axial divergence. Diffraction patterns are collected using a scatter position detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters were: 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, collection time: 720 s, scan speed: 3.2° / min., slits: DS:1 / 2°, SS:zero, rotation time: 1.0 s, mode: transmission.

[0237] Example 14 - Solution calorimetry (SolCal) analysis of crystalline forms A and B Solution calorimetry analysis for each form was performed in triplicate in methanol and the data is summarized in Table 21. Two heats of solution are obtained for each test - one calibrated and calculated prior to sample analysis and one calibrated and calculated after sample analysis. The average value from the two calibrations is also shown in the table. Clear dissolution is observed after each test.

[0238] Dissolution of Forms A and B in methanol is an endothermic event with average heats of solution 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] Form B has a higher heat of solution value than form A, indicating that form B is more stable than form A at 25° C. The calculated enthalpy of transition from form B to form A from the SolCal data is approximately 15.9 J / g. The difference in heat of fusion for the solid-state transition of form B in DSC is 15.9 J / g (see Figures 8 and 55), which is in good agreement with the SolCal results.

[0240] Solution calorimetry is performed using a semi-adiabatic Thermometric 2225 Precision Solution Calorimeter. Solution Calorimeter System v.1.2 software is used. Samples are weighed into glass crushing ampoules and sealed with silicone rubber plugs and hot wax. Experiments are performed in 100 mL of methanol at 25°C. Measurements of the heat of solution of the samples are performed before and after calibration using an internal heater. The heat of solution is calculated using the kinetics of the calibration model. [Table 28]

[0241] Example 15 - High Temperature Microscopy (HSM) of Crystalline Form A of Example 1 Hot microscopy is performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope. Samples are viewed using a 20x objective (obj.). After the sample is placed on a coverslip, a second coverslip is placed on the sample. Each sample is visually observed while the stage is heated. SPOT Insight with SPOT software v. 4.5.9 TM Images are captured using a color digital camera. The hot stage is calibrated using USP melting point standards.

[0242] HSM of form A at 182-239 °C evaporates the smallest particles and the resulting vapor recrystallizes into larger crystals. Condensation and melting are observed between 239-247 °C, with the needles appearing to melt last, consistent with the multiple endotherms observed by DSC. Two preparations are used for analysis. In the first, a discoloration (decomposition) is observed after melting. In the second, rapid cooling causes recrystallization of the melt.

[0243] Example 16 - Preparation of a mixture of crystalline forms A and B Commercially available reagents were used as received unless otherwise noted. Reactions requiring an inert atmosphere were performed under nitrogen unless otherwise noted. [Table 29]

[0244] Steps 1 and 2 2-Naphthylacetonitrile (50 Kg) is dissolved in THF (250 L) and 32 kg of (S)-(+)-epichlorohydrin is added and the solution is cooled to -10°C. 2.0 M sodium hexamethyldisilazane / THF (299 L) is then added while maintaining the internal temperature below -10°C. This addition takes 14 hours 14 minutes to complete. The reaction mixture is then stirred at about -10°C for an additional 4 hours, after which a sample of the reaction mixture is analyzed by HPLC. Borane dimethylsulfide (71 kg) is added over 4 hours 33 minutes, while maintaining the internal temperature below 0°C. After the borane addition is complete, the reaction mixture is slowly heated to 60°C to reduce the nitrile to the amine. During this heating, an exotherm is observed, indicating 45°C. After heating at 60°C for 14 hours 46 minutes, a sample of the reaction mixture is analyzed by HPLC.

[0245] The reaction mixture is then cooled to 24°C and transferred to a solution of 2M HCl over 2 hours 28 minutes, the reaction vessel is rinsed with THF (22.3 Kg) and transferred to the HCl containing reaction mixture. The biphasic mixture is heated to 45°C-55°C and stirred at this temperature for 1 hour 48 minutes before being cooled to 30°C. The pH of the quenched reaction mixture is measured and found to be 1. The reaction is quenched 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. Aqueous ammonia is added to the combined aqueous layers and the pH is measured which shows a pH of 9. The reaction is then quenched by extracting the aqueous layer twice with IPAc. The combined organic extracts are then washed with a 5% sodium chloride solution. The resulting organic layer is partially concentrated, azeotropically dried and coevaporated four times with methylene chloride, then diluted with methylene chloride and the reaction mixture is transferred to a clean dry reaction vessel through an in-line filter and diluted with IPAc. p-Toluenesulfonic acid hydrate (54 Kg) is then added portionwise to precipitate the desired product as pTsOH salt, the reaction suspension is stirred at 10°C-15°C for 3 hours and the product is isolated by filtration. The filter cake is washed with 2-methyltetrahydrofuran, followed by IPAc, and then sucked dry for 2 hours. The crude product is purified by stirring with 2-methyltetrahydrofuran at 10°C-15°C for 11 hours 36 minutes and the product is isolated by filtration. The filtered solid is washed with 2-methyltetrahydrofuran and then dried to constant weight to give 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 give a slurry. Thionyl chloride (26.4 kg) is then added over 3 hours. Upon completion of the thionyl chloride addition, the reaction mixture is stirred for an additional 3 hours. Aqueous sodium hydroxide (5M, 10 mol equivalents) is added over 3 hours, followed by stirring for an additional 2 hours. The layers are allowed to settle and the pH of the aqueous layer is checked to be 9. Water (2 mL / g, SM) is added, the reaction mixture is stirred for an additional 15 minutes at room temperature, the layers are separated, and the organic layer is washed twice with water. The aqueous layers are combined and back-extracted with 2-methyltetrahydrofuran, and the original organic layer and 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 equivalents of HCl / IPA) is added and stirred for 2 hours to form the crude salt, which is isolated by filtration, washed with 2-methyltetrahydrofuran, then IPAc, and then sucked dry under vacuum for 2 hours.

[0247] The crude product (82.6 Kg) obtained above is dissolved in 14 volumes of hot ethanol (70°C), then filtered through a capsule carbon filter to improve color. The dissolution vessel, capsule carbon filter, and transfer line are then rinsed with additional hot ethanol (70°C), and the washings are combined with the filtrate. The combined filtrate and washings are partially concentrated under reduced pressure to a total of about 5 volumes (relative to the crude product added), and then stirred at 0°C for 2 hours. The resulting solid is isolated by filtration, and the filter cake is washed with cold (0°C to 5°C) ethanol, followed by IPAc, and the washed solid is dried to obtain the product (33.6 Kg) as an off-white solid. Yield = 33.6 Kg (73% yield). Achiral HPLC = 98%.

[0248] The material is then dried by cone drying. After drying, the material is sieved.

[0249] A portion of the material (14 Kg) is then dissolved in 15 volumes of hot ethanol (70°C) and filtered through a capsule carbon filter to improve color. The dissolution vessel, capsule carbon filter, and transfer line are then rinsed with additional hot ethanol (70°C), and the wash is combined with the filtrate. The combined filtrate and wash are partially concentrated under reduced pressure to a total of about 8 volumes (relative to the 14 Kg of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride initially charged), and then stirred at 18°C ​​for 2 hours. The resulting solid is isolated by filtration, and the filter cake is washed with cold (5°C-10°C) ethanol, followed by IPAc, and the washed solid is dried to give (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (9.4 Kg, 67.1% yield) as a white solid. Achiral HPLC=98%.

[0250] The XRPD of the product is shown in Figure 56. The XRPD shows evidence of low intensity peaks at 18.9°, 19.2°, 23.6°, 23.8°, 28.2° and 28.7° 2θ attributed to crystalline form B, but is consistent with crystalline form A. XRPD patterns are collected on a PANalytical X'Pert PRO MPD diffractometer using a Cu radiation incident beam generated using an Optix long fine focus source. The Cu Kα X-rays are focused onto the sample using an elliptical stepped multilayer mirror and directed towards the detector. A silicon sample (NIST SRM 640e) is analysed prior to analysis to ensure that the observed position of the Si 111 peak matches the NIST certified position. Sample specimens are sandwiched between 3 μm thick films and analysed in transmission geometry. A beam stop, anti-scatter short extension and anti-scatter knife edge are used to minimise background generated by air. Soller slits are used on the incident and diffracted beams to minimise extension from axial divergence. Diffraction patterns are collected using a scattering position sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b.

[0251] XRPD data acquisition parameters were: 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, collection time: 721 s, scan speed: 3.2° / min., slits: 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 To a 2 L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, thermocouple, and heating mantle, add 50 g of the product from Example 16 above and EtOH Special Technical Grade (750 mL, 15 volumes). Heat the mixture to reflux (77°C). The solids dissolve at 72°C to form a clear solution. Add the thin dark grey slurry (5 g, 0.1 eq / 100 mL EtOH) and stir the mixture for 1 hour. Filter and rinse with hot EtOH (150 mL). Split the filtrate into two equal portions.

[0253] quantity 1 Concentrate to 10 volumes (250 mL) at 50 °C. A small amount of solid begins to precipitate during concentration. Transfer to a 500 mL 3-neck round bottom flask equipped with a mechanical stirrer and cool to room temperature. Stir at room temperature for 2 h. A suspension forms. Filter and rinse with EtOH (50 mL, 2 volumes) then 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 3-neck round bottom flask equipped with a mechanical stirrer and cool to room temperature. Stir at room temperature for 2 h. A suspension forms. Filter and rinse with EtOH (50 mL, 2 volumes) then IPAc (50 mL). Suction dry on the filter. Yield = 19.8 g (79.2%).

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

[0256] Example 18 - Preparation of Crystalline Forms The following crystal forms are prepared using Crystal Form A of Example 5. [Table 31]

Claims

1. P2 1 2 1 2 1 It belongs 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° The crystalline form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride has the formula:

2. 2. The crystalline form A of claim 1, having an X-ray powder diffraction (XRPD) pattern measured using an incident beam of Cu Kα radiation, the XRPD pattern including five peaks selected from those shown in FIG.

3. 3. The crystalline form A of claim 1 or 2, having an X-ray powder diffraction (XRPD) pattern measured using an incident beam of Cu Kα radiation, substantially as shown in FIG.

1.

4. The crystalline form A according to any one of claims 1 to 3, having an X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using an incident beam of Cu Kα radiation.

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

6. Crystalline form A is shown in Table A below: Table A 【Table 1】 6. The crystalline form A of any one of claims 1 to 5, having an XRPD pattern comprising the 2θ(°) values ​​shown in:

7. 7. The crystalline form A of any one of claims 1 to 6, wherein the crystalline form A exhibits an XRPD pattern comprising 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, wherein the XRPD is measured using an incident beam of Cu Kα radiation.

8. Crystalline form A is shown in Table B below: Table B 【Table 2】 The crystalline form A according to any one of claims 1 to 7, having an XRPD pattern comprising the 2θ(°) values ​​shown in:

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 and the XRPD is measured using an incident beam of Cu Kα radiation.

10. Crystalline form A is shown in Table C below: Table C 【Table 3】 10. The crystalline form A of any one of claims 1 to 9, having an XRPD pattern comprising the 2θ(°) values ​​shown in:

11. The crystalline form A according to any one of claims 1 to 10, wherein the crystalline form A exhibits an XRPD pattern comprising d-spacing (Å) values ​​of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9 and 3.

5.

12. Crystalline form A is shown in Table A below: Table A 【Table 4】 The crystalline form A according to any one of claims 1 to 11, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​as shown in:

13. 13. The crystalline form A of any one of claims 1 to 12, wherein the crystalline form A exhibits an XRPD pattern comprising d-spacing (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. Crystalline form A is shown in Table B below: Table B 【Table 5】 The crystalline form A according to any one of claims 1 to 13, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​as shown in:

15. 15. The crystalline form A of any one of claims 1 to 14, wherein the crystalline form A exhibits an XRPD pattern comprising d-spacing (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. Crystalline form A is shown in Table C below: Table C 【Table 6】 The crystalline form A of any one of claims 1 to 15, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​as shown in:

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

18. The crystalline form A according to any one of claims 1 to 17, wherein the crystalline form A exhibits an XRPD pattern substantially as shown in any one of Figures 35, 37 and 47, measured using radiation of wavelength 1.54059 Å.

19. The crystalline form A according to any one of claims 1 to 18, wherein the crystalline form A exhibits an XRPD pattern as shown in any one of Figures 35, 37 and 47, measured using radiation of wavelength 1.54059 Å.

20. P2 1 2 1 2 1 It belongs 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-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, having the formula:

21. 21. The crystalline form B of claim 20, wherein the crystalline form B exhibits an XRPD pattern comprising 2θ(°) values ​​of 6.0, 17.4, 18.9, 19.2, and 24.4, wherein the XRPD is measured using an incident beam of Cu Kα radiation.

22. Crystalline form B is shown in Table D below: Table D 【Table 7】 22. The crystalline form B of claim 20 or 21, having an XRPD pattern comprising the 2θ (°) values ​​shown in:

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

24. Crystalline form B is shown in Table E below: Table E 【Table 8】 24. The crystalline form B of any one of claims 20 to 23, having an XRPD pattern comprising the 2θ(°) values ​​shown in:

25. 25. The crystalline form B of any one of claims 20 to 24, wherein the crystalline form B exhibits an XRPD pattern comprising 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, wherein the XRPD is measured using an incident beam of Cu Kα radiation.

26. Crystalline form B is shown in Table F below: Table F 【Table 9】 26. The crystalline form B of any one of claims 20 to 25, having an XRPD pattern comprising 2θ(°) values ​​selected from those shown in:

27. 27. The crystalline form B of any one of claims 20 to 26, wherein the crystalline form B exhibits an XRPD pattern comprising d-spacing (Å) values ​​of 14.6, 5.1, 4.7, 4.6 and 3.

6.

28. Crystalline form B is shown in Table D below: Table D 【Table 10】 The crystalline form B of any one of claims 20 to 27, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​as shown in:

29. 29. The crystalline form B of any one of claims 20 to 28, wherein the crystalline form B exhibits an XRPD comprising d-spacing (Å) values ​​of 14.6, 6.7, 5.1, 4.7, 4.6, 3.8, 3.7, 3.6, and 3.

2.

30. Crystalline form B is shown in Table E below: Table E 【Table 11】 The crystalline form B of any one of claims 20 to 29, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​as shown in:

31. 31. The crystalline form B of any one of claims 20 to 30, wherein the crystalline form B exhibits an XRPD comprising d-spacing (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. Crystalline form B is shown in Table F below: Table F 【Table 12】 The crystalline form B of any one of claims 20 to 31, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​as shown in:

33. The crystalline form B according to any one of claims 20 to 32, wherein the crystalline form B exhibits an XRPD pattern substantially as shown in Figure 5, measured using radiation of wavelength 1.541871 Å.

34. The crystalline form B according to any one of claims 20 to 33, wherein the crystalline form B exhibits the XRPD pattern shown in Figure 5, measured using radiation of wavelength 1.541871 Å.

35. The crystalline form B according to any one of claims 20 to 34, wherein the crystalline form B exhibits an XRPD pattern substantially as shown in any one of Figures 7, 40 and 48, measured using radiation of wavelength 1.54059 Å.

36. The crystalline form B according to any one of claims 20 to 35, wherein the crystalline form B exhibits the XRPD pattern of any one of Figures 7, 40 and 48 measured using radiation of wavelength 1.54059 Å.

37. A pharmaceutical composition comprising crystalline form A according to any one of claims 1 to 19 and a pharma- ceutically acceptable diluent or carrier.

38. A method for preventing or treating attention deficit hyperactivity disorder, e.g. in a patient suffering from a fragile X syndrome related disorder, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline form A of any one of claims 1 to 19 or the pharmaceutical composition of claim 37.

39. 38. A method for preventing or treating a substance abuse disorder, a fragile X syndrome associated disorder, an autism spectrum disorder, for example in a patient with a fragile X syndrome associated disorder, comorbid attention deficit hyperactivity disorder and depression, comorbid attention deficit hyperactivity disorder and substance abuse, or comorbid attention deficit hyperactivity disorder and anxiety, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline form A of any one of claims 1 to 19 or the pharmaceutical composition of claim 37.

40. A pharmaceutical composition comprising crystalline form B according to any one of claims 20 to 36 and a pharma- ceutically acceptable diluent or carrier.

41. A method for preventing or treating attention deficit hyperactivity disorder, e.g. in a patient suffering from a fragile X syndrome related disorder, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline form B of any one of claims 20 to 36 or the pharmaceutical composition of claim 40.

42. 42. A method for preventing or treating a substance abuse disorder, a fragile X syndrome associated disorder, an autism spectrum disorder, for example in a patient with a fragile X syndrome associated disorder, comorbid attention deficit hyperactivity disorder and depression, comorbid attention deficit hyperactivity disorder and substance abuse, or comorbid attention deficit hyperactivity disorder and anxiety, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline form A of any one of claims 20 to 36 or the pharmaceutical composition of claim 40.

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