R-Ketamine salts and methods of use thereof

Abstract

The present disclosure relates to novel salts and salt forms of (2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (R-ketamine), and processes for their preparation. The present disclosure is also directed to pharmaceutical compositions containing at least one R-ketamine 5 salt or salt form, and to therapeutic and / or prophylactic uses of such salts, salt forms, and compositions thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 254,878, filed October 12, 2021, which is incorporated by reference herein in its entirety for all purposes.

[0002] The present disclosure relates to salts and salt forms of (2R-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (R-ketamine), processes for their preparation, and their use in the manufacture of medicaments for treating patients. The present disclosure is also directed to pharmaceutical compositions containing at least one R-ketamine salt, and therapeutic and / or prophylactic uses of such salts and compositions. [Background technology]

[0003] R-ketamine has been shown to be active in treating various neurological conditions and alleviating the corresponding symptoms. Optimizing the production of R-ketamine for preparing pharmaceutical compositions requires the development of new, stable and useful salts and polymorphs thereof. Summary of the Invention

[0004] The present disclosure is directed to novel salts and salt forms of R-ketamine for use in the manufacture of a medicament or pharmaceutical composition for the treatment of a patient in need thereof.

[0005] In one aspect, the present disclosure is directed to an R-ketamine saccharin salt.

[0006] In one embodiment, the R-ketamine saccharin salt is crystalline.

[0007] In one embodiment, the R-ketamine saccharin salt is amorphous.

[0008] In one embodiment, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 13.8°2θ, 15.6°2θ, and 23.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0009] In one embodiment, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.6°2θ, and 23.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0 2θ; Cu Kα1 radiation).

[0010] In one embodiment, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0011] In one embodiment, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those set forth in Table 2.

[0012] In one embodiment, the R-ketamine saccharin salt is a 1:1 R-ketamine:saccharin salt.

[0013] In one embodiment, the R-ketamine saccharin salt is a 2:1 R-ketamine:saccharin salt.

[0014] In one embodiment, the R-ketamine saccharin salt is a 1:2 R-ketamine:saccharin salt.

[0015] In one aspect, the present disclosure is directed to R-ketamine fumarate.

[0016] In one embodiment, the R-ketamine fumarate is crystalline.

[0017] In one embodiment, the R-ketamine fumarate is a crystalline polymorphic form of Form A.

[0018] In one embodiment, R-ketamine fumarate Form A is characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, and 14.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0019] In one embodiment, R-ketamine fumarate Form A is characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, and 14.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0020] In one embodiment, R-ketamine fumarate Form A is characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0021] In one embodiment, R-ketamine fumarate Form A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those listed in Table 3.

[0022] In one embodiment, the R-ketamine fumarate is the crystalline polymorphic form Form B.

[0023] In one embodiment, R-ketamine fumarate Form B is characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 14.5 °2θ, 15.1 °2θ, and 20.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0024] In one embodiment, R-ketamine fumarate Form B is characterized by PXRD peaks at 14.5 °2θ, 15.1 °2θ, and 20.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0025] In one embodiment, R-ketamine fumarate Form B is characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0026] In one embodiment, R-ketamine fumarate Form B is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those listed in Table 4.

[0027] In one embodiment, the R-ketamine fumarate is 1:1 R-ketamine:fumarate.

[0028] In one embodiment, the R-ketamine fumarate is 2:1 R-ketamine:fumarate.

[0029] In one embodiment, the R-ketamine fumarate is 1:1 to 1:2 R-ketamine:fumarate.

[0030] In one embodiment, the R-ketamine fumarate is a hemifumarate salt. In one embodiment, the R-ketamine fumarate is a hemifumarate salt of Form A. In one embodiment, the R-ketamine fumarate is a hemifumarate salt of Form B.

[0031] In one aspect, the present disclosure is directed to R-ketamine succinate.

[0032] In one embodiment, the R-ketamine succinate is crystalline.

[0033] In one embodiment, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 9.0°2θ, 13.5°2θ, and 18.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0034] In one embodiment, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 9.0°2θ, 13.5°2θ, and 18.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0035] In one embodiment, the R-ketamine succinate is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0036] In one embodiment, the R-ketamine succinate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those set forth in Table 5.

[0037] In one aspect, the present disclosure is directed to R-ketamine sulfate.

[0038] In one embodiment, the R-ketamine sulfate is crystalline.

[0039] In one embodiment, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 19.8°2θ, 22.5°2θ, and 26.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0040] In one embodiment, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 22.5 °2θ, and 26.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0041] In one embodiment, the R-ketamine sulfate is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0042] In one embodiment, the R-ketamine sulfate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PXRD peaks selected from those set forth in Table 6.

[0043] In one aspect, the present disclosure is directed to R-ketamine D-tartrate.

[0044] In one embodiment, the R-ketamine D-tartrate is crystalline. In one embodiment, the R-ketamine D-tartrate is non-solvated.

[0045] In one embodiment, the R-ketamine D-tartrate is a crystalline polymorphic form of Form A.

[0046] In one embodiment, R-ketamine D-tartrate Form A is characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 10.3 °2θ, 14.7 °2θ, and 15.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0047] In one embodiment, R-ketamine D-tartrate Form A is characterized by PXRD peaks at 10.3 °2θ, 14.7 °2θ, and 15.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0048] In one embodiment, R-ketamine D-tartrate Form A is characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0049] In one embodiment, R-ketamine D-tartrate Form A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 7.

[0050] In one embodiment, the R-ketamine D-tartrate is in the crystalline polymorphic form of Form B.

[0051] In one embodiment, R-ketamine D-tartrate Form B is characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 5.9 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0052] In one embodiment, R-ketamine D-tartrate Form B is characterized by PXRD peaks at 5.9 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0053] In one embodiment, R-ketamine D-tartrate Form B is characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0054] In one embodiment, R-ketamine D-tartrate Form B is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 8.

[0055] In one embodiment, the R-ketamine D-tartrate is in the crystalline polymorphic form of Form C.

[0056] In one embodiment, R-ketamine D-tartrate Form C is characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, and 12.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0057] In one embodiment, R-ketamine D-tartrate Form C is characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, and 12.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0058] In one embodiment, R-ketamine D-tartrate Form C is characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 11.0 °2θ, 13.6 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0059] In one embodiment, R-ketamine D-tartrate Form C is characterized by PXRD peaks at 11.0 °2θ, 13.6 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0060] In one embodiment, R-ketamine D-tartrate Form C is characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0061] In one embodiment, R-ketamine D-tartrate Form C is characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0062] In one embodiment, R-ketamine D-tartrate Form C is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 9.

[0063] In one embodiment, the R-ketamine D-tartrate is the crystalline polymorphic form Form D.

[0064] In one embodiment, R-ketamine D-tartrate Form D is characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 12.7 °2θ, 14.3 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0065] In one embodiment, R-ketamine D-tartrate Form D is characterized by PXRD peaks at 12.7 °2θ, 14.3 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0066] In one embodiment, R-ketamine D-tartrate Form D is characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0067] In one embodiment, R-ketamine D-tartrate Form D is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 10.

[0068] In one embodiment, R-ketamine D-tartrate Form A is 1:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form B is 1:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form C is 1:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form D is 1:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form A is 2:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form B is 2:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form C is 2:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form D is 2:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form A is 1:1 to 2:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form B is 1:1 to 2:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form C is 1:1 to 2:1 R-ketamine:D-tartrate. In one embodiment, R-ketamine D-tartrate Form D is 1:1 to 2:1 R-ketamine:D-tartrate.

[0069] In one aspect, the present disclosure is directed to R-ketamine oxalate.

[0070] In one embodiment, the R-ketamine oxalate is crystalline.

[0071] In one embodiment, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 12.8°2θ, 14.8°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0072] In one embodiment, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.8°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0 2θ; Cu Kα1 radiation).

[0073] In one embodiment, the R-ketamine oxalate is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0074] In one embodiment, the R-ketamine oxalate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 11.

[0075] In one embodiment, the R-ketamine oxalate is 2:1 R-ketamine:oxalate.

[0076] In one aspect, the present disclosure is directed to R-ketamine citrate.

[0077] In one embodiment, the R-ketamine citrate salt is crystalline.

[0078] In one embodiment, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 14.8 °2θ, 16.8 °2θ, and 21.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0079] In one embodiment, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 14.8 °2θ, 16.8 °2θ, and 21.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0080] In one embodiment, the R-ketamine citrate is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0081] In one embodiment, the R-ketamine citrate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 12.

[0082] In one embodiment, the R-ketamine citrate is 1:1 R-ketamine:citrate.

[0083] In one embodiment, the R-ketamine citrate is 2:1 R-ketamine:citrate.

[0084] In one embodiment, the R-ketamine citrate is 1:1 to 3:1 R-ketamine:citrate.

[0085] In one aspect, the present disclosure is directed to R-ketamine free base Form A.

[0086] In one embodiment, the R-ketamine free base form A is crystalline.

[0087] In one embodiment, R-ketamine free base Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 14.8 °2θ, 20.7 °2θ, and 23.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0088] In one embodiment, R-ketamine free base Form A is a crystalline polymorphic form characterized by PXRD peaks at 14.8 °2θ, 20.7 °2θ, and 23.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0089] In one embodiment, R-ketamine free base Form A is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0090] In one embodiment, R-ketamine free base Form A is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks as set forth in Table 1.

[0091] In one embodiment, R-ketamine free base Form A is characterized by an FT Raman spectrum substantially similar to that shown in FIG.

[0092] In one embodiment, R-ketamine free base Form A has a structure substantially similar to that shown in FIG. 1 Characterized by H-NMR spectrum.

[0093] In one aspect, the disclosure is directed to a pharmaceutical composition comprising one or more of the salts or salt forms described herein and a pharma- ceutically acceptable excipient, diluent, or carrier.

[0094] In one aspect, the disclosure is directed to a pharmaceutical composition comprising one or more of the salts or salt forms described herein for use in the treatment or prevention of depression or depressive symptoms in a patient in need thereof.

[0095] In one aspect, the disclosure is directed to a pharmaceutical composition comprising one or more of the salts or salt forms described herein for use in the treatment or prevention of treatment-resistant depression in a patient in need thereof.

[0096] In one aspect, the disclosure is directed to the use of a salt or salt form described herein in the preparation of a medicament for the treatment or prevention of depression or depressive symptoms in a patient in need thereof.

[0097] In one aspect, the disclosure is directed to the use of a salt or salt form described herein in the preparation of a medicament for the treatment or prevention of treatment-resistant depression or depressive symptoms in a patient in need thereof.

[0098] In one aspect, the disclosure is directed to a method of treating or preventing depression or depressive symptoms comprising administering to a patient in need thereof a salt, salt form, or pharmaceutical composition described herein.

[0099] In one aspect, the disclosure is directed to a method of treating or preventing treatment-resistant depression or depressive symptoms comprising administering to a patient in need thereof a salt, salt form, or pharmaceutical composition described herein.

[0100] Additional features, advantages, and aspects of the present disclosure are set forth in or will be apparent from consideration of the following detailed description, drawings, and claims. Moreover, it is to be understood that both the foregoing summary of the disclosure and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the present disclosure as claimed. [Brief description of the drawings]

[0101] The accompanying drawings, which are included to provide a further understanding of the present disclosure, are incorporated in and constitute a part of this specification, illustrate aspects of the disclosure, and together with the detailed description, serve to explain the principles of the disclosure.

[0102] [Figure 1] 3 depicts the PXRD pattern of R-ketamine free base.

[0103] [Diagram 2] Depicts the PXRD patterns of R-ketamine free base (top) and its hydrochloride salt starting material (bottom).

[0104] [Diagram 3] An overview of the FT Raman spectrum of R-ketamine free base from 200 to 3500 cm-1 is depicted.

[0105] [Figure 4] Depict the fingerprint region of the FT Raman spectrum of R-ketamine free base from 200 to 1800 cm-1.

[0106] [Diagram 5] A TG-FTIR thermogram of R-ketamine free base is depicted, showing residual traces of dichloromethane at 0.57%; decomposition was observed above 190° C.

[0107] [Figure 6] FIG. 1 depicts the H-NMR spectrum of R-ketamine free base recorded in DMSO-d6. The spectrum is consistent with the chemical structure of ketamine. Residual dichloromethane (less than 0.01 equivalents) is seen at 5.8 ppm.

[0108] [Figure 7A] 1 depicts the layout of a 96-well quartz plate showing the location of each salt former.

[0109] [Figure 7B] Describe the solvents used in the evaporation experiments.

[0110] [Figure 8A] 1 depicts the layout of a 96-well quartz plate showing the location of each salt former and solvent domain.

[0111] [Figure 8B] Describe the solvents used in the slurry experiments.

[0112] [Figure 9] PXRD pattern of R-ketamine saccharin salt is depicted.

[0113] [Figure 10] 1 depicts an overlay of the PXRD patterns of saccharin (bottom), R-ketamine saccharin salt (second from the bottom), R-ketamine free base (third from the bottom), and R-ketamine HCl salt (top).

[0114] [Figure 11] 1 depicts an overlay of the PXRD patterns of wet R-ketamine saccharin salt (bottom) and dry R-ketamine saccharin salt (top).

[0115] [Figure 12] 1 depicts an overview of the FT Raman spectrum of R-ketamine saccharin salt.

[0116] [Figure 13] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine saccharin salt.

[0117] [Figure 14] 1 depicts an overlay of the FT Raman spectra of R-ketamine saccharin salt from Example 3 (top) and R-ketamine saccharin salt from Example 4 (bottom). Both samples exhibit the same Raman spectrum.

[0118] [Figure 15] TG-FTIR of R-ketamine saccharin salt is depicted.

[0119] [Figure 16] 1 depicts the DSC of R-ketamine saccharin salt.

[0120] [Figure 17] 1H-NMR of R-ketamine saccharin salt is depicted. The spectrum is consistent with a 1:1 saccharin salt with water and residual isopropanol (0.009 equivalents).

[0121] [Figure 18] DVS isotherms for R-ketamine saccharin salt: Depicting the change in water content (bottom) and relative humidity (top) as a function of time.

[0122] [Figure 19] 13. DVS isotherm of R-ketamine saccharin salt—depicting the change in water content as a function of relative humidity.

[0123] [Figure 20] 1 depicts an overlay of the PXRD patterns of R-ketamine saccharin salt after DVS (bottom) and R-ketamine saccharin salt before DVS (top).

[0124] [Figure 21] 1 depicts the PXRD pattern of R-ketamine fumarate form A.

[0125] [Figure 22] 1 depicts an overlay of the PXRD patterns of fumaric acid (bottom) and R-ketamine fumarate Form A (top).

[0126] [Figure 23] 1 depicts an overlay of the PXRD patterns of R-ketamine fumarate form A (bottom), R-ketamine free base (second from the bottom), R-ketamine HCl salt (second from the top), and R-ketamine saccharin salt (top).

[0127] [Figure 24]1 depicts the 1H-NMR of R-ketamine fumarate form A. The spectrum is consistent with a 2:1 ratio of free base to fumarate.

[0128] [Diagram 25] 1 depicts an overview of the FT Raman spectrum of R-ketamine fumarate.

[0129] [Figure 26] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine fumarate.

[0130] [Figure 27] 1 depicts an overlay of FT Raman spectra of R-ketamine fumarate from Example 2 (arrow points to this trace) and R-ketamine fumarate Form A of R-ketamine. The samples exhibit distinct Raman spectra.

[0131] [Figure 28A] 1 depicts the TG-FTIR thermogram of R-ketamine fumarate form A.

[0132] [Figure 28B] 1 depicts a DSC thermogram of R-ketamine hemifumarate Form A.

[0133] [Figure 28C] DVS isotherms for Form A: Depicting the change in moisture content (top) and relative humidity (bottom) as a function of time.

[0134] [Figure 28D] DVS isotherm of R-ketamine fumarate form A: Depicting the change in water content as a function of relative humidity.

[0135] [Figure 28E] 1 depicts an overlay of the PXRD patterns of R-ketamine fumarate Form A after DVS (bottom) and R-ketamine fumarate Form A before DVS (top).

[0136] [Figure 29] 3 depicts the PXRD pattern of R-ketamine succinate.

[0137] [Diagram 30] 1 depicts an overlay of the PXRD patterns of R-ketamine succinate (bottom), R-ketamine free base (second from the bottom), R-ketamine HCl salt (middle), R-ketamine saccharin salt (second from the top), and R-ketamine fumarate (top).

[0138] [Diagram 31] FIG. 1 depicts the 1H-NMR of R-ketamine succinate. The spectrum is consistent with a 1:1 ratio of the free base to the succinate salt.

[0139] [Diagram 32] 1 depicts an overview of the FT Raman spectrum of R-ketamine succinate.

[0140] [Diagram 33] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine succinate.

[0141] [Diagram 34] 1 depicts an overlay of FT Raman spectra of salt screening with succinic acid (top, with arrow) and R-ketamine succinate (bottom).

[0142] [Diagram 35] 1 depicts the TG-FTIR thermogram of R-ketamine succinate.

[0143] [Diagram 36] PXRD pattern of R-ketamine sulfate is depicted.

[0144] [Figure 37] 1 depicts an overlay of the PXRD patterns of R-ketamine sulfate (top) and the free base (bottom).

[0145] [Figure 38] 1H-NMR of R-ketamine sulfate. The spectrum is consistent with the R-ketamine sulfate structure with some residual TBME.

[0146] [Figure 39] 1 depicts a comparison of the 1H-NMR spectra of R-ketamine sulfate (bottom) and R-ketamine free base starting material (top).

[0147] [Diagram 40] 1 depicts the PXRD pattern of R-ketamine D-tartrate Form A.

[0148] [Diagram 41] 1 depicts an overlay of the PXRD patterns of D-tartaric acid (bottom), R-ketamine D-tartrate Form A (middle), and the free base (top).

[0149] [Diagram 42] FIG. 1 depicts the H-NMR of R-ketamine D-tartrate form A. The spectrum is consistent with the structure, with approximately 0.8 equivalents of D-tartrate observed.

[0150] [Diagram 43] PXRD pattern of R-ketamine oxalate is depicted.

[0151] [Diagram 44] An overlay of the PXRD patterns of oxalic acid (bottom), R-ketamine oxalate (middle), and the free base (top) is depicted.

[0152] [Figure 45A] FIG. 1 depicts the 1H-NMR of R-ketamine oxalate. The spectrum is consistent with the R-ketamine structure.

[0153] [Figure 45B] 1 depicts the TG-FTIR thermogram of R-ketamine oxalate.

[0154] [Figure 45C] 1 depicts the DSC curve of R-ketamine oxalate.

[0155] [Figure 45D] 1 depicts an overview of the FT Raman spectrum of R-ketamine oxalate.

[0156] [Figure 45E] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine oxalate.

[0157] [Fig.45F] DVS isotherms for R-ketamine oxalate: Depicting the change in water content (top) and relative humidity (bottom) as a function of time.

[0158] [Figure 45G] DVS isotherm of R-ketamine oxalate: Depicting the change in water content as a function of relative humidity.

[0159] [Fig. 45H] Depicts an overlay of the PXRD patterns of R-ketamine oxalate after DVS (bottom) and R-ketamine oxalate before DVS (top). [Figure 46] 3 depicts the PXRD pattern of R-ketamine citrate.

[0160] [Figure 47] 1 depicts an overlay of the PXRD patterns of citric acid (bottom), R-ketamine citrate (middle), and the free base (top).

[0161] [Figure 48] 1 depicts the H-NMR of R-ketamine citrate with residual TBME and 2-propanol.

[0162] [Figure 49]Depicts an overlay of THF with free base reference (blue trace) and location b in well A7 (arrows depict different R-ketamine free base crystal forms).

[0163] [Figure 50A] 1 depicts a representative crystal image of ADI R-ketamine salt.

[0164] [Figure 50B] 1 depicts a representative crystal image of ADI R-ketamine salt.

[0165] [Figure 50C] 1 depicts a representative crystal image of BZN R-ketamine salt.

[0166] [Figure 50D] 1 depicts a representative crystal image of BZN R-ketamine salt.

[0167] [Figure 50E] 1 depicts a representative crystal image of FUM R-ketamine salt.

[0168] [Figure 50F] 1 depicts a representative crystal image of SACR-ketamine salt.

[0169] [Figure 50G] 1 depicts a representative crystal image of SUC R-ketamine salt.

[0170] [Figure 51A] 1 depicts a representative crystal image of BZN R-ketamine salt.

[0171] [Figure 51B] 1 depicts a representative crystal image of BZN R-ketamine salt.

[0172] [Figure 51C] 1 depicts a representative crystal image of FUM R-ketamine salt.

[0173] [Fig. 51D] 1 depicts a representative crystal image of FUM R-ketamine salt.

[0174] [Figure 51E] 1 depicts a representative crystal image of SACR-ketamine salt.

[0175] [Fig. 51F] 1 depicts a representative crystal image of SUC R-ketamine salt.

[0176] [Figure 52] Depicts an overlay of the PXRD patterns of R-ketamine citrate (top) and R-ketamine free base (scaled down to 0.5 for better comparison, bottom). No peaks from citric acid are present.

[0177] [Figure 53] 1 depicts the DSC curve of R-ketamine D-tartrate form A.

[0178] [Figure 54] 1 depicts an overview of the FT Raman spectrum of R-ketamine D-tartrate Form A.

[0179] [Figure 55] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine D-tartrate Form A.

[0180] [Figure 56] 1 depicts the PXRD pattern of R-ketamine D-tartrate Form B.

[0181] [Figure 57] 1 depicts an overlay of the PXRD patterns of R-ketamine D-tartrate form B (top) and R-ketamine free base (bottom).

[0182] [Figure 58]FIG. 1 depicts the H-NMR of R-ketamine D-tartrate form B. The spectrum is consistent with a 1:1 ratio of R-ketamine to D-tartrate. Residual acetone (0.01 equivalents) is observed at 2.09 ppm. [Figure 59] 1 depicts an overview of the FT Raman spectrum of R-ketamine D-tartrate form B.

[0183] [Figure 60] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine D-tartrate form B.

[0184] [Figure 61] 1 depicts the PXRD pattern of R-ketamine D-tartrate Form C.

[0185] [Figure 62] 1 depicts an overlay of the PXRD patterns of R-ketamine D-tartrate Form A (top), R-ketamine D-tartrate Form B (middle), and R-ketamine D-tartrate Form C (bottom).

[0186] [Figure 63] 1 depicts an overlay of the PXRD patterns of R-ketamine D-tartrate form C (top) and R-ketamine free base (bottom).

[0187] [Figure 64] 1 depicts the H-NMR of R-ketamine D-tartrate form C. The spectrum is consistent with a 1:1.5 ratio of R-ketamine to D-tartrate.

[0188] [Figure 65] 1 depicts an overview of the FT Raman spectrum of R-ketamine D-tartrate form C.

[0189] [Figure 66] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine D-tartrate form C.

[0190] [Figure 67]1 depicts an overlay of the Raman spectra of R-ketamine D-tartrate Form A (blue trace), R-ketamine D-tartrate Form B (red trace), and R-ketamine D-tartrate Form C (green trace).

[0191] [Figure 68] 1 depicts the PXRD pattern of R-ketamine fumarate form B.

[0192] [Figure 69] 1 depicts an overlay of the PXRD patterns of fumaric acid (bottom) and R-ketamine fumarate Form B (top).

[0193] [Figure 70] 1 depicts an overlay of the PXRD patterns of R-ketamine fumarate Form B (bottom), R-ketamine fumarate Form A (middle), and the free base (top). Arrows indicate reflections of R-ketamine fumarate Form A that can be found in R-ketamine fumarate Form B.

[0194] [Figure 71] 1 depicts the 1H-NMR of R-ketamine fumarate form B. The spectrum is consistent with a 2:1 ratio of free base to fumarate. Residual THF is observed at 3.60 ppm.

[0195] [Figure 72] 1 depicts an overview of the FT Raman spectrum of R-ketamine fumarate form B.

[0196] [Figure 73] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine fumarate form B.

[0197] [Figure 74] 1 depicts an overlay of the PXRD patterns of R-ketamine free base (top), R-ketamine D-tartrate form A (middle), and R-ketamine D-tartrate form B (bottom).

[0198] [Figure 75] 1 depicts the DSC thermogram of R-ketamine free base.

[0199] [Figure 76] FIG. 1 depicts the TG-FTIR thermogram of R-ketamine D-tartrate form A.

[0200] [Figure 77] DVS isotherms for R-ketamine D-tartrate Form A: Depicting the change in water content (top) and relative humidity (bottom) as a function of time.

[0201] [Figure 78] 14. DVS isotherm of R-ketamine D-tartrate form A: Depicting the change in water content as a function of relative humidity.

[0202] [Figure 79] 1 depicts the TG-FTIR thermogram of R-ketamine D-tartrate form B.

[0203] [Figure 80] 1 depicts the DSC curve of R-ketamine D-tartrate form B.

[0204] [Figure 81] DVS isotherms of R-ketamine D-tartrate form B: Depicting the change in water content (top) and relative humidity (bottom) as a function of time.

[0205] [Figure 82] DVS isotherm of R-ketamine D-tartrate form B: Depicting the change in water content as a function of relative humidity.

[0206] [Figure 83] FIG. 1 depicts the TG-FTIR thermogram of R-ketamine D-tartrate form C.

[0207] [Figure 84] 1 depicts the DSC curve of R-ketamine D-tartrate form C.

[0208] [Figure 85] DVS isotherms of R-ketamine D-tartrate form C: Depicting the change in water content (top) and relative humidity (bottom) as a function of time.

[0209] [Figure 86] DVS isotherm of R-ketamine D-tartrate form C: Depicting the change in water content as a function of relative humidity.

[0210] [Figure 87] 1 depicts the PXRD pattern of R-ketamine D-tartrate form D.

[0211] [Figure 88] 1 depicts an overview of the FT Raman spectrum of R-ketamine D-tartrate form D.

[0212] [Figure 89] 1 depicts the fingerprint region of the FT Raman spectrum of R-ketamine D-tartrate form D.

[0213] [Figure 90] 1 depicts the TG-FTIR thermogram of R-ketamine D-tartrate form D.

[0214] [Figure 91] 1 depicts the DSC curve of R-ketamine D-tartrate form D.

[0215] [Figure 92] DVS isotherm of R-ketamine D-tartrate form D: Depicting the change in water content (top) and relative humidity (bottom) as a function of time.

[0216] [Figure 93] DVS isotherm of R-ketamine D-tartrate form D: Depicting the change in water content as a function of relative humidity.

[0217] [Figure 94] 1 depicts an overlay of the PXRD patterns of R-ketamine D-tartrate Form C from Example 13 (top), Example 27 (middle), and Example 30 (bottom).

[0218] [Figure 95] 1 depicts the H-NMR of R-ketamine D-tartrate form D, which contains approximately 1-1.3 equivalents of tartaric acid.

[0219] [Figure 96] 1 depicts an overlay of the PXRD patterns of R-ketamine D-tartrate Form D (top), R-ketamine D-tartrate Form C (second from the top), R-ketamine D-tartrate Form B (second from the bottom), and R-ketamine D-tartrate Form A (bottom).

[0220] [Figure 97] Depicting the PXRD pattern of R-ketamine D-tartrate form D (top) and an overlay of the previously published PXRD pattern of S-ketamine L-tartrate dihydrate (bottom; calculated from SC-XRD data measured at -130°C; taken from E. Ratti-Moberg, P. Groth, AJ Aasen, Acta Chem. Scand., 1991, 45, 108). [Figure 98] 1 depicts the PXRD pattern of R-ketamine L-tartrate form A.

[0221] [Figure 99] 1 depicts the PXRD pattern of R-ketamine L-tartrate form B.

[0222] [Figure 100] 1 depicts an overlay of the PXRD patterns of R-ketamine L-tartrate Form B (top) and R-ketamine L-tartrate Form A (bottom).

[0223] [Figure 101]1 depicts the H-NMR of R-ketamine L-tartrate form A. 0.68 equivalents of tartaric acid are observed. Residual 2-propanol is observed at 1.03 ppm.

[0224] [Figure 102] 1 depicts the H-NMR of R-ketamine L-tartrate form B. The spectrum is consistent with a 1:1 ratio of the free base to the L-tartrate salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0225] The present disclosure provides salts and polymorphic salt forms of R-ketamine that are useful in the preparation of pharmaceutical agents and / or are useful as pharmaceutical agents. In some embodiments, one or more of the salts and / or salt forms described herein can be formulated into a pharmaceutical composition.

[0226] definition The terms "X-ray powder diffraction pattern", "PXRD pattern", "X-ray powder diffraction pattern", and "XRPD pattern" are used interchangeably and refer to experimentally observed diffractograms or parameters derived therefrom. X-ray powder diffraction patterns are typically characterized by peak positions (abscissa) and peak intensities (ordinate). The term "peak intensity" refers to the relative signal intensity within a given X-ray diffraction pattern. Factors that can affect the relative peak intensity are the thickness of the sample and preferred orientation (i.e., the crystalline particles are not randomly distributed). The term "peak position" as used herein refers to the X-ray reflection positions measured and observed in a powder X-ray diffraction experiment. The peak positions are directly related to the dimensions of the unit cell. Peaks identified by their respective peak positions are extracted from the diffraction patterns for various polymorphic forms of salts of R-ketamine.

[0227] The terms "2 theta value", "2θ", or "2 θ" refer to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, which is the common abscissa unit in a diffraction pattern. Generally, the experimental setup requires that the reflected beam is recorded at an angle 2 theta (2θ) when the reflection is diffracted when the incident beam forms an angle theta (θ) with a certain lattice plane. It should be understood that references herein to specific 2θ values ​​for a particular polymorphic form are intended to mean the 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0228] "Preferred orientation effect" refers to variable peak intensity or relative intensity differences between different PXRD measurements of the same sample that may be due to particle orientation. Without being bound by theory, it may be desirable to have a sample (e.g., a powder) in which the particles are randomly oriented in PXRD. However, it may be difficult or even impossible to achieve truly random particle orientation in practice. As particle size increases, the randomness of particle orientation may decrease, leading to increased challenges in achieving preferred orientation. Without being bound by theory, smaller particle size may reduce the technical challenges associated with preferred orientation and allow for more accurate representation of peaks. However, one skilled in the art will understand how to reduce or mitigate the preferred orientation effect and will recognize that preferred orientation effects may exist even between two different measurements of the same sample. By way of example, in some embodiments, differences in resolution or relative peak intensity may be due to preferred orientation effects.

[0229] As used herein, the term "substantially pure" with respect to a particular salt of a compound (or a mixture of two or more salts) indicates that the salt (or mixture) contains less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% by weight of impurities, including other salt forms of the compound. Such purity may be determined, for example, by powder X-ray diffraction.

[0230] As used herein, the term "polymorph" or "salt form" refers to different crystalline forms of the same compound, as well as other solid molecular forms, including pseudopolymorphs such as hydrates (e.g., bound water present in the crystal structure) and solvates (e.g., bound solvents other than water) of the same compound. Different crystalline polymorphs have different crystal structures due to different packing of the molecules in the lattice. This results in different crystal symmetries and / or unit cell parameters, which directly affect the physical properties of the crystal or powder, such as its X-ray diffraction properties. For example, different polymorphs generally diffract at a different set of angles, giving different values ​​for intensity. Therefore, X-ray powder diffraction can be used to identify different polymorphs, or solid forms containing more than one polymorph, in a reproducible and reliable manner (S. Byrn et al, Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations, Pharmaceutical research, Vol. 12, No. 7, p. 945-954, 1995; J. K. Haleblian and W. McCrone, Pharmaceutical Applications of Polymorphism, Journal of Pharmaceutical Sciences, Vol. 58, No. 8, p. 91 1 -929, 1969).

[0231] Crystalline polymorphic forms are of concern to the pharmaceutical industry, especially those involved in the development of suitable dosage forms. If the polymorphic form is not kept constant during clinical trials or stability testing, the exact dosage form used or tested may not be comparable between lots. Also, it is desirable to have a process for producing a compound with a selected polymorphic form in high purity when the compound is used in clinical trials or commercial products, since impurities present may cause undesired toxic effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or be more easily manufactured in large quantities with high purity, and therefore more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may exhibit other advantageous physical properties, such as lack of hygroscopic tendency, improved solubility, and enhanced dissolution rate due to different lattice energies.

[0232] The term "amorphous" refers to any solid material that (i) lacks three-dimensional order, or (ii) exhibits less than three-dimensional order, order only over short distances (e.g., less than 10 A), or both. Thus, amorphous materials include partially crystalline materials and crystalline mesophases, for example, with one- or two-dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformational disordered crystals). Amorphous solids can be characterized by known techniques, including powder X-ray diffraction (PXRD) crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or some combination of these techniques. Amorphous solids typically give a diffuse PXRD pattern consisting of one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or more).

[0233] The term "crystalline" refers to any solid material that exhibits three-dimensional order, giving a characteristic PXRD pattern with sharp, well-defined peaks, in contrast to amorphous solid materials.

[0234] The term "ambient temperature" refers to temperature conditions typically encountered in a laboratory environment, which includes the approximate temperature range of about 20 to about 30° C.

[0235] The term "detectable amount" refers to an amount, or amount per unit volume, that can be detected using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, HPLC, Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, and the like.

[0236] The term "solvate" describes a molecular complex that contains a drug substance and one or more solvent molecules (e.g., ethanol) in stoichiometric or non-stoichiometric amounts. If the solvent is tightly bound to the drug, the resulting complex has a well-defined stoichiometry that is independent of humidity. However, if the solvent is weakly bound, such as in channel solvates and hygroscopic compounds, the solvent content depends on humidity and drying conditions. In such cases, the complex may be non-stoichiometric.

[0237] The term "hydrate" describes a solvate that contains a drug substance and a stoichiometric or non-stoichiometric amount of water.

[0238] The term "relative humidity" refers to the ratio of the amount of water vapor in the air at a given temperature to the maximum amount of water vapor it can hold at that temperature and pressure, expressed as a percentage.

[0239] The term "relative intensity" refers to intensity values ​​derived from a sample X-ray diffraction pattern. The complete ordinate range scale of the diffraction pattern is assigned a value of 100. Peaks having intensities falling between about 50% and about 100% of this scale intensity are referred to as very strong (vs); peaks having intensities falling between about 50% and about 25% are referred to as strong (s). Additional weaker peaks are present in a typical diffraction pattern, also characteristic of a given polymorph, and these additional peaks are referred to as medium (m), weak (w), and very weak (vw).

[0240] The term "slurry" refers to a solid material suspended in a liquid medium, typically water or an organic solvent.

[0241] The term "under vacuum" refers to the typical pressures obtained by a laboratory oil pump or an oil-free diaphragm vacuum pump.

[0242] The term "pharmaceutical composition" refers to a composition that includes one or more of the polymorphic forms of salts of R-ketamine described herein and other chemical components, such as physiologically / pharmaceutical acceptable carriers, diluents, vehicles, and / or excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, such as a human or other mammal.

[0243] The terms "pharmaceutically acceptable," "carrier," "diluent," "vehicle," or "excipient" refer to a material (or materials) that may be included with a particular pharmaceutical agent to form a pharmaceutical composition, whether solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the carrier or diluent may include a time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with wax, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate, and the like.

[0244] The term "treating", as used herein, unless otherwise indicated, means to reverse, alleviate, or inhibit the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of "treating" as defined immediately above. For example, the terms "treat", "treating", and "treatment" can refer to a method of alleviating or eliminating a particular disorder and / or one or more of its associated symptoms.

[0245] As used herein, "subject" means a human or an animal (in the case of an animal, the subject may be a mammal). In one embodiment, the subject is a human. In one embodiment, the subject is a male. In one embodiment, the subject is a female.

[0246] The term "about" is used herein to mean approximately, within a range, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value above and below a stated value by a 20% variance, a 10% variance, a 5% variance, a 3% variance, or a 1% variance. When used in the context of XRPD peak values, the term "about" can refer to the peak value ±0.20, ±0.15, ±0.10, ±0.05, or ±0.01 °2θ. In some embodiments, when used in the context of XRPD peak values, "about" can refer to the peak value substantially exactly at the disclosed peak value.

[0247] R-Ketamine Crystal Morphology As described below, R-ketamine can form salts with different acids. In some embodiments, the R-ketamine salts described herein exist in various crystalline forms. All PXRD peaks described herein are at °2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). In addition, all PXRD spectra are obtained using Cu Kα1 X-rays at a wavelength of 1.5406 Å.

[0248] R-Ketamine free base In some embodiments, the R-ketamine of the present disclosure is a free base. In some embodiments, the R-ketamine free base is crystalline. In some embodiments, the R-ketamine free base is a crystalline polymorphic form A. In some embodiments, the R-ketamine free base form A is characterized by the PXRD peaks set forth in Table 1 below. In some embodiments, the R-ketamine free base PXRD spectrum is substantially similar to that shown in FIG. 1. In some embodiments, the R-ketamine free base FT Raman spectrum is substantially similar to that shown in FIG. 3. In some embodiments, the R-ketamine free base 1 The 1 H-NMR spectrum is substantially similar to that shown in FIG.

[0249] In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by a PXRD peak at 14.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by multiple PXRD peaks at 14.8°2θ and 20.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 14.8°2θ, 20.7°2θ, and 23.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 14.8 °2θ, 20.7 °2θ, and 23.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0250] In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 14.8 °2θ, 20.7 °2θ, and 23.8 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, the R-ketamine free base is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 14.8 °2θ, 20.7 °2θ, and 23.8 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0251] In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 14.8°2θ, 19.6°2θ, 20.7°2θ, and 23.8°2θ, (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 14.8°2θ, 19.6°2θ, 20.7°2θ, and 23.8°2θ, (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0252] In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, and 23.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, and 23.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0253] In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3°2θ, 14.8°2θ, 19.6°2θ, 20.7°2θ, 23.8°2θ, and 27.1°2θ, (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). In some embodiments, the R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3°2θ, 14.8°2θ, 19.6°2θ, 20.7°2θ, 23.8°2θ, and 27.1°2θ, (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0254] In some embodiments, the R-ketamine free base is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, and 27.1 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, and 27.1 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0255] In some embodiments, R-ketamine free base is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0256] In some embodiments, R-ketamine free base is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0257] In some embodiments, R-ketamine free base is a crystalline polymorph Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0258] In some embodiments, R-ketamine free base is a crystalline polymorph Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 15.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 15.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, and 28.3 °2θ, (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0259] In some embodiments, R-ketamine free base is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 15.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, 28.3 °2θ, and 33.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 15.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, 28.3 °2θ, and 33.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0260] In some embodiments, R-ketamine free base is a crystalline polymorph Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 15.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 22.3 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, 28.3 °2θ, and 33.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, R-ketamine free base is a crystalline polymorphic form A characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 15.8 °2θ, 16.6 °2θ, 19.6 °2θ, 20.7 °2θ, 22.3 °2θ, 23.8 °2θ, 26.1 °2θ, 27.1 °2θ, 28.3 °2θ, and 33.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0261] In some embodiments, the R-ketamine free base Form A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 1. [Table 1]

[0262] In some embodiments, the R-ketamine free base is polymorphic form B. In some embodiments, the R-ketamine free base is polymorphic form B formed with THF. In some embodiments, the R-ketamine free base is a THF solvate. In some embodiments, the R-ketamine free base is a polymorphic form B solvate. In some embodiments, the R-ketamine free base is a polymorphic form B THF solvate.

[0263] R-Ketamine salts and their crystalline forms R-Ketamine saccharin salt In one aspect, the present disclosure provides an R-ketamine saccharin salt. In some embodiments, the R-ketamine saccharin salt is amorphous. In some embodiments, the R-ketamine saccharin salt is crystalline. In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form. In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by the PXRD peaks listed in Table 2 below.

[0264] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG. 9. In some embodiments, the R-ketamine saccharin salt is characterized by an FT Raman spectrum substantially similar to that shown in FIG. 14. In some embodiments, the R-ketamine saccharin salt is characterized by a TG-FTIR spectrum substantially similar to that shown in FIG. 15. In some embodiments, the R-ketamine saccharin salt is a 2-propanol solvate. In some embodiments, the R-ketamine saccharin salt is a hydrate. In some embodiments, the R-ketamine saccharin salt is a 2-propanol:water solvate. In some embodiments, the R-ketamine saccharin salt is anhydrous.

[0265] In some embodiments, the R-ketamine saccharin salt is characterized by a DSC with a melting peak at 210.5° C. In some embodiments, the R-ketamine saccharin salt is characterized by a DSC with a melting peak onset at 209.2° C. In some embodiments, the R-ketamine saccharin salt is characterized by a DSC with an associated enthalpy of 139.3 J / g.

[0266] In some embodiments, the R-ketamine saccharin salt is substantially similar to that shown in FIG. 1 Characterized by H-NMR.

[0267] In some embodiments, the R-ketamine saccharin salt is a 1:1 R-ketamine:saccharin salt. In some embodiments, the R-ketamine saccharin salt is a 2:1 R-ketamine:saccharin salt. In some embodiments, the R-ketamine saccharin salt is a 1:2 R-ketamine:saccharin salt.

[0268] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by a PXRD peak at 13.8 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0269] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ and 23.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0270] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 13.8°2θ, 15.6°2θ, and 23.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0271] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.6°2θ, and 23.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0272] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8°2θ, 15.6°2θ, 20.5°2θ, and 23.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0273] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8 °2θ, 15.6 °2θ, 20.5 °2θ, and 23.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0274] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.5 °2θ, and 23.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0275] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.5 °2θ, and 23.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0276] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.5 °2θ, 22.0 °2θ, and 23.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0277] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.5 °2θ, 22.0 °2θ, and 23.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0278] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, and 23.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0279] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, and 23.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0280] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 23.5 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0281] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.6°2θ, 16.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 23.5°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0282] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.6 °2θ, 16.0 °2θ, 20.0 °2θ, 20.2 °2θ, 20.6 °2θ, 22.0 °2θ, 23.5 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0283] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.6°2θ, 16.0°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 23.5°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0284] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 23.5 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0285] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 23.5°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0286] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 23.5 °2θ, 25.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0287] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 23.5°2θ, 25.2°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0288] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.021.96 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0289] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0290] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 19.4 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0291] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 19.4°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 22.2°2θ, 23.5°2θ, 25.2°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0292] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 19.4 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0293] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 19.4°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 22.2°2θ, 23.5°2θ, 25.2°2θ, 26.2°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0294] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 19.4 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0295] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 7.8°2θ, 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 19.4°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 22.2°2θ, 23.5°2θ, 25.2°2θ, 26.2°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0296] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0297] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 7.8°2θ, 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 19.4°2θ, 19.7°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 22.2°2θ, 23.5°2θ, 25.2°2θ, 26.2°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0298] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, and 26.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0299] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 7.8°2θ, 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 19.4°2θ, 19.7°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 22.2°2θ, 23.5°2θ, 25.2°2θ, 26.0°2θ, 26.2°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0300] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, 26.8 °2θ, and 28.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0301] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 7.8°2θ, 13.8°2θ, 15.3°2θ, 15.6°2θ, 16.0°2θ, 19.4°2θ, 19.7°2θ, 20.0°2θ, 20.2°2θ, 20.5°2θ, 22.0°2θ, 22.2°2θ, 23.5°2θ, 25.2°2θ, 26.0°2θ, 26.2°2θ, 26.8°2θ, and 28.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0302] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 16.6 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, 26.8 °2θ, and 28.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0303] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 16.6 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, 26.8 °2θ, and 28.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0304] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 16.6 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, 26.8 °2θ, 28.7 °2θ, and 32.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0305] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 16.6 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, 26.8 °2θ, 28.7 °2θ, and 32.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0306] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 16.6 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, 26.8 °2θ, 28.7 °2θ, 32.9 °2θ, and 34.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0307] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by PXRD peaks at 7.8 °2θ, 13.8 °2θ, 15.3 °2θ, 15.6 °2θ, 16.0 °2θ, 16.6 °2θ, 19.4 °2θ, 19.7 °2θ, 20.0 °2θ, 20.2 °2θ, 20.5 °2θ, 22.0 °2θ, 22.2 °2θ, 23.5 °2θ, 25.2 °2θ, 26.0 °2θ, 26.2 °2θ, 26.8 °2θ, 28.7 °2θ, 32.9 °2θ, and 34.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0308] In some embodiments, the R-ketamine saccharin salt is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those set forth in Table 2. [Table 2-1] [Table 2-2]

[0309] R-Ketamine Fumarate Form A In one aspect, the present disclosure provides R-ketamine fumarate. In some embodiments, R-ketamine fumarate is amorphous. In some embodiments, R-ketamine fumarate is crystalline. In some embodiments, R-ketamine fumarate is crystalline polymorph form A. In some embodiments, R-ketamine fumarate form A can be characterized by the PXRD peaks listed in Table 3 below.

[0310] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 21. In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 25 or Figure 26. In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by a TG-FTIR spectrum substantially similar to that shown in Figure 28A. In some embodiments, R-ketamine fumarate Form A is anhydrous.

[0311] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by DSC with a melting peak at 144.2° C. In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by DSC with an associated enthalpy of 136.6 J / g.

[0312] In some embodiments, R-ketamine fumarate Form A has a structure substantially similar to that shown in FIG. 1 Characterized by H-NMR.

[0313] In some embodiments, R-ketamine fumarate Form A is 1:1 R-ketamine:fumarate. In some embodiments, R-ketamine fumarate Form A is 2:1 R-ketamine:fumarate. In some embodiments, R-ketamine fumarate Form A is 1:2 R-ketamine:fumarate.

[0314] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by a PXRD peak at 14.6 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0315] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 degrees 2θ, and 14.6 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0316] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, and 14.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0317] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, and 14.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0318] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, and 18.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0319] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, and 18.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0320] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0321] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0322] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0323] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0324] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0325] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0326] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0327] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, and 24.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0328] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 24.6 °2θ, and 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0329] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 24.6 °2θ, and 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0330] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0331] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0332] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, and 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0333] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, and 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0334] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, and 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0335] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, and 29.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0336] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0337] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0338] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 26.9 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0339] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 26.9 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0340] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 16.5 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 26.9 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0341] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 16.5 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 26.9 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0342] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 16.5 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 24.9 °2θ, 26.9 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0343] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 16.5 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 24.9 °2θ, 26.9 °2θ, 29.4 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0344] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 16.5 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 24.9 °2θ, 26.9 °2θ, 29.4 °2θ, 32.7 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0345] In some embodiments, R-ketamine fumarate Form A is a crystalline polymorphic form characterized by PXRD peaks at 7.3 °2θ, 10.9 °2θ, 11.6 °2θ, 13.4 °2θ, 14.6 °2θ, 16.5 °2θ, 18.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.9 °2θ, 24.6 °2θ, 24.9 °2θ, 26.9 °2θ, 29.4 °2θ, 32.7 °2θ, and 33.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0346] In some embodiments, R-ketamine fumarate Form A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 3. [Table 3-1] [Table 3-2]

[0347] R-Ketamine Fumarate Form B In one aspect, the present disclosure provides R-ketamine fumarate Form B. In some embodiments, the R-ketamine fumarate is amorphous. In some embodiments, the R-ketamine fumarate is crystalline. In some embodiments, the R-ketamine fumarate is a crystalline polymorphic form. In some embodiments, the R-ketamine fumarate is a crystalline polymorphic form characterized by the PXRD peaks listed in Table 4 below.

[0348] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 68. In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 72 or Figure 73.

[0349] In some embodiments, R-ketamine fumarate Form B has a structure substantially similar to that of FIG. 1 It is a characterized crystalline polymorphic form characterized by H-NMR.

[0350] In some embodiments, R-ketamine fumarate Form B is 1:1 R-ketamine:fumarate. In some embodiments, R-ketamine fumarate Form B is 2:1 R-ketamine:fumarate. In some embodiments, R-ketamine fumarate Form B is 1:2 R-ketamine:fumarate.

[0351] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by a PXRD peak at 15.1 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0352] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 15.1 degrees 2θ, and 20.4 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0353] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 14.5 °2θ, 15.1 °2θ, and 20.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0354] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 14.5 °2θ, 15.1 °2θ, and 20.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0355] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, and 20.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0356] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, and 20.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0357] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0358] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0359] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0360] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0361] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0362] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0363] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 13.1 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0364] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 13.1 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0365] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0366] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0367] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, 20.6 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0368] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, 20.6 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0369] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, 20.6 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0370] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, 20.6 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0371] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0372] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0373] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0374] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0375] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 10.6 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0376] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 10.6 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0377] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 10.6 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, 25.4 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0378] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 10.6 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, 25.4 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0379] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.4 °2θ, 7.2 °2θ, 10.6 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, 25.4 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0380] In some embodiments, R-ketamine fumarate Form B is a crystalline polymorphic form characterized by PXRD peaks at 6.4 °2θ, 7.2 °2θ, 10.6 °2θ, 11.5 °2θ, 12.8 °2θ, 13.1 °2θ, 13.4 °2θ, 14.5 °2θ, 15.1 °2θ, 19.0 °2θ, 20.1 °2θ, 20.4 °2θ, 20.6 °2θ, 24.1 °2θ, 25.4 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0381] In some embodiments, R-ketamine fumarate Form B is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those listed in Table 4. [Table 4-1] [Table 4-2]

[0382] R-Ketamine succinate In one aspect, the present disclosure provides R-ketamine succinate.In some embodiments, R-ketamine succinate is amorphous.In some embodiments, R-ketamine succinate is crystalline.In some embodiments, R-ketamine succinate is a crystalline polymorphic form.In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by the PXRD peaks listed in Table 5 below.

[0383] In some embodiments, the R-ketamine succinate is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 29. In some embodiments, the R-ketamine succinate is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 32. In some embodiments, the R-ketamine succinate is a hydrate. In some embodiments, the R-ketamine succinate is anhydrous.

[0384] In some embodiments, R-ketamine succinate has a structure substantially similar to that of FIG. 1 It is a crystalline polymorphic form characterized by H-NMR.

[0385] In some embodiments, the R-ketamine succinate is 1:1 R-ketamine:succinate. In some embodiments, the R-ketamine succinate is 2:1 R-ketamine:succinate. In some embodiments, the R-ketamine succinate is 1:2 R-ketamine:succinate.

[0386] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by a PXRD peak at 9.0° 2θ (±0.2° 2θ; ±0.1° 2θ; or ±0.0° 2θ; Cu Kα1 radiation).

[0387] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 9.0°2θ and 13.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0388] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 9.0°2θ, 13.5°2θ, and 18.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0389] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 9.0°2θ, 13.5°2θ, and 18.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0390] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 9.0°2θ, 13.5°2θ, 15.7°2θ, and 18.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0391] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 9.0°2θ, 13.5°2θ, 15.7°2θ, and 18.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0392] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 15.7 °2θ, and 18.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0393] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 9.0°2θ, 11.8°2θ, 13.5°2θ, 15.7°2θ, and 18.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0394] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 15.7 °2θ, 18.1 °2θ, and 32.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0395] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 9.0°2θ, 11.8°2θ, 13.5°2θ, 15.7°2θ, 18.1°2θ, and 32.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0396] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 8.6 °2θ, 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 15.7 °2θ, 18.1 °2θ, and 32.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0397] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 8.6 °2θ, 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 15.7 °2θ, 18.1 °2θ, and 32.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0398] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 8.6 °2θ, 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 15.7 °2θ, 18.1 °2θ, 24.3 °2θ, and 32.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0399] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 15.7°2θ, 18.1°2θ, 24.3°2θ, and 32.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0400] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 8.6 °2θ, 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 15.7 °2θ, 17.2 °2θ, 18.1 °2θ, 24.3 °2θ, and 32.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0401] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 24.3°2θ, and 32.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0402] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 8.6 °2θ, 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 14.7 °2θ, 15.7 °2θ, 17.2 °2θ, 18.1 °2θ, 24.3 °2θ, and 32.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0403] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 24.3°2θ, and 32.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0404] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 8.6 °2θ, 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 14.7 °2θ, 15.7 °2θ, 17.2 °2θ, 18.1 °2θ, 18.7 °2θ, 24.3 °2θ, and 32.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0405] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 24.3°2θ, and 32.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0406] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 24.3°2θ, and 32.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0407] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 24.3°2θ, and 32.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0408] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 24.3°2θ, 32.2°2θ, and 34.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0409] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 24.3°2θ, 32.2°2θ, and 34.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0410] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 24.0°2θ, 24.3°2θ, 32.2°2θ, and 34.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0411] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 24.0°2θ, 24.3°2θ, 32.2°2θ, and 34.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0412] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 4.5 °2θ, 8.6 °2θ, 9.0 °2θ, 11.8 °2θ, 13.5 °2θ, 14.7 °2θ, 15.7 °2θ, 17.2 °2θ, 18.1 °2θ, 18.7 °2θ, 22.0 °2θ, 24.0 °2θ, 24.3 °2θ, 32.2 °2θ, and 34.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0413] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 22.0°2θ, 24.0°2θ, 24.3°2θ, 32.2°2θ, and 34.7°2θ°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0414] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 22.0°2θ, 24.0°2θ, 24.3°2θ, 26.6°2θ, 32.2°2θ, and 34.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0415] In some embodiments, R-ketamine succinate is a crystalline polymorphic form characterized by PXRD peaks at 4.5°2θ, 8.6°2θ, 9.0°2θ, 11.8°2θ, 13.5°2θ, 14.7°2θ, 15.7°2θ, 17.2°2θ, 18.1°2θ, 18.7°2θ, 22.0°2θ, 24.0°2θ, 24.3°2θ, 26.6°2θ, 32.2°2θ, and 34.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0416] In some embodiments, the R-ketamine succinate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those set forth in Table 5. [Table 5-1] [Table 5-2]

[0417] R-Ketamine sulfate In one aspect, the present disclosure provides R-ketamine sulfate. In some embodiments, the R-ketamine sulfate is amorphous. In some embodiments, the R-ketamine sulfate is crystalline. In some embodiments, the R-ketamine sulfate is a crystalline polymorphic form. In some embodiments, the R-ketamine sulfate is a crystalline polymorphic form characterized by the PXRD peaks listed in Table 6 below.

[0418] In some embodiments, the R-ketamine sulfate is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in FIG.

[0419] In some embodiments, the R-ketamine sulfate is 1:1 R-ketamine:sulfate. In some embodiments, the R-ketamine sulfate is 2:1 R-ketamine:sulfate. In some embodiments, the R-ketamine sulfate is 1:2 R-ketamine:sulfate.

[0420] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by a PXRD peak at 19.8° 2θ (±0.2° 2θ; ±0.1° 2θ; or ±0.0° 2θ; Cu Kα1 radiation).

[0421] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8° 2θ and 22.5° 2θ, (±0.2° 2θ; ±0.1° 2θ; or ±0.0° 2θ; Cu Kα1 radiation).

[0422] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 19.8°2θ, 22.5°2θ, and 26.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0423] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8°2θ, 22.5°2θ, and 26.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0424] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, and 26.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0425] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, and 26.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0426] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, and 26.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0427] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, and 26.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0428] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, and 27.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0429] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, and 27.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0430] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, and 30.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0431] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, and 30.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0432] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, 30.4 °2θ, and 30.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0433] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, 30.4 °2θ, and 30.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0434] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, 30.4 °2θ, 30.9 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0435] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, 30.4 °2θ, 30.9 °2θ, and 32.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0436] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, 30.4 °2θ, 30.9 °2θ, 32.7 °2θ, and 35.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0437] In some embodiments, R-ketamine sulfate is a crystalline polymorphic form characterized by PXRD peaks at 19.8 °2θ, 20.1 °2θ, 22.5 °2θ, 24.5 °2θ, 26.1 °2θ, 27.3 °2θ, 30.4 °2θ, 30.9 °2θ, 32.7 °2θ, and 35.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0438] In some embodiments, the R-ketamine sulfate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PXRD peaks selected from those set forth in Table 6. [Table 6]

[0439] R-Ketamine D-Tartrate Form A In one aspect, the present disclosure provides R-ketamine D-tartrate. In some embodiments, the R-ketamine D-tartrate is amorphous. In some embodiments, the R-ketamine D-tartrate is crystalline. In some embodiments, the R-ketamine D-tartrate is crystalline polymorphic form A. In some embodiments, the R-ketamine D-tartrate form A can be characterized by the PXRD peaks listed in Table 7 below.

[0440] In some embodiments, the R-ketamine D-tartrate Form A PXRD spectrum is substantially similar to that shown in Figure 40. In some embodiments, R-ketamine D-tartrate Form A is a crystalline polymorphic form characterized by TG-FTIR substantially similar to that shown in Figure 76. In some embodiments, R-ketamine D-tartrate Form A is an ethanol solvate. In some embodiments, R-ketamine D-tartrate Form A is a hydrate. In some embodiments, R-ketamine D-tartrate Form A is an ethanol:water solvate. In some embodiments, R-ketamine D-tartrate Form A is anhydrous.

[0441] In some embodiments, R-ketamine D-tartrate Form A is a crystalline polymorphic form characterized by a DSC substantially similar to that shown in Figure 53. In some embodiments, R-ketamine D-tartrate Form A is a crystalline polymorphic form characterized by a melting endotherm having a peak maximum at 108°C.

[0442] In some embodiments, R-ketamine D-tartrate Form A is 1:1 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form A is 1:0.75 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form A is 1:0.8 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form A is 1:0.85 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form A is 2:1 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form A is 1:2 R-ketamine:D-tartrate.

[0443] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by a PXRD peak at 15.4 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0444] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 14.7 degrees 2θ and 15.4 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0445] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 10.3 °2θ, 14.7 °2θ, and 15.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0446] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 14.7 °2θ, and 15.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0447] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, and 15.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0448] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, and 15.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0449] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0450] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0451] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0452] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, and 30.62 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0453] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0454] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0455] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 25.5 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0456] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 25.5 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0457] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 25.5 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0458] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 25.5 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0459] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 25.5 °2θ, 27.2 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0460] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 25.5 °2θ, 27.2 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0461] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0462] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, and 30.6 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0463] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 23.0 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0464] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0465] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0466] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0467] In some embodiments, R-ketamine D-tartrate is a crystalline polymorph Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0468] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0469] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0470] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, and 31.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0471] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, 31.1 °2θ, and 32.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0472] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, 31.1 °2θ, and 32.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0473] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, 31.1 °2θ, 32.4 °2θ, and 36.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0474] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, 31.1 °2θ, 32.4 °2θ, and 36.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0475] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.9 °2θ, 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, 31.1 °2θ, 32.4 °2θ, and 36.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0476] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form A characterized by PXRD peaks at 6.9 °2θ, 10.3 °2θ, 13.2 °2θ, 13.4 °2θ, 14.7 °2θ, 15.4 °2θ, 19.9 °2θ, 20.3 °2θ, 20.8 °2θ, 21.8 °2θ, 22.9 °2θ, 24.9 °2θ, 25.5 °2θ, 27.2 °2θ, 30.6 °2θ, 31.1 °2θ, 32.4 °2θ, and 36.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0477] In some embodiments, the R-ketamine D-tartrate Form A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 7. [Table 7-1] [Table 7-2]

[0478] R-Ketamine D-Tartrate Form B In one aspect, the present disclosure provides R-ketamine D-tartrate. In some embodiments, the R-ketamine D-tartrate is amorphous. In some embodiments, the R-ketamine D-tartrate is crystalline. In some embodiments, the R-ketamine D-tartrate is crystalline polymorphic form B. In some embodiments, the R-ketamine D-tartrate form B can be characterized by the PXRD peaks listed in Table 8 below.

[0479] In some embodiments, R-ketamine D-tartrate Form B is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 57. In some embodiments, R-ketamine D-tartrate Form B is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 59. In some embodiments, R-ketamine D-tartrate Form B is an acetone solvate. In some embodiments, R-ketamine D-tartrate Form B is a hydrate. In some embodiments, R-ketamine D-tartrate Form B is an acetone:water solvate. In some embodiments, R-ketamine D-tartrate Form B is an anhydrate. In some embodiments, R-ketamine D-tartrate Form B is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 58. 1 It is a crystalline polymorphic form characterized by H-NMR.

[0480] In some embodiments, R-ketamine D-tartrate Form B is 1:1 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form B is 1:0.75 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form B is 1:0.8 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form B is 1:0.85 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form B is 2:1 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate Form B is 1:2 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by a PXRD peak at 5.9 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0481] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 degrees 2θ and 14.7 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0482] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 5.9 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0483] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0484] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0485] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0486] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0487] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0488] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, 14.7 °2θ, and 15.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0489] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, 14.7 °2θ, and 15.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0490] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, 14.7 °2θ, 15.2 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0491] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.7 °2θ, 14.7 °2θ, 15.2 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0492] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 14.7 °2θ, 15.2 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0493] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 14.7 °2θ, 15.2 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0494] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0495] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0496] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0497] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0498] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 21.8 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0499] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 21.8 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0500] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 20.8 °2θ, 21.8 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0501] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 20.8 °2θ, 21.8 °2θ, and 22.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0502] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, and 23.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0503] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, and 23.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0504] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, and 23.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0505] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, and 23.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0506] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, and 23.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0507] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, and 23.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0508] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, 23.2 °2θ, and 24.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0509] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, 23.2 °2θ, and 24.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0510] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, 22.8 °2θ, 23.2 °2θ, and 24.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0511] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, 22.8 °2θ, 23.2 °2θ, and 24.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0512] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form B characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, 22.8 °2θ, 23.2 °2θ, 24.3 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0513] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form B characterized by PXRD peaks at 5.9 °2θ, 11.0 °2θ, 12.2 °2θ, 12.7 °2θ, 13.4 °2θ, 13.7 °2θ, 14.7 °2θ, 15.2 °2θ, 16.0 °2θ, 17.9 °2θ, 20.8 °2θ, 21.8 °2θ, 22.3 °2θ, 22.8 °2θ, 23.2 °2θ, 24.3 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0514] In some embodiments, the R-ketamine D-tartrate Form B is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 8. [Table 8-1] [Table 8-2]

[0515] R-Ketamine D-Tartrate Form C In one aspect, the present disclosure provides R-ketamine D-tartrate. In some embodiments, the R-ketamine D-tartrate is amorphous. In some embodiments, the R-ketamine D-tartrate is crystalline. In some embodiments, the R-ketamine D-tartrate is crystalline polymorph form C. In some embodiments, the R-ketamine D-tartrate form C can be characterized by the PXRD peaks listed in Table 9 below.

[0516] In some embodiments, R-ketamine D-tartrate Form C is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 61. In some embodiments, R-ketamine D-tartrate Form C is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 65. In some embodiments, R-ketamine D-tartrate Form C is an ethyl acetate solvate. In some embodiments, R-ketamine D-tartrate Form C is a methanol solvate. In some embodiments, R-ketamine D-tartrate Form C is a hydrate. In some embodiments, R-ketamine D-tartrate Form C is a methanol:ethyl acetate solvate. In some embodiments, R-ketamine D-tartrate Form C is anhydrous. In some embodiments, R-ketamine D-tartrate Form C is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 64. 1 It is a crystalline polymorphic form characterized by H-NMR.

[0517] In some embodiments, the R-ketamine D-tartrate Form C is 1:1 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form C is 1:1.25 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form C is 1:1.5 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form C is 1:0.85 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form C is 2:1 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form C is 1:2 R-ketamine:D-tartrate. In some embodiments, R-ketamine D-tartrate form C is 1:1.15 R-ketamine:D-tartrate.

[0518] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by a PXRD peak at 6.1 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0519] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by a PXRD peak at 14.0 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0520] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 degrees 2θ and 11.0 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0521] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 11.0 degrees 2θ and 14.0 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0522] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, and 12.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0523] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 11.0 °2θ, 13.6 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0524] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, and 12.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0525] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 11.0 °2θ, 13.6 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0526] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0527] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 13.6 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0528] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 13.6 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0529] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0530] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, and 14.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0531] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, and 21.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0532] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, and 21.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0533] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0534] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 15.6 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0535] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0536] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 15.6 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0537] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 15.6 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0538] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.6 °2θ, 15.6 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0539] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 15.6 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0540] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.6 °2θ, 15.6 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0541] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0542] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.0 °2θ, 13.5 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, and 21.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0543] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0544] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.0 °2θ, 13.5 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, and 21.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0545] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0546] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.0 °2θ, 13.5 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0547] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0548] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.0 °2θ, 13.5 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0549] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0550] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.0 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0551] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0552] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 13.0 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, and 24.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0553] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0554] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0555] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0556] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0557] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0558] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 16.1 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0559] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 16.1 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0560] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 16.1 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 22.1 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0561] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 16.1 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 22.1 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0562] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic Form C characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 16.1 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 22.1 °2θ, 23.1 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0563] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form C characterized by PXRD peaks at 6.1 °2θ, 11.0 °2θ, 12.2 °2θ, 12.9 °2θ, 13.5 °2θ, 14.0 °2θ, 14.6 °2θ, 15.6 °2θ, 16.1 °2θ, 17.6 °2θ, 18.4 °2θ, 21.3 °2θ, 22.1 °2θ, 23.1 °2θ, 24.1 °2θ, and 24.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0564] In some embodiments, R-ketamine D-tartrate Form C is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 9.

[0565] In some embodiments, the R-ketamine D-tartrate Form C is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 10. [Table 9-1] [Table 9-2] [Table 10-1] [Table 10-2]

[0566] R-Ketamine D-tartrate form D In one aspect, the present disclosure provides R-ketamine D-tartrate. In some embodiments, the R-ketamine D-tartrate is amorphous. In some embodiments, the R-ketamine D-tartrate is crystalline. In some embodiments, the R-ketamine D-tartrate is crystalline polymorphic form D. In some embodiments, the R-ketamine D-tartrate form D can be characterized by the PXRD peaks listed in Table 11 below.

[0567] In some embodiments, R-ketamine D-tartrate Form D is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 87. In some embodiments, R-ketamine D-tartrate Form D is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 88. In some embodiments, R-ketamine D-tartrate Form D is an ethyl acetate solvate. In some embodiments, R-ketamine D-tartrate Form D is a methanol solvate. In some embodiments, R-ketamine D-tartrate Form D is a THF solvate. In some embodiments, R-ketamine D-tartrate Form D is a propanol solvate. In some embodiments, R-ketamine D-tartrate Form D is an acetonitrile solvate. In some embodiments, R-ketamine D-tartrate Form D is an acetone solvate. In some embodiments, R-ketamine D-tartrate Form D is a hydrate. In some embodiments, the R-ketamine D-tartrate Form D is a methanol:ethyl acetate solvate. In some embodiments, the R-ketamine D-tartrate Form D is anhydrous. In some embodiments, the R-ketamine D-tartrate Form D is an anhydrous form according to FIG. 1 It is a crystalline polymorphic form characterized by H-NMR.

[0568] In some embodiments, the R-ketamine D-tartrate Form D is 1:1 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form D is 1:1.25 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form D is 1:1.5 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form D is 1:0.85 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form D is 2:1 R-ketamine:D-tartrate. In some embodiments, the R-ketamine D-tartrate Form D is 1:2 R-ketamine:D-tartrate.

[0569] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by a PXRD peak at 14.3 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0570] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by a PXRD peak at 19.8 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0571] In some embodiments, R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 14.3 degrees 2θ and 19.8 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0572] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.7 °2θ, 14.3 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0573] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 12.7 °2θ, 14.3 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0574] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0575] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.7 °2θ, 14.3 °2θ, 15.1 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0576] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0577] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 12.7 °2θ, 14.3 °2θ, 15.1 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0578] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0579] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0580] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0581] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0582] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0583] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, and 19.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0584] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, 19.8 °2θ, and 21.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0585] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, 19.8 °2θ, and 22.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0586] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, 19.8 °2θ, and 23.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0587] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, 19.8 °2θ, and 24.8 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0588] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, 19.8 °2θ, and 33.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0589] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, 19.8 °2θ, and 38.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0590] In some embodiments, the R-ketamine D-tartrate is a crystalline polymorphic form D characterized by PXRD peaks at 7.6 °2θ, 12.7 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 17.0 °2θ, and 19.8 °2θ, additionally one or more, two or more, or three or more peaks selected from the group consisting of 21.5 °2θ, 22.7 °2θ, 23.9 °2θ, 24.8 °2θ, 27.4 °2θ, 27.5 °2θ, 33.1 °2θ, or 38.0 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0591] In some embodiments, the R-ketamine D-tartrate Form D is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 11.

[0592] In some embodiments, R-ketamine D-tartrate Form D is characterized by one or more peaks selected from the peaks set forth in Table 11 having a relative intensity greater than 20%.

[0593] In some embodiments, R-ketamine D-tartrate form D is characterized by two or more peaks selected from the peaks set forth in Table 11 having a relative intensity of greater than 20%.

[0594] In some embodiments, R-ketamine D-tartrate form D is characterized by three or more peaks selected from the peaks set forth in Table 11 having a relative intensity of greater than 20%.

[0595] In some embodiments, R-ketamine D-tartrate form D is characterized by four or more peaks selected from the peaks set forth in Table 11 having a relative intensity of greater than 20%.

[0596] In some embodiments, R-ketamine D-tartrate Form D is characterized by five or more peaks selected from the peaks set forth in Table 11 having a relative intensity of greater than 20%.

[0597] In some embodiments, R-ketamine D-tartrate form D is characterized by six or more peaks selected from the peaks set forth in Table 11 having a relative intensity of greater than 20%. [Table 11-1] [Table 11-2]

[0598] R-Ketamine Oxalate In one aspect, the present disclosure provides R-ketamine oxalate. In some embodiments, R-ketamine oxalate is amorphous. In some embodiments, R-ketamine oxalate is crystalline. In some embodiments, R-ketamine oxalate is a crystalline polymorphic form. In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by the PXRD peaks listed in Table 12 below.

[0599] In some embodiments, the R-ketamine oxalate is a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 43. In some embodiments, the R-ketamine oxalate is a crystalline polymorphic form characterized by an FT Raman spectrum substantially similar to that shown in Figure 45C. In some embodiments, the R-ketamine oxalate is a crystalline polymorphic form characterized by a DSC thermogram substantially similar to that shown in Figure 45C. In some embodiments, the R-ketamine oxalate is a crystalline polymorphic form characterized by a DSC thermogram having a broad endothermic signal with a maximum at 115°C.

[0600] In some embodiments, the R-ketamine oxalate is a solvate. In some embodiments, the R-ketamine oxalate is a hydrate. In some embodiments, the R-ketamine oxalate is an anhydrate.

[0601] In some embodiments, the R-ketamine oxalate is 1:1 R-ketamine:oxalate. In some embodiments, the R-ketamine oxalate is 1:2 R-ketamine:oxalate.

[0602] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by a PXRD peak at 14.8 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0603] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8° 2θ and 14.8° 2θ (±0.2° 2θ; ±0.1° 2θ; or ±0.0° 2θ; Cu Kα1 radiation).

[0604] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.8°2θ, 14.8°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0605] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.8°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0606] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.8°2θ, 14.8°2θ, 15.1°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0607] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.8°2θ, 15.1°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0608] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0609] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0610] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, and 21.3°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0611] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, and 21.3°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0612] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, and 21.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0613] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, and 21.3°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0614] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, and 25.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0615] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, and 25.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0616] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, and 25.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0617] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, 22.8°2θ, and 25.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0618] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.8 °2θ, and 25.9 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0619] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, 22.8°2θ, 23.8°2θ, and 25.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0620] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, 22.8°2θ, 23.8°2θ, 25.9°2θ, and 26.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0621] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, 22.8°2θ, 23.8°2θ, 25.9°2θ, and 26.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0622] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, and 26.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0623] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, 22.8°2θ, 23.2°2θ, 23.8°2θ, 25.9°2θ, and 26.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0624] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, and 26.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0625] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.3°2θ, 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, 22.8°2θ, 23.2°2θ, 23.8°2θ, 25.9°2θ, and 26.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0626] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, 26.1 °2θ, and 27.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0627] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 12.3°2θ, 12.8°2θ, 14.3°2θ, 14.8°2θ, 15.1°2θ, 16.2°2θ, 20.7°2θ, 21.3°2θ, 22.8°2θ, 23.2°2θ, 23.8°2θ, 25.9°2θ, 26.1°2θ, and 27.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0628] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 9.1 °2θ, 12.3 °2θ, 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, 26.1 °2θ, and 27.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0629] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 9.1 °2θ, 12.3 °2θ, 12.8 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, 26.1 °2θ, and 27.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0630] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 9.1 °2θ, 12.3 °2θ, 12.8 °2θ, 13.4 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, 26.1 °2θ, and 27.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0631] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 9.1 °2θ, 12.3 °2θ, 12.8 °2θ, 13.4 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, 26.1 °2θ, and 27.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0632] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 9.1 °2θ, 12.3 °2θ, 12.8 °2θ, 13.4 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 21.9 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, 26.1 °2θ, and 27.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0633] In some embodiments, R-ketamine oxalate is a crystalline polymorphic form characterized by PXRD peaks at 9.1 °2θ, 12.3 °2θ, 12.8 °2θ, 13.4 °2θ, 14.3 °2θ, 14.8 °2θ, 15.1 °2θ, 16.2 °2θ, 20.7 °2θ, 21.3 °2θ, 21.9 °2θ, 22.8 °2θ, 23.2 °2θ, 23.8 °2θ, 25.9 °2θ, 26.1 °2θ, and 27.5 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0634] In some embodiments, the R-ketamine oxalate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 12. [Table 12-1] [Table 12-2]

[0635] R-Ketamine Citrate In one aspect, the present disclosure provides R-ketamine citrate. In some embodiments, the R-ketamine citrate is amorphous. In some embodiments, the R-ketamine citrate is crystalline. In some embodiments, the R-ketamine citrate is a crystalline polymorphic form. In some embodiments, the R-ketamine citrate is a crystalline polymorphic form characterized by the PXRD peaks listed in Table 13 below.

[0636] In some embodiments, the R-ketamine citrate is in a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 46. In some embodiments, the R-ketamine citrate is in a crystalline polymorphic form characterized by a PXRD spectrum substantially similar to that shown in Figure 48. 1 It is a crystalline polymorphic form characterized by H-NMR spectroscopy.

[0637] In some embodiments, the R-ketamine citrate is a solvate. In some embodiments, the R-ketamine citrate is a hydrate. In some embodiments, the R-ketamine citrate is anhydrous.

[0638] In some embodiments, the R-ketamine citrate is a monocitrate. In some embodiments, the R-ketamine citrate is a 1:2 R-ketamine:citrate. In some embodiments, the R-ketamine citrate is a 2:1 R-ketamine:citrate. In some embodiments, the R-ketamine citrate is a 1:1 R-ketamine:citrate.

[0639] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by a PXRD peak at 16.8 degrees 2θ (±0.2 degrees 2θ; ±0.1 degrees 2θ; or ±0.0 degrees 2θ; Cu Kα1 radiation).

[0640] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 14.8°2θ and 16.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0641] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 14.8°2θ, 16.8°2θ, and 21.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0642] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 14.8 °2θ, 16.8 °2θ, and 21.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0643] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 14.8 °2θ, 16.8 °2θ, and 21.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0644] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 14.8 °2θ, 16.8 °2θ, and 21.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0645] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 14.8 °2θ, 16.8 °2θ, 21.4 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0646] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 14.8 °2θ, 16.8 °2θ, 21.4 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0647] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 14.8 °2θ, 16.8 °2θ, 20.7 °2θ, 21.4 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0648] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 14.8 °2θ, 16.8 °2θ, 20.7 °2θ, 21.4 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0649] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more, or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 20.7 °2θ, 21.4 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0650] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 20.7 °2θ, 21.4 °2θ, and 26.2 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0651] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 20.7 °2θ, 21.4 °2θ, 26.2 °2θ, and 27.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0652] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 20.7 °2θ, 21.4 °2θ, 26.2 °2θ, and 27.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0653] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 26.2 °2θ, and 27.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0654] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 26.2 °2θ, and 27.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0655] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.8 °2θ, 26.2 °2θ, and 27.1 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0656] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3°2θ, 13.4°2θ, 14.8°2θ, 16.8°2θ, 19.6°2θ, 20.7°2θ, 21.4°2θ, 23.8°2θ, 26.2°2θ, and 27.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0657] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.8 °2θ, 26.2 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0658] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.8 °2θ, 26.2 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0659] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0660] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 12.3°2θ, 13.4°2θ, 14.8°2θ, 16.8°2θ, 19.6°2θ, 20.7°2θ, 21.4°2θ, 23.3°2θ, 23.8°2θ, 26.2°2θ, 27.1°2θ, and 28.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0661] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0662] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 10.5°2θ, 12.3°2θ, 13.4°2θ, 14.8°2θ, 16.8°2θ, 19.6°2θ, 20.7°2θ, 21.4°2θ, 23.3°2θ, 23.8°2θ, 26.2°2θ, 27.1°2θ, and 28.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0663] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0664] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 10.5°2θ, 12.3°2θ, 13.4°2θ, 14.8°2θ, 16.8°2θ, 19.4°2θ, 19.6°2θ, 20.7°2θ, 21.4°2θ, 23.3°2θ, 23.8°2θ, 26.2°2θ, 27.1°2θ, and 28.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

[0665] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0666] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0667] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 19.9 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0668] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 19.9 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0669] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.5 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 19.9 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0670] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.8 °2θ, 16.5 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 19.9 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0671] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at two or more or three or more peaks selected from the group consisting of 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.4 °2θ, 14.8 °2θ, 16.5 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 19.9 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0672] In some embodiments, R-ketamine citrate is a crystalline polymorphic form characterized by PXRD peaks at 10.5 °2θ, 12.3 °2θ, 13.4 °2θ, 14.4 °2θ, 14.8 °2θ, 16.5 °2θ, 16.8 °2θ, 19.4 °2θ, 19.6 °2θ, 19.9 °2θ, 20.7 °2θ, 21.4 °2θ, 23.3 °2θ, 23.8 °2θ, 26.2 °2θ, 26.6 °2θ, 27.1 °2θ, and 28.4 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).

[0673] In some embodiments, the R-ketamine citrate is a crystalline polymorphic form characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those in Table 13. [Table 13]

[0674] How to use Disease indication The R-ketamine, salts, solid forms, and salt forms of the present disclosure are useful in preparing medicaments for the prevention and / or treatment of various diseases or conditions.

[0675] R-ketamine, its salts, solid forms, and salt forms herein are useful as neuroprotective, preventive, or therapeutic agents for diseases or conditions associated with glutamatergic transmission, particularly glutamatergic neurotransmission via N-methyl-D-aspartate (hereinafter abbreviated as NMDA) receptors. For example, increasing evidence suggests that abnormal glutamatergic transmission via NMDA receptors is related to the pathophysiology of mood disorders, and that NMDA receptors also play an important role in neurobiology.

[0676] R-ketamine, its salts, solid forms, and salt forms herein are useful as neuroprotective, prophylactic, or therapeutic agents for cognitive impairment, such as mood disorders, bipolar disorder, major depressive disorder, generalized anxiety disorder, panic disorder, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), eating disorders, and substance use disorders (drug dependence).

[0677] R-ketamine, its salts, solid forms, and salt forms are also useful for treating several medical diseases, including, but not limited to, neurodegenerative diseases, as well as cardiovascular diseases, cancer (also referred to as malignant tumors), inflammatory diseases, bone diseases, and the like. Exemplary inflammatory diseases and bone diseases include ulcerative colitis, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, insulin-dependent diabetes mellitus, Addison's disease, Goodpasture's syndrome, IgA nephropathy, interstitial nephritis, Sjogren's syndrome, autoimmune pancreatitis, psoriasis, atopic dermatitis, pneumonia, chronic bronchitis, bronchial asthma, systemic lupus erythematosus (SLE), scleroderma, or delirium, and bone diseases are osteoporosis, osteolytic bone metastasis, and Paget's disease of bone. Inflammatory diseases are chronic diseases that progress over a long period of time (several years), so early initiation of treatment may prevent the progression of symptoms. Additionally, R-ketamine, its salts, solid forms, and salt forms may also be used to prevent the onset of inflammatory or bone diseases by administering R-ketamine, its salts, solid forms, and salt forms to a patient with a genetic background that may predispose the patient to inflammatory diseases before the patient becomes symptomatic.

[0678] R-ketamine, its salts, solid forms, and salt forms are also useful for treating neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Lewy body disease, and the like. In some embodiments, R-ketamine, its salts, solid forms, and salt forms treat one or more symptoms of a neurodegenerative disease.

[0679] R-ketamine, its salts, solid forms, and salt forms are also useful for treating neurodevelopmental conditions or disorders, such as pediatric or fetal neurodevelopmental disorders. Exemplary neurodevelopmental disorders include schizophrenia, autism spectrum disorders, attention deficit / hyperactivity disorder, autism spectrum disorders, and other learning disorders. Symptoms include cognitive disorders, such as impaired attention, reduced verbal fluency, reduced learning and retention of verbal information, reduced processing speed, reduced declarative memory, impaired working memory, reduced executive function, or combinations thereof. In some embodiments, R-ketamine, its salts, solid forms, and salt forms treat one or more symptoms of neurodevelopmental disorders. R-ketamine, its salts, solid forms, and salt forms herein are useful as neuroprotective, prophylactic, or therapeutic agents for diseases or conditions associated with brain dopamine loss. The R-ketamine solid forms, salts, and salt forms described herein can be used to prevent or treat diseases or conditions associated with a decrease in dopamine transporters (DAT). In particular, examples of brain dopamine nervous system dysfunction or conditions include drug use disorders (drug dependence) known to stimulant or cocaine abusers, and R-ketamine is considered to be effective as a preventive or therapeutic drug for drug use disorders (drug dependence). It has been reported that dopamine transporters (DAT) are decreased in the brains of cocaine abusers and stimulant (methamphetamine) users, and it has been pointed out that the decrease in DAT is associated with cognitive dysfunction. In addition, the decrease in DAT in patients with drug use disorders is similar to the decrease in DAT seen in some neurodegenerative diseases, such as Parkinson's disease patients.

[0680] In addition, the R-ketamine solid forms, salts thereof, and salt forms described herein may participate in the signal mediated by brain-derived neurotrophic factor (BDNF), resulting in neuroprotective effects. Due to these neuroprotective effects, the R-ketamine solid forms, salts thereof, and salt forms described herein may be used not only for the prevention or treatment of depression and neurodegenerative diseases, but also for the prevention or treatment of cognitive dysfunction as described above in the explanation of the term "cognitive dysfunction". The solid forms of R-ketamine, salts thereof, and salt forms described herein can be used as preventive or therapeutic agents for neurodevelopmental disorders, neurodegenerative diseases, inflammatory diseases, bone diseases, or cognitive dysfunction, to prevent the onset of the disease or disorder, and to alleviate and improve symptoms in patients suffering from neurodevelopmental disorders, neurodegenerative diseases, inflammatory diseases, bone diseases, or cognitive dysfunction. Many of the disorders, diseases, and dysfunctions described herein progress over a long period of time (measured in years), so early treatment can also prevent the progression of symptoms or reduce the severity of symptoms.

[0681] In addition, it can also be used to prevent the onset of a disorder, disease, or impairment by administration prior to the onset of symptoms to patients with a neurodevelopmental disorder, neurodegenerative disease, inflammatory or bone disease, or a genetic background that may predispose to cognitive impairment.

[0682] In the present disclosure, the R-ketamine solid forms, salts, and salt forms thereof described herein are used for the prevention or treatment of a neurodevelopmental disorder, a neurodegenerative disease, an inflammatory or bone disease, or a cognitive impairment, and administration of the drug is scheduled to be long-term.

[0683] Therefore, by using the R-ketamine solid forms, salts, and salt forms described herein, it is possible to administer the drug for a long period of time without causing side effects, and therefore the R-ketamine solid forms, salts, and salt forms described herein can be used as preventive or therapeutic agents for neurodevelopmental disorders, neurodegenerative diseases, inflammatory diseases or bone diseases, or cognitive dysfunction.

[0684] The R-ketamine solid forms, salts, and salt forms described herein are useful as prophylactic agents for neurodevelopmental disorders, neurodegenerative disorders, inflammatory diseases, bone diseases, or cognitive dysfunction by preventing the onset of the disorders, diseases, or dysfunctions, or as drugs for preventing the progression of symptoms of disorders, diseases, or dysfunctions. In addition, the therapeutic agent may have a therapeutic effect of preventing the progression of symptoms and alleviating or improving symptoms.

[0685] The R-ketamine solid form, its salt, and salt form of the present disclosure are useful for preparing a medicament for the prevention and / or treatment of one or more symptoms associated with any of the disorders, diseases, or functional disorders described herein, such as depressive symptoms. In some embodiments, depressive symptoms include, but are not limited to, lack of interest in activities, changes in sleep patterns, changes in appetite, feelings of guilt, hopelessness, lack of energy, difficulty concentrating, stress, low or depressed mood, impaired motivation, cognitive impairment, poor thinking, anxiety, insomnia, anhedonia and negative affect, anorexia, fatigue, and suicidal thoughts. The R-ketamine solid form, its salt, and salt form of the present disclosure are useful for preparing a medicament for the prevention and / or treatment of depression. The R-ketamine solid form, its salt, and salt form of the present disclosure are useful for preparing a medicament for the prevention and / or treatment of treatment-resistant depression.

[0686] The R-ketamine solid forms, salts, and salt forms of the present disclosure are useful for preparing medicaments for the prevention and / or treatment of drug use disorders in subjects. In some embodiments, the drug use disorder includes abuse of alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), sleep aids, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, inhalants, rohypnol, gamma-hydroxybutyric acid (GHB), N,N-dimethyltryptamine (DMT), ayahuasea, mescaline, salvia, or nicotine.

[0687] The R-ketamine solid forms, salts, and salt forms of the present disclosure are useful for preparing medicaments for the prevention and / or treatment of drug use withdrawal symptoms in a subject. In some embodiments, the drug use withdrawal symptoms include alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), sleep aids, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, inhalants, rohypnol, gamma-hydroxybutyrate (GHB), N,N-dimethyltryptamine (DMT), ayahuasca, mescaline, salvia, or nicotine withdrawal symptoms.

[0688] Additional disorders and symptoms thereof that may be treated by the R-ketamine solid forms, salts, and salt forms of the present disclosure are described in International Publication Nos. 2015 / 037248 (PCT / JP2014 / 004730), 2019 / 213551 (PCT / US2019 / 030644), 2019065900 (PCT / JP2018 / 036079), 2019160057 (PCT / JP2019 / 005415), and 2020138491 (PCT / JP2019 / 051605), which are incorporated by reference in their entireties.

[0689] Route of administration The R-ketamine solid forms, salts, or salt forms described herein may be administered orally, nasally, intranasally, transdermally, pulmonary, inhalationally, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of a particular route of administration.

[0690] Dosage forms for topical or transdermal administration of the R-ketamine solid forms, salts thereof, and salt forms described herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the R-ketamine solid forms, salts thereof, and salt forms described herein can be mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives, buffers, or propellants required.

[0691] For administration by inhalation, the R-ketamine solid forms, salts, and salt forms thereof described herein of the present disclosure can be delivered in the form of an aerosol spray from a pressurized container or dispenser, which can contain a suitable propellant, e.g., a gas such as carbon dioxide, or from a nebulizer.

[0692] Systemic administration may be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved, for example, by using nasal sprays, rectal foams, or suppositories. For transdermal administration, the active compound can be formulated into ointments, salves, gels, or creams, as generally known in the art.

[0693] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent, e.g., water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, e.g., benzyl alcohol or methylparabens; antioxidants, e.g., ascorbic acid or sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid; buffers, e.g., acetates, citrates, or phosphates, and isotonicity adjusters, e.g., sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0694] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure are apparent from the various examples. The examples provided illustrate different components and methodologies useful in implementing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, one skilled in the art can identify and use other components and methods useful in implementing the present disclosure.

[0695] Isolation of R-ketamine In some embodiments, any of the R-ketamine D-tartrate or polymorphic forms or R-ketamine L-tartrate or polymorphic forms described herein may also be used in the isolation or preparation of R-ketamine. In some embodiments, any of the R-ketamine D-tartrate or polymorphic forms or R-ketamine L-tartrate or polymorphic forms described herein may be used in similar methods for isolating S-ketamine described in International Application No. PCT / EP1997 / 002360 or PCT / BR2001 / 000075. In some embodiments, the pure isomers R-ketamine D-tartrate or R-ketamine L-tartrate may be converted to the corresponding hydrochloride salt using hydrochloric acid.

[0696] All patents, patent applications, and publications mentioned herein are incorporated herein by reference in their entirety. However, when a patent, patent application, or publication containing explicit definitions is incorporated by reference, it is to be understood that those express definitions apply to the incorporated patent, patent application, or publication in which they are found, and not to the remainder of the text of this application, and in particular to the claims of this application. EXAMPLES

[0697] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and no limitation to the scope of the present disclosure is intended thereby. It should be further understood that resort can be made to various other embodiments, modifications, and their equivalents that may be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims. [Table 14]

[0698] Experimental procedure DSC Differential scanning calorimetry was performed using a TA Instruments Q2000 instrument (closed gold or aluminum sample pans, heating rates of 5 K / min or 10 K / min or 20 K / min). Melting points are taken as peak maxima.

[0699] Dynamic Vapor Sorption DVS measurements were performed using an SPS11-100n "Sorptions Prufsystem" from ProUmid (formerly "Projekt Messtechnik"), August-Nagel-Str, 23, 89079 Ulm (Germany). Approximately 5-20 mg of sample was placed in an aluminium sample pan. A humidity change rate of 5% per hour was used. The applied measurement program is as described below: Samples were placed on an aluminum or platinum holder on a microbalance and allowed to equilibrate at 50% RH before initiating a defined humidity program: (1) 50% RH for 2 hours (2) 50→0% RH (5% / hour); 5 hours at 0% RH (3) 0→95% RH (5% / hour); 5 hours at 95% RH (4) 95→0% RH (5% / hour); 5 hours at 0% RH (5) 0→95% RH (5% / hour); 5 hours at 95% RH (6) 95→50% RH (5% / hour); 2 hours at 50% RH Hygroscopicity Classification Hygroscopicity was classified based on the mass gain at 85% RH relative to the initial mass as follows: deliquescent (sufficient water is adsorbed to form a liquid), very hygroscopic (mass gain of 15% or more), hygroscopic (mass gain of less than 15% but 2% or more), slightly hygroscopic (mass gain of less than 2% but 0.2% or more), or non-hygroscopic (mass gain of less than 0.2%).

[0700] 1 H-NMR Bruker DPX300 spectrometer; proton frequency of 300.13 MHz; 30° excitation pulse; 1 second regeneration delay; accumulation of 16 scans; deuterated DMSO as solvent; solvent peak used as reference; chemical shifts reported in the TMS scale.

[0701] Powder X-ray diffraction Stoe Stadi P with Mythen 1K detector; Cu-Kα1 radiation; Standard measurement conditions: transmission; tube power of 40 kV and 40 mA; curved Ge monochromator; step size of 0.02°2θ, step time of 48 s, scan range of 1.5-50.5°2θ; detector mode: step scan; detector step of 1°2θ; Standard sample preparation: 10-20 mg of sample was placed between two sheets of acetate foil; sample holder: Stoe transmission sample holder; sample was rotated during measurement. All sample preparations and measurements were performed in ambient air atmosphere.

[0702] HPLC Agilent device, Series 1100 (with Agilent 1260 Infinity degasser) equipped with Chromeleon Version 6.8 software. The overall HPLC method used in this study is described by the following parameters: [Table 15]

[0703] HPLC Method Used to Purify R-Ketamine Fumarate Form A, R-Ketamine Oxalate, and R-Ketamine Saccharin Salt [Table 16]

[0704] Raman spectroscopy FT Raman spectra were recorded on a Bruker MultiRAM FT Raman system using a near-infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. -164 scans at a resolution of 3500~-50cm -1 However, due to the filter cutoff effect, the radiation accumulated in the range of 100 cm -1 Only data above this are evaluated. The nominal laser power is typically 100 or 300 mW.

[0705] TG-FTIR Thermogravimetric measurements were performed using a Netzsch Thermo-Microbalance TG 209 (sample pan with pinhole, N 2 The experiment was carried out using a 1000 sq. m. atmosphere and a heating rate of 10°C / min.

[0706] Example 1. Preparation of R-ketamine free base The starting material was received as R-ketamine hydrochloride. The first step was to generate the free base form from the hydrochloride salt. This HCl salt can be easily converted to the free base by neutralizing with sodium bicarbonate solution and then extracting with dichloromethane. The resulting free base was characterized and then used as the starting material for salt formation.

[0707] R-Ketamine hydrochloride was converted to the free base by neutralization with sodium bicarbonate solution and then extracted with dichloromethane, 1.0 M sodium bicarbonate solution (100 mL) was added slowly with stirring to an aqueous solution of R-ketamine hydrochloride (3.02 grams dissolved in 25 mL water, initial pH 4) until the pH of the solution was approximately 9. Immediately after the addition of the base, precipitation and foaming was observed. Stirring was continued overnight, and then the free base form of R-ketamine was extracted with dichloromethane (2 x 50 mL). The organic phase was separated and the solvent was removed by rotary evaporation. The resulting white solid was dried in a round bottom flask under vacuum (<15 mbar, room temperature) over the weekend. After drying for 3 days, 2.52 g of material was recovered (83% yield). The resulting material showed good solubility as determined by PXRD (Figure 1), TG-FTIR, FT Raman (Figures 3 and 4), and NMR (Hz) NMR (Hz) δ 1.01 to 1.53 (Hz), and δ 1.01 to 1.53 (Hz). 1It was characterized by H-NMR (Figure 6) and DSC (Figure 75). The PXRD pattern is crystalline. DSC measurements revealed a melting peak at 121°C with an associated enthalpy of about 110 J / g.

[0708] Second experiment to generate the free base R-Ketamine HCL (3.3344 g) was dissolved in 25 mL of water with stirring at room temperature. The pH was measured with pH paper to be about 4. Sodium bicarbonate (8.399 g) was dissolved in water under sonication in a 100 mL flask. 1 M aqueous sodium bicarbonate solution was obtained (pH 9) and 25 mL of sodium bicarbonate solution was slowly added to the R-Ketamine solution. Precipitation along with effervescence was observed. Water (25 mL) was added and the pH was measured to be 7. The remaining sodium bicarbonate solution was added: effervescence was observed and 15 mL of water was added. The mixture was stirred at room temperature. After stirring overnight, a solution with some suspended material (flakes) was observed. Extraction was performed with 2 x 50 mL of dichloromethane. The organic portion was collected in a round bottom flask and the solvent was evaporated on a rotary evaporator. The resulting residue was further dried under vacuum (<10 mbar, room temperature). After drying for 4 days, 2.905 g of material was recovered.

[0709] Approximate solubilities were determined for R-ketamine free base. These values ​​were determined by adding a small aliquot of the solvent or solvent mixture to approximately 10 mg of solid and shaking / sonicating for a short period of time at ambient conditions. These values ​​are only approximate. [Table 17] * The solubility of the HCl R-ketamine salt was greater than 100 mg / mL in a 20% aqueous solution of (2-hydroxypropyl)-beta-cyclodextrin.

[0710] Scale-up experiments R-Ketamine hydrochloride (10.0693 g) was dissolved in 85 mL of water with stirring at room temperature. The pH was measured with pH paper to be about 4-5. 29.4 g of sodium bicarbonate was dissolved in 350 mL of water with stirring at room temperature. 1 M aqueous sodium bicarbonate solution was obtained (pH 9). 100 mL of sodium bicarbonate solution was slowly added to the ketamine solution. Precipitation was observed along with effervescence; pH was about 8. 100 mL of water was added and the pH was measured to be 8. The remaining sodium bicarbonate solution was added to obtain a white, well-stirrable suspension (fewer bubbles were observed). 50 mL of water was added and the pH was measured to be about 8-9. The suspension was further stirred at room temperature. After stirring overnight, a solution with some suspended material (flakes) and bubbles was observed. Extraction was performed with 2 x 75 mL of dichloromethane. The organic portion was collected in a round-bottom flask and the solvent was evaporated on a rotary evaporator. The resulting residue was further dried under vacuum (<10 mbar, room temperature). After drying for 2 days, 8.9 g of material was recovered. The PXRD pattern was crystalline and corresponds to R-ketamine free drug. 0.21% water loss from 25-115° C.; 0.22% DCM loss from 115° C.-135° C. Decomposition is observed at higher temperatures.

[0711] Second scale-up experiment R-Ketamine hydrochloride (30.00 g) was dissolved in 255 mL Millipore water with stirring at room temperature. The pH was measured with pH paper to be about 4-5. 88.2 g sodium bicarbonate was dissolved in 1050 mL water with stirring at room temperature. A 1 M aqueous sodium bicarbonate solution was generated (pH about 9). 300 mL of sodium bicarbonate solution was added slowly (10 mL-steps) to the ketamine solution. Precipitation was observed along with effervescence. 100 mL of water was added and the pH was about 8. The remaining sodium bicarbonate solution was added (20 mL-steps) to give a white suspension (fewer bubbles were observed). 200 mL of water was added and the pH was measured to be about 8-9. The suspension was further stirred at room temperature. After stirring overnight, a solution with some suspended material and bubbles was observed. Extraction was performed with 3x750 mL of dichloromethane. The organic portion was collected in a round bottom flask and the solvent was evaporated on a rotary evaporator. The resulting residue was further dried under vacuum (<10 mbar, room temperature). After drying for 3 days, 25 g of material was recovered. The PXRD pattern was crystalline and consistent with R-ketamine free base. Mass loss of 0.53% from 25° C. to 210° C. The NMR spectrum was consistent with the ketamine structure. Residual DCM was found at 5.75 ppm (0.008 equiv.).

[0712] Example 2. Formation and evaluation of various R-ketamine salts Salt crystallization was performed with 11 different salts / co-crystal formers, with the free base used alone in the blank experiment. The experiments were performed in a Quartz 96 microtiter plate according to the method described in US Pat. No. 7,504,071. The first step of the HTS is the evaporation plate, referred to as Phase 1 in this study. The experiments were performed according to the plate layout in FIG. 7A by adding 0.05M free base stock solution (Phase 1) to each well, followed by the salt former stock solution specified in Table 14. The solvent was evaporated from each well at room temperature under a stream of nitrogen. The resulting solid residue in the wells was examined by Raman microscopy.

[0713] To each well of a 96-well quartz plate, 100 μL of 0.05 M free base solution was added: A1-H3 in ethanol A4-H6 in acetone A7-H9 in THF A10-H12 in methanol

[0714] Then 100 μL of a 0.05 M solution of the salt former in the corresponding solvent was added. N-acetylglycine, aspartic acid, and phosphoric acid were always added in water. Fumaric acid cannot be dissolved in acetone, so it was also added to 2-propanol. The solvent was evaporated at room temperature using a nitrogen flow (300 mL / min for 2 days, then 500 mL / min for 4 days). [Table 18]

[0715] Results from Phase 1: After solvent evaporation, visual inspection of the microtiter plate revealed several locations containing solid and possibly crystalline material. A Raman microscopy investigation was performed on the entire plate. Crystalline material was sampled and 2-7 locations for Raman spectroscopy analysis were selected in each well.

[0716] A blank experiment with the free base alone was first run to see if other crystalline forms or possibly solvates of the free base were formed. A new spectrum was obtained from the location of well A7. All other measurements correspond to the free base reference, except in some cases where the band at 1700 cm-1 disappeared. This new Raman spectrum contains the bands of the free base reference; however, this new Raman spectrum presents a strong band at 1050 cm-1 and two new bands at approximately 700 cm-1. Another polymorph of the free base could have formed during the experiment with THF. A THF solvate of the free base could be another possible hypothesis. [Table 19]

[0717] Example 3: Slurry Crystallization In the second crystallization experiment (hereafter referred to as Phase 2), eight solvent systems were selected for slurry equilibration. 100 μL of the selected solvent system was added to the residue of Phase 1 (Example 2) for slurry equilibration according to the layout in FIG. 8A (color domains) and FIG. 8B. After shaking for 2 days at room temperature, many of the wells contained solution; however, in some wells, solid material was observed at the bottom of the well, likely remnants of evaporation residue that could not be dissolved or slurried by the solvent system. The solvent was then evaporated over a weekend at room temperature under nitrogen flow (200 mL / min), and the resulting solid residue was examined by polarized light microscopy. The locations containing crystalline material were examined by Raman microscopy.

[0718] Results: After 2 days of equilibration and solvent evaporation, the second phase plates were examined by optical microscopy and crystalline material was observed in the majority of the wells. Raman investigations were performed on the wells containing crystalline material.

[0719] As with the previous evaporation plate, no salt formation was observed with N-acetylglycine, L-asparagine, glutaric acid, L-malic acid, maleic acid, or phosphoric acid, and furthermore, no salt formation was observed with adipic acid in this case.

[0720] Salt formation was found with at least benzoic acid, fumaric acid, saccharin, and succinic acid, and the Raman spectra obtained were identical to those observed with the previous first phase plates. Table 16 summarizes the results obtained for the plates from the second phase. [Table 20]

[0721] During these salt formation experiments, several leads for potential salt formation were found with benzoic acid, fumaric acid, saccharin, and succinic acid. Based on these results, the saccharin salt was further scaled up at a 100 g scale. Although the Raman studies point to a novel crystalline compound and possibly a saccharin salt, it should not be discounted that other crystalline forms of the free base could possibly be obtained.

[0722] Example 4. R-Ketamine Saccharin Salt R-Ketamine free base (300.2 mg, 1.26 mmol) was dissolved in 10 mL of 2-propanol with stirring at room temperature. A short sonication was used to dissolve the material. 231.8 mg of saccharin (1 eq, 1.26 mmol) was dissolved in 15 mL of 2-porpanol at room temperature with sonication. The solution with saccharin was slowly added to the free base solution with stirring at room temperature. After addition, a clear solution was obtained, which after a few minutes became cloudy and turned into a fine suspension. After stirring overnight, a fine suspension was obtained, and the vial was opened to evaporate the solvent under stirring. After 1 day, ¼ of the solvent was evaporated and the suspension was filtered through fritted glass (porosity 4). The filter cake was dried on the filter in vacuum for 5 minutes and 442 mg of powder was recovered (yield 83%).

[0723] Salt formation was observed with saccharin during salt / co-crystal experiments. Therefore, experiments were performed to generate a larger amount of R-ketamine saccharin salt. The free base was dissolved in 2-propanol at room temperature. An equimolar amount of saccharin was also dissolved in 2-propanol and this solution was slowly added to the free base solution with stirring at room temperature. A clear solution was observed after the addition and after a few minutes a suspension formed. After stirring for 2 days, the suspension was filtered and the wet cake was analyzed by PXRD. A new crystalline PXRD pattern was obtained (Figure 9) that was different from the PXRD patterns of the free base and saccharin (Figure 10). The wet cake was dried at room temperature overnight at 5 mbar; the dried sample was subjected to PXRD investigation and no change in the PXRD pattern was observed (Figure 11). The dried sample was used for further characterization.

[0724] FT Raman spectra were recorded and the resulting Raman spectrum was identical to that obtained during the previous experiment (Figure 14). Thus, the earlier results with saccharin could be successfully and reliably reproduced.

[0725] TG-FTIR shows a mass loss of 0.28% up to 220° C., which corresponds to traces of water and 2-propanol (FIG. 15). Thus, the obtained salt is in anhydrous form.

[0726] DSC measurements revealed a melting peak at 210.5°C with an onset of 209.2°C and an associated enthalpy of 139.3 J / g (Figure 16). The melting peak of the hydrochloride salt was seen at 270.5°C.

[0727] 1 H-NMR measurements confirmed the 1:1 stoichiometry of R-ketamine-saccharin salt; residual 2-propanol is also observed in the NMR spectrum (Figure 17).

[0728] DVS measurements revealed a non-hygroscopic saccharin salt with less than 0.1% water uptake upon storage at 95% relative humidity. The results of the DVS studies are presented in Figures 18 and 19. PXRD studies were performed on the post-DVS samples and, as expected, no change in solid form was observed (Figure 20).

[0729] The chemical identity of the R-ketamine saccharin salt was verified by elemental composition analysis using CHSNO content determination, and TG-FTIR for water and solvent content. The results obtained are summarized in Table 17. The results obtained are in excellent agreement with the theoretical content of the (1:1) saccharin salt. [Table 21]

[0730] Example 5. R-Ketamine Fumarate Form A R-Ketamine free base (301.1 mg, 1.27 mmol) was dissolved in 4 mL of ethanol at room temperature with sonication. Fumaric acid (73.5 mg, 0.63 mmol, 0.5 equiv.) was dissolved in 2 mL of ethanol at room temperature with sonication. The fumaric acid solution was then slowly added to the free base solution with stirring. After addition, a clear solution was obtained and further stirring was carried out at room temperature with an open vial. After 10 min, a suspension started to form. After 4 h, the suspension was filtered (Centrifugal Unit Filter, PVDF, 0.22 μm, 5 min, 5000 rpm, room temperature). The resulting powder was dried at room temperature at 5 mbar for 5 days.

[0731] Salt formation with fumaric acid was observed during salt / co-crystal experiments, therefore experiments were performed to regenerate R-ketamine fumarate.

[0732] In this experiment, the free base was dissolved in ethanol at room temperature. Half an equivalent amount of fumaric acid was dissolved in ethanol and this solution was slowly added to the free base solution under stirring. After addition, a clear solution was obtained; after stirring for 10 minutes at room temperature, a suspension started to form. After stirring for 4 hours, the resulting suspension was filtered and the resulting powder was dried at room temperature at approximately 5 mbar. The resulting material was analyzed by PXRD, FT Raman, 1 It was characterized by H-NMR and TG-FTIR.

[0733] A new crystalline PXRD pattern was obtained for the fumarate salt sample (Figure 21); this pattern differs from the fumaric acid reference (Figure 22) and also from the PXRD patterns of the free base and salts with saccharin and HCl (Figure 23).

[0734] About the fumarate sample 1 1 H-NMR was performed; 0.5 equivalents of fumaric acid were found, confirming a 2:1 ratio of free base to acid. 1 H-NMR is depicted in Figure 24.

[0735] FT Raman was measured on the fumarate salt sample and the spectra are depicted in Figures 25 and 26. In addition, Figure 27 shows an overlay with the lead obtained during the HTS experiment; the spectra are different. Therefore, it can be inferred that a 1:1 salt was obtained during the HTS experiment instead of a 2:1 free base to fumarate salt.

[0736] TG-FTIR measurements revealed only traces of water with a mass loss of 0.03% between 25 and 150 °C. Thus, this sample of R-ketamine fumarate form A is essentially a nonsolvated form free of any residual solvent. Furthermore, DSC analysis revealed a sharp melting peak at 144.2 °C with an associated enthalpy of 136.6 J / g (Figure 28B). R-ketamine fumarate Form A was also measured by DVS; the resulting curves are depicted in Figure 28C and Figure 28D. The fumarate salt picked up up to 6% water when stored at 95% relative humidity, and the sample lost all of its water when the humidity was returned to 0% relative humidity and scanned. PXRD studies were performed on the post-DVS sample, and no change in crystal morphology was observed (Figure 28E).

[0737] Example 6. R-Ketamine succinate R-ketamine free base (200.3 mg, 0.84 mmol) was dissolved in 5 mL of 2-propanol at room temperature. A brief sonication was used to dissolve the material, and 49.7 mg of succinic acid (0.5 eq, ca. 0.42 mmol) was dissolved in 2 mL of 2-porpanol at room temperature using sonication. The solution with succinic acid was slowly added to the free base solution with stirring at room temperature. After addition, a clear solution was obtained. Further stirring at room temperature was carried out with an open vial. After 5 days, a solution with some material was obtained; further evaporation was carried out with a nitrogen stream at room temperature. After evaporation overnight, a glassy residue was obtained and 1 mL of acetone was added. After vortexing, a solution was obtained and further stirring at room temperature was carried out. After 10 min, a viscous suspension was obtained and an additional 1 mL of acetone was added. A solution was obtained and 2 mL of heptane was slowly added. A cloudy solution was formed and changed to a viscous suspension. Filtration was carried out using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The resulting filter cake was dried overnight at room temperature in vacuum below 5 mbar.

[0738] A possible crystalline salt with succinic acid was observed. Therefore, experiments were carried out to see if this salt could be regenerated on a larger scale, i.e., 200 mg. R-ketamine succinate was obtained in the experiment with 0.5 equivalents of succinic acid in acetone by precipitation with heptane (1:1 ratio). The obtained material was analyzed by PXRD, FT Raman, 1 It was characterized by H-NMR and TG-FTIR.

[0739] PXRD analysis revealed a novel crystalline pattern (Figure 29) distinct from other crystalline forms (Figure 30).

[0740] R-ketamine succinate sample 1 The H-NMR spectrum (FIG. 31) is consistent with the R-ketamine structure, and one equivalent of succinic acid was found; this is somewhat surprising since the experiment started with 0.5 equivalents of succinic acid.

[0741] The FT Raman spectrum of the succinate salt (Figures 32 and 33) is the same as that obtained during the screening experiment (Figure 34). Thus, the 1:1 succinate salt obtained during the screening experiment could be successfully and reliably reproduced.

[0742] TG-FTIR measurements revealed only traces of water with a mass loss of 0.11% from 25 to 120 °C, thus forming a solvent-free salt (Figure 35).

[0743] Example 7. R-Ketamine Sulfate R-Ketamine free base (190.8 mg, 0.803 mmol) was dissolved in 2 mL of methanol with stirring at room temperature. Then 4.01 mL (0.5 eq, 0.402 mmol) of 0.1 M aqueous sulfuric acid was slowly added. After the addition, a clear solution was obtained. After stirring overnight at room temperature, a solution was still observed and further stirring was performed in an open vial. It was still a solution after 4 days. Further evaporation was performed using a nitrogen stream. A gel with a glassy residue was obtained. 500 μL of methanol was added to dissolve the material. 3 mL of TBME was slowly added, but no precipitation was observed. The solution was further stirred in an open vial. Dry material was obtained and 500 μL of TBME was added. A solution was obtained with sticky material on the sides. 200 μL of ethanol was added to form a suspension. After stirring for 4 hours, the suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The resulting filter cake was dried overnight at room temperature in vacuum below 5 mbar.

[0744] Salt formation with sulfuric acid was attempted in methanol. However, no precipitation was observed and the resulting solution was evaporated. TBME was added to the solid residue and a sticky material was formed. Ethanol was added and the suspension could be stirred at room temperature. After filtration, the material was dried under vacuum overnight and then characterized. A second experiment was performed but the resulting material was amorphous.

[0745] PXRD analysis of the dried material revealed a novel PXRD pattern, but low crystallinity (Figure 36). Figure 37 shows an overlay with the free base starting material.

[0746] For samples 1 H-NMR was performed (Figure 38); the spectrum obtained is consistent with the R-ketamine structure. Furthermore, changes (shifts, multiplicities, etc.) are observed compared to the NMR spectrum of the starting material, suggesting a structural change (Figure 39). Thus, salt formation can be considered. Further investigations on the sample are being performed, particularly using elemental analysis, to determine the equivalents of sulfur. Some residual TBME (less than 0.02 equivalents) is observed at 1.11 ppm and 3.08 ppm.

[0747] R-Ketamine free base (296.9 mg, 1.25 mmol) was dissolved in 2 mL of acetone at room temperature under sonication. Then, 625 uL (0.5 eq, 0.63 mmol) of 2N (1 M) aqueous sulfuric acid was slowly added. After addition, a clear solution was obtained and further stirring was continued in the open vial. A gel was obtained and 1 mL of 2-propanol was added. After sonication, a solution was obtained. After equilibration for 2 days, no precipitation was observed and 2 mL of heptane was slowly added. An emulsion with gel parts was obtained and did not crystallize after 1 day of stirring. The solvent was then evaporated under nitrogen flow and a white solid residue was obtained. 2 mL of TBME was added and a suspension was formed. After stirring over the weekend, a viscous suspension was observed. Filtration was performed using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature) and the reactor was flushed with the filtrate. The collected filter cake was dried under vacuum (<5 mbar) at room temperature. After drying overnight, 293 mg of powder was collected to give amorphous PXRD.

[0748] Example 8. R-Ketamine D-Tartrate Form A R-ketamine free base (196.3 mg, 0.826 mmol) was dissolved in 2.5 mL of ethanol at room temperature with stirring, and 62 mg of D-tartaric acid (0.413 mmol, 0.5 eq.) was dissolved in 2 mL of ethanol at room temperature. The tartaric acid solution was then slowly added to the free base solution with stirring. After addition, a clear solution was obtained and further stirring was carried out at room temperature. After stirring overnight at room temperature, a solution was still observed and further stirring was carried out in the open vial. After 4 days, a solid material was obtained on the side along with the solution. The material was scraped off with a spatula and the mixture was further stirred at room temperature. After stirring overnight, a suspension was formed. Filtration was carried out using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The obtained filter cake was dried overnight in vacuum at room temperature under 5 mbar.

[0749] Salt formation with D-tartaric acid was carried out in ethanol. The resulting dry material was first characterized by PXRD. A new crystalline PXRD was obtained (Figure 40). Figure 41 shows an overlay of the new pattern with the free base starting material and D-tartaric acid.

[0750] R-ketamine D-tartrate samples 1 H-NMR revealed a spectrum consistent with the R-ketamine structure (Figure 42). Several changes were observed compared to the spectrum of the starting material, confirming a structural change in the environment. Approximately 0.8 equivalents of tartaric acid were found at 4.25 ppm. A broad shoulder was observed under the tartaric acid peak, therefore the exact equivalent weight is difficult to predict, but could be between 0.75 and 0.85.

[0751] The DSC thermogram of R-ketamine D-tartrate Form A is presented in Figure 53. The DSC shows a fairly sharp melting endotherm with a peak maximum at 108°C, followed by two smaller signals. Current knowledge is insufficient to provide further interpretation for the smaller signals. The event near 200°C is possibly due to chemical decomposition.

[0752] An FT Raman spectrum was recorded for R-ketamine D-tartrate Form A. Figure 54 shows the full range of the spectrum, and Figure 55 shows the expanded fingerprint region (200 cm-1 to 2000 cm-1).

[0753] Reanalysis of the material after 13 months of storage in a sealed vial at ambient conditions gave a PXRD pattern corresponding to R-ketamine D-tartrate Form A. TG-FTIR showed a mass loss of 2.8%, essentially due to water (Figure 76). The mass loss is associated with a fairly distinct step beginning at about 80°C. This step suggests a stoichiometric hydrate; however, the 2.8% loss corresponds to 0.6 water per salt entity, whereas the hemihydrate contains 2.3% water. This seems unusual and a single crystal structure may be required to clarify the stoichiometry.

[0754] DVS measurements show that when the relative humidity exceeds 70%, an additional water uptake of about 3% occurs. During the course of the measurement, this water content does not change significantly any more. Water sorption is irreversible under the test conditions. The results of the DVS test are presented in Figures 77 and 78. The solids recovered after the DVS test were investigated using FT Raman, which gave a mixture of R-ketamine D-tartrate Form D and the free base.

[0755] Second experiment to generate R-ketamine D-tartrate form A R-ketamine free base (195.2 mg) was dissolved in 3.25 mL of ethanol and 0.5 equivalents of D-tartaric acid was added in the form of a solution in ethanol (1.25 mL). The solution was seeded with a few crystals of R-ketamine D-tartrate Form A. The solution was stirred at room temperature for 1 day after which fine particles were observed. The suspension was stirred at room temperature for an additional 3 days, but most of the crystalline material adhered to the glass wall of the vial. The material was resuspended and the open vial was kept under stirring at room temperature for an additional 5 days. Crystals were then obtained and examined by PXRD, which gave a mixture of R-ketamine D-tartrate Form A, R-ketamine D-tartrate Form D, and the crystalline free base form.

[0756] Example 9. R-Ketamine Oxalate R-ketamine free base (180.7 mg, 0.76 mmol) was dissolved in 2 mL of acetonitrile at room temperature. 34.2 mg of oxalic acid (0.5 eq, 0.38 mmol) was dissolved in 1 mL of acetonitrile at room temperature. Oxalic acid was then slowly added to the free base solution with stirring. After addition, no precipitation was observed and the solution was further stirred at room temperature in an open vial. A paste was obtained and 500 μL of TBME was added. Precipitation was observed. After stirring for 4 days at room temperature, some material was attached to the sides. 100 μL of ethanol was added and a good suspension was formed. After stirring for 4 hours, the suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The resulting filter cake was dried overnight at room temperature in vacuum below 5 mbar.

[0757] Salt formation with oxalic acid was attempted in acetonitrile. However, no precipitation was observed and the resulting solution was evaporated. TBME was added to the solid residue, forming a sticky material. Ethanol was added and the suspension could be stirred at room temperature. After filtration, the material was dried under vacuum overnight and then characterized.

[0758] PXRD analysis revealed a novel crystalline pattern (Figure 43). Figure 44 shows a comparison of the PXRD patterns of this experiment, the free base starting material, and oxalic acid.

[0759] This sample 1 The H-NMR spectrum is consistent with the R-ketamine structure, and the changes compared to the spectrum of the free base with respect to the previous salt suggest a new structural environment, and therefore salt formation can be considered (Figure 45A). Further aspects of the chemical identity were verified by elemental composition analysis with CHN, O, and Cl content determination. The results obtained are summarized in Table 18. These results confirm that a 2:1 ratio of free base to oxalic acid was obtained.

[0760] Scale-up experiments R-ketamine free base (1.5192 g, 6.4 mmol) was dissolved in 15 mL of ethyl acetate at 40° C. with sonication. 288 mg of oxalic acid (3.2 mmol, 0.5 equiv.) was dissolved in 3 mL of ethyl acetate at 40° C. The oxalic solution was then slowly added to the free base solution with stirring at room temperature. After addition, a precipitate was observed, which quickly turned into a sticky material. After stirring overnight at room temperature, a white suspension was obtained, and some sticky material was still observed on the sides of the reactor. After stirring for another day at room temperature, the suspension was filtered through a fritted glass filter (porosity 4). The reactor was flushed with 3 mL of mother liquor. The resulting filter cake was dried by applying vacuum on the filter for 1 hour. 955 mg of white powder was recovered (63% yield). The PXRD pattern corresponds to the previously identified form. The NMR spectrum is consistent with the R-ketamine structure. A trace of ethyl acetate was detected (0.02 equiv). [Table 22]

[0761] TG-FTIR indicates only traces of residual water (0.2%, FIG. 45B). The DSC thermogram of a sample of R-ketamine oxalate is depicted in FIG. 45C and reveals a broad endothermic signal with a maximum at 115° C., which likely corresponds to the melting peak of the oxalate salt.

[0762] An FT Raman spectrum was recorded for a sample of R-ketamine oxalate. Figure 45D shows the full range of the spectrum, and Figure 45E shows the expanded fingerprint region (200 cm-1 to 2000 cm-1).

[0763] DVS measurements revealed a highly hygroscopic oxalate salt with over 80% water uptake upon storage at 95% relative humidity. The results of the DVS study are presented in Figures 45F and 45G. PXRD studies were performed on the post-DVS sample and a dramatic loss of crystallinity was observed (Figure 45H).

[0764] Example 10. R-Ketamine Citrate R-ketamine free base (191.1 mg, 0.804 mmol) was dissolved in 4 mL of 2-propanol with sonication at room temperature, and 77.2 mg of citric acid (0.5 eq., 0.402 mmol) was dissolved in 2.5 mL of 2-propanol with sonication at room temperature. The citric acid solution was then slowly added to the free base solution with stirring. After addition, no precipitation was observed, and the solution was further stirred at room temperature in an open vial. After 1 day, no change was observed, and further evaporation was carried out under a nitrogen stream. A gel with a glassy residue was obtained, and 500 μL of TBME was added. Precipitation was observed. After stirring for 2 days at room temperature, the suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The resulting filter cake was dried overnight at room temperature in vacuum below 5 mbar.

[0765] Salt formation was attempted using R-ketamine and citric acid in 2-propanol. However, no precipitation was observed, and the resulting solution was evaporated. TBME was added to the solid residue to form a suspension. After filtration, the material was dried under vacuum overnight and then characterized.

[0766] PXRD analysis revealed crystalline material (Figure 46); the resulting PXRD pattern contained some reflections of R-ketamine free base with additional reflections not attributable to citric acid (Figure 47). Therefore, this sample is not a pure phase and is believed to contain the citrate salt, tentatively the monocitrate salt. Thus, an excess of free base is possible. An overlay with R-ketamine free base is shown in Figure 52.

[0767] For samples 11H-NMR was performed and the spectrum is shown in Figure 48. Residual 2-propanol (1.04 ppm) and residual TBME (1.11 ppm and 3.08 ppm) were observed. In the range of 2 - 3 ppm, interpretation is difficult due to peak overlap. Otherwise, the signals are consistent with the R-ketamine structure. The quartet at 2.6 ppm cannot be attributed to R-ketamine and has a very low possibility of being attributed to citric acid.

[0768] Example 11. Determination of pH and Solubility For the salts of R-ketamine with saccharin, fumaric acid, and oxalic acid, accurate solubility determinations were performed in water at 25 °C. 50 mg of R-ketamine saccharin salt was suspended in 0.5 mL of water and the suspension was equilibrated at 25 °C for 1 day (700 rpm). 10 - 15 mg of R-ketamine fumarate and R-ketamine oxalate were also equilibrated in 0.5 mL of water at 25 °C for 1 day. After 5 minutes of equilibration, a solution was obtained for the fumarate sample, and after 1 day of equilibration, a solution with some small particles was observed for both the fumarate and oxalate. Filtration was then performed and the recovered saturated solution was subjected to HPLC; furthermore, the pH was measured at 24 °C (Table 19).

[0769] R-ketamine hydrochloride has a relatively high solubility in water (63 < S < 125 mg / mL), while the solubility of the saccharin salt is as low as 6.6 mg / mL. The solubilities of R-ketamine fumarate and R-ketamine oxalate are higher than that of the R-ketamine saccharin salt.

[0770] After stirring for 1 day, a pH of 5.7 was obtained for the oxalate; this result is interesting since this pH is almost neutral. [Table 23] * Since a solution with some particles was obtained 1 day after equilibration, the solubility values obtained may be underestimated.

[0771] Additionally, approximate solubility determinations of R-ketamine free base, R-ketamine hydrochloride, and R-ketamine saccharin salt were performed in 20% (w / w) (2-hydroxypropyl)-beta-cyclodextrin (cyclodextrin) aqueous solution and also in 20% (w / w) cyclodextrin in pH 7 buffer. These values ​​were determined by adding small aliquots of the solvent or solvent mixture to approximately 10 mg of solid and shaking / sonicating for a short period at ambient conditions. Solubility was estimated by visual observation. These values ​​are only approximate. The resulting solubility values, and the pH of the resulting solutions are summarized in Table 20. [Table 24]

[0772] Example 12. R-Ketamine D-Tartrate Form B R-ketamine free base (293.4 mg, 1.23 mmol) was dissolved in 2.0 mL of acetone at room temperature under sonication. 92.6 mg of D-tartaric acid (0.62 mmol, 0.5 eq.) was dissolved in 3.0 mL of ethanol at room temperature under sonication. The tartaric acid solution was then slowly added to the free base solution with stirring. Precipitation with some sticky material was observed immediately. After stirring for 4 days at room temperature, a white suspension was obtained and filtration was carried out using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The resulting filter cake was dried overnight at room temperature in vacuum below 5 mbar. 213 mg of material was recovered. A sample with a new PXRD pattern was obtained (Figure 56). This pattern is different from D-tartaric acid as shown in Figure 57. This pattern differs from the previous R-ketamine D-tartrate Form A and the free base; an overlay of the three patterns is depicted in Figure 74. The NMR spectrum is consistent with the R-ketamine structure.

[0773] For sample R-ketamine D-tartrate form B 1H-NMR revealed 1 equivalent of tartaric acid; thus giving the 1:1 salt in Figure 58. Residual (0.01 equivalent) acetone is also seen.

[0774] The FT Raman spectrum was recorded for R-ketamine D-tartrate form B. Figure 59 shows the full range of the spectrum, and Figure 60 shows the expanded fingerprint region (200 cm-1 to 2000 cm-1).

[0775] Reanalysis of the material after 12 months of storage in a closed vial at ambient conditions gave a PXRD pattern corresponding to R-ketamine D-tartrate Form B. TG-FTIR analysis indicates that the crystalline form is essentially free of residual solvent, but thermal decomposition begins at approximately 150° C. (FIG. 79). DSC measurements revealed a main melting peak at 145° C. From the DSC results, it is not possible to determine whether R-ketamine D-tartrate Form B and R-ketamine D-tartrate Form C are monotropically or enantiotropically related. Based on the small additional peak at 150° C., it appears that R-ketamine D-tartrate Form B was partially converted to R-ketamine D-tartrate Form C during the DSC study. Due to suspected phase conversion, a meaningful value for the melting enthalpy cannot be assessed. The very small signal at 119° C. likely corresponds to traces of free base present in the sample (see FIG. 80).

[0776] This material was also tested by DVS. The results of the DVS test are presented in Figures 81 and 82. When the relative humidity exceeds 70%, R-ketamine D-tartrate Form B starts to absorb significant amounts of water and the water content rises to about 8.5%. During the course of the measurement, this water content does not change significantly anymore. The water sorption is irreversible under the test conditions and corresponds to the water content of R-ketamine D-tartrate Form D. The solid recovered after the DVS test was investigated using FT Raman and corresponds to R-ketamine D-tartrate Form D.

[0777] Example 13. R-Ketamine D-Tartrate Form C (MeOH) R-ketamine free base (249.2 mg, 1.05 mmol) was dissolved in 2.0 mL of methanol at room temperature under sonication. 78.7 mg of D-tartaric acid (0.52 mmol, 0.5 eq.) was dissolved in 1.0 mL of methanol at room temperature under sonication. The tartaric acid solution was then slowly added to the free base solution with stirring. No precipitation was observed after addition. After equilibration for 2 days, a solution was still observed and the solvent was evaporated with a nitrogen stream. After 4 hours, a wet residue was obtained and 1.0 mL of ethyl acetate was added. A solution was obtained after shaking. After stirring overnight, a suspension was formed and then filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The obtained filter cake was dried at room temperature in vacuum at less than 5 mbar for 2 days. 151.3 mg of material was obtained. A new PXRD pattern was obtained for R-ketamine D-tartrate form C with one additional peak at 14.8° corresponding to the free base. The NMR spectrum is consistent with the R-ketamine structure.

[0778] The PXRD pattern of R-ketamine D-tartrate Form C is depicted in Figure 61. Figure 62 shows an overlay of the PXRD patterns of the three tartrate salts, and Figure 63 shows an overlay of R-ketamine D-tartrate Form C with R-ketamine free base.

[0779] 1 H-NMR measurements were performed on the R-ketamine D-tartrate Form C sample and are presented in Figure 64. A broad signal is detected below the tartaric acid signal at 4.27 ppm, and therefore integration is difficult. Roughly estimated, the sample contains 1-1.5 equivalents of tartaric acid. This does not necessarily contradict the X-ray results, since the stoichiometry of the new salts may favor tartaric acid.

[0780] The Raman spectra of R-ketamine D-tartrate Form C are presented in Figure 65 and Figure 66. An overlay of the Raman spectra of all three D-tartrate samples is shown in Figure 67, confirming the distinct nature of all solid forms.

[0781] Reanalysis of the material after storage for 12 months in a closed vial at ambient conditions gave a PXRD pattern corresponding to R-ketamine D-tartrate Form C. TG-FTIR analysis showed that R-ketamine D-tartrate Form C was essentially free of residual solvent; however, thermal decomposition begins at approximately 160° C. (FIG. 83).

[0782] Example 14. R-Ketamine D-Tartrate Form C (Ethanol) and Conversion to Form D At 60° C., 481 mg of R-ketamine free base (approximately 2.0 mmol) was dissolved in 5.0 mL of ethanol. 6.0 mL of a stock solution of D-tartaric acid in ethanol (0.33 M) was added. The solution remained clear and was placed in a thermostat and cooled to 4° C. After approximately 4 hours, the solution turned into a viscous suspension. As the solid appeared to be possibly amorphous, 2.5 mL of the suspension was stirred overnight at 40° C. and then filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 2 min, room temperature). The wet cake was subjected to PXRD. The PXRD pattern corresponds to R-ketamine D-tartrate Form C.

[0783] 200 μL of water was added to 5.0 mL of a suspension of R-ketamine D-tartrate Form C (water activity approx. 0.3). The resulting suspension was stirred for 1 day and then filtered on a fritted glass (porosity 4). After drying on the filter for a few minutes, the solid was filled into a vial and subjected to PXRD. The PXRD pattern corresponds to R-ketamine D-tartrate Form D.

[0784] Example 15. R-Ketamine D-Tartrate Form C (Acetone) and Conversion to Form D At 40°C, 383 mg of R-ketamine free base (approximately 1.6 mmol) was dissolved in 3.0 mL of acetone. 8.0 mL of a stock solution of D-tartaric acid in acetone (0.20 M) was added. A cloudy solution was obtained at 40°C, and then a suspension was obtained at 35°C. The suspension was removed from the thermostat, but after stirring at room temperature for several hours, a quick examination by optical microscopy indicated that the material may be poorly crystalline. The suspension was then stirred overnight at 40°C, after which 2.5 mL was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The wet cake was subjected to PXRD. The PXRD pattern corresponds to R-ketamine D-tartrate Form C. As shown in Example 12, using a 1:0.5 ratio of R-ketamine free base to D-tartaric acid results in R-ketamine D-tartrate Form B. Here, using a 1:1 ratio results in R-ketamine D-tartrate form C.

[0785] DVS measurements reveal that at relative humidities above 70%, R-ketamine D-tartrate form C starts to absorb significant amounts of water reaching a water content of about 8.3% (Figure 85, Figure 86). During the course of the measurements, this water content does not change significantly anymore. Water sorption is irreversible under the test conditions and corresponds to the water content of R-ketamine D-tartrate form D. The solids recovered after the DVS test were investigated by FT Raman. The FT Raman spectrum corresponds to R-ketamine D-tartrate form D.

[0786] Water (500 μL) was added to 5.0 mL of the R-ketamine D-tartrate Form C suspension (a w 0.75). The resulting suspension was stirred at room temperature for 1 day and filtered through a fritted glass filter (porosity 4). After drying on the filter for a few minutes, the solid was loaded into a vial and subjected to PXRD. The PXRD pattern corresponds to R-ketamine D-tartrate form D.

[0787] Example 16. R-Ketamine D-Tartrate Form C (IPA) and Conversion to Form D R-Ketamine free base (340 mg) and D-tartaric acid (212 mg) were dissolved in 4.0 mL of IPA by heating to about 70° C. The solution was allowed to cool to room temperature by removing the vial from the temperature controller; a suspension was obtained. A quick examination by optical microscopy suggested that the material was poorly crystalline, so the suspension was stirred overnight at 40° C. 2.5 mL of the suspension was then filtered using a centrifuge unit filter. The wet cake was subjected to PXRD. 2.0 mL of the collected filtrate (saturated solution in isopropanol at approximately 40° C.) was evaporated and the residue was dried under vacuum. 7.2 mg of solid residue was obtained. The PXRD pattern corresponds to R-ketamine D-tartrate Form C.

[0788] To the remaining suspension, 2.0 mL of IPA was added. Most of the suspension (5.0 mL) was transferred to a new vial. Then, about 40 μL of water was added (0.8%, aw about 0.1) and the suspension was stirred at room temperature for 3 days. After filtration through a fritted glass filter, the solid product was dried for a few minutes and then subjected to PXRD. The PXRD pattern shows a mixture of R-ketamine D-tartrate Form C and Form D.

[0789] Example 17. R-Ketamine Fumarate Form B R-Ketamine free base (263.9 mg, 1.11 mmol) was dissolved in 1 mL of THF at room temperature with sonication. 64.4 mg of fumaric acid (0.56 mmol, 0.5 eq.) was dissolved in 2 mL of THF at room temperature with sonication. The fumaric acid solution was then slowly added to the free base solution with stirring. After addition, a clear solution was obtained, but quickly converted to a suspension. After stirring for 2 days, optical microscopy revealed crystalline material, and the suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, room temperature). The resulting filter cake was dried overnight at room temperature in vacuum below 5 mbar. 129.5 mg of material was recovered. The new PXRD pattern (Form B) may possibly contain some reflections of Form A. The NMR spectrum is consistent with the structure. 0.5 eq. of fumaric acid was detected. 0.2 eq. of THF was detected.

[0790] Fumaric acid was selected for scale-up experiments directed to the production of a salt with a free base to acid ratio of 2: 1. The first experiment yielded a crystalline hemifumarate salt Form A, which was characterized by PXRD, 1H-NMR, FT Raman, TG-FTIR, DSC, DVS, and aqueous solubility at room temperature.

[0791] Surprisingly, when a second experiment was performed in a different solvent, the resulting material appeared to contain another crystalline form, Form B. Thus, it appears that the hemifumarate salt exists in at least two different crystalline forms.

[0792] A new PXRD pattern indicative of crystalline material was obtained from this experiment and is depicted in Figure 68. R-ketamine fumarate Form B differs from fumaric acid, as shown in Figure 69. Figure 70 shows a comparison of this new PXRD pattern of R-ketamine fumarate Form B with the free base and R-ketamine fumarate Form A. The pattern for R-ketamine fumarate Form B appears to contain a small amount of R-ketamine fumarate Form A.

[0793] 1 H-NMR revealed 0.5 equivalents of fumaric acid, confirming a 2:1 ratio of free base to acid. 1 The H-NMR is depicted in Figure 71; residual THF (0.2 equiv.) is detected at 3.6 ppm. It therefore seems possible that the hemifumarate salt exists in at least two different crystalline forms.

[0794] An FT Raman spectrum was recorded for a sample of R-ketamine fumarate form B. Figure 72 shows the full range of the spectrum, and Figure 73 shows the expanded fingerprint region (200 cm-1 to 2000 cm-1).

[0795] After 11 months of storage in a closed vial at ambient conditions, the material was retested by PXRD, which gave a mixture of R-ketamine fumarate Form A and R-ketamine fumarate Form B (approximately 1:1).

[0796] Example 18. R-Ketamine L-Tartrate Form A (Ethanol) R-Ketamine free base (202.6 mg, 0.85 mmol) was dissolved in 3 mL of ethanol at 40° C. with sonication. 64.1 mg of L-tartaric acid (0.43 mmol, 0.5 equiv.) was dissolved in 1.5 mL of ethanol at 40° C. The tartaric acid solution was then slowly added to the free base solution at room temperature with stirring. After addition, a clear solution was observed. After stirring overnight at room temperature, no precipitation was observed and the cap of the reactor was pierced with two needles to allow the solvent to evaporate slowly. After stirring for 3 days at room temperature, a very fine suspension was obtained. The reactor was opened and the suspension was further stirred at room temperature. All the solvent was evaporated to obtain a dry crystalline residue. 2 mL of isopropanol was added to the residue, and a suspension was obtained. After stirring for 1 week, the suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was dried under vacuum for 1 hour and then analyzed by PXRD and 1 H-NMR was used to analyze the compound (Figure 98, Figure 101).

[0797] Example 19. R-Ketamine L-Tartrate Form B (THF) R-Ketamine free base (195.8 mg, 0.82 mmol) was dissolved in 2 mL of THF at 40° C. with sonication. 62.1 mg of L-tartaric acid (0.41 mmol, 0.5 equiv.) was dissolved in 1.5 mL of THF at 40° C. The tartaric acid solution was then slowly added to the free base solution with stirring at room temperature. After addition, a clear solution was observed, which quickly transformed into a suspension. After stirring overnight at room temperature, the white suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried over the weekend. The NMR spectrum is consistent with the R-ketamine structure (Figure 102). One equivalent of L-tartaric acid was detected. Only traces of THF were seen. A new crystalline PXRD was obtained (Figure 99).

[0798] Example 20. R-Ketamine L-Tartrate (Acetone) R-ketamine free base (199.4 mg, 0.84 mmol) was dissolved in 2 mL of acetone at 40° C. with sonication. 62.8 mg of L-tartaric acid (0.42 mmol, 0.5 equiv.) was dissolved in 3 mL of acetone at 40° C. The tartaric acid solution was then slowly added to the free base solution with stirring at room temperature. After addition, a clear solution was observed, which quickly transformed into a suspension. After stirring overnight at room temperature, the white suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried over the weekend. The PXRD pattern corresponds to R-ketamine L-tartrate Form A with small additional less intense reflections (13°, 16°, 18.7°, 21.2°, 21.3°, 22.5°, and 23° 2-theta). The NMR spectrum was consistent with the R-ketamine structure. One equivalent of L-tartaric acid was detected. Only traces of acetone were seen (0.012 equivalents).

[0799] Example 21. R-Ketamine L-Tartrate (IPA) 400 mg of R-ketamine free base and 250 mg of L-tartaric acid were dissolved in 5.0 mL of IPA by heating to about 78° C. A clear solution was obtained, which was allowed to cool by setting the temperature controller at 40° C. and stirred overnight. A white suspension was obtained, which was then filtered using a centrifuge unit filter.

[0800] 2.0 mL of the filtrate (saturated solution in isopropanol at approximately 40° C.) was evaporated and the residue was dried under vacuum. 15.4 mg of the solid residue was weighed. The PXRD pattern corresponds to R-ketamine L-tartrate Form B. Weight solubility: S approx. 7.7 mg / mL Example 22. R-Ketamine D-Tartrate Form D (1-Propanol) R-ketamine free base (203.8 mg, 0.86 mmol) was dissolved in 4 mL of 1-propanol at 40° C. with sonication. 64.2 mg of D-tartaric acid (0.43 mmol, 0.5 equiv.) was dissolved in 2 mL of 1-propanol at 40° C. The tartaric acid solution was then slowly added to the free base solution at room temperature with stirring. After addition, a clear solution was observed. After stirring overnight at room temperature, no precipitation was observed and the cap of the reactor was pierced with two needles to allow the solvent to evaporate slowly. After stirring for 3 days at room temperature, a fine suspension was obtained. The reactor was opened and the suspension was stirred for another day at room temperature. Filtration was then performed using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried overnight. The PXRD pattern is novel R-ketamine form D. The NMR spectrum is consistent with the R-ketamine structure (Figure 95). 1.3 equivalents of D-tartaric acid were detected (major signal at 3-6 ppm). Comparison of the PXRD pattern of R-ketamine D-tartrate form D with the previously published PXRD pattern of S-ketamine L-tartrate dihydrate (calculated from SC-XRD data measured at -130°C) (E. Ratti-Moberg, P. Groth, AJ Aasen, Acta Chem. Scand., 1991, 45, 108) indicates that R-ketamine D-tartrate form D is isostructural with the known form of S-ketamine L-tartrate dihydrate (Figure 97). Reanalysis of the material after six months of storage in a closed vial at ambient conditions gave a PXRD pattern corresponding to R-ketamine D-tartrate Form D.

[0801] An FT Raman spectrum was recorded for a sample of R-ketamine D-tartrate form D. Figure 88 shows the full range of the spectrum and Figure 89 shows the expanded fingerprint region (200 cm-1 to 1800 cm-1).

[0802] TG-FTIR analysis showed a mass loss of 7.6% due to water (Figure 90).

[0803] DSC measurements revealed a melting peak at 98° C. with an associated enthalpy of 147 J / g (FIG. 91). DVS measurements show small changes in water content throughout the measurements (FIGS. 92 and 93). Approximately 0.4% additional water is absorbed at high relative humidity and approximately 0.1% to 0.2% water is lost during the 4 hour equilibration period at 0% humidity. The solids recovered after the DVS test were investigated by FT Raman. The FT Raman corresponds to R-ketamine D-tartrate Form D.

[0804] Example 23. R-Ketamine D-Tartrate Form D (THF) R-ketamine free base (200.3 mg, 0.84 mmol) was dissolved in 2 mL of THF at 40° C. with sonication. 63.7 mg of D-tartaric acid (0.42 mmol, 0.5 equiv.) was dissolved in 1.5 mL of THF at 40° C. The tartaric acid solution was then slowly added to the free base solution with stirring at room temperature. After addition, a clear solution was observed, which quickly transformed into a suspension. After stirring overnight at room temperature, the white suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried over the weekend. The PXRD pattern is crystalline and corresponds to a combination of Form C and Form D. The NMR spectrum is consistent with the R-ketamine structure. 1.2 equiv. of D-tartaric acid was detected. No residual THF was detected.

[0805] Example 24. R-Ketamine D-Tartrate Form D (2-Propanol) R-ketamine free base (214.5 mg, 0.90 mmol) was dissolved in 5 mL of 2-propanol at 40 °C with sonication. 68 mg of D-tartaric acid (0.45 mmol, 0.5 equiv.) was dissolved in 2 mL of 2-propanol at 40 °C. The tartaric acid solution was then slowly added to the free base solution with stirring at room temperature. After addition, a clear solution was observed, which converted to a suspension after stirring for 2 h. After stirring overnight at room temperature, the white suspension was filtered using a centrifugation unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried over the weekend. The PXRD pattern corresponds to a combination of Form C and Form D with an orientation effect. The NMR spectrum is consistent with the R-ketamine structure. 1.3 equiv. of D-tartaric acid was detected (large signal at 3-6 ppm). No residual THF was detected. Traces of 2-propanol.

[0806] Example 25. R-Ketamine D-Tartrate Form D (MeCN) R-ketamine free base (207 mg, 0.87 mmol) was dissolved in 2 mL of acetonitrile at room temperature. 65 mg of D-tartaric acid (0.44 mmol, 0.5 equiv.) was dissolved in 0.5 mL of water at room temperature. The tartaric acid solution was then slowly added to the free base solution with stirring at room temperature. After addition, a clear solution was observed. After stirring overnight at room temperature, no precipitation was observed and the cap of the reactor was opened to allow the solvent to evaporate slowly. After 3 days, a wet residue was obtained and further dried with a stream of nitrogen. 0.5 mL of acetonitrile was added to the dry residue. A good suspension was obtained and after stirring for 1 day at room temperature, the suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried overnight. The PXRD pattern is novel R-ketamine form D.

[0807] Reanalysis of the material after 4 months of storage in a closed vial at ambient conditions gave a PXRD pattern corresponding to R-ketamine D-tartrate Form D. 7.55% water loss from 25 to 105 °C.

[0808] Example 26. Scale-up and replication of R-ketamine fumarate R-ketamine free base (1.50 g, 6.32 mmol) was dissolved in 20 mL of ethanol at room temperature with sonication. 366.16 mg of fumaric acid (3.14 mmol, 0.5 eq.) was dissolved in 10 mL of ethanol at room temperature with sonication. The fumaric acid solution was then slowly added to the free base solution with stirring. A suspension began to form very slowly. The mixture was further dried in an open vial to evaporate the solvent. After stirring overnight, the suspension was filtered through a fritted glass filter (porosity 4). The collected wet filter cake was dried overnight under vacuum (<10 mbar, room temperature). 0.253 g of material was recovered. The PXRD pattern corresponds to Form A with two additional reflections (12.9 and 14.2° 2-theta). The NMR spectrum is consistent with the R-ketamine structure as structure. 0.63 eq. of fumaric acid was detected. A small signal at 2.7 ppm that cannot be assigned.

[0809] Precipitation was observed in the mother liquor after filtration. The mother liquor was diluted with N 2 The mixture was evaporated at rt; a white suspension was obtained. After stirring overnight, the suspension was filtered through a fritted glass filter (porosity 4). The collected wet filter cake was dried overnight under vacuum (<10 mbar, room temperature). 0.87 g of material was collected. The PXRD pattern corresponds to Form A.

[0810] R-ketamine free base (1.506 g, 6.32 mmol) was dissolved in 6 mL of THF at room temperature with sonication. 366.20 mg of fumaric acid (3.14 mmol, 0.5 eq.) was dissolved in 12 mL of THF at room temperature with sonication. The fumaric acid solution was then slowly added to the free base solution with stirring. After addition, a clear solution was obtained, but quickly converted to a suspension. After stirring overnight at room temperature, the suspension was filtered through a fritted glass filter (porosity 4). The collected wet filter cake was dried overnight under vacuum (<10 mbar, room temperature). 0.816 g of material was recovered. The PXRD pattern corresponds to Form A with one additional reflection at 14.8° 2 theta. The NMR spectrum is consistent with the R-ketamine structure. 0.5 eq. of fumaric acid was detected. 0.08 eq. of THF was detected.

[0811] Precipitation was observed in the mother liquor after filtration, and the solid was filtered through a fritted glass filter (porosity 4). The collected wet filter cake was dried overnight under vacuum (<10 mbar, room temperature). 0.349 g of material was recovered. The PXRD pattern corresponds to Form A.

[0812] R-Ketamine free base (263.77 mg, 1.11 mmol) was dissolved in 1 mL of THF at room temperature. A cloudy solution was obtained and an additional 1 mL of THF was added. A solution was obtained after sonication. 64.35 mg of fumaric acid (0.56 mmol, 0.5 equiv.) was dissolved in 2 mL of THF at room temperature with sonication. The fumaric acid solution was then slowly added to the free base solution with stirring. After addition, a cloudy solution was obtained. After stirring overnight at room temperature, a fine suspension was observed and the vial was opened and the solvent was allowed to evaporate. A suspension was formed and further stirred overnight at room temperature. The white suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried overnight. The PXRD pattern corresponds to Form A, but is poorly crystalline.

[0813] Example 27. Scale-up of R-ketamine D-tartrate Form C R-Ketamine free base (3.04 g, 12.8 mmol) was dissolved in 21 mL of ethyl acetate at room temperature with stirring. 1.92 g of D-tartaric acid (12.8 mmol, 1 eq.) was dissolved in 24 mL of ethanol at room temperature under stirring and sonication. The tartaric acid solution was then slowly added to the free base solution with stirring. After approximately 2.0 mL of the tartaric solution was added, a cloudy solution was observed. The cloudy solution was seeded with R-Ketamine D-tartrate Form B and R-Ketamine D-tartrate Form C. The addition was continued and a good suspension was formed. After stirring at room temperature for 1 day, the suspension was filtered through a fritted glass filter (porosity 4). The mother liquor was a clear solution. Approximately 3 mL of the mother liquor was used to flush the reactor. The filter cake was then washed with 10 mL of a 7:8 mixture of ethyl acetate / ethanol. The cake was dried on the filter for 1 hour with vacuum applied. Further drying was then carried out under vacuum (<10 mbar, room temperature). After 2 days of drying, 4.13 g of a white powder was recovered. The PXRD pattern corresponds to R-ketamine D-tartrate form C, with slightly weaker reflections at 7°, 8.3°, and 15.2° 2theta. The NMR spectrum is consistent with the R-ketamine structure. An estimated 1.15 equivalents of D-tartrate were detected at 4.27 ppm, although it should be noted that a broad shoulder is observed from 4 ppm to 6.5 ppm.

[0814] Example 28. Solubility of R-ketamine D-tartrate Form C in water R-Ketamine D-tartrate Form C (50 mg) was suspended in 0.5 mL of water. The suspension was shaken at 700 rpm at 25° C. After 1 hour, the pH was measured to be 3.48 at 23° C. After 24 hours of stirring, almost all the material had dissolved; there were very few particles in the suspension. pH 3.42 at 23° C. Nearly clear solution. S>100 mg / mL, pH 3.42, and 23° C.

[0815] Example 29. Approximate Solubility of R-Ketamine D-Tartrate Form C Approximate solubilities were determined for R-ketamine D-tartrate Form C and are shown in Table 21 below. These values ​​were determined by visual inspection after adding a small aliquot of the solvent or solvent mixture to approximately 10 mg of solid and shaking / sonicating briefly at ambient conditions unless otherwise noted. It should be noted that these values ​​are therefore only approximations and the error in these data can be quite large in some cases. In general, the true thermodynamic values ​​are greater than the kinetic values ​​found using this protocol. The purpose of these measurements is to provide useful information for designing crystallization experiments to discover new forms. [Table 25]

[0816] Example 30. Suspension Experiments with R-Ketamine D-Tartrate Form C R-ketamine D-tartrate Form C (118.6 mg) was suspended in 1.0 mL of 2-propanol at room temperature. A white suspension was obtained. After stirring at room temperature for 1 week, the suspension was filtered using a centrifuge unit filter (PVDF, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried for 30 minutes and then subjected to PXRD. The PXRD pattern was assigned to R-ketamine D-tartrate Form C. A comparison of the PXRD patterns of R-ketamine D-tartrate Form C obtained from Example 13, Example 27, and Example 30 is shown in Figure 94, showing the free base form peak at 14.8° in 2-theta.

[0817] The material was then dried under vacuum (<10 mbar) over the weekend. DSC measurement gave a melting peak at 151.3° C. with an onset of 150.2° C. and a melting enthalpy of ΔH approximately 117.8 J / g (FIG. 84).

[0818] R-ketamine D-tartrate Form C (123.8 mg) was suspended in 1.0 mL of 2-propanol / water 98.4 / 1.6 mixture (water activity about 0.2) at room temperature. A white suspension was obtained. After stirring at room temperature for 1 week, the suspension was filtered using a centrifugation unit filter (PVDF, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried for 30 min and then subjected to PXRD. The PXRD pattern corresponds to a mixture of R-ketamine D-tartrate Form C and R-ketamine D-tartrate Form D.

[0819] R-ketamine D-tartrate Form C (108.7 mg) was suspended in 1.0 mL of 2-propanol / water 94.7 / 5.3 mixture (water activity approx. 0.5) at room temperature. A white suspension was obtained. After stirring at room temperature for 1 week, the suspension was filtered using a centrifuge unit filter (PVDF, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried for 30 min and then subjected to PXRD. The PXRD pattern corresponds to R-ketamine D-tartrate Form D, with no small reflections at 12.3°, 13.5°, 16.6°, 20.8°, 33.7°, and 37.2° 2-theta.

[0820] R-ketamine D-tartrate Form C (123.9 mg) was suspended in 1.0 mL of acetone at room temperature. A white suspension was obtained. After stirring at room temperature for 1 week, the suspension was filtered using a centrifugal unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was air-dried for 30 min and then subjected to PXRD. The PXRD pattern corresponds to R-ketamine D-tartrate Form C.

[0821] Example 31. Competitive Suspension Experiments with R-Ketamine D-Tartrate Form B and R-Ketamine D-Tartrate Form C 3.0 mL of acetone was added to 101.4 mg of R-ketamine D-tartrate Form C. The resulting suspension was stirred at room temperature for about 1 hour, and then 35 mg of R-ketamine D-tartrate Form B was added. The mixture was placed in a thermostat, the temperature was set at 2°C, and then stirred at 2°C for 1 week. The suspension was filtered using a centrifuge unit filter (PTFE, 0.22 μm, 4500 rpm, 3 min, room temperature), and the solid powder was dried under a fume hood at room temperature for 15 min before being subjected to PXRD. The PXRD pattern corresponds to R-ketamine D-tartrate Form C.

[0822] 4.0 mL of ethanol was added to 197.4 mg of R-ketamine D-tartrate Form C and the mixture was heated to 60° C. A clear solution was quickly and easily obtained and one drop of water (approximately 15 μL) was added to the clear solution. The solution was filtered through a syringe filter into a new glass vial and allowed to stand at room temperature. After 5 days, crystalline material was visible at the bottom of the vial. Most of the liquid was collected and the remainder of the suspension with crystals was left in the open vial to allow the solvent to evaporate overnight under a fume hood. The solid was then collected and subjected to PXRD. The PXRD pattern shows a mixture of R-ketamine D-tartrate Form B and Form C.

[0823] To this mixture was added a solvent mixture of 2.0 mL heptane and 1.0 mL ethanol. The slurry was kept under stirring overnight at 75° C. in a closed vial. A clear solution was obtained, with crystals adhering to the glass wall of the vial. The material was resuspended and stirred for 1 hour at 75° C. in an open vial. If fine crystalline particles were observed, the suspension was then filtered using a centrifuge unit filter (PVDF, 0.22 μm, 4500 rpm, 3 min, room temperature), after which the solid powder was dried under a fume hood at room temperature for 15 min before being subjected to PXRD. The PXRD corresponds to R-ketamine D-tartrate Form C.

[0824] R-ketamine D-tartrate Form B (47 mg) and R-ketamine D-tartrate Form C (42.9 mg) were suspended in 1.0 mL of ethyl acetate and the resulting suspension was stirred at room temperature. After stirring for 2 days at 25° C., the suspension was filtered using a centrifugation unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was subjected to PXRD. The PXRD pattern corresponds to a mixture of R-ketamine D-tartrate Form B and R-ketamine D-tartrate Form C. The material recovered from the PXRD holder was suspended in the collected mother liquor and further stirred at room temperature. After stirring for 2 weeks at room temperature, half of the suspension was filtered using a centrifugation unit filter (PTFE, 0.22 μm, 5000 rpm, 5 min, room temperature). The collected filter cake was subjected to PXRD. The PXRD pattern corresponds to a mixture of R-ketamine D-tartrate Form B and R-ketamine D-tartrate Form C. The conversion appeared to be very slow, with R-ketamine D-tartrate Form B disappearing and more R-ketamine D-tartrate Form C being produced.

[0825] R-ketamine D-tartrate Form B (60.8 mg) and 60.4 mg of R-ketamine D-tartrate Form C were suspended in 2.0 mL of n-butyl acetate. The suspension was then kept under stirring at 100° C. overnight in a sealed vial. The suspension was then filtered using a centrifugal unit filter (PTFE, 0.22 μm, 4500 rpm, 3 min, room temperature), after which the solid powder was dried under a fume hood at room temperature for 15 min before being subjected to PXRD. The PXRD corresponds to R-ketamine D-tartrate Form C.

[0826] Example 32. Accurate solubility testing of R-ketamine fumarate form A in aqueous media In this case, pH values ​​close to pH 7 were of interest, and pH 5, pH 6, and pH 7 were selected for these solubility experiments. From the approximate solubility studies, it was known that dissolution of hemifumarate in pure water results in a pH of about 5.7. For the solubility studies performed here, R-ketamine fumarate Form A was equilibrated in water and pH adjustment was performed by addition of 0.1M or 1M aqueous NaOH or HCl solutions. The resulting suspension was equilibrated at 25°C for 1 day. Filtration was then performed and the collected saturated solution was subjected to HPLC. The results are summarized in Table 22 and show that the solubility deceases rapidly by increasing the pH. PXRD of the solid residue obtained after filtration showed that the solid phase was converted to the free base form during equilibration. [Table 26]

[0827] Equivalent While the present invention has been described in conjunction with the specific embodiments outlined above, many alternatives, modifications, and other variations will be apparent to those skilled in the art, and all such alternatives, modifications, and variations are intended to be within the spirit and scope of the present invention.

Claims

1. Crystals of R-ketamine salts, including crystals of R-ketamine fumarate Form A, R-ketamine fumarate Form B, or R-ketamine oxalate.

2. 2. The crystalline R-ketamine fumarate Form A of claim 1, characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 11.6°2θ, 13.4°2θ, and 14.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

3. 2. The crystalline R-ketamine fumarate Form A of claim 1, characterized by PXRD peaks at 11.6°2θ, 13.4°2θ, and 14.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

4. The following figure 【Chemical 1】 2. A crystalline form of R-ketamine fumarate Form A according to claim 1, characterized by a PXRD spectrum substantially similar to that shown in

5. The following table 【Table 1-1】 【Table 1-2】 2. The crystal of R-ketamine fumarate Form A of claim 1, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those set forth in

6. 2. The crystal of R-ketamine fumarate Form B of claim 1, characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 14.5°2θ, 15.1°2θ, and 20.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

7. 2. The crystal of R-ketamine fumarate Form B of claim 1, characterized by PXRD peaks at 14.5°2θ, 15.1°2θ, and 20.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

8. The following figure 【Chemistry 2】 2. The crystalline R-ketamine fumarate Form B of claim 1, characterized by a PXRD spectrum substantially similar to that shown in

9. The following table 【Table 2-1】 【Table 2-2】 2. The crystal of R-ketamine fumarate Form B of claim 1, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those set forth in

10. 2. The crystal of R-ketamine fumarate according to claim 1, wherein the R-ketamine fumarate is 2:1 R-ketamine:fumarate.

11. The crystal of R-ketamine oxalate described in claim 1, characterized by PXRD peaks at two or more or three peaks selected from the group consisting of 12.8°2θ, 14.8°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

12. A crystal of R-ketamine oxalate according to claim 1, characterized by PXRD peaks at 12.8°2θ, 14.8°2θ, and 16.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).

13. The following figure 【Chemistry 3】 2. The crystalline form of R-ketamine oxalate according to claim 1, characterized by a PXRD spectrum substantially similar to that shown in

14. The following table 【Table 3-1】 【Table 3-2】 2. The R-ketamine oxalate crystal of claim 1, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 PXRD peaks selected from those set forth in

15. 2. The salt of R-ketamine oxalate of claim 1, wherein the R-ketamine oxalate crystal is 2:1 R-ketamine:oxalate.

16. 16. A pharmaceutical composition comprising one or more R-ketamine salts or crystalline salt forms of any one of claims 1 to 15, and a pharmaceutically acceptable excipient, diluent, or carrier.

17. 17. A pharmaceutical composition according to claim 16 for use in the treatment or prevention of depression or depressive symptoms in a patient in need thereof.

18. 18. The pharmaceutical composition of claim 17, wherein the depression or depressive symptoms are treatment-resistant depression.

19. A crystal of R-ketamine salt according to any one of claims 1 to 15 for use in the treatment or prevention of depression or depressive symptoms in a patient in need thereof.

20. The R-ketamine salt crystals according to claim 19, wherein the depression or depressive symptoms are treatment-resistant depression.

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