Phenethylamine compounds salts, polymorphic forms and methods of use thereof

Abstract

Disclosed herein are salts and solid forms of MDMA, (R)-MDMA, (S)-MDMA, MDE, S-MDE, R-MDE, MDAI, MBDB, S-MBDB, R-MBDB, MEAI, and 5,6-Dimethoxy-2-aminoindane, including salts, solid forms of the compound and salts thereof, as well as polymorphs of solid forms. The solid forms disclosed herein may have improved properties, such as improved physical, chemical, and/or pharmacokinetic properties. Also disclosed are methods for making the salts and solid forms and methods for administering the same. The disclosed salt and solid forms of MDMA, (R)-MDMA, (S)-MDMA, MDE, S-MDE, R-MDE, MDAI, MBDB, S-MBDB, R-MBDB, MEAI, and 5,6-Dimethoxy-2-aminoindane may be useful for treating neurological disease and/or a psychiatric disorder in a subject.

1 . A solid form of MDMA, (S)-MDMA, (R)-MDMA, MDE, (S)-MDE, (R)-MDE, MBDB, (S)-MBDB, (R)-MBDB, MDAI, MEAI, or 5,6-Dimethoxy-2-aminoindane. 
     
     
         2 . The solid form of  claim 1 , wherein the solid form is a solid form of MDMA. 
     
     
         3 . The solid form of MDMA of  claim 2 , wherein the solid form of MDMA is a salt of MDMA. 
     
     
         4 . The salt of MDMA of  claim 3 , wherein the salt of MDMA is a crystalline salt of MDMA, optionally:
 a) a solid form of MDMA fumarate Form 1, further optionally a crystalline polymorph of MDMA fumarate characterized by two or more, or three or more XRPD signals selected from the group consisting of 17.3°2θ, 18.6°2θ, and 21.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   b) a solid form of MDMA fumarate Form 2; further optionally a crystalline polymorph of MDMA fumarate characterized by two or more, or three or more XRPD signals selected from the group consisting of 14.5°2θ, 22.2°2θ, and 27.3°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   c) a solid form of MDMA maleate Form 1; further optionally a crystalline polymorph of MDMA maleate characterized by two or more, or three or more XRPD signals selected from the group consisting of 14.9°2θ, 18.1°2θ, and 25.0°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   d) a solid form of MDMA maleate Form 2; further optionally a crystalline polymorph of MDMA maleate characterized by two or more, or three or more XRPD signals selected from the group consisting of 9.4°2θ, 18.5°2θ, and 26.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   e) a solid form of MDMA phosphate; further optionally a crystalline polymorph of MDMA phosphate characterized by two or more, or three or more XRPD signals selected from the group consisting of 12.4°2θ, 19.0°2θ, and 22.0°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   f) a solid form of MDMA tartrate; further optionally a crystalline polymorph of MDMA tartrate characterized by two or more, or three or more XRPD signals selected from the group consisting of 12.5°2θ, 18.0°2θ, and 18.3°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   g) a solid form of MDMA tartrate; further optionally a crystalline polymorph of MDMA tartrate characterized by two or more, or three or more XRPD signals selected from the group consisting of 5.2°2θ, 18.9°2θ, and 19.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   h) a solid form of MDMA malate; further optionally a crystalline polymorph of MDMA malate characterized by two or more, or three or more XRPD signals selected from the group consisting of 17.2°2θ, 18.0°2θ, and 19.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   i) a solid form of MDMA galactarate; further optionally a crystalline polymorph of MDMA galactarate characterized by two or more, or three or more XRPD signals selected from the group consisting of 4.6°2θ, 18.8°2θ, and 19.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   j) a solid form of MDMA succinate; further optionally a crystalline polymorph of MDMA succinate characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.0°2θ, 21.8°2θ, and 22.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   k) a solid form of MDMA tosylate; further optionally a crystalline polymorph of MDMA tosylate characterized by two or more, or three or more XRPD signals selected from the group consisting of 15.4°2θ, 20.5°2θ, and 21.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   l) a solid form of MDMA HCl; further optionally a crystalline polymorph of MDMA HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 15.9°2θ, 18.5°2θ, and 21.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   m) a solid form of MDMA hemifumarate Form A; further optionally a crystalline polymorph of MDMA hemifumarate Form A characterized by two or more, or three or more XRPD signals selected from the group consisting of 8.3°2θ, 10.9°2θ, and 13.0°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   n) a solid form of (S)-MDMA HCl; further optionally a crystalline polymorph of (S)-MDMA HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 15.7°2θ, 17.4°2θ, and 20.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   o) a solid form of (R)-MDMA HCl; further optionally a crystalline polymorph of (R)-MDMA HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 15.7°2θ, 17.4°2θ, and 20.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).   
     
     
         5 .- 18 . (canceled) 
     
     
         19 . A mixture of solid forms of a salt of MDMA, the mixture comprising:
 a) crystalline polymorphs of MDMA fumarate Forms 1 and 2 characterized by a XRPD diffractogram substantially similar to that shown in  FIG.  10   ; or   b) crystalline polymorphs of MDMA tartrate Forms 1 and 2 characterized by a XRPD diffractogram substantially similar to that shown in  FIG.  12   .   
     
     
         20 .- 111 . (canceled) 
     
     
         112 . The solid form of  claim 1 , wherein the solid form is a solid form of MDE; optionally a salt of MDE; further optionally a crystalline salt of MDE. 
     
     
         113 .- 114 . (canceled) 
     
     
         115 . The crystalline salt of MDE of  claim 112 , wherein the crystalline salt is:
 a) MDE HCl; further optionally a crystalline polymorph of MDE HCl characterized by XRPD signals at 15.6°2θ and 21.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   b) (R)-MDE HCl; further optionally a crystalline polymorph of (R)-MDE HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 14.5°2θ, 17.0°2θ, and 22.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   c) (S)-MDE HCl; further optionally a crystalline polymorph of (S)-MDE HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 14.5°2θ, 27.6°2θ, and 31.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation); or   d) (S)-MDE tosylate; further optionally a crystalline polymorph of (S)-MDE tosylate characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.9°2θ, 19.8°2θ, and 21.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).   
     
     
         116 - 143 . (canceled) 
     
     
         144 . The solid form of  claim 1 , wherein the solid form is a solid form of MDAI; optionally a salt of MDAI; further optionally a crystalline salt of MDAI. 
     
     
         145 .- 146 . (canceled) 
     
     
         147 . The crystalline salt of MDAI of  claim 144 , wherein the crystalline salt is solid form of MDAI HCl; further optionally a crystalline polymorph of MDAI HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 16.9°2θ, 23.6°2θ, and 24.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). 
     
     
         148 .- 157 . (canceled) 
     
     
         158 . The solid form of  claim 1 , wherein the solid form is a solid form of MBDB; optionally a salt of MBDB; further optionally a crystalline salt of MBDB. 
     
     
         159 .- 160 . (canceled) 
     
     
         161 . The crystalline salt of MBDB of  claim 158 , wherein the crystalline salt is:
 a) MBDB citrate; further optionally a crystalline polymorph of MBDB citrate characterized by two or more, or three or more XRPD signals selected from the group consisting of 6.3°2θ, 19.0°2θ, and 25.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   b) MBDB fumarate; further optionally a crystalline polymorph of MBDB fumarate characterized by two or more, or three or more XRPD signals selected from the group consisting of 12.9°2θ, 20.2°2θ, and 20.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   c) MBDB fumarate; further optionally a crystalline polymorph of MBDB fumarate characterized by two or more, or three or more XRPD signals selected from the group consisting of 12.9°2θ, 20.2°2θ, and 20.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   d) MBDB galactarate; further optionally a crystalline polymorph of MBDB galactarate characterized by two or more, or three or more XRPD signals selected from the group consisting of 9.2°2θ, 19.6°2θ, and 23.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   e) MBDB maleate Form 1; further optionally a crystalline polymorph of MBDB maleate Form 1 characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.8°2θ, 22.4°2θ, and 23.8°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   f) MBDB maleate Form 2; further optionally a crystalline polymorph of MBDB maleate Form 2 characterized by two or more, or three or more XRPD signals selected from the group consisting of 9.7°2θ, 11.8°2θ, and 14.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   g) MBDB maleate Form 2; further optionally a crystalline polymorph of MBDB maleate Form 2 characterized by two or more, or three or more XRPD signals selected from the group consisting of 9.3°2θ, 9.7°2θ, and 10.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   h) MBDB phosphate; further optionally a crystalline polymorph of MBDB phosphate characterized by two or more, or three or more XRPD signals selected from the group consisting of 6.4°2θ, 12.7°2θ, and 21.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   i) MBDB succinate Form 1; further optionally a crystalline polymorph of MBDB succinate Form 1 characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.1°2θ, 20.5°2θ, and 21.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   j) MBDB succinate Form 2; further optionally a crystalline polymorph of MBDB succinate Form 2 characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.0°2θ, 20.3°2θ, and 21.5°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   k) MBDB sulfate; further optionally a crystalline polymorph of MBDB sulfate characterized by two or more, or three or more XRPD signals selected from the group consisting of 8.8°2θ, 17.5°2θ, and 26.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   l) MBDB tartrate; further optionally a crystalline polymorph of MBDB tartrate characterized by two or more, or three or more XRPD signals selected from the group consisting of 5.8°2θ, 11.5°2θ, and 17.2°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   m) MBDB malonate; further optionally a crystalline polymorph of MBDB malonate characterized by two or more, or three or more XRPD signals selected from the group consisting of 18.1°2θ, 20.4°2θ, and 22.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   n) MBDB tosylate; further optionally a crystalline polymorph of MBDB tosylate characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.1°2θ, 18.1°2θ, and 19.1°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   o) MBDB HCl Form A; further optionally a crystalline polymorph of MBDB HCl Form A characterized by two or more, or three or more XRPD signals selected from the group consisting of 14.3°2θ, 14.9°2θ, and 25.4°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   p) MBDB HCl Form B; further optionally a crystalline polymorph of MBDB HCl Form B characterized by two or more, or three or more XRPD signals selected from the group consisting of 19.7°2θ, 25.0°2θ, and 30.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   q) MBDB HCl Form A; further optionally a crystalline polymorph of MBDB HCl Form A characterized by two or more, or three or more XRPD signals selected from the group consisting of 16.7°2θ, 18.4°2θ, and 19.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation);   r) (R)-MBDB HCl; further optionally a crystalline polymorph of (R)-MBDB HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.2°2θ, 14.1°2θ, and 16.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation); or   s) (S)-MBDB HCl; further optionally a crystalline polymorph of (S)-MBDB HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 13.3°2θ, 16.7°2θ, and 19.6°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation).   
     
     
         162 .- 325 . (canceled) 
     
     
         326 . The solid form of  claim 1 , wherein the solid form is a solid form of MEAI; optionally a salt of MEAI; further optionally a crystalline salt of MEAI. 
     
     
         327 .- 328 . (canceled) 
     
     
         329 . The crystalline salt of MEAI of  claim 326 , wherein the crystalline salt is MEAI HCl; further optionally a crystalline polymorph of MEAI HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 21.6°2θ, 21.7°2θ, and 32.7°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). 
     
     
         330 .- 332 . (canceled) 
     
     
         333 . The solid form of  claim 1 , wherein the solid form is a solid form of 5,6-dimethoxy-2-aminoindane; optionally a salt of 5,6-dimethoxy-2-aminoindane; further optionally a crystalline salt of 5,6-dimethoxy-2-aminoindane. 
     
     
         334 .- 335 . (canceled) 
     
     
         336 . The crystalline salt of 5,6-dimethoxy-2-aminoindane of  claim 333 , wherein the crystalline salt is 5,6-dimethoxy-2-aminoindane HCl further optionally a crystalline polymorph of 5,6-dimethoxy-2-aminoindane HCl characterized by two or more, or three or more XRPD signals selected from the group consisting of 11.7°2θ, 18.2°2θ, and 18.9°2θ (±0.2°2θ; ±0.1°2θ; or ±0.0°2θ; Cu Kα1 radiation). 
     
     
         337 .- 366 . (canceled) 
     
     
         367 . A pharmaceutical composition, comprising a solid form according to  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         368 . A method of treating a brain disorder, a neurological disorder and/or a psychiatric disorder in a subject in need thereof, comprising administering to the subject an effective amount of a solid form according to  claim 1 , or a pharmaceutical composition thereof. 
     
     
         369 .- 376 . (canceled) 
     
     
         377 . The method of  claim 368 , further comprising administering to the subject an effective amount of an empathogenic agent. 
     
     
         378 . The method of  claim 368 , further comprising administering a 5-HT 2A  antagonist to the subject. 
     
     
         379 . The method of  claim 378 , wherein the 5-HT 2A  antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, pruvanserin, nelotanserin and lorcaserin. 
     
     
         380 .- 401 . (canceled)