SALTS OF 2-BROMOLYSERGIC ACID DIETHYLAMIDE
20240239789 ยท 2024-07-18
Assignee
Inventors
Cpc classification
C07C309/29
CHEMISTRY; METALLURGY
A61K31/48
HUMAN NECESSITIES
International classification
A61K31/48
HUMAN NECESSITIES
Abstract
The present disclosure relates to salts of 2-bromolysergic acid diethylamide (2-Br-LSD), pharmaceutical compositions thereof, and methods of preparing and using the 2-Br-LSD salts.
Claims
1. A crystalline salt of 2-bromolysergic acid diethylamide (2-Br-LSD), wherein the salt is a hydrobromide, hemi-fumarate, mesylate, or besylate salt.
2. The crystalline salt of claim 1, which is 2-Br-LSD hydrobromide.
3. The crystalline salt of claim 2, which has an X-ray powder diffraction (XRPD) pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 8.0?0.2, 14.2?0.2, 21.9?0.2, 23.3?0.2, 28.6?0.2, 30.4?0.2.
4. The crystalline salt of claim 3, which has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 12.5?0.2, 17.8?0.2, 19.0?0.2, 24.0?0.2, 24.5 0.2.
5. The crystalline salt of claim 4, which has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 26.1?0.2, 26.9?0.2.
6. The crystalline salt of claim 2 which has an XRPD pattern substantially similar to that set forth in
7. The crystalline salt of claim 2, which has an X-ray powder diffraction (XRPD) pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 4.4?0.2, 16.9?0.2.
8. The crystalline salt of claim 7, which has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 7.7?0.2, 15.0?0.2, 16.1?0.2, 18.1?0.2, 19.5 0.2, 23.0?0.2, 24.7?0.2, 25.5?0.2.
9. The crystalline salt of claim 2, which has an XRPD pattern substantially similar to that set forth in
10. The crystalline salt of claim 2, which has an X-ray powder diffraction (XRPD) pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 5.5?0.2, 10.2?0.2, 11.6 0.2, 12.1?0.2, 13.1?0.2.
11. The crystalline salt of claim 10, which has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 7.5?0.2, 13.5?0.2, 16.3?0.2, 18.9?0.2, 19.4?0.2, 20.5?0.2, 21.2?0.2, 24.1?0.2, 24.6?0.2, 24.9?0.2, 25.2?0.2, 25.7?0.2, 26.3?0.2.
12. The crystalline salt of claim 2, which has an XRPD pattern substantially similar to that set forth in
13. The crystalline salt of claim 5, which is non-hygroscopic.
14. The crystalline salt of claim 1, which is 2-Br-LSD hemi-fumarate.
15. The crystalline salt of claim 14, which has an XRPD pattern comprising the following 20 peaks measured using CuK.sub.? radiation: 4.4?0.2, 7.4?0.2, 8.3?0.2, 10.3?0.2, 14.9?0.2, 21.9?0.2.
16. The crystalline salt of claim 15, which has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 9.5?0.2, 11.5?0.2, 11.9?0.2, 13.5?0.2, 16.3?0.2, 17.1?0.2, 18.3?0.2, 19.3?0.2, 19.8?0.2, 20.5?0.2, 20.8?0.2, 21.5?0.2, 22.5?0.2, 23.2?0.2, 23.8?0.2, 25.1?0.2, 26.8?0.2, 28.7?0.2, 30.1?0.2, 30.6?0.2.
17. The crystalline salt of claim 14, which has an XRPD pattern substantially similar to that set forth in
18. The crystalline salt of claim 1, which is 2-Br-LSD mesylate.
19. The crystalline salt of claim 18, which has an XRPD pattern comprising the following 20 peaks measured using CuK.sub.? radiation: 7.5?0.2.
20. The crystalline salt of claim 19, which has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 7.2?0.2, 10.1?0.2, 10.8?0.2, 13.3?0.2, 15.1?0.2, 15.5?0.2, 17.2?0.2, 19.4?0.2, 20.5?0.2, 21.6?0.2, 22.3?0.2, 23.2?0.2, 23.5?0.2, 24.4?0.2, 26.1?0.2, 28.1?0.2.
21. The crystalline salt of claim 18, which has an XRPD pattern substantially similar to that set forth in
22. The crystalline salt of claim 1, which is 2-Br-LSD besylate.
23. The crystalline salt of claim 22, which has an XRPD pattern comprising the following 20 peaks measured using CuK.sub.? radiation: 5.9?0.2, 8.7?0.2, 17.8?0.2, 19.7?0.2, 23.4?0.2.
24. The crystalline salt of claim 23, which has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 13.4?0.2, 13.8?0.2, 14.6?0.2, 16.1?0.2, 16.3?0.2, 16.8?0.2, 20.5?0.2, 21.6?0.2, 22.3?0.2, 22.9?0.2, 23.8?0.2, 24.5?0.2.
25. The crystalline salt of claim 22, which has an XRPD pattern substantially similar to that set forth in
26. A pharmaceutical composition comprising the crystalline salt of claim 1.
27. A pharmaceutical composition comprising the crystalline salt of claim 5.
28. A method of preparing the crystalline salt of 2-Br-LSD hydrobromide (Form 1), which has an XRPD pattern substantially similar to that set forth in
29. The method of claim 28, further comprising adding seed crystals of 2-Br-LSD hydrobromide (Form 1) to the batch prior to step (c).
30. The method of claim 28, wherein the solvent comprises water and ethanol, methanol or isopropanol.
31. The method of claim 30, wherein the solvent comprises 2-12% water.
32. The method of claim 31, wherein the solvent comprises ethanol.
33. The method of claim 32, wherein the solvent comprises 88% to 98% ethanol.
34. The method of claim 33, wherein the solvent is ethanol-water in a ratio of about 95:5 v/v.
35. The method of claim 34, wherein the concentration of 2-Br-LSD in step (a) is between 0.12M and 0.6M.
36. The method of claim 35, wherein the concentration of 2-Br-LSD in step (a) is between 0.2M and 0.4M.
37. The method of claim 28, wherein the hydrobromic acid is added as a solution.
38. The method of claim 37, wherein the hydrobromic acid is added as a solution in the same solvent used in step (a).
39. The method of claim 38, wherein hydrobromic acid is added as a solution in ethanol-water at a concentration of 0.5M to 4M.
40. The method of claim 33, wherein hydrobromic acid is added as a solution in the same solvent used in step (a) at a concentration of 1M to 3M.
41. The method of claim 28, wherein the first temperature is between about 20? C. and 50? C.
42. The method of claim 41, wherein the first temperature is between 30? C. and 50? C. and the second temperature is between 0? C. and about 25? C.
43. The method of claim 42, wherein the first temperature is between 40? C. and 50? C. and the second temperature is about 20? C. to about 25? C.
44. The method of claim 43, wherein M is between 1 and 4 hours, N is between 2 and 6 hours, O is between 30 minutes and 4 hours, and P is between 8 and 24 hours.
45. The method of claim 44, further comprising: following period P and prior to step (h), cooling the batch to a fourth temperature and equilibrating the batch at the fourth temperature for a period of time Q; wherein Q is between 5 minutes and 48 hours.
46. The method of claim 45, wherein the fourth temperature is between 0? C. and 10? C.
47. The method of claim 46, wherein Q is between 0.5 hour and 4 hours.
48. The method of claim 42, wherein the first temperature is between about 20? C. and about 25? C. and the second temperature is between 0? C. and 10? C.
49. The method of claim 48, wherein M is between 1 and 4 hours, N is between 2 and 6 hours, O is between 30 minutes and 4 hours, and P is between 8 and 24 hours.
50. The method of claim 28, wherein the sum of the hydrobromic acid portions in steps (b) and (d) is 1.0 molar equivalent with respect to 2-Br-LSD.
51. The method of claim 50, wherein the portion of hydrobromic acid in step (b) is sufficient to induce the formation of crystals of 2-Br-LSD hydrobromide.
52. The method of claim 51, wherein the addition of hydrobromic acid in step (b) is halted at the first visible sign of crystallization.
53. The method of claim 52, further comprising adding seed crystals of 2-Br-LSD hydrobromide (Form 1) to the batch prior to step (c).
54. The method of claim 28, wherein hydrobromic acid is added as a gas in steps (b) and (d).
55. The method of claim 50, wherein M is 0.
56. The method of claim 50, wherein the hydrobromic acid portion in step (b) is between 0.1 and 0.4 molar equivalents with respect to 2-Br-LSD.
57. The method of claim 56, wherein the hydrobromic acid portion in step (b) is between 0.2 and 0.3 molar equivalents with respect to 2-Br-LSD.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
[0068] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present disclosure.
[0069] As used in the description and the appended claims, the singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition includes mixtures of two or more such compositions, reference to an inhibitor includes mixtures of two or more such inhibitors, and the like.
[0070] Unless stated otherwise, the terms about and substantially (as in substantially similar) mean within 10% (e.g., within 5%, 2% or 1%) of the particular value modified by the terms about and substantially.
[0071] The transitional term comprising, which is synonymous with including, containing, or characterized by, is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase consisting of excludes any element, step, or ingredient not specified in the claim. The transitional phrase consisting essentially of limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention.
[0072] The term crystalline refers to a solid form that is substantially non-amorphous. In certain embodiments, a crystal form of a salt described herein may be substantially free of amorphous solids and/or other crystal forms. In certain embodiments, a crystal form of a compound described herein may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, or less than about 10% of one or more amorphous solids and/or other crystal forms. In certain embodiments, a crystal form described herein is pure. In certain embodiments, a crystal form of a compound described herein may be about 99-99.99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure. The detection of other solid forms can be accomplished by, for example, diffraction analysis, thermal analysis, elemental combustion analysis and/or spectroscopic analysis. The detection of other chemical compounds can be accomplished by, for example, mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and/or chromatographic analysis. As used herein, the term form embraces solvates and hydrates of a salt.
[0073] As used herein, the term non-hygroscopic refers to a crystalline salt that, after drying in vacuo at 50? C. for 18 hours, exhibits less than 1% weight loss between 25? C. and 200? C. upon thermogravimetric analysis at a heating rate of 20? C./min. Also, the crystalline salt exhibits less than about 0.5% weight change upon dynamic vapor sorption analysis at 25? C. over the relative humidity (RH) range 0-90% when measured at 10% RH intervals and 60 minutes for each humidity level.
[0074] As used herein, the term anti-solvent refers to a solvent in which a compound or salt thereof is poorly soluble and which induces precipitation or crystallization of the compound or salt thereof from solution.
[0075] As used herein, the terms Good Manufacturing Practices or GMP, Current Good Manufacturing Practices or cGMP, and Active Pharmaceutical Ingredient or API, follow The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, which are a set of guidelines to ensure safe, effective, and high-quality medicines are developed and registered efficiently. These guidelines have been adopted by regulatory authorities throughout the world, for example, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, (hereinafter Q7), which are incorporated herein by reference.
[0076] The salts of the present disclosure can also be solvated (i.e., with pharmaceutically acceptable solvents such as water, ethanol, and the like, for example, as a hydrate (e.g., mono-hydrate, di-hydrate, etc.)).
[0077] Broadly, an aspect of the present disclosure is directed to a crystalline salt of 2-bromolysergic acid diethylamide (2-Br-LSD), wherein the salt is a hydrobromide, hemi-fumarate, mesylate, or a besylate salt.
[0078] The structure of 2-Br-LSD is as follows:
##STR00001##
The compound 2-Br-LSD is commercially available. Alternatively, it may be prepared by known techniques. See, e.g., U.S. Pat. No. 9,868,732.
[0079] The crystalline 2-Br-LSD salts described herein can be characterized by a number of methods including, for example, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), thermal gravimetric analysis (TGA), and hot-stage microscopy), spectroscopy (e.g., infrared, Raman, nuclear magnetic resonance (NMR), including .sup.1H, .sup.13C and other nuclei in either solution or solid state), chromatography (including high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UHPLC), ion chromatography (IC), gas chromatography (GC), and thin layer chromatography (TLC)), residue on ignition, titration, Karl Fischer moisture titration, particle size analysis, microscopy, and elemental impurities analysis by inductively coupled plasma with either optical emission spectroscopic or mass spectrometric analysis (ICP-OES or ICP-MS).
[0080] In some embodiments, the 2-Br-LSD crystalline salt is 2-Br-LSD hydrobromide.
[0081] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has an XRPD pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 8.0?0.2, 14.2?0.2, 21.9?0.2, 23.3?0.2, 28.6?0.2, 30.4?0.2. In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 12.5?0.2, 17.8?0.2, 19.0?0.2, 24.0?0.2, 24.5?0.2. In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has an XRPD pattern even further comprising the following 2? peaks measured using CuK.sub.? radiation: 26.1?0.2, 26.9?0.2.
[0082] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has an XRPD pattern substantially similar to that set forth in
[0083] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Pattern B Solvate)) has an XRPD pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 4.4?0.2, 16.9?0.2. In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Pattern B Solvate)) has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 7.7?0.2, 15.0?0.2, 16.1?0.2, 18.1?0.2, 19.5?0.2, 23.0?0.2, 24.7?0.2, 25.5?0.2.
[0084] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Pattern B Solvate)) has an XRPD pattern substantially similar to that set forth in
[0085] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 2)) has an XRPD pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 5.5?0.2, 10.2?0.2, 11.6?0.2, 12.1?0.2, 13.1?0.2. In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 2)) has an XRPD pattern further comprising the following 20 peaks measured using CuK.sub.? radiation: 7.5?0.2, 13.5?0.2, 16.3?0.2, 18.9?0.2, 19.4?0.2, 20.5?0.2, 21.2?0.2, 24.1?0.2, 24.6?0.2, 24.9?0.2, 25.2?0.2, 25.7?0.2, 26.3?0.2.
[0086] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 2)) has an XRPD pattern substantially similar to that set forth in
[0087] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) curves substantially similar to that set forth in
[0088] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has a .sup.1H nuclear magnetic resonance (NMR) spectrum substantially similar to that set forth in
[0089] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) is non-hygroscopic.
[0090] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has an XRPD pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 8.2?0.2, 14.4?0.2, 18.0?0.2, 19.2?0.2, 20.7?0.2, 22.4?0.2, 23.4?0.2, 23.8?0.2, 24.1?0.2, 24.6?0.2, 25.4?0.2, 26.2?0.2, 27.0?0.2, 27.8?0.2, 28.1?0.2, 28.7?0.2, 30.5?0.2.
[0091] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has an XRPD pattern substantially similar to that set forth in
[0092] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) is characterized by .sup.1H NMR having the following chemical shifts expressed in parts per million: 1.09 (t, 3H, J=7 Hz, CH.sub.3); 1.22 (t, 3H, J=7 Hz, CH.sub.3); 3.15 (s, 3H, NCH.sub.3); 2.98-3.78 (m, 7H, CH and CH.sub.3); 4.40 (d, 1H, CH); 6.47 (s, 1H, CH?); 7.19 (multiplet, 3H, aromatic).
[0093] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has a .sup.1H NMR spectrum substantially similar to that set forth in
[0094] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) is characterized by .sup.13C NMR having the following chemical shifts expressed in parts per million: 13.0 (CH.sub.3); 14.7 (CH.sub.3); 23.2; 36.4; 40.0 (CH.sub.3); 41.1; 41.9; 53.3 (CH.sub.2N); 60.9 (CHN); 104.8; 106.5; 110.4; 112.8; 120.2 (CH?); 123.1; 124.0; 125.3; 130.7; 134.1; 167.9 (C?O).
[0095] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has a .sup.13C NMR spectrum substantially similar to that set forth in
[0096] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) has a DSC curve substantially similar to that set forth in
[0097] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hydrobromide (Form 1)) is made according to GMP (also referred to as Example 2, Method 4).
[0098] In some embodiments, the 2-Br-LSD crystalline salt is 2-Br-LSD hemi-fumarate.
[0099] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hemi-fumarate (Form A)) salt has an XRPD pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 4.4?0.2, 7.4?0.2, 8.3?0.2, 10.3?0.2, 14.9?0.2, 21.9?0.2. In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hemi-fumarate (Form A)) has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 9.5?0.2, 11.5?0.2, 11.9?0.2, 13.5?0.2, 16.3?0.2, 17.1?0.2, 18.3?0.2, 19.3?0.2, 19.8?0.2, 20.5?0.2, 20.8?0.2, 21.5?0.2, 22.5?0.2, 23.2?0.2, 23.8?0.2, 25.1?0.2, 26.8?0.2, 28.7?0.2, 30.1?0.2, 30.6?0.2.
[0100] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD hemi-fumarate (Form A)) has an XRPD pattern substantially similar to that set forth in
[0101] In some embodiments, the 2-Br-LSD crystalline salt is 2-Br-LSD mesylate.
[0102] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD mesylate (Form B)) has an XRPD pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 7.5?0.2. In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD mesylate (Form B)) has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 7.2?0.2, 10.1?0.2, 10.8?0.2, 13.3?0.2, 15.1?0.2, 15.5?0.2, 17.2?0.2, 19.4?0.2, 20.5?0.2, 21.6?0.2, 22.3?0.2, 23.2?0.2, 23.5?0.2, 24.4?0.2, 26.1?0.2, 28.1?0.2.
[0103] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD mesylate (Form B)) has an XRPD pattern substantially similar to that set forth in
[0104] In some embodiments, the 2-Br-LSD crystalline salt is 2-Br-LSD besylate.
[0105] In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD besylate) has an XRPD pattern comprising the following 2? peaks measured using CuK.sub.? radiation: 5.9?0.2, 8.7?0.2, 17.8?0.2, 19.7?0.2, 23.4?0.2. In some embodiments, the 2-Br-LSD crystalline salt (2-Br-LSD besylate) has an XRPD pattern further comprising the following 2? peaks measured using CuK.sub.? radiation: 13.4?0.2, 13.8?0.2, 14.6?0.2, 16.1?0.2, 16.3?0.2, 16.8?0.2, 20.5?0.2, 21.6?0.2, 22.3?0.2, 22.9?0.2, 23.8?0.2, 24.5?0.2.
[0106] In some embodiments, the crystalline salt (2-Br-LSD besylate) has an XRPD pattern substantially similar to that set forth in
[0107] The crystalline salts of 2-Br-LSD were characterized by their powder X-ray diffraction patterns. Powder X-ray diffractograms of the crystalline salts of 2-Br-LSD described herein were collected on a PANalytical X'pert PRO diffractometer using Cu K? radiation (45 kV, 40 mA), ?-? goniometer, focusing mirror, divergence slit (?), soller slits at both incident and divergent beam (4 mm) and a PIXcel detector. Data was presented using X'Pert Data Viewer, version 1.2d. XRPD patterns were acquired under ambient conditions via a transmission foil sample stage (polyimideKapton?, 12.7 ?m thickness film). The data collection range was 2.994-35? 2? with a continuous scan speed of 0.202004? s.sup.?1. Lists of major XRPD peaks (relative intensity ?10%) for the crystalline salts of the present disclosure are tabulated below.
[0108] An additional XRPD pattern for 2-Br-LSD hydrobromide (Form 1) was collected using a Bruker D2 X-ray Generator (30 kV, 10 mA, scan interval 3-35?, Step 0.04?, 2 sec/step; flat plate zero-background sample holder, rotation 15 rpm). See,
[0109] A variety of factors, including instrument design, maintenance, calibration and mode of operation, specimen preparation and presentation, particle size and inhomogeneity, preferred orientation, and environmental conditions can cause variability in the measurement of diffraction angles and peak intensities. Angle measurements are presented herein as ?0.2? 2?. Relative intensities can vary widely. As used in the description and the appended claims, the phrase an XRPD pattern substantially similar to a reference pattern takes into account these sources of experimental variability. For example, the XRPD patterns for 2-Br-LSD hydrobromide (Form 1) presented in
[0110] The following tables list the 2? and intensities of lines for the crystalline salts of 2-Br-LSD. In cases where there are two or more crystalline forms of a 2-Br-LSD salt, each form can be identified and distinguished from the other crystalline form by either a single x-ray diffraction line, a combination of lines, or a pattern that is different from the x-ray powder diffraction of the other forms. Some diffraction lines that are unique to a given solid form with respect to the other known forms of the same salt are indicated in boldface type.
[0111] XRPD diffraction peaks for crystalline 2-Br-LSD mesylate Forms A, B, and C are listed in Tables 1A-1C, respectively.
TABLE-US-00001 TABLE 1A 2-Br-LSD mesylate (Form A), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 7.1 ? 0.2 20.6 8.8 ? 0.2 59.4 9.3 ? 0.2 28.3 10.6 ? 0.2 46.7 12.5 ? 0.2 16.8 13.5 ? 0.2 52.9 13.8 ? 0.2 25.0 14.1 ? 0.2 48.4 15.2 ? 0.2 33.1 16.7 ? 0.2 44.7 17.4 ? 0.2 85.0 17.6 ? 0.2 100.0 17.8 ? 0.2 94.1 18.0 ? 0.2 78.7 18.5 ? 0.2 27.9 19.4 ? 0.2 25.0 19.7 ? 0.2 19.8 19.9 ? 0.2 24.3 20.5 ? 0.2 17.5 20.9 ? 0.2 51.8 21.8 ? 0.2 99.2 22.6 ? 0.2 40.4 22.8 ? 0.2 56.5 23.7 ? 0.2 18.7 24.3 ? 0.2 19.4 25.0 ? 0.2 42.2 26.6 ? 0.2 33.6 27.3 ? 0.2 45.1 27.9 ? 0.2 20.8
TABLE-US-00002 TABLE 1B 2-Br-LSD mesylate (Form B). PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 7.2 ? 0.2 28.0 7.5 ? 0.2 19.6 10.1 ? 0.2 10.8 10.8 ? 0.2 13.3 13.3 ? 0.2 43.0 15.1 ? 0.2 18.3 15.5 ? 0.2 30.4 17.2 ? 0.2 11.8 19.4 ? 0.2 100.0 20.5 ? 0.2 31.0 21.6 ? 0.2 30.6 22.3 ? 0.2 23.4 23.2 ? 0.2 16.5 23.5 ? 0.2 15.1 24.4 ? 0.2 23.5 26.1 ? 0.2 11.5 28.1 ? 0.2 12.2
TABLE-US-00003 TABLE 1C 2-Br-LSD mesylate (Form C). PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 3.3 ? 0.2 30.3 5.0 ? 0.2 100.0 5.4 ? 0.2 78.9 6.6 ? 0.2 46.5 7.2 ? 0.2 12.2 10.1 ? 0.2 11.0 10.8 ? 0.2 14.8 12.2 ? 0.2 15.2 13.3 ? 0.2 18.9 14.3 ? 0.2 13.4 15.0 ? 0.2 17.3 15.5 ? 0.2 16.3 18.7 ? 0.2 26.5 19.4 ? 0.2 49.6 20.5 ? 0.2 22.8 21.6 ? 0.2 26.5 22.3 ? 0.2 21.0 23.2 ? 0.2 30.9 24.4 ? 0.2 37.0
[0112] XRPD diffraction peaks for crystalline 2-Br-LSD hydrobromide (Form 1), Pattern B Solvate, and Form 2 are listed in Tables 2A-2D.
TABLE-US-00004 TABLE 2A 2-Br-LSD hydrobromide (Form 1), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 8.0 ? 0.2 83.9 12.5 ? 0.2 28.8 14.2 ? 0.2 25.0 14.7 ? 0.2 10.5 16.0 ? 0.2 16.8 17.8 ? 0.2 17.6 18.3 ? 0.2 10.7 18.9 ? 0.2 15.8 19.0 ? 0.2 30.4 20.5 ? 0.2 18.0 21.9 ? 0.2 28.7 22.3 ? 0.2 10.1 23.3 ? 0.2 17.8 23.7 ? 0.2 18.1 24.0 ? 0.2 100.0 24.5 ? 0.2 55.3 24.9 ? 0.2 10.5 25.2 ? 0.2 15.3 26.1 ? 0.2 24.1 26.9 ? 0.2 25.6 27.1 ? 0.2 14.9 27.7 ? 0.2 15.4 28.0 ? 0.2 16.8 28.6 ? 0.2 19.9 30.4 ? 0.2 19.5
TABLE-US-00005 TABLE 2B 2-Br-LSD hydrobromide (Pattern B Solvate), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 4.4 ? 0.2 100.0 7.7 ? 0.2 10.9 15.0 ? 0.2 13.5 16.1 ? 0.2 11.3 16.9 ? 0.2 31.8 18.1 ? 0.2 14.7 19.5 ? 0.2 33.0 23.0 ? 0.2 15.0 24.0 ? 0.2 15.7 24.7 ? 0.2 78.0 25.0 ? 0.2 22.1 25.5 ? 0.2 33.4 25.9 ? 0.2 11.7 26.7 ? 0.2 12.9 27.1 ? 0.2 25.8 27.8 ? 0.2 10.8 29.3 ? 0.2 19.8
TABLE-US-00006 TABLE 2C 2-Br-LSD hydrobromide (Form 2), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 5.5 ? 0.2 45.9 7.5 ? 0.2 13.2 10.2 ? 0.2 32.2 11.6 ? 0.2 23.7 12.1 ? 0.2 16.3 13.1 ? 0.2 15.8 13.5 ? 0.2 12.3 16.3 ? 0.2 13.4 18.9 ? 0.2 25.1 19.4 ? 0.2 37.8 20.5 ? 0.2 11.9 21.2 ? 0.2 12.0 24.1 ? 0.2 13.5 24.6 ? 0.2 100.0 24.9 ? 0.2 23.1 25.2 ? 0.2 14.2 25.7 ? 0.2 23.3 26.3 ? 0.2 29.0
TABLE-US-00007 TABLE 2D 2-Br-LSD hydrobromide (Form 1), Bruker D2 X-ray Generator Pos. [?2Th.] Rel. Int. [%] 8.2 ? 0.2 100.0 12.7 ? 0.2 10.9 14.4 ? 0.2 11.4 16.2 ? 0.2 21.7 18.0 ? 0.2 19.4 19.2 ? 0.2 33.8 20.7 ? 0.2 22.1 22.1 ? 0.2 33.1 22.4 ? 0.2 10.6 23.4 ? 0.2 15.3 23.8 ? 0.2 15.9 24.1 ? 0.2 34.7 24.6 ? 0.2 20.6 25.4 ? 0.2 14.7 26.2 ? 0.2 19.3 27.0 ? 0.2 28.2 27.8 ? 0.2 19.1 28.1 ? 0.2 10.2 28.7 ? 0.2 13.7 30.5 ? 0.2 12.6
[0113] XRPD diffraction peaks for crystalline 2-Br-LSD xinafoate Forms A and B are listed in Tables 3A-3B.
TABLE-US-00008 TABLE 3A 2-Br-LSD xinafoate (Form A), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 5.5 ? 0.2 78.9 6.5 ? 0.2 71.5 8.9 ? 0.2 66.7 10.6 ? 0.2 67.5 11.2 ? 0.2 35.1 13.1 ? 0.2 86.3 14.9 ? 0.2 35.9 16.0 ? 0.2 87.0 16.5 ? 0.2 62.7 17.1 ? 0.2 51.3 17.6 ? 0.2 66.7 17.9 ? 0.2 43.4 18.8 ? 0.2 71.0 19.4 ? 0.2 50.7 20.1 ? 0.2 41.5 20.7 ? 0.2 13.8 21.4 ? 0.2 25.2 22.0 ? 0.2 54.7 22.4 ? 0.2 100.0 23.1 ? 0.2 21.1 24.4 ? 0.2 12.8 25.5 ? 0.2 36.0 27.4 ? 0.2 24.2
TABLE-US-00009 TABLE 3B 2-Br-LSD xinafoate (Form B), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 6.4 ? 0.2 71.7 8.6 ? 0.2 37.2 8.9 ? 0.2 59.1 9.2 ? 0.2 25.9 10.5 ? 0.2 67.8 11.1 ? 0.2 32.8 13.1 ? 0.2 80.4 13.3 ? 0.2 25.0 14.8 ? 0.2 36.0 15.4 ? 0.2 25.1 15.8 ? 0.2 79.3 16.4 ? 0.2 64.4 16.7 ? 0.2 20.2 17.0 ? 0.2 50.0 17.5 ? 0.2 67.3 17.8 ? 0.2 49.0 18.2 ? 0.2 43.8 18.5 ? 0.2 45.0 18.7 ? 0.2 68.0 19.4 ? 0.2 54.3 20.0 ? 0.2 46.1 20.7 ? 0.2 24.7 21.3 ? 0.2 32.8 21.9 ? 0.2 62.8 22.3 ? 0.2 100.0 23.0 ? 0.2 30.0 25.4 ? 0.2 43.0 26.1 ? 0.2 19.6 27.3 ? 0.2 31.5
[0114] XRPD diffraction peaks for crystalline 2-Br-LSD oxalate Forms A and B are listed in Tables 4A-4B.
TABLE-US-00010 TABLE 4A 2-Br-LSD oxalate (Form A), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 3.7 ? 0.2 11.9 5.1 ? 0.2 42.0 6.3 ? 0.2 13.7 7.8 ? 0.2 21.3 8.3 ? 0.2 100.0 12.7 ? 0.2 13.0 17.1 ? 0.2 10.6 19.5 ? 0.2 25.1 22.6 ? 0.2 31.3 23.1 ? 0.2 22.1 23.5 ? 0.2 23.1 23.8 ? 0.2 43.0 24.3 ? 0.2 17.4 24.6 ? 0.2 24.8 25.5 ? 0.2 16.9 25.9 ? 0.2 31.4 26.7 ? 0.2 11.1
TABLE-US-00011 TABLE 4B 2-Br-LSD oxalate (Form B), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 4.0 ? 0.2 32.2 5.8 ? 0.2 76.6 7.1 ? 0.2 25.5 8.7 ? 0.2 60.6 9.2 ? 0.2 48.0 9.8 ? 0.2 69.1 11.1 ? 0.2 20.3 12.0 ? 0.2 60.1 12.3 ? 0.2 85.3 13.3 ? 0.2 18.0 14.3 ? 0.2 19.0 14.9 ? 0.2 30.7 16.8 ? 0.2 50.8 17.7 ? 0.2 25.2 18.4 ? 0.2 26.8 18.6 ? 0.2 26.3 19.1 ? 0.2 42.7 19.5 ? 0.2 39.0 19.8 ? 0.2 51.8 20.6 ? 0.2 21.9 21.5 ? 0.2 48.8 22.6 ? 0.2 41.3 23.3 ? 0.2 100.0 24.3 ? 0.2 64.8 24.7 ? 0.2 38.1 25.9 ? 0.2 21.7 27.1 ? 0.2 23.4 27.7 ? 0.2 16.7
[0115] XRPD diffraction peaks for crystalline 2-Br-LSD hemi-fumarate Forms A and B are listed in Tables 5A-5B.
TABLE-US-00012 TABLE 5A 2-Br-LSD hemi-fumarate (Form A), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 4.4 ? 0.2 73.08 7.4 ? 0.2 78.0 8.3 ? 0.2 100.0 9.5 ? 0.2 10.4 10.3 ? 0.2 72.1 11.5 ? 0.2 21.3 11.9 ? 0.2 23.5 13.5 ? 0.2 11.7 14.9 ? 0.2 36.8 16.3 ? 0.2 11.5 17.1 ? 0.2 14.2 18.3 ? 0.2 14.5 19.3 ? 0.2 10.9 19.8 ? 0.2 48.8 20.5 ? 0.2 20.9 20.8 ? 0.2 10.8 21.5 ? 0.2 16.0 21.9 ? 0.2 50.9 22.5 ? 0.2 28.6 23.2 ? 0.2 33.4 23.8 ? 0.2 22.8 25.1 ? 0.2 22.2 26.8 ? 0.2 13.4 28.7 ? 0.2 21.5 30.1 ? 0.2 11.0 30.6 ? 0.2 10.0
TABLE-US-00013 TABLE 5B 2-Br-LSD hemi-fumarate (Form B), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 7.0 ? 0.2 23.5 8.8 ? 0.2 100.0 12.5 ? 0.2 31.0 15.4 ? 0.2 18.3 17.1 ? 0.2 10.3 18.7 ? 0.2 11.1 20.0 ? 0.2 25.4 20.7 ? 0.2 41.3 22.6 ? 0.2 20.9 24.5 ? 0.2 11.2 28.6 ? 0.2 13.1
[0116] XRPD diffraction peaks for crystalline 2-Br-LSD hemi-succinate Form A are listed in Table 6.
TABLE-US-00014 TABLE 6 2-Br-LSD hemi-succinate Form A, PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 5.4 ? 0.2 12.3 6.6 ? 0.2 100.0 8.7 ? 0.2 28.9 11.0 ? 0.2 13.4 12.0 ? 0.2 11.6 18.0 ? 0.2 11.8 19.1 ? 0.2 14.6 19.9 ? 0.2 24.9 20.9 ? 0.2 25.4 21.9 ? 0.2 35.9 24.9 ? 0.2 11.0 26.0 ? 0.2 21.8
[0117] XRPD diffraction peaks for crystalline 2-Br-LSD besylate are listed in Table 7.
TABLE-US-00015 TABLE 7 2-Br-LSD besylate, PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 5.9 ? 0.2 33.4 8.7 ? 0.2 100.0 13.4 ? 0.2 10.1 13.8 ? 0.2 15.6 14.6 ? 0.2 15.2 16.1 ? 0.2 12.8 16.3 ? 0.2 15.1 16.8 ? 0.2 10.0 17.8 ? 0.2 64.5 19.7 ? 0.2 37.9 20.5 ? 0.2 14.9 21.6 ? 0.2 21.0 22.3 ? 0.2 11.4 22.9 ? 0.2 13.5 23.4 ? 0.2 46.7 23.8 ? 0.2 21.6 24.5 ? 0.2 19.8
[0118] XRPD diffraction peaks for crystalline mono-succinate (Form A) are listed in Table 8.
TABLE-US-00016 TABLE 8 2-Br-LSD mono-succinate (Form A), PANalytical diffractometer Pos. [?2Th.] Rel. Int. [%] 5.4 ? 0.2 12.3 6.6 ? 0.2 100.0 8.7 ? 0.2 28.9 11.0 ? 0.2 13.4 12.0 ? 0.2 11.6 15.1 ? 0.2 9.1 18.0 ? 0.2 11.8 19.1 ? 0.2 14.6 19.9 ? 0.2 24.9 20.9 ? 0.2 25.4 21.9 ? 0.2 35.9 24.9 ? 0.2 11.0 26.0 ? 0.2 21.8 27.0 ? 0.2 8.5 29.3 ? 0.2 9.9 31.4 ? 0.2 7.7 32.3 ? 0.2 6.9
Methods of Preparation
[0119] In another aspect, a method of preparing the crystalline salt of 2-Br-LSD hydrobromide (Form 1), which has an XRPD pattern substantially similar to that set forth in
[0133] In some embodiments, the above method further comprises adding seed crystals of 2-Br-LSD hydrobromide (Form 1) to the batch prior to step (c).
[0134] In some embodiments, the solvent comprises water and ethanol, methanol or isopropanol.
[0135] In some embodiments, the solvent comprises 2-12% water. In some embodiments, the solvent comprises ethanol. In some embodiments, the solvent comprises 88% to 98% ethanol
[0136] In some embodiments, the solvent is ethanol-water in a ratio of about 95:5 v/v.
[0137] In some embodiments, the concentration of 2-Br-LSD in step (a) is between 0.12M and 0.6M.
[0138] In some embodiments, the concentration of 2-Br-LSD in step (a) is between 0.2M and 0.4M.
[0139] In some embodiments, the hydrobromic acid is added as a solution.
[0140] In some embodiments, the hydrobromic acid is added as a solution in the same solvent used in step (a).
[0141] In some embodiments, the hydrobromic acid is added as a solution in ethanol-water at a concentration of 0.5M to 4M.
[0142] In some embodiments, the hydrobromic acid is added as a solution in the same solvent used in step (a) at a concentration of 1M to 3M.
[0143] In some embodiments, the first temperature is between about 20? C. and 50? C.
[0144] In some embodiments, the first temperature is between 30? C. and 50? C. and the second temperature is between 0? C. and about 25? C.
[0145] In some embodiments, the first temperature is between 40? C. and 50? C. and the second temperature is about 20? C. to about 25? C.
[0146] In some embodiments, M is between 1 and 4 hours, N is between 2 and 6 hours, O is between 30 minutes and 4 hours, and P is between 8 and 24 hours.
[0147] In some embodiments, the method further comprises: [0148] following period of time P and prior to step (h), cooling the batch to a fourth temperature and equilibrating the batch at the fourth temperature for a period of time Q; [0149] wherein Q is between 5 minutes and 48 hours.
[0150] In some embodiments the fourth temperature is between 0? C. and 10? C.
[0151] In some embodiments, Q is between 0.5 hour and 4 hours.
[0152] In some embodiments, the first temperature is about 20? C. to about 25? C. and the second temperature is between 0? C. and 10? C.
[0153] In some embodiments, M is between 1 and 4 hours, N is between 2 and 6 hours, O is between 30 minutes and 4 hours, and P is between 8 and 24 hours.
[0154] In some embodiments, the sum of the hydrobromic acid portions in steps (b) and (d) is 1.0 molar equivalent with respect to 2-Br-LSD.
[0155] In some embodiments, the portion of hydrobromic acid in step (b) is sufficient to induce the formation of crystals of 2-Br-LSD hydrobromide.
[0156] In some embodiments, the addition of hydrobromic acid in step (b) is halted at the first visible sign of crystallization.
[0157] In some embodiments, the method further comprises adding seed crystals of 2-Br-LSD hydrobromide (Form 1) to the batch prior to step (c).
[0158] In some embodiments, the hydrobromic acid is added as a gas in steps (b) and (d).
[0159] In some embodiments, M is 0.
[0160] In some embodiments, the hydrobromic acid portion in step (b) is between 0.1 and 0.4 molar equivalents with respect to 2-Br-LSD.
[0161] In some embodiments, the hydrobromic acid portion in step (b) is between 0.2 and 0.3 molar equivalents with respect to 2-Br-LSD.
[0162] Representative methods of preparing the other 2-Br-LSD salts disclosed herein are described in various non-limiting working examples.
Pharmaceutical Compositions
[0163] Another aspect of the present disclosure is directed to a pharmaceutical composition that comprises a therapeutically effective amount of a 2-Br-LSD salt of the present disclosure and a pharmaceutically acceptable carrier. The term pharmaceutically acceptable carrier, as known in the art, refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administering a crystalline 2-Br-LSD salt of the present disclosure to mammals. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous alike, and combinations thereof), solids, encapsulating materials, and combinations thereof (e.g., semi-solids). A carrier is pharmaceutically acceptable in the sense of being physiologically inert, compatible with the other ingredients of the formulation, and not injurious to the subject or patient. Depending on the type of formulation, the composition may further include one or more pharmaceutically acceptable excipients.
[0164] Broadly, 2-Br-LSD salts of the present disclosure may be formulated into a given type of composition in accordance with conventional pharmaceutical practice such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
[0165] In some embodiments, the 2-Br-LSD salts are formulated for oral or intravenous administration (e.g., systemic intravenous injection).
[0166] The 2-Br-LSD salts of the present disclosure may be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the 2-Br-LSD salt is dissolved, suspensions in which solid particles of the 2-Br-LSD salt are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs). The 2-Br-LSD salts may also be formulated for rapid, intermediate or extended release.
[0167] In some embodiments, the pharmaceutical composition is in the form of a solid or a liquid.
[0168] As shown in Example 2 (Method 4), the 2-Br-LSD salt, e.g., a hydrobromide salt of 2-Br-LSD having the solid form referred to herein as Form 1, may be prepared in the form of a batch that is manufactured according to GMP which may be used as an API.
Dosage Amounts
[0169] Compositions may be formulated to contain an effective amount of the salt of 2-Br-LSD. As used herein, the term effective amount refers to an amount of a 2-Br-LSD salt of the present disclosure or a composition including the 2-Br-LSD salt, effective in producing the desired response in a particular patient in need thereof. Therefore, the term effective amount includes the amount of a 2-Br-LSD salt of the present disclosure, that when administered, induces a positive modification in the disease or disorder to be treated, or is sufficient to prevent development or progression of the disease or disorder, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject, for example, cluster headaches and migraines.
[0170] The total daily dosage of the crystalline salt and usage thereof may be decided in accordance with standard medical practice, e.g., by the attending physician using sound medical judgment. The specific therapeutically effective dose for any particular subject may depend upon a variety of factors including the disease or disorder being treated and the severity thereof (e.g., its present status); the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the crystalline salt; and like factors well known in the medical arts (see, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001).
[0171] The 2-Br-LSD salts of the present disclosure and pharmaceutical compositions thereof may be effective over a wide dosage range. See, for example, U.S. Pat. No. 8,415,371.
[0172] Effective daily dosage ranges for 2-Br-LSD salts of the present disclosure are generally between about 10 ?g/kg and about 100 ?g/kg body weight. In some embodiments, the desired dosage may range from about 20 ?g/kg to about 50?/kg body weight. For example, a dose of 2.4 mg may be administered to an 80 kg adult to deliver about 30 ?g/kg of a 2-Br-LSD salt of the present disclosure. In some embodiments, a dose ranging from about 1.5 to 5 mg may be administered. In some embodiments, a dose ranging from about 1.5 to 3 mg may be administered.
Pharmaceutical Kits
[0173] The 2-Br-LSD salts of the present disclosure and/or pharmaceutical compositions containing them may be assembled into kits or pharmaceutical systems. Kits or pharmaceutical systems according to this aspect of the disclosure include a carrier or package such as a box, carton, tube or the like, having in close confinement therein one or more containers, such as vials, tubes, ampoules, or bottles, which contain a 2-Br-LSD salt of the present disclosure or a pharmaceutical composition thereof. The kits or pharmaceutical systems of the disclosure may also include printed instructions for using the 2-Br-LSD salt and pharmaceutical compositions.
[0174] These and other aspects of the present disclosure will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the disclosure but are not intended to limit its scope, as defined by the claims.
EXAMPLES
Example 1: General Methods
Solution Proton Nuclear Magnetic Resonance (.SUP.1.H NMR)
[0175] .sup.1H NMR spectra were collected using a JEOL ECX 400 MHz spectrometer equipped with an auto-sampler. The samples were dissolved in a suitable deuterated solvent for analysis. The data were acquired using Delta NMR Processing and Control Software version 4.3. A Bruker Avance 300 MHz spectrometer was also used to analyze samples.
Solution Carbon-13 Nuclear Magnetic Resonance (.SUP.13.C NMR)
[0176] .sup.13C NMR spectra were collected using a Bruker Avance 75 MHz spectrometer. The samples were dissolved in a suitable deuterated solvent for analysis.
X-Ray Powder Diffraction (XRPD)
[0177] X-Ray Powder Diffraction patterns were collected as described above.
Thermo-Gravimetric Analysis (TGA)
[0178] TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position auto-sampler. The instrument was calibrated using a certified weight and certified Alumel and Nickel for temperature. A predefined amount of the sample, ca. 5 mg, was loaded into a pre-tared aluminum ACCUPIK? sample pan and platinum crucible and was heated at 20? C./min from ambient (room) temperature to 400? C. unless otherwise stated. A nitrogen purge at 25 mL/min was maintained over the sample. The instrument control, data acquisition and analysis were performed with TA Instruments TRIOS software v4.1.1.33073.
Differential Scanning Calorimetry
[0179] DSC data was collected on a TA Instruments Discovery DSC? equipped with a 50-position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of the sample, 0.5-2.0 mg, was placed in a Tzero? Pan with a Tzero? Hermetic Lid and heated at 20? C./min from 30 to 350? C., or varied as experimentation dictated. A purge of dry nitrogen at 50 mL/min was maintained over the sample. The instrument control, data acquisition and analysis were performed with TA Instruments TRIOS software v4.1.1.33073. All results feature endotherm up convention.
Dynamic Vapor Sorption
[0180] Sorption isotherms were obtained using a Hiden Isochema moisture sorption analyser (model IGAsorp), controlled by IGAsorp Systems Software V6.50.48. The sample was maintained at a constant temperature (25? C.) by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow of 250 mL/min. The instrument was verified for relative humidity content by measuring three calibrated Rotronic salt solutions (10-50-88%). The weight change of the sample was monitored as a function of humidity by a microbalance (accuracy +/?0.005 mg). A defined amount of sample was placed in a tared mesh stainless steel basket under ambient conditions. A full experimental cycle typically consisted of three scans (sorption, desorption and sorption) at a constant temperature (25? C.) and 10% RH intervals over a 0-90% range (60 minutes for each humidity level). This type of experiment demonstrates the ability of samples studied to absorb moisture (or not) over a set of well-determined humidity ranges.
HPLC Method 1
[0181] System: Agilent1100 series liquid chromatograph or equivalent [0182] Column: Xselect? CSH C18 4.6?150 mm; 3.5 ?m [0183] (Ex. Waters?; #186005270) [0184] Mobile Phase: APurified Water:MeCN:TFA(95:5:0.1) [0185] BMeCN:Purified water:TFA (95:5:0.1) [0186] Flow Rate: 1.0 mL/min [0187] Injection Volume: 5 ?L [0188] Detection: UV @ 230 nm [0189] Column Temperature: 35? C. [0190] Post run time: 5 minutes [0191] Gradient:
TABLE-US-00017 Time (min) % A % B 0 100 0 3 100 0 15 20 80 20 20 80 21 100 0
[0192] Sample preparation: Mixture of 0.4 mg/mL in Methanol:Water (1:1) was sonicated to fully dissolve sample.
HPLC Method 2
[0193] System: Agilent1100 series liquid chromatograph or equivalent [0194] Mobile Phase A: acetonitrile:water (5:95)+trifluoroacetic acid 0.05% [0195] Mobile Phase B: acetonitrile:water (95:5)+trifluoroacetic acid 0.05% [0196] Injection Volume: 5 ?L [0197] Flow: 1 mL/min [0198] Column: Kinetex? 2.6 m XB-C18 100 ?, 100?4.6 mm [0199] Column Temperature: 35? C. [0200] Autosampler Temperature: 4? C. [0201] Detection: UV 240 nm [0202] Gradient:
TABLE-US-00018 Time (min) % A % B Start 100.0 0.0 3.00 100.0 0.0 15.00 20.0 80.0 20.00 20.0 80.0 23.00 100.0 0.0
[0203] Sample preparation: Weigh about 25 mg of powder and dilute to 100 mL with Mobile Phase A: Mobile Phase B 60:40
Example 2: Preparation of Crystalline 2-Br-LSD Hydrobromide (Form 1)
Method 1
[0204] Hydrobromic acid (1M solution in ethanol) was prepared by diluting 172.15 g of HBr.sub.aq 47% w/w with ethanol to a final volume of 1000 mL, mixing well, and allowing the solution to equilibrate to ambient temperature. 2-Br-LSD free base (5.0 g, 0.012 mol, 1 equiv) was charged to a flask and ethanol (50 mL, 10 volumes) was added. The mixture was heated to 50? C. to give a yellow solution. Hydrobromic acid (1M solution in ethanol, 12.43 mL, 1 equiv) was added dropwise. Precipitation was noted following roughly 50% of the acid charge. The suspended solid was isolated via rapid evaporation in vacuo producing an off-white solid. The solid was dried in vacuo at 50? C. for 18 hours to afford 2-Br-LSD hydrobromide (Form 1) as an off-white solid (5.48 g, 91% yield). 22-Br-LSD hydrobromide (Form 1) was successfully prepared, with the XRPD pattern (
[0205] 2-Br-LSD hydrobromide (Form 1) is non-hygroscopic. After drying in vacuo at 50? C. for 18 hours, it exhibited less than 1% weight loss between 25? C. and 200? C. upon thermogravimetric analysis at a heating rate of 20? C./min (
Method 2
[0206] A 2M stock solution of hydrobromic acid in ethanol-water 95:5 was prepared by diluting 48% aqueous HBr with ethanol and deionized water to volume. 2-Br-LSD (48 g) was weighed into a 1000 mL jacketed reaction vessel fitted with overhead stirring. Ethanol (506.4 mL) and deionized (DI) water (17.5 mL) were charged to the vessel, and the mixture was stirred at ambient temperature with an agitation rate of 200 rpm for about 30 minutes to give a dark brown solution. Hydrobromic acid (2M in ethanol-water 95:5 v/v, 12.2 mL) was added in one portion, followed immediately by seeding with 2-Br-LSD hydrobromide (Form 1) (0.06 g, 0.1% w/w). Stirring was continued at ambient temperature for 2 hours after the addition, whereupon the mixture showed visible signs of crystallization development. Hydrobromic acid (2M in ethanol-water 95:5, 48.7 mL) was added over 4 hours using a syringe pump. Stirring was continued for 1 hour at ambient temperature. The mixture was cooled to 5? C. over 2 hours and stirred at this temperature for 18 hours. The solid was isolated using vacuum filtration. Ethanol-water 95:5 (57 mL) was used to rinse the vessel and passed through the damp cake. The cake was pulled dry under air/vacuum for 30 minutes. The resulting solid was dried in vacuo at 45? C. for 60 hours to afford 51 g (89% yield, Lot JMP305). HPLC analysis by Method 1 showed 99.28% purity by area. The .sup.1H NMR spectrum (
Method 3
[0207] ##STR00002##
TABLE-US-00019 LIST OF STARTING MATERIALS AND REAGENTS: Material Amount MW mmol Ratio 2-Br-LSD 150.0 g 402.33 372.8 1.0 equivalent Denatured ethanol 1275 mL 8.5 volumes Demineralized water 67.5 mL 0.45 volumes HBr.sub.aq. 47% w/w 12.8 g 80.91 74.3 0.2 equiv Denatured ethanol 27.3 mL 0.18 volumes Demineralized water 1.4 mL 0.009 volumes 2-bromolysergic acid 0.15 g 483.24 3.1 ? 10.sup.?4 0.1% w/w diethylamide hydrobromide HBr.sub.aq. 47% w/w 51.5 g 80.91 298.5 0.8 equiv Denatured ethanol 109.1 mL 0.73 volumes Demineralized water 5.7 mL 0.04 volumes Denatured ethanol 142.5 mL 0.95 volumes Demineralized water 7.5 mL 0.05 volumes
[0208] In a suitable reactor, 2-Br-LSD (150.0 g) was charged, followed by denatured ethanol (1275 mL) and water (67.5 mL). The total solvent volume (1342.5 mL) corresponded to 8.95 volumes and an ethanol/water ratio of 95:5. The mixture was heated to 45? C., resulting in complete dissolution. Aqueous (aq.) HBr (2 M) was prepared in a 200 mL volumetric flask by bringing to volume 68.8 g of aq. HBr 47% w/w with a 95:5 mixture of denatured ethanol and water to obtain a concentration of 2 M. The solution was homogenized, and then 37.3 mL of this solution (0.2 equiv, consisting of 12.8 g of aq. HBr 47% w/w, 27.3 mL of denatured ethanol and 1.4 mL of water) was added to the reaction vessel via a dropping funnel over 80 minutes while maintaining an internal temperature of 45? C. At the end of the addition, the mixture was seeded with 0.15 g of 2-bromolysergic acid diethylamide hydrobromide and stirred for two hours at 45? C. Aqueous HBr (2 M) 149.3 mL (0.8 equiv, consisting of 51.4 g of HBr.sub.aq 47% w/w, 109.1 mL of denatured ethanol and 5.7 mL of water) was added to the reaction vessel via a dropping funnel over 180 minutes while maintaining an internal temperature of 45? C. The mixture was allowed to spontaneously cool to room temperature (20-25? C.) and stirred overnight. The resulting suspension was then cooled to 0-5? C. and stirred for 60 minutes. The product was collected on a B?chner filter, washed with denatured ethanol/water (95:5, 142.5 mL of ethanol, 7.5 mL of water) and dried in a vacuum oven at 45? C. for 18 hours to give 127.5 g (70.7% molar yield, 85.0% w/w yield).
[0209] Analysis by HPLC Method 2 indicated 99.45% 2-bromolysergic acid diethylamide by area. The .sup.1H NMR spectra (
Method 4
[0210] The following process was performed in accordance with GMP appropriate for early-stage clinical use as defined in Q7. All processing steps were conducted under an atmosphere of nitrogen, unless indicated otherwise.
[0211] A clean, dry reactor was subjected to three vacuum (?400 mbar)nitrogen purge cycles. 2-Bromo-LSD (2.320 kg, prepared as described in Example 5 (STEPS 1 and 2) of Applicant's co-pending application, filed on even date herewith, and entitled PROCESS FOR SYNTHESIZING 2-BROMOLYSERGIC ACID DIETHYLAMIDE VIA CONTROLLED HYDROLYSIS OF BROMOCRIPTINE; Attorney Docket No. 58205-00003USNP1), was charged through the hatch, followed by three vacuum (?400 mbar)nitrogen purge cycles. A second clean, dry reactor was subjected to three vacuum (?400 mbar)nitrogen purge cycles. Denatured ethanol (15.5 kg) and purified water (1.0 L) were charged to the second reactor, followed by three vacuum (?400 mbar)nitrogen purge cycles, and this mixture was agitated for not less than 5 minutes. The ethanol-water mixture was transferred to the reactor containing 2-Br-LSD, agitation was begun, and the resulting mixture was heated to 43-47? C., resulting in complete dissolution of the solid. Inside a glove box, denatured ethanol (0.3 kg), purified water (0.02 L) and hydrobromic acid 48% (0.2 kg) were measured out and charged to a dropping funnel. The contents of the dropping funnel were added in not less than 120 minutes to the stirred 2-Br-LSD solution while maintaining an internal temperature of 43-47? C. Stirring was continued at this temperature for not less than 2 hours. Inside the glove box, denatured ethanol (1.3 kg), purified water (0.1 L) and hydrobromic acid 48% (0.8 kg) were measured out and charged to the dropping funnel. The contents of the dropping funnel were added in not less than 180 minutes to the batch while maintaining an internal temperature of 43-47? C. With continuous agitation, the batch was allowed to cool spontaneously to an internal temperature of 20-24? C. and maintained in this range for 18 hours. The batch was cooled to 0-5? C., stirred for 60 minutes, and filtered. Purified water (0.1 L) and denatured ethanol (1.7 kg) were charged to the reactor, and this mixture was cooled to 0-5? C. and used to wash the solid on the filter. The solid was dried in a vacuum oven at 43-47? C. for not less than 18 hours until in-process controls (IPCs) for residual solvents (?ICH limits for solvents used in the process) and moisture by Karl Fischer titration (KF; 50.5%) were met, to give 2.410 kg of off-white powder.
[0212] The product was characterized and released in accordance with GMP for early-stage clinical use as defined in Q7. Selected acceptance specifications and results are presented in Table 9. Where applicable, the results were compared to the product prepared and characterized as described in Example 2, Method 3, and which in Table 9 and the paragraph following Table 10, is referred to as a reference standard.
TABLE-US-00020 TABLE 9 Selected Release Testing Results for 2-Br-LSD hydrobromide (Form 1) Prepared According to Method 4 Test Specification Result Selected Release Tests Appearance Off-white to light brown powder Complies Identification Infrared spectrum Conforms with reference spectrum Complies .sup.a HPLC retention time .sup.b Retention time of main peak is ?5% of Complies retention time of reference standard HBr content by potentiometric 15.7-17.7% 16.8% titration (% w/w on anhydrous basis) Assay by HPLC (% w/w against 97.0-102.0% 99.7% reference standard, on anhydrous, solvent-free basis) .sup.b Chemical purity by HPLC (% a/a) .sup.b NLT 98.0% 99.4% Related substances by HPLC (% a/a) .sup.b LSD .sup.c NMT 0.05% ND .sup.d RRT 0.99 .sup.e NMT 0.50% 0.25% Iso-2-Br-LSD (RRT 1.16).sup.f NMT 0.15% ND .sup.g Largest single unknown or NMT 0.15% RRT 0.86 = 0.11% unqualified impurity RRT 1.17 = 0.05% Report all impurities greater than RRT 1.21 = 0.13% LOQ (0.05%) RRT 1.38 = 0.07% Total impurities NMT 2.0% 0.6% Residual solvents by HS-GC Methanol NMT 3000 ppm 10 ppm Dichloromethane NMT 600 ppm 10 ppm Acetonitrile NMT 410 ppm 4 ppm Diethylamine NMT 1000 ppm 90 ppm Ethyl acetate NMT 5000 ppm 13 ppm Ethanol NMT 5000 ppm 2471 ppm Acetone NMT 5000 ppm 132 ppm 2-Propanol NMT 5000 ppm 115 ppm Water content by KF (% w/w) NMT 0.5% 0.1% Residue on ignition (% w/w) NMT 0.5% 0.0% XRPD Conforms to Form 1 reference diffractogram Complies .sup.h Additional Tests for Information Only Identification .sup.1H NMR Report result - compare to reference Conforms spectrum Mass spectrometry Report result [M + H].sup.+ 402.6 .sup.a FIG. 46 .sup.b HPLC Method 2, except that diluent is Mobile Phase A:Mobile Phase B 40:60 .sup.c (6aR,9R)-N,N-diethy1-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide .sup.d No peak assignable to LSD was detected by HPLC with UV absorbance detection at 240 nm with LOD 0.02% and ion trap mass detection at m/z 324 ([M + H].sup.+) .sup.e Tentatively assigned as (6aR)-5-bromo-N,N-diethy1-7-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinoline-9-carboxamide .sup.f(6aR,9S)-5-bromo-N,N-diethy1-7-methy1-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide .sup.g LOD 0.02% .sup.h FIG. 47 % w/w = % weight-to-weight; % a/a = % of total peak area; NMT = not more than; NLT = not less than; RRT = relative retention time; ND = not detected; LOD = limit of detection; HPLC = high performance liquid chromatography; HS-GC = headspace gas chromatography; ppm = parts per million; KF = Karl Fischer moisture titration; XRPD = x-ray powder diffraction; NMR = nuclear magnetic resonance spectroscopy
[0213] The XRPD pattern for 2-bromolysergic acid diethylamide hydrobromide (Form 1) prepared according to Method 4 was collected using a Bruker D2 X-ray Generator (30 kV, 10 mA, scan interval 3-35?, Step 0.03?, 2 sec/step; flat plate zero-background sample holder, rotation 15 rpm). The results are presented graphically in
TABLE-US-00021 TABLE 10 XRPD Diffraction Peaks for 2-Bromolysergic acid diethylamide hydrobromide (Form 1) Prepared According to Method 4 Pos. [?2Th.] Rel. Int. [%] 8.0 ? 0.2 100.0 8.9 ? 0.2 4.3 12.5 ? 0.2 7.2 14.2 ? 0.2 8.2 14.7 ? 0.2 4.2 16.0 ? 0.2 28.7 17.8 ? 0.2 23.1 18.3 ? 0.2 6.5 19.0 ? 0.2 43.0 20.5 ? 0.2 29.2 21.9 ? 0.2 43.1 22.2 ? 0.2 8.4 23.2 ? 0.2 14.9 23.6 ? 0.2 13.6 23.9 ? 0.2 22.2 24.4 ? 0.2 13.1 24.9 ? 0.2 7.1 25.2 ? 0.2 12.0 26.1 ? 0.2 18.2 26.8 ? 0.2 32.6 27.1 ? 0.2 6.6 27.6 ? 0.2 22.7 27.9 ? 0.2 6.4 28.2 ? 0.2 6.2 28.6 ? 0.2 11.7 30.0 ? 0.2 6.1 30.3 ? 0.2 7.5 31.3 ? 0.2 3.8 32.3 ? 0.2 9.4 34.2 ? 0.2 5.4 36.0 ? 0.2 7.0 38.2 ? 0.2 9.3
[0214] This XRPD pattern is consistent with that of the reference standard prepared according to Example 2, Method 3, and with those presented in
Example 3: Preparation of Crystalline 2-Br-LSD Hydrobromide (Pattern B Solvate)
[0215] 2-Br-LSD hydrobromide (Form 1) (50 mg) was weighed into a crystallizations tube. Tetrahydrofuran-water (98:2 v/v; 0.500 mL, 10 volumes) was added and the mixture equilibrated at 25? C. for 24 hours. The solids were isolated by filtration and dried at 45? C. in vacuo to afford 2-Br-LSD hydrobromide (Pattern B Solvate), for which the XRP diffractogram and peak list are presented in
Example 4: Preparation of Crystalline 2-Br-LSD Hydrobromide (Form 2)
[0216] 2-Br-LSD hydrobromide (Form 1) (50 mg) was weighed into a crystallization tube. Ethyl acetate (0.500 mL, 10 volumes) was added, and the mixture was equilibrated at 25? C. for 24 hours. The solid was isolated by filtration and dried at 45? C. in vacuo to afford 2-Br-LSD hydrobromide (Form 2), for which the XRP diffractogram and peak list are presented in
Example 5: Preparation of Crystalline 2-Br-LSD Mesylate (Amorphous)
[0217] 2-Br-LSD freebase (5.0 g) was charged to a flask and IPA (50 mL, 10 volumes) was added. The mixture was heated to 50? C. and allowed to equilibrate for ?15 minutes, to give a yellow solution. Methane sulfonic acid (1M solution in ethanol, 12.43 mL, 1 equivalent) was added in one single charge. The solvent was then flash evaporated to give a light beige solid which was dried in vacuo at 45? C. for 24 hours to afford a beige solid (6.10 g, 99% yield). The XRP diffractogram, .sup.1H NMR spectrum and DSC and TGA curves (not shown) support the assignment of this product as amorphous 2-Br-LSD mesylate.
Example 6: Preparation of Crystalline 2-Br-LSD Mesylate (Form A)
[0218] 2-Br-LSD mesylate (50 mg, amorphous) was weighed into a crystallization tube, followed by 1,4-dioxane (1.00 mL, 20 volumes). The mixture was heated to 40? C. and equilibrated for ?15 minutes. Tert-Butyl methyl ether (0.05 mL, 1 volume) was charged to the solution. The mixture was equilibrated for 5 minutes. A suspension was observed. The mixture was left to cool to ambient temperature and equilibrated for 12 hours. The solid was isolated by vacuum filtration and dried at 45? C. for 24 hours. The XRP diffractogram (
Example 7: Preparation of Crystalline 2-Br-LSD Mesylate (Form B)
[0219] 2-Br-LSD mesylate (50 mg, amorphous) was weighed into a crystallization tube and charged with tetrahydrofuran-water (98:2, 0.25 mL, 5 volumes). The mixture was heated to 40? C. and equilibrated for ?15 minutes. Ethyl acetate (0.30 mL) was charged to the solution in 0.05 mL (1 volume) aliquots, with equilibrations of 5 minutes after each addition. The mixture was left to cool to ambient temperature and equilibrated for 12 hours. The solid was isolated by vacuum filtration and dried at 45? C. for 24 hours. The XRP diffractogram, XRP peak list, combined DSC/TGA curves are presented as
Example 8: Preparation of Crystalline 2-Br-LSD Mesylate (Form C)
[0220] 2-Br-LSD mesylate (200 mg) was weighed into a 14-mL type 1 glass vial. A minimum volume of ethanol was charged, and the mixture was heated to 50? C. Once a solution was obtained, it was filtered to ensure the absence of any visible particulates. One fourth of this solution, containing 50 mg of 2-Br-LSD mesylate, was charged to a crystallization tube containing 1 mL of pre-cooled (2? C.) toluene. The mixture was allowed to equilibrate for ?30 minutes at 2? C., resulting in a suspension. The solid was collected by vacuum filtration and dried in vacuo at 45? C. for 24 hours. The XRP diffractogram, XRP peak list, and combined DSC/TGA curves are presented as
Example 9: Preparation of Crystalline 2-Br-LSD Hemi-Fumarate (Form A)
[0221] 2-Br-LSD hemi-fumarate (Form B) (50 mg) was charged to a crystallization tube and suspended in 0.500 mL (10 volumes) of acetone. The mixture was heated to 50? C. and stirred for ca. 15 mins. MeOH (0.550 mL, 11 volumes) was charged to the solution at 50? C. in 0.05-mL (1 vol) aliquots with equilibrations for 5 minutes after each addition until a solution formed. The solution was clarified by filtration into a clean pre-heated tube. The mixture was equilibrated at 50? C. for about 30 mins and then cooled to 25? C. and equilibrated for about 20 hours. The resulting suspension was filtered, and the collected solid dried in vacuo at 45? C. The .sup.1H NMR spectrum (
Example 10: Preparation of Crystalline 2-Br-LSD Hemi-Fumarate (Form B)
[0222] 2-Br-LSD free base (5.0 g, 0.012 mol, 1 equiv) was charged to a flask and THE (50 mL, 10 volumes) was added. The mixture was heated to 50? C. to give a yellow solution. Fumaric acid (0.25 M solution in ethanol, 24.8 mL, 0.0062 mol, 0.5 equiv) was added, giving a yellow solution. The solvent was evaporated rapidly in vacuo, producing a pale-yellow solid, which was dried in vacuo at 50? C. for 18 hours to afford an off-white solid (5.4 g, 94% yield). The XRP diffractogram, XRP peak list, and combined DSC/TGA curves are presented as
Example 11: Preparation of Crystalline 2-Br-LSD Besylate
[0223] 2-Br-LSD free base (100 mg, 0.249 mmol, 1 equiv) was charged to a crystallization tube and toluene (1.0 mL, 10 vol) was added to give a dark orange solution. The mixture was heated to 50? C. and benzenesulfonic acid (1M solution in ethanol, 0.249 mL, 0.249 mmol, 1 equiv) was charged in one portion. The solution was equilibrated at 50? C. for 1 hour, resulting in precipitation of a gummy solid. The mixture was cooled to 25? C. and equilibrated for 24 hours, during which the solid remained gummy. The volume was reduced to 50% under a steady stream of nitrogen, resulting in a free-flowing suspension. The solid was collected by filtration and dried in vacuo at 45? C. to give an off-white solid (102 mg, 73% yield). The .sup.1H NMR spectrum (not shown) shows a significant shift of the N-methyl protons and indicates one molar equivalent of benzenesulfonic acid, confirming the successful formation of a mono besylate salt. The thermal profile (
Example 12: Preparation of Crystalline 2-Br-LSD Oxalate (Form A)
[0224] 2-Br-LSD free base (30 mg, 0.075 mmol, 1 equiv) was charged to a crystallization tube and ethanol (0.3 mL, 10 vol) was added to give a dark orange solution. The mixture was heated to 50? C. and oxalic acid (1M solution in ethanol, 0.075 mL, 0.075 mmol, 1 equiv) was charged in one portion. The solution was equilibrated at 50? C. for 1 hour, resulting in a solution, and then cooled to 25? C. and equilibrated for 24 hours, resulting in a suspension. The solid was collected by filtration and dried in vacuo at 45? C. to give 2-Br-LSD oxalate (Form A) as an off-white solid (7 mg, 19% yield). The .sup.1H NMR spectrum (
Example 13: Preparation of Crystalline 2-Br-LSD Xinafoate (Form A)
[0225] 2-Br-LSD free base (30 mg, 0.075 mmol, 1 equiv) was charged to a crystallization tube and ethanol (0.3 mL, 10 vol) was added to give a dark orange solution. The mixture was heated to 50? C. and xinafoic acid (0.5M solution in ethanol, 0.150 mL, 0.075 mmol, 1 equiv) was charged in one portion. The solution was equilibrated at 50? C. for 1 hour, resulting in a solution, and then cooled to 25? C. and equilibrated for 24 hours, resulting in a solution. The solvent was evaporated under a stream of nitrogen, and the sample was triturated with a small amount of methyl tert-butyl ether. The resulting solid was collected by filtration and dried in vacuo at 45? C. to give a beige solid (33 mg, 75% yield). The .sup.1H NMR spectrum (
Example 14: Preparation of Crystalline 2-Br-LSD Xinafoate (Form B)
[0226] A sample of 2-Br-LSD xinafoate (Form A) was placed in a TA Instruments Discovery DSC and thermally manipulated to 150? C. which was beyond the 6.1% loss shown by TGA analysis and the minor endotherm and exotherm at 129? C. shown by DSC analysis. Following XPRD analysis (
Example 15: Preparation of Crystalline 2-Br-LSD Hemi-Succinate (Form A)
[0227] 2-Br-LSD free base (100 mg, 0.249 mmol, 1 equiv) was charged to a crystallization tube and ethanol (1.0 mL, 10 vol) was added to give a dark orange solution. The mixture was heated to 50? C. and succinic acid (0.25M solution in ethanol, 0.996 mL, 0.249 mmol, 1 equiv) was charged in one portion. The solution was equilibrated at 50? C. for 1 hour, resulting in a solution, and then cooled to 25? C. and equilibrated for 24 hours, resulting in a solution. The solvent was evaporated under a stream of nitrogen, and the sample was triturated with a small amount of methyl tert-butyl ether. The resulting solid was collected by filtration and dried in vacuo at 45? C. to give a beige solid (13 mg, 11% yield). The .sup.1H NMR spectrum (not shown) suggested a hemi-succinate salt, showing 0.7 molar equivalents of succinic acid and only a minor shift of the N-methyl protons. The DSC curve of the hemi-succinate salt (
Example 16: Preparation of Crystalline 2-Br-LSD Mono-Succinate (Form A)
[0228] 2-Br-LSD free base (100 mg, 0.249 mmol, 1 equiv) was charged to a crystallization tube and toluene (1.0 mL, 10 vol) was added to give a dark orange solution. The mixture was heated to 50? C. and succinic acid (0.25 M solution in ethanol, 0.996 mL, 0.249 mmol, 1 equiv) was charged in one portion. The solution was equilibrated at 50? C. for 1 hour, resulting in a solution, and then cooled to 25? C. and equilibrated for 24 hours, resulting in a solution. The solvent was evaporated under a stream of nitrogen, and the sample was triturated with a small amount of methyl tert-butyl ether. The resulting solid was collected by filtration and dried in vacuo at 45? C. to give a faint yellow solid (89 mg, 78% yield). The 1H NMR spectrum (
[0229] All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All these publications (including any specific portions thereof that are referenced) are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated as being incorporated by reference.
[0230] Although the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present disclosure as defined by the appended claims.