Salts and crystalline forms of a TAAR1 agonist
Described herein are amorphous and crystalline forms of pharmaceutically acceptable salts of the TAAR1 agonist 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide. Also described are pharmaceutical compositions suitable for administration to a mammal that include the TAAR1 agonist, and methods of using the TAAR1 agonist, alone and in combination with other compounds, for treating diseases or conditions that are associated with TAAR1 activity.
1 . A pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I)
wherein the pharmaceutically acceptable salt is a mono hydrochloric acid salt and wherein the salt is in crystalline form.
2 . The crystalline mono hydrochloric acid salt according to claim 1 , wherein said crystalline mono hydrochloric acid salt has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 23.1, 23.2, 25.0, and 25.9 [° 2 Theta±0.2° 2 Theta, Cu Kα radiation (1.5406 Å)].
3 . The crystalline mono hydrochloric acid salt according to claim 1 , wherein said crystalline mono hydrochloric acid salt has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 19.0, 20.3, 20.8, 21.1, 22.1, 23.1, 23.2, 25.0, 25.2, and 25.9 [° 2 Theta±0.2° 2 Theta, Cu Kα radiation (1.5406 Å)].
4 . The crystalline mono hydrochloric acid salt according to claim 1 , wherein said crystalline mono hydrochloric acid salt has an X-Ray powder diffraction (XRPD) pattern as shown in FIG. 1 .
5 . A process for manufacturing the crystalline mono hydrochloric acid salt according to claim 1 , comprising:
(a) reacting 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide with hydrochloric acid; and
(b) adding seed crystals of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt to the mixture obtained from step (a).
6 . The process of claim 5 , wherein steps (a) and (b) are performed in a solvent mixture of an alcohol and water.
7 . The process of claim 6 , wherein said alcohol is 1-propanol.
8 . The process of claim 6 , wherein the ratio of alcohol to water in step (a) is 15:1 vol/vol.
9 . The process according to claim 5 , wherein the hydrochloric acid is added as an aqueous solution.
10 . The process according to claim 9 , wherein said aqueous solution of hydrochloric acid comprises 25% wt/wt of hydrochloric acid.
11 . The process according to claim 5 , further comprising step (c): reducing the water content of the reaction mixture by distillation.
12 . The process according to claim 11 , wherein the water content after said reducing the water content of the reaction mixture is 2% wt/wt.
13 . The process according to claim 5 , further comprising step (d): cooling.
14 . The process according to claim 13 , wherein said cooling is cooling to 0° C.+/−5° C.
15 . The process according to claim 5 , further comprising step (e): ageing.
16 . The process according to claim 15 , wherein said ageing is ageing at 0° C.+/−5° C.
17 . The process according to claim 15 , wherein said ageing is for at least 4 h.
18 . The process according to claim 5 , wherein said seed crystals are added as a suspension in an organic solvent.
19 . The process according to claim 18 , wherein said organic solvent is 1-propanol.
20 . A pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I)
wherein the pharmaceutically acceptable salt is a mono hydrochloric acid salt and wherein the salt is in the crystalline form obtained by the process according to claim 5 .
21 . A pharmaceutical composition comprising an effective amount of the crystalline mono hydrochloric acid salt according to claim 1 , and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.
22 . The pharmaceutical composition according to claim 21 , wherein the pharmaceutical composition is in a form suitable for oral administration to a mammal.
23 . The pharmaceutical composition according to claim 22 , wherein the oral pharmaceutical composition is a solid dosage form.
24 . The pharmaceutical composition according to claim 22 , wherein the oral pharmaceutical composition is selected from the group consisting of tablets, coated tablets, dragées, hard gelatin capsules, soft gelatin capsules, solutions, suspensions and emulsions.
25 . The pharmaceutical composition according to claim 21 , wherein the pharmaceutical composition comprises 20 mg to 400 mg of said crystalline 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt.
26 . A method of treating schizophrenia in a mammal comprising administering to the mammal an effective amount of the crystalline mono hydrochloric acid salt of claim 1 or a pharmaceutical composition comprising an effective amount of the crystalline mono hydrochloric acid salt of claim 1 and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.