Crystalline forms of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide and related products and methods
Crystalline forms of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]-phenyl}-5-methylpyridine-3-carboxamide are provided. Pharmaceutical compositions and dosage forms containing the crystal forms are also provided, including related methods for modulating kinases generally, and specifically to treatment of PAH.
1 . A solid crystalline form of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl) pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide, wherein the crystalline form is Form A characterized by an XRPD pattern having peaks at 5.5, 7.8, 11.0, 12.3 and 15.6±0.2 degrees 2-theta, or wherein the crystalline form is Form B characterized by an XRPD pattern having peaks at 5.2, 6.1, 7.6, 11.5 and 12.3±0.2 degrees 2-theta or a mixture thereof.
2 . The solid crystalline form of claim 1 , wherein the crystalline form is Form A characterized by an XRPD pattern having peaks at 5.5, 7.8, 11.0, 12.3 and 15.6±0.2 degrees 2-theta.
3 . The crystalline form of claim 2 , further characterized by an XRPD pattern substantially as shown in FIG. 9 .
4 . The solid crystalline form of claim 2 , comprising at least 80% Form A.
5 . The solid crystalline form of claim 4 , comprising at least 90% Form A.
6 . The solid crystalline form of claim 1 , wherein the crystalline form is Form B characterized by an XRPD pattern having peaks at 5.2, 6.1, 7.6, 11.5 and 12.3±0.2 degrees 2-theta.
7 . The solid crystalline form of claim 6 , further characterized by an XRPD pattern substantially as shown in FIG. 10 .
8 . The solid crystalline form of claim 6 , comprising at least 80% Form B.
9 . The solid crystalline form of claim 8 , comprising at least 90% Form B.
10 . The solid crystalline form of claim 2 , wherein the crystalline form is substantially pure Form A.
11 . The solid crystalline form of claim 6 , wherein the crystalline form is substantially pure Form B.
12 . The solid crystalline form of claim 1 , wherein the crystalline form is a mixture of Form A and Form B.
13 . A pharmaceutical composition comprising the solid crystalline form of claim 1 in combination with one or more pharmaceutically acceptable carriers.
14 . The pharmaceutical composition of claim 13 comprising an additional therapeutically active compound.
15 . The pharmaceutical composition of claim 13 , wherein the composition is formulated for administration to the respiratory track.
16 . The pharmaceutical composition of claim 13 , wherein the composition is in the form of an inhalable powder.
17 . The pharmaceutical composition of claim 13 , wherein the composition is in the form of a dry powder.
18 . The pharmaceutical composition of claim 16 , wherein the inhalable powder comprises particles having a Dv50 of 2-3 um.
19 . The pharmaceutical composition of claim 16 , wherein the inhalable powder has a mass median aerodynamic diameter of 0.9 to 4.0 um.
20 . The pharmaceutical composition of claim 16 , wherein the inhalable powder is obtained by wet-milling micronization in an aqueous solution.
21 . The pharmaceutical composition of claim 16 , wherein the inhalable powder is obtained by jet milling micronization.
22 . The pharmaceutical composition of claim 16 , wherein the inhalable powder has greater than 90% of the starting crystalline form.
23 . The pharmaceutical composition of claim 16 , wherein the inhalable powder has greater than 75% % of the starting crystalline form.
24 . The pharmaceutical composition of claim 13 , wherein the one or more pharmaceutically acceptable carriers comprises lactose.
25 . The pharmaceutical composition of claim 13 , further comprising leucine.
26 . The pharmaceutical composition of claim 25 , wherein leucine coats the solid crystalline form.
27 . The pharmaceutical composition of claim 26 , wherein the leucine coated solid crystalline form is obtained by addition of leucine to a wet-milled crystalline form suspension prior to spray drying.
28 . A pharmaceutical dosage form comprising the pharmaceutical composition of claim 13 .
29 . The pharmaceutical dosage form of claim 28 , wherein the dosage form is a capsule for administration with a dry powder inhaler.
30 . The pharmaceutical dosage form of claim 28 , wherein the dosage form is a blister for administration with a dry powder inhaler.
31 . The pharmaceutical dosage form of claim 28 , wherein the dosage form is a powder for administration with a dry powder inhaler.
32 . A solid unit dosage form comprising the solid crystalline form of claim 1 .
33 . The solid unit dosage form of claim 32 , wherein the dosage form is formulated for administration to the respiratory track.
34 . The solid unit dosage form of claim 32 , wherein the dosage form is in the form of an inhalable powder.
35 . The solid unit dosage form of claim 32 , wherein the dosage form is in the form of a dry powder.
36 . The solid unit dosage form of claim 34 , wherein the inhalable powder comprises particles having a Dv50 of 2-3 um.
37 . The solid unit dosage form of claim 34 , wherein the inhalable powder has a mass median aerodynamic diameter of 0.9 to 4.0 um.
38 . The solid unit dosage form of claim 34 , wherein the inhalable powder is obtained by wet-milling micronization in an aqueous solution.
39 . The solid unit dosage form of claim 34 , wherein the inhalable powder is obtained by jet milling micronization.
40 . The solid unit dosage form of claim 34 , wherein the inhalable powder has greater than 90% of the starting crystalline form.
41 . The solid unit dosage form of claim 34 , wherein the inhalable powder has greater than 75% % of the starting crystalline form.
42 . The solid unit dosage form of claim 32 , further comprising leucine.
43 . The solid unit dosage form of claim 42 , wherein leucine coats the solid crystalline form.
44 . The solid unit dosage form of claim 43 , wherein the leucine coated solid crystalline form is obtained by addition of leucine to a wet-milled crystalline form suspension prior to spray drying.
45 . The solid unit dosage form of claim 32 , wherein the dosage form is a capsule for administration with a dry powder inhaler.
46 . The solid unit dosage form of claim 32 , wherein the dosage form is a blister for administration with a dry powder inhaler.
47 . The solid unit dosage form of claim 32 , wherein the dosage form is a powder for administration with a dry powder inhaler.
48 . A method for treating a disease or condition comprising administering to a subject in need thereof an effective amount of the solid crystalline form of claim 1 , wherein the disease or condition is PAH, primary PAH, idiopathic PAH, heritable PAH, refractory PAH, drug-induced PAH, toxin-induced PAH, or PAH with secondary diseases.
49 . The method of claim 48 , wherein the disease or condition is PAH.
50 . A process for preparing the solid crystalline form of claim 1 by crystallization from a solvent comprising ethyl acetate.
51 . The process of claim 50 , wherein the solvent further comprises n-heptane.
52 . The process of claim 50 , wherein the crystalline form is Form A.
53 . The process of claim 50 , wherein the crystalline form is Form B.
54 . A process for preparing the solid crystalline form of claim 1 by crystallization from a solvent comprising ethanol.
55 . The process of claim 54 , wherein the crystalline form is Form B.
56 . The process of claim 50 , wherein the solvent further comprises water.
57 . A method for preparing Form B of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl) pyrazin-2-yl] amino}ethyl] phenyl}-5-methylpyridine-3-carboxamide comprising slurrying Form A of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl) pyrazin-2-yl]amino} ethyl]phenyl}-5-methylpyridine-3-carboxamide in ethyl acetate and holding its temperature from about 10° C. to about 45° C. for a period of time from about 1 minute to 90 hours, wherein Form A is characterized by an XRPD pattern having peaks at 5.5, 7.8, 11.0, 12.3 and 15.6±0.2 degrees 2-theta, and Form B is characterized by an XRPD pattern having peaks at 5.2, 6.1, 7.6, 11.5 and 12.3±0.2 degrees 2-theta.