Co-crystal forms of a novobiocin analog and proline
Disclosed are co-crystal forms of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline or D-proline, their pharmaceutical compositions, processes of manufacture, and methods of use for treating neurodegenerative disorders such as diabetic peripheral neuropathy.
1. A composition comprising
(a) a co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline (1:2), characterized by an X-ray powder diffractogram comprising the following peaks: 14.76, 16.86, 19.00, and 21.05° 2θ±0.20° 2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å (Form B); and
(b) a co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline (1:2), characterized by an X-ray powder diffractogram comprising the following peaks: 9.20, 16.19, 18.45, and 24.51° 2θ±0.20° 2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å (Form D).
2. The composition according to claim 1 , wherein the X-ray powder diffractogram of Form B further comprises peaks at 12.14, 17.51, 18.89, and 19.41° 2θ±0.20° 2θ.
3. The composition according to claim 1 , wherein the X-ray powder diffractogram of Form D further comprises peaks at 11.83, 17.16, 20.15, and 25.34° 2θ±0.2° 2θ.
4. The composition according to claim 1 , wherein the weight ratio of Form B to Form D is from about 0.05:1 to about 1:0.05.
5. The composition according to claim 4 , wherein the weight ratio of Form B to Form D is from about 0.5:1 to about 1:0.5.
6. The composition according to claim 5 , wherein the weight ratio of Form B to Form D is from about 0.2:1 to about 1:0.2.
7. The composition according to claim 1 , further comprising a pharmaceutically acceptable carrier.
8. A method for treating a neurological disorder in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of at least one cocrystal selected from the group consisting of:
(a) a co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline (1:1), characterized by an X-ray powder diffractogram comprising the following peaks: 8.52, 16.33, 19.50, and 21.22° 2θ±0.20° 2θ as determined on a diffractometer using Cu-K α1 radiation at a wavelength of 1.5405929 Å (Material A);
(b) a co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline (1:2), characterized by an X-ray powder diffractogram comprising the following peaks: 14.76, 16.86, 19.00, and 21.05° 2θ±0.20° 2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å (Form B);
(c) a co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′—[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline acetone solvate (1:1:1), characterized by an X-ray powder diffractogram comprising the following peaks: 14.64, 17.53, 18.91, and 21.33° 2θ±0.20° 2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å (Form C);
(d) a co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline (1:2), characterized by an X-ray powder diffractogram comprising the following peaks: 9.20, 16.19, 18.45, and 24.51° 2θ±0.20° 2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å (Form D);
(e) co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide, L-proline, methyl ethyl ketone, and pyrazine in a molar ratio of about 1:1.2:0.6:0.1, characterized by an X-ray powder diffractogram comprising the following peaks: 10.42, 14.62, 19.28, and 21.14° 2θ±0.20° 2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å (Form G); AND
(f) co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and D-proline (1:1), characterized by an X-ray powder diffractogram comprising the following peaks: 11.77, 14.52, 19.54, and 21.23° 2θ±0.20° 2θ as determined on a diffractometer using Cu-K a1 radiation at a wavelength of 1.5405929 Å.
9. The method according to claim 8 , wherein the co-crystal is Form B.
10. The method according to claim 8 , wherein the co-crystal is Form D.
11. The method according to claim 8 , wherein the co-crystal is a composition of Form B and Form D.
12. The method according to claim 8 , wherein the neurological disorder is selected from the group consisting of epilepsy, multiple sclerosis, spinal cord injury, schizophrenia, depression, bipolar disorder, autism, and post-traumatic stress disorder.
13. The method according to claim 12 , wherein the neurological disorder is epilepsy.
14. The method according to claim 12 , wherein the neurological disorder is multiple sclerosis.
15. The method according to claim 12 , wherein the neurological disorder is spinal cord injury.
16. The method according to claim 12 , wherein the neurological disorder is schizophrenia.
17. The method according to claim 12 , wherein the neurological disorder is depression.
18. The method according to claim 12 , wherein the neurological disorder is autism.
19. The method according to claim 12 , wherein the neurological disorder is posttraumatic stress disorder.