Crystalline form of benzylbenzene SGLT2 inhibitor
Provided are crystalline forms of a compound having an inhibitory effect on sodium-dependent glucose cotransporter SGLT2. The invention also provides pharmaceutical compositions, methods of preparing the crystalline compound, and methods of using the crystalline compound, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by SGLT or SGLT2 inhibition.
1. A method for making a crystalline form of the compound of the formula:
said method comprising the steps:
(a) combining (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol bis(L-proline) complex and a suitable solvent with mixing to form a solution;
(b) adding a precipitating solvent to said solution to provide a mixture; and
(c) isolating said crystalline form from said mixture,
wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern that comprises peaks at 11.2, 12.9, 15.5, 17.8, 19.1, 20.0, 20.6, 20.7, 21.2 and 22.8 degrees 2θ, ±0.1 degrees 2θ, wherein said XRPD is made using CuK α1 radiation.
2. The method of claim 1 , wherein the solvent of step (a) is selected from the group consisting of methanol and ethanol.
3. The method of claim 1 , wherein the solvent of step (a) is methanol.
4. The method of claim 1 , wherein the precipitating solvent is water.
5. The method of claim 1 , wherein the solvent of step (a) is methanol and the precipitating solvent is water.
6. The method of claim 5 , wherein the ratio of methanol to water in the mixture of step (b) is from about 1:1 to about 1:9 by volume.
7. The method of claim 5 , wherein the ratio of methanol to water in the mixture of step (b) is about 1:5 by volume.
8. The method of claim 1 , wherein the ratio of complex to solvent and precipitating solvent in the mixture of step (b) is from about 1:10 to about 1:25 (w/v).
9. The method of claim 1 , wherein the mixture of step (b) further comprises a base.
10. The method of claim 1 , wherein the mixture of step (b) further comprises a salt.
11. The method of claim 1 , wherein the mixture of step (b) further comprises a seed crystal of the crystalline form.
12. A method for making a crystalline form of the compound of the formula:
said method comprising the steps:
(a) combining (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and a suitable solvent with mixing to form a solution; and
(b) isolating said crystalline form from said solution,
wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern that comprises peaks at 11.2, 12.9, 15.5, 17.8, 19.1, 20.0, 20.6, 20.7, 21.2 and 22.8 degrees 2θ, ±0.1 degrees 2θ, wherein said XRPD is made using CuK α1 radiation.
13. The method of claim 12 , said method comprising the steps:
(a) combining amorphous (2 S,3R,4R,5 S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and a suitable solvent with mixing to form a solution; and
(b) adding a precipitating solvent to said solution to form a mixture; and
(c) isolating said crystalline form from said mixture.
14. The method of claim 12 , further comprising adding a precipitating solvent to said solution.
15. The method of claim 14 , wherein the solvent of step (a) is selected from the group consisting of methanol and ethanol.
16. The method of claim 14 , wherein the solvent of step (a) is methanol.
17. The method of claim 14 , wherein the precipitating solvent is water.
18. The method of claim 14 , wherein the solvent of step (a) is methanol and the precipitating solvent is water.
19. The method of claim 18 , wherein the ratio of methanol to water in the mixture of step (b) is from about 1:1 to about 1:9 by volume.
20. The method of claim 18 , wherein the ratio of methanol to water in the mixture of step (b) is about 1:5 by volume.
21. The method of claim 14 , wherein the ratio of complex to solvent and precipitating solvent in the mixture of step (b) is from about 1:1 to about 1:9 by volume.
22. The method of claim 14 , wherein the solution further comprises a seed crystal of the crystalline form.
23. The method of claim 14 , wherein the (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is amorphous (2S,3R,4R,5 S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
24. The method of claim 23 , wherein the amorphous (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is prepared from (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol bis(L-proline) by
(a2) combining (2 S,3R,4R,5 S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol bis(L-proline) complex and a suitable solvent mixture with mixing to form a solution; and
(a3) isolating amorphous (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol from said solution of step (a2).
25. The method of claim 24 , wherein said solvent mixture of step (a2) comprises an organic solvent and an aqueous solvent.
26. The method of claim 24 , wherein said solvent mixture of step (a2) comprises ethyl acetate and water.