Crystalline form of Remdesivir

Patent metadata

Field	Value
Publication number	US-11377456-B2
Application number	US-202117601493-A
Country	US
Kind code	B2
Filing date	May 25, 2021
Priority date	Jun 11, 2020
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

The present invention provides a novel crystalline form of remdesivir, remdesivir Form APO-I, including remdesivir and dimethyl sulfoxide, compositions and processes for the preparation thereof, the use of this crystalline form in the treatment of a viral infection, and methods of treating viral infections using the same, and in particular, a viral infection caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2).

First claim

What is claimed is:

1. A crystalline form of remdesivir comprising remdesivir and dimethyl sulfoxide.

2. The crystalline form of claim 1 , wherein the molar ratio of remdesivir to dimethyl sulfoxide ranges from approximately 1:0.75 to approximately 1:1.25.

3. The crystalline form of claim 1 , wherein the molar ratio of remdesivir to dimethyl sulfoxide is approximately 1:1.

4. A crystalline form of remdesivir comprising remdesivir and dimethyl sulfoxide characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 4.0°, 17.0° and 20.3°.

5. The crystalline form of claim 4 , further comprising at least three peaks in the PXRD diffractogram, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 10.4°, 13.0°, 14.1°, 15.3°, 17.5°, 18.3°, 22.1°, 23.9°, 25.1° and 25.9°.

6. The crystalline form of claim 4 , further comprising peaks in the PXRD diffractogram, expressed in degrees 2θ (±0.2°), at 10.4°, 13.0°, 14.1°, 15.3°, 17.5°, 18.3°, 22.1°, 23.9°, 25.1° and 25.9°.

7. The crystalline form of claim 6 , providing a PXRD diffractogram comprising peaks in substantially the same positions (±0.2° 2θ) as those shown in FIG. 1 .

8. The crystalline form of claim 4 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset at approximately 101° C. and a peak maximum at approximately 103° C.

9. The crystalline form of claim 8 , characterized by a DSC thermogram that is substantially the same in appearance as the DSC thermogram provided in FIG. 3 .

10. The crystalline form of claim 4 , wherein the molar ratio of remdesivir to dimethyl sulfoxide ranges from approximately 1:0.75 to approximately 1:1.25.

11. The crystalline form of claim 10 , wherein the molar ratio of remdesivir to dimethyl sulfoxide is approximately 1:1.

12. A process for the preparation of the crystalline form of remdesivir of claim 4 , the process comprising:
preparing a solution of remdesivir in dimethyl sulfoxide at a suitable temperature;
adding an organic anti-solvent to the solution to form a mixture;
cooling the mixture, if necessary, to form a suspension comprising remdesivir crystals containing dimethyl sulfoxide; and
isolating the remdesivir crystals from the suspension.

13. The process of claim 12 , wherein the suitable temperature ranges from approximately 60° C. to approximately 80° C.

14. The process of claim 13 , wherein the organic anti-solvent is a cyclic or acyclic alkyl ether.

15. The process of claim 14 , wherein the organic anti-solvent is methyl t-butyl ether.

16. A pharmaceutical composition comprising the crystalline form of remdesivir according to claim 4 , and one or more pharmaceutically acceptable excipients.

17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is a lyophilized composition or a solution composition.

18. A method of treating viral infection comprising administering a therapeutically effective amount of the crystalline form of remdesivir according to claim 4 to a patient in need thereof.

19. The method of claim 18 , wherein the viral infection is caused by a virus selected from the group consisting of an Arenaviridae virus, a Coronaviridae virus, a Filoviridae virus, a Flaviviridae virus, and a Paramyxoviridae virus.

20. The method of claim 18 , wherein the viral infection is caused by a virus selected from the group consisting of Lassa virus, Junin virus, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV), Ebola virus, Marburg virus, Zika virus, and Respiratory Syncytial virus (RSV).

21. The method of claim 20 , wherein the viral infection is caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2).

Assignees

• Apotex Inc

Inventors

• Souza Fabio E S
• Stirk Alexander J
• Rey Allan W

Classifications

• C07H13/12

  by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid · CPC title

• C07F9/6561 Primary

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title