Ledipasvir crystal form and preparation method thereof

• US 10,294,219 B2
• Filed: 06/24/2016
• Issued: 05/21/2019
• Est. Priority Date: 07/06/2015
• Status: Active Grant

• Current Assignee: Shanghai ForeFront Pharmaceutical Co., Ltd.
• Original Assignee: Shanghai ForeFront Pharmaceutical Co., Ltd.
• Inventors: Li, Wei, Ren, Yi, Huang, Chengjun, Zhu, Yanyan, Fu, Shaojun, Fu, Gang, Wei, Zhewen
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US15/741,963
• Publication Number:
  US 20180194752A1
• Time in Patent Office: 1,061 Days
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

The present invention relates to a novel Ledipasvir (LDV) crystal form and a preparation method thereof. Specifically, disclosed is an LDV solvate. The solvate is a solvate formed by LDV and a solvent A and/or a solvent B, wherein the solvent A is acetonitrile or acetone; and the solvent B is methyl tertiary butyl ether (MTBE). Also disclosed are a preparation method and an application of the solvate. The solvate has a high purity, a good crystallization property, and better optical stability. The preparation method is simple and the process is stable. The solvate can significantly improve quality control and industrial applications of LDV-containing drugs.

Claims

1. A Ledipasvir solvate, wherein which is a solvate of LDV formed with component A and component B, wherein the component A is acetonitrile or acetone, and the component B is methyl tert-butyl ether (MTBE);

and the solvate is selected from the group consisting of;

(i-1) LDV-acetonitrile-MTBE ternary solvate (crystal form A); and

(i-2) LDV-acetone-MTBE ternary solvate (crystal form B).

2. The solvate of claim 1, wherein The LDV-acetonitrile-MTBE ternary solvate has the following X-ray powder diffraction characteristic peaks:

6.7°

±

0.2°

, 8.8°

±

0.2° and

12.4°

±

0.2°

.

3. The solvate of claim 1, wherein the LDV-acetone-MTBE ternary solvate has the following X-ray powder diffraction characteristic peaks:

3.2°

±

0.2°

, 6.5°

±

0.2° and

12.2°

±

0.2°

.

4. A method for preparing the solvate of claim 1, the method comprising the steps of:

1) providing an amorphous powder of Ledipasvir, and a mixed solvent of component A and component B; and

2) mixing the amorphous powder of Ledipasvir and the mixed solvent, and crystallizing to obtain the solvate of claim 1,

wherein the component A is acetonitrile or acetone, and the component B is methyl tert-butyl ether (MTBE).

5. A method for preparing a pharmaceutical composition, the method comprising the steps of:

1) preparing a solid dispersion of Ledipasvir using the Ledipasvir solvate of claim 1 as a raw material of the active ingredient Ledipasvir;

2) mixing the solid dispersion with a pharmaceutically acceptable carrier to prepare the pharmaceutical composition.

6. A pharmaceutical composition, wherein the pharmaceutical composition comprises the solvate of claim 1 and a pharmaceutically acceptable carrier.

7. A method for treating hepatitis C comprising administering to a subject in need thereof an effective amount of the solvate of claim 1 or the pharmaceutical composition of claim 6.

8. The solvate of claim 1, wherein in the LDV-acetonitrile-MTBE ternary solvate, the molar ratio of LDV:

acetonitrile;

MTBE is about 1;

0.9-1.5;

0.7-1.2.

9. The solvate of claim 1, wherein in the LDV-acetone-MTBE ternary solvate, the molar ratio of LDV:

acetone;

MTBE is about 1;

1.2-2;

0.7-1.2.

10. The solvate of claim 1, wherein the TAG pattern of the LDV-acetonitrile-MTBE ternary solvate has a weight loss of 5.5-8% at 30-120°

C.

11. The solvate of claim 1, wherein the TAG pattern of the LDV-acetonitrile-MTBE ternary solvate has a weight loss of 3.5-5.5% at 120-200°

C.

12. The solvate of claim 1, wherein the DSC pattern of the LDV-acetonitrile-MTBE ternary solvate has a characteristic endothermic peak at 106±

5°

C.

13. The solvate of claim 1, wherein the DSC pattern of the LDV-acetonitrile-MTBE ternary solvate has a characteristic endothermic peak at 161±

5°

C.

14. The solvate of claim 1, wherein the TGA pattern of the LDV-acetone-MTBE ternary solvate has a weight loss of 9.5-11% at 30-120°

C.

15. The solvate of claim 1, wherein the TGA pattern of the LDV-acetone-MTBE ternary solvate has a weight loss of 3.5-6% at 120-200°

C.

16. The solvate of claim 1, wherein the DSC pattern of the LDV-acetone-MTBE ternary solvate has a characteristic endothermic peak at 105±

5°

C.

17. The solvate of claim 1, wherein the DSC pattern of the LDV-acetone-MTBE ternary solvate has a characteristic endothermic peak at 161±

5°

C.