DEXRABEPRAZOLE SODIUM COMPOUND AND PHARMACEUTICAL COMPOSITION THEREOF

• US 20200216414A1
• Filed: 06/22/2018
• Published: 07/09/2020
• Est. Priority Date: 06/23/2017
• Status: Active Grant

• Current Assignee: Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Beijing Aosaikang Pharmaceutical Co., Ltd.), Nanjing Hairun Pharmaceutical Co., Ltd.
• Original Assignee: Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Beijing Aosaikang Pharmaceutical Co., Ltd.)
• Inventors: CHEN, Xiangfeng, CHEN, Hongyu, LI, Xiaoxin, PAN, Xun, SUN, Min
• Granted Patent: US 11,078,184 B2
• Time in Patent Office: 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

A dexrabeprazole sodium compound includes crystal forms B and C. The crystal form B has good stability and flowability. The crystal form C is an anhydrous crystal form and has good stability and low hygroscopicity. The crystal forms are suitable for preparing a dexrabeprazole sodium preparation.

Claims

1. A dexrabeprazole sodium compound of Formula (I),

2. The dexrabeprazole sodium compound according to claim 1, wherein the dexrabeprazole sodium compound comprises one or more of the following features:

1) having an XRPD pattern which has characteristic peaks at about 6.50±

0.2°

, 8.64±

0.2°

, 10.58±

0.2°

, 13.14±

0.2°

, 14.46±

0.2°

, 14.90±

0.2°

, 15.48±

0.2°

, 15.92±

0.2°

, 16.86±

0.2°

, 17.74±

0.2°

, 18.40±

0.2°

, 19.58±

0.2°

, 20.34±

0.2°

, 21.00±

0.2°

, 21.56±

0.2°

, 22.44±

0.2°

, 22.90±

0.2°

, 23.46±

0.2°

, and 24.04±

0.2°

;

2) having an XRPD pattern;

3) having a DSC pattern with an endothermic peak at 138±

5°

C. and exothermic peaks at about 189±

5°

C. and about 226±

5°

C.;

4) having a DSC pattern;

5) having a TGA pattern; and

6) having an IR spectrogram;

3. A method for preparing the dexrabeprazole sodium compound according to claim 1, comprising the following steps:

1) adding dexrabeprazole to an organic solvent, stirring the mixture, separating an organic layer, and concentrating the organic layer to dryness;

2) adding an alcohol solvent and an aqueous solution of sodium hydroxide to the residua, stirring the mixture for reaction; and

3) adding dropwise an anti-solvent to the reaction mixture for crystallization after completion of reaction to obtain the desired compound.

4. The method according to claim 3, comprising one or more of the following features a) to e):

a) wherein in step

     1), the organic solvent is selected from a group consisting of dichloromethane, trichloromethane, and ethyl acetate;

b) wherein in step

     2), the alcohol solvent is selected from a group consisting of isopropanol, n-propanol and n-butanol;

c) wherein in step

     3), the anti-solvent is selected from a group consisting of isopropyl ether, methyl tert-butyl ether, diethyl ether and methyl ethyl ether;

d) wherein in step

     3), after completion of reaction, the reaction mixture is first concentrated to reduce the volume, and then the anti-solvent is added dropwise; and

e) wherein in step

     3), the dropwise adding of the anti-solvent is performed at low temperature.

9. A pharmaceutical composition, comprising the dexrabeprazole sodium compound according to claim 1 and a pharmaceutically acceptable carrier.

5. A dexrabeprazole sodium compound of Formula (I), wherein the dexrabeprazole sodium compound is crystal form C, which has an XRPD pattern represented by angle 2θ

with characteristic peaks at 6.22±

0.2°

, 12.14±

0.2°

, 12.46±

0.2°

, 15.82±

0.2°

, 18.90±

0.2°

, 22.38±

0.2°

, 26.56±

0.2°

, and 28.06±

0.2°

when measured by Cu target radiation.

6. The dexrabeprazole sodium compound according to claim 5, wherein the dexrabeprazole sodium compound comprises one or more of the following features:

1) having an XRPD pattern which has characteristic peaks at 6.22±

0.2°

, 12.14±

0.2°

, 12.46±

0.2°

, 13.10±

0.2°

, 15.82±

0.2°

, 17.34±

0.2°

, 17.70±

0.2°

, 18.90±

0.2°

, 20.18±

0.2°

, 20.74±

0.2°

, 21.60±

0.2°

, 22.08±

0.2°

, 22.38±

0.2°

, 23.42±

0.2°

, 26.56±

0.2°

, 28.06±

0.2°

, and 30.80±

0.2°

;

2) having an XRPD pattern;

3) having a DSC pattern with an exothermic peak at about 234°

C.±

5°

C.;

4) having a DSC pattern;

5) having a TGA pattern; and

6) having an IR spectrogram.

7. A method for preparing the dexrabeprazole sodium compound according to claim 5, comprising the following steps:

1) dissolving dexrabeprazole sodium in methanol or ethanol, concentrating the mixture to dryness under reduced pressure, and repeating the step at least once;

2) adding acetonitrile to the residue obtained in step

     1), stirring and concentrating the mixture to dryness under reduced pressure; and

3) adding a solvent toluene or xylene to the residue obtained in step

     2), and stirring the mixture for crystallization to obtain the desired compound.

8. The method according to claim 7, comprising one or more of the following features a) to c):

a) wherein in step

     1), the dexrabeprazole sodium is dissolved in methanol;

b) wherein in step

     1), the step is repeated for one to six times; and

c) wherein in step

     3), the stirring the mixture for crystallization is performed under inert gas protection.

10. (canceled)