Polymorphic form of (-)-cibenzoline succinate

Patent metadata

Field	Value
Publication number	US-12486237-B2
Application number	US-202117798406-A
Country	US
Kind code	B2
Filing date	Mar 26, 2021
Priority date	Mar 27, 2020
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

The present invention relates to a crystalline form of (−)-cibenzoline succinate. The present invention also provides a process for preparing (−)-cibenzoline succinate and crystalline form thereof. The crystalline form of (−)-cibenzoline succinate according to the present invention has low hygroscopicity, and excellent stability under accelerated conditions and long-term storage conditions, and may be stably maintained without a change in content thereof for a long period of time.

First claim

The invention claimed is:

1 . A crystalline form of (−)-cibenzoline succinate having an X-ray powder diffraction pattern (XRPD) selected from the group consisting of:
i) a crystalline form 1 having an X-ray powder diffraction spectrum comprising diffraction peaks at 9.7°, 14.9°, 21.5°, 23.4° and 24.1° (2θ±0.2°);
ii) a crystalline form 2 having an X-ray powder diffraction spectrum comprising diffraction peaks at 20.6°, 21.1°, 22.9°, 25.2° and 37.4° (2θ±0.2°); and
iii) a crystalline form 3 having an X-ray powder diffraction spectrum comprising diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ±0.2°).

2 . The crystalline form of (−)-cibenzoline succinate of claim 1 , which is wherein the crystalline form is anhydrous and has crystalline form 3.

3 . The crystalline form of (−)-cibenzoline succinate of claim 2 , wherein the XRPD pattern further comprises at least one diffraction peak selected from the group consisting of diffraction peaks at 9.7°, 12.8°, 14.6°, 16.1°, 16.3°, 17.5°, 19.4°, 22.4°, 22.7°, 23.5° and 25.4° (2θ±0.2°).

4 . The crystalline form of (−)-cibenzoline succinate of claim 1 , having a differential scanning calorimetry (DSC) endothermic peak at a temperature of 190° C. to 193° C. at a temperature rise rate of 10° C./min.

5 . The crystalline form of (−)-cibenzoline succinate of claim 1 , having a particle size distribution wherein 50% of the particles [D 50 ] have a particle size of 10 μm to 50 μm.

6 . The crystalline form of (−)-cibenzoline succinate of claim 1 , wherein the crystalline form comprises the following dynamic vapor sorption (DVS) pattern:
i) a water absorption rate of 0.3% in a sorption cycle;
ii) a water absorption rate of 0.2% at 80% relative humidity; and
iii) a complete release of 0.3% absorbed water in a desorption cycle.

7 . A crystalline form of (−)-cibenzoline succinate comprising a triclinic crystal system and has a space group of P1.

8 . The crystalline form of (−)-cibenzoline succinate of claim 7 , wherein the triclinic crystal system has the following lattice constant parameters:
a=7.87 (6) Å;
b=8.00 (9) Å;
C=9.36 (12) Å;
α=96.71 (5)°;
β=95.47 (7)°;
γ=118.51 (6)°;
V=507.06 (10) Å3; and
Z=+ (1)-1 (1).

9 . A process for preparing crystalline form 3 of (−)-cibenzoline succinate, comprising:
forming a solution utilizing a polar solvent to dissolve (−)-cibenzoline succinate represented by Formula (IA)

and
precipitating crystalline form 3 of (−)-cibenzoline succinate by adding a hydrocarbon solvent having 6 or more carbon atoms to the solution.

10 . The process of claim 9 , wherein the polar solvent is comprises one or more member of the group consisting of water, an alcohol-based solvent, an aldehyde-based solvent, an ester-based solvent, and an amide-based solvent.

11 . The process of claim 10 , wherein the alcohol-based solvent is comprises one or more member of the group consisting of methanol, ethanol, linear or branched propanol, linear or branched butanol, and linear or branched pentanol.

12 . The process of claim 9 , wherein the hydrocarbon solvent having 6 or more carbon atoms comprises one or more member of the group consisting of is cyclohexane, cycloheptane, n-hexane, and n-heptane.

13 . A pharmaceutical composition containing the crystalline form of (−)-cibenzoline succinate of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

14 . The pharmaceutical composition of claim 13 , comprising the form of a capsule or tablet for oral administration.

Assignees

• Celltrion Inc

Inventors

• Brugman Sander

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• C07D233/10 Primary

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring nitrogen atoms · CPC title