DESC:DABIGATRAN ETEXILATE 1,4-BUTANEDISULFONATE SALT AND ITS CRYSTAL FORM

FIELD OF THE INVENTION

The present invention provides a 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid, its crystal form and process for its preparation.

BACKGROUND OF THE INVENTION

Dabigatran etexilate, chemically known as ß-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-, ethyl ester, is a direct thrombin inhibitor. The structural formula of dabigatran etexilate mesylate salt is
.
Dabigatran etexilate mesylate is approved by US FDA for reduction of risk of stroke and systemic embolism in non-valvular atrial fibrillation, treatment of deep venous thrombosis & pulmonary embolism and reduction in the risk of recurrence of deep venous thrombosis and pulmonary embolism.

WO 98/37075 discloses dabigatran and dabigatran etexilate base whereas its mesylate salt is disclosed in WO 03/74056. Dabigatran etexilate mesylate is known to have low solubility and hence is classified as class II drug by Biopharmaceutics Classification System (BCS).

In order to increase the solubility, various salts of dabigatran etexilate have been prepared and are reported in literature. For example WIPO applications WO 2012/044595, WO 2011/110876, WO 2008/043759, WO 2006/114415 and Chinese applications CN 103570679, CN 103539779, CN 103304602, CN 102633777 and CN 102558153 discloses various salts of dabigatran etexilate and their polymorphs. CN103864756 discloses dabigatran etexilate 1,4-butanedisulfonate salts and their polymorphs.

DESCRIPTION OF THE DRAWINGS

Figure 1: X-ray powder diffraction (XRPD) scan for crystalline Form S of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid.

Figure 2: Differential scanning calorimetry (DSC) scan for crystalline Form S of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid.

SUMMARY OF THE INVENTION

The present invention provides a 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid.

The present invention also provides a crystalline Form S of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid having an X-ray powder diffraction pattern comprising characteristic peaks at 8.2, 12.4, 20.2, 23.0 and 26.5 ± 0.2 degrees 2?.

The salt and its polymorph of the present invention have good solubility and thus have desired pharmacokinetic profile.

DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid.

In one embodiment the present invention provides crystalline Form S of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid having an X-ray powder diffraction pattern comprising characteristic peaks at 8.2, 12.4, 20.2, 23.0 and 26.5 ± 0.2 degrees 2?.

In another embodiment, the crystalline Form S has an X-ray powder diffraction pattern comprising further characteristic peaks at 18.4, 19.1, 20.6, 21.7, 23.8 and 26.5 ± 0.2 degrees 2?. The XRPD scan of the Form S of the present invention is provided in Figure 1. Table 1 provides the list of observed peaks in XRPD for the crystalline Form S.
Table 1:
Position ( º2 ?) Relative intensity Position ( º2 ?) Relative intensity
8.2 25.0 23.8 60.5
11.8 11.3 24.0 63.5
12.4 27.3 24.3 51.4
14.1 9.3 24.8 57.2
15.0 34.5 25.8 37.9
15.8 59.6 26.5 77.2
16.5 51.0 27.1 62.9
17.5 11.8 28.1 32.8
18.4 37.0 29.3 25.5
19.1 79.5 30.5 13.8
19.7 49.8 31.5 9.1
20.2 100.0 32.8 9.7
20.6 29.5 33.6 13.6
21.7 91.4 35.9 6.5
22.1 22.0 37.0 13.8
23.0 55.9 37.7 6.0
23.3 43.1 39.0 3.6
In another embodiment, the crystalline Form S of the present invention has a DSC scan comprising an endotherm in the range of 174 ºC to 177 ºC. The DSC scan of the Form S of the present invention is provided in Figure 2.

In another embodiment the present invention provides a crystalline Form S of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid having water content of less than 2 %. The water content in the crystalline salt of the present invention can be determined by the well-known technique in the art such as Karl Fischer titration method.

The crystalline salt of the present invention can be prepared by treating a solution of dabigatran etexilate in a suitable solvent with a solution of butane-1,4-disulfonic acid in an organic solvent. Preferred solvent for dissolving dabigatran etexilate is acetone. Preferred organic solvent to form solution of butane-1,4-disulfonic acid is ethyl alcohol.

Saturated solubility in water of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid is more than 100 mg/mL.

The 1:1 butanedisulfonate salt of dabigatran etexilate of the present invention have a high high performance liquid chromatoagraphy (HPLC) purity and is substantially free of impurity F (also referred as the amide impurity) of Formula II:
.

The phrase “substantially free of impurity F” as referred herein means the content of impurity F in the crystalline salt of the present invention is less than 0.5 %. Preferably, the content is less than 0.2 %. More preferably, impurity F is not detected.

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.

Examples:
Instrument details:
XRD: X-ray powder diffraction analyses were carried out on a PANalytical Empyrean X-ray powder diffractometer using Cu K alpha radiation. The instrument was equipped with a line focus X-ray tube, and the voltage and amperage were set to 45 kV and 40 mA respectively. The scanning rate was set as 10 second per step and step size is set as 0.01º.The diffractometer was equipped with Pixcel1D solid state detector and rotating sample stage. X-ray diffractometer was used to record diffractogram from 4º to 40º (2-theta).

DSC: Differential Scanning Calorimetry (DSC) analysis was performed on a TA Instruments Q2000™. Approximately 2 mg of sample was placed into a tared DSC aluminium pan and sealed hermetically. Typically, the sample was heated under nitrogen at a rate of about 10 ºC/min from about 35 ºC up to a final temperature of about 250 ºC.

Example 1: Dabigatran etexilate free base (150 g) was dissolved in acetone (2850 mL) and heated to 52 ±2 ºC. A solution of 1,4-butanedisulfonic acid (56.0 g; 1.15 eq) in ethyl alcohol (300 mL) was slowly added to the above solution at 52 ±2 ºC within 30 min. The reaction mass was cooled to 28 ±2 ºC within 30 min, stirred for 4 hours and filtered. The product was washed with acetone (150 mL) and dried in vacuum oven at 38 ±2 ºC to obtain 175 g of crystalline Form S of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid.

,CLAIMS:1. A crystalline Form S of 1:1 salt of dabigatran etexilate with 1,4-butanedisulfonic acid having an X-ray powder diffraction pattern comprising characteristic peaks at 8.2, 12.4, 20.2, 23.0 and 26.5 ± 0.2 degrees 2?.

2. The crystalline Form S as in claim 1 having an X-ray powder diffraction pattern comprising further characteristic peaks at 18.4, 19.1, 20.6, 21.7, 23.8 and 26.5 ± 0.2 degrees 2?.

3. The crystalline Form S as in claim 1 having a Differential Scanning Calorimetry scan comprising an endotherm in the range of 174 ºC to 177 ºC.

4. The crystalline Form S as in claim 1 having water content of less than 2 %.