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Polymorphic forms of Dabigatran etexilate

IP.com Disclosure Number: IPCOM000204135D
Publication Date: 2011-Feb-14
Document File: 5 page(s) / 183K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure relates to polymorphic forms of Dabigatran etexilate.

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Polymorphic forms of Dabigatran etexilate

Dabigatran etexilate {1-methyl-2-[N-(4-(N-n-hexyloxycarbonylamidino)phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide} is a prodrug of Dabigatran {1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide}, a direct thrombin inhibitor.

The present disclosure relates to polymorphic forms of Dabigatran etexilate.

Crystallization of Dabigatran etexilate in IPA

1.83 g of Dabigatran etexilate were suspended in 22 mL of isopropyl alcohol (IPA) and the resulting mixture was heated to reflux until complete dissolution. The solution was then allowed to cool and crystallization was observed at 34-35 ºC. The suspension was agitated for about 45 minutes and filtered. The solid obtained was washed with 2 mL of cold IPA and dried under vacuum to obtain 1.53 g of the polymorphic form of Dabigatran etexilate characterized by the X-ray powder diffraction (PXRD) pattern of Figure 1 and the Differential Scanning Calorimetry (DSC) thermogram of Figure 2 (84% yield; 98.6% a/a HPLC/MS purity). No IPA was detected by 1H-NMR.

2θ (°)

d (Å)

I (%)

5.91

14.94

100

11.74

7.54

27

17.73

5.00

25

19.89

4.06

6

Figure 1. X-ray powder diffraction (PXRD) pattern and peak listing

Figure 2. Differential Scanning Calorimetry (DSC) thermogram

Crystallization of Dabigatran etexilate in ACN

49.9 mg of Dabigatran etexilate were suspended in 1.6 mL of acetonitrile (ACN) and the resulting mixture was heated to 65ºC until complete dissolution. The solution was then allowed to cool to rt and stirred for 2-3 h. The solid was filtered and dried under vacuum to obtain 41.6 mg of the polymorphic form of Dabigatran etexilate characterized by the X-ray powder diffraction (PXRD) pattern of Figure 3, the Differential Scanning Calorimetry (DSC) thermogram of Figure 4 and the thermogravimetric analysis (TGA) thermogram of Figure 5 (83% yield). No ACN was detected by 1H-NMR.

2θ (°)

d (Å)

I (%)

4.78

18.49

8

8.79

10.06

100

9.67

9.14

3

10.58

8.36

12

11.41

7.75

23

12.62

7.01

9

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