CRYSTALLINE COMPOUNDS OF DABIGATRAN ETEXILATE

Abstract

The present invention relates to new crystalline compounds of dabigatran etexilate, namely to crystalline compounds comprising mixtures of dabigatran etexilate and an acid. The invention also relates to processes for the preparation of the new crystalline compounds, pharmaceutical compositions comprising them and their use in therapy.

Description

SUMMARY OF THE INVENTION

The present invention relates to new crystalline compounds of dabigatran etexilate, namely to crystalline compounds comprising mixtures of dabigatran etexilate and an acid. The invention also relates to processes for the preparation of the new crystalline compounds, pharmaceutical compositions comprising them and their use in therapy.

TECHNICAL BACKGROUND

Dabigatran etexilate is the International Non Proprietary Name (INN) of 3-(((2-(((4-(N′-hexyloxicarbonyl-carbamidoyl)-phenyl)amino)methyl]-1-methyl-1H-benzimidazol-5-yl) carbonyl)-pyridin-2-yl-amino)-propionic acid ethyl ester of formula (I)

Dabigatran etexilate is an innovative anticoagulant that acts inhibiting, directly and reversibly, thrombin, either when it is free and when it is bound to fibrin. As it is known, in the coagulation cascade thrombin enables the conversion of fibrinogen to fibrin and its inhibition prevents the formation of clots.

Dabigatran etexilate has poor solubility in water and is currently marketed as its mesylate salt under the trade name Pradaxa®.

This poor solubility leads to a consequent low bioavailability and variability of drug blood levels. Not being able to overcome these serious problems, particular formulations have been designed, such as those described in US2003/0181488, but these formulations require the application of a complex technology for the preparation of laborious multilayer compositions.

It is known that solid crystalline forms of active ingredients may show different physico-chemical properties and may offer advantages for example in terms of solubility, stability and bioavailability. Thus, the research and discovery of new crystalline forms of active pharmaceutical ingredients can lead to more reliable and effective therapies.

For this reason, it is considered a technical contribution to the art the preparation of new crystalline mixtures of active ingredients, since these new forms may allow an improved stability, bioavailability and pharmacokinetics, limit the hygroscopicity, and/or facilitate the galenic and industrial processing of active pharmaceutical ingredients.

But the preparation of said new crystal forms is not obvious, it is not predictable and is not always possible.

So, also for dabigatran etexilate, it is of interest to search for new crystalline forms which exhibit chemical and physical properties suitable for a safe and effective therapeutic use and that improve the solubility.

OBJECTS OF THE INVENTION

It is an object of the invention to provide new crystalline compounds including dabigatran etexilate.

Another object of the invention to provide new crystalline compounds comprising dabigatran etexilate.

It is another object of the invention to provide new crystalline compounds comprising dabigatran etexilate, which are soluble, in particular equally or even more soluble the compound on the market, that is, dabigatran etexilate mesylate.

Another object of the invention to provide processes for the preparation of the said new crystalline compounds, pharmaceutical compositions containing them and their use in therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the XRPD of dabigatran etexilate acotinate anhydrous

FIG. 2 shows the FT-IR of dabigatran etexilate acotinate anhydrous

FIG. 3 shows the DSC of dabigatran etexilate acotinate anhydrous

FIG. 4 shows the XRPD of dabigatran etexilate adipate anhydrous

FIG. 5 shows the FT-IR of dabigatran etexilate adipate anhydrous

FIG. 6 shows the DSC of dabigatran etexilate adipate anhydrous

FIG. 7 shows the XRPD of dabigatran etexilate p-coumarate acetone solvate

FIG. 8 shows the XRPD of dabigatran etexilate p-coumarate acetone solvate

FIG. 9 shows the DSC of dabigatran etexilate p-coumarate acetone solvate

FIG. 10 shows the XRPD of dabigatran etexilate D-gluconate ethyl acetate solvate

FIG. 11 shows the FT-IR of dabigatran etexilate D-gluconate ethyl acetate solvate

FIG. 12 shows the DSC of dabigatran etexilate D-gluconate ethyl acetate solvate

FIG. 13 shows the XRPD of dabigatran etexilate α-chetoglutarate anhydrous

FIG. 14 shows the FT-IR of dabigatran etexilate α-chetoglutarate anhydrous

FIG. 15 shows the DSC of dabigatran etexilate α-chetoglutarate anhydrous

FIG. 16 shows the XRPD of dabigatran etexilate ippurate anhydrous Form A

FIG. 17 shows the FT-IR of dabigatran etexilate ippurate anhydrous Form A

FIG. 18 shows the DSC of dabigatran etexilate ippurate anhydrous Form A

FIG. 19 shows the XRPD of dabigatran etexilate itaconate hydrate

FIG. 20 shows the FT-IR of dabigatran etexilate itaconate hydrate

FIG. 21 shows the DSC of dabigatran etexilate itaconate hydrate

FIG. 22 shows the XRPD of dabigatran etexilate orotate hydrate Form B

FIG. 23 shows the FT-IR of dabigatran etexilate orotate hydrate Form B

FIG. 24 shows the DSC of dabigatran etexilate orotate hydrate Form B

FIG. 25 shows the XRPD of de dabigatran etexilate piruvate hydrate

FIG. 26 shows the FT-IR of de dabigatran etexilate piruvate hydrate

FIG. 27 shows the DSC of de dabigatran etexilate piruvate hydrate

FIG. 28 shows the XRPD of dabigatran etexilate sulfamate anhydrous

FIG. 29 shows the FT-IR of dabigatran etexilate sulfamate anhydrous

FIG. 30 shows the DSC of dabigatran etexilate sulfamate anhydrous

FIG. 31 shows the XRPD of dabigatran etexilate D-(−)-quinate anhydrous

FIG. 32 shows the FT-IR of dabigatran etexilate D-(−)-quinate anhydrous

FIG. 33 shows the DSC of dabigatran etexilate D-(−)-quinate anhydrous

FIG. 34 shows the XRPD of dabigatran etexilate ferulate anhydrous

FIG. 35 shows the FT-IR of dabigatran etexilate ferulate anhydrous

FIG. 36 shows the DSC of dabigatran etexilate ferulate anhydrous

FIG. 37 shows the XRPD of dabigatran etexilate gallate hydrate Form B

FIG. 38 shows the FT-IR of dabigatran etexilate gallate hydrate Form B

FIG. 39 shows the DSC of dabigatran etexilate gallate hydrate Form B

FIG. 40 shows the XRPD of dabigatran etexilate sebacate anhydrous

FIG. 41 shows the FT-IR of dabigatran etexilate sebacate anhydrous

FIG. 42 shows the DSC of dabigatran etexilate sebacate anhydrous

FIG. 43 shows the XRPD of dabigatran etexilate glutarate anhydrous

FIG. 44 shows the FT-IR of dabigatran etexilate glutarate anhydrous

FIG. 45 shows the DSC of dabigatran etexilate glutarate anhydrous

FIG. 46 shows the XRPD of dabigatran etexilate vanillate hydrate

FIG. 47 shows the FT-IR of dabigatran etexilate vanillate hydrate

FIG. 48 shows the DSC of dabigatran etexilate vanillate hydrate

FIG. 49 shows the XRPD of dabigatran etexilate caffeate hydrate Form A

FIG. 50 shows the FT-IR of dabigatran etexilate caffeate hydrate Form A

FIG. 51 shows the DSC of dabigatran etexilate caffeate hydrate Form A

FIG. 52 shows the XRPD of dabigatran etexilate caffeate hydrate Form B

FIG. 53 shows the XRPD of dabigatran etexilate ippurate hydrate Form B

FIG. 54 shows the XRPD of dabigatran etexilate gallate monohydrate Form A

FIG. 55 shows the FT-IR of dabigatran etexilate gallate monohydrate Form A

FIG. 56 shows the XRPD of dabigatran etexilate orotate anhydrous Form A

FIG. 57 shows the FT-IR of dabigatran etexilate orotate anhydrous Form A

FIG. 58 shows the kinetic dissolution of representative compounds of the invention (MES=mesylate salt; ORA=orotate salt; GLC=gallate salt; of dabigatran).

DESCRIPTION OF THE INVENTION

It has now been found that it is possible to obtain new mixtures of compounds comprising dabigatran etexilate in a crystalline form.

In particular, it was found that certain mixtures of dabigatran etexilate with acids occur in a stable crystalline form and show chemical-physical properties suitable to their use in therapy. Some of these mixtures are crystal were also shown to be more soluble of the known compounds of dabigatran etexilate, in particular of its mesylate salt.

Thus, according to one of its aspects, the invention relates to a crystalline compound that comprises a mixture of dabigatran etexilate and a monocarboxylic acid selected from gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid and vanillic acid, as well as hydrates and solvates thereof.

The crystalline compound which includes dabigatran etexilate and gallic acid is particularly preferred according to the invention.

The crystalline compound that includes dabigatran etexilate and orotic acid is also preferred according to the invention.

According to another of its aspects, the invention relates to a crystalline compound that comprises a mixture of dabigatran etexilate and an acid selected from aconitic acid, adipic acid, D-gluconic acid, α-cheto-glutaric acid, itaconic acid, pyruvic acid acid, sulfamic acid, D-quinico, sebacic acid, and glutaric acid, as well as hydrates and solvates thereof.

The anhydrous crystalline compounds as well as hydrates or solvates of all the above crystalline compounds, with water or other solvents, are a further subject-matter of the invention.

According to the present invention, the starting dabigatran etexilate may be dabigatran etexilate or a hydrated form of dabigatran etexilate preferably, but not necessary, dabigatran etexilate tetrahydrate.

By “crystalline compound” is meant here to indicate a mixture of dabigatran etexilate with one of the acids mentioned above, here also called “co-former”, said mixture having a crystalline form identifiable by X-ray diffraction.

The stoichiometry between the two components of the crystalline mixtures depends on the co-former used and/or the conditions of the process used.

According to another preferred embodiment, the invention relates to a crystalline compound dabigatran etexilate with gallic acid having the following formula

advantageously monohydrate gallate dabigatran etexilate.

According to a preferred embodiment, the invention relates to a crystalline salt or a co-crystal of dabigatran etexilate with orotic acid having the following formula

advantageously the anhydrous orotate dabigatran etexilate.

Gallate dabigatran etexilate, especially in the monohydrate form, which has a molar ratio of gallic acid/dabigatran equal to 1/1 is particularly preferred according to the invention, however, other molar ratios, for example 2/1 are however comprised within the scope of protection of the invention, as well as hydrates and solvates thereof.

Orotate dabigatran etexilate, especially in the anhydrous form, which has a molar ratio orotic acid/dabigatran equal to 1/1 is particularly preferred according to the invention, however, other molar ratios, for example 4/1 are however comprised within the scope of protection of the invention, as well as hydrates and solvates thereof.

Other crystalline compounds preferred according to the invention are selected from

• • anhydrous dabigatran etexilate aconitate;
  • anhydrous dabigatran etexilate adipate;
  • dabigatran etexilate p-cumarate acetone solvate;
  • dabigatran etexilate ethyl D-gluconate acetate solvate;
  • anhydrous α-keto-glutarate dabigatran etexilate;
  • anhydrous dabigatran etexilate hippurate;
  • dabigatran etexilate hydrate itaconate;
  • dabigatran etexilate hydrate pyruvate;
  • anhydrous sulfamate dabigatran etexilate;
  • anhydrous D-(−)-quinate dabigatran etexilate;
  • anhydrous dabigatran etexilate ferulate;
  • anhydrous dabigatran etexilate sebacate;
  • anhydrous dabigatran etexilate glutarate;
  • dabigatran etexilate vanillate hydrate.

According to a preferred embodiment, the invention relates to anhydrous dabigatran etexilate aconitate showing the X-ray diffraction pattern of FIG. 1, the FT-IR spectrum of FIG. 2, the DSC profile of FIG. 3 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.5279	4387.75	0.2676	19.51594	100.00
8.3705	53.70	0.2007	10.56349	1.22
9.1819	63.75	0.4015	9.63171	1.45
11.3508	64.32	0.2676	7.79570	1.47
12.3592	81.41	0.2676	7.16182	1.86
13.4728	143.63	0.2676	6.57224	3.27
14.3707	74.75	0.2676	6.16358	1.70
15.6869	159.86	0.4015	5.64926	3.64
17.6400	71.98	0.3346	5.02792	1.64
18.3618	120.84	0.1004	4.83189	2.75
19.0655	99.85	0.1004	4.65509	2.28
19.6087	26.60	0.5353	4.52736	0.61
20.1616	30.70	0.2676	4.40444	0.70
21.5204	86.93	0.2007	4.12931	1.98
24.4349	100.34	0.3346	3.64298	2.29
25.7230	71.29	0.4015	3.46341	1.62
27.1615	31.50	0.4684	3.28316	0.72
28.8396	15.58	0.8029	3.09583	0.36

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate adipate showing the X-ray diffraction pattern of FIG. 4, the FT-IR spectrum of FIG. 5, the DSC profile of FIG. 6 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
3.9026	150.46	0.2007	22.64148	3.93
6.0261	414.89	0.2342	14.66691	10.85
6.9935	406.28	0.1673	12.64003	10.63
7.4307	506.28	0.2007	11.89723	13.24
8.4609	1157.63	0.1004	10.45078	30.28
9.1792	1733.06	0.1506	9.63455	45.33
11.0139	973.88	0.1004	8.03338	25.47
11.8511	346.29	0.2007	7.46770	9.06
12.5035	670.38	0.3346	7.07948	17.53
13.9430	477.80	0.2342	6.35168	12.50
14.9901	547.77	0.0669	5.91027	14.33
15.9406	549.92	0.2676	5.55991	14.38
16.8429	472.77	0.2342	5.26404	12.36
17.4839	1640.48	0.0836	5.07246	42.90
18.0211	611.87	0.1004	4.92245	16.00
18.3486	679.63	0.1673	4.83533	17.77
19.0043	163.83	0.2007	4.66996	4.28
19.5662	1113.06	0.1673	4.53708	29.11
20.8014	1064.49	0.0669	4.27039	27.84
21.5729	3823.59	0.1673	4.11938	100.00
22.4527	187.42	0.1171	3.95991	4.90
23.5033	448.61	0.1004	3.78522	11.73
24.2210	968.18	0.1338	3.67467	25.32
24.8065	313.61	0.1338	3.58925	8.20
25.2475	469.32	0.1004	3.52754	12.27
26.0293	596.44	0.0836	3.42335	15.60
27.4276	351.40	0.2007	3.25191	9.19
27.8841	469.49	0.0836	3.19970	12.28
28.5841	110.10	0.1338	3.12292	2.88
29.5458	71.29	0.2342	3.02342	1.86
30.0984	80.71	0.1338	2.96915	2.11
30.8098	73.14	0.1673	2.90220	1.91
32.1040	26.38	0.2676	2.78810	0.69
32.9513	47.00	0.1673	2.71832	1.23
33.8588	51.97	0.3346	2.64751	1.36
34.7580	70.10	0.1338	2.58105	1.83
36.4467	31.27	0.4015	2.46524	0.82
37.1413	28.67	0.1673	2.42072	0.75
37.6967	29.59	0.2676	2.38632	0.77
39.1255	39.10	0.2007	2.30241	1.02

According to another preferred embodiment, the invention relates to dabigatran etexilate coumarate acetone solvate showing the X-ray diffraction pattern of FIG. 7, the FT-IR spectrum of FIG. 8, the DSC profile of FIG. 9 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.7376	7748.40	0.1673	18.65248	100.00
6.4860	315.03	0.1673	13.62788	4.07
6.6605	248.22	0.0502	13.27126	3.20
9.3152	1014.64	0.1171	9.49423	13.09
9.4677	860.22	0.1171	9.34161	11.10
10.4486	516.41	0.0669	8.46672	6.66
13.3185	15.58	0.2007	6.64807	0.20
13.9559	133.77	0.1004	6.34581	1.73
14.1509	161.73	0.1004	6.25882	2.09
14.4436	61.87	0.1338	6.13263	0.80
14.8566	34.91	0.2007	5.96306	0.45
15.4795	25.17	0.2342	5.72449	0.32
16.1435	236.87	0.1171	5.49051	3.06
16.8329	144.43	0.1338	5.26716	1.86
17.1197	98.05	0.0836	5.17956	1.27
18.1154	167.24	0.1673	4.89705	2.16
18.5986	118.58	0.0502	4.77089	1.53
18.8826	121.47	0.1338	4.69978	1.57
19.5233	139.21	0.1338	4.54695	1.80
20.1805	394.79	0.1506	4.40035	5.10
20.6925	298.84	0.1338	4.29261	3.86
20.9051	256.20	0.1004	4.24943	3.31
21.2455	184.48	0.1171	4.18211	2.38
22.5040	164.56	0.1171	3.95100	2.12
23.0773	104.95	0.1673	3.85413	1.35
23.7460	525.55	0.1171	3.74709	6.78
24.0019	430.44	0.1004	3.70771	5.56
24.6941	187.16	0.1673	3.60533	2.42
25.1872	153.78	0.2007	3.53585	1.98
25.5792	143.62	0.1673	3.48254	1.85
27.7398	109.52	0.0836	3.21602	1.41
28.4302	45.02	0.4015	3.13947	0.58
29.4516	22.06	0.2007	3.03288	0.28
31.1630	16.11	0.3346	2.87011	0.21
31.9226	17.67	0.2007	2.80353	0.23
37.2617	22.05	0.2007	2.41318	0.28
37.7099	25.85	0.2007	2.38552	0.33

According to another preferred embodiment, the invention relates to dabigatran etexilate gluconate acetate solvate showing the X-ray diffraction pattern of FIG. 10, the FT-IR spectrum of FIG. 11, the DSC profile of FIG. 12 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.0512	2072.30	0.1171	21.81095	100.00
4.1866	1796.54	0.0836	21.10581	86.69
8.6693	100.07	0.4684	10.20005	4.83
9.6597	60.32	0.4015	9.15635	2.91
12.1762	59.78	0.2676	7.26907	2.88
16.2940	134.87	0.2676	5.44011	6.51
16.9028	222.13	0.4684	5.24553	10.72
19.0274	140.10	0.3346	4.66433	6.76
20.6159	27.12	0.5353	4.30837	1.31
26.7452	45.99	0.6691	3.33331	2.22
28.7621	28.78	0.6691	3.10399	1.39

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate α-ketoglutarate showing the X-ray diffraction pattern of FIG. 13, the FT-IR spectrum of FIG. 14, the DSC profile of FIG. 15 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
3.9837	426.54	0.1338	22.18053	10.21
4.9531	4178.95	0.1673	17.84149	100.00
7.0434	46.06	0.2007	12.55057	1.10
9.0460	31.96	0.4015	9.77616	0.76
9.8424	60.97	0.2007	8.98676	1.46
14.8935	40.87	0.2676	5.94836	0.98
17.6977	19.41	0.8029	5.01168	0.46
21.3215	5.99	0.8029	4.16738	0.14
24.8289	38.69	0.2007	3.58605	0.93
27.5037	16.97	0.5353	3.24309	0.41

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate ippurate, Form A, showing the X-ray diffraction pattern of FIG. 16, the FT-IR spectrum of FIG. 17, the DSC profile of FIG. 18 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.5086	4375.81	0.1673	19.59932	100.00
7.9552	175.93	0.3346	11.11391	4.02
8.9753	838.61	0.1338	9.85298	19.16
10.4990	74.99	0.1004	8.42619	1.71
10.9475	59.51	0.1673	8.08197	1.36
11.9073	83.82	0.1004	7.43260	1.92
12.3957	80.64	0.1338	7.14084	1.84
13.0846	203.85	0.1171	6.76634	4.66
13.9190	451.18	0.1506	6.36256	10.31
14.7250	131.51	0.2007	6.01607	3.01
15.2232	160.96	0.1673	5.82030	3.68
15.8594	402.35	0.0669	5.58821	9.19
16.8446	97.23	0.1673	5.26352	2.22
17.2683	84.82	0.2007	5.13531	1.94
17.8375	95.09	0.1338	4.97270	2.17
18.1851	135.87	0.2007	4.87844	3.11
19.6391	85.21	0.1338	4.52042	1.95
20.1453	164.69	0.2342	4.40796	3.76
20.8911	232.68	0.0669	4.25225	5.32
21.5942	387.09	0.0836	4.11537	8.85
21.9641	482.52	0.1004	4.04689	11.03
22.3824	121.39	0.1338	3.97218	2.77
23.5171	92.09	0.2007	3.78304	2.10
23.9283	80.77	0.1338	3.71895	1.85
24.6395	313.76	0.2676	3.61319	7.17
26.2085	55.18	0.5353	3.40034	1.26
26.4820	81.36	0.1004	3.36584	1.86
27.9185	130.26	0.1338	3.19583	2.98
31.6045	4.43	0.5353	2.83101	0.10
35.0282	10.93	0.4015	2.56176	0.25
36.1184	13.30	0.2676	2.48690	0.30

According to another preferred embodiment, the invention relates to dabigatran etexilate hippurate, Form B, obtained by vapour digestion, showing the X-ray diffraction pattern of FIG. 53, and following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.3416	5685.21	0.1673	20.35270	100.00
7.4845	542.10	0.1171	11.81183	9.54
8.0593	754.28	0.2007	10.97070	13.27
8.6386	521.72	0.2342	10.23627	9.18
9.1840	285.99	0.1673	9.62950	5.03
10.5097	280.73	0.2007	8.41766	4.94
11.0636	103.41	0.2342	7.99739	1.82
12.3178	284.09	0.3011	7.18581	5.00
13.9061	1163.91	0.1171	6.36846	20.47
14.9584	755.51	0.1004	5.92273	13.29
16.0965	302.74	0.1673	5.50643	5.33
16.6933	243.25	0.3680	5.31090	4.28
17.7250	192.58	0.1673	5.00401	3.39
18.3204	478.17	0.2342	4.84270	8.41
19.0641	71.70	0.2676	4.65542	1.26
20.8941	236.86	0.2007	4.25165	4.17
21.7590	1415.43	0.1506	4.08456	24.90
23.8244	268.98	0.1338	3.73494	4.73
24.9454	189.38	0.4015	3.56957	3.33
26.5028	152.53	0.2342	3.36325	2.68
28.0346	134.42	0.4015	3.18286	2.36
28.9580	116.40	0.4015	3.08344	2.05
30.2562	39.45	0.5353	2.95403	0.69

According to another preferred embodiment, the invention relates to dabigatran etexilate itaconate hydrate showing the X-ray diffraction pattern of FIG. 19, the FT-IR spectrum of FIG. 20, the DSC profile of FIG. 21 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
3.8775	601.91	0.1840	22.78769	8.76
4.7549	6867.64	0.1338	18.58473	100.00
4.9074	6681.57	0.1673	18.00761	97.29
7.0357	212.65	0.1673	12.56435	3.10
7.6675	76.37	0.2007	11.53029	1.11
8.8006	185.41	0.1338	10.04812	2.70
9.4291	300.57	0.1171	9.37980	4.38
9.7575	213.86	0.1673	9.06475	3.11
10.7474	49.32	0.2676	8.23197	0.72
13.1860	420.30	0.1171	6.71456	6.12
14.0812	221.37	0.2007	6.28961	3.22
14.6308	314.69	0.2342	6.05460	4.58
15.2869	115.06	0.1673	5.79618	1.68
15.8038	65.59	0.1338	5.60774	0.96
16.6059	150.09	0.1004	5.33863	2.19
17.5283	294.47	0.0836	5.05971	4.29
17.9850	403.22	0.1673	4.93225	5.87
18.3208	305.67	0.2007	4.84260	4.45
19.2574	308.53	0.1673	4.60913	4.49
21.4051	141.57	0.1673	4.15129	2.06
22.6621	98.46	0.1338	3.92380	1.43
23.3927	95.25	0.1171	3.80287	1.39

According to another preferred embodiment, the invention relates to dabigatran etexilate orotate hydrate Form B (ratio dabigatran/orotate 1/4) showing the X-ray diffraction pattern of FIG. 22, the FT-IR spectrum of FIG. 23, the DSC profile of FIG. 24 and the following characteristics of X-ray:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
3.7023	131.45	0.2676	23.86592	2.90
4.9437	4535.80	0.2007	17.87549	100.00
7.1173	92.88	0.2676	12.42042	2.05
9.0366	191.03	0.2007	9.78630	4.21
9.6897	135.01	0.1338	9.12811	2.98
10.1967	438.24	0.1840	8.67527	9.66
10.9491	176.69	0.1673	8.08079	3.90
12.0068	162.28	0.2342	7.37121	3.58
13.0267	194.81	0.2342	6.79633	4.29
13.5286	1106.52	0.0669	6.54527	24.40
13.6197	1255.21	0.1171	6.50171	27.67
14.5138	1813.50	0.2007	6.10312	39.98
16.0484	537.15	0.0669	5.52281	11.84
16.9681	229.02	0.1338	5.22548	5.05
17.4938	527.50	0.1673	5.06964	11.63
18.5263	1419.37	0.2007	4.78934	31.29
19.3994	98.49	0.1673	4.57571	2.17
19.7933	47.18	0.1673	4.48554	1.04
20.5322	316.18	0.1673	4.32576	6.97
20.8923	618.15	0.1338	4.25200	13.63
21.2837	1010.92	0.1840	4.17469	22.29
21.9983	118.03	0.2342	4.04067	2.60
22.7673	392.96	0.0836	3.90590	8.66
23.6123	404.40	0.0669	3.76801	8.92
24.1059	685.67	0.0836	3.69196	15.12
24.7860	214.25	0.2676	3.59216	4.72
25.1731	411.67	0.1338	3.53780	9.08
25.3327	594.33	0.1004	3.51587	13.10
25.6858	579.80	0.1506	3.46833	12.78
26.1302	158.57	0.2007	3.41036	3.50
26.8105	216.83	0.2007	3.32535	4.78
27.1097	433.11	0.0836	3.28932	9.55
27.8621	169.00	0.2007	3.20217	3.73
28.3625	239.97	0.1338	3.14681	5.29
28.7867	977.27	0.1004	3.10139	21.55
30.6844	114.31	0.2007	2.91378	2.52
31.2736	112.79	0.1673	2.86021	2.49
32.1023	38.97	0.2007	2.78825	0.86
33.4696	49.08	0.2676	2.67740	1.08
33.9991	93.88	0.1338	2.63690	2.07
36.8877	25.25	0.2007	2.43678	0.56
38.2121	65.18	0.2676	2.35532	1.44

According to another preferred embodiment, the invention relates to dabigatran etexilate pyruvate hydrate showing the X-ray diffraction pattern of FIG. 25, the FT-IR spectrum of FIG. 26, the DSC profile of FIG. 27 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.0081	486.90	0.1338	22.04569	12.99
4.7132	3265.56	0.1004	18.74892	87.14
5.1331	3747.48	0.1840	17.21608	100.00
7.0593	61.56	0.1171	12.52226	1.64
7.9185	48.91	0.2007	11.16547	1.31
9.0008	160.40	0.3011	9.82509	4.28
9.4487	81.56	0.2342	9.36032	2.18
10.2235	74.07	0.2007	8.65264	1.98
11.5114	24.47	0.4015	7.68733	0.65
12.6126	86.12	0.2342	7.01847	2.30
13.4166	168.07	0.2007	6.59964	4.48
14.0523	94.42	0.2007	6.30252	2.52
15.3464	194.95	0.2007	5.77384	5.20
15.7826	222.79	0.1673	5.61523	5.95
16.3694	71.78	0.2676	5.41521	1.92
18.0767	135.57	0.2007	4.90743	3.62
19.2087	180.42	0.2007	4.62072	4.81
20.5116	51.75	0.2007	4.33006	1.38
21.5201	60.69	0.2007	4.12937	1.62
24.5712	24.25	0.3346	3.62308	0.65
27.0835	25.25	0.4015	3.29243	0.67

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate sulfamate showing the X-ray diffraction pattern of FIG. 28, the FT-IR spectrum of FIG. 29, the DSC profile of FIG. 30 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.7063	2957.15	0.2175	18.77650	100.00
9.2070	221.81	0.2007	9.60550	7.50
9.7890	64.16	0.1338	9.03566	2.17
10.5058	1110.05	0.2007	8.42075	37.54
11.2031	248.05	0.1004	7.89816	8.39
12.0391	62.66	0.1004	7.35154	2.12
12.4627	71.13	0.0836	7.10260	2.41
12.8573	143.02	0.1338	6.88544	4.84
13.2387	279.44	0.1338	6.68796	9.45
13.4302	367.57	0.1673	6.59301	12.43
13.8175	270.63	0.1673	6.40906	9.15
14.4198	77.77	0.1338	6.14271	2.63
14.8067	241.60	0.1171	5.98304	8.17
16.1079	73.06	0.1338	5.50256	2.47
16.6399	305.60	0.0669	5.32780	10.33
17.1879	140.20	0.1673	5.15915	4.74
17.7887	466.85	0.1506	4.98625	15.79
18.5684	923.75	0.1004	4.77859	31.24
19.4945	276.81	0.1338	4.55362	9.36
20.6216	601.93	0.1171	4.30720	20.36
21.2288	788.73	0.1673	4.18536	26.67
21.8407	372.02	0.1004	4.06947	12.58
22.4146	185.46	0.1338	3.96655	6.27
23.1307	229.96	0.1004	3.84535	7.78
23.4961	275.25	0.0669	3.78637	9.31
23.7882	366.83	0.1004	3.74053	12.40
25.0434	362.01	0.1004	3.55582	12.24
25.8087	191.90	0.0669	3.45210	6.49
26.4646	50.79	0.1673	3.36801	1.72
27.4987	326.77	0.1338	3.24367	11.05
27.8064	125.41	0.1004	3.20846	4.24
28.5967	177.20	0.1338	3.12157	5.99
29.6135	189.59	0.1673	3.01666	6.41
31.4741	49.84	0.3346	2.84245	1.69
32.4424	40.64	0.1338	2.75979	1.37
33.7762	40.43	0.1673	2.65380	1.37
34.5849	60.41	0.1004	2.59357	2.04
36.5442	22.50	0.2676	2.45889	0.76
37.5209	22.62	0.3346	2.39710	0.76
38.5171	21.35	0.4015	2.33736	0.72

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate D-(−)-quinate showing the X-ray diffraction pattern of FIG. 31, the FT-IR spectrum of FIG. 32, the DSC profile of FIG. 33 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
3.3667	9808.05	0.2007	26.24396	100.00
4.3670	757.67	0.3011	20.23460	7.72
6.5806	55.22	0.4015	13.43211	0.56
8.2317	88.88	0.2007	10.74129	0.91
9.0439	60.06	0.4015	9.77841	0.61
9.8218	56.84	0.2676	9.00562	0.58
11.4402	123.46	0.2007	7.73497	1.26
12.5173	75.13	0.2007	7.07170	0.77
13.0094	183.26	0.1673	6.80530	1.87
15.1401	124.93	0.1004	5.85204	1.27
15.5147	205.60	0.0669	5.71156	2.10
16.1169	403.23	0.1506	5.49950	4.11
16.8284	320.06	0.1338	5.26855	3.26
18.8733	250.39	0.1338	4.70207	2.55
19.0128	264.20	0.0669	4.66788	2.69
19.5538	132.00	0.2342	4.53994	1.35
20.2053	94.06	0.3346	4.39501	0.96
21.0493	381.34	0.0669	4.22064	3.89
23.2960	255.73	0.1171	3.81844	2.61
26.1298	105.39	0.3346	3.41040	1.07
27.6471	49.35	0.1673	3.22659	0.50
29.4563	17.74	0.4015	3.03241	0.18
32.6878	53.63	0.1338	2.73963	0.55
35.5378	24.31	0.2007	2.52618	0.25
37.1100	23.51	0.2007	2.42270	0.24
39.7022	130.29	0.0836	2.27029	1.33

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate ferulate showing the X-ray diffraction pattern of FIG. 34, the FT-IR spectrum of FIG. 35, the DSC profile of FIG. 36 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.9329	387.74	0.0836	17.91430	12.69
5.9904	74.95	0.1673	14.75409	2.45
8.6395	1460.10	0.1673	10.23515	47.78
8.9097	291.99	0.1004	9.92536	9.56
9.7773	533.53	0.1673	9.04650	17.46
11.2414	93.26	0.1673	7.87134	3.05
11.8889	760.20	0.1673	7.44404	24.88
12.8069	201.01	0.1004	6.91244	6.58
13.4916	929.06	0.1338	6.56316	30.40
13.9104	1999.65	0.1506	6.36645	65.44
15.1067	297.69	0.2342	5.86489	9.74
15.7094	671.68	0.1840	5.64121	21.98
16.0783	697.52	0.1506	5.51262	22.83
16.5740	179.50	0.1338	5.34884	5.87
16.8904	863.22	0.1171	5.24935	28.25
17.3224	861.62	0.0836	5.11941	28.20
17.8213	1618.18	0.2007	4.97720	52.95
18.5616	297.69	0.1673	4.78031	9.74
19.5157	1558.99	0.1840	4.54871	51.02
19.9169	1544.83	0.2175	4.45799	50.55
20.4936	625.48	0.1171	4.33382	20.47
20.8817	908.83	0.0836	4.25415	29.74
21.3390	3055.78	0.1673	4.16399	100.00
21.9828	262.95	0.0669	4.04349	8.61
22.5119	661.09	0.1506	3.94962	21.63
23.3423	649.91	0.1673	3.81096	21.27
23.8209	485.00	0.2342	3.73548	15.87
24.1601	344.10	0.1338	3.68379	11.26
25.0031	622.77	0.1673	3.56147	20.38
25.3961	636.44	0.0836	3.50724	20.83
26.7489	593.83	0.2342	3.33286	19.43
27.0713	407.44	0.2007	3.29390	13.33
28.0148	488.71	0.1171	3.18507	15.99
28.1939	291.32	0.1673	3.16524	9.53
29.0287	143.40	0.4015	3.07609	4.69
31.1498	107.11	0.3346	2.87130	3.51
31.6269	129.25	0.1673	2.82906	4.23
32.6074	265.91	0.0669	2.74620	8.70
33.1258	147.43	0.2007	2.70440	4.82
34.6037	32.23	0.2007	2.59221	1.05
35.3813	38.03	0.2342	2.53700	1.24
36.6945	94.46	0.1673	2.44916	3.09
37.2141	94.51	0.1338	2.41615	3.09
37.7469	53.73	0.1673	2.38327	1.76
39.1771	61.73	0.3346	2.29950	2.02

According to another preferred embodiment, the invention relates to dabigatran etexilate gallate hydrate Form B (ratio dabigatran/gallate 1/2) showing the X-ray diffraction pattern of FIG. 37, the FT-IR spectrum of FIG. 38, the DSC profile of FIG. 39 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
6.8617	185.59	0.1673	12.88250	72.12
10.4424	257.32	0.1338	8.47172	100.00
13.2774	76.22	0.2007	6.66854	29.62
14.1407	145.14	0.4015	6.26330	56.40
16.3580	25.94	0.4015	5.41898	10.08
17.6399	21.69	0.9368	5.02797	8.43
24.7258	32.64	0.3346	3.60077	12.68
25.3863	124.24	0.1004	3.50857	48.28
26.4163	82.51	0.1673	3.37406	32.06
27.6649	35.97	0.2676	3.22455	13.98

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate sebacate showing the X-ray diffraction pattern of FIG. 40, the FT-IR spectrum of FIG. 41, the DSC profile of FIG. 42 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.2236	54.70	0.3346	20.92105	7.07
6.6588	192.74	0.2007	13.27463	24.92
8.1342	208.74	0.2007	10.86984	26.99
9.2622	85.79	0.2676	9.54837	11.09
10.6376	314.17	0.1004	8.31673	40.62
12.2754	196.00	0.3011	7.21053	25.34
13.2778	127.08	0.3346	6.66835	16.43
15.8470	341.27	0.0836	5.59256	44.13
16.0051	254.39	0.1004	5.53765	32.89
16.5680	71.64	0.2676	5.35077	9.26
18.5242	303.30	0.2007	4.78990	39.22
19.4438	80.32	0.2342	4.56537	10.39
20.2156	95.11	0.3346	4.39279	12.30
21.3023	773.40	0.1171	4.17108	100.00
22.1502	488.15	0.1673	4.01330	63.12
22.4667	294.00	0.1673	3.95747	38.01
24.6341	64.43	0.2007	3.61397	8.33
25.4078	60.30	0.2676	3.50566	7.80
26.7016	63.75	0.3011	3.33865	8.24
27.8367	31.21	0.2676	3.20504	4.04
29.7420	10.00	0.8029	3.00392	1.29
32.4348	13.09	0.4015	2.76042	1.69

According to another preferred embodiment, the invention relates to anhydrous dabigatran etexilate glutarate showing the X-ray diffraction pattern of FIG. 43, the FT-IR spectrum of FIG. 44, the DSC profile of FIG. 45 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.1215	105.31	0.2007	21.43951	21.54
6.6703	162.11	0.4015	13.25165	33.16
7.4386	195.17	0.2007	11.88462	39.92
8.6000	253.01	0.2342	10.28202	51.75
9.9574	60.83	0.2007	8.88322	12.44
11.8067	73.53	0.2007	7.49567	15.04
12.4282	137.54	0.1004	7.12219	28.13
12.8757	68.75	0.2676	6.87565	14.06
13.5268	107.23	0.3346	6.54617	21.93
14.7442	233.69	0.1673	6.00826	47.80
15.0860	130.72	0.1338	5.87289	26.74
15.5039	333.55	0.0836	5.71555	68.22
15.7778	154.57	0.1004	5.61693	31.62
16.4662	61.58	0.2007	5.38362	12.60
17.4204	224.95	0.1673	5.09083	46.01
17.7474	212.58	0.1004	4.99774	43.48
18.0320	391.17	0.0836	4.91950	80.01
18.6097	212.41	0.1673	4.76808	43.45
19.0538	488.89	0.1004	4.65794	100.00
19.6893	280.41	0.1004	4.50899	57.36
20.3462	111.50	0.1338	4.36488	22.81
20.9498	253.02	0.0836	4.24047	51.75
21.5078	172.94	0.1004	4.13170	35.37
21.7500	247.38	0.1004	4.08623	50.60
22.7288	315.20	0.1338	3.91242	64.47
23.1474	191.51	0.1338	3.84262	39.17
23.6366	222.51	0.1338	3.76418	45.51
24.0209	238.70	0.1004	3.70483	48.82
24.8526	202.63	0.1673	3.58270	41.45
25.6481	103.89	0.2007	3.47335	21.25
26.6562	112.62	0.1673	3.34424	23.04
28.7702	100.36	0.1171	3.10313	20.53
30.1338	66.08	0.4015	2.96575	13.52
31.7524	42.01	0.3346	2.81816	8.59
32.5936	9.22	0.2007	2.74733	1.89
34.4040	20.97	0.5353	2.60679	4.29
35.2249	25.15	0.2676	2.54790	5.14
36.0670	46.09	0.2007	2.49032	9.43

According to another preferred embodiment, the invention relates to dabigatran etexilate vanillate hydrate showing the X-ray diffraction pattern of FIG. 46, the FT-IR spectrum of FIG. 47, the DSC profile of FIG. 48 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
5.2816	50.74	0.2007	16.73234	0.94
6.7436	5423.85	0.2007	13.10776	100.00
9.0857	140.12	0.1673	9.73347	2.58
10.3175	489.93	0.1171	8.57400	9.03
10.9731	89.18	0.1004	8.06316	1.64
11.5976	253.82	0.1171	7.63033	4.68
12.0367	182.43	0.1004	7.35300	3.36
13.3462	578.66	0.0669	6.63434	10.67
13.8232	290.46	0.0669	6.40642	5.36
14.4398	1639.75	0.2342	6.13425	30.23
14.8237	1048.52	0.1338	5.97624	19.33
15.9067	718.91	0.1506	5.57170	13.25
17.2479	3501.87	0.2509	5.14135	64.56
17.9178	2306.53	0.0836	4.95061	42.53
18.0139	2724.40	0.1020	4.92034	50.23
18.1007	2157.84	0.0836	4.90099	39.78
19.6440	1607.43	0.2509	4.51929	29.64
20.1559	902.38	0.1673	4.40566	16.64
20.6228	671.84	0.1004	4.30696	12.39
20.9891	159.07	0.1338	4.23262	2.93
21.5416	634.36	0.1171	4.12530	11.70
22.2525	416.50	0.0836	3.99509	7.68
22.9683	1107.18	0.1004	3.87217	20.41
23.4004	1691.32	0.2175	3.80164	31.18
24.3324	479.38	0.0836	3.65809	8.84
25.4472	537.65	0.1338	3.50031	9.91
26.3185	861.57	0.1171	3.38637	15.88
27.2027	339.45	0.0669	3.27828	6.26
27.6486	51.94	0.2007	3.22641	0.96
28.2403	160.25	0.1338	3.16015	2.95
29.0257	425.95	0.3346	3.07640	7.85
29.6525	150.84	0.1673	3.01279	2.78
30.2465	319.55	0.1004	2.95495	5.89
30.6759	146.84	0.1338	2.91457	2.71
30.9967	306.32	0.1673	2.88513	5.65
31.4162	312.31	0.1171	2.84756	5.76
32.0217	274.83	0.1004	2.79508	5.07
32.2239	388.44	0.1673	2.77800	7.16
33.2056	71.32	0.1840	2.69808	1.32
33.5616	65.47	0.2007	2.67027	1.21
34.6642	125.37	0.1338	2.58782	2.31
36.0577	106.84	0.1673	2.49095	1.97
36.4106	287.17	0.0836	2.46761	5.29
36.8854	80.47	0.2007	2.43693	1.48
38.3514	42.58	0.1004	2.34708	0.79
38.6773	43.98	0.2007	2.32805	0.81

According to another preferred embodiment, the invention relates to dabigatran etexilate caffeate hydrate, form A, showing the X-ray diffraction pattern of FIG. 49, the FT-IR spectrum of FIG. 50, the DSC profile of FIG. 51 and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.6953	2099.82	0.1171	18.82044	100.00
7.2873	90.28	0.1673	12.13105	4.30
9.3340	73.95	0.2676	9.47509	3.52
10.9596	106.44	0.2007	8.07308	5.07
13.0804	255.55	0.2342	6.76854	12.17
13.9968	259.82	0.2342	6.32736	12.37
15.7906	30.56	0.3346	5.61239	1.46
16.8777	101.23	0.1673	5.25328	4.82
18.2239	338.07	0.1840	4.86813	16.10
20.9374	254.90	0.0669	4.24296	12.14
21.8646	37.52	0.2676	4.06507	1.79
23.5153	187.93	0.0669	3.78333	8.95
25.1838	61.12	0.1673	3.53632	2.91
26.9983	119.09	0.3011	3.30264	5.67
27.7483	27.92	0.4015	3.21505	1.33
29.2657	22.12	0.4015	3.05171	1.05

According to another preferred embodiment, the invention relates to dabigatran etexilate caffeate, Form B, obtained by vapour digestion, showing the X-ray diffraction pattern of FIG. 52, and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.5089	640.36	0.2342	19.59794	74.43
8.7131	173.20	0.3346	10.14881	20.13
11.3042	249.77	0.2007	7.82777	29.03
11.8302	215.77	0.2676	7.48085	25.08
12.9279	518.68	0.2342	6.84802	60.29
15.6350	73.19	0.4015	5.66789	8.51
17.1947	348.64	0.2676	5.15712	40.52
17.5288	391.63	0.2007	5.05957	45.52
18.6773	316.33	0.3346	4.75097	36.77
20.4486	860.33	0.3680	4.34326	100.00
21.5978	233.91	0.3346	4.11469	27.19
23.6989	243.31	0.4015	3.75442	28.28
24.8229	226.16	0.4015	3.58691	26.29
25.8741	262.39	0.4684	3.44352	30.50
27.2284	205.53	0.5353	3.27525	23.89
33.9602	30.56	0.8029	2.63983	3.55

According to a preferred aspect, the invention relates to monohydrate dabigatran etexilate gallate Form A (ratio dabigatran/gallate 1/1), obtained by precipitation shows that the pattern of X-ray diffraction of FIG. 54, the FT-IR spectrum of FIG. 55, and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d---spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
3.6078	1829.72	0.1506	24.49073	100.00
4.0403	542.18	0.1171	21.86997	29.63
5.1009	72.08	0.2007	17.32487	3.94
7.1141	286.34	0.1338	12.42595	15.65
7.3643	311.14	0.1171	12.00435	17.00
7.9345	58.26	0.2676	11.14288	3.18
10.6881	380.86	0.0836	8.27757	20.82
11.3816	81.15	0.2676	7.77467	4.44
13.2381	407.93	0.3011	6.68824	22.29
14.2161	482.83	0.1673	6.23027	26.39
15.0720	145.92	0.1004	5.87833	7.97
17.2347	130.25	0.1673	5.14524	7.12
17.7980	126.32	0.2676	4.98366	6.90
19.4159	162.00	0.2676	4.57188	8.85
19.8410	231.61	0.1338	4.47487	12.66
21.8579	124.24	0.1673	4.06631	6.79
24.3195	72.06	0.1673	3.66001	3.94
24.9881	122.36	0.1338	3.56357	6.69
25.6717	446.68	0.2342	3.47022	24.41
26.4153	189.22	0.2342	3.37418	10.34
27.7083	113.95	0.2676	3.21960	6.23
28.6667	65.02	0.2007	3.11410	3.55
29.0123	32.99	0.5353	3.07779	1.80
33.7797	23.84	0.5353	2.65353	1.30
38.1664	22.49	0.2342	2.35803	1.23

According to another of its aspects, the invention relates to anhydrous dabigatran etexilate orotate (ratio dabigatran/orotate 1/1) obtained by precipitation which shows that the pattern of X-ray diffraction of FIG. 56, the FT-IR spectrum of

FIG. 57, and the following characteristics of X-ray diffraction:

Pos.	Height	FWHM	d---spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.3254	6936.74	0.1506	20.42927	100.00
4.6241	2931.79	0.1338	19.10994	42.26
5.3422	1077.47	0.1840	16.54293	15.53
7.0676	932.79	0.0836	12.50762	13.45
7.8630	265.63	0.1673	11.24408	3.83
8.4018	556.70	0.3346	10.52416	8.03
9.8344	248.40	0.2342	8.99407	3.58
10.8091	729.34	0.3011	8.18517	10.51
12.2591	684.33	0.0836	7.22005	9.87
12.7985	594.20	0.2007	6.91695	8.57
13.3780	491.25	0.3011	6.61860	7.08
14.0497	352.00	0.2342	6.30366	5.07
15.1084	145.87	0.3011	5.86423	2.10
15.6767	50.07	0.2007	5.65292	0.72
16.2470	602.87	0.2342	5.45575	8.69
16.6558	986.70	0.1338	5.32275	14.22
17.2098	416.99	0.1004	5.15263	6.01
17.8344	273.39	0.2007	4.97355	3.94
18.1952	146.83	0.2007	4.87575	2.12
19.2106	838.17	0.2342	4.62026	12.08
19.6955	550.55	0.1004	4.50760	7.94
20.1563	622.21	0.2342	4.40558	8.97
21.5919	207.72	0.2007	4.11580	2.99
21.9700	312.58	0.2007	4.04581	4.51
23.3022	274.72	0.1338	3.81743	3.96
23.9557	464.77	0.1171	3.71476	6.70
24.1604	512.68	0.1338	3.68375	7.39
25.1262	245.41	0.1673	3.54430	3.54
26.4109	279.86	0.3011	3.37474	4.03
27.2296	91.31	0.3346	3.27511	1.32
28.1810	291.97	0.2007	3.16666	4.21
31.8241	49.50	0.6691	2.81198	0.71
33.1134	26.99	0.6691	2.70538	0.39
35.9337	18.38	0.4015	2.49925	0.26

The new crystalline compounds of the invention, including dabigatran etexilate caffeate forms A and B as defined above, represent another subject matter of the invention.

Details of the two procedures are provided below.

The new crystalline compounds of the invention, including dabigatran etexilate caffeate hydrate as defined above, can be prepared for example by precipitation or by exposure to solvent vapors, technique known as “vapor digestion”.

According to the precipitation technique, a mixture of dabigatran etexilate and the co-former are stirred in a suitable solvent, preferably at room temperature, until the formation of a crystalline compound. If necessary, the solution may be initially heated and/or concentrated. The crystalline compound is subsequently isolated by filtration and optionally washed with a solvent and/or dried, according to the methods known in the art.

The vapor digestion technique, involve the mixing/grinding a solid mixture of dabigatran etexilate with the co-former, exposing the solid mixture to the vapor of a suitable solvent and possibly dried. This technique is therefore not usable with a co-former which is not solid.

According to another of its aspects, the invention relates to a process for the preparation of a crystalline compound according to the invention, or a hydrate or a solvate of such a crystalline compound, which comprises the following steps:

a. dissolving dabigatran etexilate in a suitable solvent and adding the co-former acid;

b. optionally concentrating and/or heating the mixture of step (a);

c. stirring the mixture at room temperature until the formation of the crystalline compound; and

d. isolating the crystalline compound and optionally washing and/or drying the crystalline compound so obtained.

Suitable solvents for the above described process are, for example, esters such as ethyl acetate, ketones such as acetone, chlorinated solvents such as dichloromethane; mixtures of solvents may also be used.

The preferred solvents for the formation of crystalline compounds of the invention with various co-former with the precipitation process are shown in Table (I) below

	TABLE I
		Code of the
	co-former acid	co-former	solvent
	trans-aconitic acid	ACO	acetone
	Adipic acid	ADI	acetone
	Caffeic acid	CAF	acetone
	p-cumaric acid	COU	acetone
	D-gluconic acid	GLUC	acetone
	α-cheto-glutaric acid	KGL	acetone
	hippuric acid	HIP	acetone
	Itaconic acid	ITA	acetone
	Orotic acid	ORA	acetone
	piruvic acid	PRV	acetone
	Sulfamic acid	SUL	acetone
	D-(−)-quinic acid	QUI	acetone
	Sebacic acid	SEB	ethyl acetate
	Gallic acid	GLC	dichloromethane

All the steps of the process are advantageously carried out at room temperature. If necessary it is however possible to heat during step (a) to favor the dissolution of the two starting compounds.

According to a preferred embodiment, a saturated solution of dabigatran etexilate is prepared to which the acid co-former is added, preferably in an amount equal to one equivalent with respect to dabigatran etexilate.

In some case, step (b) can be carried out, to facilitate the precipitation of the crystal. Step (c) is maintained until the formation of the crystalline compound and it may require from several hours to several days.

The crystalline compound obtained is subsequently processed, in step (d) according to the conventional methods, well known to those skilled in the art.

According to another of its aspects, the invention relates to a process for the preparation of a crystalline compound according to the invention, or a hydrate or a solvate of such a crystalline compound, which comprises the following steps:

a′) mixing and grinding dabigatran etexilate and co-former acid;

b′) exposing the solid mixture to vapors of a suitable solvent;

c′) optionally drying the new crystalline compound thus obtained.

As said, the vapor digestion process can be performed only with co-formers which are solid at room temperature. Examples are D-gluconic acid and pyruvic acid.

All steps of the above procedure are advantageously carried out at room temperature. Step (b′) is performed until the formation of the crystalline compound and may last from a few hours, more often, a few days or even a week. The skilled in the art is perfectly able to evaluate the development of the process, by taking samples and analyzing them according to known techniques.

The crystalline compound obtained is then isolated and processed in step (c′) according to the conventional methods well known to those skilled in the art.

For the crystalline compounds prepared from gallic acid and orobic acid, two forms have been synthesized, namely, a form in which the molar ratio dabigatran/acid is 1/1 (Forms A) and a form of which there are more equivalents of acid compared to dabigatran (Forms B).

While not wishing to be bound to any particular theory, the inventors observed that by carrying out the reaction of step (a) and, if necessary the step (b) in solution (homogeneous mixture), the crystalline compound is obtained in a ratio of 1/1, while operating in suspension (heterogeneous mixture) with more equivalents of acid, crystalline compounds with different molar ratio, such as for instance dabigatran/gallate=1/2 and dabigatran/orotate=1/4 are generated.

The vapor digestion technique is preferably applied with a co-former selected from acid, trans-aconitic acid, adipic acid, caffeic acid, p-coumaric acid, α-keto-glutaric acid, hippuric acid, itaconic acid, sulfamic acid, D-(−)-quinic acid, gallic acid, ferulic acid, D-glutaric acid and vanillic acid.

The preferred solvents for the formation of crystalline compounds of the invention with various co-former with the vapor digestion process are shown in Table (II) below

	TABLE II
		Code of the
	co-former acid	co-former	solvent
	trans-aconitic acid	ACO	acetone
	Adipic acid	ADI	acetone
	Caffeic acid	CAF	acetone
	p-cumaric acid	COU	acetone
	α-cheto-glutaric acid	KGL	acetone
	Ippuric acid	HIP	acetone
	itaconic acid	ITA	acetone
	Sulfamic acid	SUL	acetone
	D-(−)-quinic acid	QUI	acetone
	Gallic acid	GLC	dichloromethane
	Ferulic acid	FER	acetone
	D-glutaric acid	GTR	acetone
	Vanillic acid	VAN	acetone

The characterization data of the crystalline compounds of the invention are provided in the Experimental Section and the graphs of X-ray diffraction (XRPD), infrared (IR), differential scanning calorimetry (DSC) of the compounds are shown in the figures attached to the present description.

The TGA and EGA confirmed the presence or the absence of any solvent in the crystals.

The crystalline compounds of the invention showed the excellent chemical-physical properties and therefore represent valid alternatives to the currently available crystalline forms of dabigatran etexilate for administration to humans and/or in the animal.

Moreover, solubility test were carried out, according to the methods described in the Experimental Section that follows, and it was observed that some representative compounds of the invention show an excellent dissolution rate, higher than that of dabigatran etexilate mesylate available on the market. This result is unexpected and surprising and represents a significant technical advance in the pharmaceutical field, because it is known that in a better solubility results in a better bioavailability of the drug.

According to another of its aspects, the invention also relates to a solid pharmaceutical composition that comprises at least one crystalline compound of the invention together with one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions of the invention are particularly suitable for oral administration.

For the oral administration, said compositions can be in the form of tablets, capsules or granules and are prepared according to conventional methods with pharmaceutically acceptable excipients such as binding agents, bulking agents, lubricants, disintegrants, wetting agents, flavoring agents, etc. Tablets may also be coated by the methods well known in the art.

The compositions of the invention are advantageously in the form of dosage units. Preferably, each dosage unit according to the invention comprises a crystalline compound according to the invention that contains an amount of dabigatran etexilate from 10 to 200 mg, for example from 50 to 150 mg, advantageously from 70 to 120 mg, for example 75 or 110 mg, advantageously with the excipients and conventional additives well known to those skilled in the art. Other dosages may of course be provided depending on the diseases and conditions of the subject to be treated.

Preferred compositions comprise gallate dabigatran etexilate, advantageously in an monohydrate form.

Other particularly preferred compositions are the compositions comprising the orotate dabigatran etexilate, advantageously in the anhydrous form.

According to another of its aspects, the invention relates to crystalline compounds and/or the pharmaceutical compositions of the invention for their use in therapy, in particular in the tromboembolitic therapy, advantageously in the prevention of thromboembolic episodes and in the prevention of stroke and systemic embolism.

The invention also comprises a method of treatment for the prevention of thromboembolic episodes and for the prevention of stroke and systemic embolism which comprises administering, to a subject in need thereof, an effective amount of a crystalline compound of the invention, advantageously in the form of a pharmaceutical composition as defined above.

EXPERIMENTAL SECTION

Data and analytical details of the crystalline compounds of the invention are provided in the tables below.

Technique Result for Dabigatran Etexilate trans-Acotinate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at 126.9° C.
          (Onset 115.9° C.)
TGA       The TGA profile shows only the degradation of sample
          after approx. 120° C.
EGA       The EG analysis confirms sample decomposition showing
          carbon dioxide evolution.

Technique Result for Dabigatran Etexilate Adipate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic broad double peak
          at approx. 94° C. (Onset 82.7° C.)
TGA       The TGA profile shows weight loss above 120° C. due to
          decomposition.
EGA       The EG analysis confirms sample decomposition showing
          carbon dioxide and 1-hexanol evolution.

Technique Result for Dabigatran Etexilate trans-Caffeate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak (melting) at
          approx. 99.5° C. (Onset)
TGA       The TGA profile shows a mass loss at low temperature
          (approx. 50° C.) due to imbibition water. Sample
          decomposition occurs in correspondence to the melting
          (approx. 100° C.).
EGA       The EG analysis confirms the water evolution at low
          temperature and sample decomposition revealing carbon
          dioxide evolution.

Technique Result for Dabigatran Etexilate p-Coumarate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a likely co-crystal
DSC       The DSC profile shows an endothermic peak at 57.6° C.
          (Onset 54.5° C.) and a peak corresponding to the melting at
          125.9° C. (Onset 115.5° C.)
TGA       The TGA profile shows weight loss of 0.9% at approx. 80° C.
          while after 120° C. decomposition occurs
EGA       The EG analysis evidences that the first thermal event
          showed in DSC corresponds to acetone evolution while
          sample decomposition is confirmed by carbon dioxide,
          1-hexanol and ethyl acrylate evolution

Technique Result for Dabigatran Etexilate D-Gluconate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at approx.
          107° C. (Onset 98.2° C.)
TGA       The TGA shows a desolvation step between 40-120° C.
          followed by degradation
EGA       The EG analysis evidences the evolution of ethyl acetate
          and carbon dioxide

Technique Result for Dabigatran Etexilate α-Ketoglutarate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic double peak with an
          onset at 110.7° C. probably associated to a solid-solid
          transition followed by melting and decomposition
TGA       The weight loss of 23% observed in the TG profile after
          110° C. is connected to sample decomposition
EGA       The EG analysis evidences the evolution of carbon dioxide

Technique Result for Dabigatran Etexilate Hippurate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows two endothermic events at 57.5° C.
          (Onset 52.9° C. - solid-solid transition) and 141.1° C.
          (Onset 136.9° C.-melt)
TGA       The TGA profile shows a weight loss of approx. 11% at
          140° C. connected to sample decomposition
EGA       The EG analysis evidences the evolution of decomposition
          product carbon dioxide and 1-hexanol

Technique Result for Dabigatran Etexilate Itaconate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A confirms
          the formation of a new species
DSC       The DSC profile shows a large endothermic peak at 95.9° C.
          (onset 79° C.) and an endothermic event at 113° C. (Onset
          108.6° C.)
TGA       The TGA profile shows a weight loss of approx.1% at 50° C.
          and decomposition at approx.140° C.
EGA       The EG analysis evidences water evolution in correspondence
          to the firs weight loss and carbon dioxide and 1-hexanol
          connected to sample decomposition

Technique Result for Dabigatran Etexilate Orotate
XRPD      The evidenced crystalline form is labeled as Form B
FT-IR     The infrared spectrum of the form labeled as Form B confirms
          the formation of a new species
DSC       The DSC profile shows an endothermic peak at approx.
          102.3° C. (Onset 89.2° C.)
TGA       The TGA profile shows a weight loss of 4% at approx. 60° C.
          along with 11% at 150° C. due to decomposition.
EGA       The EG analysis evidence water evolution in correspondence
          of the first thermal event and carbon dioxide and 1-hexanol
          evolution connected to the sample decomposition

Technique Result for Dabigatran Etexilate Pyruvate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A confirms
          the formation of a new species
DSC       The DSC profile shows an endothermic peak at approx.
          113.4° C. (Onset 102.5° C.)
TGA       The TGA profile shows a weight loss of 0.9% at approx.
          50° C. along with 23% at 120° C. due to decomposition.
EGA       The EG analysis evidence water evolution in correspondence
          of the First thermal event and carbon dioxide and 1-hexanol
          evolution connected to the sample decomposition

Technique Result for Dabigatran Etexilate Sulfamate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at approx.
          171.2° C. (Onset 167.2° C.)
TGA       The TGA profile shows a typical profile of dried compound,
          the Weight loss due to decomposition starts after 170° C.
EGA       The EG analysis evidences the evolution of decomposition
          compounds in correspondence to the weight loss registered in
          TG

Technique Result for Dabigatran Etexilate D-(−)-Quinate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at approx.
          161.4° C. (Onset 158.6° C.)
TGA       The TGA profile shows a typical profile of dried compound,
          the weight loss due to decomposition starts after 170° C.
EGA       The EG analysis evidences the evolution of carbon dioxide
          and 1-hexanol in correspondence to the weight loss
          registered in TG

Technique Result for Dabigatran Etexilate Ferulate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows three endothermic events probably
          connected to solid-solid transitions (at 82.6° C. and 103° C.)
          and melt (at 129.2° C.)
TGA       The TGA profile shows a typical profile of dried compound,
          the weight loss due to decomposition starts after 140° C.
EGA       The EG analysis evidences only carbon dioxide evolution
          caused by decomposition

Technique Result for Dabigatran Etexilate Gallate
XRPD      The evidenced crystalline form is labeled as Form B
FT-IR     The infrared spectrum of the form labeled as Form B
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at 84.5° C.
          (Onset 78.8° C.)
TGA       The TGA profile shows a weight loss of 1.9% at approx.
          60° C. and decomposition after 160° C.
EGA       The EG analysis evidence water and carbon dioxide
          evolution in correspondence of the first thermal event (60° C.)
          before complete decomposition

Technique Result for Dabigatran Etexilate Sebacate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at approx.
          122.8° C. (Onset 128.8° C.)
TGA       The TGA profile shows a typical profile of dried compound,
          the weight loss starts after 150° C. due to decomposition
EGA       The EG analysis evidence carbon dioxide evolution during
          decomposition

Technique Result for Dabigatran Etexilate Glutarate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at approx.
          98.3° C. (Onset 85.9° C.)
TGA       The TGA profile shows a typical profile of dried compound,
          the weight loss starts after 150° C. due to decomposition
EGA       The EG analysis evidence carbon dioxide evolution during
          decomposition

Technique Result for Dabigatran Etexilate Vanillate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
DSC       The DSC profile shows an endothermic peak at 43.9° C.
          imputable to a desolvation step, while the melt of the product
          occurs at 80.0° C. (Onset 68.2° C.)
TGA       The TGA profile shows a typical profile of dried compound,
          the weight loss starts after 150° C. due to decomposition
EGA       The EG analysis evidence carbon dioxide evolution during
          decomposition

Technique Result for Dabigatran Etexilate Gallate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species
Technique Result for Dabigatran Etexilate Orotate
XRPD      The evidenced crystalline form is labeled as Form A
FT-IR     The infrared spectrum of the form labeled as Form A
          confirms the formation of a new species

X-Ray Powder Diffraction (XRPD)

Instrument type: X'Pert PRO PANalytical

The X'Pert PRO X-ray diffraction system basically consists of the following items:

• • A console which provides the working environment for the X'Pert PRO system; it includes measuring and control electronics using a microprocessor system, and high tension generator.
  • A ceramic diffraction X-ray tube, mounted onto the goniometer in a tube shield; described herein below.
  • A goniometer, the central part of the diffractometer; the goniometer is described herein below.
  • Optical modules for the incident and the diffracted X-ray beam. These modules can be mounted on PreFIX positions on the goniometer's arms.
  • A sample stage on which to mount a sample so that its characteristics can be measured.

Sample stage is the generic name given to any device onto which a sample is mounted so that it can be measured or analyzed. The sample stage used on X'Pert PRO system is the sample spinner. The purpose of spinning is to bring more crystallites into the diffraction position in order to reduce the influence of particle statistics on the measurements. The spinning rotation speed can be set at 2, 1, ½, ¼, ⅛, and 1/16 revolutions per second.

• • A detector to measure the intensity of the diffracted X-ray beam; the goniometer is described herein below.

Ceramic diffraction X-ray tubes

General Tube Specifications

Focus type: LFF (Long Fine Focus)

Focus dimensions: 12 mm×0.4 mm

Focus quality: To COCIR specifications

Take-off angle (with no intensity loss over range)

line focus: 0°-12° (also dependent on shutter opening)

point focus 0°-20° (also dependent on shutter opening)

Be window diameter: 14 mm

Be window thickness: 300 μm

Power Characteristics

High power ceramic diffraction X-ray tube with copper anode

Maximum power: 2.2 kW

Maximum high tension: 60 kV

Maximum anode current 55 mA

Advised power settings: 80%-85% of maximum power

Advised standby ratings: 30-40 kV, 10-20 mA

Spectral Purity

Foreign lines measured with a β-filter

at 40 kV relative to the Kα line: On delivery <1%

Increase per 1000 hours of tube life: <1% for tubes with Cu anode

Environmental Conditions

Operating temperature: +5° C. to +40° C.

Storage temperature: −40° C. to +70° C.

Electrical safety: IEC1010-1

Cooling Water Conditions

The cooling water used should not cause corrosions or deposit sediment in the tube. If the water is dirty or contains an unduly high concentration of salts, use of a closed cooling system employing clean, not distilled water, may be necessary.

Quality: Drinking water

Flow: 3.5-5 l/minute

Maximum pressure: 0.8 MPa

Pressure drop at 3.5 l/minute: 0.2+/−0.04 MPa

Max. Temperature: 35° C.

Min. Temperature: Depends on dew point of air

Goniometers X'Pert PRO

X'Pert PRO X-ray diffraction systems are based on the PW3065/6x Goniometer. The goniometer contains the basic axes in X-ray diffractometry: the θ and 2θ axes.

PW3050/60 X'Pert PRO Standard Resolution Goniometer:

Operation mode Horizontal or vertical, θ-θ or θ-2θ mode

Reproducibility 0.0001° 0.001° (with attachments)

Scan speed 0.000001-1.27°/s

Slew speed 12°/s (with attachments)

Minimum step size 0.001°

2θ range −40°-+220°

θ range −15°-+181°

2θ measurement range Dependent on optics, geometry and sample stage

Diffractometer radius 130-240 mm (X'Pert PRO MPD systems); 240 mm is standard setting

Distance goniometer face-diffraction plane 150 mm

RTMS Detector

X'Celerator:

Used with Line focus and point focus

Used in All systems

Radiation type Optimized for Cu radiation

99% linearity range 0-900 kcps overall 0-7000 cps local

Maximum count rate 5000 kcps overall 250 kcps local

Maximum background noise <0.1 cps

Typical energy resolution for Cu Kα radiation 25%

Efficiency for Cu Kα 93%

Detector window size 15 mm parallel to the line focus 9 mm perpendicular to the line focus

Active length 9 mm

(2.2° at 240 mm goniometer radius; 1.6° at 320 mm goniometer radius)

Smallest step size 0.0021° at 240 mm goniometer radius/0.0016° at 320 mm

goniometer radius

Operating modes Scanning mode

TG Analyses

Instrument type: Mettler Toledo Stare System

Temperature data

Temperature range RT . . . 1100° C.

Temperature accuracy ±1 K

Temperature precision ±0.4 K

Heating rate 0.02 . . . 250 K/min

Cooling time 20 min (1100 . . . 100° C.)

Sample volume ≦100 μL

Special modes

Automation 34 sample positions

TGA-FTIR coupled with Thermo Nicolet 6700 spectrometer

Balance data XP5

Measurement range ≦5 g

Resolution 1.0 μg

Weighing accuracy 0.005%

Weighing precision 0.0025%

Internal ring weights 2

Blank curve reproducibility better than ±10 μg over the whole temperature range

DSC Analyses

Instrument type: DSC 200 F3 Maia®

Technical Specifications

Temperature range: −170° C. . . . 600° C.

Heating rates: 0.001 K/min . . . 100K/min

Cooling rates 0.001 K/min . . . 100K/min(depending on temperature)

Sensor: heat flux system

Measurement range 0 mW . . . ±600 mW

Temperature accuracy: 0.1 K

Enthalpy accuracy: generally <1%

Cooling options: Forced air (down to RT), LN2 (down to −170° C.) Purge gas rate: 60 ml/min

Intracooler for the extended rate: −40° . . . 600° C.

FT-IR

Instrument type: Nicolet FT-IR 6700 ThermoFischer

Technical Specifications

Product Specifications

Spectral Range (Standard): 7800-350 cm-1

Spectral Range (Option, CsI Optics): 6400-200 cm-1

Spectral Range (Option, Extended-Range Optics): 11000-375 cm-1

Spectral Range (Option, Multi-Range Optics): 27000-15 cm-1

Optical Resolution: 0.09 cm-1

Peak-To-Peak Noise (1 minute scan): <8.68×10-6 AU*

RMS Noise (1 minute scan): <1.95×10-6 AU*

Ordinate Linearity: 0.07% T

Wavenumber Precision: 0.01 cm-1

Slowest Linear Scan Velocity: 0.158 cm/sec

Fastest Linear Scan Velocity: 6.33 cm/sec

Number of Scan Velocities: 15

Rapid Scan (Spectra/second @ 16 cm-1, 32 cm-1): 65, 95

* AU: Absorbance Units.

Smart Performer

For single-reflection ATR analysis.

Crystal Materials: ZnSe

Sampling Area: 2 mm

Spectral Range: 20000 to 650 cm-1 (ZnSe)

Depth of Penetration: 2.03 micrometers at 1000 cm-1

Refractive Index: 2.4

Useful pH: 5-9

Instrument setup

Number of sample scans: 32

Number of background scans: 32

Resolution: 4,000 cm-1

Sample gain: 8.0

Optical velocity: 0.6329

Aperture: 100.00

Detector: DTGS KBr

Beamsplitter: KBr

Example 1

General Preparation of Crystalline Compounds by Precipitation

To a saturated solution of dabigatran etexilate tetrahydrate in the selected solvent, 1 molar equivalent of the acid co-former is added. The mixture is stirred at room temperature and the precipitate is recovered by filtration, washed with a solvent and dried before proceeding with the analysis.

Example	Co-former	Solvent	Stirring timea	Drying
1.1	ACO	acetone	1 hr	air/2 hrs
1.2	ADI	acetone	24 hrs	under vacuum/40° C./18 hrs
1.3	CFA	acetonec	20 hrs	under vacuum/40° C./18 hrs
1.4	GLU	acetone	20 hrs	under vacuum/40° C./18 hrs
1.5	KGL	acetone	20 hrs	under vacuum/40° C./18 hrs
1.6	HIP	Acetonec	20 hrs	under vacuum/40° C./18 hrs
1.7	ITA	acetone	20 hrs	under vacuum/40° C./18 hrs
1.8	ORA	acetone	20 hrs	under vacuum/40° C./18 hrs (1/4)
1.9	ORA	acetone	20 hrs	under vacuum/40° C./18 hrs (1/1)
1.10	PRV	acetone	1 hr	under vacuum/40° C./18 hrs
1.12	SUL	acetone	3 hrs	under vacuum/40° C./18 hrs
1.12	QUI	acetone	3 hrs	under vacuum/40° C./18 hrs
1.13	GLC	dichoromethane	3 days	under vacuum/40° C./18 hrs (1/2)
1.14	GLC	dichoromethane	20 hrs	under vacuum/40° C./18 hrs (1/1)
1.15	SEB	ethyl acetate	18 hrsb	under vacuum/40° C./18 hrs
1.16	COU	acetone	3 days	—
astirring at room temperature
bmixture initially heated to 50° C. for 60 minutes before stirring at room temperature
cno precipitate after 3 days; evaporation to air for two days

Example 2

General Preparation of Crystalline Compounds by Vapor Digestion

100 mg of dabigatran etexilate tetrahydrate, and 1 molar equivalent of the acid co-former are mixed and homogenized in a mortar with a pestle. The mixture is then exposed to vapors of a solvent at 25° C. The powder is recovered and dried before proceeding with the analysis.

Example	co-former	solvent	conditions	drying
2.1	ACO	acetone	25° C./3 days	under vacuum/40° C./18 hrs
2.2	ADI	acetone	25° C./7 days	—
2.3	CFA	acetone	25° C./7 days	under vacuum/40° C./18 hrs
2.4	COU	acetone	25° C./7 days	under vacuum/40° C./18 hrs
2.5	KGL	acetone	25° C./3 days	under vacuum/40° C./18 hrs
2.6	HIP	acetone	25° C./3 days	under vacuum/40° C./18 hrs
2.7	ITA	acetone	25° C./7 days	under vacuum/40° C./18 hrs
2.8	SUL	acetone	25° C./3 days	under vacuum/40° C./18 hrs
2.9	QUI	acetone	25° C./3 days	under vacuum/40° C./18 hrs
2.10	GLC	dichloromethane	25° C./3 days	under vacuum/40° C./18 hrs
2.11	FER	acetone	25° C./6 days	under vacuum/40° C./18 hrs
2.12	VAN	acetone	25° C./3 days	under vacuum/40° C./18 hrs

Example 3

Dabigatran Etexilate Gallate Monohydrate Form A (Dabigatran/Gallic Acid 1/1 Mol/Mol)

In a reactor 100 g of dabigatran etexilate and 500 g of acetone are loaded. The slurry is heated at 40° C. until dissolution. A solution of 26.5 g of gallic acid in 100 g of acetone was then added dropwise within 30 minutes. The precipitation was trigged at 25° C. and the slurry was cooled to 20° C. for 16 hours, the solid was then filtered, washed with 100 g of acetone and dried under vacuum at 30° C. for 16 h. Pale yellow solid: 97.6 g. Yield 78.5%.

Example 4

Dabigatran Etexilate Gallate Hydrate Form B (Dabigatran/Gallic Acid 1/2 Mol/Mol)

In a 100-mL round bottom flask, equipped with a magnetic stirring bar and a condenser, 1 g of dabigatran etexilate was charged (1.593 mmol). 40 mL of dichloromethane were transferred into the reaction flask and the mixture was stirred at 50° C. until a total dissolution of the starting material was observed. 1 eq. of gallic acid (1.593 mmol=271 mg) was added and the mixture was stirred at 50° C. for 30 minutes but a totally dissolution of the coformer was not achieved. The mixture was slowly cooled at room temperature and stirred for 18 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 0.66 g of white solid was recovered (Y=52.1%).

1H-NMR

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H), 1.26-1.34 (m, 6H), 1.55-1.60 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.94-4.00 (m, 4H), 4.22 (t, J=7.0 Hz, 2H), 4.59 (d, J=5.2 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.91 (s, 2H), 6.92 (t, J=5.2 Hz, 1H), 7.10-7.13 (m, 1H), 7.15 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.46-7.47 (m, 1H), 7.52-7.56 (m, 1H), 7.79 (d, J=8.8 Hz, 2H), 8.37-8.40 (m, 1H), 8.83 (bb, 2H, NH2), 9.16 (bb, 3H, OH), 12.20 (bb, 1H, COOH).

Example 5

Dabigatran Etexilate Orotate Anhydrous Form a (Dabigatran/Orotic Acid 1/1 Mol/Mole)

In a reactor 8.5 g of dabigatran etexilate, 2.6 g of orotic acid and 25 mL of N,N-dimethylformamide are loaded. The mixture is heated at 50° C. until dissolution. The solution is then brought to 35° C. and 125 mL of acetone are added dropwise within 90 minutes. After precipitation, the slurry was cooled to 20° C. for 3 hours, then the solid was filtered, washed with 10 mL of acetone and dried under vacuum at 30° C. for 16 h. White solid: 8.19 g. Yield 82%.

Example 6

Dabigatran Etexilate Orotate Hydrate Form B (Dabigatran/Orotic Acid 1/4 Mol/Mol)

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of orotic acid (1.593 mmol=286 mg) was added and a total dissolution was not observed because the orotic acid was not completely soluble in the acetone. During the dissolution of the coformer a simultaneous formation of a white precipitate was observed.

The mixture was stirred at room temperature for 24 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 0.56 g of white solid were recovered (Y=43.5%).

1H-NMR

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H), 1.26-1.38 (m, 6H), 1.60-1.66 (m, 2H), 2.68 (t, J=6.9 Hz, 2H), 3.76 (s, 3H), 3.97 (q, J=7.0 Hz, 2H), 4.16 (t, J=6.9 Hz, 2H), 4.22 (t, J=6.9 Hz, 2H), 4.65 (d, J=4.8 Hz, 2H), 5.94 (d, J=2.0 Hz, 1H), 6.83 (d, J=9.2 Hz, 2H), 6.89 (d, J=8.0 Hz, 1H), 7.10-7.13 (m, 1H), 7.15 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.46-7.47 (m, 1H), 7.52-7.56 (m, 1H), 7.69 (d, J=8.8 Hz, 2H), 8.37-8.40 (m, 1H), 9.76 (bb, 2H, NH2), 10.62 (bb, OH), 11.24 (bb, COOH).

Example 7

A Pharmaceutical Composition Comprising Dabigatran Etexilate Gallate

A hard gelatine capsule contains:

75 mg of monohydrate dabigatran etexilate orotate;

Ingredients: tartaric acid, gum arabic, hypromellose, dimethicone 350, hydroxypropyl cellulose and talc.

Example 8

A Pharmaceutical Composition Comprising Anhydrous Dabigatran Etexilate Gallate

A hard gelatine capsule contains:

75 mg of anhydrous dabigatran etexilate gallate;

Ingredients: tartaric acid, gum arabic, hypromellose, dimethicone 350, hydroxypropyl cellulose and talc.

Example 9

Dabigatran Etexilate Aconitate Anhydrous

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of aconitic acid (1.593 mmol=277.4 mg) was added and a total dissolution was observed. After few minutes a large amount of white precipitate was formed. The mixture was stirred at room temperature for 3 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 1.12 g of white solid was recovered (Y=87.7%).

1H-NMR (400 MHz, DMSO-d6, d1=10 sec.) δ: 0.87 (3H, t, J=6.8 Hz), 1.12 (3H, t, J=6.8 Hz), 1.26-1.40 (6H, m), 1.59 (2H, quint, J=6.8 Hz), 2.68 (2H, t, J=6.8 Hz), 3.68 (2H, s), 3.76 (3H, s), 3.95-4.05 (4H, m), 4.22 (2H, t, J=6.8 Hz), 4.60 (2H, d, J=5.6 Hz), 6.70 (1H, s), 6.77 (2H, d, J=8.4 Hz), 6.89 (1H, d, J=7.2 Hz), 7.04 (1H, br. t), 7.10-7.14 (1H, m), 7.16 (1H, dd, J=8.4 Hz, J1,3=1.6 Hz), 7.39 (1H, d, J=8.4 Hz), 7.47 (1H, d, J1,3=1.6 Hz), 7.54 (1H, dt, J=8.0 Hz, J1,3=1.6 Hz), 7.77 (2H, d, J=8.4 Hz), 8.38-8.40 (1H, m).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Aconitic Acid.

Example 10

Dabigatran Etexilate Adipate Anhydrous

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of adipic acid (1.593 mmol=233 mg) was added and the mixture was stirred at room temperature for 24 hours but no precipitate was observed. The reaction was allowed to evaporate at room temperature. When the reaction solvent was decreased to approx. 15 mL the formation of white precipitate was observed. The flask was capped and the reaction was stirred for additional 24 hours.

The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 1H-NMR (400 MHz, DMSO-d6, d1=10 sec.) δ: 0.87 (3H, t, J=7.2 Hz), 1.12 (3H, t, J=6.8 Hz), 1.26-1.40 (6H, m), 1.34-1.52 (4H, m), 1.59 (2H, quint, J=6.8 Hz), 2.15-2.24 (4H, m) 2.68 (2H, t, J=6.8 Hz), 3.76 (3H, s), 3.95-4.05 (4H, m), 4.22 (2H, t, J=6.8 Hz), 4.59 (2H, d, J=5.2 Hz), 6.76 (2H, d, J=9.2 Hz), 6.89 (1H, d, J=8.4 Hz), 6.95 (1H, br. t), 7.10-7.14 (1H, m), 7.16 (1H, dd, J=8.0 Hz, J1,3=1.6 Hz), 7.40 (1H, d, J=8.0 Hz), 7.47 (1H, d, J1,3=1.6 Hz), 7.54 (1H, dt, J=8.0 Hz, J1,3=1.6 Hz), 7.77 (2H, d, J=9.2 Hz), 8.38-8.40 (1H, m).

By 1H-NMR the stoichiometric ratio is 1:0.25=dabigatran etexilate:Adipic Acid.

Example 11

Dabigatran Etexilate α-Keto-Glutarate Anhydrous

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of α-ketoglutaric acid (1.593 mmol=232.7 mg) was added and a total dissolution was observed. After few minutes a large amount of white precipitate was formed. The mixture was stirred at room temperature for 24 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 1.02 g of white solid were recovered (Y=83%).

1H-NMR (400 MHz, DMSO-d6, d1=10 sec.) δ: 0.87 (3H, t, J=6.8 Hz), 1.12 (3H, t, J=6.8 Hz), 1.20-1.40 (6H, m), 1.59 (2H, quint, J=8.0 Hz), 2.47 (2H, t, J=6.8 Hz), 2.68 (2H, t, J=6.8 Hz), 2.89 (2H, br. t), 3.76 (3H, s), 3.95-4.05 (4H, m), 4.22 (2H, t, J=7.2 Hz), 4.60 (2H, d, J=5.6 Hz), 6.78 (2H, d, J=8.8 Hz), 6.89 (1H, d, J=8.4 Hz), 7.06 (1H, br. t), 7.09-7.14 (1H, m), 7.16 (1H, dd, J=8.0 Hz, J1,3=1.6 Hz), 7.40 (1H, d, J=8.4 Hz), 7.47 (1H, d, J1,3=1.6 Hz), 7.54 (1H, dt, J=8.0 Hz, J1,3=1.6 Hz), 7.77 (2H, d, J=8.8 Hz), 8.38-8.40 (1H, m).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:α-Ketoglutaric Acid.

Example 12

Dabigatran Etexilate Ippurate Anhydrous

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of hippuric acid (1.593 mmol=285 mg) was added and a total dissolution was observed. After few minutes a large amount of white precipitate was formed. The mixture was stirred at room temperature for 2 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 0.932 g of product was isolated (Y=72.5%).

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H), 1.26-1.34 (m, 6H), 1.55-1.60 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.92 (d, J=5.6 Hz, 2H), 3.94-4.00 (m, 4H), 4.22 (t, J=7.0 Hz, 2H), 4.59 (d, J=5.2 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.95 (t, J=5.4 Hz, 1H), 7.10-7.13 (m, 1H), 7.15 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.46-7.57 (m, 2H+2H), 7.79 (d, J=8.8 Hz, 2H), 7.86-7.89 (m, 2H), 8.37-8.40 (m, 1H), 8.82 (t, J=5.6 Hz, 1H)

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Hippuric Acid.

Example 13

Dabigatran Etexilate Itaconate Hydrate

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of itaconic acid (1.593 mmol=277.4 mg) was added and the mixture was stirred at room temperature for 24 hours but no precipitate was observed. The reaction was allowed to evaporate at room temperature. When the reaction solvent was decreased to approx. 8 mL the formation of a white precipitate was observed. The flask was capped and the reaction was stirred for additional 24 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours.

1H-NMR (400 MHz, DMSO-d6, d1=10 sec.) δ: 0.87 (3H, t, J=6.8 Hz), 1.12 (3H, t, J=7.2 Hz), 1.25-1.38 (6H, m), 1.58 (2H, quint, J=7.6 Hz), 2.68 (2H, t, J=7.2 Hz), 3.20 (2H, s), 3.76 (3H, s), 3.95-4.05 (4H, m), 4.22 (2H, t, J=7.2 Hz), 4.59 (2H, d, J=5.2 Hz), 5.69 (1H, s), 6.09 (1H, s), 6.76 (2H, d, J=9.2 Hz), 6.88 (1H, d, J=8.0 Hz), 6.99 (1H, br. t, J=5.6 Hz), 7.07-7.14 (1H, m), 7.15 (1H, dd, J=8.4 Hz, J1,3=1.6 Hz), 7.40 (1H, d, J=8.4 Hz), 7.47 (1H, s), 7.55 (1H, dt, J=8.0 Hz, J1,3=1.6 Hz), 7.78 (2H, d, J=8.4 Hz), 8.38-8.40 (1H, m).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Itaconic Acid.

Example 14

Dabigatran Etexilate Pyruvate Hydrate

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of Pyruvic Acid (1.593 mmol=113 μL) was added and the mixture was stirred at room temperature for 90 minutes. After few minutes a large amount of white precipitate was formed. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 0.671 g of white solid was recovered (Y=58.9%).

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.2 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H), 1.26-1.34 (m, 6H), 1.55-1.63 (m, 2H), 2.29 (s, 3H), 2.68 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.94-4.05 (m, 4H), 4.22 (t, J=7.2 Hz, 2H), 4.61 (d, J=5.6 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.4 Hz, 1H), 7.06 (t, J=6.0 Hz, 1H), 7.10-7.13 (m, 1H), 7.15 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.47 (dd, 1H, J2=1.6 Hz), 7.54 (dt, J=7.2 Hz, J2=1.6 Hz, 2H), 7.77 (d, J=8.8 Hz, 1H), 8.37-8.40 (m, 1H).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Pyruvic Acid.

Example 15

Dabigatran Etexilate Sulfamate Anhydrous

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of sulfamic acid (1.593 mmol=154 mg) was added and a total dissolution was observed. After few minutes a large amount of white precipitate was formed. The mixture was stirred at room temperature for 4 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 0.81 g of white solid was recovered (Y=70%).

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=6.8 Hz, 3H), 1.12 (t, J=6.8 Hz, 3H), 1.20-1.38 (m, 6H), 1.61 (quint, 2H, J=5.6 Hz), 2.68 (t, 2H, J=7.2 Hz), 3.77 (s, 3H), 3.97 (quart, J=7.2 Hz, 2H), 4.06 (t, 2H, J=6.8 Hz), 4.22 (t, J=7.2 Hz, 2H), 4.62 (d, J=5.6 Hz, 2H), 6.79 (d, J=9.2 Hz, 2H), 6.89 (d, J=8.4 Hz, 1H), 7.09-7.20 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 7.47 (d, 1H, J1,3=1.6 Hz), 7.54 (dt, 1H, J=8.0 Hz, J1,3=1.6 Hz), 7.74 (d, J=9.2 Hz, 2H), 8.37-8.40 (m, 1H).

Example 16

Dabigatran Etexilate D-(−)-Quinate Anhydrous

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of D-(−)-quinic acid (1.593 mmol=277.4 mg) was added and a total dissolution was not observed because the D-(−)-quinic acid was not completely soluble in the acetone. During the dissolution of the coformer a contemporary formation of a yellow precipitate was observed. After few minutes a large amount of yellow precipitate was formed. The mixture was stirred at room temperature for 4 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 1.11 g of white solid was recovered (Y=84.7%).

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H), 1.26-1.34 (m, 6H), 1.55-1.60 (m, 2H), 1.66-1.78 (m, 2H), 1.83-1.89 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 3.24-3.27 (m, 1H), 3.71-3.75 (m, 1H), 3.76 (s, 3H), 3.89 (bb, 1H), 3.94-4.00 (m, 4H), 4.22 (t, J=7.0 Hz, 2H), 4.50 (bb, OH), 4.55 (bb, OH), 4.59 (d, J=5.2 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.98 (t, J=5.2 Hz, 1H), 7.10-7.13 (m, 1H), 7.15 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.46-7.47 (m, 1H), 7.52-7.56 (m, 1H), 7.79 (d, J=8.8 Hz, 2H), 8.37-8.40 (m, 1H).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:D-(−)-Quinic Acid.

Example 17

Dabigatran Etexilate Ferulate Anhydrous

1 g (1.593 mmol) of dabigatran etexilate and 1 eq. (309.3 mg) of ferulic acid were homogenized by a pestle in a mortar and then the mixture was exposed to acetone vapor at 25° C. for 3 days. The powder was recovered and dried under vacuum at 40° C. for 48 hours. 1.16 g of white solid was recovered (Y=88.8%).

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H), 1.26-1.38 (m, 6H), 1.54-1.60 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.81 (s, 3H), 3.92-4.02 (m, 4H), 4.22 (t, J=7.2 Hz, 2H), 4.59 (d, J=5.6 Hz, 2H), 4.59 (d, J=5.6 Hz, 2H), 6.36 (d, J=16.4 Hz, 1H), 6.71-6.81 (m, 1H+1H CH═CH), 6.88 (d, J=7.6 Hz, 1H), 6.95 (t, J=5.2 Hz, 1H), 7.05-7.18 (m, 1H+2HAr), 7.27 (d, J2=1.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.47 (d, J2=1.6 Hz, 1H), 7.54 (dt, J=8.0 Hz, J2=1.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 8.37-8.40 (m, 1H).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Ferulic Acid.

Example 18

Dabigatran Etexilate Glutarate Anhydrous

1 g (1.593 mmol) of dabigatran etexilate and 1 eq. (210.5 mg) of glutaric acid were homogenized by a pestle in a mortar and then the mixture was exposed to acetone vapor at 25° C. for 3 days. The powder was recovered and dried under vacuum at 40° C. for 48 hours. 0.92 g of yellow solid was recovered (Y=76.2%).

1H-NMR (400 MHz, DMSO-d6, d1=10 sec.) δ: 0.87 (3H, t, J=7.2 Hz), 1.12 (3H, t, J=7.2 Hz), 1.26-1.40 (6H, m), 1.56 (2H, quint, J=6.4 Hz), 1.69 (2H, quint, J=7.6 Hz), 2.23 (4H, t, J=7.6 Hz), 2.68 (2H, t, J=6.8 Hz), 3.76 (3H, s), 3.95-4.05 (4H, m), 4.22 (2H, t, J=6.8 Hz), 4.59 (2H, d, J=5.2 Hz), 6.76 (2H, d, J=8.8 Hz), 6.88 (1H, d, J=8.0 Hz), 6.95 (1H, br. t), 7.10-7.14 (1H, m), 7.16 (1H, dd, J=8.4 Hz, J1,3=1.6 Hz), 7.40 (1H, d, J=8.4 Hz), 7.47 (1H, d, J1,3=1.6 Hz), 7.54 (1H, dt, J=8.0 Hz, J1,3=1.6 Hz), 7.79 (2H, d, J=8.8 Hz), 8.38-8.40 (1H, m).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Glutaric Acid.

Example 19

Dabigatran Etexilate Vanillate Hydrate

1 g (1.593 mmol) of dabigatran etexilate and 1 eq. (268 mg) of vanillic acid were homogenized by a pestle in a mortar and then the mixture was exposed to acetone vapor at 25° C. for 3 days. The powder was recovered and dried under vacuum at 40° C. for 48 hours. 0.986 g of white solid was recovered (Y=77.7%).

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H), 1.26-1.38 (m, 6H), 1.54-1.60 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.80 (s, 3H), 3.92-4.02 (m, 4H), 4.22 (t, J=7.2 Hz, 2H), 4.59 (d, J=5.6 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.95 (t, J=5.2 Hz, 1H), 7.10-7.30 (m, 1H), 7.15 (dd, J=8.0 Hz, J2=1.6 Hz, 1H), 7.41 (d, J=78.4 Hz, 1H), 7.40-7.46 (m, 2H), 7.47 (d, J2=1.6 Hz, 1H), 7.54 (dt, J=8.0 Hz, J2=1.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 8.37-8.40 (m, 1H).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Vanillic Acid.

Example 20

Dabigatran Caffeate Etexilate

In a 50-mL round bottom flask, equipped with a magnetic stirring bar, 1 g of dabigatran etexilate was charged (1.593 mmol). 20 mL of acetone were transferred into the reaction flask and the mixture was stirred at room temperature until a total dissolution of the starting material was observed. 1 eq. of Caffeic Acid (1.593 mmol=287 mg) was added and the mixture was stirred at room temperature for 24 hours but no precipitate was observed. The reaction was allowed to evaporate at room temperature. When the reaction solvent was decreased to approx. 10 mL the formation of white precipitate was observed. The flask was capped and the reaction was stirred for additional 24 hours. The solid was recovered under vacuum, washed with ethyl acetate (20 mL×2) and dried at 40° C. for 72 hours. 928 mg of white solid were recovered (Y=72.1%).

1H-NMR (400 MHz, dmso-d6, 25° C.): δ ppm 0.87 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H), 1.26-1.34 (m, 6H), 1.54-1.60 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.94-4.00 (m, 4H), 4.22 (t, J=7.0 Hz, 2H), 4.59 (d, J=5.2 Hz, 2H), 6.16 (d, J=15.6 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.93-6.97 (m, 1H+1H), 7.02 (d, J=2.0 Hz, 1H), 7.10-7.13 (m, 1H), 7.15 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.41 (d, J=15.6 Hz, 1H), 7.46-7.47 (m, 1H), 7.52-7.56 (m, 1H), 7.79 (d, J=8.8 Hz, 2H), 8.37-8.40 (m, 1H).

By 1H-NMR the stoichiometric ratio is 1:1=dabigatran etexilate:Caffeic Acid.

Solubility Tests

General Procedures

The solubility tests were performed in a buffer solution at ph 4.5 and compared with the solubility data of dabigatran etexilate mesylate (commercial form). In the HPLC method herein below, acetonitrile was used to dissolve the active ingredient.

HPLC Method

Instrument: 1200 Infinity Series AGILENT

G4220B—1290 BinPumpVL

G4226A—1290 Sampler

G1316A—1260 TCC

G1314F—1260 VWD

Column: Kinetex 1.7 μm C8 100A, 100×3 mm, Phenomenex

Column Temperature: 30±0.3° C.

Mobile Phase: A: 0.1% Formic Acid in H₂O; B: ACN

Linear Gradient: t=0 A 75%-B 25%

• • t=4 A 25%-B 75%
  • t=6 A 0%-B 100%

Post run: 2 min.

Flow: 0.6 mL/min

Pressure initial: 600 bar

Flow Ramp up: 100 mL/min²

Flow Ramp down: 100 mL/min²

Jet Weaver: V100 Mixer

Detector Wavelength: 210 nm

Peakwidth: >0.0031 min (0.63 s resp. Time) (80 Hz)

Injection volume: 3 μl

Injection with needle ash: 3.0 sec.

Stop analysis: 7 min

Retention time: 2.62 min

Diluent: H₂O+0.1% Formic Acid/ACN=6/4

Thermodynamic Solubility Tests

The sample (approx. 50 mg) was weighted in a vial and left under magnetic stirring (approx. 300 rpm) in approx. 2 mL of buffer solution at 37° C. for 24 hours. The experiments were carried out at pH 4.5 and pH 6.8. The suspensions were filtered with 0.45 μm filter and analyzed by HPLC method previously reported. From the obtained area an opportune dilution of the sample was performed to obtain a value consistent with the Calibration Curve. Every diluted sample was analyzed by HPLC and the results were interpolated by the calibration curve.

Each experiment was replicated twice.

Sample          Average conc (μg/mL)
Mesylate pH 4.5 0.28
Gallate pH 4.5  0.40

Kinetic Dissolution

Experimental Conditions for Tablet Dissolution

Dissolution Medium: Phosphate Buffer pH 4.5

Temperature: 37±0.5° C.

Volume: 80 mL

Time: 2 hrs

Sample: Tablet (weight 200 mg)

Stirring: Paddle 100 rpm

Sampling time: 5 min, 15 min, 25 min, 35 min, 45 min, 60 min and 120 min.

Repetitions: 2 for each experiment

At the time fixed, withdraw 3 mL from each vessel. Reinstate the withdrawn volume.

Filter each solution with 0.20 μm filter, discarding the first 1 mL.

Preparation of the Tablet

A 13 mm tablet with 100 mg of the compound was prepared by a Digital Hydraulic Press (force applied approx 8 metric tons).

Preparation of the Sample

Each withdrawal was analyzed without further dilution.

Chromatographic Conditions

The sample was analyzed using the chromatographic conditions reported herein.

Time (min) Average Conc.
Dabigatran/mesylate 1/1 pH 4.5
5          6.86
15         9.09
25         11.40
35         13.28
45         15.96
60         18.55
120        26.44
Dabigatran/orotate 1/1 pH 4.5
5          8.76
15         11.06
25         12.26
35         13.74
45         15.52
60         17.21
120        28.89
Dabigatran/gallate 1/1 pH 4.5
5          10.01
15         28.10
25         44.94
35         62.45
45         75.18
60         90.21
120        106.50

As it can be seen from the above results, dabigatran etexilate orotate showed an unexpected high thermodynamic solubility, which is more than 1.4 times higher than the mesylate derivative.

Also in the kinetic dissolution test, dabigatran etexilate orotate showed a very high dissolution rate, which is more than 8.7 times higher than the mesylate derivative.

Also the orotate derivative showed an interesting dissolution rate which is comparable with respect to the mesylate salt.

Claims

1. A crystalline compound which comprises a mixture of dabigatran etexilate and a monocarboxylic acid selected from gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, hydrates and solvates thereof.

2. The crystalline compound according to claim 1, which is dabigatran etexilate gallate, hydrates and solvates thereof.

3. The crystalline compound according to claim 2, which comprises dabigatran etexilate gallate in a 1/1 molar ratio, hydrates and solvates thereof.

4. The crystalline compound according to claim 3, which is dabigatran etexilate gallate monohydrate showing the X-ray diffraction pattern of FIG. 54 and the FT-IT spectrum of FIG. 55.

5. The crystalline compound according to claim 1, which comprises dabigatran etexilate orotate, hydrates and solvates thereof.

6. The crystalline compound according to claim 5, which comprises dabigatran etexilate orotate in a 1/1 molar ratio, hydrates and solvates thereof.

7. The crystalline compound according to claim 6, which is dabigatran etexilate orotate anhydrous showing the X-ray diffraction pattern of FIG. 56 and the FT-IT spectrum of FIG. 57.

8. A process for the preparation of a crystalline compound according to claim 1, or a hydrate or solvate of such a crystalline compound, which comprises the following steps: a. dissolving dabigatran etexilate in a suitable solvent and add said monocarboxylic acid;b. optionally concentrating and/or heating the mixture of step (a);c. stirring the mixture at room temperature until the crystalline compound is formed; andd. isolating and optionally washing and/or drying the crystalline compound thus obtained.

9. The process according to claim 8, wherein step (a) involves the use of dabigatran etexilate tetrahydrate.

10. A process for the preparation of a crystalline compound according to claim 2, or a hydrate or solvate of such a crystalline compound, which comprises the following steps: a″. mixing and grinding dabigatran etexilate and gallic acid;b″. exposing the solid mixture to vapours of a suitable solvent;c″. optionally drying the new crystalline compound thus obtained.

11. The process according to claim 10, wherein step (a) involves the use of dabigatran etexilate tetrahydrate.

12. The process according to claim 10, wherein said solvent is dichloromethane.

13. A pharmaceutical composition which comprises a crystalline compound according to claim 1 as the active ingredient, and at least one pharmaceutically acceptable carrier or excipient.

14. A pharmaceutical composition which comprises a crystalline compound according to claim 2 as the active ingredient, and at least one pharmaceutically acceptable carrier or excipient.

15. A crystalline compound according to claim 1, for use in therapy.

16. A crystalline compound according to claim 1, for use in the prevention of thromboembolic events and in the prevention of stroke and systemic embolism.

17. A pharmaceutical composition according to claim 13, for use in therapy.

18. A pharmaceutical composition according to claim 13, for use in the prevention of thromboembolic events and in the prevention of stroke and systemic embolism.