CN105732584A - Dabigatran etexilate 2-ketoglutarate crystal form I, preparation method and application thereof - Google Patents
Dabigatran etexilate 2-ketoglutarate crystal form I, preparation method and application thereof Download PDFInfo
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- CN105732584A CN105732584A CN201410768700.5A CN201410768700A CN105732584A CN 105732584 A CN105732584 A CN 105732584A CN 201410768700 A CN201410768700 A CN 201410768700A CN 105732584 A CN105732584 A CN 105732584A
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- dabigatran etcxilate
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Abstract
The invention relates to a dabigatran etexilate 2-ketoglutarate crystal form I, a preparation method and an application thereof. According to Cu-K[alpha] radiation, the dabigatran etexilate 2-ketoglutarate crystal form I has main diffraction peaks at the reflection angles 2[theta] of 4.42 +/- 0.2 degrees, 15.20 +/- 0.2 degrees, 17.82 +/- 0.2 degrees, 18.70 +/- 0.2 degrees, 21.64 +/- 0.2 degrees and 24.66 +/- 0.2 degrees, wherein the intensity of the diffraction peak at the 4.42 +/- 0.2 degree is 100%. The dabigatran etexilate 2-ketoglutarate crystal form I has better stability and bioavailability than dabigatran etexilate mesylate, can be prepared in a reproducing manner, and can be used for preparing a medicine composition for preventing deep venous thrombosis and stroke after operation.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to the crystal formation I of a kind of dabigatran etcxilate 2-oxoglutaric acid salt, its preparation method and the purposes as medicine thereof.
Background technology
Dabigatran etcxilate (DabigatranEtexilate) is the novel anticoagulation medicine with various features of Boehringer Ingelheim company of Germany exploitation.In April, 2008, first in Germany and Britain's listing, commodity are called Pradaxa, are used for preventing and treating Acute Venous thrombosis (VTE), are that over 50 years, the anticoagulation of first listing is administered orally new drug after warfarin.
Dabigatran etcxilate is the benzimidazoles compound of a kind of replacement, chemical name 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl] (pyridine-2-base) amino] ethyl propionate, its molecular structural formula is as follows:
Molecular formula: C34H41N7O5, molecular weight: 627.74
Dabigatran etcxilate dissolubility in water is less, and under the impact of pharmaceutic adjuvant and preventing, it is not easy dissolution in pharmaceutical preparation, makes the preparation of pharmaceutical preparation be subject to many limitations.Additionally, the dabigatran etcxilate mesylate (referring to Chinese patent CN1675193A) listed has the defects such as less stable, bioavailability be low, it is thus desirable to find the compound being more suitable for medicinal dabigatran etcxilate, to meet market and the demand of relevant disease preventing and controlling.
Chinese patent CN102633777A discloses dabigatran etcxilate 2-oxoglutaric acid salt (formula A compound) and hydrate thereof and solvate, and the name of formula A compound is called 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl] (pyridine-2-base) amino] ethyl propionate 2-oxoglutaric acid salt.Report claim this compound have better water solublity and higher stability and bioavailability than mesylate.But in this patent specification, it does not have the information relevant with the crystallographic property of dabigatran etcxilate 2-oxoglutaric acid salt is provided.
For the purposes of medicine, the active substance having contained therein is necessary for homogeneous crystal modification form to guarantee reliable bioavailability.The method being highly desirable to provide the product of form uniform and pure in morphology in reproducible mode in pharmaceuticals industry.Known different polymorphic can show different key characters (such as dissolution time, chemical stability and bioavailability).
From technological standpoint, it is contemplated that polymorphic forms has different processing (filtration, dry, dissolving and tabletting) character, and in morphology, the preparation of uniform product is also important.Additionally, be also very important in terms of economic point of view, because described method is applicable to industrial scale applications, it is possible to easily reproduce and produce uniform product in morphology.
Not yet describe in the literature for preparing uniform salt method in the morphology that dabigatran etcxilate and 2-oxoglutaric acid are formed up to now, be still not provided for characterizing the analytical data (DSC spectrogram, X-ray powder diffraction figure or single crystal X-ray diffraction figure) of described crystal formation.
Summary of the invention
It is an object of the present invention to provide a kind of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I.
The preparation method that it is yet a further object of the present invention to provide a kind of described dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I.
It is yet a further object of the present invention to provide a kind of pharmaceutical composition, described compositions contains dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I and one or more medicinal supporting agent or diluent.
Further an object is that of the present invention provides a kind of described dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I preparing the application suitable in the formation and antiapoplectic medicine of postoperative prevention of deep vein thrombosis.
Dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the present invention can meet the pharmaceutical requirements about better physicochemical property and stability and higher bioavailability requirement.
The crystal formation I of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention passes through X-ray powder diffraction analysis (referring to Fig. 1), it is thus achieved that data as shown in table 1:
Table 1: the X-ray powder diffraction of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I and intensity (normalized)
In table 1 above, numerical value " 2 θ [°] " is the angle of diffraction represented with the number of degrees, and numerical value " dhkl value" be withRepresent the specific distance between lattice plane.
Within the scope of this invention, X-ray powder diffraction figure uses equipped with position sensing detector (OED) and a Cu anode (Cu-K as x-ray sourceαRadiation,40kv, 40mA) the advanced diffractometer of BrukerD8 absorb.
The crystal formation I of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention is characterized by: its fusing point Tm.p..=130 ± 5 DEG C (measure with DSC Differential Scanning Calorimetry algoscopy；Use peak-peak is assessed；The rate of heat addition: 10 DEG C/min).Shown numerical value is to use the TGA-DSC1 manufactured by MettlerToledo to measure (referring to Fig. 2).
The invention provides the method preparing dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I, can be obtained by following steps:
A) at a certain temperature, by be dissolved in acetone 2-oxoglutaric acid solution be added slowly to be dissolved in the dabigatran etcxilate of acetone, stir into salt；
B) stirring and crystallizing at a certain temperature, through filtering, washing, dried, obtains dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I.
The mol ratio of described 2-oxoglutaric acid and described dabigatran etcxilate is 0.8～1.5, it is preferred to 0.9～1.2.
Temperature described in step a be 0 DEG C to reflux temperature, it is preferred to 15～45 DEG C.
Temperature described in step b is 0～40 DEG C, it is preferred to 10～30 DEG C.It will be appreciated by those skilled in the art that, the diffraction pattern obtained by crystalline compounds is distinctive often for a kind of given crystal habit, although weak or very weak diffraction maximum is likely to not always to occur in the same diffraction pattern obtained by the crystallization of continuous sample lots.The change of the advantage orientation effect that the relative intensity of the especially low 2 θ angle X-ray incidence values of bands of a spectrum may produce because of the difference by crystal habit, particle diameter and other condition determination etc. and change, therefore, for a certain crystal habit, the relative intensity of diffraction maximum is not distinctive.When judging whether two kinds of crystal formations are same crystal formation, it is further noted that the relative position at peak rather than their amplitude.Each XRD peak in various sample is typically in about the 0.3～12 of broad peak in θ °.Wider XRD peak can be made up of the two or more peaks being closely packed together.For isolated spike, in continuous print XRD analysis, generally find peak in θ ° about 0.22.Assuming that with the XRD spectrum of identical a kind of compound of Instrument measuring in continuous print XRD analysis, then the difference of XRD peak position is mainly due in sample preparation or caused by the difference of sample self purity.When we identify, at the given position of the 2 θ values given, the XRD spike that isolates, it means that this peak is in this 2 θ value ± 0.2；When we identify an XRD broad peak at the given position of the 2 θ values given, it means that this peak is in this 2 θ value ± 0.3.
Additionally, the dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the present invention has but is not limited to following beneficial effect:
1) relative to dabigatran etcxilate mesylate, dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I provided by the present invention has good stability.Such as, dabigatran etcxilate mesylate was degraded to content less than 20% at 7 days under hot and humid condition, and dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I then still has the content of nearly 98%.
2) the dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the present invention has good water solublity, is experimentally verified that, and its dissolubility in water is up to 2.6mg/mlH2O (temperature 25 DEG C), and dabigatran etcxilate mesylate is 1.8mg/mlH2O (temperature 25 DEG C).Thus the dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the present invention has relatively, and dabigatran etcxilate mesylate is more preferably or at least suitable bioavailability.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I；
Fig. 2 is the DSC collection of illustrative plates of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I.
Detailed description of the invention
Be will assist in by following embodiment and understand the present invention, but be not intended that limitation of the present invention.In entire disclosure, any and whole publicly available lists of references arrived, each through reference and list in present patent application.Those of ordinary skill in the art it is also understood that and all fall within technical solution of the present invention is made any without departing substantially from the change of spirit and scope of the invention, amendment with equivalent replace within the scope of the present invention.
Embodiment 1: the preparation of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I
Dabigatran etcxilate 1.0g (1.6mmol) is joined in 20mL acetone, stirring and dissolving at 25～30 DEG C, drip the acetone 3mL dissolved with 2-oxoglutaric acid 0.21g (1.4mmol), 1h is stirred under said temperature, cool the temperature to 10～15 DEG C of stirring and crystallizing 2h subsequently, sucking filtration, gained is deposited in the air dry oven of 40 DEG C and dries more than 4h, obtain the dabigatran etcxilate 2-oxoglutaric acid salt of 1.02g (yield 91.4%) crystal formation I, HPLC purity is 99.60%, fusing point: 133～135 DEG C, moisture: 0.35%.
Elementary analysis:
C34H41N7O5(627.74)·1/nC4H6O5
Discovery value: C63.37N14.45H6.43O15.75
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate crystal formation I is:
Embodiment 2: the preparation of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I
Dabigatran etcxilate 1.0g (1.6mmol) is joined in 30mL acetone, stirring and dissolving at 35～40 DEG C, drip the acetone 5mL dissolved with 2-oxoglutaric acid 0.23g (1.6mmol), 1h is stirred under said temperature, cool the temperature to 20～25 DEG C of stirring and crystallizing 2h subsequently, sucking filtration, gained is deposited in the air dry oven of 40 DEG C and dries more than 4h, obtain the dabigatran etcxilate 2-oxoglutaric acid salt of 1.12g (yield 90.7%) crystal formation I, HPLC purity is 99.46%, fusing point: 129～131 DEG C, moisture: 0.33%.
Elementary analysis:
C34H41N7O5(627.74)·1/nC4H6O5
Discovery value: C63.33N14.50H6.43O15.74
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate crystal formation I is:
Embodiment 3: the preparation of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I
Dabigatran etcxilate 1.0g (1.6mmol) is joined in 25mL acetone, stirring and dissolving at 40～45 DEG C, drip the acetone 6mL dissolved with 2-oxoglutaric acid 0.28g (1.9mmol), under said temperature, stir 1h cool the temperature to 10～15 DEG C of stirring and crystallizing 2h subsequently, sucking filtration, gained is deposited in the air dry oven of 40 DEG C and dries more than 4h, obtain the dabigatran etcxilate 2-oxoglutaric acid salt of 1.09g (yield 88.5%) crystal formation I, HPLC purity is 99.36%, fusing point: 126～128 DEG C, moisture: 0.34%.
Elementary analysis:
C34H41N7O5(627.74)·1/nC4H6O5
Discovery value: C63.36N14.49H6.42O15.73
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate crystal formation I is:
Embodiment 4: the preparation of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I
Dabigatran etcxilate 1.0g (1.6mmol) is joined in 30mL acetone, stirring and dissolving at 30～35 DEG C, drip the acetone 3mL dissolved with 2-oxoglutaric acid 0.21g (1.4mmol), 1h is stirred under said temperature, cool the temperature to 15～20 DEG C of stirring and crystallizing 2h subsequently, sucking filtration, gained is deposited in the air dry oven of 40 DEG C and dries more than 4h, obtain the dabigatran etcxilate 2-oxoglutaric acid salt of 1.00g (yield 90.1%) crystal formation I, HPLC purity is 99.40%, fusing point: 129～131 DEG C, moisture: 0.37%.
Elementary analysis:
C34H41N7O5(627.74)·1/nC4H6O5
Discovery value: C63.35N14.47H6.43O15.75
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate crystal formation I is:
Embodiment 5: stability test
The dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of embodiment 1 is observed and makees assay by inventor under different temperatures and damp condition, and data are in Table 2 and table 3.
Liquid-phase condition:
Chromatographic column: AgelaVenusilMPC18 post (4.6mm × 250mm, 5 μm) NO:VA952505-0
Mobile phase: 0.01mol L-1Diammonium phosphate buffer-methanol (40:60)
Flow velocity: 1ml min-1；Detection wavelength: 250nm；Column temperature: 25 DEG C；Sample size: 20 μ l
The changes of contents of table 2 dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I and dabigatran etcxilate mesylate
Table 2 is the content contrast through influence factor's result of the test of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I and mesylate.Data show, (seal high temperature and hot and humid) under the same conditions, and the former content changes over less, and the latter's extremely unstable under hot and humid condition, can be degraded under 7 days these conditions less than 20%, show obvious unstability.
The cosmetic variation of table 3 dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I and dabigatran etcxilate mesylate
As known from Table 3, sealing under hot conditions, the color of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I is almost without change, and dabigatran etcxilate mesylate is it is observed that color produces significant change in time.Under hot and humid condition, though the former color changes but little, and the color of the latter changes clearly and the phenomenon that occurs hardening, it was shown that its moisture absorption is serious.
Embodiment 6
The present embodiment is used for the preparation of the pharmaceutical composition of the prepared dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the method according to the present invention that illustrates.
Dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Weigh dabigatran etcxilate hydrobromic acid, microcrystalline Cellulose and lactose by recipe quantity and be sufficiently mixed uniformly, add 1% (weight/volume) hypromellose aqueous solution, soft material processed, sieve, wet granular processed, dry in 55 DEG C.Polyvinylpolypyrrolidone and magnesium stearate are added in above-mentioned granule, measure intermediates content, tabletting, packaging.
Embodiment 7
The present embodiment is used for the preparation of the pharmaceutical composition of the prepared dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the method according to the present invention that illustrates.
Dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Weigh dabigatran etcxilate hydrobromic acid, microcrystalline Cellulose, pregelatinized Starch and lactose by recipe quantity and be sufficiently mixed uniformly, add 1% (weight/volume) hypromellose aqueous solution, soft material processed, sieve, wet granular processed, dry in 55 DEG C.Magnesium stearate is added in above-mentioned granule, measures intermediates content, encapsulated, packaging.
Embodiment 8
The present embodiment is used for the preparation of the pharmaceutical composition of the prepared dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the method according to the present invention that illustrates.
Dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Weigh dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I by recipe quantity, lactose, mannitol, aspartame, essence are sufficiently mixed, add 2% (weight/volume) hypromellose aqueous solution soft material, 16 mesh sieves are granulated, 55 DEG C dry, 14 mesh sieve granulate, measure intermediates content and moisture, packaging, prepare 100 bags of granules altogether.
Embodiment 9
The present embodiment is used for the preparation of the pharmaceutical composition of the prepared dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I of the method according to the present invention that illustrates.
Dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Weigh dabigatran etcxilate hydrobromic acid, polyvidone, aspartame and essence elder generation mix homogeneously by recipe quantity, then be sufficiently mixed uniformly with mannitol, microcrystalline Cellulose and lactose successively, be eventually adding magnesium stearate mix homogeneously, measure intermediates content, tabletting, packaging.
Although present invention has been a degree of description, it will be apparent that, without departing from the spirit and scope of the present invention when, can carry out the suitable change of each condition.Being appreciated that and the invention is not restricted to described embodiment, and be attributed to scope of the claims, it includes the equivalent replacement of described each factor.
Claims (8)
1. a dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I, it is characterised in that: X-ray diffraction uses Cu-KαRadiation, characterizes with angle of reflection 2 θ, and having main diffraction peak, described range of error at 4.42,15.20,17.82,18.70,21.64,24.66 places is ± 0.2.
2. dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I as claimed in claim 1, it is characterised in that: described powder X-ray diffractogram has the feature that
3. the preparation method of a dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I as claimed in claim 1 or 2, it is characterised in that: a) at a certain temperature, the 2-oxoglutaric acid being dissolved in acetone is added in the dabigatran etcxilate being dissolved in acetone, stir into salt；B) stirring and crystallizing at a certain temperature, through filtering, washing, dried, obtains dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I.
4. the preparation method of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I as claimed in claim 3, it is characterised in that: the mol ratio of described 2-oxoglutaric acid and described dabigatran etcxilate is 0.8～1.5, it is preferred to 0.9～1.2.
5. the preparation method of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I as claimed in claim 3, it is characterised in that: temperature described in step a be 0 DEG C to reflux temperature, it is preferred to 15～45 DEG C.
6. the preparation method of dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I as claimed in claim 3, it is characterised in that: temperature described in step b is 0～40 DEG C, it is preferred to 10～30 DEG C.
7. a pharmaceutical composition, it is containing, for example the dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I described in claim 1 or 2 and one or more medicinal supporting agent or diluent.
8. dabigatran etcxilate 2-oxoglutaric acid salt crystal formation I as claimed in claim 1 is applicable to the formation of postoperative prevention of deep vein thrombosis and the purposes of antiapoplectic medicine in preparation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348259A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate oxaloacetate, preparation method and applications thereof |
| CN105348260A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate hydrobromide, preparation method and applications thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008043759A1 (en) * | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
| CN102633777A (en) * | 2012-03-31 | 2012-08-15 | 天津药物研究院 | Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof |
| CN103304539A (en) * | 2012-03-07 | 2013-09-18 | 天津药物研究院 | Dabigatran etexilate malate, and preparation method and application thereof |
-
2014
- 2014-12-12 CN CN201410768700.5A patent/CN105732584A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008043759A1 (en) * | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
| CN103304539A (en) * | 2012-03-07 | 2013-09-18 | 天津药物研究院 | Dabigatran etexilate malate, and preparation method and application thereof |
| CN102633777A (en) * | 2012-03-31 | 2012-08-15 | 天津药物研究院 | Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348259A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate oxaloacetate, preparation method and applications thereof |
| CN105348260A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate hydrobromide, preparation method and applications thereof |
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Application publication date: 20160706 |