CN106032375A - Dabigatran etexilate of crystal variant form F, preparation method and uses thereof - Google Patents
Dabigatran etexilate of crystal variant form F, preparation method and uses thereof Download PDFInfo
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- CN106032375A CN106032375A CN201510117031.XA CN201510117031A CN106032375A CN 106032375 A CN106032375 A CN 106032375A CN 201510117031 A CN201510117031 A CN 201510117031A CN 106032375 A CN106032375 A CN 106032375A
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- dabigatran etcxilate
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention provides a dabigatran etexilate of a crystal variant form F, a preparation method and uses thereof, wherein the x-ray powder diffraction pattern of the dabigatran etexilate of the crystal variant form F is shown in a picture 1, and the DSC spectrum is shown in a figure 2. According to the present invention, the moisture absorption property and the stability of the dabigatran etexilate of the crystal variant form F are superior to the dabigatran etexilate of the crystal form I reported in the patent CN 101189224; and the preparation method is easy to industrialize, and the production adaptability is strong.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of crystal modification form F dabigatran etcxilate and
Preparation Method And The Use.
Background technology
Dabigatran etcxilate (Dabigatran Etexilate) is that having of Boehringer Ingelheim company of Germany exploitation is multiple
The novel anticoagulation medicine of feature.In April, 2008, first list in Germany and Britain, trade name Pradaxa,
For preventing and treating Acute Venous thrombosis (VTE), it it is the anticoagulation mouth of first listing over 50 years after warfarin
Take new drug, be anticoagulation therapy field and another milestone in potential lethal thrombus prevention field.The U.S.
Food and Drug Administration's approval Pradaxa capsule on October 19th, 2010 (dabigatran etcxilate) are
Prevention of stroke and blood coagulation in having rhythm abnormality (atrial fibrillation) patient.
Dabigatran etcxilate, chemistry entitled (Z)-3-(2-(((4-(N '-((hexyloxy) carbonyl) amidino) benzene
Base) amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzimidazole-5-formamido) ethyl propionate,
Molecular structure is shown in formula I:
It is known that solid chemical material can be to be divided into crystalline state, unformed shape and eutectic state form.Same solid
The different existences of medicine often have different physicochemical properties, such as dissolubility and dissolution etc..Medicine
Existence and polymorphous research are in the stability during guarantee pharmaceutical production storage and Clinical practice
Safety and effectiveness has and important meaning.The existence of medicine is relevant with drug molecular structure with crystal formation,
The most also relevant with method for crystallising during preparation.The most existing multinomial about dabigatran etcxilate crystal formation and preparation side thereof
The invention of method.
Summary of the invention
It is an object of the present invention to provide the dabigatran etcxilate of a kind of crystal modification form F, its Functionality, quality and appealing design
Good, HPLC detection purity reaches more than 99%.
It is a further object to provide the preparation method of the dabigatran etcxilate of above-mentioned crystal modification form F,
Technique simple possible, favorable reproducibility.
It is also another object of the present invention to provide the pharmaceutical composition of dabigatran etcxilate containing crystal modification form F
Pharmaceutical applications with the dabigatran etcxilate of this crystal modification form.
For achieving the above object, the invention provides following technical scheme:
The dabigatran etcxilate of a kind of crystal modification form F, its X-ray powder diagram is as shown in Figure 1.Enter one
Step ground, the dabigatran etcxilate of described crystal modification form F has the feature of the DSC spectrogram shown in Fig. 2.
Invention further provides the preparation method of the dabigatran etcxilate of described crystal modification form F, the method
Comprise the following steps:
(1) dabigatran etcxilate is dissolved in dichloromethane formation solution, or prepares the reaction of dabigatran etcxilate
Solution；
(2) adding petroleum ether in the solution of step (1), stirring separates out crystal, and crystal is collected by filtration,
Obtain the dabigatran etcxilate of described crystal modification form F.
The preparation method provided according to the present invention, in step (1), relative to 1 gram of dabigatran etcxilate, two
The consumption of chloromethanes is 0.5～25ml, preferably 2～20ml.Preferably, described step (1) can also include
It is heated to making dabigatran etcxilate dissolve under 30 DEG C～reflux temperature.
In step (2), relative to 1 gram of dabigatran etcxilate, the consumption of petroleum ether is 0.5～50ml, preferably
It is 5～40ml.
The preparation method provided according to the present invention, it is preferable that after described step (2) also includes adding petroleum ether
Solution is made to be cooled to-5～30 DEG C, preferably 5～25 DEG C, or in step (2), the temperature of petroleum ether is
5～30 DEG C, preferably 10～25 DEG C.
The preparation method provided according to the present invention, wherein, described step (1) also includes making in accordance with the following methods
Standby dabigatran etcxilate: by N-[[2-(((4-carbamimido-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzimidazole-5-
Base)-carbonyl]-N-(pyridine-2-base)-Beta-alanine ethyl ester and the most own ester of chloro-carbonic acid, at oxolane and water
Solution of potassium carbonate reacts under room temperature, after having reacted, separates organic layer, be dried with anhydrous magnesium sulfate, mistake
Filter obtains the reaction solution containing dabigatran etcxilate, is concentrated to dryness by this reactant liquor and i.e. obtains dabigatran etcxilate.
Above-mentioned preparation method can be carried out according to document report, such as, may refer to CN1248251A.
In a kind of preferred embodiment of the present invention, the preparation of the dabigatran etcxilate of described crystal modification form F
Method is: is dissolved in 2～20ml dichloromethane by dabigatran etcxilate 1g under 30 DEG C～reflux temperature and makes solution,
The petroleum ether 5～40ml of 5～25 DEG C adds stirring in this solution separate out, filter, be dried, obtain the present invention and carry
The dabigatran etcxilate of crystal modification form F of confession.
In another specific embodiments of the present invention, the system of the dabigatran etcxilate of described crystal modification form F
Preparation Method is: by N-[[2-(((4-carbamimido-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzimidazole-5-base)-
Carbonyl] to be dissolved in concentration of potassium carbonate be 80g/L for-N-(pyridine-2-base)-Beta-alanine ethyl ester and the most own ester of chloro-carbonic acid
Oxolane and water (volume ratio 5:1) solution in react at normal temperatures, after having reacted, separate organic
Layer, is dried with anhydrous magnesium sulfate, filters magnesium sulfate, obtain the reaction solution containing dabigatran etcxilate.Should
Reaction solution is concentrated to dryness, and then dissolves with dichloromethane, adds petroleum ether, crystallize, filter under stirring,
Washing final vacuum is dried, and obtains the dabigatran etcxilate of crystal modification form F that the present invention provides.
The dabigatran etcxilate solid of crystal modification form F prepared by the present invention or its pharmaceutical composition, concrete structure
Feature is as follows:
1.X-ray powder diffraction detects
Instrument: Rigaku D/max25000 type X-ray diffractometer；
Target: Cu-K α radiates2 θ sweep limitss: 0-50 °；
Step angle: 0.04 DEG C；
The calculating time: 0.5 second；
Pipe pressure: 40KV；
Pipe flow: 100mA；
Scanning speed: 8 DEG C/min；
Filter disc: graphite monochromator；
The X-ray powder diffraction detection of the dabigatran etcxilate solid of the present invention is shown as crystal modification form, as
Shown in Fig. 1.
2.DSC detects
Temperature range: 30～200 DEG C；
Sweep speed: 10 DEG C/min；
DSC fusing point Tmp.=135 ± 5 DEG C of the dabigatran etcxilate solid of the present invention, as in figure 2 it is shown, by
Big peak value assessment.
Invention further provides a kind of pharmaceutical composition, this pharmaceutical composition comprises the crystal modification of the present invention
The dabigatran etcxilate of form F or the dabigatran etcxilate of crystal modification form F prepared according to the inventive method,
And one or more pharmaceutic adjuvants.Wherein said pharmaceutical composition is oral formulations or injection, preferred port
Formulation.Such as tablet, capsule, granule, oral liquid etc..
The pharmaceutical composition provided according to the present invention, wherein, one or more pharmaceutic adjuvants described include: dilution
Agent, disintegrating agent, solvent, stabilizer binding agent and lubricant etc..Wherein diluent includes but not limited to: form sediment
Powder, microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose, low molecular dextran, chlorination
Sodium or mannitol etc..Described binding agent includes but not limited to: water, ethanol, starch slurry, syrup, gelatin,
Methylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium alginate or polyvinylpyrrolidine
Ketone etc..Described lubricant includes but not limited to: magnesium stearate, stearic acid, sodium stearyl fumarate etc..
Described disintegrating agent includes but not limited to: starch, carboxymethyl starch sodium, citric acid, sodium bicarbonate and low replacement
Hydroxypropyl cellulose etc..Described stabilizer includes but not limited to: BHA, BHT, vitamin C, metal chelating
Mixture EDTA-2Na etc..
Invention further provides the dabigatran etcxilate of crystal modification form F of the present invention or according to this
The dabigatran etcxilate of crystal modification form F that bright method prepares is preparation answering in the medicine treating thrombosis
With.The dabigatran etcxilate solid of crystal modification form F that present invention discover that has solid with known dabigatran etcxilate
The identical purposes of body compound itself and therapeutic effect.
What the dabigatran etcxilate of crystal modification form F that the present invention provides had has the active effect that
1. described in, the dabigatran etcxilate of crystal modification form F is easier to make pharmaceutical preparation, improves the suction of medicine
Receive.Known dabigatran etcxilate is poorly water soluble drugs, by comparison, and crystal modification form F of the present invention
Dabigatran etcxilate has more preferable dissolution release behavior when making pharmaceutical preparation.The crystal modification shape of the present invention simultaneously
The dabigatran etcxilate preparation method of state F is prone to industrialization, produces strong adaptability.
2. the dabigatran etcxilate of crystal modification form F that prepared by the present invention shows in terms of dissolution and preparation preparation
Going out valuable characteristic, have quality high, dissolubility is good, beneficially the advantage such as absorption.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
The X-ray powder diffraction spectrum of the dabigatran etcxilate of crystal modification form F that Fig. 1 present invention provides；
The DSC collection of illustrative plates of the dabigatran etcxilate of crystal modification form F that Fig. 2 present invention provides；
The X-ray of the dabigatran etcxilate crystal formation I that Fig. 3 is prepared according to the method that patent CN101189224 is reported
Powder diffraction spectrum.
Detailed description of the invention
Being further described in detail the present invention below in conjunction with detailed description of the invention, the embodiment be given is only
In order to illustrate the present invention rather than in order to limit the scope of the present invention.
Embodiment 1
By dabigatran etcxilate 1g in room temperature is dissolved in 2ml dichloromethane, in the settled solution of gained, drip stone
Oil ether 10ml, stirring separates out, and filters, and is dried, and collects the dabigatran of crystal modification form F of the present invention
It is 99.69% that ester powder 0.83g, HPLC measure content.Its X-ray powder diffraction spectrum as it is shown in figure 1,
DSC collection of illustrative plates is as shown in Figure 2.
Embodiment 2
By dabigatran etcxilate 1g in room temperature is dissolved in 5ml dichloromethane, in the settled solution of gained, drip stone
Oil ether 15ml, stirring separates out, and filters, and is dried, and collects the dabigatran of crystal modification form F of the present invention
It is 99.74% that ester powder 0.80g, HPLC measure content.Its X-ray powder diffraction spectrum as it is shown in figure 1,
DSC collection of illustrative plates is as shown in Figure 2.
Embodiment 3
Dabigatran etcxilate 1g is dissolved in 20ml dichloromethane at 5 DEG C, drips in the settled solution of gained
Petroleum ether 40ml, stirring separates out, and filters, and is dried, and collects the Da Bijia of crystal modification form F of the present invention
It is 99.52% that group ester powder 0.87g, HPLC measure content.Its X-ray powder diffraction spectrum such as Fig. 1 institute
Showing, DSC collection of illustrative plates is as shown in Figure 2.
Embodiment 4
Dabigatran etcxilate 1g is dissolved in 20ml dichloromethane at 10 DEG C, drips in the settled solution of gained
Adding petroleum ether 15ml, stirring separates out, and filters, and is dried, collect the present invention crystal modification form F reach ratio
Add crowd ester powder 0.79g, HPLC measuring content is 99.46%.Its X-ray powder diffraction spectrum such as Fig. 1
Shown in, DSC collection of illustrative plates is as shown in Figure 2.
Embodiment 5
Dabigatran etcxilate 1g is dissolved in 10ml dichloromethane at 35 DEG C, drips in the settled solution of gained
Adding petroleum ether 10ml, finish, make solution be cooled to 25 DEG C, stirring separates out, and filters, and is dried, collects this
It is 99.21% that the dabigatran etcxilate powder 0.75g, HPLC of bright crystal modification form F measures content.Its
X-ray powder diffraction spectrum as it is shown in figure 1, DSC collection of illustrative plates as shown in Figure 2.
Embodiment 6
Dabigatran etcxilate 1g is dissolved in 15ml dichloromethane under reflux temperature, to the settled solution of gained
Middle dropping petroleum ether 40ml, finishes, and makes solution be cooled to 20 DEG C, and stirring separates out, and filters, and is dried, and collects
It is 99.16% that the dabigatran etcxilate powder 0.72g, HPLC of crystal modification form F of the present invention measures content.
Its X-ray powder diffraction spectrum as it is shown in figure 1, DSC collection of illustrative plates as shown in Figure 2.
Embodiment 7
The present embodiment is for illustrating that (sample is embodiment 1 to the dabigatran etcxilate of crystal modification form F of the present invention
Obtain) with the dabigatran etcxilate hygroscopicity comparative study of crystal formation I of patent CN101189224 report.
The preparation of dabigatran etcxilate crystal formation I: 15g dabigatran etcxilate is dissolved in 120mL under reflux temperature
In ethyl acetate, this solution is cooled to 30～35 DEG C, is stirred at a temperature of this 60 minutes, then lowers the temperature
It is stirred for 60 minutes to 15～20 DEG C, sucking filtration, washs filter cake by 30mL ethyl acetate, by filter cake in 40～50
DEG C forced air drying 4h, obtains dabigatran etcxilate 12.75g, demonstrate,proves through X-ray powder diffraction (spectrogram is shown in Fig. 3)
Bright product is dabigatran etcxilate crystal formation I.
Instrument: LHS-100CL constant temperature and humidity temperature-controlled box；Mettler AE163 balance
Foundation: Japan specialized hospital pharmacists understands material in April, 2013 (the 9th edition)
Test condition: at 60 DEG C, samples after placing 7 days and weigh under conditions of 100%RH.
The results are shown in Table 1.
Table 1 hygroscopicity comparative test result
| Crystal formation/experimental condition | 60 DEG C, 100%RH, 7 days |
| Dabigatran etcxilate crystal formation I increases weight (%) | 6.87% |
| Dabigatran etcxilate crystal modification form F weightening finish (%) | 4.78% |
It is appreciated that from the data of table 1 hygroscopicity of dabigatran etcxilate crystal modification form F is better than crystal formation I.
Embodiment 8
The present embodiment is for illustrating that (sample is embodiment 1 to the dabigatran etcxilate of crystal modification form F of the present invention
Obtain) with the dabigatran etcxilate stability comparative study of crystal formation I of patent CN101189224 report.
Foundation: Japan specialized hospital pharmacists understands material in April, 2013 (the 9th edition)
Liquid-phase condition:
Chromatographic column: Agela Venusil MP C18 post (4.6mm × 250mm, 5 μm) NO:VA952505-0
Flowing 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 results are shown in Table 2.
Table 2 stability comparative test result
It is appreciated that from the data of table 2 the stability entirety of dabigatran etcxilate crystal modification form F is better than crystal formation
I。
Embodiment 9
The present embodiment is for illustrating the pharmaceutical composition of the dabigatran etcxilate of crystal modification form F of the present invention
Preparation.
The dabigatran etcxilate of crystal modification form F is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Claim by recipe quantity
Take the dabigatran etcxilate of crystal modification form F, microcrystalline Cellulose, pregelatinized Starch and lactose to be sufficiently mixed all
Even, add 1% (weight/volume) hypromellose aqueous solution, soft material processed, sieve, wet granular processed,
It is dried in 55 DEG C.Magnesium stearate is added in above-mentioned granule, measures intermediates content, encapsulated, packaging.
Embodiment 10
The present embodiment is for illustrating the pharmaceutical composition of the dabigatran etcxilate of crystal modification form F of the present invention
Preparation.
The dabigatran etcxilate of crystal modification form F is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Claim by recipe quantity
Take the dabigatran etcxilate of crystal modification form F, microcrystalline Cellulose and lactose and be sufficiently mixed uniformly, add 1% (weight
Amount/volume) hypromellose aqueous solution, soft material processed, sieve, wet granular processed, it is dried in 55 DEG C.
Polyvinylpolypyrrolidone and magnesium stearate are added in above-mentioned granule, measure intermediates content, tabletting, packaging.
The embodiment conventional due to the present invention describes, and those skilled in the art can be to it
Modifying and equivalence changes, this is understood as included within the scope of the present invention.
Claims (8)
1. a dabigatran etcxilate for crystal modification form F, its X-ray powder diffraction is as shown in Figure 1.
The dabigatran etcxilate of crystal modification form F the most according to claim 1, it is characterised in that DSC collection of illustrative plates
As shown in Figure 2.
The preparation method of the dabigatran etcxilate of crystal modification form F the most according to claim 1 or claim 2, the method
Comprise the following steps:
(1) dabigatran etcxilate is dissolved in dichloromethane formation solution, or the reaction preparing dabigatran etcxilate is molten
Liquid；
(2) adding petroleum ether in the solution of step (1), stirring separates out crystal, and crystal is collected by filtration, i.e.
Obtain the dabigatran etcxilate of described crystal modification form F.
4. according to the preparation method described in claim 3, in step (1), relative to 1 gram of dabigatran etcxilate,
The consumption of dichloromethane is 0.5～25ml, preferably 2～20ml；In step (2), relative to 1 gram
Dabigatran etcxilate, the consumption of petroleum ether is 0.5～50ml, preferably 5～40ml.
5. according to the preparation method described in claim 3, wherein, described step (2) also includes adding petroleum ether
After make solution be cooled to-5～30 DEG C, preferably 5～25 DEG C, or in step (2), the temperature of petroleum ether
Degree is 5～30 DEG C, preferably 10～25 DEG C.
Preparation method the most according to claim 3, wherein, described step (1) also includes in accordance with the following methods
Prepare dabigatran etcxilate: by N-[[2-(((4-carbamimido-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzo miaow
Azoles-5-base)-carbonyl]-N-(pyridine-2-base)-Beta-alanine ethyl ester and the most own ester of chloro-carbonic acid, at tetrahydrochysene furan
Mutter and the solution of potassium carbonate of water reacts under room temperature, after having reacted, separating organic layer, use anhydrous slufuric acid
Magnesium is dried, and is filtrated to get the reaction solution containing dabigatran etcxilate, is concentrated to dryness by this reactant liquor and i.e. obtains
Dabigatran etcxilate.
7. a pharmaceutical composition, this pharmaceutical composition comprises crystal modification form F described in claim 1 or 2
Dabigatran etcxilate or according to method according to any one of claim 3 to 6 prepare crystal modification shape
The dabigatran etcxilate of state F, and one or more pharmaceutic adjuvants.
8. crystal modification form F described in claim 1 or 2 dabigatran etcxilate or according to claim 3 to 6
According to any one of the dabigatran etcxilate of crystal modification form F for preparing of method be used for treating thrombosis in preparation
Medicine in application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510117031.XA CN106032375A (en) | 2015-03-17 | 2015-03-17 | Dabigatran etexilate of crystal variant form F, preparation method and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510117031.XA CN106032375A (en) | 2015-03-17 | 2015-03-17 | Dabigatran etexilate of crystal variant form F, preparation method and uses thereof |
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| CN106032375A true CN106032375A (en) | 2016-10-19 |
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| CN201510117031.XA Pending CN106032375A (en) | 2015-03-17 | 2015-03-17 | Dabigatran etexilate of crystal variant form F, preparation method and uses thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2669396A1 (en) * | 2006-11-16 | 2008-05-22 | Boehringer Ingelheim International Gmbh | New polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate |
| CN102633713A (en) * | 2012-03-22 | 2012-08-15 | 南京工业大学 | Dabigatran etexilate intermediate, preparation method thereof and method for preparing dabigatran etexilate |
| CN103664881A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate of crystallized variant form B as well as preparation method thereof and application |
| CN103664882A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate |
-
2015
- 2015-03-17 CN CN201510117031.XA patent/CN106032375A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2669396A1 (en) * | 2006-11-16 | 2008-05-22 | Boehringer Ingelheim International Gmbh | New polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate |
| CN102633713A (en) * | 2012-03-22 | 2012-08-15 | 南京工业大学 | Dabigatran etexilate intermediate, preparation method thereof and method for preparing dabigatran etexilate |
| CN103664881A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate of crystallized variant form B as well as preparation method thereof and application |
| CN103664882A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate |
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