WO2015131829A1 - 达比加群酯甲磺酸盐的晶型及其制备方法和用途 - Google Patents

达比加群酯甲磺酸盐的晶型及其制备方法和用途 Download PDF

Info

Publication number
WO2015131829A1
WO2015131829A1 PCT/CN2015/073650 CN2015073650W WO2015131829A1 WO 2015131829 A1 WO2015131829 A1 WO 2015131829A1 CN 2015073650 W CN2015073650 W CN 2015073650W WO 2015131829 A1 WO2015131829 A1 WO 2015131829A1
Authority
WO
WIPO (PCT)
Prior art keywords
dabigatran etexilate
etexilate mesylate
ethanol
mesylate
mixed solvent
Prior art date
Application number
PCT/CN2015/073650
Other languages
English (en)
French (fr)
Inventor
张亮
刘川
许金溢
张昭昭
陈智
柴健
杨志清
罗海荣
张相洋
Original Assignee
浙江海正药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江海正药业股份有限公司 filed Critical 浙江海正药业股份有限公司
Priority to US15/123,378 priority Critical patent/US9718802B2/en
Priority to EP15759282.5A priority patent/EP3115360A4/en
Priority to CN201580013529.XA priority patent/CN106458975B/zh
Publication of WO2015131829A1 publication Critical patent/WO2015131829A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of chemical pharmaceuticals. More particularly, the present invention relates to novel crystalline forms of dabigatran etexilate mesylate, to processes for their preparation, to pharmaceutical compositions containing them, and to their pharmaceutical use.
  • Dabigatran etexilate is a novel thrombin inhibitor, a prodrug of dabigatran, a non-peptide thrombin inhibitor, developed and produced by Boehringer Ingelheim, Germany, and the first American food in 2010.
  • the Drug Administration has approved stroke and systemic embolic prevention for patients with non-valvular atrial fibrillation, which is currently approved in more than 60 countries around the world.
  • dabigatran etexilate After oral absorption by gastrointestinal absorption, dabigatran etexilate is converted in vivo to dabigatran having direct anticoagulant activity.
  • Dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from cleavage into fibrin, thereby blocking thrombus formation. Dabigatran can be dissociated from the fibrin-thrombin complex and exerts a reversible anticoagulant effect.
  • Dabigatran etexilate mesylate chemical name 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -1-methyl- 1H-Benzamidazole-5-carbonyl)-pyridin-2-yl-amino-]-propionic acid ethyl ester-methanesulfonate.
  • Patent No. 7,932,273 B2 discloses Form I, Form II and hemihydrate of dabigatran etexilate mesylate
  • WO2012027543A1 discloses crystal forms A, B, C, D of dabigatran etexilate mesylate G, H and III
  • WO2012044595A1 discloses a crystalline form Ms2-A of dabigatran etexilate dimethanesulfonate
  • WO2011110876A1 discloses dabigatran etexilate mesylate (1:1) Form IV.
  • crystal forms can have different physicochemical properties, including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, etc., and these physical properties directly determine a specific Whether crystal forms can be used as medicines, and they affect the quality of the drug substance and preparation. Therefore, although some crystal forms of dabigatran etexilate have been disclosed in the prior art, it is still necessary to develop a new crystal form having a different performance from the known crystal form and having a promising application prospect to meet the demanding medicinal properties. demand.
  • One of the objects of the present invention is to provide dabigatran etexilate mesylate crystal forms M and N which are chemically and physically stable.
  • the crystal form has excellent properties in terms of dissolution time, biological release, chemical stability, and processing (filtration, drying, tableting) adaptability.
  • the X-ray powder diffraction pattern of the dabigatran etexilate mesylate form M of the present invention has characteristic peaks at the following 2 ⁇ : 5.7 ⁇ 0.2°, 6.2 ⁇ 0.2°, 11.2 ⁇ 0.2°, 12.4 ⁇ 0.2° , 18.2 ⁇ 0.2 °, 21.4 ⁇ 0.2 °, 21.8 ⁇ 0.2 °, 23.6 ⁇ 0.2 °.
  • the X-ray powder diffraction (XRD) pattern of the crystalline form M of dabigatran etexilate mesylate has characteristic peaks at the following diffraction angle 2 ⁇ : 5.7 ⁇ 0.2°, 6.2 ⁇ 0.2°, 11.2 ⁇ 0.2 °, 12.4 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 21.4 ⁇ 0.2 °, 21.8 ⁇ 0.2 °, 22.8 ⁇ 0.2 °, 23.6 ⁇ 0.2 °, 25.0 ⁇ 0.2 °, 27.3 ⁇ 0.2 °.
  • XRD X-ray powder diffraction
  • the X-ray powder diffraction pattern of the dabigatran etexilate mesylate form M has characteristic peaks at the following 2 ⁇ : 5.7 ⁇ 0.2°, 6.2 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.2 ⁇ 0.2 °, 12.4 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.2 ⁇ 0.2°, 21.4 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.6 ⁇ 0.2°, 25.0 ⁇ 0.2 °, 27.3 ⁇ 0.2 °, 29.0 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the dabigatran etexilate mesylate form M of the present invention has the 2 ⁇ , d and relative intensity data shown in Table 1 below:
  • the X-ray powder diffraction pattern of the dabigatran etexilate mesylate form M of the present invention has the 2 ⁇ , d and relative intensity data shown in Table 2 below:
  • the dabigatran etexilate mesylate form M of the present invention has an X-ray powder diffraction pattern as shown in FIG.
  • the crystalline form M of dabigatran etexilate mesylate of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting, which is about 3343.73 cm -1 , 3391.45 cm -1 , 2957.35 cm -1 , and 2931.08 Cm -1 , 2862.04cm -1 , 1743.33cm -1 , 1732.42cm -1 , 1650.10cm -1 , 1614.11cm -1 , 1568.80cm -1 , 1572.31cm -1 , 1472.02cm -1 , 1432.21cm -1 ,1384.33 Cm -1 , 1319.30cm -1 , 1231.52cm -1 , 1045.54cm -1 , 951.65cm -1 , 774.31cm -1 , 749.63cm -1 , 554.38cm -1 , 5
  • the infrared absorption spectrum of the crystalline form M of dabigatran etexilate mesylate is about 3343.73 cm -1 , 3391.45 cm -1 , 3067.58 cm -1 , 2957.35 cm -1 , 2931.08 cm -1 , 2862.04 cm -1 , 1743.33cm -1 , 1732.42cm -1 , 1650.10cm -1 , 1614.11cm -1 , 1568.80cm -1 , 1572.31cm -1 , 1547.89cm -1 , 1514.12cm -1 , 1472.02cm -1 ,1435.21cm -1 , 1414.83 cm -1 , 1384.33 cm -1 , 1319.30 cm -1 , 1280.88 cm -1 , 1231.52 cm -1 , 1180.00 cm -1 , 1164.18 cm -1 , 1128.71 cm -1
  • the dabigatran etexilate mesylate form M of the present invention has an infrared spectrum as shown in FIG.
  • the differential scanning calorimetry (DSC) pattern of the dabigatran etexilate mesylate form M of the present invention has a maximum absorption peak in the range of 145-150 °C.
  • the dabigatran etexilate mesylate form M of the present invention has a DSC pattern as shown in FIG.
  • the dabigatran etexilate mesylate form M of the present invention has a TGA pattern as shown in FIG. According to the results of the TGA pattern and the moisture meter (instrument model: METTLER TOLEDO DL31 Karl Fischer Titrator), it was estimated that the crystal form M contained 1.5 bound water.
  • Another object of the present invention is to provide a process for preparing the dabigatran etexilate mesylate form M, the method comprising:
  • the unit of the weight-to-volume ratio of the dabigatran etexilate mesylate and the ethanol/ethyl acetate mixed solvent may be g/ml, Kg/L, etc., depending on the specific operation scale;
  • the total water content source may include a trace amount of water contained in the raw material dabigatran etexilate mesylate, an ethanol/ethyl acetate mixed solvent.
  • the water contained in the environment and the environment such as the water naturally introduced in the air; if the water content in the system does not meet the above molar ratio requirements, the water should be added by adding water or drying the material or removing water.
  • the adjustment is carried out to the allowable range; the water content in the system can be detected by a conventional method in the art, for example, by a moisture meter or the like, or can be estimated by a known raw material, a theoretical water content in a solvent.
  • the rate of step (3) agitation cooling can be controlled at 3-20 ° C / h, more preferably 10 ° C / h.
  • the total water content in the system obtained in the step (1) may include trace water contained in the raw material dabigatran etexilate mesylate, water contained in the solvent, and environment, such as water naturally introduced in the air;
  • the total water content in the above cannot meet the requirements of the above molar ratio, and the water content should be adjusted to the allowable range by adding water or drying the material or removing water; likewise, the water content in the system can be passed through Conventional methods in the field are used for detection, for example, by moisture metering or the like, or by theoretical water content in known materials and solvents.
  • the solvent alcohol used in the step (1) is a C1-C4 alcohol, preferably methanol, ethanol, isopropanol or n-butanol;
  • the ketone is a C3-C5 ketone, preferably acetone, methyl ethyl ketone or pentanone;
  • the ester is C3-C6 An ester, preferably methyl acetate, ethyl acetate or butyl acetate;
  • the solvent is ethanol, an ethanol/acetone mixed solvent, or an ethanol/ethyl acetate mixed solvent;
  • the weight ratio by weight of the dabigatran etexilate mesylate to the ethanol solvent is from 1:10 to 100, more preferably from 1:10 to 20;
  • a preferred weight ratio of the dabigatran etexilate mesylate to the ethanol/acetone mixed solvent is from 1:10 to 100, more preferably from 1:10 to 30; wherein ethanol and acetone are used.
  • the volume ratio (v/v) is preferably from 1:0.1 to 20, more preferably from 1:0.5 to 5;
  • a preferred weight ratio of the dabigatran etexilate mesylate to the ethanol/ethyl acetate mixed solvent is from 1:10 to 100, more preferably from 1:10 to 30;
  • the volume ratio (v/v) of ethanol and ethyl acetate is preferably 1:0.1-20, more preferably 1:0.5-5;
  • the unit ratio of the weight ratio of the dabigatran etexilate mesylate to the corresponding solvent may be g/ml, Kg/L, etc., depending on the specific operation scale;
  • the rate of stirring and cooling in step (3) can be controlled at 20-80 ° C / h, more preferably 40-60 ° C / h;
  • the seed crystal of the step (4) may be a crystal form M seed crystal, which may be, for example, the crystal form M prepared according to the method 1 or the crystal form M obtained according to the method 2;
  • the crystallization time is preferably from 1 to 18 hours, more preferably from 1 to 10 hours.
  • the dabigatran etexilate mesylate starting material used in the process of the invention is commercially available or can be prepared according to known methods, for example, as described in the patent document US Pat. No. 7,932,273 B2, which is incorporated herein by reference. .
  • the solvent used in the present invention is not particularly limited, and a commercially available conventional solvent may be used.
  • the ethanol may be commercially available ethanol, including industrial ethanol, anhydrous ethanol, chromatographic ethanol, etc.; as long as the system is included in the system construction. The amount of water can meet the requirements of the method.
  • the X-ray powder diffraction (XRD) pattern of the dabigatran etexilate mesylate form N of the present invention has characteristic peaks at the following diffraction angle 2 ⁇ : 6.0 ⁇ 0.2°, 11.8 ⁇ 0.2°, 18.2 ⁇ 0.2° 21.6 ⁇ 0.2°, 24.4 ⁇ 0.2°, 27.7 ⁇ 0.2°, 29.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the dabigatran etexilate mesylate form N has characteristic peaks at the following diffraction angle 2 ⁇ : 6.0 ⁇ 0.2°, 10.7 ⁇ 0.2°, 11.8 ⁇ 0.2°, 16.1 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.6 ⁇ 0.2°, 24.4 ⁇ 0.2°, 27.7 ⁇ 0.2°, 29.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the dabigatran etexilate mesylate form N of the present invention has 2 ⁇ data as shown in Table 3 below:
  • the dabigatran etexilate mesylate form N of the present invention has an X-ray powder diffraction pattern as shown in FIG.
  • the crystalline form N of dabigatran etexilate mesylate of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting, which is about 3425.18 cm -1 , 3304.94 cm -1 , 2956.79 cm -1 , and 2933.09 Cm -1 , 2861.93cm -1 , 1741.76cm -1 , 1647.10cm -1 , 1161.66cm -1 , 1584.42cm -1 , 1571.90cm -1 , 1540.02cm -1 , 1516.58cm -1 , 1471.95cm -1 ,1435.51 cm -1, 1384.16cm -1, 1318.97cm -1 , 1231.35cm -1, 1213.37cm -1, 1165.25cm -1, 1100.00cm -1, 1039.60cm -1, 950.09cm -1, 8
  • the infrared absorption spectrum of the crystalline form N of dabigatran etexilate mesylate is about 3425.18 cm -1 , 3304.94 cm -1 , 3076.26 cm -1 , 2956.79 cm -1 , 2293.
  • the dabigatran etexilate mesylate form N of the present invention has an infrared spectrum as shown in FIG.
  • the differential scanning calorimetry (DSC) pattern of the dabigatran etexilate mesylate form N of the present invention has a maximum absorption peak in the range of 145-150 °C.
  • the dabigatran etexilate mesylate form N of the present invention has a DSC pattern as shown in FIG.
  • the dabigatran etexilate mesylate form N of the present invention has a TGA pattern as shown in FIG.
  • the crystal form N was estimated to be an anhydride based on the results of TGA and moisture meter measurements.
  • Another object of the present invention is to provide a process for preparing the dabigatran etexilate mesylate form N, which comprises the following steps:
  • the dabigatran etexilate mesylate form M is dried under a vacuum of -0.06 MPa to 0.1 MPa, preferably at a temperature of 20 to 50 ° C; and the time is preferably 10 to 100 hours, which is converted into a crystal form N. .
  • the crystal forms M and N each have a purity of 99.5% or more.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of dabigatran etexilate mesylate form M and/or N; preferably,
  • dabigatran etexilate mesylate form M and/or N may be admixed with one or more pharmaceutically acceptable solid or liquid diluents and/or excipients, and The mixture was made into a galenic formulation.
  • the present invention also provides the use of dabigatran etexilate mesylate form M and/or N for the preparation of an anticoagulant drug, and a method for anticoagulation by using the drug.
  • the drug can be used to prolong thrombin time, inhibit thrombin and related serine proteases.
  • stirring described in the process of the present invention may be carried out by conventional methods in the art, for example, stirring means including magnetic stirring, mechanical stirring, and stirring speed of 50 to 300 rpm/min, preferably 100 to 200 rpm/min.
  • the inventors of the present invention have discovered a large number of new crystalline forms M and N of dabigatran etexilate mesylate, which have good solubility, simple crystallization process, easy operation, low pollution, industrial production, and the present invention.
  • the crystalline drug has the advantages of high product purity, excellent physicochemical properties, good chemical stability, and reproducibility of processing (filtration, drying, dissolution, and tableting), and also has good dissolution rate compared with other pharmaceutical preparations.
  • the dabigatran etexilate mesylate form N of the present invention has excellent stability in a 95% ethanol solution, and has certain advantages in formulation medicinal properties.
  • Example 1 is an X-ray powder diffraction pattern of the crystalline form M of dabigatran etexilate mesylate obtained in Example 1.
  • Example 2 is an infrared absorption spectrum of the crystalline form M of dabigatran etexilate mesylate obtained in Example 1.
  • Example 3 is a DSC chart of the crystalline form M of dabigatran etexilate mesylate obtained in Example 1.
  • Example 4 is a TGA pattern of the crystalline form M of dabigatran etexilate mesylate obtained in Example 1.
  • Figure 5 is an X-ray powder diffraction pattern of the crystalline form N of dabigatran etexilate mesylate obtained in Example 10.
  • Fig. 6 is an infrared absorption spectrum of the crystalline form N of dabigatran etexilate mesylate obtained in Example 10.
  • Example 7 is a DSC chart of the crystalline form N of dabigatran etexilate mesylate obtained in Example 10.
  • Figure 8 is a TGA pattern of the crystalline form N of dabigatran etexilate mesylate obtained in Example 10.
  • the crude dabigatran etexilate mesylate used in the following examples is the crystalline form I obtained according to the preparation method in Example 1 of the patent document US Pat. No. 7,932,273 B2.
  • the X-ray powder diffraction apparatus and test conditions were: X-diffraction instrument model Rigaku D/max-2200 Cu target; operation method: scanning speed 4 ° / min, scanning step width 0.01 °.
  • Infrared spectrophotometer and test conditions are: infrared spectrophotometer model: BRWKER VECTOR22; operation method: using KBr tablet method, scanning range 400-4000cm -1 .
  • DSC test conditions are: DSC detector model: NETZSCH DSC200 F3 Maia; operation method: heating rate 10 ° C / min, temperature range: 30-250 ° C.
  • TGA test conditions are: TGA detector model: PerkinElmer TGA400; operating method: heating rate 10 ° C / min, temperature range: 30-300 ° C.
  • the liquid phase test conditions are: the column is STAR RP-18endcapped 250 ⁇ 4.6 mm, 5 ⁇ m; mobile phase A: acetonitrile, mobile phase B: 4 ml of phosphoric acid was added to 1 L of water, pH was adjusted to 3.5 with triethylamine; detection wavelength: 310 nm; flow rate: 1 ml/min; injection volume : 10 ⁇ l; column temperature: 30 ° C, liquid phase conditions are shown in Table 4:
  • the inventors investigated the chemical stability of the crystalline forms M and N of the present invention under normal temperature, refrigerated and frozen conditions, respectively, and compared with the crystalline form I, the crystalline form II and the hemihydrate crystalline form, see test example 1 -3.
  • the crystal form I, the crystal form II and the hemihydrate crystal form are all prepared according to the method disclosed in the patent document US Pat. No. 7,932,273 B2.
  • Test Example 1 6-month stability data at 25 ° C (see Table 5)
  • Test Example 2 6-month stability data at 5 ° C (see Table 6)
  • Test Example 3 Stability data at 6 °C for 6 months (see Table 7)
  • the crystalline form M and the crystalline form N of the dabigatran etexilate of the present invention can be stably stored for a long period of time under both refrigeration and freezing conditions.
  • the crystalline forms M and N exhibited better chemical stability at normal temperature and under refrigeration.
  • the crystal form N was placed in a 95% ethanol solution, and after stirring for 3, 4, and 5 hours, XRD measurement was carried out, respectively, and it was found that the XRD pattern did not change within 5 hours. This indicates that Form N is stable in a 95% ethanol solution and therefore has excellent stability during the relevant formulation process.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及达比加群酯甲磺酸盐新的晶型M和N以及它们的制备方法和用途，其中所述晶型M的X-射线粉末衍射图在以下衍射角2θ处具有特征峰：5.7±0.2°、6.2±0.2°、11.2±0.2°、12.4±0.2°、18.2±0.2°、21.4±0.2°、21.8±0.2°、23.6±0.2°；所述晶型N的X-射线粉末衍射图在以下衍射角2θ处有特征峰：6.0±0.2°、11.8±0.2°、18.2±0.2°、21.6±0.2°、24.4±0.2°、27.7±0.2°、29.7±0.2°。本发明的晶型在溶出时间、生物学释放、化学稳定性和加工适应性方面具有优异的性质。

Description

达比加群酯甲磺酸盐的晶型及其制备方法和用途
本申请要求2014年3月4日提交的申请号为201410077142.8、题为“达比加群酯甲磺酸盐的晶型及其制备方法和用途”的专利申请的优先权。
技术领域
本发明涉及化学制药领域。更具体的说，本发明涉及达比加群酯甲磺酸盐的新晶型以及所述晶型的制备方法、含有它们的药物组合物以及它们的制药用途。
背景技术
达比加群酯是一种新型的凝血酶抑制剂，是达比加群的前体药物，属非肽类凝血酶抑制剂，由德国勃林格殷格翰公司研发生产，2010年首先获得美国食品药品监督局(FDA)批准用于非瓣膜房颤患者的卒中和全身栓塞预防，目前这一适应症已在全球六十多个国家获得批准。达比加群酯口服经胃肠吸收后，在体内转化为具有直接抗凝血活性的达比加群。达比加群结合于凝血酶的纤维蛋白特异结合位点，阻止纤维蛋白原裂解为纤维蛋白，从而阻断了血栓形成。达比加群可以从纤维蛋白-凝血酶结合体上解离，发挥可逆的抗凝作用。
达比加群酯甲磺酸盐化学名为：3-[(2-{[4-(己氧基羰基氨基-亚氨基-甲基)-苯氨基]-甲基}-1-甲基-1H-苯并咪唑-5-羰基)-吡啶-2-基-氨基-]-丙酸乙酯-甲磺酸盐。
其结构式如下所示：
Figure PCTCN2015073650-appb-000001
专利文献US7932273B2公开了达比加群酯甲磺酸盐的晶型I，晶型II和半水合物；WO2012027543A1公开了达比加群酯甲磺酸盐的晶型A、B、C、D、G、H和III；WO2012044595A1公开了达比加群酯二甲磺酸盐的晶型Ms2-A；WO2011110876A1公开了达比加群酯甲磺酸盐(1∶1)晶型IV。
对于多晶型药物而言，不同的晶型可以具有不同的物理化学性质，包括熔点、化学稳定性、表观溶解度、溶解速率、光学和机械性质等，而这些物化性能直接决定了某特定的晶型是否可以成药，并且它们影响到原料药和制剂的质量。因此，尽管现有技术已经披露了达比加群酯的一些晶型，但仍有必要开发性能与已知晶型不同的，且具有优良制剂运用前景的新晶型以满足作为药物的严苛需求。
发明内容
本发明的目的之一在于提供化学和物理稳定性很好的达比加群酯甲磺酸盐晶型M和N。所述晶型在溶出时间、生物学释放、化学稳定性和加工(过滤、干燥、压片)适应性方面具有优异的性质。
本发明所述达比加群酯甲磺酸盐晶型M的X-射线粉末衍射图在以下2θ处有特征峰：5.7±0.2°、6.2±0.2°、11.2±0.2°、12.4±0.2°、18.2±0.2°、21.4±0.2°、21.8±0.2°、23.6±0.2°。
进一步地，所述达比加群酯甲磺酸盐晶型M的X-射线粉末衍射(XRD)图在以下衍射角2θ处有特征峰：5.7±0.2°、6.2±0.2°、11.2±0.2°、12.4±0.2°、16.3±0.2°、18.2±0.2°、21.4±0.2°、21.8±0.2°、22.8±0.2°、23.6±0.2°、25.0±0.2°、27.3±0.2°。
进一步地，所述达比加群酯甲磺酸盐晶型M的X-射线粉末衍射图在以下2θ处有特征峰：5.7±0.2°、6.2±0.2°、8.1±0.2°、11.2±0.2°、12.4±0.2°、13.0±0.2°、16.3±0.2°、17.1±0.2°、18.2±0.2°、21.4±0.2°、21.8±0.2°、22.8±0.2°、23.6±0.2°、25.0±0.2°、27.3±0.2°、29.0±0.2°。
进一步地，本发明的达比加群酯甲磺酸盐晶型M的X-射线粉末衍射谱图具有如下表1所示的2θ、d和相对强度数据：
表1
Figure PCTCN2015073650-appb-000002
更进一步地，本发明的达比加群酯甲磺酸盐晶型M的X-射线粉末衍射谱图具有如下表2所示的2θ、d和相对强度数据：
表2
Figure PCTCN2015073650-appb-000003
非限制性地，本发明的达比加群酯甲磺酸盐晶型M具有如图1所示的X-射线粉末衍射谱图。
此外，本发明的达比加群酯甲磺酸盐晶型M，可以用KBr压片测得的红外吸收图谱表征，其在约3433.73cm-1、3319.45cm-1、2957.35cm-1、2931.08cm-1、2862.04cm-1、1743.33cm-1、1732.42cm-1、1650.10cm-1、1614.11cm-1、1586.80cm-1、 1572.31cm-1、1472.02cm-1、1435.21cm-1、1384.33cm-1、1319.30cm-1、1231.52cm-1、1045.54cm-1、951.65cm-1、774.31cm-1、749.63cm-1、554.38cm-1、527.97cm-1处有吸收峰。
进一步地，所述达比加群酯甲磺酸盐晶型M的红外吸收图谱在约3433.73cm-1、3319.45cm-1、3067.58cm-1、2957.35cm-1、2931.08cm-1、2862.04cm-1、1743.33cm-1、1732.42cm-1、1650.10cm-1、1614.11cm-1、1586.80cm-1、1572.31cm-1、1547.89cm-1、1514.12cm-1、1472.02cm-1、1435.21cm-1、1414.83cm-1、1384.33cm-1、1319.30cm-1、1285.88cm-1、1231.52cm-1、1180.00cm-1、1164.18cm-1、1128.71cm-1、1045.54cm-1、1018.39cm-1、1006.87cm-1、990.23cm-1、951.65cm-1、884.04cm-1、863.24cm-1、836.54cm-1、774.31cm-1、749.63cm-1、715.61cm-1、663.14cm-1、624.45cm-1、554.38cm-1、527.97cm-1、506.96cm-1、448.39cm-1、414.70cm-1处有特征峰。
非限制性地，本发明的达比加群酯甲磺酸盐晶型M具有如图2所示的红外谱图。
本发明所述的达比加群酯甲磺酸盐晶型M的差示扫描量热(DSC)图谱在145-150℃的范围内有最大吸收峰。
非限制性地，本发明的达比加群酯甲磺酸盐晶型M具有如图3所示的DSC图谱。
非限制性地，本发明的达比加群酯甲磺酸盐晶型M具有如图4所示的TGA图谱。根据TGA图谱和水份测量仪(仪器型号：METTLER TOLEDO DL31 Karl Fischer Titrator)测出的结果，估算该晶型M含有1.5个结合水。
本发明的另一目的还在于提供所述达比加群酯甲磺酸盐晶型M的制备方法，所述方法包括：
方法一：
(1)将达比加群酯甲磺酸盐加入乙醇/乙酸乙酯体积比为1∶2的混合溶剂中；其中，达比加群酯甲磺酸盐与乙醇/乙酸乙酯混合溶剂的重量体积比为1∶40；并且控制所得体系中的总含水量与达比加群酯甲磺酸盐的摩尔比为1.5-10∶1；
(2)升温至50-60℃，并持续搅拌30-60min溶解；
(3)过滤，搅拌降温至0-25℃；
(4)0-25℃析晶2-18h；
(5)过滤，得达比加群酯甲磺酸盐晶型M。
其中，
该方法中，达比加群酯甲磺酸盐与乙醇/乙酸乙酯混合溶剂的重量体积比的单位可以为g/ml、Kg/L等，可以视具体的操作规模而定；所得体系中的总含水量来源可包括原料达比加群酯甲磺酸盐中含有的痕量水份、乙醇/乙酸乙酯混合溶剂 中含有的水份以及环境，例如空气中自然引入的水份；如果体系中的含水量不能满足上述摩尔比的要求，需通过加入水或烘干物料或脱去水份等方法，将水份调节到所述允许范围内；体系中的含水量可以通过本领域的常规方法来检测，例如采用水分仪等进行检测，或者，也可通过已知原料、溶剂中的理论含水量来估算。
优选地，步骤(3)搅拌降温的速率可以控制在3-20℃/h，更优选为10℃/h。
或者方法二：
(1)将达比加群酯甲磺酸盐加入到醇、醇/酮混合溶剂或醇/酯混合溶剂中；控制体系中的总含水量与达比加群酯甲磺酸盐的摩尔比为约1.5-10∶1；
(2)升温至50-60℃，并持续搅拌30-60min溶解；
(3)过滤，滤液搅拌降温至0-5℃；
(4)加晶种；
(5)0-5℃下析晶，过滤，得达比加群酯甲磺酸盐晶型M。
其中，
步骤(1)所得体系中总含水量可以包括原料达比加群酯甲磺酸盐中含有的痕量水份、溶剂中含有的水份以及环境，例如空气中自然引入的水份；如果体系中的总含水量不能满足上述摩尔比的要求，需通过加入水或烘干物料或脱去水份等方法，将水份调节到所述允许范围内；同样，体系中的含水量可以通过本领域的常规方法来检测，例如采用水分仪等进行检测，或者，也可通过已知原料、溶剂中的理论含水量来估算。
步骤(1)中所使用的溶剂醇为C1-C4醇，优选甲醇、乙醇、异丙醇或正丁醇；酮为C3-C5酮，优选丙酮、丁酮或戊酮；酯为C3-C6酯，优选乙酸甲酯、乙酸乙酯或乙酸丁酯；
优选溶剂为乙醇、乙醇/丙酮混合溶剂、或乙醇/乙酸乙酯混合溶剂；
当使用乙醇作为溶剂时，优选的达比加群酯甲磺酸盐与乙醇溶剂的重量体积比为1∶10-100，更优选1∶10-20；
当使用乙醇/丙酮混合溶剂时，优选的达比加群酯甲磺酸盐与乙醇/丙酮混合溶剂的重量体积比为1∶10-100，更优选1∶10-30；其中乙醇和丙酮的体积比(v/v)优选为1∶0.1-20，更优选1∶0.5-5；
当使用乙醇/乙酸乙酯混合溶剂时，优选的达比加群酯甲磺酸盐与乙醇/乙酸乙酯混合溶剂的重量体积比为1∶10-100，更优选1∶10-30；其中乙醇和乙酸乙酯的体积比(v/v)优选为1∶0.1-20，更优选1∶0.5-5；
该方法中，所述达比加群酯甲磺酸盐与相应溶剂的重量体积比的单位可以为g/ml、Kg/L等，视具体的操作规模而定；
优选地，步骤(3)搅拌降温的速率可以控制在20-80℃/h，更优选为40-60℃/h；
步骤(4)所述晶种可以为晶型M晶种，其可以是例如根据方法一制备得到的晶型M，也可以为依据本方法二获得的晶型M；
析晶时间优选为1-18小时，更优选为1-10小时。
本发明方法中所使用的达比加群酯甲磺酸盐原料可以商购获得，或者按照已知方法，例如专利文献US7932273B2中所记载的方法制备，该文献通过引用的方式并入本申请中。本发明所使用的溶剂没有特别的限制，可采用商购的常规溶剂，例如所述乙醇可以是市售乙醇，包括工业乙醇、无水乙醇、色谱乙醇等；只要在体系构建时保证体系中含水量符合所述方法的要求即可。
本发明所述达比加群酯甲磺酸盐晶型N的X-射线粉末衍射(XRD)图在以下衍射角2θ处有特征峰：6.0±0.2°、11.8±0.2°、18.2±0.2°、21.6±0.2°、24.4±0.2°、27.7±0.2°、29.7±0.2°。
进一步地，所述达比加群酯甲磺酸盐晶型N的X-射线粉末衍射图谱在以下衍射角2θ处有特征峰：6.0±0.2°、10.7±0.2°、11.8±0.2°、16.1±0.2°、18.2±0.2°、20.3±0.2°、21.6±0.2°、24.4±0.2°、27.7±0.2°、29.7±0.2°。
更进一步地，本发明的达比加群酯甲磺酸盐晶型N的X-射线粉末衍射谱图具有如下表3所示的2θ数据：
表3
Figure PCTCN2015073650-appb-000004
非限制性地，本发明的达比加群酯甲磺酸盐晶型N具有如图5所示的X-射线粉末衍射谱图。
此外，本发明的达比加群酯甲磺酸盐晶型N，可以用KBr压片测得的红外吸收图谱表征，其在约3425.18cm-1、3304.94cm-1、2956.79cm-1、2933.09cm-1、2861.93cm-1、1741.76cm-1、1647.10cm-1、1613.66cm-1、1585.42cm-1、1571.90cm-1、1540.02cm-1、1516.58cm-1、1471.95cm-1、1435.51cm-1、1384.16cm-1、1318.97cm-1、 1231.35cm-1、1213.37cm-1、1165.25cm-1、1100.00cm-1、1039.60cm-1、950.09cm-1、828.47cm-1、771.70cm-1、750.44cm-1、555.24cm-1、525.04cm-1处有吸收峰。
进一步地，所述达比加群酯甲磺酸盐晶型N的红外吸收图谱在约3425.18cm-1、3304.94cm-1、3067.26cm-1、2956.79cm-1、2933.09cm-1、2861.93cm-1、2426.21cm-1、1741.76cm-1、1647.10cm-1、1613.66cm-1、1585.42cm-1、1571.90cm-1、1540.02cm-1、1516.58cm-1、1471.95cm-1、1435.51cm-1、1384.16cm-1、1318.97cm-1、1287.42cm-1、1231.35cm-1、1213.37cm-1、1165.25cm-1、1100.00cm-1、1068.76cm-1、1039.60cm-1、1007.05cm-1、992.19cm-1、950.09cm-1、903.66cm-1、880.99cm-1、828.47cm-1、771.70cm-1、750.44cm-1、623.24cm-1、555.24cm-1、525.04cm-1、506.80cm-1、414.45cm-1处有吸收峰。
非限制性地，本发明的达比加群酯甲磺酸盐晶型N具有如图6所示的红外谱图。
本发明所述的达比加群酯甲磺酸盐晶型N的差示扫描量热(DSC)图谱在145-150℃的范围内有最大吸收峰。
非限制性地，本发明的达比加群酯甲磺酸盐晶型N具有如图7所示的DSC图谱。
非限制性地，本发明的达比加群酯甲磺酸盐晶型N具有如图8所示的TGA图谱。根据TGA和水份仪测定结果估算该晶型N为无水物。
本发明的另一目的还在于提供所述达比加群酯甲磺酸盐晶型N的制备方法，该方法包括下列步骤：
将达比加群酯甲磺酸盐晶型M在真空度为-0.06MPa--0.1MPa下干燥，温度优选为20-50℃；时间优选为10-100小时，使其转化为晶型N。
本发明中，晶型M和N的纯度均在99.5％以上。
本发明的另一方面还提供了一种药物组合物，所述药物组合物含有作为活性成分的治疗有效量的达比加群酯甲磺酸盐晶型M和/或N；优选地，在所述药物组合物中，达比加群酯甲磺酸盐晶型M和/或N可与一种或多种药学上可接受的固体或液体稀释剂和/或赋形剂相混合，并使混合物成为盖伦制剂。
本发明还提供了达比加群酯甲磺酸盐晶型M和/或N在制备抗凝血药物中的用途，以及通过使用该药物来抗凝血的方法。其中，所述药物可用于延长凝血酶时间、抑制有关凝血酶和有关丝氨酸蛋白酶。
除非另有说明，本发明方法中所述的“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～300rpm/min，优选100～200rpm/min。
应当强调的是，本发明技术方案中所涉及的数值或数值端点，其含义或意欲 的保护范围并不局限于该数字本身，本领域技术人员能够理解，它们包含了那些已被本领域广为接受的可允许误差范围，例如实验误差、测量误差、统计误差和随机误差等等，而这些误差范围均包含在本发明的范围之内。
本发明的发明人经过大量研究发现了达比加群酯甲磺酸盐新晶型M和N，其溶解性良好、结晶工艺简单、便于操作、污染小、可实现工业化生产，而且本发明的晶型药物同时具备产品纯度高、理化性质优异、化学稳定性良好、加工(过滤、干燥、溶出和压片)可再现的优点，而且与其他药物制剂相比同样具有良好的溶出度。另外，本发明的达比加群酯甲磺酸盐晶型N在95％的乙醇溶液中具有很好的稳定性，在制剂成药性上有一定的优势。
附图说明
图1为实施例1所得达比加群酯甲磺酸盐晶型M的X-射线粉末衍射图谱。
图2为实施例1所得达比加群酯甲磺酸盐晶型M的红外吸收光谱。
图3为实施例1所得达比加群酯甲磺酸盐晶型M的DSC图谱。
图4为实施例1所得达比加群酯甲磺酸盐晶型M的TGA图谱。
图5为实施例10所得达比加群酯甲磺酸盐晶型N的X-射线粉末衍射图谱。
图6为实施例10所得达比加群酯甲磺酸盐晶型N的红外吸收光谱。
图7为实施例10所得达比加群酯甲磺酸盐晶型N的DSC图谱。
图8为实施例10所得达比加群酯甲磺酸盐晶型N的TGA图谱。
具体实施方式
下列实施例子进一步解释说明本发明，但是，它们并不构成对本发明范围的限制或限定。
以下实施例中所用的达比加群酯甲磺酸盐粗品是按照专利文献US7932273B2中的实施例1中的制备方法得到的晶型I。
以下实施例和试验例中，X-射线粉末衍射仪器及测试条件为：X-衍射仪器型号Rigaku D/max-2200 Cu靶；操作方法：扫描速度4°/min，扫描步宽0.01°。
红外分光广度仪及测试条件为：红外分光光度仪型号：BRWKER VECTOR22；操作方法：采用KBr压片法，扫描范围400-4000cm-1。
DSC测试条件为：DSC检测仪型号为：NETZSCH DSC200 F3 Maia；操作方法：升温速率10℃/min，温度范围：30-250℃。
TGA测试条件为：TGA检测仪型号为：PerkinElmer TGA400；操作方法：升温速率10℃/min，温度范围：30-300℃。
液相测试条件为：色谱柱为
Figure PCTCN2015073650-appb-000005
STAR RP-18endcapped 250×4.6 mm，5μm；流动相A：乙腈，流动相B：1L水中加入4ml磷酸，用三乙胺调pH为3.5；检测波长：310nm；流速：1ml/min；进样量：10μl；柱温：30℃，液相条件如表4所示：
表4
t(min) A(％) B(％)
0 30 70
30 60 40
50 60 40
实施例1
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于40ml乙醇和乙酸乙酯混合溶液中(乙醇∶乙酸乙酯＝1∶2；所使用的乙醇含量＞99.5％，乙酸乙酯含量＞99.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比为1.5∶1；升温至50℃，持续搅拌30min溶解；过滤，控制搅拌速度为170rpm/min，滤液以10℃/h的速率降温至25℃，并在25℃下搅拌析晶4h，过滤，20℃下真空干燥，得0.30g晶体，HPLC＝99.6％。
该晶型的X-射线粉末衍射、红外、DSC以及TGA谱图详见图1-4，在本发明中将其命名为达比加群酯甲磺酸盐晶型M。
实施例2
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于40ml乙醇和乙酸乙酯混合溶液中(乙醇∶乙酸乙酯＝1∶2；所使用的乙醇含量＞99.5％，乙酸乙酯含量＞99.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比为5∶1；升温至50℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以10℃/h的速率降温至25℃，并在25℃下搅拌析晶4h，过滤，20℃下真空干燥，得0.32g晶体，HPLC＝99.7％，经测X-射线粉末衍射图谱(XRD)，确认为晶型M。
实施例3
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于40ml乙醇和乙酸乙酯混合溶液中(乙醇∶乙酸乙酯＝1∶2；所使用的乙醇含量＞95％，乙酸乙酯含量＞99.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比为10∶1；升温至50℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以10℃/h的速率降温至25℃，并在25℃下搅拌析晶4h，过滤，20℃下真空干燥，得0.31g晶体，HPLC＝99.6％，经测X-射线粉末衍射图谱(XRD)，确认为晶型M。
实施例4
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于18ml甲醇和丙酮混合溶液中(甲醇∶丙酮＝1∶4；所使用的甲醇含量＞98.5％，丙酮含量＞98.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比约为5∶1；升温至55℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以50℃/h的速率降温至5℃；加入由实施例1制得的晶型M晶种，并在5℃下搅拌析晶5h，过滤，20℃下真空干燥，得0.50g晶体，HPLC＝99.7％，经测XRD为晶型M。
实施例5
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于25ml甲醇和丙酮混合溶液中(甲醇∶丙酮＝1∶6；所使用的甲醇含量＞98.5％，丙酮含量＞98.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比约为3∶1；升温至55℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以50℃/h的速率降温至2℃；加入由实施例1制得的晶型M晶种，并在2℃下搅拌析晶8h，过滤，20℃下真空干燥，得0.70g晶体，HPLC＝99.6％，经测XRD为晶型M。
实施例6
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于20ml乙醇和丙酮混合溶液中(乙醇∶丙酮＝1∶1；所使用的乙醇含量＞99.5％，丙酮含量＞98.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比约为6∶1；升温至60℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以60℃/h的速率降温至0℃；加入由实施例1制得的晶型M晶种，并在0℃下搅拌析晶8h，过滤，20℃下真空干燥，得0.71g晶体，HPLC＝99.8％，经测XRD为晶型M。
实施例7
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于25ml乙醇和丙酮混合溶液中(乙醇∶丙酮＝1∶2；所使用的乙醇含量＞99.5％，丙酮含量＞98.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比约为4∶1；升温至50℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以45℃/h的速率降温至5℃；加入由实施例1制得的晶型M晶种，并在5℃下搅拌析晶18h，过滤，20℃下真空干燥，得0.67g晶体，HPLC＝99.8％，测XRD为晶型M。
实施例8
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于15ml乙醇和乙酸乙 酯混合溶液中(乙醇∶乙酸乙酯＝1∶1；所使用的乙醇含量＞95％，乙酸乙酯含量＞98.5％)，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比约为8∶1；升温至50℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以45℃/h的速率降温至5℃；加入由实施例1制得的晶型M晶种，并在5℃下搅拌析晶12h，过滤，20℃下真空干燥，得0.73g晶体，HPLC＝99.7％，经测XRD为晶型M。
实施例9
将达比加群酯甲磺酸盐粗品1g(HPLC纯度＞99％)溶于20ml乙醇中，所使用的乙醇含量＞99.5％，其中体系中的含水量和达比加群酯甲磺酸盐的摩尔比约为3∶1；升温至50℃，持续搅拌30min，溶解；过滤，控制搅拌速度为170rpm/min，滤液以45℃/h的速率降温至5℃；加入由实施例1制得的晶型M晶种，并在5℃下搅拌析晶5h，过滤，20℃下真空干燥，得0.42g晶体，HPLC＝99.6％，经测XRD为晶型M。
实施例2-9所得产物的X-射线粉末衍射谱图与实施例1相同，在此不再重复示出。
实施例10
将1g实施例1制备的达比加群酯甲磺酸盐晶型M放在50℃、真空度为-0.1MPa的烘箱中干燥10小时，得晶体。
该晶体的X-射线粉末衍射、红外、DSC以及TGA谱图详见图5-8，在本发明中将其命名为达比加群酯甲磺酸盐晶型N。
发明人分别在常温、冷藏和冷冻条件下，考察了本发明的晶型M和N的化学稳定性，并与晶型I、晶型II和半水合物晶型进行了比较，见试验例1-3。其中，晶型I、晶型II和半水合物晶型均按照专利文献US7932273B2公开的方法制备得到。
试验例1 25℃条件下6个月稳定性数据(见表5)
表5
Figure PCTCN2015073650-appb-000006
试验例2 5℃条件下6个月稳定性数据(见表6)
表6
Figure PCTCN2015073650-appb-000007
试验例3 -20℃条件下6个月稳定性数据(见表7)
表7
Figure PCTCN2015073650-appb-000008
由试验例1-3可见，本发明的达比加群酯晶型M和晶型N在冷藏和冷冻条件下均能够长期、稳定保存。与现有的达比加群酯晶型I、晶型II和半水合物晶型相比，晶型M和N在常温和冷藏下表现出了更好的化学稳定性。
另外，晶型M和晶型N不同温度下6个月稳定性留样的样品晶型均未发生转变，表明晶型稳定性良好。
试验例4晶型N的制剂稳定性
将晶型N置于95％的乙醇溶液中，搅拌3、4、5小时后，分别进行XRD测定，结果发现5小时内其XRD图谱未发生变化。这说明晶型N在95％的乙醇溶液中是稳定的，因此在相关制剂过程中具有优良的稳定性。

Claims (16)

  1. 一种达比加群酯甲磺酸盐晶型M，其特征在于，其X-射线粉末衍射图在以下衍射角2θ处具有特征峰：5.7±0.2°、6.2±0.2°、11.2±0.2°、12.4±0.2°、18.2±0.2°、21.4±0.2°、21.8±0.2°、23.6±0.2°。
  2. 如权利要求1所述的达比加群酯甲磺酸盐晶型M，其特征在于，其X-射线粉末衍射图还在以下衍射角2θ处具有特征峰：16.3±0.2°、22.8±0.2°、25.0±0.2°、27.3±0.2°。
  3. 如权利要求2所述的达比加群酯甲磺酸盐晶型M，其特征在于，其X-射线粉末衍射XRD图谱还在以下衍射角2θ处有特征峰：8.1±0.2°、13.0±0.2°、17.1±0.2°、29.0±0.2°。
  4. 根据权利要求3所述的达比加群酯甲磺酸盐晶型M，其特征在于，所述特征峰的相对强度为：
    Figure PCTCN2015073650-appb-100001
  5. 一种如权利要求1-4中任一项所述的达比加群酯甲磺酸盐晶型M的制备方法，该方法包括如下步骤：
    (1)将达比加群酯甲磺酸盐加入到乙醇/乙酸乙酯体积比为1∶2的混合溶剂中；其中，所述达比加群酯甲磺酸盐与乙醇/乙酸乙酯混合溶剂的重量体积比为1∶40； 并控制所得体系中的总含水量与达比加群酯甲磺酸盐的摩尔比为1.5-10∶1；
    (2)升温至50-60℃，并持续搅拌30-60min溶解；
    (3)过滤，搅拌降温至0-25℃；
    (4)0-25℃析晶2-18h；
    (5)过滤，得达比加群酯甲磺酸盐晶型M。
  6. 一种如权利要求1-4中任一项所述的达比加群酯甲磺酸盐晶型M的制备方法，该方法包括如下步骤：
    (1)将达比加群酯甲磺酸盐加入到醇、或醇/酮混合溶剂或醇/酯混合溶剂中；其中控制所得体系中的总含水量与达比加群酯甲磺酸盐的摩尔比为1.5-10∶1；
    (2)升温至50-60℃，并持续搅拌30-60min溶解；
    (3)过滤，滤液搅拌降温至0-5℃；
    (4)加入晶种；
    (5)0-5℃下析晶，过滤，得达比加群酯甲磺酸盐晶型M。
  7. 如权利要求6所述的达比加群酯甲磺酸盐晶型M的制备方法，其中所述醇为C1-C4醇，优选甲醇、乙醇、异丙醇或正丁醇；酮为C3-C5酮，优选丙酮、丁酮或戊酮；酯为C3-C6酯，优选乙酸甲酯、乙酸乙酯或乙酸丁酯；优选的溶剂为乙醇、乙醇/丙酮混合溶剂、乙醇/乙酸乙酯混合溶剂。
  8. 如权利要求6或7所述的达比加群酯甲磺酸盐晶型M的制备方法，其特征在于，当使用乙醇作为溶剂时，达比加群酯甲磺酸盐与乙醇溶剂的重量体积比为1∶10-100，优选1∶10-20。
  9. 如权利要求6或7所述的达比加群酯甲磺酸盐晶型M的制备方法，其特征在于，当使用乙醇和丙酮的混合溶剂作为溶剂时，达比加群酯甲磺酸盐与该混合溶剂的重量体积比为1∶10-100，优选为1∶10-30；乙醇和丙酮的体积比为1∶0.1-20，优选为1∶0.5-5。
  10. 如权利要求6或7所述的达比加群酯甲磺酸盐晶型M的制备方法，其特征在于，当使用乙醇和乙酸乙酯的混合溶剂作为溶剂时，达比加群酯甲磺酸盐与该混合溶剂的重量体积比为1∶10-100，优选为1∶10-30；乙醇和乙酸乙酯的体积比为1∶0.1-20，优选为1∶0.5-5。
  11. 一种达比加群酯甲磺酸盐晶型N，其特征在于，其X-射线粉末衍射图在以下衍射角2θ处有特征峰：6.0±0.2°、11.8±0.2°、18.2±0.2°、21.6±0.2°、24.4±0.2°、27.7±0.2°、29.7±0.2°。
  12. 如权利要求11所述的达比加群酯甲磺酸盐晶型N，其特征在于，其X-射线粉末衍射图还在以下衍射角2θ处有特征峰：10.7±0.2°、16.1±0.2°、20.3±0.2°。
  13. 根据权利要求12所述的达比加群酯甲磺酸盐晶型N，其特征在于，所述特征峰的相对强度为：
    Figure PCTCN2015073650-appb-100002
  14. 如权利要求11-13任一项所述的达比加群酯甲磺酸盐晶型N的制备方法，该方法包括将如权利要求1-4中任意一项所述的达比加群酯甲磺酸盐晶型M在真空度为-0.06Mpa--0.1MPa下进行干燥，获得达比加群酯甲磺酸盐晶型N；所述干燥温度优选为20-50℃；时间优选为10-100小时。
  15. 一种含有权利要求1-4中任意一项所述的达比加群酯甲磺酸盐晶型M或权利要求11-13任一项所述的达比加群酯甲磺酸盐晶型N的药物组合物。
  16. 根据权利要求1-4中任意一项所述的达比加群酯甲磺酸盐晶型M或权利要求11-13任一项所述的达比加群酯甲磺酸盐晶型N在制备抗凝血药物中的用途。
PCT/CN2015/073650 2014-03-04 2015-03-04 达比加群酯甲磺酸盐的晶型及其制备方法和用途 WO2015131829A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US15/123,378 US9718802B2 (en) 2014-03-04 2015-03-04 Crystal form of dabigatran etexilate mesylate and preparation method and use thereof
EP15759282.5A EP3115360A4 (en) 2014-03-04 2015-03-04 Crystal form of dabigatran etexilate mesylate and preparation method and use thereof
CN201580013529.XA CN106458975B (zh) 2014-03-04 2015-03-04 达比加群酯甲磺酸盐的晶型及其制备方法和用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410077142.8 2014-03-04
CN201410077142.8A CN104892574A (zh) 2014-03-04 2014-03-04 达比加群酯甲磺酸盐的晶型及其制备方法和用途

Publications (1)

Publication Number Publication Date
WO2015131829A1 true WO2015131829A1 (zh) 2015-09-11

Family

ID=54025588

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/073650 WO2015131829A1 (zh) 2014-03-04 2015-03-04 达比加群酯甲磺酸盐的晶型及其制备方法和用途

Country Status (5)

Country Link
US (1) US9718802B2 (zh)
EP (1) EP3115360A4 (zh)
CN (2) CN104892574A (zh)
HK (1) HK1210773A1 (zh)
WO (1) WO2015131829A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114716411B (zh) * 2022-04-29 2024-03-15 天方药业有限公司 一种从生产母液中回收制备甲磺酸达比加群酯的方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006114415A2 (de) * 2005-04-27 2006-11-02 Boehringer Ingelheim International Gmbh Physiologisch verträgliche salze von 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester
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
CN101189224A (zh) * 2005-06-04 2008-05-28 贝林格尔·英格海姆国际有限公司 3-[(2-{[4-(己氧基羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1h-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯的多晶型
CN102050815A (zh) * 2009-11-06 2011-05-11 北京美倍他药物研究有限公司 作为前药的达比加群的酯衍生物
CN102167695A (zh) * 2003-08-29 2011-08-31 贝林格尔.英格海姆国际有限公司 苯并咪唑羰基吡啶氨基丙酸乙酯半水合物及其用途
CN102391250A (zh) * 2011-08-29 2012-03-28 石药集团欧意药业有限公司 一种达比加群酯化合物、制备方法及其药物组合物
CN102858762A (zh) * 2010-02-02 2013-01-02 埃吉斯药物股份公开有限公司 用于制备药物组合物的新的盐
EP2631234A1 (en) * 2012-02-23 2013-08-28 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
CN103288800A (zh) * 2013-06-03 2013-09-11 华仁药业股份有限公司 达比加群酯苯磺酸盐及其制备方法和应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012027543A1 (en) * 2010-08-25 2012-03-01 Teva Pharmaceuticals Usa, Inc. Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof
HUE026408T2 (en) 2010-09-27 2016-06-28 Ratiopharm Gmbh Dabigatran etexylate bis-mesylate salt, solid forms and process for their preparation
EP2649060B1 (en) * 2010-12-06 2017-04-05 MSN Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
EP2522662A1 (en) * 2011-05-11 2012-11-14 Medichem, S.A. Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers
WO2014009966A2 (en) * 2012-07-12 2014-01-16 Rao Davuluri Ramamohan An improved process for the preparation of dabigatran etexilate mesylate and its intermediates thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102167695A (zh) * 2003-08-29 2011-08-31 贝林格尔.英格海姆国际有限公司 苯并咪唑羰基吡啶氨基丙酸乙酯半水合物及其用途
WO2006114415A2 (de) * 2005-04-27 2006-11-02 Boehringer Ingelheim International Gmbh Physiologisch verträgliche salze von 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester
CN101189224A (zh) * 2005-06-04 2008-05-28 贝林格尔·英格海姆国际有限公司 3-[(2-{[4-(己氧基羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1h-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯的多晶型
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
CN102050815A (zh) * 2009-11-06 2011-05-11 北京美倍他药物研究有限公司 作为前药的达比加群的酯衍生物
CN102858762A (zh) * 2010-02-02 2013-01-02 埃吉斯药物股份公开有限公司 用于制备药物组合物的新的盐
CN102391250A (zh) * 2011-08-29 2012-03-28 石药集团欧意药业有限公司 一种达比加群酯化合物、制备方法及其药物组合物
EP2631234A1 (en) * 2012-02-23 2013-08-28 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
CN103288800A (zh) * 2013-06-03 2013-09-11 华仁药业股份有限公司 达比加群酯苯磺酸盐及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3115360A4 *

Also Published As

Publication number Publication date
HK1210773A1 (zh) 2016-05-06
US9718802B2 (en) 2017-08-01
EP3115360A4 (en) 2017-10-18
EP3115360A1 (en) 2017-01-11
CN106458975B (zh) 2020-08-18
US20170073327A1 (en) 2017-03-16
CN104892574A (zh) 2015-09-09
CN106458975A (zh) 2017-02-22

Similar Documents

Publication Publication Date Title
KR102078077B1 (ko) 타이로신 키나제 억제제 다이말리에이트의 결정형 아이 및 그의 제조 방법
TW200813068A (en) Prasugrel with high purity and a method for preparing its acid addition salt
WO2017050171A1 (zh) 吡咯并喹啉醌钠盐的晶型及其制备方法和用途
CN104379582A (zh) 包含达沙替尼和所选择的共晶体形成剂的多组分晶体
CN108096200A (zh) 5,10-亚甲基-(6r)-四氢叶酸的半硫酸盐
WO2016124149A1 (zh) 一种治疗前列腺癌的抗雄激素类药物的新晶型及其制备方法
CN102070618B (zh) 一种化合物及其晶体
WO2018117267A1 (ja) 置換ピペリジン化合物の塩
EP3216790A1 (en) Crystalline form of jak kinase inhibitor bisulfate and a preparation method thereof
US10626089B2 (en) Quinoline derivative in crystal form
CA2767992A1 (en) 2 - [[[2 -[(hydroxyacetyl) amino]- 4 -pyridinyl] methyl] thio]- n -[4 - (trifluoromethoxy) phenyl]- 3 -pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof
TW201840557A (zh) (s)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)-甲醇之結晶型
WO2015131829A1 (zh) 达比加群酯甲磺酸盐的晶型及其制备方法和用途
WO2015034031A1 (ja) 新規な結晶性アリールアルキルアミン化合物およびその製造方法
KR101596554B1 (ko) 펩타이드계 물질의 결정체 및 그의 제조방법과 용도
CN105358557A (zh) 化合物的多晶型物和盐
WO2011036895A1 (ja) マレイン酸塩およびその結晶
JP5829741B2 (ja) 新規な結晶性アリールアルキルアミン化合物およびその製造方法
WO2016004873A1 (zh) 烟酰胺类衍生物的甲磺酸盐a晶型及其制备方法和应用
CN110914246B (zh) 3-(3,5-二氯-4-羟基苯甲酰)-1,1-二氧代-2,3-二氢-1,3-苯并噻唑的晶型及其盐
JP5681841B1 (ja) 新規な結晶性アリールアルキルアミン化合物およびその製造方法
CN106065016A (zh) 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法
JP6985137B2 (ja) スルホンアミド化合物の結晶形
CN106432243B (zh) 一种hedgehog信号通路抑制剂的结晶形式及其制备方法
WO2017036356A1 (zh) 磷酸氟达拉滨的晶型及其制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15759282

Country of ref document: EP

Kind code of ref document: A1

REEP Request for entry into the european phase

Ref document number: 2015759282

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015759282

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 15123378

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE