WO2015149638A1 - 达比加群酯甲磺酸盐晶型、其制备方法以及药物组合物 - Google Patents

达比加群酯甲磺酸盐晶型、其制备方法以及药物组合物 Download PDF

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WO2015149638A1
WO2015149638A1 PCT/CN2015/074956 CN2015074956W WO2015149638A1 WO 2015149638 A1 WO2015149638 A1 WO 2015149638A1 CN 2015074956 W CN2015074956 W CN 2015074956W WO 2015149638 A1 WO2015149638 A1 WO 2015149638A1
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dabigatran etexilate
etexilate mesylate
stirred
crystalline form
test
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PCT/CN2015/074956
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English (en)
French (fr)
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刘文峥
高禹哲
王国成
刘金平
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江苏天士力帝益药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • 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
    • 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
    • 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 invention belongs to the field of pharmacy, relates to a pharmaceutical crystal form, and particularly relates to a novel crystal form of an anticoagulant drug dabigatran etexilate mesylate, a preparation method thereof and a pharmaceutical composition containing the above novel crystal form.
  • Dabigatran etexilate mesylate is a novel direct thrombin inhibitor, a prodrug of dabigatran, a non-peptide thrombin inhibitor. After oral absorption by the stomach, it is converted into dabigatran having direct anticoagulant activity in vivo. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from cleavage into fibrin, thereby blocking the final steps of the coagulation network and thrombosis. Dabigatran can dissociate from the fibrin thrombin complex and exert a reversible anticoagulant effect. Its chemical structure is as follows:
  • WO2005028468 discloses two kinds of dabigatran etexilate mesylate. Preparation method of crystal form: Both Form I and Form II use acetone as solvent, but the crystallization temperature is different, and Form II can also be obtained by adding seed crystal.
  • WO2011110876 discloses a preparation method of one crystal form of dabigatran etexilate mesylate, which is prepared by using ethyl acetate as a solvent to obtain crystal form IV.
  • WO2012027543 discloses a method for preparing eight crystalline forms of dabigatran etexilate mesylate, which are respectively placed in an environment with a relative humidity of 100% for 30 days (crystal form A), Treated with water (Form B), recrystallized with p-isopropyl toluene (Form C), recrystallized with dimethyl sulfoxide (Form D), placed in n-heptane for 1 month (Form G) Recrystallization from pyridine (Form H), crystallization in 2-methyltetrahydrofuran (or recrystallization from cyclohexanone, pentanol, ethyl acetoacetate, diglyme) (Form I) It is crystallized in 2-but
  • the problem with the above method is that the crystal form of dabigatran etexilate mesylate is prepared by using acetone as a solvent, and there is a safety hazard in industrial production, using isopropyl toluene, dimethyl sulfoxide, n-heptane, pyridine.
  • a solvent 2-methyltetrahydrofuran, ethyl acetoacetate, 2-butanol or the like has a high production cost, a solvent is liable to remain, and is not a problem of industrially producing a conventional solvent. Therefore, it is necessary to find a new crystal form for pharmaceutical use, which is more desirable in the preparation of the solvent, the resulting crystal form is stable and easy to prepare.
  • the present invention provides novel crystal forms of four dabigatran etexilate mesylate salts, and a process for preparing these novel crystal forms.
  • the dabigatran etexilate mesylate salt of the present invention can be prepared by any of the methods of the prior art.
  • the first novel form of dabigatran etexilate methanesulfonate (Form 1) provided by the present invention has a powder X-ray diffraction pattern in degrees 2 ⁇ of 4.44 ⁇ 0.2, 18.04 ⁇ 0.2, 13.48 ⁇ 0.2 22.02 ⁇ 0.2 and 17.58 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific powder X-ray diffraction data is shown in Table 1, and its powder X-ray diffraction pattern is shown in Fig. 1.
  • Form 1 has a melting point of 175-179 °C.
  • the infrared spectrum of Form 1 shows that at 3272.98, 2956.67, 2931.60, 2862.24, 1731.96, 1645.17, 1608.52, 1587.31, 1537.16, 1469.66, 1434.94, 1371.29, 1337.79, 1238.21, 1205.43, 1163.00, 1045.35, 829.33, 781.12, 746.40, 557.39 and 530.39 cm -1 have characteristic absorption peaks. Its infrared spectrum is shown in Figure 2.
  • the crystal form is prepared by the following method: taking dabigatran etexilate mesylate in a reaction flask, adding 2 to 15 times (weight-volume, w/v) of dichloromethane, stirring and heating to dissolve 2 to 15 times the amount (w/v) of ethyl acetate was added, stirred, and the mixture was stirred and cooled, and the mixture was filtered, washed with ethyl acetate and dried.
  • the dabigatran etexilate mesylate is placed in a reaction flask, 2 to 15 times the amount (w/v) of dichloromethane is added, and the mixture is heated to reflux with stirring, and added in an amount of 2 to 15 times (w/ The ethyl acetate of v) was stirred for 5 to 15 minutes, and the mixture was cooled to 5 to 15 ° C and stirred for 1 hour. It was filtered, washed with ethyl acetate and dried to give.
  • the second crystalline form of dabigatran etexilate methanesulfonate (Form 2) provided by the present invention has a powder X-ray diffraction pattern of 2 ⁇ in degrees of 3.78 ⁇ 0.2, 23.78 ⁇ 0.2, 7.52 ⁇ 0.2. 8.18 ⁇ 0.2, 17.72 ⁇ 0.2, 19.88 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific powder X-ray diffraction data is shown in Table 2, and its powder X-ray diffraction pattern is shown in Fig. 3.
  • Form 2 has a melting point of 129-133 °C.
  • the infrared spectrum of Form 2 shows that at 3307.69, 2954.74, 2293.53, 1377.74, 1650.95, 1608.52, 1587.31, 1573.81, 1537.16, 1469.66, 1434.94, 1377.08, 1320.51, 1240.14, 1209.28, 1180.35, 1037.63, 835.12, 779.19, 551.60, 522.67 cm -1 has a characteristic absorption peak. Its infrared spectrum is shown in Figure 4.
  • the crystal form is prepared by the following method: taking dabigatran etexilate mesylate in a reaction flask, adding 2 to 15 times (weight-volume, w/v) of dichloromethane, stirring and heating to dissolve Add 2 to 15 times the amount (weight-volume ratio, w/v) of acetone, stir, cool and stir to crystallize, filter, wash with acetone, and dry.
  • the dabigatran etexilate mesylate is placed in a reaction flask, 2 to 15 times the amount (w/v) of dichloromethane is added, and the mixture is heated to reflux with stirring, and added in an amount of 2 to 15 times (w/ The acetone of v) was stirred for 5 to 15 minutes, and the temperature was lowered to 5 to 15 ° C and stirred for 1 hour. Filter, wash with acetone, dry, that is.
  • the third crystalline form of dabigatran etexilate mesylate (Form 3) provided by the present invention has a powder X-ray diffraction pattern in degrees 2 ⁇ of 4.54 ⁇ 0.2, 3.76 ⁇ 0.2, 22.16 ⁇ 0.2 18.16 ⁇ 0.2 and 17.76 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific powder X-ray diffraction data is shown in Table 3, and the powder X-ray diffraction pattern is shown in Fig. 5.
  • Form 3 has a melting point of 176-183 °C.
  • the infrared spectrum of Form 3 shows that at 3286.48, 2956.67, 2931.60, 2862.24, 1731.96, 1605.95, 1608.52, 1587.31, 1537.16, 1469.66, 1434.94, 1371.29, 1337.79, 1238.21, 1205.43, 1163.00, 1045.35, 831.26, 781.12, 746.40, 557.39 and 530.39 cm -1 have characteristic absorption peaks. Its infrared spectrum is shown in Figure 6.
  • the crystal form is prepared by the following method: taking dabigatran etexilate mesylate in a reaction flask, adding 2 to 15 times (weight-volume, w/v) of dichloromethane, stirring and heating to dissolve Adding 2 to 15 times (weight-volume ratio, w/v) of tetrahydrofuran, stirring, cooling and stirring, crystallizing, filtering, washing with tetrahydrofuran, drying, and obtaining.
  • the dabigatran etexilate mesylate is placed in a reaction flask, 2 to 15 times the amount (w/v) of dichloromethane is added, and the mixture is heated to reflux with stirring, and added in an amount of 2 to 15 times (w/ v) tetrahydrofuran, stirred for 5 to 15 minutes, cooled to 5 to 15 ° C and stirred for 1 hour. Filtration, washing with tetrahydrofuran, drying, that is.
  • the fourth novel form of dabigatran etexilate methanesulfonate (Form 4) provided by the present invention has a powder X-ray diffraction pattern in degrees 2 ⁇ of 4.46 ⁇ 0.2, 21.60 ⁇ 0.2, 17.92 ⁇ 0.2 19.96 ⁇ 0.2, 19.28 ⁇ 0.2, 28.20 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific powder X-ray diffraction data is shown in Table 4, and the powder X-ray diffraction pattern is shown in Fig. 7.
  • Form 4 has a melting point of 183-190 °C.
  • the infrared spectrum of Form 4 shows that at 3309.62, 2956.67, 2931.60, 2862.24, 1731.96, 1652.88, 1608.52, 1589.23, 1537.16, 1469.66, 13.7.08, 1328.86, 1244.00, 1207.36, 1166.85, 1041.49, 833.19, 769.54, 744.47, 551.60, 532.32 cm -1 has a characteristic absorption peak. Its infrared spectrum is shown in Figure 8.
  • the crystal form is prepared by dissolving dabigatran etexilate mesylate in 3 to 20 times (w/v) ethanol and heating and stirring for 10 to 20 minutes, distilling off the ethanol, and drying.
  • the invention further provides a pharmaceutical composition, in particular a solid pharmaceutical composition, comprising a novel crystalline form of dabigatran etexilate mesylate of any of the invention.
  • the pharmaceutically active substance in the pharmaceutical composition of the present invention is any novel form of dabigatran etexilate mesylate of the present invention, which may be 0.01 to 99.99% by weight in the preparation, and the rest is pharmaceutically acceptable. a.
  • Preferred in the present invention is a solid pharmaceutical composition for oral administration which can be formulated into any dosage form suitable for oral administration such as tablets, capsules, granules, pills, dry powders and the like.
  • the pharmaceutical composition of the present invention determines the dosage according to the condition of the patient at the time of use, for example, it can be taken 1 to 3 times a day.
  • the crystal form 1-3 of the present invention has the following advantages over the prior art:
  • the dabigatran etexilate mesylate form 1-3 prepared by the method of the present invention is superior to the prior art in purity and stability.
  • Form 4 is treated with ethanol and is more soluble than other crystal forms.
  • the four crystal forms of the present invention were stable in the light, high temperature, high humidity, and accelerated tests without significant changes.
  • Dabigatran etexilate mesylate salt form 2 solubility test the solubility of ethanol, water, dichloromethane, acetone, ethyl acetate, tetrahydrofuran, 0.1M HCl, and 0.1M NaOH as solvent The results are shown in Table 6.
  • Dabigatran etexilate mesylate salt form 3 solubility test, respectively, ethanol, water, dichloromethane, acetone, ethyl acetate, tetrahydrofuran, 0.1M HCl and 0.1M NaOH as solvent, the results are shown in Table 7. .
  • the crystalline form 1 of the bisgalactone mesylate salt was irradiated under the condition of a light intensity of 4500 ⁇ 500 Lx, and the samples were sampled at 5 and 10 days. The results are shown in Table 9.
  • the crystalline form 1 of dabigatran etexilate mesylate was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 10.
  • the dabigatran etexilate mesylate form 1 was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 11.
  • Dabigatran etexilate mesylate salt form 1 is sealed with a polyethylene film bag, placed at a temperature of 40 ⁇ 2 ° C, relative humidity of 75 ⁇ 5%, placed for 6 months, respectively, at 1, 2, 3 At the end of the 6-month sampling test, the results are shown in Table 12.
  • dabigatran etexilate mesylate salt form 1 was stable under strong light irradiation, high temperature, high humidity and accelerated test conditions, and the appearance color, dry weight loss, content and related substances did not change significantly, under high humidity conditions. Have moisture absorption and weight gain.
  • the crystalline form 2 of dabigatran etexilate mesylate was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled at 5 and 10 days. The results are shown in Table 13.
  • the dabigatran etexilate mesylate salt form 2 was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 14.
  • the dabigatran etexilate mesylate form 2 was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 15.
  • Dabigatran etexilate mesylate salt form 2 is sealed with a polyethylene film bag, placed at a temperature of 40 ⁇ 2 ° C, relative humidity of 75 ⁇ 5%, placed for 6 months, respectively, at 1, 2, 3 At the end of the 6-month sampling test, the results are shown in Table 16.
  • dabigatran etexilate mesylate salt form 2 was stable under strong light irradiation, high temperature, high humidity and accelerated test conditions, and the appearance color, dry weight loss, content and related substances did not change significantly, under high humidity conditions. Have moisture absorption and weight gain.
  • the bismuthide group methanesulfonate crystal form 3 was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 17.
  • the bismuthide group methanesulfonate crystal form 3 was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 18.
  • the dabigatran etexilate mesylate form 3 was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 19.
  • Dabigatran etexilate mesylate salt form 3 is sealed with a polyethylene film bag, placed at a temperature of 40 ⁇ 2 ° C, relative humidity of 75 ⁇ 5%, placed for 6 months, respectively, at 1, 2, 3 At the end of the 6-month sampling test, the results are shown in Table 20.
  • dabigatran etexilate mesylate salt form 3 was stable under strong light irradiation, high temperature, high humidity and accelerated test conditions, and the appearance color, dry weight loss, content and related substances did not change significantly, under high humidity conditions. Have moisture absorption and weight gain.
  • the crystalline form 4 of dabigatran etexilate mesylate was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 21.
  • the crystalline form 4 of dabigatran etexilate mesylate was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 22.
  • the dabigatran etexilate mesylate form 4 was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 23.
  • Dabigatran etexilate mesylate salt form 4 is sealed with a polyethylene film bag, placed at a temperature of 40 ⁇ 2 ° C, relative humidity of 75 ⁇ 5%, placed for 6 months, respectively, at 1, 2, 3 At the end of the 6-month sampling test, the results are shown in Table 24.
  • dabigatran etexilate mesylate salt form 4 was stable under strong light irradiation, high temperature, high humidity and accelerated test conditions, and the appearance color, dry weight loss, content and related substances did not change significantly, under high humidity conditions. Have moisture absorption and weight gain.
  • the dabigatran etexilate mesylate form I was prepared according to the method of patent WO2005028468.
  • the crystalline form I of dabigatran etexilate mesylate was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 25.
  • the crystalline form I of dabigatran etexilate mesylate was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 26.
  • the dabigatran etexilate mesylate form I was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 27.
  • Dabigatran etexilate mesylate salt form I is sealed with a polyethylene film bag, placed at a temperature of 40 ⁇ 2 ° C, relative humidity of 75 ⁇ 5%, placed for 6 months, respectively, on the 1, 2, 3 At the end of the 6-month sampling test, the results are shown in Table 28.
  • the dabigatran etexilate mesylate form III was prepared according to the method of patent WO2012027543.
  • the crystalline form III of dabigatran etexilate mesylate was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 29.
  • the crystalline form III of dabigatran etexilate mesylate was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 30.
  • the dabigatran etexilate mesylate form III was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 31.
  • Dabigatran etexilate mesylate salt form III is sealed with a polyethylene film bag, placed at a temperature of 40 ⁇ 2 ° C, relative humidity of 75 ⁇ 5%, placed for 6 months, respectively, at 1, 2, 3 At the end of the 6-month sampling test, the results are shown in Table 32.
  • the crystalline form of dabigatran etexilate mesylate prepared by the method of the invention has the advantages of good stability and the like, and is stable regardless of strong light irradiation, high temperature, high humidity and accelerated test conditions, and related substances. No increase. In the prior art, Form I and Form III have a slight increase in related substances under high temperature, high humidity and accelerated test conditions.
  • Figure 1 is a X-ray diffraction pattern of a Form 1 powder.
  • Figure 3 is a graph 2 powder X-ray diffraction pattern.
  • Figure 4 is a graph 2 infrared spectrum.
  • Figure 5 is a X-ray diffraction pattern of a Form 3 powder.
  • Figure 6 is a graph of the infrared spectrum of Form 3.
  • Figure 7 is a X-ray diffraction pattern of Form 4 powder.
  • Figure 8 is a graph 4 infrared spectrum.
  • the invention is further illustrated by the following examples.
  • the method of the present invention is intended to be illustrative only and not to limit the invention.
  • Example 12 Preparation of a capsule pharmaceutical composition containing dabigatran etexilate mesylate salt form 1
  • Dabigatran etexilate mesylate crystal form 1 lactose, microcrystalline cellulose, corn starch, sodium carboxymethyl starch was mixed in a high-efficiency wet granulator, and granulated by adding 2% polyvinylpyrrolidone ethanol solution. The wet granules were dried in a fluidized bed and sieved through a 18 mesh sieve. The dry granules were mixed with magnesium stearate and then filled into capsules.
  • Example 13 Preparation of a capsule pharmaceutical composition containing dabigatran etexilate mesylate form 2
  • Dabigatran etexilate mesylate salt form 2 lactose, microcrystalline cellulose, corn starch, sodium carboxymethyl starch were mixed in a high-efficiency wet granulator and granulated by adding 2% polyvinylpyrrolidone ethanol solution. The wet granules were dried in a fluidized bed and sieved through a 18 mesh sieve. The dry granules were mixed with magnesium stearate and then filled into capsules.
  • Example 14 Preparation of a capsule pharmaceutical composition containing dabigatran etexilate mesylate salt form 3
  • Dabigatran etexilate mesylate crystal form 3 lactose, microcrystalline cellulose, corn starch, sodium carboxymethyl starch were mixed in a high-efficiency wet granulator, and granulated by adding 2% polyvinylpyrrolidone ethanol solution.
  • the wet granules were dried in a fluidized bed and sieved through a 18 mesh sieve.
  • the dry granules were mixed with magnesium stearate and then filled into capsules.
  • Dabigatran etexilate mesylate form 4 lactose, microcrystalline cellulose, corn starch, sodium carboxymethyl starch were mixed in a high-efficiency wet granulator and granulated by adding 2% polyvinylpyrrolidone ethanol solution.
  • the wet granules were dried in a fluidized bed and sieved through a 18 mesh sieve.
  • the dry granules were mixed with magnesium stearate and then filled into capsules.

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Abstract

本发明提供了4种达比加群酯甲磺酸盐新晶型、其制备方法以及含有上述4种晶型的药物组合物。该方法包括将达比加群酯甲磺酸盐溶于二氯甲烷，然后再加入第二种有机溶剂进行重结晶的步骤，或者，将达比加群酯甲磺酸盐溶于乙醇中，加热溶解，蒸出乙醇的步骤。

Description

达比加群酯甲磺酸盐晶型、其制备方法以及药物组合物 技术领域
本发明属于药学领域，涉及药物晶型，特别涉及抗凝血药物达比加群酯甲磺酸盐的新晶型、其制备方法以及含有上述新晶型的药物组合物。
背景技术
达比加群酯甲磺酸盐(Dabigatran etexilate mesylate)是一种新型的直接凝血酶抑制剂，是达比加群的前体药物，属非肽类的凝血酶抑制剂。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，从而阻断了凝血网络的最后步骤及血栓形成。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。其化学结构如下：
Figure PCTCN2015074956-appb-000001
由于达比加群酯甲磺酸盐独特的药理活性，研究人员对其晶型进行了广泛研究，新的晶型不断被发现，例如WO2005028468中公开了达比加群酯甲磺酸盐2种晶型的制备方法：晶型I和晶型II均采用丙酮为溶剂，只是析晶温度不同，晶型II也可以通过加入晶种的方法获得。
WO2011110876中公开了达比加群酯甲磺酸盐1种晶型的制备方法，该方法是以乙酸乙酯为溶剂，制得晶型IV。WO2012027543中公开了达比加群酯甲磺酸盐8种晶型的制备方法，分别采用将达比加群酯甲磺酸盐在相对湿度100％的环境中放置30天(晶型A)、用水处理(晶型B)、用对异丙基甲苯重结晶(晶型C)、用二甲基亚砜重结晶(晶型D)、在正庚烷环境中放置1个月(晶型G)、用吡啶重结晶(晶型H)、在2-甲基四氢呋喃中析晶(或用环己酮、戊醇、乙酰乙酸乙酯、二甘醇二甲醚重结晶)(晶型I)、在2-丁醇中析晶(或用乙醇和2-甲基四氢呋喃、乙醇和乙酸乙酯、丁醇和乙酸乙酯、乙醇和异丁基酮重结晶)(晶型III)等。
以上方法存在的问题是用丙酮作为溶剂来制备达比加群酯甲磺酸盐的晶型，工业生产上存在安全隐患，用对异丙基甲苯、二甲基亚砜、正庚烷、吡啶、2-甲基四氢呋喃、乙酰乙酸乙酯、2-丁醇等作溶剂都存在生产成本高，溶剂易残留、不是工业化生产常规溶剂的问题。因此，有必要寻找新的晶型作为药物应用，该晶型在制备中使用的溶剂更加理想、所得晶型稳定且容易制备得到。
发明内容
为了解决上述问题，本发明提供了四种达比加群酯甲磺酸盐的新晶型，以及这些新晶型的制备方法。
本发明所述的达比加群酯甲磺酸盐可采用现有技术中的任一方法进行制备。
本发明所提供的第一种达比加群酯甲磺酸盐新晶型(晶型1)，其粉末X-射线衍射图以度表示的2θ在4.44±0.2、18.04±0.2、13.48±0.2、22.02±0.2、17.58±0.2有特征衍射峰。其具体的粉末X-射线衍射数据如表1，其粉末X-射线衍射图见图1。
表1晶型1粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I°
1 4.44 19.8851 100
2 8.94 9.8834 11
3 9.54 9.2631 4
4 10.96 8.0659 8
5 13.48 6.5632 19
6 13.98 6.3295 5
7 15.96 5.5485 4
8 16.48 5.3746 5
9 17.58 5.0407 15
10 18.04 4.9132 21
11 19.94 4.4491 10
12 21.08 4.2110 11
13 22.02 4.0333 19
14 22.82 3.8937 14
15 25.28 3.5201 7
16 26.80 3.3238 12
17 29.22 3.0538 6
18 32.00 2.7945 6
晶型1熔点为175-179℃。
晶型1的红外光谱图显示，在3272.98、2956.67、2931.60、2860.24、1731.96、1645.17、1608.52、1587.31、1537.16、1469.66、1434.94、1371.29、1330.79、1238.21、1205.43、1163.00、1045.35、829.33、781.12、746.40、557.39、530.39cm-1有特征吸收峰。其红外光谱图见图2。
该晶型采用如下方法进行制备：取达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(重量体积比，w/v)的二氯甲烷，搅拌加热使其溶解，加入2至15倍量(重量体积比，w/v)的乙酸乙酯，搅拌，降温搅拌析晶，过滤，用乙酸乙酯洗涤，干燥，即得。
更优选地，取达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(w/v)的二氯甲烷，搅拌加热至回流，加入2至15倍量(w/v)的乙酸乙酯，搅拌5至15分钟，降温到5至15℃搅拌析晶1小时。过滤，用乙酸乙酯洗涤，干燥，即得。
本发明所提供的第二种达比加群酯甲磺酸盐新晶型(晶型2)，其粉末X-射线衍射图以度表示的2θ在3.78±0.2、23.78±0.2、7.52±0.2、8.18±0.2、17.72±0.2、19.88±0.2有特征衍射峰。其具体的粉末X-射线衍射数据如表2，其粉末X-射线衍射图见图3。
表2晶型2粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I°
1 3.78 23.3555 100
2 7.52 11.7462 5
3 8.18 10.7998 5
4 8.70 10.1555 3
5 9.28 9.5220 2
6 10.60 8.3390 2
7 11.26 7.8517 1
8 12.96 6.8253 1
9 14.46 6.1205 3
10 14.98 5.9092 1
11 16.46 5.3810 4
12 17.16 5.1631 3
13 17.72 5.0012 5
14 18.66 4.7513 1
15 19.30 4.5952 2
16 19.88 4.4624 5
17 20.28 4.3753 3
18 21.14 4.1992 5
19 22.10 4.0189 3
20 23.00 3.8636 2
21 23.78 3.7386 6
22 24.42 3.6421 4
23 25.18 3.5338 1
24 26.48 3.3632 2
25 27.42 3.2500 2
26 29.24 3.0517 2
晶型2的熔点为129-133℃。
晶型2的红外光谱图显示，在3307.69、2954.74、2933.53、1737.74、1650.95、1608.52、1587.31、1573.81、1537.16、1469.66、1434.94、1377.08、1325.01、1240.14、1209.28、1180.35、1037.63、835.12、779.19、551.60、522.67cm-1有特征吸收峰。其红外光谱图见图4。
该晶型采用如下方法进行制备：取达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(重量体积比，w/v)的二氯甲烷，搅拌加热使其溶解，加入2至15倍量(重量体积比，w/v)的丙酮，搅拌，降温搅拌析晶，过滤，用丙酮洗涤，干燥，即得。
更优选地，取达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(w/v)的二氯甲烷，搅拌加热至回流，加入2至15倍量(w/v)的丙酮，搅拌5至15分钟，降温到5至15℃搅拌析晶1小时。过滤，用丙酮洗涤，干燥，即得。
本发明所提供的第三种达比加群酯甲磺酸盐新晶型(晶型3)，其粉末X-射线衍射图以度表示的2θ在4.54±0.2、3.76±0.2、22.16±0.2、18.16±0.2、17.76±0.2有特征衍射峰。其具体的粉末X-射线衍射数据如表3，其粉末X-射线衍射图见图5。
表3晶型3粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I°
1 3.76 23.4797 62
2 4.54 19.4473 100
3 7.48 11.8089 5
4 8.18 10.7998 6
5 9.06 9.7527 11
6 9.34 9.4610 9
7 9.68 9.1294 6
8 10.60 8.3390 7
9 11.06 7.9932 14
10 13.58 6.5151 18
11 14.46 6.1205 10
12 16.38 5.4071 12
13 17.76 4.9900 28
14 18.16 4.8810 30
15 18.74 4.7312 13
16 19.90 4.4579 23
17 21.12 4.2031 22
18 22.16 4.0081 32
19 22.96 3.8703 26
20 23.82 3.7324 17
21 24.38 3.6480 16
22 25.18 3.5338 14
23 26.46 3.3657 16
24 26.92 3.3092 16
25 28.28 3.1531 13
26 29.28 3.0477 12
晶型3的熔点为176-183℃。
晶型3的红外光谱图显示，在3286.48、2956.67、2931.60、2860.24、1731.96、1650.95、1608.52、1587.31、1537.16、1469.66、1434.94、1371.29、1330.79、1238.21、1205.43、1163.00、 1045.35、831.26、781.12、746.40、557.39、530.39cm-1有特征吸收峰。其红外光谱图见图6。
该晶型采用如下方法进行制备：取达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(重量体积比，w/v)的二氯甲烷，搅拌加热使其溶解，加入2至15倍量(重量体积比，w/v)的四氢呋喃，搅拌，降温搅拌析晶，过滤，用四氢呋喃洗涤，干燥，即得。
更优选地，取达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(w/v)的二氯甲烷，搅拌加热至回流，加入2至15倍量(w/v)的四氢呋喃，搅拌5至15分钟，降温到5至15℃搅拌析晶1小时。过滤，用四氢呋喃洗涤，干燥，即得。
本发明所提供的第四种达比加群酯甲磺酸盐新晶型(晶型4)，其粉末X-射线衍射图以度表示的2θ在4.46±0.2、21.60±0.2、17.92±0.2、19.96±0.2、19.28±0.2、28.20±0.2有特征衍射峰。其具体的粉末X-射线衍射数据如表4，其粉末X-射线衍射图见图7。
表4晶型4粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I°
1 4.46 19.7960 100
2 8.78 10.0631 8
3 9.78 9.0363 6
4 11.28 7.8378 7
5 12.44 7.1094 16
6 13.58 6.5151 8
7 13.98 6.3295 13
8 15.20 5.8241 12
9 16.06 5.5142 15
10 16.56 5.3488 11
11 17.38 5.0982 9
12 17.92 4.9458 39
13 18.54 4.7818 22
14 19.28 4.5999 33
15 19.96 4.4447 38
16 21.60 4.1108 43
17 22.14 4.0117 18
18 22.58 3.9345 24
19 23.46 3.7889 24
20 23.84 3.7293 24
21 24.48 3.6333 13
22 25.34 3.5119 18
23 26.04 3.4190 13
24 26.60 3.3483 14
25 26.90 3.3117 14
26 27.40 3.2524 17
27 28.20 3.1619 33
28 28.64 3.1143 18
29 36.74 2.4442 8
晶型4的熔点为183-190℃。
晶型4的红外光谱图显示，在3309.62、2956.67、2931.60、2860.24、1731.96、1652.88、1608.52、1589.23、1537.16、1469.66、1377.08、1328.86、1244.00、1207.36、1166.85、1041.49、833.19、769.54、744.47、551.60、532.32cm-1有特征吸收峰。其红外光谱图见图8。
该晶型采用如下方法进行制备：将达比加群酯甲磺酸盐溶于3至20倍(w/v)的乙醇中加热搅拌10至20分钟，蒸出乙醇，干燥，即得。
本发明还提供含有本发明任何一种达比加群酯甲磺酸盐新晶型的药物组合物，特别是固体药物组合物。
本发明的药物组合物中的药物活性物质为本发明任何一种达比加群酯甲磺酸盐新晶型，其在制剂中所占重量百分比可以是0.01至99.99％，其余为药物可接受的载体。
本发明优选的是口服用固体药物组合物，该固体药物组合物可以制剂为适于口服的任意剂型，例如片剂、胶囊剂、颗粒剂、丸剂、干粉剂等。
本发明的药物组合物在使用时根据病人的情况确定用法用量，如可每日服用1至3次。
本发明的晶型1-3和现有技术相比具有以下优点：
(1)与现有技术比较，由于二氯甲烷对达比加群酯甲磺酸盐溶解度大，精制溶剂用量小，加入另一种有机溶剂使产品收率大幅度提高；
(2)二氯甲烷和其它有机溶剂的混合物对达比加群酯甲磺酸盐中的有机杂质溶解度较高，使产品纯度大幅度提高。
用本发明的方法制得的达比加群酯甲磺酸盐晶型1-3，纯度和稳定性等均优于现有技术。
此外，晶型4经过乙醇处理，与其它晶型相比溶解性更好。
本发明的4种晶型在光照、高温、高湿和加速试验中均稳定，没有明显变化。
以下通过实验数据说明本发明的有益效果：
一、溶解性试验
1.达比加群酯甲磺酸盐晶型1溶解性试验，分别以乙醇、水、二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、0.1M HCl、和0.1M NaOH为溶剂，测定其溶解度，结果见表5。
表5达比加群酯甲磺酸盐晶型1溶解性试验结果
Figure PCTCN2015074956-appb-000002
2.达比加群酯甲磺酸盐晶型2溶解性试验，分别以乙醇、水、二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、0.1M HCl、和0.1M NaOH为溶剂，测定其溶解度，结果见表6。
表6达比加群酯甲磺酸盐晶型2溶解性试验结果
Figure PCTCN2015074956-appb-000003
3.达比加群酯甲磺酸盐晶型3溶解性试验，分别以乙醇、水、二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、0.1M HCl和0.1M NaOH为溶剂，结果见表7。
表7达比加群酯甲磺酸盐晶型3溶解性试验结果
溶剂 供试品量 溶解供试品所需 溶解1g供试品所需 溶解度
  (mg) 溶剂(ml) 溶剂(ml)  
乙醇 9.80 0.4 41 略溶
水 10.1 >100 >10000 不溶
二氯甲烷 10.5 0.09 8.5 易溶
丙酮 10.7 >100 >10000 不溶
乙酸乙酯 10.3 >100 >10000 不溶
四氢呋喃 10.2 >100 >10000 不溶
0.1M HCl溶液 9.92 0.48 48.4 略溶
0.1M NaOH溶液 10.5 >100 >10000 不溶
4.达比加群酯甲磺酸盐晶型4溶解性试验，分别以乙醇、水、二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、0.1M HCl和0.1M NaOH为溶剂，测定其溶解度，结果见表8。
表8达比加群酯甲磺酸盐晶型4溶解性试验结果
Figure PCTCN2015074956-appb-000004
二、稳定性试验
1.达比加群酯甲磺酸盐晶型1的稳定性
1.1光照射试验
取达比加群酯甲磺酸盐晶型1置于光强度4500±500Lx的条件下照射，于5、10天取样检测，结果见表9。
表9达比加群酯甲磺酸盐晶型1强光照射试验结果
Figure PCTCN2015074956-appb-000005
1.2高温试验
取达比加群酯甲磺酸盐晶型1置于60℃恒温箱中，于5、10天取样检测，结果见表10。
表10达比加群酯甲磺酸盐晶型1高温试验结果
Figure PCTCN2015074956-appb-000006
1.3高湿试验
将达比加群酯甲磺酸盐晶型1置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表11。
表11达比加群酯甲磺酸盐晶型1高湿试验结果
Figure PCTCN2015074956-appb-000007
1.4加速试验
达比加群酯甲磺酸盐晶型1用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月的月末取样检测，结果见表12。
表12达比加群酯甲磺酸盐晶型1加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.97 未检出
1月 白色粉末 99.85 未检出
2月 白色粉末 99.74 未检出
3月 白色粉末 99.96 未检出
6月 白色粉末 99.67 未检出
结果表明：达比加群酯甲磺酸盐晶型1在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、含量和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
2.达比加群酯甲磺酸盐晶型2的稳定性
2.1光照射试验
取达比加群酯甲磺酸盐晶型2置于光强度4500±500Lx的条件下照射，于5、10天取样检。结果见表13。
表13达比加群酯甲磺酸盐晶型2强光照射试验结果
Figure PCTCN2015074956-appb-000008
2.2高温试验
取达比加群酯甲磺酸盐晶型2置于60℃恒温箱中，于5、10天取样检测，结果见表14。
表14达比加群酯甲磺酸盐晶型2高温试验结果
Figure PCTCN2015074956-appb-000009
2.3高湿试验
将达比加群酯甲磺酸盐晶型2置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表15。
表15达比加群酯甲磺酸盐晶型2高湿试验结果
Figure PCTCN2015074956-appb-000010
Figure PCTCN2015074956-appb-000011
2.4加速试验
达比加群酯甲磺酸盐晶型2用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月的月末取样检测，结果见表16。
表16达比加群酯甲磺酸盐晶型2加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.95 未检出
1月 白色粉末 99.78 未检出
2月 白色粉末 99.85 未检出
3月 白色粉末 99.78 未检出
6月 白色粉末 99.83 未检出
结果表明：达比加群酯甲磺酸盐晶型2在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、含量和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
3.达比加群酯甲磺酸盐晶型3的稳定性
3.1光照射试验
取达比加群酯甲磺酸盐晶型3置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表17。
表17达比加群酯甲磺酸盐晶型3强光照射试验结果
Figure PCTCN2015074956-appb-000012
3.2高温试验
取达比加群酯甲磺酸盐晶型3置于60℃恒温箱中，于5、10天取样检测，结果见表18。
表18达比加群酯甲磺酸盐晶型3高温试验稳定性结果
Figure PCTCN2015074956-appb-000013
3.3高湿试验
将达比加群酯甲磺酸盐晶型3置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表19。
表19达比加群酯甲磺酸盐晶型3高湿度试验稳定性结果
Figure PCTCN2015074956-appb-000014
3.4加速试验
达比加群酯甲磺酸盐晶型3用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月的月末取样检测，结果见表20。
表20达比加群酯甲磺酸盐晶型3加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.90 未检出
1月 白色粉末 99.89 未检出
2月 白色粉末 99.89 未检出
3月 白色粉末 99.95 未检出
6月 白色粉末 99.73 未检出
结果表明：达比加群酯甲磺酸盐晶型3在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、含量和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
4.达比加群酯甲磺酸盐晶型4的稳定性
4.1光照射试验
取达比加群酯甲磺酸盐晶型4置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表21。
表21达比加群酯甲磺酸盐晶型4强光照射试验结果
Figure PCTCN2015074956-appb-000015
4.2高温试验
取达比加群酯甲磺酸盐晶型4置于60℃恒温箱中，于5、10天取样检测，结果见表22。
表22达比加群酯甲磺酸盐晶型4高温试验稳定性结果
Figure PCTCN2015074956-appb-000016
4.3高湿试验
将达比加群酯甲磺酸盐晶型4置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表23。
表23达比加群酯甲磺酸盐晶型4高湿度试验稳定性结果
Figure PCTCN2015074956-appb-000017
4.4加速试验
达比加群酯甲磺酸盐晶型4用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月的月末取样检测，结果见表24。
表24达比加群酯甲磺酸盐晶型4加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.93 未检出
1月 白色粉末 99.68 未检出
2月 白色粉末 99.91 未检出
3月 白色粉末 99.90 未检出
6月 白色粉末 99.75 未检出
结果表明：达比加群酯甲磺酸盐晶型4在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、含量和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
以下将按照现有技术中的方法制备两种达比加群酯甲磺酸盐晶型，并与本发明制备的晶型进行稳定性的对比：
5.达比加群酯甲磺酸盐晶型I的稳定性
按照专利WO2005028468中的方法制备达比加群酯甲磺酸盐晶型I。
5.1光照射试验
取达比加群酯甲磺酸盐晶型I置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表25。
表25达比加群酯甲磺酸盐晶型I强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质(％)
0天 白色粉末 0.31 99.97 未检出
5天 白色粉末 0.35 99.95 未检出
10天 白色粉末 0.37 99.89 未检出
5.2高温试验
取达比加群酯甲磺酸盐晶型I置于60℃恒温箱中，于5、10天取样检测，结果见表26。
表26达比加群酯甲磺酸盐晶型I高温试验稳定性结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质
0天 白色粉末 0.31 99.97 未检出
5天 白色粉末 0.35 99.90 0.02
10天 白色粉末 0.34 99.88 0.03
5.3高湿试验
将达比加群酯甲磺酸盐晶型I置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表27。
表27达比加群酯甲磺酸盐晶型I高湿度试验稳定性结果
Figure PCTCN2015074956-appb-000018
5.4加速试验
达比加群酯甲磺酸盐晶型I用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月的月末取样检测，结果见表28。
表28达比加群酯甲磺酸盐晶型I加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.97 未检出
1月 白色粉末 99.87 未检出
2月 白色粉末 99.95 0.01
3月 白色粉末 99.98 0.03
6月 白色粉末 99.89 0.07
结果表明：达比加群酯甲磺酸盐晶型I在强光照射条件下稳定，外观色泽、干燥失重、含量 和有关物质没有明显变化；而在高温、高湿和加速试验条件下，外观色泽、干燥失重、含量没有明显变化，但有关物质略有增加，在高湿条件下稍有吸湿增重。
6.达比加群酯甲磺酸盐晶型III的稳定性
按照专利WO2012027543中的方法制备达比加群酯甲磺酸盐晶型III。
6.1光照射试验
取达比加群酯甲磺酸盐晶型III置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表29。
表29达比加群酯甲磺酸盐晶型III强光照射试验结果
Figure PCTCN2015074956-appb-000019
6.2高温试验
取达比加群酯甲磺酸盐晶型III置于60℃恒温箱中，于5、10天取样检测，结果见表30。
表30达比加群酯甲磺酸盐晶型III高温试验稳定性结果
Figure PCTCN2015074956-appb-000020
6.3高湿试验
将达比加群酯甲磺酸盐晶型III置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表31。
表31达比加群酯甲磺酸盐晶型III高湿度试验稳定性结果
Figure PCTCN2015074956-appb-000021
6.4加速试验
达比加群酯甲磺酸盐晶型III用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月的月末取样检测，结果见表32。
表32达比加群酯甲磺酸盐晶型III加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.92 未检出
1月 白色粉末 99.78 0.01
2月 白色粉末 99.90 0.01
3月 白色粉末 99.94 0.02
6月 白色粉末 99.83 0.07
结果表明：达比加群酯甲磺酸盐晶型III在强光照射条件下稳定，外观色泽、干燥失重、含量和有关物质没有明显变化；而在高温、高湿和加速试验条件下，外观色泽、干燥失重、含量没有明显变化，但有关物质略有增加，在高湿条件下稍有吸湿增重。
由以上稳定性试验可知，通过本发明方法制备得到的达比加群酯甲磺酸盐晶型具有稳定性好等优点，无论强光照射、高温、高湿和加速试验条件都稳定，有关物质未见增加。而现有技术得到的晶型I和晶型III在高温、高湿和加速试验条件下有关物质略有增加。
附图说明
图1为晶型1粉末X-射线衍射图。
图2为晶型1红外光谱图。
图3为晶型2粉末X-射线衍射图。
图4为晶型2红外光谱图。
图5为晶型3粉末X-射线衍射图。
图6为晶型3红外光谱图。
图7为晶型4粉末X-射线衍射图。
图8为晶型4红外光谱图。
具体实施方式
下面通过实施例来进一步说明本发明。本发明的实施例中的方法仅仅是用于说明本发明，而不是对本发明的限制。
实施例1达比加群酯甲磺酸盐晶型1的制备
取达比加群酯甲磺酸盐20g置于反应瓶中，加入二氯甲烷40ml，搅拌加热到使其溶解，加入乙酸乙酯40ml，搅拌15分钟，降温到10-15℃搅拌析晶1小时。过滤，乙酸乙酯洗涤，干燥，得达比加群酯甲磺酸盐晶型118.4g，收率92％。
实施例2达比加群酯甲磺酸盐晶型1的制备
取达比加群酯甲磺酸盐5g置于反应瓶中，加入二氯甲烷75ml，搅拌加热使其溶解，加入乙酸乙酯75ml，搅拌15分钟，降温到10-15℃搅拌析晶1.5小时。过滤，乙酸乙酯洗涤，干燥，得达比加群酯甲磺酸盐晶型14.1g，收率82.0％。
实施例3达比加群酯甲磺酸盐晶型1的制备
取达比加群酯甲磺酸盐10g置于反应瓶中，加入二氯甲烷80ml，搅拌加热使其溶解，加入乙酸乙酯100ml，搅拌10分钟，降温到10-15℃搅拌析晶1小时。过滤，乙酸乙酯洗涤，干燥，得达比加群酯甲磺酸盐晶型19.50g，收率95.0％。
实施例4达比加群酯甲磺酸盐晶型2的制备
取达比加群酯甲磺酸盐5g置于反应瓶中，加入二氯甲烷10ml，搅拌加热使其溶解，加入丙酮10ml，搅拌5分钟，降温到10-15℃搅拌析晶1.5小时。过滤，丙酮洗涤，干燥，得达比加群酯甲磺酸盐晶型24.5g，收率90.0％。
实施例5达比加群酯甲磺酸盐晶型2的制备
取达比加群酯甲磺酸盐20g置于反应瓶中，加入二氯甲烷300ml，搅拌加热使其溶解，加入丙酮300ml，搅拌15分钟，降温到10-15℃搅拌析晶1小时。过滤，丙酮洗涤，干燥，得达比加群酯甲磺酸盐晶型218.7g，收率93.5％。
实施例6达比加群酯甲磺酸盐晶型2的制备
取达比加群酯甲磺酸盐10g置于反应瓶中，加入二氯甲烷100ml，搅拌加热使其溶解，加入丙酮150ml，搅拌15分钟，降温到10-15℃搅拌析晶1小时。过滤，丙酮洗涤，干燥，得达比加群酯甲磺酸盐晶型29.3g，收率93.0％。
实施例7达比加群酯甲磺酸盐晶型3的制备
取达比加群酯甲磺酸盐20g置于反应瓶中，加入二氯甲烷40ml，搅拌加热使其溶解，加入四氢呋喃40ml，搅拌15分钟，降温到10-15℃搅拌析晶0.5小时。过滤，四氢呋喃洗涤，干燥，得达比加群酯甲磺酸盐晶型318g，收率90％。
实施例8达比加群酯甲磺酸盐晶型3的制备
取达比加群酯甲磺酸盐20g置于反应瓶中，加入二氯甲烷300ml，搅拌加热使其溶解，加入四氢呋喃300ml，搅拌15分钟，降温到10-15℃搅拌析晶1.5小时。过滤，四氢呋喃洗涤，干燥，得达比加群酯甲磺酸盐晶型317.2g，收率86％。
实施例9达比加群酯甲磺酸盐晶型3的制备
取达比加群酯甲磺酸盐10g置于反应瓶中，加入二氯甲烷80ml，搅拌加热使其溶解，加入四氢呋喃100ml，搅拌15分钟，降温到10-15℃搅拌析晶1小时。过滤，四氢呋喃洗涤，干燥，得达比加群酯甲磺酸盐晶型39.3g，收率93％。
实施例10达比加群酯甲磺酸盐晶型4的制备
取达比加群酯甲磺酸盐5g置于反应瓶中，加入乙醇15ml，搅拌加热使其全部溶解，减压蒸出乙醇，干燥，得达比加群酯甲磺酸盐晶型44.9g，收率98％。
实施例11达比加群酯甲磺酸盐晶型4的制备
取达比加群酯甲磺酸盐20g置于反应瓶中，加入乙醇400ml，搅拌加热使其全部溶解，减压蒸出乙醇，干燥，得达比加群酯甲磺酸盐晶型419.2g，收率97％。
实施例12含有达比加群酯甲磺酸盐晶型1的胶囊剂药物组合物的制备
1、处方
Figure PCTCN2015074956-appb-000022
2、胶囊剂的制备方法
达比加群酯甲磺酸盐晶型1、乳糖、微晶纤维素、玉米淀粉、羧甲基淀粉钠加入高效湿法制粒机中混合，加入2％聚乙烯吡咯烷酮乙醇溶液制粒。湿颗粒在流化床中干燥，经18目筛整粒。干颗粒中加入硬脂酸镁适当混合后装入胶囊。
实施例13含有达比加群酯甲磺酸盐晶型2的胶囊剂药物组合物的制备
1、处方
Figure PCTCN2015074956-appb-000023
2、胶囊剂的制备方法
达比加群酯甲磺酸盐晶型2、乳糖、微晶纤维素、玉米淀粉、羧甲基淀粉钠加入高效湿法制粒机中混合，加入2％聚乙烯吡咯烷酮乙醇溶液制粒。湿颗粒在流化床中干燥，经18目筛整粒。干颗粒中加入硬脂酸镁适当混合后装入胶囊。
实施例14含有达比加群酯甲磺酸盐晶型3的胶囊剂药物组合物的制备
1、处方
Figure PCTCN2015074956-appb-000024
2、胶囊剂的制备方法
达比加群酯甲磺酸盐晶型3、乳糖、微晶纤维素、玉米淀粉、羧甲基淀粉钠加入高效湿法制粒机中混合，加入2％聚乙烯吡咯烷酮乙醇溶液制粒。湿颗粒在流化床中干燥，经18目筛整粒。干颗粒中加入硬脂酸镁适当混合后装入胶囊。
实施例15含有达比加群酯甲磺酸盐晶型4的胶囊剂药物组合物的制备
1、处方
Figure PCTCN2015074956-appb-000025
Figure PCTCN2015074956-appb-000026
2、胶囊剂的制备方法
达比加群酯甲磺酸盐晶型4、乳糖、微晶纤维素、玉米淀粉、羧甲基淀粉钠加入高效湿法制粒机中混合，加入2％聚乙烯吡咯烷酮乙醇溶液制粒。湿颗粒在流化床中干燥，经18目筛整粒。干颗粒中加入硬脂酸镁适当混合后装入胶囊。

Claims (9)

  1. 一种达比加群酯甲磺酸盐晶型，其特征在于，其粉末X-射线衍射图，以度表示的2θ在4.44±0.2、18.04±0.2、13.48±0.2、22.02±0.2、17.58±0.2有特征衍射峰；红外光谱图在3272.98、2956.67、2931.60、2860.24、1731.96、1645.17、1608.52、1587.31、1537.16、1469.66、1434.94、1371.29、1330.79、1238.21、1205.43、1163.00、1045.35、829.33、781.12、746.40、557.39、530.39cm-1有特征吸收峰；熔点为175-179℃。
  2. 如权利要求1所述的达比加群酯甲磺酸盐晶型的制备方法，其特征在于，将达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(w/v)的二氯甲烷，搅拌加热使其溶解，然后再加入2至15倍量(w/v)的乙酸乙酯，搅拌，降温搅拌析晶，过滤，加入乙酸乙酯洗涤，干燥，即得。
  3. 一种达比加群酯甲磺酸盐晶型，其特征在于，其粉末X-射线衍射图，以度表示的2θ在3.78±0.2、23.78±0.2、7.52±0.2、8.18±0.2、17.72±0.2、19.88±0.2有特征衍射峰；红外光谱图在3307.69、2954.74、2933.53、1737.74、1650.95、1608.52、1587.31、1573.81、1537.16、1469.66、1434.94、1377.08、1325.01、1240.14、1209.28、1180.35、1037.63、835.12、779.19、551.60、522.67cm-1有特征吸收峰；熔点为129-133℃。
  4. 如权利要求3所述的达比加群酯甲磺酸盐晶型的制备方法，其特征在于，将达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(w/v)的二氯甲烷，搅拌加热使其溶解，然后再加入2至15倍量(w/v)的丙酮，搅拌，降温搅拌析晶，过滤，加入丙酮洗涤，干燥，即得。
  5. 一种达比加群酯甲磺酸盐晶型，其特征在于，其粉末X-射线衍射图，以度表示的2θ在4.54±0.2、3.76±0.2、22.16±0.2、18.16±0.2、17.76±0.2有特征衍射峰；红外光谱图在3286.48、2956.67、2931.60、2860.24、1731.96、1650.95、1608.52、1587.31、1537.16、1469.66、1434.94、1371.29、1330.79、1238.21、1205.43、1163.00、1045.35、831.26、781.12、746.40、557.39、530.39cm-1有特征吸收峰；熔点为176-183℃。
  6. 如权利要求5所述的达比加群酯甲磺酸盐晶型的制备方法，其特征在于，将达比加群酯甲磺酸盐置于反应瓶中，加入2至15倍量(w/v)的二氯甲烷，搅拌加热使其溶解，然后再加入2至15倍量(w/v)的四氢呋喃，搅拌，降温搅拌析晶，过滤，加入四氢呋喃洗涤，干燥，即得。
  7. 一种达比加群酯甲磺酸盐晶型，其特征在于，其粉末X-射线衍射图，以度表示的2θ在4.46±0.2、21.60±0.2、17.92±0.2、19.96±0.2、19.28±0.2、28.20±0.2有特征衍射峰；红外光谱图在3309.62、2956.67、2931.60、2860.24、1731.96、1652.88、1608.52、1589.23、1537.16、1469.66、1377.08、1328.86、1244.00、1207.36、1166.85、1041.49、833.19、769.54、744.47、551.60、532.32cm-1有特征吸收峰；熔点为183-190℃。
  8. 如权利要求7所述的达比加群酯甲磺酸盐晶型的制备方法，其特征在于，将达比加群酯甲磺酸盐溶于3至20倍(w/v)的乙醇中加热搅拌10至20分钟，蒸出乙醇，干燥，即得。
  9. 含有权利要求1、3、5、7任意一项所述的达比加群酯甲磺酸盐晶型的药物组合物。
PCT/CN2015/074956 2014-04-04 2015-03-24 达比加群酯甲磺酸盐晶型、其制备方法以及药物组合物 WO2015149638A1 (zh)

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