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WO2015021902A1 - Nouvelle forme cristalline d'apixaban et son procédé de preparation - Google Patents

Nouvelle forme cristalline d'apixaban et son procédé de preparation Download PDF

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Publication number
WO2015021902A1
WO2015021902A1 PCT/CN2014/084155 CN2014084155W WO2015021902A1 WO 2015021902 A1 WO2015021902 A1 WO 2015021902A1 CN 2014084155 W CN2014084155 W CN 2014084155W WO 2015021902 A1 WO2015021902 A1 WO 2015021902A1
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WO
WIPO (PCT)
Prior art keywords
apixaban
crystal form
preparation
crystal
solvent
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2014/084155
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English (en)
Chinese (zh)
Inventor
王元
何训贵
张兴忠
丁旭锦
周岩锋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
2Y-CHEM Ltd
2Y CHEM Ltd
Original Assignee
2Y-CHEM Ltd
2Y CHEM Ltd
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 2Y-CHEM Ltd, 2Y CHEM Ltd filed Critical 2Y-CHEM Ltd
Publication of WO2015021902A1 publication Critical patent/WO2015021902A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry. Specifically involved in what is commonly referred to as Apixaban, ie 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)benzene A new crystalline form of -4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and a process for its preparation.
  • Apixaban has a variety of crystal forms
  • WO03026652 discloses Apixaban and its preparation method for the first time.
  • Polymorphic forms H2-2 (hydrate) and Nl (neat) crystal forms are reported for the first time in US20060069258.
  • the crystal form H2-2 obtained directly by the reaction also gives a conversion method from the crystal form H2-2 to the crystal form N-1.
  • US20060069258 WO2007001385
  • Example 9 reports a method for converting polymorphic H2-2 to N-1 crystal form, which requires first placing a small batch of H2-2 reaction solution into the transition tank shearing device.
  • the shearing and stirring are carried out to convert H2-2 into a small particle N-1 stable crystal form, and then a large amount of the reaction liquid is added together to shear-induced crystallization. Therefore, special cutting equipment needs to be installed.
  • the US20070203178 patent protects the crystalline forms DMF-5 and FA-2, which can be used to prepare hydrate (H2-2) and N-1 (neat) crystal forms.
  • Form ⁇ is disclosed in WO2012168364.
  • the crystalline forms DMF-5, FA-2 and ⁇ can all be converted to the crystalline form N1 under certain conditions, but the conversion method is not given.
  • the crystalline ⁇ 2-2 particles need to be converted into the crystalline form N-1 when used in larger form;
  • the crystalline form DMF-5 and the crystalline form FA-2 are respectively solvated forms of DMF and FA, containing DMF and FA, high temperature instability; crystal form ⁇ with static electricity, easy to crystallize, not suitable for formulation; crystal form N-1 is stable, but its preparation process requires special shearing equipment according to the literature report. Crystal form, this shearing device is not currently widely used in the pharmaceutical industry.
  • the commonly used method in the field of crystallization is to induce crystallization.
  • Induced crystallization generally requires seed-induced induction of crystallization, which means that a solute is completely dissolved to obtain a fully clarified solution.
  • the desired seed crystals are then added at the appropriate temperature and slowly deferred to form the desired crystalline form. Therefore, the preparation of seed crystals is crucial and is the key to obtaining the desired crystal form.
  • a certain solvent system may precipitate another crystal form, and when another crystal form is added for induction, it may be converted into a desired crystal form.
  • the technical problem to be solved by the present invention is that, through a large number of experiments, a stable novel apixaban crystal form has been developed, and the crystal form preparation method can be industrialized.
  • the present invention provides a novel crystalline form of apixaban and a process for its preparation, which is designated as a quinoid.
  • the apixaban form A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.
  • the apixaban Form A has a differential scanning calorimeter (DSC) pattern substantially as shown in Figure 2.
  • the DSC spectrum shows that the apixaban crystal form A has a melting endothermic peak of 235 ⁇ 242 °C, and the maximum endothermic melting temperature is about 238 °C.
  • test conditions for DSC are: 30-300 ° C, lO.OK/min, open lid, nitrogen atmosphere.
  • the apixaban form A has an infrared (IR) spectrum substantially as shown in Figure 3.
  • the invention also provides a preparation method of the apixaban crystal form A, which comprises the following steps:
  • step (2) at 0 to 150 ° C, preferably 40 to 150 ° C, adding the seed crystal of apixaban crystal form A to the solution obtained in step (1), cooling to 0 to 30 ° C, stirring 0 ⁇ 48h, preferably 0.5 ⁇ 48h, to obtain a suspension;
  • the seed crystal of the apixaban crystal form A of the step (2) is prepared by the following method:
  • the organic solvent in the step (1) and the step (2.1) is independently selected from the group consisting of an ether, an ester, a ketone, an alcohol solvent or a combination thereof; wherein the ether solvent is selected from the group consisting of methyl tert-butyl ether (MTBE), diethyl ether, Isopropyl ether or a combination thereof; the ester solvent is selected from the group consisting of methyl formate, butyl formate, ethyl acetate, methyl acetate, butyl acetate or a combination thereof; the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone or a combination thereof; The solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol or a combination thereof, and the alcohol also contains an aqueous alcohol.
  • the ether solvent is selected from the group consisting of methyl tert-butyl ether
  • the organic solvent is further preferably one or a mixture of methyl tert-butyl ether, diethyl ether, acetone, ethyl acetate, methanol, ethanol, isopropyl alcohol.
  • the organic solvent in the step (1) and the step (2.1) is a mixed solvent, it may be added at one time, or an organic solvent may be added first with an apixaban solid and then another organic solvent may be added.
  • the weight of the seed crystal of the apixaban crystal form A added in the step (2) is 1-50% of the weight of the apixaban described in the step (1), ensuring that the seed crystal of the apixaban crystal form A is not completely dissolved.
  • the timing of adding the seed crystal of apixaban crystal form A needs to be added at a substantially saturated concentration to prevent the seed crystal from being dissolved and to induce no effect.
  • Substantial saturation refers to a clear saturated solution or a small portion of the undissolved apixaban solid.
  • the method of separating in the step (3) may include filtration, and washing with the organic solvent of the step (1).
  • the method of separation described in the step (2.3) may include filtration, and washing with the organic solvent of the step (2.1).
  • the drying described in the step (4) may be carried out by conventional drying, such as a drying oven, etc., and the temperature range is not limited, preferably 30-80.
  • the room temperature of the present invention is about 25 °C.
  • the boiling point temperature of the solvent is the boiling temperature of the organic solvent to be added.
  • the preparation of apixaban polymorph A of the invention has good repeatability, simple operation, high product utilization rate and high purity, and is suitable for industrial production.
  • the apixaban crystal form A of the invention does not contain crystal water and solvent, has no static electricity, has good stability and does not absorb moisture, and its properties are obviously superior to those of the prior art crystal form H2-2 and crystal form DMF-5.
  • crystal form FA-2, crystal form ⁇ and other crystal forms According to the existing literature, the crystalline form of DMF-5 and the crystalline form of FA-2 will retain the corresponding DMF ( ⁇ , ⁇ -dimethylformamide) and formamide;
  • the crystalline form H2-2 is a hydrate, has a large crystal grain size, and is not suitable for preparation; the crystal form ex is electrostatically charged, and is not suitable for the formulation process.
  • the apixaban crystal form A of the present invention has a simple preparation method and can be obtained by crystallization and seed crystal induction, and the process does not require special equipment.
  • a preparation method of apixaban crystal form N-1 is disclosed, which requires transferring the slurry of apixaban H2-2 into a transition tank, and heating to 55-6 CTC for shearing. After conversion to small particles of N-1 crystals, special shearing processes and corresponding equipment are required.
  • the preparation method of the apixaban crystal form A of the invention is obviously simple, does not require special equipment, does not need to be converted through other crystal forms, reduces cost, and has high operability.
  • the analytical detection conditions of the present invention are as follows:
  • X-ray powder diffraction is measured by Rigaku D/max 2550 VB-pc diffractometer, using Cu/K-alphal (into 1.54040A) radiation, power: 40kVX 100mA at 2 ⁇ 3 ° -40° (or The relevant diffraction data was acquired in the range of 2° -40°, with a step width of 0.02° and a scanning speed of 6° / min.
  • the DSC is tested by the German NETZSCH DSC200F3, with a temperature range of 30-300 ° C, a heating rate of 10.0 K/min, a sealed puncture, and a nitrogen atmosphere.
  • Infrared spectroscopy is detected by PE spectrum RXI with a temperature of 23 °C and a humidity of 54%.
  • apixaban 0.5 g was added to 13 mL of a mixed solvent of ethanol and ethyl acetate (the ratio of ethanol to ethyl acetate was 4:1), the temperature was raised to 78 ° C, and stirred until a clear solution was obtained. After 1 hour, cool to 25 ° C, stir for 3 h, filter, wash with 0.5 mL of a mixed solvent of ethanol and ethyl acetate (4:1 by volume of ethanol and ethyl acetate), and dry at 30 °C. Seed crystal of apixaban crystal form A.
  • apixaban 0.5 g was added to a mixed solvent of 22.5 mL of methanol and methyl tert-butyl ether (methanol to MTBE ratio of 1:2), the temperature was raised to 60 ° C, and the mixture was stirred for 1 hour with cooling. Stirring to 25 ° C, stirring for 3 h, filtering, washing with 1 mL of a mixed solvent of methanol and MTBE (methanol to MTBE ratio of 1:2), blasting at 30 ° C to obtain the crystal of Apixaban crystal form A .
  • apixaban 0.5 g was added to a mixed solvent of 7.5 mL of methanol and methyl tert-butyl ether (methanol to MTBE ratio of 1:2), the temperature was raised to 60 ° C, and the mixture was stirred for 1 hour with cooling. Stirring to 25 ° C, stirring for 3 h, filtering, washing with 1 mL of a mixed solvent of methanol and MTBE (methanol to MTBE ratio of 1:2), blasting at 30 ° C to obtain the crystal of Apixaban crystal form A .
  • apixaban 0.2 g was added to 12 mL of a mixed solvent of acetone and ethanol (volume ratio of acetone to ethanol: 1:2), the temperature was raised to 70 ° C, stirred, and the apixa obtained in Example 3 was added. Seed crystal of Banjing type A, naturally cooled, cooled to 25 V, stirred for 3 h, filtered, washed with 1 mL of a mixed solvent of acetone and ethanol (volume ratio of acetone to ethanol: 1:2), blown at 30 ° C. Dry apixaban crystal form A.
  • apixaban 0.2 g was added to 20 mL of isopropanol, the temperature was raised to 82 ° C, stirred, and the seed crystal of Apixaban crystal form A obtained in Example 3 was added, naturally cooled, and cooled to 25 °. C, stirred for 3 h, filtered, washed with 0.5 mL of isopropyl alcohol, and dried at 30 ° C to obtain apixaban crystal form A.
  • apixaban 0.4 g was added to 8 mL of 95% ethanol, the temperature was raised to 78 ° C, stirred, and the seed crystal of Apixaban crystal form A obtained in Example 3 was added, naturally cooled, and cooled to 25 °. C, stirred for 16 h, filtered, using 0.5 mL of 95% The ethanol was washed and blasted at 30 ° C to obtain apixaban crystal form A.
  • the apixaban crystal form DMF-5 used in the present invention is prepared in Example 1 of US2007/0203178. Comparative Example 2 Preparation of Form FA-2
  • the apixaban crystal form FA-2 used in the present invention is prepared in Example 1 of US2007/0203178.
  • the apixaban crystal form H2-2 used in the present invention is prepared in Example 9 of CN200580040778.4. Comparative Example 4 Preparation of crystal form ex
  • the apixaban crystal form ⁇ used in the present invention is prepared in Example 7 of WO2012168364.
  • Test example 1 Static electricity detection
  • Example 3 The apixaban crystal form obtained in each of Example 3 and Comparative Examples 1-4 was separately contacted with the rubbed glass rod to observe whether or not static electricity was present, and the results are shown in Table 1.
  • Comparative Example 1 DSC pattern of apixaban crystal form DMF-5 and Comparative Example 2 of apixaban crystal form FA-2, showing a ratio of Apixaban crystal form DMF-5 and Comparative Example 2
  • the penzaban form FA-2 has a broad peak near the boiling point of DMF ( ⁇ , ⁇ -dimethylformamide) and FA (formamide), as shown in Figure 9-10, which proves to contain the solvents DMF and FA, while DMF (Boiling point 153 ° C) and formamide (boiling point 210 ° C) have a high boiling point and are not easily removed by drying.
  • the DSC spectrum of apixaban crystal form A obtained in Example 3 of the present invention shows that it has only a melting endothermic peak of 235 to 242 ° C, and the maximum endothermic melting temperature is about 238 ° C. No suction is found in other positions.
  • the heat and exothermic peaks prove stable, non-viscous solvent and water, and no crystal transformation occurs, see Figure 2.
  • the apixaban crystal form obtained in Example 3 was separately placed in a light, high temperature or high humidity environment, and subjected to DSC detection 6 days after the placement.
  • test conditions are:
  • Lighting conditions illumination intensity 5000 LUX; High temperature conditions: temperature 60 ° C;
  • the apixaban crystal form A of Example 3 was consistent with the DSC spectrum of 0 days and 6 days of standing, as shown in Fig. 4-6, without moisture absorption, and no change occurred, indicating that the crystal form was stable under this condition.
  • the above is only the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can change without thinking of creative work or within the technical scope of the present invention. Alternatives are intended to be covered by the scope of the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur une forme cristalline de type A d'apixaban et sur un procédé de préparation de celle-ci. Un pic caractéristique de diffraction des rayons X sur poudre et un pic caractéristique en calorimétrie différentielle à balayage de celle-ci sont respectivement représentés dans la FIG. 1 et la FIG. 2. La forme cristalline de type A selon la présente invention est stable et non hygroscopique, elle a un procédé de préparation simple et elle a une excellente reproductibilité.
PCT/CN2014/084155 2013-08-12 2014-08-12 Nouvelle forme cristalline d'apixaban et son procédé de preparation Ceased WO2015021902A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310349409.XA CN104370902A (zh) 2013-08-12 2013-08-12 一种阿哌沙班新晶型及其制备方法
CN201310349409.X 2013-08-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12540135B2 (en) 2021-06-21 2026-02-03 Guilherme Savoi Cocrystals derivatives of apixaban

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110922403B (zh) * 2019-09-26 2021-02-26 浙江天宇药业股份有限公司 阿哌沙班与羧酸形成的共晶及其制备方法

Citations (9)

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WO2003026652A1 (fr) * 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Composes contenant du lactame et leurs derives en tant qu'inhibiteurs du facteur xa
US20060069258A1 (en) * 2004-09-28 2006-03-30 Rafael Shapiro Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
US20070203178A1 (en) * 2004-09-28 2007-08-30 Malley Mary F Crystalline solvates of apixaban
WO2012168364A1 (fr) * 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Procédé de préparation d'apixaban
WO2013119328A1 (fr) * 2012-02-07 2013-08-15 Assia Chemical Industries Ltd. Formes solides de l'apixaban
CN103360391A (zh) * 2013-08-06 2013-10-23 齐鲁制药有限公司 阿哌沙班新晶型及其制备方法
CN103539795A (zh) * 2013-03-18 2014-01-29 齐鲁制药有限公司 阿哌沙班的多晶型及其制备方法
WO2014056434A1 (fr) * 2012-10-10 2014-04-17 Sunshine Lake Pharma Co., Ltd. Forme cristalline et forme amorphe de l'apixaban et leur préparation
EP2752414A1 (fr) * 2013-01-04 2014-07-09 Sandoz AG Forme cristalline d'apixaban

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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CN101065379B (zh) * 2004-09-28 2011-05-11 布里斯托尔-迈尔斯斯奎布公司 制备4,5-二氢-吡唑并[3,4-c]吡啶-2-酮的方法
US20060160841A1 (en) * 2005-01-19 2006-07-20 Chenkou Wei Crystallization via high-shear transformation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026652A1 (fr) * 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Composes contenant du lactame et leurs derives en tant qu'inhibiteurs du facteur xa
US20060069258A1 (en) * 2004-09-28 2006-03-30 Rafael Shapiro Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
US20070203178A1 (en) * 2004-09-28 2007-08-30 Malley Mary F Crystalline solvates of apixaban
WO2012168364A1 (fr) * 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Procédé de préparation d'apixaban
WO2013119328A1 (fr) * 2012-02-07 2013-08-15 Assia Chemical Industries Ltd. Formes solides de l'apixaban
WO2014056434A1 (fr) * 2012-10-10 2014-04-17 Sunshine Lake Pharma Co., Ltd. Forme cristalline et forme amorphe de l'apixaban et leur préparation
EP2752414A1 (fr) * 2013-01-04 2014-07-09 Sandoz AG Forme cristalline d'apixaban
CN103539795A (zh) * 2013-03-18 2014-01-29 齐鲁制药有限公司 阿哌沙班的多晶型及其制备方法
CN103360391A (zh) * 2013-08-06 2013-10-23 齐鲁制药有限公司 阿哌沙班新晶型及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12540135B2 (en) 2021-06-21 2026-02-03 Guilherme Savoi Cocrystals derivatives of apixaban

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