WO2014173377A2 - New crystalline forms of apixaban and a method of their preparation - Google Patents

New crystalline forms of apixaban and a method of their preparation Download PDF

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Publication number
WO2014173377A2
WO2014173377A2 PCT/CZ2014/000041 CZ2014000041W WO2014173377A2 WO 2014173377 A2 WO2014173377 A2 WO 2014173377A2 CZ 2014000041 W CZ2014000041 W CZ 2014000041W WO 2014173377 A2 WO2014173377 A2 WO 2014173377A2
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WO
WIPO (PCT)
Prior art keywords
apixaban
crystalline form
preparation
dissolved
exhibits
Prior art date
Application number
PCT/CZ2014/000041
Other languages
English (en)
French (fr)
Other versions
WO2014173377A3 (en
Inventor
Violetta Kiss
Ondrej Dammer
Lukas KREJCIK
Ludmila Hejtmankova
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2014173377A2 publication Critical patent/WO2014173377A2/en
Publication of WO2014173377A3 publication Critical patent/WO2014173377A3/en

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Classifications

    • 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 relates to new crystalline forms of Apixaban of formula (I), chemically l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin- 1 -yl)phenyl]-4,5,6,7-tetrahydro- lH-pyrazolo[3,4- c]pyridine-3-carboxamide of formula I and a method of its preparation.
  • Apixaban a substance having anticoagulant activity, which is indicated for treatment of both venous and arterial thromboembolism, was first described in EP 1 427 415, which describes the basic synthetic approaches to preparation of apixaban and similar molecules, and it also briefly describes pharmaceutical formulations.
  • WO2006078331 describes two different forms of apixaban, apixaban dihydrate H2-2 and an anhydrous form identified as N-1 there.
  • the examples included in this document indicate that the dihydrate is formed by crystallization from a water : polyethylene glycol mixture as needle-like crystals, which, after heating of the crystallizing matter in the presence of a crystallizing solvent and under treatment by an elevated temperature and/or intensive stirring, are transformed to the anhydrous form N-1. Crystals of the anhydrous form can be obtained in the desired particle size by controlling the crystallization conditions.
  • Document WO2007001385 describes the same transformation of the dihydrate to the anhydrous form.
  • Document US 20070203178 describes dimethyl formamide and formamide solvates of apixaban.
  • Apixaban is very poorly soluble in water;
  • document WO2011106478 indicates a solubility of only 40 nanog/ml and discusses dependence of the apixaban particle size during the preparation of a formulation by wet and dry granulation and their influence on the dissolution rate and bioavailability of the formulation.
  • Form AP3 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 1.
  • the diffractogram is shown in Fig. 2.
  • Form AP4 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 2.
  • the diffractogram is shown in Fig. 5.
  • Form AP5 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 3.
  • the diffractogram is shown in Fig. 8.
  • Table 2 Characteristic diffraction peaks corresponding to form AP4 of apixaban.
  • crystalline forms AP3, AP4 and AP5 of apixaban in accordance with this invention have been further characterized by differential scanning calorimetry DSC and thermogravknetry TGA.
  • the results are summarized in Table 4.
  • Figs. 3, 4, 6, 7, 9 and 10 present the respective DSC and TGA records of these forms.
  • the TGA analysis of forms AP3, AP4 and AP5 indicates that all the forms contain 5 to 7% of water.
  • the form AP4 contains ca. 13% of a solvent. This means that they are solvates.
  • Table 4 DSC and TGA analysis of the crystalline forms of apixaban
  • thermodynamic solubility of the known crystalline forms Nl and H2-2 and the new forms AP3, AP4 and AP5 were conducted.
  • An Eppendorf Thermomixer Comfort shaker was used to carry out the experiments. The samples were dosed into Eppendorf tubes and stirred up with water. The experiments were performed at 37°C and the stirring speed of 900 rpm for 24 h. The results are summarized in Table 5.
  • Table 5 Thermodynamic solubility values of crystalline forms of apixaban
  • thermodynamic solubility results show that the thermodynamic solubility of crystalline form AP3 is more than double as compared to the anhydrous form Nl and nearly 80% higher than that of the dihydrate H2-2. So the assumption can be m ade that the bioavailability of the new crystalline forms AP3 and AP5 will be better, compared to the known forms Nl and H2-2.
  • Fig. 1 Stability of individual crystalline forms
  • Fig. 2 Diffractogram of apixaban form AP3
  • Fig. 3 DSC record of apixaban form AP3
  • Fig. 4 TGA record of apixaban form AP3
  • Fig. 5 Diffractogram of apixaban form AP4
  • Fig. 6 DSC record of apixaban form AP4
  • Fig. 7 TGA record of apixaban form AP4
  • Fig. 8 Diffractogram of apixaban form AP5
  • Fig. 9 DSC record of apixaban form AP5
  • Fig. 10 TGA record of apixaban form AP5
  • the measurement was carried out using a flat powder sample that was placed on a Si plate.
  • a 10 mm mask and a 1/4° fixed anti-dispersion diaphragm were used.
  • the irradiated area of the sample was 10 mm, programmable divergence diaphn s were used.
  • programmable divergence diaphn s were used for the correction of the secondary beam 0.02 rad Soller diaphragms and 5.0 mm anti- dispersion diaphragm were used.
  • DSC measurements were conducted using a Perkin Elmer Pyris 1 DSC device. The samples were weighed and dosed into Al pots and measured in a nitrogen stream (4N 2 20 ml/min). The temperature program was set in the range of 50°C to 280°C at the heating rate op 10°C/min. The weight of the samples varied in the range of 3.2 to 3.4 mg.
  • TGA was measured using a Perkin Elmer TGA 6 device. The samples were ⁇ eighed and dosed into ceramic pots and measured in a nitrogen stream (4N 2 20 ml/min). The TGA measurements were conducted in the temperature range of 25°C to 300°C at the heating rate of 10°C/min. The weight of the samples varied in the range of 18.5 to 21.2 mg.
  • apixaban prepared in accordance with the method described in patent WO 2003/026652, in an amount of 200 mg (0.435 mmol) was dissolved apixaban in a hot state.
  • the hot solution was abruptly cooled down to 0 to 5°C and maintained at this temperature for 18 to 24 h.
  • the resulting suspension was filtered and) the product, crystalline form AP3, was dried in vacuo at the room temperature.
  • apixaban prepared in accordance with the method described in patent WO 2003/026652, in an amount of 150 mg (0.326 mmol) was dissolved in 3 ml of chloroform under reflux. The clear solution was abruptly cooled down to 0 to 5°C and maintained at this temperature for 24 to 48 h. The resulting suspension was filtered and the product, crystalline form A5, was dried in vacuo at the room temperature.
  • the individual crystalline forms H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg into an HPLC vial and suspended in 1 ml of a solvent, ethyl acetate or 2-propanol.
  • the vials were placed in an HLC shaker and shaken at 900 rpm at the room temperature for 11 days.
  • the solid residue was isolated by filtration and further characterized.
  • the individual crystalline forms H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg onto Petri dishes and placed in a Memmert vacuum drier. The samples were heated up to 80°C at the ambient humidity and at the atmospheric pressure for 24 hours.
  • the individual crystalline forms Nl, H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg into Eppendorf tubes and placed in the shaker.
  • the samples were stirred at 900 rpm at 37°C for 24 h.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
PCT/CZ2014/000041 2013-04-23 2014-04-23 New crystalline forms of apixaban and a method of their preparation WO2014173377A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2013-305 2013-04-23
CZ2013-305A CZ2013305A3 (cs) 2013-04-23 2013-04-23 Nové krystalické formy APIXABANU a způsob jejich přípravy

Publications (2)

Publication Number Publication Date
WO2014173377A2 true WO2014173377A2 (en) 2014-10-30
WO2014173377A3 WO2014173377A3 (en) 2014-12-24

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CZ (1) CZ2013305A3 (cs)
WO (1) WO2014173377A2 (cs)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017088841A1 (en) 2015-11-26 2017-06-01 Zentiva, K.S. Preparation of a drug form containing amorphous apixaban
CN111377915A (zh) * 2018-12-30 2020-07-07 山东新时代药业有限公司 一种吡唑并-吡啶酮化合物晶型d

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026652A1 (en) 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
WO2003049681A2 (en) 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2006078331A2 (en) 2005-01-19 2006-07-27 Bristol-Myers Squibb Company Crystallization via high-shear transformation
WO2007001385A2 (en) 2004-09-28 2007-01-04 Bristol-Myers Squibb Company 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
WO2011106478A2 (en) 2010-02-25 2011-09-01 Bristol-Myers Squibb Company Apixaban formulations

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026652A1 (en) 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
EP1427415A1 (en) 2001-09-21 2004-06-16 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
WO2003049681A2 (en) 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2007001385A2 (en) 2004-09-28 2007-01-04 Bristol-Myers Squibb Company 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
WO2006078331A2 (en) 2005-01-19 2006-07-27 Bristol-Myers Squibb Company Crystallization via high-shear transformation
WO2011106478A2 (en) 2010-02-25 2011-09-01 Bristol-Myers Squibb Company Apixaban formulations

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017088841A1 (en) 2015-11-26 2017-06-01 Zentiva, K.S. Preparation of a drug form containing amorphous apixaban
CN111377915A (zh) * 2018-12-30 2020-07-07 山东新时代药业有限公司 一种吡唑并-吡啶酮化合物晶型d
CN111377915B (zh) * 2018-12-30 2023-10-24 鲁南制药集团股份有限公司 一种吡唑并-吡啶酮化合物晶型d

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WO2014173377A3 (en) 2014-12-24
CZ2013305A3 (cs) 2014-11-05

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