WO2019135253A1 - Formes polymorphes de vénétoclax - Google Patents

Formes polymorphes de vénétoclax Download PDF

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Publication number
WO2019135253A1
WO2019135253A1 PCT/IN2018/050880 IN2018050880W WO2019135253A1 WO 2019135253 A1 WO2019135253 A1 WO 2019135253A1 IN 2018050880 W IN2018050880 W IN 2018050880W WO 2019135253 A1 WO2019135253 A1 WO 2019135253A1
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WO
WIPO (PCT)
Prior art keywords
venetoclax
crystalline
mixture
solvent
pxrd pattern
Prior art date
Application number
PCT/IN2018/050880
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English (en)
Inventor
Lakshmana Rao Vadali
Nagaraju GOTTUMUKKALA
Yogesh SANGVIKAR
Suresh Babu Jayachandra
Ravikanth Jaldu
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Mylan Laboratories Limited
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Publication of WO2019135253A1 publication Critical patent/WO2019135253A1/fr

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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 present invention relates generally to pharmaceutically active compounds and more specifically to novel crystalline forms of venetoclax and processes for the preparation thereof.
  • Venetoclax (also called GDC-0199, ABT-199, and RG7601) is a BCL-2 inhibitor.
  • Venetoclax is chemically known as 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-l- yl]methyl]piperazin-l-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(lH- pyrrolo[2,3-b]pyridin-5-yloxy)benzamide and has the structure shown below as Formula-I:
  • Venetoclax is marketed in the United States as VENCLEXTATM, which is indicated (1) for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17r deletion, who have received at least one prior therapy, and (2) in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.
  • U.S. Patent No. 8,546,399 which is hereby incorporated by reference, discloses venetoclax and its preparation.
  • PCT Publication Nos. WO 2012/121758 and WO 2012/058392 disclose non-crystalline solid dispersions of venetoclax.
  • PCT Publication No. WO2017/212431 Al discloses venetoclax crystalline forms RT1, RT2, RT3, RT4, and RT5.
  • the inventors of the invention disclosed herein have developed novel crystalline forms of venetoclax, process for their preparation, and processes for the preparation of amorphous venetoclax.
  • the present invention provides crystalline venetoclax form M23.
  • crystalline venetoclax form M23 may be characterized by a PXRD pattern having significant peaks at 2Q angles of 21.51, 24.47, and 28.47 ⁇ 0.2 °.
  • crystalline venetoclax form M23 may be characterized by a PXRD pattern having significant peaks at 29 angles of 6.02, 12.58, 13.33, 17.57, 18.06, 18.78, 19.03, 19.79, 20.29, 21.51, 24.47, 25.33, and 28.47 ⁇ 0.2°.
  • crystalline venetoclax form M23 may be characterized by the PXRD pattern as shown in Figure 1.
  • the present invention provides crystalline venetoclax form M24.
  • crystalline venetoclax form M24 may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.77 and 11.57 ⁇ 0.2 0
  • crystalline venetoclax form M24 may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.77, 7.01, 9.94, 10.48, 11.57, 13.00, 13.63, 14.62, 15.17, 15.75, 16.04, 16.55, 17.07, 17.50, 17.87, 18.78, 20.09, 20.28, 21.07, 21.21, 22.70, 23.10, 23.29, 24.28, 24.49, 25.42, 25.82, 26.23, and 27.30 ⁇ 0.2 0
  • crystalline venetoclax form M24 may be characterized by a PXRD pattern as shown in Figure 2.
  • the present invention provides a method for preparing crystalline venetoclax form M23.
  • crystalline venetoclax form M23 may be prepared by a process that includes the steps of: a) suspending venetoclax in a solvent to form a reaction mixture;
  • the solvent may be n-butyl acetate, dichloromethane, water, or mixtures thereof.
  • the present invention provides a method for preparing crystalline venetoclax form M24.
  • crystalline venetoclax form M24 may be prepared by a process that includes the steps of: a) dissolving venetoclax in a solvent to form a reaction mixture;
  • the solvent may be methanol, ethanol, isopropanol, dichloromethane, or mixtures thereof.
  • amorphous venetoclax may be prepared by a process that includes the steps of: a) adding a venetoclax salt to water to form a reaction mixture;
  • the salt may be hydrochloride, hydrobromide, sulfate, nitrate, p-toluenesulfonate, mesylate, oxalate, or maleate.
  • the base may be ammonia, ammonium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or mixtures thereof.
  • amorphous venetoclax may be prepared by a process that includes the steps of: a) adding a venetoclax salt to an organic solvent to form a reaction mixture;
  • the salt may be hydrochloride, hydrobromide, sulfate, nitrate, p-toluenesulfonate, mesylate, oxalate, or maleate.
  • the base may be ammonia, ammonium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or mixtures thereof.
  • the organic solvent may be dimethylsulfoxide, dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, or mixtures thereof.
  • the present invention provides a pharmaceutical dosage form comprising or prepared with crystalline venetoclax form M23.
  • the pharmaceutical dosage form may optionally contain other pharmaceutically acceptable excipients.
  • Figure 1 is an X-ray powder diffractogram of crystalline venetoclax form M23;
  • Figure 2 is an X-ray powder diffractogram of crystalline venetoclax form M24;
  • Figure 3 is an X-ray powder diffractogram of amorphous venetoclax
  • Figure 4 is a differential scanning calorimetry (DSC) thermogram of crystalline venetoclax form M23;
  • Figure 5 is a DSC thermogram of crystalline venetoclax form M24
  • Figure 6 is a thermogravimetric analysis (TGA) of crystalline venetoclax form M23
  • Figure 7 is a TGA of crystalline venetoclax form M24.
  • the present invention provides new polymorphs of venetoclax which may be characterized by powder X-ray diffraction (PXRD).
  • PXRD powder X-ray diffraction
  • samples of each disclosed polymorph were analyzed by PXRD on a BRUKER D-8 Discover powder diffractometer equipped with a goniometer of Q/2Q configuration and Lynx Eye detector.
  • the Cu-anode X-ray tube was operated at 40 kV and 30 mA.
  • the experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size, and 0.4 seconds step time.
  • the present invention provides crystalline venetoclax form M23.
  • crystalline venetoclax form M23 may be characterized by a PXRD pattern having significant peaks at 2Q angles of 6.02, 12.58, 13.33, 17.57, 18.06, 18.78, 19.03, 19.79, 20.29, 21.51, 24.47, 25.33, and 28.47 ⁇ 0.2 °.
  • a representative PXRD pattern for crystalline venetoclax form M23 is shown in Figure 1.
  • the present invention provides a process for the preparation of crystalline venetoclax form M23.
  • crystalline venetoclax form M23 may be prepared by a process that includes the steps of: a) suspending venetoclax in a solvent to form a mixture;
  • venetoclax may be suspended in a solvent.
  • the venetoclax may be crystalline or amorphous.
  • the solvent may be, for example, n-butyl acetate, dichloromethane, water, or any mixture thereof.
  • the mixture may then be heated to a temperature of about 100 °C to about 130 °C. In a particular useful embodiment, the mixture is heated to about 100 °C then further raised to about 115 °C to about 120 °C or about 130 °C.
  • the mixture may then be cooled to facilitate formation of crystalline venetoclax form M23.
  • the mixture may be cooled, for example, to about 70 °C to about 75 °C to initiate precipitation.
  • the obtained solid may be isolated by methods well known in the art, for example, by filtration.
  • crystalline form M23 is isolated by filtration.
  • the present invention provides crystalline venetoclax form M24.
  • crystalline venetoclax form M24 may be characterized by a PXRD pattern having significant peaks at 2Q angle positions of about 5.77, 7.01, 9.94, 10.48, 11.57, 13.00, 13.63, 14.62, 15.17, 15.75, 16.04, 16.55, 17.07, 17.50, 17.87, 18.78, 20.09, 20.28, 21.07, 21.21, 22.70, 23.10, 23.29, 24.28, 24.49, 25.42, 25.82, 26.23, and 27.30 ⁇ 0.2 °.
  • a representative PXRD pattern for crystalline venetoclax form M24 is shown in Figure 2.
  • crystalline venetoclax form M24 is a solvate.
  • crystalline venetoclax form M24 is an n-butyl acetate solvate having a ratio of venetoclax to n- butyl acetate of 1 : 1.
  • the present invention provides a process for the preparation of crystalline venetoclax form M24.
  • crystalline venetoclax form M24 may be prepared by a process that includes the steps of; a) dissolving venetoclax in a solvent;
  • venetoclax may be dissolved in a solvent.
  • the solvent may be, for example, methanol, ethanol, isopropanol, dichloromethane, or any mixture thereof.
  • the venetoclax may be crystalline or amorphous.
  • N-butyl acetate may then be added to facilitate formation of crystalline venetoclax form M24.
  • the temperature of the mixture then may be raised, for example, to about 38 °C to about 40 °C to facilitate precipitation of a solid.
  • Crystalline venetoclax form M24 then may be isolated by methods well known in the art, for example, by filtration.
  • the present invention provides a method for preparing amorphous venetoclax.
  • amorphous venetoclax may be prepared by a process that includes the steps of: a) suspending venetoclax salt in water to form a suspension;
  • a venetoclax salt may be suspended in water. This may be carried out at ambient temperature, for example from about 25 °C to about 35 °C.
  • suitable salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, p-toluenesulfonate, mesylate, oxalate, and maleate salts.
  • the suspension then may be combined with an aqueous basic solution to precipitate amorphous venetoclax.
  • suitable bases include, but are not limited to, ammonia, ammonium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and mixtures thereof.
  • Amorphous venetoclax may be isolated by methods well known in the art, for example, by filtration.
  • the obtained amorphous venetoclax may be dried.
  • the solid may be optionally dried, for example, from about 5 minutes to about 10 hours or longer, to remove residual solvent.
  • amorphous venetoclax may be prepared by a process that includes the steps of; a) dissolving venetoclax salt in an organic solvent to form a first solution; b) contacting the first solution with an aqueous basic second solution; and
  • a venetoclax salt may be dissolved in an organic solvent.
  • suitable solvents include, but are not limited, to dimethylsulfoxide (DMSO), dimethylformamide (DMF), alcohols, ketones, acetonitrile, and mixtures thereof.
  • suitable alcohols include, but are not limited to, methanol, ethanol, isopropanol, and mixtures thereof.
  • suitable ketones include, but are not limited to acetone, methyl isobutyl ketone, and mixtures thereof.
  • Dissolution may be facilitated by methods known in the art, for example, by heating the solution. For example, the mixture may be heated to a temperature of about 45 °C to about 65 °C.
  • the solution may be filtered to remove any particulate matter.
  • the first solution may be combined with an aqueous basic second solution. This may be carried out at room temperature, for example about 25 °C to about 35 °C. Within the context of this embodiment, the first solution may be combined with the aqueous basic second solution by gradual addition or in a single short addition, such as dumping of one into the other.
  • the mixture may be agitated (e.g., stirred) to facilitate the formation of a precipitate.
  • Other methods for facilitating formation of a precipitate include, but are not limited to, scratching the walls of the container with a spatula.
  • Isolation of amorphous venetoclax may be carried out by any methods known in the art.
  • suitable methods for isolating amorphous venetoclax include, but are not limited to, decantation, filtration by gravity or suction, centrifugation, or other techniques commonly used.
  • the obtained solid may be washed with water.
  • the obtained amorphous venetoclax may be dried.
  • the solid may be dried, for example, from about 5 minutes to about 10 hours or longer, to remove residual solvent.
  • the crystalline venetoclax form M23 may exhibit long term stability. Samples of crystalline venetoclax form M23 were stored for 6 months at 40 °C/75% relative humidity (RH) and at 25 °C/60% RH. Samples were analyzed by PXRD for changes in pattern after storage. PXRD analysis revealed no significant change in PXRD pattern under these storage conditions. These results are summarized in Table 1 below.
  • each disclosed form of venetoclax may be useful, for example, in the formulation of pharmaceutical dosage forms useful for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17r deletion, who have received at least one prior therapy, and in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.
  • Particularly useful dosage forms include oral dosage forms, for example, a tablet or capsule.
  • Tablets or capsules may contain one or more inactive ingredients or pharmaceutically acceptable excipients, including, for example, copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic.
  • Tablets and capsules in some embodiments, may be coated with a film that includes polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and artificial colorings such as red ferric oxide, yellow ferric oxide, black ferric oxide, and inks, such as black ink.
  • N,N-dimethylethylenediamine (2.25 g) was added and the reaction mixture was stirred for 6 hours.
  • the reaction mass was washed with 15 % acetic acid solution (175 mL) four times.
  • Methanol (25 mL) was added to the organic layer.
  • the organic layer was then washed with 5 % sodium bicarbonate solution (175 mL) twice.
  • Methanol (25 mL) was added to the organic layer.
  • the organic layer was washed with water (175 mL).
  • the organic layer was then completely distilled under vacuum.
  • N-butyl acetate (200 mL) was charged to the resultant mass and the mixture was heated to 115 °C to 120 °C and stirred for 3 hours.
  • the reaction mass was cooled to 70 °C to 75 °C and stirred for one hour.
  • the reaction mass was filtered and the obtained solid was washed with n-butyl acetate (50 mL).
  • the wet material was then oven dried under vacuum at 100 °C for 16 hours to obtain crystalline venetoclax form M23 (26.25 g).
  • Venetoclax (2 g) was taken in n-butyl acetate (16 mL). Dichloromethane (1 mL) was charged to the reaction mass. The reaction mass was heated to 115 °C to 120 °C and stirred for 3 hours. The reaction mass was cooled to 70 °C to 75 °C and stirred for one hour. The reaction mass was filtered and the obtained solid was washed with n-butyl acetate (4 mL). The wet material was oven dried under vacuum at 100 °C for 16 hours to obtain crystalline venetoclax form M23 (1.98 g).
  • Venetoclax (2 g) was taken in n-butyl acetate (16 mL). Water (1 mL) was charged to the reaction mass. The reaction mass was heated to 115 °C to 120 °C and stirred for 3 hours. The reaction mass was cooled to 70 °C to 75 °C and stirred for one hour. The reaction mass was filtered and the solid was washed with n-butyl acetate (4 mL). The wet material was oven dried under vacuum at 100 °C for 16 hours to obtain crystalline venetoclax form M23 (2.0 g).
  • N,N-dimethylethylenediamine (2.25 g) was added and the reaction mass was stirred for 6 hours.
  • the reaction mass was washed with 15 % acetic acid solution (175 mL) four times.
  • Methanol (25 mL) was added to the organic layer.
  • the organic layer was washed with 5 % sodium bicarbonate solution (175 mL) twice.
  • Methanol (25 mL) was added to the organic layer.
  • the organic layer was washed with water (175 mL) then distilled until at the remaining volume of the reaction mass was 250 mL.
  • Methanol (25 mL) was added to the reaction mass and n- butyl acetate (200 mL) was charged to the resultant mixture.
  • the reaction mass was stirred for 30 minutes at 38-40 °C.
  • the reaction mass was cooled to room temperature and stirred for 3 hours.
  • the reaction mass was filtered and washed with a mixture of dichloromethane (25 mL) and n-butyl acetate (25 mL).
  • the wet material (crystalline venetoclax form M24) was used for the preparation of Form M23 in Example 6 below.
  • Crystalline venetoclax form M24 (32.5 g, wet) was suspended in n-butyl acetate (200 mL) and the reaction mixture was heated to about 120 °C. The reaction mixture was stirred for about 2 hours and cooled to about 70 °C, stirred for one hour, and filtered. The obtained solid was washed with n-butyl acetate and dried at 80 °C (yield: 26.25 g).
  • Venetoclax (15 g) was suspended in acetonitrile (470 mL) at ambient temperature. Hydrochloric acid (1 N, 23.5 mL) was added. The reaction mixture was stirred for 6-8 hours and filtered. The solid was washed with acetonitrile (15 mL) then dried for 6-8 hours at 50-55 °C (yield: 13.5 g).
  • Venetoclax hydrochloride (2 g) was suspended in water (60 mL) at ambient temperature. Aqueous ammonia (1 mL) was added to the resulting mixture and the suspension was stirred for 4-6 hours. The suspension was filtered and the solid was washed with demineralized water (10 mL). The wet material was dried at 70 ⁇ 5 °C for 8-10 hours (yield: 1.8 g). PXRD analysis of samples revealed the solid to be amorphous.
  • Example 8 Preparation of amorphous Venetoclax Venetoclax hydrochloride (2 g) was dissolved in dimethyl sulfoxide (4.5 mL) at 50-55 °C. The solution was added to a mixture of aqueous ammonia (1 mL) and demineralized water (60 mL) at ambient temperature. The suspension was stirred for 4-6 hours at ambient temperature, then filtered. The obtained solid was washed with demineralized water (10 mL). The wet material was dried at 70 ⁇ 5 °C for 8-10 hours (1.78 g). PXRD analysis of samples revealed the solid to be amorphous.

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

Abstract

La présente invention concerne des formes cristallines de vénétoclax et leurs procédés de préparation. La présente invention concerne également un procédé de préparation de vénétoclax amorphe.
PCT/IN2018/050880 2018-01-02 2018-12-26 Formes polymorphes de vénétoclax WO2019135253A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN201841000196 2018-01-02
IN201841000196 2018-01-02
IN201841012605 2018-04-03
IN201841012605 2018-04-03
IN201841023399 2018-06-22
IN201841023399 2018-06-22

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WO2019135253A1 true WO2019135253A1 (fr) 2019-07-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021207581A1 (fr) * 2020-04-10 2021-10-14 Abbvie Inc. Formes cristallines d'un agent induisant l'apoptose

Citations (7)

* Cited by examiner, † Cited by third party
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WO2012058392A1 (fr) 2010-10-29 2012-05-03 Abbott Laboratories Dispersions solides contenant un agent induisant l'apoptose
WO2012071336A1 (fr) * 2010-11-23 2012-05-31 Abbott Laboratories Sels et formes cristallines d'un agent inducteur d'apoptose
WO2012121758A1 (fr) 2010-10-29 2012-09-13 Abbvie Inc. Dispersions solides extrudées en fusion contenant un agent induisant l'apoptose
US8546399B2 (en) 2009-05-26 2013-10-01 Abbvie Inc. Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
WO2017156398A1 (fr) * 2016-03-10 2017-09-14 Assia Chemical Industries Ltd. Formes solides du vénétoclax et procédés de préparation du vénétoclax
WO2017212431A1 (fr) 2016-06-09 2017-12-14 Dr. Reddy’S Laboratories Limited Formes solides de vénétoclax et procédés de préparation de vénétoclax
WO2018069941A2 (fr) * 2016-10-14 2018-04-19 Mylan Laboratories Limited Formes polymorphes de vénétoclax

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8546399B2 (en) 2009-05-26 2013-10-01 Abbvie Inc. Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
WO2012058392A1 (fr) 2010-10-29 2012-05-03 Abbott Laboratories Dispersions solides contenant un agent induisant l'apoptose
WO2012121758A1 (fr) 2010-10-29 2012-09-13 Abbvie Inc. Dispersions solides extrudées en fusion contenant un agent induisant l'apoptose
WO2012071336A1 (fr) * 2010-11-23 2012-05-31 Abbott Laboratories Sels et formes cristallines d'un agent inducteur d'apoptose
US8722657B2 (en) 2010-11-23 2014-05-13 Abbvie Inc. Salts and crystalline forms of an apoptosis-inducing agent
WO2017156398A1 (fr) * 2016-03-10 2017-09-14 Assia Chemical Industries Ltd. Formes solides du vénétoclax et procédés de préparation du vénétoclax
WO2017212431A1 (fr) 2016-06-09 2017-12-14 Dr. Reddy’S Laboratories Limited Formes solides de vénétoclax et procédés de préparation de vénétoclax
WO2018069941A2 (fr) * 2016-10-14 2018-04-19 Mylan Laboratories Limited Formes polymorphes de vénétoclax

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021207581A1 (fr) * 2020-04-10 2021-10-14 Abbvie Inc. Formes cristallines d'un agent induisant l'apoptose

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