WO2019135253A1 - Polymorphic forms of venetoclax - Google Patents

Polymorphic forms of venetoclax 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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venetoclax
crystalline
mixture
solvent
pxrd pattern
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Lakshmana Rao Vadali
Nagaraju GOTTUMUKKALA
Yogesh SANGVIKAR
Suresh Babu Jayachandra
Ravikanth Jaldu
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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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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Abstract

The present invention relates to crystalline forms of venetoclax and process for their preparation. The present invention also relates to process for preparation of amorphous venetoclax.

Description

POLYMORPHIC FORMS OF VENETOCLAX
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application No. 201841000196 filed on January 2, 2018, Indian provisional patent application No. 201841012605, filed on April 3, 2018 and Indian provisional patent application No.
201841023399 filed on June 22, 2018.
TECHNICAL FIELD
The present invention relates generally to pharmaceutically active compounds and more specifically to novel crystalline forms of venetoclax and processes for the preparation thereof. BACKGROUND ART
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:
Figure imgf000002_0001
Formula-I
Venetoclax is marketed in the United States as VENCLEXTA™, 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.
U.S. Patent No. 8,722,657, which is hereby incorporated by reference, discloses various crystalline forms of venetoclax with characteristic powder X-ray diffraction data.
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.
SUMMARY OF INVENTION In one aspect, the present invention provides crystalline venetoclax form M23.
In one embodiment, 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 °.
In another embodiment, 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°.
In another embodiment, crystalline venetoclax form M23 may be characterized by the PXRD pattern as shown in Figure 1.
In one aspect, the present invention provides crystalline venetoclax form M24. In one embodiment, 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
In another embodiment, 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
In another embodiment, crystalline venetoclax form M24 may be characterized by a PXRD pattern as shown in Figure 2.
In another aspect the present invention provides a method for preparing crystalline venetoclax form M23.
In one embodiment, 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;
b) heating the reaction mixture to a temperature of about 100 °C to about 130 °C;
c) cooling the solution to a temperature of about 70 °C to about 75 °C; and
d) isolating crystalline venetoclax form M23.
Within the context of this embodiment, the solvent may be n-butyl acetate, dichloromethane, water, or mixtures thereof.
In another aspect, the present invention provides a method for preparing crystalline venetoclax form M24.
In one embodiment, 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;
b) adding n-butyl acetate to the reaction mixture;
c) cooling the reaction mixture to about 25 °C to about 35 °C; and
d) isolating crystalline venetoclax form M24. Within the context of this embodiment, the solvent may be methanol, ethanol, isopropanol, dichloromethane, or mixtures thereof.
In one embodiment, 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;
b) combining the reaction mixture with an aqueous basic solution; and
c) isolating amorphous venetoclax.
Within the context of this embodiment, the salt may be hydrochloride, hydrobromide, sulfate, nitrate, p-toluenesulfonate, mesylate, oxalate, or maleate.
Within the context of this embodiment, the base may be ammonia, ammonium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or mixtures thereof.
In one embodiment, 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;
b) combining the reaction mixture with an aqueous basic solution; and
c) isolating amorphous venetoclax.
Within the context of this embodiment, the salt may be hydrochloride, hydrobromide, sulfate, nitrate, p-toluenesulfonate, mesylate, oxalate, or maleate.
Within the context of this embodiment, the base may be ammonia, ammonium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or mixtures thereof.
Within the context of this embodiment, the organic solvent may be dimethylsulfoxide, dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, or mixtures thereof. In another aspect, 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. BRIEF DESCRIPTION OF DRAWINGS
Further aspects of the present invention together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
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; and Figure 7 is a TGA of crystalline venetoclax form M24.
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter with reference to the accompanying examples and experiments in which illustrative embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Within the context of the invention, the term “about” when modifying an absolute measurement, such as time, mass, or volume, is meant to mean the recited value plus or minus 10% of that value. Within the context of the invention, the term“about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees.
The present invention provides new polymorphs of venetoclax which may be characterized by powder X-ray diffraction (PXRD). Thus, 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.
In one aspect, the present invention provides crystalline venetoclax form M23.
Within the context of the present invention, 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.
In another aspect, the present invention provides a process for the preparation of crystalline venetoclax form M23.
It is believed that crystalline venetoclax form M23 is unsolvated.
In one embodiment, 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;
b) heating the mixture to a temperature of about 100 °C to about 115 °C;
c) further heating the mixture to a temperature of about 115 °C to about 130 °C;
d) cooling the mixture to a temperature of about 70 °C to about 75 °C; and
e) isolating crystalline venetoclax form M23.
Within the context of this embodiment, venetoclax may be suspended in a solvent. The venetoclax may be crystalline or amorphous. Within the context of this embodiment, 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.
Within the context of this embodiment, crystalline form M23 is isolated by filtration.
In another aspect, the present invention provides crystalline venetoclax form M24.
In one embodiment, 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.
It is believed that crystalline venetoclax form M24 is a solvate. In particular, it is believed that crystalline venetoclax form M24 is an n-butyl acetate solvate having a ratio of venetoclax to n- butyl acetate of 1 : 1.
In another aspect, the present invention provides a process for the preparation of crystalline venetoclax form M24.
In one embodiment, crystalline venetoclax form M24 may be prepared by a process that includes the steps of; a) dissolving venetoclax in a solvent;
b) adding n-butyl acetate;
c) cooling the solution to about 25 °C to about 35 °C; and
d) isolating crystalline venetoclax form M24.
According to this embodiment, 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.
The mixture then may be cooled, for example, to about 25 °C to about 35 °C. Crystalline venetoclax form M24 then may be isolated by methods well known in the art, for example, by filtration.
In another aspect, the present invention provides a method for preparing amorphous venetoclax.
In one embodiment, amorphous venetoclax may be prepared by a process that includes the steps of: a) suspending venetoclax salt in water to form a suspension;
b) combining the suspension with an aqueous basic solution; and
c) isolating amorphous venetoclax.
According to the present embodiment, 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. Examples of 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. Within the context of this embodiment, examples of 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. Optionally, 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.
In another embodiment, 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
c) isolating amorphous venetoclax.
According to this embodiment, a venetoclax salt may be dissolved in an organic solvent. Examples of suitable solvents include, but are not limited, to dimethylsulfoxide (DMSO), dimethylformamide (DMF), alcohols, ketones, acetonitrile, and mixtures thereof. Examples of 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. Optionally, 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. Examples of suitable methods for isolating amorphous venetoclax include, but are not limited to, decantation, filtration by gravity or suction, centrifugation, or other techniques commonly used. Optionally, the obtained solid may be washed with water.
Optionally, the obtained amorphous venetoclax may be dried. Optionally, 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.
Table 1
Figure imgf000011_0001
The advantage of M23 form over other forms (form A, B, C and D):
• Higher thermal stability of form M23 compared to existing form A, as at higher
temperature some impurities formation was observed in form A.
• Higher light stability of form M23 compared to form A.
• Higher yield during isolation compared to form A. Yield of form M23 is more.
• Isolation in single solvent compared to other forms where it supposed to use mixture of solvent for preparation of form A, B, C and D.
• Commercial viability of form M23 as compared to form A, B, C and D. Within the context of the present invention, each disclosed form of venetoclax, (e.g., Form M23, Form M24, and amorphous) 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.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.
EXAMPLES
Example 1: Preparation of crystalline venetoclax form M23
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)-benzenesulfonamide (13.79 g),
4-dimethylaminopyridine (DMAP, 10.68 g), and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC hydrochloride, 15.05 g) were taken in dichloromethane (350 mL) to form a suspension. The suspension was stirred at ambient temperature. In a separate flask, 2-((lH-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl) methylpiprazin-l-yl)benzoic acid (“VNT- Acid,” 25 g) and triethylamine (8.84 g) were taken in to dichloromethane (100 mL) and the mixture was stirred. The resultant solution was added to the initial suspension over a period of 30 minutes. The combined reaction mixture was stirred for 14 hours. The reaction progress was monitored by HPLC. 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).
Example 2: Preparation of crystalline venetoclax form M23
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).
Example 3: Preparation of crystalline venetoclax form M23
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).
Example 4: Preparation of crystalline venetoclax form M24
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)-benzenesulfonamide (13.79 g), DMAP (10.68 g) and EDC hydrochloride (15.05 g) was taken in dichloromethane (350 mL) to form a suspension. The mixture was stirred at ambient temperature. In a separate flask, VNT-Acid (25 g) and triethylamine (8.84 g) was taken in to dichloromethane (100 mL), and the mixture was stirred. The resultant solution was added to the initial suspension over a period of 30 minutes. The reaction mixture was stirred for 14 hours. The reaction progress was monitored by HPLC. 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.
Example 5: Preparation of crystalline venetoclax form M23
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).
Example 6: Preparation of Venetoclax hydrochloride
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).
Example 7: Preparation of amorphous venetoclax
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.

Claims

We claim:
1. Crystalline venetoclax form M23, characterized by a PXRD pattern having significant peaks at 2Q angles of 21.51, 24.47, and 28.47 ± 0.2 °.
2. The crystalline venetoclax form M23 of claim 1, further 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°.
3. The crystalline venetoclax form M23 of claim 1, characterized by a PXRD pattern as shown in Figure 1.
4. A process for the preparation of crystalline venetoclax form M23, comprising the steps of: a) suspending venetoclax in a solvent to form a mixture;
b) heating the mixture to a temperature of about 100 °C to about 130 °C;
c) cooling the solution to a temperature of about 70 °C to about 75 °C; and d) isolating crystalline venetoclax form M23.
5. The process according to claim 4, wherein the solvent is selected from the group
consisting of n-butyl acetate, dichloromethane, water, and mixtures thereof.
6. Crystalline venetoclax form M24, characterized by a PXRD pattern having significant peaks at 2Q angles of 5.77 and 11.57 ± 0.2 0
7. The crystalline venetoclax form M24 of claim 6, 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
8. The crystalline venetoclax form M24 of claim 6, characterized by a PXRD pattern as shown in Figure 2.
9. A process for the preparation of crystalline venetoclax form M24, comprising the steps of: a) dissolving venetoclax in a solvent to form a mixture;
b) adding n-butyl acetate to the mixture;
c) cooling the mixture to about 25 °C to about 35 °C; and
d) isolating crystalline venetoclax form M24.
10. The process according to claim 9, wherein the solvent is selected from the group
consisting of methanol, ethanol, isopropanol, dichloromethane, and mixtures thereof.
11. The process according to claim 9, wherein the venetoclax in the dissolving step is crystalline venetoclax form M23.
12. A process for the preparation of amorphous venetoclax comprising the steps of; a) adding a venetoclax salt to a solvent to form a mixture;
b) combining the mixture with an aqueous basic solution; and
c) isolating amorphous venetoclax.
13. The process according to claim 12, wherein the salt is selected from the group
consisting of hydrochloride, hydrobromide, sulfate, nitrate, p-toluenesulfonate, mesylate, oxalate, and maleate.
14. The process according to claim 12, wherein the base is selected from the group
consisting of ammonia, ammonium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and mixtures thereof.
5. The process according to claim 12, wherein the solvent is selected from the group consisting of water, dimethylsulfoxide, dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, and mixtures thereof.
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