WO2021030843A1 - Formes solides d'abemaciclib, leur utilisation et leur préparation - Google Patents

Formes solides d'abemaciclib, leur utilisation et leur préparation Download PDF

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Publication number
WO2021030843A1
WO2021030843A1 PCT/US2020/070404 US2020070404W WO2021030843A1 WO 2021030843 A1 WO2021030843 A1 WO 2021030843A1 US 2020070404 W US2020070404 W US 2020070404W WO 2021030843 A1 WO2021030843 A1 WO 2021030843A1
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Prior art keywords
abemaciclib
substantially pure
pure form
iii
solid
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PCT/US2020/070404
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English (en)
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Clifton HAMILTON
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Johnson Matthey Public Limited Company
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Publication of WO2021030843A1 publication Critical patent/WO2021030843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to solid-state forms of abemaciclib (ABC), namely, a substantially pure hydrated form and a mixture of hydrated forms. It also relates to the preparation of the aforesaid forms and to the preparation of an anhydrous form, pharmaceutical compositions comprising the aforesaid forms and their use in treating diseases.
  • ABSC abemaciclib
  • CDK inhibitor selective for CDK4 and CDK6 that is useful for the treatment of advanced or metastatic breast cancers.
  • U.S. Patent Nos. 7,855,211 and 10,238,656 disclose the preparation of ABC and two polymorphs Form I and III.
  • Form l has xrpd peaks at 4.51, 5.89, 8.98, 11.2, 12.57, 13.09, 15.93, 16.31, 17.01,18.58, 18.82, 20.86, 21.9, 23.12, 23.53, 26.71 and 26.85 ⁇ 0.G 2Q.
  • Form III has xrpd peaks at 7.44, 10.91, 11.54, 12.13, 13.89, 14.91, 15.63, 16.06, 18.59, 18.94, 20.43, 21.29, 21.91, 22.13, 22.45, 23.12, 23.42, 25.95, and 29.42 ⁇ 0.G 2Q.
  • W02017/108781 discloses Form IV of ABC can be characterized by xrpd peak(s) at 6.0, 6.8, 7.5, 10.4, 12.0, 13.4, 13.9, 15.3,
  • Form IV of ABC is disclosed as having one endotherm with an onset temperature of 123°C ( ⁇ 5°) and a peak temperature of 133°C ( ⁇ 1°), other endotherms with an onset temperature of 174°C (+ 2°) and 181°C (+ 2°) as well as peak temperatures of 176°C ( ⁇ 1°) and 182°C ( ⁇ 1°), respectively, and an exotherm with an onset temperature of 137°C ( ⁇ 5°) and a peak temperature of 140°C ( ⁇ 2°).
  • CN107868082 discloses crystal form A of abemaciclib mesylate having xrpd peaks at 4.60, 9.16, 10.42, 11.84, 13.18, 14.28, 14.62, 16.38, 18.16, 19.26, 20.72, 21.78, 22.94, 26.60, and 30.60 ⁇ 0.2° 2Q.
  • WO2017/211268 discloses crystal form A of abemaciclib having xrpd peaks at 4.62, 11.20, 13.10, 13.68, 15.62, 17.14, 17.98, 18.86, 21.34, 22.18, 22.86, 23.78, 26.26, and 29.98 ⁇ 0.2° 2Q; crystal form B of abemaciclib having xrpd peaks at 5.98, 6.74,
  • WO2019/102492 discloses polymorphic forms of abemaciclib designated as crystalline form-Ml, form-M2, form-M3, form-M4, form-M5, and provides an amorphous solid dispersion of abemaciclib.
  • Form-Ml of abemaciclib may be characterized by xrpd peaks at 5.0, 5.6, 6.4,
  • Form-M2 of abemaciclib may be characterized by xrpd peaks at 4.9, 5.9, 9.0, 9.8, 11.1, 11.9, 12.3, 13.3, 14.1, 15.1, 15.6, 15.9,
  • Form-M3 of abemaciclib may be characterized by xrpd peaks at 5.0, 5.5, 7.0,
  • Form-M4 of abemaciclib may be characterized by xrpd peaks at 5.1, 5.6, 7.1, 8.7, 9.3, 10.3, 11.3, 11.9, 12.2, 12.7, 13.0, 13.4, 14.0, 14.4, 15.1, 15.8, 16.2, 16.7, 17.5, 18.2, 18.6, 19.4, 19.9, 20.3, 20.8, 21.4, 21.8, 22.6, 23.0, 23.8, 24.3, 24.7, 25.5, 26.2, 27.3, 27.9, and 28.3 ⁇ 0.2° 20.
  • Form-M5 of abemaciclib may be characterized by xrpd peaks at
  • the invention relates to solid-state forms of ABC designated herein as substantially pure Form III, a hydrate of abemaciclib, and to a mixture of hydrated forms (including Forms III and IV).
  • the invention is also directed to the preparation of the aforesaid solid-state forms of ABC, to the preparation of substantially pure Form II, an anhydrous form of abemaciclib, pharmaceutical compositions comprising the aforesaid forms and their use in treating diseases.
  • Figure I is an XRPD pattern of solid-state Form I, a tri-methanol solvate of ABC,
  • Figure II is a three-dimensional structure of solid-state Form I that is discerned from SCXRD.
  • Figure III is PLM of crystals of solid-state Form I.
  • Figure IV is a DSC plot of solid-state Form I.
  • Figure V is an XRPD pattern from variable humidity XRPD testing conducted at 40% RH.
  • Figure VI is an XRPD pattern from variable humidity XRPD testing conducted at 10% RH for about 6 hours.
  • Figure VII is an XRPD pattern for substantially pure Form III, a hydrate of abemaciclib.
  • Figure VIII is an overlay of XRPD patterns from variable humidity XRPD testing conducted at 80% RH for 5 hours (bottom plot) and about 6 hours (top plot).
  • solid-state form of ABC, as used herein, includes polymorphic forms, such as anhydrous forms, solvates, or an amorphous form.
  • Form I or “Form I of abemaciclib,” as used herein, refer to a tri-methanol solvate of abemaciclib.
  • Form II or “Form II of abemaciclib,” as used herein, refer to an anhydrous form of abemaciclib.
  • Form III or “Form III of abemaciclib,” as used herein, refer to a hydrate of abemaciclib.
  • Form IV or “Form IV of abemaciclib,” as used herein, refer to another hydrate of abemaciclib.
  • the terms “substantially” or “substantially pure” with respect to a polymorph or polymorphic form means that the form contains about less than 20 percent, about less than 15 percent, about less than 10 percent, about less than 5 percent, or about less than 1 percent by weight of other polymorphic forms.
  • room temperature is defined as a temperature between 15-29 °C; preferably between 20-23 °C.
  • to dry/drying/dried means to dry/drying/dried at 45 °C and under vacuum.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
  • composition is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • ABC is dissolved in warm (about 50 °C to 60 °C range, preferred about 55 °C) methanol (about 200 mg/mL) and then cooled (-10 °C to -5 °C range, preferred -5 °C) to precipitate a white powder, which is Form I, a tri-methanol solvate of ABC.
  • Form I is exposed to low levels of humidity, for example, about 10% RH, for a period of time to yield substantially pure Form II, an anhydrous form of ABC. Conversion of Form I to substantially pure Form II begins almost immediately after exposure to low levels of humidity.
  • the period of time for full conversion varies depending on numerous factors, for example, the amount of the sample, the level of humidity, the manner in which the sample is packed, temperature, etc., and thus the period of time varies from a few minutes to a few hours. In one embodiment, the period of time is from about 2 to about 4 hours, or more. In other embodiments, the period of time is less than about 2 hours.
  • Form I is exposed to high levels of humidity, for example, about 60-80% RH, for a period of time to yield substantially pure Form III, a hydrate of abemaciclib, or to about 80% RH or more to yield a mixture of the hydrated forms of abemaciclib (including Forms III and IV).
  • Conversion of Form I to a hydrated form begins almost immediately after exposure to elevated levels of humidity.
  • the period of time for full conversion varies depending on numerous factors, for example, the amount of the sample, the manner in which the sample is packed, temperature, etc. and thus the time period varies from a few minutes to a few hours. In one embodiment, the period of time is from about 2 to about 4 hours, or more. In other embodiments, the period of time is less than about 2 hours.
  • Substantially pure Form II and the hydrated forms of abemaciclib interconvert based on the relative humidity present in the environment in which they are stored.
  • a sample may contain substantially pure Form II, substantially pure Form III, a mixture of these forms of abemaciclib, or a mixture of the hydrated forms (including Forms III and IV).
  • abemaciclib is present as a mixture of the hydrated forms of abemaciclib (including Forms III and IV) or substantially pure Form III, for example, at about 80% RH, the abemaciclib sample contains a mixture of the hydrated forms of abemaciclib (including Forms III and IV), or from about 90-100 mol% of Form III (substantially pure) and about 10-0 mol% of Form II.
  • abemaciclib is present as substantially pure Form II, for example, at about 10% RH, the abemaciclib sample contains about 90-100 mol% of Form II (substantially pure) and about 10-0 mol% of Form III.
  • the invention is also directed to processes for the preparation of the various forms of abemaciclib.
  • a process for the preparation of solid-state substantially pure Form II, an anhydrous form of abemaciclib consisting essentially of: exposing Form I of abemaciclib to about 10% RH for a period of time to yield substantially pure Form II.
  • a process for the preparation of solid-state substantially pure Form II, an anhydrous form of abemaciclib comprising: exposing substantially pure Form III of abemaciclib or a mixture of Form III and Form IV of abemaciclib to about 10% RH for a period of time to yield substantially pure Form II.
  • the period of time is less than about 5 hours. In another embodiment, the period of time is about 2 hours, or less.
  • a process for the preparation of solid-state substantially pure Form III, a hydrate of abemaciclib comprising exposing:
  • Form I of abemaciclib to about 60-80% RH for a period of time to yield substantially pure Form III.
  • a process for the preparation of solid-state substantially pure Form III, a hydrate of abemaciclib comprising exposing: substantially pure Form II of abemaciclib to about 60-80% RH for a period of time to yield substantially pure Form III.
  • the period of time is about 1 hour. In another embodiment, the period of time is more than 1 hour, for example, about 2 hours. In a further embodiment, the period of time is less than 1 hour.
  • a process for the preparation of a mixture of Form III and Form IV of abemaciclib comprising: exposing substantially pure Form II of abemaciclib to about 80% RH or more for a period of time to yield a mixture of Form III and Form IV of abemaciclib having an X-ray powder diffraction peak at about 4.7° 2Q ⁇ 0.2° 2Q and 2 or more X-ray powder diffraction peaks selected from about 4.1°, 11.7°, and 27.4° 2Q ⁇ 0.2° 2Q measured by CuK a radition.
  • the period of time is about 5 hours. In another embodiment, the period of time is less than 5 hours. In another embodiment, the period of time is more than 5 hours.
  • a solid-state form of abemaciclib namely, substantially pure Form III or a mixture of the hydrated forms of abemaciclib (including Forms III and IV) for use in preparing a pharmaceutical composition; more particularly where the composition is combined with one or more pharmaceutically acceptable ingredients.
  • Relative intensities for peak values can vary depending on several factors, including sample preparation, mounting, and analytical procedure and settings of the instrument that is used to obtain the spectrum.
  • XRPD diffractograms are collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in reflection geometry.
  • the instrument is fitted with an Anton Paar CHC plus+ stage fitted with graphite/Kapton windows and equipped with air cooling coupled with a proUmid MHG32 Modular Humidity Generator.
  • a programmable divergence slit (in automatic mode), with a 10 mm fixed incident beam mask, Ni filter and 0.04 rad Sober slits are used on the incident beam.
  • a PIXce D detector, placed on the diffracted beam, is fitted with a programmable antiscatter slit (in automatic mode) and 0.04 rad Sober slits.
  • the software for data collection is X’Pert Data Collector and the data is analysed and presented using Diffrac Plus EVA or Highscore Plus.
  • the samples are prepared and analysed in an Anton Paar chromed sample holder (0.2 mm depth, sample leveled with glass slide).
  • the measurement parameters include the following: Angular range: 2.5 to 32.0° 20 or 3.5 to 40.0° 20; Step size: 0.0130° 20 or 0.00328° 20; and Collection time: 12.75 s/step (total collection time of 2.07 min) or 44.625 s/step (total collection time of 35:27 min).
  • Measurements are taken at the following humidities: 10, 80, and 10% RH.
  • the initial measurement is taken at 40% RH, as a starting reference.
  • SCXRD Single Crystal X-Ray Diffraction
  • DSC measurements are performed on a calorimeter, TA Instruments Q2000 and RSC40.
  • the samples are weighed in aluminum pans. Investigations are performed in a temperature range of 20-400 °C with a heating rate of 10 °C/min, purging with nitrogen at a flow rate of 50 mL/min.
  • TGA measurements are recorded using TA Q500 instrument. The samples are weighed in aluminum pans. TGA investigations are performed at a heating rate of 10.0 °C/min over a temperature range of 30-350 °C, purging with nitrogen at a flow rate of 60 mL/min.
  • PLM Polarized Light Microscopy
  • a tri-methanol solvate of ABC is produced by dissolving ABC in warm (55 °C) methanol (about 200 mg/mL) and then cooling (-5 °C) to force precipitation of a white powder.
  • the resulting powder is examined by XRPD while still wet ( Figure I, top pattern).
  • Single crystals are grown by slow evaporation of methanol into an antisolvent (preferably ethyl acetate) or by slowly cooling a saturated solution from 50 °C to 0 °C over the course of several hours, and not exposed to air, to obviate evaporation of the solvate and the collapse of the crystalline lattice.
  • Single crystal X-ray diffraction (SCXRD) data is undertaken at 100 K to improve diffraction quality as well as to prevent desolvation.
  • the calculated XRPD pattern for the single crystal ( Figure I, bottom pattern) does not perfectly match the XRPD pattern of the wet crystal because the conditions under which the SCXRD is collected results in small changes in the unit cell that results in shifts in the calculated XRPD peaks for the tri -methanol solvate of ABC.
  • the single crystal is determined to be Form I, a tri-methanol solvate of ABC, ( Figure II) having about 2.5-3 molecules of methanol, preferably about 2.75 molecules of methanol.
  • Form I is unstable.
  • the XRPD is directed to solid-state Form I, a tri-methanol solvate of ABC, and 2Q and relative % intensity values for peaks are shown in Table I.
  • the angle measurements are ⁇ 0.2° 2Q.
  • Key defining peaks for solid-state Form I include 10.0, 17.7, 21.8 and 26.G 2Q.
  • Crystals of Form I are examined by PLM ( Figure III) and determined to be rhomboid.
  • the DSC plot ( Figure IV) for Form I shows ill-defined endotherms related to solvent and a melt of about 184 °C.
  • Form I is vacuum dried at an elevated temperature (45 °C) for about 8 hours or more.
  • the resulting material is stored under ambient conditions (room temperature and uncontrolled humidity) for a period of time, for example, from about 2 weeks to over a year.
  • a sample (contained in a sample holder with 0.2 mm depth where the sample is leveled with a glass slide) is analyzed by VH-XRPD.
  • An XRPD pattern of the sample is obtained immediately after equilibration at 40% RH, prior to adjusting the humidity to 10%, as depicted in Figure V (initial scan 40% RH). After humidity equilibrium is reached, the sample is exposed to 10% RH for 5 hours before an XRPD measurement is begun.
  • Figure VI A comparison of the initial scan obtained at 40% RH and the scans after 5 and about 6 hour exposure to 10% RH indicates that there is conversion from the initial form to substantially pure Form II. There is no change between the XRPD pattern at 10% RH for 5 hours and the XRPD pattern at 10% RH for about 6 hours indicating that complete conversion to substantially pure Form II occurs in less than 5 hours.
  • Figure VI is a representative XRPD pattern of substantially pure Form II of abemaciclib .
  • the angle measurements are ⁇ 0.2° 2Q.
  • Key defining peaks for substantially pure Form II include 5. G, 10.4°, 17.0° 2Q.
  • Substantially pure Form II (as depicted in Figure VI) is exposed to 80% RH. After about 1 hour exposure to 80% RH, the sample is transformed to substantially pure Form III, a hydrate of abemaciclib.
  • Figure VII is a representative XRPD pattern of substantially pure Form III of abemaciclib.
  • peaks for substantially pure Form III of ABC include peaks at about 4.7°, 11.2°, and 26.0° 2Q.
  • Exposure of substantially pure Form II of ABC to 80% RH for 5 hours results in a mixture of hydrated forms, namely, Form III of abemaciclib and Form IV of abemaciclib, having an X-ray powder diffraction peak at about 4.7° 2Q ⁇ 0.2° 2Q and 2 or more X-ray powder diffraction peaks selected from about 4.1°, 11.7°, and 27.4° 2Q ⁇ 0.2° 2Q measured by CuK a radition, as depicted in Figure VIII (bottom plot).
  • Exposure to 80% RH for about another hour results in a mixture of the hydrated forms of abemaciclib (including Forms III and IV having an X-ray powder diffraction peak at about 4.7° 2Q ⁇ 0.2° 2Q and 2 or more X-ray powder diffraction peaks selected from about 4.1°, 11.7°, and 27.4° 2Q ⁇ 0.2° 2Q measured by CuK a radition) containing greater amounts of Form IV of abemaciclib, as depicted in Figure VIII (top plot).
  • Figure VIII contains XRPD patterns of a mixture of Form III of abemaciclib and Form IV of abemaciclib having an X-ray powder diffraction peak at about 4.7° 2Q ⁇ 0.2° 2Q and 2 or more
  • X-ray powder diffraction peaks selected from about 4.1°, 11.7°, and 27.4° 2Q ⁇ 0.2° 2Q measured by CuKa radition.
  • peaks for Form IV of ABC include peaks at about 4.1°, 11.7°, and 27.4° 2Q.
  • the mixture of Form III of abemaciclib and Form IV of abemaciclib having an X-ray powder diffraction peak at about 4.7° 2Q ⁇ 0.2° 2Q and 2 or more X-ray powder diffraction peaks selected from about 4.1°, 11.7°, and 27.4° 2Q ⁇ 0.2° 2Q measured by CuK a radiation is then exposed to 10% RH. After humidity equilibrium is reached, the sample is exposed to 10% RH for 5 hours before an XRPD measurement is begun. After the measurement is complete, the sample is maintained at 10% RH for an additional hour before a second measurement is begun. The XRPD patterns after both 5 and about 6 hour exposure to 10% RH indicate that the sample is completely transformed back to substantially pure Form II of ABC.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des formes solides d'abemaciclib (ABC), à savoir une forme hydratée sensiblement pure et un mélange de formes hydratées. L'invention concerne également la préparation des formes susmentionnées, la préparation d'une forme anhydre, des compositions pharmaceutiques comprenant les formes susmentionnées et leur utilisation dans le traitement de maladies.
PCT/US2020/070404 2019-08-13 2020-08-12 Formes solides d'abemaciclib, leur utilisation et leur préparation WO2021030843A1 (fr)

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US201962886097P 2019-08-13 2019-08-13
US62/886,097 2019-08-13
US201962912775P 2019-10-09 2019-10-09
US62/912,775 2019-10-09

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CN107868082A (zh) 2016-09-22 2018-04-03 上海宣创生物科技有限公司 玻玛西尼甲磺酸盐a晶型及其制备方法
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