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WO2020225827A1 - Novel polymorphs of ribociclib succinate - Google Patents

Novel polymorphs of ribociclib succinate Download PDF

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Publication number
WO2020225827A1
WO2020225827A1 PCT/IN2020/050411 IN2020050411W WO2020225827A1 WO 2020225827 A1 WO2020225827 A1 WO 2020225827A1 IN 2020050411 W IN2020050411 W IN 2020050411W WO 2020225827 A1 WO2020225827 A1 WO 2020225827A1
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Prior art keywords
ribociclib
ribociclib succinate
crystalline
succinate
crystalline form
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PCT/IN2020/050411
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French (fr)
Inventor
Ramakoteswara Rao Jetti
Daveedu BHATRAJU
Rama Mohana Rao GOLIVI
Seshadri Rao Manukonda
Sureshbabu JAYACHANDRA
Chandra Has Khanduri
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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Publication of WO2020225827A1 publication Critical patent/WO2020225827A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the inventors of the present invention have developed novel crystalline forms of Ribociclib Succinate which are suitable for formulation development.
  • the main object of the present invention is to provide novel crystalline forms of Ribociclib Succinate.
  • the present invention is to provide a novel crystalline form of Ribociclib Succinate designated as Form M10.
  • the Ribociclib Succinate crystalline form M10 is characterized by powder X-ray diffraction pattern having peaks at 5.9, 8.5, 11.4, 11.9, 12.2, 13.5, 14.1, 15.3, 15.8, 16.8, 17.5, 18.3, 19.0, 19.6, 20.4, 21.1, 21.6, 22.3, 23.3, 25.7, 27.0, 27.7, 28.5, 29.3, 30.4, 31.1, 32.4, 34.4, 35.2, 37.4, 40.9 and 42.9 ⁇ 0.2° degrees 2Q.
  • the crystalline Form M10 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 1.
  • the present invention is to provide a process for the preparation of crystalline Form M10 of Ribociclib Succinate comprising the steps of:
  • the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form Mi l.
  • the Ribociclib Succinate crystalline form Mi l is characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.9, 6.3, 7.0, 7.6, 9.1, 9.8, 10.3, 10.8, 11.2, 12.4, 13.1, 13.4, 14.0, 15.0, 15.9, 16.8, 17.8, 18.1, 19.4, 19.9, 20.6, 21.1, 21.7, 22.6, 23.9, 25.3, 25.9, 26.7, 28.9, 30.8, 31.8, .32.9 34.8 and 36.0 ⁇ 0.2° degrees 2Q.
  • the Ribociclib Succinate crystalline form M12 is characterized by powder X-ray diffraction pattern having peaks at 4.52, 6.96, 14.90, 15.86, 19.30, 19.91, 21.64, 22.58, 23.77 and 24.99 ⁇ 0.2° degrees 2Q.
  • the crystalline Form M12 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 3.
  • the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form M14.
  • the Ribociclib Succinate crystalline Form M14 is characterized by powder X-ray diffraction pattern having peaks at 4.73, 7.77, 9.35, 10.49, 12.20, 14.10, 17.78, 18.95, 19.33, 19.64, 20.43, 21.16 21.94 ⁇ 0.2° degrees 2Q.
  • the crystalline Form M14 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 4.
  • the present invention is to provide a process for the preparation of crystalline Form M14 of Ribociclib Succinate comprising the steps of:
  • step b) adding solution of step a to a solution of succinic acid in isopropyl alcohol c) isolating crystalline Form M14 of Ribociclib Succinate.
  • the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form Ml 5.
  • the Ribociclib Succinate crystalline Form M15 is characterized by powder X-ray diffraction pattern having peaks at 6.93, 9.84, 10.22, 14.35, 16.71, 18.90, 19.52, 19.77, 20.31, 20.57 ⁇ 0.2° degrees 2Q.
  • the crystalline Form M15 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 5.
  • the present invention is to provide a process for the preparation of crystalline Form M15 of Ribociclib Succinate comprising the steps of:
  • Figure 1 Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M10.
  • Figure 2 Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form Mi l.
  • Figure 3 Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M12.
  • Figure 4 Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M14.
  • Figure 5 Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M15.
  • the present invention relates to novel crystalline forms of Ribociclib Succinate.
  • the present invention relates to novel crystalline form of Ribociclib Succinate designated as Form M10.
  • the Ribociclib Succinate crystalline Form M10 is characterized by powder X-ray diffraction pattern having peaks at 5.9, 8.5, 11.4, 11.9,
  • the crystalline Form M10 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 1.
  • the present invention is to provide a process for the preparation of crystalline Form M10 of Ribociclib Succinate comprising the steps of: a) suspending Ribociclib in tertiary amyl alcohol
  • Ribociclib may be suspended in tertiary Amyl alcohol and added Succinic acid. This suspension may be heated at a temperature of about 50-55°C and stirred for lh followed by cooling to about 25 ⁇ 5°C and stirred for about 15 hours. The resultant solid may be filtered and dried to obtain crystalline Form M10 of Ribociclib Succinate.
  • the present invention relates to novel crystalline form of Ribociclib Succinate designated as Form Mi l.
  • Ribociclib and succinic acid may be suspended in an organic solvent selected from alcohols preferably Isobutanol, 2-methyl-2-butanol and 3 -methyl- 1 -butanol or ketone solvents such as methyl ethyl ketone.
  • This suspension may be heated at a temperature of about 50-80°C and stirred.
  • the resultant reaction mass may be cooled to about 25 ⁇ 5°C and stirred for about 15 hours.
  • the reaction mass was filtered and dried to obtain crystalline Form Ml 1 of Ribociclib Succinate.
  • the present invention relates to novel crystalline form of Ribociclib Succinate designated as Form M12.
  • the Ribociclib Succinate crystalline form M12 is characterized by powder X-ray diffraction pattern having peaks at 4.52, 6.96, 14.90, 15.86, 19.30, 19.91, 21.64, 22.58, 23.77 and 24.99 ⁇ 0.2° degrees 2Q.
  • the crystalline Form M12 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 3.
  • the present invention relates to a process for the preparation of crystalline Form M12 of Ribociclib Succinate comprising the steps of: a) suspending Ribociclib and succinic acid in an organic solvent.
  • Ribociclib and succinic acid may be suspended in an organic solvent selected from alcohols preferably Isobutanol, 2-methyl-2-butanol or 3 -methyl- 1 -butanol.
  • This suspension may be heated at a temperature of about 50- 70°C and stirred.
  • the resultant reaction mass may be cooled to about 25 ⁇ 5°C and stirred for about 2 hours.
  • the reaction mass was filtered and dried to obtain crystalline Form M12 of Ribociclib Succinate.
  • the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form M14.
  • the Ribociclib Succinate crystalline form M14 is characterized by powder X-ray diffraction pattern having peaks at 4.73, 7.77, 9.35, 10.49, 12.20, 14.10, 17.78, 18.95, 19.33, 19.64, 20.43, 21.16 21.94 ⁇ 0.2° degrees 2Q.
  • the crystalline Form M14 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 4.
  • the present invention is to provide a process for the preparation of crystalline Form M14 of Ribociclib Succinate comprising the steps of:
  • step b) adding solution of step a to a solution of succinic acid in isopropyl alcohol c) isolating crystalline Form M14 of Ribociclib Succinate.
  • the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form Ml 5.
  • the Ribociclib Succinate crystalline form M15 is characterized by powder X-ray diffraction pattern having peaks at 6.93, 9.84, 10.22, 14.35, 16.71, 18.90, 19.52, 19.77, 20.31, 20.57 ⁇ 0.2° degrees 2Q.
  • the crystalline Form M15 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 5.
  • the present invention is to provide a process for the preparation of crystalline Form M15 of Ribociclib Succinate comprising the steps of:
  • Ribociclib (lg) was dissolved in 1,4 Dioxane (25mL) at 70 ⁇ 5°C.The obtained clear solution was filtered to remove any undissolved particles. In another RBF, dissolved succinic acid (0.3g) in Iso propyl alcohol (20ml) at 70 ⁇ 5°C. The obtained clear solution was slowly added to reaction mass containing Ribociclib in 1,4-Dioxane and stirred the reaction mass for 30 min at 70+5°. The suspension was cooled to 30 ⁇ 5°C and stirred for 3h at 30 ⁇ 5°C. The product obtained was filtered, suck-dried under nitrogen atmosphere for 30min at 25-30°C. The solid obtained was identified as crystalline Form M14 of Ribociclib Succinate.

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

Abstract

The present invention relates to novel crystalline forms of Ribociclib Succinate and its preparation process.

Description

NOVEL POLYMORPHS OF RIBOCICLIB SUCCINATE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian provisional patent application no IN 201941018391 filed on May 08, 2019.
FIELD OF THE INVENTION:
The present invention relates to novel crystalline forms of Ribociclib Succinate and its preparation process.
BACKGROUND OF THE INVENTION:
Ribociclib Succinate, chemically known as Butanedioic acid— 7-cyclopentyl-N,N dimethyl-2- { [5-(piperazin- 1 -yl) pyridin-2-yl] amino } -7H-pyrrolo [2,3 -d]pyrimidine-6- carboxamide (1/1) and represented by Formula-I is approved for the inhibitor of cyclin D1/CDK4 and CDK6. It is similar to Palbociclib both structurally and pharmacologic ally ,
acting as a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.
Figure imgf000002_0001
Formula I
Ribociclib and it’s pharmaceutically acceptable salts thereof was first claimed in US 8415355B2 patent. This patent also disclosed a process for the preparation of ribociclib.
US 9193732B2 disclosed the polymorphic forms of succinate salt of ribociclib, characterized by XRD, DSC, TGA, post-DVS XRD, post-DVS DSC and post-DVS TGA figures and non-hydrate form, hydrate form and mixtures. US 20170342075 disclosed crystalline form I of mono- succinate salt of ribociclib, characterized by XRD peaks. This application also disclosed Hemi-succinate Form A, adipate salt Form A, Maleate salt Form A and Glycolic acid salt Form A.
EP application EP 3156406A1 claimed crystalline forms of ribociclib free base and amorphous form.
PCT application WO 2018051280 disclosed different salts, amorphous form of ribociclib and amorphous solid dispersion of ribociclib.
IN application IN 201741000072 claimed crystalline forms of ribociclib Succinate DR1, DR2, DR3, DR4, DR5, DR6, DR7 & DR8.
The inventors of the present invention have developed novel crystalline forms of Ribociclib Succinate which are suitable for formulation development.
OBJECT AND SUMMARY OF THE INVENTION:
The main object of the present invention is to provide novel crystalline forms of Ribociclib Succinate.
In one aspect, the present invention is to provide a novel crystalline form of Ribociclib Succinate designated as Form M10.
In yet another aspect, the Ribociclib Succinate crystalline form M10 is characterized by powder X-ray diffraction pattern having peaks at 5.9, 8.5, 11.4, 11.9, 12.2, 13.5, 14.1, 15.3, 15.8, 16.8, 17.5, 18.3, 19.0, 19.6, 20.4, 21.1, 21.6, 22.3, 23.3, 25.7, 27.0, 27.7, 28.5, 29.3, 30.4, 31.1, 32.4, 34.4, 35.2, 37.4, 40.9 and 42.9 ±0.2° degrees 2Q.
In yet another aspect, the crystalline Form M10 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 1.
In yet another aspect, the present invention is to provide a process for the preparation of crystalline Form M10 of Ribociclib Succinate comprising the steps of:
a) suspending Ribociclib in tertiary amyl alcohol
b) adding succinic acid c) heating and cooling the reaction mixture
d) isolating crystalline Form M10 of Ribociclib Succinate.
In another aspect, the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form Mi l.
In yet another aspect, the the Ribociclib Succinate crystalline form Mi l is characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.9, 6.3, 7.0, 7.6, 9.1, 9.8, 10.3, 10.8, 11.2, 12.4, 13.1, 13.4, 14.0, 15.0, 15.9, 16.8, 17.8, 18.1, 19.4, 19.9, 20.6, 21.1, 21.7, 22.6, 23.9, 25.3, 25.9, 26.7, 28.9, 30.8, 31.8, .32.9 34.8 and 36.0 ±0.2° degrees 2Q.
In yet another aspect, the crystalline Form Mi l of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 2.
In yet another aspect, the present invention is to provide a process for the preparation of crystalline Form Mi l of Ribociclib Succinate comprising the steps of:
a) suspending Ribociclib and succinic acid in an organic solvent.
b) heating and cooling the reaction mixture
c) isolating crystalline Form Ml 1 of Ribociclib Succinate.
In another aspect, the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form M12.
In yet another aspect, the Ribociclib Succinate crystalline form M12 is characterized by powder X-ray diffraction pattern having peaks at 4.52, 6.96, 14.90, 15.86, 19.30, 19.91, 21.64, 22.58, 23.77 and 24.99 ±0.2° degrees 2Q.
In yet another aspect, the crystalline Form M12 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 3.
In yet another aspect, the present invention is to provide a process for the preparation of crystalline Form M12 of Ribociclib Succinate comprising the steps of:
a) suspending Ribociclib and succinic acid in an organic solvent.
b) heating and cooling the reaction mixture
c) isolating crystalline Form M12 of Ribociclib Succinate. In another aspect, the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form M14.
In yet another aspect, the Ribociclib Succinate crystalline Form M14 is characterized by powder X-ray diffraction pattern having peaks at 4.73, 7.77, 9.35, 10.49, 12.20, 14.10, 17.78, 18.95, 19.33, 19.64, 20.43, 21.16 21.94 ±0.2° degrees 2Q.
In yet another aspect, the crystalline Form M14 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 4.
In yet another aspect, the present invention is to provide a process for the preparation of crystalline Form M14 of Ribociclib Succinate comprising the steps of:
a) dissolving Ribociclib in 1,4- Dioxane
b) adding solution of step a to a solution of succinic acid in isopropyl alcohol c) isolating crystalline Form M14 of Ribociclib Succinate.
In another aspect, the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form Ml 5.
In yet another aspect, the Ribociclib Succinate crystalline Form M15 is characterized by powder X-ray diffraction pattern having peaks at 6.93, 9.84, 10.22, 14.35, 16.71, 18.90, 19.52, 19.77, 20.31, 20.57 ±0.2° degrees 2Q.
In yet another aspect, the crystalline Form M15 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 5.
In yet another aspect, the present invention is to provide a process for the preparation of crystalline Form M15 of Ribociclib Succinate comprising the steps of:
a) suspending Ribociclib Succinate Form M14 in n-Heptane
b) heating and cooling the reaction mixture
c) isolating crystalline Form Ml 5 of Ribociclib Succinate.
BRIEF DESCRIPTION OF THE FIGURES: Figure 1: Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M10.
Figure 2: Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form Mi l.
Figure 3: Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M12.
Figure 4: Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M14.
Figure 5: Illustrates the powder X-ray diffraction (PXRD) pattern of Ribociclib Succinate Form M15.
DETAILED DESCRIPTION:
The present invention relates to novel crystalline forms of Ribociclib Succinate.
In one embodiment, the present invention relates to novel crystalline form of Ribociclib Succinate designated as Form M10.
In yet another embodiment, the Ribociclib Succinate crystalline Form M10 is characterized by powder X-ray diffraction pattern having peaks at 5.9, 8.5, 11.4, 11.9,
12.2, 13.5, 14.1, 15.3, 15.8, 16.8, 17.5, 18.3, 19.0, 19.6, 20.4, 21.1, 21.6, 22.3, 23.3, 25.7, 27.0, 27.7, 28.5, 29.3, 30.4, 31.1, 32.4, 34.4, 35.2, 37.4, 40.9 and 42.9 ±0.2° degrees 2Q.
In yet another embodiment, the crystalline Form M10 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 1.
In yet another embodiment, the present invention is to provide a process for the preparation of crystalline Form M10 of Ribociclib Succinate comprising the steps of: a) suspending Ribociclib in tertiary amyl alcohol
b) adding succinic acid
c) heating and cooling the reaction mixture
d) isolating crystalline Form M10 of Ribociclib Succinate. According to the present invention, Ribociclib may be suspended in tertiary Amyl alcohol and added Succinic acid. This suspension may be heated at a temperature of about 50-55°C and stirred for lh followed by cooling to about 25±5°C and stirred for about 15 hours. The resultant solid may be filtered and dried to obtain crystalline Form M10 of Ribociclib Succinate.
In yet another embodiment, the present invention relates to novel crystalline form of Ribociclib Succinate designated as Form Mi l.
In yet another embodiment, the Ribociclib Succinate crystalline Form Mi l is characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.9, 6.3, 7.0, 7.6, 9.1, 9.8, 10.3, 10.8, 11.2, 12.4, 13.1, 13.4, 14.0, 15.0, 15.9, 16.8, 17.8, 18.1, 19.4, 19.9, 20.6, 21.1, 21.7, 22.6, 23.9, 25.3, 25.9, 26.7, 28.9, 30.8, 31.8, .32.9 34.8 and 36.0 ±0.2° degrees 2Q.
In yet another embodiment, the crystalline Form Mi l of Ribociclib Succinate may be characterized by the powder X-ray diffraction pattern as given in Figure 2.
In yet another embodiment, the present invention relates to a process for the preparation of crystalline Form Mi l of Ribociclib Succinate comprising the steps of: a) suspending Ribociclib and succinic acid in an organic solvent.
b) heating and cooling the reaction mixture
c) isolating crystalline Form Ml 1 of Ribociclib Succinate.
According to the present invention, Ribociclib and succinic acid may be suspended in an organic solvent selected from alcohols preferably Isobutanol, 2-methyl-2-butanol and 3 -methyl- 1 -butanol or ketone solvents such as methyl ethyl ketone. This suspension may be heated at a temperature of about 50-80°C and stirred. The resultant reaction mass may be cooled to about 25±5°C and stirred for about 15 hours. The reaction mass was filtered and dried to obtain crystalline Form Ml 1 of Ribociclib Succinate.
In yet another embodiment, the present invention relates to novel crystalline form of Ribociclib Succinate designated as Form M12. In yet another embodiment, the Ribociclib Succinate crystalline form M12 is characterized by powder X-ray diffraction pattern having peaks at 4.52, 6.96, 14.90, 15.86, 19.30, 19.91, 21.64, 22.58, 23.77 and 24.99 ± 0.2° degrees 2Q.
In yet another embodiment, the crystalline Form M12 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 3.
In yet another embodiment, the present invention relates to a process for the preparation of crystalline Form M12 of Ribociclib Succinate comprising the steps of: a) suspending Ribociclib and succinic acid in an organic solvent.
b) heating and cooling the reaction mixture
c) isolating crystalline Form M12 of Ribociclib Succinate.
According to the present invention, Ribociclib and succinic acid may be suspended in an organic solvent selected from alcohols preferably Isobutanol, 2-methyl-2-butanol or 3 -methyl- 1 -butanol. This suspension may be heated at a temperature of about 50- 70°C and stirred. The resultant reaction mass may be cooled to about 25±5°C and stirred for about 2 hours. The reaction mass was filtered and dried to obtain crystalline Form M12 of Ribociclib Succinate.
In another aspect, the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form M14.
In yet another aspect, the Ribociclib Succinate crystalline form M14 is characterized by powder X-ray diffraction pattern having peaks at 4.73, 7.77, 9.35, 10.49, 12.20, 14.10, 17.78, 18.95, 19.33, 19.64, 20.43, 21.16 21.94 ±0.2° degrees 2Q.
In yet another aspect, the crystalline Form M14 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 4.
In yet another aspect, the present invention is to provide a process for the preparation of crystalline Form M14 of Ribociclib Succinate comprising the steps of:
a) dissolving Ribociclib in 1,4- Dioxane
b) adding solution of step a to a solution of succinic acid in isopropyl alcohol c) isolating crystalline Form M14 of Ribociclib Succinate.
According to the present invention, Ribociclib may be dissolved in 1,4 Dioxane and heated to 70-80°C to obtain clear solution. Seperately, Succinic acid may be taken in isopropyl alcohol and heated to 70-80°C. The clear Ribociclib solution may be added to the succinic acid solution and maintain the reaction mixture at 70-80°C followed by cooling to 25-35°C. The solid may be filtered, suck dried under nitrogen to obtain crystalline Form M14 of Ribociclib Succinate
In another aspect, the present invention is to provide novel crystalline form of Ribociclib Succinate designated as Form Ml 5.
In yet another aspect, the Ribociclib Succinate crystalline form M15 is characterized by powder X-ray diffraction pattern having peaks at 6.93, 9.84, 10.22, 14.35, 16.71, 18.90, 19.52, 19.77, 20.31, 20.57 ±0.2° degrees 2Q.
In yet another aspect, the crystalline Form M15 of Ribociclib Succinate has the powder X-ray diffraction pattern as given in Figure 5.
In yet another aspect, the present invention is to provide a process for the preparation of crystalline Form M15 of Ribociclib Succinate comprising the steps of:
a) suspending Ribociclib Succinate Form M14 in n-Heptane
b) heating and cooling the reaction mixture
c) isolating crystalline Form Ml 5 of Ribociclib Succinate.
According to the present invention, crystalline Form M14 of Ribociclib Succinate may be suspended in n-Heptane and heated the reaction mixture to 75-85°C. The reaction may be cooled to 25-35°C and the solid obtained may be filtered, suck dried under nitrogen or dried under vacuum to obtain crystalline Form M15 of Ribociclib Succinate
In yet another embodiment, the present invention relates to pharmaceutical composition comprising either of the crystalline Ribociclib Succinate Forms M10, Mi l, M12, M14 or M15 and pharmaceutically acceptable excipients. Indicative stability:
In yet another embodiment, the physical and chemical stability of Ribociclib Succinate Form M10 was determined by storing the samples at 5±3°C and 25°C/60% relative humidity (RH) conditions for six months. The samples were analyzed by PXRD and purity by HPLC. The results are shown in Table 1. The Ribociclib Succinate Form M10 was found to be physically and chemically stable at 5±3°C and 25°C/60% relative humidity (RH) conditions up to six months.
In yet another embodiment, the physical and chemical stability of Ribociclib Succinate Form Mi l was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for six months. The samples were analyzed by PXRD and purity by HPLC. The results are shown in Table 2. The Ribociclib Succinate Form Mi l was found to be physically and chemically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions up to six months.
Table 1
Figure imgf000010_0001
Table 2
Figure imgf000011_0001
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in anyway.
EXAMPLES:
Example 1: Ribociclib Succinate Form M10.
Charged Ribociclib (5g) and tertiary Amyl alcohol (lOOmL) into the RBF. The suspension was stirred for 10 min and charged succinic acid (1.43g) into RBF at 25±5°C. The suspension was heated to 50±5°C and stirred for lh at 50±5°C. The suspension was cooled to 25±5°C and stirred for 15 h at 25±5°C. The reaction mass was filtered, suck-dried at 25-30°C for 30minutes and further dried the material under vacuum at 30°C 24 h. The solid obtained was identified as crystalline Form M10 of Ribociclib Succinate.
Yield=5.8g
Example 2: Ribociclib Succinate Form Mil.
Charged Ribociclib (4g), succinic acid (1.14g) and Isobutanol (80 mL) into the RBF at 25±5°C. The suspension was heated to 50-55°C and stirred for lh at 50-55°C. The suspension was cooled to 25±5°C and stirred for 15 h at 25±5°C. The reaction mass was filtered and washed with Isobutanol (8mL), suck-dried at 25-30°C for 30minutes and further dried the material under vacuum at 30°C for 16 h. The solid obtained was identified as crystalline Form Mi l of Ribociclib Succinate.
Yield=4.9g
Example 3: Ribociclib Succinate Form Mil
Charged Ribociclib (2.5g), succinic acid (760mg) and 2-methyl-2-butanol (50 mL) into the RBF at 25±5°C. The suspension was heated to 50-55°C and stirred for 20h at 50-55°C. The reaction mass was filtered, suck-dried at 25-30°C for 30minutes and further dried the material under vacuum at 50-55°C for 15 h. The solid obtained was identified as crystalline Form Mi l of Ribociclib Succinate.
Yield=2.6g
Example 4: Ribociclib Succinate Form Mil
Charged Ribociclib (0.5g), succinic acid (140mg) and 3 -methyl- 1 -butanol (10 mL) into the RBF at 25±5°C. The suspension was heated to 70-75°C and stirred for lh at 70-75°C. The suspension was cooled to 25±5°C and stirred for 15 h at 25±5°C. The reaction mass was filtered and suck dried for 30 min. The solid obtained was identified as crystalline Form Mi l of Ribociclib Succinate.
Example 5: Ribociclib Succinate Form Mil
In a RBF, Charge Ribociclib (2g), Methyl ethyl ketone (40mL) and Succinic acid (0.6g) at 25±5°C. Heated the suspension to 75±5°C and stir for lh at 75±5°C. The suspension was cooled to 25±5°C and stirred for 16h at 25±5°C. The reaction mass was filtered and dried under vacuum at 40°C for 16 h. The solid obtained was identified as crystalline Form Mi l of Ribociclib Succinate.
Yield=2.3 g
Example 6: Ribociclib Succinate Form M12
Charged Ribociclib (0.5g), succinic acid (140mg) and 2-methyl-2-butanol (15 mL) into the RBF at 25±5°C. The suspension was heated to 60-65°C and stirred for lh at 60-65°C. The suspension was cooled to 25±5°C and stirred for lh at 25±5°C. The reaction mass was filtered and suck dried for 30 min. The solid obtained was identified as crystalline Form M12 of Ribociclib Succinate. Example 7: Ribociclib Succinate Form M14
Ribociclib (lg) was dissolved in 1,4 Dioxane (25mL) at 70±5°C.The obtained clear solution was filtered to remove any undissolved particles. In another RBF, dissolved succinic acid (0.3g) in Iso propyl alcohol (20ml) at 70±5°C. The obtained clear solution was slowly added to reaction mass containing Ribociclib in 1,4-Dioxane and stirred the reaction mass for 30 min at 70+5°. The suspension was cooled to 30±5°C and stirred for 3h at 30±5°C. The product obtained was filtered, suck-dried under nitrogen atmosphere for 30min at 25-30°C.The solid obtained was identified as crystalline Form M14 of Ribociclib Succinate.
Example 8: Ribociclib Succinate Form M15
Ribociclib (5g) was dissolved in 1,4 Dioxane (150mL) at 70±5°C.The obtained clear solution was filtered to remove any undissolved particles. In another RBF, dissolved succinic acid (1.5g) in Iso propyl alcohol (125ml) at 70±5°C. The obtained clear solution was slowly added to reaction mass containing Ribociclib in 1,4-Dioxane and stirred for 30 min at 70±5°C. The suspension was cooled to 30±5°C and stirred for 3h at 30±5°C. The product obtained was filtered, suck-dried under nitrogen atmosphere at 25-30°C for 30minutes. The obtained wet solid (2g) and n-Heptane (50mL) were charged into the RBF. Heated the suspension to 80±5°C and stir for 2h. Cooled the suspension to 30±5°C.The obtained solid was filtered, suck-dried under nitrogen atmosphere at 25±5°C for 30minutes. The solid obtained was identified as crystalline Form M15 of Ribociclib Succinate.
Example 9: Ribociclib Succinate Form M15.
Charge Ribociclib succinate M14 solid (2g) and n-Heptane (50mL) into the RBF. Heated the suspension to 80±5°C and stir for 2h at 80±5°C. Cooled the suspension to 30±5°C. The obtained solid was filtered and dried the material under vacuum at 45°C for 16h. The solid obtained was identified as crystalline Form M15 of Ribociclib Succinate.

Claims

We claim:
1. Crystalline Ribociclib Succinate Form Mi l characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.9, 6.3, 7.0, 7.6, 9.1, 9.8, 10.3, 10.8, 11.2, 12.4, 13.1, 13.4, 14.0, 15.0, 15.9, 16.8, 17.8, 18.1, 19.4, 19.9, 20.6, 21.1, 21.7, 22.6, 23.9, 25.3, 25.9, 26.7, 28.9, 30.8, 31.8, .32.9 34.8 and 36.0 ±0.2° degrees 2Q.
2: The crystalline Ribociclib Succinate Form Mi l as claimed in claim 1, is prepared comprising the steps of:
a) suspending Ribociclib and succinic acid in an organic solvent.
b) heating and cooling the reaction mixture
c) isolating crystalline Form Ml 1 of Ribociclib Succinate.
3. The process as claimed in claim 2, wherein the organic solvent is selected from Isobutanol, 2-methyl-2-butanol and 3 -methyl- 1 -butanol or methyl ethyl ketone.
4. The process as claimed in claim 2, wherein the reaction mixiture is heated to 50- 75°C and cooled to 20-25°C
5. Crystalline Ribociclib Succinate Form M12 characterized by powder X-ray diffraction pattern having peaks at 4.52, 6.96, 14.90, 15.86, 19.30, 19.91, 21.64, 22.58, 23.77 and 24.99 ±0.2° degrees 2Q
6. The crystalline Ribociclib Succinate Form M12 as claimed in claim 5, is prepared comprising the steps of: a) suspending Ribociclib and succinic acid in 2-methyl-2-butanol.
b) heating and cooling the reaction mixture
c) isolating crystalline Form M12 of Ribociclib Succinate.
7. Crystalline Ribociclib Succinate Form M10 characterized by powder X-ray diffraction pattern having peaks at 5.9, 8.5, 11.4, 11.9, 13.5, 15.8, 16.8, 17.5, 18.3, 19.6, 21.1, 22.3, 25.7, 27.0 and 28.5 ±0.2° degrees 2Q.
8. The crystalline Ribociclib Succinate Form M10 as claimed in claim 7, is prepared comprising the steps of:
a) suspending Ribociclib in tertiary amyl alcohol
b) adding succinic acid
c) heating and cooling the reaction mixture
d) isolating crystalline Form M10 of Ribociclib Succinate.
9. Crystalline Ribociclib Succinate Form M14 characterized by powder X-ray diffraction pattern having peaks at 4.73, 7.77, 9.35, 10.49, 12.20, 14.10, 17.78, 18.95, 19.33, 19.64, 20.43, 21.16 21.94 ±0.2° degrees 2Q.
10. The crystalline Ribociclib Succinate Form M14 as claimed in claim 9, is prepared comprising the steps of:
a) dissolving Ribociclib in 1,4 Dioxane
b) adding solution of step a to a solution of succinic acid in isopropyl alcohol c) isolating crystalline Form M14 of Ribociclib Succinate.
11. Crystalline Ribociclib Succinate Form M15 characterized by powder X-ray diffraction pattern having peaks at 6.93, 9.84, 10.22, 14.35, 16.71, 18.90, 19.52, 19.77, 20.31, 20.57 ±0.2° degrees 2Q.
12. The crystalline Ribociclib Succinate Form M15 as claimed in claim 11, is prepared comprising the steps of:
a) suspending Ribociclib Succinate form M14 in n-Heptane
b) heating and cooling the reaction mixture
c) isolating crystalline Form Ml 5 of Ribociclib Succinate.
13. The process as claimed in claim 12, wherein the reaction mixiture is heated to 75- 85°C and cooled to 20-35°C and the isolation of Form M15 is carried by filteration followed by suck drying under nitrogen or drying the material under vacuum.
14. A pharmaceutical composition comprising crystalline Ribociclib Succinate selected from M10, Mi l, M12, M14 or M15 and a pharmaceutically acceptable excipient.
PCT/IN2020/050411 2019-05-08 2020-05-07 Novel polymorphs of ribociclib succinate Ceased WO2020225827A1 (en)

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