DESC: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 pharmacologically,
acting as a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.
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.
3
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 2?.
In yet another aspect, the crystalline Form M10 of Ribociclib Succinate has the powder
X-ray diffraction pattern as given in Figure 1.
4
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 M11.
In yet another aspect, the the Ribociclib Succinate crystalline form M11 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 2?.
In yet another aspect, the crystalline Form M11 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 M11 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 M11 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 2?.
5
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 2?.
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 M15.
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 2?.
6
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 M15 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 M11.
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,
7
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 2?.
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 1h 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 M11.
In yet another embodiment, the Ribociclib Succinate crystalline Form M11 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 2?.
In yet another embodiment, the crystalline Form M11 of Ribociclib Succinate may be
characterized by the powder X-ray diffraction pattern as given in Figure 2.
8
In yet another embodiment, the present invention relates to a process for the preparation
of crystalline Form M11 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 M11 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 M11 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 2?.
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.
9
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 2?.
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
10
In another aspect, the present invention is to provide novel crystalline form of Ribociclib
Succinate designated as Form M15.
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 2?.
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 M15 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, M11, 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
11
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 M11 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 M11 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
Conditions/ Polymorph
Ribociclib Succinate
Form M10
PXRD HPLC purity
at 5±3°C
Initial Crystalline form 99.5
1 months Stable 99.5
3 months Stable 99.6
6 months Stable 99.6
at 25°C/60% RH
Initial Crystalline form 99.5
1 months Stable 99.5
3 months Stable 99.5
6 months Stable 99.4
Table 2
Conditions/ Polymorph
Ribociclib Succinate
Form M11
PXRD HPLC purity
at 40°C/75% RH
12
Initial Crystalline form 99.4
1 months Stable 99.4
3 months Stable 99.5
6 months Stable 99.4
at 25°C/60% RH
Initial Crystalline form 99.4
1 months Stable 99.5
3 months Stable 99.6
6 months Stable 99.5
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 (100mL) 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 1h 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, suckdried
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 M11.
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 1h 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 M11 of Ribociclib Succinate.
Yield=4.9g
13
Example 3: Ribociclib Succinate Form M11
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 M11 of Ribociclib Succinate.
Yield=2.6g
Example 4: Ribociclib Succinate Form M11
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 1h 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 M11 of Ribociclib Succinate.
Example 5: Ribociclib Succinate Form M11
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 1h 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 M11 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 1h at 60-65°C.
The suspension was cooled to 25±5°C and stirred for 1h 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.
14
Example ,CLAIMS:1. Crystalline Ribociclib Succinate Form M11 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 2?.
2: The crystalline Ribociclib Succinate Form M11 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 M11 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 2?
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.
16
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 2?.
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 2?.
10. The crystalline Ribociclib Succinate Form M14 as claimed in claim 9, is prepared
comprising the steps of:
d) dissolving Ribociclib in 1,4 Dioxane
e) adding solution of step a to a solution of succinic acid in isopropyl alcohol
f) 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 2?.
12. The crystalline Ribociclib Succinate Form M15 as claimed in claim 11, is prepared
comprising the steps of:
d) suspending Ribociclib Succinate form M14 in n-Heptane
e) heating and cooling the reaction mixture
f) isolating crystalline Form M15 of Ribociclib Succinate.
17
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, M11, M12, M14 or M15 and a pharmaceutically acceptable excipient.