CRYSTALLINE FORMS OF L-MALIC ACID SALT OF SUNITINIB
Field of the Invention
The present invention relates to crystalline forms of L-malic acid salt of sunitinib
and processes for their preparation. The crystalline forms of the present invention are
designated as Form V and Form VI of L-malic acid salt of sunitinib.
Background of the Invention
Sunitinib is chemically described as N -[2-(diethylamino)ethyl]-5-[(Z)-(5-fluorol,
2-dihydro-2-oxo-3 H -indol-3-ylidine)methyl]-2,4-dimethyl-l H -pyrrole-3-carboxamide as
represented by Formula I .
FORMULA I
Sunitinib is an oral multi-kinase inhibitor and useful for the treatment of
gastrointestinal stromal tumor and advanced renal cell carcinoma. Sunitinib is
commercially available as a L-malate salt, which is described chemically as butanedioic
acid, hydroxy-, (2S)-, compound with N -[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2-
dihydro-2-oxo-3H -indol-3-ylidine)methyl]-2,4-dimethyl-l H -pyrrole-3-carboxamide (1:1).
U.S. Publication Nos. 2003/0069298 and 2007/0191458 describe the preparation of
crystal Forms I and II of L-malic acid salt of sunitinib. According to the above
publications, crystal Form I of L-malic acid salt of sunitinib is prepared by slurrying a
poorly crystalline or crystal Form II of L-malic acid salt of sunitinib in acetonitrile.
Crystal Form II of L-malic acid salt of sunitinib is prepared by dissolving crystal Form I of
L-malic acid salt of sunitinib in tetrahydrofuran and water and allowing the solvent to
evaporate overnight. WO 2009/067686 describes processes for preparing crystalline
forms of racemic sunitinib malate, sunitinib hemi-L-malate and compositions containing
sunitinib base and L- or racemic malic acid.
WO 2009/104021 describes processes for preparing crystalline Forms III and IV of
sunitinib malate. WO 2009/128083 describes processes for preparing crystalline Forms A,
B, C, D, E, F and G of sunitinib base. WO 09/109388 describes processes for preparing
crystalline Forms I, II and III of sunitinib base. WO 2009/156837 describes processes for
preparing amorphous form of L-malic acid salt of sunitinib. WO 2010/004339 describes
processes for preparing crystalline Form I of sunitinib malate.
Summary of the Invention
A crystalline Form V of L-malic acid salt of sunitinib.
A crystalline Form V of L-malic acid salt of sunitinib comprising an XRPD as
depicted in Figure 1.
A crystalline Form V of L-malic acid salt of sunitinib which is characterized by an
XRPD pattern comprising interplanar spacing (d) values substantially at 6.51, 5.99, 5.83,
5.02, 4.76, 4.63, 3.85, 3.82, 3.64, 3.60, 3.56 and 3.09 + 0.02 A.
A crystalline Form V of L-malic acid salt of sunitinib which is further
characterized by an XRPD pattern further comprising interplanar spacing (d) values
substantially at 15.42, 11.68, 11.02, 10.05, 9.25, 7.97, 7.65, 6.97, 6.83, 6.73, 6.51, 5.99,
5.83, 5.66, 5.56, 5.50, 5.29, 5.25, 5.15, 5.02, 4.82, 4.76, 4.63, 4.58, 4.50, 4.35, 4.28, 4.19,
4.10, 4.06, 4.00, 3.95, 3.84, 3.82, 3.76, 3.68, 3.64, 3.60, 3.56, 3.49, 3.41, 3.39, 3.31, 3.24,
3.17, 3.09, 3.04, 2.99, 2.95, 2.91, 2.88, 2.85, 2.79, 2.76, 2.72, 2.66, 2.56, 2.52, 2.47, 2.41,
2.35 and 2.31 + 0.02 A.
A crystalline Form V of L-malic acid salt of sunitinib comprising a
dimethylsulfoxide content from about 7.5% to about 10.5%.
A crystalline Form V of L-malic acid salt of sunitinib according to the claim 5,
comprising a dimethylsulfoxide content from about 8.5% to about 9.5%.
A crystalline Form VI of L-malic acid salt of sunitinib.
A crystalline Form VI of L-malic acid salt of sunitinib comprising an XRPD as
depicted in Figures 2 and 3.
A crystalline Form VI of L-malic acid salt of sunitinib which is characterized by an
XRPD pattern comprising interplanar spacing (d) values substantially at 15.37, 7.42, 6.76,
6.40, 6.22, 5.58, 5.49, 5.06, 4.82, 4.58, 3.93, 3.68, 3.49, 3.46, 3.41, 3.35, 3.23 and 3.11 +
0.02 A.
A crystalline Form VI of L-malic acid salt of sunitinib which is further
characterized by an XRPD pattern comprising interplanar spacing (d) values substantially
at 27.72, 15.37, 9.22, 7.68, 7.42, 6.76, 6.39, 6.22, 5.58, 5.49, 5.29, 5.24, 5.15, 5.06, 4.97,
4.82, 4.70, 4.58, 4.48, 4.37, 4.23, 4.19, 4.10, 4.00, 3.93, 3.84, 3.77, 3.68, 3.49, 3.46, 3.41,
3.35, 3.23, 3.11, 3.07, 2.98, 2.92, 2.85, 2.80, 2.72, 2.6 3, 2.57, 2.52, 2.46, 2.44, 2.41, 2.35
and 2.30 + 0.02 A.
A process for the preparation of crystalline Form V of L-malic acid salt of
sunitinib, wherein the process includes:
a) treating L-malic acid salt of sunitinib with dimethyl sulfoxide; and
b) isolating the crystalline Form V of L-malic acid salt of sunitinib from the
mixture thereof.
A process according to the claim 11, wherein the treatment with dimethylsulfoxide
is carried out at a temperature of about 50°C to about 75°C.
A process according to the claim 12, wherein the treatment with dimethylsulfoxide
is carried out at a temperature of about 65°C to about 70°C.
A process according to the claim 11, wherein the crystalline Form V of L-malic
acid salt of sunitinib is isolated by stirring.
A process according to the claim 14, wherein the crystalline Form V of L-malic
acid salt of sunitinib is isolated at a temperature of about 30°C or less.
A process for the preparation of crystalline Form VI of L-malic acid salt of
sunitinib, wherein the process includes:
a) treating crystalline Form V of L-malic acid salt of sunitinib with an ester or
an alcohol; and
b) isolating crystalline Form VI of L-malic acid salt of sunitinib.
A process according to the claim 16, wherein the ester comprises methyl acetate.
A process according to the claim 16, wherein the alcohol comprises methanol.
A process according to the claim 16, wherein the treatment with an ester or an
alcohol is carried out at a temperature of about 10°C to about 50°C.
A process according to the claim 16, wherein the treatment with an ester or an
alcohol is carried out at a temperature of about 15°C to about 30°C.
A pharmaceutical composition comprising crystalline Form VI of L-malic acid salt
of sunitinib and a carrier.
A method of treating or preventing a protein kinase related disorder comprising
administering to a patient in need thereof a therapeutically effective amount of a
crystalline Form VI of L-malic acid salt of sunitinib.
Brief Description of the Drawings
Figure 1 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline
Form V of L-malic acid salt of sunitinib.
Figure 1A provides the table of values for the XRPD pattern depicted in Figure 1.
Figure 2 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline
Form VI of L-malic acid salt of sunitinib obtained according to Examples 2.
Figure 2A provides the table of values for the XRPD pattern depicted in Figure 2.
Figure 3 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline
Form VI of L-malic acid salt of sunitinib obtained according to Examples 3.
Figure 3A provides the table of values for the XRPD pattern depicted in Figure 3.
Detailed Description of the Invention
The present invention provides for crystalline Form V of L-malic acid salt of
sunitinib. The crystalline Form V of L-malic acid salt of sunitinib has substantially the
same XRPD (X-ray powder diffraction pattern) pattern as depicted in Figure 1. The
crystalline Form V of L-malic acid salt of sunitinib is characterized by an XRPD pattern
which includes interplanar spacing (d) values substantially at 6.51, 5.99, 5.83, 5.02, 4.76,
4.63, 3.85, 3.82, 3.64, 3.60, 3.56 and 3.09 + 0.02 A. The crystalline Form V of L-malic
acid salt of sunitinib is further characterized by an XRPD pattern that includes interplanar
spacing (d) values substantially at 15.42, 11.68, 11.02, 10.05, 9.25, 7.97, 7.65, 6.97, 6.83,
6.73, 6.51, 5.99, 5.83, 5.66, 5.56, 5.50, 5.29, 5.25, 5.15, 5.02, 4.82, 4.76, 4.63, 4.58, 4.50,
4.35, 4.28, 4.19, 4.10, 4.06, 4.00, 3.95, 3.84, 3.82, 3.76, 3.68, 3.64, 3.60, 3.56, 3.49, 3.41,
3.39, 3.31, 3.24, 3.17, 3.09, 3.04, 2.99, 2.95, 2.91, 2.88, 2.85, 2.79, 2.76, 2.72, 2.66, 2.56,
2.52, 2.47, 2.41, 2.35 and 2.31 + 0.02 A.
The crystalline Form V of L-malic acid salt of sunitinib has a dimethylsulfoxide
content from about 7.5% to about 10.5%, for example, from about 8.5% to about 9.5%.
The present invention also provides for crystalline Form VI of L-malic acid salt of
sunitinib. The crystalline Form VI of L-malic acid salt of sunitinib has substantially the
same XRPD (X-ray powder diffraction pattern) pattern as depicted in Figures 2 and 3.
The crystalline Form VI of L-malic acid salt of sunitinib is characterized by an XRPD
pattern that includes interplanar spacing (d) values substantially at 15.37, 7.42, 6.76, 6.40,
6.22, 5.58, 5.49, 5.06, 4.82, 4.58, 3.93, 3.68, 3.49, 3.46, 3.41, 3.35, 3.23 and 3.11 + 0.02
A. The crystalline Form VI of L-malic acid salt of sunitinib is further characterized by an
XRPD pattern that includes interplanar spacing (d) values substantially at 27.72, 15.37,
9.22, 7.68, 7.42, 6.76, 6.39, 6.22, 5.58, 5.49, 5.29, 5.24, 5.15, 5.06, 4.97, 4.82, 4.70, 4.58,
4.48, 4.37, 4.23, 4.19, 4.10, 4.00, 3.93, 3.84, 3.77, 3.68, 3.49, 3.46, 3.41, 3.35, 3.23, 3.11,
3.07, 2.98, 2.92, 2.85, 2.80, 2.72, 2.6 3, 2.57, 2.52, 2.46, 2.44, 2.41, 2.35 and 2.30 + 0.02
A.
The present invention also provides for a process for the preparation of crystalline
Form V of L-malic acid salt of sunitinib. The process includes:
a) treating L-malic acid salt of sunitinib with dimethylsulfoxide; and
b) isolating the crystalline Form V of L-malic acid salt of sunitinib from the
mixture thereof.
L-Malic acid salt of sunitinib existing in any solid form known in the prior art may
be used as the starting material. The L-malic acid salt of sunitinib may be prepared
according to the methods disclosed in Indian Patent Nos. 2337/DEL/2009, and
2386/DEL/2009. The L-malic acid salt of sunitinib is treated with dimethylsulfoxide. The
treatment with dimethylsulfoxide may be carried out at a temperature of about 50°C to
about 75°C, for example, from about 65°C to about 70°C, to obtain a solution. The
treatment with dimethylsulfoxide may be accompanied by stirring. The crystalline Form
V of L-malic acid salt of sunitinib is isolated, for example, by stirring at a temperature of
about 30°C or less, for example, for about 15°C to about 25°C. The stirring may be
carried out for about 30 minutes to about 48 hours, for example, about 6 hours to about 15
hours. The excess of dimethylsulfoxide, if any, may be removed by filtration, distillation,
decantation, vacuum drying, evaporation, or a combination thereof, to obtain the
crystalline Form V of L-malic acid salt of sunitinib. The crystalline Form V of L-malic
acid salt of sunitinib has dimethylsulfoxide content from about 7.5% to about 10.5%, for
example, from about 8.5% to about 9.5%.
The present invention also provides for a process for the preparation of crystalline
Form VI of L-malic acid salt of sunitinib. The process includes:
a) treating crystalline Form V of L-malic acid salt of sunitinib with an ester or
an alcohol; and
b) isolating crystalline Form VI of L-malic acid salt of sunitinib.
The crystalline Form V of L-malic acid of sunitinib may be prepared according to
the previous aspect of the present invention. The crystalline Form V of L-malic acid salt
of sunitinib is treated with an ester or an alcohol. The ester may be, for example, methyl
acetate and the alkanol may be, for example, methanol, or a mixture thereof. The
treatment with the solvent may be carried out at a temperature of about 10°C to about
50°C, for example, about 15°C to about 30°C accompanied by stirring. The stirring may
be carried out for about 1 hour to about 50 hours, for example, about 3 hours to 10 hours.
The crystalline Form VI of L-malic acid salt of sunitinib may be isolated by filtration,
distillation, decantation, vacuum drying, evaporation, or a combination thereof.
The present invention also provides for a pharmaceutical composition that includes
crystalline Form VI of L-malic acid salt of sunitinib and a carrier.
The present invention also provides for a method of treating or preventing a protein
kinase related disorder, which includes administering to a patient in need thereof a
therapeutically effective amount of a crystalline Form VI of L-malic acid salt of sunitinib.
The XRPD of the samples were determined by using Panalytical X'Pert Pro X-Ray
Powder Diffractometer in the range 3-40 degree 2 theta and under tube voltage and current
of 45 Kv and 40 mA, respectively. Copper radiation of wavelength 1.54 angstrom and
Xceletor detector was used.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Preparation of Crystalline Form V of L-Malic Acid Salt of Sunitinib :
L-Malic acid salt of sunitinib (20 g) was dissolved in dimethylsulfoxide (80 ml) by
stirring at 65°C to 70°C for 30 minutes. The solution was slowly cooled to 20°C to 25°C
in 1 hour and stirred at 20°C to 25°C for 15 hours. The mixture was filtered under
vacuum at 20°C to 25°C and the solid was dried under vacuum at 60°C to 65°C for 24
hours to obtain the title compound.
Yield: 14.5 g
Dimethylsulfoxide content: 9.07% (by thermo gravimetric analysis)
Example 2: Preparation of Crystalline Form VI of L-Malic Acid Salt of Sunitinib :
Crystalline Form V of L-malic acid salt of sunitinib (2 g) was stirred in methanol
(12 ml) at 20°C to 22°C for 5 hours to 6 hours. The mixture was filtered under vacuum at
20°C to 25°C and dried under vacuum at 60°C for 12 hours to 15 hours to obtain the title
compound.
Yield: 1.5 g
Example 3: Preparation of Crystalline Form VI of L-Malic Acid Salt of Sunitinib :
Crystalline Form V of L-malic acid salt of sunitinib (2 g) was stirred in methyl
acetate (12 ml) at 20°C to 22°C for 5 hours to 6 hours. The mixture was filtered under
vacuum at 20°C to 25°C and dried under vacuum at 60°C for 12 hours to 15 hours to
obtain the title compound.
Yield: 1.5 g

WE CLAIM;
1. A crystalline Form V of L-malic acid salt of sunitinib having substantially the same
XRPD (X-ray powder diffraction pattern) pattern as depicted in Figure 1.
2. A crystalline Form V of L-malic acid salt of sunitinib which is characterized by an
XRPD pattern comprising interplanar spacing (d) values substantially at 6.51, 5.99, 5.83,
5.02,4.76,4.63, 3.85, 3.82, 3.64, 3.60, 3.56 and 3.09 ± 0.02 A.
3. The crystalline Form V of L-malic acid salt of sunitinib according to the claim 2 which is
characterized by an XRPD pattern comprising interplanar spacing (d) values
substantially at 15.42, 11.68, 11.02, 10.05, 9.25, 7.97, 7.65, 6.97, 6.83, 6.73, 6.51, 5.99,
5.83, 5.66, 5.56, 5.50, 5.29, 5.25, 5.15, 5.02, 4.82,4.76,4.63,4.58, 4.50,4.35,4.28,4.19,
4.10,4.06,4.00, 3.95, 3.84, 3.82, 3.76, 3.68, 3.64, 3.60, 3.56, 3.49, 3.41, 3.39, 3.31, 3.24,
3.17, 3.09, 3.04,2.99, 2.95,2.91, 2.88, 2.85, 2.79, 2.76,2.72,2.66, 2.56, 2.52, 2.47,2.41,
2.35 and 2.31 ±0.02 A.
4. A crystalline Form V of L-malic acid salt of sunitinib having interplanar spacing (d)
values in XRPD substantially at 6.51, 5.99, 5.83, 5.02, 4.76, 4.63, 3.85, 3.82, 3.64, 3.60,
3.56 and 3.09 ± 0.02 A comprising a dimethylsulfoxide content from about 7.5% to
about 10.5%.
5. A crystalline Form VI of L-malic acid salt of sunitinib having substantially the same
XRPD (X-ray powder diffraction pattern) pattern as depicted in Figures 2 and 3.
6. A crystalline Form VI of L-malic acid salt of sunitinib which is characterized by an
XRPD pattern comprising interplanar spacing (d) values substantially at 15.37, 7.42,
6.76, 6.40, 6.22, 5.58, 5.49, 5.06, 4.82, 4.58, 3.93, 3.68, 3.49, 3.46, 3.41, 3.35, 3.23 and
3.11 ±0.02 A.
7. The crystalline Form VI of L-malic acid salt of sunitinib according to the claim 6 which
is characterized by an XRPD pattern comprising interplanar spacing (d) values
substantially at 27.72, 15.37, 9.22, 7.68, 7.42, 6.76, 6.39, 6.22, 5.58, 5.49, 5.29, 5.24,
5.15, 5.06, 4.97,4.82, 4.70, 4.58,4.48,4.37,4.23, 4.19,4.10,4.00, 3.93, 3.84, 3.77, 3.68,
3.49, 3.46, 3.41, 3.35, 3.23, 3.11, 3.07, 2.98, 2.92, 2.85, 2.80, 2.72, 2.6 3, 2.57, 2.52,
2.46, 2.44, 2.41, 2.35 and 2.30 ± 0.02 A.
8. A process for the preparation of crystalline Form V of L-malic acid salt of sunitinib
having interplanar spacing (d) values in XRPD substantially at 6.51, 5.99, 5.83, 5.02,
4.76, 4.63, 3.85, 3.82, 3.64, 3.60, 3.56 and 3.09 ± 0.02 according to claim 2, wherein the
process includes:
a) treating L-malic acid salt of sunitinib with dimethylsulfoxide; and
b) isolating the crystalline Form V of L-malic acid salt of sunitinib from the mixture
thereof.
9. The process according to the claim 8, wherein the treatment with dimethylsulfoxide is
carried out at a temperature of about 50°C to about 75°C.
10. The process according to the claim 8, wherein the crystalline Form V of L-malic acid salt
of sunitinib is isolated by stirring.
11. The process according to the claim 10, wherein the crystalline Form V of L-malic acid
salt of sunitinib is isolated at a temperature of about 30°C or less.
12. A process for the preparation of crystalline Form VI of L-malic acid salt of sunitinib
having interplanar spacing (d) values in XRPD substantially at 15.37, 7.42, 6.76, 6.40,
6.22, 5.58, 5.49, 5.06, 4.82, 4.58, 3.93, 3.68, 3.49, 3.46, 3.41, 3.35, 3.23 and 3.11 ± 0.02
A according to claim 6, wherein the process includes:
a) treating crystalline L-malic acid salt of sunitinib having interplanar spacing (d) values
in XRPD substantially at 6.51, 5.99, 5.83, 5.02, 4.76, 4.63, 3.85, 3.82, 3.64, 3.60, 3.56
and 3.09 ± 0.02 with an ester or an alcohol; and
b) isolating crystalline Form VI of L-malic acid salt of sunitinib.
13. The process according to the claim 12, wherein the ester comprises methyl acetate.
14. The process according to the claim 12, wherein the alcohol comprises methanol.
15. The process according to the claim 12, wherein the treatment with an ester or an alcohol
is carried out at a temperature of about 10°C to about 50°C.
16. A pharmaceutical composition comprising crystalline Form VI having interplanar
spacing (d) values in XRPD substantially at 15.37, 7.42, 6.76, 6.40, 6.22, 5.58, 5.49,
5.06, 4.82, 4.58, 3.93, 3.68, 3.49, 3.46, 3.41, 3.35, 3.23 and 3.11 ± 0.02 A of L-malic
acid salt of sunitinib according to claim 6 and a carrier.
17. A method of treating or preventing a protein kinase related disorder comprising
administering to a patient in need thereof a therapeutically effective amount of a
crystalline Form VI of L-malic acid salt of sunitinib according to claim 6 having
interplanar spacing (d) values in XRPD substantially at 15.37, 7.42, 6.76, 6.40, 6.22,
5.58, 5.49, 5.06,4.82,4.58, 3.93, 3.68, 3.49, 3.46, 3.41, 3.35, 3.23 and 3.11 ± 0.02 A.