NOVEL POLYMORPHIC FORMS OF SUNITINIB BASE
Field of Invention:
The present invention relates to novel polymorphic forms of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl-2,4-dimethyl-lH-pyrrole-3-carboxamide-Sunitinib base (I). The present invention also relates to methods of preparing such polymorphic crystals,

Sunitinib is a small molecule inhibitor of multiple receptor kinases involved in cancer, including
vascular endothelial growth factor receptors, platelet derived growth factor receptors and the KIT
receptor. It has been recently approved by the US FDA for the treatment of Gastro Intestinal
Stromal Tumors (GIST) and Advanced Renal Cell Carcinoma (RCC).
Studies revealed that Sunitinib malate (SUTENT®) is an oral, multi-targeted tyrosine kinase
inhibitor (TKl) that targets and blocks the signaling pathways of multiple selected receptor
tyrosine kinases (RTKs). SUTENT® is administered via oral route.
Sunitinib exists as yellow to orange powder. Sunitinib is a non-hygroscopic substance and has no
chiral center, however the final substance is optically active due to malate part of the molecule.

Background of the Invention:
Sunitinib base is having the chemical name N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl-2,4-dimethyl-lH-pyrrole'3'Carboxamide is also known as SUII248 and similar pyrrole derivatives are first disclosed in WO 0160814 (2001). In the above said patent, the manufacturing process for Sunitinib is described as shown in Scheme-1 below.

According to the above patent,:
Tertiary butylacetoacetate (II) and ethyl acetatoacetate (III) were reacted by a well-known Knorr-
pyrrole synthesis (Org. Synth., Coll. Vol. II, p 202) using sodium nitrite, zinc and acetic acid to
get the diester pyrrole derivative (IV).
Later it is selectively decarboxylated in the presence of aqueous HCl to get half-ester pyrrole
derivative (V).
The compound (V) is then formylated by a known synthetic methodology using DMF-POCKi
complex to get the formylated ester derivative (VI).

The half-ester derivative (VI) is selectively hydrolyzed to get a carboxylic acid derivative (VII).
The carboxylic acid derivative (VII) is then selectively converted to amide (IX) using 2-
(Diethylamino ethylamine (VIII) in the presence of 1 -(3-dimethylaminopropyl-3-
ethylcarbodiimide HCl,
Finally the formyl derivative (IX) is coupled with 5-Fluro-2-oxindole (X) by Knoevenagel
method using pyrrolidine as a catalyst to get Sunitinib base (I). The product was characterized by
'H NMR and Mass spectral analysis.
However, the information regarding the solid state characteristics like powder XRD, DSC, IR
data or specific crystal forms of N-[2-(diethylamino)ethyl]"5-[(5-fluoro-l,2-dihydro-2-oxo-3H-
indol-3-ylidene)methyl-2,4-dimethyl-lH-pyrrole-3-carboxamide- Sunitinib base (I) are not
disclosed in the above mentioned patent (WO 01/60814).
A study of the solid state properties of this important anti-cancer entity will be extremely useful
from the therapeutic and pharmaceutical point of view. Hence we have taken up a detailed
investigation of these aspects.
In the current scenario demanding high quality standards of drug substances and drug products,
physical characteristics (like powdered XRD, DSC and IR) play an important role in
pharmaceutical industry.
Due to poor solubility nature of Sunitinib base in ethanol or methanol, very large volumes of
solvent is required to crystallize Sunitinib base. Hence a better process for preparation of high
purity of Sunitinib base directly obtainable from the reaction mixture is highly desirable. In that
direction a detailed study was taken-up.
During our experimental work on the reactivity of Sunitinib base in various solvents, surprisingly
a wide variety of novel polymorphic forms of the said base were discovered. These novel forms
are found to be stable, reproducible, and suitable for conversion to pharmaceutically acceptable
salt preparations. Also, surprisingly the condensation of formyl derivative (IX) with 5-Fluoro-2-
oxindole (X) is found to proceed even in the absence of a catalyst.
However, certain basic and acidic catalysts are found to hasten the reaction and improve the
yields. These catalysts include inorganic bases like ammonia, alkali metal or alkaline earth
hydroxides, carbonates, phosphates, bicarbonates and alkali metal hydroxides viz sodium
hydroxide, potassium hydroxide or alkaline earth metal hydroxides viz calcium hydroxide,
magnesium hydroxide or barium hydroxide, methanolic or ethanolic ammonia, quaternary

ammonium compounds like tetra butyl ammonium hydroxide, benzyltrimethyl ammonium
hydroxide, silica gel, sodium acetate, ammonium acetate or Lewis acids like Boron trifluoride
etherate and organic bases like piperidine, piperazine, pyrrolidine, sodium ethoxide, sodium
methoxide, para toluene sulfonic acid (PTSA) are found to hasten the reaction and improve the
yields.
Objectives of the present invention;
The main objective of the present invention is to provide a detailed process/ crystallization
conditions for the synthesis of Sunitinib base (I).
Accordingly, another objective of the present invention is to provide complete physical
characterization like XRD, DSC, IR of Sunitinib base (I).
Accordingly, yet another objective of the present invention is to provide physical
characterization data like XRD, IR, and DSC for Sunitinib base (I) obtained in methanol.
Accordingly, yet another objective of the present invention is to provide physical
characterization data like XRD, IR, DSC for Sunitinib base (I) obtained in n-hexane.
Accordingly, yet another objective of the present invention is to provide physical
characterization data like XRD, IR, DSC for Sunitinib base (I) obtained in cyclohexane.
Accordingly, yet another objective of the present invention is to provide physical
characterization data like XRD, IR, DSC for Sunitinib base (I) obtained in toluene.
Accordingly, yet another objective of the present invention is to provide physical
characterization data like XRD, IR, DSC for Sunitinib base (I) obtained in isopropyl acetate.
Accordingly, yet another objective of the present invention is to provide physical
characterization data like XRD, IR, DSC for Sunitinib base (I) obtained in tetrahydrofuran.
Accordingly, yet another objective of the present invention is to provide physical
characterization data like XRD, IR, DSC for Sunitinib base (I) obtained in methyl tertiary butyl
ether.

Brief Description of the Figures:
Fig 1: Powdered X-ray diffraction of Sunitinib base (I) obtained in methanol (Form-A)
Fig 2: FTIR spectrum of Sunitinib base (I) obtained in methanol (Form-A)
Fig 3: DSC of Sunitinib base (I) obtained in methanol (Form-A)
Fig 4: Powdered X-Ray diffractogram of Sunitinib base (I) obtained in n-hexane (Form-B)
Fig 5: FTIR spectrum of Sunitinib base (I) obtained in n-hexane (Form-B)
Fig 6: DSC of Sunitinib base (I) obtained in n-hexane (Form-B)
Fig 7: Powdered X-Ray diffractogram of Sunitinib base (I) obtained in cyclohexane (Form-C)
Fig 8: FTIR spectrum of Sunitinib base (I) obtained in cyclohexane (Form-C)
Fig 9: DSC of Sunitinib base (I) obtained in cyclohexane (Form-C)
Fig 10: Powdered X-Ray diffractogram of Sunitinib base (I) obtained in toluene (Form-D)
Fig 11: FTIR spectrum of Sunitinib base (I) obtained in toluene (Forra-D)
Fig 12: DSC of Sunitinib base (I) obtained in toluene (Form-D)
Fig 13:Powdered X-Ray diffractogram of Sunitinib base (I) obtained in isopropyl acetate
(Form-E) Fig 14: FTIR spectrum of Sunitinib base (I) obtained in isopropyl acetate (Form-E) Fig 15: DSC of Sunitinib base (I) obtained in isopropyl acetate (Form-E) Fig 16: Powdered X-Ray diffractogram of Sunitinib base (I) obtained in tetrahydrofuran
(Form-F) Fig 17: FTIR spectrum of Sunitinib base (I) obtained in tetrahydrofuran (Form-F) Fig 18: DSC of Sunitinib base (I) obtained in tetrahydrofuran (Form-F) Fig 19: Powdered X-Ray diffractogram of Sunitinib base (I) obtained in methyl tert. butyl ether
(Form-G) Fig 20: FTIR spectrum of Sunitinib base (I) obtained in methyl tert. butyl ether (Form-G) Fig 21: DSC of Sunitinib base (I) obtained in methyl tert. butyl ether (Form-G)

Summary of the present invention:
In one aspect, the present invention provides a crystalline form (Form-A) of Sunitinib base also
known as N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-yliclene)methyl-
2,4-dimethyl-lH-pyrrole-3-carboxamide (I) obtained in methanol as solvent. The crystal has the
following characteristics.
Powder XRD diffraction pattern having 29 values at 4.6, 9.0, 9.9, 13.1, 15.3, 16.6, 17.8, 19.9,
22.9, 26.0, 27.2, 27.7, 33.0, 34.5, 42.3, 44.4 (Fig. 1)
FTIR (cm"') spectra: 3299.8, 1677.0, 1588.6, 1542.2, 1479.0, 1334.1, 1191.5, 860.5, 798.0,
778.4, 668.3, 585.2 (Fig. 2)
DSC (° C): Peak Max. 244.9 °C (Fig. 3)
In another aspect, the present invention provides a crystalline form (Form-B) of Sunitinib base
obtained in n-hexane as solvent. The crystal has the following characteristics.
Powder XRD diffraction pattern having 29 values at 3.9, 7.8, 9.1, 10.3, 11.8, 13.7, 15.9, 16.8,
18.0, 19.0, 20.2, 21.3, 21.9, 22.6, 23.7, 24.4, 26.0, 26.8, 28.1, 29.5, 32.1, 32.5, 33.8, 37.4, 43.1
(Fig. 4)
FTIR (cm'') spectra: 3290.1, 1673.2, 1624.1, 1570.7, 1542.3, 1477.7, 1326.9, 1195.9, 795.5,
667.8, 585.6 (Fig. 5)
DSC (° C): Principal Peak Max. 235.9 °C (Fig. 6)
In another aspect, the present invention provides a crystalline form (Form-C) of Sunitinib base
obtained in cyclohexane as solvent. The crystal has the following characteristics.
Powder XRD diffraction pattern having 20 values at 4.3, 7.7, 8.6, 10.8, 12.9, 13.8, 17.3, 17.8,
19.1, 21.2, 21.5, 22.0, 23.2, 26.2, 27.6, 32.1, 33.9 (Fig. 7)
FTIR (cm'') spectra: 3299.9, 1674.2, 1626.5, 1565.6, 1537.1, 1476.7, 1326.8, 1199.9, 1144.2,
797.1, 667.6, 606.9, 589.0 (Fig. 8)
DSC (° C): Principal Peak Max. 223.5 °C (Fig. 9)
In another aspect, the present invention provides a crystalline form (Form-D) of Sunitinib base
obtained in toluene as solvent. The crystal has the following characteristics.
Powder XRD diffraction pattern having 29 values at 4.5, 7.7, 9.0, 10.4, 15.1, 16.5, 17.1, 18.4,
19.0, 20.2, 20.8, 21.4, 21.9, 23.1, 25.8, 26.1, 28.0, 29.1, 32.1, 33.0, 33.8, 35.8, 38.6, 46.2, 46.7
(Fig. 10)

FTIR (cm"') spectra: 3299.2, 1676.0, 1626.5, 1590.5, 1542.1, 1479.0, 1327.7, 1192.4, 860.0,
797.2,777.9,668.0,584.8 (Fig. 11)
DSC (° C): Principal Peak Max. 237.4 °C (Fig. 12)
In another aspect, the present invention provides a crystalline form (Form-E) of Sunitinib base
obtained in isopropyl acetate as solvent. The crystal has the following characteristics.
Powder XRD diffraction pattern having 20 values at 4.0, 6.2, 7.3, 7.8, 8.8, 9.3, 9.8, 11.1, 11.8,
12.8, 13.7, 14.6, 15.6, 16.0, 16.6, 17.4, 18.5, 19.1, 20.4, 21.6, 22.3, 23.3, 24.1, 24.6, 25.4, 25.8,
27.2, 28.1, 29.1, 29.5, 30.9, 31.9, 32.2, 33.3, 34.0, 35.0, 35.8, 36.4, 37.9, 39.3, 39.7, 41.9, 43.9,
48.9 (Fig. 13)
FTIR (cm-') spectra: 3431.8, 3169.9, 1674.5, 1622.2, 1578.0, 1477.5, 1325.7, 1196.2, 1144.5,
793.0, 667.9, 586.8 (Fig. 14)
DSC (° C): Principal Peak Max. 226.9 °C (Fig. 15)
In another aspect, the present invention provides a crystalline form (Form-F) of Sunitinib base
obtained in tetrahydrofuran as solvent. The crystal has the following characteristics.
Powder XRD diffraction pattern having 29 values at 4.5, 9.0, 12.9, 13.6, 15.1, 16.6, 16.9. 18.2,
19.0, 20.4, 21.7, 23.1, 23.6, 25.9, 28.0, 28.9, 29.4, 32.0, 33.8, 38.6, 48.7 (Fig. 16)
FTIR (cm'-1) spectra: 3298.7, 3223.8, 1676.4, 1590.1, 1542.2, 1479.3, 1332.8, 1191.6, 797.6,
668.0, 584.5 (Fig. 17)
DSC (° C): Peak Max. 242.5 °C (Fig. 18)
In another aspect, the present invention provides a crystalline form (Form-G) of Sunitinib base
obtained in methyl tert. butyl ether as solvent. The crystal has the following characteristics.
Powder XRD diffraction pattern having 20 values at 3.0, 4.5, 7.6, 9.1,9.9, 11.6, 13.5, 15.1, 16.7,
18.4, 19.1, 20.2, 21.7, 23.1, 25.9, 33.9, 40.0 (Fig.l9)
FTIR (cm-') spectra: 3297.0, 1675.9, 1625.9, 1590.5, 1542.1, 1479.2, 1330.4, 1191.9, 797.1,
668.0, 584.4 (Fig.20)
DSC C C): Principal Peak Max. 240.1 ° C (Fig. 21)

Detailed Description of the Present Invention:
The details of the present invention for the manufacture of Sunitinib base (I) are as follows: According to the process of the present invention, 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-l,3-dihydro-indol-2-one (X) in alcoholic solvents like methanol, ethanol, isopropyl alcohol or n-butanol are reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 2-8 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a temperature ranging from 20-45° C, preferably at 25-35° and most preferably at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange crystalline solid. This synthetic procedure for the manufacture of Sunitinib base is adopted from WO 01/60814. Accordingly, the present invention provides a complete physical characteristic data (like Powdered X-Ray diffraction, FTIR, and DSC) for Sunitinib base obtained in alcoholic solvents like methanol, ethanol, isopropyl alcohol or n-butanol
Accordingly, the present invention provides the crystalline Form-A obtained in alcoholic solvents like methanol, ethanol, isopropyl alcohol or n-butanol.
According to the process of the present invention, 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyI)-amide (IX) and 5-Fluoro-l,3-dihydro-indol-2-one (X) in non-polar aliphatic hydrocarbons solvents like n-hexane, n-heptane, n-octane, n-nonane or n-decane are reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 6-12 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a temperature ranging from 20-45° C, preferably at 25-35° and most preferably at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Accordingly, the present invention provides a complete physical characterization data (like Powdered X-Ray diffraction, FTIR, and DSC) for Sunitinib base obtained in non-polar aliphatic hydrocarbons solvent like n-hexane, n-heptane, n-octane, n-nonane or n-decane. Accordingly, the present invention provides the crystalline Form-B obtained in non-polar aliphatic hydrocarbon solvent like n-hexane, n-heptane, n-octane, n-nonane or n-decane. According to the process of the present invention, 5-Formyl-2,4-dimethyMH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-l,3-dihydro-indol-2-one (X) in non-polar alicyclic hydrocarbon solvents like cyclopentane, cyclohexane or cycloheptane are

reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 1-6 hours.
The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-
2 hours and isolated at a temperature ranging from 20-45° C, preferably at 25-35° and most
preferably at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange
crystalline solid.
Accordingly, the present invention provides a complete physical characterization data (like
Powdered X-Ray diffraction, FTIR, and DSC) for Sunitinib base obtained in non-polar alicyclic
hydrocarbon solvent like cyclopentane, cyclohexane or cycloheptane.
Accordingly, the present invention provides the crystalline Form-C obtained in non-polar
alicyclic hydrocarbon solvent like cyclopentane, cyclohexane or cycloheptane.
According to the process of the present invention, 5-Formyl-2,4-dimethy-1H-pyrrole-3-
carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-FluorO"l,3'dihydro-indol-2-one (X) in
aromatic hydrocarbon solvents like benzene or toluene are reacted in presence of catalytic
amount of pyrrolidine as base at 80-85° C for 3-9 hours. The resultant Sunitinib base is again
triturated with the same solvent at 80-85° C for 1-2 hours and isolated at a temperature ranging
from 20-45° C, preferably at 25-35° and most preferably at 25-30° C and dried at 60° C for 5-20
hours to get Sunitinib base (I) as orange crystalline solid.
Accordingly, the present invention provides a complete physical characterization data (like
Powdered X-Ray diffraction, FTIR, and DSC) for Sunitinib base obtained in aromatic
hydrocarbon solvent like benzene or toluene.
Accordingly, the present invention provides the crystalline Form-D obtained in aromatic
hydrocarbon solvents like benzene, toluene, xylenes.
According to the process of the present invention, 5-Formyl-2,4-dimethyl-lH-pyrrole-3-
carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-l,3-dihydro-indol-2-one (X) in
esters like ethyl acetate, methyl acetate or isopropyl acetate are reacted in presence of catalytic
amount of pyrrolidine as base at reflux temperature for 6-15 hours. The resultant Sunitinib base
is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a
temperature ranging from 20-45° C, preferably at 25-35° and most preferably at 25-30° C and
dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.

Accordingly, the present invention provides a complete physical characterization data (like
Powdered X-Ray diffraction, FTIR, and DSC) for Sunitinib base obtained in polar aprotic
solvents like ethyl acetate, methyl acetate or isopropyl acetate
Accordingly, the present invention provides the crystalline Form-E obtained in polar aprotic
solvents like ethyl acetate, methyl acetate or isopropyl acetate.
According to the process of the present invention, 5-Formyl-2,4-dimethyl-lH-pyrrole-3-
carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-l,3-dihydro-indol-2-one (X) in
dipolar aprotic solvents like tetrahydrofuran, 1,4-dioxane is reacted in presence of catalytic
amount of pyrrolidine as base at reflux temperature for 6-15 hours. The resultant Sunitinib base
is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a
temperature ranging from 20-45° C, preferably at 25-35° and most preferably at 25-30° C and
dried at 60° C for 5-20 hours to get Sunitinib base (1) as orange crystalline solid.
Accordingly, the present invention provides a complete physical characterization data (like
Powdered X-Ray diffraction, FTIR, and DSC) for Sunitinib base obtained in dipolar aprotic
solvents tetrahydrofuran or 1,4-dioxane.
Accordingly, the present invention provides the crystalline Form-F obtained in dipolar aprotic
solvent like tetrahydrofuran or 1,4-dioxane.
According to the process of the present invention, 5-Formyl-2,4-dimethyl-lH-pyrrole-3-
carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-l,3-dihydro-indol-2-one (X) in
ether solvents like diethyl ether, isopropyl ether or methyl tertiary butyl ether are reacted in
presence of catalytic amount of pyrrolidine as base at reflux temperature for 3-9 hours. The
resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2
hours and isolated at a temperature ranging from 20-45° C, preferably at 25-35° and most
preferably at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange
crystalline solid.
Accordingly, the present invention provides a complete physical characterization data (like
Powdered X-Ray diffraction, FTIR, and DSC) for Sunitinib base obtained in ether solvent like
diethyl ether, diisopropyl ether or methyl tertiary butyl ether.
Accordingly, the present invention provides the crystalline Form-G obtained in ether solvent
diethyl ether, diisopropyl ether or methyl tertiary butyl ether.

Advantages associated with the present invention:
i) The novel polymorphic forms (Form-A, Form-B, Form-C, Form-D, Form-E, Form-F,
and Form-G) of Sunitinib base (I) of this invention may be used as alternate drug
substances with potential therapeutic benefits . ii) Present invention discloses a commercially viable process for the preparation of novel
polymorphic forms of Sunitinib base, iii) The novel polymorphic forms of Sunitinib base are suitable for pharmaceutical use.
Having thus described the present invention with reference to certain preferred embodiments, the invention will be further illustrated by the examples, which follow. These examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Examples: Powder X-Ray diffraction patterns were measured on a Siemens D5000 x-ray
powder diffractometer having a copper-Ka radiation (1.5406A), Melting points were determined
using a Mettler Toledo 823 ' differential scanning calorimeter with standard crimped pans and a
beating rate of 10.0 C/min, Residual solvent analysis for the product was done on Agilent
6890N chromatograph. All chemicals used are available from Aldrich Chemical Co., Milwaukee,
Wisconsin , unless otherwise specified. The intermediate compounds (5-Formyl'-2,4-dimethyl-
lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide and 5-Fluoro-l,3-dihydro-indol-2-
one) were prepared according to the experimental procedure given in WO 01/60814.
In all experiments, residual solvents were found to be with-in the solvent limits as per ICH
guidelines.
Example 1:
Preparation of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-
ylidene)methyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (Sunitinib base of Form-A):
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (10.0 g 0.037
moles) and 5-Fluoro-l,3-dihydro-indol-2-one (5.41 g; 0.0358 moles) in ethanol were reacted in
presence of catalytic amount of pyrrolidine (0T6 mL) as base at reflux temperature for 2-8
hours. The resultant Sunitinib base was triturated in ethanol at reflux temperature for 1-2 hours
and isolated at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange
crystalline solid.
Yield: 11.8 g HPLC Purity: 99.5% DSC: 247.2° C
Example 2:
Preparation of N-[2-'(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-
ylidene)methyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (Sunitinib base of Form-A):
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (10.0 g 0,037
moles) and 5-Fluoro-l,3-dihydro-indol-2-one (5.41 g; 0.0358 moles) in methanol were reacted
in presence of catalytic amount of pyrrolidine (0.16 mL) as base at reflux temperature for 2-8
hours. The resultant Sunitinib base was triturated in methanol at reflux temperature for 1-2 hours
and isolated at 25-30° Cand dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange
crystalline solid.
Yield: 12.0 g HPLC Purity: 99.5%
Powdered XRD: Fig. 1 FTIR: Fig. 2 DSC: Peak Max. : 244.9 °C (Fig. 3)

Example 3:
Preparation of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-
ylidene)methyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (Sunitinib base of Form-B):
5-Formyl-2,4-dimethyMH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018
moles) and 5-Fluoro-l,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in n-hexane were reacted
in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8
hours. The resultant Sunitinib base was triturated in n-hexane at reflux temperature for 1-2 hours
and isolated at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange
crystalline solid.
Yield: 6.5 g HPLC Purity: 96.0%
Powdered XRD: Fig. 4 FTIR: Fig. 5 DSC: Principal peak Max. 235.9 °C (Fig. 6)
Example 4:
Preparation of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2'dihydro-2-oxo-3H-indol-3-
ylidene)methyl-2,4-dimethy-1H-pyrrole-3-carboxamide (Sunitinib base of Form-C):
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0,018
moles) and 5-Fluoro-l,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in cyclohexane were
reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for
2-8 hours. The resultant Sunitinib base was triturated in cyclohexane at reflux temperature for 1-
2 hours and isolated at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as
orange crystalline solid.
Yield: 6.8 g HPLC Purity: 97.7%
Powdered XRD: Fig. 7 FTIR: Fig, 8 DSC: Principal Peak Max: 223.4 °C (Fig, 9)

Example 5:
Preparation of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-
ylidene)methyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (Sunitinib base of Form-D):
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018
moles) and 5-Fluoro-l,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in toluene were reacted in
presence of catalytic amount of pyrrolidine (0.08 mL) as base at 80-85° for 2-8 hours. The
resultant Sunitinib base was triturated in toluene at 80-85° for 1-2 hours and Isolated at 25-30° C
and dried at 60° C for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Yield: 6.3 g HPLC Purity: 98.7%
Powdered XRD: Fig. 10 FTIR: Fig. 11 DSC: Principal Peak Max.:237,4 °C (Fig, 12)
Example 6:
Preparation of N-[2-(diethylamino)ethyl]-5-[(5-'fluoro-l,2-dihydro-2-oxo-3H-indol-3-
ylidene)methyl-2,4-dimethyl"lH-pyrrole-3-carboxamide (Sunitinib base of Form-E):
5-Formyl"2,4-dimethyl-lH-pyrrole'3-carboxyIic acid (2-diethylaminoethyl)-amide (5.0 g 0.018
moles) and 5-Fluoro-l,3-dihydro-indol-2-One (2.705 g; 0.018 moles) in isopropyl acetate were
reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for
2-8 hours. The resultant Sunitinib base was triturated in isopropyl acetate at reflux temperature
for N2 hours and isolated at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I)
as orange crystalline solid.
Yield: 5.3 g HPLC Purity: 99.1%
Powdered XRD: Fig. 13 FTIR: Fig. 14 DSC: Principal peak Max. 226.9°C (Fig. 15)

Example 7:
Preparation of N-[2-(diethylamino)ethyl]'5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-
ylidene)methyl-2,4-dimethyl-lH-pyrrole'3-carboxamide (Sunitinib base of Form-F):
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018
moles) and 5-Fluoro-l,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in tetrahydrofuran were
reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for
2-8 hours, The resultant Sunitinib base was triturated in tetrahydrofuran at reflux temperature for
1-2 hours and isolated at 25-30° C and dried at 60° C for 5-20 hours to get Sunitinib base (I) as
orange crystalline solid.
Yield: 2.0 g HPLC Purity: 99.5%
Powdered XRD; Fig. 16 FTIR: Fig, 17 DSC: Peak Max. : 242.5 °C (Fig. 18)
Example 8:
Preparation of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2"Oxo-3H-indoL3-
ylidene)methyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (Sunitinib base of Form-G):
5-Formyl-2,4-dimethyl-=1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018
moles) and 5-Fluoro-l,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in methyl tertiary butyl
ether were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux
temperature for 2-8 hours. The resultant Sunitinib base was triturated in methyl tertiary butyl
ether at reflux temperature for 1-2 hours and isolated at 25-30° C and dried at 60° C for 5-20
hours to get Sunitinib base (I) as orange crystalline solid.
Yield: 6.4 g HPLC Purity: 99.527%
Powdered XRD: Fig. 19 FTIR: Fig. 20 DSC: Principal Peak Max.:240.1 °C (Fig, 21)

We claim:
1. Physical characterization by Powder X-Ray diffraction of crystalline Form-A of
Sunitinib base (I),

Characterized by Powdered X-Ray diffraction pattern having 20 values of 4.6, 9,0, 9.9, 13.1, 15.3, 16.6, 17.8, 19.9, 22.9, 26,0, 27.2, 27.7, 33.0, 34.5, 42.3, 44.4 as shown in Fig. 1 of the drawings accompanying this specification.
2. Physical characterization by FTIR of crystalline Form-A of Sunitinib base (I), characterized by peaks at cm'' values of 3299.8, 1677.0, 1588.6, 1542.2, 1479.0, 1334.1, 1191.5, 860.5, 798.0, 778.4, 668.3, 585.2 as shown in Fig, 2 of the drawings accompanying this specification.
3. Physical characterization by DSC melting point of crystalline Form-A of Sunitinib base (I), having peak maximum at 244.9 °C as shown in Fig. 3 of the drawings accompanying this specification.
4. Novel and stable crystalline Form-B of Sunitinib base (I) characterized by Powder X-Ray diffraction pattern having 26 values of 3.9, 7.8,9,1, 10.3, 11.8, 13.7, 15.9, 16.8, 18.0, 19.0, 20,2, 21.3, 21.9, 22.6, 23.7, 24.4, 26.0, 26.8, 28.1, 29.5, 32.1, 32.5, 33.8, 37.4, 43.1 as shown in Fig. 4 of the drawings accompanying this specification.
5. Novel and stable crystalline Form-B of Sunitinib base (I) characterized by FTIR having peaks at cm"' values of 3290.U 1673.2, 1624.1, 1570.7, 1542.3, 1477.7, 1326.9, 1195.9, 795.5, 667.8, 585.6 as shown in Fig. 5 of the drawings accompanying this specification.
6. Novel and stable crystalline Form-B of Sunitinib base (I) characterized by DSC melting points having principal peak maximum 235.9 °C as shown in Fig. 6 of the drawings accompanying this specification.

7. Novel and stable crystalline Form-C of Sunitinib base (I) characterized by Pounder X-Ray diffraction pattern having 26 values of4.3, 7.7, 8.6, 10.8, 12,9, 13.8, 17.3, 17.8, 19.1, 21.2, 2L5, 22.0, 23.2, 26.2, 27.6, 32.1, 33.9 as shown in Fig. 7 of the drawings accompanying this specification.
8. Novel and stable crystalline Form-C of Sunitinib base (I) characterized by FTIR having peaks at cm'' values of 3299.9, 1674.2, 1626.5, 1565.6, 1537.1, 1476.7, 1326.8, 1199.9, 1144.2, 797.1, 667.6, 606.9, 589.0 as shown in Fig. 8 of the drawings accompanying this specification.
9. Novel and stable crystalline Form-C of Sunitinib base (I) characterized by DSC melting point having principal peak maximum at 223.5 °C as shown in Fig. 9 of the drawings accompanying this specification.
10. Novel and stable crystalline Form-D of Sunitinib base (I) characterized by Powder X-Raydiffractionpatternhaving2evaluesof4.5, 7.7, 9.0, 10.4, 15.1, 16.5, 17.1, 18.4, 19.0, 20.2, 20.8, 21.4, 21.9, 23.1, 25,8, 26.1, 28.0, 29.1, 32.1, 33.0, 33.8, 35.8, 38,6, 46.2, 46.7 as shown in Fig. 10 of the drawings accompanying this specification.
11. Novel and stable crystalline Form-D of Sunitinib base (I) characterized by FTIR having peaks at cm'' values of 3299.2, 1676.0, 1626.5, 1590.5, 1542.1, 1479.0, 1327.7, 1192.4, 860.0, 797.2, 777.9, 668.0, 584,8 as shown in Fig. 11 of the drawings accompanying this specification,
12. Novel and stable crystalline Form-D of Sunitinib base (I) characterized by DSC melting point having principal peak maximum at 237.4 °C as shown in Fig. 12 of the drawings accompanying this specification.
13. Novel and stable crystalline Form-E of Sunitinib base (I) characterized by Powder X-Ray diffraction pattern having 29 values of 4.0, 6.2, 7.3, 7.8, 8.8, 9.3, 9.8, 11.1, 11.8, 12.8, 13.7, 14,6, 15.6, 16.0, 16.6, 17.4, 18.5, 19.1, 20.4, 21.6, 223, 23.3, 24.1, 24.6, 25.4,

25.8, 27.2, 28.1, 29,1, 29.5, 30.9, 31.9, 32.2, 33.3, 34.0, 35.0, 35.8, 36.4, 37.9, 39.3, 39,7,
41.8, 43.9, 48.9 as shown in Fig. 13 of the drawings accompanying this specification.
14. Novel and stable crystalline Form-E of Sunitinib base (I) characterized by FTIR having
peaks at cm"' values of 3431.8, 3169.9, 1674.5, 1622.2, 1578.0, 1477,5, 1325.7, 1196.2,
1144,5, 793.0, 667.9, 586.8 as shown in Fig. 14 of the drawings accompanying this
specification.

15. Novel and stable crystalline Form-E of Sunitinib base (I) characterized by DSC melting points having principal peak maximum 226.94 °C as shown in Fig. 15 of the drawings accompanying this specification,
16. Novel and stable crystalline Form-F of Sunitinib base (I) characterized by Powder X-Ray diffraction pattern having 20 values of 4.5, 9.0, 12,9, 13.6, 15.1, 16.6, 16.9, 18.2, 19.0, 20.4, 21.7, 23 J, 23.6, 25.9, 28.0, 28.9, 29.4, 32.0, 33.8, 38.6, 48.7 as shown in Fig. 16 of the drawings accompanying this specification,
17. Novel and stable crystalline Form-F of Sunitinib base (I) characterized by FTIR having peaks at cm"' values of 3298.7, 3223.8, 1676.4, 1590.1, 1542,2, 1479.3, 1332.8, 1191.6, 797.6, 668.0, 584.5 as shown in Fig. 17 of the drawings accompanying this specification.
18. Novel and stable crystalline Form-F of Sunitinib base (I) characterized by DSC mehing point having peak maximum at 242.5 °C as shown in Fig, 18 of the drawings accompanying this specification.
19. Novel and stable crystalline Form-G of Sunitinib base (I) characterized by Powder X-Ray diffraction pattern having 20 values of 3.0, 4,5, 7,6, 9,1, 9.9, 11.6, 13.5, 15.1, 16.7, 18.4, 19.1, 20.2, 21.7, 23,1, 25,9, 33.9, 40.0 as shown in Fig. 19 of the drawings accompanying this specification.
20. Novel and stable crystalline Form-G of Sunitinib base (I) characterized by FTIR spectral having peaks at cm^' values of 3297.0, 1675,9, 1625.9, 1590.5, 1542.1, 1479.2, 1330.4, 1191.9, 797.1, 668.0, 584.4 as shown in Fig. 20 of the drawings accompanying this specification.
21. Novel and stable crystalline Forra-G of Sunitinib base (I) characterized by DSC melting point having principal peak maximum at 240.1 ""C as shown in Fig. 21 of the drawings accompanying this specification.
22. A process for preparation of novel, stable & crystalline Form-A of Sunitinib base (I), which comprises reaction of 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide and 5-Fluoro-l,3-dihydro-indol-2-one in an organic solvent selected from ethanol, methanol, isopropyl alcohol or n-butanol,
23. A process for preparation of novel, stable & crystalline Form-A of Sunitinib base (I) essentially as described in Example-1 & 2.

24. A process for preparation of novel, stable & crystalline Form-B of Sunitinib base (I), which comprises reaction of 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide and 5-Fluoro-l,3-dihydro-indol-2-one in an organic solvent selected from non-polar organic solvents like n-hexane, n-heptane, n-octane, n-nonane or n-decane.
25. A process for preparation of novel, stable & crystalline Form-B of Sunitinib base (I) essentially as described in Example-3,
26. A process for preparation of novel, stable & crystalline Form-C of Sunitinib base (I), which comprises reaction of 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide and 5-Fluoro-l,3-dihydro-indol-2-one in an organic solvent selected from non-polar organic solvents like cyclopentane, cyclohexane or cycloheptane.
27. A process for preparation of novel, stable & crystalline Form-C of Sunitinib base (I) essentially as described in Example-4.
28. A process for preparation of novel, stable & crystalline Form-D of Sunitinib base (I), which comprises reaction of 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide and 5"Fluoro-l,3-dihydro-indol-2-one in an organic solvent selected from aromatic organic solvents like benzene, toluene or xylenes.
29. A process for preparation of novel, stable & crystalline Form-D of Sunitinib base (I) essentially as described in Example-5.
30. A process for preparation of novel, stable & crystalline Form-E of Sunitinib base (I), which comprises reaction of 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide and 5-Fluoro-l,3-dihydro-indol-2"One in an organic solvent selected from organic solvents like ethyl acetate, methyl acetate or isopropyl acetate.
31. A process for preparation of novel, stable & crystalline Form-E of Sunitinib base (I) essentially as described in Example-6.
32. A process for preparation of novel, stable & crystalline Form-F of Sunitinib base (I), which comprises reaction of 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide and 5-Fluoro-l,3-dihydro-indol-2-one in an organic solvent selected from organic solvents like tetrahydrofuran, 1,4-dioxane.
33. A process for preparation of novel, stable & crystalline Form-F of Sunitinib base (I) essentially as described in Example-7.

34. A process for preparation of novel, stable & crystalline Form-G of Sunitinib base (I), which comprises reaction of 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyL)-amide and 5-Fluoro-l,3-dihydro-indol-2-one in an organic solvent selected from organic solvents like diethyl ether, diisopropyl ether or methyl tertiary butyl ether,
35. A process for preparation of novel, stable & crystalline Form-G of Sunitinib base (I) essentially as described in Example-8.
36. A process for preparation of Sunitinib base polymorphic forms. Form-A, Form-B, Form-C, Form-D, Form-E, Form-F & Form-G, as claimed in claims 22, 24, 26, 28, 30, 32, & 34 wherein optionally a catalyst is employed chosen from ammonia, alkali metal or alkaline earth hydroxides, carbonates, phosphates, bicarbonates and alkali metal hydroxides viz sodium hydroxide, potassium hydroxide or alkaline earth metal hydroxides viz calcium hydroxide, magnesium hydroxide or barium hydroxide, methanolic or ethanolic ammonia, quaternary ammonium salts like tetra butyl ammonium hydroxide, benzyltrimethyl ammonium hydroxide, silica gel, sodium acetate, ammonium acetate or Lewis acids like Boron trifluoride etherate piperidine, piperazine, pyrrolidine, sodium ethoxide, sodium methoxide, para toluene sulfonic acid (PTSA).

To
The Controller of Patents,
Patents Office Chennai Branch
Chennai.