PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM II OF
L-MALIC ACID SALT OF SUNITINIB
Field of the Invention
The present invention relates to stable crystalline Form P of a L-malic acid salt of
sunitinib and a process for the preparation thereof.
Background of the Invention
Sunitinib is chemically described as N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluorol,
2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxarnide 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 the 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-lH-pyrrole-3-carboxamide (1:1).
U.S. Patent Application Nos. 2003/0069298 and 2007/0191458 describe the
preparation of crystalline Forms I and II of L-malic acid salt of sunitinib. According to
these applications, crystalline Form I of L-malic acid salt of sunitinib is prepared by
slurrying a poorly crystalline or crystalline Form II of L-malic acid salt of sunitinib in
acetonitrile. Crystalline Form II of the 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 IP and IV of
sunitinib L-malate.
WO 2009/104021 describes that Form II of sunitinib L-malate is hygroscopic,
thermodynamically unstable and appears to readily convert to Form I.
Summary of the Invention
In one general aspect, the present invention provides for a stable crystalline Form
II of L-malic acid salt of sunitinib.
Embodiments of this aspect may include one or more of the following aspects. For
example, the stable crystalline Form II of L-malic acid salt does not convert into any other
solid form on storage of about 20 days or more. The stable crystalline Form P of L-malic
acid salt absorbs moisture to a level of not more than about 2%.
In another general aspect, the present invention provides for a process for the
preparation of crystalline Form II of L-malic acid salt of sunitinib. The process includes:
a) charging a solution of L-malic acid salt of sunitinib in a solvent to a spray
dryer;
b) removing the solvent from the solution obtained in step a) by spray drying; and
c) collecting crystalline Form P of L-malic acid salt of sunitinib from the spray
dryer.
Embodiments of this aspect may include one or more of the following features.
For example, the solvent may be water, an alkanol, such as methanol, or a mixture thereof.
Brief Description of the Drawings
Figure 1 depicts the X-ray powder diffraction pattern (XRPD) of the stable
crystalline Form II of L-malic acid salt of sunitinib.
Figure 1A provides table of values for the XRPD pattern depicted in Figure 1.
Figure 2 depicts the X-ray powder diffraction pattern (XRPD) of the stable
crystalline Form P of L-malic acid salt of sunitinib after the storage of 24 days.
Figure 2A provides table of values for the XRPD pattern depicted in Figure 2.
Detailed Description of the Invention
The term "L-malic acid salt of sunitinib" includes a combination of sunitinib and .
L-malic acid in any molar ratio between about 1:0.75 and about 1:1.5.
The term "charging", according to the present invention, includes loading, filling,
introducing, pouring, infusing and/or adding.
The term "collecting", according to the present invention, includes unloading,
gathering and/or scaling.
The present invention provides a stable crystalline Form II of L-malic acid salt of
sunitinib. The stable crystalline Form II of L-malic acid salt of sunitinib has an XRPD
pattern wherein the characteristic 2Qvalues are obtained substantially at 3.08 ± 0.2, 6.14 +
0.2, 7.77 + 0.2, 9.23 + 0.2, 12.24 + 0.2, 14.55 + 0.2, 22.58 ± 0.2, 24.08 + 0.2 and 27.03 +
0.2 degree 2Q. The stable crystalline Form II of L-malic acid salt does not convert into
any other solid form upon storage for about 20 days or more. The stable crystalline Form
II of L-malic acid salt absorbs moisture to a level of not more than about 2%, for example,
not more than between about 1% to about 1.5%.
The present invention also provides for a process for the preparation of crystalline
Form II of L-malic acid salt of sunitinib. The process includes:
a) charging a solution of L-malic acid salt of sunitinib in a solvent to a spray
dryer;
b) removing the solvent from the solution obtained in step a) by spray drying; and
c) collecting crystalline Form P of L-malic acid salt of sunitinib from the spray
dryer.
L-Malic acid salt of sunitinib existing in any solid form prepared by any method
known in literature, for example, U.S. Patent Nos. 6,573,293 and 7,125,905; and WO
2004/012776 may be used for preparing the solution of L-malic acid salt of sunitinib in a
solvent.
The solution of L-malic acid salt of sunitinib in a solvent may also be prepared by
dissolving sunitinib base and L-malic acid in a solvent. The solvent may be water or an
alkanol, for example, methanol, or a mixture thereof. The solution may optionally be
filtered prior to charging to the spray dryer. The inlet and outlet temperatures, feed rate,
and atomizer type may be adjusted to optimize output and particle size. The air inlet
temperature may be controlled from about 60°C to about 150°C, for example, about 100°C
to about 140°C. The outlet temperature may be controlled from about 30°C to about 80°C,
for example, about 50°C to about 70°C. An inert gas, for example, nitrogen gas can be
used as a carrier gas. After spray drying, the crystalline Form II of L-malic acid salt of
sunitinib is collected from the spray dryer and optionally further dried under vacuum to
remove the residual solvents. The crystalline Form P of L-malic acid salt of sunitinib so
obtained is stable and has substantially the same XRPD pattern as depicted in Figure 1.
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.
EXAMPLE
Example 1: Preparation of Stable Crystalline Form Ii of L-Malic Acid Salt of Sunitinib
L-Malic acid salt of sunitinib (3 g) was dissolved in water (300 ml) at 40°C. The
solution was filtered, cooled to 20° to 25°C, and charged to a spray dryer (BUCHI mini
spray dryer B-290) at feed pump RPM of 7. The following parameters were controlled in
the spray drying process:
Nozzle Diameter: 0.7 mm
Carrier gas: Nitrogen at 2.0 to 2.5 kg/cm2
Air inlet temperature: 130°C
Outlet temperature: 60°C
Aspiration: 70 %
Type of atomizer: Co current flow (also known as to fluid pressure nozzle)
The solvent was evaporated at a temperature of about 60°C to about 65°C through
spray drying. The solid so obtained was collected from the spray dryer to obtain the title
compound having an XRPD pattern as depicted in Figure 1 initially and an XRPD pattern
as depicted in Figure 2 after storage at 20°C to 25°C for 24 days.
Yield: 1.5 g
Moisture content by KF: 4.48% (initial)
Moisture content by KF: 5.52% (after storage at 20°C to 25°C for 60 days)

We claim:
1. A stable crystalline Form II of L-malic acid salt of sunitinib.
2. A stable crystalline Form II of L-malic acid salt of sunitinib according to claim 1,
wherein the stable crystalline Form II of L-malic acid salt does not convert into any other
solid form on storage of about 20 days or more.
3. A stable crystalline Form Pof L-malic acid salt of sunitinib according to claim 1,
wherein the stable crystalline Form II of L-malic acid salt absorbs moisture to a leve of
not more than about 2%.
4. A process for the preparation of crystalline Form II of L-malic acid salt of
sunitinib, wherein the process comprises:
a) charging a solution of L-malic acid salt of sunitinib in a solvent to a spray
dryer;
b) removing the solvent from the solution obtained in step a) by spray drying; and
c) collecting crystalline Form Pof L-malic acid salt of sunitinib from the spray
dryer.
5. A process according to claim 4, wherein the solvent is water, an alkanol, or a
mixture thereof.
6. A process according to claim 5, wherein the alkanol is methanol.