HK1161593A - Crystalline forms of a 3-pyrrole substituted 2-indolinone malate salt - Google Patents

Description

Crystalline form of 3-pyrrole substituted 2-indolone malate

Cross reference to related applications

This patent application claims the benefit of U.S. provisional patent application No. 61/083,330, filed on 24/7/2008, incorporated by reference.

Background

Sunitinib (Compound I) is (Z) -N- [2- (diethylamino) ethyl]-5- [ (Z) - (5-fluoro-1, 2-dihydro-2-oxo-3H-indol-3-ylidene) methyl]-2, 4-dimethyl-1H-pyrrole-3-carboxamide is the internationally generally accepted name and has an empirical formula of C₂₂H₂₇N₄O₂F, molecular weight 398.47 g/mol. Sunitinib is an active pharmaceutical substance for abnormal cell growth, such as cancer treatment, in mammals, especially humans.

The malate salt of sunitinib has been selected for medical purposes and used as SUTENT^TMCommercially available under the trade name of renal cell carcinoma and gastrointestinal stromal tumors.

Sunitinib base and its malate salt, as used by reference, are described in U.S. patent No. 6.573.293 ("the 293 patent"), which is incorporated by reference in this patent application. In particular, example 80 of the' 293 patent discloses the preparation of sunitinib base.

U.S. patent application publication No. 2007/0191458a1 ("publication No. 458"), which is incorporated herein by reference, discloses several formulations of sunitinib malate. The crystalline form of sunitinib obtained from the process disclosed in the '458 publication' was characterized by powder X-ray diffraction (XRD) and thermal methods and was referred to as crystalline forms I and II.

International patent application publication No. WO 2009/067686A 2 ("686 publication") discloses sunitinib polymorphic racemic malic acid (forms A and B), sunitinib polymorphic semi-L-malic acid (forms E and U), and several compositions of ingredients containing sunitinib and L-malic acid (compositions: C, F to R, V-A to V-C and V-S) or racemic malic acid (composition: V-T), and processes for their preparation.

Polymorphism is defined as the ability of a substance to exist in two or more crystal phases having different molecular arrangements and/or configurations in the crystal lattice. Polymorphism is usually different in its physical properties, such as: melting point, solubility, and chemical reactivity. Thus, the particular properties of the respective polymorph can significantly affect the solubility curve, e.g., dissolution rate, of a chemical species. Furthermore, the particular properties of the respective polymorph can significantly influence pharmaceutical properties, such as dissolution rate and bioavailability.

In addition, a pharmaceutical compound in a crystalline form is preferred over the amorphous form in several respects. For example, the compounds can be easily purified by crystallization and recrystallization. Crystallization is a cheaper and more traditional large-scale purification method than some other purification methods, such as chromatography. In addition, crystalline forms are generally more stable than amorphous forms both before formulation and during subsequent storage.

Therefore, it is desirable to identify and isolate sunitinib malate in various crystalline polymorphic forms. Second, it would be desirable to have a reliable process for producing sunitinib malate in one or more polymorphic forms of sunitinib malate. In addition, various polymorphic forms of sunitinib malate may be used to prepare improved pharmaceutical compositions.

In view of the foregoing, there is a short-felt need for new polymorphic forms of sunitinib malate. In addition, there is a short-felt need for new processes for preparing crystalline sunitinib malate and pharmaceutical compositions comprising crystalline sunitinib malate.

Summary of The Invention

The present invention provides crystalline polymorphic forms of (Z) -N- [2- (diethylamine) ethyl ] -5- [ (5-fluoro-1, 2-dihydro-2-oxo-3H-indol-3-ylidene) methyl ] -2, 4-dimethyl-1H-pyrrole-3-amide malate salt of sunitinib malate. The invention also provides a preparation process of crystalline polymorphic sunitinib malate. The invention further provides a pharmaceutical composition containing crystalline polymorphic sunitinib malate.

Brief description of the drawings

Figure 1 depicts the X-ray powder diffraction pattern (XRD) of sunitinib L-malate obtained according to the process of example 1.

Figure 2 depicts an Infrared (IR) spectrum of sunitinib type III L-malate obtained according to the process of example 1.

Figure 3 depicts the XRD pattern of sunitinib form III L-malate obtained according to the process of example 2.

Figure 4 depicts an IR spectrum of sunitinib form III L-malate obtained according to the process of example 2.

Figure 5 depicts the XRD pattern of sunitinib L-malate form IV obtained according to the process of example 3.

Figure 6 depicts an IR spectrum of sunitinib L-malate form IV obtained according to the process of example 3.

Figure 7 depicts the XRD pattern of sunitinib L-malate form V obtained according to the process of example 4.

Figure 8 depicts an IR spectrum of sunitinib L-malate form V obtained according to the process of example 4.

Figure 9 depicts an XRD pattern of sunitinib L-malate form VI obtained according to the process of example 5.

Figure 10 depicts an IR spectrum of sunitinib L-malate form VI obtained according to the process of example 5.

Figure 11 depicts an XRD pattern of sunitinib L-malate VII obtained according to the process of example 6.

Figure 12 depicts an IR spectrum of sunitinib L-malate form VII obtained according to the process of example 6.

Figure 13 depicts XRD patterns of low crystalline sunitinib L-malate obtained after storage of sunitinib L-malate form IV for a period of time at standard state.

Description

Applicants have discovered crystalline sunitinib malate, i.e., sunitinib hemimalate. These forms of sunitinib malate have been prepared and characterized and are referred to as forms III, IV, V, VI and VII.

In addition, a selected group of crystalline sunitinib malate forms of the present invention, i.e., forms III and V, have been found to be highly stable in polymorphic form, thereby making them suitable for pharmaceutical formulation purposes.

The present invention provides crystalline polymorphic forms of (Z) -N- [2- (diethylamine) ethyl ] -5- [ (5-fluoro-1.2-dihydro-2-oxo-3H-indol-3-ylidene) methyl ] -2, 4-dimethyl-1H-pyrrole-3-carboxamide sunitinib malate salt, crystalline forms III, IV, V, VI and VII. The invention also provides a preparation process of the crystalline sunitinib malate. The invention further provides pharmaceutical compositions containing crystalline sunitinib malate forms III, IV, V, VI and VII.

According to the invention, sunitinib malate may be D-malate, D, L-malate; l-malate or a combination thereof. The sunitinib malate is preferably L-malate.

The invention provides sunitinib malate polymorphic form III (hereinafter referred to as sunitinib malate millime).

Figure 3 depicts an X-ray powder diffraction pattern (2 θ) for sunitinib malate form III showing characteristic peaks at approximately 5.7, 13.1, 15.9, 16.0, 17.5, 18.3, 19.3, 25.7, and 26.6 °, and other peaks at 9.6, 11.4, 13.8, 17.8, 20.9, 22.6, 27.5, 28.6, and 29.4 ° (± 0.2 °).

FIG. 4 depicts an infrared spectrum of sunitinib malate form III, shown at approximately 3226.3, 2978.7, 1679.3, 1627.6, 1586.5, 1526.4, 1477.9, 1440.5, 1326.8, 1290.7, 1259.4, 1230.8, 1196.8, 1145.2, 1050.2, 841.2, 792.8, 774.1, 666.9, 614.3 and 588.3cm^-1Characteristic absorption bands are present, and at 1101.2, 966.4, 921.0, 901.0, 876.8, 444.1 and 418.6cm^-1Other absorption bands are present.

Crystalline sunitinib malate form III of the present invention has been found to be highly stable when polymorphic. For example, a sample of sunitinib type III malate is stored under standard conditions (i.e., room temperature, standard pressure, and atmospheric environment) for a period of time, e.g., at least one year, and tested for its crystalline stability. The X-ray powder diffraction (XRD) pattern obtained is essentially the same as the XRD pattern depicted in figure 3.

The invention also provides a method for preparing crystalline sunitinib malate form III, comprising: i) mixing sunitinib malate with a selected solvent to form a suspension or solution, and ii) separating the solvent from said mixture to form crystalline sunitinib malate form III.

In a preferred embodiment, the solvent may comprise ethanol.

According to an embodiment of the invention, step i) may be carried out at a temperature of about 0 ℃ to 200 ℃.

For the consistency of the invention, step ii) may be carried out by filtration of the suspension or evaporation.

In still another preferred embodiment, the method of the present invention for preparing crystalline sunitinib malate form III comprises: i) in the presence of at least one C₁-C₅A solution of sunitinib malate in a solvent comprising an alcohol, ii) or precipitating sunitinib malate form III polymorph from the solvent to form a suspension, and III) separating the solvent.

In a preferred embodiment, the solvent for preparing crystalline sunitinib malate form III is free or substantially free of water. For example, the solvent for preparing crystalline sunitinib malate form III contains less than 1%, less than 0.5%, or less than 0.2% water.

In the most preferred embodiment, the ethanol solvent comprises at least one C₁-C₅An alcohol.

In a particularly preferred embodiment, the solvent for preparing crystalline sunitinib malate form III is absolute ethanol containing no more than 0.5% water.

For the present invention to be consistent, the solvent separation of step iii) comprises filtration of the suspension of step ii). In an alternative embodiment, the solvent separation of step iii) comprises solvent evaporation.

The sunitinib malate for preparing sunitinib malate form III can be sunitinib malate obtained by any suitable method, and can also be crystalline sunitinib malate form I, II, IV, V, VI, VII, or a mixture thereof.

The invention also provides sunitinib malate polymorphic form IV (hereinafter referred to as sunitinib malate form IV).

Fig. 5 depicts an X-ray powder diffraction pattern (2 θ) of sunitinib malate form IV showing characteristic peaks at approximately 6.2, 10.4, 15.1, 15.9, 17.7, 18.6, 26.0, 26.5, and 27.5 ° and other peaks at 8.3, 12.5, 19.9, 21.6, 23.6, and 25.2 ° (± 0.2 °).

FIG. 6 depicts an infrared spectrum of sunitinib malate form IV, shown at approximately 3220.2, 3034.9, 1677.6, 1622.8, 1586.3, 1519.8, 1479.0, 1440.6, 1327.1, 1288.1, 1259.9, 1231.9, 1195.8, 1146.3, 1127.6, 1093.6, 1043.2, 956.1, 841.1, 792.2, 775.4, 667.1, 609.5 and 588.1cm^-1When present, characteristic absorption bands, and at 897.8, 819.7, 697.8 and 443.1cm^-1Other absorption bands are present.

In the invention, sunitinib IV malate is found to lose crystallinity with the passage of time. For example, sunitinib IV malate samples are stored for a period of time, e.g., at least one year, under standard conditions (i.e., room temperature, atmospheric pressure, and ambient atmosphere) and then the crystallization stability is re-examined. Fig. 13 depicts the X-ray powder diffraction pattern (XRD) obtained.

The invention also provides a method for preparing sunitinib malate form IV, comprising: i) mixing sunitinib malate with a selected solvent to form a suspension or solution, and ii) separating the solvent from the mixture to form sunitinib malate form IV.

In a preferred embodiment, the solvent may comprise dimethyl sulfoxide (DMSO).

According to an embodiment of the invention, step i) may be carried out at a temperature of about 0 ℃ to 200 ℃.

For the consistency of the invention, step ii) can be carried out by filtration or evaporation of the suspension.

The sunitinib malate for preparing sunitinib malate form IV can be sunitinib malate obtained by any suitable method, and can also be crystalline sunitinib malate form I, II, III, V, VI, VII, or a mixture thereof.

The invention also provides sunitinib malate polymorphic form V (hereinafter referred to as sunitinib malate form V).

Fig. 7 depicts an X-ray powder diffraction pattern (2 θ) of sunitinib malate form V, showing the presence of characteristic peaks at approximately 11.2, 15.1, 16.5, 17.9, 18.2, 18.8, 21.9, 24.0, and 29.8 ° (± 0.2 °).

FIG. 8 depicts an infrared spectrum of sunitinib malate form V, shown at approximately 3459.6, 3207.1, 2999.3, 2672.3, 1649.0, 1627.3, 1574.1, 1519.5, 1473.5, 1402.7, 1388.1, 1326.3, 1277.4, 1261.1, 1234.4, 1201.0, 1177.9, 1148.1, 1048.9, 1034.5, 875.6, 840.3, 794.4, 738.1, 717.3, 664.8, 612.1, 588.6, 557.4, and 452.4cm^-1Characteristic absorption bands are present, and at 1361.5, 1095.8, 1071.5, 1012.8, 982.1 and 923.4cm^-1Other absorption bands are present.

Sunitinib malate form V was found in the present invention to be extremely stable with respect to polymorphism. For example, sunitinib malate form V samples are stored for a period of time, e.g., at least one year, under standard conditions (i.e., room temperature, atmospheric pressure, and ambient atmosphere) and then the crystallization stability is re-examined. The X-ray powder diffraction pattern (XRD) obtained was substantially the same as the XRD described in fig. 7.

The invention also provides a method for preparing sunitinib malate crystal form V, which comprises the following steps: i) forming a solution or suspension of sunitinib malate in a selected solvent, and ii) separating the solvent from said mixture to form crystalline sunitinib malate form V.

In a preferred embodiment, the solvent may comprise a mixture of butanol and water.

According to an embodiment of the invention, step i) may be carried out at a temperature of about 0 ℃ to 200 ℃.

For the consistency of the invention, step ii) can be carried out by filtration or evaporation of the suspension.

In a particularly preferred embodiment, the method of the present invention for preparing sunitinib malate form V comprises: i) in the presence of at least one C₁-C₅Forming a sunitinib malate solution in a solvent of alcohol and water, ii) alternatively, precipitating sunitinib malate form V polymorph to form a suspension, and iii) separating off the solvent.

For the sake of keeping the invention consistent, at least one C is included₁-C₅The solvent of the mixed solution of alcohol and water should contain at least one C₁-C₅A mixture of an alcoholic solvent and up to 50% (v/v) water, preferably containing at least one C₁-C₅The solvent of the mixed solution of alcohol and water should contain at least one C₁-C₅A mixture of an alcohol solvent and up to 20% (v/v) water.

In a particularly preferred embodiment, the butanol solvent comprises at least one C₁-C₅An alcohol.

According to an embodiment of the invention, the solvent separation of step iii) comprises filtration of the suspension of step ii). In an alternative embodiment, the solvent separation of step iii) comprises solvent evaporation.

The sunitinib malate for preparing sunitinib malate form V can be sunitinib malate obtained by any suitable method, and can also be crystalline sunitinib malate form I, II, III, IV, VI, VII, or a mixture thereof.

In certain embodiments, the present invention provides sunitinib form VI (hereinafter referred to as sunitinib malate form VI).

Fig. 9 depicts an X-ray powder diffraction pattern (2 θ) of sunitinib malate form VI showing characteristic peaks at approximately 8.1, 9.3, 13.0, 15.4, 19.2, 22.0, 24.1, 25.3, 27.4, and 27.7 °, and other peaks at 12.5, 13.8, 15.8, 16.9, 18.8, 19.7, 20.2, 21.6, and 24.6 ° (± 0.2 °).

FIG. 10 depicts an infrared spectrum of sunitinib malate form VI, shown at approximately 3327.7, 3225.2, 2984.6, 1677.0, 1634.7, 1572.6, 1528.5, 1478.6, 1441.2, 1326.8, 1260.6, 1230.5, 1192.4, 1146.9, 1096.1, 1028.2, 797.9, 663.6, 606.5, and 585.4cm^-1Characteristic absorption bands are present, and 925.1, 883.2, 858.5, 773.8, 695.4, 445.4 and 413.4cm^-1Other absorption bands are present.

Sunitinib malate form VI is found in the present invention to be a known sunitinib malate form I and at least one unknown crystalline mixture.

Additionally, a sunitinib malate form VI sample (i.e., a mixture of sunitinib malate form I and at least one unknown crystalline form) is stored under standard conditions (i.e., room temperature, atmospheric pressure, and ambient atmosphere) for a period of time, e.g., at least one year, and then the crystalline stability is re-examined. The X-ray powder diffractogram (XRD) obtained shows a clear transition from the unknown crystalline form to the known form I.

The invention also provides a method for preparing sunitinib malate crystalline form VI, comprising: i) mixing sunitinib malate with a selected solvent to obtain a suspension or solution, and ii) separating the solvent from said mixture to form crystalline sunitinib malate form VI.

In a preferred embodiment, the solvent may comprise nitromethane, Dimethylformamide (DMF), and mixtures thereof.

According to an embodiment of the invention, step i) may be carried out at a temperature of about 0 ℃ to 200 ℃.

For the consistency of the invention, step ii) can be carried out by filtration or evaporation of the suspension.

The sunitinib malate for preparing sunitinib malate form VI can be sunitinib malate obtained by any suitable method, and can also be crystalline sunitinib malate form I, II, III, IV, V, VII, or a mixture thereof.

In certain embodiments, the present invention provides sunitinib malate polymorphic form VII (hereinafter referred to simply as sunitinib malate form VII).

Fig. 11 depicts an X-ray powder diffraction pattern (2 θ) of sunitinib malate form VII, showing characteristic peaks at approximately 6.1, 9.4, 12.8, 16.1, 19.2, 22.1, 24.1, and 25.3 °, and other peaks at 7.4, 15.1, 16.7, and 40.5 ° (± 0.2 °).

FIG. 12 depicts an infrared spectrum of sunitinib malate form VII, shown at approximately 3326.8, 3229.6, 2984.4, 1674.0, 1634.1, 1572.9, 1528.2, 1477.5, 1439.6, 1322.4, 1277.5, 1255.8, 1229.4, 1194.5, 1146.6, 1095.5, 1027.2, 859.6, 797.6, 694.1, 663.3, 605.1, 585.3, and 446.4cm^-1When present, characteristic absorption bands, and 921.6, 883.6, 737.6, and 418.5cm^-1Other absorption bands are present.

Sunitinib malate form VII is found in the present invention to be a mixture of known sunitinib malate form I and at least one unknown crystalline form.

Additionally, a sunitinib malate form VII sample (i.e., a mixture of sunitinib malate form I and at least one unknown crystalline form) is stored under standard conditions (i.e., room temperature, atmospheric pressure, and ambient atmosphere) for a period of time, e.g., at least one year, and then the crystalline stability is re-examined. The X-ray powder diffraction pattern (XRD) obtained shows a clear transition from the unknown crystalline form to the known form I.

The present invention also provides a process for preparing crystalline sunitinib malate form VII, comprising: i) mixing sunitinib malate with a selected solvent to form a suspension or solution, and ii) separating the solvent from said mixture to form crystalline sunitinib malate form VII.

In a preferred embodiment, the solvent may comprise 2, 2, 2-trifluoroethanol.

According to an embodiment of the invention, step i) may be carried out at a temperature of about 0 ℃ to 200 ℃.

For the consistency of the invention, step ii) can be carried out by filtration or evaporation of the suspension.

The sunitinib malate for preparing sunitinib malate form VII can be sunitinib malate obtained by any suitable method, and can also be crystalline sunitinib malate form I, II, III, IV, V, VI, or a mixture thereof.

In other embodiments, the present invention provides pharmaceutical compositions comprising any of crystalline form III, sunitinib malate form IV, V, VI and VII, or mixtures thereof. For example, in one embodiment, the pharmaceutical composition of the present invention comprises any crystalline sunitinib malate form III. In another embodiment, the pharmaceutical composition of the present invention comprises any crystalline sunitinib malate form IV. Similarly, crystalline form V, VI and sunitinib malate VII can be used to form pharmaceutical compositions, respectively.

In keeping with the embodiments of the present invention, the pharmaceutical composition of the present invention includes an associated pharmaceutical carrier.

The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

Using a vertical goniometer, a copper anode tube and radioactive rays CuK_α，The RX SIEMENS D5000 diffractometer of (1) obtained an XRD diffractogram.

Fourier transform infrared spectra were obtained on a pyroelectric high force Nexus spectrometer. The polymorph is characterized as potassium bromide pellets.

Example 1: and (3) preparing sunitinib malate I.

This example describes a process for the preparation of sunitinib L-malate form I.

Sunitinib (13 g) was suspended in 2L of methanol at ambient temperature and L-malic acid (4.7 g) was added. The mixture was stirred for 30 minutes and then concentrated to dryness under vacuum. Acetonitrile (500mL) was added and the mixture was stirred at 70 ℃ for one hour. After cooling to ambient temperature, the solid was collected by filtration and dried under vacuum at 40 ℃ for 48 hours.

Analyzing data: x-ray diffractometer: form I is shown in figure 1; the infrared ray is shown in fig. 2.

Example 2: and (3) preparing sunitinib malate III.

This example describes a process for the preparation of sunitinib L-malate form III, according to a certain embodiment of the invention.

Sunitinib malate (100mg) was dissolved in 20mL of ethanol in the reflectance state. After cooling to ambient temperature, the solid was collected by filtration and dried at ambient temperature.

Analyzing data: x-ray diffractometer: form III is shown in FIG. 3; the infrared ray is shown in fig. 4. Fig. 3 shows a ray diffraction pattern of crystalline form III L-sunitinib malate, and fig. 4 shows an infrared spectrum.

Example 3: and (3) preparing sunitinib malate IV.

This example describes a process for the preparation of sunitinib L-malate form IV, according to a certain embodiment of the invention.

Sunitinib malate (100mg) was dissolved in dimethyl sulfoxide (DMSO) (1mL) under heating. After cooling to ambient temperature, the mixture was stirred for 24 hours and then concentrated under vacuum at 40 ℃ for 4 weeks.

Analyzing data: x-ray diffractometer: form IV is shown in FIG. 5; the infrared ray is shown in fig. 6. Fig. 5 shows a ray diffraction pattern of crystalline form IV sunitinib L-malate, and fig. 6 shows an infrared spectrum.

Example 4: and (3) preparing the sunitinib malate form V.

This example describes a process for the preparation of sunitinib L-malate form V, according to a certain embodiment of the invention.

Sunitinib base (130mg) was dissolved in aqueous butanol at 80 ℃ in a ratio of 80: 20. L-malic acid (47mg) was added and after 10 minutes at 80 ℃ the mixture was cooled to ambient temperature. The solid was filtered and dried under vacuum at 40 ℃ for 72 hours.

Analyzing data: x-ray diffractometer: the V form is shown in figure 7; the infrared ray is shown in fig. 8. Fig. 7 shows a ray diffraction pattern of crystalline form V L-sunitinib malate, and fig. 8 shows an infrared spectrum.

Example 5: and (3) preparing sunitinib malate IV.

This example describes a process for the preparation of sunitinib L-malate form VI, according to a certain embodiment of the invention.

Sunitinib malate (100mg) was dissolved in nitromethane (10mL) under heating. After cooling to ambient temperature, the mixture was stirred for 24 hours and the solution was evaporated.

Analyzing data: x-ray diffractometer: form VI is shown in figure 9 (i.e., a mixture of known sunitinib malate form I and at least one unknown crystalline form). The infrared ray is shown in fig. 10. Figure 9 shows an X-ray diffraction pattern of crystalline form VI L-sunitinib malate, and figure 10 shows an infrared spectrum.

Example 6: and (3) preparing sunitinib malate VII.

This example describes a process for the preparation of sunitinib L-malate form VII, according to an embodiment of the invention.

Sunitinib malate (100mg) was dissolved in 2, 2, 2-trifluoroethanol (1mL) under heating. After cooling to ambient temperature, the mixture was stirred for 24 hours and then concentrated under vacuum at 40 ℃ for 2 weeks.

Analyzing data: x-ray diffractometer: form VII is shown in fig. 11 (i.e., a mixture of known sunitinib malate form I and at least one unknown crystalline form); the infrared spectrum is shown in FIG. 12. The ray diffraction pattern of crystalline sunitinib form VII is shown in fig. 11, and the infrared spectrum is shown in fig. 12. And (3) preparing sunitinib malate VII.

Examples 7 to 9: other formulations of sunitinib malate polymorph.

This example describes a process for the preparation of sunitinib L-malate form VI, according to an embodiment of the invention.

Sunitinib malate (100mg) was dissolved by heating in the solvent shown in the following table. After cooling to ambient temperature, the mixture was stirred for 24 hours and then concentrated in vacuo at 40 ℃.

TABLE 1

Examples of the invention	Solvent(s)	Volume of	XRD results
				7	Dimethylformamide (DMF)	1	Type VI
8	2-methoxy ethanol	1	Type I
				9	Dimethylacetamide (DMA)	1.5	Type I

Analytical data for example 7: x-ray diffractometer: form VI is shown in figure 9 (i.e., a mixture of known sunitinib malate form I and at least one unknown crystalline form). Figure 9 shows an X-ray diffraction pattern of crystalline form VI sunitinib L-malate, figure 10 shows an IR spectrum.

Analytical data for examples 8 and 9: x-ray diffractometer: the infrared rays are shown in FIG. 1; figure 1 shows an X-ray diffraction pattern of crystalline form I L-sunitinib malate, and figure 2 shows an infrared spectrum.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (14)

1. Sunitinib malate polymorphic form III having an X-ray powder diffraction pattern (2 Θ) having characteristic peaks at approximately 5.7, 13.1, 15.9, 16.0, 17.5, 18.3, 19.3, 25.7, 26.1 and 26.6 degrees.

2. Sunitinib malate polymorphic form III according to claim 1, having an X-ray powder diffraction pattern (2 Θ) with additional characteristic peaks at about 9.6, 11.4, 13.8, 17.8, 20.9, 22.6, 27.5, 28.6 and 29.4 degrees.

3. A process according to claim 1 or 2 for the preparation of sunitinib malate polymorphic form III, the process comprising:

i) at least one kind of C₁-C₅Forming a sunitinib malate solution in a solvent comprising an alcohol;

ii) alternatively, precipitating the sunitinib malate polymorphic form III from the solution to form a suspension; and

iii) removing the solvent.

4. The process of claim 3 wherein at least one C₁-C₅The alcohol is ethanol.

5. The process of claim 3, wherein removing the solvent comprises filtering the suspension of step ii).

6. The process of claim 3, wherein removing the solution comprises solvent evaporation.

7. Sunitinib malate polymorphic form V has an X-ray powder diffraction pattern (2 Θ) having characteristic peaks at approximately 11.2, 15.1, 16.5, 17.9, 18.2, 18.8, 21.9, 24.0, and 29.8 degrees.

8. The process of claim 7 for preparing sunitinib malate polymorphic form V, the process comprising:

i) at least one kind of C₁-C₁Forming a sunitinib malate solution in a solvent comprising alcohol and water;

ii) alternatively, precipitating the crystalline sunitinib malate form V to form a suspension; and

iii) removing the solvent.

9. The process of claim 8 wherein the solvent comprises up to about 50% (v/v) water.

10. The process of claim 9, wherein the solvent comprises about 20% (v/v) water.

11. The process of any one of claims 8 to 10 wherein at least one C₁-C₁The alcohol is butanol.

12. The process of claim 8, wherein removing the solvent comprises filtering the suspension of step ii).

13. The process of claim 8, wherein removing the solution comprises solvent evaporation.

14. The pharmaceutical composition consists of sunitinib malate polymorphic form according to any one of claims 1, 2 or 7.