DESC:FIELD OF INVENTION:

The present invention relates to a novel crystalline form of 5-[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl] amino]-2-methyl benzenesulfonamide (pazopanib) and a method of preparation thereof.

BACKGROUND OF INVENTION:

Pazopanib hydrochloride chemically known as 5-[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl] amino]-2-methyl benzenesulfonamide hydrochloride is a pyrimidine derivative. It is known to inhibit angiogenesis. Pazopanib hydrochloride is represented by following structure.

US7105530 discloses pazopanib hydrochloride and methods of preparation thereof wherein pazopanib hydrochloride is isolated from ethyl ether. US7105530 further discloses its use in treatment of disorders associated with inappropriate or pathological angiogenesis.

The journal article ‘Crystalline form of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl) methylamino]-2-pyrimidinyl] amino]-2-methyl-benzolsulfonamide’ from IP.com, IP.com Number: IPCOM000194399D discloses crystalline polymorphic form A of pazopanib.HCl and the preparation thereof.

WO2011058179 discloses free pazopanib base, crystalline polymorphic forms of pazopanib base namely form I and form II characterized by X-ray powder diffractogram and a process for the preparation of pazopanib free base. There are no examples illustrating the preparation of Form II. In Examples 1 and 2, processes for preparing Form I are disclosed. Example 1 involves the use of sodium carbonate as the base. Example 2 involves the use of sodium hydroxide as the base. There is no disclosure of an acid being present in the reaction mass.

WO2011069053 discloses the preparation of pazopanib base. It further provides a characteristic X-ray powder diffractogram of crystalline pazopanib base in Figure 23. Examples 45, 46 and 47 relate to the preparation of pazopanib free base from pazopanib.HCl. All methods involve the use of sodium carbonate as a base. There is no disclosure of an acid being present in the reaction mass. There is no disclosure of the polymorphic nature of the pazopanib free base products formed.

SUMMARY OF THE INVENTION:

The present invention provides novel a crystalline form of pazopanib base designated as Form C and methods of preparing the novel form. The advantage of the process and thus the resulting product include simplicity, eco-friendliness and suitability for commercial use.

According to a first aspect of the present invention, there is provided crystalline Form C of pazopanib base (unless otherwise stated, it will be understood that “pazopanib” refers to pazopanib free base; not a salt thereof). The novel crystalline form of the present invention is characterized at least by a unique XRPD pattern.

The crystalline nature of Form C of pazopanib is preferably characterized by an X-ray powder diffraction pattern comprising a peak at 19.02° 2? ± 0.2° 2?. The XRPD pattern may comprise further peaks at 12.46, 16.56 and 18.44 ° 2? ± 0.2° 2?. The XRPD pattern may comprise yet further peaks at 19.46, 23.2, 25.08 and 27.54 ° 2? ± 0.2° 2?.

Suitably, the crystalline nature of Form C of pazopanib is characterized by an X-ray powder diffraction pattern comprising peaks at 12.46, 16.56, 18.44, 19.02, 19.46, 23.2, 25.08 and 27.54 ° 2? ± 0.2° 2?.
Crystalline Form C of pazopanib may be characterized by having an XRD pattern as shown in Figure 1.

In a further aspect of the present invention, there is provided a process for preparing crystalline Form C of pazopanib. The process of the present invention affords crystalline Form C of pazopanib in high purity and high yield. Advantageously, the novel form is environmentally friendly and suitable for use on a commercial scale.

According to another aspect of the present invention, there is provided a process for preparing crystalline pazopanib Form C as described herein, the process comprising:

(a) preparing a reaction mass comprising a salt of pazopanib and a strong acid;
(b) adding a base to the reaction mass, wherein the temperature of the reaction mass ranges from 20°C to 35°C; and
(c) isolating the crystalline Form C of pazopanib.

Preferably, the salt of pazopanib is the HCl salt.

Preferably, the strong acid is a hydrohalide; preferably HCl.

Preferably, the base is ammonia; more preferably, aqueous ammonia. Preferably, the base is used to adjust the pH of the reaction to a value ranging from 9.5 to 10.5.

Preferably, the temperature of the reaction mass in step (b) ranges from 25°C to 35°C, more preferably from 25°C to 30°C.

Preferably, a solvent is present in the reaction mass. Suitably, the solvent is methanol, ethanol, n-propanol, isopropanol, n-butyl alcohol or t-butyl alcohol. More preferably, the solvent is isopropanol. Preferably, the strong acid is HCl and the solvent is isopropanol.

Suitably, step (a) is carried out at a temperature ranging from 20°C to 35°C; preferably 25°C to 30°C.

Suitably, step (a) may comprise stirring of the reaction mass for a period of time ranging from about 30 minutes to about 5 hours; preferably around 30 minutes to about 2 hours; more preferably for about 45 minutes to about 1.5 hours.

Suitably, step (b) may comprise stirring of the reaction mass after addition of the base for a period of time ranging from about 30 minutes to about 5 hours; preferably around 30 minutes to about 2 hours; more preferably for about 45 minutes to about 1.5 hours.

The isolation may comprise filtration of precipitated Form C and drying under vacuum. The filtered precipitate may be washed with the same solvent used for the reaction. The drying under vacuum may be at a temperature ranging from 65°C to 80°C; preferably 70°C to 75°C.

It will be appreciated that one or more of the above preferable features may be combined. For example, the process may comprise:

(a) preparing a reaction mass comprising pazopanib.HCl, HCl and isopropanol;
(b) adding ammonia to the reaction mass, wherein the temperature of the reaction mass ranges from 20°C to 35°C (typically the pH of the reaction is adjusted to 9.5-10.5); and
(c) isolating the crystalline Form C of pazopanib.

The process may also comprise:
(a) preparing a reaction mass comprising pazopanib.HCl, HCl and isopropanol;
(b) adding ammonia to the reaction mass, wherein the temperature of the reaction mass ranges from 25°C to 30°C, whereby the pH of the reaction is adjusted to 9.5-10.5; and
(c) isolating the precipitated crystalline Form C of pazopanib drying under vacuum at a temperature ranging from 65°C to 80°C.

The pazopanib salt used in step (a) may have been obtained in a number of ways. For example, the salt may be obtained and added as such to the reaction mass (thus, the salt of pazopanib is the starting material in the process).

Alternatively, the salt of pazopanib may be prepared from another synthetic process. Suitably, the salt of pazopanib could be prepared by coupling of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of an acid. The product of the coupling may be isolated before being used in step (a) or may be prepared in situ prior to step (a). Typically, this in situ process (as it shall be referred to) involves:

i. coupling of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of a strong acid and a solvent to form a reaction mass;
ii. adding a base to the reaction mass, wherein the temperature of the reaction mass ranges from 20°C to 35°C; and
iii. isolating the crystalline Form C of pazopanib.

The coupling step will result in the salt of pazopanib, the salt being the acid addition salt based on the strong acid added to the reaction mass. As above, the strong acid may be a hydrohalide; preferably it is HCl.

All the features of steps (b) and (c) as described above may be applied to the in situ process described above. For example, the in situ process may comprise:

i. coupling of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of HCl and isopropanol to form a reaction mass;
ii. adding ammonia to the reaction mass, wherein the temperature of the reaction mass ranges from 20°C to 35°C (typically the pH of the reaction is adjusted to 9.5-10.5); and
(c) isolating the crystalline Form C of pazopanib.

The process may also comprise:
i. coupling of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of HCl and isopropanol to form a reaction mass;
ii. adding ammonia to the reaction mass, wherein the temperature of the reaction mass ranges from 25°C to 30°C, whereby the pH of the reaction is adjusted to 9.5-10.5; and
iii. isolating the precipitated crystalline Form C of pazopanib drying under vacuum at a temperature ranging from 65°C to 80°C.

In step i, the temperature of the reaction mass may range from 20°C to the reflux temperature of the solvent used.

Suitably, step (i) may comprise stirring of the reaction mass for a period of time ranging from about 30 minutes to about 20 hours; preferably around 5 hours to about 20 hours; more preferably for about 10 hours to about 15 hours; most preferably for about 12 hours to about 15 hours.

According to another aspect of the present invention, there is provided crystalline Form C of pazopanib prepared by any one of the processes described herein.

According to another aspect of the present invention, there is provided a process for the preparation of a salt of pazopanib from crystalline Form C of pazopanib. The crystalline Form C of pazopanib is prepared according to a process described herein, then reacted with the appropriate salt to obtain the corresponding acid addition salt of pazopanib. Such a reaction would be well understood by the skilled person. The crystalline Form C of pazopanib may be reacted with HCl to prepare the HCl salt of pazopanib.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form C of pazopanib and one or more pharmaceutically acceptable excipients. The composition may further comprise one or more additional active pharmaceutical ingredients.

According to another aspect of the present invention, there is provided crystalline Form C of pazopanib as described herein for use in medicine.

According to another aspect of the present invention, there is provided crystalline Form C of pazopanib as described herein for use in treating disorders associated with inappropriate or pathological angiogenesis such as advanced renal cell carcinoma.

According to another aspect of the present invention, there is provided the use of crystalline Form C of pazopanib as described herein in the manufacture of a medicament for treating disorders associated with inappropriate or pathological angiogenesis such as advanced renal cell carcinoma.

According to another aspect of the present invention, there is provided a method of treating disorders associated with inappropriate or pathological angiogenesis such as advanced renal cell carcinoma.comprising administering to a patient in need thereof a therapeutically effective amount of crystalline Form C of pazopanib as described above.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: Depicts an X-ray powder diffractogram of crystalline Form C of pazopanib measured on a Instrument Model: DMAX 2200 ; Instrument make : Rigaku
Scanning theta: 3-40 °, 2Theta

Figure 2: Depicts an IR spectrum of crystalline Form C of pazopanib measured on Fourier Transform infrared Spectrometer instrument [Make : Bruker, Model: Alpha] ( AI-66).

Figure 3: Depicts a DSC spectrum of crystalline Form C of pazopanib measured on Instrument Model: DSC -8000; Instrument make: Perkin Elmer.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to novel crystalline form of pazopanib hereinafter referred to as Form C, methods of preparing the novel form and pharmaceutical composition containing it. The advantages of the process include simplicity, eco-friendliness and suitability for commercial use.

Thus, according to a first aspect of the present invention, there is provided crystalline Form C of pazopanib.

The crystalline nature of Form C of pazopanib is preferably characterized by an X-ray powder diffraction pattern comprising a peak at 19.02° 2? ± 0.2° 2?. The XRPD pattern may comprise further peaks at 12.46, 16.56 and 18.44 ° 2? ± 0.2° 2?. The XRPD pattern may comprise yet further peaks at 19.46, 23.2, 25.08 and 27.54 ° 2? ± 0.2° 2?.

Suitably, the crystalline nature of Form C of pazopanib is characterized by an X-ray powder diffraction pattern comprising peaks at 12.46, 16.56, 18.44, 19.02, 19.46, 23.2, 25.08 and 27.54 ° 2? ± 0.2° 2?.

The X-ray powder diffraction pattern of crystalline Form C of pazopanib shown in Figure 1.

In an embodiment, the crystalline Form C of pazopanib has an XRPD pattern with peaks at 2?- values as shown in Table 1.

Diffraction angle (2? –values) Intensity I/Io (%)
9.48 4
9.9 4
10.94 2
12.46 37
13.2 9
14.82 4
15.48 6
15.9 14
16.56 22
16.88 6
17.7 2
18.44 35
19.02 100
19.46 10
19.84 7
21.2 3
21.86 10
22.34 4
23.2 33
23.62 7
24.4 4
25.08 20
25.84 10
26.38 8
27.14 5
27.54 14
28.14 12
28.72 7
32.64 5
36.84 4

Crystalline Form C of pazopanib may have an X-ray diffraction pattern or substantially the same X-ray diffraction pattern as shown in Figure 1.

It will be appreciated that other conventional analytical methods including, but not limited to, infra-red, solid state NMR and Raman spectroscopy may also be employed to characterize the crystalline form of the present invention.

The present invention further provides a in situ method of preparing crystalline Form C of pazopanib as described herein. The method may comprise:
i. coupling of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of a strong acid and a suitable solvent;
ii. treating the reaction mass with a base; and
iii. isolating crystalline Form C of pazopanib.

Preferablty, the process comprises the following steps:
i. coupling of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of a strong acid and a suitable solvent;
ia. stirring the reaction mass for about 30 minutes to about 15 hours at a temperature of about 25°C to the reflux temperature of the solvent used
ii. treating the reaction mass with a base
iia. stirring the reaction mass for a period of time ranging from about 30 minutes to about 5 hours; and
iii. isolating crystalline Form C of pazopanib.

The strong acid employed in the process may be selected from but not limited to hydrochloric acid, hydrobromic acid and sulphuric acid; more preferably hydrochloric acid; most preferably an alcoholic solution of hydrochloric acid. Suitably, the alcohol forming the alcoholic solution of the acid is methanol, ethanol, n-propanol or isopropanol; most preferably isopropanol. Most preferably, the acid is in the form of an isopropanol solution of HCl.

In an alternative embodiment, crystalline Form C of pazopanib may be prepared from a pazopanib salt, which preparation comprises:
stirring a solution of pazopanib salt with hydrochloric acid in a suitable solvent at 25-30°C and treating the reaction mass with a suitable base. The crystalline Form C of pazopanib produced in the reaction solution may be isolated by stirring for about 30 minutes to 5 hours, and isolating the precipitated product.

The pazopanib salt used in preparing the polymorph may be pazopanib hydrochloride.

The suitable solvent may be selected from one or more protic solvents, and one or more water miscible solvents. Suitably the solvent is an alcohol or a ketone; more preferably a lower alkyl (C1-C3) alcohol selected from methanol, ethanol, n-propanol or isopropanol; most preferably isopropanol or ethanol.

The novel polymorph of crystalline Form C of pazopanib obtained according to the present invention is substantially free from other crystals (i.e. crystals having a polymorphic form different to Form C) or non-crystals form (i.e amorphous forms) of pazopanib. “Substantially free” from other forms of pazopanib shall be understood to mean that the polymorph of pazopanib contains less than 10%, preferably less than 5%, of any other forms of pazopanib. The product preferably also contains less than 1% of other impurities, water or solvates.

The process of invention may be used as a method for purifying any form of pazopanib as well as for the preparation of the new polymorphic forms or salts of pazopanib.

In an embodiment the present invention provides, a preparation of pazopanib salt from crystalline Form C of pazopanib wherein, crystalline Form C of pazopanib can be treated with an acid in a suitable solvent to provide pazopanib salt.

The solvent may be selected from protic solvents, such as alcohols and ketones; more preferably lower alkyl alcohol; most preferably methanol.

The invention will now be illustrated further in relation to the following examples without restricting the scope of the invention in any way.

Example 1: Preparation of crystalline Form C of pazopanib

A solution of (15 g) of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine and 5-amino-2-methylbenzenesulfonamide (10.2g) was suspended in 150 ml of isopropanol. To the reaction mass was added 6ml of 20% hydrochloric acid in isopropanol at 25-30° C. The reaction mass was stirred for 12-15 hrs at reflux. The reaction mass was cooled and the pH was adjusted to 9.5 to 10.5 by using aqueous ammonia. The mixture was stirred for 1 hr at 25-30° C. The resulting solid was filtered and washed with isopropanol, followed by drying under vacuum at 70-75 oC to afford 21 g of pazopanib Form C (yield: 91.8%).

Example 2: Preparation of crystalline Form C of pazopanib

(2.5 gm) of Pazopanib hydrochloride (2.5g) was suspended in 25 ml of isopropanol. To the reaction mass was added 1.5ml of 20% hydrochloric acid in isopropanol at 25-30° C. The reaction mass was stirred for 1 hr at 25-30° C. The pH was adjusted to 9.5 to 10.5 by using aqueous ammonia. The mixture was further stirred for 1 hr at 25-30° C. The resulting solid was filtered, washed with isopropanol, followed by drying under vacuum at 70-75 oC to afford 1.9 g of pazopanib Form C (yield: 82.3%).

Example 3: Preparation of Pazopanib HCl from crystalline Form C of pazopanib

Crystalline Form C of pazopanib (2.0 g) was suspended in 30 ml of methanol. To the reaction mass added 4ml of hydrochloric acid in methanol, at 25-30°C. The reaction mass was stirred for 30 min. The resulting solid was filtered, washed with methanol, followed by drying under vacuum at 75-80°C to afford 1.3gm of Pazopanib HCl.

It will be appreciated that the invention may be modified within the scope of the appended claims.
,CLAIMS:We Claim,

1. Crystalline Form C of pazopanib.

2. Crystalline Form C of pazopanib according to claim 1, characterized by having an XRD pattern comprising peak at 19.02° 2?± 0.2° 2?.

3. Crystalline polymorph Form C of pazopanib according to claim 2, characterized by having an XRD pattern comprising further peaks at 12.46, 16.56 and 18.44 ° 2? ± 0.2° 2?.

4. Crystalline polymorph Form C of pazopanib according to claim 3, characterized by having an XRD pattern comprising further peaks at 19.46, 23.2, 25.08 and 27.54 ° 2? ± 0.2° 2?.

5. Crystalline Form C of pazopanib according to claim 1, characterized by having an XRD pattern as shown in Figure 1.

6. Crystalline Form C of pazopanib according to any preceding claim, characterized by having an IR spectrum as shown in Figure 2.

7. Crystalline Form C of pazopanib according to any preceding claim, characterized by having a DSC spectrum as shown in Figure 3.

8. A process for preparing crystalline Form C of pazopanib according to any preceding claim, the process comprising:-

a. coupling of N-(2-chloro-4-pyrimidinyl)-N-2,3-dimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in presence of a strong acid and a suitable solvent.
b. stirring the reaction mass for about 30 minutes to about 15 hours at a temperature of about 25°C to the reflux temperature of the solvent used
c. treating the reaction mass with a base
d. stirring for about 30 minutes to 5 hours and
e. isolating the crystalline Form C of pazopanib

9. A process according to claim 8, wherein the strong acid is selected from but not limited to hydrochloric acid, hydrobromic acid and sulphuric acid.

10. A process according to claim 9, wherein the acid is alcoholic solution of acid.

11. A process for preparing crystalline Form C of pazopanib according to any one of claims 1 to 4, the process comprising, treating a pazopanib salt with hydrochloric acid in a suitable solvent at 25-30°C, treating the reaction mass with a suitable base and stirring for about 30 minutes to 5 hours.

12. A process according to claim 11, wherein the pazopanib salt is pazopanib hydrochloride.

13. A process according to claim 11 or 12, wherein the solvent is selected from water miscible solvents like alcohol, ketones; more preferably lower alkyl alcohol, most preferably isopropanol or ethanol .

14. Crystalline Form C of pazopanib prepared by a process according to any one of claims 8 to 13.

15. A pharmaceutical composition comprising crystalline Form C of pazopanib according to any one of claims 1 to 14, together with one or more pharmaceutically acceptable excipients.

16. Crystalline Form C of pazopanib according to any one of claims 1 to 14 for use in medicine.

17. Crystalline Form C of pazopanib according to any one of claims 1 to 14 for use in treating disorders associated inappropriate or pathological angiogenesis such as advanced renal cell carcinoma.

18. Use of crystalline Form C of pazopanib according to any one of claims 1 to 14 for use in the manufacture of a medicament for treating disorders associated inappropriate or pathological angiogenesis such as advanced renal cell carcinoma.

19. A method of treating disorders associated inappropriate or pathological angiogenesis such as advanced renal cell carcinoma comprising administering to a patient in need thereof a therapeutically effective amount of crystalline Form C of pazopanib according to any one of claims 1 to 14.

20. Crystalline Form C of pazopanib substantially as herein described with reference to the examples.

21. A process substantially as herein described with reference to the examples.

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates