WO2011058179A1

WO2011058179A1 - 5- (4- (n- (2, 3 -dimethyl- 2h- indazol- 6 -yl) -n-methylamino) pyrimidin- 2 -ylamino) -2 -methylbenzenesulfonamide

Info

Publication number: WO2011058179A1
Application number: PCT/EP2010/067504
Authority: WO
Inventors: Ramesh Matioram Gidwani; Channaveerayya Hiremath
Original assignee: Ratiopharm Gmbh
Priority date: 2009-11-16
Filing date: 2010-11-15
Publication date: 2011-05-19

Abstract

The present invention relates to novel forms of Pazopanib and a process for their preparation.

Description

5- (4- (N- (2, 3 -DIMETHYL- 2H- INDAZOL- 6 -YL) -N-METHYLAMINO) PYRIMIDIN- 2 -YLAMINO) -2 -METHYLBENZENESULFONAMIDE

The present invention relates to a novel forms of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)- N-methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide as active pharmaceutical ingredient and to a process of preparing them.

The compound 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N-methylamino)pyrimidine-2- ylamino)-2-methylbenzenesulfonamide, also known as Pazopanib, is useful in the treatment of disorders associated with inappropriate or pathological angiogenesis, such as cancer, in mammals. Pazopanib has the following formula (I):

H CH,

NH₂

In WO 02/059110 the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride as well as the uses of this compound have been disclosed. In particular, this compound is an inhibitor of tyrosine kinase enzymes, namely vascular endothelial growth factor receptors, and can be used for the treatment and/or prevention of diseases which are associated with tyrosine kinase enzymes such as vascular endothelial growth factor receptors, such as cancer, particularly breast cancer and colon cancer.

Alternative methods for the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride are disclosed in WO 03/106416.

In WO 2007/064752 the use of Pazopanib for the treatment of age related macula degeneration is disclosed. WO 2007/064753 further discloses Pazopanib for the treatment of various types of cancer, e.g. brain cancer, glioblastoma multiforme, neuroendocrine cancer, prostate cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.

Typically Pazopanib is administered orally, as this route provides great comfort and convenience of dosing. Although the hydrochloride form of Pazopanib is known in the art, as described above, this form is not optimal in regard to bioavailability, inter-patient variability, and safety. Further, the known form of Pazopanib hydrochloride is not optimal with regard to mechanical and chemical stability, which is in particular necessary for manufacturing tablets, as well as not optimal in regard to flow properties, compressibility, dissolution rate. Additionally, it is at least to some extent hygroscopic and shows electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions.

It is therefore an object of the present invention to provide amorphous or crystalline forms of Pazopanib, as well as pharmaceutical compositions comprising these forms, which do not encounter the above problems. In particular the provided forms show improved bioavailability, reduced inter-patient variability, improved overall therapeutic efficacy, good mechanical and/or chemical stability, excellent flow properties, good compressibility, improved dissolution profiles. The new forms are non-hygroscopic and/or do not electrostatically charge. The forms of Pazopanib according to the invention are advantageous in at least one aspect of the above-mentioned properties.

It has now surprisingly been found that the above described problems can be overcome by providing Pazopanib in it's free base form.

Thus, in one aspect the present invention relates to the free base of Pazopanib.

In another aspect, the present invention relates to the free base of Pazopanib in crystalline form.

The term "crystalline" refers to any non-amorphous form of the substance including hydrates, solvates and different polymorphic forms of the crystalline form. The term "amorphous form" refers to a form of the substance which has no long-range order like crystalline structures. The atoms or molecules of a material present in amorphous form are arranged in a non-uniform array. It is for example possible to distinguish amorphous forms from crystalline forms of a substance by powder X-ray diffraction.

In still another aspect, the present invention relates to the free base of Pazopanib in the polymorphic form I (also referred to as "polymorph I").

Polymorph I of Pazopanib is characterized by an XRPD pattern having characteristic peaks at 7.3 +/- 0.2, 13.6 +/- 0.2, 21.6 +/- 0.2 and 26.7 +/- 0.2 degree 2-theta.

Furthermore, polymorph I of Pazopanib can be characterized by an XRPD pattern with characteristic peaks at 7.3 +/- 0.2, 12.3 +/- 0.2, 13.6 +/- 0.2, 14.5 +/- 0.2, 16.0 +/- 0.2, 18.6 +/- 0.2, 21.6 +/- 0.2, 25.8 +/- 0.2, 26.7 +/- 0.2 and 28.1 +/- 0.2 degree 2-theta.

The XRPD of polymorph I is shown in figure 1.

Polymorph I of Pazopanib shows an IR spectrum exhibiting characteristic peaks at 3338 +/- 2 cm^'1, 3266 +/- 2 cm^'1, 3098 +/- 2 cm^'1, 1616 +/- 2 cm^"1, 1581 +/- 2 cm^"1, 1551 +/- 2 cm^' ¹ and 1523 +/- 2 cm^"1.

The IR spectrum of polymorph I of Pazopanib is shown in figure 2.

Polymorph I of Pazopanib is further characterized by a melting point of 310 +/- 4°C. The DSC thermogram is shown in figure 3.

In another aspect the present invention relates to the free base of Pazopanib in the polymorphic form II (also referred to as "polymorph II").

Polymorph II of Pazopanib is characterized by an XRPD pattern having characteristic peaks at 13.1 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.

Furthermore, polymorph II of Pazopanib can be characterized by an XRPD pattern with characteristic peaks at 7.8 +/- 0.2, 9.3 +/- 0.2, 12.8 +/- 0.2, 13.1 +/- 0.2, 14.7 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2, 22.5 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta. Polymorph II of Pazopanib can further be characterized by an XRPD pattern with characteristic peaks at 6.5 +/- 0.2, 7.8 +/- 0.2, 9.3 +/- 0.2, 11.2 +/- 0.2, 12.8 +/- 0.2, 13.1 +/- 0.2, 14.7 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2, 19.0 +/- 0.2, 22.5 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.

The free base of Pazopanib according to the present invention may be obtained by

a) dissolving or suspending Pazopanib, e.g. in its hydrochloride salt form, in a suitable inert solvent, preferably in water or an organic solvent or a mixture of two or more suitable inert solvents,

b) alkalizing the solution or suspension with a suitable base, preferably a Bronsted base,

c) isolating the obtained solid, e.g. by filtration,

d) optionally washing and/or recrystallizing the obtained solid and

e) drying the solid.

Examples of suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethyl acetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Water is especially preferred.

Examples of suitable Bronsted bases are metal hydroxides, metal carbonates or amines, preferably alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, ammonia, or organic amines, such as, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, ammonia, diethylamine, triethylamine, diisopropylamine or pyridine. Sodium hydroxide and sodium bicarbonate are preferred. The base is used in an amount sufficient to obtain the free base of Pazopanib from its salt.

The present invention further relates to pharmaceutical compositions comprising the above mentioned new forms of Pazopanib. The term "pharmaceutical composition" refers to single dosage forms, such as tablets, capsules, pellets, etc., as well as powders or granules which are used in the preparation of single dosage forms. Where it is referred to the total weight of the pharmaceutical composition and the pharmaceutical composition in a single dosage form the total weight is the weight of the single dosage form excluding, if applicable, the weight of any coating or capsule shell.

The active pharmaceutical ingredient, i.e. the Pazopanib in its forms as described herein, e.g. its amorphous or crystalline form, can be present in the pharmaceutical composition in an amount of 5 to 80 % by weight, preferably 10 to 70 % by weight of the total weight of the composition.

Advantageous properties regarding solubility, homogeneity and flowability are achieved if the pharmaceutical composition of the present invention has a mean particle size of 1 to 800 m, preferably 5 to 600 μηη, more preferably 10 to 400 μηη.

A bulk density of the pharmaceutical composition ranging from of 0.3 to 0.9 g/ml, preferably of 0.4 to 0.8 g/ml is advantageous.

The pharmaceutical composition of the invention preferably possesses a Hausner factor in the range of 1.05 to 1.65, more preferably of 1.10 to 1.50. The Hausner factor is the ratio of bulk density to tapped density.

The pharmaceutical composition of the present invention can further comprise one or more pharmaceutically acceptable excipients, such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers. As pharmaceutically acceptable excipients conventional excipients known to the person skilled in the art may be used. See for example "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", edited by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London. Preferred examples of the fillers are lactose, mannitol, sorbitol and microcrystalline cellulose. The filler is suitably present in an amount of 0 to 90 % by weight, preferably of 30 to 80 % by weight of the total weight of the composition.

The binding agent can for example be microcrystalline cellulose (MCC) or hydroxypropylmethyl cellulose (HPMC). Preferably the binding agent is present in an amount of 1 to 25 % by weight, more preferably at 2 to 10 % by weight of the total weight of the composition.

The lubricant is preferably a stearate, more preferably an earth alkali metal stearate, such as magnesium stearate. The lubricant is suitably present in an amount of 0.1 to 2 % by weight, preferably about 1 % by weight of the total weight of the composition.

Preferred disintegrating agents are croscarmellose sodium, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone (crospovidone). The disintegrating agent is suitably present in an amount of 0.1 to 20 % by weight, more preferably at 0.5 to 7 % by weight of the total weight of the composition.

The flow enhancer can for example be colloidal silicon dioxide. Preferably, the flow enhancer is present in an amount of 0.5 to 8 % by weight, more preferably at 0.5 to 3 % by weight of the total weight of the composition.

The antisticking agent is for example talcum and may be present in an amount of 1 to 5 % by weight, more preferably in an amount of 1.5 to 3 % by weight of the total weight of the composition.

If desired, an improvement of the solubility of the active pharmaceutical ingredient can for example be achieved by the addition of complex forming agents/compounds (e.g. sodium benzoate, sodium salicylate or cyclodextrins), alternation of solvent properties (e.g. by adding PVP or polyethylene glycols) or the addition of solubilizers which form tenside micelles (e.g. surfactants).

Suitable solubilizers are for example surfactants such as polyoxyethylene alcohol ethers (e.g. Brij®), polysorbates (e.g. Tween®) or polyoxypropylene polyoxyethylene copolymers (poloxamer; e.g. Pluronic®) and may be present in amounts of 0.5 to 7 % by weight, more preferably 1 to 5 % by weight of the total weight of the composition.

Alternatively, a pseudo-emulsifier can be used. Its mechanism of action mainly relies on an enhancement of viscosity. However, pseudo-emulsifiers also possess emulsifying properties.

Preferred pseudo-emulsifiers of the present invention are for example cellulose ethers, gum Arabic or tragacanth and may be present in amounts of 1 to 10 % by weight, more preferably 3 to 7 % by weight of the total weight of the composition.

A person skilled in the art may use these or other excipients in regard to the selected process of preparing the pharmaceutical composition of the invention.

The pharmaceutical composition of the present invention can be formulated in any known form, preferably as tablets, capsules, granules, pellets or sachets. A particularly preferred pharmaceutical composition is in the form of capsules. The pharmaceutical composition may contain dosage amounts of 12.5, 25 and 50 mg of the active pharmaceutical ingredient. Thus the administered amount can be readily varied according to individual tolerance and safety warranting more flexible dosing than the standard dose of 50 mg once daily.

The pharmaceutical composition of the present invention can be manufactured according to standard methods known in the art. Granulates according to the invention can be obtained by dry compaction or wet granulation. These granulates can subsequently be mixed with e.g. suitable disintegrating agents, glidants and lubricants and compressed into tablets or filled into sachets or capsules of suitable size. Tablets can also be obtained by direct compression of a suitable powder mixture, i.e. without any preceding granulation of the excipients. Suitable powder or granulate mixtures according to the invention are further obtainable by spray drying, lyophilization, melt extrusion, pellet layering, coating of the active pharmaceutical ingredient or any other suitable method provided that the conditions are chosen such as to prevent amorphization of the active pharmaceutical ingredient. The so obtained powders or granulates can be mixed with one or more suitable ingredients and the resulting mixtures can either be compressed to form tablets or filled into sachets or capsules. The above mentioned methods known in the art also include grinding and sieving techniques permitting the adjustment of desired particle size distributions.

Description of the figures

Figure 1 is an XRPD pattern of polymorph I of Pazopanib. Figure 2 is an IR spectrum of polymorph I of Pazopanib. Figure 3 is a DSC thermogram of polymorph I of Pazopanib.

Abbreviations

A Angstrom

DSC differential scanning calorimetry

IR infrared

XRPD X-ray powder diffraction

Examples

XRPD samples were analyzed on a Bruker-ASX D8 Advance powder X-Ray Diffractometer.

The measurement conditions were as follows:

Measurement: in Bragg-Brentano-Geometry on vertical goniometer (reflection, theta-theta, 435 mm measurement circle diameter) with sample rotation (30 rpm) on 9 position sample stage

Radiation: CuKal (1.5406 A), Tube (Siemens FLCu2K), power 38 kV/40 mA

Detector: position sensitive detector VANTEC-1

3° capture angel (2theta)

variable antiscatter slit V6 (no divergence slit) detector slit 10.39 mm

4° soller slit

primary beam stop (< 2-theta)

Monochromator: none

Second filter: Ni filter 0.1 mm (0.5%)

Start angle: 1 °

End angle: 55° Measurement time: 11 min

Step: 0.016° 2-theta

Software: EVA (Bruker-AXS, Karlsruhe)

IR spectra were obtained using a Perkin Elmer, Model "Spectrum one", DFR mode. DSC thermograms were obtained using a Mettler Toledo Model DSC 822^e:

Heating range: 30 to 360°C

Heating rate: 10°C/min

Purge gas: nitrogen 50 ml/min

Sample holder: 40 μΙ aluminium crucible

The invention is further illustrated by the following examples which are not intended to be limiting.

Example 1 : Preparation of polymorph I of Pazopanib variant a

500 mg of Pazopanib hydrochloride was suspended in 20 ml of water. Saturated Na₂C0₃ solution was added until a thick white precipitate was formed. The reaction mixture was stirred for 10 minutes, filtered, washed with water and dried at 60°C under vacuum for 2 hours.

Yield: 415 mg

Example 2: Preparation of polymorph I of Pazopanib variant b

5.3 g of Pazopanib hydrochloride was added to 225 ml of 0.05 N NaOH and stirred at ambient temperature for 13 minutes. The resulting solid was filtered and washed with water until the filtrate was neutral. The solid was dried at 50°C under vacuum for 5 hours followed by drying at 60°C for 2 hours under vacuum.

Yield: 4.6 g

Claims

Claims:

1. Free base of Pazopanib.

2. The free base of Pazopanib according to claim 1 in crystalline form.

3. The free base of Pazopanib according to claim 1 or 2 in polymorphic form I characterized by an XRPD pattern with characteristic peaks at 7.3 +/- 0.2, 13.6 +/- 0.2, 21.6 +/- 0.2 and 26.7 +/- 0.2 degrees 2-theta.

4. Polymorph I of Pazopanib according to claim 3 characterized by an XRPD pattern with characteristic peaks at 7.3 +/- 0.2, 12.3 +/- 0.2, 13.6 +/- 0.2, 14.5 +/- 0.2, 16.0 +/- 0.2, 18.6 +/- 0.2, 21.6 +/- 0.2, 25.8 +/- 0.2, 26.7 +/- 0.2 and 28.1 +/- 0.2 degrees 2-theta.

5. Polymorph I of Pazopanib according to claim 3 or 4 characterized by the XRPD pattern shown in figure 1.

6. Polymorph I of Pazopanib according to any of claims 3 to 5 characterized by an IR spectrum exhibiting characteristic peaks at 3338 +/- 2 cm^"1, 3266 +/- 2 cm^"1, 3098 +/- 2 cm^" 1616 +/- 2 cm^"1, 1581 +/- 2 cm^"1, 1551 +/- 2 cm^"1 and 1523 +/- 2 cm^"1.

7. Polymorph I of Pazopanib according to any of claims 3 to 6 characterized by the IR spectrum shown in figure 2.

8. Polymorph I of Pazopanib according to any of claims 3 to 7 characterized by a melting point of 310 +/- 4°C.

9. The free base of Pazopanib according to claim 1 or 2 in polymorphic form II characterized by an XRPD pattern with characteristic peaks at 13.1 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.

10. Polymorph II of Pazopanib according to claim 9 characterized by an XRPD pattern with characteristic peaks at 7.8 +/- 0.2, 9.3 +/- 0.2, 12.8 +/- 0.2, 13.1 +/- 0.2, 14.7 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2, 22.5 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.

11. Polymorph II of Pazopanib according to claim 9 or 10 II characterized by an XRPD pattern with characteristic peaks at 6.5 +/- 0.2, 7.8 +/- 0.2, 9.3 +/- 0.2, 11.2 +/- 0.2, 12.8 +/- 0.2, 13.1 +/- 0.2, 14.7 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2, 19.0 +/- 0.2, 22.5 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.

12. Process for the preparation of the free base according to any of the preceding claims comprising the steps of:

a) dissolving Pazopanib, e.g. in its hydrochloride salt form, in a suitable inert solvent, preferably in water or an organic solvent or a mixture of two or more suitable inert solvents, b) alkalizing the solution with a suitable base, preferably a Bronsted base,

c) isolating the obtained solid, e.g. by filtration,

d) optionally washing and/or recrystallizing the obtained solid and

e) drying the solid.

13. Use of the free base of Pazopanib according to any of the claims 1 to 11 for the preparation of a pharmaceutical composition.

14. Pharmaceutical composition comprising the free base of Pazopanib according to any of the claims 1 to 11.