The present application claims the benefit of the following Indian provisional patent application No IN 201621006482 filed on February 24, 2016 and IN201621041371 filed on December 02, 2016.

FIELD OF THE INVENTION

The present invention relates to modified particles of crystalline palbociclib free base and its process for the preparation thereof.

BACKGROUND OF THE INVENTION

Palbociclib is a selective inhibitor of cyclin-dependent kinases and is used for the treatment of ER-positive and HER2-negative breast cancer. It is chemically known as 6- acetyl-8-cyclopentyl-5-methyl-2-{ [5-(piperazin-l-yl) pyridin-2-yl] amino }pyrido[2,3- d]pyrimidin-7(8H)-one having chemical structure of formula I.

Formula-I The U.S. Patent No. 6936612 describes palbociclib free base and a process for the preparation of its palbociclib hydrochloride salt thereof.

The U.S. Patent No. 7863278 describes Isethionate salts of palbociclib. The U.S. Patent application No. 20160002223 describes crystalline Forms A and B of palbociclib free base and palbociclib free base having a specific surface area of < 2 m ² /g.

The PCT Publication no. WO 2016/024249 describes crystalline Forms I, II, III, IV, V, V-A, VI, VII and VIII of palbociclib free base.

The PCT Publication no. WO 2016/156070 describes a crystalline palbociclib free base is having a specific surface area in the range of from 2.1 to 6.0 m /g as determined by BET- nitrogen analysis.

The PCT Publication no. WO 2017/021111 describes Palbociclib acetic acid adduct and process for the preparation thereof.

SUMMARY OF THE INVENTION

The present invention relates to a crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m /g.

The present invention further relates to a process for the preparation of crystalline

2 palbociclib free base having a specific surface area in the range from 7 to 15 m /g.

The present invention also provides a process for the preparation of crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m /g comprising:

a) dissolving palbociclib or its acid addition salt in a solvent,

b) optionally adding a base, and

c) isolating crystalline palbociclib free base.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts an X-Ray powder diffraction (XRPD) pattern of palbociclib free base form B. Figure 2 depicts an X-Ray powder diffraction (XRPD) pattern of palbociclib free base form A.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention provides a crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m Ig.

Another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m ² /g.

Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m Ig comprising:

a) dissolving palbociclib or its acid addition salt in a solvent,

b) optionally adding a base, and

c) isolating crystalline palbociclib free base. According to the present invention, wherein Palbociclib or salt thereof can be obtained by the process known in the art such as US 6936612, US 7345171 , US 7863278 or US 20160002223 and salt's includes any acid addition salt but not limited to hydrochloride, hydrobromide, sulfuric acid, and isethionate. According to the present invention, wherein solvent is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile and water or a mixture thereof. According to the present invention, wherein optionally adding base is selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate. According to the present invention, wherein the quantity of base is 1 to 5 times per mole of palbociclib or its salt thereof.

According to the present invention, wherein isolating the crystalline palbociclib free base by removal of the solvent by using suitable techniques such as distillation, distillation by using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, filtration, filtration under vacuum, decantation and centrifugation, or any other technique known in the art.

Another aspect of the present invention provides a crystalline palbociclib free base form B having a specific surface area in the range of from 3 to 15 m /g.

Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from 3 to 15 m ² /g. In yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from 3 to 15 m /g comprising:

a) dissolving palbociclib n HCl.m ¾() (wherein n, m is an integer ; n, m=0 to 3) in a solvent

b) optionally adding a base, and

c) isolating crystalline palbociclib free base form B.

Another aspect of the present invention provides a crystalline palbociclib free base form

2

B having a specific surface area in the range of from 7 to 15 m /g. Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from 7 to 15 m ² /g. In yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from

7 to 15 m /g comprising:

a) dissolving palbociclib n HCl.m H20 (wherein n, m is an integer ; n, m=0 to 3) in a solvent

b) optionally adding a base, and

c) isolating crystalline palbociclib free base form B.

Yet another aspect of the present invention provides a process for the preparation of crystalline form B of palbociclib comprising suspending palbociclib or its acid addition salt thereof in water, adding a base and isolating the crystalline form B of palbociclib.

In yet another aspect of the present invention provides a process for the preparation of crystalline form B of palbociclib comprising suspending palbociclib form A in water, adding hydrochloride salt, adding a base and isolating the crystalline form B of palbociclib freebase.

According to the present invention, wherein salt includes any acid addition salt such as hydrochloride, hydrobromide salt. According to the present invention, wherein base is inorganic or organic base .The inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate.

According to the present invention, wherein palbociclib free base form B is characterized by having PXRD pattern substantially as depicted in Figure 1. According to the present invention, wherein palbociclib free base form B is characterized by having PXRD pattern comprising peaks at diffraction angles (2Θ) of 5.9 ± 0.2, 10.9 ± 0.2, 12.7 ± 0.2, 16.3 ± 0.2,19.6 ± 0.2, 22.4 ± 0.2, and 26.6 ± 0.2. Table- 1 provides the d- spacing values (A°), the corresponding 2Θ values, and the relative intensity of crystalline palbociclib free base form B.

Table -1

According to the present invention, wherein dissolving palbociclib hydrochloride or its hydrate in water, optionally adding a base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate.

According to the present invention, wherein isolating crystalline palbociclib free base form B by filtration or centrifugation and palbociclib free base form B having a specific surface area in the range of from 3 to 15 m /g is determined by using BET-adsorption analysis.

According to the present invention, wherein palbociclib free base form B has particle size distribution characterized by a) D10 value from about 0.4 μπι to 3 μπι

b) D50 value from about 3.5 μπι to 25 μπι

c) D90 value from about 26 μπι to 90 μπι Another aspect of the present invention provides a crystalline palbociclib free base form A having a specific surface area in the range of from 7 to 15 m Ig. Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form A having a specific surface area in the range of from 7 to 15 m Ig.

In yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form A having a specific surface area in the range of from 7 to 15 m Ig comprising;

a) dissolving palbociclib n HCl.m ¾() (wherein n, m is an integer ; n, m=0 to 3) in a solvent,

b) optionally adding a base, and

c) isolating crystalline palbociclib free base form A.

According to the present invention, wherein palbociclib free base form A is characterized by having PXRD pattern substantially as depicted in Figure 2. According to the present invention, wherein palbociclib free base form A is characterized by having PXRD pattern comprising peaks at diffraction angles (2Θ) of 4.9 ± 0.2, 7.9 ± 0.2, 10+ 0.2, 10.1 ± 0.2, 11.4 ± 0.2, 17+ 0.2,22.2 + 0.2 and 22.4+ 0.2. Table-2 provides the d-spacing values (A°), the corresponding 2Θ values, and the relative intensity of crystalline palbociclib free base form A.

Table -2

According to the present invention, wherein dissolving palbociclib hydrochloride salt in a solvent is selected from ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone, water or its mixture thereof. Optionally adding a base selected from sodium hydroxide, potassium hydroxide, sodium carbonate.

According to the present invention, wherein isolating crystalline palbociclib free base form A by removal of the solvent by using suitable techniques such as distillation, distillation by using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, filtration, filtration under vacuum, decantation and centrifugation, or any other technique known in the art. various techniques like filtration or centrifugation.

According to the present invention, wherein palbociclib free base form A has particle size distribution characterized by a) D10 value from about 0.4 μπι to 1.5 μπι

b) D50 value from about 1.6 μπι to 4 μπι

c) D90 value from about 4.5 μπι to 60 μπι According to the present invention, crystalline palbociclib free base (form B or Form A) is characterized by obtained by the process of the present invention is having a purity of greater than about 95%, or greater than about 98%, or greater than about 99%, when measured by using high performance liquid chromatography (HPLC) and the details are given below;

Instrument : HPLC equipped with Pump, UV detector and Recorder.

Column : Zorbax SB-C18 (4.6 x 250mm), 5μπι.

Wavelength : UV Detector 240nm

Flow rate : 1.5mL/min Injection volume : 20 Ε. Auto sampler temperature: 10°C Column oven temperature: 50°C.

According to the present invention, crystalline palbociclib free base (form B or Form A) is characterized by having specific surface area in the range of from about 3 to 15 m /g, preferably from about 3.5 to 13 m 2 /g, more preferably from about 4 to 12 m 2 /g, as determined by the specific surface area measurements (BET nitrogen) were performed by using BET specific surface area analyzer.

The following setup has been done for measurement- BET specific surface area analyzer:

Analysis: Multi point

Software Version: Vi-connect

Adsorbate gas: Nitrogen (5%, 7%, 10%, 12% and 15%)

Sample tube: 17mm tube

Out gas Temperature: 30°C with N2 purging (99.99%)

Out gas Time: 180 min

Sample quantity: 2 grams

Isothermal collection points: 5 points BET

Equilibration time: 90 sec (point to point). The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X'Pert PRO diffractogram with Cu Ka radiation (λ = 1.54060 A), running at 45 kV and 40 mA.

The particle size was analyzed using the laser diffraction (or small angle light scattering) technique by dispersing the dry sample powder with compressed air. Specifically, the particle size distribution was analyzed using the Sympatec HELOS RODOS system equipped with a Vibri dry powder feeder. The powder sample was dispersed with a dispersion pressure of 0.5 bar. In some instances, an Aspiros micro-dosing device was used, and the powder sample was dispersed with a dispersion pressure of 0.2 bar. A suitable lens was selected to cover the particle size range of each sample.

The present invention is described in the following examples, however the scope of present invention is not limited by the examples.

Example 1

Process for the preparation of palbociclib free base crystalline form B

Palbociclib dihydrochloride trihydrate (35 g) was dissolved in water (840 ml) at room temperature. Aqueous sodium hydroxide solution (5.25 g sodium hydroxide in 53 ml of water) was added to the above slurry at 25-30 °C and stirred for 1 hr. The solid was filtered, washed with water (70 ml) and dried under vacuum. Obtained material was passed through 40 and 20 mesh, thus obtained crystalline palbociclib free base form B. Yield: 27.1 g

Specific surface area: 10.7 m g;

Purity: 99.8% (by HPLC);

Moisture content: 0.7%

Example 2

Process for the preparation of palbociclib free base crystalline form B

Palbociclib dihydrochloride trihydrate(20 g) was dissolved in water (500 ml) at room temperature. Aqueous sodium hydroxide solution (30 ml) was added to the above slurry at 25 °C and stirred for 1 hr. The solid was filtered, washed with water (80 ml) and dried under vacuum. Yield: 15 g

Specific surface area: 10.9 m7e:

Purity: 99.8% (by HPLC);

Moisture content: 0.9%

Example 3

Process for the preparation of palbociclib free base crystalline form B

Palbociclib hydrochloride (3.0 g, 5.22 mmol) was suspended in water (45 ml) and the resulting slurry was cooled to 0-5 °C. Aqueous sodium hydroxide solution (0.417 g sodium hydroxide in 15 ml water) was added to the above slurry at 5 °C and stirred for 2 hours at the same temperature. The solid was filtered, washed with chilled water (15 ml) and dried under vacuum. Yield: 1.45 g.

Specific surface area: 3.9 m ² /g Example 4

Process for the preparation of palbociclib free base crystalline form B

Palbociclib hydrochloride (3.0 g, 5.22 mmol) was suspended in water (45 ml) and the resulting slurry was cooled to 5 °C. Triethylamine (1.05 g, 10.4 mmol) was added to the above slurry at 5 °C and stirred for 2 hours at the same temperature. The solid was filtered, washed with chilled water (15 ml) and dried under vacuum. Yield: 1.9 g.

Example 5

Process for the preparation of palbociclib free base crystalline form B

Palbociclib form A (4.475 g, 10 mmol) was suspended in water (45 ml) and cone. hydrochloric acid (1 ml, 10 mmol) was added. The resulting slurry was cooled to 5 °C. Aqueous sodium hydroxide solution (0.8 g sodium hydroxide in 20 ml water) was added to the above slurry at 5 °C and stirred for 2 hours at the same temperature. The solid was filtered, washed with chilled water (15 ml) and dried under vacuum. Thus obtained palbociclib free base crystalline form B. Yield: 2.8 g. Example 6

Process for the preparation of palbociclib free base crystalline form A

Palbociclib dihydrochloride trihydrate (100 g) was dissolved in a mixture of acetone (300 ml) and water (650 ml) at room temperature 25-30°C. To the above reaction mass water (50 ml), aqueous sodium hydroxide solution (75 ml) was added and stirred the mass for 2 hours at the same temperature. The solid was filtered, washed with chilled acetone and water mixture (150 ml), and dried the material under vacuum. Obtained material was passed the through 20 mesh, thus obtained crystalline palbociclib free base form A.

Specific surface area: 8.17 m ² /g; Purity: 99.8% (by HPLC); Moisture content: 0.4%

Example 7

Process for the preparation of palbociclib free base crystalline form A

Palbociclib hydrochloride (50 g) was dissolved in a mixture of acetone (350 ml) and water (650 ml) at room temperature 25-30°C. To the above reaction mass water (50 ml), aqueous sodium hydroxide solution (75 ml) was added and stirred the mass for 2 hours at the same temperature. The solid was filtered, washed with chilled acetone and water mixture (150 ml), and dried the material under vacuum.

Yield: 38.4 g

Specific surface area: 8.8 m ² /g; Purity: 99.8% (by HPLC)

Moisture content: 0.4%