WO2017025784A1

WO2017025784A1 - A carbon dioxide adduct of palbociclib

Info

Publication number: WO2017025784A1
Application number: PCT/IB2015/059952
Authority: WO
Inventors: Vipin Tyagi; Kallimulla Mohammad; Bishwa Prakash Rai; Somenath Ganguly; Tapas PANDA
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2014-08-14
Filing date: 2015-12-23
Publication date: 2017-02-16
Anticipated expiration: 2018-02-13
Also published as: US20170240543A1; EP3180007A1; WO2016024249A1

Abstract

The present invention provides a carbon dioxide adduct of palbociclib designated as crystalline Form VA. It also relates to the preparation of a carbon dioxide adduct of palbociclib, its pharmaceutical composition, and its use for the treatment of cyclin- dependent kinase (cdk) associated diseases.

Description

A CARBON DIOXIDE ADDUCT OF PALBOCICLIB

Field of the Invention

Background of the Invention

Palbociclib of Formula I is chemically described as 6-acetyl-8-cyclopentyl-5- methyl-2- [[5 -( 1 -piperazin l)-2-pyridinyl]amino]pyrido [2,3 -<f]pyrimidin-7(8H)-one .

Formula I

U.S. Patent No. 6,936,612 provides a process for the preparation of palbociclib hydrochloride.

U.S. Patent No. 7,781,583 provides a process for the preparation of palbociclib isoethionate.

U.S. Patent No. 7,863,278 provides polymorphs of various salts of palbociclib.

PCT Publication No. WO 2014/128588 provides crystalline Forms A and B of palbociclib.

Summary of the Invention

The present invention provides a carbon dioxide adduct of palbociclib designated as crystalline Form VA. It also relates to the preparation of a carbon dioxide adduct of palbociclib, its pharmaceutical composition, and its use for the treatment of cyclin- dependent kinase (cdk) associated diseases. Brief Description of the Drawings

Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of a carbon dioxide adduct of palbociclib.

Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of a carbon dioxide adduct of palbociclib.

Figure 3 depicts an Infra-red (IR) spectrum of a carbon dioxide adduct of palbociclib.

Figure 4 depicts a Thermogravimetric analysis (TGA) thermogram of a carbon dioxide adduct of palbociclib.

Figure 5 depicts a Scanning electron microscopy (SEM) image of a carbon dioxide adduct of palbociclib.

Detailed Description of the Invention

The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

The term "ambient temperature," as used herein, refers to a temperature in the range of 25 °C to 35°C.

The term "contacting," as used herein, refers to dissolving, slurrying, stirring, suspending, or combinations thereof.

The term "cyclin-dependent kinase (cdk) associated diseases," as used herein, refers to the diseases mediated by cdk, which include, but are not limited to, the cancers of the breast, ovary, cervix, prostate, testis, esophagus, and stomach.

The term "adduct," as used herein, refers to a product of a direct combination of two or more separate molecular entities, in such a way that there is no loss of atoms.

A first aspect of the present invention provides a carbon dioxide adduct of palbociclib designated as crystalline Form VA, characterized by an XRPD pattern having peaks at d-spacing of about 11.3, 6.8, 5.3, 4.2, and 3.7 A, and further characterized by additional peaks at d-spacings of about 15.5, 10.0, 4.4, 4.1, and 3.3 A.

Table 1 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of a carbon dioxide adduct of palbociclib. Table 1

A carbon dioxide adduct of palbociclib is characterized by a DSC thermogram having endothermic peaks at about 146.0°C and 267.0°C, and an exothermic peak at about 221.5°C.

The carbon dioxide adduct of palbociclib has 0.5 moles of carbon dioxide per mole of palbociclib.

The carbon dioxide adduct of palbociclib has a water content of about 0.5%.

The carbon dioxide adduct of palbociclib has weight loss of about 4.5% to about 5% as determined through thermogravimetric analysis (TGA). The carbon dioxide adduct of palbociclib has weight loss of about 5% on drying (LOD). LOD was carried out under vacuum (5 mm of mercury) at a temperature of about 120°C for about 3 hours.

The carbon dioxide adduct of palbociclib shows a loss of carbon dioxide as determined through TGA MS technique.

The carbon dioxide adduct of palbociclib has a specific surface area (SSA) of greater than 2 m²/g. In an embodiment of the present invention, the carbon dioxide adduct of palbociclib has a specific surface area (SSA) of about 3 m²/g to about 10 m²/g.

The carbon dioxide adduct of palbociclib has a particle size distribution (PSD) having at least one of:

a) a D10 value of about 1 μπι to about 5 μπι;

b) a D50 value of about 5 μπι to about 20 μπι;

c) a D90 value of about 15 um to about 50 μπι.

The carbon dioxide adduct of palbociclib has a volume mean diameter (D[4,3]) of about 5 μπι to about 50 μπι.

The carbon dioxide adduct of palbociclib has improved filterability, electrostatic nature, flowability, and stability.

The carbon dioxide adduct of palbociclib is characterized an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, an Infra-red (IR) spectrum as depicted in Figure 3, a TGA thermogram as depicted in Figure 4, or an SEM image as depicted in Figure 5.

A second aspect of the present invention provides a process for the preparation of a carbon dioxide adduct of palbociclib, comprising:

a) contacting palbociclib hydrochloride with a mixture of water and methanol or a mixture of water or acetone; and

b) adding an inorganic base to the reaction mixture of step a) to obtain the carbon dioxide adduct of palbociclib.

Palbociclib hydrochloride used for the preparation of a carbon dioxide adduct of palbociclib may be prepared by any method provided in the art, for example, the methods as disclosed in U.S. Patent Nos. 7,863,278, 6,936,612, or 7,781,583, or by the method as described herein.

Examples of inorganic bases include sodium bicarbonate, potassium bicarbonate, and calcium bicarbonate.

The preparation of the carbon dioxide adduct of palbociclib is carried out at about

20°C to about 55°C for a period of about 30 minutes to about 5 hours, for example, for about one hour to about 4 hours.

A carbon dioxide adduct of palbociclib may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization, and dried under reduced pressure, by air drying, or vacuum tray drying.

A third aspect of the present invention provides a pharmaceutical composition comprising a carbon dioxide adduct of palbociclib and one or more pharmaceutically acceptable carriers, diluents, or excipients.

A fourth aspect of the present invention provides a method for treating cyclin- dependent kinase associated diseases comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a carbon dioxide adduct of palbociclib.

While the present invention has been described in terms of its specific aspects and 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.

Methods

XRPD of the samples was determined using a PANalytical^® instrument; Model X'pert PRO; Detector: X'celerator^®.

NMR of the samples was determined using a Bruker^® instrument, Model Avance

III 400, using a 5 mm PABBO probe. H frequency: 400 MHz; ¹³C Frequency: 100 MHZ.

IR of the samples was recorded using a PerkinElmer^® instrument, potassium bromide pellet method.

DSC of the samples was recorded using a Mettler-Toledo^® 82 le instrument.

TGA was recorded using a TA Instruments^® Q500. SEM analysis was carried out using a JEOL JSM-6010LV. The samples were coated by a platinum sputter coater (JEOL, JFC 1600, auto fine coater).

Particle size distribution was measured using a Malvern^® Mastersizer^® 2000 instrument.

Specific surface area was determined using a Micromeritics^® Gemini™ VII 2390

(Software: Gemini™ VII, version 1.03).

Water content was determined using a Metrohm^® KF Tiltrotor: Model: 795 KFT Titnno^®.

Loss on drying (LOD) was determined using a Yamato Scientific vacuum drying oven, Model: ADP200.

The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1 : Preparation of palbociclib hydrochloride

Concentrated hydrochloric acid (77.5 g) was added to a solution of fert-butyl 4-(6-

{[6-(l-butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-£/|pyrimidin- 2-yl]amino}pyridin-3-yl)piperazine-l-carboxylate (90 g) (obtained as per procedure disclosed in U.S. Patent No. 7,781,583) in a mixture of methanol (1350 mL) and water (180 mL) at 60°C to 65°C to obtain a reaction mixture. The reaction mixture was heated at 60°C to 65 °C for 4 hours and then lowered to ambient temperature. Sodium hydroxide solution (20%, 20 mL) was added to the reaction mixture at 35°C to 40°C to adjust the pH to 10.5 to 11 and to obtain a solid. The solid was stirred at 25°C to 30°C for one hour. The solid was filtered, then washed with water (180 mL), and then washed with methanol (180 mL) to obtain a wet compound. The obtained wet compound was charged in methanol (600 mL) to obtain a solution. The temperature of the solution was raised to

60°C to 65 °C, and then concentrated hydrochloric acid (27 g) was added to the solution to obtain a reaction mixture. The reaction mixture was stirred for 2 hours at 60°C to 65 °C, and then cooled to 10°C to 15°C in one hour to obtain a slurry. The slurry was stirred for 2 hours at 60°C to 65°C to obtain a yellow solid. The yellow solid obtained was filtered, and then washed with methanol (1 x 60 mL) to obtain the title compound.

Yield: 66.8 g Example 2: Preparation of a carbon dioxide adduct of palbociclib

Palbociclib hydrochloride (100 g, as obtained in Example 1) was dissolved in a mixture of water (1500 mL) and methanol (2000 mL) at 25 °C to 30°C to obtain a reaction mixture. Eno antichromos carbon (20 g) and sodium metabisulphite (2 g) were added to the reaction mixture, and then the mixture was stirred for 30 minutes. The reaction mixture was filtered through a Hyflo^®, and then washed with water (500 mL) to obtain a filtrate. The filtrate was passed through 0.45 micron filter. The filtrate obtained was heated at 40°C to 50°C. The filtrate was treated with aqueous sodium bicarbonate (5%) over a period of 90 minutes at 40°C to 50°C to adjust the pH to 7.0 to 7.2. The reaction mixture was stirred at 40°C to 50°C for 2 hours to 3 hours. The reaction mixture was filtered, and then washed with water (2x200 mL), methanol (1 ^χ200 mL), and acetone (1 x200 mL) to obtain a solid. The solid obtained was dried at 50°C to 60°C for 12 hours to obtain the title compound.

Yield: 75 g

CHN Data: C: 62.06 H: 5.81 N: 20.7

*H NMR (TFA d₆, 400 MHz): δ 9.24 (2H, s), 8.24-8.27 (1H, d), 8.16 (1H, s), 7.91-7.93 (1H, d), 5.92-5.97 (1H, m), 3.79-3.81 (8H), 2.77 (3H, s), 2.58 (3H, s), 2.33-2.34 (2H, m), 2.08 (4H), 1.79 (2H).

¹³C NMR (TFA d₆, 100 MHz): δ 208.5, 156.8, 154.2, 152.6, 143.6, 141.5, 136.1, 132.9, 125.1, 123.4, 112.3, 56.9, 45.3, 44.3, 30.3, 27.9, 25.1, 12.9.

Claims

We claim:

1. A carbon dioxide adduct of palbociclib, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacing of about 11.3, 6.8, 5.3, 4.2, and 3.7 A.

2. The carbon dioxide adduct of claim 1, characterized by an XRPD pattern having

additional peaks at d-spacings of about 15.5, 10.0, 4.4, 4.1, and 3.3 A.

3. The carbon dioxide adduct of claim 1, characterized by a differential scanning

calorimetry (DSC) thermogram having endothermic peaks at about 146.0°C and 267.0°C, and an exothermic peak at about 221.5°C.

4. The carbon dioxide adduct of claim 1, characterized by an XRPD pattern substantially as depicted in Figure 1.

5. The carbon dioxide adduct of claim 1, characterized by a DSC thermogram

substantially as depicted in Figure 2.

6. The carbon dioxide adduct of claim 1, characterized by an IR spectrum substantially as depicted in Figure 3.

7. The carbon dioxide adduct of claim 1, characterized by a scanning electron

microscopy (SEM) image substantially as depicted in Figure 5.

8. A carbon dioxide adduct of palbociclib having 0.5 moles of carbon dioxide per mole of palbociclib.

9. A carbon dioxide adduct of palbociclib having a water content of about 0.5%.

10. A carbon dioxide adduct of palbociclib having weight loss of about 4.5% to about 5% as determined through thermogravimetric analysis (TGA).

11. The carbon dioxide adduct of claim 10 is characterized by a TGA thermogram as depicted in Figure 4.

12. A carbon dioxide adduct of palbociclib having weight loss of about 5% on drying (LOD).

13. A carbon dioxide adduct of palbociclib having a specific surface area (SSA) of greater than 2 m²/g.

14. The carbon dioxide adduct of claim 13 having a specific surface area of about 3 m²/g to about 10 m²/g.

15. A carbon dioxide adduct of palbociclib having a particle size distribution (PSD) having at least one of:

a) a D 10 value of about 1 μηι to about 5 μηι;

b) a D50 value of about 5 μηι to about 20 μηι;

c) a D90 value of about 15 um to about 50 μηι.

16. The carbon dioxide adduct of claim 15 having a volume mean diameter (D[4,3]) of about 5 μιη to about 50 um.

17. A process for the preparation of a carbon dioxide adduct of palbociclib comprising a) contacting palbociclib hydrochloride with a mixture of water and methanol or a mixture of water or acetone; and

18. The process of claim 17, wherein the inorganic base is selected from the group

consisting of sodium bicarbonate, potassium bicarbonate, and calcium bicarbonate.

19. A pharmaceutical composition comprising a carbon dioxide adduct of palbociclib, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

20. A method for treating cyclin dependent kinase associated diseases comprising

administering to a patient a therapeutically effective amount of a composition comprising the carbon dioxide adduct of palbociclib according to any one of claims 1- 16.