DESC:FORM 2
THE PATENTS ACTS, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; rule 13)

“A PROCESS FOR THE PREPARATION OF PALBOCICLIB”

LAURUS LABS LIMITED, an Indian company, of DS1, IKP Knowledge Park Genome Valley, Turkapally, Shameerpet Mandal, Ranga Reddy District, Hyderabad 500078, Telengana, India;

The following specification particularly describes the invention and the manner in which it is to be performed.

PRIORITY:

This application claims the benefit under Indian Provisional Application No. 201841005582 filed on February 14, 2018, the content of which is incorporated by reference herein.

FIELD OF THE INVENTION:

The present invention relates to a process for the preparation of palbociclib, especially a process for the preparation of palbociclib having specific surface area greater than 2 m2/g.

BACKGROUND OF THE INVENTION:

Palbociclib is chemically known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-l-yl)pyridin-2yl]amino}-pyrido[2,3-d]pyrimidin-7(8H)-one and has the following structural formula:

Palbociclib is an oral, selective and reversible inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) developed by Pfizer. Palbociclib is commercially available under the brand name Ibrance and is indicated for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

Palbociclib and pharmaceutically acceptable salt thereof was first disclosed in US6936612 and this patent specifically exemplifies the preparation of palbociclib hydrochloride salt.
The WO2014128588 publication discloses that palbociclib free base prepared by traditional salt break procedures, for example as described in example 4 of WO2005005426, was highly static prone and formed as small primary particles, which agglomerated into large, hard agglomerates that were difficult disperse by sieving and were unsuitable for further developments. Hence, the WO’588 publication provides palbociclib free base, especially crystalline palbociclib having reduced specific surface area of = 2 m2/g which possessing improved physiochemical properties. Further this publication discloses two crystalline polymorphs of palbociclib, namely Form A and Form B and a process for the preparation thereof. The disclosed process involves dissolution of palbociclib free base obtained by traditional salt break procedure in a mixture of anisole and n-butanol by heating to 95-100°C; then reaction mass was cooled to 80°C followed by seeded with Form A seed crystals in n-butanol and stirred for 3 hrs at 80°C. The reaction mass then cooled to 10°C at 0.2°C/min over 350 mins and then isolated by filtration. The disclosed process involves seeding crystals, specific cooling rate for longer duration and hence seems to be hectic and more time consuming. Further involves use of butanol solvent, which results in higher levels of residual content in final product.

The WO2016156070 publication discloses a crystalline Form A of palbociclib having medium specific surface area and process for its preparation. The disclosed process involves preparation of crystalline palbociclib having specific surface area of about 3-4.5 m2/g by adding heptane to methylene chloride layer comprising palbociclib product (which is obtained by basification of palbociclib dihydrochloride in methylene chloride with triethylamine) at 30°C.

The CN106146494A publication discloses a process for the preparation of crystalline Form A of palbociclib which comprises crystallizing palbociclib from chlorobenzene.

The CN106317053A publication discloses a process for the preparation of crystalline Form A of palbociclib which comprises basifying palbociclib isethionate with sodium hydroxide in methanol/water solvent system.
The WO2017076288 publication discloses a process for the preparation of crystalline Form A of palbociclib, which comprises treating the palbociclib salts with an inorganic base in a water or water and a mixed solvent of an organic solvent miscible with water at 35-100°C to obtain palbociclib free base Form A.

The WO2017145054 publication discloses a process for crystalline Form A of palbociclib having specific surface area in the range from 7 to 15 m2/g, which comprises dissolving palbociclib dihydrochloride trihydrate or palbociclib hydrochloride in acetone/water solvent system followed by treating it with sodium hydroxide solution and isolating crystalline form A by filtration.

WO2018073574 publication discloses a process for crystalline Form A of palbociclib, which comprises basifying palbociclib dihydrochloride with sodium hydroxide in methanol/water solvent system.

Other than the above discussed patents/publications, the following patent publications such as CN105085517 (monohydrate), WO2016024249 (crystalline Form I to Form VIII), WO2016090257 (crystalline Form I and Form II), CN 106065016A (type I crystals), CN106397431 (Form C), WO2017067506 A1 (Form IX, Form X and Form XII), CN106866666A, WO2017115315 (crystalline Form M1 to Form M6 and amorphous form), WO2017197904 (Crystal Form I to Form XII and Form XIV), WO2017211788 (non-crystalline form) discloses different crystalline forms of palbociclib and process for their preparation.

Although processes for the preparation of crystalline palbociclib is known in the art, still there is a need in the art for efficient process for the preparation of crystalline palbociclib, preferably in the form of Form A of having specific surface area greater than 2 m2/g, specifically in between 2-3 m2/g; which are not static prone and do not form agglomerates and having residual solvent content well within the limits specified by ICH.

SUMMARY OF THE INVENTION:

Accordingly the present invention provides a process for the preparation of crystalline palbociclib having specific surface area greater than 2 m2/g, which are not static prone and do not form agglomerates and having residual content well within the limits specified by ICH.

In one embodiment, the present invention provides a process for the preparation of crystallinepalbociclib having specific surface area greater than about 2 m2/g, which comprises;
a) dissolving palbociclib in a mixture of an alcohol and an aromatic solvent at a suitable temperature,
b) adding step a) solution to a suitable anti-solvent selected from ethers, hydrocarbons or mixtures thereof, or vice versa; and
c) isolatingthe crystalline palbociclib having specific surface area greater than 2 m2/g.

In a specific embodiment, the crystalline palbociclib having specific surface area greater than about 2 m2/g is referred to as crystalline Form A.

In another embodiment, the present invention provides a process for the preparation of crystalline palbociclib having specific surface area greater than about 2 m2/g, which comprises:
a) dissolving palbociclib in a mixture of an alcohol and an aromatic solvent at a suitable temperature;
b) adding step a) solution to a suitable anti-solvent selected from ethers, hydrocarbons or mixtures thereof, or vice versa; and
c) isolating the crystalline palbociclib having specific surface area greater than 2 m2/g; wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and the like; the aromatic solvent is selected from the group consisting of anisole, xylene and the like;the ethersare selected from the group consisting of methyl tertiary butyl ether, diisopropylether and the like; and the hydrocarbons are selected from the group consisting of heptane, hexane, cyclohexane and the like.
In another embodiment, the present invention provides a process for the preparation of crystalline palbociclibhaving specific surface area greater than 2 m2/g, which comprises;
a) dissolving palbociclib in a mixture of an alcohol and an aromatic solvent at a suitable temperature of about 40°C to reflux,
b) optionally cooling the step a) solution to about 35°C to about65°C;
c) adding the step a) or the step b) solution to a suitable anti-solvent selected from ethers, hydrocarbons or mixtures thereof at a temperature of about 25°C to about 65°C; or vice versa;
d) optionally cooling the step c) reaction mass to about 0°C to about 45°C; and
e) isolating the crystalline palbociclib having specific surface area greater than 2 m2/g.

In another embodiment, the present invention provides a pharmaceutical composition comprising the crystalline palbociclib having specific surface area greater than 2 m2/gprepared as above and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS:

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Form A of palbociclib obtained by the present invention.

DETAILED DESCRIPTION OF THE INVENTION:

As used herein, the term “agglomerates” refers to tightly bound API crystals that are difficult to disperse into primary particles during processing and particle size analysis.

Accordingly, the present invention provides a process for the preparation of crystalline palbociclib having specific surface area greater than 2 m2/g, specifically 2 to 3 m2/g, which are not static prone and do not form agglomerates and having residual content well within the limits specified by ICH.

In one embodiment, the present invention provides a process for the preparation of crystalline palbociclib having specific surface area greater than about 2 m2/g, which comprises;
a) dissolving palbociclib in a mixture of an alcohol and an aromatic solvent at a suitable temperature;
b) adding step a) solution to a suitable anti-solvent selected from ethers, hydrocarbons or mixtures thereof, or vice versa; and
c) isolatingthe crystalline palbociclib having specific surface area greater than 2 m2/g.

As used herein, the palbociclib which is used as a starting material is known in the art and can be prepared by any known method, for example, can be prepared as per example-5 of WO2014128588. The starting palbociclib may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of palbociclib, including various solvates and hydrates known in the art.

The step a) of forgoing process includes dissolving palbociclib in a mixture of an alcohol and an aromatic solvent at a suitable temperature; preferably the dissolution achieved by heating the reaction mixture to about 40°C to about reflux temperature of the solvent used.

The alcohol solvent used herein step a) is selected from the group consisting of methanol, ethanol, isopropanol and the like; preferably methanol; and the aromatic solvent is selected from the group consisting of anisole, xylene and the like; preferably anisole.

In another embodiment, the mixture of alcohol and aromatic solvent used in the ratio of about 1:4 to about 4:1; preferably in the ratio of about 1:3.

In another embodiment, the volume of mixture of alcohol and aromatic solvent used in the range of about 35 volumes to 50 volumes; preferably about 40-45 volumes.
The step b) of forgoing process involves addition of step a) solution to a suitable anti-solvent or vice versa. Specifically the addition may be carried out either by adding step a) solution to an anti-solvent or an anti-solvent may be added to step a) solution. The sequence of addition of either way is not particularly critical.

The anti-solvent used herein is selected from the group consisting of ethers, hydrocarbons or mixtures thereof. The ethers used herein selected from the group consisting ofmethyl tertiary butyl ether, diisopropylether and the like; and the hydrocarbons is selected from the group consisting of heptane, hexane, cyclohexane and the like. Preferably, the anti-solvent is ethers and more preferably methyl tertiary butyl ether.

The process of step b) is advantageously carried out at a temperature of about 25°C to about 65°C.

Optionally, the step a) solution may be cooled down to a temperature until where the formation of palbociclib crystal is not initiated before the addition of anti-solvent; preferably the step a) solution may cool down to a temperature of about 35°C to about 65°C; more preferably about 40°C to about 60°C.

The anti-solvent used herein may advantageously pre heated to about 30°C to about 50°C prior to combining it with the solution of step a); preferably about 40 to about 45°C.

In another embodiment, the anti-solvent used herein pre heated to about 30°C to about 50°C prior to combining it with the solution of step a).

The addition of step a) solution to anti-solvent solution or vice versa can be carried out for a period from about 1 min to 60 mins; preferably for about 40-45 mins.

After the addition of an anti-solvent to the step a) solution or step a) solution to an anti-solvent, the precipitated material can be isolated by known techniques. If, required the reaction mass may be stirred for suitable time at suitable temperature until the complete precipitation achieved. The resultant crystalline palbociclib can be isolated from the reaction mixture by any conventional techniques known in the art such as filtration, centrifugation, and evaporation of the solvent or combination of one or more techniques; preferably by filtration. Typically, if stirring is involved, the temperature during stirring can be from about 0°C to about 45°C. The resultant product may optionally be further dried at atmospheric or at reduced pressure at suitable temperatures i.e. about 25°C to about 80°C for a period of about 2 to 12 hours.

In another embodiment, the crystalline palbociclib obtained by the above process having specific surface area greater than 2 m2/g, preferably about 2 to 3 m2/g, which are not static prone and do not form agglomerates.

In another embodiment, the crystalline palbociclib obtained by the above process having specific surface area greater than 2 m2/g, preferably in the range of about 2 to 3 m2/g, and having a particle size distribution (PSD) comprising at least one of:
i) a D10 value in the range from about 1 µm to about 3 µm; preferably about 1 µm to about 2 µm;
ii) a D50 value in the range from about 4 µm to about 12 µm; preferably about 6 µm to about 10 µm;
iii) a D90 value in the range from about 14 µm to about 45 µm; preferably about 16 µm to about 30 µm;

In another embodiment, the crystalline palbociclib obtained by the above process having residual content well within the limits specified by ICH. In particular, crystalline palbociclib obtained by the present invention having residual solvent content of methyl tertiary butyl ether less than 5000 ppm; methanol less than 3000 ppm and anisole less than about 5000 ppm; preferably the residual solvent content of methyl tertiary butyl ether less than 2350 ppm; methanol less than 80 ppm and anisole less than about 2250 ppm.

In a specific embodiment, crystalline palbociclib having specific surface area greater than about 2 m2/g is referred to as crystalline Form A.

The crystalline Form A of palbociclib prepared by the present invention process is characterised by a powder X-ray diffraction (XRD) pattern substantially in accordance with Figure-1.

The reported process for the preparation of crystalline Form A of palbociclib, for example process reported in WO2014128588 involves crystallization of palbociclib from n-butanol and anisole mixture. The same process was also reported in Org. Process Res. Dev., 2016, 20 (7), pp 1217–1226(“OPRD”) authored by the same applicant. The said journal states that, as both anisole and n-butanol are high boiling solvents and due to palbociclib compound itself is prone to trap solvents used in the process, therefore once solvents trapped into the crystal lattice cannot be removed by normal vacuum drying even after 24 h at higher temperatures, for example at 90 °C. Accordingly, the OPRD article suggested washings with heptane for removal of residual solvents. The present inventors prepared palbociclib using anisole and n-butanol as per the process disclosed in WO2014128588 and analyzed it for residual solvent content and found that the obtained palbociclib having higher level residual content of n-butanol and anisoleeven after washing with n-heptane and subsequent drying steps.

The present inventors working on the process to prepare palbociclib with low levels of residual solvent content and specific surface area by modifying various process parameters such as addition time, addition temperature, mode of addition, cooling time and temperature in the solvent and antisolvent methodology of the present invention. The Inventors of the present invention have surprisingly found that addition of solution of palbociclib in to a mixture of anisole and methanol to pre heated (at 30-50°C) methyltertiarybutyl ether or addition of methyl tertiary butyl ether to a solution of palbociclib in a mixture of anisole and methanol at 35-60°C,which process not only provides palbociclib with desired particle size and specific surface area and advantageously avoids trapping of residual solvents. Therefore, additional solvent crystallizations/solvent washings as suggested in the OPRD article can be avoided.

Moreover the reported process of WO2014128588 involves specific parameters and condition for the preparation of Form A, such as usage of seed crystals, seeding at specific temperature of 80°C and cooling of reaction mass to 10°C at the specific rate of 0.2°C/min over 350 mins after seeding and etc. Hence the reported process practically more tedious, time consuming and un-economic at commercial scale. In contrast, the present invention process involves dissolution of palbociclib in a mixture of alcohol and aromatic solvent followed by adding suitable anti-solvent, or vice versa, provides crystalline palbociclib having required physical parameters.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline palbociclib having specific surface area greater than 2 m2/g prepared by the process of the present invention and at least one pharmaceutically acceptable excipient.

Advantageous of the present invention:
• Provides simple and economically efficient process for the preparation of crystalline palbociclib.
• Provides a process for crystalline Form A of palbociclib which avoids seeding, specific cooling rate and other time consuming process parameters as in the prior art.
• Provides a process for palbociclib which limit the formation of residual solvent by carrying out addition of anti-solvent or solvent at specific temperature, which is otherwise not removable by methods known in the art.
• Provide a process where the final compound is not trapped even after cooling the reaction mass containing palbociclib to 0-5°C after completion of reaction mass addition to anti-solvent at 40-45°C.
• crystalline palbociclib prepared by the present invention having specific surface area in the range of 2-3 m2/g and advantageously which are not static prone and do not form agglomerates.

The X-Ray powder diffraction can be measured using PANalytical X’per3pro X-ray powder Diffractometer equipped with a Cu-anode ([?] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°2?; step size=0.01°; and Time per step= 48 sec.

The Specific Surface Area (SSA) and Particle Size (PSD) of palbociclib of the present invention can be measured as per the method of analysis disclosed in WO2014128588.

EXAMPLES:

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Example-1:Preparation of crystalline Form A of palbociclib (10 VolMeOH + 30 Vol anisole, anti-solvent reverse addition for 45 mins)

In 1 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (10 g), methanol (100 mL) and anisole (300 mL) was charged at 25-35°C. The reaction mass was heated to 66-72°C, stirred for 15 mins to get clear solution and then cooled to 53-59°C. In another 2 Lit RBF, methyl tertiary butylether (400 mL) was charged at 25-35°C and heated to 40-45°C. To this, above cooled reaction mass was added at 40-45°C over a period of 45 mins. The reaction mass was stirred for 15 mins at 40-45°C. The solid obtained was filtered off, washed with methyl tertiary butyl ether and suck dried for 15 mins. The suck dried solid was initially dried under vacuum for 2 hrs at 25-35°C and finally dried under vacuum for 8 hrsat 69-75°C to get 8.7 g of the title compound.
PSD (µm): D10 (1.41); D50 (7.59) & D90 (29.7).
SSA: 2.71 m2/g.
Residual solvents (OVI): methanol: 77 ppm; methyl tertiary butyl ether: 1646 ppm; Anisole: 1367 ppm.

Example-2:Preparation of crystalline Form A of palbociclib (10.5 VolMeOH + 31.5 Vol anisole, anti-solvent reverse addition for 45 mins):

In 1 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (10 g), methanol (105 mL) and anisole (315 mL) was charged at 25-35°C. The reaction mass was heated to 66-72°C, stirred for 15 mins to get clear solution and then cooled to 40-45°C. In another 2 Lit RBF, methyl tertiary butylether (420 mL) was charged at 25-35°C and heated to 40-45°C. To this, above cooled reaction mass was added at 40-45°C over a period of 45 mins. The reaction mass was stirred for 15 mins at 40-45°C. The solid obtained was filtered off, washed with methyl tertiary butyl ether and suck dried for 15 mins. The suck dried solid was initially dried under vacuum for 2 hrs at 25-35°C and finally dried under vacuum for 8 hrs at 69-75°C to get 7.8 g of the title compound.
PSD (µm): D10 (1.34); D50 (7.55) & D90 (27.3);
SSA: 2.69 m2/g.
Residual solvents (OVI): methanol: 54 ppm; methyl tertiary butyl ether: 1551 ppm; Anisole: 1361 ppm.

Example-3:Preparation of crystalline Form A of palbociclib (11.25 VolMeOH + 33.75 Vol anisole, anti-solvent reverse addition for 45 mins):

In 1 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (10 g), methanol (112.5 mL) and anisole (337.5 mL) was charged at 25-35°C. The reaction mass was heated to 66-72°C, stirred for 15 mins to get clear solution and then cooled to 40-45°C. In another 2 Lit RBF methyl tertiary butyl ether (450 mL) was charged at 25-35°C and heated to 40-45°C. To this, above cooled reaction mass was added at 40-45°C over a period of 45 mins. The reaction mass was stirred for 15 mins at 40-45°C. The solid obtained was filtered off, washed with methyl tertiary butyl ether and suck dried for 15 mins. The suck dried solid was initially dried under vacuum for 2 hrs at 25-35°C and finally dried under vacuum for 8 hrs at 69-75°C to get 8.2 g of title compound.
SSA: 2.68 m2/g.
OVI: methanol: 36 ppm; methyl tertiary butyl ether: 1570 ppm; Anisole: 1581 ppm
Example-4:Preparation of crystalline Form A of palbociclib (10 VolMeOH + 30 Vol anisole, anti-solvent normal addition for 20 mins):

In 1 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (5 g), methanol (50 mL) and anisole (150 mL) was charged at 25-35°C. The reaction mass was heated to 65-75°C, stirred for 15 mins to get clear solution and then cooled to 58-62°C. To this solution, methyl tertiary butyl ether (200 mL) was added at 58-62°C over a period of 20 mins. The reaction mass was then cooled to 25-35°C and stirred for 2 hrs at the same temperature. The solid obtained was filtered off, washed with methyl tertiary butyl ether and suck dried for 15 mins. The suck dried solid was further dried under vacuum for 8 hrs at 70-75°C to get 4.2 g of title compound.
PSD (µm): D10 (1.35); D50 (5.34) & D90 (16.75)
SSA: 2.55 m2/g.
Residual solvents (OVI): methanol: 36 ppm; methyl tertiary butyl ether: 525 ppm; Anisole: 1864 ppm

Example-5:Preparation of crystalline Form A of palbociclib (10 VolMeOH + 30 Vol anisole, anti-solvent reverse addition for 3 mins):

In 2 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (40 g), methanol (400 mL) and anisole (1200 mL) was charged at 25-35°C. The reaction mass was heated to 65-75°C, stirred for 15 mins to get clear solution and then cooled to 40-45°C. In another 5 Lit RBF methyl tertiary butyl ether (1600 mL) was charged at 25-35°C and heated to 40-45°C. To this, above cooled reaction mass was added at 40-45°C over a period of 3 mins. The reaction mass was stirred for 15 mins at 40-45°C, then cooled to 25-35°C and stirred for 15 mins at 25-35°C. The solid obtained was filtered off, washed with methyl tertiary butyl ether and suck dried for 15 mins. The suck dried solid was further dried under vacuum for 8 hrs at 70-75°C to get 36 g of title compound.
PSD (µm): D10 (1.61); D50 (8.28) & D90 (44.2)
Residual solvent (OVI): methanol: 44 ppm; methyl tertiary butyl ether: 2320 ppm; Anisole: 2230 ppm

Example-6: Preparation of crystalline Form A of palbociclib (11.25 VolMeOH + 33.75 Vol anisole, anti-solvent reverse addition for 45 mins):

In 1 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (10 g), methanol (112.5 mL) and anisole (337.5 mL) was charged at 25-35°C. The reaction mass was heated to 65-75°C, stirred for 15 mins to get clear solution and then cooled to 40-45°C. In another 2 Lit RBF methyl tertiary butyl ether (450 mL) was charged at 25-35°C and heated to 40-45°C. To this, above cooled reaction mass was added at 40-45°C over a period of 45 mins. The reaction mass was stirred for 15 mins at 40-45°C. The reaction mass was cooled to 0-5°C and stirred for 30-35 mins at 0-5°C. The solid obtained was filtered off, washed with methyl tertiary butyl ether and suck dried for 15 mins. The suck dried solid was dried under vacuum for 8 hrs at 70-75°C to get 8.8 g of title compound.
PSD (µm): D10 (1.46); D50 (8.03) & D90 (39.45)
Residual solvent (OVI): methanol: 34 ppm; methyl tertiary butyl ether: 1713 ppm; Anisole: 1670 ppm

Example-7: Preparation of crystalline Form A of palbociclib (11.25VolMeOH + 33.75 Vol anisole, anti-solvent reverse addition for 45 mins):

In 1 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (10 g), methanol (112.5 mL) and anisole (337.5 mL) was charged at 25-35°C. The reaction mass was heated to 66-72°C, stirred for 15 mins to get clear solution and then cooled to 40-45°C. In another 2 Lit RBF methyl tertiary butyl ether (450 mL) was charged at 25-35°C. To this, above cooled reaction mass was added at 25-35°C over a period of 45 mins. The reaction mass was stirred for 15 mins at 25-35°C. The solid obtained was filtered off, washed with methyl tertiary butyl ether and suck dried for 15 mins. The suck dried solid was initially dried under vacuum for 2 hrs at 25-35°C and finally dried under vacuum for 8 hrs at 69-75°C to get 8.3 g of title compound.
PSD (µm): D10 (1.80); D50 (12.16) & D90 (178)

Comparative Example: Preparation of crystalline Form A of palbociclib as per WO2014128588:
In 1 Lit four necked RBF equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, palbociclib (10 g), n-butanol (160 mL) and anisole (240 mL) was charged at 25-35°C. The reaction mass was heated to 95-100°C and stirred for 15 mins to get clear solution. The reaction mass was then cooled to 80°C, seeded with 0.05 g of seed crystals of Form A of palbociclib suspended in n-butanol (25 mL) and stirred for 3 hrs at 80°C. Then the slurry was cooled to 10°C at 0.2°C/min over 350 mins. The solid obtained was filtered, washed with anisole followed by heptane and then dried under vacuum to get 6.2 g of the title compound.
PSD (µm): D10 (6.12); D50 (24.8) & D90 (115)
Residual solvent (OVI): n-BuOH: 5338 ppm; Anisole: 4925 ppm
,CLAIMS:We Claim:

1. A process for the preparation of crystalline palbociclib having specific surface area greater than 2 m2/g, which comprises;
a) dissolving palbociclib in a mixture of an alcohol and an aromatic solvent at a suitable temperature of about 40°C to reflux,
b) optionally cooling the step a) solution to about 35°C to about 65°C;
c) adding the step a) or the step b) solution to a suitable anti-solvent at a temperature of about 25°C to about 65°C, or vice versa;
d) optionally cooling the step c) reaction mass to about 0°C to about 45°C; and
e) isolating the crystalline palbociclib having specific surface area greater than 2 m2/g; wherein the anti-solvent is selected from ethers, hydrocarbons or mixtures thereof.

2. The process as claimed in claim 1, where in the mixture of an alcohol and an aromatic solvent used in the ratio of about 1:4 to about 4:1.

3. The process as claimed in claim 1, wherein the alcohol is selected from methanol, ethanol and isopropanol; the aromatic solvent is selected from anisole and xylene; ethers are selected from methyl tertiary butyl ether and diisopropylether; and the hydrocarbons selected from heptane, hexane, cyclohexane and mixtures thereof.

4. The process as claimed in claim 1, wherein the alcohol is methanol, aromatic solvent is anisole; and the anti-solvent is methyl tertiary butyl ether.

5. The process as claimed in claim 1, wherein in step b) the addition of step a) solution to anti-solvent is carried out at a temperature of about 25°C to about 65°C.

6. The process as claimed in claim 1, wherein the step b) further comprise of pre-heating the anti-solvent to about 30°C to about 50°C, prior to addition of step a) solution.

7. The process as claimed in claim 1, wherein in step b) the addition of step a) solution to anti-solvent or vice versa is carried out for a period from about 1 min to about 60 mins.

8. The process as claimed in claim 1, wherein the isolation of the crystalline palbociclib having specific surface area greater than 2 m2/g is carried out by cooling the reaction mass temperature to about 25°C to about 35°C followed by filtration.

9. The process as claimed in claim 1, wherein the crystalline palbociclib obtained having residual solvent content of methyl tertiary butyl ether is less than 5000 ppm; methanol is less than 3000 ppm and anisole is less than about 5000 ppm.

10. The process as claimed in claim 1, wherein the crystalline palbociclib obtained having a particle size distribution (PSD) comprising (i) a D10 value in the range from about 1 µm to about 3 µm; (ii) a D50 value in the range from about 4 µm to about 12 µm; and (iii) a D90 value in the range from about 14 µm to about 45 µm.