DESC:FIELD OF THE INVENTION
The present invention relates to the premix of palbociclib, preferably palbociclib - microcrystalline cellulose premix and process for preparation thereof. Also provided is a pharmaceutical composition comprising premix of palbociclib - microcrystalline cellulose and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of cancer.

BACKGROUND OF THE INVENTION
“Palbociclib of Formula I is chemically described as 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one.

Formula I
Palbociclib is commercially available in Europe under the trade name IBRANCE® and is indicated for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.

US6936612 relates to substituted 2-amino pyridines that are potent inhibitors of cyclin- dependent kinase. The compounds of the invention are useful for the treatment of inflammation and cell proliferative diseases such as cancer and restenosis. US’612 also discloses a process for the preparation of palbociclib hydrochloride.

US7781583 relates to novel synthetic routes for the preparation of substituted 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones and their intermediates. It further discloses a process for preparation of palbociclib.

US7863278 relates to salt forms of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one(palbociclib). This also discloses polymorphs of mono-isethionate, mono-mesylate, di-mesylate, mono-hydrochloride and di-hydrochloride salts of palbociclib.

PCT Publication No. WO2014/128588 relates to a crystalline free base of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido [2,3-d]pyrimidin-7-one, having a specific surface area of = 2 m2/g. WO’588 further discloses crystalline Forms A and B of palbociclib free base.

PCT Publication No. WO2018/073574 Al relates to crystalline palbociclib free base Form A, B having a specific surface area = 2m2/g. This application also relates to premix of palbociclib.

Different physical properties exhibited by solid material affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Like palbociclib free base with small particle size is highly static prone and forms small particles, which generates agglomerates as also discussed in WO2014/128588.

The free base obtained from prior art processes viz. US6936612, US7863278 was highly static prone and formed small primary particles, which agglomerated into large, hard agglomerates that were difficult to disperse by sieving and were unsuitable for preparation of pharmaceutical composition for this there is still a need for palbociclib preparation with particle size suitable for handling the material during preparation of dosage form and also a process for such preparation which is efficient, easy to scale up is reproducible and economical.

The present invention provides a palbociclib premix having larger primary particle size that demonstrates improved physicochemical and manufacturability properties like better flowability and less static properties and also provides a very efficient process to preparation of the same.

OBJECTS OF THE INVENTION
It is an object of the present invention to provide palbociclib - microcrystalline cellulose premix and process for its preparation.

Another object of the present invention is to provide a palbociclib - microcrystalline cellulose premix with particle size D (90) =150µm.

Another object of the present invention is to provide a palbociclib - microcrystalline cellulose premix with specific surface area = 2 m2/g.

Another object of the present invention is to provide a pharmaceutical composition comprising palbociclib - microcrystalline cellulose premix.

SUMMARY OF THE INVENTION
It is an aspect of the present invention to provide palbociclib - microcrystalline cellulose premix.

It is another aspect of the present invention to provide palbociclib - microcrystalline cellulose premix having particle size D (90) =150 µm.

Another aspect of the present invention is to provide a palbociclib - microcrystalline cellulose premix with specific surface area = 2 m2/g.

In another aspect, the present application provides a process for the preparation of palbociclib - microcrystalline cellulose premix having particle size D (90) =150 µm comprising the steps of:
a) providing a solution of palbociclib or a salt thereof in suitable solvents or a mixture thereof;
b) adding microcrystalline cellulose;
c) removing the solvent from the mixture obtained in step b);
d) isolating premix of palbociclib - microcrystalline cellulose; and
e) optionally, combining premix of step d) with at least one additional pharmaceutically acceptable excipient.

In another aspect, the present application provides a process for the preparation of palbociclib - microcrystalline cellulose premix having particle size D (90) =150 µm comprising the steps of:
a) providing a solution of palbociclib or a salt thereof in a mixture of methanol and methylene chloride;
b) adding microcrystalline cellulose;
c) removing the solvent from the mixture obtained in step b);
d) isolating palbociclib - microcrystalline cellulose premix; and
e) optionally, combining premix of step d) with at least one additional pharmaceutically acceptable excipient.

Another aspect of the present invention is to provide a pharmaceutical composition comprising palbociclib - microcrystalline cellulose premix.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of palbociclib - microcrystalline cellulose premix.
Figure 2 is an illustrative Differential Scanning Calorimetry pattern of palbociclib - microcrystalline cellulose premix.

DETAILED DESCRIPTION OF THE INVENTION
It is an embodiment of the present invention to provide palbociclib - microcrystalline cellulose premix.

It is another embodiment of the present invention to provide palbociclib - microcrystalline cellulose premix having particle size D (90) = 150 µm.

It is another embodiment of the present invention is to provide a palbociclib - microcrystalline cellulose premix with specific surface area = 2 m2/g.

In another embodiment, the present application provides a process for the preparation of palbociclib - microcrystalline cellulose premix having particle size D (90) = 150 µm comprising the steps of:
a) providing a solution of palbociclib or a salt thereof in suitable solvents or a mixture thereof;
b) adding microcrystalline cellulose;
c) removing the solvent from the mixture obtained in step b);
d) isolating premix of palbociclib - microcrystalline cellulose; and
e) optionally, combining premix of step d) with at least one additional pharmaceutically acceptable excipient.

The solvent used for the process of step a) can be selected from group comprising of hydrocarbon, alcohol, chlorinated hydrocarbon solvents, ether, nitriles, ester, polar solvents, polar aprotic solvents, water and the like or mixture thereof.

In another aspect, the present application provides a process for the preparation of palbociclib - microcrystalline cellulose premix having particle size D (90) =150 µm comprising the steps of:
a) providing a solution of palbociclib or a salt thereof in a mixture of methanol and methylene chloride;
b) adding microcrystalline cellulose;
c) removing the solvent from the mixture obtained in step b):
d) isolating palbociclib - microcrystalline cellulose premix; and
e) optionally, combining premix of step d) with at least one additional pharmaceutically acceptable excipient.

In an embodiment, a solution of palbociclib or a salt thereof in step a) may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

The addition of microcrystalline cellulose may be performed at temperature from 10 to 40 °C, preferably at 25 to 35°C.

The removal of solvent at step c) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure /vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.

The solvent can be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures.

The product can be isolated from the reaction mixture by conventional techniques such as filtration, layer separation and distillation of solvents, spray drying, lyophilization or any other suitable technique known in the art.

In another embodiment palbociclib-microcrystalline cellulose premix obtained by the process of the present invention has a specific surface area of = 2 m2/g.

In another embodiment, the present invention provides palbociclib-microcrystalline cellulose premix particle size distribution (PSD) having D(90) value in the range of from about 150 µm to about 450 µm, preferably, in the range of from about 150 µm to about 390 µm. Most preferably 300 µm to 380 µm.

As used herein, the term "premix" means a composition formed by the admixture of palbociclib and one or more pharmaceutically acceptable polymers, such as Microcrystalline cellulose. D90 or DV(0.9) means that 90% of the total particles are smaller than this size.

In accordance with the present invention, palbociclib-microcrystalline cellulose premix prepared using microcrystalline cellulose can facilitate the bioavailability of the palbociclib. The weight ratio of palbociclib to microcrystalline cellulose can be typically from ranging about 1:4 to 4:1 or any other suitable ratio.

The palbociclib-microcrystalline cellulose premix prepared by the process of the present invention has numerous advantages in term of physical properties such as the free flow property and very less sticking tendency as compared to palbociclib free base. The palbociclib microcrystalline cellulose premix obtained by the process of present invention having larger primary particle size D (90) =150 µm that demonstrates improved physicochemical and manufacturability properties and can be easily used for preparation of pharmaceutical composition.

The palbociclib-microcrystalline cellulose premix according to the present invention can be used for the preparation of pharmaceutical composition of Palbociclib, wherein the said pharmaceutical composition relates to solid oral dosage forms, such as tablets, capsules, sachets, granules, pellets, suspensions, modified release dosage forms, etc. Further, said pharmaceutical composition of Palbociclib comprises of Palbociclib-microcrystalline cellulose premix and at least one of the pharmaceutically acceptable excipients selected from a group of diluents, disintegrants, binders, glidants, lubricants, release-controlling polymers, stabilizers (such as antioxidants, chelators, and pH-modifiers), film-coating polymers, plasticizers, surfactants, colorants, sweeteners, and flavors.

Although the following examples illustrate the present invention in more detail, but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention.

EXAMPLES
Example 1
Preparation of palbociclib - microcrystalline Cellulose Premix. (palbociclib: microcrystalline cellulose (1:2))

To the mixture of methylene chloride (350 ml) and methanol (100 ml), palbociclib (10 gm) was added. The reaction mixture was stirred at 25 to 35°C for 10 to 15 minutes to obtain the solution and microcrystalline cellulose (20 gm) was added. Further, the reaction mass was stirred for 10 to 15 minutes at 25 to 35°C, heated to 40 to 50 °C and (~ 330 ml) of solvent was distilled. Cool the reaction mass to 25 to 35°C, stirred, filtered, washed with methanol and dried to obtain the title compound. (Yield: 28.2 gm) (Particle size: D(90): 359 µm)

Example 2
Preparation of palbociclib - microcrystalline Cellulose Premix. (palbociclib: microcrystalline cellulose (1:1))

To the mixture of methylene chloride (280 ml) and methanol (120 ml), palbociclib (10 gm) was added. The reaction mixture was stirred at 25 to 35°C for 10 to 15 minutes to obtain the solution and microcrystalline cellulose (10 gm) was added. Further, the reaction mass was stirred for 10 to 15 minutes at 25 to 35°C, heated to 40 to 50 °C and (~ 270 ml) of solvent was distilled. Cool the reaction mass to 25 to 35°C, stirred, filtered, washed with methanol and dried to obtain the title compound. (Yield: 18.8 gm) ,CLAIMS:We claim:
1. A process for the preparation of palbociclib - microcrystalline cellulose premix having particle size D (90) = 150 µm comprising the steps of:
a) providing a solution of palbociclib or a salt thereof in suitable solvents or a mixture thereof;
b) adding microcrystalline cellulose;
c) removing the solvent from the mixture obtained in step b);
d) isolating premix of palbociclib - microcrystalline cellulose; and
e) optionally, combining premix of step d) with at least one additional pharmaceutically acceptable excipient.

2. The process as claimed in claim 1, wherein solvent used in step a) selected from group comprising of hydrocarbon, alcohol, chlorinated hydrocarbon, ether, nitriles, ester, polar solvents, polar aprotic solvents, water or mixture thereof.

3. The process as claimed in claim 1, wherein solvent used in step a) selected from group comprising of alcohol, chlorinated hydrocarbon solvents or mixture thereof.

4. The process as claimed in claim 1, wherein solvent used in step a) selected from methanol, dichloromethane or mixture thereof.

5. The process as claimed in claim 1 for the preparation of palbociclib - microcrystalline cellulose premix having particle size D(90) =150 µm comprising the steps of:
a) providing a solution of palbociclib or a salt thereof in a mixture of methanol and methylene chloride;
b) adding microcrystalline cellulose;
c) removing the solvent from the mixture obtained in step b);
d) isolating palbociclib - microcrystalline cellulose premix; and
e) optionally, combining premix of step d) with at least one additional pharmaceutically acceptable excipient.

6. Palbociclib - microcrystalline cellulose premix having particle size D(90)=150 µm prepared according to process as claimed in claim 1 to 5.

7. Palbociclib - microcrystalline cellulose premix having specific surface area of
= 2 m2/g prepared according to process as claimed in claim 1 to 5.

8. The pharmaceutical composition comprising premix of palbociclib - microcrystalline cellulose and one or more of pharmaceutically acceptable excipients prepared according to process as claimed in claim 1 to 5.

9. The pharmaceutical composition comprising premix of palbociclib - microcrystalline cellulose and one or more of pharmaceutically acceptable excipients prepared according to process as claimed in claim 1 to 5 use for the treatment of cancer.