PROCESS FOR PREPARING AMORPHOUS CABAZITAXEL

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

FIELD OF THE INVENTION

The present invention provides a process for preparing amorphous (2a,5fi,7fi,lQ0,\3a)-4-acetoxy-13-({(2/?,35)-3[ {tert -butoxy carbonyl) amino]-2-hydroxy-3-phenylpropanoyl }oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate or Cabazitaxel (I) from Cabazitaxel solvate.
(I)

The present application also provides that amorphous Cabazitaxel (I) obtained by the present invention may be useful as an active pharmaceutical ingredient in pharmaceutical composition having therapeutically usefulness because of its anti-cancer activity.

INTRODUCTION

Cabazitaxel is chemically also known as (2a,5/?J/U0/?,13a)-4-acetoxy-13-({(2i?,3S)-3[(ter/-butoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate (I).

It is approved in USFDA as JEVTANA™ and is chemically mentioned in the label as
(2a,5^,7y9,10y9,13a)-4-acetoxy-13-({(2i?,3S)-3[(rerr-butoxy-carbonyl) amino]-2-hydroxy-3-
phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate -propan-2-one (1:1) solvatomorph (Cabazitaxel : acetone). Cabazitaxel is a white to off-white crystalline powder and is lipophilic in nature, practically insoluble in water.

Bouchard et al in US5847170 provides the first disclosure of (2ei,5#7#10/U3a)-4-acetoxy-13-({(2R,3S)-3 [(terf-butoxy-carbonyl) amino]-2-hydroxy-3 -phenylpropanoyl} oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (also known as Cabazitaxel), which also describes the process for preparing Cabazitaxel.

Kung Liang-Rern et al in US2012149925Al disclose process for preparing Cabazitaxel by reacting beta-lactam side chain with a protected baccatin derivative in the presence of one or more Lewis acids and a base agent, wherein Lewis acid may be selected from LiBr, MgBr2, CsBr, ZnBr2, ZnCl2, CuBr, Cu(CF3S04)2, BF3.OEt2, KBr, TiCl4, SnCl2, ScCl3, VC13, A1C13, InCl3, A12C03, CeCl3, Ag20, ZnC104, LiC104, Ti{OCH(CH3)2}4 or any combination thereof.
Other disclosures related to Cabazitaxel process viz, - CN102532065A , CN102675256A and CN1023367268 also disclose similar processes.

Subsequent to process of Cabazitaxel, the concern has remains for the solid form isolated for
Cabazitaxel. As mentioned earlier, the Cabazitaxel form mentioned in the label as
(2a,5/?,7y9,10)S,13a)-4-acetoxy-13-({(2/?,35)-3[(rerr-butoxy-carbonyl) amino]-2-hydroxy-3-
phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate -propan-2-one (1:1) solvatomorph ( Cabazitaxel : acetone) is designated as Form-A in EMEA scientific discussion as well as in the subsequent patent US7241907.
Further, it appears from the literature that in order to achieve therapeutic role, it is Cabazitaxel base molecule that has to play the role and not necessarily its solvates as long as stable base form is known to exist. In line with this, applicant in US 20120301425A1 (Eq. WO 2011051894A1) on page 2 mentions that Cabazitaxel may be administered in base form, or in the form of a hydrate. It may also be a solvate, i.e. a molecular complex characterized by the incorporation of the crystallization solvent into the crystal of the molecule of the active principle (see in this respect page 1276 of J. Pharm. Sci. 1975, 64(8), 1269-1288). In particular, it may be an acetone
solvate, and, more particularly, may be the solvate described in WO 2005/02846. It may be an acetone solvate of Cabazitaxel containing between 5% and 8% and preferably between 5% and 7% by weight of acetone (% means content of acetone/content of acetone + cabazitaxelx 100). An average value of the acetone content is 7%, which approximately represents the acetone stoichiometry, which is 6.5% for a solvate containing one molecule of acetone.

Didier et al in US7241907 describes a crystalline form as acetone solvate of dimethoxy-docetaxel or 4-acetoxy-2a-benzoyloxy-5/?,20-epoxy-l-hydroxy-7/U0/^dimethoxy-9-oxotax-l 1-en-13ct-yl (2i?,3S)-3-te^butoxycarbonylamino-2-hydroxy-3-phenylpropionate and its process for preparation by crystallization from an aqueous/acetone solution.

Billot Pascal et al in US20110144362 Al appears to cover many crystalline forms, which include crystalline forms as anhydrides, solvates and ethanol hetero-solvates and hydrate forms of 4-acetoxy-2cc-benzoyloxy-5/?,20-epoxy-1 -hydroxy-7/?, 10/?-dimethoxy-9-oxotax-11 -en-13 a-yl (2i?,3S)-3-te^butoxycarbonylamino-2-hydroxy-3-phenyl-propionate. The disclosure in this application provides nearly 11 new polymorphic forms-which include five (5) new crystal forms of Cabazitaxel anhydrous material designated as Form B, C, D, E, F, which are characterized by: Form B- DSC MP. 150° C, Form C- DSC MP. 146 °C, Form D- DSC MP. 175 ° C, Form E-DSC MP. 157 °C and Form F- DSC MP. 148 °C along with their characteristic XRPD pattern.
US20110144362 Al also disclosed four new crystal forms of ethanolate and heterosolvate of Cabazitaxel designated as Form B Ethanolate, Form D Ethanolate, Form E Ethanolate, and Form F Ethanolate/ Water Heterosolvate. Two New Hydrate Forms of Cabazitaxel which include Form C as Monohydrate and Form C as Dihydrate are also part of the disclosure. This patent specification also mentioned that only Form D anhydrous is highly stable, even more stable than acetone solvate form (Form A). This patent application further discloses that other solvates with solvents DCM/ DIPE/ nPA /IPA /Toluene /MIBK /THF/ DMF etc.) were also prepared.

Though the review of the above mentioned literature discloses diverse processes for preparation of polymorphic forms of Cabazitaxel, but due to one or more reasons most of them are not particularly convenient and amenable to industrial scale-up. Thus, there is an apparent need of new improved processes for preparation of Cabazitaxel polymorphs, which may be efficient, cost-effective, industrially amenable and may overcome the drawbacks of various prior disclosed processes, e.g., multiple solvent combinations as well as multiple steps.

Therefore, inventors of the present application provide a process for preparation of amorphous
form of Cabazitaxel, which is amenable to scale up at industrial level and may solve purity/
compliance related issues of the end product.

SUMMARY OF INVENTION

Particular aspects of the present specification relate to the process for preparation of amorphous Cabazitaxel from Cabazitaxel solvate.
In one aspect of the present application, the present invention provides process for preparing amorphous form of Cabazitaxel (I) characterized by X-ray powder diffraction pattern as per Fig-1 from Cabazitaxel solvate.

In another aspect of the present application, it relates to process for preparing amorphous Cabazitaxel (I) comprising the steps of a.providing a solution of (2a,5)8,7^,10/?,13a)-4-acetoxy-13-({(2i?,3S)-3[ (tert-butoxy carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9- oxo-5,20-epoxytax-ll-en-2-yl benzoate solvate (Cabazitaxel solvate) with a water miscible alcohol solvent; b. maintaining the reaction mass under stirring to dissolve completely at temperature ranging from 10-35°C; c. heating the solution up to the temperature ranging from 40-60°C; d. holding the solution under stirring for alteast 20 minutes but not more than 60 minutes; e. removing the solvent and isolating the amorphous Cabazitaxel.

In another aspect, the present invention also relates to a composition comprising amorphous Cabazitaxel (I), of which at least 95%, by total weight of the Cabazitaxel (I) in the composition,
is the amorphous Cabazitaxel prepared according to the process of the present invention. The composition is substantially free of any known forms of Cabazitaxel solvate or any other crystalline form.

Further particular aspects of the invention are detailed in the description of invention, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of Amorphous Cabazitaxel obtained according to the process given in Example I.

Fig. 2 is an example of a differential scanning calorimetry ("DSC") curve of Amorphous Cabazitaxel obtained according to the process given in Example I.

Fig. 3 is an example of X-ray powder diffraction ("XRPD") pattern of Cabazitaxel Ethyl Acetate solvate crystalline Form-SC obtained according to the process given in Reference example-02.

Fig. 4 is an example of a differential scanning calorimetry ("DSC") curve of Cabazitaxel Ethyl Acetate solvate crystalline Form-SC obtained according to the process given in Reference example-02.

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention relate to a process for preparation of amorphous form of Cabazitaxel from Cabazitaxel solvate.

In one embodiment of the present application, it provides a process for preparing amorphous form of Cabazitaxel (I) characterized by X-ray powder diffraction pattern as per Fig-1 from Cabazitaxel solvate, indicating a solid form that lacks the long-range order (a characteristic of crystal) and having no pattern or structure.

In another embodiment of the present invention, it provides a process for preparing amorphous form of Cabazitaxel from Cabazitaxel solvate characterized by DSC curve as per Fig-2.
In an embodiment of the present application, it provides a process for preparation of amorphous Cabazitaxel, comprising the steps of-

a) providing a solution of (2a,5y9,7y9,10y9,13a)-4-acetoxy-13-({(2i?,35)-3[ (tert-butoxy carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate solvate (Cabazitaxel solvate) with a water miscible alcohol solvent;

b) maintaining the reaction mass under stirring to dissolve completely at temperature ranging from 10-35 °C;

c) heating the solution up to the temperature ranging from 40-60 °C;

d) holding the solution under stirring for alteast 20 minutes but not more than 60 minutes;

e) removing the solvent and isolating the amorphous Cabazitaxel.

The individual steps of the process according to the present invention for preparing amorphous Cabazitaxel are detailed separately herein below.

Step a) comprises providing a solution of (2a,5j8,7/U0/U3a)-4-acetoxy-13-({(2i?,3S)-3[ (tert-butoxy carbonyl) amino] -2-hydroxy-3 -phenylpropanoyl} oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate solvate (Cabazitaxel solvate) with a water miscible alcohol solvent.

A solution of (2a,5/?,7/U0/?,13a)-4-acetoxy-13-({(2#,3S)-3[ (tert-butoxy carbonyl) amino]-2-hydroxy-3-phenylpropanoyl} oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11 -en-2-yl benzoate solvate or Cabazitaxel solvate with a water miscible alcohol solvent is provided at temperature ranging between 20-30 °C. (2a,5/?,7/?,10/?,13a)-4-acetoxy-13-({(2i?,3S)-3[ (tert-butoxy carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate solvate or Cabazitaxel solvate according to the present invention may be selected from ethyl acetate solvate, acetone solvate, ethanol solvate, monohydrate or dihydrate form of Cabazitaxel.

In an embodiment of the present invention, Cabazitaxel solvate is provided as a solution in a water miscible alcohol solvent selected from optionally substituted CI to C3 alcohol (straight or branched). Non-limiting examples of water miscible alcohol solvent according to the present invention include methanol, ethanol, n-propanol, iso-propanol etc.
Step b) comprises maintaining the reaction mass under stirring to dissolve completely at temperature ranging from 10-35 °C;

The reaction mass obtained from step a) is maintained under stirring at a temperature ranging from 10-35 °C. In one of the particular embodiment, stirring of the reaction mass was done at temperature of 25-30 °C. Stirring of the reaction mass is done for the time duration ranging between 10 to 60 minutes; however, depending upon the progress of the reaction-it may extend in order to achieve the complete dissolution. Further, this step may have apparent permissible variations in certain parameters depending upon the actual reaction conditions employed, achievement of the desired solution nature more particularly a clear solution and achieving impurity profile compliance.

Step c) comprises heating the solution up to the temperature ranging from 40-60 °C. The temperature of the reaction solution obtained in step b) is raised to 40-60 °C. In a particular embodiment, the temperature of reaction solution obtained from step b) was raised to 50-55 °C.

Step d) comprises holding the solution under stirring for at least 20 minutes but not more than 60 minutes. The solution is maintained for time duration of 20-60 minutes at the raised temperature of 40-60 °C. The time duration of stirring depends upon the progress of the reaction, which is checked intermittently during the reaction.

Step e) comprises removing the solvent and isolating the amorphous Cabazitaxel. The solvent is recovered at a temperature above 40 °C, till dryness is achieved in the reaction material. This is followed by isolation of amorphous Cabazitaxel.

In certain observations by inventors of the present application, it was also found that removing the solvent incompletely (i.e. removing at least 60-90 % of the total solvent used) followed by adding an anti-solvent having higher boiling point at temperature above 40 °C may also result in amorphous form of said material, which may have composition of amorphous up to alteast 95% or more.

X-ray diffraction provides a convenient and practical means for quantitative determination of the relative amounts of crystalline and/or amorphous forms in a solid mixture. X-ray diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks, particularly long range peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture. The percent composition of amorphous Cabazitaxel in an unknown composition can be determined. Preferably, the measurements are made on solid powder Cabazitaxel or its solvate. The X-ray powder diffraction patterns of an unknown composition can be compared to known quantitative standards containing the pure amorphous form of Cabazitaxel to identify the percent ratio of amorphous /crystalline content. This is done by comparing the relative intensities of the peaks from the diffraction pattern of the unknown solid powder composition with a calibration curve derived from the X-ray diffraction patterns of pure known samples. The curve can be calibrated based on the X-ray powder diffraction pattern for the strongest peak or any distinctive peak from a pure sample of the crystalline form of Cabazitaxel or its solvate. The calibration curve may be created in a manner known to those of skill in the art.

For example, two or more artificial mixtures of crystalline forms of Cabazitaxel or its solvate, at different amounts, may be prepared. In a non-limiting example, such mixtures may contain, 2%, 5%, 7%, 8%, and 10% of the amorphous form of cabazitaxel. Then, X-ray diffraction patterns are obtained for each artificial mixture using standard X-ray diffraction techniques. Slight variations in peak positions, if any, may be accounted for by adjusting the location of the peak to be measured. The intensities of the selected characteristic peak(s) for each of the artificial mixtures are then plotted against the known weight percentages of the amorphous form. The resulting plot is a calibration curve that allows determination of the amount of the amorphous /crystalline form of cabazitaxel in an unknown sample. For the unknown mixture of the crystalline and amorphous forms of cabazitaxel, the intensities of the selected characteristic peak(s) in the mixture, relative to an intensity of this peak in a calibration mixture, may be used to determine the percentage of the given crystalline form in the composition, with the remainder determined to be the amorphous material.

Process of isolating amorphous form of Cabazitaxel comprise processes but not limited to conventional processes including scrapping, if required filtering from slurry and optional drying, which may be carried out at room temperature for the suitable durations to retain the amorphous form characteristics.

The merit of the process according to the present invention resides in that - product obtained after recovery is directly obtained in amorphous form of Cabazitaxel, with consistency in regular production batches. Said material was found devoid of any crystal lattice and adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

The process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appear in the impurity profile of the Cabazitaxel may be substantially removed by the process of the present invention resulting in the formation substantially pure amorphous form. Substantially pure amorphous form of Cabazitaxel obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% w/w.

The amorphous form of Cabazitaxel described herein may be characterized by X-ray powder diffraction pattern (XRPD) and thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of amorphous form of Cabazitaxel were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for the amorphous form of Cabazitaxel obtained in the examples are set forth in the Figs. 1-2.

In a further embodiment according to the present application, the present invention also relates to a composition containing amorphous Cabazitaxel, provided that at least 95% by total weight of Cabazitaxel in the composition is the amorphous form obtained according to the present invention. In yet another embodiment of the invention, the composition may be substantially free of any other known forms of Cabazitaxel solvate or any other crystalline form.

The amorphous form of Cabazitaxel (I) obtained by the process of the present application, may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with amorphous form of Cabazitaxel (I) obtained by the process of the present application, while retaining the amorphous nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising amorphous form of Cabazitaxel derived from the process according to the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of amorphous form of Cabazitaxel of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation. Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLE

Cabazitaxel and its solvates utilized for preparing amorphous Cabazitaxel in the present invention process were obtained by the multistep procedure, which is detailed in the stepwise demonstration mentioned herein below- Reference example-01: Process for preparation of cabazitaxel STEP-A: Preparation of T triethylsilyl protected Cabazitaxel A solution of Lithium bis(trimethylsilyl) amide (LiHMDS) (0.9 M/THF, 11.7 ml, 10.4 mmol) was added drop wise over 5 min to a stirred suspension of 7,10-Dimethoxy 10-DAB-III (SMI) (5.0 g, 8.7 mmol) in THF (125 ml) at -10 to -5°C under nitrogen atmosphere. The reaction mixture was stirred for 5-10 min at -10 to -5°C under nitrogen atmosphere. Added triethylsilyl protected lactam (SM2) (5.0 g, 13.1 mmol) to the reaction mixture at -10 to -5°C over a period of 5 min. The reaction mixture temperature was raised to 20-25°C and stirred for lh.

The reaction mixture was cooled to 10-15°C, quenched with saturated ammonium chloride (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water followed by saturated sodium chloride solution. The organic layer was dried over sodium sulphate and concentrated to yield crude triethylsilyl protected Cabazitaxel (SM3) (7.5 g, Yield: 90%, Purity: 85.59%). The crude triethylsilyl protected Cabazitaxel was further purified by column chromatography over silica gel (100-200 mesh) using ethyl acetate and hexane to get a product (5.2 g, Yield: 62.6%, Purity: 94.97%).

STEPS: Purification of 2' triethylsilyl protected Cabazitaxel

To the triethylsilyl protected Cabazitaxel (3.2 g) obtained above was added 8.64 ml of ethyl acetate. The resulting suspension was stirred for 10 min at 60-65°C. The reaction mass was cooled to 45-50°C and 17.28 ml of hexane was added drop wise over a period of 30 min. The resulting slurry was cooled to 20-25°C over a period of 1 h and stirred for 30 min. The solid was filtered and washed with 6.4 ml of hexane and dried to obtain triethylsilyl protected Cabazitaxel (1.8 g, Yield: 56.0%, Purity: 99.46%).

STEP-C: Deprotection of 2' triethylsilyl protected Cabazitaxel SM3 «

In a solution of tetra-n-butyl ammonium fluoride (1 M/THF, 3.2 ml, 3.1 mmol) was added a solution of 2' triethylsilyl protected Cabazitaxel (2.5 g, 2.6 mmol) in THF (50.0 ml) at 0-5°C under nitrogen atmosphere. The resulting solution was stirred for 1 hr at 0-5°C. The reaction mixture was diluted with ethyl acetate (50.0 ml) and quenched with saturated ammonium chloride solution (50.0 ml) at 0-5°C. The organic layer was separated and washed with water (2x50.0 ml) followed by saturated sodium chloride solution (50.0 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated to yield 2 g of crude cabazitaxel.

STEP-D: Purifying the crude Cabazitaxel Crude Cabazitaxel (2 gm) was dissolved in ethyl acetate (50mL) and heated to 60-65 °C and stirred for 10 min. The ethyl acetate was distilled up to 8 mL and the suspension was stirred for lh at room temperature and filtered. The filter bed was washed with 30% ethyl acetate in hexane (10 ml) and dried to obtain pure cabazitaxel (1.56 g, Yield: 72.0%, Purity: 99.48%).

Reference example-02: Preparation of Cabazitaxel ethyl acetate solvate (1:1) i.e. Crystalline Form-SC To the compound obtained above in Reference example-01 (1.5 g) was added ethyl acetate (7.5 ml) at 25-30 °C and the suspension was stirred for 6 hrs at 25-30°C. The solid was filtered and washed with 30% ethyl acetate in hexane (3.0 ml) an dried under vacuum at 40-45 °C for 6 h to yield Cabazitaxel ethyl acetate solvate i.e. Form-SC (1.4 g) having M. Pt. of 159-162 °C. (XRPD pattern as per Fig-3; DSC isotherm as per Fig-4)

Reference example-03: Preparation of Cabazitaxel acetone solvate In a RB flask equipped with magnetic stirrer, and thermometer, Cabazitaxel ethyl acetate solvate (2.0 g) was dissolved in acetone (10 ml x 2 ) at 25-30°C and acetone was distilled up to 1.0 vol at 45-50°C (Bath temperature) under reduced pressure. The reaction mass was cooled, diluted with acetone (18 ml) and stirred for 10 min at 25-30°C. DM water (10.0 ml) was slowly added to the above mass over a period of 30 min at 25-30°C, followed by seeding with Cabazitaxel acetone solvate (20 mg) and the resulting suspension was stirred for 22 hrs at 25-30°C. DM water (15.0 ml) was slowly added over a period of 2-3 hrs at 25-30 °C and stirred for 2 hrs. The solid was vacuum filtered and washed with acetone water mixture (10.0 ml i.e. acetone-4.5 ml and water-5.5 ml) to yield Cabazitaxel acetone solvate having melting point of 158-164 °C (1.8 g, Yield: 90.0%, HPLC Purity: 99.95%).

Example I: Preparation of Amorphous Cabazitaxel from Cabazitaxel Ethyl acetate solvate:
In a RB flask equipped with magnetic stirrer, thermometer and a gas bubbling tube was added (2a,5^,7y9,10)9,13a)-4-acetoxy-13-({(2i?,3S)-3[ (tert-butoxy carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (I) ethyl acetate solvate (200 mg) and 16 ml of methanol at room temperature. Stir the reaction mass to dissolve completely at 25-30°C for 15-20 minutes. Raise the temperature of the clear solution
up to 50-55°C. Maintain the temperature for 30 min and recover the solvent at this temperature up to dryness to afford amorphous material (XRPD pattern as per Fig-1; DSC isotherm as per Fig-2) Yield: 150 mg

Example II: Preparation of Amorphous Cabazitaxel from Cabazitaxel acetone solvate:
In a RB flask was equipped with magnetic stirrer and thermometer, Cabazitaxel acetone solvate (500 mg) was dissolved in methanol (40.0 ml) and stirred at 25-30°C for 15-20 min. The above clear solution was filtered and the temperature was raised to 50-55°C. The reaction mass temperature was maintained for 30 min and the solvent was recovered at this temperature up to dryness to afford amorphous material. Yield: 400 mg

While the foregoing provides a detailed description of the preferred embodiments of the invention, it is to be understood that the descriptions are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims: i

1) A process for preparing amorphous Cabazitaxel (I) characterized by X-ray powder
(I) diffraction pattern as per Fig-1 comprising the steps of-

a) providing a solution of (2a,5y?,7^,10/?,13a)-4-acetoxy-13-({(2i?,35)-3[ (tert-butoxy carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate solvate (Cabazitaxel solvate) with a water miscible alcohol solvent;

b) Maintaining the reaction mass under stirring to dissolve completely at temperature ranging from 10-35 °C;

c) Heating the solution up to the temperature ranging from 40-60 °C;

d) Holding the solution under stirring for alteast 20 minutes but not more than 60 minutes;

e) removing the solvent and isolating the amorphous Cabazitaxel.

2) A process for preparing amorphous Cabazitaxel (I) according to claim 1, wherein a solution of (2a,5/?,7/?,10#13a)-4-acetoxy-13-({(2i?,3S)-3[ (tert-butoxy carbonyl) amino]- 2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax- 1 l-en-2-yl benzoate solvate (Cabazitaxel solvate) with a water miscible alcohol solvent is provided at temperature ranging between 20-30 °C.

3) A process for preparing amorphous Cabazitaxel (I) according to claim 1 or 2, wherein,
(2a,5y?,7/?,10/?,13a)-4-acetoxy-13-({(2i?,35)-3[ (tert-butoxy carbonyl) amino]-2-hydroxy-
3 -phenylpropanoyl} oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11 -en-2-yl benzoate solvate (Cabazitaxel solvate) is selected from ethyl acetate solvate, acetone solvate, ethanol solvate, monohydrate or dihydrate form of Cabazitaxel.

4) A process for preparing amorphous Cabazitaxel (I) according to claim 1 or 2, wherein water miscible alcohol solvent is selected from optionally substituted CI to C3 alcohol (straight or branched).

5) A process for preparing amorphous Cabazitaxel (I) according to claim 4, wherein CI to C3 alcohol (straight or branched) is selected from methanol, ethanol, n-propanol or iso-propanol.

6) A process for preparing amorphous Cabazitaxel (I) according to claim 1, wherein the process of removing the solvent and isolating the amorphous Cabazitaxel further comprises the steps of- i.recovering the solvent at temperature above 40 °C; ii. achieving dryness in the material; iii. Isolating amorphous Cabazitaxel.

7) A pharmaceutical composition comprising amorphous Cabazitaxel prepared according to any of the preceding claims, with alteast one or more pharmaceutically acceptable carrier or excipients.