DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

PURIFICATION METHOD OF CABAZITAXEL

LAURUS LABS LIMITED, an Indian Company, of 2nd Floor, Serene Chambers, Road #7, Banjara Hills, Hyderabad – 500 034, India.

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION

The present invention generally relates to a process for purification of cabazitaxel using preparative high performance liquid chromatography (HPLC).

BACKGROUND OF THE INVENTION

Cabazitaxel is a semi-synthetic toxoid derivative, known as 4a-acetoxy-2a-benzyloxy-5ß, 20-epoxy-1-hydroxy-7ß,10ß-dimethoxy-9-oxo-11-taxen-13a-yl(2R,3S)-3-tert-butoxy carbonyl amino-2-hydroxy-3-phenylpropionate, has the following structure:

Cabazitaxel

Cabazitaxel is marketed as its acetone solvate under the trade name JEVTANA® for the treatment of hormone-refractory prostate cancer in combination with prednisone. JEVTANA® is prescribed as single use vial 60 mg of cabazitaxel/1.5 ml supplied with diluents (5.7 ml).

Cabazitaxel and a process for its preparation are disclosed in U.S. Patent No. 5,847,170 (“the ‘170 patent”). The process disclosed in the ‘170 patent is schematically represented as follows:

The ‘170 patent disclosed process involves purification of finally obtained cabazitaxel by preparative thin layer chromatography plates(12 Merck preparative silica gel 60F254 plates, thickness 1 mm) using a mixture of methanol and dichloromethane(5:95 by volume) as an eluent. After localization with UV rays of the zone corresponding to the adsorbed desired product, this zone was scraped off, and the silica collected was washed on sintered glass and evaporation of the solvents under reduced pressure to obtain ivory-coloured foam. However, the preparative thin layer chromatography is not viable on large scale manufacturing as it involves tedious manual localization with UV rays of product zone and scratching it to collect pure product. One of the other main disadvantages of using preparative thin layer chromatography is isolation of the required product as limited amount of material can only be isolated from the plates.

PCT publication No.(s)2014/184807(“the ‘807 publication”) and 2014/199401 (“the ‘401 publication”) discloses a process for preparation of cabazitaxel by involving deprotection of coupled product oxazolidine ring using formic acid as a deprotective agent to obtain free amine intermediate and converting the free amine in to cabazitaxel. The disclosed processes involve purification of the obtained cabazitaxel using silica gel column chromatography or by using crystallization methods. The process disclosed in the ‘807 and ‘401 publication is schematically represented as follows:

By repetition of the ‘807 and ‘401 process, present inventors have observed that the process of Formula D involves formation of numerous process impurities including major formyl impurity of Formula-1 by formylation of free amine of Formula-D with formic acid used for deprotection. The other process impurities are identified based on the relative retention time (RRT). The formyl impurity further reacts in subsequent step with boc-anhydride and forms corresponding boc-formyl impurity of Formula-2. The formyl impurity is very difficult to separate from cabazitaxel even after repeated purifications using either by silica gel column chromatography or by recrystallizations. The list of impurities is listed below and the details of the repetition process are captured in experimental section.

(RRT 0.59; LC-Mass: 763)
(RRT 1.25; LC-Mass: 864)
Other Impurities identified based on RRT’s:

RRT 0.21 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.26 1.34 1.37 1.42
LC-Mass 735 853 835 853 865 881 881 835 847 817 935 875

Presence of impurities in a pharmaceutical compound is undesirable, in extreme cases, might even be harmful to a patient, and health authorities in many jurisdictions (e.g. the Food and Drug Administration in the United States) have established guidelines relating to acceptable levels of impurities in pharmaceuticals. The need for and commercial utility of methods of reducing the level of impurities in any pharmaceutical are self-evident.

The process described in art are mostly involved purification of cabazitaxel either using silica-gel column chromatography or by crystallization methods only. The purification methods described in the prior-art are very difficult to eliminate the impurities completely specifically for formyl impurities; moreover the procedures are laborious and yield losses are very high.

As the selection of purification method is important for getting the high pure compound with less cumbersome techniques, the present invention aims to propose a simple purification system, which is more robust, user convenient and up-scalable process for the purification of cabazitaxel.

The present invention provides a process for purification of crude cabazitaxel by preparative high performance liquid chromatography(HPLC) that reduces the purification time by providing easy separation of impurities with higher yield and also avoiding the repetition of purifications.

SUMMARY OF THE INVENTION

In accordance with one embodiment, the present invention provides a process for purification of cabazitaxel, by subjecting the crude cabazitaxel to a preparative high performance liquid chromatography (HPLC)by eluting with a suitable eluent or a mixture of eluents to obtain pure cabazitaxel.

Cabazitaxel

In accordance with another embodiment, the present invention provides a process for purification of cabazitaxel, comprising:
a) dissolving a crude cabazitaxel in a suitable solvent or a mixture thereof,
b) subjecting the solution to a preparative high performance liquid chromatography (HPLC)by eluting with a suitable eluent or a mixture of eluents,
c) collecting pure fractions of cabazitaxel, and
d) isolating the pure cabazitaxel.

In accordance with another embodiment, the present invention provides a process for purification of cabazitaxel, comprising: subjecting crude cabazitaxel to a preparative high performance liquid chromatography (HPLC)by eluting with a suitable eluent or a mixture of eluents to obtain a pure cabazitaxel.

In accordance with another embodiment, the present invention providesa process for purification of cabazitaxel substantially free from formyl impurity of Formula-1 and boc-formyl impurity of Formula-2; comprising: subjecting crude cabazitaxel to a preparative high performance liquid chromatography (HPLC)by eluting with a suitable eluent or a mixture of eluents to obtain a pure cabazitaxel.

In accordance with another embodiment, the present invention provides cabazitaxel substantially free of one or more of following relative retention time (RRT) impurities:
RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.26 1.34 1.37 1.42
LC-Mass 735 763 853 835 853 865 881 881 835 847 817 935 875

In accordance with another embodiment, the present invention provides cabazitaxel substantially free of formyl impurity of Formula-1.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising cabazitaxel purified by the process of the invention 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 represents purification results of cabazitaxel obtained from the known purification methods and preparative HPLC method.

DETAILED DESCRIPTION OF THE INVENTION

The purification methods described for cabazitaxel in the art are involved either by silica-gel column chromatography or by crystallization methods. The known purification methods are very difficult to eliminate the process impurities completely, specifically formyl impurity of Formula-I even after repeated purifications either by silica-gel column chromatography or by crystallization methods. Moreover the known purification methods are not enough to get required purity and the known methods are laborious and yield losses are very high. To overcome the difficulties associated with the art, the inventors of the present invention have surprisingly found that purification of cabazitaxel using preparative high performance liquid chromatography (HPLC), which involves mainly eliminating process impurities, specifically formyl impurity of Formula-I and obtained more yields when compared to known purification methods of silica-gel column chromatography and crystallization methods. Therefore, cumbersome silica-gel column purifications and/or multiple crystallizations are avoided.

In accordance with one embodiment, the present invention provides a process for purification of cabazitaxel, comprising: subjecting crude cabazitaxel to a preparative high performance liquid chromatography (HPLC) by eluting a suitable eluent or a mixture of eluents, to obtain pure cabazitaxel.

Cabazitaxel

In a specific embodiment, the present invention provides a process for purification of cabazitaxel, comprising:
a) dissolving a crude cabazitaxel in a suitable solvent or a mixture thereof,
b) subjecting the solution to a preparative high performance liquid chromatography (HPLC) by eluting with a suitable eluent or a mixture of eluents,
c) collecting pure fractions of cabazitaxel, and
d) isolating the pure cabazitaxel.

All of the steps of the above process are individually described herein below.

The crude cabazitaxel may be prepared by any known processes; including process disclosed in WO2014/184807 or WO2014/199401, the content of which is incorporated herein by reference.

The "crude cabazitaxel" refers to cabazitaxel having the purity of about 96%, as measured by HPLC; preferably purity of about 98%, as measured by HPLC; more preferably purity of about 99%, as measured by HPLC; and having content of total impurities about 4%, as measured by HPLC; preferably total impurities about 2%, as measured by HPLC; more preferably total impurities about 1%, as measured by HPLC.

A purification process of the present invention is carried out by eluting cabazitaxel through a preparative high performance liquid chromatography (HPLC) column, wherein the column is packed under a dynamic axial compression mode with operating pressures up to about 100 bar with a silica gel which is suitable to separate pure cabazitaxel from its impurities, for exampleYMC-GEL-Sil250 x 30 mm to 500 x 50 mm with about 5-50 µm particles, preferably 250 x 50 mm with about 10 µm particles. Flow rate of the mobile phase may be selected from about 10 ml to 80 ml per minute, preferably about 30 ml to 60 ml per minute, more preferably about 50 ml per minute. Conditions for the preparative column chromatography are known to the person skilled in the art.

The step a) of forgoing process involves, dissolving the crude cabazitaxel in a suitable solvent or a mixture thereof at a temperature of about 25-35°C to obtain a solution.

The suitable solvent used herein in step a) is selected from a solution in which cabazitaxel can dissolve completely. Example for the suitable solvent include, but is not limited to alcohols, ketones, nitriles, ethers, halogenated hydrocarbons, esters and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, isopropanol, butanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tertiary butyl ether and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; esters include, but are not limited to ethyl acetate, methyl acetate, isopropyl acetate and the like and mixtures thereof; preferably a mixture of methylene chloride and ethyl acetate.

Optionally the step a) solution may be filtered to remove any undissolved particles present in solution.

The step b) of forgoing process involves, subjecting the step a) solution to a preparative high performance liquid chromatography (HPLC) by eluting with a suitable eluent or a mixture of eluents.

The suitable eluent used herein in step b) is selected from, but is not limited to alcohols, ketones, nitriles, ethers, halogenated hydrocarbons, esters, aliphatic hydrocarbons and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, isopropanol, butanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tertiary butyl ether and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; esters include, but are not limited to ethyl acetate, methyl acetate, isopropyl acetate and the like;aliphatic hydrocarbons include, but are not to hexane, heptane, propane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; and mixtures thereof; preferably a mixture of ethyl acetate and heptane.

The eluent may be used in a ratio of about 10:90 to about 90:10 of ethyl acetate and heptane; preferably about 40:60 to about 60:40; more preferably 60:40 of ethyl acetate and heptane.

The step c) of forgoing process involves, collecting the pure fractions of cabazitaxel from high performance liquid chromatography (HPLC) and pooling.

During elution, desired fractions are collected at regular intervals and analyzed for purity. The suitable collected fractions containing the product of similar purities may be pooled together and subjected to removal of solvent under vacuum at below 40°C to obtain pure cabazitaxel.

In another embodiment, the present invention provides cabazitaxel, obtained by the purification process described herein, substantially free of one or more of following relative retention time (RRT) impurities:

RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.26 1.34 1.37 1.42
LC-Mass 735 763 853 835 853 865 881 881 835 847 817 935 875

In another embodiment, the present invention provides cabazitaxel, obtained by the purification process described herein, having a purity of at least about 97%, as measured by HPLC, preferably at least about 99% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC; having total impurities less than 0.5%, as measured by HPLC, preferably less than 0.2%, as measured by HPLC; and substantially free of formyl impurity of Formula-I; where in the word “substantially free” refers to said impurity is less than 0.05%as measured by HPLC, preferably less than the detectable value by HPLC.

In another embodiment, the present invention provides cabazitaxel, obtained by the purification process described herein, substantially free of formyl impurity of Formula-1.

The known purification methods described for cabazitaxel in the art are involved either by silica-gel column chromatography or by crystallization methods, which methods are not effective in either decreasing the process impurities or obtaining the desired pure API. The present invention provides a process for purification of cabazitaxel using preparative high performance liquid chromatography (HPLC), which involves mainly eliminating process impurities, specifically formyl impurity of Formula-I and getting highest yield when compared to known purification methods of silica-gel column chromatography and crystallization methods. The results obtained from the known purification methods and preparative HPLC methods are summarized in Figure -1.

From the Figure 1, purification using Preparative HPLC of the current invention results Cabazitaxel with purity about 99.9% by HPLC and having yield of 0.63w/w. whereas from other methods either from silica column chromatography method or repeated crystallization procedures, Cabazitaxel obtained with less pure and lower yield. The following Table summarizes the results obtained from these three variations:

Crude Silica Chromatography Preparative HPLC RC from DCM/heptanes RC from Ethyl acetate/ heptane
Yield (w/w) -- 0.44 0.63 0.4 0.35
Purity
(%) 97.2 99.7 99.9 99.5 99.6

The present invention provides purification of cabazitaxel by preparative HPLC method, obtained by the above process, as analyzed using the high performance liquid chromatography (“HPLC”) with the conditions described below:
Column Sunfire C18, 150×4.6
Mobile phase Mobile phase-A: Potassium dihydrogen phosphate in Milli-Q-Water.
Mobile phase-B: Acetonitrile
Flow rate 1.0mL/min
Detection 220nm
Injection volume 10µL
Run time 70 minutes
Elution Gradient
Time in min Mobile phase A
(% v/v) Mobile phase B
(% v/v)
0 70 30
60 20 80
65 70 30
70 75 25

In another embodiment, the present invention provides a pharmaceutical composition comprising cabazitaxel purified by the process of the invention and at least one pharmaceutically acceptable excipient.

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

REFERENCE EXAMPLE:

Preparation of cabazitaxel from coupled product of Formula-C

To a 5lit round bottom flask fitted with a mechanical stirrer, thermometer was charged formic acid (1.5 lit) at 25-30°C. Reaction mass was allowed to cool to 18-20°C and charged coupled product of Formula-C (100 g) for 10-15 min at same temperature. Reaction mass was stirred for 3-4 hrs at same temperature. After completion of the reaction, reaction mass was allowed to cool to 10-15°C and was charged dichloromethane (1.5 lit). pH of the reaction mass was adjusted to 8-8.5 with ammonia (3.5 lit) and the reaction mass was heated to 25-35°C.Separated the organic layer and aqueous layer was extracted dichloromethane (500 ml). Then the combined organic layer was washed with aq ammonia solution (5 ml in 500 ml water), with aq sodium bicarbonate solution (25 g in 500 ml water), with water (500 ml) and with sodium chloride solution (25 g in 500 ml water) sequentially. Combined organic layer was completely distilled under vacuum at below 30°C to obtain a residue. Wt: ? 85 g.

To a 5 lit round bottom flask fitted with a mechanical stirrer, thermometer was charged the above obtained residue and ethyl acetate (2 lit) at 25-35°C. To the reaction mass was added boc-anhydride (40g) and allowed to stir for 8-10 hrs at same temperature. After completion of the reaction, to the reaction mass was added water (1 lit) and ethyl acetate (500 ml) at 25-30°C.Separated the organic layer and aqueous layer was extracted ethyl acetate (500 ml). Then the combined organic layer was washed with water (1 lit) and with aq sodium chloride solution (50 g in 1 lit) sequentially. Combined organic layer was distilled out ? 300 ml under vacuum at below 35°C.Remaining organic layer was heated to reflux for 1 hr. The reaction mass was allowed to cool to 20-25°C and precipitated solid was filtered and washed with ethyl acetate (100 ml). The wet product was dried at about 45°C to about 50°C under vacuum to provide the title compound. Wt: 100 g; Purity by HPLC: 97.2% (Retention time: 37.47).

Impurity profile of cabazitaxel according to Reference Example:

Impurity at RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.25 1.26 1.34 1.37 1.42
% by HPLC 0.01 0.9 0.01 0.09 0.01 0.05 0.02 0.01 0.41 0.36 0.03 0.44 0.23 0.23

EXAMPLE-1:

Purification of crude cabazitaxel using preparative high performance liquid chromatography (HPLC):

Preparative HPLC conditions:

HPLC instrument Knauer-Azura
Column YMC GEL SIL (250 x 50) mm,10µ
Mobile phase Hexane: Ethylacetate (60:40)
Flow rate 50 mL/min
Elution Mobile phase (100%)
Detection UV at 270 nm
Injection volume 30(±6) mL
Run time 120 mim
Mode Isocratic

Injection sample preparation: Crude cabazitaxel was dissolved in a mixture of dichloromethane and ethyl acetate at 25-35°C.

HPLC column packing: Prepared YMC GEL silica (Sil6nm S-10µ; 300g) slurry by adding ethyl acetate under stirring at 25-30°C. Column was packed with the prepared silica slurry up to the bed length of ? 25 cm. Column was compressed to a pressure of 70 bars with pressure 60-80 bar.

Procedure: Stabilized the column by washing with a mobile phase of hexane: ethylacetate (60:40) for 30 minutes. Loaded the sample solution onto the column with a flow rate of 50 mL/min and eluted with mobile phase of hexane: ethylacetate (60:40).The fractions related to pure cabazitaxel was collected from 30 to 40 minutes of retention time and the purity of collected fractions was analyzed by using YMC GEL SIL (250 x 50) mm, 10µ. Pure fractions of cabazitaxel were concentrated under vacuum at below 40°C to obtain a pure cabazitaxel.
Input wt: 30 gr; Purity by HPLC: 97.2%;
Output wt: 18.8 gr; Purity by HPLC: 99.9%; Yield: 0.63 (w/w)

Impurity profile of cabazitaxel according to Example-1:

Impurity at RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.25 1.26 1.34 1.37 1.42
Before purification
% by HPLC 0.01 0.9 0.01 0.09 0.01 0.05 0.02 0.01 0.41 0.36 0.03 0.44 0.23 0.23
After purification
% by HPLC Nil Nil Nil Nil Nil 0.04 Nil Nil Nil 0.06 Nil Nil Nil Nil

COMPARATIVE EXAMPLE-1:

Purification of crude cabazitaxel using silica-gel column chromatography

Crude cabazitaxel was purified by using silica-gel column chromatography using dichloromethane as an eluent. Fractions containing pure compound are collected and finally combined pure fractions are concentrated under vacuum at below 40°C to obtain solid compound.
Input wt: 27 gr; Purity by HPLC: 97.2%;
Output wt: 12 gr; Purity by HPLC: 99.7%; Yield: 0.44 (w/w)

Impurity profile of cabazitaxel according to Comparative Example-1:

RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.25 1.26 1.34 1.37 1.42

Before column-
% by HPLC 0.01 0.9 0.01 0.09 0.01 0.05 0.02 0.01 0.41 0.36 0.03 0.44 0.23 0.23
After column-
% by HPLC Nil Nil Nil Nil Nil 0.04 Nil 0.01 0.04 0.03 0.01 0.05 0.06 0.06

COMPARATIVE EXAMPLE-2:

Purification of crude cabazitaxelby recrystallization method using dichloromethane and heptane

Crude cabazitaxel was purified by recrystallization method using dichloromethane and heptane (4v:4 v) at room temperature. Recrystallization was performed two times to obtain a pure compound.

Results are tabulated below:
After 1st R.C After 2nd R.C
Input wt 2 gr 1.15 gr
Input purity by HPLC 97.2% 98.6%
Output wt 1.15 gr 0.8 gr
Output purity by HPLC 98.6% 99.5%
Yield 0.57 (w/w) 0.69 (w/w)
Overall yield 0.4 (w/w)

Impurity profile of cabazitaxel according to Comparative Example-2:

RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.25 1.26 1.34 1.37 1.42

Before R.C-
% by HPLC 0.01 0.9 0.01 0.09 0.01 0.05 0.02 0.01 0.41 0.36 0.03 0.44 0.23 0.23

After 1stR.C -% by HPLC Nil 0.9 Nil 0.05 0.01 0.02 Nil Nil 0.15 0.07 Nil 0.1 Nil 0.1
After 2ndR.C -% by HPLC Nil 0.4 Nil Nil Nil Nil Nil Nil Nil Nil Nil 0.02 Nil 0.03

COMPARATIVE EXAMPLE-3:

Purification of crude cabazitaxel by recrystallization method using ethyl acetate and heptanes.

Crude cabazitaxel was purified by recrystallization method using ethyl acetate and heptane at room reflux temperature. Recrystallization was performed two times to obtain a pure compound.

Results are tabulated below:
After 1st R.C After 2nd R.C
Input wt 2 gr 1.2 gr
Input purity by HPLC 97.2% 98.5%
Output wt 1.2 gr 0.7 gr
Output purity by HPLC 98.5% 99.6%
Yield 0.6 (w/w) 0.58 (w/w)
Over all yield 0.35 (w/w)

Impurity profile obtained from comparative Example-3:

RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.25 1.26 1.34 1.37 1.42

Before R.C-
% by HPLC 0.01 0.9 0.01 0.09 0.01 0.05 0.02 0.01 0.41 0.36 0.03 0.44 0.23 0.23

After 1st R.C -% by HPLC Nil 0.75 Nil 0.05 Nil Nil Nil Nil 0.1 0.1 Nil 0.3 Nil 0.2
After 2nd R.C -% by HPLC Nil 0.3 Nil Nil Nil Nil Nil Nil 0.04 0.01 Nil Nil Nil 0.05

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

,CLAIMS:WE CLAIM:

1. A process for purification of cabazitaxel, comprising: subjecting crude cabazitaxel to a Preparative high performance liquid chromatography (HPLC) by eluting with a suitable eluent or a mixture of eluents to obtain pure cabazitaxel.

2. The process as claimed in claim 1, wherein the process specifically comprises
a) dissolving crude cabazitaxel in a suitable solvent or a mixture thereof,
b) subjecting the solution to a preparative high performance liquid chromatography (HPLC) by eluting with a suitable eluent or a mixture of eluents,
c) collecting pure fractions of cabazitaxel, and
d) isolatingthe pure cabazitaxel.

3. The process as claimed in claim 2, wherein the suitable solvent of step a) is selected from alcohols, ketones, nitriles, ethers, halogenated hydrocarbons, estersand mixtures thereof.

4. The process as claimed in claim 3, wherein the suitable solvent is methylene chloride, ethyl acetate or a mixture thereof.

5. The process as claimed in claim 2, wherein the suitable eluentof step b) is selected from alcohols, ketones, nitriles, ethers, halogenated hydrocarbons, esters, aliphatic hydrocarbons and mixtures thereof.

6. The process as claimed in claim 5, wherein the suitable eluentisethyl acetate, heptane or a mixture thereof.

7. The process as claimed in claim 6, wherein the eluent is a mixture of ethyl acetate and heptane in a ratio of about 10:90 to about 90:10.

8. The process as claimed in claim 2, wherein the isolation of pure cabazitaxel is carried out by removal of solvent.
9. The process as claimed in claim 2, wherein the cabazitaxel obtained by the process is substantially free of one or more relative retention time (RRT) impurities:
RRT 0.21 0.59 0.86 0.96 1.02 1.04 1.06 1.08 1.17 1.26 1.34 1.37 1.42
LC-Mass 735 763 853 835 853 865 881 881 835 847 817 935 875

10. Cabazitaxel substantially free of formyl impurity of Formula-1.

Dated this 08th day of April, 2019

Rajeshwari H (IN/PA-358)
Agent for the Applicant
OF RAJESHWARI & ASSOCIATES