FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT (AMENDMENT) RULES, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Process For Preparing An Amorphous And Crystalline Froms Of 4-Acetoxy-2α-
Benzoyloxy-5β,20-Epoxy-1β,7β,10β-Trihydroxy-9-Oxo-11 -Taxen-13α-Y1(2R,3S)-3-
Tert-Butoxycarbonylamino-3-Phenyl-2-Hydroxypropionate
2. APPLICANT
(a) NAME : Glade Organics Private Limited
(b) NATIONALITY : IN
(c) ADDRESS : 19, Crystal, 1st Floor, Juhu Road, Santacruz West, Mumbai-400 054, India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the nature of this invention and the manner in which it is to be performed: -

Field of the Invention The present invention relates to improved processes for preparing an amorphous and crystalline forms of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate.
Background of the Invention Docetaxel, chemically known as 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-l l-taxen-13a-yl(2R,3S)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate and represented by formula (1), is an analog of paclitaxel and used for treatment of various cancers

(I)
Docetaxel is marketed under the brand name TAXOTERE®, which is available as an injection concentrate in strengths of 80 mg/2 ml and 20 mg/0.5 ml for treatment of breast cancer, non-small cell lung cancer, prostate cancer, stomach cancer and head and neck cancer. The active pharmaceutical ingredient (API) used in TAXOTERE is Docetaxel trihydrate of Formula (II).


(II)
Docetaxel of formula (I) per se was first disclosed by Colin et al. in US 4,814,470, which apart from claiming the molecule i.e. docetaxel also discloses a process for preparation thereof as well as pharmaceutical compositions comprising the same for the treatment of acute leukemia and solid tumors,
US '470 mentions that docetaxel of formula (I) as obtained by the method described in Example-1 therein is characterized by specific rotation, FTIR, PNMR and mass spectrum (FAB). Other than the spectral characteristic of the product, US 4,814,470, however does not specify the product's solid state disposition like its X-ray (powder) diffraction pattern, Solid State NMR values, Differential Scanning Calorimetry (DSC) thermogram pattern, Thermogravimetric Analysis (TGA) thermogram patterns etc.
The docetaxel trihydrate of formula (II) per se was first disclosed by Durand et al. in US 6,197,980, describes, as given in Example-2 therein, a method for preparation of docetaxel trihydrate which comprises purification of crude docetaxel (referred to as TAXOTERE therein) by a Centrifugal Partition Chromatography technique using methyl tertiary butyl ether, ethyl acetate, heptane and water as solvents to afford docetaxel trihydrate (referred to as TAXOTERE trihydrate therein) in a purity of about 99.1%.
US '980 apart from providing the purity of the product, however, does not contain any reference to other characteristics of the product such as Specific Rotation, Water Content, UV Spectrum, Mass Spectrum, DSC, and TGA thermogram patterns, as well

as Solid State dispositions like X-ray (powder) diffraction pattern, IR Spectrum, Solid State NMR Spectrum etc.
Authelin et al. in US 6,022,985 specifically disclose a process for preparation of docetaxel trihydrate comprising crystallization of docetaxel from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, and then drying the product under defined conditions of temperature of about 40°C, pressure of about 4 to about 7 kPa and humidity of about 80% to yield crystalline docetaxel trihydrate with a water content of 6.15%. US '985 further states that the trihydrate form has substantially greater stability than the corresponding anhydrous form, as disclosed in EP 0,253,738 (equivalent of US '470) and that the docetaxel trihydrate prepared by the method disclosed therein has a defined X-ray (powder) diffraction pattern, albeit not specified; a TGA thermogram; and a DSC thermogram.
As per the disclosure contained in US '985, the TGA thermogram of Docetaxel trihydrate shows a mass loss of 6.1% between 40 and 140°C, which corresponds to three molecules of water per one molecule of docetaxel and shows an endothermic signal at 132.6°C in its DSC thermogram, which indicates the absence of bulk water and moreover corresponds to the dissociation of a hydrate.
US '985 further states that the trihydrate form of docetaxel is comparatively non-hygroscopic with respect to the anhydrous form of docetaxel. From the above, it would be abundantly evident that the anhydrous form, as disclosed in US '470 and EP '738 and the trihydrate form as disclosed in US' 980 of docetaxel, as well as that prepared by the method disclosed in US '985 are both crystalline, but differing in their crystalline structure or nature.
Both the anhydrous and the trihydrate forms of docetaxel as well as other hydrates of docetaxel are crystalline and has been confirmed by the report of Zaske et.al in J Phys. IV France, 2001, 11, 221-226, wherein a very detailed analysis and report of the solid state characteristics of the anhydrous, the hemihydrate and the trihydrate forms of docetaxel. The X-ray (powder) diffraction pattern, TGA and DSC all collectively prove that the three forms are crystalline in nature differing in their crystal structure or nature.

Pontiroli et al. in WO 2007/044950 A2 disclose a crystalline anhydrous form of docetaxel, characterized by a powder X-ray (powder) diffraction patterns having peaks at about 4.9, 7.3, 8.8, 12.5, 13.1, 13.7, 17.2, 18.8, 19.8 and 20 ± 2[deg.] 20 values; an FTIR spectrum having peaks at about 719, 848, 957, 1098, 1165, 1248, 1701, 1720, 3249, 3461 cm"1; and a DSC thermogram with endothermic peaks at about 30°C to about 70°C and 173°C. Further, it discloses a method of preparation of the anhydrous crystalline docetaxel comprising crystallization of docetaxel from a mixture of methyl isobutyl ketone (MIBK) and an organic antisoivent, selected from the group consisting of a C5- C8 branched alkanes. Further disclosed are pharmaceutical compositions comprising said anhydrous crystalline docetaxel.
WO 2007/044950A2 also discloses another crystalline form of docetaxel, characterized by a powder X-ray (powder) diffraction pattern having peaks at about 8.0, 11.3, 12.5, 15.5, and 16.9 + 2° 2θ values and a method for preparation of the same comprising precipitation from a mixture of a solvent, selected from acetone and ethyl acetate, acetone and t-butanol, tetrahydrofuran, ethyl acetate, t-butanol, ethanol and mixtures thereof and an antisoivent selected from the group consisting of a C5-C8 branched alkanes. Further disclosed are pharmaceutical compositions comprising said crystalline form of docetaxel.
Palle et al. in WO 2007109654 A2 discloses the process for the preparation of amorphous docetaxel which comprises precipitating amorphous docetaxel from a solution of docetaxel in THF with hydrocarbon anti-solvent and recovering precipitated amorphous solid whereas US 20090018353 Al discloses the preparation of the amorphous docetaxel by solvent precipitation employing polar-nonpolar solvents.
While there are known techniques for preparing docetaxel in anhydrous crystalline, amorphous form as well as hydrated crystalline form, there is still a need for improved chemical processes to produce this anti-cancer compound and in a form where the compound is chemically stable.

Object and Summary of the Invention It is an object of the present invention to provide an improved process to prepare polymorphs of 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate (docetaxel), under controlled conditions, with high purity and optimum yield.
Another object of the invention is to provide a process for preparing stable amorphous docetaxel, anhydrous crystalline docetaxel as well as crystalline sesquihydrate docetaxel.
The above and other objects of the present invention are attained according to following preferred embodiments of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.
In accordance with one embodiment of the present invention, there is provided a process for preparing an amorphous 4-acetoxy-2α-benzoyloxy-5p,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-l 1-taxen-l 3a-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate, the process comprises of dissolving 4-acetoxy-2α-benzoyloxy-5(3,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate or its hydrate in a solvent system at control conditions and isolating the amorphous form by evaporating the solvent under reduced pressure or atmospheric pressure.
In accordance with another embodiment of the present invention, there is provided an improved process for preparing a crystalline 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-l 1-taxen-l3α-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate, wherein the process comprises of dissolving 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-l3α-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate in a first organic solvent at a control condition, optionally, employing second organic solvent to precipitate the product and isolating the crystalline product employing spray drying, freeze drying, distillation, filtration under reduced pressure or filtration under atmospheric pressure.

Detailed Description of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The present invention provides an improved process for preparing an amorphous and crystalline forms of 4-acetoxy-2α-benzoyloxy-5p,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate (Docetaxel).
According to the present invention, the amorphous form of docetaxel is prepared by dissolving or suspending docetaxel or its hydrate in a solvent or mixtures of solvents preferably at a temperature between 0 to 40° C and evaporating the solvent or solvent mixtures thereof by means of vacuum drying under reduced pressure or atmospheric pressure.
After repeating the steps of above process, the residual solid is typically dried in a drying oven, at temperatures of between 30°C to 80°C, preferably 40°C to 50°C.
The suitable organic solvent that can be employed, for dissolution or suspension of docetaxel or its hydrate thereof, include but not limited to chlorinated hydrocarbons such as dichloromethane, dichloroethane, trichloroethane, chloroform, carbon tetrachloride etc., aliphatic alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol etc., nitriles such as acetonitrile, benzonitrile etc., aromatic and substituted aromatic hydrocarbons such as toluene, xylene, chlorobenzene, nitrobenzene etc., ketones such as acetone, butanone etc., ester such as methyl acetate, ethyl acetate, butyl acetate etc., N,N-dimethylformamide, N,N-diethylforrnamide, N,N-dimethyIacetamide, dimethyl sulfoxide or mixture thereof.
In accordance with the present invention the crystalline form of docetaxel is prepared by dissolving the crude docetaxel employing first organic solvent or mixture of the

solvents followed by the addition of second organic solvent to precipitate out the product that further isolated by employing spray drying, freeze drying, distillation, filtration under reduced pressure or filtration under atmospheric pressure, wherein the dissolution performed at a control condition to obtain desired product. The crystal obtained by this process may be an anhydrate or sesquihydrate.
The first organic solvent used herein is selected from the group consisting of but not limited to chlorinated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, ketones such as acetone, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone; and esters such as ethyl formate, methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, whereas second organic solvent is selected from the group consisting of but not limited to water, ethers such as diisopropyl ether, diethyl ether, methyl ethyl ether, dimethyl ether; aliphatic or alicyclic hydrocarbons such as benzene, cycloheptane, cyclohexane, cyclohexene, cyclooctane, cyclopentane, heptane, hexane, pentane, petroleum ether, toluene, xylene etc.
The proportion of the solvent or mixture thereof that can be used for dissolution or suspension of docetaxel or its hydrates thereof in both embodiments depends on the polarity and the solubilizing capacity of the solvent or mixtures thereof and typically can be employed in the range of 2 to 50 times by volumes per gram of docetaxel or its hydrate thereof. The temperature at which the docetaxel or its hydrate can be dissolved or suspended and evaporation of the in respective solvents or mixture thereof generally can be from about' 20°C to 200°C, preferably 20-100°C, more preferably 25-35°C.
In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the present invention.
Example 1
Preparation of amorphous docetaxel anhydrous:
The sesquihydrate or trihydrate docetaxel (lg) was dissolved in acetonitrile (25ml) at
room temperature and the solvent was evaporated in rotavapor under reduced pressure

at 50°C, same process was repeated two more times and material kept under reduced pressure at 50° C for 45 minutes in rotavapor to give the title compound (lg).
Example 2 Preparation of amorphous docetaxel anhydrous:
The sesquihydrate or trihydrate docetaxel (lg) was dissolved in acetone (25ml) at room temperature and solvent was evaporated in rotavapor under reduced pressure at 50° C. Same process was repeated twice and material was kept under reduced pressure at 50° C for 45 minutes in rotavapor to give titled compound (lg).
Example 3
Preparation of sesquihydrate crystalline sesquihydrate docetaxel: Docetaxel (3.1 g) was dissolved in acetone (60ml) at room temperature and purified water (60ml) was slowly added thereto. The resulting mixture was stirred at room temperature for 6 hours. The separated solid was filtered and air dried under atmospheric temperature/pressure for 24 hours to furnish sesquihydrate crystalline docetaxel (2.5g) and moisture content around 3.5%.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations, would present themselves to those skilled in the art without departing from the scope and spirit of this invention. This invention is susceptible to considerable variation in its practice within the spirit and scope of the appended claims.

We Claim:
1. A process for preparing an amorphous 4-acetoxy-2α-benzoyloxy-
5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13a-yl(2r,3s)-3-tert-
butoxycarbonylamino-3-phenyl-2-hydroxypropionate, the process comprising:
dissolving 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-
trihydroxy-9-oxo-11-taxen-13α-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate or its hydrate in a solvent system at control conditions and isolating the amorphous form by evaporating the solvent under reduced pressure or atmospheric pressure.
2. The process as claimed in claim 1, wherein the solvent is selected from a group consisting of dichloromethane, dichloroethane, trichloroethane, chloroform, carbon tetrachloride; methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, acetonitrile, benzonitrile, toluene, xylene, chlorobenzene, nitrobenzene, acetone, butanone, methyl acetate, ethyl acetate, butyl acetate, N,N-dimethyl formamide, N,N-diethyI formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, water or mixtures thereof.
3. The process as claimed in claim 1, wherein the dissolving step is carried out at a temperature range between 0 to 40° C.
4. The process as claimed in claim 1, wherein the isolated amorphous form is further dried at temperature range of 30°C to 80°C.
5. An improved process for preparing a crystalline form of 4-acetoxy-2oc-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11 -taxen-13α-yl (2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate, wherein the process comprising:
dissolving 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-
trihydroxy-9-oxo-11-taxen-13a-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate in a first organic solvent at a control condition;
optionally, employing a second organic solvent to precipitate the product; and

isolating the crystalline product employing spray drying, freeze drying, distillation, filtration under reduced pressure or filtration under atmospheric pressure.
6. The process as claimed in claim 5, wherein the crystalline 4-acetoxy-2a-benzoyloxy-5 p,20-epoxy-1 p,7p, 10p-trihydroxy-9-oxo-11 -taxen-13α-yl(2r,3s)-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate obtained is anhydrate or sesquihydrate.
7. The process as claimed in claim 5, wherein the first organic solvent used is selected from group consisting of ethyl formate, methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, acetone, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone methylene chloride, ethylene chloride, chloroform or a mixture thereof.
8. The process as claimed in claim 5, wherein the second organic solvent is selected from the group consisting of diisopropyl ether, diethyl ether, methyl ethyl ether, dimethyl ether, benzene, cycloheptane, cyclohexane, cyclohexene, cyclooctane, cyclopentane, heptane, hexane, pentane, petroleum ether, toluene, xylene or a mixture thereof.
9. The process as claimed in claim 5, wherein the dissolving step is carried out at a temperature range between 20°C to 200°C.
10. The process as claimed in claim 5, wherein the dissolving step is carried out at a temperature range between 20-100°C.