PROCESS FOR PREPARATION OF HIGHLY PURE CABAZITAXEL MONOHYDRATE

FIELD OF INVENTION

The present invention relates to process for the preparation of highly pure Cabazitaxel monohydrate, more particularly crystalline form of Cabazitaxel monohydrate in which the organic solvents used in the process are controlled well with in the ICH limits and hence considered safe and the pharmaceutical compositions containing the same.

BACKGROUND OF THE INVENTION

Cabazitaxel is a semi-synthetic derivative of a natural taxoid. It is used in the treatment of variety of cancers including ovarian, lung, head, neck and prostate cancers. Particularly Cabazitaxel is a microtubule inhibitor and it is marketed under trade name as JEVTANA by Sanofi-Aventis as Cabazitaxel-acetone solvate.

Cabazitaxel which is chemically defined as (2a,5P,7P,10p,13a)-4-acetoxy-13-({(2R,3S)-3 [(tertbutoxy-carbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-l l-en-2-yl benzoate has the following chemical structure. US patent 5847170 and 6331635 describes the preparation of taxoids and pharmaceutical compositions and also claimed Cabazitaxel drug substance as 4a.-Acetoxy-2a-benzoyIoxy-5p,20-epoxy-lp-hydroxy-7p,10p-dimethoxy-9-oxo-l l-taxen-13a-yl(2R,3S)-3-tert-butoxy carbonyl amino-2-hydroxy-3-phenylpropionate.

US patent 5,438,072 disclosed injectable compositions useful for the preparation of perfusion solutions comprising taxane derivatives comprising a solution convenient for storage of said taxane derivatives in a surface active agent selected from polysorbates, ethylene oxide esters- ethers and fatty acids glycerides, and a water solution of an effective amount of a dilution additive selected from organic compounds having a hydroxyl group an amine functional group and a molecular weight of less than 200 or sodium chloride.

US5698582 disclosed a composition comprising a taxane derivative with stability more than two months, said taxane derivative is dissolved in a surfactant selected from polysorbate or polyethoxylated castor oil which is free of ethanol.

US7241907 disclosed process for the preparation of acetone solvate of 4a.-Acetoxy-2ct-benzoyloxy-5p,20-epoxy-1 p-hydroxy-7p, 10.beta.-dimethoxy-9-oxo-11 -taxen-13a-yl(2R,3S)-3-tert-butoxy carbonyl amino-2-hydroxy-3-phenylpropionate.

WO2009115655A, US2011/0144362 Al and US8378128B2 disclosed anhydrous, solvates and hydrate forms of Cabazitaxel and revealed the process for the preparation of same. The monohydrate form is obtained at ambient temperature by maintaining the anhydrous form C (anhydrous form of Cabazitaxel) in an atmosphere containing at least 10% relative humidity. The PXRD pattern of the monohydrate form C exhibits characteristic 2 theta values at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1, 11.9, 12.2, 12.6 and 13.3±0.2 degrees and the dihydrate form C is obtained at ambient temperature by maintaining the anhydrous form C in an atmosphere containing at least 60% relative humidity. The PXRD pattern of the dihydrate form C exhibits characteristic 2 theta values at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2±0.2 degrees. WO2009115655A and US2011/0144362 Al have claimed both monohydrate and dihydrate mentioning the XRD pattern in claims but US8378128B2 claimed crystalline anhydrous form D of 4a.-Acetoxy-2a-benzoyloxy-5p,20-epoxy-l p-hydroxy-7p, 10.beta.-dimethoxy-9-oxo-11 -taxen-13a-yl(2R,3S)-3-tert-butoxy carbonyl amino-2-hydroxy-3-phenylpropionate.

WO2012/142117 disclosed the process and preparation of Cabazitaxel 2-propanol solvate form and several other solvates. WO2013/034979 disclosed more than one solvate like MEK (methyl ethyl ketone/DEK (diethyl ketone). WO2014/128728 disclosed Cabazitaxel solvate forms like methyl acetate, isopropyl acetate, tertiary butyl acetate etc.

Therefore it is an object of the present invention to provide a process for preparing new polymorphic forms and solvates of Cabazitaxel with high purity, shelf-life period, and stable crystal forms. Present invention is mainly aimed to develop stable polymorphic form of Cabazitaxel which is free from organic solvents and safe for formulation.

Another object of the present invention is to control single maximum impurity below 0.10%.

 
SUMMARY OF THE INVENTION

The present invention provides the process for the preparation of highly pure Cabazitaxel monohydrate. Water is used as one of the solvent in the novel crystallization procedure described in the present invention. The Cabazitaxel monohydrate prepared by our process has residual solvents controlled well within the ICH limits and can be considered safe when compared with any solvate forms described in prior art where in the percentage of solvent present in API vary between 7 tol4%. The novel crystallization procedure described in the present invention consistently produces a highly pure, stable monohydrate of Cabazitaxel (Structure-2) which is characterized by NMR, XRD, FTIR, TGA and DSC.

The XRD results 2 theta values at about 4.3, 7.1, 8.7, 10.2, 10.9, 12.2, 13.8, 15.2, 17.6, 18.3, 19.3, 19.7, 21.2 and 23.0± 0.2 degrees which is different the crystalline form known in the art.

BRIEF DESCRIPTION OF THE FIGURES/DRAWINGS

Fig.l DSC thermogram of Cabazitaxel monohydrate from water/ethanol Fig.2 TGA thermogram of Cabazitaxel monohydrate from water/ethanol Fig.3 Powder XRD pattern of Cabazitaxel monohydrate from water/ethanol Fig.4 NMR spectrum of Cabazitaxel monohydrate from water/ethanol Fig.5 IR spectrum of Cabazitaxel monohydrate from water/ethanol Fig.6 DSC thermogram of Cabazitaxel monohydrate form water/methanol

Fig.7 TGA thermogram of Cabazitaxel monohydrate form water/methanol Fig.8 Powder XRD pattern of Cabazitaxel monohydrate form water/methanol Fig.9 DSC thermogram of Cabazitaxel monohydrate form water/PEG Fig. 10 TGA thermogram of Cabazitaxel monohydrate form water/PEG Fig. 11 powder XRD pattern of Cabazitaxel monohydrate form water/PEG

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes the process for preparation of highly pure Cabazitaxel monohydrate and the pharmaceutical compositions containing the same. Cabazitaxel monohydrate prepared by our novel crystallization procedure is characterized by NMR, XRD, FTIR, TGA and DSC.

Cabazitaxel monohydrate of the present invention has advantageous properties like chemical purity, solubility, stability and very low content of residual solvents.

The term solvate or solvate forms disclosed in the prior art refers the solvent used in the process in the final steps. If the solvent used in the final step is water, the solvate form in which the molecule exists can be referred to as hydrate. In our novel crystallization procedure, highly pure Cabazitaxel monohydrate is prepared and experimentally confirmed with the water content results obtained in the range of 2.1 to 2.5% w/w. Theoretically Cabazitaxel monohydrate should have a water content of 2.15% w/w.

Cabazitaxel monohydrate is prepared from 10-Deacetyl Baccatin III and during the final step, the material is dissolved in any one of the solvent such as ethanol, methanol, PEG 400, 2-methoxy ethanol or ethylene glycol in warm to refluxing condition and diluted with excess of water and the resulting solution concentrated to sufficient quantity to crystallize the material which is filtered and dried to yield Cabazitaxel monohydrate of high purity in the range of 99.8% which is analyzed by HPLC with single maximum impurity controlled below 0.10%. The synthetic route is depicted in the scheme I.

Cabazitaxel monohydrate prepared by the novel crystallization procedure is distinct from Cabazitaxel in any other solvate form reported in the prior art. It is further found that hydrolysis and crystallization takes place in a single step which is uniqueness of the present invention. Therefore the process is industrially not only viable but also highly economical. Cabazitaxel monohydrate thus obtained is highly pure and solvent limit is well within ICH guidelines. Therefore it is more suitable for preparing pharmaceutical preparations without any further purification, particularly for parenteral preparations. Level of any single impurity is to less than 0.1% according the present invention in the final crystalline product. The distinct characteristics possessed by Cabazitaxel monohydrate prepared by our novel crystallization procedure like crystal structure, melting point are studied using Differential Scanning Calorimetry, Thermo Gravimetric Analysis, and Powder X-ray-diffraction pattern. The study reports are provided as Fig, 1 to Fig. 11.

As seen from the figures, Cabazitaxel monohydrate prepared by novel crystallization procedure of the present invention has characteristic melting point as seen from DSC thermograms of Cabazitaxel monohydrate prepared by crystallizing from water-ethanol, water-methanol and water-PEG 400 as 5 shown in Fig 1, 6 & 9 respectively. As seen from all these thermo grams, the peak onset is between 142°C to 147°C, peak end set is between 158°C to 162°C and the peak is around 150°C which is different from Cabazitaxel.

TGA thermograms Fig 2, 7 & 10 of Cabazitaxel monohydrate prepared by our crystallization technique from water-ethanol, water-methanol and water-PEG 400 solvent mixtures respectively shows weight loss of around 3% from 40°C up to 110°C. Cabazitaxel monohydrate prepared by the novel process described in the present invention has water content in the range of 2.1 to 2.3% w/w. Theoretically the water content that should be present in Cabazitaxel to exist as a monohydrate is 2.15% w/w. The TGA results support our experiments to show that our crystallization method yields Cabazitaxel monohydrate.

XRD of Cabazitaxel monohydrate prepared by our crystallization technique from water-ethanol, water-methanol and water-PEG 400 solvent mixtures are depicted as Fig 3, 8 & 11 respectively and has 2 Theta values as shown below XRD 2 9 values for Cabazitaxel monohydrate crystalized form water/ethanol mixture 4.3, 7.1, 8.7, 10.2, 10.9, 12.2, 13.8, 15.2, 17.6, 18.3, 19.3, 19.7, 21.2 and 23.0 ± 0.2°.

XRD 2 0 values for Cabazitaxel monohydrate crystallized form water/methanol mixture 4.2, 7.1,8.7, 10.2, 10.9, 12.2, 13.7, 15.3, 17.1, 17.7, 18.2, 19.3, 19.7,21.3 and 23.0 ± 0.2°.

XRD 2 0 values for Cabazitaxel monohydrate crystallized form water/PEG mixture 4.3, 7.2, 8.7, 10.2,10.9,12.3,13.9,15.3, 16.3,17.6, 18.3, 19.3, 19.7, 21.2 and 23.0 ±0.2°.

Cabazitaxel monohydrate described in the present invention is characterized by proton NMR Fig 4 and IR spectroscopy Fig 5.

The invention can be illustrated with the few examples shown below which no way limit the scope of the present invention.

Example 1:

40 g of 10-DAB-III dissolved in 100 mL of Dimethyl Formamide under nitrogen atmosphere and cooled to -10 to -15°C and 11.7g of sodium hydride is added portion wise followed by 200 ml of methyl iodide slowly at -10 to -15°C. The reaction mixture slowly warmed to 0°C and continued stirring for two hours maintaining same temperature. 200 mL of cooled saturated ammonium chloride solution is added to the reaction mixture and extracted the compound using methylene chloride and then concentrated.

The crude compound purified using column chromatography to obtained 7,10-dimethoxy-10-DAB in 60% yield.

Ex am pie-2

20gms of 7,10-dimethoxy-lO-DAB and 20g (2R,4S,5R)-3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylic acid introduced into a RB flask containing 250 mL of Methylene chloride at ambient temperature. 27.9 g of DCC and 2.1 grams of DMAP is added followed by 4 grams of 4 A molecular sieves and continued stirring for another 3 hours at ambient temperature. The reaction mixture is diluted with lOOmL of methylene chloride and filtered, filtrate concentrate and concentrated material dissolved in methylene chloride and precipitated with n-hexane, precipitated material filtered to result 25 grams of condensed product.

Example-3

20g of condensed product from example 2 dissolved in THF (150mL) at -5 to 0°C and 34 mL of concentrated hydrochloric acid in methanol added drop wise and stirred for two hours maintaining same temperature. The reaction mixture is diluted with 2 volumes of ethyl acetate and quenched with saturated bicarbonate solution. The organic layer separated, washed with water, concentrated and the resulting material dissolved in ethyl acetate and precipitated with n-hexane. The precipitated material filtered to get crude Cabazitaxel and the wet material once again dissolved in 48 mL of ethanol and stirred at 60-65°C to dissolve completely. To the solution 320 mL of hot water added slowly and continued the stirring for 20 min at same temperature followed by concentration to 30 to 50% of total volume. Concentrated solution cooled below 10°C and allowed to stand for 2 hours at same temperature to crystallize Cabazitaxel monohydrate which was filtered, washed with water and dried under vacuum at 60°C for 4 hours to yield 12 g of highly pure Cabazitaxel monohydrate.

HPLC purity: 99.8%

Water content: 2.35%

DSC : 150.96°C as seen Fig.l

TGA: 3.1736% loss up to 110°C as seen in Fig.2

XPRD pattern: As seen in Fig.3.

Example 4:

20g of condensed product from example 2 dissolved in THF (150mL) at -5 to 0°C and 34 mL of concentrated hydrochloric acid in methanol added drop wise and stirred for two hours maintaining same temperature. The reaction mixture is diluted with 2 volumes of ethyl acetate and quenched with saturated bicarbonate solution. The organic layer separated, washed with water, concentrated and the resulting material dissolved in ethyl acetate and precipitated with n-hexane. The precipitated material filtered to get crude Cabazitaxel and the wet material once again dissolved in 24 mL of methanol and stirred at 50-55°C to dissolve completely. To the solution 320 mL of hot water added slowly and continued the stirring for 20 min at same temperature followed by concentration to 30 to 50% of total volume. Concentrated solution cooled below 0-5°C and allowed to stand for 2 hours at same temperature to crystallize Cabazitaxel monohydrate which was filtered, washed with water and dried under vacuum at 60°C for 4 hours to yield 12g of highly pure Cabazitaxel monohydrate.

HPLC purity: 99.6%

Water content: 2.5%

DSC: 151.0°CasseeninFig.6

TGA: 3.6798% loss up to 110°C as seen in Fig.7

XPRD pattern as seen in Fig. 8.

Example 5:

20g of condensed product from example 2 dissolved in THF (150mL) at -5 to 0°C and 34 mL of concentrated hydrochloric acid in methanol added drop wise and stirred for two hours maintaining same temperature. The reaction mixture is diluted with 2 volumes of ethyl acetate and quenched with saturated bicarbonate solution. The organic layer separated, washed with water, concentrated and the resulting material dissolved in ethyl acetate and precipitated with n-hexane. The precipitated material filtered to get crude Cabazitaxel and the wet material once again dissolved in 40 mL of PEG 400 and stirred at 25-30°C to dissolve completely. To the solution 240 mL of hot water added slowly and continued the stirring for 60 min at same temperature, solution cooled below 0-5°C and allowed to stand for 2 hours at same temperature to crystallize Cabazitaxel monohydrate which was filtered, washed with water and dried under vacuum at 60°C for 4 hours to yield 1 lg of highly pure Cabazitaxel monohydrate.

HPLC purity: 99.5%

Water content: 2.5%

DSC : 154.6°C as seen in Fig.9

TGA: 2.10% loss up to 110°C as seen in Fig.10

XPRD. pattern as seen in Fig. 11.

We Claim:

1. A process for the preparation of crystalline Cabazitaxel monohydrate comprising:
(a) dissolving the crude Cabazitaxel in an organic solvent;

(b) treating the mixture in reflux temperature and diluting with excess of water;

(c) Concentrating the solution to remove organic solvent and filtering the crystallized solid to yield Cabazitaxel monohydrate and subsequently drying to obtain high purity in the range of 99.8% with the water content about 2.1 to 2.5% and any single maximum impurity controlled below 0.10%.

2. The process as claimed in claim 1, wherein the organic solvents used in step (a) are such as ethanol, methanol or PEG 400 in 1:2 ratio.

3. The process as claimed in claim 1, wherein the reflux temperature in the crystallization process of step (b) is about 60 ± 10°C.

4. The process as claimed in claim 1, wherein drying is carried out in step (c) at a temperature in the range from 40 to 80°C and under a pressure in the region of 1 KPa.

5. Crystalline form of Cabazitaxel monohydrate of claim 1 characterized by a powder X-ray diffraction pattern having characteristic 2-theta values at 4.3, 7.1, 8.7, 10.2, 10.9, 12.2, 13.8, 15.2, 17.6, 18.3, 19.3, 19.7, 21.2 and 23.0 ± 0.2°.

6. Crystalline form of Cabazitaxel monohydrate of claim 1 further characterized by IR spectrum such herein described.

7. Crystalline form of Cabazitaxel monohydrate of claim 1 having the melting point with the onset in the range of 143.38 ± 4°C and end set in the range of 160.62 ± 4°C.

8. A composition comprising one or more pharmaceutical ly acceptable Excipient and Cabazitaxel monohydrate according to claim 1.