WO2008102374A1

WO2008102374A1 - Amorphous form of docetaxel

Info

Publication number: WO2008102374A1
Application number: PCT/IN2008/000098
Authority: WO
Inventors: Bhuwan Bhaskar Mishra; Anand Vardhan; Shiv Kumar Agarwal
Original assignee: Dabur Pharma Limited
Priority date: 2007-02-20
Filing date: 2008-02-19
Publication date: 2008-08-28

Abstract

A process for preparation of Amorphous Form of Docetaxel comprising: i. preparation of a solution or suspension of Docetaxel in an organic solvent or mixtures thereof; ii. evaporation of the solvent or mixtures thereof from the solution or suspension of step i ) under reduced pressure to obtain a solid substance; iii. optionally further dissolving or suspending the solid substance of step ii) in an organic solvent or mixtures thereof and evaporation of the solvent or mixtures thereof from the solution or suspension under reduced pressure to obtain a solid substance; iv. further optionally repeating step iii) one or more times; v. drying the solid substance obtained from step ii), iii) or iv) to give the amorphous form of Docetaxel. An amorphous form of docetaxel obtained by the process. A composition comprising amorphous form of Docetaxel along with pharmaceutically acceptable excipients adapted for therapy for cancer of various origins.

Description

AMORPHOUS FORM OF DOCETAXEL

FIELD OF THE INVENTION

The present invention relates to processes for preparation of an amorphous form of Docetaxel; the amorphous form of Docetaxel; and pharmaceutical compositions comprising the amorphous form of Docetaxel, useful for treatment of cancers of various origins.

The amorphous form of Docetaxel exhibits good thermal stability as well as retains its amorphous nature on prolonged exposure to heat, atmospheric air and humidity.

BACKGROUND OF THE INVENTION Docetaxel, which is chemically known as 4-Acetoxy-2α-benzoyloxy-5β, 20-epoxy-lβ, 7β,10β-trihydroxy-9-oxo-l l-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2- hydroxypropionate and represented by formula (I),

an analog of Paclitaxel is used for treatment of various cancers.

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).

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 treatment of acute leukemia and solid tumors.

US 4,814,470 mentions that Docetaxel of formula (I) as obtained by the method described in Example- 1 therein has the following characteristics, viz.

Specific Rotation, [α]_D ²³ = -36° (c = 0.74; ethanol); Ultra Violet Spectral values of λmax = 230 nm (14800), λmax = 275 nm (1730), λmax = 283 nm (1670); Characteristic Infrared Spectrum absorption bands at 3590, 3440, 1740-1700 cm^"1; Proton Nuclear Magnetic Resonance Spectrum (CDCl₃, 400 MHz) shift values in ppm of 1.12 (s, 3H), 1.24 (s, 3H), 1.35 (s, 9H), 1.77 (s, 3H), 1.87 (s, 3H), 2.28 (m, 2H), 2.37 (s, 3H), 2.58 (m, IH), 3.91 (d, J=7, IH), 4.19 and 4.32 (2d, J=9, 2H), 4.26 (m, IH), 4.62 (d, J=2, IH), 4.94 (d, J=9, IH), 5.22 (s, IH), 5.26 (dd, J=9 and J=2, IH), 5.46 (d, J=9, IH), 5.68 (d, J=7, IH), 6.22 (t, J=9, IH), 7.38 (5H), 7.50, 7.60^:'and 8.12 (5H); and Mass Spectrum (FAB) m/z values of 808 (MH⁺), 790, 752, 734, 708, 690, 527, 509, 449, 405, 387, 345, 327, 282, 226, and 185.

Other than the Spectral characteristics 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 pattern etc. r

The Docetaxel trihydrate of formula (II) per se was first disclosed by Durand et al. in US 6,197,980, which 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 6,197,980 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, Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (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 6,022,985 states that the trihydrate form of Docetaxel has substantially greater stability than the corresponding anhydrous form, as disclosed in EP 0,253,73.8 (that is an equivalent US 4,814,470) and that the Docetaxel trihydrate prepared by the method disclosed therein has a defined X-ray (powder) diffraction pattern, albeit not specified; a Thermogravimetric Analysis thermogram; and a Differential Scanning Calorimetry thermogram.

As per the disclosure contained in US 6,022,985, the Thermogravimetric Analysis 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 132.6⁰C in its Differential Scanning Calorimetry thermogram, which indicates the absence of bulk water and which, moreover corresponds to the dissociation of a hydrate.

US 6,022,985 further states that the trihydrate form of Docetaxel is comparatively non- hygroscopic with respect to the anhydrous form of Docetaxel, in that as demonstrated therein when both the trihydrate form and the anhydrous form of Docetaxel are kept in an environment having 90% relative humidity and at temperatures of 4°C, 25 °C, and 35°C:

i) The trihydrate form is stable up to 18 months without modification of its crystalline form; whereas ii) Under the same conditions the anhydrous whose crystalline form is different changes slowly to the trihydrate form.

From the above, it would be abundantly evident that the anhydrous form of Docetaxel, as disclosed in US 4,814,470 and its counterpart EP 0,253,738 and the trihydrate form of Docetaxel, as disclosed in US 6,197,980 as well as that prepared by the method disclosed in US 6,022,985 are both crystalline, but differing in their crystalline structure or nature.

Indeed that both the anhydrous and the trihydrate forms of Docetaxel as well as other hydrates of Docetaxel are crystalline has been confirmed by the report of Zaske et.al in J Phys. IV France, 2001, ϋ, 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 such as X-ray (powder) diffraction pattern, Thermogravimetric Analysis and Differential Scanning Calorimetry all collectively prove that the three forms are all crystalline in nature, but differing in their crystal structure or nature.

Amongst the reported forms such as the anhydrous, hemihydrate and the trihydrate form, the last one i.e. the trihydrate form, which has water content of about 6%, is considered and proved to be the most stable form in that it does not change its crystalline nature as well as not absorb further water when subjected to storage under highly humid conditions for prolonged duration of time. This apparently: is the reason why Docetaxel trihydrate is the preferred and chosen Active Ingredient in Pharmaceutical Compositions under clinical practice e.g. TAXOTERE^®

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° 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 3O⁰C to about 70⁰C and 173° C. Pontiroli et al. also disclose a method of preparation of the anhydrous crystalline Docetaxel comprising crystallization of Docetaxel from a mixture of methyl isobutyl ketone (MIBK) and an organic antisolvent, selected from the group consisting of a C₅- C₈ branched alkanes. Pontiroli et al. further disclose pharmaceutical compositions comprising the said anhydrous crystalline Docetaxel.

Pontiroli et al. in WO 2007/044950 A2 also disclose 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 form 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 antisolvent selected from the group consisting of a C₅- C₈ branched alkanes. Pontiroli et al. further disclose pharmaceutical compositions comprising the said crystalline form of Docetaxel.

It might, however, be noted that Pontiroli et al. in WO 2007/044950 A2 do not mention any advantages of the crystalline forms of Docetaxel disclosed therein e.g. stability.

From the foregoing it would be apparent that all the reported forms of Docetaxel including the anhydrous form and the various hydrated forms are all crystalline.

Against this background, the present inventors have found that a non-crystalline or amorphous form of Docetaxel could be prepared, which exhibits good thermal stability and retains its amorphous nature on prolonged exposure to heat, atmospheric air and humidity and, which moreover, is useful for preparation of pharmaceutical compositions for treatment of cancers of various origins.

OBJECTS OF THE INVENTION

An object of the present invention is to provide a process for preparation of an amorphous form of Docetaxel.

A further object of the present invention is to an amorphous form of Docetaxel

Another object of the present invention is to provide an amorphous form of Docetaxel, which exhibits good thermal stability.

Yet another object of the present invention is to provide an amorphous form of Docetaxel, which retains its amorphous nature on prolonged exposure to heat, atmospheric air and humidity Yet further object of the present invention is to provide pharmaceutical compositions comprising the amorphous form of Docetaxel.

Still further object of the present invention is to provide a method of treating cancers of various origins comprising administration to a patient in need thereof the pharmaceutical composition comprising the amorphous form of Docetaxel.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

Fig 1 , which represents the X-ray (powder) diffraction pattern of the amorphous form of Docetaxel of the present invention. r

Fig 2, which represents the IR Spectrum of the amorphous form of Docetaxel of the present invention.

Fig 3, which represents the X-ray (powder) diffraction patterns of the Anhydrous, Hemihydrate, and the Trihydrate forms of Docetaxel, as reproduced from that given by Zaske et.al. in J. Phys. IV France, 2001, U, 221-226.

SUMMARY OF THE INVENTION In accordance with objectives, there is provided a process for preparation of amorphous form of Docetaxel comprising the steps of: i) preparation of a solution or suspension of Docetaxel in an organic solvent or mixtures thereof; ii) evaporation of the solvent or mixtures thereof from the solution or suspension of step i ) under reduced pressure to obtain a solid substance; iii) optionally further dissolving or suspending the solid substance of step ii) in an organic solvent or mixtures thereof and evaporation of the solvent or mixtures thereof from the solution or suspension under reduced pressure to obtain a solid substance; iv) further optionally repeating step iii) one or more times; v) drying the solid substance obtained from step ii), iii) or iv) to give the amorphous form of Docetaxel.

According to another aspect there is provided a non-crystalline and amorphous form of Docetaxel which is totally and completely devoid of signals due to a crystalline form in its X- ray (powder) diffraction pattern.

According to a further aspect there is provided pharmaceutical compositions comprising the amorphous form of Docetaxel and pharmaceutically acceptable excipients

DETAILED DESCRIPTION OF THE INVENTION

The amorphous form of Docetaxel of the present invention is prepared by various methods such as spray drying, or by repeated evaporation of solvent from a solution or a suspension containing Docetaxel or its hydrates thereof, followed by drying of the residual solid by conventional methods.

Typically, Docetaxel or its hydrates thereof, which in turn are prepared by methods known in the art is dissolved or suspended in a suitable organic solvent or mixtures thereof and the solvent or solvent mixture is evaporated from the solution repeatedly to afford a residual solid, which is dried to afford the amorphous form of Docetaxel of the present invention.

The suitable solvents that can be employed, for dissolution or suspension of Docetaxel or its hydrates thereof include, but are not limited to aliphatic or alicyclic hydrocarbons such as petroleum ether, hexane, n-heptane, cyclohexane, cycloheptane etc.; chlorinated hydrocarbons such as dichloromethane, dichloroethane, trichloroethane, chloroform, carbon tetrachloride etc.; ethers having Cj-C₄ carbon atoms, either straight or branched such as dimethyl ether, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiarybutyl ether etc.; cyclic ethers such as tetrahydrofuran, dioxane etc.; aliphatic alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tertiary-butanol etc.; aromatic nitriles such as benzonitrile; aromatic and substituted aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, nitrobenzene etc.; aliphatic and aromatic ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclopentanone, cyclohexanone etc.; aliphatic acid esters such as methyl acetate, ethyl acetate, butyl acetate etc.; dialkyl amides such as N,N-dimethyl formamide, N,N-diethyl formamide, N,N-diemthyl acetamide etc.; dialkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide etc.; or mixtures thereof.

The proportion of the solvent or mixtures thereof that can be used for dissolution or suspension of Docetaxel or its hydrates thereof depends on the polarity and the solubilizing capacity of the solvent or mixtures thereof and typically can be employed in the range of between 2 to 100 times by volume per gram of Docetaxel or its hydrates thereof. The temperature at which the Docetaxel or its" hydrates can be dissolved or suspended and evaporation of the in respective solvents or mixtures thereof and their subsequent evaporation similarly depends on the solvent or solvent mixtures employed and generally can be from about 20⁰C to about 200⁰C.

After the repeated evaporation of the solvent or solvent mixtures, the residual solid is typically dried in a drying oven, under normal or reduced pressure at temperatures of between 3O⁰C to 80⁰C.

The X-ray (powder) _{ Diffraction Pattern of the Docetaxel, obtained after the process, as represented in Fig 1 is free of characteristic peaks as depicted in the known forms of Docetaxel proving that it has disordered arrangements of molecules and do not possess a distinguishable crystal lattice and hence an amorphous material.

The X-ray (powder) diffraction pattern of the amorphous Docetaxel thus obtained as represented in Fig 1 is found to be distinctly different from that reported for the known anhydrous, hemihydrate, and the trihydrate forms of Docetaxel as disclosed by Zaske et.al in J Phys. IV France, 2001, ϋ, 221-226, which are reproduced herein in Fig 3. Further, the IR spectrum of amorphous Docetaxel thus obtained as represented in Fig 2, is also found to be distinctly different from that of Docetaxel disclosed in US 4,814,470. It was found that the amorphous Docetaxel on exposure to heat, atmospheric air or humidity for prolonged periods of time, of say more than six months retains its amorphous nature.

The essential differences between the amorphous form of Docetaxel of the present invention and the known anhydrous and the trihydrate forms are summarized in Table-I.

Table-I : The Essential Differences Between The Amorphous Form Of Docetaxel Of The Present Invention And The Known Anhydrous And Trihydrate Forms Of Docetaxel

The Amorphous Form of Docetaxel of the present invention retains its amorphous nature, even after prolonged exposure of upto 70 hours to heat and humidity, as well as upto 6 months on storage at room temperature, thereby indicating that the Amorphous form of Docetaxel of the present invention exhibits comparable stability with Docetaxel trihydrate.

The present invention also provides pharmaceutical compositions comprising the amorphous form of Docetaxel of the present invention in combination with pharmaceutically acceptable excipients, which could be, inert or physiologically active, diluents or adjuvants. Such pharmaceutically acceptable excipients include antioxidants, buffering agents or tonicity adjustment agents. The parenteral route, and especially the intravenous route, is the preferred route for administration. The pharmaceutical compositions prepared with the amorphous form are used in the treatment of various forms of cancer and solid tumors.

The methods for the preparation of the Amorphous Form of Docetaxel of the present invention may be illustrated by way of the following examples, which in no way should be construed as limiting the scope of the invention.

Example-1

12.5 gms of Docetaxel was suspended in 200 ml of acetonitrile and the solvent was completely evaporated at a temperature of between 60-70° under reduced pressure (1 mb). The residue was further dissolved in 175 ml of dry ethyl acetate with stirring, to which an equivalent quantity (175 ml) of acetonitrile was added to obtain a clear solution. The solvent mixture was evaporated completely under reduced pressure (1 mb) at a temperature of between 60-70°C and the residue thus obtained was furthermore dissolved in sufficient quantity of dichloromethane and the solvent completely evaporated under reduced pressure to complete dryness. The resulting powder was dried at 60°C under reduced pressure for 2 hours to give amorphous Docetaxel, having a water content of 0.62% and exhibiting a characteristic X-ray (powder) diffraction pattern and IR Spectrum as essentially represented in Fig 1 and Fig 2 respectively.

Example-2

5.0 gms of Docetaxel was dissolved in 50rml of acetone. The solution was then filtered through 0.5 micron filter and the filtrate was concentrated at 55-60°C under 700mm Hg vacuum to get 4.4 gms of amorphous Docetaxel, having water content of 2.36% w/w and exhibiting a characteristic X-ray (powder) diffraction pattern and IR Spectrum as essentially represented in Fig 1 and Fig 2 respectively. Example-3

5.0 gms of Docetaxel was suspended in 100 ml Ethyl acetate and concentrated at 55-60°C under 700mm Hg vacuum to get 4.0 gms of amorphous Docetaxel, having water content of 2.04% w/w and exhibiting a characteristic X-ray (powder) diffraction pattern and IR Spectrum as essentially represented in Fig 1 and Fig 2 respectively.

Example-4

42.0 gms of Docetaxel was dissolved in 630 ml dichloro methane. The solution was then filtered through 0.5 micron filter and the filtrate was concentrated at 55-60°C under 700mm Hg vacuum to get 36.0 gms of amorphous Docetaxel, having water content of 1.18% w/w and exhibiting a characteristic X-ray (powder) diffraction pattern and IR Spectrum as essentially represented in Fig 1 and Fig 2 respectively.

Claims

1. A process for preparation of Amorphous Form of Docetaxel comprising the steps of: i. preparation of a solution or suspension of Docetaxel in an organic solvent or mixtures thereof; ii. evaporation of the solvqht or mixtures thereof from the solution or suspension of step i ) under reduced pressure to obtain a solid substance; iii. optionally further dissolving or suspending the solid substance of step ii) in an organic solvent or mixtures thereof and evaporation of the solvent or mixtures thereof from the solution or suspension under reduced pressure to obtain a solid substance; iv. further optionally repeating step iii) one or more times; v. drying the solid substance obtained from step ii), iii) or iv) to give the amorphous form of Docetaxel.

2. A process according to claim 1, wherein the organic solvent is selected from aliphatic or alicyclic hydrocarbons, chlorinated hydrocarbons, straight or branched ethers having Ci-C₄ carbon atoms, cyclic ethers, aliphatic alcohols, aromatic nitriles, aromatic and substituted aromatic hydrocarbons, aliphatic and aromatic ketones, aliphatic acid esters, dialkyl amides, dialkyl sulfoxides or mixtures thereof.

3. A process according to claim 2, wherein the aliphatic or alicyclic hydrocarbons are selected from petroleum ether, hexane, n-heptane, cyclohexane and cycloheptane.

4. A process according to claim 2, wherein the chlorinated hydrocarbons are selected from dichloromethane, dichloroethane, trichloroethane, chloroform and carbon tetrachloride.

5. A process according to claim 2, wherein the ethers having Ci-C₄ carbon atoms, either straight or branched are selected from dimethyl ether, diethyl ether, diisopropyl ether, dibutyl ether and methyl tertiarybutyl ether.

6. A process according to claim 2, wherein the cyclic ethers are selected from tetrahydrofuran and dioxane.

7. A process according to claim 2, wherein the aliphatic alcohols are selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tertiary- butanol.

8. A process according to claim 2, wherein the aromatic nitrile is benzonitrile.

9. A process according to claim 2, wherein the aromatic and substituted aromatic hydrocarbons are selected from toluene, xylenes, chlorobenzene and nitrobenzene.

10. A process according to claim 2, wherein the aliphatic and aromatic ketones are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclopentanone and cyclohexanone.

11. A process according to claim 2, wherein the aliphatic acid esters are selected from methyl acetate, ethyl acetate and butyl acetate.

12. A process according to claim 2, wherein the dialkyl amides are selected from N, N- dimethyl formamide, N, N-diethyl formamide and N, N-diemthyl acetamide.

13. A process according to claim 2, wherein the organic solvent or mixtures thereof are employed between 2 to 100 times by volume per gram of Docetaxel dissolved or

■ suspended.

14. A process according to claim 1, wherein the Docetaxel is dissolved or suspended in the organic solvent or mixtures thereof from about 20⁰C to about 200⁰C.

15. A process according to claim 1, wherein the Docetaxel comprises both the anhydrous and hydrated substances.

16. The Amorphous Form of Docetaxel, as obtained by the process of Claim 1, having a characteristic XRD pattern as represented in Fig 1.

17. The Amorphous Form of Docetaxel, as obtained by the process of Claim 1, having a characteristic IR Spectrum as represented in Fig 2.

18. A pharmaceutical composition comprising amorphous form of Docetaxel along with pharmaceutically acceptable excipients adapted for administration to patients for therapy for cancer of various origins.

19. A pharmaceutical composition according to claim 18, wherein the pharmaceutically acceptable excipients are selected from diluents, antioxidants, buffering agents and tonicity adjustment agents.

20. The composition according to claim 18, adapted for administration to patients for therapy for cancer selected from breast, ovarian, non-small cell lung, prostrate, stomach, head and neck and leukemia.