WO2008102374A1 - Forme amorphe du docétaxel - Google Patents

Forme amorphe du docétaxel Download PDF

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Publication number
WO2008102374A1
WO2008102374A1 PCT/IN2008/000098 IN2008000098W WO2008102374A1 WO 2008102374 A1 WO2008102374 A1 WO 2008102374A1 IN 2008000098 W IN2008000098 W IN 2008000098W WO 2008102374 A1 WO2008102374 A1 WO 2008102374A1
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WO
WIPO (PCT)
Prior art keywords
docetaxel
process according
mixtures
amorphous form
aliphatic
Prior art date
Application number
PCT/IN2008/000098
Other languages
English (en)
Inventor
Bhuwan Bhaskar Mishra
Anand Vardhan
Shiv Kumar Agarwal
Original Assignee
Dabur Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dabur Pharma Limited filed Critical Dabur Pharma Limited
Publication of WO2008102374A1 publication Critical patent/WO2008102374A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • Docetaxel exhibits good thermal stability as well as retains its amorphous nature on prolonged exposure to heat, atmospheric air and humidity.
  • Docetaxel which is chemically known as 4-Acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-l ⁇ , 7 ⁇ ,10 ⁇ -trihydroxy-9-oxo-l l-taxen-13 ⁇ -yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2- hydroxypropionate and represented by formula (I),
  • Paclitaxel 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.
  • 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%.
  • 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%.
  • 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 132.6 0 C in its Differential Scanning Calorimetry thermogram, which indicates the absence of bulk water and which, moreover corresponds to the dissociation of a hydrate.
  • 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 3O 0 C to about 70 0 C and 173° C. Pontiroli et al.
  • anhydrous crystalline Docetaxel 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 C 5 - C 8 branched alkanes. Pontiroli et al. further disclose pharmaceutical compositions comprising the said anhydrous crystalline Docetaxel.
  • MIBK methyl isobutyl ketone
  • 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° 2 ⁇ 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 C 5 - C 8 branched alkanes. Pontiroli et al. further disclose pharmaceutical compositions comprising the said crystalline form of Docetaxel.
  • Docetaxel 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.
  • 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.
  • Fig 1 which represents the X-ray (powder) diffraction pattern of the amorphous form of Docetaxel of the present invention.
  • 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.
  • 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.
  • 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.
  • compositions comprising the amorphous form of Docetaxel and pharmaceutically acceptable excipients
  • 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.
  • 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-C 4 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-butano
  • 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 20 0 C to about 200 0 C.
  • the residual solid is typically dried in a drying oven, under normal or reduced pressure at temperatures of between 3O 0 C to 80 0 C.
  • 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, ⁇ , 221-226, which are reproduced herein in Fig 3.
  • 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 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.
  • 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 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.
  • Docetaxel 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur un procédé de préparation d'une forme amorphe du Docétaxel comprenant les étapes suivantes: i) préparation d'une solution ou d'une suspension de Docétaxel dans un solvant organique ou ses mélanges; ii). évaporation du solvant ou des mélanges de la solution ou de la suspension de l'étape i); iii). facultativement nouvelle dissolution ou suspension de la substance solide de l'étape ii) dans un solvant organique ou ses mélanges et évaporation du solvant ou de ses mélanges de la solution ou de la suspension sous pression réduite pour obtenir une substance solide; iv). facultativement répétition de l'étape iii) une ou plusieurs fois; v). séchage de la substance solide obtenue aux étapes ii), iii) ou iv) pour produire la forme amorphe du Docétaxel. L'invention porte également: sur la forme amorphe du Docétaxel ainsi obtenue; et sur une composition comprenant la forme amorphe du Docétaxel et des excipients pharmaceutiquement acceptables, et servant à traiter des cancer d'origines diverses.
PCT/IN2008/000098 2007-02-20 2008-02-19 Forme amorphe du docétaxel WO2008102374A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN253KO2007 2007-02-20
IN253/KOL/2007 2007-02-20

Publications (1)

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WO2008102374A1 true WO2008102374A1 (fr) 2008-08-28

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
CN107501211A (zh) * 2017-07-05 2017-12-22 中国药科大学 多烯紫杉醇黄酮共无定形物
US10500285B2 (en) 2015-05-15 2019-12-10 Zhuhai Beihai Biotech Co., Ltd. Docetaxel and human serum albumin complexes
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
US11419842B2 (en) 2016-10-27 2022-08-23 Zhuhai Beihai Biotech Co., Ltd. Neutral pH compositions of Docetaxel and human serum albumin

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253738A1 (fr) * 1986-07-17 1988-01-20 Rhone-Poulenc Sante Dérivés du taxol, leur préparation et les compositions pharmaceutiques qui les contiennent
WO2005061474A1 (fr) * 2003-12-12 2005-07-07 Quiral Química Do Brasil Procede de preparation d'ingredients pharmaceutiques actifs hydrates et anhydres (api), compositions pharmaceutiques stables preparees a partir de ces derniers et utilisations desdites compositions
WO2007078050A2 (fr) * 2006-01-02 2007-07-12 Samyang Genex Corporation Procede preparation de docetaxel amorphe, cristallin anhydre ou cristallin hydrate
WO2007109654A2 (fr) * 2006-03-21 2007-09-27 Dr. Reddy's Laboratories Ltd. Polymorphes de docétaxel et procédés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253738A1 (fr) * 1986-07-17 1988-01-20 Rhone-Poulenc Sante Dérivés du taxol, leur préparation et les compositions pharmaceutiques qui les contiennent
WO2005061474A1 (fr) * 2003-12-12 2005-07-07 Quiral Química Do Brasil Procede de preparation d'ingredients pharmaceutiques actifs hydrates et anhydres (api), compositions pharmaceutiques stables preparees a partir de ces derniers et utilisations desdites compositions
WO2007078050A2 (fr) * 2006-01-02 2007-07-12 Samyang Genex Corporation Procede preparation de docetaxel amorphe, cristallin anhydre ou cristallin hydrate
WO2007109654A2 (fr) * 2006-03-21 2007-09-27 Dr. Reddy's Laboratories Ltd. Polymorphes de docétaxel et procédés

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QI C -M ET AL: "A novel method to synthesize docetaxel and its isomer with high yields", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 42, no. 4, May 2005 (2005-05-01), pages 679 - 684, XP002485788, ISSN: 0022-152X *
ZASKE L ET AL: "DOCETAXEL: SOLID STATE CHARACTERIZATION BY X-RAY POWDER DIFFRACTION AND THERMOGRAVIMETRY", JOURNAL DE PHYSIQUE IV, EDITIONS DE PHYSIQUE. LES ULIS CEDEX, FR, vol. 90, 1 January 2001 (2001-01-01), pages 221 - 226, XP008077819, ISSN: 1155-4339 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
US9308195B2 (en) 2012-10-01 2016-04-12 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
US9763880B2 (en) 2012-10-01 2017-09-19 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
US10500285B2 (en) 2015-05-15 2019-12-10 Zhuhai Beihai Biotech Co., Ltd. Docetaxel and human serum albumin complexes
US10780172B2 (en) 2015-05-15 2020-09-22 Zhuhai Beihai Biotech Co., Ltd. Docetaxel and human serum albumin complexes
US11419842B2 (en) 2016-10-27 2022-08-23 Zhuhai Beihai Biotech Co., Ltd. Neutral pH compositions of Docetaxel and human serum albumin
CN107501211A (zh) * 2017-07-05 2017-12-22 中国药科大学 多烯紫杉醇黄酮共无定形物

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