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WO2012160568A1 - Procédé pour préparer un polymorphe de docétaxel trihydraté - Google Patents

Procédé pour préparer un polymorphe de docétaxel trihydraté Download PDF

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Publication number
WO2012160568A1
WO2012160568A1 PCT/IN2011/000587 IN2011000587W WO2012160568A1 WO 2012160568 A1 WO2012160568 A1 WO 2012160568A1 IN 2011000587 W IN2011000587 W IN 2011000587W WO 2012160568 A1 WO2012160568 A1 WO 2012160568A1
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Prior art keywords
docetaxel
docetaxel trihydrate
trihydrate
crystalline form
peak
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Inventor
Vimal Kumar Shrawat
Veereshappa .
Prashant Purohit
Vinod Kumar Singh
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Shilpa Medicare Ltd
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Shilpa Medicare Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • compositions comprising of novel polymorphic form of docetaxel trihydrate that are useful in the treatment of various cancerous disorders.
  • DOCETAXEL TRIHYDRATE is the generic name for the compound (2R, 3S)-N-carboxy-3- phenylisoserine, N-tert-butyl ester, 13-ester with 5( ⁇ )-20- ⁇ -1,2( ⁇ ), 4,7( ⁇ ), 10( ⁇ ), 13(a)- hexahydroxy tax-ll-en-9-one 4-acetate 2-benzoate, trihydrate and is represented by the formula (I)
  • Docetaxel possess activity against different kinds of cancer, including breast cancer, non-small cell lung cancer and other malignant tumors. It is well known anticancer agent of taxoid family and is sold under the trade name TAXOTERE ® in the form of a sterile, non-pyrogenic injection in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL) of the drug.
  • TAXOTERE ® injection comprises a two part component formulation that requires two- step dilution before infusion. The first step involves dilution with the contents of a diluents vial (about 13% w/w ethanol in water for injection) without significant foaming, and the second step involves further dilution with infusion fluid for parenteral administration.
  • Zaske et al in Journal de Physique IV France, Vol. 11, PrlO-221 - 226 (2001) discloses the solid- state characterization of anhydrous, hemihydrate and trihydrate forms of docetaxel.
  • Durand et al, in US 6,197,980 discloses 4-acetoxy-2a-benzoyloxy-5p, 20-epoxy-l3,7 ,10 -tri hydroxy-9-oxo-ll-taxen-13a-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxy propionate trihydrate (i.e.
  • docetaxel trihydrate obtained by a process of centrifugal partition chromatography, comprising centrifuging impure 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy- 1 ⁇ ,7 ⁇ , 10 -trihydroxy-9-oxo-ll-taxen-13a-yl(2R,3S)-3-t-butoxycarbonyl. amino-3-phenyl-2- hydroxy propionate (docetaxel) utilizing at least four solvents, wherein the solvents are selected from an aliphatic hydrocarbon, an ester, an alcohol, and water.
  • Authelin et al in US 6,022,985, discloses a process for the preparation of Docetaxel trihydrate, wherein Docetaxel is crystallized using a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, and then the product obtained is subjected to drying under defined conditions of temperature, pressure and humidity. Further, the patent discloses that 4-acetoxy-2a-benzoyloxy-53, 20-epoxy-l ,73,103-trihydroxy-9-oxo-ll-taxen-13a-yl(2R,3S)- 3-t-butoxy carbonyl amino-3-phenyl-2-hydroxy propionate trihydrate has a better stability than that of the anhydrous docetaxel product.
  • Sharma et al in US 6,838,569 discloses a process for converting paclitaxel or docetaxel to its trihydrate in a mixture of alkane and chlorinated alkane to provide a crude product of 65-75% purity and the crude product subsequently dissolved in an alkyl ketone, followed by addition of an alkane to provide a product of enhanced chromatographic purity.
  • This product with an aliphatic nitrile solvent, followed by addition of water provides taxane trihydrate.
  • WO 2005/061474 Al discloses a process for the preparation of amorphous, anhydrous, and trihydrate forms of docetaxel. The process for docetaxel trihydrate involves solubilizing docetaxel in a solvent which is chemically inert.
  • This solvent may be a linear or branched alcohol (containing between 1 and 8 carbons), an organic acid, an aliphatic or cyclic ether, a polar, aprotic solvent, a halogenated solvent, an aromatic solvent, a polyethoxylated sorbitol, lecithin or castor oil, or another solvent of adequate polarity to effect the complete solubilization of docetaxel and is capable of solubilizing, or is miscible with, at least 3 molar equivalents of water.
  • the solution so obtained is admixed with an amount of distilled water between 3 and 200,000 molar equivalents relative to docetaxel. Crystallization is induced and the docetaxel trihydrate is isolated by means of conventional processes such as filtration, decantation or centrifugation.
  • Li Jinliang et al in US2006/0217436A1 discloses a process for preparing docetaxel trihydrate, which involves repeated dissolution and removal of the solvent by concentration of docetaxel in acetone. The final precipitation of the product is by addition of water to the solution of the compound in acetone.
  • WO 2007/044950 A2 discloses crystalline forms of docetaxel and processes for their preparation.
  • One of the claimed form of docetaxel is characterized by data selected from the group consisting of a powder XRD pattern having peaks at about 7.3, 8.8, 13.7, 17.2 and 20.2 ⁇ 0.2 ° 2 ⁇ , and an FTIR spectrum having peaks at about 1098, 1165, 1248, 1701 and 1720 (cm '1 )
  • Kim Namdu et al in US2010/00099897A1 discloses stable anhydrous crystalline docetaxel and method for the preparation thereof.
  • Said form of anhydrous docetaxel is characterized by XRD pattern having major peaks at about 2 ⁇ values of 4.88, 9.22, 9.72, 10.38, 11.30, 11.88, 13.34, 14.56, 15.14, 16.62, 17.28, 17.66, 19.02, 19.62, 19.86, 20.86, 21.86, 24.58, and 26.98; and which contains 0.1% or less of the 7-epimer thereof.
  • the process comprises dissolving docetaxel in a dichioromethane-methanol mixture as an organic solvent followed by adding hexane to the resulting solution; and recovering the resulting crystals.
  • Palle et al in US2010/0197944 discloses new crystalline forms of docetaxel as Form -X and Form- XI and processes for preparation thereof.
  • Crystalline Form X is characterized by an X-ray powder diffraction (XRPD) pattern with characteristic peaks at diffraction angles 2- ⁇ of about 5.3, 8.9, 10.0, 10.6, 11.2, 12.2, 13.7, 14.1, 15.8, 20.4, 21.2, 21.6, and 21.9 ⁇ 0.2°; differential scanning calorimetry (DSC) thermogram curve having endotherm peaks at about 106°C and 175°C and thermogravimetric analysis (TGA) curve corresponding to a weight loss of about 2.6%.
  • Process for preparing Form -X comprise providing a solution of docetaxel in ethyl acetate followed by crystallizing a solid from the solution and isolating the obtained crystalline form.
  • Crystalline Form XI is characterized by an XRPD pattern with characteristic peaks at diffraction angles 2- ⁇ of about 4.4, 4.5, 7.0, 8.0, 8.7, 9.1, 11.0, 11.4, 12.3, 12.5, 13.5, 14.1, 15.4, 16.5, 16.9, 17.4, 18.4, 19.5, and 20.4+0.2 °; DSC thermogram curve with an endotherm having an onset at about 66° C and an end set at about 161°C and TGA curve corresponding to a weight loss of about 1.9%.
  • Process for preparing Form -XI comprises providing a solution of docetaxel in acetone followed by precipitating a solid by adding ether and isolating the obtained crystalline form as Form-XI.
  • Inventors also provided a process for preparing docetaxel trihydrate, which providing a mixture of docetaxel and water followed by maintaining the mixture at 25-30°C with stirring and isolating the obtained trihydrate crystalline form, which characterized by XRPD pattern with characteristic peaks at diffraction angles 2 ⁇ of about 4.5, 7.3, 8.9, 10.5, 11.2, 12.4, 12.7, 13.1, 13.6, 14.1, 15.4, 16.6, 17.2, 17.8, 18.5, 19.4 and 19.9+0.2 °.
  • Polymorphism is a phenomenon, wherein existence of different physical forms including shape, size, and arrangement of molecules in the physical state or polymorphs of same compound is known in the nature.
  • a single compound, or a salt complex may give rise to a variety of solids having distinct physical properties, which often results in substantial differences in bioavailability, stability, and other differences between production lots of formulated pharmaceutical products. Due to this reason, since polymorphic forms can vary in their chemical and physical properties, regulatory authorities often require that efforts be made to identify all polymorphic forms, e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un-solvated forms, etc. of the drug substances. However, the existence, and possible numbers, of polymorphic forms for a given compound cannot be predicted. In addition, there are no "standard” procedures that can be used to prepare polymorphic forms of a substance.
  • New forms of pharmaceutically active / useful compounds provide an opportunity to improve the drug performance characteristics of such product. Further, discovery of additional polymorphic forms may help in the identification of the polymorphic content of a batch of an active pharmaceutical ingredient. Therefore, there is a need for preparing new crystalline forms of a drug substance and processes for preparation thereof. Though the review of the above mentioned literature disclose diverse polymorphic crystalline forms and processes for the preparation of docetaxel and its trihydrate, but due to one more reasons they are not particularly convenient and amenable to industrial scale-up for preparing docetaxel trihydrate.
  • the present invention provides a substantially pure docetaxel trihydrate crystalline Form (hereinafter referred to as Form-VK) characterized by X- ray powder diffraction pattern comprising at least 5 characteristic 2 ⁇ ° peaks selected from the XRPD peak set of 4.29, 7.11, 10.30, 12.21, 13.87, 15.21, 17.62, 19.26, 21.51, 22.19, 23.16, 27.34 +0.1 29° and characterized by DSC isotherm comprising the endothermic peaks ranging between- a. Peak -1- Between 135 to 145°C
  • the present invention provides a process for preparation of novel crystalline polymorphic Form-VK of docetaxel trihydrate of formula (I),
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of docetaxel trihydrate- Form-VK prepared by using 2-methoxy ethanol.
  • XRPD X-ray powder diffraction
  • Fig. 2 is an example of a differential scanning calorimetry ("DSC") curve of docetaxel trihydrate Form-VK prepared by using 2-methoxy ethanol.
  • DSC differential scanning calorimetry
  • Fig. 3 is an example of X-ray powder diffraction ("XRPD") pattern of docetaxel trihydrate- Form-VK prepared by using DMSO.
  • XRPD X-ray powder diffraction
  • Fig. 4 is an example of a differential scanning calorimetry ("DSC") curve of docetaxel trihydrate Form-VK prepared by using DMSO.
  • DSC differential scanning calorimetry
  • embodiments of the present invention relates to substantially pure docetaxel trihydrate new crystalline form designated as Form- VK and process for preparation thereof.
  • Form-VK substantially pure Docetaxel trihydrate crystalline Form
  • Form-VK characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 4.29, 7.11, 10.30, 12.21, 13.87, 15.21, 17.62, 19.26, 21.51, 22.19, 23.16, 27.34 ⁇ 0.1 2 ⁇ ° and characterized by DSC isotherm comprising the endothermic peaks ranging between- s
  • Substantially pure Crystalline Docetaxel trihydrate ' Form-VK * exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1 and 3.
  • the prominent and characteristic 2 ⁇ ° and ' d ' spacing values for the Form-VK of the present invention includes 4.29 (20.58 d value), 7.11 (12.42 d value), 10.30 (8.59 d value), 12.21 (7.24 d value), 13.87 (6.38 d ' value), 15.21 (5.82 d value), 17.62 (5.03 d value), 19.26 (4.61 d value), 21.51 (4.13 d value), 22.19 (4.00 d value), 23.16 (3.83 d value) and 27.34 (3.26 d value) ⁇ 0.1° 2 ⁇ .
  • the Crystalline Docetaxel trihydrate ' Form-VK ' produced by the inventors of the present application was characterized by the 2 theta values (in degrees) in the X-ray diffractograms are shown in Table
  • the crystalline Form-VK of Docetaxel trihydrate may be characterized by an X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes five or more peaks selected from the group consisting of 4.29 ⁇ 0.10, 7.11 ⁇ 0.10, 10.30 ⁇ 0.10, 12.21+0.10, 13.8710.10, 15.21 ⁇ 0.10, 17.62 ⁇ 0.10, 19.26 ⁇ 0.10, 21.51 ⁇ 0.10, 22.19 ⁇ 0.10, 23.16 ⁇ 0.10, 27.34 ⁇ 0.10 2 ⁇ °
  • Docetaxel trihydrate Form-VK were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Kct radiation using the wavelength 1.5418 A and lynx Eye detector.
  • the crystalline Form-VK of Docetaxel trihydrate is hydrated form.
  • IR Infrared spectroscopy
  • Crystalline Form-VK is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak -1- Between 135 to 145°C b. Peak -2- Between 210 to 220°C
  • the Differential Scanning Calorimetry (DSC) thermogram of crystalline form of Docetaxel trihydrate obtained by the inventors is shown in Fig. 2 and 4. It exhibits a significant endo-exo pattern with 2 well identified peaks around 137.97°C and 214.04 °C.
  • the DSC thermogram was measured on a Perkin Elmer instrument model Zade DSC. It is known to one of skill in the art that the endothermic peak location may be affected by the heating rate in the DSC. Thus, slight variation of the peak may be acceptable.
  • Illustrative examples of analytical data for the crystalline ' Form-VK * obtained in the Examples are set forth in the Figs. 1-4.
  • the invention also relates to a composition containing crystalline Docetaxel trihydrate of which at least 95%, by total weight of the crystalline form of Docetaxel trihydrate in the composition, is the crystalline Form-VK.
  • the composition may substantially free of any other known forms of Docetaxel trihydrate.
  • X-ray diffraction provides a convenient and practical means for quantitative determination of the relative amounts of crystalline forms in a solid mixture.
  • X-ray diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks, particularly long range peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture.
  • the percent composition of crystalline Docetaxel trihydrate in an unknown composition can be determined.
  • the measurements are made on solid powder Docetaxel trihydrate.
  • the X-ray powder diffraction patterns of an unknown composition can be compared to known quantitative standards containing the pure crystalline Form-VK of Docetaxel trihydrate to identify the percent ratio of a particular crystalline form.
  • This may be done by comparing the relative intensities of the peaks from the diffraction pattern of the unknown solid powder composition with a calibration curve derived from the X-ray diffraction patterns of pure known samples.
  • the curve can be calibrated based on the X-ray powder diffraction pattern for the strongest peak or any distinctive peak from a pure sample of the crystalline Form-VK of Docetaxel trihydrate.
  • the calibration curve may be created in a manner known to those of skill in the art. For example, five or more artificial mixtures of crystalline forms of Docetaxel trihydrate, at different amounts, may be prepared. In a non-limiting example, such mixtures may contain, 2%, 5%, 10% and 15% of the Form-VK of Docetaxel trihydrate.
  • X-ray diffraction patterns are obtained for each artificial mixture using standard X-ray diffraction techniques. Slight variations in peak positions, if any, may be accounted for by adjusting the location of the peak to be measured.
  • the intensities of the selected characteristic peak(s) for each of the artificial mixtures are then plotted against the known weight percentages of the crystalline form. The resulting plot is a calibration curve that allows determination of the amount of the crystalline form Form-VK of Docetaxel trihydrate in an unknown sample.
  • the intensities of the selected characteristic peak(s) in the mixture may be used to determine the percentage of the given crystalline form in the composition. Similar quantitative analysis may be carried out using IR spectroscopy, particularly with attenuating total reflectance (ATR) technology.
  • Step i) of the process involves the combining docetaxel anhydrous or any hydrate form with a polar organic solvent selected from 2-alkoxy ethanol or dimethylsulfoxide.
  • Combining the docetaxel or any hydrated form and polar organic solvent comprise preparing solution of docetaxel or its hydrate with polar organic solvent selected from 2-alkoxy ethanol or dimethylsulfoxide. The solution is prepared by combining docetaxel with polar solvent upto the range between 10 to 18 times by weight of docetaxel.
  • docetaxel solution was prepared in 2-methoxy ethanol only by combining 40 gm of docetaxel with 664 ml (specific gravity 0.965 gm/ml) of 2-methoxy ethanol (16.6 times w/v or 16 time w/w).
  • Step ii) of the process involves cooling the combined mixture of step i)
  • This step of cooling the combined mixture of step a) involves slow cooling upto less than 15°C but more than 5°C comprise a slow and constant cooling.
  • a fast cooling rate of more than 10 °C may be avoided in view of any probable inconsistency in the further steps.
  • Step iii) of the process involves combining the reaction mass with water slowly in 1-5 hrs at 0°-15°C
  • Adding the water into a solution docetaxel in a polar solvent ( as per step i) for preparing Form-VK comprise lot wise addition of the water in two to four lots at a time interval of 10 to 30 mins, however, it may be added in continuous ways also, with slow addition rate. In one of the preferred embodiment, the time interval used was 10 minutes for two lots of water addition. Water addition was carried out at a temperature of not more than 15°C. The water is combined with the reaction mass or solution mixture of step i) upto the range between 20 to 35 times by weight of docetaxel. In a particular embodiment, 1660 gm of water was combined with reaction mixture containing 50 gm of docetaxel with 660 gm of 2- methoxy ethanol ( ⁇ 33 time w/w).
  • Step iv) of the process involves optionally maintain the reaction mass for about 2- 10 hrs.
  • the combined mixture may be maintained for about 1-5 hrs, however, this time may be more, but, depending upon achieving the desired solution nature and equilibration to impurity profile compliance.
  • the process related impurities including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appears in the impurity profile of the Docetaxel trihydrate can be substantially removed by the process of the present invention resulting in the formation crystalline Form-VK.
  • the process may require in-process quality checks.
  • Step v) of the process involves isolating the crystalline Form-VK.
  • Process of isolating Form-VK comprise processes but not limited to conventional processes including filtering and optional drying, which may be carried out at room temperature for the suitable durations to retain the crystalline polymorphic form characteristics.
  • Substantially pure Crystalline Docetaxel trihydrate Form-VK obtained according to the process of the present invention results in matter purity by HPLC of more than 99% w/w.
  • the crystalline solid ' Form VK ⁇ described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis.
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the samples of docetaxel trihydrate Form-VK were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector.
  • Illustrative examples of analytical data for the crystalline solid ' Form-VK ' obtained in the Examples are set forth in the Figs. 1-4.
  • Docetaxel or (2R, 3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5, 20- epoxy-1, 2,4,7, 10,13-hexahydroxy tax-ll-en-9-one 4-acetate 2-benzoate (I) or its any hydrate including any trihydrate may be obtained by any of the processes known in the prior art or any of its less stable form or impure form available from any source may be utilized. However in the present invention for polymorphic form and its process for preparation, materials obtained by the process schematically shown in scheme-l was utilized.
  • the crystalline "Form-VK" of docetaxel trihydrate obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating.
  • compositions comprising Crystalline Form- VK of docetaxel trihydrate of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like;
  • compositions of Crystalline Form-VK of docetaxel trihydrate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Example -01 Preparation of Pure Docetaxel Trihydrate Crystalline Form-VK by using the polar solvent as 2-Methoxy Ethanol
  • Example-02 Preparation of Pure Docetaxel Trihydrate Crystalline Form-VK by using the polar solvent as Dimethylsulfoxide (DMSO)

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Abstract

La présente invention concerne une forme cristalline de docétaxel trihydraté appelée forme VK et un procédé pour la préparation de celle-ci. La présente invention concerne en outre un produit cristallin trihydraté sensiblement pur obtenu par le procédé. Le produit cristallin du procédé qui a un profil XRPD conformément à la figure 1 est utile en tant qu'agent pharmaceutique actif dans une composition pharmaceutique et a une activité anticancéreuse.
PCT/IN2011/000587 2011-05-23 2011-08-29 Procédé pour préparer un polymorphe de docétaxel trihydraté Ceased WO2012160568A1 (fr)

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Cited By (4)

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US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
US20150141673A1 (en) * 2013-11-15 2015-05-21 Honghai SONG Novel crystalline for w of cabazitaxel and method for preparing it
CN105712996A (zh) * 2015-02-12 2016-06-29 苏州晶云药物科技有限公司 Ipi-145的新晶型及其制备方法
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

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JP2010138084A (ja) * 2008-12-10 2010-06-24 Mercian Corp 結晶性ドセタキセル三水和物の製造方法
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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
US20150141673A1 (en) * 2013-11-15 2015-05-21 Honghai SONG Novel crystalline for w of cabazitaxel and method for preparing it
CN105712996A (zh) * 2015-02-12 2016-06-29 苏州晶云药物科技有限公司 Ipi-145的新晶型及其制备方法
US10196395B2 (en) * 2015-02-12 2019-02-05 Crystal Pharmatech Co., Ltd Crystalline form alpha of IPI-145 and preparation method thereof

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