WO2020249507A1 - Forme cristalline anhydre du cabazitaxel, procédé pour sa préparation et compositions pharmaceutiques la contenant - Google Patents

Forme cristalline anhydre du cabazitaxel, procédé pour sa préparation et compositions pharmaceutiques la contenant Download PDF

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Publication number
WO2020249507A1
WO2020249507A1 PCT/EP2020/065809 EP2020065809W WO2020249507A1 WO 2020249507 A1 WO2020249507 A1 WO 2020249507A1 EP 2020065809 W EP2020065809 W EP 2020065809W WO 2020249507 A1 WO2020249507 A1 WO 2020249507A1
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WIPO (PCT)
Prior art keywords
cabazitaxel
suspension
crystalline form
hydrocarbon
solution
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PCT/EP2020/065809
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English (en)
Inventor
Luca Domenighini
Nicola Sardone
Andrea Gambini
Federico Peterlongo
Daniele Ciceri
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Indena S.P.A.
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Application filed by Indena S.P.A. filed Critical Indena S.P.A.
Publication of WO2020249507A1 publication Critical patent/WO2020249507A1/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

Definitions

  • the present invention relates to an anhydrous crystalline form of Cabazitaxel, to a process for its preparation and to pharmaceutical compositions containing it.
  • Form H is obtained by crystallization at room temperature of crude Cabazitaxel from a mixture of decanoyl- and octanoyl triglycerides, or from glycerol trioctanoate.
  • the crystallization process comprises dissolving crude Cabazitaxel in a mixture of decanoyl- and octanoyl triglycerides or glycerol trioctanoate and stirring until a product starts to crystallize, then adding heptane to complete precipitation of Cabazitaxel Form H. Form H is then filtered and dried.
  • a large volume of solvents is used with respect to the weight of crude Cabazitaxel (28 mL of mixture of decanoyl- and octanoyl triglycerides or glycerol trioctanoate and 112 mL heptane per gram of crude Cabazitaxel).
  • Form H is advantageous with respect to another Cabazitaxel crystalline form, Form D, disclosed in W02009/115655 (Aventis Pharma)also obtained by means of a process making use of an oil (namely MiglyolTM) and heptane at room temperature.
  • the advantage of Form H over Form D lies in the fact that it absorbs less humidity and presents significantly lower levels of impurities A (2-debenzoyl-2-tigloyl Cabazitaxel), B (methyl Cabazitaxel) and C (2’-BOC Cabazitaxel); in fact, the overall amount of impurities A, B and C in Form H is as twice as less than that of Form D.
  • Figure 1 XRPD pattern of anhydrous crystalline Form H-l of Cabazitaxel.
  • Figure 2 FTIR spectrum of anhydrous crystalline Form H-l of Cabazitaxel in the 4000-550 cm 1 spectral range.
  • FIG 3 DSC profile of anhydrous crystalline Form H-l of Cabazitaxel.
  • Figure 4 TG and DTA profiles of anhydrous crystalline Form H-l of Cabazitaxel (solid line: DT profile; dashed line: TG profile).
  • Figure 5 13C SS-NMR profiles of Cabazitaxel Form H and Form H-l .
  • a novel anhydrous form of Cabazitaxel herein after referred to as Form H-l, showing a 13 C SS-NMR spectrum featuring one single polymorph, can be obtained from crude Cabazitaxel or from any one of known crystalline forms A - H, through a crystallization process that comprises the use of oily solvents, followed by precipitation with a hydrocarbon, said process comprising heating steps and using the solvents in specific amounts with respect to Cabazitaxel.
  • Anhydrous Form H-l of Cabazitaxel according to the present invention has a water content lower than 1% wt.
  • Form H-l is characterized by an X-ray powder diffraction (X-RPD) pattern obtained using the copper wavelengths l ⁇ and l2 of 1.54056 A and 1.54439 A showing a crystalline structure and comprising distinctive reflections, expressed as 2-theta degrees values, at 4.7 - 5.7 - 6.7 - 8.1 - 9.3 - 10.9 - 11.3 - 12.4 - 13.3 - 14.0 - 14.3 - 15.2 - 17.0 - 17.3 - 18.6 - 18.8 - 20.1 - 21.0 - 21.8 - 23.5 ( ⁇ 0.2 2Q degrees).
  • X-RPD X-ray powder diffraction
  • Form H-l according to the invention is further characterized by a Fourier-Transform InfraRed Spectroscopy (FTIR) spectrum in the 4000-550 cm 1 spectral range in ATR mode comprising characteristic absorption frequencies at approximately 3443- 2981 - 2891 - 2825 - 1741 - 1709 - 1486 - 1451 - 1391 - 1368 - 1315 - 1262 - 1247 - 1172 - 1098 - 1072 - 1028 - 989 - 946 - 918 - 886 - 833 - 802 - 781 - 719 - 704 - 674 ⁇ 4 cm 1 .
  • FTIR Fourier-Transform InfraRed Spectroscopy
  • Form H-l is further characterized by a Differential Scanning Calorimetry (DSC) profile characterized by a melting peak with onset at about 190.4°C, maximum at about 194.6°C, and DH of about - 49 J/g, followed by decomposition which takes place above 210°C.
  • DSC Differential Scanning Calorimetry
  • Form H-l is further characterized by a Differential Thermal Analysis (DTA) profile showing a melting peak with onset at about 187.4°C and maximum at 194.3°C followed by an intense exothermic peak due to decomposition.
  • Form H-l is further characterized by a Thermogravimetric profile (TG) showing a very low weight loss ( ⁇ 0.1% at 120°C), which is coherent with an anhydrous product, free of moisture and residual solvents.
  • DTA Differential Thermal Analysis
  • TG Thermogravimetric profile
  • Form H-l is further characterized by 13 C SS-NMR chemical shift values at 205.2, 174.5, 171.0, 166.0, 155.5, 138.1, 136.2, 131.8, 129.4, 128.5, 127.8, 126.3, 125.3, 83.4, 83.1, 81.7, 81.0, 79.0, 78.4, 74.9, 74.6, 72.6, 68.4, 57.3, 56.8, 56.0, 55.3, 47.7, 43.5, 33.2, 33.0, 28.6, 28.0, 26.1, 21.4, 18.5, 14.6, 11.2.
  • Form H-l can be obtained through a process which comprises the following steps: a) providing amorphous Cabazitaxel or any one of its crystalline forms A - H;
  • solution (SI) a triglyceride selected from 1) a mixture of decanoyl- and octanoyl triglycerides and 2) glycerol trioctanoate to obtain a solution [solution (S2)] of Cabazitaxel in alcohol or in chlorinated hydrocarbon and in triglyceride ;
  • suspension (SP-1) with an aliphatic hydrocarbon selected from «-hexane and «-heptane, and heating at the reflux temperature of the hydrocarbon for at least four hours to obtain a second suspension [suspension (SP-2)];
  • step e suspending filtrate in the same hydrocarbon as used in step e) to obtain a third suspension [suspension (SP-3)] and heating suspension (SP-3) at the reflux temperature of the hydrocarbon, for at least 4 hours;
  • Amorphous Cabazitaxel can be obtained according to methods known in the art, for example according to WO 96/30355 or WO 99/25704. Alternatively, Cabazitaxel can be prepared following the teaching of US 2008/200700 A1 , with appropriate modifications, as explained in detail in the experimental section.
  • Crystalline forms A - F can be obtained as disclosed in W02009/115655, while crystalline form H can be obtained as disclosed in WO2015/05896
  • the process of the invention is carried out using amorphous Cabazitaxel as starting material.
  • amorphous Cabazitaxel having an HPLC purity of at least 90% is used.
  • the alcohol used in step b) is typically methanol, ethanol or a straight or branched C3-C10 aliphatic alcohol; preferably, the alcohol is methanol, ethanol, propanol or isopropanol; most preferably methanol.
  • the chlorinated hydrocarbon is methylene chloride.
  • the alcohol or chlorinated hydrocarbon is used in the minimum amount required to dissolve amorphous Cabazitaxel, i.e. the minimum amount required to obtain a solution that, upon naked eye inspection, appears clear, i.e. free of suspended particles.
  • the alcohol is methanol, from 4 to 10 ml methanol per gram Cabazitaxel are used; preferably, 5 ml methanol per gram Cabazitaxel are used.
  • Step b) is carried out in a suitable vessel and at room temperature.
  • room temperature means from 15°C to 25°C, preferably from 20°C to 25°C.
  • decanoyl- and octanoyl triglycerides that can be used to perform step c) are available on the market with tradename MiglyolTM; preferably, MiglyolTM 812 is used.
  • the mixture of decanoyl- and octanoyl triglycerides or glycerol trioctanoate to be added to solution (S-l) is in an amount ranging from 5 to 10 volumes (ml), preferably 5 volumes, per gram Cabazitaxel; preferably, the volume (ml) of mixture of decanoyl- and octanoyl triglycerides or glycerol trioctanoate is the same as that of alcohol (A) or chlorinated hydrocarbon (clH) used in step b).
  • step d the expression“complete evaporation” means that no more evaporation of alcohol or chlorinated hydrocarbon is observed upon naked eye inspection and formation of a suspension (SP-1) is observed.
  • the aliphatic hydrocarbon is «-heptane.
  • the hydrocarbon solvent preferably «-heptane
  • the hydrocarbon solvent is used in an amount ranging from 3 to 4 volumes (ml) with respect to the volumes (ml) of triglyceride; preferably, 4 volumes «-heptane are used.
  • «-heptane is used in an amount ranging from 3 to 4 volumes (ml) with respect to the volumes (ml) of triglyceride; preferably, 15volumes «- heptane are used with respect to the weight amount of filtrate (F-l).
  • Optional drying step 1) is carried out under vacuum, usually at a temperature ranging from 75°C to 85°C for a time ranging from 12 to 72 hours, preferably for 12 hours, independently of the amount of product to dry.
  • crystalline Form H-l shows a 13 C SS-NMR spectrum featuring one single polymorph, and retains the other advantages of known Form H over known Form D; in particular it is endowed with high stability to humidity and contains low amounts of impurities, in particular of impurity A.
  • Miglyol® 812 was purchased from Cremer.
  • X-RPD patterns were collected on a Bruker D2-Phaser Diffractometer.
  • the X-ray generator was operated at 30kV and 10 mA, using the CuKa line as the radiation source.
  • the sample was packed on a suitable slit and the irradiated length was 10 mm.
  • Data were collected between 2 and 50 deg 2-theta with a step size of 0.02 deg 2-theta and a counting time per step of 3 sec.
  • the infrared spectrum was recorded in Attenuated Total Reflectance (ATR) mode using the Fourier-Transform spectrometer NicoletTM iSlO Thermo Scientific, equipped with Specac’s Golden Gate MT ATR accessory.
  • the spectrum was the result of the acquisition and transformation of 32 co-added scans in the 4000-550 cm 1 spectral region at a resolution of 4 cm 1 .
  • DSC analysis was performed using a Mettler DSC1 System. Heat flow was recorded from 25 to 250°C with linear heating rate (10°C/min) under a 50 ml/min nitrogen flow. About 5 mg of powder was used for the measurement, in a closed aluminium crucible (40 pi volume) with a pinhole.
  • TG/DTA was performed using a Seiko TG/DTA7200 simultaneous system using open aluminum pans (40 ml volume).
  • the TG/DT signals were recorded from 25 to 250°C with linear heating rate (10°C/min) under a 200 ml/min nitrogen flow. About 10 mg of powder was used for the measurement.
  • the solid-state NMR spectra were acquired on a Jeol ECZR 600 instrument operating at 150.91 MHz respectively for 13 C nucleus.
  • the powder samples were packed in cylindrical zirconia rotors with a diameter of 3.2 mm and a volume of 60 pL. The samples were used as such, without further preparation, to fill in the rotors.
  • the 13 C CPMAS spectra were acquired at a rotation frequency of 20 kHz with a sequence of ramp cross-polarization pulses with a contact time of 3.5 ms, a 1H pulse at 90° of 2.1 ps, optimized recycling times of 3.1 s for a number of scans of 250 or 850, depending on the sample.
  • a two-pulse phase modulation (TPPM) decoupling scheme was used, with a 108.5 kHz radio frequency field.
  • the chemical shift scale was calibrated through the methylene glycine signal (at 43.7 ppm) as external standard.
  • Solvent A water / MeOH 96/4 (V/V) containing formic acid 50 ppm.
  • Solvent B acetonitrile / MeOH 96/4 (V/V) containing formic acid 50 ppm.
  • Form H-l of Cabazitaxel is characterised by an X-ray powder diffraction (X-RPD) pattern obtained using the copper wavelengths l ⁇ and l2 of 1.54056 A and 1.54439 A, respectively, essentially as depicted in Figure 1.
  • the X-RPD pattern shows a crystalline structure and comprises distinctive reflections, expressed as 2-theta degrees values, at 4.7
  • Form H-l is further characterized by a Fourier- Transform InfraRed Spectroscopy (FTIR) spectrum in the 4000-550 cm 1 spectral range in ATR mode essentially as depicted in Figure 2.
  • the FTIR spectrum of Form H-l comprises characteristic absorption frequencies at approximately 3443- 2981 - 2891 - 2825 - 1741 - 1709 - 1486 - 1451 - 1391 - 1368 - 1315 - 1262 - 1247 - 1172 - 1098 - 1072 - 1028 - 989 - 946 - 918 - 886 - 833 - 802 - 781 - 719 - 704 - 674 ⁇ 4 cm 1 .
  • DSC Differential scanning calorimetry
  • Form H-l is further characterized by a DSC profile as depicted in Figure 3.
  • the DSC analysis shows a thermal profile characterized by a melting peak with onset at about 190.4°C, maximum at about 194.6°C, and DH of about - 49 J/g, followed by decomposition which takes place above 210°C.
  • Form H-l is further characterized by Thermogravimetric (TG) and Differential Thermal Analysis (DTA) profiles as depicted in Figure 4.
  • the DTA profile is characterised by a melting peak with onset at about 187.4°C and maximum at 194.3°C followed by an intense exothermic peak due to decomposition.
  • Form H of Cabazitaxel also having a weight loss at 120°C ⁇ 0.1%, shows a DTA profile characterized by a melting peak with onset at about 184.4°C and maximum at 192.9°C.
  • DVS analysis was performed using the DVS Intrinsicl system (Surface Measurement Systems Ltd UK).
  • the DVS curves were acquired by Intrinsic Control Software and elaborated by the software DVS Analysis Suite. The analysis was run at a fixed temperature of 25 ⁇ 0.1°C.
  • the sample was dried for 6 hours under a continuous flow of dry air (Relative Humidity, RH ⁇ 0.1 %) to establish the dry mass (preconditioning step).
  • the relative humidity was then increased from 0% to 90% RH (in 10% RH steps) and then decreased to 0% RH in a similar way, until the completion of two full sorption/desorption cycles.
  • the instalment was ran in a dm/dt mode (mass variation over time variation) and a fixed dm/dt value of 0.002%/min was selected, in order to let equilibrium to be reached at each step.
  • Form H-l shows the same hygroscopicity as Form H; therefore, as far as humidity adsorption is concerned, it retains the same advantages as Form H with respect to Form D.
  • Table 3 shows a comparison between 13 C SS-NMR chemical shift values for the peaks appearing in the 13 C CPMAS NMR spectra of crystalline Form H and Form H-l of Cabazitaxel. It stems from the comparison that Form H-l is a single form, while Form H is actually a mixture of Form H-l with another crystalline form.
  • Table 4 below shows the results of the determination of total impurities A (2-debenzoyl-2-tigloyl Cabazitaxel), B (methyl Cabazitaxel) and C (2’-BOC Cabazitaxel) and impurity A in amorphous Cabazitaxel, Form H-l according to the present application, Form H and Form D. It stems from the results that although the amount of total impurities in Form H-l is slightly higher than that of Form H, the amount of impurity A is the same. Table 4
  • Form H-l in addition to featuring one single crystalline form, shows the same advantages in terms of stability to humidity and impurities levels as Form H with respect to Form D.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme cristalline anhydre du cabazitaxel [forme (H-1)]. La forme H-1 possède un spectre RMN en phase solide du 13C représentant un seul polymorphe et présentant les mêmes avantages que la forme H connue par rapport à la forme D connue en termes de stabilité à l'humidité et d'impuretés A, B et C. L'invention concerne également un procédé d'obtention de la forme H-1.
PCT/EP2020/065809 2019-06-11 2020-06-08 Forme cristalline anhydre du cabazitaxel, procédé pour sa préparation et compositions pharmaceutiques la contenant WO2020249507A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113933441A (zh) * 2021-09-30 2022-01-14 无锡紫杉药业有限公司 一种卡巴他赛及其中间体的测定方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030355A1 (fr) 1995-03-27 1996-10-03 Rhone-Poulenc Rorer S.A. Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent
WO1999025704A1 (fr) 1997-11-18 1999-05-27 Aventis Pharma S.A. Procede de preparation de derives de la classe des taxoides
WO2005028462A1 (fr) 2003-09-19 2005-03-31 Aventis Pharma S.A. Solvat acetonique du dimethoxy docetaxel et son procede de preparation
US20080200700A1 (en) 2004-10-08 2008-08-21 Indena S.P.A. Semisynthesis process for the preparation of 10 deacetyl-n-debenzoyl-paclitaxel
WO2009115655A2 (fr) 2008-01-17 2009-09-24 Aventis Pharma S.A. Formes cristallines du dimethoxy docetaxel et leurs procedes de preparation
WO2015005896A1 (fr) 2013-07-08 2015-01-15 Orr Timothy E Appareil de stockage et de distribution de liquide
EP2865675A1 (fr) * 2013-10-23 2015-04-29 INDENA S.p.A. Forme cristalline anhydre de Cabazitaxel, procédé de préparation et ses compositions pharmaceutiques

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030355A1 (fr) 1995-03-27 1996-10-03 Rhone-Poulenc Rorer S.A. Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent
WO1999025704A1 (fr) 1997-11-18 1999-05-27 Aventis Pharma S.A. Procede de preparation de derives de la classe des taxoides
WO2005028462A1 (fr) 2003-09-19 2005-03-31 Aventis Pharma S.A. Solvat acetonique du dimethoxy docetaxel et son procede de preparation
US20080200700A1 (en) 2004-10-08 2008-08-21 Indena S.P.A. Semisynthesis process for the preparation of 10 deacetyl-n-debenzoyl-paclitaxel
WO2009115655A2 (fr) 2008-01-17 2009-09-24 Aventis Pharma S.A. Formes cristallines du dimethoxy docetaxel et leurs procedes de preparation
WO2015005896A1 (fr) 2013-07-08 2015-01-15 Orr Timothy E Appareil de stockage et de distribution de liquide
EP2865675A1 (fr) * 2013-10-23 2015-04-29 INDENA S.p.A. Forme cristalline anhydre de Cabazitaxel, procédé de préparation et ses compositions pharmaceutiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113933441A (zh) * 2021-09-30 2022-01-14 无锡紫杉药业有限公司 一种卡巴他赛及其中间体的测定方法

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