WO2015000451A1 - Salts of abiraterone acetate - Google Patents

Salts of abiraterone acetate Download PDF

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Publication number
WO2015000451A1
WO2015000451A1 PCT/CZ2014/000073 CZ2014000073W WO2015000451A1 WO 2015000451 A1 WO2015000451 A1 WO 2015000451A1 CZ 2014000073 W CZ2014000073 W CZ 2014000073W WO 2015000451 A1 WO2015000451 A1 WO 2015000451A1
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WO
WIPO (PCT)
Prior art keywords
salt
abiraterone acetate
crystalline
acid
preparation
Prior art date
Application number
PCT/CZ2014/000073
Other languages
English (en)
French (fr)
Inventor
Violetta Kiss
Ludek Ridvan
Marcela Tkadlecova
Ondrej Dammer
Lukas KERJCIK
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2015000451A1 publication Critical patent/WO2015000451A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention provides new solid forms of abiraterone acetate of formula I
  • the compound 3 -acetoxy-17-(3-pyridyl)-androsta-5,16-diene known under the name abiraterone acetate (CAS 154229-18-2), is an inhibitor of biosynthesis of androgens. It selectively inhibits the enzyme 17a-hydroxylase/C17,20-lyase (CYP17), which catalyses the conversion of pregnenolone and progesterone to the precursors of testosterone, DHEA, or androstenedione by 17a-hydroxylation and cleaving of the CI 7,20 bond.
  • CYP17 17a-hydroxylase/C17,20-lyase
  • Abiraterone acetate is used together with prednisone or prednisolone for treatment of metastatic castration- resistant prostate cancer in adult men.
  • Abiraterone acetate is in vivo metabolized to abiraterone.
  • abiraterone acetate and tartaric, acetic, malic, methanesulfonic, ditoluoyl tartaric, hydrochloric and sulphuric acids is described in international application WO2006021776. Further disclosed is a method for the preparation of abiraterone acetate or its pharmaceutically acceptable salt, comprising isolation of the abiraterone acetate salt, e.g. methanesulfonate, of from methyl tert-butyl ether.
  • a method of purification of abiraterone acetate using the trifluoromethanesulfonate salt of abiraterone acetate is further described in the patent document CN 102030798.
  • the invention provides new pharmaceutically acceptable salts of abiraterone acetate of formula I
  • Figure 13 1 H-NMR spectrum of the salt of abiraterone acetate and p-toluenesulfonic
  • This invention provides salts of abiraterone acetate from the group of benzenesulfonate, p- toluenesulfonate and fumarate. These salts have proven to be suitable for pharmaceutical application, especially for their convenient physical-chemical properties and an easily reproducible preparation procedure, which is suitable even for industrial-scale production.
  • the advantage of these solid forms also includes their good processability during the preparation of a pharmaceutical composition and high yield and high purity achievable during their preparation.
  • the invention comprises the salts of abiraterone acetate with benzenesulfonic, p- toluenesulfonic and fumaric acids in a crystalline or amorphous form.
  • the invention further comprises the salts of abiraterone acetate with benzenesulfonic, p- toluenesulfonic and fumaric acids in a non-solvated form, solvated form and in the form of hydrates.
  • the salts in accordance with the invention can exist in several solid forms depending on the selected preparation conditions. These forms differ in their internal structure (polymorphism) and may exhibit different physical-chemical characteristics.
  • the invention comprises these individual polymorphs as well as their mixtures in any proportion. All the salts in accordance with the invention were prepared by reaction of abiraterone acetate with an acid from the group comprising benzenesulfonic, p-toluenesulfonic and fumaric acids in a solvent selected from the group of C1-C4 alkyl alcohols. These solvents have proven to be suitable for the preparation of the salts of abiraterone acetate in accordance with this invention in a high yield and high purity.
  • solvents from the group of C1-C4 alkyl alcohols are suitable from the safety point of view during the preparation of pharmaceutically suitable substances.
  • 2-propanol is used out of the group of C1-C4 alkyl alcohols.
  • the reaction of abiraterone acetate with benzenesulfonic, p-toluenesulfonic or fumaric acid is conducted at a temperature of 40 to 60 °C, preferably at a temperature of about 50 °C.
  • the resulting salt is isolated from the reaction mixture after cooling to the room temperature, or to a temperature of 20 °C to -10 °C.
  • the crystalline salt of abiraterone acetate and benzenesulfonic acid in accordance with the invention exhibits a characteristic XPRD pattern, which is shown in Figure 1.
  • the XRPD pattern was recorded using an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the crystalline salt of abiraterone acetate and benzenesulfonic acid can be further characterized by means of thermal analytical techniques.
  • the DSC curve Perkin Elmer Pyris 1 DSC
  • the TGA curve (Perkin Elmer TGA 6) in Figure 3 shows a weight loss of abiraterone acetate benzenesulfonate of 0.39 in the temperature range of 20 to 250 °C.
  • the DVS analysis in Figure 4 shows a slight change in the weight of crystalline abiraterone acetate benzenesulfonate of 1.1 % in the range of the ambient relative humidity of 0 to 90 %. This salt is hence slightly hygroscopic.
  • the crystalline salt of abiraterone acetate and benzenesulfonic acid obtained by the above mentioned method in accordance with the invention, was isolated in a high yield (62.6 %) and in excellent purity (99.8 %).
  • the amorphous salt of abiraterone acetate and -toluenesulfonic acid in accordance with the invention exhibits a characteristic XPRD pattern, which is shown in Figure 8.
  • the XRPD pattern was recorded using an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the amorphous salt of abiraterone acetate and p-toluenesulfonic acid can be further characterized by means of thermal analytical techniques.
  • the TGA curve (Perkin Elmer TGA 6) in Figure 10 shows a weight loss of abiraterone acetate p- toluenesulfonate of 2.91% in the temperature range of 20 to 240 °C.
  • the DVS analysis in Figure 11 shows the change in the weight of crystalline abiraterone acetate -toluenesulfonate in the range of the ambient relative humidity of 0 to 90 %.
  • the established water absorption is 15.5 % and water loss during desorption is 13.8 %, i.e., water is retained in the amount of 1.7 %.
  • the crystalline salt of abiraterone acetate and fumaric acid in accordance with the invention exhibits a characteristic XPRD pattern, which is shown in Figure 15.
  • the XRPD pattern was recorded using an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the crystalline salt of abiraterone acetate and fumaric acid can be further characterized by means of thermal analytical techniques.
  • the DSC curve Perkin Elmer Pyris 1 DSC
  • T on set 162.9 °C
  • T pea k 165.1 °C.
  • the TGA curve (Perkin Elmer TGA 6) in Figure 17 shows a weight loss of abiraterone acetate fumarate of 0.19 % in the temperature range of 20 to 250 °C.
  • the DVS analysis in Figure 18 shows a negligible change in the weight of crystalline fumarate of abiraterone acetate of 0.1 % in the range of the ambient relative humidity of 0 to 90 %. This means that this salt is not hygroscopic.
  • the new salts of abiraterone acetate in accordance with the invention are easy to prepare using a single-stage process in the environment of a solvent or a mixture of solvents from the group of C1-C4 alcohols, preferably 2-propanol, namely in a good to excellent yield and chemical purity.
  • the stoichiometric proportion of abiraterone acetate and benzenesulfonic acid was determined to be approximately 1:1 using the 'H-NMR technique.
  • the stoichiometric proportion of abiraterone acetate and j-toluenesulfonic acid was determined to be approximately 1:1 using the 1H-NMR technique.
  • the 13 C CP-MAS ss NMR spectra were recorded using a Bruker 400 WB spectrometer (4 mm rotors, frequency 13 kHz). The spectra of the salts were compared to the spectrum of the original API.
  • the measurement was carried out with a flat powder sample placed on a Si plate.
  • the DSC measurement was carried out using a Perkin Elmer Pyris 1 DSC device.
  • the charge of the sample in a standard Al pot was approximately 3.5 mg and the heating up rate was 10 °C/min.
  • the temperature program that was used consists of 1 stabilization minute at the temperature of 50 °C and then heating to 250 °C at the heating up rate of 10 °C/min. 4.0N2 at a flow rate of 20 ml/min was used as the carrier gas.
  • the TGA measurement was conducted using a Perkin Elmer TGA 6 device. The samples were weighed (19 to 22 mg) and dosed into a ceramic pot, nitrogen was used as the carried gas. The measurement was carried out in the temperature range of 20 to 250 °C at the heating up rate of 10 °C/min.
  • the dynamic vapour sorption records were obtained using a DVS Advantage 1 device from Surface Measurement Systems.
  • the charge of a sample in a quartz dish was between 18.5 and 20.1 mg and the temperature in the device varied in the range of 25.3 to 25.4 °C.
  • Measurement program used the sample was loaded with two sorption and desorption cycles, wherein the sample is first exposed to increasing relative humidity in the range of 0 % to 90 % (sorption) and then to decreasing relative humidity of 90 % to 0 % (desorption) and the whole process is repeated again. Nitrogen was used as the carrier gas.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/CZ2014/000073 2013-07-04 2014-07-01 Salts of abiraterone acetate WO2015000451A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2013-526A CZ306623B6 (cs) 2013-07-04 2013-07-04 Soli abirateronu acetátu
CZPV2013-526 2013-07-04

Publications (1)

Publication Number Publication Date
WO2015000451A1 true WO2015000451A1 (en) 2015-01-08

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CZ (1) CZ306623B6 (cs)
WO (1) WO2015000451A1 (cs)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015086596A1 (en) * 2013-12-12 2015-06-18 Basf Se Solid form of abiraterone acetate
WO2017133360A1 (zh) * 2016-02-02 2017-08-10 深圳市塔吉瑞生物医药有限公司 一种甾体类化合物及包含该化合物的组合物及其用途
US10722527B2 (en) 2015-04-10 2020-07-28 Capsugel Belgium Nv Abiraterone acetate lipid formulations
WO2023114264A1 (en) 2021-12-15 2023-06-22 Eli Lilly And Company Combination for treatment of high-risk metastatic hormone-sensitive prostate cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113061154B (zh) * 2021-03-25 2022-07-08 天津海润家和创新医药研究有限责任公司 新型注射用阿比特龙衍生物的制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021776A1 (en) 2004-08-24 2006-03-02 Btg International Limited Methanesulfonate salts of abiraterone-3-esters and recovery of salts of abirater one-3-esters from solution in methyl tert-butyl ether
CN102030798A (zh) 2010-12-17 2011-04-27 深圳万乐药业有限公司 一种醋酸阿比特龙的纯化方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021776A1 (en) 2004-08-24 2006-03-02 Btg International Limited Methanesulfonate salts of abiraterone-3-esters and recovery of salts of abirater one-3-esters from solution in methyl tert-butyl ether
CN102030798A (zh) 2010-12-17 2011-04-27 深圳万乐药业有限公司 一种醋酸阿比特龙的纯化方法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015086596A1 (en) * 2013-12-12 2015-06-18 Basf Se Solid form of abiraterone acetate
US10045998B2 (en) 2013-12-12 2018-08-14 Basf Se Solid form of abiraterone acetate
US10722527B2 (en) 2015-04-10 2020-07-28 Capsugel Belgium Nv Abiraterone acetate lipid formulations
WO2017133360A1 (zh) * 2016-02-02 2017-08-10 深圳市塔吉瑞生物医药有限公司 一种甾体类化合物及包含该化合物的组合物及其用途
US10519193B2 (en) 2016-02-02 2019-12-31 Shenzhen Targetrx, Inc. Steroidal compound, composition containing the same and use thereof
WO2023114264A1 (en) 2021-12-15 2023-06-22 Eli Lilly And Company Combination for treatment of high-risk metastatic hormone-sensitive prostate cancer

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Publication number Publication date
CZ306623B6 (cs) 2017-04-05
CZ2013526A3 (cs) 2015-01-14

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