WO2024023836A1 - Forme polymorphe de sulfate de larotrectinib - Google Patents

Forme polymorphe de sulfate de larotrectinib Download PDF

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Publication number
WO2024023836A1
WO2024023836A1 PCT/IN2023/050703 IN2023050703W WO2024023836A1 WO 2024023836 A1 WO2024023836 A1 WO 2024023836A1 IN 2023050703 W IN2023050703 W IN 2023050703W WO 2024023836 A1 WO2024023836 A1 WO 2024023836A1
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WO
WIPO (PCT)
Prior art keywords
solvent
ether
larotrectinib
sulfate
crystalline form
Prior art date
Application number
PCT/IN2023/050703
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English (en)
Inventor
Ramakoteswara Rao Jetti
Ramamohana Rao Golivi
Sureshbabu JAYACHANDRA
Original Assignee
Mylan Laboratories 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 Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Publication of WO2024023836A1 publication Critical patent/WO2024023836A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed 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 disclosure generally relates to the field of pharmaceutical sciences and more specifically relates to process for the preparation of Larotrectinib sulfate polymorphic form.
  • Larotrectinib sulfate chemically known as (3S)-N- ⁇ 5-[(2R)-2-(2,5-difluorophenyl)-l- pyrrolidinyl] pyrazolo[l,5-a] pyrimidin-3-yl)-3-hydroxy-l-pyrrolidinecarboxamide sulfate having the structure shown in Formula-I, is a kinase inhibitor.
  • Larotrectinib sulfate is approved and is being marketed under the brand name Vitrakvi® for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory alternative treatments .
  • NRRK neurotrophic receptor tyrosine kinase
  • the inventors of the present disclosure have developed novel crystalline form of Larotrectinib sulfate which is stable, and also provided processes for the preparation of the same. OBJECT AND SUMMARY OF THE INVENTION
  • the present invention provides crystalline Form Ml of Larotrectinib sulfate.
  • the present invention provides a process for the preparation of crystalline Form Ml of Larotrectinib sulfate comprising the steps of: a) dissolving Larotrectinib sulfate in a suitable solvent optionally in presence of a coformer; b) adding an anti-solvent; and c) isolating crystalline Form Ml of Larotrectinib sulfate.
  • the present invention provides a process for the preparation of crystalline Form Ml of Larotrectinib sulfate comprising the steps of: a) taking Larotrectinib in a suitable solvent; b) adding sulfuric acid; c) adding an anti-solvent optionally in presence of a coformer; and d) isolating crystalline Form Ml of Larotrectinib sulfate.
  • the present invention provides a process for the preparation of crystalline Form Ml of Larotrectinib sulfate comprising the steps of: a) heating Larotrectinib sulfate in a first solvent; b) removing the solvent and adding second solvent; c) optionally seeding; d) diluting with third solvent; and e) isolating crystalline Form Ml of Larotrectinib sulfate.
  • FIGURE 1 X-ray powder diffractogram of crystalline Form Ml of Larotrectinib sulfate.
  • FIGURE 2 Differential scanning calorimetry ("DSC") thermogram of crystalline Form Ml of Larotrectinib sulfate.
  • FIGURE 3 Thermogravimetric analysis ("TGA”) thermogram of crystalline Form Ml of Larotrectinib sulfate.
  • FIGURE 4 ’H-NMR spectrum of crystalline Form Ml of Larotrectinib sulfate.
  • FIGURE 5 FT-IR spectra of crystalline Form Ml of Larotrectinib sulfate.
  • FIGURE 6 Overlay of FT-IR spectra of Form 1-HS (top) and Form Ml (bottom).
  • the present invention provides crystalline Form Ml of Larotrectinib sulfate and process for the preparation of the same.
  • the powder X-ray diffraction patterns of said polymorphs of the invention were measured on a Bruker D8 ADVANCE powder diffractometer equipped with a goniometer of 0/20 configuration and LYNXEYE detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, using a 0.033° step size and 62 seconds step time.
  • the DSC measurement was carried out on a TA Q2000 instrument.
  • the scan was performed from 50°C to 250°C at a heating rate of 10.0°C/min with nitrogen purging at a flow rate of 50 mL/min.
  • Standard aluminum pans covered by lids with three pinholes were used.
  • the TGA measurement was carried out on a TA Q5000 instrument.
  • the scan was performed from ambient temperature to 350°C at a heating rate of 10.0 °C/min and purging with nitrogen at a flow rate of 25 mL/min.
  • FTIR spectra were recorded on a PerkinElmer SpectrumTM One instrument in the range of 400-4000 cm-1 by using KBr pellets.
  • the present invention provides crystalline Form Ml of Larotrectinib sulfate.
  • crystalline Form Ml of Larotrectinib sulfate may be characterized by a PXRD pattern having significant peaks at 20 angle positions at about 7.07, 9.12, 13.96, 20.44, 20.71 and 22.45 ⁇ 0.2 °0.
  • crystalline Form Ml of Larotrectinib sulfate may further characterized by a PXRD pattern having significant peaks at 20 angle positions at about 7.07, 9.12, 13.96, 17.36, 19.67, 20.44, 20.71, 22.45 and 25.44 ⁇ 0.2 °0.
  • the crystalline Form Ml of Larotrectinib sulfate may further characterized by a PXRD pattern having significant peaks at 20 angle
  • the present invention provides a process for the preparation of crystalline Form Ml of Larotrectinib sulfate comprising the steps of: a) taking Larotrectinib in a suitable solvent; b) adding sulfuric acid; c) adding an anti-solvent optionally in presence of a coformer; and d) isolating crystalline Form Ml of Larotrectinib sulfate.
  • Larotrectinib is dissolved in a suitable solvent and added sulfuric acid optionally in presence of a coformer.
  • the suitable solvent includes, but not limited to polar solvents such as alcohols selected from methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol and 1-pentanol; preferably methanol.
  • the sulfuric acid used in the present invention may a precooled sulfuric acid solution in a suitable solvent.
  • the addition of sulfuric acid solution is performed at 10-30 °C, preferably 20-25 °C, more preferably 15-20 °C.
  • the suitable solvent for the preparation of sulfuric acid solution includes, but not limited to polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 1-propanol, 1- butanol, 2-butanol and 1-pentanol; preferably methanol.
  • the suitable co- former includes, but not limited to organic acids such as maleic acid, salicylic acid, fumaric acid, adipic acid, L- pyroglutamic acid, succinic acid and the like.
  • the above resulting reaction solution may heated to 70-90 °C; preferably at 60-80 °C; more preferably at 50-55 °C.
  • the resulting reaction solution is cooled to ambient temperature and an anti-solvent is added is added to isolate the crystalline Form Ml of Larotrectinib sulfate.
  • the suitable anti-solvent includes but not limited to ethers such as methyl tert-butyl ether, cyclopentylmethyl ether, diethyl ether and diisopropyl ether; preferably methyl tert-butyl ether.
  • the ratio of the solvent and anti-solvent is 1:5; preferably 1:4; more preferably 1:2.5-3.
  • the present invention provides a process for the preparation of crystalline Form Ml of Larotrectinib sulfate comprising the steps of: a) heating Larotrectinib sulfate in a first solvent; b) removing the solvent and adding second solvent; c) optionally seeding; d) diluting with third solvent; and e) isolating crystalline Form Ml of Larotrectinib sulfate.
  • Larotrectinib sulfate is heated in a first solvent.
  • the first solvent includes but not limited alcohols such as methanol, ethanol, propanol, isopropanol, 1 -butanol, 2- butanol and 1-pentanol.
  • the suitable solvent is methanol.
  • the Larotrectinib sulfate reaction mixture is heated to 45-55 °C; preferably 47 ⁇ 2 °C for 40-50 hrs; preferably 45-50 hrs; and the solvent is removed to retain 2-5 volumes with respect to the Larotrectinib sulfate.
  • the second solvent may in the form of mixture of solvents or a second solvent in combination with water.
  • the second solvent includes but not limited to alcohols such as methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol and 1-pentanol and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate; ethers such as tertbutyl methyl ether, cyclopentylmethyl ether, diethyl ether and diisopropyl ether and the like.
  • the suitable second solvent is a combination of water-ethyl acetate, water-methyl tert-butyl ether and water-ethanol.
  • reaction mixture is optionally seeded with crystalline Larotrectinib sulfate Form Ml and diluted with a third solvent or mixtures thereof and isolated crystalline Form Ml of Larotrectinib sulfate.
  • the second solvent of the above embodiment may also be used as a third solvent.
  • the third solvent includes but not limited to esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate; ethers such as tert-butyl methyl ether, cyclopentylmethyl ether, diethyl ether and diisopropyl ether and the like.
  • the suitable solvent is ethyl acetate, methyl-tert-butyl ether.
  • isolation can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation.
  • the solid is isolated by filtration followed by washing and drying.
  • Larotrectinib or its pharmaceutically acceptable salt can be prepared as per the process known in US WO 2010048314; WO 2017201241 and in literature.
  • the Larotrectinib sulfate may in a crystalline form or may in an amorphous form.
  • DSC measurements were carried out on a Q2000 DSC instrument manufactured by TA instruments.
  • TGA data were recorded using a Q5000 TGA instrument manufactured by TA instruments.
  • DSC of Form Ml shows a transition around 130°C, which can be attributed to a dehydration event, followed by conversion to an anhydrous form which melts around 199°C.
  • Figure 3 shows the TGA data of Form Ml, which shows a weight loss of around 1.5% till its melting.
  • Form Ml Moisture content analysis of Form Ml was carried out using a KF instrument (Metrohm, 901 titrando).
  • Form Ml shows a moisture content in the range of 1.5-1.7%, further confirming Form Ml is a hydrate, preferably a hemihydrate.
  • FTIR data of Larotrectinib sulfate Form Ml is significantly different in comparison with Form 1-HS ( Figure 4).
  • the characteristic IR bands for Form Ml are 3428 cm' 1 , 1682cm' 1 , 1251 cm' 1 , 1060 cm' 1 , 751 cm' 1 ( Figure 4).
  • the physical and chemical stability of Larotrectinib sulfate Form Ml were determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% RH conditions for six months as shown in Table 1. The samples were analyzed by PXRD and HPLC. Larotrectinib sulfate Form Ml was found to be physically and chemically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for up to six months.
  • the product obtained was filtered, washed with mixture of ethanol and ethyl acetate (l:5v/v, ImL) and suck-dried for 10-15min at 25-30 °C.
  • the solid obtained was further dried at 25-30 °C under vacuum for 16 hrs and identified by PXRD as novel crystalline form of Larotrectinib sulfate Form ML Yield: 910 mg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (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)

Abstract

La présente invention concerne une forme cristalline M1 de sulfate de Larotrectinib et son procédé de préparation éventuellement en présence d'un co-formeur.
PCT/IN2023/050703 2022-07-27 2023-07-21 Forme polymorphe de sulfate de larotrectinib WO2024023836A1 (fr)

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IN202241043027 2022-07-27
IN202241043027 2022-07-27

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010048314A1 (fr) 2008-10-22 2010-04-29 Array Biopharma Inc. Composés de pyrazolo[1,5-a]pyrimidine substitués comme inhibiteurs de la trk kinase
WO2016077841A1 (fr) * 2014-11-16 2016-05-19 Array Biopharma, Inc. Forme cristalline d'hydrogénosulfate de (s)-n-(5-((r)-2-(2,5-difluorophényl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US20170281632A1 (en) * 2016-04-04 2017-10-05 Loxo Oncology, Inc. Methods of treating pediatric cancers
WO2017201241A1 (fr) 2016-05-18 2017-11-23 Mark Reynolds Préparation de (s)-n-(5-((r)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
WO2020108408A1 (fr) * 2018-11-28 2020-06-04 安礼特（上海）医药科技有限公司 Forme cristalline du sel de sulfate d'hydrogène de larotrectinib, son procédé de préparation et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010048314A1 (fr) 2008-10-22 2010-04-29 Array Biopharma Inc. Composés de pyrazolo[1,5-a]pyrimidine substitués comme inhibiteurs de la trk kinase
US8513263B2 (en) 2008-10-22 2013-08-20 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
WO2016077841A1 (fr) * 2014-11-16 2016-05-19 Array Biopharma, Inc. Forme cristalline d'hydrogénosulfate de (s)-n-(5-((r)-2-(2,5-difluorophényl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US20170281632A1 (en) * 2016-04-04 2017-10-05 Loxo Oncology, Inc. Methods of treating pediatric cancers
WO2017201241A1 (fr) 2016-05-18 2017-11-23 Mark Reynolds Préparation de (s)-n-(5-((r)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
WO2020108408A1 (fr) * 2018-11-28 2020-06-04 安礼特（上海）医药科技有限公司 Forme cristalline du sel de sulfate d'hydrogène de larotrectinib, son procédé de préparation et son utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MINO R CAIRA ED - MONTCHAMP JEAN-LUC: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022, [retrieved on 19990226], DOI: 10.1007/3-540-69178-2_5 *

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