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WO2023248240A1 - Formes polymorphes de bictégravir sodique - Google Patents

Formes polymorphes de bictégravir sodique Download PDF

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Publication number
WO2023248240A1
WO2023248240A1 PCT/IN2023/050585 IN2023050585W WO2023248240A1 WO 2023248240 A1 WO2023248240 A1 WO 2023248240A1 IN 2023050585 W IN2023050585 W IN 2023050585W WO 2023248240 A1 WO2023248240 A1 WO 2023248240A1
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WO
WIPO (PCT)
Prior art keywords
sodium
bictegravir
crystalline form
reaction mass
bictegravir sodium
Prior art date
Application number
PCT/IN2023/050585
Other languages
English (en)
Inventor
Sureshbabu JAYACHANDRA
Ramakoteswara Rao Jetti
Aggi Ramireddy Bommareddy
Subramanyam Dandala
Narasimha Murty PILLI
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 WO2023248240A1 publication Critical patent/WO2023248240A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present disclosure relates to novel crystalline forms of bictegravir sodium and processes for their preparation.
  • Bictegravir sodium is approved as part of a single tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection under the brand name of BIKTARVY®, marketed by Gilead Sciences.
  • Bictegravir sodium is chemically known as (2R,5S,13aR)- 2,5- Methanopyrido[r,2’:4,5]pyrazino[2,l-b][l,3]oxazepine-10-carboxamide,
  • polymorphs may provide different advantages in a variety of capacities, for example, in ease of formulation, stability of the polymorphic form, stability of the formulation, and in pharmacokinetic profiles. These advantages may arise from the different properties present in each polymorph.
  • the present invention provides novel polymorphic forms of bictegravir sodium and process for the preparation thereof.
  • a first aspect of the present invention is to provide crystalline Form Ml of bictegravir sodium.
  • One aspect of the present invention is to provide crystalline Form Ml of bictegravir sodium, which is characterized by powdered X-ray diffraction pattern as shown in Fig 1.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Form Ml of bictegravir sodium comprising the steps of: a) providing bictegravir or its sodium salt in organic solvent at elevated temperature; b) optionally adding sodium source and stirring the reaction mass at the same temperature; c) cooling the reaction mass to 20-35 °C; and d) isolating crystalline Form Ml of bictegravir sodium.
  • a second aspect of the present invention is to provide crystalline Form M2 of bictegravir sodium.
  • the present invention is to provide crystalline Form M2 of bictegravir sodium, which is characterized by powdered X-ray diffraction pattern as shown in Fig 2.
  • Other aspect of the present invention is to provide a process for the preparation of crystalline Form M2 of bictegravir sodium comprising the steps of: a) providing bictegravir or its sodium salt in organic solvent at elevated temperature; b) optionally adding sodium source and stirring the reaction mass at the same temperature; c) optionally cooling the reaction mass to 0-5 °C; and d) isolating crystalline Form M2 of bictegravir sodium.
  • a third aspect of the present invention is to provide crystalline Form M3 of bictegravir sodium.
  • the present invention is to provide crystalline Form M3 of bictegravir sodium, which is characterized by powdered X-ray diffraction pattern as shown in Fig 3.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Form M3 of bictegravir sodium comprising drying the crystalline Form Ml or crystalline Form M2 of bictegravir sodium at 100-150 °C.
  • Figure. 1 is an X-ray powder diffractogram of crystalline Form Ml of bictegravir sodium.
  • Figure. 2 is an X-ray powder diffractogram of crystalline Form M2 of bictegravir sodium.
  • Figure. 3 is an X-ray powder diffractogram of crystalline Form M3 of bictegravir sodium. DETAILED DESCRIPTION OF THE DISCLOSURE
  • the polymorph of the present disclosure is characterized by its X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of the polymorphs of the disclosure were measured on BRUKER D-8 Discover powder diffractometer equipped with goniometer of 9/29 configuration and Lynx Eye detector.
  • the Cu- anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
  • the present disclosure relates to crystalline forms of bictegravir sodium.
  • the present disclosure also relates to process for the preparation of crystalline forms of bictegravir sodium.
  • the present disclosure is to provide crystalline Form Ml of bictegravir sodium.
  • the present disclosure is to provide crystalline Form Ml of bictegravir sodium, characterized by Powder X-ray diffraction pattern having 29 angle positions at about 5.94, 19.78, 20.97, 23.64, 25.20, and 26.10 ⁇ 0.2° degrees two-theta.
  • crystalline Form Ml of bictegravir sodium is further characterized by Powder X-ray diffraction pattern having 29 angle positions at about 5.94, 11.93, 12.38, 13.59, 17.06, 20.97, 22.30, 23.64, 25.20, 26.09 and 31.67 ⁇ 0.2° degrees two-theta.
  • crystalline Form Ml of bictegravir sodium is further characterized by Powder X-ray diffraction pattern having 29 angle positions at about 5.94, 6.13, 7.09, 11.92, 12.38, 12.76, 13.59, 14.24, 15.11, 16.48, 16.89, 17.06, 17.73, 17.95, 18.68, 19.34, 19.78, 20.54, 20.97, 21.30, 21.43, 21.75, 22.30, 23.28, 23.64, 24.17, 25.20, 26.10, 26.33, 27.16, 27.43, 28.01, 28.32, 28.67,, 29.63, 29.86, 30.12, 31.67, 32.37, 34.52, 39.05 and 45.39 ⁇ 0.2° degrees two-theta.
  • the present invention is to provide a process for the preparation of crystalline Form Ml of bictegravir sodium comprising the steps of: a) providing bictegravir or its sodium salt in organic solvent at elevated temperature; b) optionally adding sodium source and stirring the reaction mass at the same temperature; c) cooling the reaction mass to 20-35 °C; and d) isolating crystalline Form Ml of bictegravir sodium.
  • organic solvent employed may include chloroethanol solvent.
  • organic solvent is 2- chloroethanol.
  • sodium source employed may include sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxide.
  • Sodium source may be dissolved in water and added to the reaction mass.
  • sodium source is sodium hydroxide.
  • 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 drying under vacuum.
  • bictegravir sodium is suspended in an organic solvent and heated to elevated temperature of about 40-70 °C and stirred for about 16-20 hours.
  • the reaction mass is cooled to 20-30 °C, filtered and then dried under vacuum.
  • the obtained solid is crystalline Form Ml of bictegravir sodium.
  • bictegravir is dissolved in an organic solvent and heated to elevated temperature of about 40-70 °C.
  • sodium source is added and stirred for about 12-16 hours.
  • the reaction mass is cooled to 20-30 °C, filtered and then dried under vacuum.
  • the obtained solid is crystalline Form Ml of bictegravir sodium.
  • the present disclosure is to provide crystalline Form M2 of bictegravir sodium.
  • the present disclosure is to provide crystalline Form M2 of bictegravir sodium, characterized by Powder X-ray diffraction pattern having 29 angle positions at about 5.90, 12.30, 19.78, 23.71 and 25.19 ⁇ 0.2° degrees two- theta.
  • crystalline Form M2 of bictegravir sodium is further characterized by Powder X-ray diffraction pattern having 29 angle positions at about 5.90, 6.56, 10.67, 11.97, 12.30, 12.71, 13.33, 15.59, 16.09, 16.70, 17.79, 18.26, 18.67, 18.97, 19.40, 19.80, 20.18, 20.55, 21.39, 21.66, 22.29, 22.81 23.70, 25.19, 26.02, 26.36, 26.70, 28.36, 28.63, 29.08, 29.64, 30.31, 31.03, 31.63, 33.66, 41.14, 43.47 and 45.32 ⁇ 0.2° degrees two-theta.
  • the present invention is to provide a process for the preparation of crystalline Form M2 of bictegravir sodium comprising the steps of: a) providing bictegravir or its sodium salt in organic solvent at elevated temperature; b) optionally adding sodium source and stirring the reaction mass at the same temperature; c) optionally cooling the reaction mass to 0-5 °C; and d) isolating crystalline Form M2 of bictegravir sodium.
  • organic solvent employed may include chloroethanol solvent.
  • organic solvent is 2- chloroethanol.
  • sodium source employed may include sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxide.
  • Sodium source may be dissolved in water and added to the reaction mass.
  • sodium source is sodium hydroxide.
  • 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 drying under vacuum.
  • bictegravir sodium is suspended in 2- chloroethanol and heated to elevated temperature of about 40-70 °C and stirred for about 16-20 hours.
  • the reaction mass is filtered at the same temperature and then dried under vacuum.
  • the obtained solid is crystalline Form M2 of bictegravir sodium.
  • bictegravir is dissolved in 2-chloroethanol and heated to elevated temperature of about 60-70 °C.
  • sodium source is added to the reaction mass.
  • the reaction mass is cooled to 0-5 °C, filtered, and then dried under vacuum at 40-70 °C.
  • the obtained solid is crystalline Form M2 of bictegravir sodium.
  • the present disclosure is to provide crystalline Form M3 of bictegravir sodium.
  • Another embodiment, the present disclosure is to provide crystalline Form M3 of bictegravir sodium, characterized by Powder X-ray diffraction pattern having 29 angle positions at about 7.14, 13.95, 19.33, 20.92 and 31.70 ⁇ 0.2° degrees two- theta.
  • crystalline Form M3 of bictegravir sodium is further characterized by Powder X-ray diffraction pattern having 29 angle positions at about
  • crystalline Form M3 of bictegravir sodium is further characterized by Powder X-ray diffraction pattern having 29 angle positions at about
  • the present invention is to provide a process for the preparation of crystalline Form M3 of bictegravir sodium comprising drying the crystalline Form Ml or crystalline Form M2 of bictegravir sodium at 110-140 °C.
  • drying is performed under atmospheric pressure or under reduced pressure.
  • drying is performed under reduced pressure.
  • the input bictegravir or bictegravir sodium is prepared by any prior-art process for example PCT publication No. WO2015196116A1.
  • the physical and chemical stability of the crystalline bictegravir sodium Form M3 was determined by storing the samples at 25 °C and 60% RH and 40°C and 75% RH conditions for three months, followed by analysis of the samples by PXRD and HPLC purity. The results of the study are summarized in the below table.
  • the novel Bictegravir sodium Form M3 was found to be physically and chemically stable at 25°C and 60% RH and at 40°C and 75% RH conditions stable up to 3months.
  • Bictegravir (3g) was dissolved in 2 -chloroethanol (24 mL) at 25+2 °C.
  • the reaction mass was heated to 50-55 °C and added slowly drop-wise aqueous sodium hydroxide solution (Dissolved 534mg sodium hydroxide in 6 mL water at 25+2 °C) at 50-55 °C for 5 minutes.
  • the resulting clear solution was further maintained under stirring at 50-55°C for 14 hours.
  • the reaction mass was then cooled to 25-30 °C, maintained for 1 hour, filtered and suck-dried under vacuum for 30 minutes.
  • the solid obtained was identified by PXRD as novel crystalline bictegravir sodium Form Ml.
  • the Bictegravir sodium Form Ml or Form M2 obtained as per above example 1-4 was dried under vacuum at 130 °C for 10-15 hours.
  • the solid obtained was identified by PXRD as novel crystalline bictegravir sodium Form M3.
  • Bictegravir (2g) was dissolved in 2-chloroethanol (12 mL) at 25-30 °C and the obtained clear solution was heated to 35-40 °C.
  • Added aqueous sodium hydroxide solution (dissolved 267 mg NaOH in 2 mL water) at 35-40 °C for 5-10minutes.
  • the thick reaction mass was then maintained under stirring at 35-40 °C for 6-8 hours.
  • the thick reaction mass was then cooled to 25-30 °C, added water (6 mL) slowly for 5-10 minutes at 25-30 °C and stirred the reaction mass at 25-30 °C for 60 minutes.
  • the resulting reaction mass was filtered, washed with mixture of 3 mL 2-chloroethanol and 1 mL water and suck dried for Ihour under vacuum.
  • the PXRD of the wet material was identified by PXRD as crystalline form of bictegravir sodium Form ML
  • the wet material was further dried under vacuum at 130°C for 8-12 hours.
  • the solid obtained was identified by PXRD as novel crystalline form of Bictegravir sodium Form M3.

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Abstract

La présente invention concerne de nouvelles formes cristallines de bictégravir sodique et leurs procédés de préparation.
PCT/IN2023/050585 2022-06-21 2023-06-19 Formes polymorphes de bictégravir sodique WO2023248240A1 (fr)

Applications Claiming Priority (2)

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IN202241035593 2022-06-21
IN202241035593 2022-06-21

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
WO2015196137A1 (fr) * 2014-06-20 2015-12-23 Gilead Sciences, Inc. Formes cristallines de (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-méthanpyrido[1',2':4,5]pyrazino 2,1-b][1,3]oxazépine-10-carboxamide
WO2015196116A1 (fr) 2014-06-20 2015-12-23 Gilead Sciences, Inc. (2r,5s,13ar)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-méthanopyrido[1',2':4,5]pyrazino[2,1-b]oxazépin-8-olate de sodium
WO2020161744A1 (fr) * 2019-02-07 2020-08-13 Cipla Limited Nouveaux polymorphes d'inhibiteur d'intégrase
WO2020255004A1 (fr) * 2019-06-18 2020-12-24 Laurus Labs Limited Procédé et formes polymorphes de bictegravir et de ses sels ou co-cristaux pharmaceutiquement acceptables
IN202041046541A (fr) * 2020-10-26 2022-04-29

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
WO2015196137A1 (fr) * 2014-06-20 2015-12-23 Gilead Sciences, Inc. Formes cristallines de (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-méthanpyrido[1',2':4,5]pyrazino 2,1-b][1,3]oxazépine-10-carboxamide
WO2015196116A1 (fr) 2014-06-20 2015-12-23 Gilead Sciences, Inc. (2r,5s,13ar)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-méthanopyrido[1',2':4,5]pyrazino[2,1-b]oxazépin-8-olate de sodium
US9708342B2 (en) 2014-06-20 2017-07-18 Gilead Sciences, Inc. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2, 1-b][1, 3]oxazepin-8-olate
WO2020161744A1 (fr) * 2019-02-07 2020-08-13 Cipla Limited Nouveaux polymorphes d'inhibiteur d'intégrase
WO2020255004A1 (fr) * 2019-06-18 2020-12-24 Laurus Labs Limited Procédé et formes polymorphes de bictegravir et de ses sels ou co-cristaux pharmaceutiquement acceptables
IN202041046541A (fr) * 2020-10-26 2022-04-29

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