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WO2015092752A1 - Nouvelle forme cristalline de dolutegravir sodium - Google Patents

Nouvelle forme cristalline de dolutegravir sodium Download PDF

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Publication number
WO2015092752A1
WO2015092752A1 PCT/IB2014/067106 IB2014067106W WO2015092752A1 WO 2015092752 A1 WO2015092752 A1 WO 2015092752A1 IB 2014067106 W IB2014067106 W IB 2014067106W WO 2015092752 A1 WO2015092752 A1 WO 2015092752A1
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WO
WIPO (PCT)
Prior art keywords
dolutegravir sodium
crystalline
sodium
solution
sodium form
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2014/067106
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English (en)
Inventor
Ramakoteswara Rao Jetti
Satish BEERAVELLY
Madhu Murthy Nadella
Phani Kumar BALUSU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mylan Laboratories Ltd
Original Assignee
Mylan Laboratories Ltd
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 Ltd filed Critical Mylan Laboratories Ltd
Publication of WO2015092752A1 publication Critical patent/WO2015092752A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present disclosure relates to novel crystalline dolutegravir sodium Form-Mi, which is an N-methyl-2-pyrrolidone (NMP) solvate.
  • NMP N-methyl-2-pyrrolidone
  • Dolutegravir (DTG, GSKl 349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-l infection.
  • TIVICAY® tablets contain dolutegravir sodium, which is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI).
  • Dolutegravir sodium is chemically known as sodium (4R, 12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4- methyl-6, 8-dioxo-3 ,4, 6, 8, 12, 12a-hexahydro-2H- pyrido [l ',2' :4,5] pyrazino[2, 1- b] [l,3]oxazin-7-olate, having the structure below:
  • Formula-I PCT Publication No. WO2006116764A1 (which is hereby incorporated by reference) discloses a crystalline form of dolutegravir sodium characterized by the following X- ray powder diffraction pattern having peaks at 6.4° ⁇ 0.2°, 9.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 19.2° ⁇ 0.2° and 21.8° ⁇ 0.2° degrees 2 ⁇ .
  • PCT Publication No. WO2013038407A1 discloses amorphous dolutegravir sodium characterized by the following characteristic peaks in infrared absorption spectrum at about 662 ⁇ 4, 766 ⁇ 4, 851 ⁇ 4, 886 ⁇ 4, 959 ⁇ 4, 1025 ⁇ 4, 1055 ⁇ 4, 1090 ⁇ 4, 1133 ⁇ 4, 1206 ⁇ 4, 1233 ⁇ 4, 1248 ⁇ 4, 1279 ⁇ 4, 1318 ⁇ 4, 1356 ⁇ 4, 2325 ⁇ 4 and 2348 ⁇ 4 cm "1 .
  • the present disclosure provides a novel crystalline form of dolutegravir sodium. SUMMARY OF THE DISCLOSURE
  • One aspect of the present disclosure provides crystalline dolutegravir sodium Form- Ml, which is an N-methyl-2-pyrrolidone (NMP) solvate, and may also be characterized by powdered X-ray diffraction pattern as shown in Figure 1.
  • NMP N-methyl-2-pyrrolidone
  • the present disclosure provides a process for the preparation of crystalline dolutegravir sodium Form-Ml that may be prepared by the following steps:
  • Another embodiment of the present disclosure provides a process for the preparation of crystalline dolutegravir sodium Form-Mi that includes the steps of:
  • Figure 1 is an X-ray powder diffractogram of crystalline dolutegravir sodium Form- Mi .
  • the present invention encompasses novel crystalline form of dolutegravir sodium Form-Mi , which is an N-methyl-2-pyrrolidone solvate.
  • the polymorphs of the present invention may be characterized by 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 ⁇ /2 ⁇ configuration and Lynx Eye detector.
  • the Cu- anode X-ray tube was operated at 40 kV and 30 mA.
  • the experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
  • the present disclosure provides crystalline dolutegravir sodium Form-Ml, characterized by powder X-ray diffraction pattern having 2 ⁇ angle positions at about 5.88, 17.57, 20.55, 21.38 and 24.77 ⁇ 0.2° degrees 2 ⁇ .
  • crystalline dolutegravir sodium Form-Ml is further characterized by powder X-ray diffraction pattern having 2 ⁇ angle positions at about 6.37, 7.76, 9.54, 11.81, 12.24, 13.01, 14.55, 14.85, 15.20, 15.62, 16.10, 16.84, 17.97, 18.61, 19.07, 19.36, 19.73, 20.12, 22.23, 22.64, 22.95, 23.32, 24.09, 25.26, 25.81, 26.21, 26.67, 27.11, 27.69, 28.41, 29.65, 30.67, 31.21, 31.90, 32.55, 33.12, 34.09, 35.01, 35.44 and 36.06 ⁇ 0.2° degrees 2 ⁇ .
  • the present invention relates to a process for the preparation crystalline dolutegravir sodium Form-Ml including the general steps of:
  • dolutegravir sodium is dissolved in NMP at an elevated temperature and filtered the solution.
  • the solution is then optionally seeding with crystalline dolutegravir sodium Form-Ml.
  • the solution is then stirred, filtered, and washed with NMP before isolating the crystalline solid of dolutegravir sodium Form-Ml . If seeding is not performed, the solution may be stirred for a longer period of time to allow crystals of dolutegravir sodium Form-Ml to form slowly on their own.
  • dolutegravir sodium is dissolved in NMP at an elevated temperature, which may range from about 70 to about 85 °C.
  • the solution is then filtered, for example, through a Hyflo bed or through membrane filters.
  • the filtered solution is stirred at a temperature of about 20-35 °C for about 12- 15 hours.
  • the stir time may be reduced to 3-4 hours, if the solution is seeded with about 0.1 to 1.0% w/v crystalline dolutegravir sodium Form-Mi.
  • the solution is then filtered (for example, through a Hyflo bed or membrane filter), washed with NMP, and the final crystalline dolutegravir sodium Form-Mi is isolated.
  • the present invention relates to a process for the preparation crystalline dolutegravir sodium Form-Mi, including the general steps of: a) dissolving dolutegravir in NMP at ambient temperature to create a solution; b) optionally seeding with crystalline dolutegravir sodium Form-Mi ;
  • dolutegravir sodium is dissolved in NMP at ambient temperatures.
  • the solution may then be optionally seeded with an N- methyl-2-pyrrolidone solvate of dolutegravir sodium.
  • a source of sodium cations may then be added to the solution.
  • the solution is then stirred and filtered.
  • the solid is then washed with NMP to isolate crystalline dolutegravir sodium Form-Mi.
  • the final crystalline solid may further be dried under vacuum.
  • dolutegravir sodium is dissolved in NMP at a temperature of about 20-35 °C.
  • the solution is then optionally seeded with crystalline dolutegravir sodium and a sodium cation source is added.
  • the solution is further stirred at about 20-35 °C for about 3-4 hours, during which Form M-l crystals grow slowly.
  • the solution is then filtered.
  • the resultant solid is washed with NMP to obtain the crystalline dolutegravir sodium Form-Mi.
  • the final crystalline solid may optionally further be dried under vacuum at about 80 °C for about 12-15 hours.
  • sodium cation source is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, and an alcoholic sodium hydroxide solution, such as methanolic sodium hydroxide.
  • the crystalline dolutegravir sodium Form-Mi of the present invention may be incorporated into a pharmaceutical formulation for the treatment of HIV in human patients.
  • the pharmaceutical formulation may be an oral dosage form and in some embodiments a tablet.
  • the tablet may include such excipients as D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate.
  • the tablet may be coated in a film that may contain the inactive ingredients iron oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.
  • the crystalline dolutegravir sodium Form-Mi may be administered in conjunction with other active pharmaceutical ingredients, including efavirenz, fosamprenavir, ritonavir, tipranavir, and rifampin.
  • Example 1 Preparation of crystalline dolutegravir sodium Form-Ml (NMP solvate).
  • Dolutegravir sodium (3 g) was dissolved in N-methyl 2-pyrrolidone (300 mL) at 75- 80 °C. The clear solution was filtered through a Hyflo bed and washed with N- methyl-2-pyrrolidone (15 mL) at 25-30 °C. The clear solution was stirred at 25-30 °C for 12-15 hours. The product obtained was filtered, washed with N-methyl-2- pyrrolidone (15 mL) at 25-30 °C and dried under vacuum at 80 °C for 12-15 hours. The resulting solid was identified as crystalline dolutegravir sodium Form-Ml, through the following analytical methods:
  • Example 2 Preparation of crystalline dolutegravir sodium Form-Ml (NMP solvate).
  • Dolutegravir sodium (1 g) was dissolved in N-methyl-2-pyrrolidone (100 mL) at 75- 80°C. The clear solution was filtered through a Hyflo bed and washed with N-methyl 2-pyrrolidone (5 mL) at 25-30 °C. The clear solution was seeded with N-methyl-2- pyrrolidone solvate of dolutegravir sodium Form-Ml (10 mg) and stirred at 25-30°C for 3-4 hours. The product obtained was filtered, washed with N-methyl-2- pyrrolidone (5 mL) at 25-30 °C and dried under vacuum at 80 °C for 12-15 hours. The resulting solid was identified as crystalline dolutegravir sodium Form-Ml, through the following analytical methods:
  • Dolutegravir (200 mg) was dissolved in N-methyl-2-pyrrolidone (6 mL) at 25-30 °C. The clear solution was seeded with N-methyl-2-pyrrolidone solvate of dolutegravir sodium Form-Ml (2 mg) and then 0.25 N methanolic sodium hydroxide solution (2 mL) was added and stirred at 25-30 °C for 3-4 hours. The product obtained was filtered and washed with N-methyl-2-pyrrolidone (5 mL) and dried under vacuum at 80 °C for 12-15 hours. The resulting solid was identified as crystalline dolutegravir sodium Form-Ml, through the following analytical methods:

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

Abstract

La présente invention concerne une forme MI cristalline de dolutegravir sodium, qui est un solvate de N-méthyl-2-pyrrolidone, et leur procédé de préparation. Formule (I).
PCT/IB2014/067106 2013-12-20 2014-12-19 Nouvelle forme cristalline de dolutegravir sodium Ceased WO2015092752A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN6001/CHE/2013 2013-12-20
IN6001CH2013 2013-12-20

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WO2015092752A1 true WO2015092752A1 (fr) 2015-06-25

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017029642A2 (fr) 2015-08-19 2017-02-23 Laurus Labs Private Limited Nouveaux polymorphes du dolutégravir et leurs sels
WO2017046131A1 (fr) * 2015-09-15 2017-03-23 Ratiopharm Gmbh Procédés de préparation de formes à l'état solide de dolutégravir de sodium
WO2017208105A1 (fr) 2016-05-30 2017-12-07 Lupin Limited Nouvelle forme cristalline de dolutégravir sodique
WO2019048808A1 (fr) 2017-09-07 2019-03-14 Cipla Limited Nouveaux polymorphes du dolutégravir sodique
EP3177629B1 (fr) * 2014-07-29 2020-01-29 LEK Pharmaceuticals d.d. Nouveaux hydrates de sodium de dolutegravir

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006116764A1 (fr) 2005-04-28 2006-11-02 Smithkline Beecham Corporation Derive polycyclique de la carbamoylpyridone a activite inhibitrice sur l'integrase du vih
WO2010068253A1 (fr) * 2008-12-11 2010-06-17 Shionogi & Co., Ltd. Synthèse d'inhibiteurs carbamoylpyridone de l'intégrase du vih et intermédiaires
WO2013038407A1 (fr) 2011-09-14 2013-03-21 Mapi Pharma Ltd. Forme amorphe de dolutegravir

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006116764A1 (fr) 2005-04-28 2006-11-02 Smithkline Beecham Corporation Derive polycyclique de la carbamoylpyridone a activite inhibitrice sur l'integrase du vih
WO2010068253A1 (fr) * 2008-12-11 2010-06-17 Shionogi & Co., Ltd. Synthèse d'inhibiteurs carbamoylpyridone de l'intégrase du vih et intermédiaires
WO2013038407A1 (fr) 2011-09-14 2013-03-21 Mapi Pharma Ltd. Forme amorphe de dolutegravir

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3177629B1 (fr) * 2014-07-29 2020-01-29 LEK Pharmaceuticals d.d. Nouveaux hydrates de sodium de dolutegravir
WO2017029642A2 (fr) 2015-08-19 2017-02-23 Laurus Labs Private Limited Nouveaux polymorphes du dolutégravir et leurs sels
US10597404B2 (en) 2015-08-19 2020-03-24 Laurus Labs Ltd. Polymorphs of dolutegravir and salts thereof
US10647729B1 (en) 2015-08-19 2020-05-12 Laurus Labs Limited Polymorphs of dolutegravir and salts thereof
US10654872B1 (en) 2015-08-19 2020-05-19 Laurus Labs Limited Polymorphs of dolutegravir and salts thereof
WO2017046131A1 (fr) * 2015-09-15 2017-03-23 Ratiopharm Gmbh Procédés de préparation de formes à l'état solide de dolutégravir de sodium
WO2017208105A1 (fr) 2016-05-30 2017-12-07 Lupin Limited Nouvelle forme cristalline de dolutégravir sodique
WO2019048808A1 (fr) 2017-09-07 2019-03-14 Cipla Limited Nouveaux polymorphes du dolutégravir sodique

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