WO2011114212A1 - Sels d'ammonium, de calcium et de tris de fosamprénavir - Google Patents

Sels d'ammonium, de calcium et de tris de fosamprénavir Download PDF

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Publication number
WO2011114212A1
WO2011114212A1 PCT/IB2011/000530 IB2011000530W WO2011114212A1 WO 2011114212 A1 WO2011114212 A1 WO 2011114212A1 IB 2011000530 W IB2011000530 W IB 2011000530W WO 2011114212 A1 WO2011114212 A1 WO 2011114212A1
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WO
WIPO (PCT)
Prior art keywords
fosamprenavir
calcium
iii
process according
preparation
Prior art date
Application number
PCT/IB2011/000530
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English (en)
Inventor
Surinder Kumar Arora
Samir Shanteshwar Shabade
Radhakrishna B. Shivdavkar
Purna Chandra Ray
Girij Pal Singh
Ajinath Tukaram Pathade
Gajanan Jijaba Chavan
Gaurav Kumar
Yuvraj Atmaram Chavan
Original Assignee
Lupin 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.)
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Publication date
Application filed by Lupin Limited filed Critical Lupin Limited
Publication of WO2011114212A1 publication Critical patent/WO2011114212A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention relates to fosamprenavir ammonium salt (II), fosamprenavir tris salt (III), conversion of II or III to fosamprenavir calcium salt (IV), polymorph of fosamprenavir ammonium salt (II), polymorph of fosamprenavir tris salt (III) and to novel processes for preparation of amorphous fosamprenavir calcium.
  • Fosarrn enavir is chemically known as (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4- aminophenyl) sulfonyl] (isobutyl) amino] -l-benzyl-2-(phosphonooxy)propyl carbamate.
  • Fosamprenavir salts have HIV aspartyl protease inhibitory activity and are particularly well suited for inhibiting HIV-1 and HIV -2 viruses.
  • Patent application US 2009/0075942 discloses deuterium enriched fosamprenavir and its quaternary ammonium salts, however specific quaternary ammonium salts are not disclosed.
  • the present invention is directed to novel fosamprenavir ammonium (II) and fosamprenavir tris (III) salts and process for their preparation.
  • Tris is abbreviation for organic compound chemically known as tris(hydroxymethyl)aminomethane.
  • Fosamprenavir calcium is a prodrug of amprenavir (V), and it is described in patent US 6 436 989.
  • Amprenavir has poor solubility and therefore it is used as a solution in gel capsules which results in a high pill burden.
  • fosamprenavir calcium is formulated as a tablet and has the potential to reduce the perceived pill burden.
  • polymorphs i.e. amorphous and crystalline forms of various existing drug molecules to obtain suitable polymorph that has improved performance characteristics such as solubility, stability, shelf life etc.
  • the ability of a compound to exist in different crystal structure is known as polymorphism. While polymorphs have the same chemical composition, they differ in packing and geometrical arrangement and exhibit different physical properties such as melting point, shape, density, stability, dissolution and the like.
  • the patent US 6 514 953 describes Crystalline Form I of fosamprenavir calcium. Typically Form I contains 4 to 5 moles of water and is obtained by crystallization from a mixture of industrial methylated spirit and water.
  • Patent US 6 436 989 covers fosamprenavir calcium, however it does not give enabling process for its preparation. Instead, example 30 of US 6 436 989 describes isolation of sodium salt of fosamprenavir by lyophilization of 1% acetonitrile and water solution.
  • PCT application WO 2010/134045 provides amorphous fosamprenavir calcium.
  • amorphous fosamprenavir calcium has appreciable solubility oyer the relevant physiological pH range; the solubility of amorphous is superior to that of crystalline form and the amorphous fosamprenavir calcium is essentially non-hygroscopic, stable on storage, reproducible and suitable for developing pharmaceutical dosage form.
  • WO 2010/134045 further provides process for preparation of amorphous form, wherein crystalline fosamprenavir calcium, as prepared by example of US 6 514 953, is converted to amorphous fosamprenavir calcium by utilizing thin film dryer or spray dryer processes or isolating amorphous fosamprenavir calcium from a mixture of solvent and an anti-solvent.
  • PCT application WO 201 1/001383 provides crystalline Form II of fosamprenavir calcium and process for preparation of the same.
  • Fosamprenavir calcium as prepared by example of US 6 514 953, is converted to crystalline Form II by dissolving fosamprenavir calcium in a water miscible organic solvent comprising a propanol, treating the solution with water and isolating Form II from the mixture.
  • the present invention is directed to various processes for preparation of amorphous fosamprenavir calcium and is discussed in detail herein below. DESCRIPTION OF DRAWING
  • Figure 1 Infrared spectrum of fosamprenavir ammonium salt (II);
  • FIG. 1 Infrared spectrum of fosamprenavir tris salt (III);
  • Figure 3 X-ray powder diffraction pattern of fosamprenavir ammonium salt (II);
  • Figure 4 X-ray powder diffraction pattern of fosamprenavir tris salt (III).
  • Figure 5 X-ray powder diffraction pattern of amorphous fosamprenavir calcium (IV).
  • the present invention provides novel salts of fosamprenavir (I); fosamprenavir ammonium salt (II), fosamprenavir tris salt (III), their novel polymorphic forms and process for their preparation. It further provides process for conversion of fosamprenavir ammonium (II) and fosamprenavir tris (III) to fosamprenavir calcium (IV).
  • the present invention provides various processes for preparation of amorphous fosamprenavir calcium (IV) such as:
  • the present invention provides novel ammonium and tris salts of fosamprenavir.
  • One embodiment of the present invention is to provide novel fosamprenavir ammonium salt (II) and its process for preparation.
  • Preparation of fosamprenavir ammonium salt (II) involves dissolution of fosamprenavir (I) in a polar aprotic solvent selected from esters, preferably ethyl acetate and subjecting the solution to source of ammonia.
  • a polar aprotic solvent selected from esters, preferably ethyl acetate
  • the product is isolated using antisolvent selected from hydrocarbons like hexanes, cyclohexanes etc. The entire process was carried out at ambient temperature.
  • Another embodiment of the present invention provides polymorphic form of fosamprenvir ammonium salt (II) which exhibits ' infrared spectrum as depicted in figure 1 and X-ray powder diffraction as depicted in figure 3.
  • Yet another embodiment of the present invention is to provide novel fosamprenavir tris salt (III) and its process of preparation. Preparation of fosamprenavir tris salt (III) comprising:
  • Preparation of fosamprenavir tris salt (III) involves dissolution of fosamprenavir (I) in an organic solvent selected from alcohols, like methanol ethanol, isopropanol or mixtures thereof, preferably methanol; followed by addition of tris buffer.
  • the solution is further added to a polar aprotic solvent selected from ester like ethyl acetate, isobutylacetate etc, preferably ethyl acetate; the product is isolated by concentration of solvent.
  • the invention also provides polymorphic form of fosamprenavir tris salt (III) which exhibits infrared spectrum as depicted in figure 2 and X-ray powder diffraction as depicted in figure 4.
  • Fosamprenavir ammonium and the tris salt of the present invention can be utilized in the process for preparation of fosamprenavir calcium.
  • the source of calcium ions is selected from calcium carbonate, calcium acetate, calcium chloride, calcium hydroxide, preferably calcium acetate.
  • Organic solvent is selected from an alcohol like methanol, ethanol, isopropanol; ketone like acetone, methyl ethyl ketone; ethers like tetrahydrofuran, dioxane; nitriles such as acetonitrile, propionitrile; amides like dimethylformamide, N-methyl pyrrolidine; mixtures thereof; preferred organic solvent is methanol.
  • the preparation of fosamprenavir calcium (IV) can be performed at ambient temperature
  • Fosamprenavir calcium (IV) is isolated by conventional methods such as filtration, concentration, evaporation etc.
  • the fosamprenavir calcium thus obtained can be converted to amorphous form.
  • the present invention provides various novel methods to obtain amorphous fosamprenavir calcium.
  • process for preparation of amorphous fosamprenavir calcium involves addition of a non-polar solvent to a solution of fosamprenavir calcium in polar solvent.
  • the appropriate polar solvent being an alcohol selected from methanol, ethanol, isopropanol or mixtures thereof.
  • the appropriate non-polar solvent being ether selected from diethyl ether, diisopropyl ether, t-butyl methyl ether or mixtures thereof.
  • the process is carried out by heating slurry of fosamprenavir calcium in alcohol to obtain a clear solution followed by addition of ether solvent in hot condition and then cooling the solution to temperature of 30 to -5°C, preferably 0-5 °C.
  • process for preparation of amorphous fosamprenavir calcium involves dissolving fosamprenavir calcium in polar solvent followed by isolation of solid either by concentration of a solution under reduced pressure or by cooling of solution.
  • Solution of fosamprenavir calcium is prepared in a polar solvent.
  • Polar solvent being an alcohol selected from methanol, ethanol, isopropanol.
  • concentration being carried out under reduced pressure of 10-40 mmHg, preferably at 20-25 mmHg, at a bath temperature of 40-50°C, using Buchii rota vapour.
  • Cooling of the solution is carried out to a temperature of 30 to -5°C, preferably 0-5°C.
  • process for preparation of amorphous fosamprenavir calcium involves conversion of crystalline fosamprenavir calcium to amorphous form by heating.
  • Crystalline fosamprenavir calcium is heated at a temperature of 100-200°C; preferably at a temperature of 100-150°C, more preferably at 1 10-120°C.
  • Heating is carried out for duration of 5-30 hours. Preferred conditions to obtain amorphous form is by heating at 1 15-120°C for 20-25 hours.
  • the amorphous fosamprenavir calcium obtained by the processes of present invention is characterized by X-ray powder diffraction pattern as depicted in Figure 5, which shows a very broad peak at 5.056 ⁇ 0.2 degree 2theta.
  • the amorphous fosamprenavir calcium obtained by the process of present invention is stable and hence suitable for pharmaceutical formulation.
  • Fosamprenavir calcium Form I It was prepared by crystallization from mixture of industrial methylated spirit and water as described in example 4 of patent US 6 514 953 or by the process as described in Example 3.
  • Example 3 Preparation of fosamprenavir calcium (IV) from fosamprenavir tris (III) salt.
  • fosamprenavir tris (II) To a solution of 15 g (0.006 mol) of fosamprenavir tris (II) in 150 ml water and 150 ml methanol was added a solution of 3.2 g (0.006) calcium acetate in 15 ml water at 27-28°C, mixture stirred for 1 hour. The solid was filtered and dried to obtain fosamprenavir calcium (IV); Yield: 6.0 g (53.87 %), HPLC purity: 99.09%.
  • Example 4 Preparation of amorphous fosamprenavir calcium (IV) as per method (i) A mixture of fosamprenavir calcium Form I (5 g.) and ethanol (50 ml) was heated at 70-72°C to obtain a clear solution. Diisopropyl ether (75 ml) was slowly added to the mixture at 70- 72°C. The mixture was cooled to ambient temperature, solid was filtered, washed with diisopropyl ether and dried under vacuum at 50°C to obtain amorphous fosamprenavir calcium (3.4 g); melting point: 245-246°C (decomposition); X-ray powder diffraction pattern is as shown in Figure 5.
  • Example 5 Preparation of amorphous fosamprenavir calcium (IV) as per method (ii)
  • a mixture of fosamprenavir calcium Form I (5 g.) and ethanol (75 ml) was heated at 70- 75°C, the reaction mass maintained for 10-15 minutes at 70-75°C.
  • the reaction mass was cooled to 0-5°C and stirred for 15-30 minutes.
  • the mixture was filtered and the solid was dried to obtain amorphous fosamprenavir calcium (2.0 g).
  • Fosamprenavir calcium Form I (1 g) was heated at a 120°C for 20 hours. Cooled at ambient temperature to obtain amorphous fosamprenavir calcium (0.9 g.)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau sel d'ammonium (II) de fosamprénavir, de TRIS (III) de fosamprénavir, la conversion de II ou III en sel de calcium (IV) de fosamprénavir, un polymorphe de sel d'ammonium (II) de fosamprénavir, un polymorphe de sel de TRIS (III) de fosamprénavir et de nouveaux processus de préparation de calcium amorphe (IV) de fosamprénavir, consistant à : i) ajouter un solvant non polaire à la solution de calcium de fosamprénavir dans le solvant polaire; ii) dissoudre le calcium de fosamprénavir dans un solvant polaire, puis isoler un solide soit par concentration, soit par refroidissement de la solution; iii) et convertir le calcium cristallin de fosamprénavir en une forme amorphe par chauffage.
PCT/IB2011/000530 2010-03-19 2011-03-14 Sels d'ammonium, de calcium et de tris de fosamprénavir WO2011114212A1 (fr)

Applications Claiming Priority (4)

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IN277KO2010 2010-03-19
IN277/KOL/2010 2010-03-19
IN1162/KOL/2010 2010-10-19
IN1162KO2010 2010-10-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172563A3 (fr) * 2011-06-14 2013-03-28 Hetero Research Foundation Nouveaux polymorphes de fosamprénavir calcique

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033815A1 (fr) * 1997-12-24 1999-07-08 Vertex Pharmaceuticals Incorporated Derives de sulfamide utilises comme precurseurs d'inhibiteurs de l'aspartyl protease
US6514953B1 (en) 1998-07-18 2003-02-04 Smithkline Beecham Corporation Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
US20090075942A1 (en) 2007-09-13 2009-03-19 Protia, Llc Deuterium-enriched fosamprenavir
WO2010134045A1 (fr) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Fosamprenavir calcique amorphe
WO2011001383A1 (fr) 2009-06-30 2011-01-06 Ranbaxy Laboratories Limited Forme cristalline de fosamprénavir calcium
WO2011033469A1 (fr) * 2009-09-16 2011-03-24 Ranbaxy Laboratories Limited Procédé pour préparer du fosamprénavir calcium

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033815A1 (fr) * 1997-12-24 1999-07-08 Vertex Pharmaceuticals Incorporated Derives de sulfamide utilises comme precurseurs d'inhibiteurs de l'aspartyl protease
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
US6514953B1 (en) 1998-07-18 2003-02-04 Smithkline Beecham Corporation Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
US20090075942A1 (en) 2007-09-13 2009-03-19 Protia, Llc Deuterium-enriched fosamprenavir
WO2010134045A1 (fr) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Fosamprenavir calcique amorphe
WO2011001383A1 (fr) 2009-06-30 2011-01-06 Ranbaxy Laboratories Limited Forme cristalline de fosamprénavir calcium
WO2011033469A1 (fr) * 2009-09-16 2011-03-24 Ranbaxy Laboratories Limited Procédé pour préparer du fosamprénavir calcium

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Title
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"THE COMPLETE BLOG FOR THE PREPARATION OF PHARMACEUTICAL SALTS", INTERNET CITATION, 11 February 2008 (2008-02-11), pages 1 - 10, XP002513555, Retrieved from the Internet <URL:http://kilomentor.chemicalblogs.com/55_kilomentor/archive/552_the_com plete_blog_for_the_preparation_of_pharmaceutical_salts.html> [retrieved on 20090204] *
HANCOCK B C ET AL: "CHARACTERISTICS AND SIGNIFICANCE OF THE AMORPHOUS STATE IN PHARMACEUTICAL SYSTEMS", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 86, no. 1, 1 January 1997 (1997-01-01), pages 1 - 12, XP000929450, ISSN: 0022-3549, DOI: DOI:10.1021/JS9601896 *
OUYANG ET AL: "Fosamprenavir: a prodrug of amprenavir", 1 January 2007, PRODRUGS CHALLENGES AND REWARDS PART 1 (BOOK SERIES: BIOTECHNOLOGY: PHARMACEUTICAL ASPECTS), SPRINGER NEW YORK, US, PAGE(S) 541 - 549, ISBN: 978-0-387-49782-2, XP008138094 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172563A3 (fr) * 2011-06-14 2013-03-28 Hetero Research Foundation Nouveaux polymorphes de fosamprénavir calcique

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