WO2007013086A1 - Nouveaux polymorphes de tenofovir disoproxil fumarate - Google Patents

Nouveaux polymorphes de tenofovir disoproxil fumarate Download PDF

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Publication number
WO2007013086A1
WO2007013086A1 PCT/IN2005/000248 IN2005000248W WO2007013086A1 WO 2007013086 A1 WO2007013086 A1 WO 2007013086A1 IN 2005000248 W IN2005000248 W IN 2005000248W WO 2007013086 A1 WO2007013086 A1 WO 2007013086A1
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WO
WIPO (PCT)
Prior art keywords
tenofovir disoproxil
disoproxil fumarate
solution
solvent
pharmaceutical composition
Prior art date
Application number
PCT/IN2005/000248
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Kesireddy Subash Chander Reddy
Original Assignee
Hetero Drugs 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 Hetero Drugs Limited filed Critical Hetero Drugs Limited
Priority to PCT/IN2005/000248 priority Critical patent/WO2007013086A1/fr
Publication of WO2007013086A1 publication Critical patent/WO2007013086A1/fr

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Classifications

    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the present invention relates to novel polymorphs of tenofovir disoproxil fumarate, to processes for their preparation and to pharmaceutical compositions comprising them.
  • Tenofovir disoproxil chemically (R)-9-(2-phosphonomethoxypropyl) adenine bis(isopropyloxycarbonyloxymethyl) ester is a highly potent antiviral agent having particular potential for the therapy or prophylaxis of retroviral infections.
  • Tenofovir disoproxil is represented by the following structure:
  • tenofovir disoproxil fumarate is obtained as a crystalline form and may be designated as form I (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at about 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1 and 30.4 degrees).
  • Form A Two stable novel crystalline forms (designated as Form A, Form B) of tenofovir disoproxil fumarate.
  • the novel forms are at least as stable as the reported form (Form I).
  • the novel crystalline forms are stable over the time and has good flow properties and so, the novel crystalline forms are suitable for formulating tenofovir disoproxil fumarate.
  • Amorphous form of tenofovir disoproxil fumarate has not been reported in the prior art. So, there is a need for stable amorphous form of tenofovir disoproxil fumarate for better pharmaceutical preparations.
  • One object of the present invention is to provide stable novel crystalline forms of tenofovir disoproxil fumarate, process for preparing them and pharmaceutical compositions containing them.
  • Another object of the present invention is to provide a novel stable amorphous form of tenofovir disoproxil fumarate, process for preparing it and a pharmaceutical composition containing it.
  • tenofovir disoproxil fumarate form A a novel crystalline form of tenofovir disoproxil fumarate, designated as tenofovir disoproxil fumarate form A and typical X-ray powder diffraction spectrum of tenofovir disoproxil fumarate form A is shown in figure 1.
  • Tenofovir disoproxil fumarate form A is characterized by peaks in the powder X-ray diffraction pattern having 2 ⁇ angle positions at about 7.7, 8.0, 11.8, 13.6, 14.2, 16.0, 16.6, 17.9, 19.1 , 20.3, 21.1, 21.5, 22.4, 22.7, 24.2, 24.6 and 25.2 + 0.2 degrees.
  • Crystalline tenofovir disoproxil fumarate form A is prepared by dissolving * tenofovir disoproxil fumarate in isopropyl alcohol and then crystallizing tenofovir disoproxil fumarate form A from the solution.
  • Crystallization may be initiated by any conventional methods usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof. Crystallization is preferably initiated by cooling the solution to below about 40 0 C and more preferably to about 20 - 30 0 C.
  • tenofovir disoproxil fumarate form B a novel crystalline form of tenofovir disoproxil fumarate, designated as tenofovir disoproxil fumarate form B and typical X-ray powder diffraction spectrum of tenofovir disoproxil fumarate form B is shown in figure 2.
  • Tenofovir disoproxil fumarate form B is characterized by peaks in the powder X-ray diffraction pattern having 2 ⁇ angle positions at about 5.2, 15.4, 20.6, 25.8 and 31.0 + 0.2 degrees.
  • a process is provided for preparation of crystalline tenofovir disoproxil fumarate form B.
  • Crystalline tenofovir disoproxil fumarate form B is prepared by dissolving tenofovir disoproxil fumarate in methanol or ethanol and then crystallizing tenofovir disoproxil fumarate form B from the solution.
  • Crystallization may be initiated by any conventional methods usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
  • Crystallization is preferably initiated by cooling the solution to below about 40 0 C and more preferably to about 20 - 30 0 C.
  • a novel amorphous form of tenofovir disoproxil fumarate is provided.
  • the amorphous tenofovir disoproxil fumarate is characterized by having broad x-ray diffraction spectrum as in figure 3.
  • a process is provided for preparation of amorphous tenofovir disoproxil fumarate.
  • Amorphous tenofovir disoproxil fumarate is prepared by dissolving tenofovir disoproxil fumarate in a suitable solvent and removing the solvent by freeze-drying.
  • Preferable solvent is selected from alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol; ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; tetrahydrofuran; dimethylformamide, dimethylsulfoxide; and a mixture thereof. More preferable solvent is selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. Most preferable solvent is ethanol.
  • alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol
  • ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone
  • Tenofovir disoproxil fumarate used as starting materials may be obtained by processes described in the art, for example by the processes described in U.S. Patent No. 5,922,695, U.S. Patent No. 5,935,946.
  • the novel crystalline forms can be produced in a consistently reproducible manner by simple procedures.
  • the novel crystalline forms are obtained polymorphically pure with no or less contamination with other crystalline forms.
  • a pharmaceutical composition comprising crystalline tenofovir disoproxil fumarate form A and a pharmaceutically acceptable excipient.
  • Preferable pharmaceutical composition of tenofovir disoproxil fumarate form A is a solid oral dosage form.
  • a pharmaceutical composition comprising crystalline tenofovir disoproxil fumarate form B and a pharmaceutically acceptable excipient.
  • Preferable pharmaceutical composition of tenofovir disoproxil fumarate form B is a solid oral dosage form. According to another aspect of the present invention there is provided a pharmaceutical composition comprising amorphous tenofovir disoproxil fumarate and a pharmaceutically acceptable excipient.
  • Preferable pharmaceutical composition of amorphous tenofovir disoproxil fumarate is a solid oral dosage form.
  • Figure 1 is a X-ray powder diffraction spectrum of crystalline tenofovir disoproxil fumarate form A.
  • Figure 2 is a X-ray powder diffraction spectrum of crystalline tenofovir disoproxil fumarate form B.
  • Figure 3 is a X-ray powder diffraction spectrum of amorphous tenofovir disoproxil fumarate.
  • X-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance X-ray powder diffractometer having a Copper-K ⁇ radiation. Approximately 1 gm of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • the following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
  • Tenofovir disoproxil fumarate crude (2 gm) is added to methanol (20 ml) at 25 - 30 0 C and then heated to 50 - 55 0 C to form a clear solution. The solution is cooled to 25 - 30 0 C and stirred for 1 hour at 25 - 30 0 C. Filtered the solid and dried at 50 - 60 0 C to give 1.6 gm of crystalline tenofovir disoproxil fumarate form
  • Example 1 is repeated using tenofovir disoproxil fumarate form B instead of tenofovir disoproxil fumarate crude to give 4.7 gm of tenofovir disoproxil fumarate form A.
  • Example 2 is repeated using tenofovir disoproxil fumarate form A instead of tenofovir disoproxil fumarate crude to give 1.6 gm of tenofovir disoproxil fumarate form B.
  • Tenofovir disoproxil fumarate (5 gm) is dissolved in a mixture of ethanol (75 ml) and water (20 ml) and then filtered the solution on hi-flow bed. The solution is subjected to freeze drying to give 4.6 gm of amorphous tenofovir disoproxil fumarate.
  • Example 6 is repeated using tenofovir disoproxil fumarate form A instead of tenofovir disoproxil fumarate to give 4.7 gm of amorphous tenofovir disoproxil fumarate.

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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)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux polymorphes de tenofovir disoproxil fumarate, des procédés pour leur préparation et des compositions pharmaceutiques contenant lesdits polymorphes.
PCT/IN2005/000248 2005-07-26 2005-07-26 Nouveaux polymorphes de tenofovir disoproxil fumarate WO2007013086A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000248 WO2007013086A1 (fr) 2005-07-26 2005-07-26 Nouveaux polymorphes de tenofovir disoproxil fumarate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000248 WO2007013086A1 (fr) 2005-07-26 2005-07-26 Nouveaux polymorphes de tenofovir disoproxil fumarate

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008140302A1 (fr) * 2007-05-14 2008-11-20 Ultimorphix Technologies B.V. Formes polymorphes de ténofovir disoproxil fumarate
WO2008143500A1 (fr) * 2007-05-22 2008-11-27 Ultimorphix Technologies B.V. Co-cristaux de tenofovir disoproxil acide hémi-fumarique
WO2009064174A1 (fr) * 2007-11-14 2009-05-22 Ultimorphix Technologies B.V. Forme polymorphe du ténofovir disoproxil fumarate, son procédé de préparation et son utilisation
WO2009074351A2 (fr) * 2007-12-12 2009-06-18 Ultimorphix Technologies B.V. Formes solides de ténofovir disoproxil
CN101781335A (zh) * 2010-03-04 2010-07-21 福建广生堂药业有限公司 富马酸替诺福韦酯的新晶型及其制备方法
WO2010142761A1 (fr) * 2009-06-10 2010-12-16 Ultimorphix Technologies B.V. Succinate de ténofovir disoproxil
JP2011518815A (ja) * 2008-04-25 2011-06-30 シプラ・リミテッド 結晶形態のテノホビルジソプロキシル及びその製造方法
WO2012027972A1 (fr) * 2010-08-30 2012-03-08 杭州和素化学技术有限公司 FORME CRISTALLINE α DU TÉNOFOVIR DISOPROXIL FUMARATE, PROCÉDÉ POUR LA PRÉPARER ET SON UTILISATION
CN103626803A (zh) * 2012-08-23 2014-03-12 四川海思科制药有限公司 替诺福韦二吡呋酯的固体及其制备方法和用途
WO2015051875A1 (fr) 2013-10-09 2015-04-16 Zentiva, K.S. Sel dihydrogénophosphate de ténofovir disoproxil
US9296769B2 (en) 2011-08-16 2016-03-29 Gilead Sciences, Inc. Tenofovir alafenamide hemifumarate
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
CN109867696A (zh) * 2017-12-04 2019-06-11 国药集团国瑞药业有限公司 一种替诺福韦二吡呋酯三聚体化合物、其制备方法及应用
CN110372748A (zh) * 2018-04-12 2019-10-25 湖南千金湘江药业股份有限公司 一种无定形半富马酸替诺福韦二吡呋酯及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922695A (en) * 1996-07-26 1999-07-13 Gilead Sciences, Inc. Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
US5935946A (en) * 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922695A (en) * 1996-07-26 1999-07-13 Gilead Sciences, Inc. Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
US5935946A (en) * 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008140302A1 (fr) * 2007-05-14 2008-11-20 Ultimorphix Technologies B.V. Formes polymorphes de ténofovir disoproxil fumarate
WO2008143500A1 (fr) * 2007-05-22 2008-11-27 Ultimorphix Technologies B.V. Co-cristaux de tenofovir disoproxil acide hémi-fumarique
JP2010527996A (ja) * 2007-05-22 2010-08-19 ウルティモルフィクス・テクノロジーズ・ベー・フェー テノホビルジソプロキシル−ヘミフマル酸共結晶
WO2009064174A1 (fr) * 2007-11-14 2009-05-22 Ultimorphix Technologies B.V. Forme polymorphe du ténofovir disoproxil fumarate, son procédé de préparation et son utilisation
WO2009074351A2 (fr) * 2007-12-12 2009-06-18 Ultimorphix Technologies B.V. Formes solides de ténofovir disoproxil
WO2009074351A3 (fr) * 2007-12-12 2009-11-12 Ultimorphix Technologies B.V. Formes solides de ténofovir disoproxil
CN101918418A (zh) * 2007-12-12 2010-12-15 阿尔迪默菲克斯技术有限责任公司 替诺福韦地索普西的固体形式
JP2011518815A (ja) * 2008-04-25 2011-06-30 シプラ・リミテッド 結晶形態のテノホビルジソプロキシル及びその製造方法
WO2010142761A1 (fr) * 2009-06-10 2010-12-16 Ultimorphix Technologies B.V. Succinate de ténofovir disoproxil
CN101781335A (zh) * 2010-03-04 2010-07-21 福建广生堂药业有限公司 富马酸替诺福韦酯的新晶型及其制备方法
WO2012027972A1 (fr) * 2010-08-30 2012-03-08 杭州和素化学技术有限公司 FORME CRISTALLINE α DU TÉNOFOVIR DISOPROXIL FUMARATE, PROCÉDÉ POUR LA PRÉPARER ET SON UTILISATION
US9296769B2 (en) 2011-08-16 2016-03-29 Gilead Sciences, Inc. Tenofovir alafenamide hemifumarate
EP2744810B1 (fr) 2011-08-16 2016-10-05 Gilead Sciences, Inc. Hémifumarate de ténofovir alafénamide
CN103626803A (zh) * 2012-08-23 2014-03-12 四川海思科制药有限公司 替诺福韦二吡呋酯的固体及其制备方法和用途
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
WO2015051875A1 (fr) 2013-10-09 2015-04-16 Zentiva, K.S. Sel dihydrogénophosphate de ténofovir disoproxil
CN109867696A (zh) * 2017-12-04 2019-06-11 国药集团国瑞药业有限公司 一种替诺福韦二吡呋酯三聚体化合物、其制备方法及应用
CN110372748A (zh) * 2018-04-12 2019-10-25 湖南千金湘江药业股份有限公司 一种无定形半富马酸替诺福韦二吡呋酯及其制备方法
CN110372748B (zh) * 2018-04-12 2023-04-07 湖南千金湘江药业股份有限公司 一种无定形半富马酸替诺福韦二吡呋酯及其制备方法

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