WO2011016044A1 - Nouveaux polymorphes d’adéfovir dipivoxil - Google Patents

Nouveaux polymorphes d’adéfovir dipivoxil Download PDF

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Publication number
WO2011016044A1
WO2011016044A1 PCT/IN2009/000440 IN2009000440W WO2011016044A1 WO 2011016044 A1 WO2011016044 A1 WO 2011016044A1 IN 2009000440 W IN2009000440 W IN 2009000440W WO 2011016044 A1 WO2011016044 A1 WO 2011016044A1
Authority
WO
WIPO (PCT)
Prior art keywords
adefovir dipivoxil
crystalline form
pharmaceutical composition
crystalline
adefovir
Prior art date
Application number
PCT/IN2009/000440
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Musku Madhan Mohana Reddy
Bandi Vamsi Krishna
Donikena Sridhar
Original Assignee
Hetero Research Foundation
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 Research Foundation filed Critical Hetero Research Foundation
Priority to PCT/IN2009/000440 priority Critical patent/WO2011016044A1/fr
Publication of WO2011016044A1 publication Critical patent/WO2011016044A1/fr

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Classifications

    • 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
    • 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 System
    • 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

Definitions

  • the present invention provides novel crystalline form of adefovir dipivoxil, process for its preparation and pharmaceutical composition comprising it.
  • Adefovir dipivoxil is a known nucleotide reverse transcriptase inhibitor used in clinic for the treatment of retrovirus infections, in particular HIV and HBV infections.
  • Adefovir is represented by the following structure:
  • Patent No. 5,663,159 discloses a patent No.
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice.
  • polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules.
  • Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
  • Adefovir dipivoxil can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • US Patent No. 6,451,340 disclosed various polymorphic forms, crystalline form 1 (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at about 6.9 degrees), form 2 (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at about 9.6, 18.3,
  • form 3 characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at about 8.1 , 19.4, 25.4 and 30.9 degrees
  • form 4 characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at about 9.8, 15.2, 26.3 and 31.7 degrees
  • WO Patent Publication No. 2009/015892 disclosed various polymorphic forms, monohydrate form A and form B of adefovir dipivoxil.
  • An object of the present invention is to provide a novel crystalline form of adefovir dipivoxil, process for their preparation and pharmaceutical composition comprising it.
  • the present invention provided a novel crystalline form of adefovir dipivoxil designated as form H1 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 4.2, 8.5, 17.1 , 21.4 and 25.8 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing adefovir dipivoxil crystalline from H1 , which comprises:
  • step (b) adding water to the solution obtained in step (a);
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline form H1 of adefovir dipivoxil and a pharmaceutically acceptable excipient.
  • Figure 1 is X-ray powder diffraction spectrum of adefovir dipivoxil crystalline form H1.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-K ⁇ radiation. Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 10.4 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.
  • a novel crystalline form of adefovir dipivoxil designated as form H1 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 4.2, 8.5, 17.1 , 21.4 and 25.8 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of adefovir dipivoxil crystalline form H1 is shown in figure 1.
  • the crystalline form H1 may be identified and differentiated from the known crystalline forms by its characteristic PXRD pattern.
  • peak at 32.8 ⁇ 0.2 degrees 2 ⁇ is absent in the PXRD of the crystalline form H1 of the present invention, but is present in the PXRD of the crystalline Form 2 of adefovir dipivoxil disclosed in the U. S. Patent No. 6,451 ,340.
  • the water content of the novel crystalline form, form H1 is in range 6.0 to 7.5 by weight.
  • a process for the preparation of adefovir dipivoxil crystalline form H1 which comprises:
  • step (b) adding water to the solution obtained in step (a);
  • the ketonic solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of a methyl ethyl ketone, acetone, methyl isobutyl ketone and methyl isopropyl ketone.
  • Preferable ketonic solvent is methyl ethyl ketone.
  • isolation of adefovir dipivoxil crystalline from H1 may be performed by conventional techniques such as centrifugation and filtration.
  • the temperature at which slurrying is carried out is not critical and the slurrying may conveniently be carried out at room temperature.
  • a pharmaceutical composition comprising adefovir dipivoxil crystalline from H1 and a pharmaceutically acceptable excipient.
  • compositions may be in the form of tablets, capsules, solutions, suspensions or emulsions.
  • the invention will now be further described by the following examples, which are illustrative rather than limiting.
  • Adefovir dipivoxil (10 gm) was dissolved in a mixture of N- methylpyrrolidone (60 ml) and methyl ethyl ketone (40 ml). The reaction mixture was stirred for 30 minutes at room temperature and filtered. To the filtrate was added water (1600 ml) and stirred for 12 hours. The solid obtained was collected by filtration and the solid was washed with water, and then dried at 35 to 40 0 C under vacuum for 2 hours to obtain 9.3 gm of adefovir dipivoxil crystalline form Hl Example 2
  • Adefovir dipivoxil (5 gm) was dissolved in a mixture of N- methylpyrrolidone (30 ml) and methyl isobutyl ketone (25 ml). The reaction mixture was stirred for 30 minutes at room temperature and filtered. To the filtrate was added water (800 ml) and stirred for 10 hours, filtered. The solid obtained washed with water and dried at 35 to 40 0 C under vacuum for 2 hours to obtain 4.2 gm of adefovir dipivoxil crystalline form H1.

Abstract

Cette invention concerne une nouvelle forme cristalline d’adéfovir dipivoxil, son procédé de fabrication et une composition de pharmaceutique la renfermant. Ainsi, de l’adéfovir dipivoxil a été dissous dans un mélange de N-méthylpyrrolidone et de méthyl éthyl cétone, filtré et, après adjonction d’eau au filtrat, agité pendant 12 heures. La substance solide séparée a été filtrée, rincée à l’eau et séchée pour donner une forme cristalline H1 d’adéfovir dipivoxil.
PCT/IN2009/000440 2009-08-03 2009-08-03 Nouveaux polymorphes d’adéfovir dipivoxil WO2011016044A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2009/000440 WO2011016044A1 (fr) 2009-08-03 2009-08-03 Nouveaux polymorphes d’adéfovir dipivoxil

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2009/000440 WO2011016044A1 (fr) 2009-08-03 2009-08-03 Nouveaux polymorphes d’adéfovir dipivoxil

Publications (1)

Publication Number Publication Date
WO2011016044A1 true WO2011016044A1 (fr) 2011-02-10

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Application Number Title Priority Date Filing Date
PCT/IN2009/000440 WO2011016044A1 (fr) 2009-08-03 2009-08-03 Nouveaux polymorphes d’adéfovir dipivoxil

Country Status (1)

Country Link
WO (1) WO2011016044A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1903863A (zh) * 2006-07-28 2007-01-31 齐鲁制药有限公司 一种阿德福韦酯结晶的制备方法
CN1935818A (zh) * 2006-09-22 2007-03-28 闫敬武 阿德福韦酯新晶态、晶态组合物、制备方法及应用
CN101343290A (zh) * 2008-05-24 2009-01-14 广东肇庆星湖生物科技股份有限公司 一种阿德福韦酯无水结晶物的制备方法、所得的阿德福韦酯无水结晶物及其应用
WO2009015892A1 (fr) * 2007-08-02 2009-02-05 Solmag S.P.A. Forme monohydratée cristalline d'adéfovir dipivoxil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1903863A (zh) * 2006-07-28 2007-01-31 齐鲁制药有限公司 一种阿德福韦酯结晶的制备方法
CN1935818A (zh) * 2006-09-22 2007-03-28 闫敬武 阿德福韦酯新晶态、晶态组合物、制备方法及应用
WO2009015892A1 (fr) * 2007-08-02 2009-02-05 Solmag S.P.A. Forme monohydratée cristalline d'adéfovir dipivoxil
CN101343290A (zh) * 2008-05-24 2009-01-14 广东肇庆星湖生物科技股份有限公司 一种阿德福韦酯无水结晶物的制备方法、所得的阿德福韦酯无水结晶物及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Derwent World Patents Index; AN 2007-604594, THOMPSON DATABASE *
DATABASE WPI Derwent World Patents Index; AN 2009-E31810, THOMPSON *

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