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WO2009127996A1 - Nouvelle forme cristalline de lamivudine - Google Patents

Nouvelle forme cristalline de lamivudine Download PDF

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Publication number
WO2009127996A1
WO2009127996A1 PCT/IB2009/051493 IB2009051493W WO2009127996A1 WO 2009127996 A1 WO2009127996 A1 WO 2009127996A1 IB 2009051493 W IB2009051493 W IB 2009051493W WO 2009127996 A1 WO2009127996 A1 WO 2009127996A1
Authority
WO
WIPO (PCT)
Prior art keywords
lamivudine
crystalline form
mixture
antisolvent
methanol
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/IB2009/051493
Other languages
English (en)
Inventor
Hashim Nizar Poovanathil Nagoor Meeran
Sayeed Mukhtar
Rita Santhakumar
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.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy 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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2009127996A1 publication Critical patent/WO2009127996A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention relates to a novel crystalline form of lamivudine.
  • the novel crystalline form of the present invention is designated as Form IV.
  • the present invention further relates to a process for the preparation of crystalline Form IV of lamivudine.
  • Lamivudine is a substituted 1,3-oxathiolane and it is presently available in the market as an antiretroviral agent. Lamivudine is a cis-(-)-isomer and it is chemically (2R,cis)-4-amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one of Formula I having the structure as depicted below.
  • U.S. Patent No. 5,905,082 provides a process for preparing lamivudine by enzymatic separation of (+)-cis-4-amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)- pyrimidine-2-one.
  • lamivudine so obtained has an enantiomeric excess of only about 90% and it is referred as "Intermediate 5".
  • the Intermediate 5 is dissolved in water by heating to 45°C and cooled to 30 0 C.
  • U.S. Patent No. 6,329,522 provides a process for purification of lamivudine by the formation of salicylate salt and a crystallization method for lamivudine from isopropyl acetate.
  • both the preparation of lamivudine salicylate and crystallization of lamivudine involve seeding, and US '522 patent does not disclose any method to obtain the seed crystals of lamivudine salicylate as well as lamivudine.
  • WO 03/027106 provides a process for preparing Form II of lamivudine from lamivudine salicylate using ethyl acetate and acetonitrile as solvents and triethylamine as a base.
  • WO 03/027106 application does not disclose any specific method to obtain lamivudine salicylate.
  • PCT Publication No. WO 2007/119248 provides a process for the preparation of Form III of lamivudine.
  • Form III is prepared by dissolving Form II in water by heating to 45°C and subsequent cooling to 30 0 C. However, the time involved for reducing the temperature from 45°C to 30 0 C varies form 15 minutes to 1 hour 40 minutes. The mixture so obtained is further stirred at 10 0 C for 1 hour, filtered and dried in vacuum at 45°C for 24 hours to obtain Form III. The process also involves optional washing with ethanol or industrial methylated spirit.
  • Form III is also prepared by dissolving Form I in water by heating to 45°C and subsequent cooling to 10 0 C. However, the time involved for reducing the temperature from 45°C to 10 0 C is 10 minutes.
  • Form III is also prepared by stirring a suspension of Form I or Form II in water at 25°C for 24 hours or 48 hours. The mixture is further stirred at 10 0 C for 1 hour, filtered and dried in vacuum at 45°C for 24 hours to obtain Form III.
  • WO 2007/119248 application also provides processes for preparing Form I and Form II of lamivudine.
  • Form I is prepared by dissolving lamivudine in water by heating to 45°C and subsequent cooling to 30 0 C in 0.5 minute.
  • the solid product crystallized as unstirrable mass is broken up, stirred at 10 0 C, filtered and washed with industrial methylated spirit.
  • the washed material is dried in vacuum at 45°C for 24 hours to obtain Form I.
  • Form I is also prepared in a similar way from a mixture of water and denaturated spirit. However, in this process, the time involved for reducing the temperature from 45°C to 30 0 C is 12 minutes and it also involves seeding with Form I crystals.
  • Form II is prepared refluxing lamivudine in ethanol and partially removing the solvent by distillation. The concentrated solution is cooled to 15°C in 35 minutes, stirred at 15°C for 1 hour, filtered and washed with ethanol. The washed product is dried in vacuum at 50 0 C for 12 hours to obtain Form II.
  • Figure 1 depicts X-Ray Powder Diffractogram (XRPD) of crystalline Form IV of lamivudine.
  • FIG. 1 depicts Differential Scanning Calorimetry (DSC) thermogram of crystalline Form IV of lamivudine.
  • Figure 3 depicts Fourier- Transform Infra-red (FTIR) spectrum of crystalline Form IV of lamivudine.
  • Figure 4 depicts Thermo gravimetric Analysis (TGA) of crystalline Form IV of lamivudine.
  • FTIR Fourier- Transform Infra-red
  • Figure 5 depicts comparative XRPD of crystalline Form IV, Form I and Form II of lamivudine.
  • the present inventors have now prepared a novel crystalline form of lamivudine designated as Form IV.
  • the crystalline Form IV of lamivudine has different physical characteristics as compared to the known crystalline forms of lamivudine.
  • the crystalline for of the present invention is reproducible and stable to develop pharmaceutical dosage forms.
  • a first aspect of the present invention provides crystalline Form IV of lamivudine.
  • the crystalline Form IV of lamivudine has an XRPD pattern substantially as depicted in Figure 1 of the accompanied drawing.
  • the XRPD of Form IV shows characteristic d- spacing values substantially at 16.933, 13.223, 10.381, 9.174, 8.938, 8.692, 8.478, 7.852, 7.734, 7.612, 7.173, 7.024, 6.891, 6.696, 6.140, 6.069, 5.903, 5.654, 5.481, 5.350, 5.045, 4.934, 4.894, 4.738, 4.651, 4.593, 4.495, 4.432, 4.380, 4.238, 4.168, 4.078, 3.928, 3.867, 3.789, 3.655, 3.624, 3.563, 3.514, 3.463, 3.446, 3.349, 3.310, 3.262, 3.234, 3.194, 3.161, 3.128, 3.033,
  • the crystalline Form IV of lamivudine has a DSC thermogram substantially as depicted in Figure 2 of the accompanied drawing.
  • the DSC thermogram shows a first endotherm at about 130° to about 135°C followed by an exotherm at about 136° to about 144°C and a second endotherm at about 173° to about 183°C.
  • the crystalline Form IV of lamivudine has an FTIR pattern substantially as depicted in Figure 3 of the accompanied drawing.
  • the TGA of the crystalline Form IV of lamivudine shows a single step weight loss of about 1.8%.
  • a second aspect of the present invention provides a process for the preparation of crystalline Form IV of lamivudine, wherein the process comprises, a) dissolving lamivudine in methanol, b) cooling the solution obtained in step a) to a temperature of about 15°C or below, and c) isolating crystalline Form IV of lamivudine from the mixture thereof.
  • Lamivudine existing in any solid form known in the art may be used as a starting material. Lamivudine is dissolved in methanol. Methanol may also be used as a mixture with any other organic solvent. The dissolution process may be carried out at about 25°C or above, for example, at about 25° to about 65°C. The solution obtained is cooled in about 10 minutes to about 40 minutes to a temperature of about 15°C or below, for example, about 0° to about 15°C. The solution is further stirred at a temperature of about 0° to about 5°C for sufficient time to obtain crystalline Form IV of lamivudine. The crystalline Form IV of lamivudine is isolated from the mixture thereof by filtration, concentration, distillation, decantation, evaporation or a combination thereof.
  • a third aspect of the present invention provides a process for the preparation of crystalline Form IV of lamivudine, wherein the process comprises, a) dissolving lamivudine in methanol, b) treating the solution obtained in step a) with an antisolvent, and c) isolating crystalline Form IV of lamivudine from the mixture thereof.
  • Lamivudine existing in any solid form known in the art may be used as a starting material.
  • Lamivudine is dissolved in methanol.
  • the dissolution process may be carried out at about 25°C or above, for example, at about 25° to about 65°C.
  • the solution obtained is treated with an antisolvent.
  • the antisolvent is selected from the group consisting of aliphatic or aromatic hydrocarbons, esters, ketones, nitriles, halogenated hydrocarbons and ethers, or a mixture thereof.
  • the antisolvent may be, for example, n-hexane, cyclohexane, toluene, acetone, ethylacetate, acetonitrile, diethyl ether, methyl t-butyl ether, heptane or petroleum ether, or a mixture thereof.
  • the treatment with antisolvent may be carried out at a temperature of about 20° to about 35°C.
  • the mixture obtained is cooled to about 15°C or below, for example, about 0° to about 15°C and stirred for sufficient time to obtain crystalline Form IV of lamivudine.
  • the crystalline Form IV of lamivudine is isolated from the mixture thereof by filtration, concentration, distillation, decantation, evaporation or a combination thereof.
  • a fourth aspect of the present invention provides a pharmaceutical composition comprising crystalline Form IV of lamivudine optionally containing an excipient/ diluent.
  • a fifth aspect of the present invention provides a method of treating HIV or HBV infections which comprises of administering to a human in need thereof a therapeutically effective amount of crystalline Form IV of lamivudine.
  • the XRPD was determined by using Panalytical X' Pert Pro X-Ray Powder Diffractometer in the range 3° to 40° 2 ⁇ and under tube voltage and current of 45 Kv and 40 mA respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector was used.
  • Moisture content was determined on a Metrohm 831KF coulometer.
  • the FTIR was recorded in KBr on Perkin Elmer FTIR (Spectrum One) instrument. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • Lamivudine 50 g was dissolved in methanol (500 ml) at reflux temperature. The solution obtained was cooled to 0° to 15°C in 20 to 30 minutes and stirred at 0° to 5°C for
  • Lamivudine 50 g was dissolved in methanol (500 ml) at reflux temperature. The solution obtained was added to cyclohexane (1000 ml), kept at 20° to 25°C and stirred for
  • Lamivudine (50 g) was dissolved in methanol (500 ml) at reflux temperature. The solution obtained was added to diisopropyl ether (1000 ml), kept at 20° to 25°C and stirred for 2 hours. The solution obtained was cooled to 5° to 10 0 C in 15 to 20 minutes and stirred for 2 hours. The solid obtained was filtered and dried at 45° to 50 0 C to obtain the title compound. Yield: 42 g
  • Lamivudine 50 g was dissolved in methanol (500 ml) at reflux temperature. The solution obtained was added to ethyl acetate (1000 ml) and kept at 20° to 25°C for 2 hours. The solution obtained was cooled to 5° to 10 0 C in 15 to 20 minutes and stirred for 2 hours. The solid obtained was filtered and dried at 45° to 50 0 C to obtain the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur une nouvelle forme cristalline de lamivudine, c'est-à-dire celle qui est représentée par la formule (I). La nouvelle forme cristalline de la présente invention est désignée comme étant la forme IV. La présente invention porte, en outre, sur un procédé de préparation de la forme cristalline IV de lamivudine. Formule (I)
PCT/IB2009/051493 2008-04-17 2009-04-08 Nouvelle forme cristalline de lamivudine Ceased WO2009127996A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN997DE2008 2008-04-17
IN997/DEL/2008 2008-04-17

Publications (1)

Publication Number Publication Date
WO2009127996A1 true WO2009127996A1 (fr) 2009-10-22

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/051493 Ceased WO2009127996A1 (fr) 2008-04-17 2009-04-08 Nouvelle forme cristalline de lamivudine

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WO (1) WO2009127996A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796452B2 (en) 2010-02-12 2014-08-05 Merck Sharp & Dohme Corp. Preparation of lamivudine form I

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0517145A1 (fr) * 1991-06-03 1992-12-09 Glaxo Group Limited Dérivés d'oxathiolane cristallisés
WO2007119248A1 (fr) * 2006-04-18 2007-10-25 Lupin Limited Nouvelle forme cristalline de la lamivudine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0517145A1 (fr) * 1991-06-03 1992-12-09 Glaxo Group Limited Dérivés d'oxathiolane cristallisés
WO2007119248A1 (fr) * 2006-04-18 2007-10-25 Lupin Limited Nouvelle forme cristalline de la lamivudine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. K. HARRIS ET AL: "Polymorphism in a novel anti-viral agent: Lamivudine", JOURNAL OF CHEMICAL SOCIENTY, PERKIN TRANS., vol. 2, 1997, pages 2653 - 2659, XP002432450 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796452B2 (en) 2010-02-12 2014-08-05 Merck Sharp & Dohme Corp. Preparation of lamivudine form I

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