WO2013168066A1 - Procédé amélioré de fabrication de lamivudine de forme i - Google Patents

Procédé amélioré de fabrication de lamivudine de forme i Download PDF

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Publication number
WO2013168066A1
WO2013168066A1 PCT/IB2013/053537 IB2013053537W WO2013168066A1 WO 2013168066 A1 WO2013168066 A1 WO 2013168066A1 IB 2013053537 W IB2013053537 W IB 2013053537W WO 2013168066 A1 WO2013168066 A1 WO 2013168066A1
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WIPO (PCT)
Prior art keywords
lamivudine
process according
mixture
water
alcohol
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PCT/IB2013/053537
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English (en)
Inventor
Girij Pal Singh
Dhananjai Srivastava
Radhakrishna Bhikaji SHIVDAVKAR
Harishchandra Sambhaji Jadhav
Arjun Nishant VINCHURKAR
Umesh Parasharam AHER
Pramod Sudhakar UTEKAR
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Lupin Limited
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Publication of WO2013168066A1 publication Critical patent/WO2013168066A1/fr

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    • 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

Definitions

  • the present invention is directed to animproved process for the manufacture of Lamivudine Form I.
  • Lamivudine commonly known as "3TC” is potent nucleoside analogue reverse transcriptase inhibitors. It has been used for the treatment of chronic hepatitis B virus and Human Immunodeficiency Virus (HIV) infections.
  • 3TC is potent nucleoside analogue reverse transcriptase inhibitors. It has been used for the treatment of chronic hepatitis B virus and Human Immunodeficiency Virus (HIV) infections.
  • HIV Human Immunodeficiency Virus
  • Lamivudine is an analogue of cytidine, chemically known as (2R, cis)-4-amino- l-(2- hydroxymethyl- l,3-oxathiolan-5-yl)-(lH)-pyrimidine-2-one; or (2R, cis)-hydroxymethyl- 5 - (cy to syl ⁇ -y 1) - 1 , 3 - oxa thio lane (I )
  • EPIVIR® is a commercial pharmaceutical composition of Lamivudine and is marketed by GlaxoSmithKline. Lamivudine was first disclosed in U.S. Patent No. 5,047,407, the patent also discloses preparation of cis and trans isomers of 2,5-substituted 1,3- oxatholane derivatives .
  • WO 91 / 17159 describes the preparation of Lamivudine, its antiviral activity and its use in medicine. The application describes preparation of Lamivudineas a freeze dried powder.
  • WO 92/21676 describes the crystallization of Lamivudine from aqueous solution or by azeotropic distillation with propanol to obtain short rods or long thin needle-shaped orthorhombic crystals termed as a Form I.
  • Form I is a hydrate of Lamivudine consisting of one molecule of water per five molecules of Lamivudine.
  • Lamivudine in the form of needle-like crystals (Form I) has a melting point of less than about 130°C in particular about 124- 127°C in pure form.
  • Lamivudine Form I show a characteristic endotherm in its DSC profile with an onset temperature at 124- 127°C.
  • the TGA of Lamivudine Form I show a single step sharp weight loss of 2%.
  • WO 92/21676 provides preparation of Lamivudine form I by heating a suspension of 64.8 gm of Lamivudine in 200 ml of water at 45°C to obtain a solution and cooling the said solution at 30°C. As per the description therein the product crystallises as an unstirrable mass. Further breaking the lumps and stirring this mass at 10°C for 1 h, and filtering followed by washing with ethanol provides the product. The specification further provides drying of the product in vacuo at 45°C for 24 hour toobtain Lamivudine as Form I crystals.
  • Lamivudine is crystallized from aqueous solution, it is obtained in the form of needle-shaped crystals (hereinafter form I) which are less stable.
  • J. Pharm. Sci., (1996), 85 (2): 193- 199 disclose the process for the preparation of Lamivudine Form I by dissolving Lamivudine in hot water, adding an equal volume of methanol and cooling in a refrigerator.
  • Lamivudine Form I is crystallized as needles from solutions in water, methanol or aqueous alcohols . However it does not disclose the crystallization conditions and quantities.
  • WO 2007/ 119248 provides the process for the preparation of LamivudineForm I by suspending Lamivudine in a mixture of water and denatured spirit (DNS)and heating to 45°C to obtain a solution. Then cooling the solution to 30°C and seeding with Form I seed to obtain an unstirrable mass. Further cooling the saidmass to 10°C, filtering, washing with aqueous DNS and drying under vacuum at 45°C to obtain Lamivudine form I crystals. Theunstirrable mass obtained during crystallization and seeding makes the processes difficult to operate at large scale.
  • DNS denatured spirit
  • WO 2008/ 1 14279 discloses the process for preparation of LamivudineForm Iby dissolving Lamivudine in a binary mixture of organic solvent such as N,N-dimethyl acetamide and 1,4-dioxane, nitromethane and methanol, methanol and diethyl ether, or 1-butanol and methanol at 80°C. Allowingthe resulting solution for crystallization at ambient temperature overnight to obtain form I.
  • organic solvent such as N,N-dimethyl acetamide and 1,4-dioxane, nitromethane and methanol, methanol and diethyl ether, or 1-butanol and methanol
  • Lamivudine form I As provided in WO 2008/ 114279 are provided below:
  • WO 2009/069013 discloses the process for the preparation of LamivudineForm I by dissolving Lamivudine in water at 38-45°C. Cooling the resulting solution at about 30°C to obtain Lamivudine Form I solid which is then isolating by filtration.
  • precipitated Form I solid becomes unstirrable and causing problem in filtration because of specific volume of water used in crystallization and thus rendering crystallization process difficult to operate on large scale.
  • use of more quantity of water in crystallization and washing result in loss of yield.
  • WO 2009/037538 discloses the process for the preparation of Lamivudine Form I by dissolving Lamivudine in a mixture of ethanol and water at 45-55°C. Evaporating the solution under reduced pressure at42°C to obtain solid residue. Precipitating the said residue by adding ethyl acetate/methyl isobutyl ketone to obtain Lamivudine form I which is then isolating by filtration. Removal of ethanol under reduced pressure results hard and thick solid residue which adheres to the walls of the reactor and stirrer blades, thus creating difficulties in agitation. Slow and interrupted agitation lead to the formation of lumps, with high solvent entrapment, such product requires longer drying time which increases the overhead expenditure. Therefore the process is not economically attractive.
  • WO 2010/023676 provides the process for the preparation of Lamivudine Form I by dissolving Lamivudine in alcohol under reflux for about 45 minutes. Cooling the resulting solution at 0°Cto precipitate Lamivudine form I which is thenisolating by filtration, and drying at 70°C. The resulting solid product is again dissolving in alcohol and water at 45°C to obtain solution which is then cooling at 25-35°C to precipitate solid product. Filtering and drying the solid product at 50° C to obtain the Lamivudine form I. However by repeating the number of crystallization steps and drying the material twice at higher temperature increase the utility and higher occupancy in the unit operation rendering the process not economically viable. Moreover precipitated Form I solid becomes unstirrable in water and alcohol and causing the problem in filtration.
  • WO 201 1 / 100381 discloses the process for the preparation of LamivudineForm I by treating Lamivudine or its acid salt in a solvent system comprising water and organic solvent selected from C3-8 alkanones and Ci-e alkyl acetates at a temperature of about 0 to 50°C.
  • the process involves seeding and yield disclosed is only 10%.
  • the main aspect of the present invention is provision of animprovedprocess for the manufacture of Lamivudine Form I using water, C1-4 alcohol and C3-8 ketone.
  • LamivudineForm I comprising:
  • Lamivudine Form I a) adding solution of Lamivudine in a mixture of water and Ci- 4 alcoholinto C3-8 ketone; and b) isolatingLamivudine Form I from the mixture obtained after step a) .
  • the improved process for the manufacture of Lamivudine Form I comprising:
  • step iv) dissolving the mixture obtained after step iii) in C1- alcohol, optionally filteringthe solution or optionally treating with charcoal;
  • the present invention provides animprovedprocess for the manufacture of Lamivudine Form I by dissolving Lamivudine in a mixture of water and alcohol at 45°C to 70°C to obtain a solution of Lamivudine and precipitating the Lamivudine Form I by the adding the said solution of Lamivudine intoC3 eketone at below 15°C.
  • Lamivudine Form I Although a number of processes for the preparation of Lamivudine Form I are reported in the literature, all are suffering from one or another drawback.
  • Lamivudine Form I of present invention does not involve any vacuum distillation resulting the formation of residue which adheres to the walls of the reactor and stirrer blades and thus creating difficulties in agitation.
  • Slow and interrupted agitation lead to the formation of lumps, which yield coarse product with high solvent entrapment and thus require longer drying time which increases the steam cost and batch cycle time. Therefore because of higher occupancy in the unit operation of drying rendering the process less economicallyviable and practicable on commercial scale.
  • the process of present invention does not involves a single solvent like water or binary mixture like water and alcohol but a ternary mixture of solvent like water, denatured spirit (DNS) and acetone wherein the precipitated Lamivudine Form I is stirrable and filtered easily.
  • DNS denatured spirit
  • Lamivudine Form I of present invention does not involves any type of seeding to precipitate Lamivudine Form I.
  • the one aspect the improved process for the manufacture of Lamivudine Form I comprising:
  • step iv) dissolving the mixture obtained after step iii) in C 1- alcohol, optionally filtering the solution or optionally treating with charcoal;
  • Lamivudine Form II the starting Lamivudine used in the process are selected from Lamivudine Form II, mixture of Lamivudine Form I and Form II, any other Form of Lamivudine, Lamivudine hydrate or mixture thereof.
  • water and C1- alcohol is used in the proportion of 1: 1 to 1: 5 volume/volume.
  • lamivudine and water is used in the proportion of 1: 0.5 to 1: 2 weight /volume.
  • Lamivudine and acetone is used in the proportion of 1: 5 to 1: 15 weight /volume.
  • Lamivudine is dissolved in a mixture of water and C 1- alcohol at 45-70°C .
  • the temperature of C3-8 ketone is in between -5°C to 15°C.
  • Lamivudine BINOL complex is dissolved in a mixture of water and ethylacetate at 40-50°C .
  • lamivudine slurry obtained after concentrating the aqueous layer is dissolved in C1- alcohol at 45-70°C.
  • organic solvent is selected from ethylacetate, dichloromethane, toluene, and chloroform.
  • Lamivudine Form I is isolated by filtration, washed with C3-8 alkanone of 0 to 5°C and dried under vacuum at 25 to 45°C for 6 to 8 hr.
  • C1-4 alcohol is selected from methanol, ethanol, 2-propanol, tertiary butanol, n-butanol or mixture thereof; preferably selected from ethanol.
  • C3-8 ketone is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof; preferably selected from acetone.
  • Lamivudine Form I is carried out at room temperature, preferably at 30 to 40°C, until moisture content is less than 2%.
  • one of the aspect of the present invention provides an improved process for the manufacture of Lamivudine Form I comprising: dissolving Lamivudine in water and ethanol at 45 to 70°C; filtering the clear solution so obtained at 45 to 70°C;adding the said lamivudine solution into acetone at -5°C to 15°C;stirring the precipitated solid at -5°C to 15°C for 45 to 60 min; filtering the solidof lamivudine Form I; washing with acetoneof -5°C to 15°C anddrying under vacuum at 30 to 40°C for 6 to 8 hr to obtain stable Lamivudine Form I.
  • More specifically another aspect of the present invention provides an improved process for the manufacture of lamivudine Form I comprising: dissolving lamivudine. BINOL complex in a mixture of ethylacetate and water at 40-50°C; cooling the solution to room temperature and separating the aqueous layer; washing the resulting aqueous layer with ethylacetate; filtering the aqueous layer so obtained; concentrating the aqueous layer under vacuum at 50-55°C as a stirrable slurry; dissolving the resulting slurry of lamivudine in Ci- alcohol at 45-70°C and filtering the clear solution to obtain the lamivudine solution; adding the said lamivudine solution into acetone at -5°C to 15°C; stirring the precipitated solid at -5°C to 15°C for 45 to 60 min; filtering the solid of lamivudine Form I; washing with acetone of -5°C to 15°C and drying under
  • the yield of Lamivudine Form I obtained by following the process of present invention is more than 85%, more preferably 90%.
  • Lamivudine Form I is stable for 3 months at 40°C ⁇ 2°C / Rh 75% ⁇ 5% and at 25°C ⁇ 2°C / Rh 60% ⁇ 5%.
  • the chiral purityof Lamivudine Form I is 99.6%, more preferably 99.8%.
  • Lamivudine BINOL complex (125 gm) was dissolved in ethylacetate (625 ml) and water
  • Aqueous layer was washed with ethylacetate (625 ml) and filtered through 0.45 micron filter paper.
  • the aqueous layer was concentrated under vacuum at 55°C as stirrable slurry.
  • the resulting slurry was dissolved by adding DNS (110 ml) at 65°C, filtered through 0.45 micron filter paper and maintained at the same temperature.
  • the precipitated solid was stirred at 0 to 5°C for 60 min.
  • the solid product was filtered and washed with acetone:water:DNS (10:0.6:2) (40 ml) of 0-5°C.
  • the product was suck dried and dried under vacuum at 45°C till the water content is not more than 2% to obtain 44 gm of Lamivudine Form I. Moisture content: 1.68%.
  • Powder X-ray diffractogram (Fig. 1) 2 ⁇ : 5.06, 6.69, 8.80, 9.85, 10.18, 10.46, 10.77, 1 1.38, 11.64, 12.37, 12.63, 12.96, 13.23, 14.60, 15.20, 15.83, 16.03, 16.50, 16.85, 17.77, 18. 15, 18.76, 19.28, 19.56, 19.70, 20.44, 20.73, 21.22, 21.62, 21.83, 22. 13, 22.37, 22.88, 23.38, 23.71 , 24.
  • IR spectra (KBr) (cm- 1 ): 3550, 3369, 3236, 3076, 2927, 2884, 2094, 1643, 1613, 1570, 1492, 1480, 1432, 1403, 1356, 1336, 1310, 1289, 1252, 1229, 1198, 1 166, 1146, 1 139, 1 108, 1064, 1053, 966, 932, 913, 872, 839, 818, 786, 747, 722, 696, 669, 604, 538, 496, 472, 443, 419 and 41 1.
  • DSC Differential scanning calorimetric
  • Thermogravemetric analysis exhibits one-step weight loss of 2.234%.
  • Lamivudine (10 gm) was dissolved in water (6 ml) andDNS (20 ml)at 55-60°C to get clear solution. The resulting solution was filtered hot at 55 to 60°C and maintained at the same temperature. Simultaneously acetone (100 ml) was charged into another reactor and stirred at 0 to 5°C. The hot solution of Lamivudine was added to acetone at 0 to 5°C in 3 to 10 min. The precipitated solid was stirred at 0 to 5°C for 45 min. The solid product was filtered and washed with acetone (10 ml) of 5- 10° C. The product was suck dried and dried under vacuum at 25-30°C till the water content is not more than 2% to obtain 8.33gm (yield: 83%) of Lamivudine Form I. PXRD of the product matches with figure 1.
  • Lamivudine (10 gm) was dissolved in water (10 ml) and DNS (10 ml) at 50-60°C to get a clear solution. The resulting solution was filtered hot at 50 to 60°C and maintained at the same temperature. Simultaneously acetone (100 ml) was charged into another reactor stirred at 0 to 5°C. The hot solution of Lamivudine was added to acetone at 0 to 5°C in 5 to 10 min. The precipitated solid was stirred at 0 to 5°C for 45-60 min. The solid product was filtered and washed with acetone (10 ml) of 0 to 5°C. The product was suck dried and dried under vacuum at 40-45°C till the water content is not more than 2% to obtain 7.5 gm (yield: 75%) of Lamivudine Form I. PXRD of the product matches with figure 1.

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

Abstract

La présente invention concerne un procédé amélioré de fabrication de lamivudine de forme I consistant à ajouter une solution de lamivudine dans un mélange d'alcool aqueux en C1-C4 et de cétone en C3-C8.
PCT/IB2013/053537 2012-05-05 2013-05-03 Procédé amélioré de fabrication de lamivudine de forme i WO2013168066A1 (fr)

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IN499/KOL/2012 2012-05-05

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047407A (en) 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
WO1991017159A1 (fr) 1990-05-02 1991-11-14 Iaf Biochem International Inc. Analogues de nucleosides de 1,3-oxathiolane
WO1992021676A1 (fr) 1991-06-03 1992-12-10 Glaxo Group Limited Derives d'oxathiolane cristallins
WO2007119248A1 (fr) 2006-04-18 2007-10-25 Lupin Limited Nouvelle forme cristalline de la lamivudine
WO2008114279A2 (fr) 2007-03-19 2008-09-25 Matrix Laboratories Ltd Nouvelles formes polymorphiques de la lamivudine
WO2009037538A2 (fr) 2007-09-17 2009-03-26 Aurobindo Pharma Ltd Procédé de préparation de lamivudine de forme i
WO2009069013A1 (fr) 2007-11-29 2009-06-04 Ranbaxy Laboratories Limited Forme cristalline i de lamivudine et sa préparation
WO2010023676A2 (fr) 2008-09-01 2010-03-04 Hetero Research Foundation Procédé de préparation d'une forme polymorphe de lamivudine
WO2011100381A1 (fr) 2010-02-12 2011-08-18 Merck Sharp & Dohme Corp. Préparation de la forme i de la lamivudine

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047407A (en) 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
WO1991017159A1 (fr) 1990-05-02 1991-11-14 Iaf Biochem International Inc. Analogues de nucleosides de 1,3-oxathiolane
WO1992021676A1 (fr) 1991-06-03 1992-12-10 Glaxo Group Limited Derives d'oxathiolane cristallins
WO2007119248A1 (fr) 2006-04-18 2007-10-25 Lupin Limited Nouvelle forme cristalline de la lamivudine
WO2008114279A2 (fr) 2007-03-19 2008-09-25 Matrix Laboratories Ltd Nouvelles formes polymorphiques de la lamivudine
WO2009037538A2 (fr) 2007-09-17 2009-03-26 Aurobindo Pharma Ltd Procédé de préparation de lamivudine de forme i
WO2009069013A1 (fr) 2007-11-29 2009-06-04 Ranbaxy Laboratories Limited Forme cristalline i de lamivudine et sa préparation
WO2010023676A2 (fr) 2008-09-01 2010-03-04 Hetero Research Foundation Procédé de préparation d'une forme polymorphe de lamivudine
WO2011100381A1 (fr) 2010-02-12 2011-08-18 Merck Sharp & Dohme Corp. Préparation de la forme i de la lamivudine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J. CHEM SOC., PERKIN TRANS., vol. 2, 1997, pages 2653 - 2659
J. PHARM. SCI., vol. 85, no. 2, 1996, pages 193 - 199
MICHAEL J JOZWIAKOWSKI ET AL: "Solubility behavior of lamivudine crystal forms in recrystallization solvents", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 85, no. 2, 1996, pages 193 - 199, XP002210585, ISSN: 0022-3549, DOI: 10.1021/JS9501728 *

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