WO2013168066A1 - An improved process for the manufacture of lamivudine form i. - Google Patents
An improved process for the manufacture of lamivudine form i. Download PDFInfo
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- 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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- 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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Abstract
The invention provides an improved process for the manufacture of Lamivudine Form I by adding a solution of Lamivudine in a mixture of water C1-4 alcohol into C3-8 ketone.
Description
AN IMPROVED PROCESS FOR THE MANUFACTURE OF LAMIVUDINE FORM I.
Field of the Invention
The present invention is directed to animproved process for the manufacture of Lamivudine Form I.
Cr oss-Reference to a related application
The present application claims the benefit of Indian Provisional Patent Application number 499/KOL/2012, filed on 5th May 2012, the disclosure of which is incorporated herein by reference in its entirety.
Background of the invention
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.
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 Γ -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. The process described is tedious and time-consuming and involves formation of an unstirrable mass that needs manual breaking up followed by multiple washings .According to WO 92/21676 when 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.
J. Chem Soc, Perkin trans., (1997), 2: 2653-2659 discloses that 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.
J. Pharm. Set, (1996), 85 (2): 193- 199 and J. Chem. Soc, Perkin trans., (1997), 2: 2653- 2659 provide characterization methods of Form I by XRPD, DSC, Scanning Electron Micrographs and single crystal analysis.
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.
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.
Few other ways of preparation of Lamivudine form I as provided in WO 2008/ 114279 are provided below:
(1) dissolving Lamivudine in dimethyl formamide or 2-methoxy ethanol at 80°C and evaporatingthe resulting solution on watch glass; (2) suspending amorphous Lamivudine in a single solvent such as methanol, acetone, n-heptane or isopropyl ether and stirring the mixture overnight at RT; and (3) keeping amorphous Lamivudine in humidifier (RH> 90%) for several day or by heating amorphous Lamivudine at about 40°C for several days.
All these differentprocesses disclosed in WO 2008/ 114279 applicationare not attractive at larger scales as the process involves prolonged stirring, evaporation on watch glass, or keeping the material for several days under humid conditions.
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. However 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. On the other hand 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%.
All reported Lamivudine Form I processes suffer from one or another drawbacks and are difficult to operate at large scale due to the reasons stated above and thus rendering them unsuitable for commercial scale.
Thus, there is a need to find improved process for the manufacture of Lamivudine Form I. In the present invention there is provided animproved process for the manufacture of Lamivudine Form I on commercial scale which overcome all the present limitations.
Summary of the Invention
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.
In one aspect of the present invention the improved process for the manufacture of LamivudineForm I comprising:
a) adding solution of Lamivudine in a mixture of water and Ci-4alcoholinto C3-8 ketone; and b) isolatingLamivudine Form I from the mixture obtained after step a) .
In another aspect of the present invention the improved process for the manufacture of Lamivudine Form I comprising:
i) dissolving Lamivudine.BINOL complexin a mixture of organic solventand water; ii) separating the aqueous layers, optionally washing with organic solvent, and optionally filtering the aqueous layer;
iii) concentrating the aqueous layerobtained after the step ii) as a stirrable slurry of lamivudine;
iv) dissolving the mixture obtained after step iii) in C1- alcohol, optionally filteringthe solution or optionally treating with charcoal;
v) adding the solution into C3-8 ketone; and
vi) isolatingLamivudine Form I from the mixture obtained after step v) .
Detailed Description of the Invention
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.
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.
Unlike other processes reported in the literature, the process for the preparation of Lamivudine Form I of present invention does not involves 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. The processes reported in the literature involves a single solvent or binary mixture wherein the Lamivudine Form I solid becomes unstirrable and causing the problem in filtration.
Moreover unlike other processes, the process for the preparation of 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:
a) adding solution of Lamivudine in a mixture of water and C 1- alcohol into C3-8 ketone; and
b) isolatingLamivudine form I from the mixture obtained after step a) .
In another aspect of the present invention the improved process for the manufacture of Lamivudine Form I comprising:
i) dissolving Lamivudine. BINOL complex in a mixture of organic solvent and water; ii) separating the aqueous layers, optionally washing with organic solvent, and optionally filtering the aqueous layer;
iii) concentrating the aqueous layer obtained after the step ii) as a stirrable slurry of lamivudine;
iv) dissolving the mixture obtained after step iii) in C 1- alcohol, optionally filtering the solution or optionally treating with charcoal;
v) adding the solution into C3-8 ketone; and
vi) isolatingLamivudine Form I from the mixture obtained after step v) .
According the present invention 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.
In one embodiment of the present invention water and C1- alcohol is used in the proportion of 1: 1 to 1: 5 volume/volume.
In another embodiment of the present invention lamivudine and water is used in the proportion of 1: 0.5 to 1: 2 weight /volume.
In another embodiment of the present invention Lamivudine and acetone is used in the proportion of 1: 5 to 1: 15 weight /volume.
Yet in another embodiment of the present invention Lamivudine is dissolved in a mixture of water and C 1- alcohol at 45-70°C .
Still in another embodiment of the present invention the temperature of C3-8 ketone is in between -5°C to 15°C.
In further embodiment Lamivudine. BINOL complex is dissolved in a mixture of water and ethylacetate at 40-50°C .
In one more embodiment lamivudine slurry obtained after concentrating the aqueous layer is dissolved in C1- alcohol at 45-70°C.
In another embodiment organic solvent is selected from ethylacetate, dichloromethane, toluene, and chloroform.
According to the process of present invention 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.
According to the process of present invention C1-4 alcohol is selected from methanol, ethanol, 2-propanol, tertiary butanol, n-butanol or mixture thereof; preferably selected from ethanol.
According to the process of present invention C3-8 ketone is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof; preferably selected from acetone.
According to process of present invention the drying of Lamivudine Form I is carried out at room temperature, preferably at 30 to 40°C, until moisture content is less than 2%.
More specifically 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 vacuum at 30 to 40°C for 6 to 8 hr to obtain stable Lamivudine Form I.
The yield of Lamivudine Form I obtained by following the process of present invention is more than 85%, more preferably 90%.
According to the process of present invention the 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%.
According to the present invention the chiral purityof Lamivudine Form I is 99.6%, more preferably 99.8%.
The following examples are provided to further illustrate the present invention and therefore should not be construed in any way to limit the scope of the present invention. Example 1 : Preparation of Lamivudine Form I
Lamivudine. BINOL complex (125 gm) was dissolved in ethylacetate (625 ml) and water
(625 ml) at 40-45°C. The resulting solution was cooled to RT and layers were separated.
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.
Simultaneously acetone (550 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 5 to 10 min.
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%.
Analysis: Purity by HPLC: 99.92%. [a]D at 20°C = -97.6° (c=0.5).
Ή NMR (400 MHz, MeOD) δ (ppm): 8.06-8.08 (d, 1H), 6.28-6.31 (t, 1H), 5.88-5.90 (d, 1H), 5.27-5.29 (t, 1H), 3.85-3.97 (m, 2H), 3.49-3.54 (m, 1H), 3.1 1-3.16 (m, 1H).
Powder X-ray diffractogram (PXRD) (Fig. 1) 2Θ: 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. 13, 24.63, 25.43, 26.07, 26.31, 26.67, 27.33,27.69, 28.52, 29.37, 30.24, 31.29, 31.88, 32.41, 32.91 , 33.43, 34.06, 34.91, 35.27, 35.98, 36.64, and 38.30 ± 0.2°.
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.
Differential scanning calorimetric (DSC) analysis at the rate of heating 10°C/min shows first peak of endotherm at 129.89°C and second at 176.91°C.
Thermogravemetric analysis exhibits one-step weight loss of 2.234%.
Example 2: Preparation of Lamivudine Form I
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.
Example 3: Preparation of Lamivudine Form I
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.
Claims
1. A process for the preparation of Lamivudine Form I, comprising:
a) adding solution of Lamivudine in a mixture of water and C1- alcoholinto C3-8 ketone; and
b) isolatingLamivudine Form I from the mixture obtained after step a).
2. The process according to claim 1 , wherein lamivudine solution in a mixture of water and C1-4 alcohol is prepared by the step comprising:
i) dissolving Lamivudine. BINOL complex in a mixture of organic solvent and water;
ii) separating the aqueous layers, optionally washing with organic solvent, and optionally filtering the aqueous layer;
iii) concentrating the aqueous layer obtained after the step ii) as a stirrable slurry of lamivudine; and
iv) dissolving the mixture obtained after step iii) in C1- alcoholand optionally filtering the solution so obtained.
3. The process as claimed in claim 1 , wherein the solution of Lamivudine in a mixture of water and C1-4 alcohol is optionally pre-charcolized before addition to C3-8 ketone.
4. The process as claimed in claim 2, wherein the lamivudine solution obtained after step iv) is further treated with charcoal.
5. The process according to any one of the claims 1-4, wherein water and C1-4 alcohol is used in the proportion of 1: 1 to 1 :5 volume /volume.
6. The process according to any one of the claims 1-5, wherein Lamivudine or slurry of lamivudine is dissolved in a mixture of water and C1-4 alcohol at 45-70°C.
7. The process according to any one of the claims 1-6, wherein Lamivudine. BINOL complex is dissolved in a mixture of water and organic solvent at 40-50°C .
8. The process according to any one of the claims 1-7, wherein Lamivudine. BINOL complex is dissolved in a mixture of water and organic solvent selected from ethylacetate, dichloromethane, toluene, and chloroform.
9. The process according to claim 8, wherein organic solvent is selected from ethylacetate.
10. The process according to any one of the claims 1-9, wherein temperature of C3- eketoneis below 15°C.
11. The process according to any one of the claims 1- 10, wherein precipitated Lamivudine Form I is stirred at -5°C to 15°C for about 1 to 3 hr.
12. The process according to any one of the claims 1- 11 , wherein Lamivudine Form I is isolated by filtration.
13. The process according to claiml2, wherein Lamivudine Form I is further washed with Cs-sketone of -5°C to 15°C.
14. The process according to claiml2, wherein Lamivudine Form I is further dried under vacuum at 30 to 40°C for 6 to 8 hr.
15. The process according to any one of the claims 1- 14, wherein the Lamivudine Form I is free from any other Form.
16. The process according to any one of theclaims l- 15, wherein the C1- alcohol is selected from methanol, ethanol, 2-propanol, tertiary butanol, n-butanol or mixture thereof.
17. The process according to claim 16, wherein alcohol is ethanol.
18. The process according to any one of the claims 1- 17, wherein the C3-eketoneis selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof.
19. The process according to claiml8, wherein Cs sketone is acetone.
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