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WO2008114279A2 - Nouvelles formes polymorphiques de la lamivudine - Google Patents

Nouvelles formes polymorphiques de la lamivudine Download PDF

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Publication number
WO2008114279A2
WO2008114279A2 PCT/IN2008/000155 IN2008000155W WO2008114279A2 WO 2008114279 A2 WO2008114279 A2 WO 2008114279A2 IN 2008000155 W IN2008000155 W IN 2008000155W WO 2008114279 A2 WO2008114279 A2 WO 2008114279A2
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Prior art keywords
lamivudine
crystalline
preparation
depicted
solvent
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Ceased
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PCT/IN2008/000155
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English (en)
Inventor
Ramakoteswara Rao Jetti
Asha Rani Gorantla
Dutt Tyagi Om
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Mylan Laboratories Ltd
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Matrix Laboratories Ltd
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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 invention in general relates to novel polymorphic forms of Lamivudine. More particularly, the present invention is directed to novel amorphous form and novel crystalline forms III, IV and V of Lamivudine and the processes for preparing the same. Further, the present invention is also directed to novel processes for the preparation of crystalline Lamivudine Form I and Form II.
  • Lamivudine (2R, cis)-4-amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)- pyrimidine-2-one, is an antiviral drug particularly used against the human immunodeficiency viruses (HIVs), the causative agents of AIDS.
  • HMVs human immunodeficiency viruses
  • US 5,047,407 disclose the process for producing the cis racemic Lamivudine.
  • WO 03/027106Al discloses a new process for making form II starting from its salicylate salt or from its hydrates, for e.g. salicylate monohydrate.
  • Lamivudine can exist, in addition to the above mentioned crystalline forms, also in novel crystalline forms stable at room temperature, herein referred to as crystalline Form III, Form IV and Form V along with amorphous form. Therefore, the invention relates to said crystalline forms and amorphous form, process for preparing the same and novel processes for the preparation of prior art Lamivudine Form I and Form II.
  • Lamivudine referred to herein after as crystalline Form III, IV as a solvates
  • Form V as anhydrous along with amorphous form characterized by X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), moisture content and/or melting point.
  • the present invention is also directed to the novel process for the preparation of amorphous and crystalline Form III, IV and V of Lamivudine by using different solvent system and conditions.
  • a crystalline Lamivudine Form III as a N,N-dimethylacetamide solvate with a dimethylacetamide content of 12-18% w/w supported by thermo gravimetric analysis (TGA) and moisture content of 1-3 % supported by KF method.
  • TGA thermo gravimetric analysis
  • the solvate is hemi-dimethylacetamide solvate.
  • a crystalline Lamivudine Form IV is l-methyl-2-pyrrolidinone solvate with l-methyl-2- pyrrolidinone content of 28-30%, which is analyzed by TGA as shown in Figure 6 and moisture content of 4-6 % w/w supported by KF method.
  • the solvate is mono-l-methyI-2- pyrrolidinone solvate.
  • Further embodiment of the present invention is to provide a crystalline Lamivudine Form V as anhydrous form and moisture content of 0.3 to 1.0 % by KF method.
  • Another embodiment provides a novel processes for the preparation of crystalline Lamivudine Form I and Form II.
  • Fig 1 is the X-ray powder diffraction pattern of Lamivudine Form III.
  • Fig 2 is the Differential scanning calorimetric (DSC) curve of Lamivudine Form HI.
  • Fig 3 is the Thermo gravimetric analysis of the Form III.
  • Fig 4 is the X-ray powder diffraction pattern of Lamivudine Form IV.
  • Fig 5 is the Differential scanning calorimetric curve of Lamivudine Form IV.
  • Fig 6 is the Thermo gravimetric of Lamivudine Form IV.
  • Fig 7 is the X-ray powder diffraction pattern of Lamivudine Form V.
  • Fig 8 is the Differential scanning calorimetric (DSC) curve of Lamivudine Form V.
  • Fig 9 is the Thermo gravimetric of Lamivudine Form V.
  • Fig 10 is the X-ray powder diffraction pattern of amorphous Lamivudine.
  • Fig 11 is the Differential scanning calorimetric curve of amorphous Lamivudine
  • the present invention describes the amorphous form and crystalline Lamivudine Form III, Form IV which may exists in solvate forms along with the anhydrate Form V and are intended to be encompassed with in the scope of the present invention.
  • the said forms differ from each other in their physical properties, spectral data and method of preparation and characterized by their X- ray powder diffraction patterns, differential scanning calorimetry and thermo gravimetric analysis. Powder X-ray Diffraction (PXRD)
  • the PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu- anode X-ray tube is operated at 4OkV and 3OmA.
  • the experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • the DSC measurements were carried out using the instrument TA QlOOO of TA instruments.
  • the experiments were performed at a heating rate of 10.0 °C/minute over a temperature range of 30°C-300 °C purging with nitrogen at a flow rate of 50ml/minute.
  • TGA is carried out using instrument TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/minute over a temperature range of 30 °C-250 °C purging with nitrogen at a flow rate of 25ml/minute.
  • Water content was determined on Metrohm Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.
  • the crystalline Lamivudine Form IH is characterized by powder diffraction pattern as shown in Figure 1 with peaks at 3.89, 11.46, 12.25, 13.22, 13.49, 15.26, 15.50, 15.89, 17.25, 17.78, 18.10, 18.49, 19.09, 20.69, 21.01, 24.46, 24.87, 25.27, 27.04, 27.46, 27.86, 28.31, 29.23, 30.03, 30.74, 31.20, 31.83, 33.06, 35.06, 37.11, 38.21 and 40.93 ⁇ 0.2 ⁇ values.
  • Crystalline Lamivudine Form III is further characterized by the DSC as shown in Figure 2 with two melting endothermic peaks, first at about 130.6 0 C attributed to desolvation and later at 176.9 0 C corresponding to the melting of the product.
  • Crystalline Lamivudine Form IH is N 5 N dimethyl acetamide solvate with a dimethyl acetamide content of 12-18% w/w, which is analysed by thermogravimetric analysis as shown in Figure 3 and moisture content of 1-3 % supported by Karl Fisher method.
  • the solvate is hemi- dimethyl acetamide solvate.
  • the present invention also provides the process for the preparation of crystalline Lamivudine Form III, which comprises the steps of preparing a solution of Lamivudine in a solvent like N,N- dimethylacetamide and heating the solution at about 70-90 0 C preferably at 8O 0 C.
  • the resultant solution is either kept at overnight for slow evaporation at room temperature or precipitated by the addition of an anti-solvent like acetone and recovering the isolated Lamivudine Form III.
  • the crystalline product is isolated by filtration followed by drying.
  • Lamivudine used herein selected from group consisting of but not limited to anhydrous or hydrated form.
  • the crystalline Lamivudine Form IV is characterized by powder diffraction pattern as shown in Figure 4 with peaks at 11.59, 13.80, 14.70, 15.44, 17.04, 17.99, 18.34, 19.24, 20.09, 21.34, 22.89, 23.34, 25.33, 25.85, 26.50, 27.87, 29.00, 30.03, 30.79, 31.41, 33.20, 33.80, 35.07, 35.50, 36.87, 38.80, 40.32, 41.67, 42.56, 44.51, 46.89 and 47.93 ⁇ 0.2 ⁇ values.
  • Crystalline Lamivudine Form IV is further characterized by the DSC as shown in Figure 5 which shows two melting endothermic peaks, first at an extrapolated onset temperature ranging from 30 to 85 °C corresponding to loss due to the moisture, which is identified with a peak at 62°C (maxima), and a second broad endothermic peak at 137.9 °C (maxima), corresponding to desolvation followed by complete melting of the product.
  • Crystalline Lamivudine Form IV is l-methyl-2-pyrrolidinone solvate with l-methyl-2- pyrrolidinone content of 28-30%, which is analyzed by TGA as shown in Figure 6 and moisture content of 4-6 % w/w supported by KF method.
  • the solvate is mono-l-methyl-2- pyrrolidinone solvate.
  • the present invention also provides a process for the preparation of crystalline Lamivudine polymorphic Form IV, which comprises the dissolving Lamivudine in l-methyl-2-pyrrolidinone at about 70-90 0 C preferably 8O 0 C, and followed by either agitation for 12 hrs at ambient temperature or kept at slow or fast evaporation for several days preferably 1-2 days, more preferably 1 day.
  • the crystalline product Form IV is isolated by filtration followed by drying, e.g. at room temperature and atmospheric pressure or under vacuum at about 60-80 °C.
  • Lamivudine used herein selected from group consisting of but not limited to anhydrous or hydrated form.
  • the anhydrous Lamivudine Form V is characterized by powder diffraction pattern as shown in Figure 7 with peaks at 12.91, 14.08, 15.69, 17.25, 17.70, 18.13, 19.38, 19.94, 20.47, 21.27, 23.37, 26.95, 27.59, 30.39, 31.24, 33.57 and 37.22 ⁇ 0.2 ⁇ values.
  • Anhydrous Lamivudine Form V is further characterized by DSC with an endothermic peak at 161.2 0 C corresponding to melting of the product as shown in Figure 8.
  • TGA of Lamivudine Form V shows no significant weight loss ( ⁇ 1%) as shown in Figure 9 further confirms it as anhydrate form.
  • the water content determined by the Karl-Fisher method is 0.3 to 1.0 %.
  • the present invention provides a novel process for preparing anhydrous Lamivudine Form V by contacting Lamivudine in a suitable solvent selected from the group consisting of aprotic polar solvents, lower aliphatic ketones, ethers, carbonates or mixtures thereof such as l-methyl-2-pyrrolidinone, acetone, tetrahydrofuran and dimethyl carbonate, using the methods such as slurry or anti-solvent method, followed by filtration and drying e.g., under vacuum at 80-85 °C.
  • a suitable solvent selected from the group consisting of aprotic polar solvents, lower aliphatic ketones, ethers, carbonates or mixtures thereof such as l-methyl-2-pyrrolidinone, acetone, tetrahydrofuran and dimethyl carbonate, using the methods such as slurry or anti-solvent method, followed by filtration and drying e.g., under vacuum at 80-85 °C.
  • An amorphous form of Lamivudine is characterized by powder diffraction pattern shown in Figure 10.
  • Amorphous form is further characterized by the DSC as shown in Figure 11 which shows a glass transition onset (T g ) at about 56°C followed by a exothermic peak at an extrapolated onset temperature ranging from 125 to 140 0 C, corresponding to the transition from amorphous phase to an crystalline phase which is identified with a peak at 129°C, and a second endothermic peak at 16O 0 C (maxima), corresponding to the complete melting of the product.
  • the present invention provides a process for preparation of amorphous Lamivudine by forming a melt by heating the crystalline Form V followed by cooling the melt to form amorphous Lamivudine.
  • the present invention provides a process for preparing Form I of Lamivudine comprising the steps of suspending Lamivudine in a solvent selected from the group consisting of aprotic polar solvents, chlorinated solvents, ether, esters, lower aliphatic ketones, amides, carbonates, nitroalkane, hydrocarbons or mixtures thereof and the obtained solid is filtered and dried under vacuum to get the crystalline Lamivudine Form I.
  • a solvent selected from the group consisting of aprotic polar solvents, chlorinated solvents, ether, esters, lower aliphatic ketones, amides, carbonates, nitroalkane, hydrocarbons or mixtures thereof.
  • the solvents used are preferably, N,N-dimethylacetamide, methanol, nitromethane, acetone, 1,4-dioxane, chloroform, methanol, butanol, heptane, isopropyl ether and diethyl ether respectively.
  • Lamivudine used herein selected from group consisting of but not limited to anhydrous, hydrated form or amorphous form.
  • Lamivudine polymorphic Form I is obtained by dissolving in dimethyl formamide, 2-methoxy ethanol and subsequently the solution was subjected to slow or fast evaporation.
  • the present invention provides a process for preparing crystalline Lamivudine Form I comprising the steps of storing Lamivudine amorphous form at RH >90% for several days.
  • the present invention provides a process for preparing crystalline Lamivudine Form I comprising the steps of heating Lamivudine amorphous form at about 40°C for several days.
  • the present invention provides a process for preparing Form II of Lamivudine by refluxing Lamivudine in either N,N-dimethylacetamide or l-methyl-2-pyrrolidinone and adding the suitable solvent selected from the group consisting of aprotic polar solvents, chlorinated solvents, ethers, esters, lower aliphatic ketones, amides, carbonates or mixtures thereof such as acetone, dimethyl carbonate, methylene chloride as an anti-solvent to the above reaction mixture, and subsequently cooling the solution, and recovering the crystalline Lamivudine Form II.
  • aprotic polar solvents selected from the group consisting of aprotic polar solvents, chlorinated solvents, ethers, esters, lower aliphatic ketones, amides, carbonates or mixtures thereof such as acetone, dimethyl carbonate, methylene chloride as an anti-solvent
  • Lamivudine polymorphic Form II by converting Lamivudine Form III or Form IV wherein the said Form III or Form IV is dried to obtain the Lamivudine Form H.
  • Example 1 Preparation of Lamivudine Form III A sample of Lamivudine (3g) was taken in N,N-dimethylacetamide (6ml) and heated to 80°C to obtain a clear solution. The resulting solution was kept overnight for slow evaporation at room temperature. The precipitate obtained was filtered and dried at ambient temperature. XRD of the sample showed it to be Form III
  • Lamivudine 3g was dissolved in 6ml of N,N-dimethyl acetamide and heated to 80°C and the solution was cooled and agitated for 12 hours at room temperature. The precipitate obtained was filtered and dried at ambient temperature. XRD of the sample showed it to be Form III
  • Lamivudine 3g was dissolved in 6ml of N,N-dimethyl acetamide at 80 °C and the solution was cooled followed by addition of 20ml of acetone as an anti-solvent. The precipitate obtained was filtered and dried at ambient temperature. XRD of the sample showed it to be Form IH
  • Lamivudine was dissolved in 2ml of N,N-dimethyl acetamide at 8O 0 C followed by addition of 25ml of acetone and cooling the solution to 0 0 C.
  • the precipitate obtained was filtered and dried at ambient temperature. XRD of the sample showed it to be Form III
  • Lamivudine Form IH obtained as described above was kept in a static dryer and heated at 80-85 0 C under vacuum. The resulting solid was identified as Lamivudine Form II. XRD of the sample showed it to be Form II.
  • Lamivudine Form IV 2g of Lamivudine was dissolved in 4ml of 1 -methyl-2-pyrrolidinone at 80°C, the solution was cooled and the resulting saturated solution was agitated for 12 hours at room temperature. The precipitate obtained was filtered and dried under vacuum at 80-85°C. The resulting solid was identified as Lamivudine Form IV.
  • Example 8 Preparation of Lamivudine Form II from Lamivudine Form IV by heating.
  • Lamivudine Form IV obtained as described above (examples 6 & 7) was kept in a static dryer and heated at 80-85°C under vacuum. The resulting solid was identified as Lamivudine Form II.
  • Lamivudine 3g of Lamivudine dissolved in 6ml of 1 -methyl 2-pyrrolidinone at 8O 0 C, the solution was cooled and 200ml of acetone was added as an anti-solvent. The precipitate obtained was filtered and dried under vacuum at 80-85 °C for overnight. The resulting solid was identified as Lamivudine Form V.
  • Lamivudine 3g of Lamivudine dissolved in 6ml of 1 -methyl-2-pyrrolidinone at 80°C, cool the solution and 30ml of tetrahydron was added as an anti-solvent. The precipitate obtained was filtered and dried under vacuum at 80-85 0 C for over night. The resulting solid was identified as Lamivudine Form V.
  • Lamivudine Form V Ig of Lamivudine dissolved in 2ml of 1 -methyl-2-pyrrolidinone at 80 0 C, the solution was cooled and 10ml of dimethyl carbonate was added as an anti-solvent. The precipitate obtained was filtered and dried under vacuum at 80-85 0 C. The resulting solid was identified as Lamivudine Form V.
  • Example 12 Preparation of anhydrous Form V Ig of Lamivudine was dissolved in 2ml of l-methyl-2-pyrrolidinone at 80°C followed by addition of 25ml of acetone and cooling the solution to 0°C. The precipitate obtained was filtered and dried under vacuum at 80-85°C. The resulting solid was identified as Lamivudine Form V.
  • Lamivudine 2g was dissolved in 4ml of N,N-dimethylacetamide at 80°C, the solution was cooled and 15 ml of acetone was added as an anti-solvent. The resulting precipitate was refluxed for 4hr. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form II
  • Lamivudine 2g was dissolved in 4ml of N,N-dimethylacetamide at 80 0 C the solution was cooled and 15ml of dimethyl carbonate was added as an anti-solvent. The resulting precipitate was refluxed for 4hr. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form II
  • Lamivudine 2g was dissolved in 4ml of N,N-dimethylacetamide at 80°C the solution was cooled and 15ml of methylene dichloride was added as an anti-solvent. The resulting precipitate was refluxed for 4hr. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form II
  • Lamivudine 2g was dissolved in 6 ml of l-methyl-2-pyrrolidinone at 80 0 C the solution was cooled and 10ml of dimethyl carbonate was added as an anti-solvent. The resulting precipitate was refluxed for 4hr. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form II
  • Example 17 Preparation of Lamivudine Form I 3g of Lamivudine was dissolved in 5ml of N,N-dimethyl acetamide at 8O 0 C and the solution was cooled and 20 ml of 1,4-dioxane was added. The resulting solution was allowed for crystallization at ambient temperature for overnight. The obtained needle-crystals was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form I.
  • Lamivudine 5g was dissolved in 60ml methanol and 10ml chloroform was added at 8O 0 C followed by cooling the solution to ambient temperature. The resulting precipitate was further stirred at same temperature for 0.5 hr. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form I.
  • Lamivudine 2g was dissolved in 10ml of nitromethane at 80 0 C to obtain a super saturated solution then 6ml of methanol was added. The resulting clear solution was allowed for crystallization at ambient temperature for overnight. The needle-like crystals precipitated was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form I
  • Lamivudine 2g was dissolved in 20ml of methanol at 80 0 C the solution was cooled and 16ml of diethyl ether was added as an anti-solvent. The precipitate obtained was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form I
  • Lamivudine 2g was dissolved in 20ml of 1-butanol and 30ml of methanol mixture at 80 0 C and the solution was cooled, allowing the solution for crystallization at ambient temperature for overnight. The precipitate obtained was filtered and dried under vacuum at ambient temperature. XRD of the sample showed it to be Form I
  • Example 22 Preparation of Lamivudine Form I 0.5g of Lamivudine was dissolved in 2ml of dimethyl formamide at 80 0 C and the resulting clear solution was allowed for fast evaporation on watch glass. The precipitate obtained after 2 days was identified as Lamivudine Form I. XRD of the sample showed it to be Form I
  • Lamivudine Form I XRD of the sample showed it to be Form I
  • Example 28 Preparation of crystalline Lamivudine Form - 1 1 g of Amorphous Lamivudine was kept in humidifier (RH >90%) for several days. Solid obtained was identified as crystalline Lamivudine Form - I. XRD of wet sample showed it to be Form I
  • Lamivudine amorphous was prepared by holding the Lamivudine Form V at about 160 0 C for about 5-10 minutes to form a melt then cooling the melt to obtain amorphous Lamivudine.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention a trait à de nouvelles formes polymorphiques cristallines et à une forme amorphe de la lamivudine caractérisées par différentes techniques à l'état solide. L'invention décrit également de nouveaux procédés permettant de préparer lesdites formes. Par ailleurs, l'invention concerne aussi de nouveaux procédés permettant de préparer la forme I et la forme II de la lamivudine cristalline.
PCT/IN2008/000155 2007-03-19 2008-03-17 Nouvelles formes polymorphiques de la lamivudine Ceased WO2008114279A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009069013A1 (fr) * 2007-11-29 2009-06-04 Ranbaxy Laboratories Limited Forme cristalline i de lamivudine et sa préparation
WO2009037538A3 (fr) * 2007-09-17 2009-08-13 Aurobindo Pharma Ltd Procédé de préparation de lamivudine de forme i
CN101531656B (zh) * 2009-03-24 2010-12-08 福建广生堂药业有限公司 拉米夫定晶型及其制备方法
WO2011045815A2 (fr) 2009-10-14 2011-04-21 Matrix Laboratories Ltd. Procédé pour la préparation de lamivudine et nouveaux sels dans sa fabrication
CN101993439B (zh) * 2009-03-24 2013-04-24 福建广生堂药业股份有限公司 拉米夫定晶型及其制备方法
WO2013168066A1 (fr) 2012-05-05 2013-11-14 Lupin Limited Procédé amélioré de fabrication de lamivudine de forme i
US8796452B2 (en) 2010-02-12 2014-08-05 Merck Sharp & Dohme Corp. Preparation of lamivudine form I

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009037538A3 (fr) * 2007-09-17 2009-08-13 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
CN101531656B (zh) * 2009-03-24 2010-12-08 福建广生堂药业有限公司 拉米夫定晶型及其制备方法
CN101993439B (zh) * 2009-03-24 2013-04-24 福建广生堂药业股份有限公司 拉米夫定晶型及其制备方法
WO2011045815A2 (fr) 2009-10-14 2011-04-21 Matrix Laboratories Ltd. Procédé pour la préparation de lamivudine et nouveaux sels dans sa fabrication
WO2011045815A3 (fr) * 2009-10-14 2011-06-23 Matrix Laboratories Ltd. Procédé pour la préparation de lamivudine et nouveaux sels dans sa fabrication
US8796452B2 (en) 2010-02-12 2014-08-05 Merck Sharp & Dohme Corp. Preparation of lamivudine form I
WO2013168066A1 (fr) 2012-05-05 2013-11-14 Lupin Limited Procédé amélioré de fabrication de lamivudine de forme i

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