WO2008114279A2

WO2008114279A2 - Novel polymorphs of lamivudine

Info

Publication number: WO2008114279A2
Application number: PCT/IN2008/000155
Authority: WO
Inventors: Ramakoteswara Rao Jetti; Asha Rani Gorantla; Dutt Tyagi Om
Original assignee: Matrix Laboratories Ltd
Current assignee: Mylan Laboratories Ltd
Priority date: 2007-03-19
Filing date: 2008-03-17
Publication date: 2008-09-25
Anticipated expiration: 2009-09-19

Abstract

The present invention provides novel crystalline polymorphic forms and amorphous form of Lamivudine characterized by different solid state techniques. The novel processes for their preparation are also disclosed. Further, the present invention is also directed to novel processes for the preparation of crystalline Lamivudine Form I and Form II.

Description

Title: NOVEL POLYMORPHS OF LAMIVUDINE FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

Lamivudine (LMV), (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. US 5,047,407 disclose the process for producing the cis racemic Lamivudine.

US 5,905,082 reports two anhydrous crystalline forms of (-)-enantiomer of Lamivudine, Form I and Form II, the methods for their preparation and pharmaceutical formulations thereof.

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.

During our investigation, it has now been found that 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.

SUMMARY OF THE INVENTION

It is the principal aspect of the present invention to provide novel crystalline polymorph of the 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.

Furthermore, 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.

In accordance with one preferred embodiment of the present invention, there is provided 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. Preferably, the solvate is hemi-dimethylacetamide solvate.

In accordance with another preferred embodiment of the present invention, there is provided 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. Preferably, 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.

Furthermore, in another embodiment of the present invention, there is provided a novel stable Lamivudine in amorphous state with the glass transition onset at about 56°C supported by modulated DSC.

Another embodiment provides a novel processes for the preparation of crystalline Lamivudine Form I and Form II.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein: 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

DETAILED DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

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 θ/θ configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 4OkV and 3OmA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Differential Scanning Calorimetry (DSC)

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.

Thermogravimetric Analysis (TGA)

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.

Karl-Fisher

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 ± 0.2Θ 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 ⁰C attributed to desolvation and later at 176.9 ⁰C corresponding to the melting of the product.

Crystalline Lamivudine Form IH is N₅N 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. Preferably, 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 70-90⁰C preferably at 8O⁰C. 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 ± 0.2Θ 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. Preferably, 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 70-90⁰C preferably 8O⁰C, 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 ± 0.2Θ values.

Anhydrous Lamivudine Form V is further characterized by DSC with an endothermic peak at 161.2 ⁰C 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 %.

In another aspect, 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.

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 140⁰C, 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 16O⁰C (maxima), corresponding to the complete melting of the product.

In another aspect, 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.

In another aspect, 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. 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.

Alternatively, 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, of the present invention, there is provided a process for the preparation of 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.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

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

Example 2: Preparation of Lamivudine Form III

3g of Lamivudine 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

Example 3: Preparation of Lamivudine Form III

3g of Lamivudine 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

Example 4: Preparation of Lamivudine Form III

Ig of Lamivudine was dissolved in 2ml of N,N-dimethyl acetamide at 8O⁰C followed by addition of 25ml of acetone and cooling the solution to 0⁰C. The precipitate obtained was filtered and dried at ambient temperature. XRD of the sample showed it to be Form III

Example 5: Preparation of Lamivudine Form II from Lamivudine Form III by heating

2g of Lamivudine Form IH obtained as described above was kept in a static dryer and heated at 80-85⁰C under vacuum. The resulting solid was identified as Lamivudine Form II. XRD of the sample showed it to be Form II.

Example 6: Preparation of Lamivudine Form IV

A sample of Lamivudine (2g) was taken in l-methyl-2-pyrrolidinone (4ml) and heated to 80⁰C to obtain a clear solution. The 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 IV Example 7: Preparation of 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.

2g of 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.

Example 9: Preparation of anhydrous Form V

3g of Lamivudine dissolved in 6ml of 1 -methyl 2-pyrrolidinone at 8O⁰C, 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.

Example 10: Preparation of anhydrous Form V

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 80-85⁰C for over night. The resulting solid was identified as Lamivudine Form V.

Example 11: Preparation of anhydrous Form V

Ig of Lamivudine dissolved in 2ml of 1 -methyl-2-pyrrolidinone at 80⁰C, 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 80-85⁰C. 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.

Example 13: Preparation of Lamivudine Form II

2g of Lamivudine 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

Example 14: Preparation of Lamivudine Form II

2g of Lamivudine was dissolved in 4ml of N,N-dimethylacetamide at 80⁰C 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

Example 15: Preparation of Lamivudine Form II

2g of Lamivudine 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

Example 16: Preparation of Lamivudine Form II

2g of Lamivudine was dissolved in 6 ml of l-methyl-2-pyrrolidinone at 80⁰C 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 8O⁰C 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.

Example 18: Preparation of Lamivudine Form I

5g of Lamivudine was dissolved in 60ml methanol and 10ml chloroform was added at 8O⁰C 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.

Example 19: Preparation of Lamivudine Form I

2g of Lamivudine was dissolved in 10ml of nitromethane at 80⁰C 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

Example 20: Preparation of Lamivudine Form I

2g of Lamivudine was dissolved in 20ml of methanol at 80⁰C 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

Example 21: Preparation of Lamivudine Form I

2g of Lamivudine was dissolved in 20ml of 1-butanol and 30ml of methanol mixture at 80⁰C 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 80⁰C 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

Example 23: Preparation of Lamivudine Form I

0.5g of Lamivudine was dissolved in 2 ml of 2-methoxy ethanol at 80°C and the resulting clear solution was allowed for fast evaporation on watch glass. The precipitate obtained after 2days was identified as Lamivudine Form I. XRD of the sample showed it to be Form I

Example 24: Preparation of crystalline Lamivudine Form - 1

Ig of Amorphous Lamivudine was suspended in 10 ml of methanol at room temperature and stir for overnight. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of wet sample showed it to be Form I

Example 25: Preparation of crystalline Lamivudine Form - 1

Ig of Amorphous Lamivudine was suspended in 10 ml of acetone at room temperature and stir for overnight. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of wet sample showed it to be Form I

Example 26: Preparation of crystalline Lamivudine Form - 1

Ig of Amorphous Lamivudine was suspended in 10 ml of n-heptane at room temperature and stir for overnight. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of wet sample showed it to be Form I

Example 27: Preparation of crystalline Lamivudine Form - 1

1 g of Amorphous Lamivudine was suspended in 10 ml of IPE at room temperature and stir for overnight. The solid obtained was filtered and dried under vacuum at ambient temperature. XRD of wet 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

Example 29: Preparation of crystalline Lamivudine Form - I

1 g of Amorphous Lamivudine was heated at about 40°C for several days. Solid obtained was identified as crystalline Lamivudine Form - I. XRD of wet sample showed it to be Form I

Example 30: Preparation of Amorphous Lamivudine

Ig of Lamivudine amorphous was prepared by holding the Lamivudine Form V at about 160⁰C for about 5-10 minutes to form a melt then cooling the melt to obtain amorphous Lamivudine.

Claims

We Claim

1. A crystalline Lamivudine Form III.

2. The crystalline Lamivudine Form III according to claim 1 having an X-ray powder diffraction pattern characterized by peaks at about 3.89, 12,24, 13.21, 17.78, 18.10, 19.09, 21.09, 24,46, 24.86, 27.46 ± 0.2 2Θ values.

3. The crystalline Lamivudine Form III according to claim 1 is having a substantially similar X-ray powder diffraction pattern as depicted in Figure 1.

4. The crystalline Lamivudine Form III according to claim 1 characterized by a differential scanning calorimetry (DSC) as depicted in Figure 2 and thermo gravimetric analysis as depicted in Figure 3.

5. The crystalline Lamivudine Form III according to claim 1, wherein said polymorphic form_. Ill is a solvate containing 12-18% w/w of N,N-dimethylacetamide.

6. A process for preparing crystalline Lamivudine Form III, which comprises:

(a) dissolving Lamivudine in a solvent such as N,N-dimethylacetamide;

(b) optionally adding the anti-solvent such as acetone; and

(c) isolating the crystalline Lamivudine polymorphic Form III.

7. A crystalline Lamivudine Form IV.

8. The crystalline Lamivudine Form IV according to claim 7 having an X-ray powder diffraction pattern characterized by peaks at about 14.44, 19.24, 20.09, 21.34, 25.33, 27.87, 30.79, 33.20, 38.80, 44.51, 47.93 ± 0.2 2Θ.

9. The crystalline Lamivudine Form IV according to claim 7 is having a substantially similar X-ray powder diffraction pattern as depicted in Figure 4.

10. The crystalline Lamivudine Form IV according to claim 7 characterized by a differential scanning calorimetry (DSC) as depicted in Figure 5 and thermo gravimetric analysis as depicted in Figure 6.

11. A process for the preparing crystalline Lamivudine Form IV, which comprises:

(a) dissolving Lamivudine in l-methyl-2-pyrrolidinone;

(b) evaporating the solution of step (a); and

(c) isolating Lamivudine Form IV.

12. A process for the preparing crystalline Lamivudine Form IV, which comprises :

(a) dissolving Lamivudine in l-methyl-2-pyrrolidinone;

(b) agitating the resulting solution; and

(c) isolating the Lamivudine polymorphic Form IV.

13. A crystalline Lamivudine Form V.

14. The crystalline Lamivudine Form V according to claim 13 having an X-ray powder diffraction pattern characterized by peaks at about 17.25, 17.70, 18.12, 19.38, 19.93 ± 0.2 2Θ.

15. The crystalline Lamivudine Form V according to claim 13 is having a substantially similar X-ray powder diffraction pattern as depicted in Figure 7.

16. The crystalline Lamivudine Form IV according to claim 13 characterized by a differential scanning calorimetry (DSC) as depicted in Figure 8 and thermo gravimetric analysis as depicted in Figure 9.

17. A process for preparation of anhydrous Lamivudine polymorphic Form V, which comprises:

(a) dissolving Lamivudine in a l-methyl-2-pyrrolidinone;

(b) adding anti-solvent to the resultant reaction mixture, (c) isolating the crystalline Lamivudine polymorphic Form V.

18. The process according to claim 17 wherein anti-solvent used are tetrahydrofuran, acetone and dimethyl carbonate.

19. An amorphous form of Lamivudine.

20. The amorphous form of Lamivudine according to claim 19 is having a substantially similar X-ray powder diffraction pattern as depicted in Figure 10.

21. The amorphous form of Lamivudine according to claim 19 is having a substantially similar differential scanning calorimetry (DSC) as depicted in Figure 1 1.

22. A process for the preparation of amorphous form of Lamivudine which comprises the heating of crystalline Form V followed by cooling the melt.

23. A process for preparation of crystalline Lamivudine polymorphic Form II comprising the steps of :

(a) dissolving Lamivudine at reflux temperature in an organic solvent such as N,N-dimethylacetamide or l-methyl-2-pyrrolidinone;

(b) adding anti-solvent to the resultant reaction mixture,

(c) isolating the crystalline Lamivudine polymorphic Form II.

24. The process according to claim 23 wherein anti-solvent used are acetone, dimethyl carbonate and methylene chloride.

25. A process for preparation of crystalline Lamivudine Form II which comprises further drying the crystalline polymorphic Form III or IV of Lamivudine.

26. A process for preparation of crystalline Lamivudine polymorphic Form I, which comprises: (a) contacting Lamivudine in organic solvent;

(b) isolating the crystalline Lamivudine polymorphic Form I.

27. The process according to claim 26, wherein the organic solvent is selected from the group consisting of aprotic polar solvents, chlorinated solvents, ether, esters, lower aliphatic ketones, amides, carbonates, nitroalkane, hydrocarbons or mixtures thereof.

28. The process according to claim 27 wherein the solvents employed are N,N-dimethyl acetamide, methanol, nitromethane, acetone, 1,4-dioxane, chloroform, methanol, butanol, heptane, isopropyl ether and diethyl ether.

29. The process according to claim 26, wherein Lamivudine used herein is selected from anhydrous, hydrated form or amorphous form.

30. A process for the preparation of crystalline Lamivudine Form I, which comprises:

(a) dissolving Lamivudine in an organic solvent;

(b) evaporating the resultant solution; and

(c) isolating Lamivudine Form I.

31. The process according to claim 30, where in the solvent employed is N,N-dimethyl formamide and 2-methoxy ethanol.

32. A process for the preparation of crystalline Lamivudine Form I which comprises the storing of Lamivudine amorphous form at RH >90% for several days.

33. A process for the preparation of crystalline Lamivudine Form I which comprises the heating of Lamivudine amorphous form at about 40°C for several days.