FIELD OF THE INVENTI0N
The present invention provides novel crystalline polymorphic forms of Atovaquone characterized by different solid state techniques and preparation thereof Further, the present invention is also directed to novel processes for the preparation of crystalline Atovaquone Form 1 and Form 111.
BACKGROUND OF THE INVENITON
Atovaquone is an antiprotazoal agent for oral administration. It is chemically trans-2-|4-(4-chlorophenyl)cyclohexyl|-3-hydroxy-l,4-naphthalenedione the represented by Formula 1:

Atovaquone is a unique naphthoquinone with broad-spectrum antiprotozoal activity. It is effective for the treatment and prevention of Pneumocystis caring pneumonia (PCP), a common parasitic lung infection of imniunocompromised patients. It is not only used for the treatment of" PCP, but also displays potent activity as an ant malarial agent, and has been used in the treatment of laxoplasmosis and babesiosis.
Atovaquone is marketed under the brand name of MIFPRON® oral suspension containing about 750 mg of Atovaquone. MFPRON suspension is indicated for the prevention of Pneumocystis caring pneumonia.
Atovaquone and its pharmaceutically acceptable salts are first known in US 5,053,432, and process for the preparation of Atovaquone is specifically disclosed in US 4,981,874.
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PCI' tipplication WO2006/008752 Al discloses crystalline polymorphic forms (Form-Il & Form-Ill), of Atovaquone, preparation and pharmaceutical composition. In this application, process for preparing Atovaquone Form I is disclosed, 'fhis patent application discloses that the Form-I is a prior art Form.
In addition to the above mentioned crystalline forms, we found Atovaquone in different crystalline forms stable at room temperature while crystallizing the Atovaquone in different solvents at different parameters, herein reJerred to as crystalline Form IV and Form V. I'hereJbre, the invention relates to said crystalline forms and preparation thereof The present invention also relates to novel processes for the preparation of the prior art Atovaquone Form 1 and Form III.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide novel crystalline polymorphs of the Atovaquone, hereinafter referred to as crystalline Form IV and Form V, which are characterized by X-ray powder diffraction pattern, thei'mo gravimetric analysis ('fGA), differential scanning calorimetry (DSC), moisture content (MC).
Furthermore, the present invention is related to processes for the preparation of crystalline Form IV and Form V of Atovaquone.
Another aspect of the present invention is to provide novel processes for the preparation ol" the I'orm I and Form III of Atovaquone by using diiTerent solvent system and conditions.
Another aspect of the present invention is to provide a crystalline Atovaquone Form IV as a dimethyl sulfoxide solvate with a dimethyl sulfoxide content of 30-40% w/w supported by thermo gravimetric analysis (TOA) and moisture content of 4-6% supported by KF method.

Yet another aspect of the present invention is to provide a crystalline Atovaquone Form V as l-methyl-2-pyrrolidinone solvate wiUi l-methyl-2-pyrrolidinonc content of 32-45% w/\v supported by thcrmo gravimetric analysis (d'OA) and moisture content of 4-7% supported by KF method,
BRIEF DESClilPTION OF THE DRAWINGS
Fig 1 is the X-ray powder diffraction pattern of Atovaquone Form IV.
Fig 2 is the Differendal scanning calorimctric (DSC) curve of Atovaquone Form IV.
Fig 3 is the 'FGA Atovciquone of the Form JV.
Fig 4 is the X-ray powder diffraction pattern of Atovaquone Form V.
Fig 5 is the Differential scanning calorimctric (DSC) curve of Atovaquone Form V.
Idg 6 is the 'FGA Atovaquone ol'lhc Form V.
Fig 7 is the X-ray powder dillraction pattern of Atovaquone Form I.
Idg 8 is the X-ray powder diffraction pattern of Atovaquone Form II (As per examplc-3 of
WO20()6/008752).
Fig 9 is the f^iffcrential scanning calorimctric (DSC) curve of Atovaquone Form IF
Fig 10 is the X-ray powder diffraction pattern of Atovaquone Form ill.
1)E lAlLED DESCRIPTION OF THE INVENTION
fhc present invention describes the crystalline Atovaquone Form IV and Form V, which exist as solvates and are encompassed with in the scope of the present invention, 'fhe present invention also relates to processes for the preparation of the 1-orm I, III, IV and V of Atovaquone. The said Ibrms differ from each other in their physical properties, spectral data like PXRD, TGA & DSC.

Powder X-ray Diffraction (PXRD)
The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/0 contlguration and X'Celerator detector. The Cu-anode X-ray lube is operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0"-50.0°, 0.030° step size and 50 seconds step time.
Differential Scanning Calorinietry (DSC)
The DSC measurements were carried out on Mettler Toledo 822 Star*"' and TA QIOOO 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. Standard aluminum crucibles covered by lids with three pin holes were used.
rhermogravimctric Analysis (T(iA)
TGA is carried out using instrument TCA/SDTA 851. 'fhe experiments were performed at a heating rate of 10.0°C/minute over a temperature range of 30-250°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.
■fhe crystalline Alovaquone Form IV is characterized by X-ray powder diftraction pattern as shown in Figure 1 with peaks at 7.39, 10.22, 10.99, 14.86, 15.75, 17.98, 20.04, 20.54, 20.94, 22.11, 22.42, 23.60, 25.08, 26.91 and 27.81 ±0.20 values.
Crystalline Alovaquone Form IV is further characterized by the DSC as shown in FTgure 2 with several melting endothermic peaks ranging from 60-126°C, 140-180°C and finally at 218T. which corresponds to the melting of the product.

\ Crystalline Atovaquone Form IV is Dimethyl sulfoxide solvate with a Dimcthly sulfoxide content of 30-40%w/w, which is analysed by Ihermo gravimetric analysis as shown in Figure 3 and moisture content of 4-6% supported by Karl Fisher method.
llie present invention also provides the process for the preparation of crystalline Atovaquone i'orm IV, comprising the steps of: a) dissolving Atovaquone in Dimethyl sulfoxide to form a clear solution b) removing the solvent completely and c) isolating crystalline Atovaquone Form IV,
y\ccording to the present invention, Atovaquone is dissolved in dimethyl sulfoxide at hot condition to get clear solution. The solution is then subjected to distillation under vaccum for complete removal of the solvent, 'fhe solid obtained is seperatcd and identified as the crystalline Atovaquone form-lV. 'fhe dissolution temperature ranges from 80 to 100°C, preferably at 90°C.
'fhe crystalline Atovaquone Form V is characterized by X-ray powder di(fraction pattern as shown in Figure 4 with peaks at 7.67, 9.87, 10.09, n.54, 15.41, 17.44, 19.03, 19.26, 19.67, 19.87, 20.27, 25.79, 25.95, 26.26 and 28.78 ±0.20 values.
Crystalline Atovaquone Form V is further characterized by the DSC as shown in Figure 5 with three melting endothermic peaks; first at an extrapolated onset temperature ranging from 60-75"C corresponding to loss due to the moisture, which is identified with a peak at 69"C (maxima), and a second at an extrapolated onset temperature ranging from 110-161°C, corresponding to desolvation, which is identified with a peak at 154"C and finally at 218"C which corresponds to the melting of the product.
Crystalline Atovaquone Form V is l-methyl-2-pyrrolidinone solvate with a l-melhyl-2-pyrrolidinone content of 32-45%w/w, which is analysed by thcrmo gravimetric analysis as shown in Figure 6 and moisture content of 4-7% supported by Karl Fisher method.

The present invention further provides (he process for the preparation of crystalline Atovaquone I'orm V, comprising the steps of: a) dissolving Atovaquone in l-methyl-2-pyrrolidinone b) cooling the solution and c) isolating crystalline Atovaquone Form V.
According to the present invention, Atovaquone is dissolved in l-n-iethyl-2-pyrrolidinone to get clear solution at hot condition, 'fhe resulting solution is then cooled to room temperature and stirred for Ihr. The solid obtained is Filtered, washed, dried and identified as crystalline Atovaquone Form-V. The dissolution temperature ranges from 80 to 100°C, preferably at 90"C.
In another aspect, the present invention provides a process for preparing Form I, comprising the steps of: a) dissolving Atovaquone Form IV in acetonitrile b) adding anti-solvent or cooling and c) isolating the crystalline Atovaquone Form 1.
In another aspect, the present invention provides a novel process for preparing crystalline Atovaquone frorm I by contacting Atovaquone in a suitable solvent selected from dichloromethane, acetonitrile (ACN), water or mixtures thereof using the methods such as anti-solvent or slow crystallization method, followed by filtration and drying eg., under vacuum at 50-60°C.
In another aspect, the present invention provides a process lor preparing Form 1 of Atovaquone by drying crystalline Atovaquone Form V. 'fhe drying temperature ranges from 45 to 60°C preferably at 50°C for about l-2hrs.
In another aspect, the present invention provides a process for preparing Form 111 of Atovaquone by drying crystalline Atovaquone From IV. The drying temperature ranges from 45 to 60"C preferably at 50°C for about l-2hrs.
According to our present invention crystalline Atovaquone is dissolved in a solvent at hoi condition followed by slow or fast crystallization to give crystalline Atovaquone Form-Ill. The solvent selected for dissolution is dimcthyllbrmamide (DMF), dimethylsulfoxde (DMSO) and 1-

mcthyl-2-pyrrolidinone (NMP), 1lie dissolution temperature ranges from 80 to 100"C, preferably at 90°C.
In another aspect, the present invention provides a novel process for preparing crystalline Atovaquone Form III by contacting Atovaquonc in a suitable solvent selected from pyridine, 1-methyl-2-pyrrolidinone (NMP), isopropyl ether (IPE), water, dimethylformamide (DMf), dichloromethane (DCM) or mixtures thereof, using the methods such as slurry or anti-solvent method or by removal of the solvent, followed by filtration and drying under vacuum at 50-60°C.
'fhc 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.
EXAMPLES
Example-1: Preparation of Atovaquone Form IV.
lOg of Atovaquone was taken in DMSO (200ml) at 25-30°C and heated to 80"C to obtain a clear solution. The hot solution filtered through hyflo bed to remove undissolved solid particulate. The resulting solution was distilled completely under vacuum at 90°C to get crystalline Form IV.
Examplc-2: Preparation of Atovaquone Form IV.
Ig of Atovaquone was dissolved in DMSO (20ml) at 80"C to obtain a clear solution. The hot solution was Filtered through hyllowbed to remove undissolved solid particulate and the resulting clear solution was allowed for fast evaporation on watch glass to get crystalline Atovaquonc Form IV.
ExampIc-3: Preparation of Atovaquonc Form V.
lOg of Atovaquone was dissolved in I-mcthyl-2-pyrrolidinone (40 ml) at 80-100°C to obtain a clear solution. The hot solution was filtered Un-ough hyllowbed to remove undissolved solid particulate and the resulting clear solution was cooled to 25-30°C. The solid obtained was filtered to get crystalline Atovaquonc Form V.

Example-4: Prcpiiration of Atovaquone Form 1.
Ig of Atovaque:»ne was suspended in appropriate solvents in appropriate volumes at 25-3()"C., heated for complete dissolution and subjected to different crystallization methods. The results obtained arc displayed in the tablc-l:

Example-S: Preparation of Atovaquone Form 1.
2g of crystalline Atovaquone Form V was kept in a vacuum oven dryer and heated at 5()"C under vacuum for 1 hr. The resulting solid was identified as Atovaquone Form I.
Example-6: Preparation of Atovaquone Form III.
Ig of crystalline Atovaquone was suspended in appropriate solvents in appropriate volumes at 25-30T, heated for complete dissolution and subjected to different crystallization methods. The results obtained are displayed in the table-lJ:
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Example-7: Preparation of Atovaquone Form 111.
2g of crystalline Atovaquone Ibrm IV was kept in a vacuum oven dryer and heated at 50"C under vacuum for 1 hr. The resulting solid was identified as Atovaquone Form 111. XRD of dried sample showed it to be h'orm III.
Kxample-8: Preparation of Atovaquone Form 11. (As per exampie-3 of WO20()6/0()8752)
Ig of crystalline Atovaquone Form 1 was talcen in 1,4-dioxane (5ml) and heated to reflux. The resulting clear solution was allowed to cool to room temperature for 30 min and then cooled to 5°C for 4 hrs. The solid obtained was then filtered and dried to get Atovaquone Form II. XRD of the dried sample showed it to be Form 11.
Example-9: Preparation of Atovaquone Form HI.
2g of crystalline Atovaquone form II obtained as described in example-8 was kept in a vacuum oven dryer and heated at 50°C under vacuum lor 1-2 hrs. The resulting solid was identified as Atovaquone Form 111. XRD of dried sample showed it to be Form III.
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We Claim:
1. A crystalline Atovaquone From IV.
2. The crystalline Atovaquone From IV according to claim 1 having the peaks at about 7.39, 10.22, 10.99, 14.86, 15.75, 17.98, 20.04, 20.54, 20.94, 22.11, 22.42, 23.60, 25.08, 26.91 and 27.81 ±0.20 values.
3. lire crystalline Atovaquone Form IV according to claim 1 is having X-ray powder diffraction pattern as dipicted in l-igure 1.
4. The crystalline Atovaquone I'orm IV according to claim 1 characterized by a differential scanning caloroimetry (DSC) as depicted in Figure 2 and thermo gravimetric analysis (TGA) as depicted in Figure 3.
5. The crystalline Atovaquone Form IV according to claim 1, wherein said polymorphic Form IV is a Dimethly sulfoxide solvate.
6. A process for preparing crystalline Atovaquone Form IV, which comprises:

a) dissolving Atovaquone in Dimethly sulfoxide,
b) removing the solvent and
c) isolating the crystalline Atovaquone Form IV.

7. A crystalline Atovaquone Form V.
8. The crystalline Atovaquone Form V according to claim 7 having the peaks at about 7.67, 9.87, 10.09, 11.54, 15.41, 17.44, 19.03, 19.26, 19.67, 19.87, 20.27, 25.79, 25.95, 26.26 and 28.78 ±0.20 values.
9. lire crystalline Atovaquone Form V according to claim 7 is having X-ray powder diffraction pattern as dipicted in Figure 4.
10. 'Fhe crystalline Atovaquone Form V according to claim 7 characterized by a diiTerential scanning caloroimetry (13SC) as depicted in Figure 5 and thermo gravimetric analysis (TGA) as depicted in Figure 6.
1!. The crystalline Atovaquone I'orm V according to claim 7, wherein said polymorphic
Form V is l-methyl-2-pyrrolidinone solvate. 12. A process for preparing crystalline Atovaquone Form V, which comprises:
a) dissolving Atovaquone in l-methyl-2-pyiTolidinone;
b) cooling the solution and
c) isoladng the crystalline Alovaquone Form V
II

13. A process for preparing crystalline Atovaquone Form I, which comprises:
a) dissolving crystalline Atovaquone Form IV in acetonitrile;
b) adding water and
c) isolating the crystalline Atovaquone Form I.
14. A process for preparing crystalline Atovaquone Form I, which comprises:
a) dissolving crystalline Atovaquone form V in solvent,
b) cooling the solution and
c) isolating the crystalline Atovaquone Form 1.

15. A process according to claim 14, wherein the used solvent is selected from dichloromethane and acetonitrile.
16. A process for preparing crystalline Atovaquone Form 1 by drying crystalline Atovaquone 1^'orm V.
17. A process for preparing crystalline Atovciquone Form III, which comprises:

a) dissolving crystalline Atovaquone in a solvent,
b) cooling and
e) isolating the crystalline Atovaquone Form 111.
18. A process according to claim 17, wherein the used solvent is selected from dimelhylformamide (DMF'), dimethylsuUbxide (DMSO) and dichloromethane (DCM).
19. A process for preparing crystalline Atovaquone Form III, which comprises:

a) dissolving crystalline Atovaquone in a solvent;
b) adding antisolvent and
c) isolating the crystalline Atovaquone Form III.

20. A process according to claim 19, wherein the solvent used for dissolution is pyridine. 1-melhyl-2-pyrrolidinone (NMF) and the antisolvents are isopropyl ether and water respectively.
21. A process for preparing crystalline Atovaquone Form III, which comprises:

a) dissolving crystalline Atovaquone in a solvent;
b) removing the solvent and
c) isolating the crystalline Atovaquone Form III.
22. A process according to claim 21, wherein the solvent used is selected from l-methyl-2-
pyrrolidinone (NMP), dimelhylformamide (DMF), dichloromethane or mixtures thereof.
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23. A process for preparing crystalline Alovaquone Form III, which comprises:
a) suspending crystalline Atovaquone in water;
b) stirring For 1-2 hrs and
c) isolating the crystalline Atovaquone Form III.
24. A process for preparing anhydrous crystalline Atovaquone Form 111 by drying crystalline
Atovaquone form IV.