FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
AND
THE PATENTS RULES, 2003
(See Section 10; rule 13)
PROVISIONAL SPECIFICATION
"A PROCESS FOR THE PREPARATION OF ATOVAQUONE"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification describes the nature of the invention:

The invention relates to a process for the preparation of atovaquone. Atovaquone is chemically described as trans-2-[4-( 4- chlorophenyl) cyclohexyl]- 3- hydroxy- 1,4-naphthalenedione and has the following structural Formula I

Atovaquone is an antiprotozoal agent and is useful in the treatment of PNEUMOCYSTIS CARINII pneumonia and is commercially available in the market under the brand name MEPRON® as tablets and suspension.
US Patent No. 5,053,432 describes atovaquone and a pharmaceutical composition thereof. It exemplifies crystallization of atovaquone in acetonitrile.
US Patent Application Publication No. 2006/0241311 describes atovaquone crystalline forms designated as Form II and Form III there in and processes for preparation thereof.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like atovaquone may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and solid state NMR spectrum; One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC'), which have been used to distinguish polymorphic forms.
Polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex. One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal

tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Hence, there is a need for a simple, industrially feasible, inexpensive, and scaleable process for the preparation of Atovaquone.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Atovaquone. In one aspect, the present invention provides a process a process for preparation of atovaquone characterized by an X-ray powder diffraction pattern with key reflections at approximately: 7.0, 9.7, 14.2, 14.8,17.0, 19.2,20.4,22.1, 22.7, 26.9 and 28.7 ± 0.2 (2-theta) comprising:
a) providing a solution of atovaquone in aprotic polar solvent
b) adding a suitable anti solvent to precipitate atovaquone
c) isolating the resultant solid.
In another aspect, the present invention relates to a pharmaceutical composition comprising atovaquone produced by the process of present invention and at least a pharmaceutically acceptable carrier.
The present invention provides simple, cost effective, ecofriendly, reproducible, robust and industrially scalable process to produce atovaquone that is free flowing, and can be directly compressed into pharmaceutical formulations.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a X-ray powder diffraction of USP reference standard

Fig. 2 is a Differential Scanning calorimetry thermogram of USP reference
standard
Fig. 3 is a characteristic X-ray powder diffraction pattern of atovaquone prepared
by Example 1.
Fig. 4 is a Differential Scanning calorimetry thermogram of atovaquone prepared
by Example 1.
Fig. 5 is a X-ray powder diffraction of atovaquone prepared by Example 2.
Fig. 6 is a Differential scanning calorimetry thermogram of atovaquone prepared by
Example 2.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention there is provided a process for the preparation of atovaquone. The present invention provides a process for preparation of atovaquone characterized by an X-ray powder diffraction pattern with key reflections at approximately:
7.0,9.7,14.2,14.8,17.0,19.2,20.4,22.1,22.7,26.9 and 28.7 ± 0.2 (2-theta) comprising:
a) providing a solution of atovaquone in aprotic polar solvent
b) adding a suitable anti solvent to precipitate atovaquone
c) isolating the resultant solid.
Atovaquone is official in United States Pharmacopoiea, (see USP 30 Page number 14160). Atovaquone USP reference standard lot # FOB 190 released in the market in November-December 2002 was subjected to Powder X-ray diffraction analysis (PXRD) and Differential scanning calorimetry (DSC).
Fig. 1 provides powder X-ray diffraction profile of USP reference standard lot # FOB 190.
Fig. 2 provides the DSC thermogram of the USP reference standard lot # FOB 190 single endotherm at about 219.65°C.
It is noted that the USP ref. standard shows the characteristic peaks of Form III of US'311 publication.

Table-2: Peak Table Results for USP Reference Standard Lot # F0B190

Pos.[°2Th.] d-spacing[Al Rel. Int.[%1
7.0271 12.57966 57.75
9.2536 9.55721 5.60
9.6870 9.13064 70.39
12.6880 6.97693 1.35
14.2629 6.20992 17.15
14.8254 5.97556 22.17
15.2119 5.82458 4.31
17.0951 5.18694 10.51
18.4622 4.80582 73.69
18.5991 4.77077 82.73
19.2236 4.61716 100.00
20.0966 4.41854 16.38
20.4639 4.34003 26.80
22.1107 4.02039 38.23
22.7502 3.90879 52.67
23.3148 3.81541 13.59
23.7573 3.74533 3.10
24.3451 3.65621 12.68
25.1728 3.53784 7.82
25.6000 3.47977 2.14
26.3171 3.38655 46.13
26.8738 3.31765 32.14
27.2403 3.27384 9.84
27.7518 3.21466 6.80
28.5214 3.12963 13.33
28.7378 3.10656 15.84
29.6993 3.00814 1.76
30.5604 2.92532 2.64
31.0824 2.87737 1.09
32.7646 2.73338 3.37
33.4983 2.67518 4.76
34.0363 2.63411 3.04
34.8208 2.57654 3.36
35.2141 2.54866 2.58
36.9745 2.43126 2.89
37.6607 2.38852 3.67
39.5083 2.28098 4.05
40.8482 2.20920 2.25
41.6078 2.17061 2.65
42.2519 2.13900 2.21
44.4530 2.03807 4.64
45.1760 2.00712 4.78
46.0294 1.97187 2.57
47.9429 1.89754 0.95
48.8894 1.86146 1.16
The present invention provides atovaquone having polymorphic form that matches with the USP reference standard. The process of the present invention can be carried out by

providing a solution of atovaquone in a protic polar solvent or mixture thereof under suitable conditions. For example solvents that can be used include but are not limited to aprotic polar solvents such as N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA) and the like; acidic solvents such as acetic acid and the like; alcoholic solvents like methanol, ethanol, isopropanol, n-butanol and the like; ketones such as acetone, 2-butanone, methylisobutylketone and the like; or mixtures thereof in various proportions without limitation.
The temperature for dissolution of atovaquone can range from about 0°C to about 150°C or reflux temperature of solvents used preferably 70 -80° C. The starting atovaquone used may be of indefinite morphology crystalline or amorphous or mixture thereof or it may be crude atovaquone resulting from synthetic processing step known in the art, for example US Patent No. 5,053,432 incorporated herein by reference. If desired any suspended insoluble matter may be removed by filtration or decantation. In one preferred embodiment the polar aprotic solvent used to prepare a solution of atovaquone is DMF.
The suitable anti solvents that can be used include but are not limited to water, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, and the like; ethers such as dimethylether, diethyl ether, diisopropylether, and the like. Mixtures of any of these solvents are also contemplated. In one preferred embodiment water is used as antisolvent.
The volume of the solvent used to solubilize atovaquone may range from about 2 to about 20 volumes to the weight of the atovaquone. Advantageously the antisolvent may be used in a range from about 5 to 100 volumes with reference to volume of the solvent used. The solution of atovaquone may be added to the antisolvent or the antisolvent may be added to the solution of atovaquone in the solvent to precipitate out atovaquone. The resultant reaction mixture may be cooled if so desired and product can be isolated by any known technique such as filtration, centrifugation and the like, or removal of solvent for example, substantially complete evaporation of the solvent, or partially concentrating the solution, cooling and isolating the product.

The product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 90° C. The drying can be carried out for any desired time, time periods from about 1 to 20 hours frequently being sufficient.
Atovaquone obtained by the process of present invention is characterized by X-ray powder diffraction pattern having the characteristic peaks approximately at: 7.0, 9.7, 14.2,14.8,17.0,19.2,20.4, 22.1, 22.7,26.9,, and 28.7 ± 0.2 degrees 2 theta, which is substantially in accordance with the Fig. 3. which was determined by powder x-ray diffraction patterns obtained by methods known in the art using a Philips X-Ray powder diffractometer, Goniometer model 1050/70 at a scanning speed of 2degree per minute, with a Cu radiation of .lambda.=l .5418 A.
Atovaquone resulting form the process of the present invention has differential scanning calorimetry (DSC) thermogram curve approximately at 221.23°C, which is substantially in accordance with the Fig. 4.
Accordingly, D90 particle size of the unformulated atovaquone obtained by the process of present invention is used as starting material in preparing a pharmaceutical composition generally is less than 400 microns preferably less than about 200 microns, more preferably less than 150 microns, still more preferably less than about 50 microns and still more preferably less than about 15 microns.
Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the solid state atovaquone form III into any desired particle size range as set forth above.
In another embodiment of the present invention there is provided pharmaceutical compositions containing atovaquone obtained by the process of present invention. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The atovaquone form III disclosed herein also may be administered as suppositories,

ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the atovaquone form III of the present invention is oral. The dosage forms may contain the atovaquone form III as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients.
Capsule dosages will contain the atovaquone which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate;

flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
The process for the preparation of atovaquone of the present invention is simple, eco-friendly and easily scaleable.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLES EXAMPLE-1:
72gm of atovaquone was dissolved in 345 ml of N,N-dimethyl formamide (DMF) at 70°C-75°C to get a clear solution. 2 liters of water was added under stirring to precipitate the solid. The resultant solution was cooled to about 25-35°C followed by filtration of the solid separated and the solid was washed with water, dried at about 85°C under vacuum. The material was milled to yield 64 gms of the title compound. Atovaquone obtained by the above process is characterized by X-ray powder diffraction pattern having the characteristic peaks at 7.04,9.27,9.69, 12.72, 14.09, 14.27,14.82, 15.21,17.09,17.98,18.46,18.61, 19.22,20.11,20.47,22.11,22.75,23.33,23.78,24.33, 25.17,25.60,26.31, 26.90,27.20, 27.74,28.55,28.75, 29.73, 30.52, 31.11, 32.74, 33.52, 34.04, 34.50, 34.85, 35.23, 36.98, 37.69, 38.42, 39.51, 39.85,40.85,41.62,42.29,43.69, 44.45, 45.17, 45.95, 47.99 and 48.86 + 0.2 degree 29 which is substantially in accordance with the Fig. 3. The DSC thermogram shows sharp endotherm at 221.23°C which is substantially in accordance with the Fig 4.
Peak List:

Pos. [°2Th.] d-spacing [A] Rel. Int. [%] Height [cts] Area [cts*°2Th.]
7.0405 12.55575 54.14 7110.26 469.32
9.2725 9.53783 4.62 606.59 50.05
9.6908 9.12706 66.79 8771.51 578.97
12.7298 6.95412 1.33 174.63 20.17
14.0978 6.28228 6.37 836.99 41.43
14.2720 6.20596 17.32 2274.20 187.64
14.8227 5.97662 21.46 2818.71 279.07
15.2198 5.82157 4.64 608.82 50.23
17.0996 5.18559 9.89 1299.13 107.19

17.9823 4.93298 1.38 181.86 18.01
18.4605 4.80626 49.39 6486.26 428.13
18.6132 4.76718 83.22 10929.79 901.78
19.2291 4.61585 100.00 13133.34 1517.02
20.1121 4.41515 15.89 2086.79 241.04
20.4737 4.33799 23.52 3088.92 356.80
22.1157 4.01948 38.05 4997.53 494.80
22.7550 3.90798 54.46 7152.44 826.17
23.3375 3.81175 13.74 1804.80 238.25
23.7836 3.74125 2.49 327.28 32.40
24.3381 3.65726 13.15 1726.75 199.46
25.1781 3.53711 8.06 1058.93 87.37
25.6036 3.47928 1.73 227.22 18.75
26.3192 3.38629 45.13 5926.81 684.60
26.9027 3.31415 30.18 3964.22 392.49
27.2039 3.27814 9.54 1252.80 103.36
27.7499 3.21486 6.57 863.20 71.22
28.5539 3.12615 10.74 1409.93 116.33
28.7585 3.10437 13.73 1802.95 119.00
29.7356 3.00455 1.87 246.21 32.50
30.5224 2.92887 2.87 377.38 24.91
31.1114 2.87476 1.10 144.32 19.05
32.7433 2.73511 3.00 393.44 77.91
33.5229 2.67326 4.17 547.08 45.14
34.0407 2.63378 2.04 268.18 35.40
34.5035 2.59950 2.88 378.80 50.01
34.8563 2.57400 2.49 327.57 43.24
35.2349 2.54720 2.13 279.46 36.89
36.9869 2.43047 2.19 287.05 47.37
37.6957 2.38639 3.17 416.23 96.16
38.4239 2.34282 0.50 66.05 21.80
39.5155 2.28058 3.19 419.12 41.50
39.8591 2.26171 2.17 285.59 37.70
40.8579 2.20870 1.53 201.10 26.55
41.6287 2.16957 1.79 235.53 38.86
42.2953 2.13690 1.43 188.32 62.15
43.6944 2.07167 0.74 96.58 25.50
44.4545 2.03800 3.63 476.98 55.10
45.1725 2.00726 3.80 499.07 98.82
45.9507 1.97507 1.45 190.01 50.17
47.9979 1.89550 0.86 113.50 37.46
48.8659 1.86230 1.17 153.06 41.63
EXAMPLE-2:
Atovaquone crude dried obtained as per Prior Art patent 4,981,874 was dissolved in 100 volumes of acetonitrile under reflux and solution was stirred at reflux temperature for 1 hour. The solution was allowed to cool immediately to 0-5 °C. Slurry obtained was stirred for 4 hrs at this temperature. Solid obtained was filtered off and dried under

vacuum at 80°C for 10-12 hrs. The powder X-ray diffraction profile of the solid obtained is given in Fig. 5 and its details of characteristic spectral lines observed are given in Table-5 and compared with that of reported in the Patent US 2006/0241311 Al. The DSC thermogram given in Fig 6 shows a single sharp endotherm at 220°C.

Form III of US 2006/0241311 USP Standard Lot # B OF 190 Example 2
Pos. [°2Th.] Pos. [°2Th.] d-spacing [A] Rel. Int. [%] Pos. [°2Th.] d-spacing [A] Rel. Int. [%]
6.99 7.0271 12.57966 57.75 7.0311 12.57254 72.52
9.2536 9.55721 5.6 9.2594 9.55126 6.67
9.65 9.687 9.13064 70.39 9.6874 9.13021 94.1
12.67 12.688 6.97693 1.35 12.7156 6.96187 1.96
14.0928 6.2845 8.29
14.2629 6.20992 17.15 14.2683 6.2076 21.85
14.8254 5.97556 22.17 14.8173 5.97879 30.68
15.2119 5.82458 4.31 15.2114 5.82477 5.24
17.0951 5.18694 10.51 17.0897 5.18858 8.68
18.4622 4.80582 73.69 18.4388 4.81187 48.38
18.5991 4.77077 82.73 18.6038 4.76958 100
19.2236 4.61716 100 19.215 4.61921 90.99
20.07 20.0966 4.41854 16.38 20.1045 4.41681 22.1
20.65 20.4639 4.34003 26.8 20.4563 4.34164 23.69
20.99
22.1 22.1107 4.02039 38.23 22.1131 4.01996 37.09
22.7502 3.90879 52.67 22.7415 3.91026 53.58
23.3148 3.81541 13.59 23.3251 3.81375 18.46
23.7573 3.74533 3.1 23.7648 3.74416 4.14
24.3451 3.65621 12.68 24.345 3.65623 15.92
25.1728 3.53784 7.82 25.1647 3.53897 9.61
25.6 3.47977 2.14 25.5858 3.48167 3.83
26.3171 3.38655 46.13 26.3108 3.38735 47.41
26.8738 3.31765 32.14 26.8951 3.31507 33.72
27.2403 3.27384 9.84 27.193 3.27943 12.32
27.7518 3.21466 6.8 27.743 3.21565 8.41
28.5214 3.12963 13.33 28.5476 3.12682 13.6
28.7378 3.10656 15.84 28.7499 3.10528 15.87
29.6993 3.00814 1.76 29.7282 3.00528 2.78
30.5604 2.92532 2.64 30.5403 2.9272 3.25
EXAMPLE-3:
Crude atovaquone 80 gm was taken up in 1.0 lit acetone and 450 ml methanol, 75 ml triethyl amine was added and stirred, yellow colored solution changed to wine red color, this solution was filtered and cooled to 10-15°C. 172 ml acetic acid was added to

neutralize the solution to acidic pH. The resultant yellow precipitate was cooled to 0-5° C and filtered, washed with water to yield 73 gms of purified material. Purity by HPLC: >99%.

The present invention particularly provides
A. A process for preparation of atovaquone characterized by an X-ray powder diffraction pattern with key reflections at approximately:
7.0, 9.7,14.2,14.8, 17.0,19.2, 20.4,22.1,22.7, 26.9 and 28.7 + 0.2 (2-theta) comprising:
a) providing a solution of atovaquone in aprotic polar solvent
b) adding a suitable anti solvent to precipitate atovaquone
c) isolating the resultant solid.
B. The process as described in A above wherein aprotic polar solvent is
selected from N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
C. The process as described in A above wherein the antisolvent is water.