WO2006008752A1 - Novel polymorphs of atovaquone and process of preparation thereof - Google Patents

Novel polymorphs of atovaquone and process of preparation thereof Download PDF

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Publication number
WO2006008752A1
WO2006008752A1 PCT/IN2004/000213 IN2004000213W WO2006008752A1 WO 2006008752 A1 WO2006008752 A1 WO 2006008752A1 IN 2004000213 W IN2004000213 W IN 2004000213W WO 2006008752 A1 WO2006008752 A1 WO 2006008752A1
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WO
WIPO (PCT)
Prior art keywords
process
atovaquone
form
preferably
solvent
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PCT/IN2004/000213
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French (fr)
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WO2006008752A8 (en
Inventor
Venkatasubramanian Radhakrishnan Tarur
Dhananjay Govind Sathe
Narayana Rao Mantripragada
Kamlesh Digambar Sawant
Gautam Ramjibhai Patel
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Usv Limited
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Priority to PCT/IN2004/000213 priority Critical patent/WO2006008752A1/en
Publication of WO2006008752A1 publication Critical patent/WO2006008752A1/en
Publication of WO2006008752A8 publication Critical patent/WO2006008752A8/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00Quinones
    • C07C50/26Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/32Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00Preparation of quinones
    • C07C46/10Separation; Purification; Stabilisation; Use of additives

Abstract

Novel crystalline forms of anti Pneumocystis carinii compound (2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-­naphthoquinone) commonly known as Atovaquone and methods for producing the same is disclosed herein. This also provides pharmaceutical compositions comprising the said polymorphs of Atovaquone and method of treating Pneumocystis carinii pneumonia, the method comprising administering to a warm blooded animal an effective amount of a product-by-process composition of matter comprising polymorphic forms of Atovaquone.

Description

Novel polymorphs of Atovaquone and process of preparation thereof

Technical Field

The present invention relates to novel crystalline forms of anti Pneumocystis carinii compound (2- [4-(4-Chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone) commonly known as Atovaquone and methods for producing the same.

Background and Prior Art

Pneumocystis carinii is a parasite, which has a natural habitat in lung tissue, in a host with normal immune system. Without treatment Pneumocystis carinii pneumonia is almost always fatal in immuncompromised host. U.S. patent 4,981,874 discloses the process of preparation and the activity of the Atovaquone.

Polymorphs of Atovaquone are not reported yet. The term 'polymorphs', is meant to include different physical forms, crystalline /liquid crystalline/amorphous forms.

Polymorphic studies have become very interesting and important as many active pharmaceutical ingredients exhibit polymorphism and some/one of the polymorphic form exhibit high bio-availability and also much better activity as compared to other polymorphs.

We have focused our research to develop new polymorphic forms with an object to develop novel polymorphic forms of anti Pneumocystis carinii compound Atovaquone. Summary of the invention

U. S. Pat. No. 4,981,874 discloses the recrystallization/purification of Atovaquone using solvent acetonitrile. The polymorphic form obtained by this method is referred hereafter as Form I, characterized by an X-ray powder diffraction pattern having peaks at about 7.2, 11.04, 11.77, 19.34, 21.14, 24.61, 25.28, 28.4 ± 0.2 degrees. The DSC thermogram of Form I shows a small endotherm at 1970C followed by a sharp endotherm at 222°C.

The present invention provides crystalline Atovaquone Form II, characterized by an X- ray powder diffraction pattern having peaks at about 7.02, 9.68, 10.68, 11.70, 14.25, 14.83, 18.60, 19.29, 23.32, 24.54 ± 0.2 degrees. The DSC thermogram of Form II shows a small endotherm at 169°C followed by a sharp endotherm at 222°C

The present invention also provides crystalline Atovaquone Form III, characterized by an X-ray powder diffraction pattern having peaks at about 6.99, 9.65, 12.67, 20.07, 20.65, 20.99, 21.88, 22.10, 25.56+ 0.2 degrees. The DSC thermogram of Form III shows characteristic sharp endotherm at 222°C

The present invention also provides a process for preparing Form I comprising of dissolution of crude Atovaquone in a solvent; adding anti-solvent to the solution, cooling the resultant solution and, collecting the crystals of Form I.

The present invention also provides a process for converting crystalline Atovaquone Form I to Form II, comprising dissolution of Atovaquone Form I in a solvent by heating; cooling the resultant solution and, collecting the crystals of Form II.

The present invention also provides a process for converting crystalline Atovaquone Form I to Form III, comprising dissolution of Atovaquone Form I in a solvent by heating; cooling the resultant solution and, collecting the crystals of Form III. The present invention also provides a process for preparing crystalline Atovaquone Form III, comprising dissolution of Atovaquone Form I in a solvent; adding anti-solvent to the solution, cooling the resultant solution and, collecting the crystals of Form III.

Pharmaceutical compositions comprising therapeutically effective amount of polymorphs II and III of Atovaquone are also disclosed herein.

A method of treating Pneumocystis carinii pneumonia , the method comprising administering to a warm blooded animal an effective amount of a product-by-process composition of matter comprising polymorphic forms of Atovaquone is also envisaged as part of this invention.

Description of the Invention

The present invention provides new crystal forms of Atovaquone. The discovery of new crystalline form of Active pharmaceutical ingredient will be advantageous with regard to improvement in performance of the product.

The present invention also relates to the solid-state forms (i.e. Polymorphs) of Atovaquone that can be prepared by the methods described herein.

As used herein, a solvent is any liquid substance which has capacity to dissolve the organic compound Atovaquone, either at room temperature or higher. Antisolvent is an organic solvent in which organic compound such as Atovaquone has poor solubility.

As used herein, room temperature means a temperature from about 250C to 300C. X-ray powder diffraction pattern has been obtained on D 8 -Advance, Broker AXE, Germany, diffractometer equipped with scintillation detector using Copper Ka (λ = 1.5406 A) radiation with scanning range between 2-50 θ at scanning speed of 2 ° / min.

Differential Scanning Calorimeter was performed on Mettler DSC 20 instrument. Samples of 2 mg to 3 mg weighed in aluminum crucible with holes were scanned at a heating rate of 100C per minute under Nitrogen atmosphere at a rate of 35 ml / min.

Atovaquone Form I

Atovaquone is prepared by the method described in US, 4,981,874 which is referred as Form I. The X-ray powder diffraction diagram and DSC thermograms of Form I are shown in Figs. 1 and 4 respectively.

Preparation of Atovaquone Form I

Example 1

Ig. of crude Atovaquone Form I was dissolved in 10 mJL methylene dichloride at room temperature. To this solution 20 mL of methanol was added drop wise under stirring at same temperature. The slurry obtained was stirred for 4 hrs. at the same temperature. The solid was filtered and dried to get Form I.

Example 2

Ig. of crude Atovaquone Form I was dissolved in 10 mL methylene dichloride at room temperature. To this solution 20 mL of n-Heptane was added drop wise under stirring at same temperature. The slurry obtained was stirred for 4 hrs. at the same temperature. The solid was filtered and dried to get Form I. Preparation of Atovaquone Form II

Atovaquone Form II is prepared from Form I by the method described below and the DSC thermogram, X-ray powder diffraction diagram of Form II are shown in Figs. 2 and 5 respectively

Example 3

Ig. of Atovaquone Form I was dissolved in 5 niL 1,4-Dioxane under reflux condition. The clear solution was allowed to cool to room temperature for 30 minutes and then cooled at 5°C for 4 hours. The solid obtained was then recovered on Buchner funnel and dried to get Form II.

Preparation of Atovaquone Form III

Atovaquone Form III is prepared from Form I by the method described below and the DSC thermogram, X-ray powder diffraction diagram of Form III are shown in Figs. 3 and 6 respectively

Example 4

0.5 g Atovaquone Form I was dissolved in 20 niL Acetone under reflux condition. 40 ml of water was maintained at O0C and to this cold water, the hot solution of the Atovaquone was added dropwise with stirring. The solution was maintained at the same temperature for 1 hr. The solid thus obtained was filtered and dried to get Form III.

Example 5

0.5 g. Atovaquone Form I was dissolved in 15 niL chloroform at room temperature. To this solution 20 mL of methanol was added drop wise under stirring at same temperature. The slurry obtained was stirred for 4 hrs. at the same temperature. The solid was filtered and dried to get Form III. Example 6

0.5 g. Atovaquone Form I was dissolved in 80 mL diisopropyl ether under reflux condition. The solution was cooled to room temperature and maintained at same temperature for 4 hrs. The solid was filtered and dried to get Form III.

Description of the figures:

Fig. 1 Shows the X-ray Diffraction Diagram of Atovaquone Form I Fig. 2 Shows the X-ray Diffraction Diagram of Atovaquone Form II Fig. 3 Shows the X-ray Diffraction Diagram of Atovaquone Form III Fig. 4 Shows the DSC Thermogram of Atovaquone Form I Fig. 5 Shows the DSC Thermogram of Atovaquone Form II Fig. 6 Shows the DSC Thermogram of Atovaquone Form III

The polymorphic form I obtained by this method is characterized by an X-ray powder diffraction pattern (Fig. 1) having peaks at about 7.2, 11.04, 11.77, 19.34, 21.14, 24.61, 25.28, 28.4 ± 0.2 degrees. The DSC thermogram of Form I (Fig. 2) shows a small endotherm at 197°C followed by a sharp endotherm at 222°C.

The present invention provides crystalline Atovaquone Form II, characterized by an X- ray powder diffraction pattern having peaks at about 7.02, 9.68, 10.68, 11.70, 14.25, 14.83, 18.60, 19.29, 23.32, 24.54 ± 0.2 degrees as shown in Fig. 2. The DSC thermogram of Form II in Fig. 3 shows a small endotherm at 169°C followed by a sharp endotherm at 222°C

The present invention also provides crystalline Atovaquone Form III, characterized by an X-ray powder diffraction pattern (Fig. 4) having peaks at about 6.99, 9.65, 12.67, 20.07, 20.65, 20.99, 21.88, 22.10, 25.56± 0.2 degrees. The DSC thermogram of Form III (Fig. 5) shows characteristic sharp endotherm at 222°C Pharmaceutical compositions comprising therapeutically effective amount of polymorphs II and III of Atovaquone are prepared by conventional methods.

A method of treating Pneumocystis carinii pneumonia, the method comprising administering to a warm blooded animal an effective amount of a product-by-process composition of matter comprising polymorphic forms of Atovaquone is also envisaged as part of this invention

Claims

We claim,
1. Atovaquone polymorphic Form II
2. Atovaquone Form II as claimed in claim 1 having Characteristic X-ray diffraction peaks at values of 2Θ values of about 7.02, 9.68, 10.68, 11.70, 14.25, 14.83, 18.60, 19.29, 23.32, 24.54.
3. Atovaquone Form II as claimed in claim 1 exhibiting a DSC thermogram that has small endotherm at 169°C followed by sharp endotherm at 222°C
4. A process for making Atovaquone Form II comprising: a) Dissolving Atovaquone Form I in a solublizing solvent at an elevated temp to form a solution. b) Cooling the solution to precipitate Atovaquone c) Collecting the precipitated product at suction d) Drying the product
5. The process as claimed in claim 4 wherein the solublizing solvent is a cyclic ether preferably 1,4-Dioxane
6. The process as claimed in claim 4 wherein the elevated temperature that is between 35°C and about 900C, preferably 700C.
7. The process as claimed in claim 4 wherein the cooling is done between 00C to 3O0C, preferably 5°C.
8. The process as claimed in claim 4 wherein the drying is done between 500C to 900C5 preferably 65°C.
. Atovaquone polymorphic Form III
10. Atovaquone Form III as claimed in claim 9 having characteristic X-ray diffraction peaks at values of 20 values of about 6.99, 9.65, 12.67, 20.07, 20.65, 20.99, 21.88, 22.10, 25.56,
11. Atovaquone Form III as claimed in claim 9 exhibiting a DSC thermogram that has characteristic sharp endotherm at 222°C
12. A process for making Atovaquone Form III comprising of the steps of a) Dissolving Atovaquone Form I in a solublizing solvent at an elevated temperature to form a solution. b) Cooling the solution to precipitate Atovaquone c) Collecting the precipitated product at suction d) Drying the product
13. The process as claimed in claim 12 wherein the solublizing solvent is an ether, preferably diisopropyl ether.
14. The process as claimed in claim 12 wherein the elevated temperature that is between 35°C and about 800C, preferably at 7O0C.
15. The process as claimed in claim 12 wherein the cooling is done between 00C to 300C, preferably 5°C.
16. The process as claimed in claim 12 wherein the drying is done between 500C to 900C, preferably 65°C.
17. A process of making Atovaquone Form III also comprising: a) Dissolving Atovaquone Form I in Solublizing solvent at an elevated temperature to form a solution. b) Adding an anti-solvent to the solution till turbidity is obtained. c) Stirring the solution while cooling d) Collecting the precipitated solid and drying
18. The process as claimed in claim 17 wherein the solublizing solvent is either chlorinated solvent like chloroform or a ketone preferably acetone.
19. The process as claimed in claim 17 wherein the dissolving is at an elevated temperature that is between 25° and about 70°C, preferably at 70°C.
20. The process as claimed in claim 17 wherein the anti-solvent added to regenerate the solid is selected from the group consisting of methanol, ethanol, isopropanol, preferably methanol.
21. The process as claimed in claim 17 wherein the anti-solvent added to regenerate the solid is water.
22. A process of making Atovaquone Form I comprising a) Dissolving crude Atovaquone in Solublizing solvent at an elevated temperature to form a solution. b) Adding an anti-solvent to the solution till turbidity is seen c) Stirring the solution while cooling d) Collecting the precipitated solid and drying
23. The process as claimed in claim 22 wherein the solublizing solvent is chlorinated solvents like methylene dichloride, ethylene dichloride preferably methylene dichloride.
24. The process as claimed in claim 22 wherein the dissolving is at an elevated temperature that is between 25° and 50°C, preferably at 500C.
25. The process as claimed in claim 22 wherein the anti-solvent added to regenerate the solid is selected from the group consisting of methanol, ethanol, isopropanol, preferably methanol.
26. The process as claimed in claim 22 wherein the anti-solvent added to regenerate the solid is selected from the group consisting of aliphatic hydrocarbon like n- pentane, n-hexane, n-heptane, preferably n-heptane.
27. A composition comprising the said polymorphs as prepared by process claimed in any of the above claims.
28. A method of treating Pneumocystis carinii pneumonia , the method comprising administering to a warm blooded animal an effective amount of a product -by- process composition of matter comprising polymorphic forms of Atovaquone wherein the said polymorphic forms of Atovaquone manufactured by the process as claimed in any of the claims 1 to 26.
PCT/IN2004/000213 2004-07-16 2004-07-16 Novel polymorphs of atovaquone and process of preparation thereof WO2006008752A1 (en)

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PCT/IN2004/000213 WO2006008752A1 (en) 2004-07-16 2004-07-16 Novel polymorphs of atovaquone and process of preparation thereof

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
CA 2549871 CA2549871A1 (en) 2004-07-16 2004-07-16 Novel polymorphs of atovaquone and process of preparation thereof
AU2004320912A AU2004320912A1 (en) 2004-07-16 2004-07-16 Novel polymorphs of atovaquone and process of preparation thereof
EP20040806730 EP1768944A1 (en) 2004-07-16 2004-07-16 Novel polymorphs of atovaquone and process of preparation thereof
PCT/IN2004/000213 WO2006008752A1 (en) 2004-07-16 2004-07-16 Novel polymorphs of atovaquone and process of preparation thereof
CN 200480032876 CN1878741A (en) 2004-07-16 2004-07-16 Novel polymorphs of atovaquone and process of preparation thereof
JP2006539076A JP2007510715A (en) 2004-07-16 2004-07-16 Atovaquone novel polymorphs and processes for the preparation of
EA200700332A EA200700332A1 (en) 2004-07-16 2004-07-16 The new polymorphs of atovaquone and their method of preparation
US10/569,036 US7847112B2 (en) 2004-07-16 2004-07-16 Polymorphs of atovaquone and process of preparation thereof
KR1020067012150A KR20070033317A (en) 2004-07-16 2004-07-16 The novel polymorph of ATO on wheels and methods for their preparation

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WO2006008752A1 true WO2006008752A1 (en) 2006-01-26
WO2006008752A8 WO2006008752A8 (en) 2006-06-15

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EP (1) EP1768944A1 (en)
JP (1) JP2007510715A (en)
KR (1) KR20070033317A (en)
CN (1) CN1878741A (en)
AU (1) AU2004320912A1 (en)
CA (1) CA2549871A1 (en)
EA (1) EA200700332A1 (en)
WO (1) WO2006008752A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008122988A1 (en) * 2007-04-05 2008-10-16 Cadila Healthcare Limited Process for preparation of atovaquone and the conversion of cis-isomer to trans- isomer
WO2009007991A2 (en) * 2007-04-19 2009-01-15 Ipca Laboratories Limited A new process for preparation of atovaquone and novel intermediates thereof
WO2009001367A3 (en) * 2007-06-26 2010-02-18 Hetero Drugs Limited Novel crystalline forms of atovaquone
US8222273B2 (en) 2008-02-04 2012-07-17 Pfizer Limited Polymorphic form of a [1,2,4]triazole[4,3-A] pyridine derivative inflammatory diseases

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013098832A2 (en) 2011-09-08 2013-07-04 Dishman Pharmaceuticals & Chemicals Ltd. Novel process for selective isolation and purification of 2-[4-(4-chlorophenyl) cyclohexyl]-3-chloro-1, 4-naphthoquinone and atovaquone

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EP0123238A2 (en) * 1983-04-14 1984-10-31 The Wellcome Foundation Limited Naphthoquinone derivatives
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US2553647A (en) * 1946-03-20 1951-05-22 Research Corp Naphthoquinone antimalarials
EP0123238A2 (en) * 1983-04-14 1984-10-31 The Wellcome Foundation Limited Naphthoquinone derivatives
US4981874A (en) * 1988-08-16 1991-01-01 Latter Victoria S Medicaments

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008122988A1 (en) * 2007-04-05 2008-10-16 Cadila Healthcare Limited Process for preparation of atovaquone and the conversion of cis-isomer to trans- isomer
WO2009007991A2 (en) * 2007-04-19 2009-01-15 Ipca Laboratories Limited A new process for preparation of atovaquone and novel intermediates thereof
WO2009007991A3 (en) * 2007-04-19 2009-11-12 Ipca Laboratories Limited A new process for preparation of atovaquone and novel intermediates thereof
US7847127B2 (en) 2007-04-19 2010-12-07 Ipca Laboratories Limited Process for preparation of atovaquone and novel intermediates thereof
WO2009001367A3 (en) * 2007-06-26 2010-02-18 Hetero Drugs Limited Novel crystalline forms of atovaquone
EP2213647A1 (en) * 2007-06-26 2010-08-04 Hetero Drugs Limited Novel crystalline forms of atovaquone
EP2216315A1 (en) * 2007-06-26 2010-08-11 Hetero Drugs Limited Novel crystalline forms of atovaquone
US8222273B2 (en) 2008-02-04 2012-07-17 Pfizer Limited Polymorphic form of a [1,2,4]triazole[4,3-A] pyridine derivative inflammatory diseases

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JP2007510715A (en) 2007-04-26
CN1878741A (en) 2006-12-13
US20060241311A1 (en) 2006-10-26
EP1768944A1 (en) 2007-04-04
US7847112B2 (en) 2010-12-07
EA200700332A1 (en) 2007-08-31
AU2004320912A1 (en) 2006-04-27
AU2004320912A8 (en) 2008-08-21
KR20070033317A (en) 2007-03-26
WO2006008752A8 (en) 2006-06-15
CA2549871A1 (en) 2006-01-26

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