WO2006008752A1 - Novel polymorphs of atovaquone and process of preparation thereof - Google Patents
Novel polymorphs of atovaquone and process of preparation thereof Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- atovaquone
- solvent
- solution
- solublizing
- elevated temperature
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
- C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/10—Separation; Purification; Stabilisation; Use of additives
Definitions
- 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.
- 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.
- 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 197 0 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.
- 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.
- compositions comprising therapeutically effective amount of polymorphs II and III of Atovaquone are also disclosed herein.
- a method of treating Pneumocystis carinii pneumonia 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.
- 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.
- 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.
- room temperature means a temperature from about 25 0 C to 30 0 C.
- Atovaquone is prepared by the method described in US, 4,981,874 which is referred as Form I.
- Form I The X-ray powder diffraction diagram and DSC thermograms of Form I are shown in Figs. 1 and 4 respectively.
- Atovaquone Form II 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
- Atovaquone Form I 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.
- 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
- Atovaquone Form I 0.5 g Atovaquone Form I was dissolved in 20 niL Acetone under reflux condition. 40 ml of water was maintained at O 0 C 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.
- 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
- 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.
- 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 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
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006539076A JP2007510715A (en) | 2004-07-16 | 2004-07-16 | A new polymorph of atobacon and its preparation process |
US10/569,036 US7847112B2 (en) | 2004-07-16 | 2004-07-16 | Polymorphs of atovaquone and process of preparation thereof |
EP04806730A EP1768944A1 (en) | 2004-07-16 | 2004-07-16 | Novel polymorphs of atovaquone and process of preparation thereof |
CA002549871A CA2549871A1 (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 |
AU2004320912A AU2004320912A1 (en) | 2004-07-16 | 2004-07-16 | Novel polymorphs of atovaquone and process of preparation thereof |
EA200700332A EA200700332A1 (en) | 2004-07-16 | 2004-07-16 | NEW ATOVAKHONA POLYMORPHES AND METHOD FOR THEIR PRODUCTION |
CNA2004800328769A CN1878741A (en) | 2004-07-16 | 2004-07-16 | Novel polymorphs of atovaquone and process of preparation thereof |
KR1020067012150A KR20070033317A (en) | 2004-07-16 | 2004-07-16 | Novel Polymorphs of Atobaquion and Methods for Making the Same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN2004/000213 WO2006008752A1 (en) | 2004-07-16 | 2004-07-16 | Novel polymorphs of atovaquone and process of preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2006008752A1 true WO2006008752A1 (en) | 2006-01-26 |
WO2006008752A8 WO2006008752A8 (en) | 2006-06-15 |
Family
ID=34959816
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2004/000213 WO2006008752A1 (en) | 2004-07-16 | 2004-07-16 | Novel polymorphs of atovaquone and process of preparation thereof |
Country Status (9)
Country | Link |
---|---|
US (1) | US7847112B2 (en) |
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)
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)
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 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5856362A (en) * | 1994-09-02 | 1999-01-05 | Glaxo Wellcome Inc. | Medicaments for the treatment of toxoplasmosis |
-
2004
- 2004-07-16 US US10/569,036 patent/US7847112B2/en not_active Expired - Fee Related
- 2004-07-16 CA CA002549871A patent/CA2549871A1/en not_active Abandoned
- 2004-07-16 CN CNA2004800328769A patent/CN1878741A/en active Pending
- 2004-07-16 JP JP2006539076A patent/JP2007510715A/en not_active Withdrawn
- 2004-07-16 KR KR1020067012150A patent/KR20070033317A/en not_active Application Discontinuation
- 2004-07-16 AU AU2004320912A patent/AU2004320912A1/en not_active Abandoned
- 2004-07-16 EA EA200700332A patent/EA200700332A1/en unknown
- 2004-07-16 WO PCT/IN2004/000213 patent/WO2006008752A1/en active Application Filing
- 2004-07-16 EP EP04806730A patent/EP1768944A1/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Non-Patent Citations (2)
Title |
---|
BERNSTEIN J: "Polymorphism of pharmaceuticals", POLYMORPHISM IN MOLECULAR CRYSTALS, 2002, pages 253 - 255, XP002308143 * |
BRITAIN ET AL: "Polymorphism in Pharmaceutical Solids passage", POLYMORPHISM IN PHARMACEUTICAL SOLIDS, 1999, pages 235 - 238, XP002278123 * |
Cited By (8)
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 |
Also Published As
Publication number | Publication date |
---|---|
EP1768944A1 (en) | 2007-04-04 |
JP2007510715A (en) | 2007-04-26 |
AU2004320912A1 (en) | 2006-04-27 |
CA2549871A1 (en) | 2006-01-26 |
US7847112B2 (en) | 2010-12-07 |
US20060241311A1 (en) | 2006-10-26 |
EA200700332A1 (en) | 2007-08-31 |
WO2006008752A8 (en) | 2006-06-15 |
KR20070033317A (en) | 2007-03-26 |
AU2004320912A8 (en) | 2008-08-21 |
CN1878741A (en) | 2006-12-13 |
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