FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"Novel polymorph of Atovaquone."
2. APPLICANT
(a) NAME : IPCA LABORATORIES LIMITED
(b)NATIONALITY : Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS : 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification describes the invention

Technical Field of the Invention
The present invention relates to a novel polymorphic form of Atovaquone. More particularly, it relates to novel crystalline form, that has improved solubility and other bulk characteristics suitable for pharmaceutical application. The present invention also relates to processes for preparing such form of Atovaquone and its use in industry. Atovaquone is a useful medicine for the treatment and prophylaxis of Pneomcystis carinii infections.
Background of the Invention
Atovaquone, chemical name being trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, is a hydroxy-l,4-naphtoquinone, an analog of ubiquinone, with antipneumocystic activity. Atovaquone is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. Due to its inhibitory effect in sensitive parasites, atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis.
Atovaquone is the trans-isomer of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone whose synthesis, activity and uses are disclosed in the patent Nos. US5053432 and EP0362996.
There are few reports available for the preparation of Atovaquone exploring various synthetic alternatives. However, there is only single report on the production of a various crystalline form of Atovaquone, as disclosed in WO2006008752. The '752 patent discloses that Atovaquone can exist in three different polymorphic forms (designated as Form I and Form II and Form III) and provided analytical characterization for those polymorphs. The product obtained by the basic molecule patent was characterized for the first time in this publication, and designated as Form I. The stability data of the reported forms are not reported. There are other reports on microparticles of Atovaquone, for


example US6018080 & US6649659 discloses such particles and processes for producing the same. The microparticles of Atovaquone has been ascribed to have increased bioavailability. It has been also narrated that the US5053432 process yielded macroparticles of Atovaquone, and is not suitable to be administered as such or even by conventional milling, due to poor solubility of the crystals in common organic/aqueous solvents. Therefore there is a need in the art to search new forms of Atovaquone, which are having better solubility and improved bioavailability for making suitable dosage forms for pharmaceutical application.
Summary of the Invention:
It has been seen that all the crystalline forms form disclosed in the prior art are substantially coarser crystals and the solubility of those forms are found to be very poor. It has now surprisingly been found that the Atovaquone crystals can occur in a structurally different physical form. Thus the present invention provides Atovaquone in a substantially pure polymorphic form, hereinafter referred to as the compound of the invention. The novel polymorph can be obtained as a well defined compound and is herein after designated as "Form IPCA-ATO". The character of the new form can be defined either by distinct peaks in powder X-Ray pattern, distinct endotherms in DSC or peaks in IR spectrum.
The present invention also provides a process to obtain and a method of differentiating the novel form of Atovaquone from other forms of Atovaquone. The compound of the invention is advantageous because it is found to be stable and well defined crystals with lower bulk density than the corresponding morphologically different Atovaquone compounds in prior art and is therefore appear to have better solubility properties leading to higher bioavailability. The compound of the invention is also easier to characterize because it exists in a well defined state. The compounds are useful for pharmaceutical application and thus the invention includes pharmaceutical compositions containing the compound of the present invention.


Brief Description of the Drawings:
Fig. 1 shows an X-Ray Powder Diffractogram of an exemplary batch of "Form IPCA-
ATO" of Atovaquone obtained in accordance with the invention.
Fig 2. shows Infra -Red spectra of "Form IPCA-ATO" of Atovaquone obtained in
accordance with the invention.
Fig.3 shows an Differential Scanning calorimetry analysis diagram of an exemplary batch
of "Form IPCA-ATO" of Atovaquone obtained in accordance with the invention
Detailed Description of the Invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
The term "isolating" is used to indicate separation or collection or recovery of the compound of the invention being isolated in the specified form. The term "separating from a solvent" with respect to the solids described herein means obtaining a solid of specified characteristics from a solution or a partial solution.


The term "treating" means adding or combining or mixing the stated reagent or materials to the things being treated. The term "forming a solution" means obtaining a solution of a substance in a solvent in any manner. It encompasses partial solutions.
The term 'stable' as used herein, refers to the tendency to remain substantially in the same physical form for at least a month, preferably at least 6 months, more preferably at least a year, still more preferably at least 3 years, when stored under ambient conditions (20 °C/60% RH) without external treatment. Substantially the same physical form in this context means that at least 70%, preferably at least 80% and more preferably at least 90% of the crystalline form remains.
For the purposes of this description and claims of the present invention, the phrase "Atovaquone 'Form IPCA-ATO' refers to the novel form of Atovaquone, wherein the TPCA-ATO', is referring to a crystalline form of Atovaquone that one of skill in the art can identify as a distinct entity distinguishable from other crystalline forms of Atovaquone based on the characterization details provided herein with the present invention. As used herein, the phrase having "at least one characteristic of "Form IPCA-ATO" ', refers to a crystalline form of Atovaquone that possesses at least one of the characteristic PXRD peaks or distinct peaks in Infra Red spectrum provided herein. For example, a single or a combination of PXRD peaks which are not found in another crystalline form of Atovaquone is enough to show at least one of the characteristics of "Form IPCA-ATO" of Atovaquone, the compound of the present invention. A single or a combination of peaks in an FT IR spectrum provided herein with this invention may also serve the same purpose.
Identification of solids obtained by the present invention can be made by methods known in the art per se such as X-Ray powder diffraction, Fourier Transform Infrared (FT-IR) spectra and of course, it should be understood that operator, instrument and other similar changes may result in some margin of error with respect to analytical characterization of the solid.


The FTIR, DSC and XRPD methods used for the identification and characterization of the novel form of Atovaquone are described below:
a) FT-IR spectral analysis
FTIR spectra of novel form were recorded directly on untreated powder by means of spectrometer. Spectra was recorded at room temperature from 4000 cm-1 to 650 cm-1, for each sample 32 scans were collected at a resolution of 4 cm-1.
b) X-ray powder diffraction studies.
Analytical characterization of the compound according to the invention was carried out by using X-ray powder diffraction using a PANalytical XpertPRO X-Ray machine of Philips make. The X-ray powder diffraction patterns were recorded with Cu K alpha-1 radiation source (voltage of 45 kV; current: 40 mA)„ The step scan mode was performed with a step size of 0.008 °, at a scan rate of 14.59 step/s.
c) Differential Scanning Calroimetry (Abbreviated as DSC).
Differential scanning calorimetry analysis of the novel form was recorded at a heating rate of 10 °C per minute at a temperature range from 50 °C to 250 °C.
The compound of the invention is characterized by the positions of the major peaks in the X-ray powder diffractogram, but may also be characterized by conventional FT-IR spectroscopy and endotherms in DSC diagram. These characteristics are not exhibited by any other form of Atovaquone and accordingly, the "Form IPCA-ATO" of the present invention is easily distinguishable from any other crystal form of the Atovaquone disclosed in prior art.
Thus, the character of this new form ("Form IPCA-ATO") is confirmed either by PXRD patterns, DSC endotherms and FT IR spectra obtained from a sample thereof which are provided as Figures 1 to 3 respectively. The PXRD pattern shows at least one characteristic and exclusive peak at about 6.66 & 10.05 ±0.2 degrees 2 theta angles. More particularly the PXRD pattern shows characteristic and exclusive peaks at 6.66, 10.05, 13.11, 18.27, and 23.10 ±0.2 degrees 20 angles.


The novel form of Atovaquone "Form IPCA-ATO" is further characterized by FT-IR spectra having peaks at 3369, 2935, 1633, 1383, 1338, 1312, 1231and 1053 cm-1, which are characteristic for the present form. More particularly the FTIR spectra shows characteristic peaks at 6.66, 10.05, 13.11, 18.27, and 23.10 ±0.2 degrees 29 angles.
The novel form of Atovaquone "Form IPCA-ATO" is further characterized by endotherms in a DSC. Thermal analysis results in a Differential Scanning calorimeter thermogram taken at a heating rate of 10 degree Celsius per minute in a open pan that exhibits a melting endotherm with a peak temperature of about 117-130 °C, and a second endotherm having peak at about 220-222 °C. The position of the first endotherm can shift the position depending upon the heating rate and any contaminations resulting there from.
The main peaks, with positions and relative intensities, have been extracted from the diffractogram in FIG. 1 and are given below in table 1. The relative intensities are less reliable and some additional very weak peaks found in the diffractogram have been omitted from table 1.
Table 1;

2q values in d spacing Percentage relative
degrees intensity
6.6 13.42 30.06
9.9 8.8 12.58
13.1 6.7 6.36
18.2 4.8 100.00
23.0 3.8 28.93
32.9 2.7 4.87
In a further aspect, the present invention provides processes for the preparation of the Atovaquone "Form IPCA-ATO" which comprises; i) contacting Atovaquone of any physical form in an organic solvent to obtain a solution at a suitable temperature for a


suitable time; ii) subjecting it to rapid chilling; and recovering the novel form from the reaction solution.
In one embodiment of the present invention, preparation of "Form IPCA-ATO" comprises i) subjecting a solution of Atovaquone to chilling either in a cold bath of liquid nitrogen or dry ice bath prepared in a suitable solvent medium until frozen and removing the solvent from the mass thus obtained to recover the new crystals of Atovaquone. Alternately the atovaquone solution may be added to either liquid nitrogen or dry ice to precipitate the new form followed by removing the solvent. The solvent may be removed under vacuum in a lyophilizer. The organic solvents may be selected from, but not limited to, chlorinated solvent, especially dichloromethane.
By a suitable temperature is meant a temperature which the solution can be formed and be able to induce the transformation of atovaquone into the novel form. Examples of such suitable temperatures include, but are not limited to, room temperature, preferably lower than room temperature, still preferably less than 0 °C and more preferably less than minus 30 °C. By a suitable time is meant a time that results in better conversion of the starting material into novel crystalline form without causing any decomposition of either compounds, i.e. results in a good yield. This suitable time will vary depending on the mode of chilling used, can be established by routine experimentation. The faster the rate of cooling, the shorter time is needed to give the desired conversion. The amount of solvent is not crucial and will depend on the process conversion & conditions desired. To have complete conversion to the novel form of the present invention, complete dissolution of Atovaquone in the selected solvent is desired. The process conditions are further illustrated in the Examples.
Atovaquone has been indicated for use in the following indications: Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. It may be used alone or concomitantly with other classes of agents like mefloquine or proguanil (Anti-malarials).


In a further aspect the invention thus provides new compound which is Atovaquone "Form IPCA-ATO" for use in treating Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii, either alone or in combination with other antimalarials. In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of Atovaquone "Form IPCA-ATO" in any given case will depend on the nature and severity of the disease to be treated. The dose, dose frequency may also vary according to the age, body weight and response of the individual patient.
The invention thus provides pharmaceutical compositions containing Atovaquone "Form IPCA-ATO" which may optionally contain other crystalline forms and/or other active pharmaceutical drugs. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention can contain one or more commonly used pharmaceutical excipients. Excipients are added to the composition for a variety of purposes.
The comparative solubility studies indicating the bioavailablity of the new form is under evaluation. The starting Atovaquone may be obtained by following any known process disclosed in the literature.
The examples provided below are illustrative and are not intended to limit the scope of the claimed invention.
Example:
Example 1
1.0 grams of Atovaquone (Form I) was taken in 35 ml of dichloromethane at room temperature. It was dissolved completely and filtered out any undissolved particles. The solution was then chilled on a nitrogen bath until the dichloromethane solution solidified. The material was lyophilized and dichloromethane was removed completely to obtain novel crystalline form. Yield 1.0 gm. The XRPD, IR spectra & DSC of the sample were recorded and are reproduced in figure 1 to 3.


Example 2
1.0 grams of Atovaquone (Form I) was taken in 35 ml of dichloromethane at room temperature. It was dissolved completely and filtered out of any undissolved particles. The solution was poured on a liquid nitrogen taken in another vessel until the dichloromethane solution solidified. The solid obtained lyophilized and dichloromethane was removed completely to obtain novel crystalline form. Yield 1.0 gm. The XRPD, IR spectra & DSC of the sample were recorded and are reproduced in figure 1 to 3.