DESCRIPTION

The present invention provides a chemical process for controlling the particle size of Atovaquone.

Atovaquone  chemically known as trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1 4-naphthalenedione of Formula I
Formula I

Atovaquone is a widely used antiprotozoal and is potently active (in animals and in vitro) against Pneumocystis carinii  Plasmodia  and tachyzoite and cyst forms of Toxoplasma gondii. It is a highly lipophilic compound resembling ubiquinone and has a low aqueous solubility. This is the reason for the poor bioavailability of atovaquone after oral administration.

U.S. Patent No. 4 981 874 discloses the use of atovaquone against Pneumocystis carinii infection in a mammal. EP Patent No. 0 123 238 and U.S. Patent No. 5 053 432 disclose the use of atovaquone against Plasmodium falciparum and also against Eimeria species such as E. tenella and E. acervulina which are causative organisms of coccidiosis. Further  use of atovaquone against Toxoplasmosis and Cryptosporidiosis is disclosed in EP Patent No. 0 445 141 and 0 496 729 respectively.

Currently  atovaquone suspension marketed under trade name MEPRON is a formulation of micro-fine particles of atovaquone. The atovaquone particles are reduced in size to facilitate absorption. These particles are significantly smaller than those in the previously marketed tablet formulation. Further  U.S. Pat. Nos. 6 018 080 and 6 649 659 disclose microfluidized particles of atovaquone having improved bioavailability  wherein at least 90% of atovaquone particles have a volume diameter in the range of 0.1-3 micron. The process disclosed in US ‘080 and US ‘659 utilizes subjecting a mixture of Atovaquone with liquid vehicle to at least 3 passes throgh microfluidizer to provide a microfluidised particles  which is not a conventional technique of reducing the particle size of atovaquone. This method can be time consuming  costly  and not suitable for industrial implementation.

PCT application No. 2009001367 discloses a process for the prepaption of atovaquone substantially free of isomeric impurity by using potassium hydroxide solution and hydrochloric acid.

US application No. 20080241254 A1 discloses atovaquone having d90 particle size value of about 4-15 mm obtained by air jet milling.

PCT application No. 2010023686 A2 discloses a process of micronization to provide particle size d90 of atovaquone between 3 to 10 mm.

US application No. 2011206770 A1 discloses atovaquone having particle size diameter range with a d90 between greater than 3 to about 10 mm. The ‘770 patent application discloses conventional comminution and de-agglomeration techniques  for example grinding in an air-jet mill or impact mill  a ball mill  vibration mill  mortar mill or pin mill  micro-fluidisation and Chemical techniques such as controlled precipitation and/or recrystallisation to provide controlled particle size. However  it does not disclose feasible and conventional controlled method to obtain required particle size of Atovaquone.

Therefore  there is a need to develop an improved process for controlling particle size of Atovaquone. The inventors of the present invention found a conventional and industrially feasible process to provide contronlled particle size of Atovaquone.

In an aspect of the present invention  there is provided a process for the preparation of microparticles of Atovaquone  which comprises:
a) providing a solution of Atovaquone in a solvent;
b) treating the solution of Atovaquone with base; and
c) combining the solution of step (b) with an organic acid to provide microparticles of Atovaquone.

The step a) involves providing a solution of atovaquone in a solvent. The solution may be obtianed by the dissolution of in a suitbale solvent or it may be obtained from a previous processing step where atovaquone is formed in a solution. Any form of atovaquone is acceptable for providing solution  for example  amorphous and crystalline. The suitable solvent includes but are not limited to alcohol such as methanol  ethanol  isopropyl alcohol  n-butyl alcohol and the like; ketone such as acetone and the like; ether such as tetrahydrofuran and the like; or water combination thereof.

The solution may be prepared at any temperatures up to the boiling point of the solvent  which may range from about 20°C to about 180°C.

The step b) involves treating the solution of Atovaquone with base. The suitable base is selected from inorganic base such as sodium hydroxide  potassium hydroxide  ammonium hydroxide  sodium bicarbonate  potassium bicarbonate  and the like.

The solution may be optionally treated with an agent such as activated charcoal to enhance the color of the compound  then typically will be filtered through an inert medium  such as through a bed of flux calcined diatomaceous earth (e.g.  HYFLO)  to remove the carbon.

The solution may optionally be filtered by passing through paper  glass fiber  or other membrane material  or a bed of a clarifying agent  such as CELITE. Depending upon the equipment used and the concentration and temperature of the solution  the filtration apparatus may need to be heated to avoid premature crystallization.

The step c) combincing the solution of step (b) with an organic acid to provide microparticles of Atovaquone.

The suitable organic acid is selected from formic acid  acetic acid  trifluoroacetic acid and the like. The suitable temperature may be at any temperature  preferably  room temperature.

The addition of acid may be performed in a sigle lot at once to influence the particle size of Atovaquone. The reaction may be stirred for a period of 30 minutes to 1 hour or more to enhance the formation of microparticles of Atovaquone.

The resultant particles of Atovaquone have volume diameter for at least 90% particles less than or equal to 3 microns.

The particles of Atovaquone obtained from the process of the present invention can be utilized for the preparation of pharmaceutical composition along with one or more pharmaceutically acceptable carrier  wherein at least 90% particles of Atovaquone have a volume diameter less than 3 microns.

The present invention is further illustrated by the following example  which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLE:
Chloroatovaquone (50 g  0.129 mol) was charged into methanol (900 ml) and heated it to reflux. At reflux temperature  10 % aqueous solution of Potassium hydroxide (21.8 g  0.389 mole) was added in 15-20 minutes. The reaction mixture was stirred for 2.5- 3 hours. The reaction mixture was filtered and then acetic acid (162 ml) was charged to the filtrate at 60 °C in 10-15 min to get the pH 3-4. The reaction mixture was stirred for 30-45 minutes  filtered at 50-60 0C and then washed the cake with warm water. The solid was suck dried.

Wet wt 72 .0 g
m/c 37.8 % w/w.
HPLC purity 98.94 % rel.
Particle size distribution (d90) : 24.55

Atovaquone wet (8.0 g  m/c 37.8% w/w) was dissolved in methanol (80 ml). Potassium hydroxide solution (prepared from 3 mole eq. KOH (2.2 g and 80 ml of water) was added  stirred for 15-20 minutes  filtered through filter paper to remove foreign particle and then washed with 40 ml 1:1 methanol water mixture. Acetic acid (20 ml) was charged at once to the resultant filtrate to get pH 3-4. The reaction mixture was stirred for 45-60 minutes  filtered and then washed with water. The solid was dried under vacuum at 60 0C.

Dry wt 4.5 g
PSD 1.96
PXRD Form-1
HPLC purity: 99.6 %

We Claim:

1. A process for the preparation of microparticles of Atovaquone  which comprises:
a) providing a solution of Atovaquone in a solvent;
b) treating the solution of Atovaquone with base; and
c) combining the solution of step (b) with an organic acid to provide microparticles of Atovaquone.

2. The process of claim 1  wherein said solvent is selected from alcohol.

3. The process of claim 1  wherein said base is inorganic base.

4. The process of claim 1  wherein said organic acid is selected from formic acid  acetic acid and trifluoracetic acid.

5. The process of claim 1  wherein said organic acid is charged at once.

6. The process of claim 1  wherein said microparticles at least 90% have volume diameter less than or equal to 3 microns.