The present invention provides a process for the preparation of pure citalopram or acid addition salts thereof.
Citalopram is chemically a racemic mixture of 1-(3-dimethylaminopropyl)-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile of Formula I,
(Formula Removed)
Formula I
Citalopram is commercially available in the form of its hydrochloride or hydrobromide salt which is indicated for the treatment of depression. Citalopram is known to be a selective centrally active serotonin reuptake inhibitor.
US Patent No 4,136,193 discloses a process for preparation of citalopram from corresponding 5-bromo derivative by reaction with cuprous cyanide. The processes disclosed in WO 00/11926 and WO 00/13648 involves the exchange of 5-halogen with cyano group in order to obtain citalopram. The processes comprising such cyanide exchange reactions result in the formation of desmethyl citalopram of formula II in unacceptable quantities.
(Formula Removed)
Formula II
WO 01/45483 provides a method for purification of crude citalopram by removing desmethyl impurity as its acetamide. This method provides free base of citalopram having desmethyl impurity less than 0.1% mol/mol.
US Patent No 6,781,003 discloses a process for methylation of desmethyl impurity present in the citalopram and the pure citalopram is subsequently isolated as an oxalate salt, wherein desmethyl impurity is not detected. The pure citalopram oxalate so obtained is further converted into its hydrobromide salt having HPLC purity of 99.8%.
WO 03/057132 provides a method to remove desmethyl citalopram and other impurities from free base of citalopram by using the oxy compounds of phosphorous. The free base of citalopram so obtained is then converted into citalopram hydrobromide by conventional methods.
WO 03/072565 discloses a method to prepare citalopram oxalate and hydrobromide salts having desmethyl impurity less than 0.1%. As per this disclosure, citalopram free base is converted into its oxalate salt, followed by the liberation of free base of citalopram, and the free base is once again converted into its oxalate salt, wherein the oxalate salt contains desmethyl citalopram less than 0.1%. The oxalate salt so obtained is liberated into a free base, which is
subsequently dissolved in isopropyl alcohol and treated with aqueous hydrobromic acid to obtain citalopram hydrobromide having a purity of 99.7%.
Preparation of citalopram salts, which are free from desmethyl impurity, through the prior art methods are not simple. These methods involve either the use of chemical reactions such as methylation or amidation, reagents like phosphoryl chloride or the repeated oxalate salt formation and free base liberation technique.
The present inventors have found that the use of peroxide containing organic solvents in the preparation of citalopram or its acid addition salts thereof, the level of desmethyl impurity increases through oxidative mechanism. The present inventors have further found that the treatment of a crude citalopram or acid addition salt thereof with a peroxide free water miscible organic solvent eliminates the presence of desmethyl impurity in the final compound and provides a pure citalopram or acid addition salt thereof having purity more than about 99.80%.
The acid addition salts of citalopram of the present invention are preferably salts of pharmaceutically acceptable non-toxic acids such as mineral acid, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like, and organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, embonic acid and the like.
A first aspect of the present invention provides a process for the preparation of a pure citalopram or acid addition salt thereof, which comprises
a) treating citalopram or acid addition salt thereof with a peroxide free organic solvent,
b) isolating pure citalopram or acid addition salt thereof.
Citalopram or acid addition salt thereof is treated with a peroxide free water miscible organic solvent preferably at a temperature more than or equal to 40°C. The peroxide free organic solvent may optionally contain water to effect complete dissolution of the salt. The mixture was then treated with activated carbon to remove the coloring impurities and then filtered. The reaction mixture is then cooled and stirred for sufficient time at a temperature less than or equal to 35°C to effect the precipitation of the solid. The solid so obtained can be washed with the same or different peroxide free water miscible organic solvent. The solid is then dried under vacuum to obtain pure citalopram or acid addition salt thereof.
The peroxide free organic solvent is selected from a group comprising of peroxide free alkanol, esters, ketones, polar aprotic solvents or mixtures thereof. Some examples of peroxide free solvents which can be used are methanol, ethanol, n-propanol, isopropyl alcohol, acetone, dimethylfomnamide, tetrahydrofuran, ethyl acetate, dimethylsulphoxide and acetonitrile. The peroxide free solvent can be prepared by methods known in the art. Some examples include passing through silica or activated alumina bed, treating solvent with reducing agent such as ferrous ions, hydroquinone, BHA, BHT, etc. The level of peroxide in the organic solvent can be checked by peroxide testing strip available from Aldrich®. The strip can be dipped in the solvent to be used and if it shows no change in color, the solvent can be employed for purification.
The HPLC conditions employed for determination of purity of citalopram and for
determination of N-desmethyl impurity are provided below:
Column: Luna C18 (2), 3 micro m (100 mm x4.6 mm)
Guard Column: Kromasil C18, 5 micro m (10 mm x 3.2 mm)
Flow rate: 1.5 ml/min
Detector: UV at 230 nm
Injection Volume: 20 µlit
The LOD of desmethyl impurity is found to be 1 ppm.
While the present invention has been described in terms of its specific embodiments, 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 invention.
EXAMPLE 1
PREPARATION OF PURE CITALOPRAM HYDROBROMIDE
Peroxide free isopropyl alcohol (1.4 L, showing no color change to peroxide testing strip) and de-ionized water (10.0 ml) were taken in a round-bottom flask and heated to reflux at 80°- 82°C. Crude citalopram hydrobromide (100 g) having 0.2% w/w of desmethyl impurity was added to the refluxing solution so obtained and the mixture was stirred for 15 minutes to obtain a clear solution. Activated carbon (10 g) was added to the clear solution so obtained and stirred for 10 minutes, followed by filtration and washing with peroxide free isopropyl alcohol (100 ml X 2). The filtrate was cooled to ambient temperature and stirred for 5 hours at the same temperature. The slurry so obtained was filtered, washed with peroxide free isopropyl alcohol (100 ml X 2) and dried under vacuum at 40° -45°C for 12 h to obtain the title compound.
Yield: 87 g
HPLC Purity: 99.80%
Desmethyl impurity: Not detectable.
REFERENCE EXAMPLE 1
PURIFICATION OF CITALOPRAM BASE
Isopropyl alcohol (1.4 L, showing color change to peroxide testing strip) and de-ionized water (10.0 ml) were taken in a round-bottom flask and heated to reflux at 80°- 82°C. Crude citalopram (100 g) having 0.2% w/w of desmethyl impurity was
added to the refluxing solution so obtained and the mixture was stirred for 15 minutes to obtain a clear solution. Activated carbon (10 g) was added to the clear solution so obtained and stirred for 10 minutes, followed by filtration and washing with isopropyl alcohol (100 ml X 2). The filtrate was cooled to ambient temperature and stirred for 5 hours at the same temperature. The slurry so obtained was filtered, washed with isopropyl alcohol (100 ml X 2) and dried under vacuum at 40°- 45°C for 12 h to obtain the title compound.
Yield: 78 g
Desmethyl impurity: 0.42%

WE CLAIM:
1. A process for the preparation of a pure citalopram or acid addition salt thereof,
which comprises
a) treating acid addition salt of citalopram with a peroxide free water miscible organic solvent,
b) isolating pure acid addition salt of citalopram.
2. A process as claimed in claim 1, wherein the acid addition salt of citalopram is
mineral acid salt.
3. A process as claimed in claim 2, wherein the mineral acid salt is selected from
a group comprising of hydrochloric, hydrobromic, phosphoric and sulfuric acid salts.
4. A process as claimed in claim 1, wherein the acid addition salt of citalopram is
a pharmaceutically acceptable organic acid salt.
5. A process as claimed in claim 4, wherein the organic acid salt is selected from
a group comprising of acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, embonic acid salts.
6. A process as claimed in claim 1, wherein the peroxide free organic solvent is
selected from a group comprising of peroxide free methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylsulphoxide and acetonitrile.
7. A process as claimed in claim 1, wherein the peroxide free water miscible
organic solvent contains water.
8. Pure citalopram or acid addition salt thereof having less than 0.2% of desmethyl impurity prepared by a process which comprises of purification of citalopram or salt thereof from peroxide free organic solvent.
9. Pure citalopram or acid addition salt thereof as claimed in claim 8 having no detectable desmethyl impurity.
10. A process of claim 1 wherein the organic solvent is isopropanol.