The present invention provides a process for the preparation of pure acid addition salts of citalopram.
Citalopram is chemically a racemic mixture of 1-(3-dimethylaminopropyl)-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile of Formula I,
(Formula Removed)
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)
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%.
EP Publication No 1,169,314 A1 provides a process for the preparation of crystalline citalopram base from citalopram hydrobromide or from a mixture of citalopram and sulfuric acid. This process provides citalopram base with a purity of about 99.8%.
Preparations of citalopram salts, which are free from impurities 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 acid addition salts of citalopram can be prepared with high purity by a simple process from crude citalopram salts. The present process does not require the isolation of citalopram base and subsequent crystallization steps. Thus the processing steps are minimized in the present invention, while ensuring the purity of the final product. The present invention provides a way to eliminate process related impurities from crude citalopram having purity of 99% or less and to obtain pure acid addition salts of citalopram having purity up to 100%.
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.
The term "crude acid addition salt of citalopram" of the present invention refers to an acid addition salt of citalopram having purity of about 99% or less.
A first aspect of the present invention provides citalopram hydrobromide having HPLC purity of 100%.
A second aspect of the present invention provides a process for the preparation of a pure acid addition salt of citalopram, which comprises
a) treating a crude acid addition salt of citalopram with first organic solvent.
b) treating the reaction mixture obtained in step a) with a base,
c) treating the reaction mixture obtained in step b) with second organic solvent,
d) treating the reaction mixture obtained in step c) with an acid, and
e) isolating a pure acid addition salt of citalopram from the reaction mixture thereof, characterized by the fact that citalopram base is not isolated from the reaction mixture at any step.
A crude acid addition salt of citalopram is treated with a first organic solvent preferably at a temperature of 40°C or less. The first organic solvent is selected from a group comprising of aromatic hydrocarbons, halogenated hydrocarbons, ethers and esters. A base is added to the reaction mixture optionally as an aqueous solution. The base can be an alkali hydroxide, or a primary, secondary or tertiary amine. The reaction mixture is stirred for sufficient time to effect complete liberation of citalopram base. A second organic solvent is added to the reaction mixture followed by the addition of an acid. The second organic solvent is preferably water miscible organic solvent selected from the group comprising of isopropyl alcohol, ethanol, methanol, acetone and acetonitrile. The second organic solvent is optionally free from peroxide. The acid is selected from a group comprising 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. The reaction mixture is optionally treated with activated carbon to remove the coloring impurities. The reaction mixture is then stirred for sufficient time at a temperature less than or equal to 35°C to effect precipitation of the solid. The solid so obtained can be washed with the same or different water miscible organic solvent. The solid is dried under vacuum to obtain pure acid addition salt of citalopram.
Figure 1 depicts HPLC chromatogram of citalopram hydrobromide having 100% purity.
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:
Aqueous ammonia (8.75 ml) was added to a well-stirred solution of crude citalopram hydrobromide (25 g; HPLC purity: 98%) in toluene (125 ml) and water (125 ml) at 15° to 25°C. The resultant biphasic reaction mixture was stirred for 10 minutes and allowed to settle. The aqueous layer was discarded and the organic layer was washed twice with water (125 ml x 2). Peroxide free isopropyl alcohol (280 ml) was added to the organic layer and stirred for 10 minutes. Activated carbon was added to the solution, stirred for 15 minutes and filtered. Aqueous hydrobromic acid (48%; 7 ml) was added to the filtrate, and stirred for 5 h at 25° to 30°C. The solid was separated by filtration and washed with peroxide free isopropyl alcohol. The wet solid so obtained was added to a refluxing solution of peroxide free isopropyl alcohol and deionised water, and the mixture was heated for 15 minutes to obtain a clear solution. Activated carbon was added to the clear solution and heated for 15 minutes followed by filtration with Celite bed and washing with peroxide free isopropyl alcohol. The filtrate was allowed to attain the temperature of about 25°C and stirred for 5 h at the same temperature. The solid was filtered and washed with peroxide free isopropyl alcohol. The solid was dried under vacuum at 40° to 45°C for 12 h to obtain the title compound. Yield: 18 g Purity by HPLC: 100%.

WE CLAIM:
1. Citalopram hydrobromide having HPLC purity of 100%.
2. A process for the preparation of a pure acid addition salt of citalopram, which comprises

a) treating an acid addition salt of citalopram with first organic solvent,
b) treating the reaction mixture obtained in step a) with a base,
c) treating the reaction mixture obtained in step b) with second organic solvent,
d) treating the reaction mixture obtained in step c) with an acid, and
e) isolating a pure acid addition salt of citalopram from the reaction mixture thereof, characterized by the fact that citalopram base is not isolated from the reaction mixture at any step.
3. A process as claimed in claim 2, wherein step a) is carried out at a temperature of
40°C or less.
4. A process as claimed in claim 2, wherein the first organic solvent is selected from
a group comprising of aromatic hydrocarbons, halogenated hydrocarbons, ethers and esters.
5. A process as claimed in claim 2, wherein the base is an alkali hydroxide, or a
primary, secondary or tertiary amine.
6. A process as claimed in claim 2, wherein the second organic solvent is a water
miscible organic solvent.
7. A process as claimed in claim 6, wherein the water miscible organic solvent is
selected from a group comprising of isopropyl alcohol, ethanol, methanol, acetone and acetonitrile.
8. A process as claimed in claim 7, wherein the water miscible organic solvent is free
from peroxide.
9. A process as claimed in claim 2, wherein the acid is selected from a group comprising of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid and embonic acid.
10. A process as claimed in claim 2, wherein step d) is accompanied by stirring at a temperature of 35°C or less.

WE CLAIM:
1. Citalopram hydrobromide having HPLC purity of 100%.
2. A process for the preparation of a pure acid addition salt of citalopram, which comprises

a) treating an acid addition salt of citalopram with first organic solvent,
b) treating the reaction mixture obtained in step a) with a base,
c) treating the reaction mixture obtained in step b) with second organic solvent,
d) treating the reaction mixture obtained in step c) with an acid, and
e) isolating a pure acid addition salt of citalopram from the reaction mixture thereof, characterized by the fact that citalopram base is not isolated from the reaction mixture at any step.
3. A process as claimed in claim 2, wherein step a) is carried out at a temperature of
40°C or less.
4. A process as claimed in claim 2, wherein the first organic solvent is selected from
a group comprising of aromatic hydrocarbons, halogenated hydrocarbons, ethers and esters.
5. A process as claimed in claim 2, wherein the base is an alkali hydroxide, or a
primary, secondary or tertiary amine.
6. A process as claimed in claim 2, wherein the second organic solvent is a water
miscible organic solvent.
7. A process as claimed in claim 6, wherein the water miscible organic solvent is
selected from a group comprising of isopropyl alcohol, ethanol, methanol, acetone and acetonitrile.
8. A process as claimed in claim 7, wherein the water miscible organic solvent is free
from peroxide.
9. A process as claimed in claim 2, wherein the acid is selected from a group comprising of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid and embonic acid.
10. A process as claimed in claim 2, wherein step d) is accompanied by stirring at a temperature of 35°C or less.