FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)

"PURIFICATION OF CITALOPRAM

»

CIPLA LIMITED, of 289 Bellasis Road, Mumbai Central, Mumbai - 400 008, India.



The following specification particularly describes the invention and the manner in which it is to be performed.


FIELD OF INVENTION
This invention relates to pharmaceutical purification, more particularly to purification of citalopram.
BACKGROUND OF THE INVENTION
Citalopram is a well known antidepressant drug whose systematic name is l-[3-
(diinethylamino)propyl]-K4-mi^^ It is
a selective centrally acting serotonin (S-hydroxytryptamine; S-HT) reuptake inhibitDr. It is marketed as the hydrobromide or hydrochloride salt An important enantiomer is S-citalopram.
Citalopram was first described in GB-A-1526331 and, subsequently, a number of different processes have been described for its preparation. In many of these, the final step is to introduce the 5-cyano group but there have been problems in purifying the final product to remove intermediates and by-products. Among the purification processes used has been isolation of the free base as an oil (bp 175°C/0.03 mm Hg) and subsequent thin film distillation followed by conversion to the desired salt Another purification process involves conversion to a salt and recrystallisation thereof. Neither of these techniques has been particularly satisfactory.
Recently, another purification procedure has been described in GB-B-2357762. Here, citalopram base is set free and precipitated in crystalline form, and after optional recrystallisation for purification, converted to the desired salt. This process is said to be particularly effective at removal of 5-substituted intermediate contaminants. However, a disadvantage of this process is that it requires repeated crystallisations to achieve high purity and this is undesirable.
We have now found another way of purifying citalopram which has a number of advantages over prior known processes.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with one aspect of the present invention, crude citalopram is purified by adsorption on iusglid supported sufep
1. A method of purifying citalopram base which comprises adsorbing the base
on a solid support and subsequently releasing the purified base therefrom.
2. A method as claimed in claiml, wherein the solid support is in loose particulate form.
3. A method as claimed in claim 1 or 2, wherein the solid support is diatomaceous earth, clay, silica or alumina.

4. A method as claimed in claiml, 2 or 3, wherein the weight ratio of citalopram base to solid support is from 1: 0.5 to 1: 20.
5. A method as claimed in any of claims 1 to 4, wherein the solid support having said citalopram base adsorbed thereon is washed to leach out impurities.
6. A method as claimed in claim 5, wherein the solid support is washed with an organic solvent comprising an aliphatic hydrocarbon, optionally in combination with a lower alcohol or an aromatic solvent.
7. A method as claimed in any of claims 1 to 6, wherein the citalopram base is desorbed from the solid support by washing with a polar solvent for the base.
8. A method as claimed in claim 7, wherein the solvent is an aliphatic ketone, an ester, an open chain or cyclic ether, or a Ci to C4 alcohol, and particularly acetone, ethyl acetate, methanol, isopropanol, ethanol or tetrahydrofuran.
9. A method as claimed in any of claims 1 to 8 to purify Citalopram base.
10. A method of making a pharmaceutically acceptable salt of citalopram which comprises directly converting a solution of citalopram base purified by the method as claimed in any of claims 1 to 8, to a pharmaceutically acceptable salt thereof.