FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"PROCESS FOR PREPARING ALMODIPINE MESYLATE
MONOHYDRATE"
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
The present invention is concerned with a process for preparing amlodipine mesylate monohydrate.
BACKGROUND OF THE INVENTION
Amlodipine is the international non-proprietary name of 2- [(2-Aminoethoxy)- methyl]-4- (2-chlorophenyl)-l, 4-dihydro-6-methyl-3, 5-pyridinecarboxylic acid 3-ethyl 5- methyl ester. Amlodipine is known to be a calcium channel blocker and has therapeutic applications in the treatment or prevention of a number of cardiac conditions, such as angina pectoris, cardiac arrythmias, heart attacks, cardiac hypertrophy and related cardiac conditions, and also as an antihypertensive agent, for example in the treatment of coronary vasospasm. Amlodipine is the title compound of Example 9 of European Patent 0089167B and its preparation is described therein. European Patent 0089167B describes suitable pharmaceutically acceptable salts of the compounds described therein, including the hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleat, fumarate, lactate, tartrate, citrate and gluconate salts. Maleate is described as the preferred salt. The preparation of the maleate salt of amlodipine is described in Examples 11 and 12 of European Patent 0089167B.
European Patent Application 0244944A describes further salts of amlodipine, and describes the besylate salt of amlodipine as being a particularly preferred salt.
US Patent 6057344 describes the use of (-) amlodipine, substantially free of its (+) stereoisomer, in eliciting an antihypertensive effect and also for use in the treatment of angina. Preferred pharmaceutically acceptable salts described in US Patent 6057344 are derived from besylate, hydrobromic, hydrochloric, phosphoric and sulphuric acids. US Patent Application 2002/0045648 describes a pharmaceutical composition comprising an NO-releasing amount of the R (+) enantiomer of amlodipine or of a pharmaceutically acceptable salt thereof, an antihypertensive amount of the S (-) enantiomer of amlodipine or of a pharmaceutically acceptable salt thereof and a suitable excipient, diluent or carrier, wherein the enantiomers are present in a ratio by weight (based on free base) of R (+) enantiomer: S (-) enantiomer of greater than 1:1.

iropean patent application 1221438A describes the preparation of two different crystalline forms of amlodipine mesylate. The first described crystal form, referred to as form A, has a melting point of 1844EC and is described as being essentially water free and as such having a water content of 0. 2% by weight. The second described crystal form, referred to as form B, has a melting point of 1453EC and has a water content of 3.4% by weight and is described as the monohydrate. The preparation of the monohydrate form B from amlodipine free base is described in Example 2.
STATEMENT OF INVENTION
The provision of a monohydrate form of amlodipine, such as for example, amlodipine mesylate monohydrate, can be desirable as the monohydrate can exhibit advantageous stability and non-hygroscpic properties, and as such can also exhibit good handling properties. We have now developed an improved process of preparing amlodipine mesylate monohydrate, which can yield a highly pure and stable product.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, there is provided by the present invention a process for preparing
amlodipine mesylate monohydrate, which process comprises preparing amlodipine mesylate
monohydrate either from anhydrous amlodipine mesylate, or in the presence of a water
immiscible solvent medium from amlodipine free base and methane sulphonic acid.
In a first aspect of the present invention wherein amlodipine mesylate monohydrate is
prepared from anhydrous amlodipine mesylate, a process according to the present invention
comprises dissolving anhydrous amlodipine mesylate in a water miscible solvent medium,
and crystallising amlodipine mesylate monohydrate therefrom.
Suitably the water miscible solvent medium can comprise one or more lower alcohols, such
as any of CI 3 alcohols. Preferably methanol may be employed in the water miscible solvent
medium. The use of methanol can be particularly desirable as it can yield highly pure, stable,
white crystalline amlodipine mesylate monohydrate.
In a second aspect according to the present invention wherein amlodipine mesylate
monohydrate is again prepared from anhydrous amlodipine mesylate, a process according to
the present invention comprises exposing anhydrous amlodipine mesylate to an atmosphere
saturated with moisture so as to yield amlodipine mesylate monohydrate.
In a third aspect according to the present invention wherein amlodipine mesylate
monohydrate is prepared from amlodipine free base, suitably the water immiscible

solvent medium comprises ethylcmer, ethylaoetate, dichlororacthanc or the like, preferably ethyl acetate. It is also generally preferred that a first reaction mixture comprising amlodipine free base dissolved in the water immiscible solvent medium, typically ethyl acetate, is prepared, a second reaction mixture comprising methane sulphomc acid dissolved in a water immiscible solvent medium, again typically ethyl acetate, is prepared, and the fast and second reaction mixtures are contacted under conditions to yield amiodipine mesylate monohydrate.
The present invention will now be illostrsted by tliefollovwng Examples vvhich do inrtlinTitmeswpeoftoiimintionm in any way.
Figure 1 shows a DSC thermogram of amlodipme mesylate monohydrate as obtained by the following Example* 1,2 and 3.
Example 1
Anhydrous amlodipme mesylate 75% was dissolved in a mixture of methanol 50ml
and isopropanol 250ml at SOEC and the resulting solution was filtered under nitrogen.
The dear filtrate was cooled to lOBC and the resulting crysials filtered The material was
dried under vacuum at 35EC for 4 hours to give anUompmen3esylatenionobydrate22.4g. The water content was about 3.5%.
Anhydrous amiodipine mesylate was exposed to an atmosphere saturated with moisture tor 2 to 4 hours. Amiodipine mesylate monohydrate was unloaded and the moisture content thereof was about 3.4%.
Bxamole3
Amiodipine free base (25gms) was dissolved in ethyl acetate (300mi) at room temperature. 6.25gms of methane sulphonic acid was separately dissolved in 250ml of ethyl acetate. The amiodipine tree base solution was cooled to 20EC under a nitrogen blanket and me clear methane sulphonic acid solution was added The reaction mass was stirred for 1 hour and filtered. The material was dried under vacuum and nitrogen, to yield amiodipine mesylate monohydrate having a moisture content of about 3.32%.

100 grams of pirfhaloyl amlodipine is stirred in a mixture of 40% aqueo
monomethylamine (700 ml) and dfehloromethane (500ml) at ambient temperature for
hours. After reaction completion, the dichloramethane layer is separated and the organ
layer is washed with water. The dichloromethane layer is dried over sodium sulfate an
distilled to about half the original volume. Ethyl acetate (1000 ml) is added and tfa
distillation continued till a total volume of 600 ml is left behind. The contents are the
cooled to 25-30°C.
Methane sulfonic acid (18 gm) is dissolved in 100 ml of ethyl acetate and is added to the above solution in 30- 45 mins. at 20 » 2S°C maintaining an inert atmosphere. Then the contents are stirred for 1 hour at 0 - 5 "C for 30 nims atri filtered to give aridodipine mesylate monohydrate 60 gm.
SsamnJe^S
100 grams of phthaloyl amlodipine is stirred in 20% methanobe moiwmethylamine (1000 ml.) for 12 hours at room temperature. After reaction completion, the reaction mass is distilled to half of its original volume and 800 ml of dichloromethane is added and further distilled till a total of 500 ml remains in the reaction flask. The dichloromethane layer is washed wim water and dried over sodium sulfate. The ctfchloromethane layer is distilled to half the original volume. 1000 ml ethyl acetate is added and further distilled till 600ml of solution is retaiiied The ointeiito are then cooled to25-30°C.
18 gm of methane sulfonic acid dissolved in 100 ml of ethyl acetate is added to the above solution in 30 - 45 mins. at 20 - 25°C under an inert atmosphere. 100 ml methanol and 10 ml purified water are added and warmed to 40-45°C. The contents are men stirred at 25 - 30°C for 1 hour, cooled and filtered to give amlodipine mesylate monohydrate 55 gm.
Anhydrous amlodipine mesylate 25 gm was dissolved in a mixture of methanol 25 ml isopropanol 250 ml and water 2.5 ml at 50EC and tile resulting solution was filtered

under nitrogen. The clear filtrate was cooled to 20EC and the resulting crystals filtered The material was dried under vacuum at 35EC for 4 hours to give amlodipine mesylate monohydrate 21.8 gin. The water content was about 3.5%.
Example 7
Anhydrous amlodipine mesylate 25 gm was dissolved in ethyl acetate 300 ml at 50EC. Methanol 20 ml and water 5 ml were added and the resulting solution was filtered under nitrogea The clear filtrate was cooled to 10BC and the resulting crystals filtered The material was dried under vacuum at 35EC for 4 hours to give amlodipine mesylate monohydrate. The water content was about 3.6%.
Anhydrous amlodipine mesylate 50 gm was dissolved in methanol 150 ml and
water 20 mL Methanol was distilled off and simultaneously replaced with an equal
quantity of acetone. When crystals began to appear, the distillation was stopped and me
contents cooled to I0°C and the crystals filtered ITic material was dric^imdcr vacuum at
35EC for 4 hours to give amlodipine mesylate monohydrate 43 gm. The water content
was about 3.4%.

We Claim:
1. A process for preparing amlodipine mesylate monohydrate, which process comprises preparing amlodipine mesylate monohydrate from amlodipine free base and methane sulphonic acid in the presence of the ethyl acetate.
2. A process as claimed in claim 1, wherein a first reaction mixture comprising amlodipine free base dissolved in ethyl acetate is prepared, a second reaction mixture comprising methane sulphonic acid dissolved in a water immiscible solvent medium is prepared, and first and second reaction mixtures are contacted under conditions to yield amlodipine mesylate monohydrate.
3. A process as claimed in claim 2, wherein the water-immiscible solvent is ethyl acetate.
4. A process as claimed in claims 2 or 3, wherein the first reaction mixture is cooled to 20°C under a nitrogen blanket.
5. A process as claimed in claims 2, 3 or 4, wherein the first and second reaction mixtures are contacted and stirred for 1 hour.
6. A process as claimed in any preceding claim, wherein the amlodipine mesylate monohydrate is isolated by filtration.
7. A process as claimed in any preceding claim, wherein the amlodipine mesylate monohydrate is dried under vacuum.