FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"IMPROVED PROCESS FOR PREPARING ANHYDROUS TIOTROPIUM
BROMIDE"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

Field of the Invention:
The present invention relates to an improved process for preparing anhydrous tiotropium bromide.
Background and Prior Art:
Tiotropium bromide, an anticholinergic bronchodilator, is used in the management of chronic obstructive pulmonary disease. It was first disclosed in EP0418716.
EP1401445 describes anhydrous form of tiotropium bromide and the process for its preparation. The process involves carefully drying the monohydrate form at 80 to 100°C under reduced pressure, preferably under vacuum or storing the crystalline tiotropium bromide monohydrate over dried silica gel at ambient temperature for atleast 24 hours.
WO2006117299 discloses preparation of crystalline anhydrous tiotropium bromide by dissolving crystalline tiotropium bromide monohydrate in a solvent mixture comprising N,N-dimethylacetamide, heating to about 30-70°C, cooling below 15°C, isolating and drying the crystals.
WO2006117300 describes a process for preparing anhydrous form of tiotropium bromide wherein a solution of crystalline tiotropium bromide monohydrate in dimethylformamide is added to acetonitrile and cooled to a temperature below 20°C.
CN100410254 discloses the preparation of anhydrous tiotropium bromide using scopolamine.
Objects of the Invention:
The main object of the present invention is to provide an improved process for preparing non-hygroscopic and stable anhydrous tiotropium bromide.
Another object of the present invention is to provide a simple, efficient and economical process for preparation of anhydrous tiotropium bromide.

Description of the Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Tiotropium bromide is administered preferably by the inhalation route. Inhalation mode of delivery significantly reduces the clinically effective dose of tiotropium while maintaining high local drug concentration. During the manufacture of an inhalation composition many factors play an important role, for example, nature of the active drug substance. Crystalline form mainly due to its higher stability is more acceptable over the amorphous form. Any change to the solid state of a pharmaceutical composition which is capable of improving its physical and chemical stability gives a significant advantage over less stable forms of the same medicament. It is particularly desirable that the active substance should be prepared in the form of a uniform and clearly defined crystalline modification.
It is known from prior art that an anhydrous crystalline modification of tiotropium bromide meets these stringent requirements mentioned above. Accordingly the process of present invention provides an improved, simpler and commercially economical technique for preparing pure, stable and non-hygroscopic anhydrous tiotropium bromide.
The process of present invention comprises use of distillation technique for preparation of anhydrous tiotropium bromide.
The various distillation techniques known in the art are simple distillation, fractional distillation, vacuum distillation and azeotropic distillation. In simple distillation, liquids dissolving in each other and having boiling point below 150°C are used. All the hot vapors produced are immediately allowed to pass through a condenser that cools and condenses the vapors. For effective separation the liquids used need to have large boiling point differences. The separation technique works well with relatively pure liquids.

Fractional distillation uses fractionating column which is inserted between the distillation flask and the distillation head. The technique is effective in separating components of liquid mixtures, which have boiling point difference of more than 25°C at a temperature below 200°C, but the setup is more complicated than simple distillation and it takes longer for liquids to distill. Thus the technique is not feasible for commercial use.
In vacuum distillation solvent is distilled out by causing reduction in the applied pressure using a vacuum pump, this in turn leads to lowering of the temperature at which the liquid boils. Distillation is carried out at a pressure less than one atmosphere.
Azeotropic distillation technique comprises use of solvent capable of removing water under azeotropic conditions. The distillation involves adding a substance to the mixture to be separated in order to form azeotropic mixture with one or more of the constituents of the original mixture. The azeotropes thus formed have boiling points different from the boiling points of the original mixture. The setup of this distillation method is simple and economical. Also this technique enables continuous preparation of anhydrous tiotropium bromide.
In an embodiment the process of present invention comprises:
a) preparing a solution of tiotropium bromide in water;
b) adding to the aqueous tiotropium bromide a solvent capable of removing water by azeotropic distillation to prepare said anhydrous crystalline tiotropium bromide;
c) isolating the anhydrous crystalline tiotropium bromide.
The tiotropium bromide used in the process of the present invention may be in any form. It may be in amorphous or crystalline form for example, hydrate or solvate crystalline form.
The solvents useful in practicing the present invention include any solvent that is capable of co-distilling with water or forming an azeotrope with water. Suitable solvents include but are not limited to alkanes, esters, ethers or aromatic solvents. The solvents may be selected from n-hexane, n-heptane, cyclopentane, cyclohexane, ethyl acetate, butyl acetate, isopropyl acetate, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl

methyl ketone, methyl isobutyl ketone, toluene, xylene (ortho, meta or para), methylene dichloride, ethylene dichloride. Additional solvents capable of removing water by azeotropic distillation which may be used in the process of the present invention can be readily determined by those skilled in the art. The solvent preferred in the process of the present invention is ethyl acetate.
The solvent is added to aqueous tiotropium bromide under azeotropic distillation conditions. The solution is heated, preferably with agitation, to the boiling point of the solvent. The reaction is continued for a period of time sufficient to separate the water from the starting material, thus resulting in the anhydrous crystalline tiotropium bromide of the present invention.
Various solvents used for azeotropic distillation have varied effect on the yield of final product i.e., anhydrous tiotropium bromide. The comparative results are shown in the below table. Table

Organic Solvent Yield of anhydrous tiotropium bromide
(% w/w)
Ethyl acetate 98.0
Toluene 93.0
Diisopropyl ether 95.0
n-Heptane 96.6
Methyl isobutyl ketone 97.0
The advantage of the azeotropic distillation technique is that it is a continuous process capable of completely removing water and yielding highly pure, stable and non-hygroscopic anhydrous tiotropium bromide.
Stability data
A) The anhydrous form, obtained by process of present invention, packed in double transparent polythene bags inside a fibre drum with silica gel desiccant under the following conditions:

30 ± 2°C/ 65 ± 5% RH for 2 months
X-ray diffraction pattern analysis of the product at the end of the storage period showed
no change in the spectra.
B) The anhydrous form, obtained from prior art process, packed in double transparent
polythene bags inside a fibre drum with silica gel desiccant under the following
conditions:
30 ± 2°C/ 65 ± 5% RH for 4 weeks
X-ray diffraction pattern analysis of the product at the end of the storage period showed
some additional peaks similar to monohydrate form in the spectra.
Thus the stability data indicates that the anhydrous form obtained from the process of the
present invention is stable and non-hygroscopic.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention any way.
Example:
10 g of tiotropium bromide and 50 ml of water was stirred in a flask at 25-28°C under inert atmosphere. The reaction mass was then heated to 60°C. 1000 ml of ethyl acetate was added and reaction mass was heated to reflux using Dean Stark apparatus. The reaction mass was cooled to 25-28°C and filtered under inert atmosphere. The solid obtained was washed with ethyl acetate and dried at 60°C to yield 9.8 g of anhydrous tiotropium bromide.

We Claim,
1. A process for preparing anhydrous tiotropium bromide comprises:
(a) preparing a solution of tiotropium bromide in water;
(b) forming an azeotrope of the aqueous tiotropium bromide with a soivent;
(c) isolating the anhydrous crystalline tiotropium bromide.

2. A process for preparing anhydrous tiotropium bromide as claimed in claim 1, wherein tiotropium bromide used is in any form like amorphous or crystalline.
3. A process for preparing anhydrous tiotropium bromide as claimed in claim 1, wherein solvent used is capable of co-distilling with water or forming an azeotrope with water.
4. A process for preparing anhydrous tiotropium bromide as claimed in claim 1 and 3, wherein the solvent may be selected from alkanes, esters, ethers or aromatic solvents.
5. A process for preparing anhydrous tiotropium bromide as claimed in claim 1, 3 and 4, wherein the solvent may be selected from n-hexane, n-heptane, cyclopentane, cyclohexane, ethyl acetate, butyl acetate, isopropyl acetate, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl methyl ketone, methyl isobutyl ketone, toluene, xylene (ortho, meta or para), methylene dichloride, ethylene dichloride.
6. A process for preparing anhydrous tiotropium bromide substantially as herein described with reference to the example.