FIELD OF THE INVENTION
The present invention provides a process for preparation of hydronopol, a key intermediate of pinaverium bromide. Specifically, the present invention relates to a single step process for the preparation of hydronopol from nopol with high chiral purity, yield and without use of toxic reagents. The present invention further relates to the process for preparation of pinaverium bromide.
BACKGROUND OF THE INVENTION
Pinaverium bromide, chemically known as 4-(2-bromo-4,5-dimethoxybenzyl)-4-(2-(2-(6,6-dimethyl bicyclo[3.1.1] heptan-2-yl)ethoxy]ethyl)morpholin-4-ium bromide having structure:
OMe
MeO JL
1 O A
Pinaverium bromide marketed under the brand names Dicetel and Eldicet, is a medication used for functional gastrointestinal disorders. It belongs to a drug group called antispasmodics and acts as a calcium channel blocker in helping to restore the normal contraction process of the bowel. It is most effective when taken for a full course of treatment and is not designed for immediate symptom relief or sporadic, intermittent use. It is indicated for the symptomatic treatment of irritable bowel syndrome (IBS) and functional disorders of the biliary tract.
Several processes for the preparation of pinaverium are known in the prior arts. For example, US3845048 discloses pinaverium bromide and also the process for preparation of the same. Pinaverium bromide possess geometric isomerism, e.g. cis and trans isomerism. The cis isomer of pinaverium bromide is the active pharmaceutical ingredient (API) and trans (-) pinaverium bromide is the undesired isomer.
Hydronopol of Formula II is the key intermediate for the preparation of pinaverium bromide. The purity of this intermediate is very critical for the preparation of pinaverium bromide.

US5175347 discloses process for preparing cis-dihydronopol, which involves the first conversion of (-)-nopol to its corresponding ester by treating with acetyl chloride, further hydrogenated with hydrogen in the presence of solid catalyst to obtain cis-dihydronopol acetate and finally reacted with sodium hydroxide to yield cis-dihydronopol.
This patent involves multistep process for preparation of hydronopol. Specifically, said patent involves three steps process for the conversion of nopol to hydronopol and the use of heavy metals and reagents such as acetyl chloride which generates huge quantity of effluent and so large quantity of base will be required to neutralize the high quantity of acidic effluent generated. In addition to this, due to multiple steps involve in said process, this process requires large manpower and utilities cost. Further, the process involves use high pressure (about 80-95 bar) during the preparation of dihydronopyl acetate and yields the undesired trans isomer of dihydronopyl acetate is in higher amount i.e. 0.12-0.34%. Therefore, this process is not suitable for commercial scale production.
US7241770 discloses the process for the preparation of dihydronopol intermediate which involves first the synthesis of myrtanyl mesylate which is then converted to myrtanyl cyanide using potassium cyanide. Potassium cyanide is a highly toxic reagent and use of such a toxic reagent is not suitable at commercial scale. Myrtanyl cyanide thus obtained in converted to myrtanyl ethyl ester followed by subsequent reduction in presence of Lithium aluminium hydride to yield dihydronopol.
The process discloses in this patent involves the use of toxic reagent and a strong base, which is not safe at commercial scale and generate large number of impurities. Therefore, this process is also not suitable for commercial scale production.
Thus, there is a need to develop an improved process for preparation of hydronopol of Formula II and further conversion to pinaverium bromide that can be adapted to industrial scale production. The inventors have developed simple process for preparation of hydronopol with high chiral purity, yield, cost effective and eco-friendly manner to obviate one or more of the problems associated with prior art processes. Specifically, Present invention provides single step process for the preparation of hydronopol from nopol. Further, present invention provides a process which

provides better yield and a good control of undesired trans isomer. Additionally, hydrogenation as per the process of the instant invention is carried out at low hydrogen pressure, which is safe and commercially feasible.
OBJECT OF THE INVENTION
It is a principal object of the present invention to improve upon limitations in the prior arts by providing a process for the preparation of hydronopol of Formula II.
It is another object of the present invention to provide a simple, commercially viable, economical and environment friendly process for preparing hydronopol of Formula II in high yield and purity.
It is yet another object of the present invention to provide a commercially viable single step process for the preparation of hydronopol of Formula II.
It is another object of the present invention to provide process for the preparation of hydronopol of Formula II wherein level of undesired trans isomer is less than about 1%.
It is yet another object of the present invention to provide hydronopol of Formula II wherein level of undesired trans isomer is less than about 1%.
It is still another object of the present invention to provide a commercially viable process for the preparation of pinaverium bromide using hydronopol prepared by process of the present invention.
SUMMARY OF THE INVENTION
In one aspect of the present invention provides a simple, economic and efficient process for the preparation of hydronopol intermediate of Formula II.
In another aspect of the present invention provides a process for the preparation of hydronopol intermediate of Formula II and its conversion to pinaverium bromide.
It is yet another aspect of the present invention to provide a commercially viable single step process for the preparation of hydronopol of Formula II.

It is another aspect of the present invention to provide process for the preparation of hydronopol of Formula II wherein level of undesired trans isomer is less than about 1%.
It is yet another aspect of the present invention to provide hydronopol of Formula II wherein level of undesired trans isomer is less than about 1%.
In further, another aspect of the present invention provides process for the preparation of pinaverium bromide comprising the steps of as in Scheme 1:
SCHEME 1




OH
■OH
Formula I

Formula II

.HCI Formula III

o
Formula IV(cmde)

o

o

COOH COOH

MeO
Formula IV (Pure)
A ^ Br

Formula V

Pinaverium bromide

DETAIL DESCRIPTION OF THE INVENTION
One aspect of the present invention provides a process for the preparation of hydronopol intermediate of Formula II by hydrogenating compound of Formula 1 in presence of hydrogen using suitable hydrogenating catalyst, solvent and optionally adding reaction promotor.
Generally, reaction may be carried out at a temperature of 5 to 60°C for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at a temperature of 10 to 50°C, more preferably, reaction is conducted at a temperature of 20 to 40°C and it takes 12 to 15 hours for completion of the reaction. The reaction completion is monitored by suitable known techniques.
The solvent is selected from group comprising of aliphatic hydrocarbons alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like or mixture thereof. Preferably, solvent selected is cyclohexane.
The catalyst may be selected from platinum, platinum oxide, palladium/carbon (Pt/C), rhodium, and ruthenium/carbon and the like or combination thereof. Preferably, catalyst selected is palladium/carbon (Pt/C).
The promotor may be selected from sodium acetate, potassium acetate, lithium acetate, cesium acetate, rubidium acetate and the like or mixture thereof. Preferably, promotor selected is sodium acetate.
In another aspect of the present invention provides a process for the preparation of hydronopol intermediate of Formula II and further converting to pinaverium bromide.
In yet another aspect the present invention provides process for the preparation of pinaverium bromide comprising the steps of:
a) hydrogenating compound of Formula I in presence of hydrogen using suitable hydrogenating catalyst, solvent, optionally adding reaction promotor, to obtain compound of Formula II; and



OH
OH

Formula I

Formula II

b) converting compound of Formula II to pinaverium bromide.
In another aspect of the present invention provides process for the preparation of pinaverium bromide comprising the steps of:
a) hydrogenating compound of Formula I in presence of hydrogen using suitable hydrogenating catalyst, solvent, optionally adding reaction promotor, to obtain compound of Formula II;



OH
OH

Formula I

Formula II

b) coupling compound of Formula II with compound of Formula III in presence of solvent and a base to obtain crude compound of Formula IV;

OH
N ^
o-

.HCI Formula III

XX
N
Formula II
Formula IV(Crude)
c) reacting crude compound of Formula IV with oxalic acid in presence of solvents to obtain compound of Formula V;


o^■o-
■ COOH COOH
N

N

■a

o-

Formula IV(cmcie) Formula V
d) converting compound of Formula V using base in presence of solvent to pure compound of Formula IV; and


o-
N
N
COOH COOH
o-
O
Formula V
Formula IV (Pure)
e) condensing pure compound of Formula IV with 2-bromo-4,5-dimethoxy benzyl bromide, compound of Formula VI in presence of a solvent to obtain pinaverium bromide.
O y. Br
Br
MeO
OMe
O'
Formula VI
N
X>
O'
Formula IV (Pure)
Pinaverium bromide
Br

e

In step a) The solvent is selected from group comprising of aliphatic hydrocarbon alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like or mixture thereof. Preferably solvent selected is cyclohexane. Generally, reaction may be carried out at a temperature of 5 to 60°C for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at a temperature of 10 to 50°C, more preferably, reaction is conducted at a temperature of 20 to 40°C and it takes 12 to 15 hours for completion of the reaction. The reaction completion is monitored by suitable known techniques.

The catalyst may be selected from platinum, platinum oxide, palladium/carbon (Pt/C), rhodium, and ruthenium/carbon and the like or combination thereof. The reaction promotor may be selected from sodium acetate, potassium acetate, lithium acetate, cesium acetate, rubidium acetate and the like or mixture thereof. Preferably, reaction promotor used is sodium acetate.
In step b) The solvent is selected from group comprising of aromatic hydrocarbons such as toluene, xylene, benzene and the like or mixture thereof. Preferably, solvent used is toluene.
The base may be selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, sodium with liquid ammonia, sodamide or the like and mixture thereof. Preferably, base used is sodium hydroxide. The reaction may be carried out at a reflux temperature for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at reflux temperature and it takes to 24 to 30 hours for completion of the reaction.
In step c) the crude compound of Formula IV with or without isolation is reacted with oxalic acid. The solvent is selected from group comprising of water, aromatic hydrocarbons such as toluene, xylene, benzene or the like and mixture thereof. Preferably, solvents used are toluene and water. The reaction may be carried out at a 40 to 60°C for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at 50 to 55°C and it takes to 1 to 2 hours for completion of the reaction.
In step d) The solvent is selected from group comprising of aliphatic hydrocarbons alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like or mixture thereof. Preferably, solvent used is cyclohexane.
The base may be selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates and liquid ammonia or the like and mixture thereof. Preferably, base used is liquid ammonia. The reaction may be carried out at a 20 to 30°C for few minutes to few hours or till completion of

reaction. Preferably, reaction is conducted at 25 to 30°C and it takes to 1 to 2 hours for completion of the reaction.
In step e) The solvent is selected from group comprising of ketone such as acetone, propanone, butanone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile, butyronitrile, valeronitrile and the like or mixture thereof. Preferably, solvent used is acetone. The reaction may be carried out at a 40 to 60°C for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at 45 to 50°C and it takes 7 to 8 hours for completion of the reaction.
In another aspect the present invention provides process for the preparation of pinaverium bromide comprising the steps of:
a) coupling compound of Formula II, obtained by the process of the present invention, with compound of Formula III in presence of solvent and base to obtain crude compound of Formula IV:

OH


O
N

XT
.HCI Formula III
Formula II
Formula IV(Crude) b) reacting crude compound of Formula IV with oxalic acid in presence of solvents to obtain compound of Formula V;

o
o

N

N

COOH COOH

O

O

Formula IV(Crude) Formula V
c) converting compound of Formula V using base in presence of solvent to pure compound of Formula rV; and

o
'■ COOH t^^O

COOH IsT
■cr
Formula V °
Formula IV (Pure)
d) condensing pure compound of Formula IV with 2-bromo-4,5-dimethoxy benzyl bromide, compound of Formula VI in presence of solvent to obtain pinaverium bromide.
O /. Br

v. A JL Br O O'
A |^*| Formula VI
O"
Formula IV (Pure)
Pinaverium bromide
In step a) The solvent is selected from group comprising of aromatic hydrocarbons such as toluene, xylene, benzene and the like or mixture thereof. Preferably, solvent used is toluene.
The base may be selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, sodium with liquid ammonia, sodamide or the like and mixture thereof. Preferably, base used is sodium hydroxide. The reaction may be carried out at a reflux temperature for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at reflux temperature and it takes to 24 to 30 hours for completion of the reaction.
In step b) the crude compound of Formula IV with or without isolation is reacted with oxalic acid. The solvent is selected from group comprising of water, aromatic hydrocarbons such as toluene, xylene, benzene or the like and mixture thereof. Preferably, solvents used are toluene and water. The reaction may be carried out at a 40 to 60°C for few minutes to few hours or till completion of

reaction. Preferably, reaction is conducted at 50 to 55°C and it takes to 1 to 2 hours for completion of the reaction.
In step c) The solvent is selected from group comprising of aliphatic hydrocarbons alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like or mixture thereof. Preferably, solvent used is cyclohexane.
The base may be selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates and liquid ammonia or the like and mixture thereof. Preferably, base used is liquid ammonia. The reaction may be carried out at a 20 to 30°C for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at 25 to 30°C and it takes to 1 to 2 hours for completion of the reaction.
In step d) The solvent is selected from group comprising of ketone such as acetone, propanone, butanone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile, butyronitrile, valeronitrile and the like or mixture thereof. Preferably, solvent used is acetone. The reaction may be carried out at a 40 to 60°C for few minutes to few hours or till completion of reaction. Preferably, reaction is conducted at 45 to 50°C and it takes 7 to 8 hours for completion of the reaction.
In yet another aspect, there is provided a use of a pharmaceutical composition that includes a therapeutically effective amount pinaverium bromide according to the process of the present invention; and one or more pharmaceutically acceptable carriers, excipients or diluents.
As used herein, the term "pharmaceutical compositions" includes pharmaceutical formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations or other pharmaceutical forms.
The major advantages realized in the present invention are that the single step process for the preparation of hydronopol intermediate of Formula II in high yield and provide control of trans isomer below 1 % level by use of sodium acetate catalyst as a promoter. In addition to this, no yield loss since the process involves isolation of hydronopol intermediate of Formula II as an oil by distillation of solvent. Also, hydrogenation is done at very low hydrogen pressure (about 7-8 bar), which is safe and commercially feasible. The use of cyclohexane has additional advantage over

other solvent like toluene which have reducing group. It has been observed that during hydrogenation toluene is hydrogenated to methyl cyclohexane. Therefore, suffers commercially disadvantage, increase in consumption of platinum catalyst and simultaneously increase the cost of production. The present process can be easily and conveniently scaled-up for industrial large scale production. The process is simple economic with high throughput, operationally efficient and environment friendly.
It is yet another aspect of the present invention to provide a commercially viable single step process for the preparation of hydronopol of Formula II.
It is another aspect of the present invention to provide process for the preparation of hydronopol of Formula II wherein level of undesired trans isomer is less than about 1%.
It is yet another aspect of the present invention to provide hydronopol of Formula II wherein level of undesired trans isomer is less than about 1%.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of pinaverium bromide according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.
In yet another aspect there is provided a use of a pharmaceutical composition that includes a therapeutically effective amount of pinaverium bromide according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents to treat conditions in a subject in need thereof.
Although the following examples illustrate the present invention in more detail but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features modifications and variation of the concepts herein

disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention.
EXAMPLES:
Example-1:
Preparation of 2-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)ethan-l-ol (hydronopol)
To the mixture of nopol (100 g) and cyclohexane (250 ml) in a clean autoclave flask was added Pt/C (7 g) and sodium acetate (5%). The reaction mixture was cooled to 20 to 30°C and stirred for 12 to 14 hours maintaining hydrogen pressure at 7-8kg/cm2. After completion of the reaction, the solvent was distilled out to obtain the title compound as an oil. (weight: 97 g; GC purity: 97(%); Yield: 95.8%)
Example-2:
Preparation of crude 4-(2-(2-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)
ethyl)morpholine
To the mixture of hydronopol (100 g) in toluene (300 ml) was added 4-(2-chloro ethyl) morpholine hydrochloride (116 g). The reaction mixture was stirred at 25 to 30°C and sodium hydroxide (72 g) was added. The mixture was stirred at reflux temperature for 24 to 30 hours and distilled off water azeotropically. After the completion of the reaction, 200 ml water was added, the mixture was stirred and separated layers. The aqueous layer was extracted with toluene (100 ml x 2). The combined organic layer was washed with water and aq. acetic solution (100 ml). The organic layer was again washed with water and distilled out the solvent till 6 V to yield the title compound. (GC Purity: 85-90%)
Example-3:
Preparation of 4-(2-(2-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy) ethyl)morpholine oxalate

The reaction mass obtained from example 2 was heated to 50 to 55°C and oxalic acid (72 g) lot wise over a period of 30 to 40 minutes at 50 to 55°C was added. The reaction mixture was stirred at 50 to 55°C for 1 to 2 hours and 300 ml water was added. The reaction mass further stirred for 1 to 2 hours at 50 to 55°C and separated layers. The aqueous layer was cooled to 25 to 30°C, stirred for 8 hours, further stirred for 2 hours at 0 to 5 °C. Filtered, wash with water to yield the title compound, (wet weight: 220-230g)
Example-4:
Preparation of pure 4-(2-(2-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)
ethyl)morpholine
To the compound obtained from example 3 cyclohexane (200 ml) was added at 25 to 30°C. The pH of the reaction was adjusted to 9.5 to 10.5 using liq. ammonia (200 ml) at 25 to 30°C. The reaction mixture was heated at 50 to 55°C and stirred to get clear solution. The layers were separated and organic layer was washed twice with water (100) ml at 50 to 55°C. To the organic layer 1% aqueous acetic acid (75 ml) was added and stirred at 50 to 55°C for 30 minutes and separated the organic layer. Further, organic layer was washed with water (100 ml) at 50 to 55°C and added charcoal (5 g) in organic layer at 25 to 30°C, stirred, filtered through hyflo. The solvent was distilled and acetone (50 ml) was added, distilled out solvent under vacuum at 50 to 55°C to obtain the title compound, (weight 140 g; GC Purity: 97.0%)
Example-5:
Preparation of pinaverium bromide
The mixture of 4-(2-(2-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl) ethoxy) ethyl) morpholine (110 g) in acetone (220 ml) was added activated carbon (5.5 g). The reaction mixture was stirred at 25 to 30°C for 30 to 60 minutes. Filtered the reaction mass through hyflo bed and washed the hyflo bed with acetone (55 ml). In a separate flask, acetone (330 ml) was added to 2-bromo-4,5-dimethoxy benzyl bromide (121 g), stirred at 25 to 30°C to get clear solution and activated carbon (5.5 g) was added. The reaction mixture was stirred at 25 to 30°C for 30 to 60 minutes. Filtered the reaction mass through hyflo bed and washed the hyflo bed with acetone (55 ml). Further, combined both the reaction mixtures, acetone (300 ml) was added and stirred the reaction mass at 45 to 50°C for

8 hours. After the completion of reaction, distilled out acetone till reaction mixture volume about (6 to 7), cooled the reaction mixture to 25 to 30°C and stirred for 2 hours. Further, the reaction mixture was stirred at 0 to 5°C for 2 hours. Filtered, washed with acetone (220 ml), dried under vacuum at 40-50°C to obtained the title compound. (Weight 187g, HPLC Purity: 99.94 %)

We Claim:

1. A process for the preparation of pinaverium bromide comprising the steps of:
a) hydrogenating compound of Formula I in presence of hydrogen using suitable hydrogenating catalyst, solvent, optionally adding reaction promotor, to obtain compound of Formula II; and

Formula I Formula II
b) converting compound of Formula II to pinaverium bromide.
wherein compound of formula I is converted to compound of formula II in a single step.
2. The process as claimed in claim 1 for the preparation of pinaverium bromide further comprising the steps of:
a) coupling compound of Formula II with compound of Formula III in presence of solvent and base to obtain crude compound of Formula IV;
or



.HCI
Formula III f "O
N

Formula II
XT Formula IV(Crude)
b) reacting crude compound of Formula IV with oxalic acid in presence of solvents to obtain compound of Formula V;



N < > ^ I/\I- COOH
COOH

^ ""XT
Formula IV(cmcie) Formula V
c) converting compound of Formula V using base in presence of solvent to pure compound of Formula IV; and

j<^ COOH _ ft_
XT

Formula V °'
Formula IV (Pure)
d) condensing pure compound of Formula IV with 2-bromo-4,5-dimethoxy benzyl bromide, compound of Formula VI in presence of solvent to obtain pinaverium bromide.
O y. Br
|| ^f OMe
" 0-/\^\/Br MeO.
O'
O"
Formula IV (Pure)
A kr^J Formula VI
The process as claimed in claim 1, wherein step a) solvent is selected from group
comprising of aliphatic hydrocarbons alkanes or cycloalkanes such as pentane, hexane,
heptane, octane, cyclohexane, cyclopentane or mixture thereof.
The process as claimed in claim 1, wherein step a) catalyst is selected from platinum,
platinum oxide, palladium/carbon (Pt/C), rhodium, and ruthenium/carbon or combination
thereof.
The process as claimed in claim 1, wherein step a) promotor may be selected from sodium
acetate, potassium acetate, lithium acetate, cesium acetate, rubidium acetate or mixture
thereof.
The process as claimed in claim 2, wherein step a) solvent is selected from group
comprising of aromatic hydrocarbons such as toluene, xylene, benzene or mixture thereof.

The base may be selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates or mixture thereof.
7. The process as claimed in claim 2, wherein step b) solvent is selected from group comprising of water, aromatic hydrocarbons such as toluene, xylene, and benzene or mixture thereof.
8. The process as claimed in claim 2, wherein step c) solvent is selected from group comprising of aliphatic hydrocarbons alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane or mixture thereof. The base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates and liquid ammonia or mixture thereof.
9. The process as claimed in claim 2, wherein step d) The solvent is selected from group comprising of ketone such as acetone, propanone, butanone, methyl isobutyl ketone; nitriles such as acetonitrile, propionitrile, butyronitrile, valeronitrile or mixture thereof.
10. A pharmaceutical composition comprising a therapeutically effective amount of a pinaverium bromide prepared according to process as claimed in claim 1.