DESC:FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of highly pure fesoterodine fumarate having assay in range 98 to 102% w/w, using a suitable crystallization solvent system, in which fesoterodine fumarate is soluble and fumaric acid is insoluble.

BACKGROUND OF THE INVENTION
Fesoterodine represented by formula I is a prodrug of 5-hydroxymethyl tolterodine and is chemically known as isobutyric acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxymethyl-phenyl ester or [2-[(1R)-3-(di(propan-2-yl)amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl]2-methyl propanoate.

Formula I

It is a new, potent, competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence. It is commercially available under the brand name of Toviaz® in the form of fumarate salt as represented by formula Ia.

Formula Ia
Fesoterodine and its pharmaceutically acceptable salts are first disclosed in US patent 6,858,650, herein referred as ‘650 which describe the preparation of active ingredient by salification of fesoterodine with fumaric acid in 2-butanone and cyclohexane as represented below in scheme 1:

According to exemplified process, a solution of fesoterodine is taken in 2-butanone and fumaric acid is added while heating. After complete dissolution of the acid, cyclohexane is added slowly under agitation until the onset of turbidity. The colourless, homogenous deposit is initially left for 18 hours at room temperature, and then for several hours at 0o C. The colourless crystals that have precipitated are sucked off, washed with a little cyclohexane/2-butanone (90:10) and dried in the vacuum at 30oC to yield fesoterodine fumarate in the form of colourless flakes. The reported yield is 83.1% having melting point 98.8oC and the molar ratio of fesoterodine and fumaric acid are taken as 1:1. The resulting product was recrystallized using same solvent mixture i.e. 2-butanone and cyclohexane that provides a product with a melting point of 103oC. Patent is silent about purity or assay and even yield is not reported after recrystallization.
In our hands we have found that in 2-butanone and cyclohexane, resulting product have very less assay [around 93%] and need further purification to meet the purity and assay as per regulatory requirement. In view of the above, the disclosed process of preparation of fesoterodine fumarate is not suitable, because it yields desired product of less assay and requires further step of purification to achieve desired assay.
US publication US2011/0282094A1 discloses salification reaction using equimolar quantity of fesoterodine base and fumaric acid in the presence of solvent system comprising 2-butanone and diisopropylether. The resulting fesotrodine fumarate is further recrystallized using 2-butanone and diisopropylether. This publication is also silent about assay and fumaric acid content.
Few other patents/publications such as US7,985,873; US8,445,716; US2010/0292502A1 and US2010/0292503A1 disclose crystallization of fesoterodine fumarate in 2-butanone. Among these, in one publication US2010/0292502A1 although the salification reaction is carried out in 2-butanone, but crystallization is favored by seeding or lyophilization. Further recrystallization is also carried out. In this publication the fesoterodine base and fumaric acid molar ratio is 1:1.01.
We have observed that using 2-butanone alone as crystallization solvent does not precipitate out the product, even after prolonged time. This observation is also supported by US patent US8,049,031 which states that crystallization of fesoterodine fumarate from just 2-butanone is failed. Therefore process for preparation of fesoterodine fumarate using 2-butanone is not suitable.
In PCT publications WO2011/029005A1 and WO2011/110556A1, although an equimolar quantity of fesoterodine base and fumaric acid are used with the solvent combination of 2-butanone and cyclohexane as is mentioned in the product patent US ‘650 hereto the patent publication is silent about assay and fumaric acid content of isolated fesoterodine fumarate.
In another PCT publication WO2012/098560A2, although the fesoterodine fumarate is prepared using 2-butanone and cyclohexane as given in US ‘650 but herein the molar ratio of fesoterodine base and fumaric acid content used is 1:1.6; but reason of using higher molar ratio of fumaric acid is not given, yield is reported as about 62%. Repetition of this example results in fesoterodinde fumarate having fumarate content around 31.14% w/w.
There are few more patent publications such as WO2012/025941A2, US2010/0297241,wherein the different solvents are used for the salification reaction of fesoterodine base and fumaric acid. In PCT publication WO2012/025941A2 isopropyl alcohol and diisopropylether is used along with equimolar fesoterodine base and fumaric acid. Although in patent publication purity by HPLC 99.47% is mentioned but assay and fumarate acid content is not disclosed.
In US publication US2011/0282094A1 salification reaction using equimolar quantity of fesoterodine base and fumaric acid is carried out in presence of solvents such as 2-butanone and diisopropylether. Resulting fesotrodine fumarate is further recrystallized using the same solvent system. Patent publication is silent about assay and fumaric acid content, wherein the content of fumaric acid and assay is a crucial factor to characterize fesoterodine fumarate API.
Great efforts have been dedicated to the preparation of pharmaceuticals having minimum amounts of impurities. The control of impurities is a key parameter to evaluate the efficiency of a process and a huge number of variables have to be taken into account in order to select the reaction conditions and the control protocols necessary to ensure that marketed medicaments are pure and therefore safe. Assay determination is one of the key parameter to ensure the purity of product. For most of the marketed pharmaceutical product assay around 98-102% w/w has been considered to be acceptable, same should be applicable to fesoterodine fumarate also. In respect to fumaric acid content, theoretically in fesoterodine fumarate, fumarate content should be 22.0% w/w.
In view of the above, it is clear that there is a gap regarding the salification reaction for the preparation of fesoterodine fumarate wherein no details available with respect to assay of fesoterodine fumarate and fumaric acid content in final product and most of the inventions use recrystallization steps to prepare pure fesoterodine fumarate, hence there is an imperative need for an efficient process which results in fesoterodine fumarate passing in assay as well as in fumaric acid content, without performing further steps of recrystallization of fesoterodine fumarate.

The inventor of present invention have invented a process of salification reaction, using a suitable crystallization solvent system, which results in highly pure fesoterodine fumarate having assay in range 98 to 102% w/w and acceptable amount of fumaric acid content, without involving step of recrystallization of fesoterotine fumarate.

OBJECT OF THE INVENTION
It is the foremost object of the present invention to provide a process for the preparation of highly pure fesoterodine fumarate.

Yet another object of the present invention is to provide a fesoterodine fumarate having assay in range 98 to 102% w/w and acceptable fumaric acid content.

Yet another object of the present invention is to provide a fesoterodine fumarate having assay in range 98 to 102% w/w and acceptable fumaric acid content, without recrystallizing fesoterodine fumarate.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an efficient and industrially advantageous process for the preparation of highly pure fesoterodine fumarate of formula Ia having assay in range 98 to 102% w/w and acceptable fumaric acid content.

Formula Ia

According to one embodiment, the present invention provides a process for preparation of highly pure fesoterodine fumarate having assay in range 98 to 102% w/w and acceptable fumaric acid content comprising the steps of;
a). dissolving the fesoterodine base in a suitable first solvent in which fesoterodine and fesoterodine fumarate are soluble;
b). adding fumaric acid;
c). stirring the reaction mass at suitable temperature till complete formation of fesoterodine fumarate salt;
d). filtering the reaction mass to remove the unreacted fumaric acid;
e). adding a suitable second solvent to filterate to induce crystallization; and
f). isolating pure fesoterodine fumarate.

According to another embodiment, the present invention provides a process for the preparation of highly pure fesoterodine fumarate having assay in range 98 to 102% w/w and acceptable fumaric acid content comprising the steps of;
a). dissolving the fesoterodine base in a suitable first solvent in which fesoterodine and fesoterodine fumarate are soluble;
b). adding fumaric acid;
c). stirring the reaction mass at suitable temperature till complete formation of fesoterodine fumarate salt;
d). filtering the reaction mass to remove the unreacted fumaric acid;
e). adding a suitable second solvent to filtrate to induce crystallization;
f). optionally seeding with fesoterodine fumarate; and
g). isolating pure fesoterodine fumarate.

According to another embodiment, the present invention provides a fesoterodine fumarate having assay in range 98 to 102% w/w and acceptable fumaric acid content.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term 'assay' represents a quantitative measurement of the major component in the drug substance. It refers to content or potency to provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.

Accordingly, the present invention provides a process for the preparation of highly pure fesoterodine fumarate of formula Ia having assay in range 98 to 102% w/w, preferably in the range 99 to 101% w/w, more preferably 99.5 to 100.5% w/w, herein the range 98 to 102% w/w refers that assay content is not less than 98% w/w and not more than 102% w/w; and acceptable fumaric acid content. According to one embodiment the process involves the steps of dissolving fesoterodine base in a suitable first solvent in which fesoterodine and fesoterodine fumarate are soluble; stirring to obtain the clear solution; adding fumaric acid; stirring for sufficient time till complete formation of fesoterodine fumarate salt; filtering the reaction mass; adding a suitable second solvent; optionally seeding with fesoterodine fumarate and isolating pure fesoterodine fumarate.

As per the invention, fesoterodine base is dissolved in a suitable first solvent. A suitable first solvent includes but not limited to a class of halogenated solvent. Halogenated solvent used can be selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, among these solvents dichloromethane is particularly preferred.
Fumaric acid can be used in molar ratio comprised in the range at least one molar with respect to fesoterodine base. Generally the preferred molar ratio of fesoterdine base to fumaric acid can be 1.0 to 2.0 preferably 1:1.5 more preferably 1: 1.2. The molar ratio of fesoterodine base and fumaric acid is selected that fumaric acid should be available in sufficient quantity for salification reaction, and still fumaric acid should be available in little more quantity.
Generally, process involves dissolution of fesoterodine base in a suitable first solvent by stirring. The dissolution can be affected by heating at temperature range 10oC to reflux temperature of solvent used. The preferred temperature range for the purpose of present invention is 10oC-40oC and most preferred is at ambient temperature.
After complete dissolution, addition of fumaric acid in the clear solution can be carried out. It is not critical, how to add fumaric acid, it can be added slowly or in one lot thereafter reaction mixture is stirred at ambient temperature for sufficient time till complete salification reaction occurs. Generally reaction completion can be accomplished in 30 minutes to 2 hours and preferably 1 hour is sufficient time to complete the salification reaction.

In accordance with the present invention in a particularly preferred embodiment, after completion of salification reaction, reaction mixture is filtered to remove unreacted fumaric acid from the reaction mass. It is beneficial to remove the unreacted fumaric acid from the reaction mass and it is a most important part of the present invention, because presence of excess of free fumaraic acid in reaction mass prevents the precipitation of desired fesoterodine fumarate. The molar ratio of fesoterdine base to fumaric acid is very crucial during salt formation from fesoterodine to fesoterodine fumarate. If less moles of fumaric acid are used, then unreacted fesoterodine remains in reaction mass and resulting fesoterodine fumarate may fail in assay and fumaric acid content. If excess moles of fumaric acid are used, then unreacted fumaric acid remains in reaction mass, prevents the crystallization of fesoterodine fumarate and resulting product fails in assay and fumaric acid content.

It is advantageous to use slightly more than equimolar of fumaric acid and remove unreacted excess of free fumaric acid from reaction mass to achieve desired assay and fumaric acid content.

Removal of unreacted fumaric acid can be facilitated by any technique which is suitable to remove excess of fumaric acid. Generally, removal can be achieved by filtration employing a filtration media of filter paper, by centrifuge or by decantation preferably filtration by filter paper is employed.

The resulting filtrate having fesoterodine fumarate in solution is then followed by step of addition of a second solvent in it. The second solvent can be any class of organic solvent which results in precipitation of fesoterodine fumarate and can be selected from the aliphatic esters, aliphatic ethers, hydrocarbons, alkyl cynates or mixtures thereof. The aliphatic esters such as methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate; aliphatic ethers such as diethylether, diisopropylether, methyl-tert-butyl ether tetrahydrofuran, dioxane; hydrocarbons such as benzene, toluene, hexane, pentane, cyclohexane; alkyl cynates such as acetonitrile or mixtures thereof.

A suitable second solvent is added to the reaction mass to facilitate the precipitation of fesoterodine fumarate. The addition of second solvent in reaction mass can be carried out while stirring. The reaction mixture can be stirred over a period of 10 to 15 hours more preferably till completion of precipitation of the desired uniform and homogeneous particles. The crystallization process can optionally be accelerated using seeding process by using the seeds of fesoterodine fumarate. Crystallization can also be accelerated by cooling down and later on partial removal of the solvent from the solution. The precipitation reaction can be carried out at ambient temperature ranging between from 10-40oC, preferably 20-25oC.

The resulting fesoterodine fumarate, as crystallized out, can be isolated using known techniques of filtration such as filtration, filtration under vacuum, centrifugation, decantation or a combination thereof or any other suitable techniques. In a preferred embodiment of the invention the product is isolated by filtration employing a filtration media of, filter paper or filter cloth. The filtered material can be washed with suitable solvents. The solvents used for the washing can be selected from a class of second solvents which is used for the precipitation of fesoterodine fumarate as described above.

The resulting fesoterodine fumarate is dried by employing any suitable drying techniques such as air drying, vacuum drying, mainly vacuum tray dryer, rotocon vacuum dryer, a vacuum paddle dryer or a pilot plant rota vapor etc is used. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.

The assay of fesoterodine fumarate obtained by employing the above process as disclosed herein is in range 98 to 102% w/w, preferably in the range 99 to 101% w/w, more preferably 99.5 to 100.5% w/w and having fumaric acid content between 21.5-22.5% w/w more preferably 22% w/w as determined by suitable techniques.

Assay procedures are intended to measure the analyte present in a given sample and can be measured by an accurate and precise analytical method such as by titration, colorimetric or gravimetric method or chromatographic method. In the present invention assay for fesoterodine fumarate as a drug product is determined by high performance liquid chromatography (HPLC) using di-sodium hydrogen phosphate and acetonitrile as mobile phase, whereas fumarate content in fesoterodine fumarate is determined by potentiometric titration using 1 M sodium hydroxides volumetric solutions.

The present inventors have tried several experiments to prepare pure fesoterodine fumarate having assay and fumaric acid in acceptable limits and comparative results are summarized below:

S.N. Molar Ratio of fesoterodine: fumaric acid First Solvent: Second Solvent Assay % w/w % w/w of Fumaric acid in final product
1. 1:1 2-Butanone: Cyclohexane 93.0% 26.2 %
2. 1:1.13 Acetone: Ethyl acetate 95.14% 20.47%
3. 1:1 Isopropyl alcohol: Methyl tert-butyl ether 97.7% 21.8%
4. 1:1 Isopropyl alcohol: Diisopropylether 97.0%
21.9 %
5. 1:1.21 Dichloromethane:Ethyl acetate 100.3% 21.9 %
6. 1:1.42 Dichloromethane:Ethyl acetate 99.6% 21.9%.
7. 1:1.21 Dichloromethane:Ethyl acetate 100.1% 22%
It is clear from comparative data that the results fail in assay and few in fumaric acid content also. This may be correlated to solubility of fesoterodine fumarate and insolubility of fumaric acid in first solvent. The choice of halogenated solvents forms the preferred embodiment of present invention as fesoterodine fumarate is soluble in selected halogenated solvents. This makes easier to remove out the unreacted fumaric acid by simple filtration and thus achieving more than 99.5% w/w assay. In a similar reaction condition, since fesoterodine fumarate is soluble in ketonic and alcoholic solvents, the resulting fesoterodine fumarate is not of desired quality. As shown above in table, fesoterodine fumarate obtained by using acetone and ethyl acetate ends up with assay only 95% w/w and fumaric acid content 20.50% w/w, despite the use of equimolar fesoterodine base and fumaric acid. Similarly use of solvent system isopropanol and methyl tert-butyl ether ends up with assay 97% w/w and fumaric acid content 21.80% w/w. This clearly distinguishes the advantage of halogenated solvents.
Fesoterodine base, starting material to prepare fesoterodine fumarate, in the present invention can be obtained by following any of the methods reported in the literature. Generally, hydroxymethyl phenol intermediate of formula II is acylated to prepare the fesoterodine base.

Formula II

Hydroxymethyl phenol intermediate of formula II is very well known compound and can be prepared by the known literature processes and it is not the limitation of present invention. Fesoterodine base obtained by any means can be used for salification reaction as per the invention described herein. Further the polymorphic forms of fesoterodine base do not impose any hurdle for the salification reaction as described herein. The starting material fesoterodine base can be in any form amorphous, crystalline or mixtures thereof or in oily residue form.
Main advantage of the present invention is to obtain highly pure fesoterodine fumarate having assay is in range 98 to 102% w/w, preferably in the range 99 to 101% w/w, more preferably 99.5 to 100.5% w/w and fumaric acid content between 21.5-22.5% w/w preferably 22% w/w by making use of a suitable solvent system during salt preparation that includes a step of removing unreacted fumaric acid and avoiding recrystallization of resulting fesoterodine fumarate. None the less by the use of this particular preferred crystallization procedure as set out in disclosure, fesoterodine fumarate of formula Ia may be conveniently obtained having acceptable purity and assay that is particularly suitable for use in medicaments.

Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

EXAMPLES:
Example 1: Preparation of Fesoterodine Fumarate:
To a solution of fesoterodine base (165g) in dichloromethane (300ml), fumaric acid (56.25g) was added and stirred for 1 hour at 20 to 25oC. The resulting mass was filtered to remove unreacted fumaric acid and washed with dichloromethane (150 ml). To the filtrate, ethyl acetate (3000ml) was added and further stirred for 12.0 hours at 20 to 25oC. The resulting suspension was filtered, washed with ethyl acetate and dried to give 117g of fesoterodine fumarate having assay 100.3% w/w and fumaric acid content 21.9% w/w.

Example 2: Preparation of Fesoterodine Fumarate:
Fesoterodine base (11g) was dissolved in dichloromethane (20ml) and stirred at 20 to 25oC to get clear solution; fumaric acid (4.42g) was added and stirred for 2 hours. The resulting solution was filtered under vacuum and washed with dichloromethane (10ml). Ethyl acetate (150ml) and seeds of fesoterodine fumarate (0.05g) were added to filterate, and further stirred for 15.0 hours at 20 to 25oC. The resulting suspension was filtered under vacuum, washed with ethyl acetate and dried at 25 to 30oC for 24.0 hours under vacuum to give 7.5g white powdered fesoterodine fumarate having assay 99.6% w/w and fumaric acid content 21.9% w/w.

Example 3: Preparation of Fesoterodine Fumarate:
To a solution of fesoterodine base (55g) in dichloromethane (100ml), fumaric acid (18.75g) was added while stirring at 20 to 25oC and stirred for one more hour for complete dissolution. The resulting solution was filtered under vacuum and washed with dichloromethane (100 ml). To the filtrate, ethyl acetate (1000ml) was added and stirred for 20.0 hours at 20 to 25oC. The resulting suspension was filtered under vacuum and dried at 25 to 30oC for 24.0 hours under vacuum to give 37.5g white powdered fesoterodine fumarate having assay 100.1% w/w and fumaric acid content 22% w/w.

Comparative Examples
Example 1: Preparation of Fesoterodine Fumarate using 2-butanone and cyclohexane
To a stirred solution of fesoterodine base (41.87g) in 2-butanone (90ml), fumaric acid (11.81g) was added at 25 to 30oC and the reaction mass was stirred. Cyclohexane (30.0ml) was added in the reaction medium and stirred for 18 hours at 20 to 25oC and then stirred for several hours at 0oC. The resulting suspension was filtered and dried to give 42.0g of fesoterodine fumarate having assay 93.0% w/w and fumaric acid content 26.2% w/w.

Example 2: Preparation of Fesoterodine Fumarate using isopropyl alcohol and diisopropyl ether
A solution of fesoterodine base (42 g) in isopropyl alcohol (240 ml) was heated to 50 to 55oC and fumaric acid (17g) was added to the resulting mass. After 30 minutes of stirring the reaction mass was cooled to 25 to 30oC, diisopropyl ether (840 ml) was added in it, stirred for 12 hours at 25-30oC and the resulting solution was filtered, washed with diisopropyl ether and dried to give fesoterodine fumarate 29.4g having assay 97.0% w/w and fumaric acid content 21.9% w/w.

Example 3: Preparation of Fesoterodine Fumarate using 2-butanone
Fesoterodine base (27.5 g) was taken in 2-butanone (100ml), the mixture was evaporated to half of its initial volume, further 2-butanone (100 ml) and fumaric acid (8.04 g) was added successively to the solution. The suspension was heated at 35oC till complete dissolution. It was cooled to 20oC, seeds of fesoreodine fumarate was added and stirred initially for 1 hour at ambient temperature and for 2 hours at 0oC. Material was not crystallized even after several hours of stirring at 0oC.

Example 4: Preparation of Fesoterodine Fumarate using acetone and ethyl acetate:
To a stirred solution of fesoterodine base (6.0g) in acetone (10.0ml), fumaric acid (1.91g) was added at 20 to 25oC. The resulting solution was filtered; ethyl acetate (75.0ml) was added to the filtered solution, stirred for 15-20 hours at 20 to 25oC. The resulting suspension was filtered, washed and dried to give 4.1g of fesoterodine fumarate having assay 95.14% w/w and fumaric acid content 20.47% w/w.

Example 5: Preparation of Fesoterodine Fumarate using isopropanol and methyl tertiary butyl ether
To a stirred solution of fesoterodine base (15.0g) in isopropyl alcohol (62.5ml), fumaric acid (4.25g) was added at 25 to 30oC in the resulting clear solution; methyl tertiary butyl ether (187.5ml) was added, seeded with fesoterodine fumarate and stirred for 20.0 hours at 25 to 30oC. The resulting suspension was cooled at 0 to 5oC, stirred for 2.0 hours, filtered, washed and dried to give 10.0g of fesoterodine fumarate having assay 97.7% w/w and fumaric acid content 21.8% w/w.
,CLAIMS:We Claim

1. A process for the preparation of highly pure fesoterodine fumarate of formula Ia having assay in range 98 to 102% w/w and acceptable fumaric acid content

Formula Ia
comprises the steps of;
a). dissolving fesoterodine base in a suitable first solvent in which fesoterodine and fesoterodine fumarate are soluble;
b). adding fumaric acid;
c). stirring the reaction mass at a suitable temperature till complete formation of fesoterodine fumarate salt;
d). filtering the reaction mass to remove unreacted fumaric acid;
e). adding a suitable second solvent to filtrate to induce crystallization;
f). optionally seeding with fesoterodine fumarate; and
g). isolating pure fesoterodine fumarate.

2. The process as claimed in claim 1 wherein in step a) first solvent is selected from a class of halogenated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene.
3. The process as claimed in claim 2 wherein first solvent is preferably dichloromethane.
4. The process as claimed in claim 1 wherein in step b) the molar ratio of fesoterodine base to fumaric acid is at least one mole.

5. The process as claimed in claim 1 wherein in step b) the molar ratio of fesoterodine base to fumaric acid is 1.0 to 2.0 preferably 1:1.5 more preferably 1:1.2.
6. The process as claimed in claim 1 wherein in step e) second solvent is selected from aliphatic esters such as methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate; aliphatic ethers such as diethylether, diisopropylether, methyl-tert-butyl ether tetrahydrofuran, dioxane; hydrocarbons such as benzene, toluene, hexane, pentane, cyclohexane; alkyl cynates such as acetonitrile or mixtures thereof.
7. The process as claimed in claim 1 wherein in step e) second solvent is ethyl acetate.
8. The process as claimed in claim 1 wherein in step g) isolated fesoterodine fumarate have fumaric acid content between 21.5-22.5% w/w.
9. The process as claimed in claim 1 wherein in step g) isolated fesoterodine fumarate have fumaric acid content between 21.9- 22% w/w.
10. Fesoterodine fumarate having assay in range of 98 to 102% w/w and fumaric acid content between 21.5-22.5% w/w, prepared as per process as claimed in claim 1.