CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority to Indian provisional application No. 1708/CHE/2009, filed on July 20, 2009, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of solifenacin succinate crystalline polymorph.

BACKGROUND OF THE INVENTION

Solifenacin succinate, chemically named (3R)-l-azabicyclo[2.2.2]oct-3-yl (lS)-3,4-dihydro-l-phenyl-2(lH)-isoquinolinecarboxylate butanedioic acid (1:1) salt, is a competitive muscarinic receptor antagonist. Solifenacin is represented by the following structural formula:

and its first synthesis was disclosed in U.S. Patent No. 6,017,927 (hereinafter referred to as the '927 patent). Solifenacin succinate is sold by Astellas under the brand name VESICARE® for the treatment of overactive bladder with symptoms of urinary incontinence, urgency and high urinary frequency. It is orally administered as tablets containing 5 mg or 10 mg of solifenacin succinate.

The '927 patent describes two different processes for the preparation of quinuclidine derivatives, which includes solifenacin, and their pharmaceutically acceptable salts, pharmaceutical compositions thereof, and methods of using such compositions in the treatment of urologic diseases, respiratory diseases or digestive diseases. Solifenacin has been exemplified as a free base and a hydrochloride salt in the '927 patent.

Solifenacin succinate is reported to be a white to pale-yellowish-white crystal or crystalline powder and which is freely soluble at room temperature in water, glacial acetic acid, dimethylsulfoxide, and methanol.

IP.com Electronic Publication No. IPCOM000137408D, published on June 19, 2006 (herein after referred to as the 'IP.com publication 408') discloses two crystalline forms (see Figure 2 and Figure 6) and an amorphous form (see Figure 9) of solifenacin succinate, characterizes them by powder X-ray diffraction (P-XRD), Infra red (IR) spectroscopy and Differential Scanning Calorimetry (DSC). According the IP.com publication, the first crystalline form (Vesikur 10 mg tablet) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta at about 3.7, 5.4, 7.4, 8.2, 9.4, 11.1, 11.8, 12.5, 13.5, 14.1, 14.4, 15.5, 16.4, 17.1, 17.6, 18.1, 18.6, 19.1, 19.6, 20.0, 20.8, 21.2, 21.8, 22.8, 23.2, 23.8, 24.7, 25.2, 25.6, 26.2, 26.5, 26.8, 27.5, 28.2, 28.5, 29.0, 29.5 and 30.2 ± 0.2 degrees; the second crystalline form (precipitated from acetone) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta at about 3.7, 7.4, 11.1, 11.9, 13.5, 14.1, 14.8, 15.5, 15.8, 17.6, 18.1, 18.5,
19.2, 20.2, 21.0, 21.8, 22.3, 22.7, 23.0, 23.9, 25.1, 25.8, 26.1, 26.6, 27.2, 27.6, 28.6 and 29.5 ± 0.2 degrees.

IP.com Electronic Publication No. IPCOM000147748D, published on March 25, 2007 (herein after referred to as the 'IP.com publication 748') discloses that the process for the preparation of solifenacin succinate exemplified in the Example 1 of PCT Publication No. WO 2005/105795 produces crystalline form, denominated as crystalline form I, which is characterized by an X-ray powder diffraction pattern having main peaks expressed as 2-theta at about 3.9, 11.2, 14.3 and 18.8 ± 0.2 degrees and further characterized by X-ray powder diffraction peaks expressed as 2-theta at about 7.6, 19.3, 21.1, 23.2 and 25.2 ± 0.2 degrees.

PCT Publication No. WO 2008/013851 (herein after referred to as the '851 application) discloses a crystalline form of solifenacin succinate, denominated as Form II, characterized by X-ray powder diffraction peaks expressed as 2-theta at about 4.3, 14.7 and 16.2 ± 0.2 degrees. The crystalline Form II is further characterized by X-ray powder diffraction peaks expressed as 2-theta at about 11.7, 18.3, 19.9, 22.3, 23.7 and 25.6 ± 0.2 degrees. The '851 application further describes various processes for preparing solifenacin succinate crystalline Form I using various solvents and solvent mediums, which is characterized by an X-ray powder diffraction pattern having main peaks expressed as 2-theta at about 3.9, 11.2, 14.3 and 18.8 ± 0.2 degrees.

According to a first method as described in the '851 application, solifenacin succinate crystalline Form I is prepared by a process comprising combining solifenacin, succinic acid, and a solvent selected from the group consisting of C3-C5 carbonate, acetonitrile, dimethoxypropane, C6-C9 aromatic hydrocarbon, diethyl ether, diisopropyl ether, C5-C9 ester, C1-C4 alcohol, C3-C9 ketone, cyclohexane, heptane, and mixtures thereof to obtain a precipitate of the crystalline form.

According to a second method as described in the '851 application, solifenacin succinate crystalline Form I is prepared by a process comprising slurrying amorphous solifenacin succinate in a solvent selected from the group consisting of heptane, petroleum ether, cyclohexane, methyl t-butyl ether, ethyl acetate, methyl isobutylketone, carbon tetrachloride, toluene, diethyl carbonate, ethyl lactate, isobutyl acetate,
methylethylketone, diethyl ether, isopropanol, dimethyl carbonate, and mixtures thereof.
According to a third method as described in the '851 application, solifenacin succinate crystalline Form I is prepared by a process comprising combining solifenacin succinate with a solvent selected from the group consisting of ethanol, methanol, 1-propanol, tetrahydrofuran, dioxane, ethyl lactate, dichioromethane, 1,2-dichloroethane, acetonitrile, dimethylacetamide, dimethylformarnide, t-butanol, 2-butanol, isopropanol, methylethylketone, toluene, carbon tetrachloride, methyl t-butyl ether, di-isopropyl ether, methyl acetate, ethyl acetate, acetone, isopropylmethyl ketone, and mixtures thereof to form a solution.

According to a fourth method as described in the '851 application, solifenacin succinate crystalline Form I is prepared by a process comprising exposing solifenacin succinate to solvent vapors, wherein the solvent is selected from the group consisting of cyclohexane, isopropanol, ethanol, n-butanol, diethyl ether, methyl t-butyl ether, ethyl acetate, butyl acetate, acetone, methyl isobutylketone, toluene, isopropylether, methyl acetate, 1-propanol, 2-butanol, acetonitrile, tetrahydrofuran, and mixtures thereof.
The processes described in the '851 application suffers from drawbacks since solifenacin succinate crystalline Form I obtained by the processes does not have satisfactory purity, and mainly the yields of solifenacin succinate crystalline Form 1 obtained are low and not consistent because they vary in the range from 23-82%.

Based on the aforementioned drawbacks, prior art processes find to be unsuitable for preparation of solifenacin succinate crystalline Form I at lab scale and commercial scale operations.

Hence, a need still remains for an improved and commercially viable process of preparing pure solifenacin succinate crystalline Form I that will solve the aforesaid problems associated with processes described in the prior art and will be suitable for large-scale preparation, in terms of consistency, purity and yield of the product.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an improved, commercially viable, environment friendly and consistently reproducible process for the preparation of substantially pure solifenacin succinate crystalline Form I, characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 3.66, 7.36, 11.06, 11.82, 13.46, 14.11, 14.78, 15.50, 15.82, 17.61, 18.09, 18.58, 19.21, 20.14, 20.91, 21.74, 22.31, 22.64, 22.96, 23.84, 25.04, 25.79, 26.14, 26.53, 27.17, 27.56, 28.56, 29.45 and 34.91 ± 0.2 degrees, which is free of other polymorphs and solvating agents such as water and organic solvents, comprising dissolving solifenacin base in 2-methyltetrahydrofuran, or a solvent medium comprising 2-methyltetrahydrofuran and a second solvent selected from the group consisting of an alcohol, an ester and mixtures thereof, to form a clear solution, adding succinic acid to the solution to form a mixture, stirring the mixture at ambient temperature to form a slurry, and then recovering substantially pure solifenacin succinate crystalline Form I.

It has been surprisingly and unexpectedly found that the use of a specific solvent medium, preferably a mixture of 2-methyltetrahydrofuran and ethyl acetate, in the salt formation reaction under suitable conditions, for preparing solifenacin succinate crystalline Form I, allows the product to be easily isolated and purified, thereby consistently producing the product with significantly higher yields (88-95%) when compared with the lower and inconsistent yields (ranging from 23-82%) obtained by the processes exemplified in the above mentioned prior art.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of solifenacin succinate crystalline Form I obtained according to Example 1.

Figure 2 is a characteristic powder X-ray diffraction (XRD) pattern of solifenacin succinate crystalline Form I obtained according to Example 2.

Figure 3 is a characteristic powder X-ray diffraction (XRD) pattern of solifenacin succinate crystalline Form I obtained according to Example 3.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided a process for the preparation of solifenacin succinate crystalline Form I, comprising:

a) providing a solution of solifenacin base in 2-methyltetrahydrofuran or a solvent medium comprising 2-methyltetrahydrofuran and a second solvent selected from the group consisting of an alcohol, an ester and mixtures thereof;

b) optionally, filtering the solvent solution to remove any extraneous matter;

c) combining the solution with succinic acid to form a slurry; and

d) recovering solifenacin succinate crystalline Form I from the slurry.

In one embodiment, the crystalline Form I of solifenacin succinate is characterized by at least one, or more, of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with any one of the Figures 1, 2 and 3; ii) a powder X-ray diffraction pattern having peaks at about 3.66, 11.06, 14.11 and 18.58 ± 0.2 degrees 2-theta; and iii) a powder X-ray diffraction pattern having additional peaks at about 7.36, 11.82, 13.46, 14.78, 15.50, 15.82, 17.61, 18.09, 19.21, 20.14, 20.91, 21.74, 22.31, 22.64, 22.96, 23.84, 25.04, 25.79, 26.14, 26.53, 27.17, 27.56, 28.56, 29.45 and 34.91 ± 0.2 degrees 2-theta.

The process can produce crystalline Form I of solifenacin succinate in substantially pure form.

The term "substantially pure solifenacin succinate crystalline Form I" refers to the solifenacin succinate crystalline Form I having purity greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.9% (measured by HPLC). For example, the purity of solifenacin succinate crystalline Form I obtained by the process disclosed herein can be about 99% to about 99.95%, or about 99.5% to about 99.99%, as measured by HPLC.

Exemplary alcohol solvents include, but are not limited to, C( to C6 straight or branched chain alcohol solvents such as methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, and mixtures thereof. A specific alcohol solvent is isopropyl alcohol.

Exemplary ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, and the like and mixtures thereof. A specific ester solvent is ethyl acetate.

Step-(a) of providing a solution of solifenacin base includes dissolving solifenacin base in the solvent, or obtaining an existing solution from a previous processing step.

In one embodiment, the solifenacin base is dissolved in the solvent at a temperature of below boiling temperature of the solvent used, specifically at about 20°C to about 80°C, and more specifically at about 25°C to about 35°C.

In another embodiment, the solution in step-(a) is prepared by reacting (15)-Ethyl-1-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate with (3i?)-quinuclidinol in the presence of a base in a reaction inert solvent under suitable conditions to produce a reaction mass containing crude solifenacin base, followed by usual work up such as washings, extractions, evaporations, acid base treatments, layer separations, or a combination thereof. In one embodiment, the work¬up includes dissolving or extracting the resulting solifenacin base in 2-methyltetrahydrofuran or a solvent medium comprising 2-methyltetrahydrofuran and the second solvent at a temperature of below boiling temperature of the solvent used, specifically at about 20°C to about 80°C, and more specifically at about 25°C to about 35°C.

In one embodiment, the base used for facilitating the reaction between (15)-Ethyl-1-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate and (3i?)-quinuclidinol is an inorganic base.

Exemplary inorganic bases include, but are not limited to, hydrides, hydroxides, alkoxides, carbonates and bicarbonates of alkali or alkaline earth metals. Specific inorganic bases are sodium hydride, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. A specific inorganic base is sodium hydride.

Exemplary reaction inert solvents suitable for facilitating the reaction between (15)-Ethyl-1-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate and (3/?)-quinuclidinol include, but are not limited to, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, polar aprotic solvents, and the like, and mixtures thereof. In one embodiment, the solvent is selected from the group consisting of methylene chloride, dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. A specific reaction inert solvent is 2-methyltetrahydrofuran.

The solution obtained in step-(a) is optionally subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 15 minutes, specifically at a temperature of about 40°C to about 70°C for at least 30 minutes; and filtering the resulting mixture through hyflo to obtain a filtrate containing solifenacin base by removing charcoal or silica gel. Preferably, finely powdered carbon is an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

Combining of the solution with succinic acid in step-(c) is done in a suitable order, for example, the solution is added to the succinic acid, or alternatively, the succinic acid is added to the solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at a temperature of below about 50°C, and more specifically at about 20°C to about 35°C under stirring. After completion of addition process, the resulting mass is stirred at a temperature of about 20°C to about 50°C for at least 1 hour and specifically at a temperature of about 25°C to about 35°C for about 2 hours to about 20 hours to form the slurry containing solifenacin succinate.

The recovering in step-(d) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof. In one embodiment, solifenacin succinate crystalline Form I can be recovered by filtration employing a filtration media of, for example, a silica gel or celite.

The substantially pure solifenacin succinate crystalline Form I obtained by above process may be further dried in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 70°C. The drying can be carried out for any desired time period that achieves the desired result, such as about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

The total purity of the solifenacin succinate crystalline Form I obtained by the process disclosed herein is of greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.9% as measured by HPLC.

Solifenacin base used as starting material can also be obtained by processes described in the prior art, for example by the process described in the U.S. Patent No. 6,017,927.
According to another aspect, there is provided a one pot process for the preparation of solifenacin succinate crystalline Form I, comprising:

a) reacting (15)-l-Phenyl-l,2,3,4-tetrahydro-isoquinoline with ethyl chloroformate in the presence of an organic base in 2-methyltetrahydrofuran solvent to produce a reaction mass containing (1S)-ethyl-1 -phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate;

b) isolating the (liS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate as a pale yellow oil from the reaction mass;

c) reacting the (15)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate obtained in step-(b) with (3^)-quinuclidinol in the presence of an inorganic base in 2-methyltetrahydrofuran solvent to produce a first reaction mass containing solifenacin base;

d) subjecting the first reaction mass to washings, extractions, evaporations, acid base treatments, layer separations, or a combination thereof to produce a second reaction mass containing solifenacin base;

e) extracting the second reaction mass containing solifenacin base with 2-methyltetrahydrofuran solvent to produce an organic layer containing solifenacin base;

f) combining the organic layer with succinic acid to form a slurry; and

g) recovering solifenacin succinate crystalline Form I from the slurry.

In one embodiment, the organic base used in step-(a) is an organic amine base such as triethyl amine, dimethyl amine and tert-butyl amine. A specific organic amine base is triethyl amine.

The reaction in step-(a) is specifically carried out at a temperature of below 40°C for at least 1 hour, more specifically at a temperature of about 0°C to about 35°C for about 2 hours to about 25 hours, and more specifically at a temperature of about 20°C to about 30°C for about 3 hours to about 15 hours.

The reaction in step-(c) is carried out at a temperature of about 0°C to the reflux temperature of the solvent for at least 1 hour, specifically at a temperature of about 25°C to the reflux temperature of the solvent for about 2 hours to about 10 hours, and most specifically at the reflux temperature of the solvent for about 4 hour to about 9 hours.
In one embodiment, the inorganic base used in step-(c) is selected from the group as described above. A most specific inorganic base is sodium hydride.

The combining in step-(f) and recovering in step-(g) are carried out by methods as described above.

INSTRUMENTAL DETAILS: X-Ray Powder Diffraction (P-XRD):

The X-Ray powder diffraction was measured by an X-ray powder Diffractometer equipped with CuKa-radiations (40kV, 40 mA) in wide-angle X-ray Diffractometer of BRUKER axs, D8 ADVANCE. The sample was analyzed using the following instrument parameters: measuring range = 3-45° 2-theta; step width = 0.01579°; and measuring time per step = 0.11 seconds.

The following examples are given for the purpose of illustrating the present disclosure and should not be considered as limitation on the scope or spirit of the disclosure.

EXAMPLES

Example 1

Preparation of Solifenacin Succinate Crystalline Form I

Step-I: Preparation of (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate
(lS)-l-Phenyl-l,2,3,4-tetrahydro-isoquinoline (100 gm) and triethylamine (53 gm) were added to 2-methyltetrahydrofuran (1000 ml) at 25-30°C and the mixture was cooled to 0-5°C. The resulting mixture was followed by slow addition of ethyl chloroformate (50 ml) over a period of 3 hours at 0-5°C and then stirred for 14 hours at 25-30°C. The reaction mass was washed initially with water (500 ml) and then with IN hydrochloric acid (2 x 100 ml). The resulting organic layer was again washed with water (300 ml) followed by separation of the layers to get 133 gm of (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate as a pale yellow oil.

Step-II: Preparation of Solifenaein Succinate Crystalline Form I (15)-Ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate (50 gm, obtained in step-I) was added to 2-methyltetrahydrofuran (500 ml) followed by heating to reflux temperature while removing water azeotropically. The resulting mass was cooled to 40-50°C and followed by the addition of (3i?)-quinuclidinol (27.2 gm) and 2-methyltetrahydrofuran (150 ml). The resulting mixture was heated to reflux temperature while removing water azeotropically followed by cooling to 40-50°C. Sodium hydride (3.42 gm) and 2-methyltetrahydrofuran (150 ml) were added to the resulting mass, and then heated to reflux temperature for 6 to 8 hours. The reaction mass was cooled to 25-30°C, followed by the addition of brine solution (100 ml) and separation of the layers. A solution of hydrochloric acid (50 ml) in water (200 ml) was added to the resulting organic layer, followed by the separation of layers. The aqueous layer was washed with 2-methyltetrahydrofuran (50 ml) and the resulting aqueous layer was followed by cooling to 0-5°C and then adjusting the pH to 10 to 12 with 20% sodium hydroxide solution. The reaction mass was extracted two times with 2-methyltetrahydrofuran (2 x 250 ml) and followed by separation of the layers. The resulting organic layer was washed with water (50 ml) and then subjected to azeotropical distillation to remove water. The resulting organic layer was cooled to 25-30°C followed by the addition of succinic acid (17.2 gm) and then stirred for 4 hours at 25-30°C. The separated solid was filtered, washed with 2-methyltetrahydrofuran (25 ml) and then dried the product under vacuum at 50°C to yield 26.4 gm of solifenacin succinate crystalline form I (Purity by HPLC: 99.67%; and Chiral Purity by HPLC: 99.69%).

Example 2

Preparation of Solifenacin Succinate Crystalline Form I

Solifenaein base (3.0 gm) was dissolved in 2-methyltetrahydrofuran (30 ml) at 25-30°C, succinic acid (1.07 gm) was added to the solution and the mixture was stirred for 16 hours at 25-30°C to form a slurry. The product was isolated from the slurry by vacuum suction, washed with 2-methyltetrahydrofuran (10 ml) and then dried in a vacuum oven at 50°C overnight to obtain 3.14 gm of solifenaein succinate crystalline form I (Purity by HPLC: 98.55%; and Chiral Purity by HPLC: 97.51%).

Example 3

Preparation of Solifenacin Succinate Crystalline Form I

Solifenacin base (3.0 gm) was dissolved in a mixture of 2-methyltetrahydrofuran (15 ml) and isopropyl alcohol (15 ml) at 25-30°C. To the solution, succinic acid (1.07 gm) was added and the mixture was stirred for 15 hours at 25-30°C to form a slurry. The product was isolated from the slurry by vacuum suction, washed with 2-methyltetrahydrofuran (10 ml) and then dried in a vacuum oven at 50°C overnight to obtain 2.77 gm of solifenacin succinate crystalline form I (Purity by HPLC: 99.63%; and Chiral Purity by HPLC: 99.91%).

Example 4 Preparation of Solifenacin Succinate Crystalline Form I

Solifenacin base (3.0 gm) was dissolved in a mixture of 2-methyltetrahydrofuran (28 ml) and ethyl acetate (12 ml) at 25-30°C. To the solution, succinic acid (1.03 gm) was added and the mixture was stirred for 16 hours at 25-30°C to form slurry. The product was isolated from the slurry by vacuum suction, washed with 2-methyltetrahydrofuran/etyl acetate (14ml/6ml) and then dried in a vacuum oven at 50°C overnight to obtain 3.54 gm of solifenacin succinate crystalline form I (Purity by HPLC: 99.66%; and Chiral Purity by HPLC: 99.83%).

We claim:

1. A process for the preparation of solifenacin succinate crystalline Form I, comprising:

a) providing a solution of solifenacin base in 2-methyltetrahydrofuran or a solvent medium comprising 2-methyltetrahydrofuran and a second solvent selected from the group consisting of an alcohol, an ester and mixtures thereof;

b) optionally, filtering the solvent solution to remove any extraneous matter;

c) combining the solution with succinic acid to form a slurry; and

d) recovering solifenacin succinate crystalline Form I from the slurry.

2. The process of claim 1, wherein the second solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, and mixtures thereof; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment or silica gel treatment; wherein the combining in step-(c) is accomplished either by adding the solution to the succinic acid or by adding the succinic acid to the solution; wherein recovering in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof; wherein the substantially pure solifenacin succinate crystalline Form I obtained in step-(d) is further dried under vacuum or at atmospheric pressure, at a temperature of about 35°C to about 70°C; and wherein the solifenacin succinate crystalline Form I obtained in step-(d) has a total purity of about 99% to about 99.95% as measured by HPLC.

3. The process of claim 2, wherein the second solvent is isopropyl alcohol or ethyl acetate; wherein the addition in step-(c) is carried out at a temperature of below about 50°C under stirring; and wherein the reaction mass obtained after completion of addition process is stirred at a temperature of about 20°C to about 50°C for at least 1 hour.

4. The process of claim 3, wherein the addition in step-(c) is carried out at a temperature of about 20°C to about 35°C; and wherein the reaction mass obtained after completion of addition process is stirred at a temperature of about 25°C to about 35°C for about 2 hours to about 20 hours.

5. The process of claim 1, wherein the solution in step-(a) is provided either by dissolving solifenacin base in the solvent at a temperature of below boiling temperature of the solvent used; or by reacting (15)-Ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate with (3R)-quinuclidinol in the presence of a base in a reaction inert solvent under suitable conditions to produce a reaction mass containing crude solifenacin base; subjecting the reaction mass to washings, extractions, evaporations, acid base treatments, layer separations, or a combination thereof; and dissolving or extracting the resulting solifenacin base in 2-methyltetrahydrofuran or a solvent medium comprising 2-methyltetrahydrofuran and the second solvent at a temperature of below boiling temperature of the solvent.

6. The process of claim 5, wherein the dissolution is carried out at a temperature of about 25°C to about 35°C; wherein the base used in the reaction between (lS)-Ethy 1-1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate and (3i?)-quinuclidinol is an inorganic base; and wherein the reaction inert solvent used in the reaction between (lS)-Ethyl-l-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate and (3i?)-quinuclidinol is selected from the group consisting of methylene chloride, dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.

7. The process of claim 6, wherein the inorganic base is sodium hydride; and wherein the reaction inert solvent is 2-methyltetrahydrofuran.

8. A one pot process for the preparation of solifenacin succinate crystalline Form I, comprising:

a) reacting (liS)-l-Phenyl-l,2,3,4-tetrahydro-isoquinoline with ethyl chloroformate in the presence of an organic base in 2-methyltetrahydrofuran solvent to produce a reaction mass containing (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate;

b) isolating the (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate as a pale yellow oil from the reaction mass;

c) reacting the (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate obtained in step-(b) with (3i?)-quinuclidinol in the presence of an inorganic base in 2-methyltetrahydrofuran solvent to produce a first reaction mass containing solifenacin base;

d) subjecting the first reaction mass to washings, extractions, evaporations, acid base treatments, layer separations, or a combination thereof to produce a second reaction mass containing solifenacin base;

e) extracting the second reaction mass containing solifenacin base with 2-methyltetrahydrofuran solvent to produce an organic layer containing solifenacin base;

f) combining the organic layer with succinic acid to form a slurry; and

g) recovering solifenacin succinate crystalline Form I from the slurry.

9. The process of claim 8, wherein the organic base used in step-(a) is selected from the group consisting of triethyl amine, dimethyl amine and tert-butyl amine; wherein the reaction in step-(a) is carried out at a temperature of below 40°C for at least 1 hour; wherein the reaction in step-(c) is carried out at a temperature of about 0°C to the reflux temperature of the solvent for at least 1 hour; and wherein the inorganic base used in step-(c) is sodium hydride.

10. The process of claim 9, wherein the organic base used in step-(a) is triethyl amine; wherein the reaction in step-(a) is carried out at a temperature of about 0°C to about 35°C for about 2 hours to about 25 hours; and wherein the reaction in step-(c) is carried out at a temperature of about 25°C to the reflux temperature of the solvent for about 2 hours to about 10 hours.