Field of the Invention
The present invention relates to amorphous Darifenacin hydrobromide and process for the preparation thereof. The present invention further relates to novel process for the preparation of crystalline Darifenacin hydrobromide.
Background of the Invention
Darifenacin is used to treat urinary incontinence. Darifenacin works by blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. It thereby decreases the urgency to urinate.
Darifenacin is administered as the hydrobromide salt, Darifenacin is chemically known as (S)-2-{l-[2 (2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide having the chemical structure,

Darifenacin and its pharmaceutically acceptable acid addition salts are first known in US 5,096,890, whereas this patent discloses only process for the preparation of Darifenacin hydrobromide. However, this patent does not discuss about the polymorphic forms.
In US 2007/0197630 application claims process for preparation of Darifenacin hydrobromide having oxidized Darifenacin less than 0.1%. Process for the preparation of Darifenacin hydrobromide followed according to US' 630 rhesus in the formation of crystalline or amorphous Darifenacin hydrobromide. In US '630 application does not give the examples for preparation of Darifenacin hydrobromide amorphous, crystalline and characterization of the same.
According to prior art literature, we have not found the specific process for the preparation of amorphous Darifenacin hydrobromide, crystalline Darifenacin

hydrobromide and characterization of amorphous Darifenacin hydrobromide. In view of the prior art literature survey, there is a need to prepare amorphous Darifenacin hydrobromide and develop process for the preparation of amorphous Darifenacin hydrobromide and crystalline Darifenacin hydrobromide.
We have crystallized Darifenacin hydrobromide in different solvent, solvent mixtures, employing different parameters and found out process for the preparation of amorphous Darifenacin hydrobromide, crystalline Darifenacin hydrobromide and characterization of the same.
Object of the Invention
The main object of the present invention is to provide amorphous Darifenacin hydrobromide and process for the preparation of Darifenacin hydrobromide.
Yet another object of the present invention is to provide the novel process for the preparation of crystalline Darifenacin hydrobromide.
Summary of the Invention
The main aspect of the present invention relates to amorphous Darifenacin hydrobromide characterized by X-ray powder diffraction pattern. Infrared absorption spectrum. Differential scanning calorimetric (DSC).
In another aspect of the present invention relates to process for the preparation of amorphous Darifenacin hydrobromide by using different solvent systems and conditions.
Yet another aspect of the present invention relates to novel process for the preparation of crystalline Darifenacin hydrobromide.
Brief Description of the Drawings
Fig 1 is a X-ray powder diffraction pattern of amorphous Darifenacin hydrobromide.
Fig 2 is a Differential scanning calorimetric (DSC) curve of amorphous Darifenacin hydrobromide
Fig 3 is a FTIR spectrum of amorphous Darifenacin hydrobromide.

Detailed Description of the Invention
The present invention relates to amorphous Darifenacin hydrobromide and process for the preparation thereof The present invention further relates to novel process for the preparation of crystalline Darifenacin hydrobromide. Amorphous Darifenacin hydrobromide is characterized by its physical properties as well as by spectral data which includes moisture content, X-ray powder diffraction pattern. Differential Scanning Calorimetry (DSC) and FTIR absorption spectrum (FTIR).
Powder X-rav Diffraction (?XRD)
The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 9/0 configuration and X'Celerator detector. The Cu-anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 26 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Differential Scanning Calorimetry (DSC) Glass Transition
The glass transition temperature (Tg) of the amorphous Darifenacin hydrobromide was measured on TA QIOOO of TA instrument with modulated DSC software. The experiments were performed at a heating rate of 3.0°C/min up to a final temperature of 300° with modulation amplitude ±1.0°C, modulation period 80sec and nitrogen purging at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with five pin holes were used.
Karl-Fisher
Water content was determined on Metrohm Karl-Fisher titrate (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.
Infrared spectroscopy
Fourier transform infrared (FT-IR) spectra were recorded with a Perkin-Elmer spectrum one spectrophotometer. The samples were prepared as 13mm thickness potassium

bromide discs by triturating 1 to 2mg of sample with 300mg to 400mg of KBR by applying pressure of about 1000 Ibs/sq inch. Then theses discs were scanned in the spectral range of 4000 to 650 cm'* with a resolution of 4 cm"^
The present invention relates to amorphous Darifenacin hydrobromide and process for the preparation thereof Amorphous Darifenacin hydrobromide is characterized by powder X-ray diffraction pattern as shown in Figure 1.
Amorphous Darifenacin hydrobromide is further characterized by the DSC (Figure 2), which shows three characteristic peaks; first weak endothermal glass transition peak at an extrapolated onset temperature (Tg) 105°C (Figure 2, inset), second an exothermic peak at an extrapolated onset temperature ranging from 165 to 180°C, corresponding to the transition from amorphous phase to an anhydrous crystalline phase which is identified with a peak at 173°C, and a third endothermal peak at 233°C (maxima), corresponding to the complete melting of the product. The amorphous form contains the water up to approximately 1.0 to 4.0 % by weight, preferably 2.0 to 3.0 % determined by the Karl-Fisher method.
Amorphous Darifenacin hydrobromide is further characterized by IR with absorption bands at 3470, 3055, 2924,2854, 2567, 1671, 1492, 1444, 1242, 981, 757, 704, 637, 497(cm'') as depicted in Figure 3.
The present invention also relates to the process for the preparation of amorphous Darifenacin hydrobromide comprising the steps of: a) dissolving Darifenacin hydrobromide in first solvent b) removing solvent from the solution c) optionally treating with second solvent and d) isolating amorphous Darifenacin hydrobromide.
According to our present invention, amorphous Darifenacin hydrobromide is prepared by dissolving Darifenacin hydrobromide in a first solvent selected from the group comprising of alcoholic solvents, polar aprotic solvents, chlorinated solvents, water or mixtures thereof
The alcoholic solvents is selected from methanol, ethanol, propanol, isopropyl alcohol, n-butanol, iso-butanol, the polar aortic solvent is selected from tetrahydrofuran, N,N-

dimethylformamide, dimethylsulfoxide, the chlorinated solvents is selected from chloroform, methylene dichloride or mixtures thereof
Darifenacin hydrobromide dissolved in a solvent is removed from the reaction mass by using known techniques such as atmospheric distillation, distillation under reduced pressure, evaporation, spray drying, freeze-drying and filtration. The solid obtained is optionally treated with second solvent selected from pentane, hexane, heptane, toluene, cyclohexane, isopropyl ether or mixture thereof to give amorphous Darifenacin hydrobromide.
The present invention also provides the process for the preparation of crystalline Darifenacin hydrobromide comprising the steps of: a) treating amorphous Darifenacin hydrobromide in solvent and b) isolating crystalline darifenacin hydrobromide.
According to our present invention, crystalline Darifenacin hydrobromide is prepared by slurrying amorphous Darifenacin hydrobromide in a solvent selected from but not limited to hexane, heptane, pentane, cyclohexane, toluene, acetonitrile, water, isopropyl ether, diethyl ether or mixture thereof, followed by filtration to give crystalline Darifenacin hydrobromide. The present invention further relates to another process for the preparation of crystalline Darifenacin hydrobromide by heating the amorphous Darifenacin hydrobromide at 130-180° C under a vacuum of 600 mm Hg for 16 hours to give crystalline Darifenacin hydrobromide.
The crystalline Darifenacin hydrobromide is also prepared by storing the amorphous Darifenacin hydrobromide at relative humidity >90% for two days.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.
Example 1: Preparation of amorphous Darifenacin hydrobromide
5g of Darifenacin hydrobromide was dissolved in 50ml of methanol at hot condition. The resulting clear solution was distilled off completely under vacuum at 50°C leaving white foam. Additional drying under reduced pressure for Ihour results free solid product of amorphous Darifenacin hydrobromide.
Example 2: Preparation of amorphous Darifenacin hydrobromide
5g of Darifenacin hydrobromide was dissolved in 75 ml of methylene dichloride at hot condition. The resulting clear solution was distilled off completely under vacuum at 50°C leaving white foam. Additional drying under reduced pressure for Ihour results free solid. Then 10ml of heptane was added to the resulting solid product and maintained under agitation for 15 minutes and filtered to give amorphous Darifenacin hydrobromide.
Example 3: Preparation of amorphous Darifenacin hydrobromide
5g of Darifenacin hydrobromide was dissolved in 75 ml of chloroform at hot condition. The resulting clear solution was distilled off completely under vacuum at 50°C leaving white foam. Additional drying under reduced pressure for Ihour results free solid product of amorphous Darifenacin hydrobromide.
Example 4: Preparation of amorphous Darifenacin hydrobromide
5g of Darifenacin hydrobromide was dissolved in a mixture of methanol and water 1:1 ratio (50:50ml) at hot condition. The resulting clear solution was distilled off completely under vacuum at each leaving white foam. Additional drying under reduced pressure for Ihour results free solid product of amorphous Darifenacin hydrobromide.

Example 5: Preparation of amorphous Darifenacin hydrobromide
lOg of crystalline Darifenacin hydrobromide was suspended in 5% methanol (50 ml) at ambient temperature. The resulting solution was slowly heated to 65-70°C for 30 min to get clear solution which was subjected to spray drying in a mini spray dryer (model Buchi - 290) at a temperature of 80-90°C using nitrogen gas. The resulting solid was isolated to give amorphous Darifenacin hydrobromide.
Example 6: Preparation of amorphous Darifenacin hydrobromide
lOg of crystalline Darifenacin hydrobromide was suspended in a mixture of methylene dichloride and methanol in the ratio 9:1 v/v at ambient temperature. The resulting solution is slowly heated to 65-70°C for 30 min to get clear solution which was subjected to spray drying in a mini spray dryer (model Buchan - 290) at a temperature of 80-90°C using nitrogen gas. The resulting solid was isolated to give amorphous Darifenacin hydrobromide.
Example 7: Preparation of amorphous Darifenacin hydrobromide
lOg of crystalline Darifenacin hydrobromide was suspended in 1:1 mixture of methanol and water (50:50 v/v) at ambient temperature. The rescuing solution is slowly heated to 65-70°C for 30 min to get clear solution which was subjected to freeze-drying (Model: Virtues Genesis SQ Freeze Dryer) at -104°C and below 200 Torr vacuum. The resulting solid was isolated to give amorphous Darifenacin hydrobromide.
Example 8: Anhydrous Crystalline Darifenacin Hydrobromide
10 ml of heptane was placed into a round bottom flask along with Ig of amorphous Darifenacin hydrobromide. The mixture was then stirred at ambient temperature for 12 hours. The mixture was filtered under a vacuum of 600 mm Hg and the solid was finally dried under vacuum at ambient temperature to give crystalline Darifenacin hydrobromide.

Example 9: Anhydrous Crystalline Darifenacin Hydrobromide
10ml of isopropyl ether (IPE) was placed into a round bottom flask along with Ig of amorphous Darifenacin hydrobromide. The mixture was then stirred at ambient temperature for 12 hours. The mixture was filtered under a vacuum of 600 mm Hg and the solid was finally dried under vacuum at ambient temperature to give crystalline Darifenacin hydrobromide.
Example 10: Anhydrous Crystalline Darifenacin Hydrobromide
10ml of water was placed into a round bottom flask along with Ig of amorphous Darifenacin hydrobromide. The mixture was then stirred at ambient temperature for 12 hours. The mixture was filtered under a vacuum of 600 mm Hg and the solid was finally dried under vacuum at ambient temperature to give crystalline Darifenacin hydrobromide.
Example 11: Anhydrous Crystalline Darifenacin Hydrobromide
10ml of acetonitrile was placed into a round bottom flask along with Ig of amorphous Darifenacin hydrobromide. The mixture was then stirred at ambient temperature for 12 hour. The mixture was filtered under a vacuum of 600 mm Hg and the solid was finally dried under vacuum at ambient temperature to give crystalline Darifenacin hydrobromide.
Example 12: Anhydrous Crystalline Darifenacin Hydrobromide
Ig of amorphous Darifenacin hydrobromide was taken in a clean Petri dish. The compound was heated in a vacuum oven maintained at 140°C under a vacuum of 600 mm Hg for 16 hours to give crystalline Darifenacin hydrobromide.
Example 13: Anhydrous Crystalline Darifenacin Hydrobromide
Ig of amorphous Darifenacin hydrobromide was taken in a clean Petri dish. The compound was then stored in desiccators maintained at relative humidity greater than 90% for 2days to give crystalline Darifenacin hydrobromide.

We Claim;
1. Amorphous Darifenacin hydrobromide having PXRD pattern as shown in figure 1.
2. A process for the preparation of amorphous Darifenacin hydrobromide comprising the steps of

a) dissolving Darifenacin hydrobromide in first solvent,
b) removing solvent from the solution,
c) optionally treating with second solvent and
d) isolating amorphous Darifenacin hydrobromide.

3. The process according to claim 2a, wherein the first solvent is selected from methanol, ethanol, propanol, isopropyl alcohol, w-butanol, iso-butanol, water, N,N-dimethylformamide, dimethylsulfoxide, chloroform, methylene dichloride or mixture thereof
4. The process according to claim 2b, wherein solvent is removed from the solution by using techniques such as atmospheric distillation, distillation under reduced pressure, evaporation, spray drying, freeze drying and filtration.
5. The process according to claim 2c, wherein second solvent is selected from pentane, hexane, heptane, toluene, cyclohexane, isopropyl ether or mixture thereof.
6. A process for the preparation of crystalline Darifenacin hydrobromide comprising the steps of:

a) treating amorphous Darifenacin hydrobromide in solvent and
b) isolating crystalline darifenacin hydrobromide.

7. The process according to 6a, wherein solvent is selected from pentane, hexane, heptane, octane, cyclopentane, cyclohexane, acetonitrile, water, isopropyl ether, methyl ethyl ether or mixture thereof
8. A process for the preparation of crystalline Darifenacin hydrobromide comprising the steps of:

a) heating amorphous Darifenacin hydrobromide and
b) isolating crystalline Darifenacin hydrobromide.
9. The process according to claim 8a, wherein heating amorphous Darifenacin
hydrobromide is carried out at 130-180° C, optionally under vacuum.
10. A process for the preparation of crystalline Darifenacin hydrobromide which
comprises subjecting amorphous Darifenacin hydrobromide to relative humidity greater
than 90% for two days to form crystalline Darifenacin hydrobromide.