Technical field of invention:
The present invention relates to novel crystalline form D of varenicline L-tartarate, which is a nicotine partial agonist used for the treatment of nicotine dependency and several CNS disorders. The present invention also encompasses process for preparation of the novel crystalline form D of varenicline L-tartarate.
Background of the invention:
Varenicline is nicotinic partial agonist and is known by chemical name 5,8,14-triazatetracyclo[10.3.1.02,11.04'9]hexadeca-2(ll)-3,5,7,9-pentaene. The L-tartarate salt of varenicline marketed by Pfizer under the trade name Chantix in USA is used for the treatment of nicotine dependency. Varenicline represented by structural formula I is disclosed in US patent 6,410,550 and its L-tartarate salt represented by structural formula II is disclosed in US patent 6,890,927.

The survey of prior art reveals that ample efforts have not been taken for studying polymorphs of varenicline L-tartarate. The US patent 7,265,119 is the lone reference in the prior art which describe various polymorphs of varenicline L-tartarate which are discussed in details below:
US patent 7,265,119 discloses three different polymorphic forms, viz., anhydrous form A, anhydrous form B and hydrated form C of varenicline L-tartarate. Form A is a kinetically favored polymorph, which will convert under appropriate conditions to thermodynamically more favored form B. Form C is a monohydrate, which maintains its one equivalent of water under vacuum at moderate temperature for 24 hours but eventually over time will lose water and convert to anhydrous form B. Anhydrous form B is thermodynamically stable polymorph of varenicline L-tartarate.

The existence of sole prior art document points towards the fact that efforts to find out different crystalline forms of varenicline tartarate are meager. In the hands of inventors of present invention, a new crystalline form of varenicline tartarate is obtained, which is referred to as crystalline Form D.
Summary of the invention:
The present invention describes a novel crystalline form D of varenicline L-tartarate and process for its preparation. The process for preparation of crystalline form D of varenicline L-tartarate involves crystallization of varenicline L-tartarate from a mixture of nitrile solvent and water.
Description of the drawings:
Figure 1 illustrates powder x-ray diffraction pattern of crystalline form D of varenicline
L-tartarate. Figure 2 illustrates differential scanning calorimetry (DSC) thermogram of crystalline
form D of varenicline L-tartarate. Figure 3 illustrates thermogravimetric analysis (TGA) thermogram of crystalline form D
of varenicline L-tartarate. Figure 4 illustrates FT-infrared spectrum of crystalline form D of varenicline L-tartarate.
Description of the invention:
The present invention discloses a novel crystalline form of varenicline L-tartarate. This novel crystalline form of L-tartarate salt of varenicline is referred to herein as form D. In one embodiment of the invention, the crystalline form D of varenicline L-tartarate is characterized by the following characterization data:
PXRD: Powder x-ray diffraction pattern of crystalline form D is as depicted in figure 1. The x-ray diffraction pattern has significant reflections at following 29 values: 9.5, 10.0, 10.9, 13.5, 14.4, 15.5, 19.8.

DSC: The differential scanning calorimetry thermogram for the novel crystalline form D is as depicted in figure 2. The crystalline form D of varenicline L-tartarate is characterized in that it has an onset of melt at about 209°C and an endothermic peak at 215°C.
TGA: The thermogravemetric analysis thermogram (TGA) for the novel crystalline form D is as depicted in figure 3. TGA reveals a weight loss of 3.4% in the temperature range of60-105°C.
FT-IR spectrum: The infrared spectrum of crystalline form D is as depicted in figure 4. Crystalline form D is characterized in that the infrared spectrum exhibit following principal peaks in cm"1: 3325.2, 3030.5, 2973.2, 2813.5, 2615.4, 1674.5, 1613.7, 1474.8, 1304.2, 1264.2, 1216.1, 1134.8, 1072.3, 1026.4, 936.5, 891, 843.3, 773, 681.
Moisture content: 5.5 % (by Karl Fischer titration method).
In another embodiment, the invention provides a process for preparation of varenicline L-tartarate salt by:
(i) contacting varenicline free base with L(+)-tartaric acid in suitable organic solvent; and
(ii) isolating varenicline L-tartarate;
Suitable organic solvent employed for the reaction of varenicline free base with L(+)-tartaric acid is selected from the group consisting of ethers such as tetrahydrofuran, diethyl ether; diisopropyl ether, ter-butylmethyl ether; lower alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol; lower aliphatic ketones such as acetone, ethylmethyl ketone, diethyl ketone; esters such as ethyl acetate, propyl acetate, isopropyl acetate; and acetonitrile or any mixtures thereof. Most preferred solvent is tetrahydrofuran.
The molar ratio of L(+)-tartaric acid with respect to varenicline free base is in the range of 1 to 3 molar equivalents, more preferably in the range of 1 to 2 molar equivalents, most preferably 1 to 1.3 molar equivalents.

The salt formation is carried out in a temperature range of 20°C to 150°C, more preferably at 40°C to 80°C, most preferably at 55°C to 60°C. Stirring of the reaction mixture is carried out for 10 minutes to 5 hours, more preferably for 0.5 hours to 3 hours, most preferably for 1 to 1.5 hours.
In a preferred embodiment the present invention provides process for obtaining crystalline form D of varenicline L-tartarate comprising the steps of:
(i) preparing a solution of varenicline L-tartarate in water;
(ii) adding a water miscible nitrile solvent;
(iii) stirring for 2-20 hours; and
(iv) isolating crystalline form D.
The varenicline L-tartarate employed for preparation of crystalline form D can be amorphous or any crystalline form.
The water miscible nitrile solvent is selected from acetonitrile, propionitrile, butyronitrile; most preferred solvent is acetonitrile.
The volume of water employed is in the range of 2 to 10 volumes, more preferably 4 volumes. The volume of nitrile solvent is in the range of 10 to 100 volumes, more preferably 60 volumes.
Crystallization is carried out at a temperature of 15 to 50°C, preferably at 25-30°C. Stirring of the reaction mixture is carried out for 2-20 hours, more preferably for 2-10 hours.
The crystalline form D is isolated by standard techniques such as filtration, removal of solvent by distillation or concentration of the reaction mixture.
The invention is further illustrated by following examples, which should not be construed as limiting to the scope of invention.

Experimental:
Varenicline free base employed for the preparation of crystalline form D of the present invention was procured from M/s Zhejiang Medicine & health products Import & export Co. Ltd, China.
Example 1:
Preparation of varenicline tartarate from varenicline free base
1.56 g of L(+)-tartaric acid was charged in a vessel and tetrahydrofuran (10 ml) was added. The mixture was stirred at 45-50°C to obtain a clear solution and filtered. Varenicline free base (2 g) was dissolved under stirring in 40 ml of tetrahydrofuran in another vessel, treated with carbon and filtered. The solution of varenicline free base was added over a period of 1-2 minutes to the solution of L(+) Tartaric acid at 45-50°C. The reaction mixture was stirred at 55-60°C for 1 hour. The resulting slurry was cooled to room temperature and then allowed to stir at 5-10°C for 1 hour. The product obtained was filtered and dried under vacuum at 35-40°C to afford crystalline varenicline L-tartarate salt. Yield = 1.8 g; m. p = 198°C -198.4°C.
Example 2:
Preparation of crystalline form D of varenicline L-tartarate
1 g of varenicline L-tartarate salt obtained in example 1, was charged in a reaction vessel and 4 ml of water was added. The mixture was stirred for 5 minutes at room temperature to get clear solution and filtered. Acetonitrile (60 ml) was slowly added to the filtrate. The resulting slurry was stirred for 2 hours at room temperature. Solid obtained was filtered and dried under vacuum at 35°C for 15-17 hours. Yield = 0.6 g; m. p = 200.8°C -201°C.

We claim:
1. A novel crystalline form D of varenicline L-tartarate.
2. A crystalline form according to claim 1, which exhibits powder x-ray diffraction pattern as depicted in figure 1.
3. A crystalline form according to claim 1 characterized by following powder x-ray diffraction pattern peaks expressed in terms of 20 values 9.5, 10.0, 10.9, 13.5, 14.4, 15.5, 19.8.
4. A process for preparation of varenicline L-tartarate salt comprising the steps of:
(i) contacting varenicline free base with L(+)-tartaric acid in suitable
organic solvent; and (ii) isolating varenicline L-tartarate.
5. A process according to claim 4, wherein the suitable organic solvent is selected from the group consisting of ethers such as tetrahydrofuran, diethyl ether; diisopropyl ether, ter-butylmethyl ether; lower alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol; lower aliphatic ketones such as acetone, ethylmethyl ketone, diethyl ketone; esters such as ethyl acetate, propyl acetate, isopropyl acetate; and acetonitrile or mixtures thereof.
6. A process according to claim 4, wherein tetrahydrofuran is used as a solvent.
7. A process according to claim 4, wherein molar ratio of L(+)-tartaric acid is in the range of 1 to 3 molar equivalents, more preferably 1 to 2 molar equivalents, most preferably 1 to 1.3 molar equivalents with respect to varenicline free base.
8. A process according to claim 4, wherein salt formation step is carried out at a temperature ranging from 20°C to 150°C, more preferably at 40°C to 80°C, most preferably at 55°C to 60°C.
9. A process for preparation of crystalline form D of varenicline L-tartarate comprising the steps of:
(i) preparing a solution of varenicline L-tartarate in water;
(ii) adding a water miscible nitrile solvent;
(iii) stirring for 2-20 hours; and
(iv) isolating crystalline form D.

10. A process according to claim 9, wherein water miscible nitrile solvent employed in step (ii) is selected from acetonitrile, propionitrile and butyronitrile.
11. A process according to claim 9, wherein the preferred solvent is acetonitrile.
12. A process according to claim 9, wherein step (ii) involving crystallization to obtain crystalline form D is carried out at a temperature of 15 to 50°C, more preferably at 25-30°C.
13. A process according to claim 9, wherein varenicline L-tartarate employed is in amorphous or crystalline form.
14. A process according to claim 9, wherein volume of water is in the range of 2 to 10 volumes, more preferably 4 volumes.
15. A process according to claim 9, wherein volume of nitrile solvent is in the range of 10 to 100 volumes, more preferably 60 volumes.
16. A process according to claim 9, wherein stirring is preferably carried out for 2 to 10 hours.

The present invention relates to novel crystalline form D of varenicline L-tartarate and process for its preparation that involves crystallization from acetonitrile-water mixture.