DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR PREPARING CRYSTAL OF SITAGLIPTIN HYDROCHLORIDE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:
FIELD OF THE INVENTION

The present invention relates to a process for preparing Sitagliptin hydrochloride monohydrate crystals having bulk density at least about 0.2 gm/ml.

BACKGROUND OF THE INVENTION

Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP-IV) enzyme inhibitor that improves glycemic control in patients with Type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Sitagliptin is chemically designated as (3R)-3-amino-l-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8~dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, is represented by the following structural Formula I:

I

Sitagliptin is currently marketed in its phosphate salt in the United States under the trade name JANUVIA™ in its monohydrate form. JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.

U.S. Patent No. 6,699,871 ("the '871 patent") discloses Sitagliptin and salts thereof. The US ‘871 also discloses a process for the preparation of hydrochloride salt of Sitagliptin, which involves treatment of Sitagliptin base with methanol saturated hydrogen chloride to obtain Sitagliptin hydrochloride foamy solid.

PCT publication No, WO 2005/072530 A1 discloses a process for preparing a crystalline Sitagliptin hydrochloride monohydrate, which involves dissolution of Sitagliptin freebase in 90% isopropanol/methanol, treatment with a solution of HC1 in diethyl ether to get thick slurry of crystals, heated the mixture to 55oC and then slowly cooled to room temperature to obtain crystalline Sitagliptin hydrochloride monohydrate.

Indian patent publication IN 2266/CHE/2014 A discloses a process for preparing Sitagliptin hydrochloride Form-L9, which involves slurring of Sitagliptin hydrochloride in ethyl acetate at 30±5°C.

PCT publication No. WO 2010/000469A2 discloses a process for preparing Sitagliptin hydrochloride, which involves dissolution of Sitagliptin HCl in ethyl acetate and warmed in oil bath, which is preheated at 125°C. The solution is allowed to cool to RT, added ethyl acetate and filtered to obtain Sitagliptin hydrochloride.

The inventors of the present invention found that Sitagliptin hydrochloride with a higher bulk density is desirable during the manufacture of pharmaceuticals containing Sitagliptin hydrochloride, particularly oral dosage forms, because low bulk density material not free flowing material and has handling difficulties. None of the above prior arts describe the bulk density of Sitagliptin hydrochloride.

Further, the inventors of the present invention observed that the prior art processes ends up with one or the other problems, for example, solvated forms, unstable and having lower bulk density, when they have conducted experiments.

Therefore, there is a need to develop a process, which provides free flowing material of Sitagliptin hydrochloride having bulk density at least about 0.2 gm/ml and which is suitable for manufacturing the desired dosage forms.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a process for the preparation of Sitagliptin hydrochloride crystals having bulk density at least about 0.2 gm/ml and process thereof.

SUMMARY OF THE IVENTION

In an aspect, the present invention provides Sitagliptin hydrochloride having bulk density at least about 0.2 gm/ml.

In an aspect, the present invention provides Sitagliptin hydrochloride monohydrate having bulk density of about 0.2 gm/ml to about 0.65 gm/ml.

In another aspect, the present invention provides a process for the preparation of Sitagliptin hydrochloride monohydrate crystals having bulk density at least about 0.2 gm/ml comprising the steps of:
a) providing a solution of Sitagliptin hydrochloride in a mixture of an ethyl acetate and water;
b) azeotropic distillation to remove water;
c) cooling the solution of step b) to room temperature; and
d) isolating crystals of Sitagliptin hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is powder X-ray power diffraction ("PXRD") pattern of crystals of Sitagliptin hydrochloride prepared according to the Example 1.

DETAILED DESCRIPTION OF THE IVENTION

One important physicochemical characteristics of powders/crystalline are the density properties such as bulk and tapped density, weight variation and flow properties such as angle of repose. Bulk density is the undisturbed packing density of that substance and tapped bulk density relates to the packing density after tapping a bed of substance until no change in the packing density is seen.

These two parameters are important in the overall tabletting process, which requires that loose powders be compacted into a durable solid form with the correct mechanical strength, permeability and dissolution characteristics. These parameters are also important in the formation of oral suspensions, which ideally contain particles of high bulk density, enabling even dispersion of the particles throughout the suspension after shaking and before consumption.

Knowledge of the true and bulk densities of the drug substance is very useful in forming some idea as to the size of the final dosage form. Obviously, this parameter is very critical for drugs of low potency, which may constitute the bulk of the final granulation or table. Bulk density of a compound varies substantially with the method of crystallization. It can affect powder flow properties. It affects the size of high dose capsule product or the homogeneity of a low dose formulation in which there are large differences in drug and excipients densities.

A crystal or crystals means free flowing crystals of Sitagliptin hydrochloride or in crystalline form or polymorph, which may be referred to herein as pure or polymorphically pure from other crystalline or polymorphic forms and/or as being characterized by graphical data as shown in the present application as a Figure. Such data include, for example, powder X-ray diffractograms.

In an aspect of the present invention, there is provided Sitagliptin hydrochloride crystals having bulk density at least about 0.2 gm/ml. The Sitagliptin hydrochloride is an anhydrous or monohydrate, preferably Sitagliptin HCl is a monohydrate.

In another aspect, the present invention provides a process for the preparation of Sitagliptin hydrochloride monohydrate crystals having bulk density at least about 0.2 gm/ml comprising the steps of:
a) providing a solution of Sitagliptin hydrochloride in a mixture of an ethyl acetate and water;
b) azeotropic distillation to remove water;
c) cooling the solution of step b) to room temperature; and
d) isolating crystals of Sitagliptin hydrochloride.

Providing solution of step (a) may be provided by dissolution of Sitagliptin hydrochloride crude in a mixture of ethyl acetate and water or it may be provided directly from a reaction mixture containing it that is obtained during the course of its manufacture. The volumes of ethyl acetate may be about 4 - 10 times or about 5.0-7.5 times per gram of Sitagliptin HCl. The volume of water in mixture may be about 0.3 to 2 times or about 0.5 times per gram of Sitagliptin HCl.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 70°C or less than about 30°C or any other suitable temperatures, as long as a clear solution of Sitagliptin hydrochloride is obtained without affecting its quality.

The resultant solution optionally treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials to improve clarity of the solution, and/or remove impurities adsorbable on such material.

The azeotropic distillation of step (b) involves recovery of water by dehydrated azeotropically at 70-75°C till initiation of precipitation. The water content of this slurry mass is at around 2.16% w/w after distillation at 70-75°C. Ethyl acetate forms a positive azeotrope with water that boils at 70.4°C (with azeotropic composition 35.9% mole water and 64.1% mole ethyl acetate). After completion of azeotrope distillation, the reaction mass is maintained at 70 ± 3°C under reflux for a period of 10 minutes or more to obtain a thick slurry mass.

The cooling of step (c) involves slow cooling while slurring the reaction mass obtained in step (b). The inventors of the present invention found that the gradual cooling enhance the bulk density of Sitagliptin hydrochloride.

The gradual cooling of the reaction mass from reflux temperature to room temperature, for example, 20 to 30°C, may be achieved over a period of about 0.5 hours to about 4 hours or it may be around 3 to 4 hours per batch size of 150 gm of Sitagliptin hydrochloride crude.

The obtained pure crystals of Sitagliptin hydrochloride monohydrate may be isolated from the suspension of above by conventional methods such as filtration and then dried using suitable techniques know in the art.

The inventors of the present invention further found that the use of drying techniques such as fluid bed dryer or air tray dryer a temperature of 80-85°C are more suitable to produce Sitagliptin hydrochloride monohydrate with retention of water, resulting in desired polymorph and with low level of residual ethyl acetate.

The specific ratios of solvent i.e. ethyl acetate/water and gradual cooling to obtain desired bulk density of Sitagliptin hydrochloride monohydrate in provided in the following table:

S.No Volume ration (EtOAc/water) Cooling Time (Hrs) Input Qty.
(g) Output Qty.
(g) Yield
(w/w) Bulk Density
(g/ml)
1 7.50V : 0.62V 5.5 1660 1480 0.89 0.44
2 7.50V : 0.62V 5.0 1660 1430 0.86 0.41
3 7.50V : 0.90V 4.5 60 51 0.85 0.27
5 7.50V : 0.62V 5.0 60 52 0.88 0.42
6 9.44V:0.56V 2.10 4.0 3.6 0.90 0.12
7 9.44V:0.56V 2.30 3.8 3.7 3.7 0.14

The resulted Sitagliptin hydrochloride monohydrate of present invention further converted into pharmaceutical composition thereof. The composition comprises Sitagliptin hydrochloride monohydrate having bulk density at least about 0.2 g/ml and at least one pharmaceutically acceptable carrier.

The pharmaceutically acceptable carriers comprises: (1) sugars, such as lactose, glucose and sucrose: (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

Having described the invention with reference to certain aspects embodiments, embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing the preparation of high bulk density Sitagliptin hydrochloride crystals. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES
EXAMPLE1: PREPARATION OF SITAGLIPTIN HYDROCHLORIDE MONOHYDRATE:

Sitagliptin hydrochloride-crude (150 g) was dissolved in a mixture of ethyl acetate (825 ml) and DM water (84 ml) at 20-30°C, which was heated to 35-40°C and stirred for 15-20 min to get clear solution. Carbon enoanticromos was charged to the solution at 35-40°C, stirred for 35-40 min., filtered the carbon through hyflo bed and washed with ~3% v/v aqueous ethyl acetate at 35-40°C. The filtrate was passed through a micro-filter at 35-40°C and washed with ~3% v/v aqueous ethyl acetate. The resultant filtrate was heated to reflux at 70 ± 3°C and removed water azeotropically with ethyl acetate. The reaction mass was stirred for 10-15 minutes at the same temperature to observe precipitation. Thereafter, the reaction mass was slowly cooled to 20-30°C in a period of 4-5 hours and stirred for 1 hour ±10 min. Ethyl acetate was added (300 ml) to the suspension and continued stirring at for 10-15 min. The product was filtered, washed with ~3% v/v aqueous ethyl acetate and dried at 80- 85°C till ethyl acetate is < 4000 ppm.
Yield (w/w): 0.88 w/w;
Bulk Density (gm/ml): 0.42

EXAMPLE2: PREPARATION OF SITAGLIPTIN HYDROCHLORIDE MONOHYDRATE:

Sitagliptin hydrochloride-crude (60 g) was dissolved in a mixture of ethyl acetate (330 ml) and DM water (50.4 ml) at 20-30°C, which was heated to 35-40°C and stirred for 15-20 min to get clear solution. Carbon enoanticromos was charged to the solution at 35-40°C, stirred for 35-40 min., filtered the carbon through hyflo bed and washed with ~3% v/v aqueous ethyl acetate at 35-40°C. The filtrate was passed through a micro-filter at 35-40°C and washed with ~3% v/v aqueous ethyl acetate. The resultant filtrate was heated to reflux at 70 ± 3°C and removed water azeotropically with ethyl acetate. The reaction mass was stirred for 10-15 minutes at the same temperature to observe precipitation. Thereafter, the reaction mass was slowly cooled to 20-30°C in a period of 4.5 hours and stirred for 1 hour ±10 min. Ethyl acetate was added (300 ml) to the suspension and continued stirring at for 10-15 min. The product was filtered, washed with ~3% v/v aqueous ethyl acetate and dried at 80- 85°C till ethyl acetate is < 4000 ppm.

Yield (w/w): 0.86 w/w Bulk Density (gm/ml): 0.27 ,CLAIMS:WE CLAIM:

1. A process for the preparation of Sitagliptin hydrochloride monohydrate crystals having bulk density at least about 0.2 gm/ml comprising the steps of:
a) providing a solution of Sitagliptin hydrochloride in a mixture of an ethyl acetate and water;
b) azeotropic distillation to remove water;
c) cooling the solution of step b) to room temperature; and
d) isolating crystals of Sitagliptin hydrochloride.

2. The process as claimed in claim 1, wherein the ethyl acetate in a mixture is about 4 - 10 times per gram of Sitagliptin HCl.

3. The process as claimed in claim 1, wherein the water in a mixture is about 0.3 to 2 times per gram of Sitagliptin HCl.

4. The process as claimed in claim 1, wherein the azeotropic distillation is carried out at 70-75°C.

5. The process as claimed in claim 1, wherein the drying is carried out using fluid bed dryer or air tray dryer.

6. The process as claimed in claim 5, wherein the drying is carried out at a temperature of 80-85°C

7. The process as claimed in claim 1, wherein the Sitagliptin hydrochloride has bulk density of about 0.2 gm/ml to about 0.65 gm/ml.

8. A pharmaceutical composition comprising Sitagliptin hydrochloride monohydrate crystals having bulk density at least about 0.2 gm/ml and a pharmaceutically acceptable carrier.