DESC:FIELD OF THE INVENTION

The present invention relates to a novel anhydrous crystalline form A of Canagliflozin (formula-1), chemically known as (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxy methyl-tetrahydro-pyran-3,4,5-triol, its method of preparation and its pharmaceutical compositions thereof.

Formula-I

BACKGROUND OF THE INVENTION

Diabetes is one of the most important and prevalent chronic diseases today. Pathophysiology of diabetes remains multi-factorial and hence any drug acting on a particular receptor has limitation arising out due to resistance. Varying degree of insulin resistance and insulin deficiency exist in almost all diabetic patient.
The kidney has a key role in regulating glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood; this is a crucial evolutionary adaptation to maintaining glucose homeostasis and to retaining calories. This process contributes to the sustained elevated serum glucose levels observed in individuals with diabetes, as they have an increased capacity for renal glucose reabsorption. Inhibiting this glucose reabsorption, thereby allowing its excretion in the urine (glycosuria), is therefore emerging as a potential new approach to the treatment of diabetes.
Sodium–glucose co-transporters (SGLTs) are responsible for renal glucose reabsorption, with SGLT2 performing most of this task and the remainder by SGLT1. As SGLT2 inhibitors do not target the major pathophysiology defects in diabetes namely insulin resistance and impaired insulin secretion they represent a potentially promising new option in the treatment of diabetes. There are various SGLT inhibitors which are currently marketed for diabetes like dapagliflozin, Canagliflozin, empagliflozin and many are under development like sergliflozin, remogliflozin, DSP-3235, LX-4211, TS-07, etc.
US7943788 discloses the compound of formula (I) per se. A procedure for the preparation of the compound of formula (I) is disclosed generically in example 1 of the same application. However, the application is silent about the solid state form obtained.
US7943582 discloses a crystalline hemihydrate of the compound of formula (I) and a process for the preparation thereof.
WO2009035969A1 discloses a crystalline form of the compound of formula (I) and a process for the preparation thereof.
WO2011003976A1 discloses a process for preparing the crystalline hemihydrate of the compound of formula (I) having a narrow particle size distribution, wherein a suspension of the hemihydrate of formula (I) in an organic solvent or a mixture of an organic solvent and water is subjected to at least one temperature oscillation and at least one mechanical particle size reduction step.
WO2014180872A1 discloses a crystalline form of a non-stoichiometric hydrate of the compound of formula (I) and a process for the preparation thereof.
According to the prior art literature, Canagliflozin hemihydrate is obtained by crystallization/precipitation from an organic solvent containing some water and optionally an organic antisolvent. However the use of organic solvents in crystallization process is associated with certain draw backs as residual solvents are often not completely removed from API. Furthermore, US7943788 mentions that amorphous Canagliflozin suffers from stability and handling issues such as poor filterability. Therefore, crystalline Canagliflozin is preferred as it is more stable and easier to isolate.
Crystalline forms of Canagliflozin obtained using improved process will always be more beneficial for large scale synthesis having improved physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.

OBJECT OF THE INVENTION

In one aspect, the present invention relates to anhydrous crystalline form A of Canagliflozin, characterized by Differential scanning calorimetry (DSC) having sharp endotherm at about 123.5 + 0.5 ºC.
In another aspect of the present invention provides anhydrous crystalline form A of Canagliflozin which is further characterized by powder X-ray diffraction pattern as shown in figure I.
In yet another aspect, anhydrous crystalline form A of Canagliflozin is further characterized by powder X-ray diffraction pattern having characteristic peaks expressed in terms of two theta values at about 5.12, 10.25, 14.87, 17.34, 18.27, 20.02, 20.51 and 27.94.
In another aspect, the present invention relates to a process for preparing anhydrous crystalline form A of Canagliflozin, comprising the steps of
(a) treating amorphous Canagliflozin in a suitable solvent(s) or mixture thereof,
(b) isolating anhydrous crystalline form A of Canagliflozin.
In yet another aspect, the present invention relates to a process for preparing anhydrous crystalline form of Canagliflozin, comprising the steps of:
(a) treating amorphous form of compound of formula-I in suitable organic solvent(s),
(b) heating reaction mixture at suitable temperature followed by cooling the reaction mixture and
(c) isolating anhydrous crystalline form A of compound of formula-I.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustration of a PXRD pattern of an anhydrous crystalline form of Canagliflozin
Figure 2 is an illustration of a DSC pattern of an anhydrous crystalline form of Canagliflozin.

DETAILED DESCRIPTION OF THE INVENTION

One of the embodiments of the present invention relates to an anhydrous crystalline form A of Canagliflozin and process for preparing the same. crystalline form A of Canagliflozin is characterized by Differential scanning calorimetry (DSC) having sharp endotherm at about 123.5 + 0.5 ºC as shown in figure 2.
In another embodiment of the present invention, anhydrous crystalline form A of Canagliflozin is characterized by powder X-ray diffraction pattern as shown in figure 1.
In yet another embodiment, anhydrous crystalline form A of Canagliflozin is further characterized by powder X-ray diffraction pattern having characteristic peaks expressed in terms of two theta values as listed below in Table 1:

TABLE I

Position (2o theta) d-spacing (o A) Relative Intensity (%)
2.56 34.42 18.26
5.12 17.22 2.31
7.42 11.90 4.68
7.67 11.51 2.79
8.08 10.93 2.17
10.25 8.62 13.06
11.16 7.92 1.45
12.12 7.30 0.45
12.80 6.91 1.94
13.17 6.71 4.68
14.21 6.23 0.40
14.87 5.95 28.76
15.31 5.78 23.64
16.14 5.49 8.64
17.34 5.11 100.00
18.27 4.85 34.83
18.50 4.79 21.68
18.79 4.72 9.89
19.12 4.64 6.45
20.02 4.43 7.22
20.51 4.33 23.42
21.22 4.18 12.23
22.38 3.97 17.90
22.94 3.87 8.69
23.41 3.79 7.94
23.64 3.76 5.07
24.36 3.65 7.64
25.16 3.53 1.00
25.78 3.45 1.87
26.50 3.36 1.52
27.10 3.29 2.17
27.94 3.19 18.14

In one of the embodiments of the present invention relates to a process for preparing anhydrous crystalline form of Canagliflozin, comprising the steps of:
(a) treating amorphous Canagliflozin in a suitable solvent(s) or mixture thereof,
(b) isolating anhydrous crystalline form A of Canagliflozin.
In yet another embodiment of present invention relates to a process for preparing anhydrous crystalline form of Canagliflozin, comprising the steps of:
(a) treating amorphous form of compound of formula-I in suitable organic solvent(s),
(b) heating reaction mixture at suitable temperature followed by cooling the reaction mixture and
(c) isolating anhydrous crystalline form A of compound of formula-I.
Another embodiment of the present invention is to provide a pharmaceutical composition comprising anhydrous crystalline Canagliflozin as characterized by X-ray diffraction pattern shown in figure 1.
Amorphous form of Canagliflozin which is used as starting material for present invention can be obtained according to process as disclosed in WO2013064909.
Anhydrous crystalline form A of Canagliflozin can be isolated using suitable conventional techniques as known in art.
The suitable "conventional techniques" as used herein to isolate anhydrous crystalline form A of Canagliflozin includes but not limited to distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent.
The term “solvent(s)” as used hereinabove includes but not limited to alcohols, ethers, esters, halogenated hydrocarbons, hydrocarbons, nitriles, ketones, DMF, DMSO, water or mixture thereof.
Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1, 2-propane diol and S (+)-1, 2-propane diol.
Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1, 2-dichloro ethane.
Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
Nitriles include but not limited to such as acetonitrile, propionitrile and benzonitrile.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
The following examples are provided to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

Example: 1

Add toluene (40 ml) to a round bottom flask containing amorphous Canagliflozin (1 g) and heat the reaction mass to 85-90oC along with stirring till solid dissolves completely. Distill out half of the volume of solvent. Further cool the reaction mixture to about 50-55oC and stir for about 15 hr. Again cool the reaction mixture to about 25oC and stir for about 2 hr. Filter the reaction mixture followed by drying to obtain solid compound (0.72 g) HPLC purity 99.8%.

Example: 2

Add xylene (35 ml) to a round bottom flask containing amorphous Canagliflozin (1 g) and heat the reaction mass to 100-110oC along with stirring till solid dissolves completely. Distill out half of the volume of solvent. Further cool the reaction mixture to about 50-55oC and stir for about 15 hr. Again cool the reaction mixture to about 25oC and stir for about 2 hr. Filter the reaction mixture followed by drying to obtain solid compound (0.68 g) HPLC purity 99.9%.

Dated this 16th day of October 2017

,CLAIMS:We claim:

1. A process for preparation of anhydrous crystalline form A of compound of formula-I, comprising of following steps:

Formula-I
(a) treating amorphous form of compound of formula-I in suitable organic solvent(s);
(b) optionally heating reaction mixture at suitable temperature followed by cooling the reaction mixture and
(c) isolating anhydrous crystalline form A of compound of formula-I.
2. The process according to claim 1, wherein anhydrous crystalline form A of compound of formula-I comprising the following pXRD peaks (o2?): 2.56, 10.25, 14.87, 15.31, 17.34, 18.27, 18.50, 20.51, 21.22, 22.38 and 27.94 + 0.02.
3. The process according to claim 1, wherein anhydrous crystalline form A of compound of formula-I comprising of differential scanning calorimetry (DSC) having sharp endotherm at about 123.5 + 0.5 ºC.
4. The process according to claim 1, wherein isolation of anhydrous crystalline form A is carried out using distillation, distillation under reduced pressure or vacuum, evaporation and solvent-antisolvent.
5. The process according to claim 1, step (a) wherein suitable solvents are selected from the group consisting of alcohols, hydrocarbons, ethers, nitriles, esters, halogenated hydrocarbons, ketones, DMF or DMSO.
6. The process according to claim 3, wherein suitable hydrocarbon solvent are selected from toluene, xylene, hexane or heptane.
7. The process according to claim 1, step (b) wherein reaction mixture is heated at suitable temperature in the range of from about 50 to 150 oC.
8. A pharmaceutical composition comprising compound of formula-I obtained according to claim 1 and suitable pharmaceutically acceptable excipients.

Dated this 16th day of October 2017