Description:FIELD OF INVENTION:
The present invention discloses various novel processes for preparation of crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate.

BACKGROUD OF INVENTION:
Dapagliflozin propanediol hydrate or (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro -2H-pyran-3,4,5-triol Propanediol Monohydrate, an orally active sodium glucose cotransporter type 2 (SGLT-2) inhibitor, was developed by Bristol–Myers Squibb (BMS) and AstraZeneca for the once-daily treatment of type 2 diabetes. As opposed to competitor SGLT-2 inhibitors, dapagliflozin was not associated with renal toxicity or long-term deterioration of renal function in phase III clinical trials. The drug exhibits excellent SGLT-2 potency with more than 1200-fold selectivity over the SGLT-1 enzyme. It has the Formula I, as given below:

(Formula I)
Dapagliflozin (INN/USAN, trade name Farxiga in the US and Forxiga in the EU) is a drug of the gliflozin class, used to treat type 2 diabetes.

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine. In clinical trials, Dapagliflozin lowered HbA1c by 0.6 versus placebo percentage points when added to Metformin.

Approximately 100 million people worldwide suffer from type II diabetes (NIDDM - non-insulin-dependent diabetes mellitus), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, and is likely to contribute directly to the impairment of insulin secretion seen in advanced NIDDM. Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion

U.S. Patent Nos. 6,515, 117, 7,375,213, 7,932,379, and 7,919,598 disclose processes for the purification of Dapagliflozin, comprising the step of acetylating crude Dapagliflozin to (lC)-2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-D-glucitol in pyridine. As pyridine is toxic and therefore its use as a solvent is avoided for industrial production of a pharmaceutical ingredient. Thus, there was a need to develop a process for the preparation of Dapagliflozin that avoids the use of pyridine as a solvent.

U.S. Patent Nos. 7,919,598 B2, discloses crystalline complexes of Dapagliflozin with propylene glycol, ethanol, ethylene glycol, L-proline, and L-phenylalanine, and processes for their preparation. It mainly describes the process for the synthesis of various solvates of Dapagliflozin mainly (S)-propylene glycol i.e. Dapagliflozin Propanediol Monohydrate which is being used in various formulations. This patent also discloses the crystalline form as well as its synthesis which is now known as (S)-PG-Ia. Dapagliflozin Propanediol Monohydrate which is chemically designated as (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxyl methyl)tetrahydro-2H-pyran-3,4,5-triol,-(S)-propylene glycol Monohydrate and is marketed for the treatment of type 2 Diabetes mellitus, is the Propanediol solvate of Dapagliflozin and is Monohydrate in nature as reported in its basic product patent US 7,919,598 B2 which reports the form SC-3 of Dapagliflozin Propanediol Monohydrate.

In WO 2008/002824 A1, solvates of Dapagliflozin with several alcohols and co-crystals with proline and phenylalanine are disclosed. However, the presence of the alcohols disclosed in said reference is undesirable since they may detrimentally affect the patient.

WO 2008/116179 A1 refers to an immediate release pharmaceutical composition comprising Dapagliflozin propylene glycol hydrate. (S)-propanediol is chiral and is very expensive. Consequently, also the immediate release pharmaceutical composition is more expensive. Moreover, the presence of said propylene glycol in the medicament may detrimentally affect the patient
PCT Publication No. WO 2012/163546 discloses inclusion complexes of Dapagliflozin and cyclodextrin, and processes for their preparation.

PCT Publication No. WO 2013/079501 discloses crystalline Dapagliflozin hydrate and processes for its preparation.

PCT Publication No. WO 2014/178040 discloses Dapagliflozin lactose co-crystals and Dapagliflozin asparagine co-crystals.

WO2015198227 of Sun Pharma, discloses a Dapagliflozin-citric acid co-crystal, processes for its preparation, and its use for the treatment of type 2 diabetes mellitus.

In the pharmaceutical industry, there is a constant need to identify the critical physicochemical parameters such as novel salts, polymorphic forms, and co-crystals that affect the drug's performance, stability, etc., which may play a key role in determining a drug's market acceptance and success.

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5 discloses process for the preparation of amorphous Dapagliflozin.

WO 2015104658 of Dr. Reddy’s, discloses a process for the preparation of amorphous Dapagliflozin, comprising: a) dissolving Dapagliflozin in a solvent selected from methanol, dichloromethane, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, 2-methyl tetrahydrofuran or mixtures thereof; followed by its complete recovery to give amorphous Dapagliflozin.

WO2015/117538 of Jiangsu Hansoh Pharmaceutical Group Co., Ltd relates to a new crystalline form of Dapagliflozin. The crystalline form has a characteristic absorption peak at about 4.318(20.45) in X-ray powder diffraction pattern shown by angle 2 theta and interplanar spacing (value d). It can be prepared by dissolving Dapagliflozin into organic solvents, adding anti-solvents, agitating, crystallizing, filtering and drying. The new crystalline form of Dapagliflozin of the present invention has the following superior features: good solubility, low hygroscopicity, high stability and good preparation reproducibility.

In Journal, Bioorganic & Medicinal Chemistry titled “Novel thiophenyl C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents” Novel thiophene C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different types of thiophene derivatives were readily prepared. Among the compounds tested, ethylphenyl at the distal ring 71p showed the best in vitro inhibitory activity in this series to date (IC50 = 4.47 nM) against SGLT2

New crystalline polymorphic forms of a drug substance may display different melting point, hygroscopicity, stability, solubility and/or dissolution rate, crystallinity, Crystal habits, bioavailability, toxicity and formulation handling characteristics, which are among the numerous properties that need to be considered in preparing medicament that can be effectively administered. Therefore, the regulatory agencies require a definitive control of polymorphic form of the active component in solid pharmaceutical dosage forms.

Accordingly, there was an ongoing need to search novel processes of Dapagliflozin Propanediol Monohydrate that may have better stability and good material flow character, lower residual solvent contents, and may offer advantages for preparing reproducible pharmaceutical formulations. The novel processes for polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate of present invention is rugged and commercially more viable, therefore will be of use.

BFIEF DESCRIPTION OF DRAWINGS
Figure 1: XRD diffractogram (as reported in Literature) of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 1A of U.S. Patent 7,919,598 B2 or Example 1 of this invention.

Figure 2: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 2 as disclosed in this example using Methylene Chloride as solvent.
Figure 3: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 3 as disclosed in this example using Acetone-Cyclohexane as solvent system.
Figure 4: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 4 as disclosed in this example using Toluene as solvent.
Figure 5: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 5 as disclosed in this example using THF-Cyclohexane as solvent system.
Figure 6: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 6 as disclosed in this example using Methyl tert-Butyl ether as solvent.
Figure 7: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 7 as disclosed in this example using Acetonitrile as solvent.
Figure 8: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 8 as disclosed in this example using Diisoproplyether as solvent.
Figure 9: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 9 as disclosed in this example using Cyclohexane as solvent.
Figure 10: XRD diffractogram of Polymorphic form SC-3 of Dapagliflozin Propanediol Monohydrate prepared as per example 1.

SUMMARY OF INVENTION:
The present invention discloses various novel processes for the preparation of Crystalline Polymorph SC-3 of Dapagliflozin Propandiol Monohydrate using different solvents / solvent systems.
The Form SC-3 of Dapagliflozin Propandiol Monohydrate, was originally prepared & disclosed is US Patent 7,919,598, Example 1A. It is characterized by XRD peaks at 2?±0.2° 3.8, 7.6, 8.1, 8.7, 15.2, 15.7, 17.1, 18.9 & 20.1. The XRD is as given in Figure 1(from US 7,919,598 B2) & 10 (As per example 1).
As per this invention any polymorphic form of Dapagliflozin Propanediol can be dissolved in various solvents such as methylene chloride, Toluene, Methyl tert-Butyl ether, Acetonitrile, Diisopropyl ether & Cyclohexane and recrystallized to give form SC-3.
Two other Solvent Systems, Acetone-Cyclohexane & THF-Cyclohexane were surprisingly found to consistently product form SC-3.

The details of invention are elaborated in the next section, of this invention.

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel process for preparation of Dapagliflozin Propanediol monohydrate polymorphic form SC-3, is disclosed which comprises:
1) Charging of any polymorphic form of Dapagliflozin Propanediol in an organic solvent & water.
2) Heating of the reaction mass to ensure complete dissolution.
3) Stirring for 1-2 hours
4) Fine filtered the reaction mass via hyflow bed.
5) Allowed the reaction mass to attain room temperature naturally.
6) Stirring the reaction mass at this temperature.
7) Continued the Stirring of the reaction mass for 1-5 hours.
8) Filtration of product as wet cake.
9) Running washing with the solvent.
10) Drying at 30-40 °C for 10-20 hours to get Crystalline form SC-3 of Dapagliflozin Propanediol monohydrate.

According to the first aspect of this embodiment, the solvent being used in step 1) & 9) is a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
According to second aspect of the first embodiment, the temperature in step 2) & 3) is 40-45°C, in step 6) is 10-15 °C, in step 7) is 0-5 °C when solvent being used is a halogenated hydrocarbon & stirring time is 1-2 hours.

According to the third aspect of this embodiment, the solvent being used in step 1) & 9) can also be selected from aromatic hydrocarbons like benzene, toluene, xylenes etc or a mixture thereof.
According to fourth aspect of this embodiment, the temperature in step 2) & 3) is 80-90°C, in step 6) & step 7) is 20-30 °C when solvent being used is an aromatic hydrocarbon & stirring time is 1-2 hours.

According to fifth aspect of this embodiment, the solvent being used in step 1) & 9) can also be selected from aliphatic ethers such as Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or mixture thereof.
According to Sixth aspect of this embodiment, the temperature in step 2) & 3) is 50-70°C, in step 6) & step 7) is 20-30 °C when solvent being used is aliphatic ether & stirring time is 1-2 hours.

According to seventh aspect of this embodiment, the solvent being used in step 1) & 9) can also be selected from an aliphatic nitrile such as acetonitrile, propionitrile or a mixture thereof.
According to eighth aspect of this embodiment, the temperature in step 2) & 3) is 40-50°C, in step 6) 20-30°C & in step 7) is -5 to -10°C, when solvent being used is aliphatic nitrile & stirring time is 3-4 hours for step 6) & 1-2 hours for step 7).
According to ninth aspect of this embodiment, the solvent being used in step 1) & 9) can also be selected from cyclic or acyclic aliphatic hydrocarbon selected from cyclohexane, hexane, heptane or a mixture thereof.
According to tenth aspect of this embodiment, the temperature in step 2) & 3) is 70-80°C, in step 6) & step 7) is 20-30 °C when solvent being used is a cyclic or acyclic aliphatic hydrocarbon & stirring time is 1-2 hours.
According to the Second embodiment of the present invention, a novel process for preparation of Dapagliflozin Propanediol monohydrate polymorphic form SC-3, is disclosed which comprises:
a) Charging of any polymorphic form of Dapagliflozin Propanediol in aliphatic straight or branched chain ketone selecting from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof & water.
b) Heating of the reaction mass to 40-45 °C under stirring to ensure proper dissolution.
c) Fine filtered hot reaction mass.
d) Allowed the temperature to attain room temperature naturally
e) Cooling of reaction mass to 10-15 °C.
f) Added more aliphatic straight or branched chain ketone as used in step a) to make ensure proper stirring.
g) Further stirring of reaction mass, followed by addition of cyclic or acyclic aliphatic hydrocarbon selected from cyclohexane, hexane, heptane or a mixture thereof.
h) Further cooling reaction mass to 0-5 °C.
i) Stirring for 1-2 hours.
j) Filtered the product as wet cake with running washing with aliphatic straight or branched chain ketone as used in step a).
k) Drying the wet cake at 30-40 °C for 10-20 hours.
According to the third embodiment of the present invention, a novel process for preparation of Dapagliflozin Propanediol monohydrate polymorphic form SC-3, is disclosed which comprises:
a) Charging of any polymorphic form of Dapagliflozin Propanediol in cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether or a mixture thereof & water.
b) Stirring to dissolve at 20-30 °C.
c) Fine filtered the reaction mass
d) Performed slow addition of cyclic or acyclic aliphatic hydrocarbon selected from cyclohexane, hexane, heptane or a mixture thereof.
e) Continued stirring at 20-30 °C
f) Stirring for 1-2 hours to ensure proper crystallization.
g) Filtered the product as wet cake & given running washing mixture of solvent being using in step a) & d).
h) Drying the wet cake at 30-40 °C for 10-20 hours.

According to the fourth embodiment of the present invention, a novel process for preparation of Dapagliflozin Propanediol monohydrate polymorphic form SC-3, is disclosed which comprises:
a) Charging of any polymorphic form of Dapagliflozin Propanediol in a C1-C3 aliphatic ester. e.g. ethyl acetate, propyl acetate, butyl acetate or a mixture thereof & water.
b) Stirring to dissolve at 30-40 °C.
c) Fine filtered the reaction mass
d) Performed slow addition of cyclic or acyclic aliphatic hydrocarbon selected from cyclohexane, hexane, heptane or a mixture thereof.
e) Cooling of reaction mass & continued stirring at 5-15 °C
f) Stirring for 1-2 hours to ensure proper crystallization.
g) Filtered the product as wet cake & given running washing mixture of solvent being using in step a) & d).
h) Drying the wet cake at 30-40 °C for 10-20 hours.

EXAMPLES:
Example 1: (Reference example as per US 7,919,598)
To a suspension of Tetraacetyl Dapagliflozin (20 g) in methanol (30 ml) was added 3N caustic solution (50 ml), under stirring at room temperature. Heated the reaction mass to 80 °C and stirred under reflux till reaction completion. It normally takes 3 hours. After reaction completion the reaction mass is cooled to 20 °C and adjusted its pH to 6.0-7.5 using conc. Hydrochloric acid. The product is then extracted in isopropyl acetate (100 ml). Now (S)-(+)-1,2-propanediol is added to reaction mass followed by seeding with Dapagliflozin Propanediol Monohydrate. Further crystallized the material by addition of cyclohexane (160 ml) at 5 °C and stirring for 1-2 hours. Filtered the material & provided it running wash with Isopropyl acetate & cyclohexane mixture. Dried the wet cake at 30 °C in vacuum oven till moisture content is 3.6-4.1%, to get Dapagliflozin Propanediol Monohydrate Form SC-3. Its powder XRD pattern is as given in figure 1 & 10.
Yield = 16.80 g
Purity by HPLC = 99.81%
Propylene Glycol (PG) Content = 15.1-15.8 % by GC.
Moisture Content = 3.6-4.1 %

Example 2:
A suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in methylene chloride (80 ml) in presence of water, is heated to 40-45 °C followed by its stirring till complete dissolution. Fine filtered the reaction mass to separate any un-dissolved particles. Then cooled the reaction mass to 10-15 °C and continued stirring till complete crystallization. Further cooled reaction mass to 0-5 °C and stirred for 10-20 min followed by filtration and running washing with chilled Methylene chloride (5 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (3.4 g) as final product. XRD is as given in figure 2.
Yield = 3.4 g
Purity by HPLC = 99.82 %
Propylene Glycol (PG) Content = 14.36% by GC.
Moisture Content = 3.69 % w/w.

Example 3:
A suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in acetone (12 ml) in presence of water under stirring, is heated to 40-45 °C under stirring to ensure complete dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Stirred the filtrate for 30-60 min at 10-15 °C to ensure proper crystallization. Now added acetone (4 ml) to the thick slurry of reaction mass & continued stirring for 10-20 min. Now performed addition of cyclohexane (32 ml) and further stirred reaction mass at 0-5 °C for 1-2 hours. Filtered the product as wet cake and provided running washing with mixture of acetone (1.6 ml) & cyclohexane (3.2 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (3.1 g) as final product. XRD is as given in figure 3.
Yield = 3.1 g
Purity by HPLC = 99.85 %
Propylene Glycol (PG) Content = 14.02 % by GC.
Moisture Content = 3.99 % w/w.

Example 4:
A suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in toluene (24 ml) in presence of water under stirring, is heated to 80-90°C to ensure complete dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Now slowly cooled the reaction mass to 20-30 °C followed by its continuous stirring at this temperature for 1-2 hours. Under stirring material begins to crystallize out. Filtered the product as wet cake and provided running washing with Toluene (8 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (3.8 g) as final product. XRD is as given in figure 4.
Yield = 3.8 g
Purity by HPLC = 99.80 %
Propylene Glycol (PG) Content = 14.40% by GC.
Moisture Content = 3.78 % w/w.

Example 5:
A suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in Tetrahydrofuran (6 ml) in presence of water under stirring, is heated to 20-30 °C to ensure complete dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Now performed slow addition of cyclohexane (40 ml) and slowly cooled the reaction mass to 20-30 °C followed by its continuous stirring at this temperature for 1-2 hours. Under stirring material begins to crystallize out. Filtered the product as wet cake and provided running washing with mixture of Tetrahydrofuran (4 ml) & cyclohexane (12 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (3.7 g) as final product. XRD is as given in figure 5.
Yield = 3.7 g
Purity by HPLC = 99.79 %
Propylene Glycol (PG) Content =13.81 % by GC.
Moisture Content = 3.97 % w/w.

Example 6:
A suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in methyl tert-butyl ether (30 ml) in presence of water, is heated to 50-60 °C under stirring to ensure proper dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Now slowly cooled the reaction mass to 20-30 °C followed by its continuous stirring at this temperature for 1-2 hours. Under stirring material begins to crystallize out. Just added more methyl tert-butyl ether (10 ml) to ensure proper stirring. Filtered the product as wet cake and provided running washing with methyl tert-butyl ether (12 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (1.9 g) as final product. XRD is as given in figure 6.
Yield = 1.9 g
Purity by HPLC = 99.89 %
Propylene Glycol (PG) Content = 13.99 % by GC.
Moisture Content =3.89 % w/w.

Example 7:
A suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in acetonitrile (12 ml) in presence of water, is heated at 50-60 °C under stirring to ensure proper dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Now slowly cooled the reaction mass to 20-30 °C followed by its continuous stirring at this temperature for 3-4 hours. Further cooled reaction mass to -5 to -10 °C and continued stirring. Under stirring material begins to crystallize out. Just added more acetonitrile (10 ml) to ensure proper stirring. Filtered the product as wet cake and provided running washing with acetonitrile (10 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (2.7 g) as final product. XRD is as given in figure 7.
Yield = 1.9 g
Purity by HPLC = 99.87%
Propylene Glycol (PG) Content = 13.20 % by GC.
Moisture Content = 4.21 % w/w.

Example 8:
To a suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in Diisopropyl ether (20 ml) in presence of water, heated to reflux at 60-70 °C under stirring to ensure proper dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Now slowly cooled the reaction mass to 20-30 °C followed by its continuous stirring at this temperature for 3-4 hours. Under stirring material begins to crystallize out. Filtered the product as wet cake and provided running washing with Diisopropyl ether (10 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (2.7 g) as final product. XRD is as given in figure 8.
Yield = 3.0 g
Purity by HPLC = 99.75 %
Propylene Glycol (PG) Content = 13.65% by GC.
Moisture Content = 3.74 % w/w.

Example 9:
To a suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in cyclohexane (20 ml) in presence of water, heated to 70-80 °C under stirring to ensure proper dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Now slowly cooled the reaction mass to 20-30 °C followed by its continuous stirring at this temperature for 3-4 hours. Under stirring material begins to crystallize out. Filtered the product as wet cake and provided running washing with cyclohexane (10 ml). Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (2.7 g) as final product. XRD is as given in figure 9.
Yield = 4.0 g
Purity by HPLC = 99.72 %
Propylene Glycol (PG) Content = 15.75 % by GC.
Moisture Content = 3.76 % w/w.

Example 10:
A suspension of any polymorphic form of Dapagliflozin Propanediol (4.0 g) in Ethyl acetate (16 ml) in presence of water, is heated to 30-40 °C under stirring to ensure proper dissolution. Fine filtered the reaction mass to ensure removal of any un-dissolved particles. Now slowly cooled the reaction mass to 20-30 °C followed by its continuous stirring at this temperature for 1-2 hours.. Added Cyclohexane (10 ml) to ensure proper stirring. Filtered the product as wet cake and provided running washing with Ethyl acetate (4 ml) & cyclohexane mixture. Dried the wet cake at 30-40 °C for 10-20 hours to give Crystalline form SC-3 of Dapagliflozin Propanediol Monohydrate (1.9 g) as final product.
Yield = 1.9 g
Purity by HPLC = 99.86 %
Propylene Glycol (PG) Content = 13.89 % by GC.
Moisture Content =3.79 % w/w.

, Claims:WE CLAIM:
1. A novel process for preparation of Dapagliflozin Propanediol monohydrate polymorphic form SC-3 which comprises,
i. Dissolution of any polymorphic form of Dapagliflozin Propanediol in aliphatic nitrile selected from acetonitrile, propionitrile or aliphatic ether selected from Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or halogenated hydrocarbon selected from methylene dichloride, chloroform in presence of water.;
ii. Heating the reaction mass to 40-50°C under stirring for 1-2 hours, to ensure proper dissolution.
iii. Fine filtration of the reaction mass through hyflow bed.
iv. Stirring of the reaction mass at 20-30°C for 3-4 hours followed by at -5 to -10°C for further 1-2 hours to ensure complete crystallization.
v. Isolation of product using routine filtration & drying at 30-40°C for 10-20 hours to give Dapagliflozin Propanediol monohydrate polymorphic form SC-3

Dated this 17th day of October, 2023

NEHA CHUGH
PATENT AGENT
IN/PA-862