DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

AMORPHOUS FORM OF REMOGLIFLOZIN AND REMOGLIFLOZIN ETABONATE AND PROCESS FOR THE PREPARATION THEREOF

Glenmark Pharmaceuticals Limited
B/2, Mahalaxmi Chambers,
22 Bhulabhai Desai Road,
Mumbai – 400026, India.

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).

Formula I

Formula II
The present invention also relates to substantially pure amorphous Remogliflozin or amorphous Remogliflozin etabonate having a mean particle size equal to or less than about 90 µm.

BACKGROUND OF THE INVENTION
Remogliflozin etabonate is a pro-drug of Remogliflozin, the active entity that inhibits the sodium dependent glucose transporter 2 (SGLT2). Remogliflozin etabonate is chemically known as 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-ß -D-glucopyranoside.
Remogliflozin is another class of antidiabetic agent useful for the treatment of type
II diabetes. Remogliflozin is a highly selective sodium glucose co-transporter 2 (SGLT2) inhibitor. The low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes. Remogliflozin works by inhibiting the sodium-glucose transport (SGLT) proteins which are responsible for glucose reabsorption in the kidney (Fujimori et al., Journal of Pharmacology and Experimental Therapeutics 2008, 327, 268-276). Remogliflozin etabonate is a prodrug of remogliflozin. Remogliflozin etabonate is chemically known as 5 -methyl-4-[4-(l -methylethoxy)benzyl]-l-(l -methyl ethyl)- 1H- pyrazol-3-yl 6-o-(ethoxycarbonyl)- -D-glucopyranoside. Remogliflozin etabonate is also known as GSK 189075 or KGT-1681. Upon administration and absorption, the prodrug is converted to its active form remogliflozin and acts selectively on the SGLT2. It has been shown that oral administration of Remogliflozin etabonate increases urinary glucose excretion in a dose-dependent manner in both rodents and humans (Fujimori et al., Journal of Pharmacology and Experimental Therapeutics 2008, 327, 268-276).
Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type II diabetes in human subjects suffering from diabetes. Efforts have been made to develop oral formulations of remogliflozin for the treatment of type II diabetes.
The process for preparation of Remogliflozin etabonate is disclosed in US Patent 7,084,123, US Patent 8,022,192 and WO2010127067 which are incorporated here for reference.
It was observed that the techniques employed such as solvent removing techniques in the prior art processes and other techniques always left with some residual solvent thus decreasing the purity of the final compound. To remove the solvent completely, the material has to be dried for prolonged time which may again lead to the formation of impurities such as dimer impurity. The residual solvents present in the final product should be within the limits of ICH guidelines. Therefore, there is a need to develop an improved process for producing amorphous Remogliflozin etabonate with desired particle size and suitable packing.
It was observed that the processes provided in prior art suffers from following disadvantages:
1. The processes disclosed in prior art require several purification steps to obtain pure Remogliflozin and Remogliflozin etabonate to meet the requirements of ICH guidelines.
2. Multiple solvents are used at various stages of the processes, and thus a complete removal of said solvents can be difficult.
3. None of the prior art discloses amorphous Remogliflozin or amorphous Remogliflozin etabonate which is efficient and scalable to industrial scale.
To overcome the prior-art problems, the present inventors have now developed an amorphous form of Remogliflozin of formula (I) and its amorphous prodrug Remogliflozin etabonate of formula (II) having mean particle size equal to or less than about 90 µm and its preparation thereof for use in pharmaceutical composition for treating diabetes mellitus.
Amorphous forms of pharmaceutical products are usually known to have better dissolution properties than their crystalline forms. It can be formulated to a pharmaceutical composition having good dissolution properties. So, there is a need for stable amorphous form of Remogliflozin or Remogliflozin etabonate for better pharmaceutical preparations.
The existence of amorphous form of Remogliflozin has now been discovered. We have also found that Remogliflozin in amorphous form has higher bioavailability than when in crystalline form and that the amorphous form of Remogliflozin has adequate chemical stability upon storage and therefore can be used in pharmaceutical formulation. The object of the present invention is to provide a stable, consistently reproducible substantially pure amorphous form of Remogliflozin or Remogliflozin etabonate.

OBJECT OF THE INVENTION
It is an object of invention to provide an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).
It is another object of present invention is to provide substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).
It is another object of present invention is to provide an improved process for preparation of an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
It is still another object of present invention is to provide an amorphous or crystalline Remogliflozin etabonate having a mean particle size equal to or less than about 90 µm. It is another object of present invention to provide the crystalline or amorphous Remogliflozin particles having a D90 not exceeding 200µm for use in pharmaceutical composition for treating diabetes mellitus.
It is another object of present invention is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
It is another object of present invention is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the crystallinity of around 5 to 10%. It is still another object of present invention is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the crystallinity of around 5%.
It is another object of present invention is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the 5 to 10% of crystalline with mean particle size up to 90 µm.
Yet another object of present invention is to provide a stable, consistently reproducible and industrially viable process for preparation of an amorphous form of Remogliflozin of formula (I) or amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
Yet another object of present invention is to provide a solid oral pharmaceutical formulation comprising substantially pure amorphous remogliflozin of compound of formula (I) and (II).
It is another object of present invention is to provide a substantially pure amorphous remogliflozin of compound of formula (I) and (II) for use in pharmaceutical composition for treating diabetes mellitus.

SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).

Formula I

Formula II
According to another aspect of present invention, there is provided a process for preparation of an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
According to another aspect of the present invention, there is to provide an amorphous or crystalline Remogliflozin etabonate having a mean particle size equal to or less than about 90 µm.
It is another object of present invention to provide the crystalline or amorphous Remogliflozin particles having a D90 not exceeding 200µm.
According to another aspect of present invention, there is to provide substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).
According to another aspect of the present invention, there is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
According to another aspect of the present invention, there is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the crystallinity of around 5 to 10%. It is still another aspect of present invention is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the crystallinity of around 5%.
According to another aspect of the present invention, there is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the 5 to 10% of crystalline with mean particle size up to 90 µm.
Still another aspect of present invention is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the mean particle size up to 70 µm. A preferred mean particle size of amorphous Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) particles is equal to or less than 50 µm. The range of mean particle sizes preferred for use in the invention is 2 to 50 µm, more preferably 5 to 50 µm, even more preferably 5 to 40 µm, and most preferably 5 to 30 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 1µm to about 90µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in range from about 1µm to about 70µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 2 µm to about 50 µm.
Yet another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 5 µm to about 40 µm.
In yet another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 5 µm to about 30 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D10 value in the range from about 0.3µm to about 10µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D10 value in the range from about 0.5µm to about 8 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D10 value in the range from about 0.5 µm to about 5 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 4 µm to about 200 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 5 µm to about 180 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 5 µm to about 160 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 5 µm to about 140 µm.
According to another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II). For the purpose of the present invention, the term “substantially pure” as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example by HPLC.
In yet another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having purity greater than about 98% by HPLC.
In yet another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having purity greater than about 99% by HPLC.
In yet another aspect of present invention, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having purity greater than about 99.9% by HPLC.
In another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) for use in pharmaceutical composition for treating diabetes mellitus.
Yet another aspect of present invention, there is provided a stable, consistently reproducible and industrially viable process for preparation of an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
It has now been determined that compositions comprising crystalline or amorphous form of Remogliflozin of formula (I) or Remogliflozin etabonate of formula (II) (herein sometimes collectively referred to as "Remogliflozin " for convenience) having a mean particle size equal to or less than about 90 µm exhibit good dissolution properties at physiologic pH. Surprisingly, formulations comprising particles of Remogliflozin free base or Remogliflozin etabonate equal to or less than about 90 µm are substantially bioequivalent, meaning that, whatever the factors are that affect the bioequivalence of Remogliflozin etabonate, they are largely independent of particle size below about 90 µm. Accordingly, the invention provides a pharmaceutical composition comprising crystalline or amorphous Remogliflozin or Remogliflozin etabonate particles having a mean particle size equal to or less than about 90 µm as measured by Malvern light scattering, and a pharmaceutically acceptable diluent or carrier. It is preferred that the crystalline or amorphous Remogliflozin particles in the composition have a D90 not exceeding 200µm. It is noted the notation Dx means that X% of the particles have a diameter less than a specified diameter D. Thus a D90 of 200 µm means that 90% of the particles in crystalline or amorphous Remogliflozin or Remogliflozin etabonate composition preferably have a diameter less than 200µm.
A preferred mean particle size of crystalline or amorphous Remogliflozin or Remogliflozin etabonate particles is equal to or less than 90 µm. The range of mean particle sizes preferred for use in the invention is up to 70 µm. A preferred mean particle size of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) particles is equal to or less than 50 µm. The range of mean particle sizes preferred for use in the invention is 2 to 50 µm, more preferably 5 to 50 µm, even more preferably 5 to 40 µm, and most preferably 5 to 30 µm. The particle sizes stipulated herein and in the claims refer to particle sizes determined with Malvern light scattering.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts differential scanning calorimetric (DSC) thermogram of an amorphous Remogliflozin of formula (I).
Figure 2 depicts powder X-ray diffraction (PXRD) pattern of an amorphous Remogliflozin of formula (I).
Figure 3 depicts TGA thermogram of an amorphous Remogliflozin of formula (I).
Figure 4 depicts IR of an amorphous Remogliflozin of formula (I).
Figure 5 depicts differential scanning calorimetric (DSC) thermogram of amorphous Remogliflozin etabonate of formula (II).
Figure 6 depicts powder X-ray diffraction (PXRD) pattern of amorphous Remogliflozin etabonate of formula (II).
Figure 7 depicts TGA thermogram of amorphous Remogliflozin etabonate of formula (II).
Figure 8 depicts IR of an amorphous Remogliflozin etabonate of formula (II).

DETAILED DESCRIPTION OF THE INVENTION
Those skilled in art will be aware that invention described herein is subject to variations and modifications other than those specifically described. It is to be understood that the invention described herein includes all such variations and modifications. The invention also includes all such steps, features, compositions and methods referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more said steps or features.
Definitions:
For convenience, before further description of the present invention, certain terms employed in the specification, examples are described here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. The terms used throughout this specification are defined as follows, unless otherwise limited in specific instances.
The terms used herein are defined as follows.
The term “hydrate” means a compound, in which water molecule/s is/are chemically bound to another compound or molecule or element. The term “hydrate” used herein is inclusive of hemihydrate.
The term “solution” used in the specification is intended to include mixture, suspension and other variations known in art and is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only.
As used in the specification and the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only.
The term “Remogliflozin” as used herein, includes Remogliflozin free base and is used interchangeably throughout the disclosure.
The term “salt” or “pharmaceutically acceptable salt” as used herein, is intended to mean those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
The term "amorphous" as used herein, means essentially without regularly repeating arrangement of molecules or external face planes.
The term “crystalline” as used herein, means having a regularly repeating arrangement of molecules or external face planes.
Unless stated otherwise, percentages stated throughout this specification are weight/weight (w/w) percentages.
The term “room temperature” unless stated otherwise, essentially means temperature in range of 25-30 °C.
As used herein, the term, “substantially pure,” when used in reference to an amorphous or crystalline form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II), refers to a amorphous or crystalline form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) which is greater than about 95% pure. This means that the form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) does not contain more than about 5% of any other form or phase or compound and, in one embodiment, does not contain more than about 10% of any other phase[s] or form[s] of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).
The term “substantially pure” includes a phase or form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) that is greater than about 96% pure. In still another embodiment the term “substantially pure” includes a phase or form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) that is greater than about 97%, 99%, 99.5%, or 99.8% pure.
Similarly, the term “substantially in the absence of a second component” or “substantially free of other form or a second component” when used in reference to an amorphous, phase or crystalline form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II), refers to a phase or crystalline form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) that does not contain more than about 5 to 10 % of the other form or phase or second component. More preferably, the term “substantially in the absence of a second component” refers to a phase or form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II)that does not contain more than about 5% of the other form or phase or second component, and even more preferably no more than about 3%, 1%, 0.5%, or 0.2%.
According to one embodiment of the present invention relates to an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).
The amorphous Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) are characterized by having broad x-ray powder diffraction spectrum as in figure 2 and 6. The amorphous nature of the compound was confirmed by X-ray diffraction pattern shows no peaks and the presence of ‘halo’ effect signifies that it is present in the amorphous state.
According to another embodiment, the present invention relates to provide an improved process for preparation of an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
According to another embodiment, the present invention relates to provide substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).
According to another embodiment, the present invention relates to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
According to another embodiment, the present invention relates to an amorphous Remogliflozin etabonate having a mean particles is equal to or less than 90 µm.
According to yet another embodiment, the present invention relates to a stable, consistently reproducible and industrially viable process for the preparation of an amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
According to yet another embodiment, the present invention relates to an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) and its preparation thereof.
According to yet another embodiment, the present invention relates to an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the crystallinity of around 5 to 10%. It is still another object of present invention is to provide an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the crystallinity of around 5%.
It is another embodiment, the present invention relates to an improved process for preparation of substantially pure amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) having the 5 to 10% of crystalline with mean particle size up to 90 µm.
In another embodiment, the present invention is to provide a process for the preparation of amorphous or crystalline Remogliflozin or amorphous Remogliflozin etabonate particles having a mean particle size equal to or less than about 90 µm comprising the steps of:
a) dissolving Remogliflozin or Remogliflozin etabonate in a solvent or mixture of solvents,
b) removing the solvent under moisture controlled conditions,
c) drying the wet mass to isolate amorphous or crystalline Remogliflozin or amorphous Remogliflozin etabonate having a mean particle size equal to or less than about 90 µm under moisture controlled conditions.
The process includes the removal of the solvent comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film dyring ("ATFD"), freeze drying (lyophilization), filtration, decantation, and centrifugation.
A preferred mean particle size of crystalline or amorphous Remogliflozin or Remogliflozin etabonate particles is equal to or less than 90 µm. The range of mean particle sizes preferred for use in the invention is up to 70 µm. A preferred mean particle size of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II) particles is equal to or less than 50 µm. The range of mean particle sizes preferred for use in the invention is 2 to 50 µm, more preferably 5 to 50 µm, even more preferably 5 to 40 µm, and most preferably 5 to 30 µm. The particle sizes stipulated herein and in the claims refer to particle sizes determined with Malvern light scattering.
Yet another embodiment of the present invention is crystalline or amorphous Remogliflozin or Remogliflozin etabonate particles having a mean particle size equal to or less than about 90 µm as measured by Malvern light scattering, and a pharmaceutically acceptable diluent or carrier. It is preferred that the crystalline or amorphous Remogliflozin particles in the composition have a D90 not exceeding 200µm. It is noted the notation Dx means that X% of the particles have a diameter less than a specified diameter D. Thus a D90 of 200 µm means that 90% of the particles in crystalline or amorphous Remogliflozin or Remogliflozin etabonate composition preferably have a diameter less than 200µm.
In another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 1µm to about 90µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in range from about 1µm to about 70µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 2µm to about 50µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 5µm to about 40µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having an average particle size value (D50) in the range from about 5µm to about 30µm.
In another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D10 value in the range from about 0.3µm to about 10µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D10 value in the range from about 0.5µm to about 8µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D10 value in the range from about 0.5µm to about 5µm.
In another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 4µm to about 200µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 5µm to about 180µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 5µm to about 160 µm.
In yet another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) having a D90 value in the range from about 5µm to about 140µm.
In another aspect of the application there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II). For the purpose of the present invention, the term “substantially pure” as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example by HPLC.
In yet another embodiment, the present invention relates to substantially pure amorphous remogliflozin of compound of formula (I) and (II) having purity greater than about 98% by HPLC.
In yet another embodiment, the present invention relates to substantially pure amorphous remogliflozin of compound of formula (I) and (II) having purity greater than about 99% by HPLC.
In yet another embodiment, the present invention relates to substantially pure amorphous remogliflozin of compound of formula (I) and (II) having purity greater than about 99.9% by HPLC.
In another embodiment, there is provided a substantially pure amorphous remogliflozin of compound of formula (I) and (II) for use in pharmaceutical composition for treating diabetes mellitus.
In yet another embodiment, the present invention relates to a solid oral pharmaceutical formulation comprising substantially pure amorphous remogliflozin of compound of formula (I) and (II) in combination with one or more pharmaceutically acceptable excipients.
In yet another embodiment, the present invention relates to a solid oral pharmaceutical formulation comprising substantially pure amorphous remogliflozin of compound of formula (I) and (II), wherein the solid oral pharmaceutical formulation is immediate release formulation suitable for twice daily administration
In yet another embodiment, the present invention relates to the solid oral immediate release formulation of substantially pure amorphous remogliflozin can include an intragranular portion and an extragranular portion. The intragranular portion can include a quantity of substantially pure amorphous remogliflozin in combination with at least one disintegrant and at least one binder. The extragranular portion can include at least one disintegrant and at least one lubricant.
In yet another embodiment, the present invention relates to a solid oral pharmaceutical formulation comprising substantially pure amorphous remogliflozin of compound of formula (I) and (II), wherein the solid oral pharmaceutical formulation is extended release formulation suitable for once daily administration.
The pharmaceutical composition comprising substantially pure amorphous remogliflozin of compound of formula (I) and (II), and at least one or more pharmaceutically acceptable carriers, diluents, binder, lubricant, disintegrate and stabilizing agent.
The solid oral pharmaceutical formulation may further comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to one or more of diluents, disintegrant, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, opacifiers, colorants, gelling agents / viscosity modifying agents, antioxidants, solvents, co-solvents, and combinations thereof. Formulations may comprise polymeric excipients for extended release of the drug.
Non-limiting examples of diluents include one or more of microcrystalline cellulose, silicified microcrystalline cellulose (e.g., Prosolv®), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sugars such as dextrose, mannitol, sorbitol, or sucrose and combinations thereof. The diluents according to current invention are present in an amount 5-75% w/w.
Non limiting examples of disintegrants suitable for use herein include, povidone, crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, pregelatinised starch, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Several specific types of disintegrant are suitable for use in the formulations described herein. For example, any grade of crospovidone can be used, including for example crospovidone XL-10, and includes members selected from the group consisting of Kollidon CL.RTM., Polyplasdone XL.RTM., Kollidon CL-M. RTM., Polyplasdone XL-10.RTM., and Polyplasdone INF-10.RTM. In one embodiment, the disintegrant, if present, of the stock granulation is sodium starch glycolate, croscarmellose sodium and/or crospovidone. These materials are also referred to as insoluble polyvidone, insoluble PVP, crosslinked PVP and PVPP. The crospovidone can be substituted with croscarmellose sodium, sodium starch glycolate. The disintegrant according to current invention are present in an amount 1-30% w/w.
Non-limiting examples of glidants and lubricants include one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate. The glidant according to current invention are present in an amount 0.1-5% w/w.
Non limiting examples of binder include starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols. The binder according to current invention are present in an amount 0.5-10% w/w.
Non-limiting examples of preservatives include one or more of phenoxyethanol, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and mixtures thereof. Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof. Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives. The binder according to current invention are present in an amount 0.1-2% w/w.
Non-limiting examples of polymers include one or more of gum arabic, guar gum, sodium based lignosulfonate, polyethylene oxide, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate and cellulosic polymers including hydroxyl propyl cellulose, carboxy methyl cellulose, hydroxyl propyl methyl cellulose.
In yet another embodiment, the present invention is to provide a process for the preparation of amorphous Remogliflozin or amorphous Remogliflozin etabonate wherein the solvent is removed by using distillation, evaporation, spray drying or by agitated thin film evaporator under moisture controlled conditions.
In yet another embodiment, the particles are optionally reduced by micronization to obtain the desired particle size under moisture controlled conditions.
In yet another embodiment of the present invention is suitable packing to maintain polymorphic and chemical stability. The amorphous Remogliflozin and amorphous Remogliflozin etabonate prepared, isolated and stored according to the present invention with desired particle size under moisture controlled conditions provides a stable Remogliflozin or Amorphous Remogliflozin etabonate.
Amorphous form of Remogliflozin and amorphous form of Remogliflozin etabonate are further characterized by IR spectrum in potassium bromide pellet having main absorption bands at about 3392, 2977, 1611, 1579, 1384, 1280, 1181, 892 cm"1and 3790, 3408, 2979, 2933, 1746, 1611, 1505, 1371, 1181, 955 790 cm"1.
Amorphous form of Remogliflozin and amorphous form of Remogliflozin etabonate are further characterized by DSC as in the figure number 1 & 5.
According to another embodiment of the present invention, a process is provided for preparation of Remogliflozin of formula (I) or amorphous Remogliflozin etabonate of formula (II), which comprises spray drying or vacuum drying a solution of Remogliflozin in a solvent.
The solution of Remogliflozin of formula (I) or amorphous Remogliflozin etabonate of formula (II) are obtained by dissolving in a solvent.
Preferable solvent is selected from alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol; ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; ether solvents such as diethyl ether, diisopropyl ether and tert-butyl methyl ether; chlorinated hydrocarbon solvents such as methylene chloride, ethylene chloride and chloroform; hydrocarbon solvents such as toluene and xylene; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, ethyl formate and methyl formate; acetonitrile; tetrahydrofuran; dimethylformamide, dimethylsulfoxide; 1,4-dioxane; water; acetic acid; acetic anhydride and a mixture thereof. More preferable solvent is selected from acetonitrile, methanol and acetone. Most preferable solvent is acetonitrile.
Remogliflozin used as starting material may be obtained by processes described in the art, for example by the processes described in U.S. Patent No. 7,084,123, US Patent 8,022,192 and WO2010127067A1.
According to another aspect of present invention, an amorphous form of Remogliflozin or Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram, a powder X-ray diffraction (PXRD) pattern or a thermogravimetric analysis curve (TGA).
According to an embodiment of present invention, an amorphous form of Remogliflozin or Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram represented by figure 1 and 5.
According to another aspect of present invention, an amorphous form of Remogliflozin or Remogliflozin etabonate characterized by an X-ray powder diffraction pattern represented in figure 2 and 6.
According to another aspect of present invention, an amorphous form of Remogliflozin or Remogliflozin etabonate characterized by thermogravimetric analysis curve (TGA) represented in figure 3 and 7.

EXAMPLES
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The examples provided below are merely illustrative of the invention and are not intended to limit the same to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention.
Methods
Differential scanning calorimetry (DSC) thermogram was measured by a Differential scanning calorimeter (DSC 822, Mettler Toledo) having temperature range of 30 to 350 °C with heating rate of 10°C/min.
X-ray powder diffraction method (XPRD) pattern was collected on Phillips X-ray diffractometer model XPERT-PRO (PANalytical) Detector Xcelerator. The radiation source used was copper (Cu, 15 Ka1=1.54060Å and Ka2=1.54443Å) at a constant temperature within 2O range of 2.0°-5.0°. It is meant to be understood that peak heights in a powder x-ray diffraction pattern may vary and will be dependent on variables such as the temperature, crystal size, crystal habit, sample preparation or sample height in the analysis well of the Scintag×2 Diffraction Pattern System.
All FTIR spectra were recorded using KBr on Perkin-Elmer instrument (Model: Spectrum One). The data was processed using Spectrum One Software. About 200 mg of KBr, previously dried at 200°C and cooled was grinded into a mortar and grind to a Fine powder. Added 2-3 mg of test sample and mixed well to obtain a uniform sample. Taken a small portion of the blend and put it into die and then compressed it by applying 10-15 pound pressure to obtain a semi-transparent pellet and recorded the IR spectrum of the pellet from 4000 cm-1 to 450 cm-1 taking air as reference.
All TGA were recorded by using TA Instruments (Waters) of Model: Q250. The instrument is allowed to equilibrate at room temperature. Approximately 5-6 mg sample is accurately weighed into Platinum TGA pan previously tarred on microbalance inbuilt with the instrument. The pan is then inserted into the furnace of TGA instrument (TA, Q500). The nitrogen gas is used for purging at a flow rate of 60 mL/minute in order to produce inert atmosphere during the heating. The sample is then heated with ramp 10°C/minute to 250°C. The obtained thermogram is integrated using Universal 2000 Software and a percentage total weight loss by the sample is recorded from ambient temperature to 150°C.
As used herein, the term "average particle size" (or synonymously, "mean particle size") refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined average particle size value. This can be identified by the term "D50" or “d (0.5)”.
The term "D10" refers to the distribution of particles, wherein about 10 volume percent of all the particles measured have a size less than the defined particle size value. This can be identified by the term “d(0.1)” as well. Similarly, as used herein, the term "D90" refers to the distribution of particles, wherein about 90 volume percent of all the particles measured have a size less than the defined particle size value. This can be identified by the term or “d (0.9)” as well.
The average particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy and Coulter’s principle. Typically, instruments like ZETASIZER® 3000 HS (Malvern® Instruments Ltd., Malvern, United Kingdom), NICOMP 388TM ZLS system (PSS-Nicomp Particle Sizing Systems, Santa Barbara, CA, USA), or Coulter Counter are generally used to determine the mean particle size.
Preferably, Mastersizer 2000 (Malvern® Instruments Ltd., Malvern, United Kingdom) is used to determine the particle size of the particles.
Example 1
Preparation of Remogliflozin free base of formula (I)
3.64 g of lithium hydroxide monohydrate was added to the mixture of 100 ml of tert. butanol, 10 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one and 21.38 g of O-Acetyl D glucopyranosyl bromide. The reaction mass was stirred for about 5 hours at about 40 oC. After completion of reaction, sodium hydroxide solution was added and the mixture was stirred for another 2 hours. The layers were separated and the organic layer was washed with 20 % brine solution. The organic layer was distilled out under vacuum and to it was added to 120 ml of water. The mixture was stirred for another 4-5 hours. The product obtained was filtered and washed with water. The wet cake was then dried in vacuum try drier at 40 oC for 8 to 10 hours to get 6 g of Remogliflozin free base having HPLC purity of >99% by HPLC.
Example 2
Preparation of isopropyl solvate of Remogliflozin Etabonate
To mixture of 1350 ml of toluene, 135 g of Remogliflozin free base, 57.8 g of 2,6-lutidine and 1.35 g of pyridine was slowly added 45.51 g of Ethyl chloro formate and the reaction mass was cooled to about -10o C and stirred for 3 to 4 hours. After the completion of the reaction, 675 ml of water was added to reaction mass and the mixture was stirred. The layers were separated and the organic layer was washed with 675ml of dilute hydrochloric acid and 675 ml water. The organic layer was concentrated under vacuum. To the residue was then added mixture of 810 ml of ethanol and 810 ml of n-heptane and the mixture was heated to about 70 oC to obtain a clear solution. The clear solution was then cooled to 25 oC and stirred for 8 to 10 hours. The solid thus obtained was isolated by filtration and crystallized from 1350 ml of isopropyl alcohol to obtain isopropyl alcohol solvate of Remogliflozin etabonate.
Example 3
Preparation of Remogliflozin Etabonate Hemihydrate of Formula (II)
Isopropyl alcohol solvate of Remogliflozin etabonate obtained in example 2, was subjected to conversion to stable hemihydrate Remogliflozin etabonate by dissolving in 1:1 acetonitrile and water mixture followed by addition of 18 volumes of water. The hemihydrate Remogliflozin etabonate obtained was dried at 40 oC for 10 hours to get 81g (0.6 w/w) of final product having HPLC purity of > 99%.
Example 4
Preparation of amorphous form of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy) benzyl]-1H-pyrazol-3-yl 2, 3, 4, 6-tetra-O-acetyl-ß-D-glucopyranoside (Remogliflozin)
Dissolve 25 g Remogliflozin i.e. 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy) benzyl]-1H-pyrazol-3-yl 2, 3, 4, 6-tetra-O-acetyl-ß-D-glucopyranoside, in 125 ml Methylene dichloride and stir to get clear solution. Distilled out solvent completely under vacuum at 40-45°C and degas for 12 hrs to get 23g of final product product i.e., substantially pure amorphous Remogliflozin having HPLC purity of > 99%.
Example 5
Preparation of amorphous form of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy) benzyl]-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (Remogliflozin Etabonate)
Dissolve 50 g Remogliflozin etabonate i.e. 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy) benzyl]-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-ß-D-glucopyranoside, in 500 ml Methylene dichloride and stir to get clear solution. Distilled out solvent completely under vacuum at 40-45°C and degas for 9.0 hrs. at 50°C to get 48g of final product i.e., substantially pure amorphous Remogliflozin Etabonate having HPLC purity of > 99%.
Example 6
Solid oral immediate release formulation of 100 mg substantially pure amorphous Remogliflozin Etabonate
Table-1:
Strength 100 mg
Ingredients mg % w/w
Intragranular Portion
Substantially pure amorphous Remogliflozin Etabonate 100.000 31.25
Croscarmellose Sodium 4.800 1.50
Microcrystalline cellulose 20.668 6.46
Binder
Povidone K 29/32 6.665 2.08
Purified Water q.s -
Extragranular Portion
Croscarmellose Sodium 6.720 2.10
Microcrystalline cellulose 178.267 55.71
Magnesium Stearate 2.880 0.90
320
Film Coating
Opadry White YS-1-18202A 8.000 2.50
Total Film Coated Tablet 328 ,CLAIMS:We Claim:
1. An amorphous form of Remogliflozin of formula (I) and amorphous Remogliflozin etabonate of formula (II).

Formula I Formula II
2. The amorphous form of Remogliflozin according to claim 1, characterized by a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 1.
3. The amorphous form of Remogliflozin according to claim 1, characterized by a XRPD pattern shown in Figure 2.
4. The amorphous form of Remogliflozin according to claim 1, characterized by a TGA profile characterized by figure 3.
5. The amorphous form of Remogliflozin according to claim 1, further characterised by the FT-IR spectrum shown in Figure 4.
6. An amorphous form of Remogliflozin etabonate of formula II

Formula II
7. The amorphous compound according to claim 6, characterized by a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 5.
8. The amorphous compound according to claim 6 characterized by a XRPD pattern shown in Figure 6.
9. The amorphous compound according to claim 6, characterized by a TGA profile characterized by a figure 7.
10. The amorphous compound according to claim 6, further characterised by the FT-IR spectrum shown in Figure 8.
11. A process of preparing the amorphous compound of formula (I) or (II), as defined in claim 1, comprising the steps of:
(a) dissolving the compound of formula (I) or (II) in a solvent;
(b) removing the possible residual solvents coming from the synthetic process by heating the solution at 55° C. under vacuum;
(c) isolating amorphous Remogliflozin or amorphous Remogliflozin etabonate.
12. The process according to claim 11, wherein the removal of the solvent comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film dyring ("ATFD"), freeze drying (lyophilization), filtration, decantation, and centrifugation.
13. An amorphous or crystalline Remogliflozin or amorphous Remogliflozin etabonate particles having a mean particle size equal to or less than about 90 µm.
14. An amorphous or crystalline Remogliflozin or amorphous Remogliflozin etabonate particles having an average particle size value (D50) in range from about 1µm to about 70µm.
15. An amorphous or crystalline Remogliflozin or amorphous Remogliflozin etabonate particles having an average particle size value (D50) in range from about 2µm to about 50µm.
16. An amorphous or crystalline Remogliflozin or amorphous Remogliflozin etabonate particles having an average particle size value (D50) in range from about 5µm to about 40µm.
17. An amorphous or crystalline Remogliflozin or amorphous Remogliflozin etabonate particles having an average particle size value (D50) in range from about 5µm to about 30µm.
18. A process of preparing the amorphous compound as defined in claim 11 comprising the steps of:
a) dissolving Remogliflozin etabonate in a solvent or mixture of solvents,
b) removing the solvent under moisture controlled conditions,
c) drying and degas the wet mass to isolate amorphous Remogliflozin or amorphous Remogliflozin etabonate having a mean particle size equal to or less than about 90 µm under moisture controlled conditions.
19. Substantially pure Remogliflozin etabonate having a purity of at least about 99% by weight.
20. A pharmaceutical composition comprising substantially pure amorphous Remogliflozin of compound of formula (I) and (II), in an amount of 10-50% by weight of the composition and at least one or more pharmaceutically acceptable carriers, diluents, binder, lubricant and disintegrant optionally coated with a film coating.
21. The pharmaceutical composition as claimed in claim 20, comprising substantially pure amorphous Remogliflozin of compound of formula (I) and (II), wherein the solid oral pharmaceutical formulation suitable for twice daily administration.
22. The pharmaceutical compositions as claimed in claim 20, comprising
(a) Substantially pure amorphous Remogliflozin of compound of formula (I) and (II);
(b) microscrystalline cellulose in an amount from 10-70% w/w,
(c) povidone in an amount from 1-20%,
(d) magnesium stearate in an amount from 0.1– 5%,
(e) croscarmellose sodium in an amount 1-30% w/w.
23. The pharmaceutical compositions as claimed in 20, comprising co-administering the substantially pure amorphous Remogliflozin of compound of formula (I) and (II), in combination with at least one other drug useful for the treatment of type II diabetes.

Dated this 17th Day of June, 2020.
Signature__________________________
Dr. Pramod Sagar
Deputy General Manager – IPM