FIELD OF THE INVENTION

[0001] The present invention relates to solid state forms of Sotagliflozin, processes for preparation thereof and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

[0002] Sotagliflozin has the chemical name (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H- pyran-3,4,5-triol. Sotagliflozin has the following chemical structure:

[0003] Sotagliflozin is an orally available L-xyloside based molecule that apparently inhibits both sodium-glucose transporter type 1 (SGLT1) and type 2 (SGLT2). SGLT1 is primarily responsible for glucose and galactose absorption in the gastrointestinal tract, and SGLT2 is responsible for most of the glucose reabsorption performed by the kidney.

[0004] Sotagliflozin is known from WO 2008/109591. Amorphous forms and crystalline forms (i.e. Form 1 and Form 2) of Sotagliflozin are disclosed in WO2010/009197.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Sotagliflozin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Sotagliflozin.

SUMMARY OF THE INVENTION

[0008] The present invention relates to solid state forms of Sotagliflozin, to processes for preparation thereof, and to pharmaceutical compositions comprising these solid state forms.

[0009] The present invention also provides the use of any one of the solid state forms of Sotagliflozin for preparing other solid state forms of Sotagliflozin or its salts, and solid state forms thereof.

[0010] In another embodiment, the present invention encompasses any one of the above described solid state forms of Sotagliflozin and /or combinations thereof for use in the preparation of pharmaceutical compositions and/or formulations, preferably for the treatment of type 1 and/or 2 diabetes mellitus. [0011] The present invention further provides pharmaceutical compositions comprising any one of or a mixture of the solid state forms of Sotagliflozin according to the present invention.

[0012] In yet another embodiment, the present invention encompasses

pharmaceutical formulations comprising any one of the above described solid state forms of Sotagliflozin and /or combinations thereof and at least one pharmaceutically acceptable excipient.

[0013] The present invention encompasses processes to prepare said pharmaceutical formulations of Sotagliflozin comprising combining any one of the above solid state forms and /or combinations thereof and at least one pharmaceutically acceptable excipient.

[0014] In another embodiment the present invention encompasses the use of any one of the above described solid state forms of Sotagliflozin and /or combinations thereof for the preparation of pharmaceutical compositions and/or formulations.

[0015] Any of the solid state forms as defined herein and /or combinations thereof as well as the pharmaceutical compositions or formulations of the solid state forms of Sotagliflozin can be used as medicaments, particularly for the treatment of type 1 and/or 2 diabetes mellitus.

[0016] The present invention also provides a method of treating type 1 and/or 2 diabetes mellitus; comprising administering a therapeutically effective amount of any one of the solid state forms of Sotagliflozin of the present invention and /or combinations thereof, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from type 1 and/or 2 diabetes mellitus, or otherwise in need of the treatment.

[0017] The present invention also provides the use of any one of the solid state forms of Sotagliflozin of the present invention and /or combinations thereof, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating type 1 and/or 2 diabetes mellitus.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows a powder X-ray diffraction pattern ("powder XRD" or "PXRD") of Sotagliflozin Form A.

[0019] Figure 2 shows a powder X-ray diffraction pattern of Sotagliflozin Form B.

[0020] Figure 3 shows a powder X-ray diffraction pattern of Sotagliflozin Form C.

[0021] Figure 4 shows a powder X-ray diffraction pattern of Sotagliflozin Form D.

[0022] Figure 5 shows a powder X-ray diffraction pattern of Sotagliflozin Form E. [0023] Figure 6 shows a powder X-ray diffraction pattern of Sotagliflozin Form F.

[0024] Figure 7 shows a powder X-ray diffraction pattern of Sotagliflozin Form G.

[0025] Figure 8 shows a powder X-ray diffraction pattern of Sotagliflozin Form H.

[0026] Figure 9 shows a powder X-ray diffraction pattern of Sotagliflozin Form I.

[0027] Figure 10 shows a powder X-ray diffraction partem of Sotagliflozin Form K.

[0028] Figure 11 shows a powder X-ray diffraction partem of Sotagliflozin form-2 according to WO 2010009197.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention relates to Sotagliflozin, to solid state forms thereof, such as crystalline Forms A, B, C, D, E, F, G, H, I and K; to processes for preparation thereof and to pharmaceutical compositions comprising at least one of, or a combination of, these solid state forms. The invention also relates to the conversion of Sotagliflozin Forms A, B, C, D, E, F, G, H, I and/or K to other solid state forms of Sotagliflozin or to its salts and solid state forms thereof.

[0030] The solid state forms of Sotagliflozin of the present invention may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density.

[0031] A crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called "fingerprint") which can not necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Sotagliflozin, e.g. Sotagliflozin Form A, referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of the Sotagliflozin, e.g., Sotagliflozin Form A, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0032] A solid state form (or polymorph) may be referred to herein as

polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other forms of the subject compound as measured, for example, by PXRD. Thus, solid state of Sotagliflozin described herein as substantially free of any other solid state forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject solid state form of Sotagliflozin. Accordingly, in some embodiments of the invention, the described solid state forms of Sotagliflozin may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one or more other solid state forms of Sotagliflozin.

[0033] As used herein, unless stated otherwise, PXRD peaks reported herein are preferably measured using CuK _a radiation, λ = 1.54A.

[0034] As used herein, the term "isolated" in reference to solid state forms of Sotagliflozin of the present invention corresponds to a solid state form of Sotagliflozin that is physically separated from the reaction mixture in which it is formed.

[0035] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "room temperature", often abbreviated "RT." This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0036] A process or step may be referred to herein as being carried out "overnight. " This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, typically about 16 hours.

[0037] As used herein, the expression "wet crystalline form" refers to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but are not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.

[0038] As used herein, the expression "dry crystalline form" refers to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples of such conventional techniques can be, but are not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.

[0039] As used herein, and unless stated otherwise, the term "anhydrous" in relation to crystalline forms of Sotagliflozin, relates to a crystalline form of Sotagliflozin which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an "anhydrous" form would typically not contain more than about 1 % (w/w), of either water or organic solvents as measured for example by TGA.

[0040] The term "solvate", as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate". The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0041] The amount of solvent employed in a chemical process, e.g., a reaction or a crystallization may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding methyl tert-butyl ether (MTBE) (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.

[0042] As used herein the term non-hygroscopic in relation to crystalline

Sotagliflozin refers to less than 0.2% (w/w) absorption of water at 25°C and 75% relative humidity (RH), by the crystalline Sotagliflozin as determined for example by TGA.

Preferably the term non-hygroscopic in relation to crystalline Sotagliflozin refers to less than 0.2% (w/w) absorption of water at 25°C and 75% relative humidity (RH) after 24 hours, by the crystalline Sotagliflozin as determined for example by TGA and/or KF.

Water can be for example atmospheric water. It is understood that the term w/w (weight per weight) refers to weight percentage of a starting material prior to the test conditions. For example, by less than 0.2% (w/w) water it is meant that following storage at the test conditions, the weight gain of the starting material is less than 0.2%. As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 50 mbar.

[0043] As used herein, and unless indicated otherwise, the term "thermo-dynamical stability" in relation to solid state forms of Sotagliflozin refers to resistance of the solid state form to polymorphic conversion under certain conditions, for example, heating, melting or dissolving. In some embodiments, the term refers to less than 20%, 10%, 5%, 1 %, or 0.5% (w/w) conversion of crystalline Sotagliflozin to any other solid state form of Sotagliflozin as measured by PXRD. In some embodiments, the conversion is l%-20%, 1%-10% or l%-5% (w/w). Preferably the term "thermo-dynamical stability" refers to less than: 20%, 10%, 5%, 1%, or 0.5% (w/w) conversion of crystalline Sotagliflozin to any other solid state form of Sotagliflozin as measured by PXRD.

[0044] As used herein, Sotagliflozin Form-2 as described in WO 2010009197, has an XRPD partem depicted in figure 11. Form -2 of Sotagliflozin as described in WO 2010009197, contains peaks at one or more of about 4.4, 4.8, 14.5, 14.7, 15.5, 21.2, 22.1 and/or 23.8 degrees (deg) 2-theta.

[0045] The present invention comprises a crystalline form of Sotagliflozin designated as Form A. The crystalline Form A of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 3.7, 9.0, 9.6, 10.9, 12.7, 14.7 and 17.2 deg-2-theta ± 0.1 deg 2-theta; a PXRD pattern as depicted in figure 1 ; and combinations of these data.

[0046] Crystalline Form A of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 3.7, 9.0, 9.6, 10.9, 12.7, 14.7 and 17.2 deg-2-theta ± 0.1 deg 2-theta, and also having one, two, three, four or five additional peaks selected from 10.4, 14.1 , 15.6, 18.8 and 21.0 deg-2-theta ± 0.1 deg 2-theta.

[0047] In an embodiment, crystalline Form A of Sotagliflozin may be a hydrate, specifically a monohydrate. Form A of Sotagliflozin may contain from about 3% to about 6% of water by weight, preferably about 3 to 4 % of water by weight as measured by Karl Fischer titration and/or TGA.

[0048] Further, the present invention comprises a crystalline form of Sotagliflozin designated as Form B. The crystalline Form B of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 3.6, 13.3, 14.6, 18.1 and 22.8 deg-2-theta ± 0.1 deg 2-theta; a PXRD pattern as depicted in Figure 2; and combinations of these data. [0049] Crystalline Form B of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 3.6, 13.3, 14.6, 18.1 and 22.8 deg-2-theta ± 0.1 deg 2-theta, and also having one, two, three or four additional peaks selected from 4.4, 9.1 , 10.5 and 20.7 deg-2-theta ± 0.1 deg 2-theta.

[0050] Further, the present invention comprises a crystalline form of Sotagliflozin designated as Form C. The crystalline Form C of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 4.9, 7.3, 7.8, 9.6, 10.7, 11.1 , and 20.1 deg-2-theta ± 0.1 deg 2-theta, a PXRD pattern as depicted in Figure 3; and combinations of these data.

[0051] Crystalline Form C of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 4.9, 7.3, 7.8, 9.6, 10.7, 11.1, and 20.1 deg-2-theta ± 0.1 deg 2- theta, and also having one, two, three or four additional peaks selected from 3.7, 13.4, 20.7, and 21.5 deg-2-theta ± 0.1 deg 2-theta.

[0052] Further, the present invention comprises a crystalline form of Sotagliflozin designated as Form D. The crystalline Form D of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 5.4, 6.5, 6.8, 9.9, 12.2 and 15.1 deg-2-theta ± 0.1 deg 2-theta, a PXRD pattern as depicted in Figure 4; and combinations of these data.

[0053] Crystalline Form D of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 5.4, 6.5, 6.8, 9.9, 12.2 and 15.1 deg-2-theta ± 0.1 deg 2-theta, and also having one, two, three or four additional peaks selected from 10.4, 13.6, 17.6 and 24.2 deg-2-theta ± 0.1 deg 2-theta.

[0054] Further, the present invention comprises a crystalline form of Sotagliflozin designated as Form E. The crystalline Form E of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 12.6, 12.9, 14.7, 15.0 and 19.7 deg-2-theta ± 0.1 deg 2-theta, a PXRD pattern as depicted in Figure 5; and combinations of these data.

[0055] Crystalline Form E of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 12.6, 12.9, 14.7, 15.0 and 19.7 deg-2-theta ± 0.1 deg 2-theta, and also having one, two or three additional peaks selected from 18.0, 21.1 and 24.6 deg-2- theta ± 0.1 deg 2-theta.

[0056] In an embodiment, crystalline Form E of Sotagliflozin may be anhydrous. In an embodiment, crystalline Form E of Sotagliflozin is non-hygroscopic. Form E of Sotagliflozin may contain from about 0% to about 1 % of water by weight, preferably about less than 1 % of water by weight as measured by Karl Fischer titration and/or TGA.

[0057] Further, the present invention comprises a crystalline form of Sotagliflozin designated as Form F. The crystalline Form F of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.4, 6.9, 12.2, 13.0, 14.0 and 20.3 deg-2-theta ± 0.1 deg 2-theta, a PXRD pattern as depicted in Figure 6; and combinations of these data.

[0058] Crystalline Form F of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 6.4, 6.9, 12.2, 13.0,14.0 and 20.3 deg-2-theta ± 0.1 deg 2- theta, and also having one or two additional peaks selected from 3.4 and 22.2 deg-2-theta ± 0.1 deg 2-theta.

[0059] Further, the present invention comprises a crystalline form of Sotagliflozin designated as Form G. The crystalline Form G of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 5.6, 8.8, 13.0, 13.7, 18.4 and 22.5 deg-2-theta ± 0.1 deg 2-theta, a PXRD pattern as depicted in Figure 7; and combinations of these data.

[0060] Crystalline Form G of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 5.6, 8.8, 13.0, 13.7, 18.4 and 22.5 deg-2-theta ± 0.1 deg 2- theta, and also having one, two or three additional peaks selected from 8.1, 12.1 and 17.7 deg-2-theta ± 0.1 deg 2-theta.

[0061] Further, the present invention comprises a crystalline form of Sotagliflozin designated as Form H. The crystalline Form H of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 13.3, 16.0, 17.5, 21.0, 21.9 and 28.7deg-2-theta ± 0.2 deg 2-theta, a PXRD pattern as depicted in Figure 8; and combinations of these data.

[0062] Crystalline Form H of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 13.3, 16.0, 17.5, 21.0, 21.9 and 28.7 deg-2-theta ± 0.2 deg 2- theta, and also having one, two or three additional peaks selected from 9.7, 19.7 and 27.7 deg-2-theta ± 0.2 deg 2-theta.

[0063] The present invention comprises a crystalline form of Sotagliflozin designated as Form I. The crystalline Form I of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 5.3, 7.9, 15.9, 18.2, 19.1, 19.5 and 21.0 deg-2-theta ± 0.2 deg 2-theta, a PXRD pattern as depicted in Figure 9; and combinations of these data. [0064] Crystalline Form I of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 5.3, 7.9, 15.9, 18.2, 19.1 , 19.5 and 21.0 deg-2-theta ± 0.2 deg 2-theta, and also having one, two or three additional peaks selected from 4.5, 10.6 and 14.6 deg-2-theta ± 0.2 deg 2-theta.

[0065] The present invention comprises a crystalline form of Sotagliflozin designated as Form K. The crystalline Form K of Sotagliflozin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.2, 6.4, 10.9, 17.8, 18.7, 19.3 and 20.0 deg-2-theta ± 0.1 deg 2-theta, a PXRD pattern as depicted in Figure 10; and combinations of these data.

[0066] Crystalline Form K of Sotagliflozin may be further characterized by the PXRD pattern having peaks at 6.2, 6.4, 10.9, 17.8, 18.7, 19.3 and 20.0 deg-2-theta ± 0.1 deg 2-theta and also having one, two or three additional peaks selected from 3.7, 10.5 and 15.7 deg-2-theta ± 0.1 deg 2-theta.

[0067] The solid forms of the present disclosure may exhibit favorable specific surface area properties.

[0068] The present invention also provides the use of any one of the solid state forms of Sotagliflozin for preparing other solid state forms of Sotagliflozin or Sotagliflozin salts, and solid state forms thereof.

[0069] In another embodiment the present invention encompasses any one of the above described solid state forms of Sotagliflozin and/ or combinations thereof for use in the preparation of pharmaceutical compositions, preferably for the treatment of type 1 and/or 2 diabetes mellitus.

[0070] The present invention further provides pharmaceutical compositions comprising any one of or a mixture of the solid state forms of Sotagliflozin according to the present invention.

[0071] The present invention comprises a process for preparing the above mentioned pharmaceutical compositions.

[0072] In yet another embodiment, the present invention encompasses

pharmaceutical formulations comprising any one of the above described solid state forms of Sotagliflozin and/ or combinations thereof and at least one pharmaceutically acceptable excipient.

[0073] The present invention encompasses a process to prepare said formulations of Sotagliflozin comprising combining any one of the above solid state forms and/or combinations thereof and at least one pharmaceutically acceptable excipient. [0074] In another embodiment the present invention encompasses the use of any one of the above described solid state forms of Sotagliflozin and/or combinations thereof for the preparation of pharmaceutical compositions and/or formulations.

[0075] Any one of the solid state forms as defined herein and/or combinations thereof, as well as the pharmaceutical compositions or formulations of Sotagliflozin can be used as medicaments, particularly for the treatment of type 1 and/or 2 diabetes mellitus.

[0076] The present invention also provides a method of treating type 1 and/or 2 diabetes mellitus, comprising administering a therapeutically effective amount of any one of the solid state forms of Sotagliflozin of the present invention and/or combinations thereof, or at least one of the above pharmaceutical compositions or formulations, to a subj ect suffering from type 1 and/or 2 diabetes mellitus, or otherwise in need of the treatment.

[0077] The present invention also provides the use of any one of the solid state forms of Sotagliflozin of the present invention and/or combinations thereof, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating type 1 and/or 2 diabetes mellitus.

[0078] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. 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.

Powder X-ray diffraction pattern ("PXRD") method:

[0079] X-ray diffraction was performed on X-Ray powder diffractometer. X'Pert PRO PANalytical; CuK_ radiation (λ = 1.5418 A); X'Celerator detector; laboratory temperature 22-25 °C. The samples were gently ground by means of mortar and pestle in order to obtain a fine powder. Measurement parameters

Scan range (°) 3.0010 - 39.9997

Step size (°) 0.0167

Counting time (s) 12.700

No. of points 2214

Scan mode Continuous

Sample spinning (Rotation time (s)) : 1.0

EXAMPLES

Sotagliflozin Form-2 may be prepared according to WO2010/009197. Sotaglifiozin Form-2 may also be prepared according to Example 16 below.

Working examples:

Example- 1 : Preparation of Sotagliflozin (Amorphous Form)

[0080] 2 g of Sotagliflozin (Form-2) was taken in 250ml round bottom flask and applied vacuum (approx. 50 mbar) with continuous rotation of the flask. The flask was externally heated by hot air flow maintained at few centimetres from the rotating flask wall for few minutes until the compound melts at around 130°C and the melt was quenched to room temperature (25°C) with water bath. The amorphous solid (1.8 g) was scratched from the walls of the flask.

Example-2: Preparation of Sotagliflozin Form A

[0081] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of water, was left at variable temperature as follows: heating from 10°C to 50°C at the rate of 20°C/hr, held at 50°C for 3 hrs; cooling from 50°C to 10°C at the rate of 20°C/hr, held at 10°C for 3hrs; again heating from 10°C to 50°C at the rate of 10°C/hr, held at 50°C for 3hrs; again cooling from 50°C to 10°C at the rate of 10°C/hr, held at 10°Cfor 3hrs; further heating from 10°C to 50°C at the rate of 5°C/hr, held at 50°C for 3hrs; further cooling from 50°C to 10°C at the rate of 5°C/hr, held at 10°C for 3hrs; followed by raising the temperature from 10°C to 25°C at the rate of 10°C/hr, held at 25°C for 24hrs. The suspension was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form A has been confirmed by PXRD as presented in figure 1. Example-3 : Preparation of Sotagliflozin Form B

[0082] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Toluene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD as presented in figure 2.

Example-4: Preparation of Sotagliflozin Form B

[0083] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Heptane at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-5 : Preparation of Sotagliflozin Form B

[0084] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Mesitylene at room temperature (20-25°C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-6: Preparation of Sotagliflozin Form B

[0085] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of p-Xylene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-7: Preparation of Sotagliflozin Form C

[0086] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Water at 50°C. The suspension was stirred for 72hrs which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form C has been confirmed by PXRD as presented in figure 3.

Example-8: Preparation of Sotagliflozin Form D

[0087] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of ethanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20 ml vial and left open to allow evaporation of the solvent (25°C/1 atm). Solid was observed after 3 days; it was collected and analyzed by PXRD. Sotagliflozin Form D has been confirmed by PXRD as presented in figure 4.

Example-9: Preparation of Sotagliflozin Form E

[0088] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of isopropyl acetate. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. The crystals were observed after 9 days; it was collected and analyzed by PXRD. Sotagliflozin Form E has been confirmed by PXRD as presented in figure 5.

Example-9: Preparation of Sotagliflozin Form F

[0089] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 2-propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened to allow evaporation of the solvent (4-7°C/l atm). The crystals were observed after 13 days; it was collected and analyzed by PXRD. Sotagliflozin Form F has been confirmed by PXRD as presented in figure 6.

Example- 10: Preparation of Sotagliflozin Form G

[0090] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 1 -propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. Solid was observed after 24 days; it was collected and analyzed by PXRD.

Sotagliflozin Form G has been confirmed by PXRD as presented in figure 7.

Example- 11 : Preparation of Sotagliflozin Form H

[0091] 15 mg of Sotagliflozin (Form- A) was kept in DVS (dynamic vapor sorption) instrument. The kinetic sorption measurement was performed at 25 °C in two full cycle of sorption and desorption as follows, from 40%RH to 90%RH, 90%RH to 0%RH then again from 0% to 90%RH, 90%RH to 0%RH. After completion of experiment, the powder was collected and analyzed by PXRD. Sotagliflozin Form H has been confirmed by PXRD as presented in figure 8.

Example- 12: Preparation of Sotagliflozin Form I [0092] Procedure to prepare saturated solution: 1500 mg of Sotagliflozin were dissolved in 1ml of 2-Methoxyethanol and the solution was stirred overnight at 25°C; the solution was then filtered. Taken ΙΟΟμί from above saturated stock solution, 500μί of Diisopropylether was added drop by drop, no solid was observed left the solution overnight under stirring, added again 500μί of Diisopropylether into the entire solution. The solid was precipitated, stirred for 30min and filtered under vacuum. Sotagliflozin Form I has been confirmed by PXRD as presented in figure 9.

Example-13: Preparation of Sotagliflozin Form K

[0093] 10-20mg of Sotagliflozin (Form D) was kept for drying in a natural air convection oven (MPM instruments modelM40-VN) at 60°C for lh. Sotagliflozin Form K has been confirmed by PXRD as presented in figure 10.

Example-14: Preparation of Sotagliflozin Form E:

[0094] Sotagliflozin (2g) and ethyl acetate (6ml) were heated to reflux temperature (71-74°C). Heptane (6ml) was added at reflux, reaction mass was stirred for additional 15 minutes and then cooled to room temperature. Solid was precipitated out during cooling at about 57°C. A mixture of ethyl acetate and heptane (1 : 1 v/v, 24 ml) was added and the reaction mixture was heated to reflux temperature (71-74°C) to obtain a clear solution which was maintained for 15 minutes. Reaction mass was cooled to room temperature (25-30°C) and stirred for 3 hours. The slurry was filtered, washed with a mixture of ethyl acetate and heptane (l : lv/v, 8ml) and dried under vacuum at 50°C for 2Hrs. The obtained solid (1.8g) was analyzed by PXRD-Form E.

Example-15: Preparation of Sotagliflozin Form D:

[0095] 2g of sotagliflozin Form F was kept in glass petri-dish and exposed to 80%RH for 60hrs at room temperature. Solid was collected (2g) and analyzed for PXRD- Form D.

Example-16: Preparation of Sotagliflozin Form 2:

[0096] 50 gm of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (Methylthio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (SOT-1) and 500ml of methanol were charged in round bottom flask, the slurry was cooled to 20°C then added sodium methoxide solution prepared in methanol (2.45gm of sodium methoxide in 50ml of methanol) at 20°C over the period of 10 min and stirred the mass for 2hr at 20°C.The reaction completion was ensured by HPLC. Once the reaction is completed added 2.5gm Norit carbon to the reaction mass at 23°C and stirred for 30min. Filtered the reaction mass through Hyflo bed and washed with 20ml of methanol. Taken the filtrate into the flask and concentrated under vacuum at 45°C up to 3 volumes with respect to SOT-1 then cooled to 21°C over the period of 60 min, added 560ml of Water at 21°C over the period of 30min and stirred for 30min at 21 °C, the reaction mass left overnight (without stirring) and stirred for lhr. The obtained slurry was filtered under vacuum and washed with 55ml*3times of water then kept for suction at 20- 30°C for 30min. The material was dried at 50-60°C for 9hrs under vacuum to obtain 35gm of Sotagliflozin. 5.7gm of Sotagliflozin (5.7gr, Sotagliflozin) and 28.5ml of Methyl ethyl ketone (28.5ml) were charged in round bottom flask, the slurry was stirred at 22-25°C for 5-10min gradually raised the temperature to 78°C then added 114 ml of n-Heptane (114ml) at 78°C over the period of 55min. Once the addition of n-heptane was completed, seeds of Form-2 (20 mg) were added, the slurry was gradually cooled down to 25-27°C over the period of 60 min. The obtained slurry was stirred for 2-3hrs at 25-27°C and the mass was kept overnight (without stirring) at 25-27°C then stirred for 3hr at 23 °C. The mass was filtered under vacuum and washed with 10ml of n-Heptane then kept for suction for 30min at 25-30°C. The material was dried at 50°C for 2hrs under vacuum to obtain Form-2 of Sotagliflozin.

Preparation of Form 2- Seeds

[0097] Sotagliflozin (2gr, amorphous) was dissolved in methyl ethyl ketone (10ml) The slurry was heated to 80°C, then n-Heptane (40ml) was added over 60mins. The hazy solution was cooled to 20-30° over 60mins and stirred for 3hr. The slurry was kept overnight at 20-30°C (without stirring). The obtained slurry was filtered under vacuum and washed with n-Heptane (10ml) . The material was dried at 50 °C for 4hrs under vacuum to obtain the 1.9gm of Sotagliflozin Form -2 as confirmed by PXRD.