DESC:TITLE: SOLID FORMS OF DANUGLIPRON AND PROCESS THEREOF

FIELD OF THE INVENTION
The present application relates to crystalline forms of Danuglipron and processes for preparation thereof. Specifically, the present application relates to crystalline forms of DN1, DN2, DN3 of Danuglipron and processes for preparation thereof. The present application also relates to use of crystalline forms of Danuglipron for the preparation of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.

BACKGROUND OF THE INVENTION
Danuglipron is the adopted name for a drug chemically described as 2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-{[(2 S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid and is represented by structural Formula I.
Formula I
Danuglipron is currently under clinical investigation for the treatment of type 2 diabetes mellitus and obesity.
U.S. patent no. 10208019 B2 discloses Danuglipron and its tris salt (also known as “tris(hydroxymethyl)aminomethane salt”, or “tromethamine salt”)
Journal of Medicinal Chemistry, 2022, 65, 8208-8226 discloses an amorphous Danuglipron and a crystalline Danuglipron tris salt having melting point at 194 ?C.

PCT publication WO 2023/031741 A1 (hereinafter the WO’371 application) discloses solid state forms of Danuglipron tris salt such as crystalline Form 1 and crystalline Form 2 and amorphous.
On the other hand, it is always desirable to develop a pharmaceutical product with Danuglipron which is simple and commercially more viable over tris salt of Danuglipron.
Accordingly, there remains a need to develop stable solid forms of Danuglipron of formula (I).
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods, and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
SUMMARY OF THE INVENTION
One aspect of the present application relates to crystalline Danuglipron.
Another aspect of the present application relates to crystalline Form DN1 of Danuglipron characterized by Powder X-Ray Diffraction (PXRD) pattern having peaks at about 5.7, 9.4, 15.8, 19.0 and 22.3 ± 0.2 ° 2?.
Yet another aspect of the present application relates to crystalline Form DN2 of Danuglipron characterized by PXRD pattern having peaks at about 6.3, 8.2, 8.6, 10.8, 12.0, 12.7, 14.3, 16.5, 17.3, 17.8, 19.2, 20.0 and 23.3 ± 0.2 ° 2?.
Still another aspect of the present application provides crystalline Form DN3 of Danuglipron characterized by Powder X-Ray Diffraction (PXRD) pattern having peaks at about 6.0, 8.1, 13.3, 19.0 ± 0.2 ° 2?.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form DN1 of Danuglipron.
Figure 2 is an illustrative Differential Scanning Calorimetry (DSC) of crystalline Form DN1 of Danuglipron.
Figure 3 is an illustrative Thermogravimetric Calorimetry (TGA) crystalline Form DN1 of Danuglipron
Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form DN2 of Danuglipron.
Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Form DN3 of Danuglipron.
Figure 6 is an illustrative Differential Scanning Calorimetry (DSC) of crystalline Form DN3 of Danuglipron.
Figure 7 is an illustrative Thermogravimetric Calorimetry (TGA) of crystalline Form DN3 of Danuglipron.
Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous form of Danuglipron.
Figure 9 is an illustrative diagram of Transformation between Forms DN1 & DN3.
Figure 10 is an illustrative DVS plot of crystalline Form DN1 of Danuglipron.
DETAILED DESCRIPTION OF INVENTION
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ± 10%, specifically within a range of ± 5%, more specifically within a range of ± 2%, still more specifically within a range of ± 1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, specifically within the range of 9.5 to 10.5, more specifically within the range of 9.8 to 10.2, and still more specifically within the range of 9.9 to 10.1.
The term "crystalline Form" refers to the characterization by the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. It is well known to those skilled in the art that the intensities and peak positions may vary in X-ray diffraction pattern with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In addition, the diffraction angle (2?) generally allows an error of ±0.2 °. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the intensities and peak positions in X-ray diffraction pattern of one crystalline form in the present invention need not be identical to the intensities and peak positions in X-ray diffraction pattern in the examples referred to herein. Any crystalline form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystalline form to verify whether the two sets of maps reflect the same or different crystalline forms.
It should also be understood that other measured values from DSC/TGA experiments, such as endotherm onset and water content etc., can vary as a result of, for example, sample preparation and/or storage and/or environmental conditions, and yet the measured values will still be considered to be representative of a particular crystalline form described herein.
The names used herein to identify a specific form, e.g. “Form DN1” or “Form DN2” or “Form DN3”, should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
The term “treatment” encompasses both treatment and prophylaxis/prevention of diseases or pathologic conditions.
One aspect of the present application relates to crystalline Danuglipron.
One embodiment of the present application relates to crystalline anhydrate Danuglipron. The crystalline anhydrate Danuglipron may have a moisture content less than about 1% w/w.
Another embodiment of the present application relates to crystalline hydrate Danuglipron. The crystalline hydrate Danuglipron may have a moisture content about 8% to about 14% w/w. Specifically, the crystalline hydrate Danuglipron may have a moisture content of about 9% w/w.
One embodiment of the present application relates to the crystalline Danuglipron selected from a group of crystalline Form DN1 of Danuglipron, crystalline Form DN2 of Danuglipron, crystalline Form DN3 of Danuglipron and mixture thereof.
Another embodiment of the present application relates to the crystalline Danuglipron, wherein the crystalline form is crystalline Form DN1 of Danuglipron. Another embodiment of the present application relates to the crystalline Danuglipron, wherein the crystalline form is crystalline Form DN3 of Danuglipron. Yet another embodiment of the present application relates to the crystalline Danuglipron, wherein the crystalline form is a mixture of crystalline Form DN1 and crystalline form DN3 of Danuglipron.
Still another embodiment of the present application relates to use of crystalline Danuglipron for treating a disease for which an agonist of GLP-1 receptor is indicated. In one embodiment, the crystalline Danuglipron is selected from a group of crystalline anhydrate Danuglipron and crystalline hydrate Danuglipron. In another embodiment, the crystalline Danuglipron is selected from a group of crystalline Form DN1 of Danuglipron, crystalline Form DN2 of Danuglipron, crystalline Form DN3 of Danuglipron and mixture thereof. Specifically, the crystalline Danuglipron is used for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.
Another embodiment of the present application relates to use of the crystalline Danuglipron for the manufacture of a medicament for treatment and/or prevention of the diseases mentioned above, specifically Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases. In one embodiment, the crystalline Danuglipron is selected from a group of crystalline anhydrate Danuglipron and crystalline hydrate Danuglipron. In another embodiment, the crystalline Danuglipron is selected from a group of crystalline Form DN1 of Danuglipron, crystalline Form DN2 of Danuglipron, crystalline Form DN3 of Danuglipron and mixture thereof.
Yet another embodiment of the present application relates to use of the crystalline Danuglipron for the manufacture of a pharmaceutical composition comprising Danuglipron. In one embodiment, the crystalline Danuglipron is selected from a group of crystalline anhydrate Danuglipron and crystalline hydrate Danuglipron. In another embodiment, the crystalline Danuglipron is selected from a group of crystalline Form DN1 of Danuglipron, crystalline Form DN2 of Danuglipron, crystalline Form DN3 of Danuglipron and mixture thereof.
Another aspect of the present application relates to a crystalline Form DN1 of Danuglipron characterized by Powder X-Ray Diffraction (PXRD) pattern having peaks at about 5.7, 9.4, 15.8, 19.0 and 22.3 ±0.2 ° 2 ?.
One embodiment of the present application relates to the crystalline Form DN1 of Danuglipron, further characterized by PXRD pattern having additional peaks at about 11.4, 14.6, 16.4, 20.4 and 24.9 ± 0.2 ° 2?.
Another embodiment of the present application relates to a crystalline Form DN1 of Danuglipron, characterized by Powder X-Ray Diffraction (PXRD) pattern having peaks at about 5.7, 9.4, 11.4, 14.6, 15.8, 16.4, 19.0, 20.4, 22.3 and 24.9 ± 0.2 ° 2?.

Still another embodiment of the present application relates to a crystalline Form DN1 of Danuglipron, characterized by PXRD pattern having peaks at about 5.7, 8.9, 9.4, 10.2, 11.4, 12.3, 14.3, 14.6, 15.1, 15.8, 16.4, 17.0, 17.9, 19.0, 19.8, 20.4, 21.0, 21.5, 22.3, 24.9, 26.7, 28.3 and 28.8 ± 0.2 ° 2?.
Yet another embodiment of the present application relates to a crystalline Form DN1 of Danuglipron, characterized by a PXRD pattern substantially as illustrated in Figure-1.
Another embodiment of the present application relates to a crystalline Form DN1 of Danuglipron, characterized by Differential Scanning Calorimetry (DSC) having endotherm onset at about 103 ± 5 °C.
Yet another embodiment of the present application relates to a crystalline Form DN1 of Danuglipron, characterized by Differential Scanning Calorimetry (DSC) as illustrated in Figure-2.
Another embodiment of the present application relates to a crystalline Form DN1 of Danuglipron, characterized by Thermal Gravimetric Analysis (TGA), as illustrated in Figure-3.
The crystalline Form DN1 of Danuglipron may be an anhydrate crystalline form of Danuglipron. The crystalline Form DN1 of Danuglipron may have a moisture content of less than about 1% w/w.
Still another embodiment of the present application relates to a process for preparation of crystalline Form DN1 of Danuglipron, comprising:
a) providing a mixture of Danuglipron in water;
b) isolating the solid;
c) drying the isolated solid.
In embodiments of step-a), the mixture of Danuglipron and water may be prepared at ambient temperature. In embodiments, the mixture obtained in step-a) may optionally be mixed with suitable carboxylate salts such as sodium acetate, potassium acetate, calcium acetate and magnesium acetate and the like. The mixture obtained may be further stirred for 2-24 hours or suitable time till the formation of crystalline Form DN1 of Danuglipron.

In embodiments, isolation of crystalline Form DN1 of Danuglipron may be performed by any technique known in the art. Specifically crystalline Form DN1 of Danuglipron may be isolated from the mixture of step b) by filtration. Optionally, the crystalline Form DN1 may be dried under suitable condition. Drying may suitably be carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80°C. Specifically, the drying may be carried out under vacuum at about 50 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 10 minutes to about 10 hours, or longer.
Another embodiment of the present application relates to a pharmaceutical composition comprising crystalline Form DN1 of Danuglipron and one or more pharmaceutical acceptable excipients.
Yet another embodiment of the present application relates to use of the crystalline Form DN1 of Danuglipron for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.
Still another embodiment of the present application relates to use of the crystalline Form DN1 of Danuglipron for the manufacture of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.
Yet another aspect of the present application relates to a crystalline Form DN2 of Danuglipron characterized by PXRD pattern having peaks at about 6.3, 8.2, 8.6, 10.8, 12.0, 12.7, 14.3, 16.5, 17.3, 17.8, 19.2, 20.0 and 23.3 ± 0.2 ° 2?.
One embodiment of the present application relates to a crystalline Form DN2 of Danuglipron further characterized by a PXRD pattern as substantially as illustrated in Figure-4.
Another embodiment of the present application relates to a process for preparation of a crystalline Form DN2 of Danuglipron comprising:
a) providing a mixture of Danuglipron in 1-propanol;
b) isolating crystalline Form DN2 of Danuglipron.
In embodiments of step-a), the mixture of Danuglipron and 1-propanol may be prepared at 25-30°C. In embodiments, the mixture obtained in step-a) may optionally be mixed with suitable carboxylate salts such as sodium acetate, potassium acetate, calcium acetate and magnesium acetate and the like. In one embodiment, the mixture obtained in step-a) may be mixed with sodium acetate. The mixture obtained further stirred for 2-24 hours or any other suitable time for the formation of crystalline Form DN2 of Danuglipron.
Isolation of crystalline Form DN2 of Danuglipron may be performed by any technique known in the art. Specifically crystalline Form DN2 of Danuglipron may be isolated by filtration. Optionally, the crystalline form DN2 may be dried under suitable condition.
In another embodiment of the present application relates to a pharmaceutical composition comprising a crystalline Form DN2 of Danuglipron and one or more pharmaceutical acceptable excipients.
Yet another embodiment of the present application relates to use of the crystalline Form DN2 of Danuglipron for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.
Still another embodiment of the present application relates to use of the crystalline Form DN2 of Danuglipron for the manufacture of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.
Still another aspect of the present application relates to a crystalline Form DN3 of Danuglipron, characterized by Powder X-Ray Diffraction (PXRD) pattern having peaks at about 6.0, 8.1, 13.3, 19.0 ± 0.2 ° 2?.
One embodiment of the present application relates to the crystalline Form DN3 of Danuglipron, further characterized by PXRD pattern having additional peaks at about. 8.6, 10.8, 12.1, 17.3, 21.2 ± 0.2 ° 2?.
Another embodiment of the present application relates to a crystalline Form DN3 of Danuglipron, characterized by PXRD pattern having peaks at about 6.0, 8.1, 8.6, 10.8, 12.1, 13.3, 17.3, 19.0 and 21.2 ± 0.2 ° 2?.
Still another embodiment of the present application relates to a crystalline Form DN3 of Danuglipron characterized by Powder X-Ray Diffraction (PXRD) pattern having peaks at about 6.0, 8.1, 8.6, 10.8, 11.4, 12.1, 12.9, 13.3, 14.4, 15.1, 16.4, 17.3, 18.0, 18.2, 18.9, 20.7, 21.2, 22.0, 23.6, 24.4, 25.3, 25.9, 26.5, 27.6, and 29.6 ± 0.2 ° 2?.
Yet another embodiment of the present application relates to a crystalline Form DN3 of Danuglipron, characterized by a PXRD pattern substantially as illustrated in Figure-5.
Another embodiment of the present application relates to a crystalline Form DN3 of Danuglipron, characterized by Differential Scanning Calorimetry (DSC) as illustrated in Figure-6.
Still another embodiment of the present application relates to a crystalline Form DN3 of Danuglipron, characterized by Thermal Gravimetric Analysis (TGA), as illustrated in Figure-7.
The crystalline Form DN3 of Danuglipron may be a hydrated crystalline form. The crystalline Form DN3 of Danuglipron may have a moisture content of about 8% w/w to about 14% w/w. Specifically, crystalline Form DN3 of Danuglipron may have a moisture content of about 9% w/w.
One embodiment of the present application relates to a process for the preparation of crystalline Form DN3 of Danuglipron, comprising humidifying of crystalline Form DN1 of Danuglipron under suitable condition.
In embodiments, humidification may be suitably carried out by exposing crystalline Form DN1 of Danuglipron to the atmosphere which is having about more than 50% of relative humidity to about 95% of relative humidity. Specifically, the crystalline Form DN1 of Danuglipron may be exposed from about 60% of relative humidity to about 90% of relative humidity. More specifically, the crystalline Form DN1 of Danuglipron may be exposed from about 75% of relative humidity to about 85% of relative humidity. The humidification may be carried out for a time period from about 1 hour to about 72 hours, or longer. Specifically, the humidification may be carried out for about 48 hours.
Another embodiment of the present application relates to a pharmaceutical composition comprising crystalline Form DN3 of Danuglipron and one or more pharmaceutical acceptable excipients.
Yet another embodiment of the present application relates to use of the crystalline Form DN3 of Danuglipron for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.
Still another embodiment of the present application relates to use of the crystalline Form DN3 of Danuglipron for the manufacture of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH, and cardiovascular diseases.
In the embodiments, crystalline Form DN1 is thermodynamically stable at and below 40% RH and crystalline Form DN3 is thermodynamically stable at and above 60% RH. The same has been illustrated in Figure-9.
In the embodiments, crystalline Form DN3 of Danuglipron is more stable than amorphous form of Danuglipron, as known in the literature.
In the embodiments, crystalline Form DN1 of Danuglipron is more stable than amorphous form of Danuglipron, as known in the literature.
Yet another aspect of the present application relates to a pharmaceutical composition comprising crystalline Danuglipron and one or more pharmaceutically acceptable excipients. The crystalline Danuglipron may be selected from a group of crystalline Form DN1, crystalline Form DN2, crystalline Form DN3 or mixture thereof. Danuglipron crystalline form together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Yet another embodiment of the present application relates to use of the crystalline Form of Danuglipron for treating a disease for which an agonist of GLP-1 receptor is indicated. Specifically, the crystalline Danuglipron is used for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases. Specifically, the crystalline Form DN3 of Danuglipron is used for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases. Alternatively, the crystalline form DN1 of Danuglipron is used for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases. Another embodiment of the present application relates to use of a mixture of crystalline Form DN1 and crystalline Form DN3 of Danuglipron for treating and/or preventing cardiometabolic and associated diseases, including Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases.
Another embodiment of the present application relates to use of the crystalline Danuglipron for the manufacture of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases. Specifically, the crystalline Form DN3 of Danuglipron is used for the manufacture of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases. Alternatively, the crystalline Form DN1 of Danuglipron is used for the manufacture of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases. Yet another embodiment of the present application relates to use of a mixture of crystalline Form DN1 and crystalline Form DN3 of Danuglipron for the manufacture of a medicament for treatment and/or prevention of Type 2 Diabetes Mellitus, pre-diabetes, obesity, NASH and cardiovascular diseases.
All PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer and Bruker D8 advance X-ray Diffractometer with copper Ka radiation.
Differential Scanning Calorimetry (DSC) analysis of crystalline forms of the present application was carried out using a Discovery Series DSC with a heating ramp of 10°C/ minute from 25°C up to 300°C.

TGA analysis of crystalline forms of the present application was carried out in a Discovery Series instrument with a heating ramp of 10°C/minute from 25°C up to 300°C.
High performance liquid chromatography (HPLC) method for the analysis utilizes the following protocol:
Column: YMC Triat C 18 150 X 4.6 mm, 3.0 mm;
Wavelength: 220 nm;
Elution: Gradient;
Diluent: Acetonitrile: water (500:500) v/v;
Mobile Phase-A: Buffer solution (1.36 g of potassium dihydrogen phosphate into 1000 ml of MQ water and pH was adjusted to 6.50 with dilute KOH solution) and acetonitrile in the ratio of 900:100 v/v;
Mobile Phase-B: Mix acetonitrile and Milli W water in the ratio of 800:200 v/v.
DVS was analyzed by the following protocol:
The sample was equilibrated at 0%RH at 25°C for 30 min and then exposed from 0%-90%-0% with step intervals of 10% humidity. At each humidity condition, the sample was either held till wt% change was less than 0.01% or max. of 3 hours.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES

Example-1: Preparation of crystalline Form DN1 of Danuglipron.
A mixture of Danuglipron (100 mg) and water (2 mL) were stirred at 25-30°C. Sodium acetate trihydrate (24 mg) was added to the obtained mixture and stirred for 2 hours at 25-30°C. The obtained material was filtered and then dried at 50°C to afford the title compound.
PXRD of the obtained compound illustrated in Figure-1.

Example-2: Preparation of crystalline Form DN1 of Danuglipron
A mixture of Danuglipron (100 mg) and water (2 mL) were stirred at 25-30°C. Calcium acetate (29 mg) was added to the obtained mixture and stirred for 2 hours at 25-30°C. The obtained material was filtered and then dried at 50°C to afford the title compound.

Example-3: Preparation of crystalline Form DN1 of Danuglipron
A mixture of Danuglipron (100 mg) and water (2 mL) were stirred at 25-30°C. Potassium acetate (18 mg) was added to the obtained mixture and stirred for 2 hours at 25-30°C. The obtained material was filtered and then dried at 50°C to afford the title compound.

Example-4: Preparation of crystalline Form DN1 of Danuglipron
A mixture of Danuglipron (100 mg) and water (1.5 mL) were stirred at 25-30°C. Magnesium acetate tetrahydrate (40 mg) was added to the obtained mixture and stirred for 24 hours at 25-30°C. The obtained material was filtered and then dried at 50°C to afford the title compound.

Example-5: Preparation of crystalline Form DN1 of Danuglipron
Danuglipron tris salt (5 g) was added to water (40 mL), acetic acid (2 ml) and stirred for 1 hour at 25-30°C. The reaction mass was extracted into the organic layer using ethyl acetate (2 x 40 ml). The organic and aqueous layers were separated, and the solvent was distilled off completely from the organic layer. Water (40 ml) was added to the obtained compound at 25-30°C and stirred overnight at same temperature. The obtained material was filtered and dried at 50°C to get the title compound.
DSC: Illustrated in Figure-2.
TGA: Illustrated in Figure-3.
Moisture Content: 0.88% w/w

Example-6: Preparation of crystalline Form DN2 of Danuglipron
A mixture of Danuglipron (100 mg) and 1-propanol (2 mL) were stirred at 25-30°C. Sodium acetate (19 mg) was added to the obtained mixture and stirred for 20 hours at 25-30°C. The obtained material was filtered and then dried to afford the title compound.
PXRD of the obtained compound illustrated in Figure-4.

Example-7: Preparation of crystalline Form DN3 of Danuglipron
Crystalline Form DN1 of Danuglipron (2.6 g) was exposed to relative humidity of 80% for about 48 hours at 25°C to get crystalline Form DN3 of Danuglipron.
Yield: 2.65 g
PXRD of the obtained compound illustrated in Figure-5.
DSC: Illustrated in Figure-6.
TGA: Illustrated in Figure-7.
Moisture Content: 9.06% w/w.

Example-8: Preparation of crystalline Form DN3 of Danuglipron
Crystalline Form DN1 of Danuglipron (1.5 g) was kept in a chamber having relative humidity of about 80% for about 48 hours at 25°C to get crystalline Form DN3 of Danuglipron.

Example-9: Stability of crystalline Form DN1 of Danuglipron
Crystalline Form DN1 of Danuglipron was subjected to stability studies. The sample was kept at 80% RH under open conditions for 24 hours, at 25°C /60% RH under open conditions for 24 hours and at 40/75% RH under open conditions for 24 hours.
Crystalline Form DN1 of Danuglipron was also subjected to photo stability studies. The sample of DN1 was exposed to visible light at 1.2 million lux hours and UV light at 200 watt hours/square meter for 16 hours.

Study PXRD
Initial Form DN1
Hygroscopicity
(80% RH-Open condition for 24 hours) Form DN3
25°C/60% RH-Open condition for 24 hours Form DN3
40°C/75% RH-Open condition for 24 hours Form DN3
Photostability Form DN3

From the above results, it is evident that Form DN1 was converted to Form DN3 at and above 60% RH in open condition at 25°C. Crystalline Form DN1 was also converted to Form DN3 in presence of light.

Example-10: Stability study of crystalline Form DN3 of Danuglipron
Crystalline Form DN3 of Danuglipron was subjected to stability studies. The sample was kept at 80% RH under open conditions for 24 hours, at 25°C /60% RH under open conditions for 24 hours and at 40/75% RH under open conditions for 24 hours.
Crystalline Form DN3 of Danuglipron was also subjected to photo stability studies. The sample of DN3 was exposed to visible light at 1.2 million lux hours and UV light at 200 watt hours/square meter for 16 hours.
Study Purity by HPLC PXRD
Initial 98% Form DN3
Hygroscopicity
(80% RH-Open condition for 24 hours) 98% Form DN3
25°C/60% RH-Open condition for 24 hours 98% Form DN3
40°C/75% RH-Open condition for 24 hours 98% Form DN3
Photostability 97% Form DN3

Crystalline Form DN3 was subjected to long term stability studies at 25°C/60% RH and results are shown as follows:
Parameter Purity by HPLC PXRD
Initial
0 Day 98% Form DN3
1st month
25°C/60%RH-Closed 97% Form DN3
03rd month
25°C/60%RH-Closed 97% Form DN3

From the above results, it is understood that Form DN3 is stable at all above conditions, both chemically and physically.

Example-11: Study of crystalline Form DN3 at low RH conditions
Crystalline Form DN3 (20 mg) was kept at 40% RH at 25°C for about 30 hours. The PXRD revealed that the crystalline Form has been converted to crystalline form DN1.
The results were further corroborated by the DVS of crystalline Form DN1 (Figure-10) during the adsorption and desorption curve.
Figure-9 shows interconversion of crystalline Forms DN1 and DN3 at different RH conditions.

Reference Example-1: Process for the preparation of amorphous form of Danuglipron
Acetic acid (1 ml) was added slowly to a mixture of Danuglipron tris salt (2.5 g) and water (15 ml) at 30°C. The reaction mass was stirred for about 1 hour and extracted with ethyl acetate (2 x 30 ml). The obtained organic layer was dried over sodium sulfate and the solvent was evaporated completely to obtain the title compound.
PXRD: Illustrated in Figure-8
Purity: 93.89% (by HPLC).

Reference Example 2: Stability study of amorphous form of Danuglipron
The amorphous Danuglipron, as obtained in Reference Example 1, was kept at 25°C/60% RH for 1 month in closed condition and the purity was reduced to 92.51% while retaining same PXRD.
Also, amorphous Danuglipron was found to be deliquescent material and absorbed water rapidly from atmosphere to turn to a residue, if left unattended at ambient temperature within 1 hour.
Hence, it was concluded that amorphous Danuglipron is unstable and cannot be used as a Drug Substance for preparation of a pharmaceutical composition comprising Danuglipron.

,CLAIMS:We Claim:
1. A process for preparation of crystalline Form DN1 of Danuglipron comprising:
a) providing a mixture of Danuglipron in water;
b) isolating the solid;
c) drying the isolated solid.

2. The process for preparation of crystalline Form DN1 of Danuglipron, as claimed in claim 1,
wherein the drying is performed under vacuum at about 50 °C.

3. The crystalline Form DN1 of Danuglipron, as claimed in claim 1, is characterized by PXRD peaks at about 11.4, 14.6, 16.4, 20.4 and 24.9 ± 0.2 ° 2?.

4. A process for preparation of crystalline form DN3 of Danuglipron comprising humidifying crystalline Form DN1 of Danuglipron under suitable condition.

5. The process for preparation of crystalline Form DN3 of Danuglipron, as claimed in claim 4,
wherein the humidification is carried out at about 75% of relative humidity to about 85% of relative humidity.

6. The crystalline form DN3 of Danuglipron, as claimed in claim 4, wherein the crystalline Form DN3 of Danuglipron is characterized by PXRD peaks at about 6.0, 8.1, 13.3, 19.0 ± 0.2 ° 2?.

7. A process for preparation of crystalline Form DN2 of Danuglipron comprising:
a) providing a mixture of Danuglipron in 1-propanol;
b) isolating the solid.

8. The crystalline form DN2 of Danuglipron, as claimed in claim 7, wherein the crystalline Form DN2 of Danuglipron is characterized by PXRD peaks at about 6.3, 8.2, 8.6, 10.8, 12.0, 12.7, 14.3, 16.5, 17.3, 17.8, 19.2, 20.0 and 23.3 ± 0.2 ° 2?.

9. Crystalline Danuglipron, as prepared by a process of claims 1-2, 4-5 and 7.