Solid forms of milvexian

Abstract

The present invention relates to the solid forms of Milvexian. The present invention also relates to a process for the preparation of solid forms of Milvexian.

Description

[0001] SOLID FORMS OF MILVEXIAN

[0002] FIELD OF THE INVENTION:

[0003] The present invention relates to the solid forms of Milvexian.

[0004] The present invention also relates to a process for the preparation of solid forms of Milvexian.

[0005] BACKGROUND OF THE INVENTION:

[0006] Milvexian is chemically known as ((67?,10S')-10-[4-[5-Chloro-2-(4-chloro-l / Z-l,2,3-triazol- 1 -yl)phenyl] -6-oxo- 1 (6H)-py ri m i d i ny 1 ] - 1 -(difluoromethyl)- 1 ,4,7 , 8 ,9 , 10-hexahydro-6-methyl-ll,15-metheno-15 / Z-pyrazolo[4,3-Z?][l,7]diazacyclotetradecin-5(6H)-one, having the structure of Formula I,

[0007]

[0008] [Formula I].

[0009] Milvexian has been developed by Bristol-Myers Squibb. Milvexian is a smallmolecule FXIa inhibitor currently in phase III clinical trials and is being developed to prevent and treat thrombotic events.

[0010] U.S. patent number US9453018 first discloses Milvexian and a method of preparation of Milvexian.

[0011] U.S. patent application number US20230151010 discloses amorphous form and crystalline forms of Milvexian namely Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, and Form J.

[0012] U.S. patent application number US20230416252 discloses crystalline Milvexian acetone solvate.Discovering new solid-state forms of a pharmaceutical product may yield 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 polymorphic forms. New solid-state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. 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 (chemical physical stability). For these reasons, there is a significant need for additional solid-state forms of Milvexian.

[0013] OBJECT OF THE INVENTION:

[0014] The main object of the present invention is to provide novel crystalline forms of Milvexian namely, Crystalline form AL1, AL2 and process thereof.

[0015] Another object of the present invention is to provide solvates of Milvexian and process thereof.

[0016] SUMMARY OF INVENTION:

[0017] The main aspect of the present invention is to provide novel crystalline forms of Milvexian designated as AL1, AL2 and process thereof.

[0018] First aspect of the present invention is to provide crystalline Form- AL 1 of Milvexian, characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure- 1. Second aspect of the present invention is to provide crystalline Form-AL2 of Milvexian characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-2.

[0019] Third aspect of the present invention is to provide Milvexian.2-butanol solvate characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-3.Fourth aspect of the present invention is to provide Milvexian.Dimethylsulfoxide solvate characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-4.

[0020] Fifth aspect of the present invention is to provide Milvexian.Isopropyl alcohol solvate characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-5. Sixth aspect of the present invention is to provide Milvexian. Methyl isobutyl ketone solvate characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-6.

[0021] Seventh aspect of the present invention is to provide Milvexian.2-methyltetrahydrofuran solvate characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-7.

[0022] Eighth aspect of the present invention is to provide Milvexian.Methyl acetate solvate. Ninth aspect of the present invention is to provide Milvexian.Tetrahydrofuran solvate. Tenth aspect of the present invention is to provide Milvexian.Dimethyl formamide solvate.

[0023] Eleventh aspect of the present invention is to provide Milvexian. Benzyl alcohol solvate.

[0024] Twelfth aspect of the present invention is to provide Milvexian.Methyl ethyl ketone solvate.

[0025] Thirteenth aspect of the present invention is to provide Milvexian.Isopropyl acetate solvate.

[0026] Fourteenth aspect of the present invention is to provide Milvexian.Toluene solvate. Fifteenth aspect of the present invention is to provide Milvexian. Anisole solvate. Sixteenth aspect of the present invention is to provide Milvexian. tert-amyl alcohol solvate.

[0027] Seventeenth aspect of the present invention is to provide Milvexian. Nitromethane solvate.Eighteenth aspect of the present invention is to provide Milvexian. Methylene dichloride solvate.

[0028] Nineteenth aspect of the present invention is to provide process for the preparation of crystalline Form-ALl of Milvexian comprising the steps of:

[0029] a) treating Milvexian with solvent selected from methylene dichloride, tetrahydrofuran, 1,4-dioxane, tert-butanol or mixture thereof; and

[0030] b) isolating crystalline Form-ALl of Milvexian.

[0031] Twentieth aspect of the present invention is to provide process for the preparation of crystalline Form-AL2 of Milvexian comprising the steps of:

[0032] a) treating Milvexian with nitromethane or nitroethane in presence of ether solvent; and

[0033] b) isolating crystalline Form-AL2 of Milvexian.

[0034] Twenty first aspect of the present invention is to provide a process for the preparation of Milvexian.Solvate of Formula-II,

[0035]

[0036] [Formula-II]

[0037] “Wherein X is selected from 2-butanol, dimethyl sulfoxide, isopropyl alcohol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl acetate, tetrahydrofuran, dimethyl formamide, benzyl alcohol, methyl ethyl ketone, isopropyl acetate, toluene, anisole, tert-amyl alcohol, nitromethane, methylene dichloride or mixture thereof” comprising interacting Milvexian of Formula-I,

[0038]

[0039] [Formula-I]

[0040] with solvent X, wherein solvent X is selected from 2-butanol, dimethyl sulfoxide, isopropyl alcohol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl acetate, tetrahydrofuran, dimethyl formamide, benzyl alcohol, methyl ethyl ketone, isopropyl acetate, toluene, anisole, tert-amyl alcohol, nitromethane, methylene dichloride or mixture thereof.

[0041] BRIEF DESCRIPTION OF DRAWINGS:

[0042] Figure-1: X-ray powder diffractogram (XRPD) of crystalline Form-ALl of Milvexian obtained according to Example 1.

[0043] Figure-2: X-ray powder diffractogram (XRPD) of crystalline Form-AL2 of Milvexian obtained according to Example 2.

[0044] Figure-3: X-ray powder diffractogram (XRPD) of Milvexian.2-butanol solvate obtained according to Example 3.

[0045] Figure-4: X-ray powder diffractogram (XRPD) of Milvexian.Dimethylsulfoxide solvate obtained according to Example 4.

[0046] Figure-5: X-ray powder diffractogram (XRPD) of Milvexian. Isopropyl alcohol solvate obtained according to Example 5.

[0047] Figure-6: X-ray powder diffractogram (XRPD) of Milvexian.Methyl isobutyl ketone solvate obtained according to Example 6.

[0048] Figure-7: X-ray powder diffractogram (XRPD) of Milvexian.2-methyltetrahydrofuran solvate obtained according to Example 7.DETAILED DESCRIPTION OF INVENTION:

[0049] In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.

[0050] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”.

[0051] As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), or are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0052] The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.

[0053] According to first embodiment, the present invention provides crystalline Form-ALl of Milvexian characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure- 1.

[0054] In the first embodiment, crystalline Form-ALl of Milvexian can be characterized by X-ray powder diffraction (XRPD) pattern comprising peak at 4.9, 8.7, 11.0 and 20.5 ± 0.2° 20.

[0055] In the first embodiment, crystalline Form-ALl of Milvexian can be further characterized by X-ray powder diffraction (XRPD) pattern comprising peak 4.9, 8.7, 11.0, 16.4, 16.8, and 20.5 ± 0.2° 20.

[0056] According to second embodiment, the present invention provides crystalline Form-AL2 of Milvexian characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-2.According to third embodiment, the present invention provides Milvexian.2-butanol solvate.

[0057] In the third embodiment, Milvexian.2-butanol solvate can be characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-3.

[0058] In the third embodiment, Milvexian.2-butanol solvate can be obtained according to Example 3.

[0059] According to fourth embodiment, the present invention provides Milvexian.Dimethyl sulfoxide solvate.

[0060] In the fourth embodiment, Milvexian.Dimethyl sulfoxide solvate can be characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-4.

[0061] In the fourth embodiment, Milvexian.Dimethyl sulfoxide solvate can be obtained according to Example 4.

[0062] According to fifth embodiment, the present invention provides Milvexian. Isopropyl alcohol solvate.

[0063] In the fifth embodiment, Milvexian.Isopropyl alcohol solvate can be characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-5.

[0064] In the fifth embodiment, Milvexian.Isopropyl alcohol solvate can be obtained according to Example 5.

[0065] According to sixth embodiment, the present invention provides Milvexian.Methyl isobutyl ketone solvate.

[0066] In the sixth embodiment, Milvexian.Methyl isobutyl ketone solvate can be characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-6. In the sixth embodiment, Milvexian.Methyl isobutyl ketone solvate can be obtained according to Example 6.

[0067] According to seventh embodiment, the present invention provides Milvexian.2-methyltetrahydrofuran solvate.In the seventh embodiment, Milvexian.2-methyltetrahydrofuran solvate can be characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-7. In the seventh embodiment, Milvexian.2-methyltetrahydrofuran solvate can be obtained according to Example 7.

[0068] According to eighth embodiment, the present invention provides Milvexian.Methyl acetate solvate.

[0069] In the eighth embodiment, Milvexian.Methyl acetate solvate can be obtained according to Example 8.

[0070] According to ninth embodiment, the present invention provides Milvexian.Tetrahydro furan solvate.

[0071] In the ninth embodiment, Milvexian.Tetrahydrofuran solvate can be obtained according to Example 9.

[0072] According to tenth embodiment, the present invention provides Milvexian.Dimethyl formamide solvate.

[0073] In the tenth embodiment, Milvexian.Dimethyl formamide solvate can be obtained according to Example 10.

[0074] According to eleventh embodiment, the present invention provides Milvexian.Benzyl alcohol solvate.

[0075] In the eleventh embodiment, Milvexian.Benzyl alcohol can be obtained according to Example 11.

[0076] According to twelfth embodiment, the present invention provides Milvexian.Methyl ethyl ketone solvate.

[0077] In the twelfth embodiment, Milvexian.Methyl ethyl ketone solvate can be obtained according to Example 12.

[0078] According to thirteenth embodiment, the present invention provides Milvexian.Isopropyl acetate solvate.In the thirteenth embodiment, Milvexian.Isopropyl acetate solvate can be obtain according to Example 13.

[0079] According to fourteenth embodiment, the present invention provides Milvexian.Toluene solvate.

[0080] In the fourteenth embodiment, Milvexian.Toluene solvate can be obtained according to Example 14.

[0081] According to fifteenth embodiment, the present invention provides Milvexian.Anisole solvate.

[0082] In the fifteenth embodiment, Milvexian.Anisole solvate can be obtained according to Example 15.

[0083] According to sixteenth embodiment, the present invention provides Milvexian. tertamyl alcohol solvate.

[0084] In the sixteenth embodiment, Milvexian. tert-amyl alcohol solvate can be obtained according to Example 16.

[0085] According to seventeenth embodiment, the present invention provides Milvexian.Nitromethane solvate.

[0086] In the seventeenth embodiment, Milvexian.Nitromethane solvate can be obtained according to Example 17.

[0087] According to eighteenth embodiment, the present invention provides Milvexian. Methylene dichloride solvate.

[0088] In the eighteenth embodiment, Milvexian.Methylene dichloride solvate can be obtained according to Example 18.

[0089] According to nineteenth embodiment, the present invention provides a process for the preparation of crystalline Form-ALl of Milvexian comprising the steps of:

[0090] a) treating Milvexian with solvent selected from methylene dichloride, tetrahydrofuran, 1,4-dioxane, tert-butanol or mixture thereof; andb) isolating crystalline Form-ALl of Milvexian.

[0091] In the nineteenth embodiment, step a) can be carried out by slurry wash or by heatcool method or by solvent-anti solvent method.

[0092] Anti-solvent can be selected from cyclohexane, diisopropyl ether, ethyl acetate, methyl tert-butyl ether, tertiary butyl alcohol, cyclopentyl methyl ether, or mixture thereof.

[0093] In the nineteenth embodiment, crystalline Form-ALl of Milvexian can be isolated by various methods such as cooling, crystallization, evaporation, distillation or by solvent- anti solvent method.

[0094] In the nineteenth embodiment, crystalline Form-ALl of Milvexian can be isolated by filtration and can be dried at a temperature of about 50°C to 160°C.

[0095] In the nineteenth embodiment, crystalline Form-ALl of Milvexian can also be obtained according to Example- 1.

[0096] According to twentieth embodiment, the present invention provides process for the preparation of crystalline Form-AL2 of Milvexian comprising the steps of:

[0097] a) treating Milvexian with nitromethane or nitroethane in presence of ether solvent; and

[0098] b) isolating crystalline Form-AL2 of Milvexian.

[0099] In the twentieth embodiment, ether solvent can be selected from cyclopentyl methyl ether, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran or mixture thereof.

[0100] In the twentieth embodiment, step a) can be carried out by slurry wash or by heat-cool method.

[0101] In the twentieth embodiment, crystalline Form-AL2 of Milvexian can be isolated by filtration and can be dried at a temperature of about 50°C to 160°C.In the twentieth embodiment, crystalline Form-AE2 of Milvexian can be isolated by various methods such as cooling, crystallization, evaporation or distillation.

[0102] In the twentieth embodiment, crystalline Form-AL2 of Milvexian can also be obtained according to Example-2.

[0103] According to twenty first embodiment, the present invention provides a process for the preparation of Milvexian. Solvate of Formula-II,

[0104]

[0105] [Formula-II]

[0106] “Wherein X is selected from 2 -butanol, dimethyl sulfoxide, isopropyl alcohol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl acetate, tetrahydrofuran, dimethyl formamide, benzyl alcohol, methyl ethyl ketone, isopropyl acetate, toluene, anisole, tert-amyl alcohol, nitromethane, methylene dichloride or mixture thereof” comprising interacting Milvexian of Formula-I,

[0107]

[0108] [Formula-I]

[0109] with solvent X, wherein X is selected from 2-butanol, dimethyl sulfoxide, isopropyl alcohol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl acetate, tetrahydrofuran, dimethyl formamide, benzyl alcohol, methyl ethyl ketone, isopropyl acetate, toluene, anisole, tert-amyl alcohol, nitromethane, methylene dichloride or mixture thereof.In the twenty first embodiment of the present invention, interaction of Milvexian with corresponding solvent can be carried out by stirring at temperature of about 20°C to reflux temperature of corresponding used solvent.

[0110] In the twenty first embodiment, respective Milvexian. Solvates can be isolated by filtration and can be dried under Vacuum Tray Drier at a temperature of about 25 °C to 40°C for about 30 minutes to 24 hours.

[0111] In the twenty first embodiment, respective Milvexian.Solvates can be obtain by filtration or slow evaporation at a temperature of about 25 °C to 40°C.

[0112] In the twenty first embodiment, solvates of Milvexian can be obtain according to Example 3 to Example 18.

[0113] The present invention provides a stable crystalline form of AL1 and AL2 at 25°C / 60% relative humidity (RH), 30°C / 65% relative humidity (RH), and 40°C / 75% relative humidity (RH).

[0114] All Powder X-ray Diffraction (PXRD) data reported in present invention are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.

[0115] XRPD Conditions:

[0116]

[0117] While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0118] EXAMPLES:The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

[0119] Example 1: Preparation of Crystalline Form-ALl of Milvexian

[0120] Mixture of Milvexian (1.0 g) and methylene dichloride (16.0 mL) was heated to 40°C. Cyclohexane (64.0 mL) was added to the resulting solution, followed by cooling to 20°C to 25°C. Resulting mixture was stirred for 15 hours. Resulting solid was filtered, dried at 150°C to obtain a titled compound (0.80 g).

[0121] Example 2: Preparation of Crystalline Form-AL2 of Milvexian

[0122] Mixture of Milvexian (0.2 g) and nitromethane (2.0 mL) was heated to 45°C. Methyl tertiary butyl ether (8.0 mL) was added to the resulting solution, followed by cooling to 20°C to 25 °C. Resulting mixture was stirred for 24 hours at same temperature. The obtained solid was filtered, dried at 150°C for 8 hours to obtain a titled compound (0.15 g).

[0123] Example 3: Preparation of Milvexian.2-butanol solvate

[0124] Mixture of Milvexian (0.05 g) and 2-butanol (1.8 mL) was heated to 40°C. Resulting solution left for slow evaporation at 25°C to 30°C to obtain a titled compound (0.03 g)- Example 4: Preparation of Milvexian.Dimethyl sulfoxide solvate

[0125] Mixture of Milvexian (0.2 g) and Dimethyl sulfo xide / Water (1:1, 4.0 mL) stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.16 g).

[0126] Example 5: Preparation of Milvexian.Isopropyl alcohol solvate

[0127] Mixture of Milvexian (1.0 g) and isopropyl alcohol (10.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.78 g).

[0128] Weight loss of Isopropyl alcohol by Thermogravimetric Analysis (TGA): 9%.

[0129] Example 6: Preparation of Milvexian.Methyl isobutyl ketone solvate Mixture of Milvexian (0.5 g) and Methyl isobutyl ketone (5.0 mL) stirred for 24 hoursat 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.14 g).

[0130] Weight loss of Methyl isobutyl ketone by TGA: 15%.

[0131] Example 7: Preparation of Milvexian.2-methyltetrahydrofuran solvate Mixture of Milvexian (0.2 g) and 2 -methyltetrahydrofuran (2.0 mL) stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.16 g).

[0132] Weight loss of 2-methyltetrahydrofuran by TGA: 11%.

[0133] Example 8: Preparation of Milvexian.Methyl acetate solvate

[0134] Mixture of Milvexian (0.2 g) and methyl acetate (2.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 30°C for 12 hours to obtain a titled compound (0.18 g).

[0135] Example 9: Preparation of Milvexian.Tetrahydrofuran solvate

[0136] Mixture of Milvexian (0.2 g) and tetrahydrofuran / water (1:1, 4.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.19 g).

[0137] Example 10: Preparation of Milvexian.Dimethyl formamide solvate

[0138] Mixture of Milvexian (0.2 g) and Dimethyl formamide / water (1:1, 4.0 mL) stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.18g).

[0139] Weight loss of Dimethyl formamide by TGA: 11%.

[0140] Example 11: Preparation of Milvexian.Benzyl alcohol solvate

[0141] Mixture of Milvexian (0.2 g) and benzyl alcohol (1.2 mL) was heated to 45°C. n-heptane (4.8 mL) was added to the resulting solution, followed by slow cooling to 20°C to 25°C. Resulting mixture was stirred for 24 hours at same temperature. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.19 g).Example 12: Preparation of Milvexian.Methyl ethyl ketone solvate

[0142] Mixture of Milvexian (1.0 g) and Methyl ethyl ketone (10.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.92 g).

[0143] Weight loss of Methyl ethyl ketone by TGA: 10%.

[0144] Example 13: Preparation of Milvexian.Isopropyl acetate solvate

[0145] Mixture of Milvexian (1.0 g) and isopropyl acetate (10.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.93 g).

[0146] Weight loss of Isopropyl acetate by TGA: 14%.

[0147] Example 14: Preparation of Milvexian.Toluene solvate

[0148] Mixture of Milvexian (0.5g) and toluene (10.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.40 g).

[0149] Weight loss of Toluene by TGA: 13%.

[0150] Example 15: Preparation of Milvexian. Anisole solvate

[0151] Mixture of Milvexian (0.5 g) and anisole (10.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.42 g).

[0152] Weight loss of Anisole by TGA: 15%.

[0153] Example 16: Preparation of Milvexian. tert-amyl alcohol solvate

[0154] Mixture of Milvexian (0.5g) and tert-amyl alcohol (10.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 12 hours to obtain a titled compound (0.42 g).

[0155] Weight loss of tert-amyl alcohol by TGA: 14%.

[0156] Example 17: Preparation of Milvexian.Nitrome thane solvate

[0157] Mixture of Milvexian (0.2 g) and nitromethane (2.0 mL) was heated to 45°C. Cyclopentyl methyl ether (8.0 mL) was added to the resulting solution, followed byslow cooling to 20°C to 25 °C. Resulting mixture was stirred for 24 hours at same temperature. Resulting solid was filtered, dried at 25 °C to 35 °C for 12 hours to obtain a titled compound.

[0158] Weight loss of Nitromethane by TGA: 12%.

[0159] Example 18: Preparation of Milvexian.Methylene dichloride solvate Mixture of Milvexian (0.2 g) and methylene dichloride (3.2 mL) was heated to 40°C. Resulting solution was left for evaporation at 25°C to 30°C to obtain a titled compound (0.17 g).

[0160] Weight loss of Methylene dichloride by TGA: 15%.

[0161] Example 19: Preparation of Crystalline Form-ALl of Milvexian

[0162] Mixture of Milvexian (0.1 g) and tetrahydrofuran (1.0 mL) was heated to 45°C. Diisopropyl ether (4.0 mL) was added to the resulting solution, followed by slow cooling to 20°C to 25°C. Resulting mixture was stirred for 24 hours at same temperature. Resulting solid was filtered, dried at 25 °C to 35 °C to obtain a titled compound.

[0163] Example 20: Preparation of Crystalline Form-ALl of Milvexian

[0164] Mixture of Milvexian (0.1 g) and 1,4-dioxane (1.4 mL) was heated to 70°C. Ethyl acetate (5.6 mL) was added to the resulting solution, followed by slow cooling to 20°C to 25°C. Resulting mixture was stirred for 24 hours at same temperature. Resulting solid was filtered, dried at 25°C to 35°C to obtain a titled compound (0.08 g)- Example 21: Preparation of Crystalline Form-ALl of Milvexian

[0165] Mixture of Milvexian (0.1 g) and 1,4-dioxane (1.4 mL) was heated 70°C. Methyl tertiary butyl ether (5.6 mL) was added to the resulting solution, followed by slow cooling to 20°C to 25°C. Resulting mixture was stirred for 24 hours at same temperature. Resulting solid was filtered, dried at 25 °C to 35 °C to obtain a titled compound (0.08 g).Example 22: Preparation of Crystalline Form-ALl of Milvexian

[0166] Mixture of Milvexian (0.2 g) and 1,4-dioxane (2.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 4 hours to obtain a titled compound (0.17 g).

[0167] Example 23: Preparation of Crystalline Form-ALl of Milvexian

[0168] Mixture of Milvexian (0.2 g) and tert-butyl alcohol (2.0 mL) was stirred for 24 hours at 25°C to 30°C. Resulting solid was filtered, dried at 25°C to 35°C for 4 hours to obtain a titled compound (0.18 g).

[0169] Example 24: Preparation of Crystalline Form-AL2 of Milvexian

[0170] Mixture of Milvexian (0.2 g) and nitromethane (2.0 mL) was heated to 45°C. Diisopropyl ether (8.0 mL) was added to the resulting solution, followed by slow cooling to 20°C to 25°C. Resulting mixture was stirred for 24 hours at same temperature. Resulting solid was filtered, dried at 150°C to obtain a titled compound (0.17 g).

Claims

We Claim:

1. A crystalline polymorphic Form- AL 1 of Milvexian,[Formula I]characterized by X-ray powder diffraction pattern comprising at least two or more characteristic peaks at 2-theta values selected from the group consisting of 4.9, 8.7, 11.0, 16.4, 16.8, and 20.5 ± 0.2° 20.

2. The process for preparation of crystalline polymorphic form AL1 of Milvexian according to claim 1, wherein the process comprising the steps of:a) treating Milvexian with solvent selected from methylene dichloride, tetrahydrofuran, 1,4-dioxane, tert-butanol or mixture thereof; andb) optionally, adding antisolvent in step (a);c) isolating crystalline Form-ALl of Milvexian.

3. The process according to claim 2, wherein antisolvent used in step b) is selected from cyclohexane, diisopropyl ether, ethyl acetate, methyl tert-butyl ether, tertiary butyl alcohol, cyclopentyl methyl ether, and mixture thereof.

4. A crystalline polymorphic Form-AL2 of Milvexian,[Formula I]characterized by X-ray powder diffraction pattern comprising at least two or more characteristic peaks at 2-theta values selected from the group consisting of 9.04, 11.62, 12.81, 16.66, 18.06, 20.48, 21.26, 21.96, 22.84, 23.96, 25.56, and 30.07 ± 0.2° 20.

5. The process for preparation of crystalline polymorphic form AL2 of Milvexian according to claim 4, wherein the process comprising the steps of:a) treating Milvexian with nitromethane or nitroethane in presence of ether solvent; andb) isolating crystalline Form-AL2 of Milvexian.

6. The process according to claim 5, wherein ether solvent used in step (a) is selected from cyclopentyl methyl ether, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, and mixture thereof.

7. A Milvexian Solvate of Formula- II,[Formula-II]“Wherein X is selected from 2-butanol, dimethyl sulfoxide, isopropyl alcohol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl acetate, tetrahydrofuran, dimethyl formamide, benzyl alcohol, methyl ethyl ketone, isopropyl acetate, toluene, anisole, tert-amyl alcohol, nitromethane, methylene dichloride or mixture thereof”.

8. The process for preparation of Milvexian solvate of the formula-II according to claim 7, wherein the process comprising the steps of:a) comprising interacting Milvexian of Formula-I,[Formula-I]with solvent X, wherein solvent X is selected from 2-butanol, dimethyl sulfoxide, isopropyl alcohol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl acetate, tetrahydrofuran, dimethyl formamide, benzyl alcohol, methyl ethyl ketone, isopropyl acetate, toluene, anisole, tert-amyl alcohol, nitromethane, methylene dichloride or mixture thereof; andb) optionally heating the mixture of step a);c) isolating Milvexian solvate of the formula-II.

Images