DESC:POLYMORPHIC FORMS OF VERICIGUAT
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 202341044234 filed on June 30, 2023.

BACKGROUND OF THE INVENTION

FIELD OF THE DISCLOUSRE
The present disclosure relates to novel polymorphic forms of vericiguat, in embodiments crystalline polymorphs of vericiguat, processes for preparation thereof.
DESCRIPTION OF THE RELATED ART
Vericiguat is soluble guanylate cyclase (sGC) stimulator and is approved for reducing the risk of cardiovascular death and heart failure (HF) hospitalization. Vericiguat is marketed under the brand name VERQUVO in the U.S. The chemical name of vericiguat is methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate. and molecular formula is C19H16F2N8O2 . The chemical structure of vericiguat is:

Vericiguat disclosed in International Publication No. WO2011/147809A1 (WO ‘809). WO ‘809 also discloses hydrochloride, sulphate, phosphate, mesylate, ethane- 1,2-di sulphonate, maleate and nitrate salts of Vericiguat.

International Publication No. WO2013/076168A1 discloses various crystal forms and solvates designated as modifications modification I, Modification II, Modification III, Modification IV, Modification V, dimethylformamide water solvate, di-dimethyl sulfoxide solvate, tri-acetic acid solvate, monohydrate and dihydrate.

International Publication No. WO2023/034364A1 disclosed different crystalline forms of Vericiguat designated as Form VI, V2, V3, V4, V5, V6, VT1, VT2, VT3, Form VT4 and crystalline forms of Vericiguat hydrochloride designated as Form VTHC11, VTHC12.

Different polymorphs may provide different advantages in a variety of capacities, for example, in ease of formulation, stability of the polymorphic form, stability of the formulation, and in pharmacokinetic profiles. These advantages may arise from the different properties present in each polymorph. The present invention provides novel polymorphic forms of vericiguat and process for the preparation thereof.
SUMMARY OF THE DISCLOSURE

A first aspect of the present invention is to provide crystalline vericiguat Form M1.

Another aspect of the present invention is to provide a process for the preparation of crystalline vericiguat Form M1 comprising the steps of:
a) providing vericiguat in ethyl formate;
b) adding hydrocarbon solvent to the above reaction mixture;
c) heating the reaction mixture to 45-60 °C; and
d) isolating crystalline vericiguat Form M1.

Other aspect of the present invention is to provide a process for the preparation of crystalline vericiguat Form M1 comprising the steps of:
a) suspending vericiguat in ethyl formate;
b) adding hydrocarbon solvent; and
c) isolating crystalline vericiguat Form M1.

A second aspect of the present invention is to provide crystalline vericiguat Form M2.

Another aspect of the present disclosure provides a process for the preparation of crystalline vericiguat Form M2 by drying crystalline vericiguat Form M1.

BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure. 1 is an X-ray powder diffractogram of crystalline vericiguat Form M1.
Figure. 2 is an X-ray powder diffractogram of crystalline vericiguat Form M2.

DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The powder X-ray diffraction patterns of said polymorphs of the invention were measured on a PANalytical X’Pert PRO powder diffractometer equipped with a goniometer of ?/? configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°–50.0°, 0.033° step size and 50 seconds step time.
Within the context of the invention, the term “about” when modifying an absolute measurement, such as time, mass, or volume, is meant to mean the recited value plus or minus 10% of that value. Within the context of the invention, the term “about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees.

The present disclosure relates to crystalline forms of vericiguat. The present disclosure also relates to processes for the preparation of crystalline forms of vericiguat.

In one embodiment, the present disclosure is to provide crystalline vericiguat M1.

In another embodiment, the present disclosure is to provide crystalline vericiguat M1, characterized by Powder X-ray diffraction pattern having 2? angle positions at about
4.6, 7.6, 17.3 ±0.2° degrees two-theta.
In yet another embodiment, crystalline vericiguat M1 is further characterized by Powder X-ray diffraction pattern having 2? angle positions at about 4.6, 7.6, 10.0, 13.7, 14.6, 17.3, 18.4, 20.1, 26.9 ±0.2° degrees two-theta.
In still another embodiment the present invention is to provide a process for the preparation of crystalline vericiguat Form M1 comprising the steps of:
a) providing vericiguat in ethyl formate;
b) adding hydrocarbon solvent to the above reaction mixture;
c) heating the reaction mixture to 45-60 °C; and
d) isolating crystalline vericiguat Form M1.

Within the context of this embodiment, the hydrocarbon solvent employed may include, but not limited to hexane, heptane, cyclohexane, toluene or mixtures thereof. In particular useful embodiments hydrocarbon solvent is heptane.

Within the context of this embodiment, isolation can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation. In particular useful embodiments the solid is isolated by filtration followed by suck-drying.

According to the present disclosure, vericiguat is suspended in ethyl formate and hydrocarbon solvent. The reaction mass is heated to 45-60 °C and stirred for 15-20 hours. The reaction mass filtered and then suck-dried. The obtained solid is crystalline vericiguat Form M1.

Another embodiment of the present invention is to provide a process for the preparation of crystalline vericiguat Form M1 comprising the steps of:
a) suspending vericiguat in ethyl formate;
b) adding hydrocarbon solvent; and
c) isolating crystalline vericiguat Form M1

Within the context of this embodiment, the hydrocarbon solvent employed may include, but not limited to hexane, heptane, cyclohexane, toluene or mixtures thereof. In particular useful embodiments hydrocarbon solvent is heptane.

Within the context of this embodiment, isolation can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation. In particular useful embodiments the solid is isolated by filtration followed by suck-drying.
According to the present disclosure, vericiguat is suspended in ethyl formate at a temperature of about 45-55 °C and stirred. The solution is cooled to 35-40 °C and added hydrocarbon solvent. The reaction mass is filtered and then suck-dried. The obtained solid is crystalline vericiguat Form M1.

In another embodiment, the present disclosure is to provide crystalline vericiguat M2.

Another embodiment, the present disclosure is to provide crystalline vericiguat M2, characterized by Powder X-ray diffraction pattern having 2? angle positions at about 5.0, 7.2, 13.7, 14.9, 16.5, 23.5, 25.5 ±0.2° degrees two-theta.
In yet another embodiment, crystalline vericiguat M2 is further characterized by Powder X-ray diffraction pattern having 2? angle positions at about 5.0, 7.2, 9.9, 10.5, 13.7, 14.9, 16.5, 18.6, 19.9, 21.2, 22.3, 23.5, 27.2, 27.8, 29.1, 32.3 ±0.2° degrees two-theta.
In still another embodiment the present invention is to provide a process for the preparation of crystalline vericiguat Form M2 by drying crystalline vericiguat Form M1.

According to the present disclosure, crystalline vericiguat Form M1 is dried at 100-130 °C under reduced pressure to yield crystalline vericiguat Form M2.

In yet another embodiment, the physical stability of crystalline vericiguat Form M2 was determined by storing the samples at 40 °C/75% relative humidity (RH) and at 25 °C/60% RH conditions for six months and samples were analyzed by PXRD. The results are shown in the below table. The crystalline vericiguat Form M2 was found to be physically stable at 40 °C/75% relative humidity (RH) for six months and at 25 °C/60% relative humidity (RH) conditions up to nine months
Conditions/ Polymorph Crystalline vericiguat Form M2
PXRD
at 40 °C/75% RH
Initial Crystalline
1 month Stable
2 months Stable
3 months Stable
6 months Stable
at 25 °C/60% RH
1 month Stable
2 months Stable
3 months Stable
6 months Stable
9 months Stable

According to the present invention, the input vericiguat is prepared by any prior-art process for example PCT publication No. WO2011/147809A1.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES
Example 1: Crystalline Vericiguat Form M1

Vericiguat (500 mg) was suspended in ethyl formate (5 mL) at 25±5°C and then added heptane (5 mL) at 25±5°C. The reaction mass was heated to 50±2°C and maintained under stirring at 50±2°C for 18 hours. Filtered the reaction mass and suck-dried for 10 minutes. The solid obtained was identified by PXRD as novel crystalline Vericiguat Form M1.
Yield: 470 mg

Example 2: Crystalline Vericiguat Form M1

Vericiguat (1 g) was suspended in ethyl formate (10 mL) at 25±5°C and then added heptane (10 mL) at 25±5°C. The reaction mass was heated to 50±2°C and maintained under stirring at 50±2°C for 18 hours. Filtered the reaction mass and suck-dried for 10 minutes. The solid obtained was identified by PXRD as novel crystalline Vericiguat Form M1.
Yield: 960 mg

Example 3: Crystalline Vericiguat Form M1

Vericiguat (500 mg) was suspended in ethyl formate (5 mL) at 25±5°C. The reaction mass was heated to 50±2°C and maintained under stirring at 50±2°C for 18h. Cooled to 40±2°C and added heptane (5mL) and maintained at 40±2°C for 30minutes. Filtered the reaction mass and suck-dried for 30minutes. The solid obtained was identified by PXRD as novel crystalline Vericiguat Form M1.
Yield: 480 mg

Example 4: Crystalline Vericiguat Form M2

Vericiguat Form M1 (340 mg) obtained as per the above examples was dried at 130°C under vacuum for 60 minutes. The solid obtained was identified by PXRD as novel crystalline Vericiguat Form M2.
Yield: 320mg

Example 5: Crystalline Vericiguat Form M2
Vericiguat Form M1 (100 mg) obtained as per the above examples was dried at 120°C under vacuum for 18 hours. The solid obtained was identified by PXRD as novel crystalline form of vericiguat Form M2.
Yield: 75 mg

Example 6: Crystalline Vericiguat Form M2
Vericiguat Form M1 (100 mg) obtained as per the above examples was dried at 110°C under vacuum for 18 hours. The solid obtained was identified by PXRD as novel crystalline form of vericiguat Form M2.
Yield: 86 mg

Example 7: Crystalline Vericiguat Form M2
Vericiguat (5g) was suspended in ethyl formate (100 mL) at 28±2 °C. The reaction mass was heated to 50±2 °C and maintained under stirring for 18h at 50±2 °C. Filtered the reaction mass, washed with ethyl formate (20 mL) and suck-dried for 20min. Dry the solid at 120 °C for 36h and the solid obtained was identified by PXRD as Vericiguat Form M2.
,CLAIMS:Claims
What is claimed is
1. A crystalline vericiguat sodium Form M1, which has a powder X-ray diffraction pattern having 2? angles positions at about 4.6, 7.6 and 17.3 ±0.2° and characterized by a PXRD pattern as shown in Figure 1.

2. A process for the preparation of crystalline vericiguat Form M1 comprising the steps of:
a) providing vericiguat in ethyl formate;
b) adding hydrocarbon solvent to the above reaction mixture;
c) heating the reaction mixture to 45-60 °C; and
d) isolating crystalline vericiguat Form M1.

3. A process for the preparation of crystalline vericiguat Form M1 comprising the steps of:
a) suspending vericiguat in ethyl formate;
b) adding hydrocarbon solvent; and
c) isolating crystalline vericiguat Form M1.

4. The process as claimed in claim 2 and claim 3, wherein the hydrocarbon solvent is selected from the group consisting of hexane, heptane, cyclohexane, toluene or mixtures thereof.

5. A crystalline vericiguat sodium Form M2, which has a powder X-ray diffraction pattern having 2? angles positions at about 5.0, 7.2, 13.7, 14.9, 16.5, 23.5 and 25.5 ±0.2° and characterized by a PXRD pattern as shown in Figure 2.

6. A process for the preparation of crystalline vericiguat Form M2 by drying crystalline vericiguat Form M1.

7. The process as claimed in claim 6, wherein the step of drying is at about 100 – 130 °C under reduced pressure.