DESC:
FIELD OF THE INVENTION
The present invention relates to a solid form comprising Daprodustat and co-former Nicotinamide.
The present invention also relates to a process for the preparation of solid forms comprising Daprodustat and co-former Nicotinamide.

BACKGROUND OF THE INVENTION
Daprodustat is chemically known as N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine, having Formula I,

[Formula I].
Daprodustat has been developed by GlaxoSmithKline (GSK) and approved by United States Food and Drug Administration (USFDA) on Feb. 01, 2023 under the proprietary name Jesduvroq®. Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anaemia due to chronic kidney disease in adults who have been receiving dialysis for at least four months.
U.S. patent number US8324208 first disclosed Daprodustat.
U.S. patent number US11117871 discloses two crystalline forms of a Daprodustat compound known as crystal form CS1 and crystal form CS9.
U.S. patent application US20210387952 discloses four crystalline forms of Daprodustat namely crystalline Form 1, Form 2, Form 3, and Form 4.
U.S. patent application US20220169619 discloses crystal Form M and Form K of Daprodustat.
Chinese patent application CN115260108 (herein after CN’108) discloses co-crystals of Daprodustat with isoniazid, isonicotine, propionamide, urea, and 3-aminopyridine. CN’108 also discloses tromethamine and piperazine salts of Daprodustat.
Chinese patent application CN116903547 discloses crystalline a-form, ß-form, and ?-form of Daprodustat.
From the analysis of the prior art, although Daprodustat has multiple solid forms, most of the forms have problems such as poor stability, poor solubility, poor flowability or unsuitability for industrial production. Therefore, it is necessary to conduct further investigation of Daprodustat to find a novel solid form which solves problems of prior art like stability, solubility, flowability, which is more suitable for drug product development.
Solid-state modification of Active Pharmaceutical Ingredients (APIs), encompassing various solid forms such as polymorph, amorphous forms, solvates, hydrates, salts, and eutectics has been a focal point for optimizing API physicochemical properties. However, challenges like phase transformation and desolvation/dehydration issues often observed during their stability study. In response to these challenges, pharmaceutical co-crystallization has emerged as a promising strategy to generate a new crystalline form for an API with improved physiochemical properties. Pharmaceutical cocrystal is a non-ionic supramolecular complex with definite stoichiometry, predominantly exist through hydrogen bonds. For pharmaceutical cocrystal one component must be API and second component preferably a Generally Regard as Safe (GRAS) chemical approved by US-FDA. Pharmaceutical cocrystals widely accepted in pharma industry to improve solubility, stability, flowability, compatibility, bioavailability, and other properties for APIs. Accordingly, variation of the solid form comprising Daprodustat and co-former is one way in which physical properties of the Daprodustat can be modulated. It has now been found that new solid form i.e., solid form comprising Daprodustat and co-former Nicotinamide can be obtained which may modulate the properties of Daprodustat as compared to traditional solid forms such as salts, polymorphs, hydrates, solvates etc.

OBJECT OF THE INVENTION
The main object of the present invention is to provide solid form comprising Daprodustat of Formula I and co-former Nicotinamide of Formula II.
Another object of the present invention is to provide an industrially advantageous process for the preparation of solid form comprising Daprodustat of Formula I and co-former Nicotinamide of Formula II.

SUMMARY OF INVENTION
First aspect of the present invention is to provide a solid form comprising Daprodustat of Formula I,

[Formula I]
and co-former Nicotinamide of Formula II,

[Formula II]

Second aspect of the present invention is to provide a co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II.

Third aspect of the present invention is to provide a process for the preparation of solid form comprising Daprodustat of Formula I,

[Formula I]
and co-former Nicotinamide of formula II,

[Formula II]
comprising reacting Daprodustat of Formula I with Nicotinamide of formula II.
Fourth aspect of the present invention is to provide pharmaceutical composition comprising solid form of Daprodustat of Formula I,

[Formula I]
with co-former Nicotinamide of Formula II,

[Formula II]
and a pharmaceutically acceptable excipient or carrier.

Fifth aspect of the present invention is to provide a process for the preparation of co-crystal of Daprodustat with Nicotinamide comprising the steps of:
a) reacting ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)] acetate of Formula III,

[Formula III]
with base to obtained in situ Daprodustat of Formula I;

[Formula I]
b) interacting in situ obtained Daprodustat of Formula I with with co-former Nicotinamide of Formula II,

[Formula II]
to obtain a co-crystal of Daprodustat with Nicotinamide.

BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Illustrates the X-ray powder diffractogram (XRPD) of co-crystal Form-AL1 of Daprodustat of Formula I with Nicotinamide obtained according to example 1.
Figure 2: Illustrates the Differential Scanning Calorimetry (DSC) of co-crystal Form-AL1 of Daprodustat of Formula I with Nicotinamide obtained according to example 1.
Figure 3: Illustrates the Thermogravimetric Analysis (TGA) of co-crystal Form-AL1 of Daprodustat of Formula I with Nicotinamide obtained according to example 1.
Figure 4: Illustrates the X-ray powder diffractogram (XRPD) of co-crystal Form-AL2 of Daprodustat of Formula I with Nicotinamide obtained according to example 2.
Figure 5: Illustrates the X-ray powder diffractogram (XRPD) of co-crystal Form-AL3 of Daprodustat of Formula I with Nicotinamide obtained according to example 3.
Figure 6: Dissolution profile of Daprodustat (Form-CS1) and co-crystal Form-AL1 of Daprodustat of Formula I with Nicotinamide in aqueous media.

DETAILED DESCRIPTION OF INVENTION:
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.
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”. Similarly, the word “another” may mean at least a second or more.
As used in this specification, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
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.
According to first embodiment, the present invention provides a solid form comprising Daprodustat of Formula I,

[Formula I]
and co-former Nicotinamide of Formula II,

[Formula II].
In the first embodiment, Daprodustat of Formula-I used as a starting material can be prepared by process known in the prior art.
According to second embodiment, the present invention provides a co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II.
In the second embodiment, Daprodustat of Formula-I can be interacted with Nicotinamide of Formula II in presence of solvent to obtain co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II.
The solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the second embodiment, Daprodustat of Formula-I can be reacted with Nicotinamide of Formula II at temperature in the range of 30°C to reflux temperature of solvent used. A co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II can be obtained by methods selected from distillation, spray drying or lyophilization.
Resulting solid can be dried below 60°C to obtain co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II.
In the second embodiment, co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II can be Form-AL1, which can be characterized by X-ray powder diffraction (XRPD) peaks at 5.3, 7.7, 14.5, 16.1, 20.0, and 27.3 ± 0.2° 2?.
In the second embodiment, co-crystal Form-AL1 of Daprodustat of Formula I with Nicotinamide of formula II can be further characterized by X-ray powder diffraction (XRPD) peaks at 9.8, 11.9, 17.3, 19.0, and 26.6 ± 0.2° 2?.
In the second embodiment, co-crystal Form-AL1 of Daprodustat of Formula I with Nicotinamide of formula II can be further characterized by DSC having endotherms at about 122°C and 198°C.
In the second embodiment, co-crystal Form-AL1 of Daprodustat of Formula I with Nicotinamide of formula II can be further characterized by TGA as shown in Figure-3.
In the second embodiment, co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II can be Form-AL2, which can be characterized by X-ray powder diffraction (XRPD) peaks at 5.3, 5.7, 6.6, 7.9, and 16.4± 0.2° 2?.
In the second embodiment, co-crystal Form-AL2 of Daprodustat of Formula I with Nicotinamide of formula II can be further characterized by X-ray powder diffraction (XRPD) peaks at 14.6, 17.7, 18.7, 26.4, and 26.9± 0.2° 2?.
In the second embodiment, co-crystal form of Daprodustat of Formula I with Nicotinamide of formula II can be Form-AL3, which can be characterized by X-ray powder diffraction (XRPD) peaks at 6.5, 6.8, 7.5, 9.1, 9.6, and 15.9± 0.2° 2?.
In the second embodiment, co-crystal Form-AL3 of Daprodustat of Formula I with Nicotinamide of formula II can be further characterized by X-ray powder diffraction (XRPD) peaks at 14.7, 15.0, 16.1, 17.0, 17.9, 19.6, 22.0, 27.0, 27.3, and 27.9± 0.2° 2?.
According to third embodiment, the present invention provides a process for the preparation of solid form comprising Daprodustat of Formula I,

[Formula I]
and co-former Nicotinamide of Formula II,

[Formula II]
comprising interacting Daprodustat of Formula I with Nicotinamide of formula II.
In the third embodiment, Daprodustat of Formula-I can be interacted with Nicotinamide of Formula II in presence of solvent.
The solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; aliphatic hydrocarbonssuch as propane, iso-propane, n-butane, n-heptane; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.In the third embodiment, Daprodustat of Formula-I can be reacted with Nicotinamide of Formula II at temperature in the range of 30°C to reflux temperature of solvent used.
After completion of reaction, resulting mixture can be either distilled to obtain a solid form comprising Daprodustat of Formula I and Nicotinamide of formula II or resulting mixture can be cooled at temperature in the range of 0°C to 30°C to obtain a solid, which on further drying below 60°C results into solid form comprising Daprodustat of Formula I and Nicotinamide of formula II.
Alternatively, after completion of reaction, solid form comprising Daprodustat of Formula I and Nicotinamide of formula II can be obtained by methods selected from distillation, slurry, heat-cool of reaction mixture, spray drying or lyophilization.
According to fourth embodiment, the present invention provides pharmaceutical composition comprising solid form of Daprodustat of Formula I,

[Formula I]
with co-former Nicotinamide of Formula II,

[Formula II]
and pharmaceutically acceptable excipient or carrier.
In the fourth embodiment, pharmaceutical composition can be any pharmaceutical form which contains solid forms of the present invention.
In the fourth embodiment, pharmaceutical composition can be solid form such as tablet, powder, capsule, liquid suspension or an injectable.
In the fourth embodiment, dosage forms can be prepared as sustained, controlled, modified, and immediate release dosage forms.
In the fourth embodiment, suitable excipients and the amounts to use can be radially determined by the standard procedures and reference works in the field, e.g., buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents, disintegrates etc.

According to fifth embodiment, the present invention provides a process for the preparation of co-crystal of Daprodustat with Nicotinamide comprising the steps of:
a) reacting ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)] acetate of Formula III,

[Formula III]

with base to obtained in situ Daprodustat of Formula I;

[Formula I]

interacting in situ obtained Daprodustat of Formula I with with co-former Nicotinamide of Formula II,

[Formula II]
to obtained a co-crystal of Daprodustat with Nicotinamide.

In the fifth embodiment, reaction of ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)] acetate of Formula III with base can be carried out in presence of solvent.
In the fifth embodiment, base can be selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or lithium hydroxide; preferably the base is sodium hydroxide.
In the fifth embodiment, solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; aliphatic hydrocarbonssuch as propane, isopropane, n-butane, n-heptane; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.

According to fifth embodiment, co-crystal of Daprodustat with Nicotinamide can be co-crystal forms namely Form-AL1, Form-AL2 or Form-AL3.

Co-crystal Form-AL1 of Daprodustat with nicotinamide as per the present invention is having improved solubility and dissolution against Form-CS1 of Daprodustat as shown in Table-01.

API Name Solubility
(mg/mL) Dissolution at 90min (mg/100mL)
Daprodustat 0.7 3.4
Co-crystal Form-AL1 of Daprodustat with nicotinamide 1.8 19.3
Table-01
Co-crystal Form-AL1 of Daprodustat with nicotinamide is having improved dissolution against Daprodustat (CS1) as shown in figure 6.

Co-crystal Form-AL1 of Daprodustat with nicotinamide as per the present invention is physically stable for at least 3 and 6 months at 25oC/60% relative humidity (RH), 30oC/65% relative humidity (RH), and 40oC/75% relative humidity (RH).

All PXRD data reported in present invention are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.
XRPD Conditions:
Instrument Name X-ray diffractometer
Make & model Malvern PANalytical and Empyrean
Source CuLFF (Long fine focus)
Wavelength 1.5406 A?
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.

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.
Example 01: Preparation of a co-crystal Form-AL1 of Daprodustat with Nicotinamide
Daprodustat (1.0 g) and Nicotinamide (0.31 g) were ground together in a mortar using a pestle and ball mill. Ethanol (0.5 mL) was added followed by further ground for 30 minutes to obtain a title compound.

Example 02: Preparation of a co-crystal Form-AL2 of Daprodustat with Nicotinamide
To a stirred mixture of Daprodustat (5.0 g) and acetone (250 mL), Nicotinamide (1.6 g) was added at 20°C to 30°C. The resulting mixture was heated to 55°C to 60°C for 30 minutes. Resulting mixture was distilled to remove solvent and to obtain a solid. Resulting solid was dried under vacuum at 45°C for 12 hours to obtain the title compound.

Example 03: Preparation of a co-crystal Form-AL3 of Daprodustat with Nicotinamide
To a stirred mixture of Daprodustat (50 g) and ethanol (2.5 L), Nicotinamide (16 g) was added at 20°C to 30°C. The resulting mixture was heated to 65°C to 70°C for 30 minutes. Resulting mixture was distilled to remove solvent to obtain a solid. Resulting solid was dried under vacuum at 60°C for 12 hours to obtain the title compound.

Example 04: Preparation of Daprodustat-Nicotimainde co-crystal (Form-AL1)
To a stirred mixture of ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)]acetate (100.0 g) and water (0.5 L), sodium hydroxide (38.0 g) was added. The resulting mixture was stirred for 3 hours at 85°C to 95°C. After completion of reaction, the reaction mixture cooled to 45°C to 60°C and toluene (0.075 L) was added to the mixture at same temperature. Resulting layers were separated to obtain an organic and aqueous layer. Water (0.8 L) was added to the obtained aqueous layer and filtered through a hyflo bed. Water (0.5 L) and 2-methyltetrahydrofuran (2.5 L) were added to the filtrate and pH was adjusted to below 2 using concentrated hydrochloric acid (116.0 g). The resulting mixture was allowed to separate organic and aqueous layer. Resulting organic layer was washed with purified water and filtered through a hyflo bed. To the resulting filtrate, nicotinamide (34.8 g) was added slowly at 40°C to 45°C and stirred for 1 hour. Resulting mixture was distilled under vacuum at 45° to 50°C. Resulting solid was stirred in presence of n-Heptane. Resulting mixture was filtered and dried under vacuum at 60°C to obtain a title compound (107.0 g) having HPLC purity of 99.83%.

Dated this 31st day of January 2025.

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

I /We claim:
1. A process for preparation of co-crystal of Daprodustat with Nicotinamide comprising the steps of:
a) reacting ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)] acetate of Formula III,

[Formula III]
with base to obtained in situ Daprodustat of Formula I;

[Formula I]
b) interacting in situ obtained Daprodustat of Formula I with with co-former Nicotinamide of Formula II,

[Formula II]
to obtain a co-crystal of Daprodustat with Nicotinamide.
2. The process according to claim 1, wherein reaction of ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)] acetate of Formula III with base can be carried out in presence of solvent.
3. The process according to claim 1, wherein interaction of in situ obtained Daprodustat of Formula I with with co-former Nicotinamide of Formula II,
can be carried out in presence of solvent.
4. The process according to claim 1, wherein base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or lithium hydroxide.
5. The process according to claim 3, wherein solvent is selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; aliphatic hydrocarbonssuch as propane, isopropane, n-butane, n-heptane; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
6. The process according to claim 1, wherein Daprodustat of Formula-I is interacted with Nicotinamide of Formula II at temperature in the range of 30°C to reflux temperature of solvent used.
7. The process according to claim 1, wherein co-crystal of Daprodustat with Nicotinamide is co-crystal Form-AL1, Form-AL2 or Form-AL3.
8. A stable co-crystal Form-AL1 of Daprodustat of Formula I,

[Formula I]
with co-former Nicotinamide of Formula II,

[Formula II]
which is stable at 25oC/60% relative humidity (RH), 30oC/65% relative humidity (RH), and 40oC/75% relative humidity (RH).
9. A stable co-crystal Form-AL1 according to claim-7, wherein Form-AL1 is characterized by X-ray powder diffraction (XRPD) peaks at 5.3, 7.7, 14.5, 16.1, 20.0, and 27.3 ± 0.2° 2?.

Dated this 31st day of January 2025.

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

ABSTRACT

“SOLID FORM OF DAPRODUSTAT WITH NICOTINAMIDE”

The present invention relates to solid form comprising Daprodustat of Formula I,

[Formula I]
and co-former Nicotinamide of Formula II,

[Formula II].

The present invention also relates to a process for the preparation of co-crystal forms of Daprodustat with Nicotinamide.

Dated this 31st day of January 2025.

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 01 of 06

Figure-1

Dated this 31st day of January 2025.

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 02 of 06

Figure-2

Dated this 31st day of January 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 03 of 06

Figure-3

Dated this 31st day of January 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 04 of 06

Figure 4

Dated this 31st day of January 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 05 of 06

Figure 5

Dated this 31st day of January 2025.

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 06 of 06

Figure 6

Dated this 31st day of January 2025.

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.
,CLAIMS:I /We claim:
1. A process for preparation of co-crystal of Daprodustat with Nicotinamide comprising the steps of:
a) reacting ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)] acetate of Formula III,

[Formula III]
with base to obtained in situ Daprodustat of Formula I;

[Formula I]
b) interacting in situ obtained Daprodustat of Formula I with with co-former Nicotinamide of Formula II,

[Formula II]
to obtain a co-crystal of Daprodustat with Nicotinamide.
2. The process according to claim 1, wherein reaction of ethyl 2-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyridimine-5-carboxamido)] acetate of Formula III with base can be carried out in presence of solvent.
3. The process according to claim 1, wherein interaction of in situ obtained Daprodustat of Formula I with with co-former Nicotinamide of Formula II,
can be carried out in presence of solvent.
4. The process according to claim 1, wherein base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or lithium hydroxide.
5. The process according to claim 3, wherein solvent is selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; aliphatic hydrocarbonssuch as propane, isopropane, n-butane, n-heptane; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
6. The process according to claim 1, wherein Daprodustat of Formula-I is interacted with Nicotinamide of Formula II at temperature in the range of 30°C to reflux temperature of solvent used.
7. The process according to claim 1, wherein co-crystal of Daprodustat with Nicotinamide is co-crystal Form-AL1, Form-AL2 or Form-AL3.
8. A stable co-crystal Form-AL1 of Daprodustat of Formula I,

[Formula I]
with co-former Nicotinamide of Formula II,

[Formula II]
which is stable at 25oC/60% relative humidity (RH), 30oC/65% relative humidity (RH), and 40oC/75% relative humidity (RH).
9. A stable co-crystal Form-AL1 according to claim-7, wherein Form-AL1 is characterized by X-ray powder diffraction (XRPD) peaks at 5.3, 7.7, 14.5, 16.1, 20.0, and 27.3 ± 0.2° 2?.

Dated this 31st day of January 2025.

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.