DESC:The present invention provides co-crystal of Ferric maltol and its process for the preparation and pharmaceutical composition thereof.

The drug compound having the adopted name “Ferric maltol” has chemical name 3-hydroxy-2-methyl-4H-pyrane-4-one iron (III) complex (3:1) and has the molecular formula (C6H5O3)3Fe and a molecular mass of 431.2 g/mol. The structure of Ferric maltol is represented in formula I.

Formula (I)
Ferric maltol is developed and marketed by Shield Therapeutics (also known as Iron Therapeutics) as ACCRUFER oral capsules. Accrufer is an iron replacement product indicated for the treatment of iron deficiency in adults.
Ferric maltol has been known since decades. Several literature has disclosed the process for the preparation of Ferric maltol.
WO2016066555A1 patent application described four different crystalline forms of Ferric maltol (Form I, Form II, Form III and Form IV). It also discloses the process for the preparation of those forms. Further, the use of these crystalline forms containing ferric maltol for the preparation of pharmaceutical composition.
US2021/0139518A1 patent application discloses crystalline form alfa of Ferric maltol characterized by PXRD peaks and its process.
However, there remains a need for alternate solid forms of Ferric maltol and preparative processes thereof, exhibiting desired properties such as bioavailability and stability. Hence, it is desirable to provide a viable solid form of Ferric maltol.
Different forms of Active pharmaceutical ingredients (API) in pharmaceutical compositions can be prepared. For example, API may be prepared in amorphous form, crystalline forms, solvate or hydrate and salt form. This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Accordingly, variation of the crystalline state of Ferric maltol is one way in which physical properties of the Ferric maltol can be modulated. It has now been found that new co-crystalline forms of Ferric maltol can be obtained which improve the properties of Ferric maltol as compared to such Ferric maltol in a non-co-crystalline state.

SUMMARY
In the first aspect, the present invention provides a co-crystal of Ferric maltol comprising; Ferric maltol and a co-crystal former.
In the second aspect, the present invention provides a co-crystal of Ferric maltol comprising Ferric maltol and Saccharin.
In the third aspect, the present invention provides a co-crystal of Ferric maltol (crystalline form S1) comprising Ferric maltol and saccharin wherein the co-crystal is characterized by powder X-ray diffraction position at about 5.50, 10.98, 13.04, 14.05, 18.47, 21.79 ±0.2° 2?. In an embodiment, the application provides co-crystal of Ferric maltol with Saccharin is further characterized by PXRD additional peaks at about 8.73, 17.45, 26.80 ±0.2° 2?.

In the fourth aspect, the present invention provides a process for preparation of co-crystal of Ferric maltol (crystalline form S1), comprising;
a) grinding or contacting Ferric maltol with the co-crystal former;
b) optionally drying; and
c) isolating co-crystals of Ferric maltol.
In the fifth aspect, the present invention provides a pharmaceutical composition comprising crystalline form S1 of Ferric maltol or mixtures thereof together with at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction of co-crystal of Ferric maltol with Saccharin prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction of co-crystal of Ferric maltol with Saccharin prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction of co-crystal of Ferric maltol with Saccharin prepared by the method of Example-3.

DETAILED DESCRIPTION
In the first aspect, the present invention provides a co-crystal of Ferric maltol comprising; Ferric maltol and co-crystal former.
The term “co-crystal” as used herein means a crystalline material comprises two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion. The co-crystals of the present invention comprise a co-crystal former hydrogen bonded to Ferric maltol. The additional molecule may be hydrogen bonded to the Ferric maltol or bound ionically or covalently to Ferric maltol. The Ferric maltol and the co-crystal former may have other noncovalent interactions, including p-stacking and van der Waals interactions.
Ferric maltol input material may be in the form of salts, solvates, hydrates,
crystalline or amorphous forms known in the literatures.

The co-crystal former is selected from saccharine, caffeine, adenine, thymine and the like.
The ratio of Ferric maltol to co-crystal former may be stoichiometric or non-stoichiometric according to the present invention. The ratio of Ferric maltol to co-crystal former is from about 1:1 to about 1:5.
In the second aspect, the present invention provides a co-crystal of Ferric maltol comprising Ferric maltol and Saccharin.
The ratio of Ferric maltol to saccharine may be stoichiometric or non-stoichiometric according to the present invention. The ratio of Ferric maltol to co-crystal former is from about 1:1 to about 1:5.
In the third aspect, the present invention provides a co-crystal of Ferric maltol (crystalline form S1) comprising Ferric maltol and saccharin wherein the co-crystal is characterized by powder X-ray diffraction position at about 5.50, 10.98, 13.04, 14.05, 18.47, 21.79 ±0.2° 2?. In an embodiment, the application provides co-crystal of Ferric maltol with Saccharin is further characterized by PXRD additional peaks at about 8.73, 17.45, 26.80 ±0.2° 2?.
In an embodiment, the present application provides co-crystal of Ferric maltol with Saccharin, characterized by a PXRD substantially as shown in Figure 1.
In an embodiment, the present application provides co-crystal of Ferric maltol with Saccharin, characterized by a PXRD substantially as shown in Figure 2.
In an embodiment, the present application provides co-crystal of Ferric maltol with Saccharin, characterized by a PXRD substantially as shown in Figure 3.
In the fourth aspect, the present invention provides a process for preparation of co-crystal of Ferric maltol (crystalline form S1), comprising;
a) grinding or contacting Ferric maltol with the co-crystal former;
b) optionally drying; and
c) isolating co-crystals of Ferric maltol.
The grinding process comprises grinding of Ferric maltol with co-crystal former. Grinding in a mortar involves physical grinding of Ferric maltol and co-crystal. The solvent for grinding process includes but are not limited to: water, aprotic solvents such as ethers which includes tetrahydrofuran, 1,4-dioxane and the like; halogenated hydrocarbon which includes dichloromethane, trichloromethane and the like or mixtures thereof.
The amount of solvent used for grinding is in the range of up to about 40% by weight (w/w). For example, a weight percent of less than or equal to about 1, 2, 3, 4, 5 10, 15, 20, 25, 30 and 35 may be used.
Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
Co-crystal may be formed by contacting the Ferric maltol with the co-crystal former in solution. The process comprises a) dissolving Ferric maltol and the co-crystal former in a suitable solvent; b) cooling the solution and c) isolation of the co-crystal formed.
In the process according to the invention, contacting Ferric maltol with the co-crystal former involves either solubilizing Ferric maltol and adding co-crystal former, or solubilizing co-crystal former and adding Ferric maltol to it.
Suitable solvents which can be used for preparing the solution include but are not limited to water, aprotic solvents such as ethers which includes tetrahydrofuran, 1,4-dioxane and the like; halogenated hydrocarbon which includes dichloromethane, trichloromethane and the like or mixtures thereof.
The dissolution temperatures can range from about 20 to 120° C. depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution is obtained.
For isolation to occur, the reaction mass may be maintained further at temperatures lower than the dissolution temperatures such as for example below about 10° C. to about 25° C., for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete crystallization can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
Optionally isolation may be initiated or enhanced by methods such as cooling, seeding, partial removal of the solvent from the solution, using anti-solvent or a combination thereof.
The method by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as filtration by gravity or by suction, decantation, centrifugation, and the like.
Optionally, the obtained product is further dried. Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like.
Co-crystal may be formed from the slurry by contacting the Ferric maltol with the co-crystal former in solvent. The process comprises a) contacting Ferric maltol and the co-crystal former in a suitable solvent; and b) drying the slurry.
Suitable solvents which can be used for preparing the solution include but are
not limited to water, aprotic solvents such as ethers which includes tetrahydrofuran, 1,4-dioxane and the like; halogenated hydrocarbon which includes dichloromethane, trichloromethane and the like or mixtures thereof.
In the fifth aspect, the present invention provides a pharmaceutical composition comprising crystalline form S1 of Ferric maltol or mixtures thereof together with at least one pharmaceutically acceptable excipient.
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.
Definitions
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%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

EXAMPLES
Example-1: Preparation of co-crystal of Ferric maltol with Saccharin.
Charged 1:3 mole ratio of Ferric maltol: Saccharin (500mg:637mg) in 10 ml ball milling capsule. Ball milled the reaction mixture with 20 frequency for 4.5 hours. Added 0.5 ml of water into the reaction mixture in the capsule. Again started ball milling for the mixture for 1.5 hours with water and unloaded the compound after milling. Checked the PXRD of the resultant solid material.

Example-2: Preparation of co-crystal of Ferric maltol with Saccharin.
Charged 1:1 mole ratio of Ferric maltol: Saccharin (100mg:42.5mg) in mortar. Blended the mixtures together with pestle. Added totally 0.5 ml of water into the mixture in mortar step by step and ground gradually. Ground the reaction mixture for 20 minutes in mortar pestle with water and unloaded the compound from the mortar after grinding. Checked the PXRD of the resultant solid material.

Example-3: Preparation of co-crystal of Ferric maltol with Saccharin.
Charged 1:1 mole ratio of Ferric maltol: Saccharin (100mg:42.5mg) in 10 ml ball milling capsule. Added 0.5 ml of water into the reaction mixture in the capsule. Ball milled the reaction mixture with 20 frequency for one hour with water. After milling unloaded the compound from the capsule. Checked the PXRD of the resultant solid material.
,CLAIMS:1) A co-crystal of Ferric maltol comprising Ferric maltol and co-crystal former.

2) A co-crystal of Ferric maltol comprising Ferric maltol and Saccharin.

3) A co-crystal of Ferric maltol comprising Ferric maltol and Saccharin (crystalline form S1) wherein the co-crystal is characterized by power X-ray diffraction (PXRD) peaks at about 5.50, 10.98, 13.04, 14.05, 18.47, 21.79 ±0.2° 2?.

4) A co-crystal of Ferric maltol comprising Ferric maltol and Saccharin substantially as shown in Figure-1.

5) A process for preparation of co-crystal of Ferric maltol (crystalline form S1), comprising;
a) grinding or contacting Ferric maltol with the co-crystal former;
b) optionally drying; and
c) isolating co-crystals of Ferric maltol.

6) A pharmaceutical composition comprising crystalline form S1 of Ferric maltol or mixtures thereof together with at least one pharmaceutically acceptable excipient.