DESC:SOLID FORMS OF FERRIC MALTOL

INTRODUCTION
The present invention provides co-crystals of Ferric maltol and its process for the preparation and pharmaceutical composition thereof. The present invention also provides amorphous form 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 Urea.
In the third aspect, the present invention provides a co-crystal of Ferric maltol (crystalline form S2) comprising Ferric maltol and Urea wherein the co-crystal is characterized by powder X-ray diffraction position at about 5.45, 12.89, 14.25, 16.44, 22.01, 25.77, 27.62 ± 0.2 2?. In an embodiment, the application provides co-crystal of Ferric maltol with Urea is further characterized by PXRD additional peaks at about 8.72, 21.27, 22.75, 23.38, 34.06 ± 0.2° 2?.

In the fourth aspect, the present invention provides a process for preparation of co-crystal of Ferric maltol (crystalline form S2), comprising;
a) providing/ dissolving urea solution with Ferric maltol;
b) optionally, heating the solution of step a);
c) isolating co-crystals of Ferric maltol (Crystalline form S2).
In the fifth aspect, the present invention provides a co-crystal of Ferric maltol comprising Ferric maltol and potassium carbonate.
In the sixth aspect, the present invention provides a co-crystal of Ferric maltol (crystalline form S3) comprising Ferric maltol and potassium carbonate wherein the co-crystal is characterized by powder X-ray diffraction position at about 12.00, 24.29, 28.72, 30.08, 31.15, 34.14 ± 0.2 2?. In an embodiment, the application provides co-crystal of Ferric maltol with potassium carbonate is further characterized by PXRD additional peaks at about 18.02, 31.81, 36.75, 37.78, 39.19 ± 0.2° 2?.
In the seventh aspect, the present invention provides a process for preparation of co-crystal of Ferric maltol (crystalline form S3), comprising;
a) providing/ dissolving potassium carbonate solution with Ferric maltol;
b) optionally, heating the solution of step a);
c) isolating co-crystals of Ferric maltol (Crystalline form S3).
In the eighth aspect, the present invention provides amorphous form of Ferric maltol.
In the ninth aspect, the present invention provides amorphous form of Ferric maltol which may be characterized by a PXRD pattern substantially as illustrated in Figure-3 and Figure-4.
In the tenth aspect, the present invention provides a process for preparing amorphous form of Ferric maltol comprising:
a) dissolving ferric maltol in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture; and
d) drying the product at suitable temperature.

In the eleventh aspect, the present invention provides a pharmaceutical composition comprising crystalline form S2 of Ferric maltol or crystalline form S3 of Ferric maltol or amorphous form of Ferric maltol 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 Urea prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction of co-crystal of Ferric maltol with Potassium carbonate prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous form of Ferric maltol as prepared by the method of Example-3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous form of Ferric maltol as prepared by the method of Example-4.
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 forms known in the literatures.
The co-crystal former is selected from urea, potassium carbonate, sodium carbonate 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 1:35.
In the second aspect, the present invention provides a co-crystal of Ferric maltol comprising Ferric maltol and Urea.
The ratio of Ferric maltol to Urea 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 1:33.
In the third aspect, the present invention provides a co-crystal of Ferric maltol (crystalline form S2) comprising Ferric maltol and Urea wherein the co-crystal is characterized by powder X-ray diffraction position at about 5.45, 12.89, 14.25, 16.44, 22.01, 25.77, 27.62 ± 0.2 2?. In an embodiment, the application provides co-crystal of Ferric maltol with Urea is further characterized by PXRD additional peaks at about 8.72, 21.27, 22.75, 23.38, 34.06 ± 0.2° 2?.
In an embodiment, the present application provides co-crystal of Ferric maltol with Urea, characterized by a PXRD substantially as shown in Figure 1.
In the fourth aspect, the present invention provides a process for preparation of co-crystal of Ferric maltol (crystalline form S2), comprising;
a) providing/ dissolving urea solution with Ferric maltol;
b) optionally, heating the solution of step a);
c) isolating co-crystals of Ferric maltol (Crystalline form S2).
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 solvent that may be used in step (a) include, but are not limited to water, alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone or the like; ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxy ethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or mixtures thereof.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The temperature at which the above steps may be carried out in between about 20 °C and about 100 °C, preferably at about 25°C and about 50°C.
The isolation of step c) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
Drying in the embodiments of the present invention may be suitably carried out by using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, filtration flask 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 and more specifically less than about 50 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
In the fifth aspect, the present invention provides a co-crystal of Ferric maltol comprising Ferric maltol and potassium carbonate.
The ratio of Ferric maltol to potassium carbonate 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 1:20.
In the sixth aspect, the present invention provides a co-crystal of Ferric maltol (crystalline form S3) comprising Ferric maltol and potassium carbonate wherein the co-crystal is characterized by powder X-ray diffraction position at about 12.00, 24.29, 28.72, 30.08, 31.15, 34.14 ± 0.2 2?. In an embodiment, the application provides co-crystal of Ferric maltol with potassium carbonate is further characterized by PXRD additional peaks at about 18.02, 31.81, 36.75, 37.78, 39.19 ± 0.2° 2?.
In an embodiment, the present application provides co-crystal of Ferric maltol with potassium carbonate, characterized by a PXRD substantially as shown in Figure 2.
In the seventh aspect, the present invention provides a process for preparation of co-crystal of Ferric maltol (crystalline form S3), comprising;
a) providing/ dissolving potassium carbonate solution with Ferric maltol;
b) optionally, heating the solution of step a);
c) isolating co-crystals of Ferric maltol (Crystalline form S3).
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 solvent that may be used in step (a) include, but are not limited to water, alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone or the like; nitriles such as acetonitrile, propionitrile or the like; ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxy ethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or mixtures thereof.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The temperature at which the above steps may be carried out in between about 20 °C and about 100 °C, preferably at about 25°C and about 50°C.
The isolation of step c) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
Drying in the embodiments of the present invention may be suitably carried out by using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, filtration flask 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 and more specifically less than about 50 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
In the eighth aspect, the present invention provides amorphous form of Ferric maltol.
In the ninth aspect, the present invention provides amorphous form of Ferric maltol which may be characterized by a PXRD pattern substantially as illustrated in Figure-3 and Figure-4
In the tenth aspect, the present invention provides a process for preparing amorphous form of Ferric maltol comprising:
a) dissolving ferric maltol in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture; and
d) drying the product at suitable temperature.
Suitable solvents of step a) for dissolving Ferric maltol include, but are not limited to water, alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone or the like; nitriles such as acetonitrile, propionitrile or the like; ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxy ethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or mixtures thereof.
Suitable techniques that may be used for the removal of solvent in step c) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
The isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The resulting solid may be collected by using techniques such as by scraping, or by shaking the container or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous form of Ferric maltol.
The steps of the above embodiment may be performed at a temperature of
about 0°C to about the boiling point of the solvent. Specifically, Ferric maltol may be dissolved in a suitable solvent at a temperature of about 0°C to about 110°C.
In the eleventh aspect, the present invention provides a pharmaceutical composition comprising crystalline form S2 of Ferric maltol or crystalline form S3 of Ferric maltol or amorphous form of Ferric maltol 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.
EXAMPLES
Example-1: Preparation of co-crystal of Ferric maltol with Urea.
Charged 1:33 mole ratio of Ferric maltol: Urea (50mg:200mg) in 2 ml well of HTS block. Added 1 ml of 50:50 Isopropyl alcohol: acetone solvent mixture into the reaction mixture in the well. Slurried the mixture at 30°C for 7 days and unloaded the compound after slurry. Checked the PXRD of the resultant solid material.

Example-2: Preparation of co-crystal of Ferric maltol with Potassium carbonate.
Charged 1:14 mole ratio of Ferric maltol: Potassium Carbonate (50mg:200mg) in 2 ml well of HTS block. Added 1 ml of 50:50 methanol:acetonitrile solvent mixture into the reaction mixture in the well. Slurried the mixture at 30°C for 7 days and unloaded the compound after slurry. Checked the PXRD of the resultant solid material.

Example-3: Preparation of amorphous form of Ferric maltol.
Charged 4 g of Ferric maltol in 500 ml of Methanol in 1000 ml conical flask. Stirred the mixture for 4 hours at RT then clear solution is obtained. Filtered the reaction mixture under vacuum to make particle free. The obtained clear solution was spray dried to get amorphous form of Ferric maltol and it was dried under vacuum at 50°C for 8 hours to get the final product. Checked the PXRD of the resultant solid material.

Example-4: Preparation of amorphous form of Ferric maltol.
Charged 4 g of Ferric maltol in 500 ml of 50:50 THF:water mixture in 1000 ml conical flask. Stirred the mixture for 7 days at RT then clear solution is obtained. Filtered the reaction mixture under vacuum for particle free. The obtained clear solution was spray dried to get amorphous form of Ferric maltol and it was dried under vacuum at 50°C for 10 hours to get the final product. Checked the PXRD of the resultant solid material.

Example-5: Preparation of amorphous form of Ferric maltol.
Charged 150 g of Ferric maltol in 3000 ml of dichloromethane in RB flask. Stirred the reaction mixture for 1-2 hours at RT then clear solution is obtained. Filtered the reaction mixture through hyflow bed at RT to get clear solution. The obtained clear solution was spray dried to get amorphous form of Ferric maltol and it was dried under vacuum at 60°C for 10-12 hours to get the final product. Checked the PXRD of the resultant solid material.
,CLAIMS:1) A co-crystal of Ferric maltol comprising Ferric maltol and Urea.

2) A co-crystal of Ferric maltol comprising Ferric maltol and Urea (crystalline form S2) wherein the co-crystal is characterized by power X-ray diffraction (PXRD) peaks at about 5.45, 12.89, 14.25, 16.44, 22.01, 25.77, 27.62 ± 0.2 2?.

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

4) A process for preparation of co-crystal of Ferric maltol (crystalline form S2), comprising;
a) providing/ dissolving urea solution with Ferric maltol;
b) optionally, heating the solution of step a);
c) isolating co-crystals of Ferric maltol (Crystalline form S2).

5) A co-crystal of Ferric maltol comprising Ferric maltol and potassium carbonate.

6) A co-crystal of Ferric maltol comprising Ferric maltol and potassium carbonate (crystalline form S3) wherein the co-crystal is characterized by power X-ray diffraction (PXRD) peaks at about 12.00, 24.29, 28.72, 30.08, 31.15, 34.14 ± 0.2 2?.

7) A co-crystal of Ferric maltol comprising Ferric maltol and potassium carbonate substantially as shown in Figure-2.

8) A process for preparation of co-crystal of Ferric maltol (crystalline form S3), comprising;
a) providing/ dissolving potassium carbonate solution with Ferric maltol;
b) optionally, heating the solution of step a);
c) isolating co-crystals of Ferric maltol (Crystalline form S3).
9) A process for preparing amorphous form of Ferric maltol comprising:
a) dissolving ferric maltol in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture; and
d) drying the product at suitable temperature.

10) Amorphous form of Ferric maltol of Formula (I) substantially as shown in Figure-4.