Claims:We Claim:
1. A process for the preparation of highly pure Ferric maltol, comprising:
a) providing an aqueous solution of ferric chloride in water at room temperature;
b) adding maltol to the aqueous solution of ferric chloride obtained in step-(a) at room temperature to form a solution;
c) optionally, adding seed crystals of crystalline Form II of Ferric maltol to the solution obtained in step-(b) to produce a reaction mixture;
d) adding an aqueous solution of an inorganic base to the solution of step-(b) or the reaction mixture of step-(c) to produce Ferric maltol as a wet solid;
e) combining the wet solid obtained in step-(d) with water at room temperature to form a suspension;
f) heating the suspension obtained in step-(e) while stirring at a temperature above 40ºC to form a hot slurry;
g) cooling the hot slurry obtained in step-(f) at a temperature of below about 35°C; and
h) collecting the highly pure Ferric maltol obtained in step-(g).

2. The process as claimed in claim 1, wherein the quantity of water employed in step-(a) is about 8 volumes to about 18 volumes with respect to the quantity of Ferric chloride used; wherein the inorganic base used in step-(d) is selected from the group consisting of hydroxides, bicarbonates and carbonates of alkali or alkaline earth metals; wherein the quantity of water employed in step-(e) is about 8 volumes to about 18 volumes with respect to the quantity of Ferric maltol used; wherein the Ferric maltol obtained in step-(h) has a chemical purity of greater than about 99.8% as measured by HPLC; and wherein the highly pure Ferric maltol obtained in step-(h) is a crystalline form.
3. The process as claimed in claim 2, wherein the quantity of water employed in step-(a) is about 14 volumes to about 16 volumes with respect to the quantity of Ferric chloride used; wherein the inorganic base used in step-(d) is sodium carbonate; wherein the quantity of water employed in step-(e) is about 9 volumes to about 12 volumes with respect to the quantity of Ferric maltol used; wherein the Ferric maltol obtained in step-(h) has a chemical purity of about 99.8% to about 99.99% as measured by HPLC; and wherein the crystalline form of highly pure Ferric maltol obtained in step-(h) is Form II.
4. The process as claimed in claim 1, wherein the aqueous solution of ferric chloride in step-(a) is prepared by dissolving Ferric chloride in water while stirring at a temperature of about 25ºC to about 35ºC; wherein the addition of maltol to the aqueous solution of ferric chloride in step-(b) is carried out in one portion or in more than one portion while stirring at a temperature of about 25°C to about 35°C; wherein the addition of an aqueous solution of an inorganic base in step-(d) is carried out while stirring at a temperature of about 25°C to about 35°C; wherein the combining of the Ferric maltol with water in step-(e) is done by adding Ferric maltol to water, or by adding water to the Ferric maltol; wherein the suspension in step-(f) is heated under stirring at a temperature of about 40ºC to about 80ºC for at least 15 hours; wherein the hot slurry in step-(g) is cooled under stirring to a temperature of below about 35ºC for at least 15 minutes; wherein the highly pure Ferric maltol obtained in step-(h) is collected by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; and wherein the highly pure Ferric maltol obtained in step-(h) is further dried at atmospheric pressure or under vacuum at a temperature of about 40°C to about 100°C for a period of about 5 hours to about 30 hours.
5. The process as claimed in claim 4, wherein the resulting mixture obtained after completion of the addition process in the step-(b) is further stirred at a temperature of about 25°C to about 35°C; wherein the addition in step-(e) is carried out at a temperature of about 25ºC to about 35ºC; wherein the suspension in step-(f) is heated under stirring at a temperature of about 40ºC to about 70ºC for about 16 hours to about 40 hours; wherein the hot slurry in step-(g) is cooled under stirring to a temperature of about 20ºC to about 35ºC for about 20 minutes to about 6 hours; and wherein the highly pure Ferric maltol obtained in step-(h) is dried at atmospheric pressure or under vacuum at a temperature of about 70°C to about 80°C for a period of about 10 hours to 20 hours.
6. A process for the preparation of highly pure Ferric maltol, comprising:
(a1) providing an aqueous solution of ferric chloride in water at room temperature;
(b1) adding maltol to the aqueous solution of ferric chloride obtained in step-(a1) at room temperature to form a solution;
(c1) optionally, adding seed crystals of Form II of Ferric maltol to the solution obtained in step-(b1) to produce a reaction mixture;
(d1) adding an aqueous solution of an inorganic base to the solution of step-(b1) or the reaction mixture of step-(c1) to cause crystallization; and
(e1) collecting the highly pure Ferric maltol obtained in step-(d1).

7. The process as claimed in claim 6, wherein the quantity of water employed in step-(a1) is about 8 volumes to about 18 volumes with respect to the quantity of Ferric chloride used; wherein the aqueous solution of ferric chloride in step-(a1) is prepared by dissolving Ferric chloride in water while stirring at a temperature of about 25ºC to about 35ºC; wherein the addition of maltol to the aqueous solution of ferric chloride in step-(b1) is carried out in one portion or in more than one portion while stirring at a temperature of about 25°C to about 35°C; wherein the inorganic base used in step-(d1) is sodium carbonate; wherein the addition of an aqueous solution of an inorganic base in step-(d1) is carried out while stirring at a temperature of about 25°C to about 35°C; and wherein the highly pure crystalline Form II of Ferric maltol obtained in step-(e1) is collected by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

8. A process for the preparation of highly pure crystalline Form II of Ferric maltol, comprising:
(a2) combining Ferric maltol with water at room temperature to form a suspension;
(b2) heating the suspension obtained in step-(a2) while stirring at a temperature above 40ºC to form a hot slurry;
(c2) cooling the hot slurry obtained in step-(b2) at a temperature of below about 35°C; and
(d2) collecting the highly pure crystalline Form II of Ferric maltol essentially free of other crystalline forms obtained in step-(c2).
9. The process as claimed in claim 8, wherein the quantity of water employed in step-(a2) is about 8 volumes to about 18 volumes with respect to the quantity of Ferric maltol used; wherein the combining of the Ferric maltol with water in step-(a2) is done by adding Ferric maltol to water, or by adding water to the Ferric maltol; wherein the suspension in step-(b2) is heated under stirring at a temperature of about 40ºC to about 80ºC for at least 15 hours; wherein the hot slurry in step-(c2) is cooled under stirring to a temperature of below about 35ºC for at least 15 minutes; wherein the highly pure Ferric maltol obtained in step-(d2) is collected by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; wherein the highly pure Ferric maltol obtained in step-(d2) is further dried at atmospheric pressure or under vacuum at a temperature of about 40°C to about 100°C for a period of about 5 hours to about 30 hours; and wherein the crystalline Form II of Ferric maltol obtained in step-(d2) has a chemical purity of greater than about 99.8% as measured by HPLC.
10. The process as claimed in claim 9, wherein the quantity of water employed in step-(a2) is about 9 volumes to about 12 volumes with respect to the quantity of Ferric maltol used; wherein the suspension in step-(b2) is heated under stirring at a temperature of about 40ºC to about 70ºC for about 16 hours to about 40 hours; wherein the hot slurry in step-(c2) is cooled under stirring to a temperature of about 20ºC to about 35ºC for about 20 minutes to about 6 hours; wherein the highly pure crystalline Form II of Ferric maltol obtained in step-(d2) is dried at atmospheric pressure or under vacuum at a temperature of about 70°C to about 80°C for a period of about 10 hours to 20 hours; and wherein the crystalline Form II of Ferric maltol obtained in step-(d2) has a chemical purity of about 99.8% to about 99.99% as measured by HPLC.
11. The process as claimed in claim 8, wherein the highly pure crystalline Form II of Ferric maltol obtained in step-(d2) is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks expressed as 2-theta angle positions at about 8.36, 9.58, 11.82, 12.55, 13.47, 14.55, 15.66, 16.00, 16.30, 16.76, 18.73, 19.26, 19.95, 20.65, 21.21, 21.81, 22.82 and 23.71 ± 0.2 degrees substantially in accordance with Figure 1; an infra-red (IR) spectrum having one or more characteristic bands at about 3444, 3125, 3062, 2958, 2920, 1605, 1569, 1501, 1463, 1276, 1241, 1204, 1087, 1040, 917, 849, 853, 824 and 719 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 293.49°C substantially in accordance with Figure 3.
12. Highly pure Ferric maltol having a chemical purity of greater than about 99.8% as measured by HPLC.
13. The compound as claimed in claim 12, wherein the chemical purity of Ferric maltol is about 99.8% to about 99.99% as measured by HPLC.
14. The compound as claimed in claim 12, wherein the Ferric maltol is in the form of crystalline Form II which is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks expressed as 2-theta angle positions at about 8.36, 9.58, 11.82, 12.55, 13.47, 14.55, 15.66, 16.00, 16.30, 16.76, 18.73, 19.26, 19.95, 20.65, 21.21, 21.81, 22.82 and 23.71 ± 0.2 degrees substantially in accordance with Figure 1; an infra-red (IR) spectrum having one or more characteristic bands at about 3444, 3125, 3062, 2958, 2920, 1605, 1569, 1501, 1463, 1276, 1241, 1204, 1087, 1040, 917, 849, 853, 824 and 719 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 293.49°C substantially in accordance with Figure 3.
15. The compound as claimed in claim 12, wherein the Ferric maltol has the content of maltol in an amount of greater than about 80% (w/w) as measured by HPLC; the content of iron in an amount of greater than 11% (w/w) as measured by UV; and/or the content of acetaldehyde impurity in an amount of less than 20 ppm as measured by GC.
16. The compound as claimed in claim 15, wherein the Ferric maltol has the content of maltol in an amount of greater than about 85% (w/w) as measured by HPLC; the content of iron between about 11% (w/w) to about 13% (w/w) as measured by UV; and/or the content of acetaldehyde impurity in an amount of less than 1 ppm as measured by GC.
17. Highly pure crystalline Form II of Ferric maltol has a D90 particle size of less than or equal to about 200 microns and/or a D50 particle size of less than or equal to about 80 microns.
18. The compound as claimed in claim 17, wherein the crystalline Form II of Ferric maltol has a D90 particle size of about 2 microns to about 150 microns and/or a D50 particle size of about 1 micron to about 70 microns.
19. A pharmaceutical composition comprising highly pure crystalline Form II of Ferric maltol and one or more pharmaceutically acceptable excipients, wherein the crystalline Form II of Ferric maltol has a D90 particle size of less than or equal to about 200 microns and/or a D50 particle size of less than or equal to about 80 microns.
20. The pharmaceutical composition as claimed in claim 19, wherein the crystalline Form II of Ferric maltol has a D90 particle size of about 2 microns to about 150 microns and/or a D50 particle size of about 1 micron to about 70 microns.
, Description:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULES 2003
(SECTION 10 AND RULE 13)

COMPLETE SPECIFICATION

“NOVEL PROCESSES FOR THE PREPARATION OF HIGHLY PURE FERRIC MALTOL AND ITS CRYSTALLINE FORMS”

SYMED LABS LIMITED
An Indian Company having its Office at
8-2-293/174/3, B.N. Reddy Colony,
Road No. 14, Banjara Hills,
Hyderabad-500 034,
Telangana, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASSERTAINS THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to a cost effective, consistently reproducible and industrially advantageous process for the preparation of highly pure Ferric maltol substantially free of genotoxic impurities. The present invention also relates to an improved process for the preparation of stable and highly pure crystalline Form II of Ferric maltol essentially free of other polymorphic forms.
BACKGROUND OF THE INVENTION
Ferric maltol is approved by the United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) as an iron replacement product for the treatment of iron deficiency in adults. The finished product is sold under the trade name Accrufer in the US, Ferracru in Europe and it is orally administered as capsules containing 30 mg iron as Ferric maltol. Ferric maltol contains iron in a stable ferric state as a complex with a trimaltol ligand. Ferric maltol is chemically named as 3-hydroxy-2-methyl-4H-pyrane-4-one iron (III) complex and it is represented by the following structural formula I:

Various processes for the preparation of Ferric maltol and its crystalline forms are described in U.S. Patent No. US 9,802,973 B1; U.S. Patent Application No. US20210139518A1; European Patent No. EP0159917B1; PCT Publication Nos. WO03/097627A1 and WO2012/101442A1; Journal of Chemical Society Dalton Trans. 1988, pages 1159-1163; and Chemistry for Sustainable development 15 (2007) 448-458.
Crystalline form of Ferric maltol along with its characterization data was disclosed in the scientific journal “J. Chem. Soc., Dalton Trans., 1988, 1159-1163” (hereinafter referred to as the JCS’1988 publication). According to the JCS’1988 publication, the crystalline form of Ferric maltol is characterized by the following crystal data: C18H15FeO9, M = 431.2, monoclinic, space group P21/c, a = 7.369(1), b = 14.720(3), c = 19.964(5) Å, β = 100.41(2)º, U = 2098.1Å3, Z = 4, Dc = 1.36g cm-3, Mo-Kα radiation (graphite monochromated), λ = 0.71069 Å, u(Mo-Ka) = 7.07cm-1, F(000) = 884. As per the process described in the JCS’1988 publication, Ferric maltol is prepared by dissolving 3-Hydroxy-2-methyl-4H-pyran-4-one and iron (III) chloride in ethanol-water mixture, raising the pH of the solution to 7.5 using an ammonia solution, removing ethanol in vacuo and then extracting into chloroform, followed by removal of the solvent in vacuo to yield the solid product and then producing the crystals by the slow evaporation of an almost saturated solution in chlorobenzene.
Chemistry for Sustainable development 15, (2007), 448-458 (hereinafter referred to as the CSD’2007 publication) discloses a process for the preparation of Ferric maltol. As per the process described in the CSD’2007 publication, Tris-(3-hydroxy-2-methyl-4-pyronato)iron(III) is prepared by the following process steps: (i) the solution of FeCl3•6H2O in water was added to the solution of maltol in water; (ii) to the resulting dark-red solution (pH 1.8), 2 M NaOH solution (pH 7.2) was added; (iii) the reaction mixture was stirred for 10 minutes, and then evaporated in a rotary evaporator; (iv) the dry residue was extracted with chloroform to remove the inorganic part, which is insoluble in chloroform; (v) the chloroform extract was evaporated to the dry state; (vi) the resulting complex was purified by re-precipitation from methanol to diethyl ether; and (vii) the precipitated small purple crystals were separated by filtering and dried under reduced pressure to produce tris-(3-hydroxy-2-methyl-4-pyronato)iron(III) [Tmelt = 320ºC; Found, %: C 50.01, H 3.92, Fe 12.29].
EP0159917B1 (hereinafter referred to as the EP’917 patent) discloses pharmaceutical compositions containing iron compounds, specifically neutral (i.e., charge balanced) iron (III) maltol complexes, for the treatment of iron deficiency anaemia. As per the process exemplified in Example 1 of the EP’917 patent, Ferric maltol is prepared by mixing chloroform solution of maltol with ethanol solution of 1M Ferric chloride to provide a 3:1 solution of maltol: ferric chloride in the mixture after which 10M excess solid sodium carbonate is added and then stirred for 10 minutes. The reaction mass is filtered and the solvent is evaporated to give the neutral complex containing maltol and the ferric cation in 3:1 proportion. Recrystallization of the 3:1 complex from ethanol gives wine red needle crystals in an essentially quantitative yield, m.p. 275°C, vmax (nujol) 1600 cm-1. The present applicant has conducted experiments for repetition of the process exemplified in Example 1 of the EP’917 patent and found that the XRPD pattern of the resulting sample is matching with the XRPD pattern of Ferric maltol crystalline Form II as reported in Figure 5 of US9802973B2.
WO03/097627A1 (hereinafter referred to as the WO’627 publication) discloses methods of forming ferric trimaltol using ferric citrate, ferrous fumarate and ferrous gluconate.
WO2012/101442A1 discloses a method of forming an iron hydroxypyrone compound comprising reacting a hydroxypyrone with a non-carboxylate iron salt in an aqueous solution and precipitating the iron hydroxypyrone compound from the aqueous solution having a pH of greater than 7, wherein the hydroxypyrone is in an aqueous alkaline solution to which the non-carboxylate salt is added, or wherein the hydroxypyrone is added to an aqueous solution, the solution is heated, the non-carboxylate salt is added to the heated solution and the resulting solution is combined with an aqueous alkaline solution comprising the hydroxypyrone.
U.S. Patent No. 9,802,973 B1 (hereinafter referred to as the US’973 patent), assigned to Shield TX (UK) Limited, discloses four crystalline forms of ferric maltol namely, Form I, Form II, Form III and Form IV, process for their preparation and characterizes the crystalline forms I to IV by X-ray powder diffraction (XRPD), melting point, Differential Scanning Calorimetry (DSC) and Thermo gravimetric Analysis (TGA). The US’973 patent states that Ferric maltol has been known for about 100 years but no polymorphs have been identified or studied prior to the said patent. The US’973 patent discloses methods of forming ferric trimaltol using ferric citrate.
However, the prior art processes suffer from several disadvantages such as lack of reproducibility, formation of genotoxic impurities such as acetaldehyde, low yields and low quality of the product, use of excess quantities of organic solvents, multiple process steps, tedious workup procedures and formation of mixture of crystalline forms. The main drawback of the processes described in the aforementioned prior art literature is that the Ferric Maltol obtained according to the prior art processes contains highly unacceptable amounts of acetaldehyde as an impurity (more than 100 parts per million). Acetaldehyde is a potential genotoxic carcinogen which is difficult to remove from the final API.
It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in Ferric maltol or any active pharmaceutical ingredient (API) are undesirable and might be harmful. Regulatory authorities worldwide require that drug manufacturers isolate, identify and/or characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels.
Hence, a need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing highly pure crystalline Form II of Ferric maltol which is essentially free of other crystalline forms and genotoxic impurities.

SUMMARY OF THE INVENTION
The object of the present invention is to provide a cost effective and consistently reproducible process for the preparation of highly pure Ferric maltol substantially free of genotoxic impurities.
In one aspect, provided herein is a highly pure Ferric maltol substantially free of genotoxic impurities such as acetaldehyde.
Specifically, the highly pure Ferric maltol obtained by the process disclosed herein has acetaldehyde impurity in an amount of less than 20 ppm as measured by GC, more specifically less than 10 ppm as measured by GC, and most specifically less than 1 ppm as measured by GC.
In another aspect, provided herein is a highly pure Ferric maltol essentially free of genotoxic impurities such as acetaldehyde.
As used herein, the term “Ferric maltol essentially free of acetaldehyde impurity” refers to the Ferric maltol contains a non-detectable amount of the acetaldehyde impurity as measured by GC.
In another aspect, provided herein is a simple, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form II of Ferric maltol using water as a solvent.
In another aspect, provided herein is a highly pure crystalline Form II of Ferric maltol essentially free of other crystalline forms.
In another aspect, provided herein is a simple, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form II of Ferric maltol using water as a solvent.
The highly pure crystalline Form II of Ferric maltol obtained by the process disclosed herein is essentially free from other solid state forms of Ferric maltol detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “crystalline Form II of Ferric maltol essentially free of other crystalline forms” means that no other polymorphic forms of Ferric maltol can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Ferric maltol” is intended to mean the polymorphic forms of Ferric maltol other than crystalline Form II.
The processes for the preparation of Ferric maltol described in the present invention have the following advantages over the processes described in the prior art:
i) the process produces the Ferric maltol with high purity and quality which is substantially and/or essentially free of genotoxic impurities such as acetaldehyde;
ii) the process involves the use of water as a solvent;
iii) the process avoids the use of toxic, flammable and/or expensive organic solvents such as chloroform, methanol, ethanol and diethyl ether;
iv) the process consistently produces the crystalline Form II of Ferric maltol with high chemical and polymorphic purity; and
v) the process involves the use of easy work-up procedures and simple isolation methods and produces the product with good yield.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form II of Ferric maltol.
Figure 2 is a characteristic Infra-red (IR) spectrum of crystalline Form II of Ferric maltol.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form II of Ferric maltol.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of highly pure Ferric maltol, comprising:
a) providing an aqueous solution of ferric chloride in water at room temperature;
b) adding maltol to the aqueous solution of ferric chloride obtained in step-(a) at room temperature to form a solution;
c) optionally, adding seed crystals of Form II of Ferric maltol to the solution obtained in step-(b) at room temperature to produce a reaction mixture;
d) adding an aqueous solution of an inorganic base to the solution of step-(b) or the reaction mixture of step-(c) to produce Ferric maltol as a wet solid;
e) combining the Ferric maltol obtained in step-(d) with water at room temperature to form a suspension;
f) heating the suspension obtained in step-(e) while stirring at a temperature above 40ºC to form a hot slurry;
g) cooling the hot slurry obtained in step-(f) at a temperature of below about 35°C; and
h) collecting the highly pure Ferric maltol obtained in step-(g).
The highly pure Ferric maltol obtained by the process disclosed herein has a chemical purity of greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.98% as measured by HPLC. For example, the chemical purity of the highly pure Ferric maltol obtained by the processes disclosed herein is about 99.8% to about 99.99% as measured by HPLC.
As used herein, the term “room temperature” refers to a temperature of about 20ºC to about 37ºC, specifically refers to a temperature of about 25ºC to about 35ºC, and most specifically refers to a temperature of about 25ºC to about 30ºC.
The present inventors have surprisingly and unexpectedly found that the quantity of water used for dissolving Ferric chloride in step-(a) and the addition of maltol directly in the form of a solid (crystalline powder) to the aqueous ferric chloride solution in step-(b) are the important parameters, which avoid the formation of lumps and unwanted impurities, for producing highly pure Ferric maltol.
In one embodiment, the quantity of water employed in step-(a) is about 8 volumes to about 18 volumes, specifically about 10 volumes to about 17 volumes, and most specifically about 14 volumes to about 16 volumes, with respect to the quantity of Ferric chloride used.
In another embodiment, the aqueous solution of ferric chloride in step-(a) is prepared by dissolving ferric chloride in water while stirring at a temperature below about 35ºC, specifically at a temperature of about 20ºC to about 35ºC, and most specifically at a temperature of about 25ºC to about 35ºC.
In another embodiment, the addition of maltol to the aqueous solution of ferric chloride in step-(b) is carried out in one portion or in more than one portion while stirring at a temperature of about 25°C to about 35°C. After completion of the addition process, the resulting mixture is stirred at a temperature of about 25°C to about 35°C for at least 5 minutes, and most specifically for about 10 minutes to about 50 minutes, to form a solution.
Specifically, the addition of seed crystals of Ferric maltol crystalline Form II to the solution in step-(c) is carried out under stirring at a temperature of about 25°C to about 35°C. The seeding material of Ferric maltol crystalline Form II may be prepared as per the process exemplified in Example 1 of EP0159917B1, or as per the processes described in the present invention.
The inorganic base used in step-(d) includes, but is not limited to, hydroxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specifically, the inorganic base used in step-(d) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and mixtures thereof. A most preferable inorganic base is sodium carbonate.
In one embodiment, the sodium carbonate is used in the form of an aqueous solution.
Specifically, the addition of aqueous solution of an inorganic base to the solution or the reaction mixture in step-(d) is carried out while stirring at a temperature of about 25°C to about 35°C. After completion of the addition process in step-(d), the resulting mass is stirred at a temperature of about 25°C to about 35°C for at least 30 minutes, more specifically for about 1 hour to about 10 hours, and most specifically for about 3 hours to about 5 hours to obtain Ferric maltol.
In another embodiment, the Ferric maltol formed in step-(d) is collected by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
Combining of the Ferric maltol with water in step-(e) is done in a suitable order, for example, the Ferric maltol is added to water, or alternatively, water is added to the Ferric maltol. The addition of water is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at the room temperature, and most specifically at a temperature of about 25ºC to about 35ºC.
In one embodiment, the quantity of water employed in step-(e) is about 8 volumes to about 18 volumes, and specifically about 9 volumes to about 12 volumes, with respect to the quantity of Ferric maltol used.
In another embodiment, the suspension in step-(f) is heated under stirring at a temperature of about 40ºC to about 80ºC for at least 15 hours, specifically at a temperature of about 40ºC to about 70ºC for about 16 hours to about 40 hours, and most specifically at a temperature of about 40ºC to about 60ºC for about 20 hours to about 25 hours.
In another embodiment, the hot slurry in step-(g) is cooled under stirring to a temperature of below about 35ºC for at least 15 minutes, specifically at a temperature of about 20ºC to about 35ºC for about 20 minutes to about 6 hours, and specifically at a temperature of about 25ºC to about 35ºC for about 30 minutes to about 3 hours.
The collection of the highly pure Ferric maltol in step-(h) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
The highly pure Ferric maltol obtained in the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or under vacuum at a temperature of about 40°C to about 100°C, and most preferably at a temperature of about 70°C to about 80°C. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 5 hours to about 30 hours, and more preferably about 10 hours to about 20 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
In one embodiment, the highly pure Ferric maltol obtained in the above process step-(h) is a crystalline form. In another embodiment, the crystalline form of highly pure Ferric maltol obtained in step-(h) is crystalline Form II.
According to another aspect, there is provided a process for the preparation of highly pure Ferric maltol, comprising:
(a1) providing an aqueous solution of ferric chloride in water at room temperature;
(b1) adding maltol to the aqueous solution of ferric chloride obtained in step-(a1) at room temperature to form a solution;
(c1) optionally, adding seed crystals of Form II of Ferric maltol to the solution obtained in step-(b1) to produce a reaction mixture;
(d1) adding an aqueous solution of an inorganic base to the solution of step-(b1) or the reaction mixture of step-(c1) to cause crystallization; and
(e1) collecting the highly pure Ferric maltol obtained in step-(d1).
The preparation of the highly pure Ferric maltol as described in the above process steps-(a1) to (e1) can be carried out as per the methods, parameters and conditions as described in the preceding process steps (a) to (d) and (h) respectively.
According to another aspect, there is provided a process for the preparation of highly pure crystalline Form II of Ferric maltol, comprising:
(a2) combining Ferric maltol with water at room temperature to form a suspension;
(b2) heating the suspension obtained in step-(a2) while stirring at a temperature above 40ºC to form a hot slurry;
(c2) cooling the hot slurry obtained in step-(b2) at a temperature of below about 35°C; and
(d2) collecting the highly pure crystalline Form II of Ferric maltol essentially free of other crystalline forms obtained in step-(c2).
The highly pure crystalline Form II of Ferric maltol obtained by the process disclosed herein has a chemical purity of greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.98% as measured by HPLC. For example, the chemical purity of the highly pure crystalline Form II of Ferric maltol obtained by the processes disclosed herein is about 99% to about 99.99% as measured by HPLC.
In one embodiment, the quantity of water employed in step-(a2) is about 8 volumes to about 18 volumes, and specifically about 9 volumes to about 12 volumes, with respect to the quantity of Ferric maltol used.
Combining of the Ferric maltol with water in step-(a2) is done in a suitable order, for example, the Ferric maltol is added to water, or alternatively, water is added to the Ferric maltol. The addition of water is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at the room temperature, and most specifically at a temperature of about 25ºC to about 35ºC.
In another embodiment, the suspension in step-(b2) is heated under stirring at a temperature of about 40ºC to about 80ºC for at least 15 hours, specifically at a temperature of about 40ºC to about 70ºC for about 16 hours to about 40 hours, and most specifically at a temperature of about 40ºC to about 60ºC for about 20 hours to about 25 hours.
In another embodiment, the hot slurry in step-(c2) is cooled under stirring to a temperature of below about 35ºC for at least 15 minutes, specifically at a temperature of about 20ºC to about 35ºC for about 20 minutes to about 6 hours, and more specifically at a temperature of about 25ºC to about 35ºC for about 30 minutes to about 3 hours.
The collection of the highly pure crystalline Form II of Ferric maltol essentially free of other crystalline forms in step-(d2) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
The highly pure crystalline Form II of Ferric maltol obtained by the above process may be further dried by the methods or techniques as described hereinabove. In one embodiment, the drying is carried out at atmospheric pressure or under vacuum at a temperature of about 40°C to about 100°C, and most preferably at a temperature of about 70°C to about 80°C. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 5 hours to about 30 hours, and more preferably about 10 hours to about 20 hours.
In one embodiment, the crystalline Form II of Ferric maltol obtained by the processes described herein is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks expressed as 2-theta angle positions at about 8.36, 9.58, 11.82, 12.55, 13.47, 14.55, 15.66, 16.00, 16.30, 16.76, 18.73, 19.26, 19.95, 20.65, 21.21, 21.81, 22.82 and 23.71 ± 0.2 degrees substantially in accordance with Figure 1; an infra-red (IR) spectrum having one or more characteristic bands at about 3444, 3125, 3062, 2958, 2920, 1605, 1569, 1501, 1463, 1276, 1241, 1204, 1087, 1040, 917, 849, 853, 824 and 719 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 293.49°C substantially in accordance with Figure 3.
The processes disclosed herein above advantageously produces the crystalline Form II of Ferric maltol with high chemical and polymorphic purity.
In another aspect, the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein is substantially free of acetaldehyde impurity.
In one embodiment, the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein has the content of acetaldehyde impurity in an amount of less than 20 ppm as measured by GC, specifically less than 10 ppm as measured by GC, and more specifically less than 1 ppm as measured by GC.
In another embodiment, the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein is essentially free of acetaldehyde impurity.
In another aspect, the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein has maltol content of greater than about 80% (w/w), specifically greater than about 85% (w/w), and most specifically greater than about 89% (w/w) as measured by HPLC.
In another aspect, the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein has iron content of greater than 11% (w/w), specifically greater than about 12% (w/w), and most specifically between about 11% (w/w) to about 13% (w/w) as measured by UV.
The highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form II of Ferric maltol obtained by the processes disclosed herein exhibits properties making it suitable for formulating Ferric maltol.
Further encompassed herein is the use of the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In another aspect, the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, made by the process disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 2 microns to about 150 microns, and most specifically about 5 microns to about 80 microns.
In another aspect, the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, made by the process disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 80 microns, specifically about 1 micron to about 70 microns, and most specifically about 4 microns to about 20 microns.
According to another aspect, there is provided a pharmaceutical composition comprising highly pure crystalline Form II of Ferric maltol and one or more pharmaceutically acceptable excipients, wherein the crystalline Form II of Ferric maltol has a D90 particle size of less than or equal to about 200 microns, specifically about 2 microns to about 150 microns, and most specifically about 5 microns to about 80 microns.
According to another aspect, there is provided a pharmaceutical composition comprising highly pure crystalline Form II of Ferric maltol and one or more pharmaceutically acceptable excipients, wherein the crystalline Form II of Ferric maltol has a D50 particle size of less than or equal to about 80 microns, specifically about 1 micron to about 70 microns, and most specifically about 4 microns to about 20 microns.
In another embodiment, the particle sizes of the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “μm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups, etc. Dosage forms may be adapted for administration to the patient by oral, buccal or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, suspensions, powders and the like.
In a most preferred embodiment, the pharmaceutical composition comprising the highly pure Ferric maltol, or the highly pure crystalline Form II of Ferric maltol, obtained by the processes disclosed herein is orally administered as capsules containing 30 mg iron as Ferric maltol.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Kα radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees 2-theta per step and a step time of 0.8 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 350°C.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.

HPLC Method for measuring Maltol content:
The maltol content was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Kromasil C18, (250 × 4.6) mm; 5µm; Detector wavelength = 274 nm; Flow Rate = 0.8 ml/minute; Injection volume = 10 μL; Oven temperature = 30°C; Run time = 20 minutes; Diluent = A mixture Water : Methanol (70:30, v/v); Elution = Isocratic; and Sample Concentration: 0.1 mg/ml. Mobile Phase: A mixture of buffer : Methanol (70:30, v/v).
UV Spectroscopy method for Iron content:
The Iron content was measured by UV spectroscopy with UV 3000 + model (Lab India Make) under the following conditions: Detector wavelength = 540 nm; Cell dimensions: 1 cm2; Diluent = concentrated hydrochloric acid and water.
GC Method for Acetaldehyde content:
The acetaldehyde content was measured by GC with FID under the following conditions: Column Name = DB-624 (60 m x 0.53mm x 3.0µm) or Equivalent; Injector Temperature = 170ºC; Detector Temperature = 260ºC (FID); Column flow (Nitrogen) = 3.0 mL/min (Constant flow); Split Ratio = 1:2; Run time: 25.0 min; and Injection volume: 2.0µL.
Particle Size Method of Analysis (PSD):
Particle Size Distribution (PSD) is determined by laser diffraction in a Malvern Mastersizer 3000 (Ver. 3.63) equipment or its equivalent under the following conditions: Accessory Name = Aero S; Dispersant = Dry dispersion; Dispersant Refractive Index = 1; Absorption = 0.01; Obscuration limit = 0.5% to 8%; Measurement time = 10 seconds; Background time = 10 seconds.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of highly pure Ferric maltol crystalline Form II
Step-1: Preparation of Ferric maltol (Tech)
Ferric chloride (35 g) was added to water (525 ml) at 25-35ºC and the resulting mixture was stirred for 10-15 minutes at the same temperature to form a clear solution. The resulting ferric chloride solution was filtered at 25-35ºC and washed with water (100 ml). To the resulting filtrate, Maltol (101 g) was added at 25-35ºC and then stirred the mixture for 20-30 minutes at the same temperature to form a solution. To the resulting solution, seeding material of crystalline Form II (4.0 g, prepared as per the process exemplified in Example 1 of EP0159917B1) was added under stirring, followed by slow addition of sodium carbonate solution (prepared by dissolving 106 g of sodium carbonate in 350 ml of water) at 25-35ºC for about 30-40 minutes, and then stirring the mass for 3-4 hours at the same temperature. The solid obtained was filtered, washed with water (70 ml) and then suck dried for 20-30 minutes to produce Ferric maltol as a wet solid [wet weight: 90 g].
Step-2: Preparation of highly pure Ferric maltol Crystalline Form II
Water (900 ml) was added to the resulting wet solid (obtained in Step-1) at 25-35ºC, the mixture was heated to 40-45ºC under stirring and the resulting hot slurry was maintained under stirring for 20-22 hours at 40-45ºC. The resulting mass was cooled to 25-35ºC and then stirred for 30-45 minutes at the same temperature. The separated solid was filtered, washed with water (70 ml) and then suck dried for 20-30 minutes. The resulting wet solid was dried under vacuum at 70-75ºC for 10-15 hours to produce 75 g of pure crystalline Form II of Ferric maltol [Iron assay by UV: 12.6% w/w; Maltol content by HPLC: 91.4%w/w; Purity by HPLC: 99.984%; Particle Size: (D90): 23.65 µm; (D50): 7.43 µm].

Example 2
Preparation of highly pure Ferric maltol
Ferric chloride (35 g) was added to water (525 ml) at 25-35ºC and the resulting mixture was stirred for 10-15 minutes at the same temperature to form a clear solution. The resulting ferric chloride solution was filtered at 25-35ºC and washed with water (100 ml). To the resulting filtrate, Maltol (101 g) was added at 25-35ºC and then stirred the mixture for 20-30 minutes at the same temperature to form a solution. To the resulting solution, sodium carbonate solution (prepared by dissolving 106 g of sodium carbonate in 350 ml of water) was added at 25-35ºC for about 30-40 minutes, and then stirring the mass for 3-4 hours at the same temperature. The solid obtained was filtered, washed with water (70 ml) and then suck dried for 20-30 minutes to produce Ferric maltol as a wet solid. The resulting wet solid was dried under vacuum at 70-75ºC for 10-15 hours to produce 77 g of pure Ferric maltol [Iron assay by UV: 12.5% w/w; Maltol content by HPLC: 87%w/w; Purity by HPLC: 99.98%].

Example 3
Preparation of highly pure Ferric maltol
Step-1: Preparation of Ferric maltol
Ferric chloride (35 g) was added to water (525 ml) at 25-35ºC and the resulting mixture was stirred at the same temperature for 10-15 minutes to form a clear solution. The resulting ferric chloride solution was filtered at 25-35ºC and washed with water (100 ml). To the resulting filtrate, Maltol (101 g) was added at 25-35ºC and then stirred the mixture for 20-30 minutes at the same temperature to form a solution. To the resulting solution, sodium carbonate solution (prepared by dissolving 106 g of sodium carbonate in 350 ml of water) was added at 25-35ºC for about 30-40 minutes, and then stirring the mass for 3-4 hours at the same temperature. The solid obtained was filtered, washed with water (70 ml) and then suck dried for 20-30 minutes to produce Ferric maltol as a wet solid (wet weight: 87 g).
Step-2: Preparation of highly pure Ferric maltol
Water (900 ml) was added to the resulting wet solid (obtained in Step-1) at 25-35ºC, the mixture was heated to 40-45ºC under stirring and the resulting hot slurry was maintained under stirring for 23-25 hours at 40-45ºC. The resulting mass was cooled to 25-35ºC and then stirred for 30-45 minutes at the same temperature. The separated solid was filtered, washed with water (70 ml) and then suck dried for 20-30 minutes. The resulting wet solid was dried under vacuum at 70-75ºC for 10-15 hours to produce 73 g of pure crystalline Form II of Ferric maltol [Iron assay by UV: 12.6% w/w; and Maltol content by HPLC: 89.1%w/w].

Example 4
Preparation of highly pure Ferric maltol
Water (900 ml) was added to the Ferric maltol (90 g, prepared as per the process described in step-1 of example 1) at 25-35ºC, the mixture was heated to 70-75ºC under stirring and the resulting hot slurry was maintained under stirring for 18-20 hours at 70-75ºC. The resulting mass was cooled to 25-35ºC and then stirred for 30-45 minutes at the same temperature. The separated solid was filtered, washed with water (70 ml) and then suck dried for 20-30 minutes. The resulting wet solid was dried under vacuum at 70-75ºC for 10-15 hours to produce 73 g of pure crystalline Form II of Ferric maltol [Iron assay by UV: 12.66% w/w; Maltol content by HPLC: 90.6%w/w].
Example 5
Ferric maltol crystalline Form II (obtained in step-2 of example 1) was grinded in a Mixer Grinder for 10-15 minutes to obtain the material with reduced particle size [Particle Size: (D90): 11.43 µm; (D50): 4.78 µm].

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.