FIELD OF INVENTION
[001] The present invention relates to a novel polymorphic form of Fe (III) maltol. Particularly, the present invention provides a novel polymorph ‘S’ of Fe (III) maltol having high solubility, greater stability, higher purity and better efficacy as compared to the existing polymorphic forms of ferric maltol. The present invention also provides an economical process of preparation of the novel polymorphic form of ferric maltol that uses lower iron grades and limited wash cycles whilst producing a novel polymorphic form of ferric trimaltol of adequate purity and better efficacy.
BACKGROUND OF THE INVENTION
[002] Ferric Maltol, also known as Iron (III) maltol is a coordination complex of Iron (III) with three maltol molecules, having formula, 3-hydroxy-2-methyl-4H-pyrane-4-one iron (III) complex, or ST10, or ferric trimaltol. It is used for treatment of iron deficiency anaemia (IDA) associated with inflammatory bowel disease (IBD) and chronic kidney disease.

[003] The maltol molecule strongly chelates with the Ferric (III), rendering the iron stable and available for absorption. Maltol binds metal cations mainly in the form of a dioxobidentate ligand in a similar manner proposed for other 4-(1H)-pyranones:

[004] The ferric maltol complex dissociates to the maltol molecules and are absorbed and glucuronidated in the intestinal wall, and within the liver during first pass metabolism, and subsequently eliminated from the body in urine. The iron is absorbed via the endogenous dietary iron uptake system. This metal-ligand complex has increased bioavailability of Iron as compared to Iron (II) and it does not get deposited in the duodenum as insoluble ferric hydroxide and phosphate. Ferric (III) maltol is well absorbed in contrast to some other ferric iron supplements, fortificants and therapies, and appears well tolerated even in populations highly susceptible to gastrointestinal side-effects, such as IBD patients (Harvey et al., 1998), and as such it provides a valuable alternative to patients who are intolerant of oral ferrous iron products, notably in place of intravenous iron. Ferric maltol is commercially available as red hard gelatine capsules containing 30 mg iron (III) and its recommended dosage is one capsule twice a day empty stomach.
[005] Clinical development of ferric trimaltol, however, has been limited by the absence of adequate synthetic routes. Most manufacturing processes require use of organic solvents, which increase manufacturing costs. Further, post-synthesis solvent removal requires additional safety measures, for instance, to deal with flammability of the solvent. Importantly, solvent-based syntheses are not robust and often generate ferric hydroxide, described in the prior art to be an unwanted impurity of the synthesis.
[006] Patent publication number WO 03/097627 describes synthesis of the ferric trimaltol from iron salts of carboxylic acids in aqueous solution at a pH greater than 7. In a first synthesis, ferric citrate is added to a solution of sodium hydroxide at room temperature and maltol is added to a second solution of sodium hydroxide at pH 11.6. The ferric citrate solution is added to the maltol solution, leading to the production of a deep red precipitate. This composition is then evaporated until dryness and the material is powdered and dried. Alternative syntheses are described using ferrous fumarate or ferrous gluconate as the iron carboxylate salt, the starting material. The maltol is dissolved in sodium carbonate solution in place of sodium hydroxide. However, despite being fully aqueous, the process is very expensive. This is due to the reason that for preparation of pharmaceutical grade ferric trimaltol suitable for human administration, most of the iron carboxylate salts employed in the prior art processes are expensive. More importantly, this process introduces high levels of carboxylates (equimolar to iron or greater) to the synthesis that are not easily removed by filtration or centrifugation of the ferric trimaltol cake. Although, these water-soluble contaminants can be washed off (e.g., water washed), but this would result in considerable losses of the product due to the amphipathic nature of ferric trimaltol.
[007] The patent publication number WO 2012/101442 discloses synthesis of ferric trimaltol by reacting maltol and a non- carboxylate iron salt in an aqueous solution at alkaline pH. The cost of non-carboxylate iron salts is lower as compared to the carboxylate iron salts. However, despite the lower cost of non-carboxylate iron salts, pharmaceutically appropriate grades are still required if the ferric trimaltol is to be suitable for human administration and, hence are comparatively expensive starting materials accordingly. Importantly, the use of non-carboxylate iron salts (e.g., ferric chloride) results in the addition of considerable levels of the respective counter-anion (e.g., three moles of chloride per every mole of iron) of which a significant part is retained in the filtration (or centrifugation) cake and thus must be washed off. As such, WO 2012/101442 does not address the problem of product losses in WO 03/097627. Furthermore, the addition of a non-carboxylate iron salt (e.g., ferric chloride) to a very alkaline solution, as described in WO 2012/101442, promotes formation of stable iron oxides, which is an unwanted contaminant in ferric trimaltol. Consequently, further costly and time-consuming processing of the material would be required for manufacturing.
[008] Thus, the prior art processes for preparation of quality grade Ferric maltol prepared by aqueous synthetic routes are expensive, as this cost is driven by regulatory demands for low levels of toxic heavy metals and residual reagents in the final pharmaceutical formulation, which force the use of highly purified, and thus expensive, iron salts as well as thorough washing of the final product (resulting in significant losses of product). This impacts final pricing of the ferric trimaltol and potentially limits patient’s access to this therapy.
[009] Ferric maltol crystallizes in various polymorphic forms. Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement, resulting in different thermodynamic properties and stabilities specific to the polymorphic form. The thermodynamic properties that are dependent on the structure of the polymorphs are primality melting point, dissolution rate, solubility, solid state reactivity, hygroscopicity and stability.
[0010] Solubility of a drug substance is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is a major problem encountered with formulation development of new chemical entities. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth.
[0011] EP 3 160 951 B1 describes polymorphic forms I, II, III and IV of Ferric maltol. Another literature describes polymorphic form of ‘alpha’. Although Ferric maltol has been known for years, but no polymorphs have been identified or studied properly. This is due to the reason that the characteristic peak in XRD for forms I, II III and IV are very close to each other. In some the cases the 2 theta values are so close that it is difficult to distinguish the forms.
[0012] In view of the above problems associated with the state of the art, there is a need for a process that can use lower iron grades and limited wash cycles, whilst producing a novel polymorphic form of ferric trimaltol of adequate purity.
OBJECTIVES OF THE INVENTION
[0013] The primary objective of the present invention is to provide a process for preparation of a novel polymorphic form of Fe (III) maltol.
[0014] Another objective of the present invention is to provide a simple, economic and effective process for preparation of a novel polymorphic form of Fe (III)maltol.
[0015] Yet another objective of the present invention is to provide a process of preparation of quality grade novel polymorphic form of Ferric (III) maltol from lower iron grades of iron precursors using limited wash cycles.
[0016] Another objective of the present invention is to provide a a novel polymorphic ‘S’ form of Fe (III) maltol.
[0017] Yet another objective of the present invention is to provide a novel polymorphic form of Ferric (III) maltol having high solubility and better efficacy as compared to the existing forms.
[0018] Still another objective of the present invention is to provide a novel polymorphic form of Ferric (III) maltol having high stability.
[0019] Other objects and advantages of the present invention will become apparent from the following description taken in connection with the accompanying examples to disclose the aspects of the present invention.
SUMMARY OF THE INVENTION
[0020] The present invention relates to a novel polymorphic form ‘S’ of Fe (III) maltol having high solubility and purity, greater stability and better efficacy as compared to the existing polymorphic forms of ferric maltol. The ‘S’ form of ferric maltol has a triple layer structure, wherein the innermost core is iron chelate, the second layer consists of L-lycine and the external layer consists of ascorbic acid as shown in Figure 1. The present invention also provides an economical process of preparation of the novel polymorphic form of ferric maltol that uses lower iron grades and limited wash cycles whilst producing a novel polymorphic form of ferric trimaltol of adequate purity. The process comprises simultaneous co-precipitation of ferric maltol, ascorbic acid and L-lycine that results in structural rigidity of the metal chelate.

BRIEF DESCRIPTION OF FIGURES
[0021] Figure 1 illustrates triple layered structure of novel polymorphic form of Ferric (III) maltol.
[0022] Figure 2 illustrates X-ray diffraction of novel polymorphic form of Ferric (III) maltol.
[0023] Figure 3 illustrate Differential Scanning calorimetry (DSC) of polymorphic form of Ferric (III) maltol.
[0024] Figure 4 illustrates Unique IR Spectra of polymorphic form of Ferric (III) maltol.
[0025] Figure 5 illustrates HPLC graph of standard Maltol molecule.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure.
[0027] Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.
[0028] Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.
[0029] The terms and words used in the following description and claims are not limited to the bibliographical meanings but are merely used to enable a clear and consistent understanding of the invention.
[0030] It is to be understood that the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
[0031] It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, steps, or components but does not preclude the presence or addition of one or more other features, steps, components, or groups thereof. The equations used in the specification are only for computation purpose.
[0032] The present invention discloses Ligand modification of Ferric hydroxide to produce ligand modified Ferric maltol. Ligand modified ferric hydroxides are formed when a ferric iron salt is dissolved and then induced to precipitate by an increase in pH leading to the formation of polymorphic ferric hydroxide in the presence of one or more ligand species. This process results in some of the ligand species becoming incorporated into the solid phase structure of the ferric hydroxide. A range of ligands may be used in the production of the ligand modified or ligand coated ferric hydroxides used in the synthesis of ferric maltols, such as ferric trimaltol. In the methods of the present invention, the ligand modified ferric hydroxides may comprise one, two, three, four or more different species of ligands.
[0033] Typically, ligands are incorporated in the ligand modified ferric hydroxides to aid in the modification of a physico-chemical property of the material, for instance, as compared to unmodified or uncoated ferric hydroxide, and, to aid in reaction that allows for the synthesis of ferric Tri maltol.
[0034] The ligands used herein may be well recognized in the art as having high affinity for a certain metal ion in solution or as having only low affinity or not be typically recognized as a ligand for a given metal ion at all. Typically, at least one or two ligands of differing affinities for the metal ion are used in the production of these materials although zero, one, two, three, four, five or more different species of ligands may be useful in certain embodiments of the method of the present invention.
[0035] The ligand may be a carboxylic acid ligand, or an ionized form thereof (i.e., a carboxylate ligand), such as tartaric acid or tartrate. A more preferred group of carboxylic acid ligands include tartaric acid or tartrate, ascorbic acid, citric acid, adipic acid (or adipate), glutaric acid (or glutarate), pimelic acid (or pimelate), succinic acid (or succinate), and malic acid (or malate). A further preferred type of ligand is amino acid such as lysine, tryptophan, glutamine, proline, valine, or histidine. Preferably, a low-cost amino acid such as lysine is used in the synthesis. Whether the ligand is present as the acid or is partially or completely ionised and present in the form of an anion will depend on a range of factors such as the pH at which the material is produced and/or recovered, the use of post-production treatment or formulation steps and how the ligand becomes incorporated into the oxo-hydroxy metal ion material.
[0036] Examples of ligands that may be employed in the present invention include, but are by no means limited to: carboxylic acids such as adipic acid, glutaric acid, tartaric acid, malic acid, succinic acid, aspartic acid, pimelic acid, citric acid, gluconic acid, lactic acid or benzoic acid; food additives such as maltol, ethyl maltol or vanillin; amino acids such as lysine, tryptophan, glutamine, proline, valine, or histidine; and/or ionised forms thereof.
[0037] In a preferred embodiment, with carboxylic acids, at least a proportion of the ligand is present in the carboxylate form as the ferric hydroxide materials are typically recovered at pH>4 and because the interaction between the ligand and the positively charged iron would be greatly enhanced by the presence of the negatively charged carboxylate ion. Nonetheless, the use of carboxylic acid ligands in accordance with the present invention covers all of these possibilities, i.e. the ligand present as a carboxylic acid, in a non-ionised form, in a partially ionised form (e.g., if the ligand is a dicarboxylic acid) or completely ionised as a carboxylate ion, and mixtures thereof. Similarly, the use of the word amino acid covers all its possible ionisation forms.
[0038] More specifically, the present invention provides novel polymorphic form of Ferric (III) maltol. Particularly, the present invention provides a novel polymorphic form (referred herein as ‘S’ form) of Ferric maltol. The novel polymorphic form ‘S’ of Ferric (III) maltol comprises L-lycine coated/encapsulated Ferric maltol, having structure:
[0039] Fig. 1 illustrates the structure of novel polymorphic form (‘S’) of Ferric maltol, wherein the dotted Arrow shows the Energy flow vis., Ligand metal charge transfer (LMCT) and Metal ligand charge transfer (MLCT). The novel polymorphic form of Ferric maltol is stabilized by ascorbic acid, which is added to maintain the isoelectric point and pH and there by the pH of the final API along with L-lycine remains constant.

Fig 1
[0040] The ‘S’ form of ferric maltol has a triple layer structure, wherein the innermost core is iron chelate, the second layer consists of L-Lysine and the external layer consists of Ascorbic acid as shown in Figure 1. The Figure 1 illustrates stabilized diagram of Ferric Maltol encapsulated with L-lysine. The blue coloured boundary indicates the Ascorbic Acid.
[0041] The present invention also provides a process of preparation of L-lycine coated/encapsulated Ferric maltol and its novel polymorphic form ‘S’. The process comprises simultaneous co-precipitation of ferric maltol, ascorbic acid and L-lycine. The advantage of this co-precipitation is structural rigidity of metal chelate. The stabilized ferric maltol forms a triple layer structure. The inner core is iron chelate, the second layer is consisting of L-lycine and the external layer is consist of ascorbic acid as shown in Figure 1. The amino acid forms a triple-decker complex with metal chelates due to hydrogen bonding, leading to a stable complex.
[0042] The process of preparation of ‘S’ polymorph of Fe(III) maltol according to the present invention comprising the steps of:
a. preparing aqueous solution of 4 to 4.1M alkali metal hydroxide (alkali metal selected from Na, Li or K) and stirring for about 20 min at ambient temperature;
b. adding 3 to 3.1 moles Maltol to the solution prepared in step (a) under stirring to dissolve it at 25 to 35 deg C;
c. preparing 15-25% of aqueous solution of L-lycine under stirring at 25 to 35 deg C;
d. adding step c solution in Step b solution followed by 1 to 1.1% of Ascorbic Acid.
e. adding aq. ferric chloride solution into reaction mixture of step (d) slowly at a temperature in the range of 25 to 35 deg C; such that molar ratio of L-lysine to Ferric chloride is in ratio of 1:1.5 to 1:2.
f. Stir the solution mixture for 2 -3 h at 25 to 35 deg C; and
g. obtaining ‘S’ form of Ferric maltol by isolation and drying.
[0043] The co-precipitation technique of the present invention gives a triple layer structure of ferric maltol (API) which prevents the degradation of the API and enhance its stability.
[0044] The process of the present invention is a very robust process, scalable up to multi ton level. The added advantage of this process is that the final product obtained can be dried either in vacuum tray dryer or a spray drier with inlet temperature about 200 deg C and outlet temperature about 110 deg C without any decomposition.
[0045] The pharmaceutical grade Ferric maltol obtained by the process of the present invention is called pre-formulated API. The advantage of these types of API are Solubility Profile (solubility, pH and pKa) (Ref: Pre-formulation I, Solubility Profile (solubility, pH and pKa).
[0046] Examples
[0047] The following examples are provided hereinbelow as illustrative implementations of various embodiments and have been provided merely for explanation and are in no way construed to be limiting the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only.
[0048] Comparative Example 1 (Without adding stabilizer):
[0049] In process/DM water, ferric chloride hexahydrate was added and stirred for about 20 min at ambient temperature. Aqueous solution of Ferric Citrate monohydrate was prepared by first preparing aqueous solution of Sodium Hydroxide. The sodium hydroxide solution was then charged into the citric acid drop wise at ambient temperature to form sodium citrate, and to that solution, ferric chloride solution was added at ambient temperature. The reaction mass was heated at 60-65 deg C for 1 h followed by cooling. Alkaline solution of ferric citrate was added into alkaline solution of maltol. Usual isolation and drying afforded the desirable API. The main disadvantage of this process is drying of the API. Up to 20-30 kg product can be dried under VTD but not in spray drier. Spray drying reduces the maltol content from 80% about 50%. This is due to degradation of ferric maltol at high temperature during spray drying.
The degradation pathway of the Ferric maltol is as follows:

[0050] Example 2 (Improved process of the present invention with adding stabilizer): In process/DM water sodium hydroxide was added and stirred for about 20 min at ambient temperature to form 4 to 4.1M NaOH . Maltol was charged to the above solution under stirring to dissolve it at 25 to 35 deg C. 20% of aqueous solution of L-lycine was charged into the mixture under stirring at 25 to 35 deg C followed by addition of 1 to 1.1 % ascorbic Acid to this solution. Ferric chloride solution (104 g of L-lycine in 530 mL process water for 215 g of anhyd, Ferric Chloride) was added and mixed slowly at 25 to 35 deg C. The mixture was stirred for 15 to 20 mins at 25 to 35 deg C. The stirring was continued for 2 hrs. Usual isolation and drying (VTD or Spray Drying) affords the desirable API. The main advantage of this process is drying of the API and the ease of scale up to multi metric ton scale. Here after spray drying, we never observed the degradation of API. This is a unique process for the preparation of multi ton ferric maltol API.
[0051] Structural Elucidation of the Form ‘S’ of Ferric (III) maltol: Figure 4 and Table 1 below shows the difference in IR spectrum of the novel polymorphic form as compared to the known Ferric maltol.
Ferric Maltol (cm-1) Ferric Maltol Polymorph S (cm-1) Assignment Remarks
1566 New peak at 1600 C=0 Shift of peak due to new polymorph.
1560 New peak at 1453 C=C Shifting of peak due to hydrogen bonding with amino acid.
1243 New peak at 1269 C-0-C Shifting of peak due to hydrogen bonding with amino acid.
918 New peak at 1600 N-H Due to hydrogen bonding
823 New peak at 846 N-0 Due to hydrogen bonding
469 469 0-Fe

[0052] The polymorphic forms differ in their internal solid-state structure, which in turn affects the apparent solubility of a drug substance. Accordingly, when a drug substance exhibits polymorphism, aqueous solubilities and dissolution rates for different polymorphic forms may differ. Differences in apparent solubilities of the various polymorphic forms leads to differences in bioavailability (BA) and bioequivalence (BE). The effect of differences in apparent solubilities of the various polymorphic forms on BA and/or BE depends on the various physiological factors that govern the rate and extent of drug absorption including gastrointestinal motility, drug dissolution, and intestinal permeability.
[0053] For a drug whose absorption is only limited by its dissolution, large differences in the apparent solubilities of the various polymorphic forms are likely to affect BA/BE. On the other hand, for a drug whose absorption is only limited by its intestinal permeability, differences in the apparent solubilities of the various polymorphic forms are less likely to affect BA/BE. Furthermore, when the apparent solubilities of the polymorphic forms are sufficiently high and drug dissolution is rapid in relation to gastric emptying, differences in the solubilities of the polymorphic forms are unlikely to affect BA/BE.
[0054] Drug product dissolution testing frequently provides a suitable means to identify and control the quality of the product from both the bioavailability and physical (stability) perspectives. Inadvertent changes to the polymorphic form that may affect drug product BA/BE can often be detected by drug product dissolution testing.
[0055] The polymorph ‘S’ of the present invention has higher solubility as compared to the known polymorphs. Because of its higher apparent solubility, it has higher dissolution rate and consequently the bioequivalence and bioavailability of ‘S’ polymorphic form of Ferric maltol is high.
[0056] The Form ‘S’ of Ferric (III) maltol of the present invention has improved solubility as compared to known forms I and II of the Ferric (III) maltol. Table 1 below discloses the solubility profile of the novel S form in water
Table 1: Comparative Solubility Profile

[0057] Figure 2 shows XRD characteristic peak at 2 theta degree for polymorph of the present invention. Table 2 below shows comparative data of XRD characteristic peak of different polymorphs of Ferric Maltol.
Polymorph XRD characteristic peak (2 theta deg)
Form I 15.6 and 22.5
Form II 8.3
Form III 7.4 and 9.3
Form IV 9.5, 14.5 and 15.5
Novel Form ‘S’ of the present invention 32 and 45.41
Polymorph A and C Not known

TABLE 2 thus denotes the characteristic peaks of XRD of Polymorph S Vs. other forms.
[0058] Figure 3 shows DSC thermogram (heat flow endo down) of the polymorph ‘S’ of the present invention. The endothermic peak of the polymorph is seen at a temperature of 276.56oC, which represents the melting point of the polymorph.
[0059] Figure 5 shows that from the High-performance liquid chromatography (HPLC) analysis of polymorph ‘S’ of Ferric maltol, purity of the polymorph ‘S’ of Ferric maltol is 100%.
[0060] The present invention provides preformulated API and same is not known in any literature.
[0061] Ferric maltol polymorph S is a chemically stable complex of ferric iron and maltol, specifically formulated for improved absorption from oral administration; ferric iron is delivered to the intestinal mucosa in a biologically labile complex, allowing the efficient uptake of elemental ferric iron into enterocytes at a relatively low daily dose while avoiding free iron in the gut, thereby minimizing gastrointestinal toxicity.
[0062] In phase 3 clinical trials in patients with quiescent or mild to moderate IBD and mild to moderate IDA, ferric maltol of the present invention provided highly statistically significant and clinically meaningful improvements in Hb vs placebo within 12 weeks that were maintained for up to 64 weeks. The rate of gastrointestinal adverse events with ferric maltol was low and similar to that of seen with placebo.
[0063] Secondary efficacy endpoints were analyzed using an analysis of covariance model to calculate the difference in the treatment group least-squares mean (LSM) and the corresponding 95% CIs and P values. In a post hoc analysis, time to first additional IV iron (i.e., beyond the first planned IV infusions scheduled according to local prescribing information and standard practice) was assessed using Kaplan-Meier plots.
[0064] for patients enrolled in the 52-week protocol. Patients who did not receive additional IV iron were censored at their study end. The mean total amount of IV iron taken during the trial was summarized descriptively.
[0065] It will be understood by those skilled in the art, having the benefit of the teachings of this specification, that the embodiments disclosed herein are capable of modifications and other embodiments may be affected and changes may be made thereto, without departing from the scope of the embodiments disclosed herein.
, Claims:WE CLAIM:

1. A process of preparation of ‘S’ polymorph of Fe(III) maltol comprising the steps of:
a. preparing aqueous solution of 4 to 4.1 M alkali metal hydroxide and stirring for about 20 min at ambient temperature;
b. adding 3 to 3.1 moles Maltol to the solution prepared in step (a) under stirring to dissolve it at 25 to 35 deg C;
c. preparing 15-25% of aqueous solution of L-lycine under stirring at 25 to 35 deg C;
d. Adding step c solution in Step b solution followed by addition of 1.1% of Ascorbic Acid.
e. adding aq. ferric chloride solution into reaction mixture of step (c) slowly at a temperature in the range of 25 to 35 deg C; such that molar ratio of L-lysine to Ferric chloride is in ratio of 1:1.5 to 1:2.
f. Stir the solution mixture for 2 -3 h at 25 to 35 deg C; and
g. obtaining ‘S’ form of Ferric maltol by isolation and drying.

2. The process as claimed in claim 1, wherein the alkali metal is selected from the group of sodium (Na), potassium (K) and lithium (Li).
3. The process as claimed in claim 1, wherein the drying of the Ferric maltol prepared in step (l) may be carried out using a spray drier or a vacuum tray dryer.
4. A polymorphic form ‘S’ of Fe (III) maltol, comprising:
an innermost core of iron chelate;
a second layer consisting of L- Lysine; and
an external layer consisting of Ascorbric Acid

5. The ‘S’ form of ferric maltol; characterized in:
a. Melting point of 276.56oC;
b. XRD characteristic peak at 32 and 45.41 (at 2-theta degree); and
c. Solubility profile of 12.6 mg/ml;