Process for the Preparation of Iron (III) Polymaltose Complex with Controlled Molecular Weight

Abstract

The present invention relates to a novel process for the preparation of Iron (III)-Polymaltose Complex (IPC), a widely used pharmaceutical agent for treating iron-deficiency anemia. The process involves the preparation of ferric hydroxide by three alternative methods: (1) reaction of ferric chloride with sodium carbonate, (2) reaction of ferric chloride with sodium hydroxide, (3) oxidation of ferrous sulfate with hydrogen peroxide, followed by precipitation. The ferric hydroxide is then reacted with maltodextrin and citric acid under controlled conditions to form IPC. The process ensures a controlled molecular weight ranging from 50,000 to 200,000 Da and a polydispersity index (PDI) of < 2, ensuring consistent quality and therapeutic performance. Post-reaction treatments such as pH adjustment, filtration, and spray drying yield a stable, free-flowing IPC powder with high purity. The invention further ensures the absence of genotoxic and nitrosamine impurities. The resulting IPC exhibits improved solubility, stability, and bioavailability, meeting stringent standards

Specification

Description:Field of the Invention

The present invention relates to a novel process for the preparation of Iron (III)-Polymaltose Complex (IPC), which is widely used in treating iron-deficiency anemia. The invention ensures consistent molecular weight distribution, high purity, and enhanced stability suitable for pharmaceutical applications.

Background of the Invention

Iron deficiency remains a prevalent global health concern, necessitating effective supplementation strategies.According to the World Health Organization (WHO), more than 1 billion peopleshow iron deficiency, the most common nutritional deficiency. About 700 million areanemic (WHO 2008). Iron-deficiency anemia is associated with reduced qualityof life, decreased physical and cognitive performance, but also with adverse clinicaloutcome. Iron deficiency anemiais a major finding for chronically ill patients and represents a major complicatingfactor for women of childbearing age and during pregnancy.
Traditional iron supplements often pose challenges such as gastrointestinal side effects and poor tolerability. Carbohydrate based iron, utilizing advanced delivery technology, presents a promising solution to enhance iron uptake and mitigate adverse effects. This elucidates the distinctive features and advantages of iron over conventional preparations, highlighting its efficacy, tolerability, and suitability across diverse populations, including pregnant women, children, and the elderly.
Iron (III) polymaltose complex is a macromolecular complex in which metallic ferric ion is complexed with long chain carbohydrate unit. It has a variable mol. weight starts from about 50000 Da and soluble in water. Unlike other simple ferric salt, it does not precipitate in alkaline condition.
Iron (III)-Polymaltose Complex (IPC) is a widely accepted iron supplement due to its non-ionic nature, high bioavailability, and reduced gastrointestinal side effects. The IPC is composed of nano particles constituted of a polynuclear iron(III)-hydroxide core surrounded and stabilizedby polymaltose ligands. Due to the unique features resulting from the proprietary manufacturing process, the tolerability of IPC appears to be superior to iron (II) salts.
The research article Iron (III)-hydroxide Polymaltose Complex in Iron Deficiency Anemia (Toblli JE & Brignoli R. Iron(III)-hydroxide polymaltose complex in iron deficiency anemia/ review and meta-analysis. Arzneimittelforschung 2007;57:431‒8. https://doi.org/10.1055/s-0031-1296692) The meta-analysis of studies in adults with iron deficiency anemia comparing IPC and iron sulfate at the same dosage showed that similar haemoglobin values were achieved with both preparations, which indicates comparable effectiveness. The tolerability of IPC in adults was significantly better than that of iron sulfate. There was also a significant difference in terms of individual side effects and undesirable effects. This probably reflects a better risk-benefit ratio of IPC in adults.
The research article Efficacy and safety of oral iron(III) polymaltose complex versus ferrous sulfate in pregnant women with iron-deficiency anemia: a multicenter, randomized, controlled study (Ortiz R, Toblli JE, Romero JD et al.J Matern Fetal Neonatal Med 2011;24:1-6. https://doi.org/10.3109/14767058.2011.599080) concluded oral iron(III) polymaltose complex offers at least equivalent efficacy and a superior safety profile compared to ferrous sulfate for the treatment of iron-deficiency anemia during pregnancy.
The Prior art US3076798A discloses the Process for preparing a ferric hydroxide polymaltose complex where Dextrin (aqueous)+Fe 3+ + Alkali hydroxide/Alkali Carbonate heating at 60-100 °C reaction followed to obtain ferrous hydroxide polymaltose then oxidized to ferric hydroxide polymaltose complex where iron content lies between 15-25% only while polymaltose content 70-50%. In this process first form ferrous hydroxide polymaltose then oxidized to Ferric hydroxide polymaltose and use of exchanger of cation and anion to neutralize the reaction make the process difficult. In this process the purification process of final product is absent like how to remove alkali impurity from the final product.
The Prior art CH397628A discloses Process for the preparation of therapeutically useful iron (III) hydroxide-polymaltose complexes where non-retrograding dextrin react with iron (III) hydroxide and an excess of alkali into solution by heating to 60°C to 1000°C to obtain iron (III) hydroxide-polymaltose complexes. In this process the cation exchanger (HCl/H2SO4) is used to neutralized the reaction. The preparation produced iron (III) hydroxide-polymaltose complexes with 15-25% iron and about 70-50% polymaltose content. In this process heating with temperature range is large and timing of reaction is absent. The additional neutralization process of reaction make difficult process to obtained the desired result of product. This process also did not discuss the Molecular weight and polydispersity index of product.
The prior art EP3197444B1 discloses Iron (III) hydroxide complexes with activated glucose syrups and process for preparing same where glucose syrup (aqueous) (at a temperature in the range of from 25°C to 80°C and at a pH in the range of from 6 to 13) and added hydrogen peroxide maintaining the pH and temperature within the range, allowing the solution to cool down to a temperature in the range of from 10°C to 45°C, keeping the solution at this temperature for 5 min to 24 hours, thereby obtaining the activated glucose syrup and converting said activated glucose syrup into a complex with iron (III) hydroxide. In this process the molecular weight of the iron (III) hydroxide complex is in the range of from 100 kDa to 150 kDa. This process is silent on polydisperity index and impurity obtained from the process.
The Prior art KR1020010058885 discloses the method for manufacturing of antianemic complex where partially hydrolyzed dextrin react with Iron (III) sulfate and sodium carbonate aqueous solution having a concentration of 10 to 25% is used after adjusting pH 1.8 to 2.2 and heated the mixture to 25 to 50°C, a monohydric or dihydric acid having a normal concentration of 2 N to 6 N is added, the pH is adjusted to 5.5 to 7.5, and finally, the mixture is heated to 35 to 95°C for 15 to 35 minutes and then cooled and the reaction mixture after cooling is passed through a 100,000 dalton membrane to perform molecular filtration or dialysis to remove reaction residues, iron ions, maltose oligomers, low-molecular-weight maltose oligomers, and complexes with inorganic salts, and at the same time, concentrates the iron (III) hydroxide polymaltose complex salt in the liquid solution, and finally directly dries the mixture by a conventional freeze-drying or warm-air pulverizer method. In this process the prepared complex salt has a residual amount of sodium chloride of 1.0% or less. In this process other impurities like Nitrosamine, genotoxic etc., did not get considered. This process also did not consider molecular weight and polydispersity index as parameter to check the stability of obtained iron (III) hydroxide polymaltose complex.

The Prior art US 8759320B2 discloses the Process for the preparation of trivalent iron complexes with mono-, di- and polysaccharide sugars where maltose react with sodium bromide and then sodium hydroxide and sodium carbonate and sodium hypochloriteis used at different stage of reaction on different pH value range to obtain the ferric hydroxide/maltose Complex. In this process polydispersityindex is greater than 2.
The existing production methods often struggle to control molecular weight distribution and purity, resulting in inconsistent pharmacokinetics and stability profiles.The presence of impurities such as nitrosamines poses additional risks, complicating regulatory approval.
The iron carbohydrate interacts with cells of the innate immune system for uptake and release of iron into the physiological iron metabolic pathways: i.e. phagocytes is by cells of the RES (Reticulo Endothelial System), cleavage of thecarbohydrate shell from the iron core which has to deliver the iron to physiological pools after release into and transport through the blood. They are non-biological complex drugs (NBCDs) i.e. showing polydispersity (non-homomolecular structures),cannot be fully characterized, and are highly dependent on a well-controlled manufacturing process.
The present invention introduces a robust process to preparation of Iron (III)-Polymaltose Complexthat controls molecular weight and polydispersity index (PDI), eliminates genotoxic impurities, and ensures a stable IPC product. The present invention produces the Iron (III)-Polymaltose Complex of molecular weight 50,000 kDa to 200,000 kDa with PDI <2 where Iron content 26 to 36% w/w and carbohydrate content as polymaltose 25 to 50% w/w.

Importance of Molecular Weight and Polydispersity Index (PDI)
Molecular weight (Mw) and Polydispersity Index (PDI) are critical parameters influencing the performance and stability of IPC.
Molecular Weight (Mw):
The molecular weight of IPC determines its solubility, viscosity, and bioavailability. IPC with Mw between 50,000 to 200,000 Da ensures optimal absorption in the gastrointestinal tract without causing excessive viscosity or precipitation.
Polydispersity Index (PDI):
PDI reflects the uniformity of molecular weight distribution. A PDI < 2 indicates a narrow distribution, which is essential for consistent therapeutic performance. Variability in PDI can lead to batch-to-batch inconsistencies, affecting bioavailability and stability.
Objective of the Invention
The present invention the process of preparation of Iron(III) polymaltose complex Controlling molecular weight and Polydispersity Index helps ensure that the IPC exhibits uniform dissolution rates, predictable pharmacokinetics, and reduced side effects. The process described herein achieves this through optimized reaction conditions and precise control of reagent proportions.

Summary of the Invention

The present invention provides an improved process for the preparation of IPC, involving the following key steps:
Step 1: Preparation of ferric hydroxide using three alternative methods.
Step 2: Reaction of ferric hydroxide with maltodextrin and citric acid under controlled conditions to form IPC.
Step 3: Post-reaction treatments including pH adjustment, filtration, and spray drying.
This process ensuresMolecular weight (Mw) in the range of 50,000 to 200,000 Da and a polydispersity index (PDI) < 2and absence of genotoxic impurities and nitrosamines and enhanced solubility, stability, and controlled bioavailability of the IPC.The control of molecular weight and PDI plays a pivotal role in determining the physicochemical properties and therapeutic efficacy of IPC.


There are some figures, tables and graphs which details as follows
Fig.1: Structure of Iron (III) Polymaltose Complex
Fig. 2: Synthetic Scheme
Fig. 3. Genotoxic impurities
Fig. 4: Nitrosamine impurities
Fig. 5: Decomposition of Nitrosamine
Table 1: Risk Assessment (In line with FDA guidelines)
Table 2: Physical Properties (Typical values)
Table 3: Variable Molecular weight with PDI
Table 4: Assignment of Prominent IR bands
Table 5: pH with different batches
Table 6: Carbohydrate content as Polymaltose with different batches
Table 7: Fe(III) content with different batches
Graph 1: Infrared Spectrum of Iron (III) Polymatose Complex
Graph 2: PXRD









Detailed Description of the Invention

The preparation of Iron (III) Polymaltose (IPC, Fig 1) is a three-step process.

Fig. 1: Structure of Iron (III) Polymaltose Complex

Step 1: Preparation of Ferric Hydroxide
Iron hydroxides are insoluble and generally precipitate from the solution. However, by means of surface interactions with organic molecules such as proteins in the body or different carbohydrates, polynuclear (p) units with the composition [Fe(OH)3]p or [FeO(OH)]p can be kept in solution as colloidal particles.
The first step involves the preparation of ferric hydroxide. This can be prepared in three different ways:
i) The reaction of ferric chloride with sodium carbonate in water affords ferric hydroxide.
Dissolve ferric chloride in deionized water and slowly add a 20% sodium carbonate solution under constant stirring.Adjust the pH to 5-6 to precipitate ferric hydroxide and filter and wash the precipitate until the chloride content is less than 2%.

ii) The reaction of ferric chloride with aq. sodium hydroxide affords ferric hydroxide.
Prepare a ferric chloride solution and add sodium hydroxide solution under stirring to precipitate ferric hydroxide and maintain the pH at 5-6 after that filter and wash to reduce chloride levels below 2%.
iii) The oxidation of aq. ferrous sulphate heptahydrate in sulphuric acid and hydrogen peroxide and addition of sodium hydroxide affords ferric hydroxide.
Dissolve ferrous sulfate in dilute sulfuric acid and oxidize ferrous ions using hydrogen peroxide.Precipitate ferric hydroxide by adding sodium hydroxide and wash to reduce sulfate impurities below 2%.
The usual process of water washing to be adopted to remove chloride (or halide) and sulphate.

Step 2: Preparation of Iron (III)-Polymaltose Complex
The second step involve the reaction of aq. ferric hydroxide cake with maltodextrin in presence of citric acid under heating (Fig. 2).
Materials:Ferric hydroxide cake (from any of the above methods in step 1), Maltodextrin, Citric acid.
In this step pH is adjusted with suitable base from 4 to 6.5, preferably 4 to 6, more preferably 4.5 to 6 and more preferably 5 to 6. In the second step heating is required and it is a critical process parameter to achieve the desired molecular weight (Mw). The heating is carried out at 60 to 120 deg C, preferably at 70 to 110 deg C, preferably at 80 to 110 deg C and more preferably at 90 to 110 deg C. Variation of temperature will vary the Mw of the desired iron(III) polymaltose complex. The process described in this patent give rise the Mw in the range of 50000Da to 200000Da. The heating was carried out for 6 to 12h, preferably for 7 to 11h, more preferably 8 to 10h. After completion of reaction, the reaction mass cooled to 60 deg C and pH is again adjusted to 6.5 to 9 with suitable base, preferably 6 to 8.5, more preferably 6.5 to 8, more preferably 7 to 8. After pH adjustment the product mass was filtered followed by isolation through spray drying.

Fig. 2: Synthetic Scheme


Role of Chelating Agents
The use of citric acid plays an important role to form the chelate the metal ion with carbohydrate unit by enhancing the extent of hydrogen bonding. It also enhances the solubility in water, controls the pH in a stable manner and reduces the oxidative stress. The use of citric acid is not limited but to be extended with the use of adipic acid, fumaric acid, malic acid and other di or tri carboxylic acid with C3 to C6 unit
Example:
3000 Lit of process water charged in a reactor followed by addition of about 550 kg of ferric chloride (based on assay) at ambient temperature under stirring. About 600 kg of sodium carbonate was charged in another reactor to make 20% solution of it. The resulting 20% solution of sodium carbonate was charged in ferric chloride solution slowly under stirring. pH of the resulting reaction mixture become 5 to 6. About 4000 Lit of process water charged and the resulting mixture was allowed to settle for 8h. The upper layer of the heterogeneous mixture was decanted and the settled ferric hydroxide was sent to PP press filter. The ferric hydroxide cake was washed thoroughly with water to minimize the chloride (or halide) content below 2%.
The above cake of ferric hydroxide was collected and suspended in 6000 Lit of process water. About 162kg of maltodextrin was charged slowly in the above suspension of ferric hydroxide under stirring. About 125 kg of citric acid was charged in a lot wise under stirring. The resulting reaction mixture was heated for about 6-12 h at specific temperature depending upon requirement of Mw of the iron (III) hydroxy polymaltose complex.
The above reaction mass was cooled to 60 deg C naturally and pH was adjusted to 7 to 8 with sodium carbonate. The resultant product solution was filtered through sparkler filter to remove unwanted solid particle and impurities. The final iron (III) polymaltose complex was isolated through spray drier (600 to 620 kg) as a brown free flowing powder.
Quality Control and Characterization
Related Impurity profile:
The active substance is a brown to deep brown powder, very dispersible in water and has multiple chiral centres. The manufacturing process has adequately been reviewed and the starting materials are acceptable. The active substance, including the carbohydrate structure, has been adequately characterized and controlled, and the manufacturing process thereof. The active substance specification is considered adequate to control the quality and meets the specifications. The specification of a substance is the total of quality tests, analytical procedures and acceptance criteria (limits) this substance has to adhere to. Batch analytical data demonstrating compliance with this specification. Stability data on the active substance have been demonstrated in accordance with applicable guidelines, demonstrating the stability of the active substance for at long-term conditions and accelerated conditions. The product is an established pharmaceutical form and its development is adequately described in accordance with the relevant guidelines. The aim of the development is to develop a product similar to the reference product. The proposed product is qualitatively same as the reference product. The active substance and water quantity are identical or near to identical to the proposed product. The development was guided by risk assessments to identify the critical drug substance attributes, critical material attributes and critical process parameters. To mitigate the identified risks, an adequate control strategy was implemented.
The main development studies were the characterization of the test and reference product and physicochemical comparison. The in vitro comparative studies are acceptable based on the results of qualitative and quantitative tests. The main manufacturing process development studies were the optimization of preparation of the API. The manufacturing process has been validated according to relevant guidelines.
The finished product specifications were adequate to control the relevant parameters for the API. The specification includes tests for: colour of content, appearance of content, carbohydrate content, average molecular weight (Mw), PDI, XRD, IR, pH, free iron content, bacterial endotoxins; and found the results of these parameters are in agreement with that of reference standard with adequate analytical MoA.
From the above logic it can be concluded that the present invention is free from above related impurities.
Genotoxic impurity Profile:
Genotoxic impurities can occur in drug products based on the manufacturing of the API, degradation of the API, or in some cases, from the excipients. The source of genotoxic impurities in the API and drug product generally is the API manufacturing process, including starting materials and reagents. Reagents used in API synthesis are often highly reactive, and genotoxic impurities can result from leftover reagents carried through the manufacturing process, by-products of the chemical transformations, or the subsequent degradation/interactions of the API. Although rare, genotoxic impurities occasionally form in the drug product as a result of interaction of the API with excipients.
The presence of following structural part (in totality or by parts) can lead to the formation of Genotoxic impurity in iron (III) hydroxy polymaltose complex.


Fig. 3. Genotoxic impurities
As the IPC synthetic process does not use any reagent having the above structural part during manufacturing process hence our API is free from Genotoxic impurity.

Nitrosamine Impurity:
The term nitrosamine describes a class of compounds having the chemical structure of a nitroso group bonded to an amine (R1N(-R2)-N=O), as shown in the below figures. The compounds can form by a nitrosating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions).
Representative Reaction to Form Nitrosamines:
FDA has identified seven nitrosamine impurities that theoretically could be present in drug products: NDMA, N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA). Five of them (NDMA, NDEA, NMBA, NIPEA, and NMPA) have actually been detected in drug some substances or drug products. As in our process any amine, nitric acid, nitrate, nitrite, azide, 2nd crop of the product, recovered solvent i.e., waterare not used, hence it has been declared thatthe obtained Iron (III) Polymaltose Complex are free any nitrosamine impurities.

Fig. 4: Nitrosamine impurities



Risk Assessment (In line with FDA guideline):
Risk Factors Assessment
Are nitrites (NO2-), nitrous acid, amine, nitrates (NO3-), nitric acid, or azides (N3-) or their sources present in any excipients (e.g., microcrystalline cellulose), processing aids (e.g., water, nitrogen)?
No
Are peroxides present in any of the excipients, processing aids?
Are nitrites (NO2-), nitrous acid, nitrates (NO3-), nitric acid, or azides (N3-) or their sources present in packaging components (including ink, and materials permeability factors)?
Are any components containing/potentially containing nitrites present together in solution or in suspension during processing?
Are nitrites (NO2-), nitrous acid, nitrates (NO3-), amine, nitric acid, or azides (N3-) or their sources present in chemically synthesized APIs? No
Based on the structure of drug substance, is there any possibility of formation of nitroso compounds by interaction of drug substance? No
Based on the structure of excipients/KSM, is there any possibility of formation of nitroso compounds by interaction between excipients/KSM?
Are any components containing/potentially containing nitrites and amines maintained together at elevated temperatures (about 200 deg C, e.g., during drying, coating stages, autoclaving, etc.)? No
Do solvents or any other process materials undergo recycling/recovery? No
In the manufacturing process of the drug product, are any of the solvents, spent solvents, or process materials treated prior to or during recovery (in-house or by a third party) such that the treatment could lead to formation of amines or nitrosonium ions that could be introduced back into the process through the recovered solvents?
Are the recovered materials, if any, dedicated to the process? No
Is there a potential for nitrosamine impurity formation during the finished product manufacturing, through degradation and by-products (i.e., if certain excipients, APIs, or packaging components containing sources of amines and nitrite are used together)?
No
Are there nitrosonium ions (degradation and by-products) likely to come into contact with each other either in the same processing step or through carryover into subsequent processing steps?
Is there any potential of nitrosamine formation during storage throughout the finished product's shelf life? No
Is chloramine used as part of water treatment, used for cleaning, or as part of the production process? No
Have the cleaning solvents/cleaning agents used been assessed for nitrosamine or nitrosamine precursor risk? Only the purified water is used as cleaning solvent.
Manufacturing of oral drug product typically involves (e.g., solid oral dry, wet, or direct compression) manufacturing processes utilizing specific equipment. Do any of the processes contribute toward formation of N-Nitrosamines? No
Are sartan drug products manufactured in the same facility? No
Manufacturing equipment design. Reviewed the equipment and it meets the current GMP and validation/qualification standards. Confirm continued suitability to the manufacturing and cleaning process.
Manufacturing equipment material of construction. The adequacy of the contact surfaces and their suitability respect to the qualified cleaning method, cleaning solvent used, and frequency verified.
Are chemicals such as sodium azide or sodium nitrite, which are primary sources of nitrosamine impurity, used in the facility? No

Table 1: Risk Assessment (In line with FDA guidelines)
The above review is expected to provide us high level of confidence for the absence of Nitrosamine impurities in our product.
For the sake of argument, if we consider traces of nitrosamine impurities formed due to environmental contamination it undergoes decomposition under acid catalysed reaction condition of Fe(III)(Ref:J. Org. Chem.,1979, 44, 784-786.) in the following mechanistic pathway. The general mechanism is proposed by the inventors.

Fig. 5: Decomposition of Nitrosamine
From the above logic, it can be concluded confidently that the present Iron (III) polymaltose complex (IPC) has no nitrosamine impurity.


Physico-chemical Data:
Batch No. Description pH (50% w/v aq. Soln., Limit 5.5 to 7.5) Free Iron (limit NMT 10 ppm) Carbohydrate Content as Polymaltose (Limit 25.0 to 50.0 % w/w) Fe(III) Content (Limit 26.0 to 36.0 % w/w)
1 Brown colour free flowing powder 6.71 Absent 27.58 % w/w 31.88% w/w
2 Brown colour free flowing powder 7.02 Absent 26.65 % w/w 31.26 % w/w
3 Brown colour free flowing powder 6.81 Absent 27.52 % w/w 30.69 % w/w
4 Brown colour free flowing powder 6.11 Absent 30.55 % w/w 29.94 % w/w
5 Brown colour free flowing powder 6.65 Absent 27.98 % w/w 31.59 % w/w
6 Brown colour free flowing powder 6.49 Absent 27.17 % w/w 31.92 % w/w
Table 2: Physical Properties (Typical values)
GPC:
As mentioned in the manufacturing process the reaction temperature is a critical process parameter to achieve the desired molecular weight (Mw). Variation of temperature will give rise IPC with variable Mw with PDI NMT 2 which are depicted in the below table:

Batch No. Mw Mn PDI
1 60015 37315 1.6
2 74364 44768 1.66
3 74440 46044 1.61
4 77524 46146 1.67
5 105302 58617 1.79
6 120339 84306 1.42
7 131555 95592 1.37
8 183698 133521 1.37
Table 3: Variable Molecular weight with PDI
Infrared Spectroscopy:
The Infrared spectrum of Iron (III) Polymaltose Complex was recorded as a dispersion in KBr on a Perkin Elmer instrument in the range of 600 cm-1 to 4000 cm-1. The assignments of prominent IR bands are given below:

Assignment Frequency (cm-1)
OH-stretching 3419.43
-CH-Stretching 2959.0,2923.86
-C=O 1630.78
Table 4: Assignment of Prominent IR bands


Graph 1: Infrared Spectrum of Iron (III) Polymatose Complex
Above graph 1 confirms the presence of functional groups indicating complex formation.


Powder X-Ray Diffraction:
The polymorphic nature was confirmed by PXRD as amorphous. It implies the amorphous nature of IPC, crucial for its solubility and stability

Graph 2: PXRD
Robustness of the Manufacturing Process:
The present manufacturing process of IPC is controlled by Quality by design (QbD) and Design of experiment (DoE). The following graph is self-explanatory about the robustness of the process. The pH, Fe(III) content and carbohydrate content of the six batches are very consistent. The details are as follows:

Table 5: pH with different batches


Table 6: Carbohydrate content as Polymaltose with different batches

Table 7: Fe(III) content with different batches
Industrial Applicability
The process is scalable and environmentally friendly, ensuring consistent production of IPC with controlled molecular weight and stability.




, Claims:We claim

1. A process for preparing Iron (III)-Polymaltose Complex (IPC), comprising:
preparing ferric hydroxide by one of three methods: ferric chloride-sodium carbonate reaction, ferric chloride-sodium hydroxide reaction, or ferrous sulfate oxidation;
reacting ferric hydroxide with maltodextrin and citric acid under controlled heating to form IPC;
post-reaction treatments including pH adjustment and spray drying.
2. The process as claimed in claim 1, wherein the ferric hydroxide obtained by reaction of ferric chloride with sodium carbonate in water.
3. The process as claimed in claim 1, wherein the ferric hydroxide obtained oxidation of aqueous ferrous sulphate heptahydrate in sulphuric acid and hydrogen peroxide and addition of sodium hydroxide.
4. The process as claimed in claim 1, wherein the ferric hydroxide obtained by reaction of ferric chloride with sodium carbonate in water.
5. The process as claimed in claim 1, wherein ferric hydroxide is washed to reduce impurities of halides and sulfates below 2%.
6. The process as claimed in claim 1, wherein the molecular weight of the IPC is controlled within 50,000 to 200,000 Da and the PDI of IPC is <2 to ensure uniform molecular weight distribution.
7. The process as claimed in claim 1, wherein citric acid is used as a chelating agent to stabilize the IPC and alternative chelators like malic acid, fumaric acid, or adipic acid may be used.
8. The process as claimed in claim 1, wherein the reaction temperature is maintained between 60°C and 120°C and more preferably at 90°C to 110°C.
9. The process as claimed in claim 1, wherein the IPC is characterized by GPC, IR, and PXRD for quality assurance.
10. The process as claimed in claim 1, wherein the final IPC product is free from impurities especially from genotoxic and nitrosamine impurities.
11. The process as claimed in claim 1, wherein the spray-dryerused to isolate IPC.
12. The process as claimed in claim 1, wherein IPC exhibits enhanced solubility and stability under pharmaceutical conditions.
13. The process as claimed in claim 1, wherein the settle time for ferric hydroxide is 8 hrs and reaction time is 6-12 hours to ensure optimal complex formation of the IPC and more preferably reaction time 8-10 hours

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