Description:FIELD OF THE INVENTION

This invention relates to a novel, eco-friendly, and scalable process for synthesizing calcium gluconate. Specifically, it addresses the production of monohydrate and essentially anhydrous forms by controlling the pH of the reaction, ensuring high purity, and minimizing impurities such as nitrosamines, halides, and heavy metals.
BACKGROUND OF THE INVENTION
It is well recognized that calcium plays an important role inmammals. Calcium, accounting for approximately 1.5–2.2%of body weight, is a necessary major element in the humanbody. Approximately, 99% of calcium is in the bone andplays a key role in maintaining bone strength.Moreover, a wide range of biological functions of calciumhave been found, such as muscle contraction and nerveimpulse transmission. However, calcium deficiency hasalready become a worldwide nutritional deficiency publichealth problem. Calcium is essential for the maintenance of the functional integrity of the nervous, muscular and skeletal systems, and cell-membrane and capillary permeability. This cation is an important activator in many enzymatic reactions and is essential to a number of physiologic processes including the transmission of nerve impulses; contraction of cardiac, smooth, and skeletal muscles; renal function; respiration; blood coagulation. Calcium also plays a regulatory role in the release and storage of neurotransmitters and hormones, in the uptake and binding of amino acids, in cyanocobalamin (vitamin B12) absorption and in gastrin secretion.
The Calcium gluconate is a water-soluble organic calcium salt of gluconic acid. The chemical structure of calcium gluconate consists of a six-carbon chain with five hydroxyl (-OH) groups terminating in a carboxylic acid group. Additionally, the salt is composed of one calcium ion (Ca2+) for every two gluconate anions. The close proximity of the oxygen atoms within the chemical structure lends to its function as a highly efficient chelating agent. Chelating agents bind to positively charged metal ions in solution and prevent them from forming insoluble precipitates with other ions that may be present. Calcium gluconate functions as a chelating agent over a wide pH range. It is efficient in forming stable chelates with divalent and trivalent metal ions such as potassium, copper, iron, aluminum, and other metals, reducing the adverse effects these metals can have on systems. In addition, calcium gluconate acts as a humectant, which means that it attracts water and increases hydration in products such as moisturizers and otherpersonal care products. Calcium gluconate is used as a chelating agent, sequestrant, humectant, andskin conditioning agent in a variety of applications and product sectors.
The Calcium gluconate is an organic calcium salt of gluconic acid, widely used in:
1. Pharmaceuticals: Treatment of calcium deficiencies such as hypocalcemia, osteoporosis, and rickets.
2. Industrial Applications: Chelating agent in cleaning formulations, scale removal, and water treatment.
3. Cosmetics and Food: As a humectant and mineral supplement.
The many studies of the EPA and OECD and their experimental data show that calcium gluconate show the less concern over the toxicity profile of Reproductive and Developmental Toxicity, Genotoxicity, Carcinogenicity, Neurotoxicity etc.
In prior art CN112552167titled Preparation method of calcium gluconate where gluconic acid-delta-lactone reacted with calcium carbonate at the temperature of 80-90 ℃ to obtain a calcium gluconate aqueous solution, adding medicinal active carbon, and preserving the temperature of 80-90 ℃ for 30min. This prior art is silent on pH adjustment and it is also silent on impurities obtained from the process.
In prior art CN115850057 titled Preparation method of calcium gluconate monohydrate where preparation method of calcium gluconate monohydrate, which takes gluconic acid-delta-lactone, calcium carbonate and water as initial raw materials and obtains the calcium gluconate monohydrate through hydrolysis, decoloration, crystallization and drying. This prior art only consider temperature is parameter and do not consider timing of reaction and pH adjustment of reaction which is essential to obtain high yield calcium gluconate monohydrate.
In prior art HU190016 titled Process for producing anhydrous calcium-gluconate-c of tetragonal structure where process involves mixing an aqueous solution of calcium gluconate with a water-immiscible organic solvent, by distillation from the heterogeneous system at a temperature of between 80 0C and 110 0C. The process involves the use of water-immiscible organic solvents such as toluene, xylene, and tetrachloroethane. These solvents can pose environmental and health hazards due to their toxicity and volatility, requiring stringent handling and disposal measures. This patent used organic solvent but silent about obtained organic impurities from the process.
Limitations in Existing Processes
1. Impurities: Residual nitrosamines, heavy metals, halides, and organic solvents affect the product's safety and quality.
2. Hydration State Control: Difficulty in selectively producing monohydrate or anhydrous forms.
3. Process Complexity: Inefficient and inconsistent multistep methods.
OBJECTIVES OF THE INVENTION
The invention aims to:
1. Provide a one-pot process for synthesizing calcium gluconate monohydrate and essentially anhydrous forms.
2. Enable hydration state control through pH modulation.
3. Produce a high-purity product free from harmful impurities.
4. Ensure reproducibility and scalability through Quality by Design (QbD) and Design of Experiments (DoE).
5. Eliminate the use of organic solvents for an eco-friendly approach.
The present invention has significant industrial applicability across multiple sectors, including pharmaceuticals, food, cosmetics, and industrial cleaning.
1. Pharmaceutical Industry:
• The calcium gluconate produced through this process serves as a high-purity active pharmaceutical ingredient (API) for treating calcium deficiencies, including hypocalcemia, osteoporosis, and rickets.
• Its impurity-free nature ensures safety and compliance with stringent pharmaceutical standards.
2. Food and Nutraceutical Industry:
• Calcium gluconate is widely used as a mineral supplement in fortified foods and beverages.
• The eco-friendly process ensures the product's suitability for direct consumption and dietary applications.
3. Cosmetic Industry:
• Its humectant properties make calcium gluconate an essential ingredient in moisturizers and other skincare products.
• The controlled hydration states enhance the stability and performance of cosmetic formulations.
4. Industrial Cleaning and Water Treatment:
• The chelating properties of calcium gluconate make it ideal for removing metal ions in cleaning agents and water treatment formulations.
• Its anhydrous form is particularly suitable for applications requiring long shelf-life and high solubility.
5. Eco-Friendly and Scalable Manufacturing:
• The one-pot process is scalable for large-scale production, meeting industrial demands while minimizing environmental impact.
• The absence of organic solvents and harmful by-products aligns with global environmental and regulatory standards.
The present invention ensures a robust, cost-effective, and versatile production process, addressing the growing industrial demand for high-quality calcium gluconate across various applications.
The present invention addresses the need for a scalable, efficient, and impurity-free synthesis of calcium gluconate in both monohydrate and essentially anhydrous forms. It targets pharmaceutical, nutraceutical, and cosmetic applications requiring high purity and compliance with stringent regulatory standards.
The present invention integrates the conversion of glucono-delta-lactone (GDL) and chelation with calcium salts into a streamlined process with precise pH control. Unlike existing methods, it eliminates the use of organic solvents and ensures the absence of harmful impurities such as nitrosamines and heavy metals.
SUMMARY OF THE INVENTION
The invention involves a two-step, one-pot synthesis:
1. Step 1: Hydrolysis of glucono-delta-lactone (GDL) to gluconic acid in water at 60 to 100 deg C for the period of 30 min to 4 hours till pH comes 1 to 4.
2. Step 2: Chelation of gluconic acid with calcium salts to form calcium gluconate at 60 to 120 deg C over a period 1 to 4 hours.
Hydration state is determined by the pH of the reaction:
• Monohydrate: pH 6.0–6.5.
• Essentially Anhydrous: pH 8.5–9.5.
The process yields a high-purity product free from nitrosamines, halides, and heavy metals.
FIGURES AND TABLES
Figures and tables provide theChemical structure, synthetic scheme, HPLC graphs, and analytical spectraetc. which visually clarify the process and results.
Figures
• Figure 1: Chemical structure of calcium gluconate monohydrate.
• Figure 2: Chemical structure of calcium gluconate anhydrous.
• Figure 3: Schematic of the synthetic process illustrating two steps and pH control for hydration state determination
• Figure 4: HPLC Graph of Glucono delta lactone
• Figure 5: List of Nitrosamine Impurity
• Figure 6: Proposed Mechanism of decomposition of nitrosamine impurity
• Figure 7: IR spectra of Calcium gluconate monohydrate
• Figure 8: IR spectra of Calcium gluconate essentially anhydrous
• Figure 9: XRD of Calcium gluconate monohydrate
• Figure 10: H-NMR Spectra of calcium gluconate
• Figure 11: Mass spectra of calcium gluconate
• Figure 12: DSC of calcium gluconate monohydrate
• Figure 13: TGA of calcium gluconate monohydrate
TABLES
Table 1: List of Related Impurity
Table 2: Risk Assessment (In line with FDA guideline)
Table 3: Physical Properties of calcium gluconate
Table 4: Assay of different batches
Table 5: LOD of different batches of Calcium Gluconate Monohydrate
Table 6: LOD of different batches of calcium gluconate anhydrous/essentially anhydrous
Table 7: pH of different batches
Table 8: Infrared absorption of calcium gluconate

DETAILED DESCRIPTION OF THE INVENTION
The molecular weight of the Calcium gluconate monohydrate: 448.4 Da.
CAS No.:[66905-23-5]
The molecular formula: C12H22CaO14.H2O
Chemical structure:

Fig. 1: Chemical Structure of Calcium Gluconate Monohydrate

The molecular weight of the Calcium gluconate anhydrous: 430.37 Da.
CAS No.:[299-28-5]
The molecular formula: C12H22CaO14
Chemical structure:

Fig. 2: Chemical Structure of Calcium Gluconate Anhydrous
Glucono delta lactone has been the subject of a large number of coordination chemical research investigations.Its complexationproperties are especially remarkable in alkaline to hyperalkaline pH conditions, where the deprotonationof one or more of its alcoholics OH groups provide a favorable frame for the formation of very stablechelate complexes with a large variety of metal cations. With the aim to show the state of the art of somerelevant issues in the aqueous chemistry of the gluconate ion and its chelation with calcium salt, the current invention focusses on the acidbaseproperties and calcium(II) complexation of the compound encompassing the formation of calcium gluconate (monohydrate as well as anhydrous or essentially anhydrous) in a one pot synthetic method by modulating the pH in aq. solution.
The present invention integrates two critical steps—hydrolysis of glucono-delta-lactone (GDL) to gluconic acid and chelation with calcium salts—into a single, streamlined procedure. The novelty lies in the precise pH control, which determines the hydration state of the final product, enabling selective synthesis of monohydrate or anhydrous/essentially anhydrous forms. The process excludes organic solvents, aligns with regulatory requirements, and ensures impurity-free products. Such innovations are not obvious from prior art, as typical methods require separate steps and more extensive purification.
The preparation of calcium gluconate is a two-step process as mentioned in Figure 3. The first step involved in the insitupreparation of gluconic acid from glucono-delta lactone (GDL) in aqueous solvent. This step is carried out by heating GDL in water at 60 to 100 deg C, preferably at 70 to 90 deg C more preferably at 80 to 85 deg C. The heating is carried out for the period of 30 min to 4h, preferably 30 min to 2h more preferably 30 min to 1h till the pH comes 1 to 4, preferably 1 to 3 more preferably 1 to 1.5, more preferably 1 to 1.25 with a transparent solution.

Figure3: Synthetic Scheme

Step 1: Hydrolysis of GluconoDelta Lacton (GDL) to Gluconic Acid
1. Materials:
o GDL: A polyhydroxy carboxylic acid derivative from glucose.
o Water: UV-purified to ensure no contaminants.
The GDL is free from related impurities such as glucuronic acid and 5-hydroxymethylfurfural, as verified by HPLC and NMR. Calcium carbonate and calcium hydroxide are preferred due to their cost-effectiveness and compatibility with the process.
2. Process Conditions:
o Dissolve GDL in water.
o Heat the solution at 60 to 100 deg C, preferably at 70 to 90 deg C more preferably at 80 to 85 deg C. The heating is carried out for the period of 30 min to 4h, preferably 30 min to 2h more preferably 30 min to 1h.
o Hydrolysis lowers the pH to 1 to 4, preferably 1 to 3 more preferably 1 to 1.5, more preferably 1 to 1.25 with a transparent solution of gluconic acid.
The second step involves the chelation with proper calcium salt namely calcium hydroxide, calcium carbonate or/and mixture thereof. This chelation is carried out by means of lot wise or controlled addition of appropriate calcium salt on gluconic acid derived from glucono-delta lactone. This reaction is carried out at 60 to 120 deg C preferably at 70 to 100 deg C, more preferably at 80 to 85 deg C over a period of 1 to 4h, preferably 1 to 3 h, more preferably 2 to 3 h. The end point of the reaction is pH of the reaction mass. This pH is a critical process parameter for the preparation of calcium gluconate. The pH in the above step to be maintained at slightly acidic preferably 6 to 6.5 to get calcium gluconate monohydrate. The corresponding cool solution to be filtered to get a clear solution and to be isolated through spray drying.
To get the calcium gluconate anhydrous/essentially anhydrous, the reaction mixture having pH 6 to 6.5 was further basified preferably to 8.5 to 9.5, preferably with calcium hydroxide. The resulting solution was cooled and filtered to get a clear solution followed by isolation through spray drying.
Step 2: Chelation with Calcium Salts
1. Materials:
Calcium Carbonate: Neutralizes acidity and provides calcium ions.
Calcium Hydroxide: Adjusts pH to control hydration state.
2. Process Conditions:
• Gradually add calcium salts to the gluconic acid solution over 1 to 4h, preferably 1 to 3 h, more preferably 2 to 3 hours while maintaining 60–120°Cpreferably at 70 to 100 deg C, more preferably at 80 to 85 deg C.
• Monohydrate: Maintain pH at 6.0–6.5.
• Anhydrous/Essentially Anhydrous: Adjust pH to 8.5–9.5 using additional calcium hydroxide.
3. Isolation:
• Cool the reaction mass, filter, and spray dry to obtain the final product.
EXAMPLES
Example 1: Preparation of Calcium Gluconate Monohydrate
1. Add 1500 L of UV-purified water into a clean reactor.
2. Charge 500 kg of glucono-delta-lactone (GDL) into the reactor under stirring.
3. Heat the solution to 80°C and maintain for 30–45 minutes until the pH drops to 1.1, forming a transparent gluconic acid solution.
4. Prepare a mixture of 125 kg calcium carbonate and 25 kg calcium hydroxide. Add this mixture to the gluconic acid solution lot-wise over 1–2 hours while maintaining 80°C.
5. Continue heating for an additional 1–2 hours until the pH stabilizes at 6.0–6.5.
6. Cool the reaction mass, filter to remove insoluble impurities, and spray dry the filtrate to obtain ~560 kg of calcium gluconate monohydrate.
Example 2: Preparation of Calcium Gluconate Anhydrous/Essentially Anhydrous
1. Repeat Steps 1–5 of Example 1 to form the calcium gluconate monohydrate solution.
2. Adjust the pH of the reaction mixture to 8.5–9.5 by adding additional calcium hydroxide under stirring.
3. Cool the solution, filter, and spray dry to obtain ~560 kg of calcium gluconate anhydrous/essentially anhydrous.
Impurity Profile
Related Impurity profile
According to the method for detecting 4 related substances in calcium gluconate are possible which are tabulated below (Table 1):
Sl. No. Impurity Origin of impurity Fate of the impurity
1 Glucuronic acid or the corresponding D isomer.
Key starting material (KSM) Below detection limit (BDL) in the starting material by HPLC.
2 Glucuronolactone or Glucurolactone
KSM Note detected (ND) in the starting material by HPLC and 1H-NMR.
3 D-gluconic acid-gamma-lactone
KSM ND in the starting material by HPLC and 1H-NMR.
4 5-Hydroxymethylfurfural
KSM ND in the starting material by HPLC and 1H-NMR.
Table 1: List of related impurities
Since our glucono delta lactone is free from above related impurity as supported by following HPLC graph (Figure 4), we can say that we are controlling the related impurity in the KSM itself.

Figure 4: HPLC Graph of Glucono delta lactone
The corresponding product of Calcium gluconate has the HPLC purity about 100% as gluconic acid which gives the certainty of absence of any related impurity.

Nitrosamine Impurity (In Line With FDA):
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) (Figure 5). 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., water are not used, hence we declare thar our APIs are free any nitrosamine impurities.

Figure 5: List of Nitrosamine Impurity
Table 2: 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
The above review (Table 2) 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 impurityis formed due to environmental contamination it undergoes decomposition under acid catalyzed reaction condition of Ca(II); (Ref:J. Org. Chem.,1979, 44, 784-786) in the following mechanistic pathway (Fig. 6). The general mechanism is proposed by the inventors.

Figure 6: Proposed Mechanism of decomposition of nitrosamine impurity
From the above logic and data, we have established that in our calcium gluconate there is no nitrosamine impurity.
Physio-chemical Data:
Physical Properties (Typical values):
Description White Color Powder
Solubility Sparingly Soluble in Water
pH (in 5% w/v in aq. soln) 6.89
Assay (as is basis) 99.76%
Table 3: Physical properties of Calcium gluconate
Typical Value of Untapped Density: 0.29 g/cc, Typical Value of Tapped Density: 0.38 g/cc
Robustness of the Manufacturing Process:
The present manufacturing process of Calcium gluconate 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 assay, pH and loss on drying (LOD) of different batches are very consistent as presented below:
The following graphical presentation is self-explanatory for the robustness of the manufacturing process so far, the assay is concern.

Table 4: Assay of different batches
Similarly, the QbD and DoE driven manufacturing process in a GMP/GLP unit also the ensure the robustness of the process which is reflected in the value of LOD and pH of the final API which is presented below:

Table 5: LOD of different batches of calcium gluconate monohydrate

Table 6:LOD of different batches of calcium gluconate anhydrous/essentially anhydrous

Table 7: pH of different batches

The process has been scaled up from laboratory to pilot-scale production. Batch consistency is validated through parameters such as assay, pH, and loss on drying (LOD). The robustness of the process is evident from minimal variation across batches. Implementation of QbD (Quality by Design) and DoE (Design of Experiments) ensures reproducibility and adherence to good manufacturing practices (GMP) guidelines.

Structural Characterization of Calcium (II) Gluconate:
Infrared Absorption (IR):
Calcium gluconate could be anhydrous or monohydrate. It can be distinguished by IR only. The characteristic peaks are presented below:
Region Characteristic peak for anhydrous (cm-1) WBCIL results for anhydrous/essentially anhydrous(cm-1) Characteristic peak for monohydrate (cm-1) WBCIL results for monohydrate (cm-1)
-OH Only broad peak at 3485 Broad peak at 3322 Medium sharp broad peak at 3485 3485
-C=O Strong peak at 1618 1698 1595 1594
Fingerprint region 1329 1339 Absent
1305 (not observed) 1305 1305
1263-1250 1256 Absent
1236 (not observed) 1236 1236
1007 1042 Absent
1045 (not observed) 1045 1044
948 947 Absent
972 (not observed) 972 971
865 884 Absent
878 (not observed) 878 878
766 784 Absent
Table 8: Infrared adsorption of calcium gluconate
IR spectra calcium gluconate monohydrate:

Figure 7: IR spectra of calcium gluconate monohydrate
IR spectra calcium gluconate anhydrous/essentially anhydrous manufactured by WBCIL:

Figure 8: IR spectra of calcium gluconate anhydrous/essentially anhydrous

XRD:
The crystalline nature of calcium gluconate monohydrate was further supported by XRD which shows the characteristic peak at 2 theta 7.95 deg and 8.99 deg which is in line with Figure 6 of European patent application 0235514A1.

Figure 9: XRD of Calcium gluconate monohydrate

1H-NMR spectra of calcium gluconate:
The structure of calcium gluconate was confirmed by 1H-NMR which is presented below:


Figure 10: H-NMR Spectra of calcium gluconate
Mass Spectra of calcium gluconate:
The mass spectra (ESI, -ve mode) indicates the presence of gluconate moiety as it is confirmed by the base peak at m/z 195.

Figure 11: Mass spectra of calcium gluconate
DSC of calcium gluconate monohydrate:
The DSC curve shows an endothermic peak in the temperature 161 deg C due to dehydration. In addition, thistemperature is significantly higher than the boiling point ofwater, implying a strong interaction between water and calciumgluconate molecules. Next, a heat absorption peak occurs at 194.21 deg C without mass loss, which is assigned to the melting ofcalcium gluconate.

Figure 12: DSC of calcium gluconate monohydrate

TGA of calcium gluconate monohydrate:
TGA thermograms of calcium gluconatemonohydrate show a weight loss of 4.41% at about 150 deg C, which coincides with the theoretical value of one watermolecule in the single crystal structure (4.01%).

Figure 13: TGA of calcium gluconate monohydrate

The present invention solves multiple challenges in the synthesis of calcium gluconate. Traditional methods often involve multiple steps, organic solvents, or complex equipment, making them costly, environmentally unfriendly, or challenging to scale. The one-pot method simplifies the process, ensuring higher efficiency, better yield, and reduced environmental impact. By targeting pharmaceutical, nutraceutical, and cosmetic sectors, this process caters to industries requiring high-purity compounds. The invention also enables the production of both monohydrate and anhydrous forms, widening its application scope
, Claims:We Claim

1. A one-pot synthesis method for calcium gluconate, comprising:
Hydrolyzing glucono-delta-lactone (GDL) in water to form gluconic acid by heating at 60–100°C, preferably 80–85°C, until the pH reduces to 1 to 4, preferably 1 to 1.25, for 30 min to 4 hours, preferably 30 min to 1 hour;
Adding calcium salts, selected from calcium carbonate, calcium hydroxide, or a mixture thereof, to the gluconic acid solution under stirring at 60–120°C, preferably 80–85°C, for 1 to 4 hours to chelate gluconic acid, preferably 2 to 3 hour;
Modulating the pH during or after chelation to:
 6.0–6.5 for producing calcium gluconate monohydrate; or
 8.5–9.5 for producing calcium gluconate anhydrous and or essentially anhydrous;
Cooling, filtering, and isolating the product by spray drying.

2. The method of claim 1, wherein the process is free from organic solvents and harmful impurities, including nitrosamines, halides, and heavy metals.

3. The method of claim 1, wherein glucono-delta-lactone is hydrolyzed in UV-purified water to ensure a contaminant-free environment, producing a transparent gluconic acid solution.

4. The calcium gluconate monohydrate product obtained by the process of claim 1, having:
-Purity >99%;
-No detectable related impurities; and
-Consistent hydration state, as confirmed by thermal and spectroscopic analysis.

5. The calcium gluconate anhydrous product obtained by the process of claim 1, characterized by:
-Absence of residual water;
-Thermal stability as verified by TGA and DSC; and
-High purity (>99%).

6. The method of claim 1 wherein theprocess for controlling hydration states of calcium gluconate, comprising modulating the pH during the chelation step:
-A pH of 6.0–6.5 produces calcium gluconate monohydrate; and
-A pH of 8.5–9.5 produces calcium gluconate anhydrous or essentially anhydrous.

7. The method of claim 1, wherein the calcium salts are added in a lot-wise or controlled manner to ensure uniform chelation and consistent product quality.

8. The process claimed in claim 1, validated by Quality by Design (QbD) and Design of Experiments (DoE), ensuring batch-to-batch consistency in terms of assay, pH, and loss on drying (LOD).

9. The process claimed in claim 1 is robust and scalable process for calcium gluconate production, applicable to pharmaceutical, industrial, food, and cosmetic formulations, ensuring compliance with global standards for safety, purity, and environmental sustainability