Description:Field of the Invention:

The present invention relates to an eco-friendly, cost-effective, and scalable synthetic method for producing white calcium ascorbate dihydrate, a stable compound widely used in pharmaceuticals, nutraceuticals, and food industries as a source of vitamin C and calcium. The invention emphasizes green chemistry principles, ensuring minimal environmental impact and high product stability.
Background of the Invention:
Calcium Ascorbate combines the potent antioxidant properties of vitamin C with the essential mineral calcium, creating a synergistic blend that delivers a myriad of advantages. Calcium ascorbate has dual usage for calcium supplementation and curing deficiency of vitamin C. Calcium ascorbate is increasingly being used in intravenous vitamin C therapy, particularly in the treatment of certain cancers and other chronic diseases. Its high bioavailability and antioxidant properties make it an effective choice for delivering therapeutic doses of vitamin C directly into the bloodstream.
Calcium ascorbate, a compound combining calcium and ascorbic acid, is recognized for its nutritional benefits and stability. Calcium Ascorbate Dihydrate is a calcium salt of ascorbic acid (Vitamin C) and the structure forms a lattice with alternating layers of calcium ions, ascorbate molecules, and water molecules. The two water molecules enhance the solubility and bioavailability of the compound. These water molecules are tightly bound in the crystal structure and help maintain its physical integrity.
Conventional methods of producing calcium ascorbate and calcium ascorbate dihydrateoften involve organic solvents, hazardous reagents, and energy-intensive processes, leading to environmental concerns and high production costs. Additionally, these methods yield light yellow calcium ascorbate dihydrate, which is less stable than its white counterpart.
Stability of white calcium ascorbate dihydrate is more than the light-yellow calcium ascorbate dihydrate. The yellowing of the latter suggests some degree of oxidation, which can degrade the vitamin C content and reduce its efficacy. The storage and synthesis of white calcium dihydrate is complex.
The prior art US2596103 titled ‘Crystalline calcium ascorbate and method of preparing same’ disclosed process for the manufacturing of crystalline calcium ascorbate dihydraewhich comprises preparing a solution of calcium ascorbate in water, mixing such solution with a quantity of ethyl alcohol.
The prior art CN106866592 titled ‘Preparation method of L-calcium ascorbate’ disclosed preparation method of L-calcium ascorbate where methanol used as solvent.
The Prior art CN1112418 titled ‘Preparing method of calcium ascorbate’ disclosed the preparation method where heating and high temperature is essential part of the method. The prior art discloses the temperature range till 80 deg C require high energy source of heating. The prior art also disclosed that the weight ratio of ascorbic acid and water and is 1:0.8 to 1 which imply that more or equal amount of ascorbic acid is required with respect to water that means there is no step of dissolution in the preparation method. The prior art required reactor and heating equipment to complete the process.
The present invention addresses these challenges by providing a novel, greener process for synthesizing white calcium ascorbate dihydrate. This method adheres to green chemistry principles, including the use of water as the sole solvent, elimination of toxic reagents, energy efficiency, and scalability for industrial production and cost effective.
The present invention is to manufacture of white calcium ascorbate dihydrate with cost effective, higher yield, robust and green manufacturing process.
Summary of the Invention:
The present invention is a process for preparing white calcium ascorbate dihydrate by reacting ascorbic acid with calcium carbonate in water. The process eliminates the use of organic solvents, operates under mild conditions below 30°C, and ensures high yield and purity. The resulting product is stable, free from toxic impurities, and suitable for industrial applications.

Key features include:
1. Eco-Friendly Solvent: Only water is used, avoiding toxic and hazardous solvents.
2. Mild Reaction Conditions: Reaction occurs below 30°C, reducing energy consumption.
3. High Yield and Purity: The product is white, non-hygroscopic, and stable.
4. Industrial Scalability: Simplified process with minimal equipment requirements.
5. No toxic by-products.
Figures and Tables:
Fig. 1: Chemical Structure of Calcium Ascorbate Dihydrate.
Fig. 2: Reaction Scheme.
Fig. 3: Representative Reaction to Form Nitrosamines
Fig. 4: Chemical Structures of Potential Small-Molecule Nitrosamine Impurities in APIs and Drug Products
Fig. 5: Proposed Mechanism of decomposition of nitrosamine impurity
Table 1: Comparison table of Conventional Methods vs Present Invention
Table 2: List of related impurities
Table 3: Risk Assessment (In line with FDA guideline)
Table 4: Physio-chemical data
Table 5: Assay of batches
Table 6: LOD of batches
Table 7: pH of batches
Table 8: SOR of batches
Table 9: Calcium Content of batches
Table 10: Infrared Absorption
Graph 1: HPLC Graph of Ascorbic acid
Graph 2: Infrared Absorption (IR)
Graph 3: H-NMR spectra of Calcium Ascorbate Dihydrate
Graph 4: Mass spectra of calcium ascorbate dihydrate
Graph 5: DSC data of calcium ascorbate dihydrate
Graph 6: TGA of Calcium ascorbate dihydrate
Detailed Description of the Invention:
Physicochemical properties:
The molecular weight of the Calcium ascorbate dihydrate: 426.34.
CAS No.: [5743-28-2]
The molecular formula: C12H18CaO14
Chemical structure:

Fig. 1: Chemical Structure of Calcium Ascorbate Dihydrate
Procedure for the preparation of calcium ascorbate dihydrate as mentioned in Fig. 2. The steps are involved, addition of ascorbic acid and calcium carbonate in water followed by crystallization, filtration and drying. Reaction is performed by the stoichiometric ratio of ascorbic acid and calcium carbonate (Generally 2:1 ratio). Water and ascorbic acid ratio are used in maximum 3:1. This step is carried out for maximum 30 minutesunder stirringat below 30⁰C. Calcium carbonate is added slowly at this temperature. The reaction is carried out for the period of maximum 30 minutes at below 30⁰C. The reaction mass is filtered and further stirred at below 30⁰C over a period of maximum 60 minutes for removal of excess carbon dioxide from the reaction mass as well as completion of the reaction.
Seed material is added 0.005 to 0.011 parts with respect to input ascorbic acid. This reaction is carried out at below 30⁰C over a period of maximum 90 minutes under stirring for the formation of crystals. Finally, the reaction mass is stirred at below 30⁰C for maximum 300 minutes under stirring for completion of crystal formation. The solid is filtered and dried at 35⁰C to 45⁰C for 8-10 hrs. or the reaction mass is spray dried to get the white calcium ascorbate dihydrate with higher yield.
The stirrer RPM is maintained 60-100 throughout the process.

Fig.2: Reaction scheme
1. Reaction Scheme
The reaction involves the direct combination of ascorbic acid (C6H8O6) and calcium carbonate (CaCO3) in stoichiometric proportions (2:1 molar ratio):
C6H8O6 + CaCO3 + H2O → C12H18CaO14·2H2O + CO2
This reaction is environmentally benign as it occurs in water and produces no hazardous by-products.
2. Process Steps:
I. Preparation of Reaction Mixture:
o Addition of ascorbic acid in water for uniform mixing.
o The water-to-ascorbic acid ratio is maintained at approximately 3:1, ensuring the optimal reactivity.
o The mixture is stirred at below 30°C for 30 minutes to achieve uniform mixing.
II. Addition of Calcium Carbonate:
o Slowly addition of calcium carbonate to prepare ascorbic acid mixture.
o The addition is gradual to avoid excessive effervescence from CO2 evolution.
o Stirring is continued for 30 minutes at below 30°C.
o The reaction mass is filtered to remove the unreacted calcium carbonate if any.
o The reaction mass is further stirred at below 30⁰C over a period maximum 60 minutes to ensure complete reaction.
III. Crystallization:
o Seed material, typically qualified calcium ascorbate dihydrate, is added at a concentration of 0.005–0.011 parts relative to the weight of ascorbic acid.
o The mixture is stirred for maximum 300 minutes at below 30°C, facilitating nucleation and growth of the crystalline product.
IV. Filtration and Drying:
o The reaction mass is filtered to separate the solid calcium ascorbate dihydrate from the liquid phase.
o The product is dried under vacuum at 35–45°C for 8–10 hours or alternatively spray-dried to achieve a free-flowing powder.
o The yield typically ranges from 95% to 98%, with high purity and confirmed by analytical techniques.
3. Advantages of Mild Reaction Conditions:
• Operating below 30°C minimizes energy requirements and prevents thermal degradation of ascorbic acid.
• The low-temperature process aligns with the green chemistry principles by reducing the overall environmental impact.
4. Quality of the Product and it’s Characterization:
The quality of the final product, calcium ascorbate dihydrate, is obtained as per the following properties:
• Description: White powder practically odorless powder.
• Assay: 98.0-101.0%w/w as confirmed by HPLC.
• Loss on drying: Below 0.1%w/w.
• pH: Neutral range of 6.8–7.4.
• Solubility: Freely soluble in water, slightly soluble in alcohol, insoluble in ether.
• Stability: Non-hygroscopic and stable for extended storage.
5. Other analytical Data:
The invention ensures that the product meets the stringent quality standards:
• HPLC Analysis: Confirms the absence of related impurities of L-ascorbic acid (Such as dehydroascorbic acid and 2,3-diketogluconic acid etc.).
• TGA and DSC analysis: Demonstrate the thermal stability and dehydration characteristics of the product.
• IR, 1H-NMR and LC-MS spectral data: Confirmsthe chemical structure of calcium ascorbate dihydrate.
6. Comparative Data:
The invention’s greener aspects are highlighted through a comparison with conventional methods (Table-1):

Parameter Conventional Methods Present Invention
Solvent Used Organic solvents Water
Temperature >50°C <30°C
By-products Toxic Non-toxic
Energy Consumption High Low
Product Color Light Yellow White
Stability Moderate High
Table 1:Comparison table of Conventional Methods vs Present Invention
7. Environmental Impact:
• No use of hazardous solvents or reagents.
• Minimal waste generationbeing environmentally benign.
• Energy-efficient process contributes to lower carbon footprint.
Example
50 kg ascorbic acid is added in about 100 L water. The mass is stirred about 20 minutes. About 15 kg of calcium carbonate is added slowly in the reaction mass and stirred for about 30 minutes at below 30⁰C. The reaction mixture is filtered and further stirred for about 60 minutes for removal of excess carbon dioxide. About 0.5kg seed material (Qualified Calcium ascorbate dihydrate) is added and then stirred about 60 minutes. The mixture is further stirred at below 30⁰C for about 4 hrs. Solid is filtered and dried for about 10 hrs. at about 45⁰C or the reaction mass is spray dried to get the white crystalline solid of calcium ascorbate dihydrate with higher yield (48-50 Kg).

Related Impurity profile:
According to the procedureand key starting material, four related substances in calcium ascorbatedihydrate are possible which are tabulated below (Table-2):
Sl. No. Impurity Origin of impurity Fate of the impurity
1 D-Ascorbic acid(corresponding D isomer)
KSM BDL in the starting material by HPLC.
2 Dehydroascorbic acid
KSM ND in the starting material by HPLC and 1H-NMR.
3 2,3-Diketogluconic acid
KSM ND in the starting material by HPLC and 1H-NMR.
4 Furfural
KSM ND in the starting material by HPLC and 1H-NMR.
Table 2: List of related impurities
Since our ascorbic acid (KSM) is free from the above related impurities as supported by the following HPLC graph (Graph 1), we can conclude that, the related impurities are controlled in the quality of KSM.

Graph 1: HPLC Graph of Ascorbic acid
The corresponding product of Calcium ascorbate dihydrate has the HPLC purity about 100% as ascorbic acid which provides the confirmation for the 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 (R1 N(-R2 )-N=O), as shown in Fig.3. The compounds can form by a nitro sating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions).

Fig.3Representative 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) (Fig. 4). 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 are not used, hence we declare that, our APIs are free from any nitrosamine impurities.
Fig.4. Chemical Structures of Potential Small-Molecule Nitrosamine Impurities in APIs and Drug Products:

Table 3: 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 3) is expected to provide us high level of confidence for the absence of Nitrosamine impurities in our calcium ascorbate dihydrate product.
For the sake of argument, if we consider traces of nitrosamine impurity is 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. 5). The general mechanism is proposed by the inventors.

Fig. 5: Proposed Mechanism of decomposition of nitrosamine impurity
From the above mechanism and reaction scheme, we can establish that,there is no nitrosamine in our calcium ascorbate dihydrate material.
Physio-chemical Data:
Physical Properties (Typical values):
Description A white odorless crystalline Powder
Solubility Freelysoluble in Water
pH (in 5% w/v in aq. Soln.) ~7.0
Assay (as is basis) 100.76%
Table 4: Physio-chemical data

Typical Value of Untapped Density: 0.5 g/cc
Typical Value of Tapped Density: 0.71 g/cc
Robustness of the Manufacturing Process:
The WBCIL manufacturing process of Calcium ascorbatedihydrate is controlled by optimization of thedifferent reaction parameters. To check the robustness of the manufacturing process, the process is repeated by the scale up from 20 g to 5000g in the laboratory. All the analytical results are found consistent. Some analytical data (Assay, pH, SOR, LOD and calcium content)of different batches are presented as graphical presentation to explain the robustness of the manufacturing process:
Assay of seven batches:
Experiment No. Assay (98.0-101.0%w/w)
1 100.02
2 100.76
3 100.02
4 100.1
5 100.6
6 99.57
7 99.5

Table 5: Assay of batches

LOD of seven batches:
Experiment No. LOD (NMT 0.1%w/w)

1 0.08
2 0.02
3 0.05
4 0.01
5 0.04
6 0.05
7 0.05
Table 6: LOD of batches
pH of seven batches: Maintained ~7.0

Experiment No. pH (6.8-7.4)

1 6.97
2 6.92
3 7.14
4 7.21
5 7.35
6 7.3
7 7.2
Table 7: pH of batches

SOR of seven batches:
Experiment No. SOR(⁰) [+95.0 to +97.0)

1 96.64
2 96.75
3 96.12
4 96.11
5 96.02
6 96.07
7 95.12
Table 8: SOR of batches

Calcium content of seven batches:

Experiment No. Calcium content (9.0-10.0%)
1 9.13
2 9.69
3 9.24
4 9.65
5 9.28

6 9.6
7 9.15 Table 9: Calcium Content of batches
As per the above analytical data, we can conclude that, the batches are compiled as per targeted specifications. So, we can say the manufacturing process is robust.
Infrared Absorption (IR):
The major characteristic peaks of Calciumascorbate dihydrate are identified by IR are presented below:

Graph 2: Infrared Absorption
Region Characteristic peaks for the functional group (cm-1) WBCIL results for calcium ascorbate dihydrate (cm-1)
-OH Broad peak from 3550 to 3200 3521.4, 3483.2
-C=O Strong peak from 1850 to 1650 1720.2, 1699.7
Fingerprint region Weak peaks below 1500 993.3, 755.7
-C=C Strong peak from 1680 to 1630 1559.0
-C-O Weak peak from 1300 to 1000 1075.3, 1139.6
Table 10: Infrared absorption
1H-NMR spectra of calcium ascorbate dihydrate:
The structure of calcium ascorbate dihydrate was confirmed by 1H-NMR which is presented below:


Graph 3: H-NMR spectra of Calcium ascorbate dihydrate

Mass Spectra of calcium ascorbate dihydrate:
The base peak at 351.28 in ESI, -ve mode of the HRMS spectra corresponds to dimer of ascorbic acid unit (176*2-1 = 351).So, the HRMS data indicate that the presence of ascorbate moiety of calcium ascorbate dihydrate.

Graph 4: Mass Spectra of calcium ascorbate dihydrate
DSC data of calcium ascorbate dihydrate:
The DSC (Differential Scanning Calorimetry) data in the graph represents the thermal behavior of calcium ascorbate dihydrate as the temperature is increased.

Graph 5: DSC data of calcium ascorbate dihydrate
Analysis of DSC graphs:
Dehydration Process:
The first endothermic peak has an onset temperature at 145.99°C and a peak temperature of 154.36°C. This represents the release of bound water (dehydration) from calcium ascorbate dihydrate.The associated enthalpy (normalized) is 159.68 J/g, indicating the energy required for this dehydration process.
Melting/Decomposition:
The second major endothermic peak has an onset temperature at 184.04°C and a peak temperature of 209.89°C.The enthalpy (normalized) for this transition is 531.80 J/g, which indicates a more energy-intensive process, likely the melting or thermal decomposition of the compound after dehydration.
Material Stability:
The material is stable up to 145.99°C, beyond which it undergoes significant thermal events, starting with the loss of water molecules.After dehydration, the compound may transition to its anhydrous form, which undergoes melting or decomposition at higher temperatures (184.04°C and above).
TGA (Thermogravimetric analysis) of calcium ascorbate dihydrate:
TGA thermograms of calcium ascorbate dihydrate showsthe following characteristics natures:

Graph 6: TGA
Analysis of TGA graph:
Thermal Stability and Decomposition:
Calcium ascorbate dihydrate remains thermally stable up to 179.58°C, as there is no significant weight loss below this temperature.The sharp weight loss starting at 179.58°C indicates the onset of dehydration, where the compound loses its water molecules.
Dehydration Process:
The weight loss of 50.39% in the range of 179.58°C to 206.22°C is attributed to the removal of two water molecules (dehydration process). This confirms that calcium ascorbate dihydrate loses its bound water in this temperature range, transitioning to its anhydrous form.
Thermal Decomposition:
Beyond 206.22°C, no further significant weight loss is observed up to 400°C, suggesting that the anhydrous form of calcium ascorbate is thermally stable in this range.
Material Characterization:
The TGA data confirms the composition and thermal behavior of calcium ascorbate dihydrate characteristic weight loss associated with dehydration provides a quantifiable measure of its water content and purity.

, Claims:We claim

1. A greener process for synthesizing white calcium ascorbate dihydrate, comprising:
a. properly mixing of water and ascorbic acid maintaining ratio of maximum 3:1 ensuring optimal solubility and reactivity;
b. stirring under mild conditions below 30°C and continue stirring the reaction mass for the period of maximum 30 minutes;
c. adding of calcium carbonate as per optimal stoichiometric ratio to obtain reaction mass;
d. filtering of reaction mass and further stirring at below 30⁰C over a period of maximum 60 minutes for removal of excess carbon dioxide;
e. adding seed material 0.005 to 0.011 parts with respect to input ascorbic acid and stirring at below 30⁰C over a period of maximum 90 minutes for the formation of crystals;
f. stirring further the obtained reaction mass at below 30⁰C for maximum 300 minutes for completion of crystal formation; and
g. filtering and drying at 35⁰C to 45⁰C for 8-10 hrs under vacuum or spray drying to get the white calcium ascorbate dihydrate at pH 6.8 -7.4.
2. The process claimed in claim 1, wherein the reaction of ascorbic acid and calcium carbonate in water, under mild conditions below 30°C.
3. The process claimed in claim 1, wherein the stoichiometric ratio 2:1 of ascorbic acid and calcium carbonate.
4. The process claimed in claim 1, wherein stirring speed 60-100 rpm maintained during the process.
5. The process claimed in claim 1, wherein the reaction does not involve any organic solvents or catalysts.
6. The process claimed in claim 1, wherein the seed material is qualified calcium ascorbate dihydrate material.
7. The process claimed in claim 1, wherein the pH range 6.8 to 7.4 of final product aligns with the body’s natural pH environment (blood pH: 7.35–7.45), improving absorption and bioavailability.
8. The process claimed in claim 1, wherein the assay of calcium ascorbate dihydrate is not less than 98.0% w/w.
9. The process claimed in claim 1, wherein the process is stable, and free from nitrosamine impurities, organic volatile impurities, related impurities or any degradation product and toxicity.
10. The process claimed in claim 1, wherein the process is greener and safer where no organic solvents are used and not releases any toxic or environmental hazardous wastes.
11. The process claimed in claim 1, wherein the final product is highly stable and non-hygroscopic.
12. The process claimed in claim 1, wherein the yield is higher as well as cost effective and easily industrially scalable