Description:FIELD OF THE INVENTION

The present invention relates to the field of green chemistry and pharmaceutical synthesis, specifically concerning a sustainable, non-toxic, and organic solvent-free method of preparing white zinc ascorbate. The present invention relates to a green synthetic method for preparing zinc ascorbate, a chelated compound with significant applications in human health, veterinary medicine, and agriculture. It particularly addresses an eco-friendly, scalable method yielding high-purity white zinc ascorbate.

BACKGROUND OF THE INVENTION

Zinc Ascorbate is a chelated complex of zinc ion (Zn²⁺) with ascorbic acid (Vitamin C), recognized for its dual biological roles in supporting immunity, antioxidant activity, wound healing, antiviral action, and nutritional supplementation.
Zinc ascorbate is a potent, well-tolerated compound that combines the immune-boosting and antioxidant effects of both zinc and vitamin C, making it ideal for daily supplementation and therapeutic use. In veterinary nutrition, zinc ascorbate offers a bioavailable source of essential nutrients that improves health, productivity, and immunity across species. Zinc ascorbate is also a superior micronutrient solution for sustainable agriculture, enhancing crop health and resistance under abiotic and biotic stress conditions.
Generally, appearance of zinc ascorbate in literature is off white to yellowish white, slight cream or pale-yellow tint may appear depending on moisture content. Zinc ascorbate is known in the literature, most reported methods involve the use of organic solvents, pH adjustments using strong acids or bases, or indirect salt metathesis approaches. The white zinc ascorbate is superior than any existing appearance of zinc ascorbate but there are no process has been disclosed in any literature to prepare the white zinc ascorbate without using of organic solvent.
Prior art literature titled “Zinc ascorbate: A combined experimental and computational study for structure elucidation” (Ref: C. Unaleroglu, Journal of Molecular Structure, 605 (2002), 227-233) wherein the yellowish white Zinc ascorbate prepared after using solvent (acetone) and zinc sulfate (ZnSO4.7H2O ) and Barium hydroxide (Ba(OH)2. 8H2O). The process disclosed in the literature to prepare white yellowish zinc ascorbate in lab for academic interest which lacks the industrial applicability. The prior art silent on the environmental aspects and also silent on impurity profile of process.
Prior art literature titled “An ambient complexation reaction of zinc acetate and ascorbic acid leads to a new form of nanoscale particles with emergent optical properties” (Ref: https://doi.org/10.1039/D1NA00023C) wherein the product formed mixture of zinc acetate and ascorbate which is totally different from zinc ascorbate of pure form.
Existing synthetic methods involve multiple steps, using organic solvents, strong acids/bases, or indirect salt metathesis methods, often leading to environmental concerns, impurity formation, and lower yield. Moreover, by-products and waste treatment in conventional approaches increase costs and reduce scalability. Hence, there is a demand for a simple, greener process for manufacturing of zinc ascorbate that maintains product purity and environmental sustainability.
Objective of the Invention:
The primary objective of the present invention is to provide a novel, environmentally sustainable, one-pot method for the synthesis of white zinc ascorbate. The invention aims to:
1. Develop a greener, eco-friendly process that eliminates the need for organic solvents, toxic reagents, and complex downstream processing.
2. Provide a cost-effective and scalable synthesis method for high-purity zinc ascorbate suitable for large-scale industrial production.
3. Ensure high yield and robust product quality, free from nitrosamine and other hazardous impurities.
4. Deliver a process aligned with green chemistry principles, minimizing environmental impact, and reducing energy consumption during production.
5. The process for the preparation of white zinc ascorbate that maintains its bioavailability and dual functional properties, making it ideal for pharmaceutical, veterinary, and agricultural applications.
Features of the Invention:
1. One-Pot Synthesis: The invention involves a straightforward one-pot synthesis method for producing white zinc ascorbate in aqueous medium, eliminating the need for toxic solvents, acids, or bases.
2. Environmental Sustainability: The process is free from harmful organic solvents and by-products, ensuring minimal environmental pollution and adherence to green chemistry principles.
3. Energy Efficiency: The process operates at low temperatures (<30°C), which reduces energy consumption, making the method cost-effective and suitable for large-scale production.
4. High Purity Product: The resulting zinc ascorbate is of high purity, with a zinc content of 14.0–18.8% w/w and ascorbic acid content of NLT 80% w/w. The product is free from nitrosamine impurities and other toxic contaminants, ensuring safety for human, veterinary, and agricultural applications.
5. No Nitrosamine Formation: The process avoids any nitrosamine impurity formation by eliminating the use of amines, nitrates, nitrites, and their precursors, thus ensuring compliance with FDA guidelines.
6. Scalable and Industrially Feasible: The method is scalable from laboratory to industrial scale, making it commercially viable for production in large quantities with consistent product quality.
7. Robust Process: The manufacturing process has been optimized for robustness, with consistent results across different production scales, confirming the method’s reliability in commercial production.
8. Dual Application: The final product is versatile, being suitable for human health supplements, veterinary use in livestock, and agricultural applications, where it acts as a micronutrient that enhances growth, immunity, and stress tolerance in plants.
The present invention overcomes the limitationof prior arts by providing a one-step, water-based synthetic method that avoids organic solvents and yields a high-purity, white solid Zinc Ascorbate product suitable for use in human and veterinary nutrition as well as agriculture.
The present invention is sustainable, solvent-free, cost effective, scalable and higher yield synthetic method for zinc ascorbate. The process aligns with green chemistry principles, potentially utilizing aqueous media and plant-based reducing agents to minimize environmental impact.

SUMMARY OF THE INVENTION
The present invention provides a green, one-pot synthetic route for producing white zinc ascorbate through the direct reaction of ascorbic acid and zinc oxide in aqueous medium. The reaction is carried out at ambient temperatures (below 30°C) with no use of organic solvents or external pH modifiers. The reaction mass is then filtered and spray-dried directly to obtain solid white zinc ascorbate. Analytical data confirms robustness, purity, and absence of impurities including nitrosamines. The process provides significant improvements over existing prior arts in terms of cost, environmental impact, and product quality.
Summary of Figures
Fig 1: Chemical Structure of Zinc Ascorbate
Fig 2: Reaction scheme
Fig 3: HPLC Graph of Ascorbic acid
Fig 4: Representative Reaction to Form Nitrosamines
Fig 5: List of Nitrosamine Impurity
Fig 6: Proposed Mechanism of decomposition of nitrosamine impurity
Fig 7: Infrared Absorption (IR)
Fig 8: 1H-NMR spectra of Zinc ascorbate
Fig 9: Mass Spectra of Zinc ascorbate
Fig 10: DSC data of Zinc ascorbate
Fig 11: TGA (Thermogravimetric analysis) of Zinc ascorbate

DETAILED DESCRIPTION OF THE INVENTION
Molecular Details:
• Molecular formula: C12H14O12Zn
• Molecular weight: 415.62 g/mol
• CAS number: [331242-75-2]
• Zinc ion coordinated with two ascorbate ligands
• Chemical structure:

Fig. 1: Chemical Structure of Zinc Ascorbate
Process Description:
I. Reaction Composition:
• Ascorbic acid: 2 molar parts
• Zinc oxide: 1 molar part
• Solvent: Water (ascorbic acid to water ratio: max 1:20)
The used Ascorbic acid as key starting material (KSM) is free from related impurity such as D-Ascorbic acid, Dehydroascorbic acid, Furfural and 2,3-Diketogluconic acid. The possible related impurities listed in Table 1 with their status as per HPLC and 1H-NMR data.
Table-1
Impurity Origin of impurity Fate of the impurity
D-Ascorbic acid(corresponding D isomer)
KSM Below detection level (BDL) in the starting material by HPLC.
Dehydroascorbic acid
KSM Note detected (ND) in the starting material by HPLC and 1H-NMR.
2,3-Diketogluconic acid
KSM Not detected (ND) in the starting material by HPLC and 1H-NMR.
Furfural
KSM Not detected (ND) in the starting material by HPLC and 1H-NMR.

The present invention used zinc oxide as reactant instead of Zinc carbonate due to following reasons:
1. Zinc oxide contains higher zinc content (>80%) than zinc carbonate (~ 52-57%).
2. Smaller quantity is required than zinc carbonate as per stoichiometry ratio.
3. Industrially available as well as cost effective.
4. During reaction, no poisonous gas released using zinc oxide whereas, CO2 gas is released when zinc carbonate is used.
II. Reaction Conditions:
• Temperature: Below 30°C
• Reaction Time: Up to 200 minutes
• Method: Zinc oxide added slowly to the ascorbic acid solution under stirring
III. Post-Reaction:
• Filtration
• Spray drying to yield a white solid Zinc Ascorbate
Process Steps:
1. Dissolve ascorbic acid in purified water under constant stirring.
2. Add slowly zinc oxide while maintaining the temperature below 30°C.
3. Continue stirring for maximum period of 200 minutes.
4. Filter the reaction mixture to remove any unreacted solids.
5. Spray the filtrate through spray drier to obtain white solid zinc ascorbate.
The preparation of zinc ascorbate is an one-step process as mentioned in Fig. 2. The step is involved, addition of ascorbic acid and zinc oxide in water followed by spray drying. Reaction is performed by stoichiometric ratio of ascorbic acid and zinc oxide (Generally 2:1 ratio). Water and ascorbic acid ratio aremaximum1:20. This step is carried out at below 30⁰C.Zinc oxide is added slowly. The reaction is carried out for the period of maximum 200 minutes. The reaction mass is filtered and spray dried to get the white zinc ascorbate with higher yield.

Fig.2: Reaction scheme

Physio-chemical Data:
Physical Properties (Typical values):
Description A white powder
Solubility Freely soluble in Water
pH (in 5% w/v in aq. Soln.) 2 to 6
Assay as Zinc (On dried basis) 14 to 18.8% w/w
Assay as ascorbic acid (On dried basis) NLT 80.0% w/w
Loss on drying (at 105 ⁰C for 2 hrs.) NMT 6.0% w/w
Specific optical rotation +85°±3°

Typical Value of Untapped Density: 0.468 g/cc
Typical Value of Tapped Density: 0.682 g/cc
Working Example
Method for manufacturing of Zinc ascorbate

100 kg ascorbic acid is added in about 500 L water in a reactor or vessel. The mass is stirred about 20 minutes. 24 kg of zinc oxide is added slowly in the reaction mass and stirred for about 60 minutes at below 30⁰C. The reaction mixture is filtered through a filtering assembly. The filtrate is spray dried through spray drier to get the white solid of zinc ascorbate with higher yield (108-110 Kg).
Impurity Profile
Related Impurity profile:
According to the procedure and key starting material (KSM), four related substances in Zinc ascorbate are possible which are tabulated above (Table-1). Since our ascorbic acid (KSM) is free from the above related impurities as supported by the following HPLC graph (Fig. 3), we can conclude that, the related impurities are controlled in the quality of Key starting material (KSM).

Fig. 3: HPLC Graph of Ascorbic acid
The corresponding product of Zinc ascorbate 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.4. 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.4 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) (Fig. 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 are not used, hence we declare that, our APIs are free from any nitrosamine impurities.
Chemical Structures of Potential Small-Molecule Nitrosamine Impurities in APIs and Drug Products:

Fig 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 Zinc ascorbate product.
For 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. 6). The general mechanism is proposed by the inventors.

Fig. 6: Proposed Mechanism of decomposition of nitrosamine impurity
From the above mechanism and reaction scheme, we can establish that, there is no nitrosamine in our Zinc ascorbate material.
Robustness of the Manufacturing Process:
The WBCIL manufacturing process of white Zinc ascorbate is controlled by optimization studies of the different reaction parameters. To check the robustness of the manufacturing process, the process is repeated by the scale up from 50 g to 100 g in the laboratory. On the basis of the Lab scale batches 100 Kg batch has been performed in the plant as a trial batch. All the analytical results are found consistent. Analytical data (Assay of ascorbic acid, SOR, pH, Zinc content and LOD) of different batches are presented as graphical presentation to explain the robustness of the manufacturing process:
Assay of Ascorbic acid:
Experiment No. Assay as ascorbic acid (NLT 80.0%w/w)
1 85.66
2 84.16
3 84.90
4 85.5
5 85.14
6 84.22
7 84.79
8 84.32

Specific Optical Rotation (SOR) of Zinc ascorbate:
Experiment No. SOR (+85°±3°)

1 86.53
2 87.91
3 87.17
4 86.92
5 82.5
5 86.9
7 87.8
8 86.7

pH of Zinc ascorbate:
Experiment No. pH (2-6)

1 5.18
2 5.23
3 5.31
4 5.36
5 5.2
5 5.35
7 5.4
8 5.22
Zinc content in Zinc ascorbate:
Experiment No. Zinc content (14.0-18.8%w/w)

1 15.36
2 15.31
3 15.81
4 15.31
5 14.95
6 15
7 15.22
8 14.96

LOD of Zinc ascorbate:
Experiment No. LOD (NMT 6%w/w)

1 5.18
2 5.23
3 5.31
4 5.36
5 5.2
6 5.35
7 5.4
8 5.22

Based on the above analytical data, All the batches are compiled as per the desired specifications. So, we can say the manufacturing process of present invention is robust.
Infrared Absorption (IR):
The major characteristic peaks of Zinc ascorbate are identified by IR are presented below:

Fig 7: Infrared Absorption (IR)
Region Characteristic peaks for the functional group (cm-1) WBCIL results for Zinc ascorbate (cm-1)
-OH Broad peak from 3550 to 3200 3303, 3324, 3258
-C-H Weak peak C-H stretching 2800 to 3000 2976
-C=O Strong peak from 1800 to 1600 1688
-C=C and C-H bending Strong peak from 1400 to 1600 1574, 1372, 1351
-C-O Weak peak from 1300 to 1000 1084, 1064, 1032, 1024

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

Fig 8: 1H-NMR spectra of Zinc ascorbate
Mass Spectra of Zinc ascorbate:
HRMS (m/z): Calculated for C8H8O6 [M]+, 176.12; Found, 178.01 for [M+2H]+ and 175.40 for [M-H]-. Calculated for C12H16O12[M+], 352.24; Found, 353.55 for [M+H]+ and 351.36 for [M-H]-. Calculated for C12H14O12Zn[M]+, 415.6; Found, 415.50 for [M+] and 413.80 for [M-2H]-.

Fig 9: Mass spectra of Zinc Ascorbate

DSC data of Zinc ascorbate:
The DSC (Differential Scanning Calorimetry) data in the graph represents the thermal behavior of Zinc ascorbate as the temperature is increased.

Fig 10: DSC data of Zinc Ascorbate
The DSC graph of zinc ascorbate confirms:
i) It is hydrated (significant water content lost at ~103°C)
ii) It is thermally sensitive, degrading above ~180°C
TGA (Thermogravimetric analysis) of Zinc ascorbate:
Thermogravimetric analysis (TGA) of Zinc ascorbate shows the following characteristics natures:

Fig 11: TGA (Thermogravimetric analysis) of Zinc Ascorbate
The TGA graphs of zinc ascorbate confirms:
1. Zinc ascorbate is thermally stable up to ~150°C
2. Major decomposition starts at ~155°C and peaks by ~193°C
3. Nearly 38% weight loss corresponds to breakdown of the organic portion (ascorbate)
4. The result confirms DSC findings: thermal instability begins at ~180°C.
, Claims:We claim

1. A one-pot green process for synthesizing white Zinc Ascorbate comprising:
-dissolving ascorbic acid in water
-adding zinc oxide slowly at below 30°C
-stirring for up to 200 min at below 30 °C
-filtering and spray drying to obtain white Zinc Ascorbate with higher yield.
2. The process claimed in the claim 1, wherein the stoichiometric ratio of ascorbic acid and zinc oxide is 2:1.
3. The process claimed in claim 1, wherein ratio of water and ascorbic acid are maximum 1:20.
4. The process claimed in claim 1 wherein the spray drying of the reaction mass directly after filtration.
5. The process claimed in claim 1 wherein solvent used as water only and avoids use of any organic solvents, amines, nitrates, or nitrites.
6. The process claimed in claim 1 wherein the ascorbic acid is free from related impurity such as D-Ascorbic acid, Dehydroascorbic acid, Furfural and 2,3-Diketogluconic acid.
7. The process claimed in claim 1 wherein the final obtained product zinc ascorbate is free from nitrosamine impurities.
8. The process claimed in claim 1 is robust process wherein
-assay of the ascorbic acid not less than 80% w/w
-specific optical rotation (SOR) of the zinc ascorbate 85°±3°
-pH of the zinc ascorbate 2-6
-zinc content in the zinc ascorbate 14.0-18.8 % w/w
-loss on drying (LOD) not more than 6% w/w
9. The process claimed in claim 1 wherein the obtained white Zinc Ascorbate is free from nitrosamine impurity, related impurities, and toxic elements like arsenic and fluoride.
10. The process claimed in claim 1 wherein no by-products or toxic waste generates after the process.
11. The process claimed in claim 1 wherein no toxic gas is evolved from the reaction mass during the process.
12. The process claimed in claim 1 wherein the manufacturing process is industrially scalable.