| HS Code | 400983 |
| Product Name | Calcium Orotate Pharma Grade API |
| Chemical Name | Calcium bis(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate) |
| Synonyms | Calcium orotate; Orotic acid calcium salt; Calcium 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate |
| Cas Number | 22454-86-0 (anhydrous); 20631-73-4 (dihydrate) |
| Molecular Formula | C10H6CaN4O8 (anhydrous); C10H10CaN4O10 (dihydrate) |
| Molecular Weight | 350.25 g/mol (anhydrous); 386.29 g/mol (dihydrate) |
| Appearance | White to off-white crystalline powder |
| Assay | 98.0% to 102.0% on dried basis |
| Purity | ≥ 98.0% |
| Grade | Pharma Grade / API |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Route Of Administration | Oral, Injectable |
| Solubility | Soluble in water; practically insoluble in ethanol |
| Ph | 6.5 to 8.0 (1% aqueous solution) |
| Loss On Drying | ≤ 10.0% (dihydrate); ≤ 1.0% (anhydrous) |
| Heavy Metals | ≤ 20 ppm |
| Residual Solvents | Conforms to ICH Q3C |
| Microbial Limits | Total aerobic count ≤ 1000 CFU/g; yeast and mold ≤ 100 CFU/g; E. coli absent |
| Sterility | Non-sterile for oral; sterile grade available for injectable |
| Endotoxin | ≤ 0.25 EU/mg for injectable grade |
| Storage Conditions | Store in a cool, dry place, protected from light, in tightly closed containers |
| Shelf Life | 2 years from date of manufacture when stored as recommended |
| Packaging | Fiber drum with double polyethylene bags |
| Pharmacopoeia Standard | In-house / USP / EP / IP as applicable |
| Particle Size | Customizable as per customer requirement |
| Therapeutic Category | Mineral supplement; orotic acid derivative |
As an accredited Calcium Orotate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
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In direct compression lines producing uncoated oral calcium orotate tablets, the dose-to-tablet mass ratio creates an immediate conflict between elemental calcium target and powder compressibility. For a 50 mg elemental calcium label claim, the quantity of calcium orotate dihydrate required at an assumed 10.4% w/w elemental calcium content is 480.8 mg per tablet. If total tablet mass is held at 650 mg, API fraction becomes 74.0% w/w, leaving only 169.0 mg for all excipients and raising ejection force drift above 25 kN on rotary presses. A 750 mg total mass reduces API fraction to 64.1% w/w; an 850 mg total mass reduces API fraction to 56.6% w/w. Direct compression is limited to the 850 mg configuration unless a compaction aid such as microcrystalline cellulose 102 is increased. The production sequence consists of screening the API through an 800 µm sieve, blending in a bin blender at 10 rpm for 20 min, adding crospovidone 3.0% w/w, colloidal silicon dioxide 0.5% w/w, and magnesium stearate 0.75% w/w, then compressing on a 19-station B-tooling rotary tablet press with precompression 4–6 kN, main compression 14–22 kN, and turret speed 35–55 rpm. Tablet hardness is maintained at 60–90 N, friability is controlled to ≤1.0% per USP <1216>, content uniformity is assessed by USP <905>, and dissolution is assessed by USP <711> in 0.1 N HCl at 37±0.5°C with paddle speed 50 rpm. In-process blend uniformity sampling follows 21 CFR 211.110(a). The terminal dosage form is an uncoated immediate-release tablet.
| Total tablet mass | API fraction | Microcrystalline cellulose 102 | Crospovidone | Colloidal silicon dioxide | Magnesium stearate |
|---|---|---|---|---|---|
| 650 mg | 74.0% w/w | 21.7% w/w | 3.0% w/w | 0.5% w/w | 0.75% w/w |
| 750 mg | 64.1% w/w | 32.2% w/w | 3.0% w/w | 0.5% w/w | 0.75% w/w |
| 850 mg | 56.6% w/w | 39.2% w/w | 3.0% w/w | 0.5% w/w | 0.75% w/w |
A high-shear granulation route becomes necessary when direct-compression API fraction exceeds 74.0% w/w and capping frequency crosses the 2% threshold on B-tooling rotary presses. The dry granule composition is set at 58.0–62.0% w/w calcium orotate dihydrate, 18.0–22.0% w/w microcrystalline cellulose, 13.0–17.0% w/w lactose monohydrate, 2.0–3.0% w/w croscarmellose sodium, and 2.0–3.0% w/w povidone K30 as binder. Purified water is added at 8–12% w/w of dry charge in a top-drive high-shear granulator, impeller speed 100–200 rpm, chopper speed 1000–1500 rpm, to a torque end point of 12–18 N·m. Wet mass is passed through a 1.5 mm screen and dried in a fluid bed with inlet air 55–65°C, product temperature 30–40°C, final loss on drying 2.0–3.5%. Dried granules are milled through an 0.8 mm screen, then lubricated with magnesium stearate 0.5–1.0% w/w. Uniformity of mass is controlled by Ph. Eur. 2.9.5, content uniformity by USP <905>, and dissolution by USP <711>. Terminal product is an immediate-release tablet core intended for subsequent film coating or for oral use as an uncoated tablet.
Size 0 hydroxypropyl methylcellulose capsules containing calcium orotate dihydrate exhibit weight sort failures if the fill formulation drops below 48.0% w/w API and mannitol 200 SD exceeds 46.0% w/w, because the irregular crystal habit of the API segregates during dosator-type filling. The addition ratio is calcium orotate dihydrate 48.0–52.0% w/w, mannitol 42.0–46.0% w/w, sodium stearyl fumarate 1.0–1.5% w/w, and colloidal silicon dioxide 0.5–1.0% w/w. Blending is conducted in a tumble blender at 12 rpm for 20 min, followed by powder fill on a dosator capsule machine at 280–320 mg fill weight per size 0 shell. HPMC shell moisture is held at 4.0–8.0%; below 4.0%, shell brittleness increases, and above 8.0%, deformation under the dosator pin causes closure defects. Weight sorting is performed to reject capsules outside ±5% of target. Content uniformity uses USP <905>, and dissolution uses USP <711> with 0.1 N HCl. The terminal dosage form is a hard capsule for oral administration.
Before stick-pack oral granules are filled, the top-spray fluid bed must be operated below the overwetting point that converts the spray zone into paste and blocks the bottom screen. The batch formula uses calcium orotate dihydrate 35.0–40.0% w/w, mannitol q.s. to 100.0% w/w, maltodextrin 8.0–10.0% w/w, hydroxypropyl cellulose 2.0–3.0% w/w, and anhydrous citric acid 0.5–1.0% w/w. Granulation is performed in a top-spray fluid bed with inlet air 55–65°C, product temperature 30–38°C, atomization air 1.5–2.5 bar, and binder spray rate 8–15 g/min/kg of dry charge. Dried granules are screened to 100–500 µm, and stick packs are filled to 1.0–2.0 g per unit. Uniformity of dosage units follows USP <905>, dissolution follows USP <711>, and elemental impurity limits follow ICH Q3D. The terminal product is an oral granule in stick-pack packaging intended for dispersion in water or direct oral administration.
At the target of 5 mg/mL elemental calcium, the required calcium orotate dihydrate input is 48.1 mg/mL when the certificate of analysis reports 10.4% w/w elemental calcium; published solubility data for this specific configuration is limited, and pre-formulation solubility screening in Water for Injection at 25±2°C and pH 6.0–7.5 is required before batching. The compounding sequence consists of dissolving the API in Water for Injection preheated to 70–80°C, cooling to 25–30°C, adjusting pH with dilute sodium hydroxide or hydrochloric acid if visual clarity permits, and filtering through a 0.22 µm PVDF membrane. The solution is filled into 10 mL amber borosilicate ampoules with a fill volume of 10.5 mL under a nitrogen overlay. Terminal sterilization is applied at 121°C for 15 min. Each batch is tested for bacterial endotoxins per USP <85>, subvisible particulate matter per USP <788>, visible particulates per USP <790>, and sterility per USP <71>; contamination control during filling follows 21 CFR 211.113(b) in conjunction with aseptic filling controls under ISO 14644-1:2015 Class 5. Phosphate buffers are avoided because calcium phosphate precipitation occurs above pH 7.5. The terminal product is an injectable solution in a single-dose ampoule.
| Test | Standard / method | Limit / target |
|---|---|---|
| Bacterial endotoxins | USP <85> | Product-specific limit derived from maximum elemental calcium dose; action limit NMT 0.25 EU/mL |
| Subvisible particles | USP <788> | ≥10 µm: NMT 6000/container; ≥25 µm: NMT 600/container |
| Visible particles | USP <790> | No visible particles |
| Sterility | USP <71> | No growth after 14 days |
The aqueous film coating step is not independent of the intragranular lubricant concentration; if magnesium stearate is added in a low-shear drum blender for more than 5 min at 0.75% w/w, tablet hardness falls below 50 N and the coating pan produces edge erosion during the 2.0–4.0% w/w weight gain. The core formula uses calcium orotate dihydrate 55.0–60.0% w/w, microcrystalline cellulose 25.0–30.0% w/w, lactose monohydrate 10.0–15.0% w/w, intragranular croscarmellose sodium 1.0–2.0% w/w, extragranular croscarmellose sodium 1.0–2.0% w/w, and magnesium stearate 0.5–1.0% w/w. Granules are produced by roller compaction at roll pressure 30–50 bar, gap 1.5–2.5 mm, and screened through an 0.8–1.25 mm oscillating sieve. Ribbon density is controlled at 0.65–0.85 g/cm³, and fines below 100 µm are limited to ≤30% w/w to avoid die filling variation. Tablets are compressed on a 16-station D-tooling press at 15–25 kN, hardness 80–120 N, then film coated in a 48-inch side-vented pan with inlet air 60–70°C, product bed temperature 40–45°C, pan speed 2–8 rpm, and spray rate 2–5 g/min/kg of tablet charge. Film coating is applied to 2.0–4.0% w/w weight gain with a ready-to-use polyvinyl alcohol-based coating system. Content uniformity follows USP <905>, disintegration time is controlled by USP <701>, friability by USP <1216>, and dissolution by USP <711>. The terminal product is a film-coated immediate-release tablet.
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Calcium Orotate Pharma Grade API is identified as product code CaOr-PG-01 for the oral-grade micronized dihydrate and CaOr-PG-02 for the injectable-grade material. The chemical substance is calcium bis(2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinecarboxylate) dihydrate, CAS 22454-86-0, with molecular formula Ca(C5H3N2O4)2·2H2O and molecular weight 386.29 g/mol. The product is supplied as a white to off-white crystalline powder with a theoretical elemental calcium content of 10.4% w/w for the dihydrate and 11.4% w/w for the anhydrous form. The powder is micronized to a D90 of ≤ 75 µm and is intended solely as an active pharmaceutical ingredient for further manufacture into tablets, hard gelatin capsules, granulate sachets, or injectable preparations. Manufacture is conducted under ICH Q7 GMP for active pharmaceutical ingredients; the product is not a finished dosage form and is not intended for direct administration.
Calcium orotate is not currently described by a standalone United States Pharmacopeia monograph; therefore the API is controlled by a validated in-house release specification that references pharmacopoeial general chapters. The following framework is applied to each batch.
| Parameter | Acceptance criterion | Analytical method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Identification | Infrared spectrum corresponds to calcium orotate dihydrate reference | Ph.Eur. 2.2.24 |
| Assay, dried basis | 98.0–102.0% w/w | HPLC-UV, USP <621> |
| Loss on drying | ≤ 1.0% | Ph.Eur. 2.2.32, 105°C for 3 h |
| Sulfated ash | ≤ 0.1% | Ph.Eur. 2.4.14 |
| Heavy metals | ≤ 10 ppm | Ph.Eur. 2.4.8 |
| Elemental impurities | Meets ICH Q3D Option 1 limits for oral and parenteral routes | ICP-MS |
| Particle size distribution | D90 ≤ 75 µm | Laser diffraction, ISO 13320:2020 |
| Bulk density | 0.50–0.70 g/mL | USP <616> Method 1 |
| Residual solvents | Class 3 solvents only | USP <467> |
| Microbial limits | TAMC ≤ 10² CFU/g; TYMC ≤ 10¹ CFU/g; Escherichia coli absent | USP <61>, USP <62> |
| Bacterial endotoxins, CaOr-PG-02 only | ≤ 0.25 EU/mg | USP <85>, Ph.Eur. 2.6.14 |
Assay values are corrected for loss on drying. The HPLC assay uses an octadecylsilyl column and an aqueous mobile phase buffered to pH 3.0 with phosphoric acid; detection is by ultraviolet absorbance at 280 nm, with peak purity confirmation by photodiode array from 200 nm to 400 nm. Solid-state characterization by X-ray powder diffraction and differential scanning calorimetry is used to distinguish the dihydrate from the anhydrous phase. The certificate of analysis includes polymorphic identity by XRPD; the dihydrate pattern is compared against an in-house reference pattern. Thermogravimetric analysis shows a two-stage water loss profile consistent with dihydrate stoichiometry; published data for this specific phase transition are limited. The micronized grade is engineered to reduce the aspect ratio of needle-shaped crystals, which otherwise orient under compression and increase capping risk.
In high-shear wet granulation, the API is blended with microcrystalline cellulose and spray-dried mannitol, and granulated with a 5% w/v povidone K30 solution. Granulation temperature is controlled to avoid premature dehydration of the dihydrate; the loss on drying method uses 105°C for 3 h, and processing temperatures above 50°C in the presence of water should be avoided. A top-spray fluid-bed granulator with inlet air temperature of 50–55°C and product temperature of 30–35°C allows deposition of binder while preserving the crystalline hydration state. Milled granules are screened through a 1.0 mm conical sieve and lubricated with sodium stearyl fumarate at 1.0–2.0% w/w; magnesium stearate is avoided in formulas where sticking to punch faces is observed on rotary tablet presses, because the carboxylate groups may interact with magnesium ions under prolonged mixing. Tablet hardness is targeted at 60–100 N for oral tablets, with disintegration testing per USP <701>.
During dry granulation, ribbons are milled through an oscillating granulator fitted with a 0.8 mm screen. The resulting granules are blended with croscarmellose sodium at 2.0% w/w and lubricated with sodium stearyl fumarate at 1.0–2.0% w/w. Hard gelatin capsule filling uses a tamping-pin machine; fill weight uniformity is confirmed by weight variation testing per USP <905>. For sachet granules, the target fill weight is 1.5–2.0 g for a 100 mg elemental calcium dose, and the granule moisture content is maintained at ≤ 1.0% after drying. Direct compression of raw API is not recommended because the micronized dihydrate may exhibit poor flow; co-processing with colloidal silicon dioxide at 0.2–0.5% w/w improves flowability in low-dose tablet formulations.
For injectable presentations, model CaOr-PG-02 is controlled for bacterial endotoxins at ≤ 0.25 EU/mg and is processed in an ISO 14644-1 Class 8 or tighter environment with terminal filtration through a 0.22 µm polyethersulfone membrane. Aqueous solubility of calcium orotate dihydrate at neutral pH is limited; published quantitative solubility data for this specific configuration are limited. Solutions are commonly prepared by suspending the API in water for injection at 20–25°C, adjusting pH to 7.0–8.0 with diluted hydrochloric acid or sodium hydroxide under nitrogen blanketing, and protecting the solution from atmospheric carbon dioxide to avoid calcium carbonate precipitation. Sterile filtration is preferred where terminal moist-heat sterilization at 121°C for 15 min has not been validated, because pH drift and precipitation may occur during autoclaving in unbuffered solutions. The injectable-grade lot is tested for particulate matter per USP <788> when supplied as a sterile powder; if formulated as a solution, the solution is tested after filling for subvisible particles per USP <787> and Ph.Eur. 2.9.19. Calcium orotate injectable is not an established pharmacopoeial injection monograph in many jurisdictions; its parenteral use requires sponsor-generated stability and safety data.
Substitution of calcium carbonate in a tablet formula is not mass-equivalent because the elemental calcium content of calcium orotate dihydrate is lower. The calculated mass of API required to deliver 100 mg of elemental calcium is 963 mg for calcium orotate dihydrate, 250 mg for calcium carbonate, 474 mg for calcium citrate tetrahydrate, and 1119 mg for calcium gluconate monohydrate. These figures are theoretical and exclude excipient mass. The practical consequence is that high-load oral tablets may require granulation or split dosing.
| Attribute | Calcium Orotate Dihydrate | Calcium Carbonate | Calcium Citrate Tetrahydrate | Calcium Gluconate Monohydrate |
|---|---|---|---|---|
| Molecular weight | 386.29 g/mol | 100.09 g/mol | 570.49 g/mol | 448.40 g/mol |
| Elemental calcium content | 10.4% w/w | 40.0% w/w | 21.1% w/w | 8.9% w/w |
| Acid reaction | No carbon dioxide generated | Carbon dioxide generated | No carbon dioxide generated | No carbon dioxide generated |
| Water solubility behavior | Sparingly soluble; pH-dependent | Practically insoluble; acid-soluble | Slightly soluble; acid-assisted | Slowly soluble; pH-dependent |
| Mass to deliver 100 mg elemental calcium | 963 mg | 250 mg | 474 mg | 1119 mg |
The orotic acid moiety distinguishes calcium orotate from carbonate, citrate, gluconate, lactate, and chloride salts. Orotic acid is a biosynthetic precursor of uridine monophosphate, but oral orotate undergoes first-pass hepatic metabolism and systematic clinical absorption studies for calcium orotate are limited. The absence of effervescence on acid contact is a processing advantage; it does not establish a documented therapeutic advantage. Identification tests differentiate calcium orotate from other calcium salts by infrared spectrum and by high-performance liquid chromatographic retention time of the organic anion. Carbonate salts effervesce on addition of dilute hydrochloric acid, while orotate does not. Citrate and gluconate salts have distinct infrared fingerprint regions and do not show the characteristic orotate carbonyl stretching bands observed in the reference spectrum. When replacing calcium carbonate in existing monograph formulations, formulators should not assume equivalent calcium absorption on a milligram-for-milligram basis.
Micronization is performed on a fluidized-bed opposed-jet mill; the starting crystalline material is milled to D90 ≤ 75 µm, and particle size distribution is confirmed by laser diffraction per ISO 13320:2020 after dispersion in a suitable non-aqueous vehicle. Because the dihydrate contains water of crystallization, the product is stored in double low-density polyethylene bags inside an aluminium foil laminate outer bag with a desiccant. Recommended storage is ≤ 25°C and ≤ 60% RH. Bulk material should be re-evaluated for loss on drying and assay if the container is open for extended periods. The product is incompatible with strong oxidizing agents; complexation with chelating agents such as ethylenediaminetetraacetic acid can sequester calcium and alter the dissolution profile. When the dihydrate is dried above 105°C, the hydration state may change; that material is not automatically suitable for the same formulation without revalidation. Batch release documentation includes the certificate of analysis, residual solvent statement, elemental impurities statement per ICH Q3D Option 1, and a declaration of compliance with ICH Q7 for active pharmaceutical ingredients.
