| HS Code | 394660 |
| Product Name | Calcium Acetate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Api Name | Calcium Acetate |
| Chemical Name | Calcium diacetate |
| Cas Number | 62-54-4 (anhydrous); 5743-26-0 (monohydrate) |
| Molecular Formula | C4H6CaO4 (anhydrous); C4H6CaO4·H2O (monohydrate) |
| Molecular Weight | 158.17 g/mol (anhydrous); 176.18 g/mol (monohydrate) |
| Appearance | White crystalline powder or granules |
| Assay | 99.0%–100.5% (anhydrous basis) |
| Purity | Pharma grade, USP/EP compliant |
| Grade | Pharmaceutical Grade API |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Solubility | Soluble in water; practically insoluble in ethanol and acetone |
| Ph | 6.0–8.5 (10% aqueous solution) |
| Storage Conditions | Store in tight containers, protected from light, at controlled room temperature |
| Packaging | 25 kg fiber drum with double polyethylene bags |
| Pharmacopoeia Compliance | USP, EP, BP, JP |
| Therapeutic Category | Phosphate binder; calcium supplement |
| Shelf Life | 2–3 years when stored properly |
| Regulatory Status | cGMP manufactured; DMF available |
As an accredited Calcium Acetate 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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Calcium acetate, supplied as a hydrous pharmaceutical-grade active, is manufactured into oral products that bind dietary phosphate in the gastrointestinal tract. The API is formulated primarily as a 667 mg solid oral unit, delivering 169 mg elemental calcium per dose; this strength appears across tablets, capsules, granules, and oral solution formulations. The high active mass fraction, combined with the substance’s free water solubility and hygroscopic behavior, means that downstream operations are dominated by physical process limits rather than chemical conversion. Solid oral products must comply with USP 905 for uniformity of dosage units, USP 701 for disintegration, and USP 711 for dissolution where applicable; liquid and parenteral routes are covered by microbial, preservative, sterility, and particulate standards. The chemical function of calcium acetate in oral administration is the formation of poorly soluble calcium phosphate, which reduces phosphate absorption from meals; this reaction is pH-dependent and occurs in the proximal small intestine. Elemental impurity control under ICH Q3D applies to all dosage forms because the API is a mineral salt and may contain lead, cadmium, mercury, and arsenic at trace levels. Tableting, encapsulation, granulation, liquid filling, and injectable compounding each present different process constraints. The following downstream routes are therefore separated by unit operation and by the specific compendial controls that govern each terminal dosage form.
| Dosage form | Technical risk | Control standard |
|---|---|---|
| Oral tablet | Content uniformity, disintegration, friability | USP 905, USP 701, USP 1216 |
| Oral capsule | Dissolution, shell integrity, fill weight variation | USP 711, USP 905 |
| Oral granules or powder sachet | Particle size distribution, flow, fill weight | USP 786, USP 905 |
| Oral solution | Microbial enumeration, preservative efficacy, dose delivery | USP 1111, USP 51 |
| Parenteral compounded preparation | Sterility, endotoxin, particulate matter | USP 71, USP 85, USP 790, USP 797 |
When the active represents the dominant tablet mass fraction, compaction behavior is not comparable to low-dose formulations. Calcium acetate is freely soluble, so it can undergo localized dissolution in adsorbed moisture on raw particle surfaces; this creates liquid bridges that first improve then degrade powder flow and can produce picking on punch surfaces if the compression environment is not controlled. On a rotary tablet press using B-tooling, the process design begins with precompression to remove entrapped air, then main compression force is adjusted to obtain friability below 1.0% according to USP 1216 without creating tablets that fail disintegration. Hardness, thickness, and ejection force are not specified in the compendium but must be controlled because they correlate with splitting, capping, and tool wear. The tablet weight for a 667 mg calcium acetate product is typically high due to the active load alone; this requires careful feeder control and powder flow management. Disintegration time is controlled to the general compendial limit for uncoated tablets, and dissolution is evaluated by the approved USP 711 method using an aqueous medium. Since the API is soluble, dissolution failures for this product are usually process-induced: overcompaction, excessive lubrication, or recrystallized bridges formed during wet granulation can delay tablet breakup. Tooling surface treatments such as chromium nitride are used in development to reduce sticking, but they do not replace low-humidity storage for granule feed. The finished tablet delivers 169 mg elemental calcium per 667 mg unit and is intended for oral administration with meals. Published data for this specific API in an instrumented rotary press system is limited, so compression parameters are derived from small-scale compaction simulator studies and confirmed during scale-up.
Dry granulation via roller compaction is frequently selected over aqueous wet granulation because calcium acetate’s solubility makes wet-mass behavior difficult to control. Ribbon relative density is maintained between 0.70 and 0.85 during initial development; material densified above this range loses post-milling compactibility, while material below this range produces excess fines. These values are not fixed pharmacopoeial limits but represent typical starting points for high-dose soluble actives. The ribbons are milled through an oscillating mill with screens commonly in the 800–1000 μm range, and fines below 125 μm are controlled by recycle or formulation adjustment because they increase segregation risk during filling and compression. Alternatively, high-shear aqueous granulation can be used, but the endpoint must be determined by torque or power consumption rather than by fixed water volume alone, since free water dissolves a proportion of the API and changes granule growth. Fluid-bed drying is restricted to low inlet air temperatures; excessive heat can harden granules through surface dissolution and recrystallization. The dried granulation is milled and blended with extragranular disintegrant, glidant, and lubricant. Particle size distribution is measured under USP 786; flow properties are assessed by Carr index and Hausner ratio because granule flow governs die filling and sachet weight uniformity. The terminal product from this route may be compressed into tablets, filled into capsules, or packed into single-dose stick packs at a 667 mg calcium acetate content. Batch-to-batch variance in granule density and particle size is a known manufacturing failure mode when roller compactor wear changes the relationship between roll gap and roll speed; therefore, the process is monitored by ribbon density and granule size rather than by visual appearance alone.
Capsule filling for a 667 mg calcium acetate product is constrained less by the active’s potency than by the interaction between fill mass, powder flow, and shell moisture. The total fill weight can exceed 900 mg when functional excipients are included, so size 00 or larger hard capsules are typically selected. Encapsulation on a tamping-pin or dosator machine requires a blend with low segregation tendency; if the granulation contains fines outside control limits, capsule-to-capsule weight variation increases and may fail USP 905. Calcium acetate’s hygroscopicity affects both the fill and the shell: at low relative humidity, hard gelatin shells can become brittle, while at high relative humidity the fill may soften and reduce dissolution stability. Hypromellose shells are often preferred in accelerated stability evaluations because they have lower equilibrium moisture and lower water transfer to the fill. Dissolution is performed under the approved USP 711 method; gelatin shell cross-linking after storage under elevated temperature and humidity can produce slower release in acid media even when the fill itself is solubilized. The finished capsule delivers 169 mg elemental calcium per unit and is swallowed whole with meals. Because the capsule shell must remain intact until dissolution, storage conditions are specified to avoid shell deformation. Direct-fill blends may be developed without granulation, but lubrication with a hydrophobic excipient such as magnesium stearate must be controlled because over-lubrication delays dissolution of the high-solubility API.
Calcium acetate oral solution is a distinct finished dosage form with compendial controls separate from solid oral products. A marketed strength is 667 mg calcium acetate per 5 mL, delivering 169 mg elemental calcium per 5 mL. The manufacturing process begins with purified water USP; calcium acetate dissolves rapidly under light agitation, and the resulting solution is filled into multi-dose bottles fitted with a dosing cup or oral syringe. Unlike tablets and capsules, the solution is not subjected to USP 711 dissolution because the drug is already in solution; instead, the critical release attributes are pH, density, fill volume, preservative effectiveness, and microbial enumeration. USP 1111 establishes microbial examination limits for non-sterile aqueous oral products. Preservative effectiveness is evaluated under USP 51 to ensure that the antimicrobial system reduces microbial inoculum within specified time intervals. Oral solution filling uses volumetric piston equipment; because the solution density is higher than water, fill weight and volume are calibrated against each other during line setup. The product is sensitive to evaporation in multi-dose containers; storage conditions and closure tightness are controlled to prevent concentration changes. If the solution is diluted or administered through a feeding tube, compatibility is confirmed by the applicant because calcium salts can interact with tube flush solutions containing phosphates or citrates. The terminal finished product is a clear-to-slightly opalescent oral solution intended for use with meals. Published data for this specific configuration is limited; packaging and preservative selection are therefore based on site-specific stability trials rather than compendial fixed formulae.
No harmonized pharmacopoeial monograph currently defines a calcium acetate injection finished product in major markets, so any parenteral application is handled as a compounded or investigational preparation rather than a licensed commercial dosage form. The acetate ion serves as a metabolizable buffer precursor, and calcium is the active electrolyte; however, injectable eligibility depends on general standards for parenterals, not on the oral phosphate-binding indication. Sterility is demonstrated under USP 71, bacterial endotoxins are controlled under USP 85, subvisible particulates are measured under USP 790, and compounded sterile preparations must comply with USP 797 for compounding practice. Terminal steam sterilization of a calcium acetate solution may be possible, but the container-closure system, solution pH, and headspace composition must be shown to avoid calcium precipitation and rubber stopper degradation. Calcium ions are physically incompatible with phosphate and carbonate anions at neutral-to-alkaline pH; any injectable calcium acetate admixture must therefore be assessed for precipitation before combining with parenteral nutrition solutions. Osmolality is a critical quality attribute for intravenous administration; the formulation would need to be approximately isotonic with blood, but published data for this specific configuration is limited. The acetate anion is rapidly metabolized in muscle and liver to bicarbonate, so infusion rate must be limited to avoid metabolic alkalosis and hypercalcemia. A parenteral product, if developed, would be labeled in calcium and acetate concentration per litre rather than in tablet milligram strengths; its container would be a sterile single-dose vial or pharmacy bulk package. The absence of a dedicated monograph means that each batch would be released against a sponsor-specific specification using injectable-grade drug substance and validated methods. This limitation should not be extrapolated to oral products, where the API is already supported by approved phosphate-binder dosage forms and their associated monographs. For injectable route decisions, the operator must enforce stricter raw material controls than those employed for tablet or capsule manufacture.
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The product herein specified is the Calcium Acetate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable, supplied as a white to off-white crystalline powder in the monohydrate form with the molecular formula Ca(CH3COO)2·H2O, CAS 5743-26-0, and molar mass 176.18 g/mol. The anhydrous form, CAS 62-54-4, has a molar mass of 158.17 g/mol and an elemental calcium content of 25.3% w/w; the monohydrate contains 22.8% w/w elemental calcium. The material is controlled against the USP–NF Calcium Acetate monograph and the Ph.Eur. calcium acetate monohydrate monograph for use in tablet, capsule, granule, oral solution, and injectable compounding. This pharma grade is manufactured under ICH Q7 active pharmaceutical ingredient GMP expectations; technical-grade calcium acetate is not interchangeable because its impurity profile is not controlled against the pharmacopoeial limit tests for oral and injectable use. Injectable presentation is supplied under reduced-bioburden conditions with bacterial endotoxin testing according to USP<85> and Ph.Eur. 2.6.14; oral grades are released under USP<61> and USP<62> microbial enumeration.
Assay is performed by complexometric titration with 0.05 M edetate disodium after drying at 150°C to constant weight; the compendial assay acceptance range is 99.0–100.5% on the dried basis. The pH of a 1 in 20 aqueous solution is controlled to 6.3–9.6 by potentiometric measurement. Loss on drying is determined by USP<731>, and water content by Karl Fischer titration according to USP<921> method Ia is used to confirm the hydration state. Residual solvents are controlled according to ICH Q3C and measured by headspace gas chromatography under USP<467>. Elemental impurities are controlled according to ICH Q3D and analyzed by inductively coupled plasma–mass spectrometry or optical emission spectrometry under USP<232> and USP<233>.
The theoretical water content of the monohydrate is 10.2% w/w. Commercial material may deviate from this value because of surface moisture or partial dehydration. The API is freely soluble in water, allowing oral solution concentrates and liquid dosage forms to be prepared without co-solvents in most formulations. The powder is not a sterile product in its standard oral grade; therefore, terminal sterilization or aseptic processing is required for injectable applications.
| Parameter | Procedure | Release control |
|---|---|---|
| Appearance | Visual inspection | White to off-white crystalline powder |
| Assay on dried basis | USP Calcium Acetate monograph: 0.05 M edetate disodium titration | 99.0–100.5% as C4H6CaO4 |
| pH, 1 in 20 aqueous solution | Potentiometric | 6.3–9.6 |
| Loss on drying | USP<731> | Report value; monohydrate theoretical water 10.2% w/w |
| Elemental impurities | USP<232>/<233> | ICH Q3D oral and parenteral limits |
| Residual solvents | USP<467> | ICH Q3C Class 2 and Class 3 limits |
| Microbial enumeration | USP<61>/<62> | TAMC ≤10³ CFU/g, TYMC ≤10² CFU/g, Escherichia coli absent |
| Bacterial endotoxins | USP<85> | Route-specific; injectable grade limit justified by dose |
Particle size distribution is an internal specification and not a pharmacopoeial requirement. For direct compression and capsule filling, the API is typically milled and classified to a D90 below 250 µm using laser diffraction per USP<429> or ISO 13320. Sieve analysis according to Ph.Eur. 2.9.38 is used for granulation-grade material. Because the powder is freely soluble, wet processing can alter particle size; dry milling with low-humidity air or nitrogen is preferred to avoid surface dissolution and agglomeration. Bulk density, tapped density, and flow behavior are measured under USP<616> and USP<1174>. A Hausner ratio above 1.35 or an angle of repose above 40° indicates cohesive flow that usually requires granulation or a glidant addition.
Calcium acetate differs from calcium carbonate in dissolution pH dependence. Calcium carbonate is practically insoluble in water and requires gastric acid for dissolution; calcium acetate dissolves in the weakly acidic to neutral pH range encountered in the small intestine. In oral phosphate-binding dosage forms, this difference is relevant because in vitro phosphate-binding studies at pH 5.5–7.5 show that calcium acetate binds phosphate without an acid-neutralizing step. In solid-dose processing, calcium carbonate is an inorganic, dense powder with high acid-neutralizing capacity, while calcium acetate is an organic, water-soluble salt that can dissolve partially during wet granulation and form crystalline bridges after drying.
Calcium citrate tetrahydrate supplies 21.1% w/w elemental calcium; calcium acetate monohydrate supplies 22.8% w/w, and the anhydrous base supplies 25.3% w/w. Calcium gluconate monohydrate supplies 8.9% w/w elemental calcium and is frequently used as an intravenous calcium source because of lower tissue irritancy than calcium chloride. Calcium chloride is deliquescent and corrosive to tablet tooling; it is not normally compressed into oral tablets. These mass-fraction differences mean that a lower mass of calcium acetate is needed to deliver the same elemental calcium as calcium gluconate, but a higher mass is needed compared with calcium carbonate.
| Calcium salt | Common solid form | Elemental calcium | Water solubility | Principal pharmaceutical use |
|---|---|---|---|---|
| Calcium acetate | Monohydrate | 22.8% w/w monohydrate; 25.3% w/w anhydrous | Freely soluble | Oral phosphate binder, oral solution |
| Calcium carbonate | Calcite or aragonite | 40.0% w/w | Practically insoluble in water; acid-soluble | Antacid, calcium supplement |
| Calcium citrate | Tetrahydrate | 21.1% w/w | Slightly soluble | Calcium supplement |
| Calcium gluconate | Monohydrate | 8.9% w/w | Slowly soluble | Injectable and oral calcium |
| Calcium chloride | Dihydrate | 27.3% w/w dihydrate; 36.1% w/w anhydrous | Very soluble, deliquescent | Electrolyte replenisher, injection after dilution |
Because calcium acetate is an acetate salt, it contributes acetate ion that is metabolized to bicarbonate; this can influence acid-base balance in injectable and high-dose oral applications. In oral phosphate-binder therapy, the acetate component is generally not considered an acid load in the same manner as chloride; however, high doses require calculation of total calcium and acetate load. Published data for specific injectable formulation configurations is limited, so compatibility studies with phosphate, carbonate, and sulfate-containing admixtures are mandatory before use.
Calcium acetate cannot be treated as a direct substitute for calcium carbonate or calcium citrate in an existing tablet or capsule formulation without reformulation. Calcium carbonate is a high-density inorganic solid that can be compressed directly by brittle fracture; calcium acetate is an organic salt with high aqueous solubility and a greater tendency to cake under humidity, so it generally requires granulation or moisture-controlled direct compression. The soluble nature of calcium acetate can accelerate disintegration if the tablet matrix allows rapid water penetration, but dissolution testing per USP<711> is required because the API can dissolve and then precipitate as less soluble calcium species in phosphate-containing dissolution media.
During tablet and capsule manufacture, calcium acetate granules are usually prepared by dry granulation to avoid the dissolution and recrystallization issues observed in aqueous wet granulation. The powder is compacted between counter-rotating rolls with force instrumentation; the resulting ribbons are milled to a D50 between 200 µm and 600 µm. Because the material can adhere to metal rolls, 0.5–1.0% w/w magnesium stearate is added before compaction, but the lubricant must be mixed gently to avoid over-lubrication that reduces tablet strength. Final blend uniformity is tested according to USP<905>.
When aqueous wet granulation is selected, purified water is added slowly to a high-shear mixer while monitoring impeller torque or power consumption. Calcium acetate is freely soluble, so overwetting can produce a paste that stalls the impeller and creates non-uniform granules after drying. The granulation endpoint is better defined by power draw or torque than by fixed time; at laboratory scale, water quantities above approximately 15% w/w of dry blend frequently produce an over-wetted mass for microcrystalline cellulose-lactose systems, but the exact level depends on the filler blend. Fluidized-bed drying at inlet air temperature of 50–70°C and product temperature below 40°C is preferred because high drying rates can cause migration of dissolved calcium acetate to the granule surface, producing hard surface crusts and variable tablet hardness. Dried granule moisture is measured by Karl Fischer titration per USP<921>.
Calcium acetate is freely soluble in water, so oral solution and compounded liquid formulations can be prepared without organic co-solvents. The solution pH should be measured because a 1 in 20 solution has a compendial pH range of 6.3–9.6; unbuffered solutions can drift with dissolved carbon dioxide and storage container type. For oral liquid dosage forms, preservative compatibility should be confirmed because acetate can buffer the solution and shift the fraction of active preservative in the ionized form; methylparaben and propylparaben assay recovery should be verified per USP<51> antimicrobial effectiveness testing.
For injectable compounding, the API is dissolved in Water for Injection and filtered through a sterilizing-grade membrane with nominal pore size 0.22 µm. The solution must meet particulate matter limits of USP<788> for injections, depending on container volume. Bacterial endotoxins are controlled by USP<85>; the release limit is dose-specific and must be derived from the maximum intended bolus or daily dose. Terminal steam sterilization at 121°C for 15 min is common for heat-stable parenteral formulations, but calcium acetate solutions should be tested for pH shift, visible precipitation, and assay stability after the sterilization cycle because acetate can react with trace carbonates or leachables from glass. Published data for this specific injectable configuration is limited; compatibility studies with phosphate, sulfate, and bicarbonate-containing solutions are required because calcium phosphate, calcium sulfate, and calcium carbonate precipitation can occur when the solubility products are exceeded.
Solutions of calcium acetate should not be mixed with phosphate-containing parenteral nutrition solutions without compatibility data. The acetate ion is metabolized to bicarbonate, so infusion of large amounts may contribute to alkalosis or affect acid-base status; this is a clinical boundary, not a formulation defect. For oral administration, the same precipitation risk applies to admixture with phosphate-rich beverages or milk; therefore, patient instructions should state that the dose is taken with water or as directed, not with dairy products or phosphate supplements.
Stability data generated under ICH Q1A long-term conditions at 25°C/60% RH and accelerated conditions at 40°C/75% RH are used to establish retest dating. Because the monohydrate can gain or lose water, the inner packaging should include a desiccant when the facility ambient relative humidity exceeds 60% RH. The powder should not be stored in open containers because carbon dioxide uptake can form calcium carbonate on the particle surface and reduce clarity of reconstituted solutions. For bulk API, double polyethylene liners inside a fiber drum are typical; the outer container should be sealed after each use. Avoiding carbonate and bicarbonate excipients in aqueous granulation is necessary because carbon dioxide evolution and calcium carbonate precipitation can occur.
Blend uniformity analysis per USP<905> is used to set mixing time and sampling points. A poorly flowing API can cause segregation during transfer from bin to press, particularly when API particle size is below 50 µm and the excipient carrier has a larger mean diameter. For direct compression, a dry granulation step or addition of microcrystalline cellulose at 20–40% w/w reduces segregation risk. In capsule filling, dosator and tamping-pin machines require different granule densities; process development should measure the Carr index and Hausner ratio per USP<1174> before selecting the filling method.
Tablet compression of calcium acetate granules is typically performed on rotary presses with precompression force between 2 kN and 8 kN and main compression force between 8 kN and 20 kN, depending on tablet size and hardness specification. These values are equipment-specific and must be established by force-displacement profiling; compression data are used to set acceptance limits for tablet hardness, thickness, and friability per USP<1216> and USP<1217>. Overcompression can reduce tablet porosity and slow disintegration, so friability below 1.0% is targeted while maintaining disintegration per USP<701> and dissolution per USP<711>.
In granule and sachet products, particle size and water content are the main processing variables. The API is usually milled to a D90 below 250 µm for blends intended for capsule filling and oral granules. Milled material is characterized by laser diffraction under USP<429> or ISO 13320; sieve analysis may be performed according to Ph.Eur. 2.9.38. Flowability is evaluated using the Hausner ratio and angle of repose under USP<1174>; a Hausner ratio above 1.35 indicates cohesive powder behavior and usually justifies dry granulation or addition of a glidant such as colloidal silicon dioxide at 0.5–1.5% w/w. Bulk density and tapped density values are process-specific and should be set as internal release limits after three consecutive production-scale lots.
