| HS Code | 178006 |
| Product Name | Calcium Chloride Dihydrate Pharma Grade API |
| Chemical Name | Calcium chloride dihydrate |
| Molecular Formula | CaCl2·2H2O |
| Molecular Weight | 147.01 g/mol |
| Cas Registry Number | 10035-04-8 |
| Appearance | White crystalline powder, granules, or pellets; odorless; hygroscopic |
| Assay | 99.0% to 107.0% (USP) or 97.0% to 103.0% (EP) as CaCl2·2H2O |
| Ph | 4.5 to 9.2 (1 in 10 aqueous solution) |
| Solubility | Freely soluble in water; soluble in ethanol; practically insoluble in ether |
| Loss On Drying | 22.0% to 27.0% |
| Grade | Pharmaceutical grade API; GMP compliant |
| Dosage Forms | Tablet, capsule, granule, injection |
| Routes Of Administration | Oral and injectable |
| Storage Conditions | Store in a tight container, protected from moisture, at controlled room temperature |
| Packaging | 25 kg fiber drum with double polyethylene liner |
| Regulatory Status | Complies with USP/EP/BP/JP monographs as applicable |
As an accredited Calcium Chloride Dihydrate 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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Injectable calcium chloride dihydrate in the 10% w/v presentation is manufactured to provide 100 mg/mL CaCl2·2H2O, equivalent to 27.3 mg/mL elemental calcium and 1.36 mEq/mL calcium ion. The undiluted solution has a theoretical osmolarity of 2,040 mOsmol/L, calculated from complete dissociation into one calcium cation and two chloride anions per formula unit. Terminal moist heat sterilisation at 121 °C for 15 min is applied because the dihydrate is thermally stable in aqueous solution when the pH is maintained within the compendial range of 5.5–7.5. The primary container is a Type I borosilicate glass vial conforming to USP <660>, closed with a halobutyl rubber stopper that is fluoropolymer coated on the product-contact side; uncoated elastomers in contact with 10% w/v calcium chloride exhibit migration of zinc and sulphur-containing accelerators during accelerated stability storage at 40 °C/75% RH. The strong electrolyte is not suitable for subcutaneous or intramuscular administration because extravasation produces tissue calcification and necrosis. Batch release occurs only after the test matrix below is completed.
| Test | Method | Acceptance |
|---|---|---|
| pH | USP <791> | 5.5–7.5 |
| Assay | Complexometric titration with edetate disodium | 95.0–105.0% of label claim |
| Bacterial endotoxins | USP <85> kinetic chromogenic LAL | Calculated by K/M from maximum acute dose; K = 5 EU/kg/h |
| Particulate matter | USP <788> light obscuration | ≥10 μm: NMT 6,000/container; ≥25 μm: NMT 600/container |
| Sterility | USP <71> membrane filtration | No growth after 14 days |
| Elemental impurities | USP <233> ICP-MS; ICH Q3D | As 15 μg/day, Cd 2 μg/day, Hg 3 μg/day, Pb 5 μg/day |
In haemodialysis acid concentrate production, calcium chloride dihydrate is charged into 316L stainless steel mixing vessels together with sodium chloride, magnesium chloride hexahydrate, potassium chloride and acetic acid. The acid concentrate is deliberately maintained at pH 2.5–3.5; at pH values above 3.5, dissolved carbon dioxide originating from ambient air is converted to carbonate ion, and the solubility product of calcium carbonate is exceeded when the concentrate is diluted with softened water. The acid and bicarbonate concentrates are produced in physically separated circuits because any cross-contamination generates calcium carbonate before the dialyser. After proportioning at 1:45 with purified water and bicarbonate concentrate, the final dialysate calcium concentration is typically 1.25 mmol/L, 1.5 mmol/L or 1.75 mmol/L depending on the prescription; each batch is assayed by ion-selective electrode before release. ISO 23500-5:2019 requires standard dialysis fluid to contain total viable microbial counts below 100 CFU/mL and endotoxin below 0.25 EU/mL at the point of use, which forces concentrate suppliers to control the acid concentrate through 0.45 μm filtration and periodic sanitisation of storage loops. Calcium chloride dihydrate selection for this application is driven by its low aluminium and heavy metal burden, because aluminium in dialysate is restricted by ISO 13959:2014 to 0.01 mg/L in water for dialysis. Dissolution exotherms are managed by adding the calcium chloride to chilled water at 15–20 °C before other salts; batch temperatures above 40 °C accelerate chloride-induced pitting of 316L surfaces and are avoided. Residual turbidity after 24 h settling is below 1.0 NTU; if not, the batch is quarantined for carbonate contamination assessment.
For tablet and capsule lines handling calcium chloride dihydrate, the deliquescence point at approximately 30% RH at 25 °C imposes a processing ceiling. Direct compression is limited to suites with supply air dried to below 25% RH and product hoppers fitted with dry nitrogen purge; without this, the powder cakes rapidly and mass uniformity fails outside ±5% relative standard deviation on rotary presses. Calcium chloride dihydrate reacts with sodium bicarbonate in the presence of moisture to form insoluble calcium carbonate, sodium chloride and carbon dioxide; effervescent granule manufacture therefore segregates the acid and carbonate fractions into separate granulations or uses solvent-free dry granulation. The moisture-sensitive hydrate is rarely suitable for hard gelatin capsules stored in high-humidity zones, because the capsule shell loses mechanical strength above 60% RH while the calcium chloride dissolves in its own sorbed water. HPMC capsules in cold-form aluminium/aluminium blisters with desiccant canisters provide a more stable barrier. When direct compression is attempted, in-process moisture is monitored by loss on drying USP <731> or Karl Fischer titration USP <921>; granulation end point is set at water activity below 0.30. Lubrication with sodium stearyl fumarate at 1.0–1.5 wt% is preferred because magnesium stearate can form insoluble calcium stearate films at tablet surfaces, slowing disintegration. Published data for direct-compression calcium chloride dihydrate tablets as oral calcium supplements are limited; most oral solid applications use the salt in granulated or coated multi-particulate forms to isolate the deliquescent core from the film coating and from coexisting carbonate excipients.
Calcium chloride dihydrate is less commonly selected than calcium gluconate monohydrate for total parenteral nutrition compounding, but its use is specified when a higher ionic calcium fraction is required. The incompatibility boundary is set by the solubility product of dibasic calcium phosphate in the admixture; when calcium chloride and sodium phosphate are combined in the same bag, the free ionised calcium concentration is higher than with calcium gluconate of equivalent elemental calcium content because gluconate forms weak soluble complexes with calcium. This kinetic advantage becomes a precipitation risk if the admixture pH rises above 6.0 or if the phosphate concentration exceeds the calcium-phosphorus solubility curve for the amino acid matrix. The solubility curve shifts with temperature, amino acid concentration and pH; pharmacists compound calcium and phosphate in separate compartments or use automated total parenteral nutrition compounders with order-of-entry algorithms that sequence amino acid, dextrose and lipid phases before electrolyte additions. In-line 1.2 μm air-eliminating filters and visual inspection for crystalline precipitates are used before administration. The table below compares calcium chloride dihydrate with calcium gluconate monohydrate on the measurements used in compounding decisions.
| Property | Calcium chloride dihydrate | Calcium gluconate monohydrate |
|---|---|---|
| Elemental calcium per gram | 273 mg | 89 mg |
| Calcium ion per gram | 13.6 mEq | 4.46 mEq |
| Solution pH of 10% injection | 5.5–7.5 | 6.0–8.0 |
| Phosphate compatibility in amino acid admixtures | Higher free Ca2+; precipitation risk increases above pH 6.0 | Weak gluconate complexation reduces free Ca2+; wider working pH before precipitation |
| Preferred compounding route | Rapid repletion protocols | TPN maintenance and phosphate-containing admixtures |
Oral liquid compounding is constrained by the same hygroscopicity but is more tolerant of moisture control than solid dosage forms. Calcium chloride dihydrate is dissolved in purified water to a final concentration of 10–20 mg/mL elemental calcium for oral electrolyte replenishment; the solution is acidified with citric acid to pH 4.0–5.0 to reduce the perception of a salty-bitter taste. Flavouring with sucrose or xylitol is required before the solution is filled into amber PET bottles; without adequate headspace inert gas flushing, the solution slowly attacks aluminium sealing foils because chloride ion induces pitting corrosion at pH below 5.5. The pharmacopoeial assay by complexometric titration with edetate disodium is used to confirm label claim; preservative efficacy is tested by USP <51> when multidose containers are used. Oral granules are prepared by wet granulation of the calcium chloride with microcrystalline cellulose and povidone in an absolute ethanol granulation fluid; water is not used because the hydrate dissolves into a viscous brine that cannot be dried under normal fluidised-bed conditions. The granules are dried in a vacuum dryer at 40–50 °C and 10–20 kPa absolute pressure until the water activity is below 0.35. Since oral calcium chloride is a gastrointestinal irritant at high bolus doses, the formulated granules are usually coated with ethylcellulose or mixed with food-grade delayed-release polymer systems to moderate release in the stomach. No standardised dissolution monograph specific to calcium chloride oral granules exists, so in-process release testing is based on disintegration USP <701> and assay uniformity rather than a universal dissolution acceptance.
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Calcium chloride dihydrate, supplied as a pharmacopoeial active pharmaceutical ingredient, is a white or almost white crystalline powder with molecular formula CaCl2·2H2O, CAS 10035-04-8, and molar mass 147.01 g/mol. The product identity is the hydrate stoichiometry itself; no physical device model number is assigned, although bulk dossiers generally list the material by monograph grade and route, such as CaCl2·2H2O, USP, Ph.Eur., injectable grade. The theoretical calcium chloride content is 75.49%, the water of crystallization is 24.51%, and the elemental calcium content is 27.26%. It is used as an active pharmaceutical ingredient in oral electrolyte tablets, capsules, granules, and injectable solutions requiring calcium ion supplementation. Compared with anhydrous calcium chloride, the dihydrate has less aggressive moisture-scavenging behavior during wet granulation, but both forms require low-humidity processing. Pharmacopoeial assay acceptance commonly spans 97.0–103.0% for Ph.Eur. and 99.0–107.0% for USP; water is determined by USP <921> Method I and pH by USP <791>. Formula transfer from anhydrous salt uses the factor 1.32, because 1 g anhydrous CaCl2 corresponds to 1.32 g of the dihydrate.
Anhydrous calcium chloride generates a more pronounced heat of solution and more aggressive moisture uptake than the dihydrate. In wet granulation, anhydrous material can create local temperature gradients that alter binder hydration and produce non-uniform granule porosity. The dihydrate reduces this effect because part of the water is already coordinated in the lattice. Both forms are deliquescent above a critical relative humidity of approximately 28–30% at 25 °C; manufacturing suites for tablet and capsule processing are therefore maintained below 30% RH. High-shear wet granulation with a chopper impeller is typically followed by fluid-bed drying at low inlet humidity; roller compaction is used for dry granulation when high-dose tablets are required because direct compression of highly hygroscopic calcium chloride blends can produce picking, sticking, and feed-frame accumulation on rotary tablet presses. Solubility in water is approximately 74 g/100 mL at 20 °C, permitting rapid dissolution from oral granules and immediate-release tablets. Granule moisture and particle size are controlled because residual water in coarse granules can increase caking and reduce flow on automatic capsule dosators.
| Parameter | Calcium chloride dihydrate API | Anhydrous calcium chloride API | Technical-grade calcium chloride |
|---|---|---|---|
| Molecular formula | CaCl2·2H2O | CaCl2 | CaCl2 with variable hydrate/water |
| Molar mass | 147.01 g/mol | 110.98 g/mol | 110.98 g/mol anhydrous basis |
| Elemental calcium | 27.26% | 36.11% | Variable, not standardized |
| Water of crystallization | 24.51% theoretical | None | Variable |
| Primary controls | Assay, water, pH, sulfate, barium, iron, aluminum, heavy metals, residual solvents, endotoxin for injectable grade | Assay, loss on drying, sulfate, barium, iron, aluminum, heavy metals, residual solvents | Not controlled to pharmaceutical impurity limits |
The pharmacopoeial profile for oral and injectable-grade calcium chloride dihydrate extends beyond assay and water. Elemental impurity risk is assessed under ICH Q3D, and routine release testing includes aluminum, iron, barium, sulfate, and where regional monographs require, arsenic and lead. Residual solvents are controlled under USP <467> or Ph.Eur. 5.4; microbiological quality is set by USP <61> and <62> for non-sterile oral grade. Injectable grade carries a bacterial endotoxin specification based on maximum adult dose; the limit is calculated from the K/M ratio in USP <85>. For a representative injectable application with a 1 g maximum dose of calcium chloride dihydrate, an API endotoxin target of ≤ 0.5 EU/mg provides a conservative control point. Particle size is controlled by sieve analysis or laser diffraction; oral granulation grades are commonly milled to a D90 below 250 µm, while injectable grades are controlled for solution clarity and filterability. Water content is specified at 20.0–25.0% by USP <921> Method I, consistent with the theoretical hydrate water of 24.51% and limited surface moisture. The pH of a 5% w/v aqueous solution is measured using USP <791>; product-specific acceptance intervals are typically in the range 4.5–8.0. A certificate of analysis documents these attributes for each batch.
| Quality attribute | Acceptance basis | Method/standard |
|---|---|---|
| Assay | 97.0–103.0% (Ph.Eur.) or 99.0–107.0% (USP) | Complexometric titration |
| Water | 20.0–25.0% | USP <921> Method I / Ph.Eur. 2.5.12 |
| pH | 4.5–8.0 for 5% w/v solution | USP <791> |
| Elemental impurities | Permitted daily exposure-based limits | ICH Q3D, USP <232>/<233> |
| Residual solvents | Class 1/2/3 limits | USP <467> |
| Microbial quality, oral | Compendial non-sterile API criteria | USP <61>/<62> |
| Bacterial endotoxin, injectable | Dose-based, API target ≤ 0.5 EU/mg | USP <85> / Ph.Eur. 2.6.14 |
Injectable manufacture imposes additional control. The API is dissolved in Water for Injection, pH-adjusted with hydrochloric acid or sodium hydroxide to maintain a slightly acidic-to-neutral range, and filtered through a 0.22 µm sterilizing-grade membrane. Terminal sterilization of sealed glass ampuls or vials at 121 °C for 15 min is typical; the dihydrate is compatible with this thermal cycle. Solutions must be protected from atmospheric carbon dioxide because calcium carbonate precipitation can occur at higher pH. Nitrogen overlay and closed vessels are used during compounding and filling. Calcium chloride injection is used as a calcium ion source in hypocalcemia, hyperkalemia, and calcium channel blocker toxicity; it is also used in electrolyte replacement protocols. The chloride salt is selected over calcium gluconate when more rapid ionized calcium availability and higher calcium content are required, but it is a hypertonic concentrate that must be diluted and administered slowly. The theoretical osmolar contribution of CaCl2 is 3 osmoles per mole; a 10% w/v calcium chloride dihydrate solution has a theoretical osmolarity near 2040 mOsmol/L. Incompatibilities include phosphate, carbonate, and sulfate salts in compounded admixtures unless compatibility is demonstrated by visual and subvisible particle analysis under USP <788>.
For tablet and capsule production, calcium chloride dihydrate is generally incorporated at a level that delivers the intended elemental calcium dose but does not dominate the formulation. The API is freely soluble and can be processed by wet granulation, roller compaction, or direct compression when the blend is maintained below 30% RH. Dry granulation is selected when hygroscopic fillers or aqueous granulation would trigger deliquescence. Automatic capsule filling with dosator or tamping-pin machines requires controlled powder flow; colloidal silicon dioxide is added as a glidant, and fill weight uniformity is validated after humidity stress. Dissolution testing uses USP <711> apparatus 2 with 0.1 M hydrochloric acid or water as the medium. Oral granules are packaged in barrier films or desiccant-protected containers because moisture uptake above the critical relative humidity can cause granule fusion and loss of free-flowing properties. Calcium ions interact with alginate, pectin, and some carboxymethylcellulose grades; these excipient incompatibilities are assessed during preformulation. The dihydrate is preferred over anhydrous calcium chloride in many oral formulations because the hydration water reduces the initial wetting exotherm and improves batch-to-batch granule moisture consistency.
Conversion between hydrates is a recurring source of formula error. The correction factor is 147.01 / 110.98 = 1.3247; therefore 1 g anhydrous CaCl2 is replaced by 1.325 g CaCl2·2H2O to deliver the same CaCl2 equivalent. On an elemental calcium basis, the dihydrate contains 27.26% calcium, whereas anhydrous calcium chloride contains 36.11% calcium. A 1 g quantity of the dihydrate supplies 272.6 mg elemental calcium and approximately 13.6 mEq of calcium. In injectable electrolyte concentrates and oral supplement tablets, this distinction determines both the label claim and the safety margin for dose calculation. Pharmacopoeial requirements for content uniformity in oral solids, such as USP <905>, apply to the labeled elemental calcium content and require the formulation batch record to state the hydrate basis explicitly. For a formula originally developed with anhydrous calcium chloride, the dihydrate substitution must be accompanied by recalculation of excipient mass, water content, and expected tablet weight to avoid a calcium deficiency or excess. The use of the dihydrate also changes the water activity of the blend; where a formulation is transferred from anhydrous to dihydrate, stability studies under ICH Q1A conditions are performed to establish the operational boundary.
Handling of calcium chloride dihydrate at manufacturing scale requires humidity-controlled dispensing and validated cleaning. Residual calcium chloride on equipment surfaces attracts moisture and can promote corrosion of stainless steel components if not removed; cleaning procedures are validated under 21 CFR 211.67. Packaging for the API is typically double polyethylene bags inside fiber drums, with desiccant where required, and storage is maintained in dry conditions at controlled room temperature. In tablet and capsule processing, the operational boundary is set by the moisture sorption isotherm of the specific formulation; published data for a given filler blend may be limited, so preformulation studies are used to define the maximum allowable room humidity and compression speed. The use of technical grade calcium chloride in place of this API is not acceptable for pharmaceutical manufacture because of uncontrolled water content, potential aluminum and barium contamination, and absence of endotoxin and residual solvent documentation.
