Calcium Citrate Tetrahydrate (5785-44-4): Uses & Safety

Introduction to Calcium Citrate Tetrahydrate (5785-44-4)

Calcium citrate tetrahydrate (CAS Number: 5785-44-4) is a readily absorbed form of calcium, an essential mineral for human health. It is the calcium salt of citric acid and exists as a white, odorless crystalline powder. Its primary significance lies in its use as a highly bioavailable calcium source in dietary supplements and pharmaceutical preparations, playing a crucial role in maintaining bone health and supporting various metabolic functions. Due to its favorable absorption profile, particularly for individuals with reduced stomach acid, calcium citrate tetrahydrate is often a preferred choice for calcium supplementation.

Chemical Properties of Calcium Citrate Tetrahydrate

Understanding the chemical properties of Calcium Citrate Tetrahydrate helps in appreciating its applications, especially in pharmaceuticals.

• Molecular Formula: C12​H10​Ca3​O14​⋅4H2​O (though often represented as [Ca3​(C6​H5​O7​)2​(H2​O)2​]⋅2H2​O or simplified to Ca3​(C6​H5​O7​)2​⋅4H2​O). The exact representation can vary, but it signifies tricalcium dicitrate with four water molecules.
• Molecular Weight: Approximately $570.49\text{ g/mol}$.
• Appearance: It is a fine, white, odorless crystalline powder. This physical form makes it suitable for formulation into tablets, capsules, and powders.
• Solubility: Calcium citrate tetrahydrate is sparingly soluble in water but its solubility increases in acidic environments. Compared to some other calcium salts like calcium carbonate, it does not require high stomach acid levels for dissolution and absorption, which is a key advantage.
• Stability: It is stable under normal storage conditions. It should be stored in a cool, dry, well-ventilated place, away from direct sunlight and moisture, in tightly closed containers. It is a combustible solid but does not ignite readily.
• pH: The pH of a solution can affect its solubility. Calcium citrate’s solubility tends to increase as pH decreases (becomes more acidic). In distilled water, the salt itself will influence the pH, but in buffered systems or the gastrointestinal tract, the ambient pH is more critical for its dissolution.

These properties, particularly its good bioavailability and relatively neutral taste, contribute to its widespread use in nutritional supplements and food fortification.

Uses and Applications of Calcium Citrate Tetrahydrate (5785-44-4)

Calcium citrate tetrahydrate (CAS Number: 5785-44-4) is valued for its versatility and is utilized in several key sectors.

• Pharmaceutical Uses:

  • Dietary Calcium Supplement: This is its primary pharmaceutical role. It is widely used to prevent and treat calcium deficiencies. It helps in maintaining strong bones and teeth, supports nerve function, muscle contraction (including heartbeat), and blood clotting. It is often recommended for individuals who may not get enough calcium from their diet, including those with osteoporosis, osteomalacia (softening of bones), or hypoparathyroidism (decreased parathyroid gland activity).
  • Phosphate Binder: In some cases, calcium salts can be used to bind excess phosphate in patients with kidney disease, although other binders are often preferred.
  • Excipient in Tablet/Capsule Formulation: While primarily an active ingredient, its properties can also lend it to use as an excipient, for example, as a direct compression agent in tablet manufacturing.

• Food and Beverage Industry:

  • Food Fortification: It is added to foods like juices, cereals, dairy alternatives, and infant formulas to increase their calcium content. This is a common strategy to help populations meet their daily calcium requirements. (E-number: E333)
  • Acidity Regulator: It can be used to adjust or maintain the pH (acidity or alkalinity) of food products like jams, jellies, and soft drinks.
  • Firming Agent: It helps to maintain the texture and firmness of processed foods, such as canned vegetables and tofu.
  • Stabilizer and Emulsifying Salt: It can improve the texture and stability of certain food products.
  • Preservative: Similar to sodium citrate, it can act as a mild preservative in some applications.

• Other Industrial Roles:

  • Water Softener: Citrate ions can chelate (bind to) unwanted metal ions in water, effectively softening it.
  • Component in Cleaning Agents: Due to its chelating properties, it can be found in some cleaning formulations.

The pharmaceutical uses of Calcium Citrate Tetrahydrate are primarily driven by its excellent bioavailability as a calcium source, making it effective for supporting bone health and overall calcium homeostasis in the body.

Benefits of Calcium Citrate Tetrahydrate in Pharmaceutical Applications

Calcium citrate tetrahydrate offers several distinct advantages in pharmaceutical applications, particularly as a calcium supplement.

• High Bioavailability: One of the most significant benefits of Calcium Citrate Tetrahydrate is its superior bioavailability compared to some other calcium salts, like calcium carbonate. This means a greater proportion of the ingested calcium is absorbed by the body.
  • It is particularly well-absorbed in individuals with achlorhydria (low stomach acid), which is more common in older adults or those taking acid-reducing medications. Unlike calcium carbonate, calcium citrate does not require a highly acidic environment for absorption.
  • It can be taken with or without food, offering more flexibility for patients.
• Reduced Gastrointestinal Side Effects: Calcium citrate is often associated with a lower incidence of gastrointestinal side effects, such as constipation and gas, compared to calcium carbonate. This can improve patient compliance with supplementation regimens.
• Lower Risk of Kidney Stones (in some contexts): Some studies suggest that calcium citrate may have a lower risk of contributing to kidney stone formation compared to calcium oxalate, as citrate is an inhibitor of calcium oxalate crystal formation. However, individuals with a history of kidney stones should always consult their healthcare provider before taking any calcium supplement.
• Effective in Preventing and Treating Calcium Deficiency: It is clinically effective in:
  • Preventing and treating osteoporosis by helping to maintain bone mineral density.
  • Managing conditions like hypocalcemia (low blood calcium levels) due to various causes, including hypoparathyroidism.
  • Supporting bone health during pregnancy, lactation, and postmenopausal periods when calcium demands are higher.
• Supports Broader Metabolic Functions: Adequate calcium intake, facilitated by bioavailable forms like calcium citrate tetrahydrate, is crucial for:
  • Normal nerve transmission.
  • Muscle function, including the heart muscle.
  • Blood coagulation processes.
  • Enzyme function.

The U.S. Food and Drug Administration (FDA) recognizes calcium as an essential nutrient, and calcium citrate is a commonly used form in supplements that meet FDA regulations for dietary supplements. Similarly, it is approved as a food additive (E333) in Europe, indicating its recognized safety and utility.

Safety Profile: Understanding Side Effects and Precautions for Calcium Citrate Tetrahydrate

While Calcium Citrate Tetrahydrate is generally considered safe when used as directed, it’s important to be aware of potential side effects and necessary precautions.

Common Potential Side Effects:

• Constipation: This is a common side effect with many calcium supplements, though often reported as less severe with calcium citrate compared to calcium carbonate.
• Stomach Upset: Some individuals may experience mild gas, bloating, or an upset stomach.
• Nausea or Vomiting: Less common, but can occur.
• Loss of Appetite.

Serious Potential Side Effects (rare, seek medical advice if experienced):

• Signs of high calcium levels (hypercalcemia): Nausea/vomiting, loss of appetite, unusual weight loss, mental/mood changes (e.g., confusion, lethargy), bone/muscle pain, headache, increased thirst and urination, weakness, fatigue, fast/pounding heartbeat.
• Signs of kidney problems: Change in the amount of urine, difficult or painful urination, pink/bloody urine (indicating possible kidney stones).
• Serious allergic reaction (very rare): Rash, itching/swelling (especially of the face, tongue, or throat), severe dizziness, trouble breathing.

Contraindications (Situations where it should not be used or used with extreme caution):

• Hypercalcemia: Pre-existing high levels of calcium in the blood.
• Known hypersensitivity or allergy to calcium citrate.
• Severe kidney disease or kidney stones: Use should be guided by a healthcare professional.
• Sarcoidosis or other conditions predisposing to hypercalcemia.

General Safety Guidelines and Precautions:

• Dosage: Do not exceed the recommended dosage without consulting a healthcare professional. Excessive calcium intake can lead to hypercalcemia and other complications.
• Drug Interactions: Calcium supplements can interact with various medications, affecting their absorption or efficacy. Inform your doctor or pharmacist about all medications, supplements, and herbal products you are taking. Notable interactions include:
  • Tetracycline and Quinolone Antibiotics: (e.g., doxycycline, ciprofloxacin) Calcium can decrease their absorption. Take these antibiotics at least 2 hours before or 4-6 hours after calcium citrate.
  • Bisphosphonates: (e.g., alendronate, used for osteoporosis) Calcium can interfere with their absorption. Administer at different times of the day as advised by a doctor.
  • Thyroid Hormones: (e.g., levothyroxine) Calcium can reduce absorption. Separate doses by at least 4 hours.
  • Certain Antiviral Medications: (e.g., dolutegravir)
  • Iron Supplements: Calcium can interfere with iron absorption.
  • Thiazide Diuretics: Can increase calcium levels; use with calcium supplements requires monitoring.
  • Digoxin (Lanoxin): High calcium levels can increase the risk of digoxin toxicity.
• Medical Conditions: Discuss with your doctor before use if you have a history of kidney disease, kidney stones, heart disease, parathyroid gland disorders, or malabsorption syndromes.
• Pregnancy and Breastfeeding: Calcium is essential during pregnancy and breastfeeding, but supplementation should be guided by a healthcare provider to ensure appropriate dosage.
• Monitoring: For long-term use, especially at higher doses or in individuals with pre-existing conditions, your doctor may recommend periodic monitoring of blood calcium levels or kidney function.
• Seek Medical Advice: If you experience any concerning side effects or have questions about the suitability of Calcium Citrate Tetrahydrate for your health needs, always consult a qualified healthcare professional.

Following these guidelines helps ensure the safe and effective use of Calcium Citrate Tetrahydrate for its intended pharmaceutical benefits.

How Calcium Citrate Tetrahydrate is Manufactured

The manufacturing of Calcium Citrate Tetrahydrate, while involving specific chemical processes, can be understood through a general overview. The core principle is the reaction of citric acid with a calcium source.

1. Starting Materials:

   • Citric Acid: This organic acid is the primary acidic component. It can be produced through fermentation of sugar sources by microorganisms like Aspergillus niger.
   • Calcium Source: A suitable source of calcium is needed. Common choices include:
     • Calcium Hydroxide (Ca(OH)2​): Also known as slaked lime.
     • Calcium Oxide ($CaO$): Also known as quicklime. This would first be slaked with water to form calcium hydroxide.
     • Calcium Carbonate (CaCO3​): Though less common for direct synthesis of the citrate due to potential impurities and reaction characteristics, it’s a basic calcium salt.

2. Reaction (Neutralization):

   • The citric acid solution is reacted with the calcium source. This is essentially an acid-base neutralization reaction. For example, if calcium hydroxide is used, the simplified reaction can be thought of as: 2C6​H8​O7​ (citric acid)+3Ca(OH)2​ (calcium hydroxide)→Ca3​(C6​H5​O7​)2​ (calcium citrate)+6H2​O (water)
   • The reaction conditions, such as temperature and pH, are carefully controlled to ensure the desired form of calcium citrate is produced and to maximize yield.

3. Precipitation and Crystallization:

   • Calcium citrate is sparingly soluble in water. As the reaction proceeds, calcium citrate precipitates out of the solution.
   • The conditions are managed to encourage the formation of Calcium Citrate Tetrahydrate crystals specifically. This often involves controlling the temperature and concentration of the reactants. Sometimes, existing calcium citrate salt crystals might be dissolved in an acid (like hydrochloric acid), filtered to remove impurities, and then re-precipitated by reacting the clean filtrate with a calcium base like calcium hydroxide or calcium oxide.

4. Filtration and Washing:

   • Once the precipitation is complete, the solid calcium citrate tetrahydrate is separated from the liquid mixture, typically through filtration.
   • The collected solid is then washed, usually with water, to remove any unreacted starting materials, by-products, or other impurities.

5. Drying:

   • The washed calcium citrate tetrahydrate crystals are then dried to remove excess water. The drying process is controlled to ensure the tetrahydrate form (containing four water molecules of crystallization) is maintained and the product is not over-dried to an anhydrous or different hydrate form.

6. Milling and Sieving (Optional):

   • Depending on the desired particle size for its final application (e.g., in tablets or food powders), the dried product may be milled (ground) and sieved to achieve a uniform powder consistency.

7. Quality Control:

   • Throughout the process, and for the final product, quality control tests are performed. These tests ensure the purity, identity (confirming it is Calcium Citrate Tetrahydrate, CAS 5785-44-4), calcium content, moisture content, and absence of contaminants meet pharmacopeial standards (like USP – United States Pharmacopeia, or FCC – Food Chemicals Codex) or other relevant regulatory requirements.

This simplified overview describes the general steps. Industrial manufacturing involves precise control over each step to ensure consistent quality and purity of the final Calcium Citrate Tetrahydrate product for pharmaceutical and food-grade applications.

Frequently Asked Questions (FAQ) about Calcium Citrate Tetrahydrate

Here are some frequently asked questions about Calcium Citrate Tetrahydrate:

• Is Calcium Citrate Tetrahydrate safe during pregnancy?

  Calcium is vital during pregnancy for both the mother and the developing baby’s bone health. Calcium Citrate Tetrahydrate is generally considered safe for use during pregnancy when taken as recommended by a healthcare professional. It’s important to discuss your individual calcium needs and any supplementation with your doctor, who can advise on the appropriate dosage based on your diet and specific health requirements. Do not self-prescribe high doses.

• How is Calcium Citrate Tetrahydrate different from Calcium Carbonate?

  The main differences lie in their absorption and how they are taken. Calcium Citrate Tetrahydrate can be absorbed on an empty stomach or with food and doesn’t require high stomach acid for absorption, making it a good option for older adults or those on acid-reducing medications. Calcium carbonate, on the other hand, is typically better absorbed when taken with food and requires adequate stomach acid. Calcium citrate may also be less likely to cause constipation for some individuals. Calcium citrate provides about 21% elemental calcium by weight, while calcium carbonate provides about 40%, so dosage amounts for equivalent elemental calcium will differ.

• What should I do if I miss a dose of Calcium Citrate Tetrahydrate?

  If you miss a dose of Calcium Citrate Tetrahydrate, take it as soon as you remember, unless it is almost time for your next scheduled dose. In that case, skip the missed dose and resume your regular dosing schedule.1 Do not take a double dose to make up for a missed one. If you2 frequently miss doses, speak with your healthcare provider or pharmacist for advice.

• Can Calcium Citrate Tetrahydrate interact with other medications?

  Yes, Calcium Citrate Tetrahydrate can interact with several medications, potentially reducing their effectiveness. These include certain antibiotics (like tetracyclines and quinolones), bisphosphonates (for osteoporosis), thyroid medications (like levothyroxine), and iron supplements. It’s crucial to inform your doctor or pharmacist about all medications and supplements you are taking. They can advise on the best way to schedule your doses to avoid interactions, often by separating the calcium supplement from other medications by several hours.

• How much elemental calcium is in Calcium Citrate Tetrahydrate?

  Calcium Citrate Tetrahydrate contains approximately 21% elemental calcium by weight. This means that for every 1000 mg of Calcium Citrate Tetrahydrate, you get about 210 mg of actual (elemental) calcium that your body can use. It’s important to check the product label for the amount of elemental calcium per serving, as this is the figure that counts towards your daily calcium intake.