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Calcium pyrophosphate

Calcium pyrophosphate is an inorganic compound with the chemical formula Ca₂P₂O₇, formed by the combination of calcium ions and the pyrophosphate anion (P₂O₇⁴⁻). It appears as a white, odorless crystalline powder with a density of 3.09 g/cm³ and a melting point of 1353 °C, and it is insoluble in water but dissolves in dilute acids such as hydrochloric and nitric acid. The dihydrate form, calcium pyrophosphate dihydrate (Ca₂P₂O₇·2H₂O), is the most biologically relevant variant, as its rhomboid-shaped crystals can deposit in joint tissues, triggering inflammation through immune activation. These deposits are the hallmark of calcium pyrophosphate deposition (CPPD) disease, a crystal arthropathy that manifests as acute pseudogout attacks, chronic arthritis resembling osteoarthritis or rheumatoid arthritis, or asymptomatic chondrocalcinosis. CPPD disease predominantly affects individuals over age 60, with radiographic chondrocalcinosis present in approximately 4% of the general population and increasing with age (up to 30–50% in those over 80 years); the point prevalence of diagnosed disease is about 5 per 1,000, often involving weight-bearing joints like the knees, wrists, and shoulders. Beyond its medical implications, calcium pyrophosphate has industrial applications, including use as a mild in , and as a recognized as generally safe (GRAS) by the U.S. for nutrient fortification in foods. Associated metabolic conditions, such as , hemochromatosis, or hypomagnesemia, can predispose individuals to CPP crystal formation, though many cases occur idiopathically in the elderly.

Chemical overview

Formula and nomenclature

Calcium pyrophosphate is an with the Ca_2P_2O_7 for its form, while hydrated variants are denoted as Ca_2P_2O_7 \cdot nH_2O where n can be 0, 2, or 4, reflecting different degrees of incorporation in the . The systematic IUPAC name for the compound is diphosphoric acid calcium salt (1:2), reflecting its composition as the calcium salt of , though it is more commonly referred to as calcium diphosphate or simply calcium pyrophosphate. It is frequently abbreviated as in , particularly when distinguishing it from other calcium phosphates such as (Ca_{10}(PO_4)_6(OH)_2), which features discrete orthophosphate (PO_4^{3-}) anions rather than the linked (P_2O_7^{4-}) central to CPP's structure. The nomenclature of calcium pyrophosphate traces its historical origin to the "pyro" prefix, derived from word for , indicating its formation through the of orthophosphoric acid (H_3PO_4) to yield (H_4P_2O_7), followed by neutralization with a calcium source. This highlights its place among pyrophosphate salts, such as sodium pyrophosphate (Na_4P_2O_7), which similarly incorporate the P_2O_7^{4-} anion but with different cations influencing solubility and reactivity.

Physical appearance and basic characteristics

Calcium pyrophosphate is typically observed as a white, odorless crystalline powder. The molecular weight of its form, Ca₂P₂O₇, is 254.10 g/mol, while its is 3.09 g/cm³. The form has a of 1353 °C, though some hydrated variants may decompose before reaching this temperature. In terms of basic handling, calcium pyrophosphate is insoluble in and most organic solvents, non-flammable, and (GRAS) in pure form for use as a or when handled according to good manufacturing practices.

Structure

Anhydrous form

The anhydrous form of calcium pyrophosphate, denoted as Ca₂P₂O₇, adopts a with the P2₁/n. This is characteristic of the high-temperature α-polymorph, which features a three-dimensional network stabilized by the coordination of calcium ions to the pyrophosphate anions. The core structural unit is the pyrophosphate (P₂O₇⁴⁻), composed of two PO₄ tetrahedra connected via a bridging oxygen atom in a P-O-P linkage. Each phosphorus atom resides at the center of a tetrahedral coordination environment with terminal P-O bonds, while the bridge exhibits a typical P-O-P angle of approximately 130°, ranging from 123° to 134° depending on the local geometry. The Ca²⁺ cations occupy two inequivalent sites, each coordinated to eight oxygen atoms from multiple pyrophosphate units, forming distorted polyhedra that link the structure into a cohesive framework. X-ray diffraction analysis of the α-form reveals unit cell parameters of a = 12.66 Å, b = 8.542 Å, c = 5.315 Å, and β = 90.3°. These dimensions reflect the compact packing absent in hydrated variants, contributing to greater thermal stability in the anhydrous phase. Infrared (IR) and Raman spectroscopy provide confirmatory evidence of the P-O-P bridge, with characteristic asymmetric stretching vibrations appearing at approximately 900 cm⁻¹ (typically in the 850–920 cm⁻¹ range). These peaks arise from the bridging oxygen's motion and are diagnostic for the anhydrous pyrophosphate motif.

Hydrated forms

Calcium pyrophosphate forms several hydrated phases, with the dihydrate (Ca_2P_2O_7 \cdot 2H_2O) and tetrahydrate (Ca_2P_2O_7 \cdot 4H_2O) being the most commonly studied. The dihydrate exists in two polymorphs: monoclinic (m-CPPD, P2_1/n) and triclinic (t-CPPD). In m-CPPD, the features anions oriented on the (010) with an inversion , where calcium ions are coordinated to oxygen atoms from both groups and molecules, with Ca-O distances ranging from 2.257 to 2.648 . The t-CPPD polymorph exhibits a dichromate-like configuration of the ions with a P-O-P angle of approximately 123.1°, contrasting with the 133.6° angle in m-CPPD. These structural differences arise from variations in the bridging molecules and the arrangement of the tetrahedral PO_4 units within the anion. The tetrahydrate, primarily known in its monoclinic β form (m-CPPT β, P2_1/c), displays a layered structure along the {100} plane, consisting of chains of calcium coordination polyhedra interconnected by groups. Calcium atoms in this phase are seven-coordinated, forming polyhedra between capped octahedral and pentagonal bipyramidal geometries, with five oxygen atoms from and three from molecules; acts as a bridge between Ca²⁺ ions, stabilizing the layers. parameters for m-CPPT β are a = 12.288 , b = 7.512 , c = 10.776 , and \beta = 112.51^\circ. The P-O-P is about 134.1°, similar to that in m-CPPD. Less common hydrated forms include the monohydrate (Ca_2P_2O_7 \cdot H_2O, P2_1/n), which has a denser monoclinic structure with calcium in sixfold coordination, and rare phases like an ammonium-containing hexahydrate (Ca_5(NH_4)_2(P_2O_7)_3 \cdot 6H_2O), formed under specific excess conditions. Dehydration behavior among these hydrates is stepwise and often reversible under controlled conditions. The tetrahydrate loses one loosely bound (forming only bonds) below 353 (80°C), followed by additional waters between 100–200°C to yield the monohydrate or dihydrate intermediates; full to the anhydrous β-Ca_2P_2O_7 occurs around 450°C. The dihydrate phases show greater thermal stability, with reversible loss starting at approximately 100–150°C, transitioning back upon rehydration in moist environments. Phase diagrams derived from synthesis conditions indicate stability ranges influenced by and : m-CPPD forms stably at pH 5.8 and 90°C, t-CPPD at pH 3.6 and 90°C, and m-CPPT β at pH 4.5 and 25°C, with amorphous hydrated phases (≈3.87 H₂O) persisting across broader ranges (pH 5.8–7.4, 25–90°C) before crystallizing into di- or tetrahydrates. These levels affect , with tetrahydrates generally more soluble than dihydrates under physiological conditions. Analytical identification of these hydrates relies on X-ray (XRD) patterns, which provide distinct signatures for differentiation. The tetrahydrate β form exhibits characteristic peaks in the 2θ range of 10–30°, including prominent reflections corresponding to its monoclinic lattice, while dihydrate polymorphs show unique sets: m-CPPD with broader features due to its unresolved , and t-CPPD with sharp triclinic peaks. The monohydrate displays a more compact pattern reflective of its higher (2.60 Mg/m³). XRD and neutron are often employed for precise refinement, enabling distinction from forms or amorphous precursors.

Synthesis and preparation

Laboratory methods

One common laboratory method for synthesizing calcium pyrophosphate involves a precipitation reaction between a calcium salt, such as (Ca(NO₃)₂), and a pyrophosphate salt, such as potassium pyrophosphate (K₄P₂O₇), in at stoichiometric ratios. The reaction proceeds as 2 Ca²⁺ + P₂O₇⁴⁻ → Ca₂P₂O₇↓, forming a white precipitate of the hydrated form. To perform the synthesis, solutions are prepared to achieve [Ca²⁺] = 0.15 / and [P₂O₇⁴⁻] = 0.075 / in a buffered medium at 3.6–5.8 and to 90 °C, followed by stirring for 45 minutes. The resulting precipitate is then filtered, washed with deionized to remove soluble byproducts, and dried at °C. This method yields hydrated calcium pyrophosphate phases, such as the dihydrate (Ca₂P₂O₇·2H₂O), with high purity confirmed by . Further purification can be achieved via recrystallization from dilute acid solutions to eliminate impurities. Lab-scale equipment such as magnetic stirrers ensures uniform mixing, while meters are used to control the reaction environment for phase selectivity. An alternative acid-base method entails the neutralization of (H₄P₂O₇) with (Ca(OH)₂) in aqueous medium, governed by the equation H₄P₂O₇ + 2 Ca(OH)₂ → Ca₂P₂O₇ + 4 H₂O. The procedure involves slowly adding a suspension of Ca(OH)₂ to a solution of H₄P₂O₇ while stirring to control the exothermic reaction and maintain a neutral , followed by of the precipitate and at low (e.g., 37–60 °C). Yields are generally high, with similar purification via recrystallization from dilute acid to enhance crystallinity and remove residual acids. Safety considerations are critical, particularly when handling pyrophosphoric acid, which is highly corrosive and can cause severe skin burns and eye damage upon contact. Protective gear including gloves, , and lab coats is essential, along with proper ; spills should be neutralized with a before cleanup. Standard equipment like stirrers and meters facilitates safe control of the reaction conditions. These methods are suited for small-scale production, differing from larger that prioritize cost efficiency.

Industrial production

Calcium pyrophosphate is primarily produced on an industrial scale through the of (CaHPO₄), typically the dihydrate form (CaHPO₄·2H₂O), at temperatures ranging from 500–1000°C. This dehydration process converts the orthophosphate to the via the reaction 2CaHPO₄ → Ca₂P₂O₇ + H₂O, yielding the form in a continuous or batch setup optimized for high throughput. The method leverages readily available feedstocks and is energy-efficient for large-scale operations, with systems in modern facilities enhancing overall efficiency. Alternative production routes include the reaction of with (CaO) or in rotary kilns, followed by thermal dehydration to form the . This approach allows for continuous processing and integration with existing production lines, where byproducts like wet-process can be utilized. Additionally, continuous precipitation methods from industry effluents, involving controlled addition of calcium sources to streams, provide a sustainable pathway, though these are less common for high-purity grades. Production is driven by demand in dental applications, with key manufacturers including in . emphasizes in the 1–10 μm range for optimal abrasiveness and flowability, alongside of content through spectroscopic and sieving analyses to ensure consistency across batches.

Properties

Solubility and stability

Calcium pyrophosphate demonstrates very low in , with values reported around 38–60 μM in neutral buffer solutions at physiological temperatures ( 7.4, 37°C), equivalent to approximately 0.001 g per 100 mL. This limited dissolution arises from the strong between calcium ions and the anion (P₂O₇⁴⁻), resulting in a highly stable precipitate under aqueous conditions. increases modestly in acidic environments, as of the ion (e.g., to H₂P₂O₇²⁻) diminishes its coordination with Ca²⁺, facilitating greater release; for instance, measurements show a near-linear rise below 7. The compound remains chemically stable at neutral , where it resists rapid degradation and maintains without significant alteration. In strong acidic conditions, however, calcium pyrophosphate undergoes slow of the P–O–P bond in the moiety, yielding orthophosphate ions (HPO₄²⁻) via the P₂O₇⁴⁻ + H₂O → 2 HPO₄²⁻, though this is gradual and typically requires elevated temperatures or prolonged exposure for completion. Environmentally, calcium pyrophosphate exhibits resistance to oxidation, showing no notable reactivity with atmospheric oxygen or common oxidants under ambient conditions, which contributes to its durability in various chemical settings. For optimal long-term storage, it should be maintained in dry environments to avoid unintended conversion between and hydrated phases, as exposure to moisture can promote without affecting overall chemical integrity.

Thermal and mechanical properties

Calcium pyrophosphate hydrates undergo primarily through stepwise upon heating. For the dihydrate forms, reveals weight losses corresponding to the release of approximately two molecules between 30 and 400 °C, leading to the β-Ca₂P₂O₇ . These processes are accompanied by endothermic peaks in (DTA), observed at 315 °C and 330 °C for the triclinic dihydrate (t-CPPD) and at 300 °C and 305 °C for the monoclinic dihydrate (m-CPPD). The anhydrous form of calcium pyrophosphate demonstrates high thermal stability, with polymorphic phase transitions occurring at elevated temperatures. Heating β-Ca₂P₂O₇ to 1275 °C for several hours, followed by , yields the α-Ca₂P₂O₇ polymorph. Mechanically, calcium pyrophosphate exhibits properties that support its use as an material. Its further enhances durability in applications like formulations, where variants provide controlled action.

Biological and medical significance

Role in calcium pyrophosphate deposition disease (CPPD)

Calcium pyrophosphate deposition disease (CPPD), also known as pseudogout or , is a crystal-induced characterized by the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in articular , synovium, and periarticular tissues, leading to a spectrum of clinical manifestations from asymptomatic to acute or chronic . The disease primarily affects individuals over the age of 60, with radiographic prevalence increasing to approximately 4% in those aged 65 and older, and up to 50% in individuals over 80. The crystals involved in CPPD are rhomboid or rod-shaped calcium pyrophosphate dihydrate (CPPD) , primarily in monoclinic and triclinic polymorphs, with typical dimensions ranging from 1 to 20 μm in length. These exhibit weak positive when examined under , appearing blue when parallel to the compensator and yellow when perpendicular, which aids in their identification in analysis. deposition occurs due to an imbalance in , where elevated extracellular pyrophosphate levels, often linked to dysfunction, promote and in joint tissues. Risk factors for CPPD include advanced age, genetic predispositions such as mutations in the gene that enhance pyrophosphate transport, leading to elevated extracellular levels, and associated metabolic disorders like , hemochromatosis, and hypomagnesemia. Familial forms are rare but can present earlier in life, highlighting the role of inherited defects in inorganic pyrophosphatase activity or pyrophosphate generation. In terms of , CPPD crystals act as danger signals that activate the in synovial cells and neutrophils, resulting in the cleavage and release of interleukin-1β (IL-1β), which drives the acute inflammatory response and manifests as sudden, painful attacks often mimicking . Chronic CPPD , by contrast, involves persistent low-grade inflammation and structural joint damage, clinically resembling with features like joint space narrowing and osteophytes. This crystal-mediated inflammation underscores the disease's classification as a , distinct from infectious or autoimmune arthritides.

Diagnosis, treatment, and recent developments

Diagnosis of calcium pyrophosphate deposition disease (CPPD) primarily relies on analysis using compensated (CPLM), which identifies characteristic rhomboid-shaped, weakly positively birefringent calcium pyrophosphate (CPP) crystals in the of affected joints. The 2023 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria provide a standardized scoring system (≥56 points) for CPPD in research settings, integrating clinical features, , and analysis. modalities, such as plain X-rays, play a supportive role by detecting , characterized by linear or punctate calcifications in and , particularly in the knees, wrists, and . While and dual-energy computed (DECT) are emerging for non-invasive detection of crystal deposits, CPLM remains the gold standard for definitive . Treatment for CPPD focuses on symptom management rather than crystal dissolution, as no disease-modifying therapies currently exist to reduce CPP crystal burden. For acute flares, first-line options include nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin or naproxen, (typically 0.6 mg once or twice daily), or intra-articular corticosteroid injections to rapidly alleviate pain and inflammation. In chronic CPPD arthritis, low-dose (0.5–1 mg daily) or NSAIDs are used prophylactically to prevent recurrent attacks, with considered for refractory cases unresponsive to standard therapy. For advanced chronic cases with significant joint damage, surgical interventions such as joint replacement or may be necessary to restore function. Recent developments as of 2025 have expanded options for refractory CPPD, particularly with interleukin-1 (IL-1) inhibitors like , which has shown efficacy in reducing acute flares and chronic inflammation in patients unresponsive to conventional treatments, including those on . Genetic screening for familial forms of CPPD, involving mutations in genes such as , is increasingly recommended in younger patients or those with family history to identify hereditary predispositions and guide counseling. Ongoing into anti- therapies, including analogs aimed at inhibiting crystal formation, holds promise for future disease-modifying approaches, though clinical trials remain in early stages. Additionally, intra-articular sustained-release formulations have demonstrated potential in preclinical models for prolonged anti-inflammatory effects. CPPD is a that can be effectively managed but not cured, with depending on early and of comorbidities like osteoarthritis. The prevalence of CPPD increases with age, affecting approximately 5–10% of elderly populations over 60 years, often presenting asymptomatically until triggered by joint stress or metabolic factors.

Applications

In dentistry and abrasives

Calcium pyrophosphate serves as a polishing agent in toothpaste formulations, functioning as a mild abrasive to clean and polish tooth surfaces gently. Its use in oral care products dates back to the mid-20th century, with s describing its incorporation into dentifrices as early as 1959. The material's is controlled to a of 6–10 μm, with at least 80% of particles ranging from 3–20 μm, allowing for effective removal of surface stains and plaque without causing significant enamel wear. The abrasivity of calcium pyrophosphate is characterized by a relative dentin abrasion (RDA) value of 100, which positions it as a medium-level suitable for daily use in promoting . It operates through mechanical action, dislodging extrinsic deposits like plaque and food particles from and surfaces while minimizing the risk of excessive . In commercial toothpastes, it is typically included at concentrations of 10–60% by weight, often as the primary or sole , and has been featured in products such as Optic White whitening s since their development. As a biocompatible and non-toxic compound, calcium pyrophosphate offers advantages over some synthetic abrasives, including its low toxicity profile similar to other pyrophosphates used in food and industrial applications. It provides a viable alternative to hydrated silica, though silica remains more prevalent in modern formulations. This compatibility ensures safety for regular use, even in sensitive oral care routines.

Biomedical and material science uses

Calcium pyrophosphate (CPP), a calcium phosphate bioceramic with a Ca/P molar ratio of 1.0, exhibits enhanced solubility and bioresorbability compared to hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), making it suitable for biomedical applications such as bone tissue engineering. Its biocompatibility, non-toxicity, and osteoconductive properties support integration with host bone, while its absorbability allows gradual degradation and replacement by natural tissue. A 2025 systematic review confirms CPP's potential as a biomaterial for bone regenerative therapy, highlighting its use in various forms and supporting evidence from preclinical and clinical studies. In bone regeneration, CPP serves as a bone graft substitute in forms like granules or porous scaffolds, demonstrating good osteoconductivity and faster resorption than in animal models including rabbits, , and rats. It has been applied as a on porous alumina scaffolds to improve bioactivity and as a carrier for recombinant bone morphogenetic protein-2 (rhBMP-2), enhancing osteogenic differentiation and bone formation. Clinically, CPP has been evaluated as a bone graft extender in procedures, showing comparable fusion rates to autologous graft in a randomized involving 46 patients. Beyond bone repair, CPP nanostructures, such as self-assembled microspheres and nanotubes formed at ambient without harsh chemicals, enable systems. These structures, with high specific surface areas (up to 125 m²/g) and nanoporosity (53%), facilitate enteric protection of proteins like and , releasing them controllably in simulated intestinal conditions (pH 7) while minimizing gastric degradation (pH 4). In vivo studies in mice confirm intact transit through the to the intestines within 90 minutes, preserving protein activity by over 15% relative to free forms. In material science contexts intersecting with , CPP's role as an in biological mineralization supports its use in developing bioactive composites for orthopedic and dental implants, though evidence remains preliminary and further clinical validation is needed.

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