Calcium Citrate Complex Research Articles

Efficacy for Bone Deterioration in Mice with Osteoporosis and Pharmaceutical Properties of a Novel Compound Calcium Carbonate Granule

Osteoporosis (OP) has been a global health concern, and calcium supplements are still an effective method to relieve the disease. In this study, we investigated the pharmaceutical properties, antiosteoporosis, and adverse effects of a novel calcium supplement named compound calcium carbonate granule (CCCG). The dissolution rate, stability of vitamin D3, and drug permeability of the calcium supplements were explored. And the osteoporosis was constructed in mice with retinoic acid (100 mg/kg/d) for 21 days, and orally treated with CCCG (0.34, 0.68, and 1.36 g/kg/d) for 36 days to evaluate the efficacy against osteoporosis and the occurrence of kidney stones. The results showed that CCCG exhibited higher dissolution rate and better vitamin D3 stability than the standard calcium carbonate granule. CCCG also displayed more absorption in Caco-2 cell model. On the other hand, CCCG alleviated the deterioration in femur microstructure and oxidative stress in the liver and kidney, and increased the expression of bone metabolic markers. CCCG also exhibited lower risk of nephrolithiasis than the commercial calcium carbonate granule. In summary, from the perspectives of both pharmaceutics and efficacy, we illustrated the profiles of an intriguing calcium supplement, which could possibly be an alternative of commonly used ones. Practical Application. Calcium carbonate is widely used to supplement calcium, primarily because of its high calcium load, low cost, and good efficacy. Now, we provided a new calcium supplement named CCCG, which was prepared by inclusion and complexation techniques. Vitamin D3 in CCCG was made into vitamin D-β-cyclodextrin inclusion complex by inclusion technology, which improved the stability of vitamin D3. And calcium carbonate was converted to a water-soluble calcium citrate complex via complexation techniques to accelerate the release of calcium ions and minimize the risk of kidney stone formation. From the perspective of both pharmaceutics and efficacy, we illustrated the profiles of an intriguing calcium supplement, which could possibly be an alternative for the supplemental and preventive treatment of osteoporosis.

Spectroscopic and X-ray structural investigations of the active calcium preparation

Structural studies of calcium citrate obtained by IR irradiation of calcium carbonate and citric acid in various ratios by spectroscopic and X-ray structural analysis has been carried out. It is shown that in the obtained samples of calcium carbonate there are polymorphic states in the form of aragonite, vaterite, calcite, as well as ikaite and in calcium citrate complex calcium compounds with different coordination numbers are observed.

Biological responses of MC3T3-E1 on calcium carbonate coatings fabricated by hydrothermal reaction on titanium

Titainum (Ti) implants have been successfully used in orthopaedic and dental surgery. However, poor early bone tissue integration is still a common cause of implant failure. This could be modulated by improving the material bonding or adhesion directly to the bone by surface roughening and/or a bioresorbable and osteoconductive coating. In this study, we report on the biological behaviours of the Ti substrate with modified surface roughness and/or a calcium carbonate (CaCO3) coating. The roughened Ti surface was prepared using an acid etching reaction, and the CaCO3 coating on the substrates was synthesized by the hydrothermal treatment of Ti in calcium citrate complexes. This study demonstrates that surface roughening of Ti alone does not improve the biological response of the MC3T3-E1 cells, but a CaCO3 coating on the smooth Ti surface increases cell responses, and these effects are further enhanced by the combination of coating a roughened Ti surface with CaCO3. The larger the cell area, the greater the cell proliferation and increased bone-like nodule formation were observed on the CaCO3 coating of the roughened Ti surface. This observation was also supported by a higher ALP value. The cell behaviours found in the current study further support the development of CaCO3 coatings towards clinical application.

Experiment and kinetic modeling for leaching of blast furnace slag using ligand

Abstract Blast furnace (BF) slag is recognized as an excellent source of precipitated calcium carbonate (PCC) and CO2 sequestrating agents because it contains a significant amount of calcium. The pH-swing method is a promising process for commercialization of the slag carbonation process among the other indirect carbonation methods due to the high selectivity of calcium extraction and production of high quality PCC. In this study, ligand-based solvents, such as acetic acid, gluconic acid, and citric acid, were examined as new leachates for the extraction step in the pH-swing process. Citric acid showed the highest efficiency, and the extraction efficiencies were estimated based on particle size distribution, concentration of solvent, solid-to-liquid ratio, stirring speed, and temperature. The calcium extraction rate increased with decreasing particle size and S/L ratio and with increasing concentration of solvent and stirring speed. However, extraction efficiency decreased significantly at high temperature because calcium-citrate complexes were precipitated. Along with the experiments, a kinetic study based on the shrinking core model was carried out at temperatures lower than 30 °C. Our results demonstrated that the extraction process was controlled by a surface chemical reaction, and the activation energy was estimated to be 50.74 kJ mol−1.

Supersaturation of calcium citrate as a mechanism behind enhanced availability of calcium phosphates by presence of citrate

Dissolution of amorphous calcium phosphate (ACP) in aqueous citrate at varying pH has been studied with perspective of increasing availability of calcium from sidestreams of whey protein, lactose and/or cheese production or on development of new functional foods. ACP formed as an initial precipitate in 0.10 mol L−1 equimolar aqueous calcium chloride, sodium citrate, and sodium hydrogenphosphate was used as model for mineral residues formed during milk processing. Upon acidification of the ACP suspension by hydrochloric acid decreasing pH from 6.5 to 4.5, the transformations of ACP occurred through an 8 h period of supersaturation prior to a slow precipitation of calcium citrate tetrahydrate. This robust supersaturation, which may explain increased availability of calcium phosphates in presence of citrate, presented a degree of supersaturation of 7.1 and was characterized by precipitation rates for 0.10 mol L−1 equimolar aqueous calcium chloride, sodium hydrogencitrate, and sodium hydrogenphosphate with pH 5.5, and for 0.10 mol L−1 equimolar aqueous calcium chloride, sodium hydrogencitrate, and sodium dihydrogenphosphate with pH 4.1, with a degree of supersaturation of 2.7. The crystallization processes were similar according to Avrami's model with a half-life for precipitation of approximately 5 h independent of the degree of supersaturation. Ion speciation based on measurement of pH, and total concentrations of calcium, phosphate and citrate, and of conductivity and calcium ion activity during precipitation indicates a low driving force for precipitation with calcium citrate complex dominating at pH 5.5 and calcium hydrogencitrate complex dominating at pH 4.1. Calcium hydrogencitrate is suggested to be the species involved in the crystal growth followed by solid state transformation to calcium citrate tetrahydrate.

Some aspects of the aqueous solution chemistry of the Na+/Ca2+/OH−/Cit3− system: The structure of a new calcium citrate complex forming under hyperalkaline conditions

In the present study, we show that in hyperalkaline (pH > 13) aqueous solutions, Ca2+ forms a new, so far unknown complex species with the citrate ion, the structure of which is different from the well-known CaCit−(aq) species present in solutions of close to neutral pH. The solubility of Ca3Cit2(s) was found to increase significantly under hyperalkaline conditions. The decrease in the electric conductivity and the variations observed in the freezing point depression of such solutions also indicate complexation. From 1H NMR measurements, in this complex, the citrate ion is suggested to be in quadruply deprotonated form. From the variation of the 2JHH geminal proton coupling constant, two neighboring carboxylate groups are coordinated to the calcium ion in a monodentate mode (besides the alcoholate). The optimal structure of the complex with the composition of CaCitH−12−(aq) has also been calculated using DFT calculations, applying the Polarizable Continuum Model. Sodium ion-pairing was found to compete efficiently with this calcium complexation process, and in solutions with high Na-ion content, the equilibria are shifted towards the formation of NaCit2−(aq) and Na2Cit−(aq) ion pairs.

Reliable high strength alumina fabricated by DCC-HVCI using submicron calcium citrate complex

Ceramics with high strength and reliability are highly demanded in engineering applications. In this paper, a modified direct coagulation casting via high valence counter ions (DCC-HVCI) method for alumina using calcium citrate complex assisted by glycerol diacetate was investigated. Calcium citrate complex suspensions were prepared by mixing tri-ammonium citrate and calcium chloride in water. Effect of reaction time on the chelating properties of the prepared suspensions was investigated. Concentrated alumina suspensions with a solid loading of 50vol% were prepared by mixing the calcium citrate complex suspensions and alumina powder at pH of 10.5. Then the suspensions were coagulated by adding 3–6vol% glycerol diacetate at temperatures of 40–70°C for 2–6h. The compressive strength of the coagulated wet samples is in the range 1.1–2.4MPa. Alumina ceramics sintered at 1550°C shows homogeneous microstructures with flexural strength and Weibull modulus of 455±17MPa and 30, respectively.

Morphology control of hydroxyapatite microcrystals: Synergistic effects of citrate and CTAB

Using hydrothermal treatment and with the synergistic regulating effects of citrate and CTAB, various 3D hierarchical superstructure of hydroxyapatite (HAp) microcrystals were synthesized by simply adjusting the Ct/CTAB ratio and calcium–citrate complex (CC) morphology. The resulting superstructure was characterized using X-ray diffraction (XRD), Fourier Transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy (FESEM) etc. With the shape transformation of CC from sphere-like colloid, nano-needle to lamellar-like particles, the final products were hollow spheres, bunched-like microrods and nanorod clusters, respectively. A possible mechanism for the formation of HAp hierarchical microstructure was proposed.

Impact of citrate pretreatment on ventricular arrhythmia and myocardial capase-3 expression in ischemia/reperfusion injury

Ischemia/reperfusion (I/R) injury often triggers ventricular arrhythmia. Citrate binds calcium ions, forming a soluble calcium citrate complex that may reduce I/R injury by affecting calcium ion concentration. We tested the effects of citrate pretreatment on ventricular heart rate and related factors in a rat I/R model. Fifty male Sprague Dawley rats weighing 350-400 g were randomly divided into equally sized control (A), model (B), and 0.1 M (C), 0.05 M (D), and 0.025 M (E) citrate groups. An I/R model was established by ligating the left anterior descending coronary artery. Serum calcium ion concentration was measured before and after citrate treatment. Triphenyltetrazolium chloride staining and spectrophotometry were used to determine infarction area and caspase-3 protein levels in myocardial tissue, respectively. Polymerase chain reaction was performed to test myocardial calmodulin (CAM) expression. The frequency of ventricular arrhythmia in group B was significantly higher than in the sham surgery group (P < 0.05). Citrate pretreatment resulted in lower and higher frequencies than those observed in the model and control groups, respectively, in a dose-independent manner. The most obvious reduction in ventricular arrhythmia was seen in Group D. Serum calcium ion concentration decreased markedly after citrate treatment (P < 0.05), with a specific pattern emerging over time. Infarction area and caspase-3 and CAM levels were significantly lower in the citrate groups compared with the model group (P < 0.05). Citrate can reduce myocardial cell apoptosis, alleviating ventricular arrhythmia and protecting the myocardium by reducing serum calcium ion concentration and downregulating caspase-3 and CAM expression.

The effect of citric acid on the sintering of calcium phosphate bioceramics

Biphasic calcium phosphate particles were prepared using a rapid increase of the pH value by adding an amount of concentrated ammonia solution, into a well-mixed solution containing Ca(H 2PO 4) 2·H 2O and CaCl 2 with Ca/P = 1.667 molar ratio; with or without the presence of citric acid (CiA). The precipitation of Calcium Phosphates took place at 97 °C using high-speed dispersing equipment. The samples were characterized using XRD, FT-IR, BET and SEM techniques. The thermal behaviour was studied by TG, DTG and DTA techniques. The modified precipitation method leads to the formation of biphasic needle-like particles consisted of crystalline hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP). The presence of CiA in the initial solution leads to the formation of aggregated nonporous small spheroidal particles consisted of low crystallinity phases of HA and octacalcium phosphate (OCP). The later facilitates the sintering process. The calcined samples at 900 °C were consisted of calcium pyrophosphate (CPP) and TCP. α-TCP is formed in the presence of a large amount of calcium citrate complexes. The main sintering process took place at the temperature range between 750 and 1150 °C, which were strongly depended on the initial amount of the CiA in the precipitation process. These results indicated that the citrate presence in the initial solution have a strong influence on the nucleation and growth processes by complexation with calcium ions and incorporation into the solid structure during particle growth.

Safety and Efficacy of Regional Citrate Anticoagulation During 8-Hour Sustained Low-Efficiency Dialysis

Patients who may benefit from sustained low-efficiency dialysis therapy are often at risk for bleeding. A safe and simple "regional" anticoagulation strategy would be beneficial. The modification of existing regional citrate anticoagulation protocols to typically performed 8-h sustained low-efficiency dialysis is necessary. Sustained low-efficiency dialysis was performed at blood and dialysate rates of 250 and 300 ml/min, respectively. The circuit was anticoagulated with 4% sodium citrate (citrate 136, sodium 408 mmol/L) and reversed with CaCl(2). Every 2 h, electrolytes, ionized circuit, and patient calcium were monitored during the first two versions. The second version differed by an increased infusion of CaCl(2) and lower infusion of citrate, both by 10%. The third version measured only laboratory values before and after sustained low-efficiency dialysis. There were 41 treatments in the first iteration, 42 in the second, and 34 in the final iteration. All versions were titrated to maintain patient ionized calcium of 4.0 to 4.8 mg/dl (1.0 to 1.2 mmol/L) and the circuit ionized calcium between 0.8 and 1.6 mg/dl (0.2 and 0.4 mmol/L). The final protocol infusion was 31 mmol/h citrate and 41 mmol/h elemental calcium, which kept circuit and patient ionized calcium at targets. No unexpected metabolic complications occurred. Compared with continuous renal replacement therapy, one must increase the calcium infusion because of the more efficient removal of the calcium citrate complex. Safe and effective regional citrate anticoagulation can be performed in 8-h sustained low-efficiency dialysis without metabolic complications with laboratory surveillance only before and after sustained low-efficiency dialysis treatment; however, certain safeguards are mandatory.

Hydroxyapatite micro- and nanoparticles: Nucleation and growth mechanisms in the presence of citrate species

Hydroxyapatite (HAP) particles with different morphologies were precipitated from homogeneous calcium/citrate/phosphate solutions at physiological temperature. Small variations of the starting solution pH in the range 7.4 < pH < 8.5 made it possible to switch the precipitated particle morphology from a micrometric bundlelike to a nanometric needlelike shape. The role of the existing citrate species as calcium chelates is here discussed within the framework of particle nucleation and growth mechanisms. While temperature-dependent calcium citrate complex (Cacit) stability is here suggested to control the free calcium availability and thereby the nucleation rate, the adsorbed citrate species are proposed to control the nanoparticle stability. Moreover, an attempt to detail the role of citrate species in the ordered aggregation of HAP nuclei leading to the observed peanut and bundlelike microparticles morphology is also presented.

A study of primary nucleation of calcium oxalate monohydrate: II. Effect of urinary species

AbstractKidney stones consist of various organic and inorganic compounds. Calcium oxalate monohydrate (COM) is the main inorganic constituent of kidney stones. However, the mechanisms for the formation of calcium oxalate kidney stones are not well understood. In this regard, there are several hypotheses including nucleation, crystal growth and/or aggregation of formed COM crystals. The effect of some urinary species such as oxalate, calcium, citrate, and protein on nucleation and crystallization characteristics of COM is determined by measuring the weight of formed crystals and their size distributions under different chemical conditions, which simulate the urinary environment. Statistical experimental designs are used to determine the interaction effects among various factors. The data clearly show that oxalate and calcium promote nucleation and crystallization of COM. This is attributed to formation of a thermodynamically stable calcium oxalate monohydrate resulting from supersaturation. Citrate, however, inhibits nucleation and further crystal growth. These results are explained on the basis of the high affinity of citrate to combine with calcium to form soluble calcium citrate complexes. Thus, citrate competes with oxalate ion for binding to calcium cations. These conditions decrease the amount of free calcium ions available to form calcium oxalate crystals. In case of protein (mucin), however, the results suggest that no significant effect could be measured of mucin on nucleation and crystal growth. (© 2004 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

A study of primary nucleation of calcium oxalate monohydrate: II. Effect of urinary species

AbstractKidney stones consist of various organic and inorganic compounds. Calcium oxalate monohydrate (COM) is the main inorganic constituent of kidney stones. However, the mechanisms for the formation of calcium oxalate kidney stones are not well understood. In this regard, there are several hypotheses including nucleation, crystal growth and/or aggregation of formed COM crystals. The effect of some urinary species such as oxalate, calcium, citrate, and protein on nucleation and crystallization characteristics of COM is determined by measuring the weight of formed crystals and their size distributions under different chemical conditions, which simulate the urinary environment. Statistical experimental designs are used to determine the interaction effects among various factors. The data clearly show that oxalate and calcium promote nucleation and crystallization of COM. This is attributed to formation of a thermodynamically stable calcium oxalate monohydrate resulting from supersaturation. Citrate, however, inhibits nucleation and further crystal growth. These results are explained on the basis of the high affinity of citrate to combine with calcium to form soluble calcium citrate complexes. Thus, citrate competes with oxalate ion for binding to calcium cations. These conditions decrease the amount of free calcium ions available to form calcium oxalate crystals. In case of protein (mucin), however, the results suggest that no significant effect could be measured of mucin on nucleation and crystal growth. (© 2004 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

An interfacial equilibria model for the electrokinetic properties of a fat emulsion

A semi-empirical model is developed that may be used to describe the zeta potential behaviour of fat emulsions in complex electrolyte systems. The model encompasses specific adsorption at the interface, ionic strength effects according to the Guoy-Chapman theory and chemical speciation analysis of the bulk electrolyte using competitive thermodynamic equilibria. An example of the model is given for the competitive equilibria between calcium binding at the interface and calcium-citrate complex formation in the bulk electrolyte. Unless one uses sophisticated models patient benefit: risk ratios may be compromised through oversimplification.

Enhanced calcium bioavailability from a solubilized form of calcium citrate.

An improved formulation of calcium citrate with higher aqueous solubility and bioavailability was sought. Mixtures of calcium hydroxide and citric acid, with a calcium to citrate molar ratio ranging from 0.67-1.5, dissolved rapidly in water, creating a metastably supersaturated solution. The presence of an excess of citrate in the mixture delayed the precipitation of calcium citrate and kept calcium in solution longer. Thus, the mixture with a calcium to citrate molar ratio of 1.25, containing 500 mg elemental calcium, dissolved in 300 mL water within 2 min and could be kept in solution for 1 h at a wide pH range between 2 and 7. Intestinal calcium absorption, measured from the increment in urinary calcium during the second 2 h following an oral calcium load (500 mg) in 15 normal subjects was significantly higher from the mixtures (calcium to citrate molar ratios of 1.5 and 1.25) than from tricalcium dicitrate. The fractional calcium absorption, obtained from fecal recovery of radiocalcium after oral administration of 500 mg calcium prelabeled with 47Ca in 11 normal subjects, was also higher for the mixture with a calcium to citrate molar ratio of 1.25. The most efficient calcium absorption was obtained with the mixture of calcium hydroxide and citric acid with a calcium to citrate molar ratio of 1.25. The increment in urinary calcium after an oral load with this mixture was 62.4% greater than that obtained with tricalcium dicitrate [0.138 +/- 0.056 (+/- SD) vs. 0.085 +/- 0.086 mg/dL glomerular filtrate; P less than 0.05]. The fractional calcium absorption was 88.4% higher (0.324 +/- 0.107 vs. 0.172 +/- 0.061; P less than 0.05). This mixture provided the highest concentration of ionic calcium, indicating that calcium (rather than calcium-citrate complex) is the fraction absorbed from the intestinal tract. This study, therefore, suggests that a liquid calcium preparation formulated from the mixture of calcium hydroxide and citric acid is more effective than a solid preparation of tricalcium dicitrate in providing soluble and bioavailable calcium.

Formation constants for magnesium and calcium citrate complexes

centration formation constants for magnesium and calcium citrate complexes have been redetermined from pH titrations of citric acid in the absence and presence of the divalent metal ions in aqueous solution at 2° Values for the constants, corrected for the presence of potassium citrate complex, are presented and critically compared with literature values. Values for the formation constants of strontium and barium citrate complexes are also reported.

Effects of High-Heat Treatment on Stability of Calcium Caseinate Aggregates in Milk

Under standard conditions of centrifugation, the concentration and composition of the nonsedimenting nitrogen content of heated milks are found to vary. It decreases in concentration with increasing temperature to between 103 and 110C, where its concentration increased again with temperature. Below 103C the nonsedimenting nitrogen fraction was found to consist of whey proteins and the proteosepeptone fraction; at 110C and above the nonsedimenting nitrogen fraction consisted predominantly of caseinate. The amounts of nonsedimenting nitrogen produced above 110C was dependent on the temperature of heating, the concentration of milk solids, and on the phosphate and citrate concentrations. It has been reported by others, and also found in this investigation, that the soluble calcium and phosphate concentrations of milk decreased during heating, whereas those of citrate remained constant. Soon after heating, the soluble calcium concentration of milk returned to its former value. Formation of dissociated caseinate at temperatures of 110C and above may be attributed to removal of calcium from caseinate aggregates by the free citrate ion. Since the citrate concentration was not changed by heating, its formation of a soluble calcium citrate complex also returns the soluble calcium concentration to its value before heating.

Active transport of Ca45 by the small intestine and its dependence on vitamin D.

Everted gut-sacs prepared from segments of the proximal small intestine of young rabbits, rats and guinea pigs transport Ca45 in vitro from the mucosal to the serosal surfaces against concentration gradients. The active transport mechanism is limited in capacity, is dependent on oxidative phosphorylation, and appears to be relatively specific for Ca++ and Mg++ in contrast to Sr++ and Ba++. Vitamin D deprivation in rabbits and rats markedly impairs the capacity for active Ca45 transport in vitro. The vitamin thus has an effect directly on the upper small intestine. Neither the active Ca45 transport nor the effect of vitamin D on the transport can be explained by an accumulation of citrate and the formation of the calcium-citrate complex.

Further studies of the effects of citrate feeding on the calcium, phosphorus, and citrate metabolism of rachitic infants

Summary Observations were made on three rachitic infants during the course of treatment with a citrate mixture without vitamin D. The studies included determinations of calcium, phosphorus, citrate, and phosphatase in the serum and the daily excretions of calcium, phosphorus, and citrate in the urine. X-rays of the long bones were taken at intervals so that the evidences of deposition of bone salt in the rachitic cartilage could be correlated with the concentrations of calcium and phosphorus in the serum. The citrate solution consisted of an equimolar mixture of citric acid and trisodium citrate which was added to the milk feedings in amounts ranging from 30 to 60 mM. of citrate per day. In two infants with advanced floridrickets citrate administration resulted in a rapid drop of the concentrations of serum calcium to hypocalcemic levels while the serum phosphorus values remained low. Deposition of bone salt in the rachitic cartilage was evident by x-ray during the period in which the concentrations of calcium and phosphorus in the serum were below the normal range and Ca×P ratios were less than 30. The urinary excretion of calcium remained low during the period of citrate treatment and the urinary excretion of phosphorus was unchanged. The concentrations of citrate in the serum were not consistently increased during citrate treatment but rose after vitamin D was given. A third infant with early ricketsand tetany showed a somewhat different pattern of response to citrate feedings. The serum calcium level which had risen following high calcium intake decreased somewhat when citrate was given but the concentration of phosphate and of citrate rose to normal values while the alkaline phosphatase activity in the serum decreased. X-rays of the bones showed normal growth and calcification during the period of citrate therapy without vitamin D. It is suggested that the antirachiticeffect of citrate feeding is not simply due to the formation of a diffusible calcium citrate complex in the intestinal contents, nor in the extracellular fluids, but that there is a local action upon proliferating cartilage and bone matrix resulting in increased calcifiability. An analogy is drawn between the sequence of events following citrate feeding to rachitic infants and that seen in patients with decalcification of the skeleton due to hyperparathyroidism when the hyperfunctioning parathyroid tissue is removed. In both instances mineralization of the skeleton is associated with decreased levels of calcium and phosphorus in the serum. In one patient of this series, however,a 2-month-old infant with early rickets, citrate feeding seemed to be a more complete substitute for vitamin D. While on citrate therapy the levels of serum phosphorus and of citrate rose to normal; the alkaline phosphatase activity of the serum decreased; and bone x-rays showed normal ossification. This is another suggestion of an interrelationship between citrate metabolism and the physiological effects of vitamin D.