Il citrato trisodico è il sale sodico dell’acido citrico, una sostanza naturalmente presente negli agrumi e ampiamente utilizzata in ambito cosmetico, alimentare, farmaceutico e industriale. Si presenta come una polvere cristallina bianca o come granuli inodori, solubile in acqua.

In cosmetica, viene impiegato per regolare l’acidità (pH) delle formulazioni, chelare ioni metallici e aumentare la stabilità dei prodotti sensibili all’ossidazione o al cambiamento di colore.

1. Struttura chimica e proprietà fisiche

• Nome IUPAC: trisodio 2-hydroxy-1,2,3-propane-tricarbossilato

• Formula molecolare: C₆H₅Na₃O₇

• Massa molare: 258,06 g/mol

• Classe chimica: sale organico (sale dell’acido carbossilico)

• Gruppi funzionali: carbossilati (-COONa)

Aspetto fisico:

• Stato: solido cristallino

• Colore: bianco

• Odore: inodore

• Punto di fusione: 300 °C (decompone)

• Solubilità: altamente solubile in acqua (~72 g/100 ml a 25 °C); insolubile in etanolo

• pH (sol. acquosa 5%): 7.5–9.0

2. Principali sostanze contenute

Essendo un composto puro, il citrato trisodico non contiene altre sostanze in forma naturale. Tuttavia, può interagire in formula con:

• Acido citrico (per creare tamponi pH)

• EDTA o suoi sali (agenti chelanti complementari)

• Antiossidanti (es. tocoferolo) per stabilizzazione sinergica

3. Metodo di produzione o estrazione

Il citrato trisodico viene ottenuto industrialmente attraverso:

• Neutralizzazione dell’acido citrico con idrossido di sodio o carbonato di sodio

• Cristallizzazione della soluzione concentrata

• Essiccazione e macinazione in polvere o granuli

Non è ottenuto da fonti vegetali o animali, quindi è adatto a formulazioni vegan e cruelty-free.

4. Proprietà funzionali e sensoriali

5. Applicazioni

In cosmetica:

• Creme e lozioni: stabilizzazione della formula e controllo del pH

• Detergenti delicati (shampoo, saponi liquidi): tamponamento dell’acidità

• Gel, sieri, tonici: prevenzione dell’ossidazione e stabilità del colore

• Prodotti contenenti metalli (es. pigmenti): chelazione per evitare variazioni di colore

CAS    68-04-2 / 6132-04-3

EC number    200-675-3

Funzioni INCI:

Agente tampone. E' un ingrediente che può portare una soluzione alcalina o acida a un determinato livello di pH e impedirne la modifica, in pratica uno stabilizzatore di pH che può resistere efficacemente all’instabilità ed all'eventuale cambiamento del pH.

Agente chelante. Ha la funzione di evitare reazioni instabili e migliorare la biodisponibilità di componenti chimici all'interno di un prodotto, elimina i cationi di calcio e magnesio che possono causare una velatura nei liquidi limpidi.

Fragranza. Ha un ruolo importante nella formulazione di prodotti cosmetici in quanto fornisce la possibilità di migliorare, mascherare o aggiungere profumo al prodotto finale aumentandone la commerciabilità. E' in grado di creare un odore gradevole percepibile, mascherare un cattivo odore. Il consumatore si aspetta sempre di trovare un profumo gradevole o particolare in un prodotto cosmetico. 

Altri usi:

• Farmaceutico: eccipiente e regolatore di pH

• Alimentare (E331): acidulante, conservante, sequestrante

• Dentifrici e collutori: riduzione della formazione di tartaro

6. Sicurezza e normativa

• Tossicità: praticamente assente alle dosi d’uso cosmetiche

• Allergenicità: non allergenico, non sensibilizzante

• Non comedogeno, non irritante

• Regolamento (CE) 1223/2009: non incluso negli allegati II (sostanze vietate) né III (restrizioni)

• IFRA: nessuna limitazione

• ECOCERT / COSMOS: ammesso nelle formulazioni naturali

• GRAS (FDA): considerato sicuro anche per uso alimentare

7. Conclusione

Il citrato trisodico è un ingrediente funzionale essenziale nella cosmetica moderna per la sua versatilità, stabilità chimica, assenza di tossicità, e ampia compatibilità con altri ingredienti. Grazie alla sua azione tampone e chelante, contribuisce significativamente alla stabilità microbiologica e fisico-chimica delle formulazioni cosmetiche.

È una valida alternativa ai chelanti di sintesi più controversi, ed è ben tollerato da tutti i tipi di pelle, inclusa quella sensibile o reattiva.

Bibliografia__________________________________________________________________________

Phillips R, Hanchanale VS, Myatt A, Somani B, Nabi G, Biyani CS. Citrate salts for preventing and treating calcium containing kidney stones in adults. Cochrane Database Syst Rev. 2015 Oct 6;(10):CD010057. doi: 10.1002/14651858.CD010057.pub2.

Abstract. Background: Kidney stones affect people worldwide and have a high rate of recurrence even with treatment. Recurrences are particularly prevalent in people with low urinary citrate levels. These people have a higher incidence of calcium phosphate and calcium oxalate stones. Oral citrate therapy increases the urinary citrate levels, which in turn binds with calcium and inhibits the crystallisation thus reduces stone formation. Despite the widespread use of oral citrate therapy for prevention and treatment of calcium oxalate stones, the evidence to support its clinical efficacy remains uncertain. Objectives: The objective of this review was to determine the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones. Search methods: We searched the Cochrane Kidney and Transplant Specialised Register to 29 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Selection criteria: We included randomised controlled trials (RCTs) that assessed the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones in adults treated for a minimum of six months. Data collection and analysis: Two authors assessed studies for inclusion in this review. Data were extracted according to predetermined criteria. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Main results: We included seven studies that included a total of 477 participants, most of whom had oxalate stones. Of these, three studies (247 participants) compared potassium citrate with placebo or no intervention; three (166 participants) compared potassium-sodium citrate with no intervention; and one (64 participants) compared potassium-magnesium citrate with placebo. Overall, quality of the reporting of the included studies was considered moderate to poor, and there was a high risk of attrition bias in two studies.Compared with placebo or no intervention, citrate therapy significantly reduced the stone size (4 studies, 160 participants: RR 2.35, 95% CI 1.36 to 4.05). New stone formation was significantly lower with citrate therapy compared to control (7 studies, 324 participants: RR 0.26, 95% CI 0.10 to 0.68). The beneficial effect on stone size stability was also evident (4 studies, 160 participants: RR 1.97, 95% CI 1.19 to 3.26). Adverse events were reported in four studies, with the main side effects being upper gastrointestinal disturbance and one patient reported a rash. There were more gastrointestinal adverse events in the citrate group; however this was not significant (4 studies, 271 participants: RR 2.55, 95% CI 0.71 to 9.16). There were significantly more dropouts due to adverse events with citrate therapy compared to control (4 studies, 271 participants: RR 4.45, 95% CI 1.28 to 15.50). The need for retreatment was significantly less with citrate therapy compared to control (2 studies, 157 participants: RR 0.22, 95% CI 0.06 to 0.89). Authors' conclusions: Citrate salts prevent new stone formation and reduce further stone growth in patients with residual stones that predominantly contain oxalate. The quality of reported literature remains moderate to poor; hence a well-designed statistically powered multi-centre RCT is needed in order to answer relevant questions concerning the efficacy of citrate salts.

Xia Y, Zhang X, Bo A, Sun J, Li M. Sodium citrate inhibits the proliferation of human gastric adenocarcinoma epithelia cells. Oncol Lett. 2018 May;15(5):6622-6628. doi: 10.3892/ol.2018.8111.

Abstract. The objective of the present study was to investigate the cytotoxic effects of sodium citrate on human gastric adenocarcinoma epithelia AGS cells. Numerous cytotoxicity-associated sodium citrate-induced effects were assessed, including cell viability and proliferation, cytokine expression and caspase activity. In vitro studies demonstrated that incubation with sodium citrate (>3.125 mM) inhibited AGS cell viability and proliferation in a dose-dependent manner. Incubation with sodium citrate for 24 h revealed that the levels of interleukin-1β (IL-1β), IL-8 and tumor necrosis factor increased with an increasing of dose of sodium citrate, whereas the IL-6 levels exhibited only a slight alteration. In addition, increases in caspase-3 and -9 activities were associated with increased duration of treatment and dosage of sodium citrate. Collectively, the results of the present study demonstrated that treatment with sodium citrate at higher concentrations or for longer durations exerts a cytotoxic effect on AGS cells via the induction of the intrinsic apoptosis pathway and the alteration in the levels of certain cytokines.

Lok CE, Appleton D, Bhola C, Khoo B, Richardson RM. Trisodium citrate 4%--an alternative to heparin capping of haemodialysis catheters. Nephrol Dial Transplant. 2007 Feb;22(2):477-83. doi: 10.1093/ndt/gfl570.

Abstract. Background: Central venous catheters (CVCs) continue to be used at a high rate for dialysis access and are frequently complicated by thrombus-related malfunction. Prophylactic locking with an anticoagulant, such as heparin, has become standard practice despite its associated risks. Trisodium citrate (citrate) 4% is an alternative catheter locking anticoagulant. Methods: The objective was to prospectively study the clinical effectiveness, safety and cost of citrate 4% vs heparin locking by comparing rates of CVC exchanges, thrombolytic use (TPA) and access-associated hospitalizations during two study periods: heparin period (HP) (1 June 2003-15 February 2004) and Citrate Period (CP) 15 March-15 November 2004. Incident catheters evaluated did not overlap the two periods. Results: There were 176 CVC in 121 patients (HP) and 177 CVC in 129 patients (CP). The event rates in incident CVC were: CVC exchange 2.98/1000 days (HP) vs 1.65/1000 days (CP) (P = 0.01); TPA use 5.49/1000 (HP) vs 3.3/1000 days (CP) (P = 0.002); hospitalizations 0.59/1000 days (HP) vs 0.28/1000 days (CP) (P = 0.49). There was a longer time from catheter insertion to requiring CVC exchange (P = 0.04) and TPA (P = 0.006) in the citrate compared with the heparin lock group. Citrate locking costs less than heparin locking but a formal economic analysis including indirect costs was not done. Conclusion: Citrate 4% has equivalent or better outcomes with regards to catheter exchange, TPA use and access-related hospitalizations compared with heparin locking. It is a safe and less expensive alternative. Randomized trials comparing these anticoagulants with a control group would definitively determine the optimal haemodialysis catheter locking solution.

Milla P, Viterbo ML, Mosca S, Arpicco S. Chemical and microbiological stability, anticoagulant efficacy and toxicity of 35 and 90 mM trisodium citrate solutions stored in plastic syringes. Eur J Hosp Pharm. 2018 Oct;25(e2):e83-e87. doi: 10.1136/ejhpharm-2016-001094.

Abstract. Background: Trisodium citrate is an interesting alternative to heparin for the prevention of circuit clotting during extracorporeal procedures, but some protocols require non-commercially available citrate concentrations. Little published information is available about the stability of diluted citrate solutions. Objectives: To evaluate the long-term stability, efficacy and toxicity of 35 mM and 90 mM trisodium citrate solutions prepared by diluting a commercially available sterile solution, stored in plastic syringes and used as an anticoagulant during citrate bag changes in the coupled plasma filtration adsorption (CPFA) technique in the COMPACT-2 clinical trial. Methods: The chemical stability of trisodium citrate solutions was evaluated by high-performance liquid chromatography after 7, 14, 21 and 28 days of storage. Sterility tests were performed both immediately after preparation and after 28 days of storage. Results: After 28 days of storage, the concentration of trisodium citrate had not changed in comparison with day 1, and both solutions passed the sterility test. A preliminary test indicated that a 35 mM solution is insufficient to ensure an effective anticoagulant action on an extracorporeal circuit, but the 90 mM solution was successfully used for 7 CPFA treatments in 2 patients, without clinical signs of toxicity. Conclusions: Both the 35 mM and 90 mM solutions are chemically and microbiologically stable for 28 days when stored at room temperature in 50 mL syringes protected by light. The 90 mM solution is an effective and safe regional anticoagulant in the CPFA protocol. Trial registration number: NCT01639664.

Duncan EM, Casey CR, Duncan BM, Lloyd JV. Effect of concentration of trisodium citrate anticoagulant on calculation of the International Normalised Ratio and the International Sensitivity Index of thromboplastin. Thromb Haemost. 1994 Jul;72(1):84-8. 

Abstract. The aim of this study was to determine whether the concentration of trisodium citrate used to anticoagulate blood has an effect on the INR of the sample and the ISI of the thromboplastin. Five thromboplastins including and Australian reference material were used to measure the prothrombin time of normal and patient samples collected into two concentrations of trisodium citrate--109 mM and 129 mM. There was no effect of citrate concentration on the INRs determined with the reference material. However for the other four thromboplastins there was a significant difference between INRs for the two citrate groups. The prothrombin times of the samples collected into 129 mM were longer than those collected into 109 mM. This difference was only slight in normal plasma but more marked in patients receiving oral anticoagulants, causing the INRs for patient plasmas collected into 129 mM citrate to be higher then the corresponding samples collected into 109 mM citrate. From orthogonal regression of log prothrombin times by the reference method against each thromboplastin, we found that the ISI for each thromboplastin was approximately 10% lower when determined with samples collected into 129 mM citrate than with samples collected into 109 mM. These results suggest that the concentration of trisodium citrate used for collection of blood samples can affect the calculation of the INR and the calibration of the ISI of thromboplastin. This was found both for commercial thromboplastins prepared by tissue extraction and for a recombinant tissue factor.

Ozcan-Yilsay T, Lee WJ, Horne D, Lucey JA. Effect of trisodium citrate on rheological and physical properties and microstructure of yogurt. J Dairy Sci. 2007 Apr;90(4):1644-52. doi: 10.3168/jds.2006-538.

Abstract. The effect of trisodium citrate (TSC) on the rheological and physical properties and microstructure of yogurt was investigated. Reconstituted skim milk was heated at 85 degrees C for 30 min, and various concentrations (5 to 40 mM) of TSC were added to the milk, which was then readjusted to pH 6.50. Milk was inoculated with 2% yogurt culture and incubated at 42 degrees C until pH was 4.6. Acid-base titration was used to determine changes in the state of colloidal calcium phosphate (CCP) in milk. Total and soluble Ca contents of the milk were determined. The storage modulus (G') and loss tangent (LT) values of yogurts were measured as a function of pH using dynamic oscillatory rheology. Large deformation rheological properties were also measured. Microstructure of yogurt was observed using confocal scanning laser microscopy, and whey separation was also determined. Addition of TSC reduced casein-bound Ca and increased the solubilization of CCP. The G' value of gels significantly increased with addition of low levels of TSC, and highest G' values were observed in samples with 10 to 20 mM TSC; higher (> 20 mM) TSC concentrations resulted in a large decrease in G' values. The LT of yogurts increased after gelation to attain a maximum at pH approximately 5.1, but no maximum was observed in yogurts made with > or = 25 mM of TSC because CCP was completely dissolved prior to gelation. Partial removal of CCP resulted in an increase in the LT value at pH 5.1. At low TSC levels, the removal of CCP crosslinks may have facilitated greater rearrangement and molecular mobility of the micelle structure, which may have helped to increase G' and LT values of gels by increasing the formation of crosslinks between strands. At high TSC concentrations the micelles were completely disrupted and CCP crosslinks were dissolved, both of which resulted in very weak yogurt gels with large pores obvious in confocal micrographs. Gelation pH and yield stress significantly decreased with the use of high TSC levels. Lowest whey separation levels were observed in yogurt made with 20 mM TSC, and whey separation greatly increased at > 25 mM TSC. In conclusion, low concentrations of TSC improved several important yogurt characteristics, whereas the use of levels that disrupted casein micelles resulted in poor gel properties. We also conclude that the LT maximum observed in yogurts made from heated milk is due to the presence of CCP because the modification of the CCP content altered this peak and the removal of CCP eliminates this feature in the LT profiles.