COMMENTARY Calcium and phosphates COMMENTARY • The influence of other drugs and Calcium and phosphate compatibility: nutrients.4-8,10-18 Revisited again The application of knowledge about calcium and phosphate com- DAVI D W. NE W TO N A nd DAVI D F. DRISCOLL patibility in i.v. therapy has been fa- 3-6 Am J Health-Syst Pharm. 2008; 65:73-80 cilitated by four hallmark articles, several editions of the Handbook on he subject of the compatibility • The clinically relevant dissocia- Injectable Drugs17 since 1983, and between calcium and phosphates tion equilibria for which the pKa2 of Trissel’s Calcium and Phosphate Com- was revisited in an April 1994 phosphoric acid is 7.2 (i.e., the pH patibility in Parenteral Nutrition.18 T 1,2 FDA safety alert, 6–16 years after at which the concentrations or, ther- Despite the availability of these the four seminal research articles modynamically, the ionic activities of literature sources, calcium and phos- 3 4 5 2– – appeared in 1978, 1980, 1982, HPO4 and H2PO4 are equal) (Table phate compatibility continues to be a and 1988.6 In the 1980s there were 1): clinical enigma. two case reports of nonfatal adverse Physicochemical factors. Calcium – – 2– events involving calcium phosphate OH + H2PO4 ↔ HPO4 + H2O; shifts and phosphate solubility chemistry. precipitation in total parenteral nu- to right when pH increases (1) The aqueous chemistry and solubil- 7,8 – 2– + trient (TPN) admixtures. A review H2O + H2PO4 ↔ HPO4 + H3O ; ity of the two phosphate anions and of the main determinants of paren- shifts to left when pH decreases (2) their calcium salts that are important teral drug and admixture compat- to the safety of i.v. therapy are sum- ibility and stability also appeared • T h e Henderson–Hasselbach marized in Table 1. The main facts during that decade.9 Soon after equations9,19: are as follows: The lower the solution the April 1994 safety alert, several pH is below 7.2, which is the critical pH = pK + log ([A–]/[HA]); percent publications on calcium phosphate a pKa2 of phosphoric acid in practice, precipitation in TPN formulations ionized, A–, = 100/(1 + antilog the greater is the majority percentage 10-18 [pK – pH]) = 100{[A–]/([A–] + – appeared. Thus, this article is a of the desired H2PO4 anion (dihy- yet another revisit of calcium and [HA])} (3) drogen or monobasic phosphate). pH = pK + log ([HPO 2– ]/[H PO –]); – phosphate compatibility with i.v. a 4 2 4 H2PO4 , with two dissociable pro- percent HPO 2– = 100/(1 + anti- 2– formulations. 4 tons, is an acid relative to HPO4 , log [pK – pH]) = 100{[HPO 2–]/ 2– This article discusses the chem- a 4 and HPO4 (i.e., monohydrogen 2– – istry and practical compatibility ([HPO4 ] + [H2PO4 ])} (4) or dibasic phosphate) is a base or – or solubility factors relevant to the weaker acid relative to H2PO4 . • The compatibility curves for calcium safe administration of combination Ca[H2PO4]2 (calcium dihydrogen gluconate versus phosphate concen- therapy with calcium gluconate and phosphate) is 60 times more soluble 4,5,17,18 trations in clinical mixtures. potassium or sodium phosphate in- than CaHPO4 (calcium monohydro- jections. Patient case reports that led to adverse events and pharmaceuti- cal and clinical factors important to calcium phosphate solubility are also DAVI D W. NE W TO N , B.S.PHARM ., PH.D., Address correspondence to Dr. Newton presented. FAPHA, is Professor and Chairman, Depart- at the Bernard J. Dunn School of Phar- pH and pK equilibria relevant ment of Biopharmaceutical Sciences, Ber- macy, Shenandoah University, 1460 Univer- a nard J. Dunn School of Pharmacy, Shenan- sity Drive, Winchester, VA 22601 (dnewton@ to calcium and phosphate compat- doah University, Winchester, VA. DAVI D su.edu). ibility. The keys to understanding the F. DRI S COLL , B.S.PHARM ., PH.D., is Senior chemical reactions and relative risks Researcher, Department of Medicine, Beth Copyright © 2008, American Society of Israel Deaconess Medical Center, and Assis- Health-System Pharmacists, Inc. All rights for calcium phosphate precipitation tant Professor of Medicine, Harvard Medical reserved. 1079-2082/08/0101-0073$06.00. are as follows: School, Boston, MA. DOI 10.2146/ajhp070138 Am J Health-Syst Pharm—Vol 65 Jan 1, 2008 73 COMMENTARY Calcium and phosphates of CaHPO reactions stated in the Table 1. 4 1967 source ended in 1968 with the Chemistry and Water Solubility of Phosphates and Calcium 21 Phosphates report that launched TPN, which made reactions between calcium Ion or Salta Names Solubility (mg/mL)5,10 and phosphates in i.v. formulations a –- b c H2PO4 Monobasic phosphate, dihydrogen NA matter of life and death. phosphate Calcium and phosphate solubility HPO 2– Dibasicd phosphate, monohydrogen NA 4 for i.v. therapy. It is unlikely that any phosphate patient-specific i.v. admixture con- Ca[H PO ] Monobasic calciumphosphate, 18 2 4 2 taining calcium and phosphates will calcium dihydrogen phosphate exactly duplicate the compatibility CaHPO4 Dibasic calcium phosphate, calcium 0.3 monohydrogen phosphate results of published studies. Three common variables are (1) practition- a – + 2– 3– + The phosphoric acid aqueous equilibria H3PO4 ↔ H2PO4 + H (for which pKa1 = 2.1) and HPO4 ↔ PO4 + H 19 14 er and device volume-measurement (for which pKa3 = 12.3 ) are clinically negligible. b – + + Monobasic refers to neutralization of the –1 charge on H2PO4 by one +1 cation (e.g., K or Na , from bases accuracy and precision, (2) content [alkali] such as potassium hydroxide or sodium hydroxide or carbonate). cNA = not applicable. and pH ranges from The United d 2– + + Dibasic refers to neutralization of the –2 charge on HPO4 by two +1 cations (e.g., 2 K or 2 Na , or one +2 States Pharmacopeia and The Na- 2+ cation, e.g., Ca ). tional Formulary (USP) for calcium gluconate injection (i.e., 95–105% of labeled content and pH 6.0–8.2) and gen phosphate), because CaHPO4 is should be expressed in millimoles for potassium and sodium phosphate less dissociated.19,20 Note that, typi- per liter, not in milliequivalents per injections (i.e., 95–105% of labeled cal of most divalent cation–divalent liter. In the article by Schuetz and content),22 and (3) other drugs and 3 anion salts, CaHPO4 is minimally King, phosphates were reported in nutrients that may be included in i.v. dissociated into its constituent ions. milliequivalents per liter but without admixtures (i.e., the variable compo- 2+ – Consequently, most of the Ca and specific concentrations of H2PO4 sition of TPN formulations, which 2– 2– HPO4 ions cannot be solvated by and HPO4 . The appendix shows the are often patient specific). Even dipolar water molecules via ion– calculation for milliequivalents of small differences in the USP-allowed dipole intermolecular forces, result- potassium and for millimoles of phos- percent content ranges of calcium ing in 0.3-mg/mL solubility in water. phates per milliliter in commercial gluconate and potassium or sodium Ion–dipole forces generally result in Potassium Phosphates Injection, USP, phosphate injections may contribute greater solubility in water than do and for milliequivalents of calcium to the precipitation or nonprecipita- other types of solute–water inter- per milliliter in commercial 10% Cal- tion of CaHPO4 in clinical practice. molecular forces.19,20 The contrasting cium Gluconate Injection, USP. The main factors that are impor- high solubility of the divalent cation– Before the transition to the tant to ensuring total solubility or divalent anion, magnesium sulfate, Pharm.D. degree began achieving compatibility of calcium and phos- at more than 500 mg/mL, results national momentum in the 1970s, phates in TPN and other i.v. therapy from dipole–dipole forces between most U.S. pharmacy schools required are as follows1-18: water and the mostly nondissociated courses in qualitative and quantita- MgSO4 ion pairs, which are dipoles. tive chemical analysis and inorganic • The mixture should be agitated to The efficient water solubility of some pharmaceutical chemistry. Those achieve homogeneity after each ingre- nonionic organic compounds (e.g., courses were particularly pertinent dient is added. sugars) results from accepting and to the solubility of calcium salts, as • Potassium or sodium phosphate donating multiple intermolecular illustrated by the following excerpt injection should be added early, and hydrogen bonds with water (i.e., one from a monograph on CaHPO4 calcium gluconate injection should hydrogen bond for at least every four in a standard pharmacy textbook be added last or nearly last to the carbon atoms).20 from 1967: “Because this salt is al- most dilute phosphate concentration – 1,2,17,18 The percentages of H2PO4 and most insoluble in water, its chemi- possible. 2– HPO4 decrease and increase, re- cal reactions are few and relatively • A 0.2-mm air-eliminating sterile spectively, by 1.6% to 5.7% for each unimportant. It is soluble in diluted inline filter should be used for non- 19 0.1 pH unit increase over the pH hydrochloric acid.” That CaHPO4 fat-emulsion-containing i.v. admix- range of 6.0–7.6.14 Because 1 meq is more soluble at increasingly acidic tures, and a 1.2-mm filter should be 2– of HPO4 corresponds to 2 meq of pH represents the leftward shift in used for fat-emulsion-containing i.v. – 1-3,10,13,14,17,18 H2PO4 , phosphate concentration equation 2, and the “unimportance” admixtures. 74 Am J Health-Syst Pharm—Vol 65 Jan 1, 2008 COMMENTARY Calcium and phosphates • Calcium chloride injection should example, in one study of a simulated cipitation would occur