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Calcium and phosphate compatibility: • The influence of ...

COMMENTARy Calcium and phosphates COMMENTARy Calcium and phosphate compatibility : The influence of other drugs and ,10-18. Revisited again The application of knowledge about Calcium and phosphate com- David W. Newton and David F. Driscoll patibility in therapy has been fa- Am J Health-Syst Pharm. 2008; 65:73-80 cilitated by four hallmark articles,3-6. several editions of the Handbook on T. 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 ( , the pH patibility in Parenteral FDA safety alert,1,2 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- appeared in 1978, 3 1980, 4 1982, 5 HPO42 and H2PO4 are equal) (Table phate compatibility continues to be a and In the 1980s there were 1): clinical enigma.

COMMENTARy Calcium and phosphates Am J Health-Syst Pharm—Vol 65 Jan 1, 2008 73 COMMENTARy Calcium and phosphate compatibility: Revisited again Dav i D W. Ne W t o N a ND Dav i D F. Driscoll Am J Health-Syst Pharm. 2008; 65:73-80 Dav i D W. N e W to N, B.S.Pharm., Ph.D., FaPha, is Professor and Chairman, Depart- ment of Biopharmaceutical Sciences, Ber-

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1 COMMENTARy Calcium and phosphates COMMENTARy Calcium and phosphate compatibility : The influence of other drugs and ,10-18. Revisited again The application of knowledge about Calcium and phosphate com- David W. Newton and David F. Driscoll patibility in therapy has been fa- Am J Health-Syst Pharm. 2008; 65:73-80 cilitated by four hallmark articles,3-6. several editions of the Handbook on T. 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 ( , the pH patibility in Parenteral FDA safety alert,1,2 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- appeared in 1978, 3 1980, 4 1982, 5 HPO42 and H2PO4 are equal) (Table phate compatibility continues to be a and In the 1980s there were 1): clinical enigma.

2 Two case reports of nonfatal adverse Physicochemical factors. Calcium events involving Calcium phosphate OH + H2PO4 HPO42 + H2O; shifts and phosphate solubility chemistry. precipitation in total parenteral nu- to right when pH increases (1) The aqueous chemistry and solubil- trient (TPN) ,8 A review H2O + H2PO4 HPO42 + 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 therapy are sum- ibility and stability also appeared T h e H e n d e r s o n H a s s e l b a c h 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 , which is the critical publications on Calcium phosphate pH = pKa + log ([A ]/[HA]); percent pKa2 of phosphoric acid in practice, precipitation in TPN formulations ionized, A , = 100/(1 + antilog the greater is the majority percentage Thus, this article is [pKa pH]) = 100{[A ]/([A ] + of the desired H2PO4 anion (dihy- yet another revisit of Calcium and [HA])} (3) drogen or monobasic phosphate ).

3 phosphate compatibility with pH = pKa + log ([HPO42 ]/[H2PO4 ]); H2PO4 , with two dissociable pro- formulations. percent HPO42 = 100/(1 + anti- tons, is an acid relative to HPO42 , This article discusses the chem- log [pKa pH]) = 100{[HPO42 ]/ and HPO 42 ( , monohydrogen istry and practical compatibility ([HPO42 ] + [H2PO4 ])} (4) or dibasic phosphate ) is a base or or solubility factors relevant to the weaker acid relative to H 2 PO 4 . safe administration of combination The compatibility curves for Calcium Ca[H 2PO 4] 2 ( Calcium dihydrogen therapy with Calcium gluconate and gluconate versus phosphate concen- phosphate ) is 60 times more soluble potassium or sodium phosphate in- trations in clinical ,5,17,18 than CaHPO4 ( Calcium monohydro- jections.)

4 Patient case reports that led to adverse events and pharmaceuti- cal and clinical factors important to Calcium phosphate solubility are also D avid W. N ewton , harm ., P h .D., Address correspondence to Dr. Newton presented. FAPhA, is Professor and Chairman, Depart- at the Bernard J. Dunn School of Phar- pH and pKa equilibria relevant ment of Biopharmaceutical Sciences, Ber- macy, Shenandoah University, 1460 Univer- nard J. Dunn School of Pharmacy, Shenan- sity Drive, Winchester, VA 22601 to Calcium and phosphate compat- doah University, Winchester, VA. D avid ). ibility. The keys to understanding the F. Driscoll, , , 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.

5 All rights for Calcium phosphate precipitation tant Professor of Medicine, Harvard Medical reserved. 1079-2082/08/0101-0073$ are as follows: School, Boston, MA. DOI Am J Health-Syst Pharm Vol 65 Jan 1, 2008 73. COMMENTARy Calcium and phosphates Table 1. of CaHPO4 reactions stated in the Chemistry and Water Solubility of Phosphates and Calcium 1967 source ended in 1968 with the Phosphates report that launched TPN,21 which made reactions between Calcium Ion or Salta Names Solubility (mg/mL)5,10 and phosphates in formulations a H2PO4 - Monobasicb phosphate , dihydrogen NAc matter of life and death. phosphate Calcium and phosphate solubility HPO42 Dibasicd phosphate , monohydrogen NA for therapy. It is unlikely that any phosphate patient-specific admixture con- Ca[H2PO4]2 Monobasic Calcium phosphate , 18.

6 Taining Calcium and phosphates will Calcium dihydrogen phosphate CaHPO4 Dibasic Calcium phosphate , Calcium exactly duplicate the compatibility monohydrogen phosphate results of published studies. Three common variables are (1) practition- a The phosphoric acid aqueous equilibria H3PO4 H2PO4 + H+ (for which pKa1 = ) and HPO42 PO43 + H+. (for which pKa3 = ) are clinically er and device volume-measurement b Monobasic refers to neutralization of the 1 charge on H2PO4 by one +1 cation ( , K+ or Na+, from bases accuracy and precision, (2) content [alkali] such as potassium hydroxide or sodium hydroxide or carbonate). c NA = not applicable. and pH ranges from The United d Dibasic refers to neutralization of the 2 charge on HPO42 by two +1 cations ( , 2 K+ or 2 Na+, or one +2 States Pharmacopeia and The Na- cation, , Ca2+).

7 Tional Formulary (USP) for Calcium gluconate injection ( , 95 105% of labeled content and pH ) and gen phosphate ), because CaHPO4 is should be expressed in millimoles for potassium and sodium phosphate less ,20 Note that, typi- per liter, not in milliequivalents per injections ( , 95 105% of labeled cal of most divalent cation divalent liter. In the article by Schuetz and content),22 and (3) other drugs and anion salts, CaHPO4 is minimally King,3 phosphates were reported in nutrients that may be included in dissociated into its constituent ions. milliequivalents per liter but without admixtures ( , the variable compo- Consequently, most of the Ca2+ and specific concentrations of H 2PO4 sition of TPN formulations, which HPO42 ions cannot be solvated by and HPO42.

8 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 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 ,20 The contrasting cium Gluconate Injection, USP.

9 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, 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 therapy from dipole dipole forces between most 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 ( , courses were particularly pertinent dient is added.)

10 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 ( , one from a monograph on CaHPO 4 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 The percentages of H2PO4 and most insoluble in water, its chemi- ,2,17,18. HPO42 decrease and increase, re- cal reactions are few and relatively A m m air-eliminating sterile spectively, by to for each unimportant. It is soluble in diluted inline filter should be used for non- pH unit increase over the pH hydrochloric acid.


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