Drug Incompatibility Chemistry

David W. Newton, B.S.PHARM., P.H.D., FAPHA


Am J Health Syst Pharm. 2009;66(4):348-357. 

In This Article

Abstract and Introduction


Purpose: The chemical interactions that cause drug incompatibility in solutions, with emphasis on the acid-base and ionized-nonionized forms of organic, weak, electrolyte drugs, are examined.
Summary: When the dilution or mixing of the salt or ionized forms of organic drugs results in precipitation, the most likely cause is formation of the nonionized drug forms. More than 90% of drugs are organic, weak electrolytes, especially those compounded, manufactured, or reconstituted as injections in predominantly ionized or salt forms. Acid-base reactions are the most common causes of drug incompatibility as precipitation of nonionized drug forms. Precipitation is likely when oppositely charged, organic drug ions that contain aromatic rings are combined in relatively strong concentrations. Salts of polyvalent anions and cations are generally less soluble than salts in which both ions are monovalent or in which one ion is monovalent and its opposite ion is polyvalent. The most clinically important potential precipitates among these ions are dibasic and monohydrogen calcium phosphate.
Conclusion: Incompatibility of drug and nutrient injections is clinically hazardous. Knowledge of products' chemical facts, organic acid-base equilibria in relation to ionization and nonionization and aqueous solubility, and ranges of pH and ingredient strength from United States Pharmacopeia monographs and product labeling is the foundation of expertise in drug incompatibility. Precipitation in injectable drug solutions should be suspected, particularly when oppositely charged drug salts are mixed in relatively strong concentrations and when pH values of dilutions create more than 1% of nonionized drug forms.


This article reviews the chemical interactions that cause drug incompatibility in solutions, with emphasis on the acid-base and ionized-nonionized forms of organic, weak, electrolyte drugs. This review was prompted by pharmacists' unexpected and unexplained reports of i.v. drug precipitation, such as the following:

  • A visual evaluation of furosemide, phenylephrine hydrochloride, and vasopressin injection admixtures,[1] which was based on the 1:1 volume-mixing method of a prototypic simulated infusion tubing Y injection site study,[2] and

  • An observation of a patient's i.v. tubing when daptomycin was infused after flushing and infusing vancomycin sulfate (personal communication, contact not recorded, 2007 Oct).

Both of these reports lacked pH measurements and interpretation of drug structures and pH and pKa values in relation to ionization and nonionization and solubility, all of which are necessary to deduce causes of and preclude most incompatibilities.

Pharmacy prerequisite and professional curricula provide more courses on drug chemistry than do those of other health care professions. Health care practitioner colleagues expect hospital pharmacists, in particular, to articulate expertise on drug compatibility.[3] There is in-traprofessional and extraprofessional merit for pharmacists to elucidate, explain, and predict, and not just observe and communicate compatible or incompatible results of drug-drug and drug-diluent mixtures.[3,4,5,6,7,8]


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