Drug Incompatibility Chemistry

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

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

Abstract and Introduction

Abstract

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.

Introduction

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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Cite this: Drug Incompatibility Chemistry - Medscape - Feb 15, 2009.

Table 1. Symbols for Drug and Nondrug Ions and Molecules
Drug or Nondrug^a	Symbol	Description^b
Drug	A^-, A^n-	Anionic conjugate bases of organic HA or H_nA acids, nearly all containing at least one aromatic ring, from which one or more H⁺ have dissociated
	B, B_n	Nonionized conjugate bases of HB⁺ or H_nBⁿ⁺ form acids; organic molecules, nearly all containing at least one aromatic ring, with one or more primary (CNH₂), secondary (C₂NH), or tertiary (C₃N) amino groups that are H ⁺ acceptors
	C_{2- 4}N⁺	Quaternary ammonium compounds in which a nitrogen atom shares four covalent bonds with two to four carbon atoms (i.e., C=N⁺=C, C=N⁺C₂, or C₄N ⁺); the structure may be aromatic, cyclic nonaromatic, or acyclic
	HA, H_nA	Nonionized conjugate acids of A^- or A^n- bases; organic molecules with one or more acid groups that can dissociate H⁺
	HB⁺, H_nB ⁿ⁺	Cationic conjugate acids of B and B_n bases; organic molecules with one or more primary (CNH₂), secondary (C₂NH), or tertiary (C₃N) amino groups that have associated H⁺
Nondrug	H⁺	Proton; hydrogen ion
	H₂O	Water
	H₃O⁺	Hydronium ion
	M⁺, Mⁿ⁺	Metal cation^c (e.g., calcium, Ca²⁺; potassium, K⁺; sodium, Na⁺)
	OH^-	Hydroxyl or hydroxide ion
	X^-, X^n-	Inorganic anion (e.g., chloride, nitrate, sulfate) or organic anion (e.g., acetate, citrate, edisylate, gluconate, lactate, mesylate)

^aFor the purposes of this review, drug = organic molecules that do and are purposed to cause pharmacologic effects, and nondrug = ions or molecules that do not or are not purposed to cause pharmacologic effects.
^bFor the purposes of this review, H⁺ dissociation by acids and association by bases is relative to the clinical and practical pH range of 2-12.
^cAn exception to footnote a is calcium in calcium gluconate because calcium is the ion purposed for therapeutic effect.

Table 2. Identification of Organic Drug Anions and Cations According to Three-letter Suffixes of Their Salt Ion Names ^{[12,13,16,56]}
Salt Ion Suffixes	Drug Ion, Symbol^a	Drug Salt Symbol^a,b	Drug Acid-Base Conjugate Pair^c	Examples
-ate, -ide	HB⁺	HB⁺X^-	HB⁺↔ B	Fentanyl citrate, naloxone hydrochloride, prochlorperazine edisylate
	HB⁺	2HB⁺X^2-	HB⁺↔ B	Morphine sulfate
	H₂B²⁺	H₂B²⁺2X^-	H₂B²⁺↔ B	Hydroxyzine dihydrochloride
-ium	A^-	M⁺A^-	HA ↔ A^-	Penicillin G potassium, phenytoin sodium
	A^2-	2M⁺A^2-	H₂A ↔A^2-	Cefotetan disodium, ticarcillin disodium
	A^2-	M²⁺A^2-	H₂A ↔A^2-	Leucovorin calcium
-ium -ate^d	A^-	M⁺A^-	HA ↔ A^-	Dexamethasone sodium phosphate,^e methylprednisolone sodium succinate^f
-ium -ate^d	A^2-	M²⁺2A^-	2HA ↔ 2A^-	Calcium gluconate^g

^aRefer to Table 1 for descriptions of the symbols.
^bAmong Food and Drug Administration-approved drug salts up to the year 1974, hydrochlorides comprised the greatest percentage (43%) of HB⁺X^- types; and sodium was the cation in 62% of M⁺A^- types.^[32]
^cA proton (H⁺), which in water is a hydronium ion (H₃O⁺), was intentionally omitted from the right side of each ↔ equilibrium.
^dThese are ester salts. One of the few -ium -ate suffix exceptions is bretylium tosylate, which is a quaternary ammonium salt (see Table 3).
^eOne OH group on phosphoric acid is esterified with the position 21 OH group of dexamethasone, and the hydrogens from the other two phosphoric acid OH groups are replaced to make the disodium salt.
^fOne COOH group on succinic acid is esterified with the position 21 OH group of methylprednisolone, and the hydrogen from the other succinic COOH is replaced to make the sodium salt.
^gInorganic calcium is the ion purposed for therapeutic effect.

Table 3. Identification of Quaternary Ammonium Drugs According to Three-letter Suffixes of Their Salt Ion Names
Salt Ion Suffixes	Drug Ion, Symbol^a	Drug Salt Symbol^a,b	Drug Acid-Base Conjugate Pair^c	Examples
-ate, -ide	HB⁺	HB⁺X^-	HB⁺↔ B	Fentanyl citrate, naloxone hydrochloride, prochlorperazine edisylate
	HB⁺	2HB⁺X^2-	HB⁺↔ B	Morphine sulfate
	H₂B²⁺	H₂B²⁺2X^-	H₂B²⁺↔ B	Hydroxyzine dihydrochloride
-ium	A^-	M⁺A^-	HA ↔ A^-	Penicillin G potassium, phenytoin sodium
	A^2-	2M⁺A^2-	H₂A ↔A^2-	Cefotetan disodium, ticarcillin disodium
	A^2-	M²⁺A^2-	H₂A ↔A^2-	Leucovorin calcium
-ium -ate^d	A^-	M⁺A^-	HA ↔ A^-	Dexamethasone sodium phosphate,^e methylprednisolone sodium succinate^f
-ium -ate^d	A^2-	M²⁺2A^-	2HA ↔ 2A^-	Calcium gluconate^g

Table 4. Pairs of Organic Cation and Anion Salts That Are Potentially Incompatible when Mixed in Relatively High Concentrations
Salts with Organic Cations		Salts with Organic Anions
Name Suffixes	Drugs	Name Suffixes	Drugs
-ate, -ide^a	Gentamicin sulfate, promethazine hydrochloride	-ium, -ium -ate^b	Heparin sodium, dexamethasone sodium phosphate
-ate -ide, -ium -ate, -ium -ide^c	Examples in Table 3	-ium, -ium -ate^b	Penicillin G potassium, methylprednisolone sodium succinate

^aThese are the HB⁺ and H_nBⁿ⁺ ions described in Tables 1 and 2.
^bThese are the A^– and A^n– ions described in Tables 1 and 2.
^cThese are the C_2–4N⁺ ions described in Tables 1 and 3.

Table 5. Theoretical Solubility Differences between Hypothetical *United States Pharmacopeia* ( *USP*)-compliant Sources I and II of Phenytoin Sodium Injection 50 mg/mL Diluted to 2 mg/mL in 0.9% Sodium Chloride Injection
			Assayed Concentration			Concentration of Nonionized Phenytoin (µg/mL)
Component^a	Measured pH	Nonionized Phenytoin (%)^b	Phenytoin^c (mg/mL)	Alcohol (%)	Propylene Glycol (%)	Present	Soluble
Source I 50 mg/mL	10.4	0.801	47.6	9.8	40.2	381.3^d	All^e
Source II 50 mg/mL	12.1	0.016	46.2	10.7	42.5	7.4^d	All^f
0.9% Sodium chloride injection	6.7	NA^g	NA	NA	NA	NA	NA
Source I 2 mg/mL dilution	9.8	3.07	NA	NA	NA	58.5^h	~20ⁱ
Source II 2 mg/mL dilution	11.2	0.126	NA	NA	NA	2.3^h	All^f

^aPhenytoin Sodium Injection, USP, contains 95.0-105.0% of phenytoin sodium (C₁₅H₁₁N₂NaO₂), 9.0-11.0% of alcohol (94.9-96.0% by volume of ethanol, or C₂H₅OH), and 37.0-43.0% of propylene glycol, with a pH from 10.0 to 12.3. Sodium Chloride Injection, USP, has a pH from 4.5 to 7.0.^[60]
^bNonionized phenytoin is the HA acid form. The percentage is calculated from equation 5c in the text with the phenytoin pKa of 8.3.^[24,25]
^cFrom the USP 31 phenytoin sodium injection monograph, the weight of assayed phenytoin (mg) × (274.25/252.27) = the weight of phenytoin sodium (mg).^[60]
^dThe concentration of nonionized phenytoin is calculated from ([assayed phenytoin concentration × [1000 µg/mg] × [% nonionized phenytoin/100]). For example, the Source II phenytoin sodium injection phenytoin concentration = ([46.2 mg/mL] × [1000 µg/mg] × [0.016/100]) = 7.392 µg/mL.
^eThe saturated solubility of Phenytoin, USP, in carbon dioxide-free, fresh-deionized water at pH 7 at 25 °C was reported to be 20 µg/mL.¹³ In the original phenytoin sodium injection, the 9.8% alcohol and 40.2% propylene glycol dissolve any nonionized phenytoin exceeding water solubility.
^fThe calculated 7.4 µg/mL of nonionized phenytoin present is less than the 20-µg/mL saturated water solubility of nonionized phenytoin.
^gNot applicable.
^hDilutions are based on 2 mL of the phenytoin sodium injection being diluted to 50 mL, or a 25-fold dilution. The concentration of nonionized phenytoin present is calculated from ([2 mL × assayed phenytoin concentration, mg/mL]/50 mL) × [1000 µg/mg] × [% nonionized phenytoin/100]. For example, for the Source 1 dilution, the concentration = {([2 mL × 47.6 mg/mL]/50 mL) × [1000 µg/mg] × [3.07/100]} = 58.45 µg/mL.
ⁱThe soluble concentration of nonionized phenytoin might be slightly greater than the 20-µg/mL water solubility because there is 4% of the original 9.8% alcohol and 40.2% propylene glycol concentrations in the dilution.

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Drug Incompatibility Chemistry

Abstract and Introduction

Abstract

Introduction

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Appendix-References for Drug Structures

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