Drug Incompatibility Chemistry

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

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

Causes of Precipitation Incompatibility

Incompatibility describes preventable or reversible precipitation or insolubility. In contrast, instability describes degradation, such as hydrolysis, oxidation, and covalent chemical reactions that may be slowed but not stopped.^{[12,13,14,15,16]} Visible precipitation (and all precipitation that may be clinically significant is not visible^[17]) has been described as physical incompatibility. However, precipitates are physical products of intermolecular and interionic forces (i.e., chemical reactions).

The main chemical causes of visibly observable precipitation, such as crystals, haziness, or turbidity, in mixed and diluted drug solutions are summarized in the following six subsections. The acid-base section is further detailed later. Acid-base solubility chemistry is essential to predicting and explaining the compatibility and incompatibility results of most drug-drug and drug-diluent combinations that may not be included in sources such as the Handbook on Injectable Drugs.^[18] Furthermore, such compilations do not explain causes for most combinations classified as incompatible. The treatment of specific cases of incompatibility and instability has been deemphasized in favor of generalization; however, drug compounds will still obey chemical and physical laws.^[19]

Acid-base Reactions

More than 90% of drugs are organic, weak electrolytes, especially those compounded, manufactured, or reconstituted as injections in predominantly ionized or salt form.^[18] Consequently, acid-base reactions are the most common causes of drug incompatibility as precipitation of nonionized drug forms. Nonionized and nonelectrolyte are not synonymous because nonelectrolytes cannot become ionized (i.e., they can neither gain or lose protons to become charged nor dissociate into ions). The ratio or percentages of ionized and nonionized forms of weak electrolytes depend on the solution's pH and drug pK_a values via the Henderson-Hasselbalch equation.^{[2,3,12,13,14,20,21,22,23,24,25,26,27,28,29]} Facile identification of acid and base reactive groups on organic drug molecules and pH ranges at which those groups are predominantly ionized or nonionized is the foremost priority for deducing, predicting, and precluding drug-drug and drug-diluent incompatibilities.^{[3,22,27,28,29]}

The aqueous solubility of most nonionized molecules that contain fewer than one hydrogen bond donor-acceptor group (e.g., amino, hydroxy) per every four or more carbon atoms ranges from 0.1 to 0.001 of their ionized forms. This approximation may be confirmed by comparing water solubilities of the salt and nonionized forms of many drugs.^{[12,13,14,22,23,24,25,26,27,28,29,30,31,32,33]} Insoluble concentrations of nonionized drug forms may occur in clinical preparations in the following circumstances:

Combining organic anions and organic cations (i.e., opposite salts).
Diluting organic drug salt solutions such that resulting pH values generate more nonionized forms than were present in the original drug solutions.
Mixing organic drug ions that have the same charge, such as sodium salts of different drugs or hydrochloride salts of different drugs, where there is more than 1 unit of difference in drug pK_a and solution pH values. In such cases, the drugs act as an acid and base relative to each other. There are multiple examples of incompatible combinations of hydrochloride drug salts with each other and sodium drug salts with each other in the Handbook on Injectable Drugs.^[18]

Nondissociated Salts of Organic Ions

Precipitation is likely when oppositely charged, organic drug ions that contain aromatic rings are combined in relatively strong concentrations.^[12,13,14] Close intermolecular or interionic approach by carbon atoms in planar, nonpolar molecular regions induces attraction via dispersion or induced dipole type intermolecular forces. These are generally called van der Waals forces but are specifically known as London dispersion forces.^{[22,23,27,34,35,36,37,38,39]} Dispersion forces result from nonsymmetrical displacement of outer shell electrons, which creates temporary molecular polarity, or dipoles.^{[23,27,34,35,36,37,38,39]} Dispersion forces increase with molecular size (i.e., with increasing outer shell electrons). For example, dispersion forces account for increasing boiling and melting points of non-branched alkanes, which change from gases (e.g., propane) to volatile liquids (e.g., octane) to non-volatile liquids (e.g., mineral oil) to semisolids (e.g., petrolatum) to solids (e.g., paraffin) with increasing -CH₂-units, CH₃-(CH₂)_n-CH₃, at standard conditions.^[40]

Polarity is better induced in aromatic rings than aliphatic rings, which is why many opposite drug ions can precipitate and why benzene-water solubility is 36 times that of cyclohexane.^[40] Dispersion forces between carbon atoms are essential to native conformational folding in proteins and polypeptides, including drugs, enzymes, and receptors, and to drugs that bind with enzymes, receptors, and serum proteins.^{[27,34,35,36,37,38,39]} Dispersion forces are a major component of hydrophobic forces in proteins and polypeptides.^[22,34,39] Hydrophobic indicates that water cannot dissociate London dispersion forces as it does ionic bonds and that water is not a hydrogen bond donor and acceptor in such interactions.

Salts that require greater than 1000 mL/g to dissolve, or have <0.1% solubility, may be preferred to provide prolonged slow absorption while achieving effective plasma concentrations for some therapeutic uses, which is the case for benzathine and procaine penicillin G intramuscular injections. These salts are also used to prevent i.v. abuse of drugs in oral formulations while providing effective oral absorption, which is the case for propoxyphene napsylate. The aromatic rings in these molecules may be observed in references such as The Merck Index.^[41] Potential precipitation of opposite aromatic drug ions is illustrated by the water volumes required to dissolve 1 g of the drug salts listed below:

Salts of benzyl penicillin or penicillin G: benzathine 5,000 mL; procaine 250 mL; and sodium 40 mL,^[22,33]
Salts of propoxyphene: napsylate (napthalenesulfonic acid) 10,000 mL and hydrochloride 2 mL,^[33]
Salts of imipramine: pamoate (pamoic acid), >10,000 mL or United States Pharmacopeia (USP) insoluble^[33] and hydrochloride 5 mL,^[42] and
Salts of hydroxyzine: pamoate 1000 mL and hydrochloride 1 mL.^[22]

Salting Out

Salting out results when highly hydrated inorganic ions (e.g., Cl^-, K⁺, Na⁺) deprive organic ions and molecules of adequate water molecules to remain dissolved.^{[12,13,14,23,43,44]} An example of salting out would be the immediate release of carbon dioxide gas from carbonated beverages when sodium chloride is added.^[23] The weaker induced dipole-dipole forces between carbon dioxide and water are displaced by stronger sodium-water and chloride-water ion-dipole forces.

Salts of Inorganic Divalent Ions

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.^[26] The most clinically important potential precipitates among these ions are dibasic or monohydrogen calcium phosphate, CaHPO₄.^[13,45]

Desolvation of Nonionized Organic Drugs

Precipitation on dilution in aqueous i.v. fluids is common with nonionized drugs, such as diazepam and lorazepam, that are formulated as injections with ≥40% by volume of alcohols (e.g., alcohol, ethanol, glycerin, polyethylene glycols, propylene glycol).^[46,47] When such injections are diluted in aqueous solutions (e.g., 5% dextrose solution and 0.9% sodium chloride), the intermolecular hydrogen bonding of the water-alcohol deprives the drugs of weaker van der Waals forces by which the alcohols solubilize the drugs.^{[2,12,13,14,46,47]} Precipitation is also possible when injections formulated as colloidal solutions with surfactant micelles (and alcohols), such as etoposide, are improperly diluted for i.v. infusion. Extensive dilution results in the loss of drug-solubilizing micelles when the surfactant concentration falls below its critical micelle concentration.^[23,48]

Organic Ion-inorganic Ion Salts

Though rare, one instance that has caused expense, inconvenience, harm, and death is the precipitation of ceftriaxone with calcium (e.g., a divalent organic anion, divalent inorganic cation salt).^[9,49] The approved generic name, ceftriaxone sodium, belies that the drug is actually a disodium salt formed from two structurally different acid groups with pK_a values of 3 and 4.^[41] Most calcium salts of divalent organic acids are less soluble than the sodium salts. For example, calcium succinate and tartrate are slightly soluble, but the sodium salts of those carboxylic acids are freely soluble, or 100 times more soluble than the calcium salts.^[41]

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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

Causes of Precipitation Incompatibility

Acid-base Reactions

Nondissociated Salts of Organic Ions

Salting Out

Salts of Inorganic Divalent Ions

Desolvation of Nonionized Organic Drugs

Organic Ion-inorganic Ion Salts

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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Appendix-References for Drug Structures

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