primer  Drug incompatibility

primer

Drug incompatibility chemistry

David W. Newton

T
his article reviews the chemi-
cal 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’ un-
expected 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 simu-
lated infusion tubing Y injection site
study,2 and
• An observation of a patient’s i.v. tub-
ing when daptomycin was infused
after flushing and infusing vancomy-
cin sulfate (personal communication,
contact not recorded, 2007 Oct).
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 com-
pounded, manufactured, or reconstituted
as injections in predominantly ionized or
salt forms. Acid–base reactions are the
most common causes of drug incompat-
ibility as precipitation of nonionized drug
forms. Precipitation is likely when op-
positely 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 mon-
ovalent and its opposite ion is polyvalent.
The most clinically important potential pre-
cipitates 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 incom-
patibility. 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.
Index terms: Concentration; Electrolytes;
Hydrogen ion concentration; Incompat-
ibilities; Injections; Polarity; Precipitation;
Salts; Solubility; Solutions; Stability
Am J Health-Syst Pharm. 2009; 66:348-57

Both of these reports lacked pH mea-

surements and interpretation of drug
structures and pH and pKa values in
relation to ionization and nonioniza-
tion and solubility, all of which are
necessary to deduce causes of and
preclude most incompatibilities.
Pharmacy prerequisite and pro-
fessional curricula provide more
courses on drug chemistry than do
those of other health care profes-
sions. Health care practitioner col-
leagues 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 ob-
serve and communicate compatible
or incompatible results of drug–drug
and drug–diluent mixtures.3-8
Chemical facts and reasoning
elucidate unexpected
incompatibilities
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. Yet, for
example, when ceftriaxone sodium
is diluted in lactated Ringer’s injec-

David W. Newton, B.S.Pharm., Ph.D., FAPhA, is Professor and
Chairman, Department of Biopharmaceutical Sciences, Bernard J.
Dunn School of Pharmacy, Shenandoah University, Winchester, VA
22601 (dnewton@su.edu).
The author has declared no potential conflicts of interest.
Copyright © 2009, American Society of Health-System Pharma-
cists, Inc. All right reserved. 1079-2082/09/0202-0348$06.00.
DOI 10.2146/ajhp080059

348 Am J Health-Syst Pharm—Vol 66 Feb 15, 2009


tion, precipitation can occur despite
the alkaline pH of lactated Ringer’s
maintaining the ionized water-soluble
form of ceftriaxone. The problem in
this case is the formation of a poorly
soluble calcium salt of ceftriaxone,
the ionized form of which is a di-
valent anion.9 The general basis for
this divalent cation–divalent anion
precipitate is elaborated later.
In the vancomycin–daptomycin
case, the sulfate salt of vancomycin
indicates that vancomycin is a cation.
From its generic name and lack-
ing interpretation of its structure,
however, it is not obvious that dap-
tomycin in solution is expected to be
incompatible with acidic pH values
and organic cations. Dissolved dap-
tomycin is deduced to be an anion
based on the following prescribing
information10:
• The only inactive ingredient is sodium
hydroxide used for pH adjustment.
Sodium hydroxide removes a proton
from nonionized daptomycin, form-
ing the more water-soluble anionic,
ionized, or salt form of daptomycin.
• Daptomycin is compatible with
0.9% sodium chloride injection and
lactated Ringer’s injection and is not
compatible with dextrose-containing
diluents. Dextrose-containing injec-
tions are more acidic, which makes
more of the less water-soluble non-
ionized form of daptomycin. The
chemical science behind this example
is elaborated later.
Another example of unexpect-
ed incompatibility is ketorolac
tromethamine with several salts
in which the organic drug is a
cation (e.g., haloperidol lactate,
hydroxyzine hydrochloride, thieth-
ylperazine maleate).11 In this case,
the authors did not recognize that
the carboxylic acid on ketorolac be-
comes anionic by donating a proton
to the strongly basic primary amino
group on tromethamine. Like other
aromatic organic anions, ketorolac
is prone to form insoluble salts with
primer  Drug incompatibility
aromatic organic cations, which is
elaborated later.
Causes of precipitation
incompatibility
Incompatibility describes prevent-
able or reversible precipitation or
insolubility. In contrast, instabil-
ity describes degradation, such as
hydrolysis, oxidation, and covalent
chemical reactions that may be
slowed but not stopped.12-16 Visible
precipitation (and all precipitation
that may be clinically significant is
not visible17) 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 vis-
ibly observable precipitation, such
as crystals, haziness, or turbidity, in
mixed and diluted drug solutions are
summarized in the following six sub-
sections. The acid–base section is fur-
ther detailed later. Acid–base solubil-
ity 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 compila-
tions do not explain causes for most
combinations classified as incompat-
ible. The treatment of specific cases
of incompatibility and instability has
been deemphasized in favor of gener-
alization; however, drug compounds
will still obey chemical and physical
laws.19
Acid–base reactions. More than
90% of drugs are organic, weak elec-
trolytes, especially those compound-
ed, 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 pre-
cipitation of nonionized drug forms.
Nonionized and nonelectrolyte are
not synonymous because nonelec-
trolytes cannot become ionized (i.e.,
they can neither gain or lose protons
Am J Health-Syst Pharm—Vol 66 Feb 15, 2009
to become charged nor dissociate
into ions). The ratio or percentages
of ionized and nonionized forms of
weak electrolytes depend on the so-
lution’s pH and drug pKa values via
the Henderson-Hasselbalch equa-
tion.2,3,12-14,20-29 Facile identification
of acid and base reactive groups
on organic drug molecules and pH
ranges at which those groups are
predominantly ionized or nonion-
ized is the foremost priority for
deducing, predicting, and preclud-
ing drug–drug and drug–diluent
incompatibilities.3,22,27-29
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.12-14,22-33 Insoluble concentra-
tions of nonionized drug forms may
occur in clinical preparations in the
following circumstances:
• Combining organic anions and or-
ganic cations (i.e., opposite salts).
• Diluting organic drug salt solutions
such that resulting pH values gener-
ate 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
pKa 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
349
 primer  Drug incompatibility
are combined in relatively strong
concentrations.12-14 Close intermo-
lecular or interionic approach by
carbon atoms in planar, nonpolar
molecular regions induces attrac-
tion via dispersion or induced
dipole type intermolecular forces.
These are generally called van
der Waals forces but are specifi-
cally known as London dispersion
forces. 22,23,27,34-39 Dispersion forces
result from nonsymmetrical dis-
placement of outer shell electrons,
which creates temporary molecular
polarity, or dipoles.23,27,34-39 Disper-
sion forces increase with molecular
size (i.e., with increasing outer shell
electrons). For example, disper-
sion forces account for increasing
boiling and melting points of non-
branched alkanes, which change
from gases (e.g., propane) to vola-
tile liquids (e.g., octane) to non-
volatile liquids (e.g., mineral oil)
to semisolids (e.g., petrolatum) to
solids (e.g., paraffin) with increas-
ing –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 ben-
zene–water solubility is 36 times
that of cyclohexane.40 Dispersion
forces between carbon atoms are
essential to native conformational
folding in proteins and polypep-
tides, including drugs, enzymes,
and receptors, and to drugs that
bind with enzymes, receptors, and
serum proteins. 27,34-39 Dispersion
forces are a major component of
hydrophobic forces in proteins and
polypeptides.22,34,39 Hydrophobic in-
dicates 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 absorp-
tion while achieving effective plasma
350 Am J Health-Syst Pharm—Vol 66 Feb 15, 2009
concentrations for some therapeutic
uses, which is the case for benzathine
and procaine penicillin G intramus-
cular 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 mol-
ecules 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) insoluble33 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 ad-
equate water molecules to remain
dissolved.12-14,23,43,44 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 be-
tween 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 or-
ganic drugs. Precipitation on dilu-
tion in aqueous i.v. fluids is com-
mon with nonionized drugs, such
as diazepam and lorazepam, that
are formulated as injections with
≥40% by volume of alcohols (e.g.,
alcohol, ethanol, glycerin, polyeth-
ylene 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 bond-
ing of the water–alcohol deprives the
drugs of weaker van der Waals forces
by which the alcohols solubilize the
drugs.2,12-14,46,47 Precipitation is also
possible when injections formulated
as colloidal solutions with surfac-
tant micelles (and alcohols), such as
etoposide, are improperly diluted for
i.v. infusion. Extensive dilution re-
sults in the loss of drug-solubilizing
micelles when the surfactant concen-
tration 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 ap-
proved generic name, ceftriaxone
sodium, belies that the drug is
actually a disodium salt formed
from two structurally different acid
groups with pKa 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
Aqueous chemistry of organic
weak electrolytes and their salts
Acid–base or ionized–nonionized
conjugate pairs. Most organic drugs
contain one acid group, usually a
carboxylic acid, –COOH, or one
basic primary, secondary, or tertiary
 primer  Drug incompatibility

amino group, NC1–3,3,22,27-29 that de-
termines the acid–base reactivity at
clinical and pharmaceutical pH val-
ues. For adequate aqueous solubility
for injections and oral absorption,
most drugs are manufactured as
salts.22,26,27,31 Table 1 describes the
letter symbols used in this review to
represent the organic drug ions and
molecules and the inorganic and
organic nondrug ions that comprise
drug acid–base conjugate pairs and
salts.3,12-14,22-25,27-29,43,50 Structures of
specific drugs that represent the
symbols in Table 1, and that are
referred to elsewhere in this article,
may be found in the books listed in
the appendix.
Soluble drug salts consist of the
following types described in Tables
2 and 3, in which organic drug mol-
ecules A and B are nearly always
aromatic:
• M +A – (e.g., clavulante potassium,
phenytoin sodium),
• 2M+A2– (e.g., cefotetan disodium, ti-
carcillin disodium),
• M2+2A– (e.g., calcium gluconate),
• M2+A2– (e.g., leucovorin calcium),
• HB + X – (e.g., codeine phosphate,
fentanyl citrate, milrinone lactate,
ondansetron hydrochloride),
• HB+A– where A is the drug and B is a
nonaromatic organic (e.g., ketorolac
tromethamine),
• H2B2+2X– (e.g., hydroxyzine
dihydrochloride),
• 2HB+X2– (e.g., morphine sulfate),
• HBn+Xn– where n is 2 or greater (e.g.,
amikacin sulfate, gentamicin sulfate,
vincristine sulfate), and
• C 2–4N +X – (e.g., bretylium tosylate,
doxacurium chloride, pyridostigmine
bromide).

In aqueous solutions, weak electro-

Table 1. lytes exist as pH and pKa-dependent
Symbols for Drug and Nondrug Ions and Molecules conjugate pairs of their acid and base
forms or species and of their ionized
Drug or (or salt) and nonionized (or mo-
Nondruga Symbol Descriptionb lecular) forms. These four forms differ
Drug A–, An– Anionic conjugate bases of organic HA or only by the presence or absence of a
HnA acids, nearly all containing at least one proton, H+, which is the Brønsted-
aromatic ring, from which one or more H+ have Lowry definition of acids and bas-
dissociated es.22,27-29,35,43,50 Depending on its mo-
B, Bn Nonionized conjugate bases of HB+ or HnBn+ form lecular structure, the nonionized drug
acids; organic molecules, nearly all containing
form is either an HA acid or a B base
at least one aromatic ring, with one or more
primary (CNH2), secondary (C2NH), or tertiary
for which the respective conjugate ion-
(C3N) amino groups that are H+ acceptors ized forms are an A– base and an HB+
C2– 4N+ Quaternary ammonium compounds in which a acid. The pH-dependent conversion
nitrogen atom shares four covalent bonds with equilibria between these conjugate
two to four carbon atoms (i.e., C=N+=C, C=N+C2, forms are shown in equations 1a and
or C4N+); the structure may be aromatic, cyclic 2a, where the pKa symbol represents
nonaromatic, or acyclic pH values of essentially equal con-
HA, HnA Nonionized conjugate acids of A– or An– bases; centrations (thermodynamic activi-
organic molecules with one or more acid ties, formally) of the species to either
groups that can dissociate H+ side of the equilibrium arrows in the
HB+, HnBn+ Cationic conjugate acids of B and Bn bases; organic
subsequent equations.3,12-14,22-25,27-29,34,43
molecules with one or more primary (CNH2),
secondary (C2NH), or tertiary (C3N) amino
Equations 1b and 2b represent poly-
groups that have associated H+ protic acid forms, in which example
Nondrug H+ Proton; hydrogen ion acid form drugs are ceftriaxone (H2A)
H2O Water and hydroxyzine dihydrochloride
H3O+ Hydronium ion (H2B2+).25,41
M+, Mn+ Metal cationc (e.g., calcium, Ca2+; potassium, K+;
sodium, Na+) pKa
OH– Hydroxyl or hydroxide ion HA ↔ A– + H2O (1a)
X–, Xn– Inorganic anion (e.g., chloride, nitrate, sulfate) or
organic anion (e.g., acetate, citrate, edisylate, pKa1 pKa2
gluconate, lactate, mesylate) H2A ↔ HA– ↔ A2– (1b)
a
For the purposes of this review, drug = organic molecules that do and are purposed to cause pharmacologic pKa
effects, and nondrug = ions or molecules that do not or are not purposed to cause pharmacologic effects.
b
For the purposes of this review, H+ dissociation by acids and association by bases is relative to the clinical HB+ ↔ B + H2O (2a)
and practical pH range of 2–12.
c
An exception to footnote a is calcium in calcium gluconate because calcium is the ion purposed for pKa1 pKa2
therapeutic effect. H2B2+ ↔ HB+ ↔ A2– (2b)

Am J Health-Syst Pharm—Vol 66 Feb 15, 2009 351

 primer  Drug incompatibility

Table 2.
Identification of Organic Drug Anions and Cations According to Three-Letter Suffixes of Their Salt Ion
Names12,13,16,56
Salt Ion Drug Ion, Drug Salt Drug Acid–Base
Suffixes Symbola Symbola,b Conjugate Pairc Examples
-ate, -ide HB +
HB X+ –
HB ↔ B
+
Fentanyl citrate, naloxone hydrochloride,
prochlorperazine edisylate
HB+ 2HB+X2– HB+ ↔ B Morphine sulfate
H2B2+ H2B2+2X– H2B2+ ↔ B Hydroxyzine dihydrochloride
-ium A– M+A– HA ↔ A– Penicillin G potassium, phenytoin sodium
A2– 2M+A2– H2A ↔ A2– Cefotetan disodium, ticarcillin disodium
A2– M2+A2– H2A ↔ A2– Leucovorin calcium
-ium -ated A– M+A– HA ↔ A– Dexamethasone sodium phosphate,e
methylprednisolone sodium succinatef
A2– M2+2A– 2HA ↔ 2A– Calcium gluconateg
a
Refer to Table 1 for descriptions of the symbols.
b
Among 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
c
A proton (H+), which in water is a hydronium ion (H3O+), was intentionally omitted from the right side of each ↔ equilibrium.
d
These are ester salts. One of the few -ium -ate suffix exceptions is bretylium tosylate, which is a quaternary ammonium salt (see Table 3).
e
One 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.
f
One 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.
g
Inorganic 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 Drug Ion, Drug Salt Drug Acid–Base
Suffixesa Symbola,b Symbola Conjugate Pair Examples
-ate -ide C2–4N +
C2–4N X+ –
None Echothiophate iodide
-ide C2–4N+ C2–4N+X– None Bethanecol chloride, neostigmine bromide,
succinylcholine chloride
-ium -ate C2–4N+ C2–4N+X– None Atracurium besylate, bretylium tosylate
-ium -idec C2–4N+ C2–4N+X– None Doxacurium chloride, ipratropium bromide
a
Refer to Table 1 for descriptions of the symbols.
b
All quaternary ammoniums are cations in the conventional pH range of 0–14.
c
The -ium -ide suffixes also identify compatible inorganic salts of alkaline metals (e.g., potassium iodide, sodium chloride).

The second pKa or pKa2 of polypro-
tic acids, H2A or H2B2+, with acid
groups separated by ≤ 3 atoms is
usually 1–5 units higher (10–100,000
times weaker in acid dissociation or
requires pH values 1–5 units higher
than pKa1 for 50% H+ dissociation)
because the negative (HA –) and
less positive (HB + versus H 2B 2+)
charged ions induce intramolecular
electrostatic attraction for the other
dissociable proton.23,25,27-29,51,52 (The
following sources are recommended
to seek drug pKa values: AHFS Drug
Information, Clarke’s Analysis of
Drugs and Poisons, Foye’s Principles
of Medicinal Chemistry, reference 25
in this article, The Merck Index, and
Wilson and Gisvold’s Textbook of Or-
ganic Medicinal and Pharmaceutical
Chemistry).
An H2O, from the reactions of
H3O+ with A–, A2–, and B and of OH–
with HA, H2A, HB+, and H2B2+, and
H3O+ and OH– for which concentra-
tions are pH dependent were pur-
posely omitted from the equations.
The equilibria in the equations shift
left when pH decreases and shift right
when pH increases. The pH of most
commercial drug injections creates
≥99% of the A–, A2–, HB+, or HB2+
form for effective solubility when
such pH also provides adequate
chemical stability.
Ampholytes. Amphoteric electro-
lytes, the most common of which are
amino acids, peptides, and proteins,
can react as both acids and bases de-
pending on the pH, or they can exist
as zwitterions with equal positive and
negative charges22,23,27,39,43 (e.g., am-
picillin, lorazepam).12,13 Ampholytes
are least soluble at their isoelectric
pH, pI, or zwitterion point, which

352 Am J Health-Syst Pharm—Vol 66 Feb 15, 2009


equals the mean of the pKa values for
their HA and HB+ acid groups.22,23,39
For example, ampicillin has a pI of
4.9 from the mean of its –COOH pKa
of 2.5 and –CNH3+ pKa of 7.2.25 At
the pI, the ionic charges of zwitteri-
ons attract and neutralize each other
internally,39 which decreases ionic
attraction to water, thus decreasing
solubility.23,27,43
Ampicillin’s pI of 4.9 contrib-
utes to its poor oral bioavailability
because pH 4.9 is in the pH range
of jejunal contents. Nearly all oral
drugs and nutrients that are dis-
solved in small intestinal contents
enter the bloodstream by diffusing
into membrane capillaries, which
ultimately drain into the hepatic
portal vein.50,53,54 Lorazepam is a zwit-
terion at its pI of 6.4, and lorazepam’s
solubility in 0.9% sodium chloride
injection at pH 6.3 is half that in both
5% dextrose injection at pH 4.4 (at
which lorazepam is mainly a cation)
and lactated Ringer’s injection at pH
7.2 (at which lorazepam is mainly an
anion).55
Guidelines to identify and pre-
dict incompatibility of organic drug
ions. The three-letter suffixes of the
nondrug ion names in organic drug
salts listed in Table 2 permit rapid,
accurate identification of organic
drug cations and anions in at least
95% of cases.12,13,16,56 Table 3 lists suf-
fixes of quaternary ammonium drug
salts, where -ium and -ate identify
a drug cation, C2–4N+ , instead of an
anion, A–, as in Table 2. Nevertheless,
the probability of a mistaken iden-
tity is low because there are very few
injectable -ium and -ate quaternary
ammonium drugs. The particular
drug structure may be observed in
a pharmaceutical reference source
to confirm whether it is a cation or
anion.
Precipitation should be expected,
though it may not occur, and its
immediate absence should not be
assumed to be permanent when
pairs of salts (Table 4) are mixed in
relatively high concentrations and
primer  Drug incompatibility
when individual salts are diluted
approximately 20-fold or less from
their original concentrations12-14,56 as
follows:
• When salts with the suffix -ate or -ide
are diluted at either pH > 7 or pH
> (pKa – 2) of the HB+ or H2B2+ acid
forms, making 1% or more of the
nonionized B form (e.g., diphenhy-
dramine hydrochloride in lactated
Ringer’s injection). The pH values of
-ate and -ide salt injections are usu-
ally lower, more acidic, or less alkaline
than those of diluent solutions. The
final dilution pH is usually greater
than that of the original -ate or -ide
salt injection and less than that of the
original diluent solution, which may
account for an insoluble concentra-
tion of the nonionized B form.
• When salts with the suffix -ium or
-ium and -ate are diluted at either pH
< 7 or pH < (pKa + 2) of the HA or
H2A forms, making 1% or more of the
HA nonionized form (e.g., phenytoin
sodium in 5% dextrose injection).
The pH values of -ium or -ium and
-ate salt injections are usually greater,
less acidic, or more alkaline than
those of diluent solutions. The final
dilution pH is usually less than that of
the original -ium or -ium and -ate salt
injection and greater than that of the
original diluent solution, which may
account for an insoluble concentra-
tion of the nonionized HA form.
An infamous example of quater-
nary ammonium, C2–4N+, incompat-
ibility with an organic anion, A –,
occurred during the 1994 execution
of convicted serial murderer, John
Wayne Gacy. His i.v. tubing was
blocked by precipitation from pan-
curonium bromide and sodium
pentothal injections57 (i.e., a concen-
trated mixture of polycyclic pancuro-
nium+ and aromatic pentothal– op-
posite ions).
Aqueous solubility of salts. Wa-
ter is a strong dipolar molecule, and
it has a high dielectric constant or
the ability to dissociate ionic bonds.
Am J Health-Syst Pharm—Vol 66 Feb 15, 2009
Therefore, water extensively sepa-
rates most salts composed of one 1+
cation and one 1– anion, one 2+
cation and two 1– anions, or two 1+
cations and one 2– anion into their
composite ions. Upon ionic disso-
ciation, several water molecules are
attracted to each ion via ion–dipole
intermolecular forces, insulating
the ions from each other and result-
ing in good solubility.22,23,26,33,35,43,47,58
Intravenous carbohydrate and
electrolyte solutions have polarity
like water, but they have either a
mildly acidic or alkaline pH—not
the neutral pH 7 of freshly distilled
water.13,14,47,55
Because of thermodynamic fac-
tors (e.g., hydration energies, extents
or degrees of dissociation), different
salts of the same organic drug ion
do not have equal water solubili-
ty. 22,23,26,32,58 For example, codeine
phosphate’s water solubility is 1 g in
2.5 mL and codeine sulfate’s water
solubility is 1 g in 30 mL; pilocarpine
hydrochloride’s water solubility is 1
g in 0.3 mL and pilocarpine nitrate’s
water solubility is 1 g in 4 mL.33 At
equal concentrations, calcium glu-
conate dissociates fewer free calcium
ions (Ca2+) than does calcium chlo-
ride, which is why the gluconate salt
permits compatibility at greater cal-
cium and monohydrogen or dibasic
phosphate (HPO42–) concentrations
in i.v. preparations.45
Most salts in which the drug ion is
organic and its opposite ion is either
inorganic or nonaromatic organic
dissolve at least 1 g in 10–30 mL of
water, the USP definition of soluble.31
Water and low-molecular-weight,
semipolar organic solvents, such as
1–3 carbon alcohols, can also dissolve
nondissociated ion pairs of some
salts by dipole–dipole intermolecular
forces,22,23,26,34,58 like the attraction of
opposite poles of magnets.
The dissociation equilibria of
-ium and -ium and -ate salts (Table
2) are depicted in equations 3a and
3b, in which M+ is most often sodium
(Na+)18,32 from having reacted the HA
353
 primer  Drug incompatibility

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, -idea Gentamicin sulfate, promethazine -ium, -ium -ateb Heparin sodium, dexamethasone
hydrochloride sodium phosphate
-ate -ide, Examples in Table 3 -ium, -ium -ateb Penicillin G potassium, methylprednisolone
-ium -ate, sodium succinate
-ium -idec
a
These are the HB+ and HnBn+ ions described in Tables 1 and 2.
b
These are the A– and An– ions described in Tables 1 and 2.
c
These are the C2–4N+ ions described in Tables 1 and 3.

drug acid with the cation hydroxide
(MOH):
M+A– ↔ M+ + A–; salt dissociation
(3a)
A– + H2O ↔ HA + OH–; base hydrolysis leftward, increasing the fraction of
(3b)
The right side of equation 3b shows
why the pH values of -ium and -ium
and -ate solutions are usually alkaline
(>7) and often greater than pKa + 1.
Equation 3b also shows that a greater
OH– (hydroxyl ion) concentration,
or higher pH, shifts the equilibrium
leftward, increasing the fraction of
drug in the most soluble A– base
or ionized form and decreasing the
fraction of the nonionized HA acid
form.
The dissociation equilibria of -ate
and -ide salts (Table 2) are depicted
in equations 4a–4c, where X– is most
often chloride (Cl–)18,32 but may be
the inorganic ion from another inor-
ganic acid, or an organic ion from an
organic acid (e.g., lactate– from lactic
acid, succinate2– from succinic acid):
HB+X– ↔ HB+ + X– ; salt dissociation
(4a)
HB + + H 2 O ↔ B + H 3 O + ; acid
dissociation (4b)
X– + H2O ↔ HX + OH–; base hydro-
lysis when X– is organic (4c)
The right side of equation 4b shows
why -ate and -ide salt solutions are
usually acidic, pH < 7, often with pH
< (pKa + 1). Equation 4b also shows
that a greater H3O+ concentration,
or lower pH, shifts the equilibrium
drug in the most soluble HB+ acid or
ionized form. Equation 4c shows the
base hydrolysis in which HX is analo-
gous to HA in equation 3b.
When HA acids alone are diluted
in water, they dissociate less than
100% to decrease pH, and when B
bases are diluted in water, they hy-
drolyze less than 100% to increase
pH compared to equal molarities
of strong acids (e.g., hydrochloric,
nitric, sulfuric) and strong bases
(e.g., potassium hydroxides, sodium
hydroxides), respectively. That is
why such organic acids and bases are
termed weak electrolytes.22,23,26-29,34,43
Deducing phenylephrine
hydrochloride and furosemide
incompatibility
Phenylephrine hydrochloride
and furosemide were the most con-
centrated injections cited in a drug
incompatibility letter.1 Phenyleph-
rine hydrochloride is a B and HB+
conjugate pair, or HB+X– salt, and
furosemide is an HA and A– conju-
gate pair, or M+A– salt (Table 2). The
Handbook on Injectable Drugs does
not expressly list this combination of
drugs, but it contains the following
relevant statements: “Furosemide
is soluble in alkaline solutions and
is prepared as a mildly buffered
alkaline product. It should not be
mixed with acidic solutions having
a pH below 5.5.”59
The percentage of each form of
these and other weak electrolyte
drugs depends on the pKa of the acid
form and the solution pH (i.e., on
the Henderson-Hasselbalch equa-
tion, 5a–5e)3,12-14,20-25,27-29,34,43:
pH = pKa + log ([base form]/[acid
form]), where [ ] represents
concentration (5a)
% A– form = 100/(1 + 10[pKa–pH]) =
(100% – %HA form) (5b)
% HA form = 100/(1 + 10[pH–pKa]) =
(100% – %A– form) (5c)
% HB+ form = 100/(1 + 10[pH–pKa]) =
(100% – %B form) (5d)
% B form = 100/(1 + 10[pKa–pH]) =
(100% – %HB+ form) (5e)
According to the furosemide in-
jection title, it is not obvious that the
drug in this sterile solution is actually
ionized furosemide, or furosemide–.
This is determined from informa-
tion such as that above59 and by
identifying the acid group and its pKa
or pKa range from organic and me-
dicinal chemistry instructions and

354 Am J Health-Syst Pharm—Vol 66 Feb 15, 2009

 pKa of 7.8.27
carboxylic acid group, COOH.

is great probability of precipitation.

than the lowest official pH (3.0) of

that the furosemide injection pH of

of furosemide and phenylephrine

show that in their original injec-

rine hydrochloride and furosemide

furosemide–) and phenylephrine is

phenylephrine hydrochloride injec-

tions, furosemide exists at >99%

-ide salt (Tables 2 and 4), in which there

references3,22,27-29,40 and interpreting

mixtures1 were doubtlessly higher

is named and labeled for the original
is dissolved (as with daptomycin for

spective pH ranges for 5% dextrose

claim and pH 3.0–6.5; and the re-
The USP strength and pH ranges
drug form—not the in situ salt. Such
(inactive ingredients) that provide a
as a dry solid with added substances
solution by pH adjustment (as with
formulation, a nonionized drug is ei-
Unlabeled drug salts. If, during

sent a mixture of an -ium salt and an

Therefore, these two injections repre-
in its anionic base form (i.e., A– or
semide and 8.8 for phenylephrine,25
facts and pKa values of 3.9 for furo-
are 3.2–6.5 and 4.5–7.0.60 Using those
and 0.9% sodium chloride injections
in extensive H+ dissociation from a

hydrochloride injections are, respec-

B-type base (Table 1), and famotidine
nonionized famotidine structure as a
the injection pH range of 5–5.6,58
as calculated from equation 5d with
interpretation is necessary for a few
injection), then the product injection
particular pH range when the drug
ther converted to its ionized form in
Drugs,59 or USP monograph60) results
information, Handbook on Injectable
8.0–9.3 (obtainable from the product

The pH values of the phenyleph-

minimally 91% in its cationic acid
which is >99% HB+ ionized form

pH 8.0–9.3 and 90–115% of label

equations 5b and 5d calculations

tively, 90–110% of label claim and
furosemide injection) or combined

form (i.e., HB+ or Hphenylephrine+).

other injections, such as famotidine,
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
c
Phenytoin (mg/mL)
Nonionized Phenytoin Alcohol Propylene Glycol
Componenta Measured pH Phenytoin (%)b (mg/mL) (%) (%) Present Soluble
d
Source I 50 mg/mL 10.4 0.801 47.6   9.8 40.2 81.3
3 Alle
Source II 50 mg/mL 12.1 0.016 46.2 10.7 42.5 7.4d Allf
0.9% Sodium chloride injection 6.7 NAg NA NA NA NA NA
Source I 2 mg/mL dilution 9.8 3.07 NA NA NA 58.5h ~20i
Source II 2 mg/mL dilution 11.2 0.126 NA NA NA 2.3h Allf
primer 

a
Phenytoin 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
b
Nonionized 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
c
From the USP 31 phenytoin sodium injection monograph, the weight of assayed phenytoin (mg) × (274.25/252.27) = the weight of phenytoin sodium (mg).60
d
The concentration of nonionized phenytoin is calculated from ([assayed phenytoin concentration × [1000 mg/mg] × [% nonionized phenytoin/100]). For example, the Source II phenytoin sodium injection phenytoin
concentration = ([46.2 mg/mL] × [1000 mg/mg] × [0.016/100]) = 7.392 mg/mL.
e
The saturated solubility of Phenytoin, USP, in carbon dioxide-free, fresh-deionized water at pH 7 at 25 °C was reported to be 20 mg/mL.13 In the original phenytoin sodium injection, the 9.8% alcohol and 40.2% propylene glycol
dissolve any nonionized phenytoin exceeding water solubility.
f
The calculated 7.4 mg/mL of nonionized phenytoin present is less than the 20-mg/mL saturated water solubility of nonionized phenytoin.
g
Not applicable.
h
Dilutions 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,

Am J Health-Syst Pharm—Vol 66 Feb 15, 2009

mg/mL]/50 mL) × [1000 mg/mg] × [% nonionized phenytoin/100]. For example, for the Source 1 dilution, the concentration = {([2 mL × 47.6 mg/mL]/50 mL) × [1000 mg/mg] × [3.07/100]} = 58.45 mg/mL.
i
The soluble concentration of nonionized phenytoin might be slightly greater than the 20-mg/mL water solubility because there is 4% of the original 9.8% alcohol and 40.2% propylene glycol concentrations in the dilution.
Drug incompatibility

355
 primer  Drug incompatibility
tion, making >10% of nonionized
phenylephrine, B, and less than the
greatest official pH (9.3) of furose­
mide injection, making >1% of
nonionized furosemide, HA. Besides
nonionized forms, another likely
precipitate was (Hphenylephrine +
furosemide –) nondissociated ion
pairs, symbolized as (HB+A–). Vaso-
pressin in the report probably either
did not precipitate or contributed
a miniscule amount, because of its
relatively small concentration com-
pared to furosemide and phenyleph-
rine and the unlikelihood of pH
values at the pI of vasopressin.
USP article compliance may not
assure compatibility equivalence
Products that comply with the
quality standards in a particular USP
article monograph may be presumed
to be pharmaceutically equivalent.
However, the chemical compatibility
of such products in mixtures and di-
lutions can be determined by differ-
ences within official USP ranges for
ingredient strength and pH values.
Such USP compliant differences may
occur between both different lots
from the same manufacturer and lots
from different manufacturers.
The potential compatibility versus
incompatibility results of multi-
source USP compliant injections is
illustrated in Table 5 for hypothetical
sources I and II of phenytoin sodium
injection diluted in 0.9% sodium
chloride injection. Although sources
I and II and the diluent meet USP
standards, 60 the 25-fold dilution
of source I would probably result
in precipitation, based on 58.5 mg/
mL of nonionized phenytoin pres-
ent compared to approximately 20
mg/mL being soluble14 (Table 5). In
a comparable actual observation,
phenytoin precipitated within five
minutes in three out of four sources
of phenytoin sodium injection di-
luted from 50 to 5 mg/mL in 0.9%
sodium chloride injection.61 The four
sources were USP compliant for the
pH range, but they were not assayed
356 Am J Health-Syst Pharm—Vol 66 Feb 15, 2009
for phenytoin. It took approximately
three hours for phenytoin crystals to
appear in the sample prepared from
the injection with the highest pH,
which made the lowest percentage of
nonionized phenytoin.24,61,62
Mixtures of calcium gluconate
injection with potassium or sodium
phosphates injections45,62 may also
evidence variable compatibility re-
sults of multisource, USP-compliant
injections. Furthermore, slightly dif-
ferent temperature and mixing vigor
of compatibility samples, which
affect crystalline growth rates and
supersaturation, can also determine
solubility versus precipitation in bor-
derline cases.
Conclusion
Incompatibility of drug and nutri-
ent injections is clinically hazardous.
Knowledge of products’ chemical
facts, organic acid–base equilibria in
relation to ionization and nonion-
ization and aqueous solubility, and
ranges of pH and ingredient strength
from USP monographs and product
labeling is the foundation of expertise
in drug incompatibility. Precipitation
of injectable drug solutions should
be suspected, particularly when op-
positely charged drug salts are mixed
in relatively strong concentrations
and when pH values of dilutions
create more than 1% of nonionized
drug forms.
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Appendix—References for drug
structures
Clarke’s Analysis of Drugs and Poisons
Foye’s Principles of Medicinal Chemistry
Goodman & Gilman’s the Pharmacological
Basis of Therapeutics
Index Nominum International Drug Directory
Martindale: The Complete Drug Reference
Physicians’ Desk Reference
Remington: The Science and Practice of Pharmacy
The Merck Index
USP Dictionary of USAN and International
Drug Names
Wilson and Gisvold’s Textbook of Organic Me-
dicinal and Pharmaceutical Chemistry
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