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134 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 5-5.Acid-catalyzed degradation of erythromycin. The three-step reaction
sequence involves the C6 and C12 hydroxyl groups and the C9 ketone. These oxygen atoms
have been highlighted in bold. All other atoms have been removed for the purpose of
simplicity and clarity.
Similarities Among Organic Salts and Esters
The advantages described above for both water- and lipid-soluble organic salts can also be achieved
through the use of water- and lipid-soluble esters. A more complete discussion of water- and lipidsoluble esters, as well as examples, is provided later in this chapter; however, it is important to note
that inorganic or organic salts are used more often to enhance the water solubility of a drug molecule than are water-soluble esters. In fact, although numerous acidic and basic molecules are used
to make inorganic and organic salts, most water-soluble esters are produced by using only three
molecules: succinic acid, sulfuric acid, or phosphoric acid. In contrast, lipid-soluble esters are used
much more often than lipid-soluble salts.
Organic Salts and Drug Interactions
The beneficial effects of the organic salts discussed above are the direct result of specific planning
and the application of a given salt’s properties to a desired therapeutic need. In other words, specific
types of organic salts are purposely designed and administered to meet specific therapeutic goals.
In contrast, the formation of unwanted organic salts can lead to specific drug interactions and detrimental effects. This occurs most commonly in the preparation and administration of parenteral
solutions and is best illustrated in the following two examples.
β-Lactam antibiotics, exemplified by cefepime (Figure 5-6), inhibit bacterial cell wall synthesis
and hence provide a bactericidal effect for many systemic infections. In some cases, such as endocarditis and community-acquired pneumonia, combination antibiotic therapy with an aminoglycoside,
exemplified by gentamicin (Figure 5-6), is recommended. The combination use of drugs from these
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FIGURE 5-6.Cefepime and gentamicin. Acidic and basic functional groups have been
highlighted with boxes.
two classes of antibiotics has been shown to produce a synergistic bactericidal effect along with
a decrease in the ability of the microorganism to develop resistance. Although this combination
provides beneficial therapeutic outcomes, caution must be used when administering these drugs in
combination. As noted in Figure 5-6, cefepime contains an acidic carboxylic acid whereas gentamicin
contains multiple primary and secondary amines. Thus, if these drugs are mixed in the same IV bag
or are administered through the same IV line, it is possible for one molecule of gentamicin to form
a salt complex with up to five cefepime molecules. The probability of this occurring depends on the
concentrations of each drug; however, once formed, this organic salt is much less water soluble than
either individual drug and may precipitate in the IV bag or tubing, leading to both decreased efficacy
and potential harm to the patient.
A second example of this type of drug interaction is seen with heparin, an anticoagulant indicated
for the treatment of a variety of thrombotic and embolic conditions. Chemically, heparin is a sulfated
polysaccharide containing numerous negatively charged, ionized functional groups. A partial structure
of heparin is shown below. Due to its chemical structure, heparin is highly water soluble, is not orally
absorbed, and must be administered as either an IV infusion or a subcutaneous injection.
When given in IV form, it is important that solutions of basic drugs not be administered in the
same IV bag or IV line as heparin. A hospital pharmacy in the Pittsburgh area provided the author
with a list of medications that they have designated as “Cannot be administered in the same IV line
as heparin.” A sample of selected agents from this list is shown in Figure 5-7. Please note that all of
these drugs are basic and would form organic salts with heparin. The resulting organic salts would
be more lipid soluble than heparin and could lead to the precipitation in an IV administration line.
Similar to what was previously discussed with gentamicin, one molecule of heparin can be involved
in a salt complex with numerous molecules of any one of the drugs on this list.
136 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 5-7.Basic drugs that would cause a drug interaction with heparin if infused
simultaneously through the same IV line. The basic nitrogen atom has been highlighted
with a box for each drug molecule.
USING NAMES OF SALTS TO IDENTIFY ACIDIC
AND BASIC DRUG MOLECULES
Chapter 3 focused on the identification of acidic and basic functional groups; however, situations
may arise in which it is necessary to identify the acidic and/or basic nature of a drug molecule
without the benefit of viewing a specific drug structure. In these instances, if the drug is available
as a salt form, it is possible to use the name of the salt to identify the acid/base nature of the drug
molecule or the ionizable functional group. Please note that the following discussion is valid if the
drug molecule has only one ionizable functional group or if all of its ionizable functional groups are
either acidic or basic.
Remember that a salt is the product that results when an acid reacts with a base. Thus, if the
organic or inorganic molecule used to make the salt is a base, then the functional group involved
in the salt is an acid, and vice versa. As an example, let us consider heparin. Heparin is marketed as
heparin sodium. If you find yourself in a situation when you simply can’t remember anything about
the structure of heparin, you can use the name of this salt to deduce the acidic nature of heparin.
The sodium part of this salt comes from sodium hydroxide, a strong inorganic base; thus, the drug
molecule must contain an acidic functional group. In the case of heparin, there are multiple acidic
functional groups, each of which can form a salt with sodium hydroxide. Another way of correctly
deducing this fact is to examine the charges on the molecule used to make the salt. The sodium ion
has a positive charge, thus the ionizable functional group on the drug molecule must have a negative charge. As discussed in Chapter 3, ionized acids have a negative charge and ionized bases have
a positive charge.
Using this method, it is possible to determine that ceftriaxone sodium, etidronate disodium,
penicillin V potassium, leucovorin calcium, and pemirolast potassium are all salts of drug molecules
that contain acidic functional groups. Similarly, it is easy to deduce that hydrochloride salts and
hydrobromide salts are the product of hydrochloric or hydrobromic acid and drug molecules that
contain a basic functional group (e.g., pseudoephedrine hydrochloride, citalopram hydrobromide).
A brief review of nomenclature is required when acids other than hydrochloric acid or hydrobromic acid are used to make salts of basic drug molecules. In most instances, the names of the salt
CH 5 - SALTS AND SOLUBILITY 137
==
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forms of these other acids follow the simple convention of removing the “-ic acid” from the end of
the name and replacing it with an “-ate” suffix. For example, when sulfuric acid and phosphoric acid
are used to make salts, the resulting products are termed sulfate and phosphate salts, respectively.
The same is true for organic salts made with molecules containing carboxylic acids. Thus, the salt
forms of acetic acid, citric acid, fumaric acid, and maleic acid are known as acetate, citrate, fumarate,
and maleate salts, respectively.
Organic salts of drug molecules containing acidic functional groups are not as prevalent as
organic salts of drug molecules containing basic functional groups; however, because they are
normally produced from amines, the names of these salts often provide a helpful hint as to the
acid/base nature of the drug molecule. This is exemplified by the tromethamine salt of ketorolac.
The “amine” part of this name easily identifies it as a base; thus, the drug molecule must contain an
acidic functional group.
The key point here is that the simple names of the acids and bases commonly used to prepare
inorganic or organic salts can often help identify the acid/base nature of an unknown drug. While
there are a multitude of drugs available for therapeutic use, there are a limited number of common acids and bases that are used to formulate salt preparations. It is strongly suggested that you
become familiar with the acids and bases that are used to prepare the salt forms of drugs. A sample
is provided in Table 5-1.
TABLE 5-1.A Sample of Salt Forms of Drug Molecules and the Acid/
Base Nature of the Drug and the Molecule Involved in Salt Formation
Name of Salt Form
of Drug Molecule
Carboprost tromethamine Tromethamine (organic base) Acidic
Ciclopirox olamine Olamine (organic base) Acidic
Clavulanate potassium Potassium hydroxide (inorganic base) Acidic
Clomipramine hydrochloride Hydrochloric acid (inorganic acid) Basic
Disopyramide phosphate Phosphoric acid (inorganic acid) Basic
Fosphenytoin sodium Sodium hydroxide (inorganic base) Acidic
Guanabenz acetate Acetic acid (organic acid) Basic
Metoprolol tartrate Tartaric acid (organic acid) Basic
Pitavastatin calcium Calcium hydroxide (inorganic base) Acidic
Quetiapine fumarate Fumaric acid (organic acid) Basic
Streptomycin sulfate Sulfuric acid (inorganic acid) Basic
Inorganic or Organic Molecule
Used to Formulate Salt
Acid/Base Nature
of Drug Molecule
SOLUBILITY AND PARTITION COEFFICIENTS
The partition coefficient of a drug molecule is defined as the ratio of the solubility of the unionized
drug in an organic solvent to the solubility of the same unionized drug in an aqueous environment.
A variety of organic solvents have been used in measuring partition coefficients; however, n-octanol
is generally considered to be the standard. The aqueous environment should be buffered such that
acidic and basic functional groups are primarily unionized. The partition coefficient, designated as P,
is a dimensionless term (i.e., without units) and is often expressed as a log value, log P.
[Drug]
[Drug]
lipidenvironment
aqueousenvironment
or loglog
[Drug]
[Drug]
lipidenvironment
aqueousenvironment
138 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
D
[Drug]
or
ionizedaq.envir.unionized aq.envir.
While partition coefficients should be calculated at an aqueous pH in which the drug molecule
is primarily unionized, this information is often not provided when partition coefficient values are
published. In many cases, neutral (i.e., pH = 7.0) or physiologic (i.e., pH = 7.4) conditions are often
used for partition coefficient determinations, and ionization is ignored. Additionally, a number of
computer programs are available to calculate log P values. The designation cLog P (or clog P) is used
to represent a calculated log P.
A related parameter, known as the distribution coefficient and designated as D, does account
for the pH of the aqueous environment as well as the percent of the drug that is ionized. Similar to
the partition coefficient, the distribution coefficient is a dimensionless term and is often expressed
as a log value. Log D values for acidic and basic drug molecules are not constant and change according to the pH of the aqueous environment. For those drug molecules that do not contain ionizable
acidic or basic groups, the log D value is constant and is the same as the log P value. The following
discussion focuses solely on partition coefficients.
=
[Drug] [Drug]
=
Dloglog
[Drug] [Drug]
lipidenvironment
+
[Drug]
lipidenvironment
ionizedaq. envir. unionizedaq. envir.
+
Partition coefficients are often used to compare the relative water or lipid solubility of a series
of drug molecules. In reviewing the equation, it should be obvious that partition coefficients, or log P
values, will be larger for those drug molecules that are more lipid soluble as compared with similar
drug molecules that are either less lipid soluble or more water soluble. In contrast, log P values will
be small for those drug molecules that are more water soluble. As an example, consider the following two hypothetical compounds. Compound A has a log P value of 0.38 while Compound B has a
log P value of 1.26. Given this information, you should be able to determine that Compound B is
more lipid soluble than Compound A. Moving from hypothetical compounds and log P values, let us
examine the log P values of the seven commercially available HMG-CoA reductase inhibitors. These
drugs are used to favorably alter plasma LDL and HDL levels and are indicated for several dyslipidemic conditions as well as the prevention of stroke and myocardial infarction. As seen in Table 5-2,
pravastatin and rosuvastatin are much more water soluble than the other five drugs in this class
of agents.
TABLE 5-2.The Calculated Log
HMG-CoA Reductase Inhibitors
P
Values for
a
Drug Calculated Log P (cLog P)
Atorvastatin 4.13
Fluvastatin 3.62
Lovastatin 4.07
Pitavastatin 3.45
Pravastatin 1.44
Rosuvastatin 0.42
Simvastatin 4.42
a
The cLog P values were calculated using ACD/ChemSketch, version
12.01.
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Analyzing a Drug Molecule for Its Water- and
Lipid-Soluble Components
The term hydrophilic is commonly used to describe water-soluble molecules whereas the terms
hydrophobic and lipophilic are commonly used to describe lipid-soluble molecules. The term lipophobic has also been used to describe water-soluble molecules; however, its use is not very com-
mon. It is strongly suggested that you become familiar with this terminology as these descriptions
are often used interchangeably.
The partition coefficient of any given drug molecule is the result of the additive contributions
and interrelationships of all of its functional groups. Each functional group helps to determine the
overall hydrophobic or hydrophilic nature of the drug molecule. As such, the ability to recognize
the hydrophobic and hydrophilic components of a drug molecule is an important skill. As discussed
in Chapter 2, functional groups that are able to ionize and/or form hydrogen bonds contribute the
most to the overall hydrophilicity of a drug molecule while halogens, aromatic rings, and hydrocarbon rings and chains contribute the most to the overall hydrophobicity of a drug molecule. A
review of common hydrophilic and hydrophobic functional groups is shown in Figure 5-8. A more
extensive list can be found in Chapter 2. Please note that each functional group is attached to one or
more adjacent “R” groups. In most cases, these “R” groups represent the hydrocarbon ring or chain
to which the functional group is attached. Examples of this are discussed in Chapter 2 with phenols,
ethers, esters, and anilines. The hydroxyl group of a phenol, the oxygen atom of an ether, and the
primary amine of an aniline are hydrophilic; however, the aromatic rings and alkyl chains to which
they are attached are hydrophobic. The oxygen atoms of an ester are hydrophilic; however, esters
are commonly designated as either water soluble or lipid soluble based on the composition of the
“R” groups. Fluorine has been intentionally excluded from this list because its effect on solubility
can vary. Fluorine can act as a hydrogen bond acceptor and, in some instances, can increase the
water solubility of a drug molecule; however, studies have shown that the substitution of a fluorine
atom for a hydrogen atom generally tends to slightly enhance the lipid solubility of a drug molecule.
One specific fluorine-containing functional group that is known to enhance the lipid solubility of a
drug molecule is the trifluoromethyl group (CF3).
Using these functional groups, let us analyze a sample drug. Bimatoprost is a semisynthetic
prostaglandin that is used to treat open angle glaucoma and ocular hypertension. This drug is formulated and administered as an ophthalmic solution. This drug contains four functional groups—
three secondary hydroxyl groups and one amide—that are capable of forming hydrogen bonds with
water. These functional groups contribute to the overall water solubility of the drug. The remainder
of the molecule, or the “R” groups to which the hydrophilic groups are attached, consists exclusively
of hydrocarbon chains, aromatic rings, and alicyclic rings that contribute to the overall lipid solubility
of the molecule.
Although this type of analysis does not directly calculate a log P value, it does allow for a better
understanding of published or calculated log P values. This type of analysis is useful in understanding the differences in log P values for a series of related drug molecules, in the comparison of specific
structures and their log P values, and in prediction of log P values of analogs. Additionally, the actual
140 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 5-8.Common hydrophilic and hydrophobic functional groups. (Note: Fluorine has
been intentionally omitted here; see text for an explanation of its role in solubility.)
log P values are often not as important as the relative hydrophilicity or lipophilicity of a given drug
molecule within a series of drug molecules.
Important Skills to Master
First, you should be able to identify drug molecules that are either highly hydrophilic or highly
hydrophobic. As an example, consider the four drug molecules shown in Figure 5-9. Alendronic acid
is a small molecule that contains a tertiary hydroxyl group and three ionizable functional groups
whereas tobramycin contains a large number of hydroxyl groups and primary amines. All of these
functional groups are capable of undergoing ionization or participating in hydrogen bonds. As a
result, both of these drug molecules are extremely hydrophilic. In contrast, vitamin K1, also known
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FIGURE 5-9.Examples of highly hydrophilic and highly hydrophobic drug molecules.
as phytonadione, and estrone lack any ionizable groups and are comprised primarily of hydrocarbons. Both drugs are highly hydrophobic.
Unlike the examples in Figure 5-9, most drug molecules contain a more balanced distribution
of hydrophilic and hydrophobic functional groups and thus cannot be immediately categorized as
either a hydrophilic or hydrophobic drug molecule. Therefore, a second important skill is the ability
to compare the relative hydrophilicity or hydrophobicity of a specific drug molecule with structurally related drugs based on the relative solubilities of their respective functional groups. As an initial
example, let us look at the series of hypothetical compounds shown in Figure 5-10. All of these
compounds are structurally similar, with the only variation at the ortho position of the phenyl ring.
Because Compound B in this series has an unsubstituted phenyl ring, we will use this compound
as our reference point. In looking at the remaining three analogs, you can see that Compounds A
and D contain hydrophilic functional groups at the ortho position, while Compound C contains a
hydrophobic propyl group. Therefore, Compounds A and D are predicted to be more water soluble
than Compound B, whereas Compound C is predicted to be more lipid soluble than Compound B.
The only task remaining is to determine the relative water solubilities of Compounds A and D. Due
to its ability to be primarily ionized in most physiologic environments, the carboxylic acid present
FIGURE 5-10.Structurally related compounds with differing water solubilities.
142 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
in Compound D is predicted to impart more water solubility than the methoxy group present on
Compound A. Thus, the rank order of these four compounds in terms of their water solubility is
Compound D > Compound A > Compound B > Compound C.
Let us now extend this type of evaluation to specific drug molecules by returning to Table 5-2
and examining the cLog P values for pravastatin (cLog P = 1.44) and simvastatin (cLog P = 4.42).
Evaluation of these cLog P values reveals that simvastatin is approximately three log units more
lipophilic than pravastatin. This significant difference can be explained by comparing their chemical
structures. As shown in Figure 5-11, there are three sites of structural variation between these two
drugs. At site A, simvastatin contains a lactone bond whereas in pravastatin, this bond has been
broken to reveal an acidic carboxylic acid and a secondary hydroxyl group. While lactones can participate in hydrogen bonds, their capacity for increasing water solubility of a drug is far exceeded by
an ionizable carboxylic acid and a hydroxyl group. At site B, simvastatin contains an extra methyl
group that is not present on pravastatin, and at site C, simvastatin contains a methyl group whereas
pravastatin contains a hydroxyl group. Compared with either a hydrogen atom or a hydroxyl group,
a methyl group enhances lipid solubility. Thus, at all three of these sites, the functional group present in simvastatin is more lipophilic than the functional group present in pravastatin. This is very
much consistent with the known log P values of these two drugs.
FIGURE 5-11.Simvastatin and pravastatin.
A second example of this type of evaluation is seen with temazepam and quazepam (Figure 5-1 2),
two benzodiazepines used in the treatment of insomnia. Similar to lovastatin and pravastatin, there
are four structural variations between these two drug molecules. At site A, temazepam contains
a methyl group, while quazepam contains a trifluoroethyl group. The additional carbon atom, as
FIGURE 5-12.Temazepam and quazepam.
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well as its three fluorine atoms, enhances the lipid solubility of quazepam as compared with temazepam. At site B, the substitution of the oxygen atom in temazepam with a sulfur atom in quazepam
also enhances the lipid solubility of quazepam. This is because oxygen is more electronegative than
sulfur, creates a stronger dipole, and is better able to interact with water than is sulfur. At site C,
temazepam contains a hydrophilic hydroxyl group instead of the hydrogen present in quazepam,
while at site D quazepam contains a fluorine atom instead of the hydrogen present in temazepam.
In this case, the fluorine atom also enhances the overall lipid solubility of quazepam. At all four sites
of variation, the functional groups present in quazepam are more lipophilic than those present in
temazepam; thus, quazepam would be predicted to be more lipophilic (or hydrophobic) than temazepam. This is verified by comparing the log P values of these two drugs. Quazepam has a reported
log P value of 4.1 ± 0.8, while temazepam has a reported log P value of 2.2 ± 0.6. Although both
drug molecules could be considered lipophilic, this relative comparison reveals that temazepam is
considerably less lipophilic than quazepam.
Both of the above examples illustrate the third important skill you need to learn and master.
Because the log P value of any given drug molecule is the result of the additive contributions of all of
its functional groups, you should be able to explain the log P differences between two or more drug
molecules by comparing the chemical differences of their respective functional groups.
A final skill to master is prediction of how structural alterations alter the hydrophilic and hydrophobic nature of a drug molecule. Also implicit in this skill is the ability to match log P changes with
structural changes. As an example, let us revisit bimatoprost and compare its hydrophobic nature
with the two hypothetical analogs shown in Figure 5-13. Analog 1 lacks the aromatic ring seen in
bimatoprost while Analog 2 contains a meta trifluoromethyl group on the aromatic ring. The cLog P
value for bimatoprost is 3.25, and the cLog P values for the analogs, from highest to lowest, are
4.13 and 1.64 (Accelrys Draw 4.0). Because an aromatic ring adds lipid solubility to a drug molecule,
Analog 1 would be predicted to be less hydrophobic than bimatoprost; thus, the log P value of 1.64
would be consistent with this analysis. The trifluoromethyl group of Analog 2 is more hydrophobic
than an unsubstituted hydrogen atom; thus, Analog 2 would be predicted to be more hydrophobic
than bimatoprost, and the log P value of 4.13 would be consistent with this analysis.
FIGURE 5-13.Bimatoprost and two hypothetical analogs.
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