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74 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 3-18.Examples of basic drug molecules that are highly bound to the plasma
protein `1-acid glycoprotein.
basic drugs bind to two different plasma proteins, acidic drugs generally do not cause displacement
interactions with basic drugs and vice versa.
Ionization is also important in the metabolism and elimination of drug molecules. As discussed
in more detail in Chapter 8, one of the main purposes of drug metabolism is to ensure that the
body can eliminate the drug. In general, this is accomplished by altering existing functional groups
or adding more water-soluble groups. Some examples include the oxidation of a hydroxyl group to
a carboxylic acid, the hydrolysis of an amide to an amine and a carboxylic acid, the addition of an
amino acid, and the addition of glucuronic acid. Drug molecules that inherently contain multiple
ionizable acidic and/or basic functional groups already possess significant water solubility and generally do not require extensive metabolism. Examples of this are seen with the aminoglycosides and
bisphosphonates (Figure 3-19). These drug molecules contain multiple ionizable functional groups,
are highly water soluble, do not require metabolism, and are excreted in the urine.
Specific transport proteins for organic acids are present within the renal tubules. These proteins
can actively secrete acidic molecules (e.g., penicillins and cephalosporins) from the plasma to the
FIGURE 3-19.Examples of drug molecules that contain multiple acidic or basic functional
groups.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 75
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urine, thus decreasing their half-lives. They can also actively transport other acidic molecules from
the urine back into the plasma, thus increasing the half-lives of these molecules. Two key points need
to be made here.
y First, drug interactions or adverse effects can occur if two acidic drug molecules simultane-
ously require this transport/secretion pathway since the pathway is saturable.
y Second, basic drug molecules do not use the same transport/secretion proteins as acidic
drug molecules and thus would not cause a drug interaction via this mechanism.
As an example, thiazide diuretics are acidic drug molecules that require this active secretion
process to gain access to their site of biological action. Uric acid, a natural breakdown product of
purines, also requires active secretion to be eliminated from the body. Thiazides compete with uric
acid for the transport sites and block the normal secretion of uric acid. This can lead to hyperuricemia and contribute to the development of gout in some patients.
Acidic and basic functional groups present on a drug molecule can be used to produce commercially available salt formulations. As discussed in more detail in Chapter 5, a salt is simply the product that is produced when an acid is combined with a base. As an example, sodium sulfacetamide can
be produced by reacting sulfacetamide with sodium hydroxide.
Salts can be formed by using either organic or inorganic acids or bases. Inorganic salts, such
as sodium sulfacetamide, are generally used to enhance the water solubility and dissolution of a
drug molecule. Water-soluble organic salts, such as butorphanol tartrate (Figure 3-20), are similar to inorganic salts and can further enhance water solubility, dissolution, and the ability to form
FIGURE 3-20.Examples of a water-soluble organic salt (butorphanol tartrate) and a lipid-
soluble organic salt (penicillin G benzathine).
76 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
concentrated IV and ophthalmic solutions. In contrast, lipid-soluble organic salts, such as penicillin G
benzathine (Figure 3-20), are used to formulate suspensions for intramuscular (IM) injection (i.e., IM
depot injections). After injection, these lipid-soluble salts are slowly released from the injection site
and impart a longer duration of action for the drug.
Although salts can provide important therapeutic benefits, it must be noted that the indiscriminate combination of acidic and basic drugs can produce significant interactions. Acidic and basic
drugs should never be combined in the same IV infusion bag or infused through the same IV line due
to the possibility of organic salt formation and precipitation. Thus, a thorough understanding of
the acid/base nature of drug molecules and their functional groups can help prevent these types of
drug interactions. In addition, the acid/base nature of any single drug impacts its overall suitability
for a given parenteral formulation because its acidity or basicity contributes to the overall pH of the
formulation and affects buffers and other components. This is also true in solid formulations. The
combination of acidic and basic drugs in solid formulations may lead to the degradation of one or
both of the drug molecules.
Summary: The Influence of the Acid/Base Nature of a Drug
Molecule on Its Chemical, Pharmaceutical, and Therapeutic
Properties
The acid/base nature of a drug molecule influences the following conditions:
• the overall water solubility of a drug molecule
• the oral absorption of a drug molecule
• the passive reabsorption of a drug molecule within the urinary tract
• the ability for a drug molecule to interact with its biological target (e.g., target recep-
tor, transport protein, enzyme, or another endogenous biomolecule)
• the metabolism and elimination of a drug molecule
• the ability to form water- or lipid-soluble salts
• the suitability of a drug molecule for a given pharmaceutical formulation and route of
administration.
STRUCTURAL ANALYSIS CHECKPOINT
Checkpoint Drug 1: Venetoclax
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 77
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1. Identify all acidic and basic functional groups present within the structure of venetoclax
and provide the normal pKa ranges for these functional groups.
2. Using your answer to Question 1, identify if this drug is an acidic drug, a basic drug, an
amphoteric drug, an electrolyte, or a nonelectrolyte. Provide a reason for your answer.
3. The sulfonamide functional group in venetoclax has a predicted pKa value of 4.3. Provide an
explanation as to why this functional group has a pKa value that is slightly lower than the
normal range for sulfonamides.
4. The structure of venetoclax contains a pyrrolopyridine, a bicyclic ring system containing
two aromatic nitrogen atoms. The nitrogen atom in the six-membered pyridine ring is basic,
while the nitrogen atom in the five-membered pyrrole ring is not. Provide an explanation
for the differences in these nitrogen atoms.
Draw the ionized form of the strongest basic functional group present within the structure
5.
of venetoclax.
Checkpoint Drug 2: Elamipretide
1. Consider the structure of elamipretide and evaluate the boxed functional groups in the grid
provided.
Name of Functional
Group
A
B
C
D
Character:
Acidic, Basic, Neutral
pKa Value or Range
(NA is acceptable)
2. Consider the answer that you provided for the acidic/basic/neutral character of functional
group C in the previous question and provide a rationale for this answer.
78 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. For each of the boxed functional groups, identify its ionization state and acid/base character in each of the indicated physiologic locations.
Stomach
(pH = 1)
Ionized,
Unionized,
NA
A
B
C
D
Acid/Base
Character
at pH = 1
Intestine
(pH = 8)
Ionized,
Unionized, NA
Acid/Base
Character
at pH = 8
Urine (pH = 5)
Ionized,
Unionized, NA
Acid/Base
Character at
pH = 5
4. Show the ionized form of all of the acidic and basic functional groups.
REVIEW QUESTIONS
1. For each drug molecule, circle each of the acidic and basic functional groups and identify
them by name in the grid provided.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 79
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Drug Name Acidic Functional Groups Basic Functional Groups
Olapatadine
Lisinopril
Olmesartan
Baclofen
Brilanestrant
Aplaviroc
2. Directly modify each acidic functional group to show the ionized form. The ionized form of
each of these functional groups represents the conjugate base form of the functional group.
3. Directly modify each basic functional group to show the ionized form. The ionized form of
each of these functional groups represents the conjugate acid form of the functional group.
80 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
4. Consider the ionized form of each functional group in Questions 2 and 3. List all of the
functional groups that are acidic when they are in their ionized form. If no functional groups
meet this criterion, then leave the cell/column empty.
Olmesartan Lisinopril Aplaviroc
Consider the ionized form of each functional group in Questions 2 and 3. List all of the
functional groups that are basic when they are in their ionized form. If no functional groups
meet this criterion, then leave the cell/column empty.
Olmesartan Lisinopril Aplaviroc
5. Provide a brief definition for the term amphoteric. Determine which structures in Question
1 are amphoteric in nature.
6. For each drug molecule shown below, identify each functional group that is capable of
being ionized, the normal pKa range for the functional group, and whether the drug is acidic,
basic, or amphoteric in character.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 81
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Drug Name
Besafloxacin
Tinlorafenib
Nezulcitinib
Name of Functional
Group(s) Normal pKa Range(s)
Acidic, Basic, or
Amphoteric
7. Bile acids are secreted from the liver into the intestine to help emulsify dietary fat and
cholesterol. This enhances the absorption of these dietary substances into the body. In
the treatment of high cholesterol, it is important to decrease the intake and absorption of
dietary fat and cholesterol.
Colestipol (Colestid®) is a polymeric drug that can be used in the management of high
cholesterol. This polymer acts like an ion exchange resin and exchanges one bile acid (negatively charged) for one chloride ion (negatively charged). Once the bile acid is associated
with the polymer, it is readily eliminated. If the bile acids are removed, then they are unable
to emulsify dietary fat and cholesterol.
A. Is colestipol acidic, basic, or amphoteric? Is it an electrolyte or a nonelectrolyte?
B.
Colestipol (and others in the bile acid sequestrant class of agents) is not used fre-
quently because of a significant drug interaction between the polymer and drugs that
are anionic in an environment of pH ∼8. Describe what you expect to happen when
drugs that are anionic are administered at the same time as colestipol.
C. Based on the chemistry associated with this drug interaction, predict which of the fol-
lowing drugs should not be coadministered with colestipol.
82 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
8. Consider the structures of arformoterol, atorvastatin, sampatrilat, and furosemide found
in Question 7 and do the following:
A. Determine if there are any ionizable functional groups and list each group in the table
in the appropriate column.
Drug Name Acidic Functional Groups Basic Functional Groups
Arformoterol
Atorvastatin
Furosemide
Sampatrilat
B. Based on your evaluation in Part A, determine if each drug molecule can be classi-
fied as having acidic character, basic character, or both acidic and basic character
(amphoteric).
Both Acidic and Basic
Drug Name Acidic Character Basic Character
Arformoterol
Atorvastatin
Furosemide
Sampatrilat
Character (Amphoteric)
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 83
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9. Each of the drug molecules below contains at least one ionizable functional group.
Determine whether the drug molecule is acidic, basic, or amphoteric in character.
10. For each of the drugs or experimental drugs shown below, identify all of the acidic and basic
functional groups and their pKa ranges.
Drug Name Acidic Functional Groups Basic Functional Groups
Bromfenac
Sorbinil
Zanamivir
Experimental antidiabetic
agent
Experimental oral
coagulant
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