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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5323_Библиотеки_им_академика_М_И_Перельмана
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124 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
B. In this formulation moxifloxacin is present as a hydrochloride salt. Modify the struc-
ture to show the hydrochloride salt form of the drug. Which is more water soluble: the
salt form of the drug or the parent drug (i.e., the drug without salt)? Provide a brief
rationale for your answer.
C. The pH of the moxifloxacin hydrochloride formulation is ∼7.4. Determine which, if
any, of the functional groups will be predominantly ionized in this environment. Also,
determine the percent to which the functional group(s) will be ionized.
10. Shown below are the structures of cefotaxime, nitrofurantoin, atenolol, and ezetimibe.
Each of these drug molecules contains one ionizable functional group. The pKa values have
been provided.
A. Match the pKa values provided with the appropriate functional groups. For each func-
tional group, identify the name of the group and whether it is acidic or basic.
B. For each functional group, indicate whether it would be primarily ionized or primarily
unionized at a stomach pH = 1.8, a urinary pH = 6.1, or a cellular pH of 7.4. Provide an
explanation for each of your responses.
Drug (pKa Value) Stomach (pH = 1.8) Urine (pH = 6.1) Cell (pH = 7.4)
Cefotaxime (3.4)
Nitrofurantoin (7.1)
Atenolol (9.6)
Ezetimibe (10.2)
CH 4 - SOLVING pH AND pKa PROBLEMS 125
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11. Shown below is the structure of natamycin. It contains two functional groups that could be
potentially ionized. The pKa values for natamycin are 4.6 and 8.4.
A. Match the pKa values provided to the appropriate functional groups and identify if the
functional group is acidic or basic.
B. Using the Henderson-Hasselbalch equation, calculate the percent ionization that
would occur for each of these functional groups at an intestinal pH of 6.2.
12. The most basic functional group present within the struct ure of ranitidine has a pKa value of
8.2. Identify this functional group and calculate the pH that is necessary for this functional
group to be 70% ionized.
5
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SALTS AND SOLUBILITY
LEARNING OBJECTIVES
After completing this chapter, students will be able to
• Identify water-soluble inorganic salts as well as water-soluble and lipid-soluble organic
salts.
• Explain the therapeutic advantages that can be achieved by using water-soluble salts and
lipid-soluble salts.
• Explain how organic salt formation can lead to unwanted drug interactions.
• Explain how partition coefficients are determined and link these values to the water and
lipid solubility of a drug molecule.
• Evaluate drug structures and identify those functional groups that contribute to the water
solubility of the drug and those functional groups that contribute to the lipid solubility of
the drug.
• Compare the relative water/lipid solubility of two or more structurally related drug
molecules.
Predict how structural alterations will alter the water/lipid solubility of a drug molecule.
•
• Explain the need for a drug molecule to have an adequate water/lipid balance.
• Discuss common strategies used to optimize the desired water or lipid solubility of a drug
molecule.
• Explain how the overall water/lipid solubility of a drug molecule will influence its
metabolism.
• Identify specific therapeutic advantages for enhancing either the water or lipid solubility of
a drug molecule.
Drug molecules can be formulated as a wide variety of salts. Depending on the chemical nature,
these salt forms can be used to enhance either the water or lipid solubility of the drug molecule
and thus affect oral absorption, dosage formulation availability, and the route(s) of administration. Additionally, the metabolism, duration of action, and route(s) of elimination of a drug can be
altered by structural modifications that alter water and lipid solubility (i.e., addition, deletion, or
DOI 10.37573/9781585286959.005
127
128 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
alteration of functional groups). This chapter reviews commonly used organic and inorganic salts,
the effect these salts have on the overall solubility of a drug molecule, partition coefficients, advantages of increasing solubility (both lipid and water), the importance of a balance between lipid and
water solubility, common strategies used to alter solubility in the desired direction, and the influence that water and lipid solubility can have on drug metabolism.
WHAT IS A SALT?
A salt is an ionic compound that is produced when an acid reacts with a base. Salts consist of a positively charged cation and a negatively charged anion and are electronically neutral. As an example,
let us look at something very familiar: sodium chloride (aka table salt). This compound is formed by
reacting sodium hydroxide, a base, with hydrochloric acid, an acid.
It is important to understand the underlying chemistry that is occurring here. Hydrochloric acid
and sodium hydroxide are strong acidic and basic chemicals, respectively. As a result, they rapidly dissociate into their respective ionic components. The positively charged sodium ion is attracted to the
negatively charged chloride ion, resulting in the formation of sodium chloride, a salt. Additionally,
the positively charged proton (H+) and the negatively charged hydroxide ion (OH–) are also attracted
to one another, resulting in the formation of a water molecule. The key difference between these
two compounds is that sodium chloride, the salt, can easily dissociate into its constituent ions while
the water molecule cannot.
Application to Drug Molecules
The same type of reaction can be accomplished by using acidic and basic drug molecules. Penicillin V
can be classified as an acidic drug molecule as it contains only one ionizable functional group, a
carboxylic acid. Reaction of this functional group with the base, potassium hydroxide, produces the
commercially available salt form of this drug, potassium penicillin V (aka Pen VK).
A similar example can be seen with thioridazine, an antipsychotic agent that contains a basic
tertiary amine. The major difference here is that a water molecule is not formed. In this example, hydrochloric acid dissociates, and the resulting proton binds to the basic functional group. The
remaining chloride anion serves as the counterion to the positively charged amine, resulting in the
hydrochloride salt of thioridazine.
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Although similar, it is important to note that the ionized forms of acidic and basic drug molecules are distinctively different than their salt forms. The salt forms shown above are the products
of reactions that occur between the drug molecules and other basic and acidic molecules, respectively. As a result, these salt forms contain a counterion, a positively or negatively charged inorganic
ion that is opposite of the charge on the drug molecule (e.g., K+ for penicillin V and Cl– for thioridazine). In contrast, the ionized forms of penicillin V and thioridazine result from the removal or addition of a proton, respectively. Please note that the ionized forms of these drug molecules do not
have counterions.
INORGANIC SALTS
With respect to chemical structures, the term organic pertains to a molecule that is either carbonbased or contains carbon as part of its structure whereas the term inorganic pertains to those molecules that do not contain carbon. Almost all drugs are carbon-based, or contain carbon, and thus
can be classified as organic molecules. Hence, the terms inorganic salt and organic salt depend on
the chemical nature of the molecule reacting with the drug. When inorganic acids or bases react
with basic or acidic functional groups of drug molecules, respectively, the resultant products are
termed inorganic salts. Thus, both penicillin V potassium and thioridazine hydrochloride can correctly be classified as inorganic salts. Additional inorganic salts can be seen in Figure 5-1. Inorganic
salts of acidic drug molecules are commonly made using sodium hydroxide, potassium hydroxide,
and calcium hydroxide, whereas inorganic salts of basic drug molecules are commonly made using
hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.
The primary advantage of converting a drug molecule to an inorganic salt is that the inorganic
salt form enhances solvation, dissolution, and water solubility. Because the positive and negative
constituents of a salt are not covalently bound, they can easily and quickly dissociate in an aqueous environment. An example of this is illustrated in Figure 5-2 with naproxen sodium. Once these
ionic components separate, they can form multiple ion-dipole bonds with water molecules due to
the partial charges on the oxygen and hydrogen atoms of the water molecules. These interactions
enhance the rate and extent of solvation and dissolution in an aqueous environment. Because orally
administered drug molecules in solid dosage formulations (i.e., tablets and capsules) must first
undergo solvation and dissolution prior to absorption, the use of inorganic salts augments this initial
step and allows for an increased rate and extent in oral absorption.
The same process can also occur without using an inorganic salt; however, as illustrated in
Figure 5-3, this requires an additional step and thus occurs at a slower rate. The free acid, or unionized form, of naproxen must first undergo ionization of its carboxylic acid. This is different from
the dissociation of salts in two ways. First, ionization of a carboxylic acid involves the breaking of a
covalent bond as compared with a noncovalent ionic bond. Second, the ionization of acidic and basic
functional groups involves an equilibrium. This process is both slower and less extensive (i.e., not
100%) than the dissociation of a salt. As a result, the overall effects on solvation and dissolution are
slower and less extensive.
130 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 5-1.Examples of inorganic salts of acidic and basic drug molecules.
FIGURE 5-2.Solvation and dissolution of naproxen sodium.
FIGURE 5-3.Solvation and dissolution of naproxen.
CH 5 - SALTS AND SOLUBILITY 131
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Although inorganic salts can provide the abovementioned beneficial effects, it is important to
note that other factors contribute to the overall water solubility of a drug molecule. As discussed
later in this chapter, the presence of other water-soluble functional groups also plays a key role
in the ability of a drug molecule to dissolve in an aqueous environment. Thus, some drug molecules are marketed as their inorganic salts while others are marketed as their unionized free acids or
free bases.
ORGANIC SALTS
Similar to inorganic salts, organic salts are simply the products of the reactions between acidic or
basic drugs and other basic or acidic molecules, respectively. Two differences need to be noted. First,
the drugs are combined with organic molecules containing acidic or basic functional groups rather
than inorganic molecules. Second, the organic molecules used to produce these salts can be classified as either water soluble or lipid soluble depending on their chemical composition.
Water-Soluble Organic Salts
Similar to what was observed with inorganic salts, water-soluble organic salts can increase the solvation, dissolution, and water solubility of drug molecules. Sugars, analogs of sugars, and glycolysis intermediates are commonly used to produce water-soluble organic salts. All of these organic
molecules contain multiple hydrophilic functional groups. As an example, let us consider ketorolac
tromethamine. Similar to naproxen, ketorolac is a nonsteroidal anti-inflammatory drug (NSAID). It
is indicated for the short-term treatment of acute moderate to moderately severe pain as well as a
number of ocular conditions, including allergic conjunctivitis, ocular pain, ocular pruritus, and postoperative ocular inflammation. Ketorolac is marketed as its tromethamine salt and is available as an
oral tablet, a nasal solution, an ocular solution, and a parenteral solution for either intravenous (IV)
or intramuscular (IM) administration. The tromethamine salt possesses a positively charged primary
amine as well as three primary hydroxyl groups. The ionized amine can form an ion–dipole interaction with a water molecule whereas each of the hydroxyl groups can form hydrogen bonds. All of
these interactions enhance solvation, dissolution, and water solubility.
Figure 5-4 highlights a number of other commercially available drug molecules that are formulated using water-soluble organic salts. Sulfisoxazole diolamine is a good example of how watersoluble, organic salts can provide enhanced water solubility compared with their analogous
inorganic salts. Sulfisoxazole diolamine can be solubilized at physiologic pH whereas the analogous
sulfisoxazole sodium requires a much more basic environment. Given the fact that the instillation or
injection of basic solutions can produce burning and stinging in the eyes and at injection sites, the
diolamine salt is much better suited for the preparation of parenteral and ophthalmic dosage forms
than is a simple sodium or potassium salt.
An additional advantage of using either inorganic salts or water-soluble organic salts is that
the enhanced solvation and dissolution allows these salts to be formulated in highly concentrated
solutions. This advantage is extremely important for the development of ophthalmic, nasal, and
parenteral solutions, in which the ability to deliver a significant amount of drug in a very small
volume is often desired.
132 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 5-4.Examples of water-soluble organic salts.
Lipid-Soluble Organic Salts
Contrary to water-soluble organic salts, lipid-soluble organic salts decrease the solvation, dissolution, and water solubility of drug molecules and enhance their lipid solubility. These salts are primarily used to form lipid-soluble suspensions or oil-based formulations that are administered as
IM depot injections. They can also be used to enhance the oral bioavailability of acid labile drug
molecules and increase the palatability of liquid formulations. Let us look at examples that highlight
each of these beneficial effects.
Penicillin G can be used to treat a variety of moderate to severe infections, including lower respiratory tract infections, septicemia, bacteremia, and meningococcal infections caused by susceptible organisms. It can be administered via IV formulations as its sodium or potassium salt; however,
due to rapid tubular secretion, which results in rapid elimination, penicillin G has a short half-life and
must be administered every 4 to 6 hours. The frequency of administration can be greatly decreased
by using penicillin G benzathine, a lipid-soluble organic salt of penicillin G. Due to its lipid solubility,
this salt can be formulated as a suspension and administered as an IM depot injection. Once administered, penicillin G slowly dissolves and is released from its injection site in a consistent manner
over an extended period of time. A key therapeutic advantage of the benzathine salt is a reduction in
the frequency of dosing as well as a consistent blood concentration. One potential disadvantage of
IM depot injections is that once administered, the effects of administered drug are not immediately
reversible due to the slow and steady release.
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A similar advantage is seen with NPH (or isophane) insulin. Regular, unmodified insulin is classified as a short-acting insulin and is often administered as a subcutaneous injection in conjunction
with meals. If taken as the only insulin product, regular insulin would need to be administered up to
four times daily, depending on the timing of meals and blood glucose levels. A more convenient and
reliable dosing regimen involves the combination use of regular insulin with NPH insulin. NPH insulin is an organic salt that is formed when regular insulin is combined with protamine, a low molecular
weight, arginine rich polypeptide obtained from salmon and other fish. Regular insulin has a net
negative charge due the presence of more acidic amino acids than basic amino acids. The resulting
salt, cocrystallized with zinc, can be formulated for injection. Similar to penicillin G benzathine, the
protamine/insulin/zinc complex slowly dissolves and is released from its subcutaneous injection site
in a consistent manner over an extended period of time. The resulting zinc insulin hexamer dissociates to release dimeric insulin. The dimeric insulin then further dissociates to the monomeric active
form of insulin. The combination use of NPH insulin and regular insulin often reduces the frequency
of administration and affords more consistent plasma glucose levels throughout the day.
A final example of the benefits of organic salts can be seen with erythromycin stearate. Similar
to a number of antibiotics, erythromycin has a bitter taste. When formulated as a tablet or capsule,
this undesired effect can easily be masked; however, young children and some adult populations
have difficulties swallowing these types of formulations. A solution to this initial problem is to prepare a liquid formulation. Given that the antibiotic has a bitter taste, the use of a liquid solution,
even a flavored one, may not be desirable. To increase the palatability of erythromycin, it can be
converted to its lipid-soluble stearate salt and formulated as a suspension. When the suspension is
given orally with water or another liquid, the lipid-soluble salt does not have time to dissolve in the
saliva, and the patient is not able to taste the bitterness of this drug. In contrast, the patient tastes
the water-soluble flavoring that is often added to these suspensions, thus increasing palatability and
patient adherence.
The lipid-soluble salt also provides a second advantage. Erythromycin is acid labile and can
undergo degradation in the acid environment of the stomach. As shown in Figure 5-5, an acidcatalyzed attack of the C6 hydroxyl group on the C9 ketone results in an intramolecular cyclization
to form a hemiketal. Subsequent dehydration and attack by the C12 hydroxyl group leads to the formation of a ketal and an inactivation of erythromycin. Similar to the fact that sweet or bitter tasting
molecules must first dissolve in the saliva before a patient can experience this taste, the ability of
any drug molecule to undergo an acid-catalyzed degradation in the stomach requires that the drug
dissolve in the stomach. Due to its lipid solubility, erythromycin stearate dissolves much slower in
the stomach than does the free base form of erythromycin. As a result, there is less acid-catalyzed
degradation of the stearate salt and hence greater bioavailability as compared with the free base
form of erythromycin. This lipid-soluble organic salt does eventually dissolve in the small intestine
and erythromycin is absorbed there.
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