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144 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Summary of Key Skills to Master When Evaluating the Solubility
of a Drug Molecule
Based upon a chemical analysis of the functional groups that comprise a drug molecule, you
should be able to
• Identify those drug molecules that are comprised almost exclusively of water- or
lipid-soluble functional groups.
• Rank order a series of structurally related drug molecules in terms of their predicted
water or lipid solubility.
• Explain the log P differences between two or more drug molecules based on the chem-
ical differences of their respective functional groups.
• Predict how a specific structural alteration will alter the overall water and lipid solubil-
ity of the drug molecule.
A Balance Between Water and Lipid Solubility
The previous discussions focused upon an understanding of partition coefficients and the ability to analyze the functional groups of drug molecules to either predict or explain the differences
in partition coefficient values. Given this information, a common question often arises, “What is
more important for a drug molecule, water solubility or lipid solubility?” The simple answer is both;
however, this answer requires some additional explanation. Although some drug molecules have
enhanced pharmaceutical properties based on the fact that they are either highly lipid soluble or
highly water soluble, most drug molecules need to have a balance between these two extremes. The
therapeutic benefits of enhancing lipid and water solubility are discussed in subsequent sections;
however, let us first consider the need for a balance between lipid and water solubility.
In very general terms, the human body can be described as a group of hydrophilic regions (e.g.,
the blood, the gastrointestinal [GI] tract, the cytosol of individual cells) separated by hydrophobic
barriers (e.g., lipid bilayers, the blood brain barrier). When viewed in this context, it should be easy
to recognize that most drug molecules require a balance of water and lipid solubility to traverse
these hydrophilic and hydrophobic regions. In instances in which a drug molecule is either too lipid
soluble or too water soluble, specific transport proteins are required to allow drugs to move through
the blood or cross specific lipid barriers, respectively.
The need for a balance between water and lipid solubility is best exemplified by drugs that are
orally administered as either a tablet or capsule. Once swallowed, the drug molecules present in
either of these dosage formulations must first dissolve in the aqueous environment of the saliva,
stomach, or small intestine to be absorbed. This initial step requires that the drug molecule have
sufficient water solubility for adequate solvation and dissolution to occur. If there are problems in
this initial step due to the lack of sufficient water solubility, it is possible that a substantial amount
of the drug will not undergo dissolution and absorption but rather will be excreted in the feces. Once
the drug has dissolved, it must possess adequate lipid solubility to be able to cross the lipid bilayer
that comprises the GI mucosal membrane. If a drug molecule lacks sufficient lipid solubility, it will
have difficulty being absorbed into the bloodstream. Consequently, a highly water-soluble drug
may instead be primarily excreted in the feces.
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For orally administered drugs, studies have shown that there is a parabolic relationship between
lipid solubility and drug action. Within a series of drug molecules, lipid solubility enhances the activity
only to a certain point, beyond which it begins to decrease activity. This is illustrated in Figure 5-14,
Graph A. Whereas some drug molecules possess a lipid solubility that is at or near their optimal lipid
solubility, many others possess lipid solubility that lies on either the ascending or descending portions of this parabolic curve. Drug molecules that possess a lipid solubility corresponding to either
position 1 or position 2 of Graph A tend to have a more hydrophilic nature. Although they should
have no problems dissolving within the aqueous contents of the GI tract, they may have difficulty
getting across the GI mucosal membranes and into the bloodstream. In these two scenarios, structural analogs with increased lipid solubility (i.e., a larger log P value) are predicted to have enhanced
oral absorption and activity. In contrast, drug molecules that possess a lipid solubility corresponding
to position 3 have exceeded their optimal lipid solubility and have a high hydrophobic nature. These
types of molecules can easily pass through GI mucosal membranes; however, they may exhibit poor
absorption due to a failure to adequately dissolve in the aqueous environment of the GI tract. In
this scenario, structural analogs with increased water solubility (i.e., a smaller log P value) would be
expected to have greater oral absorption and overall activity.
You may occasionally encounter a graph that depicts a linear relationship between lipid solubility and drug activity, as illustrated in Figure 5-14, Graph B. It is important to note that these types
of graphs are consistent with the parabolic relationship shown in Graph A and are simply magnifications of a specific subsection of this parabolic curve. As an example, there are some instances in
which an entire chemical or pharmacological class of drugs is much more hydrophilic than hydrophobic. In this instance, the lipid solubility of all of the drug molecules in this class lies at or around
position 1or between positions 1 and 2 of Graph A. Magnification of this small subsection of Graph A
can result in a linear depiction of lipid solubility and drug action, as seen in Graph B. The only caution
here is that at some point the maximum lipid solubility will be exceeded, and both absorption and
drug action will decrease.
FIGURE 5-14.The parabolic (Graph A) and linear (Graph B) relationships between lipid
solubility and the action of orally administered drugs.
146 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
STRATEGIES FOR OPTIMIZING THE DESIRED WATER
OR LIPID SOLUBILITY
Up to this point, we have discussed partition coefficients, the analysis of a drug molecule to identify
its water- and lipid-soluble functional groups, specific skills that help to associate differences in log P
values with structural differences between and among specific drug molecules, and the need to have
an appropriate balance between water and lipid solubility based upon a given therapeutic need. In
this section, we discuss three common strategies that are used to favorably alter the overall water/
lipid solubility of a specific drug molecule to meet specific therapeutic goals.
Strategy 1: Use Inorganic and Organic Salts
This simple strategy to enhance either water or lipid solubility has already been discussed in this
chapter. Inorganic salts and water-soluble organic salts enhance the water solubility of drug molecules by enhancing their solvation and dissolution. These properties alter the water/lipid balance
and can result in an increase in the rate and extent of oral absorption. Additionally, the enhanced
water solubility allows for the preparation of concentrated parenteral, ophthalmic, or otic solutions. Examples of water-soluble salts can be found in Figures 5-1 and 5-4. Lipid-soluble organic
salts decrease water solubility and enhance lipid solubility. As previously discussed with penicillin
G benzathine, NPH insulin, and erythromycin stearate, lipid-soluble salts can enhance the duration
of action, decrease the acid degradation in the stomach, and/or increase the palatability of a drug
molecule.
Strategy 2: Convert the Parent Drug Molecule to a Water- or
Lipid-Soluble Ester Prodrug
A prodrug is defined as a drug molecule that has been covalently modified to either an inactive or
weakly active analog to achieve a specific therapeutic benefit. Once the prodrug is administered,
it undergoes metabolic activation to release the original active drug molecule. This process is also
known as bioactivation (or programmed metabolism). Esterification of carboxylic acids, hydroxyl
groups, and phenol groups is often used to produce a prodrug with an enhanced water or lipid solubility compared with the parent drug molecule. The resulting ester prodrugs are cleaved in vivo by
either esterase enzymes or acid/base catalyzed hydrolysis within the GI tract. Esterase enzymes
are ubiquitous within the human body, and the active drug molecules are released in the liver, the
bloodstream, the GI tract, or the target tissue.
In comparing the use of water- and lipid-soluble salts to water- and lipid-soluble esters, there
is one main similarity—both types of modification eventually release the parent or active drug molecule. There are also two main differences. First, esters require covalent modification and in vivo
bioactivation whereas salts simply require the dissociation of noncovalently bound ionic molecules.
Second, salts are used more often than esters to enhance water solubility while esters are used more
often than salts to enhance lipid solubility.
The two most commonly used water-soluble ester prodrugs are those that contain a sodium
phosphate or a sodium succinate ester. Compared with the hydroxyl group present on the parent
drug molecule, a phosphate or succinate ester contains ionizable functional groups that will further
enhance water solubility. Examples of each of these are shown in Figure 5-15. Please note that the
names directly indicate that these are water-soluble esters. As previously discussed, the inclusion
of the term sodium in the name indicates the presence of an inorganic salt, specifically a sodium
salt of an acidic functional group. The sodium salts have been highlighted in the figure. Watersoluble formulations of prednisolone sodium phosphate are used for ophthalmic purposes whereas
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FIGURE 5-15.Examples of water-soluble esters.
water-soluble formulations of chloramphenicol sodium succinate are available for IV, ophthalmic,
or otic use.
Lipid-soluble esters are commonly used to produce prodrugs with enhanced oral bioavailability.
In these situations, the parent (or active) drug molecule possesses sufficient water solubility for dissolution but lacks sufficient lipid solubility to allow it to pass through the GI mucosal membrane.
An example of this is seen below with fenofibrate, which is used for the treatment of several dyslipidemias. It is administered orally as an inactive isopropyl prodrug and is metabolized in vivo to the
active agent, fenofibric acid.
In general, lipid-soluble esters of carboxylic acids tend to be somewhat chemically simplistic, as
the key strategy involves masking an ionizable and hydrophilic group as a more hydrophobic ester.
As such, carboxylic acids are generally converted to their respective methyl, ethyl, propyl, isopropyl,
or tert-butyl esters. In some situations, more complex esters, such as that seen with candesartan
cilexetil (Figure 5-16), are used to optimize the overall water/lipid solubility of the drug molecule.
FIGURE 5-16.Candesartan cilexetil and its conversion to candesartan.
148 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Another common use of lipid-soluble esters is in the preparation of depot injections. Similar
to penicillin G benzathine and NPH insulin, the addition of a lipid-soluble ester to a drug molecule
significantly decreases its water solubility and allows it to be formulated as a suspension for IM or
subcutaneous injection. After injection, the lipid-soluble ester dissolves slowly and moves from its
initial injection site to the plasma in a consistent manner over an extended period of time. Once in
the plasma, the ester is hydrolyzed and releases the active drug molecule. These types of esters are
commonly made by combining hydroxyl groups or phenols present on the parent drug molecule
with carboxylic acids containing various hydrocarbons chains and/or rings. Carboxylic acids commonly used for this purpose are illustrated in Figure 5-17, and two examples of this concept are
illustrated by haloperidol decanoate and estradiol valerate, shown in Figure 5-18. In both examples,
a hydrophilic hydroxyl group has been replaced with a lipid-soluble ester. Both of these drug molecules are highly lipophilic and greatly enhance the duration of action of the parent drug molecules
when administered as an IM injection. Both drug molecules can be used either once a month or
every 4 weeks. Haloperidol decanoate is used for the treatment of a number of psychotic disorders whereas estradiol valerate is used to treat the symptoms of menopause or is used as estrogen
replacement therapy.
FIGURE 5-17.Carboxylic acids commonly used to prepare lipid-soluble esters.
FIGURE 5-18.Examples of lipid-soluble ester prodrugs: haloperidol decanoate and
estradiol valerate.
Finally, lipid-soluble esters can be used to enhance either the pulmonary or topical absorption of drug molecules. Two examples of this can be seen within the glucocorticoid class of drugs
(Figure 5-19). These drugs are used to treat a variety of disorders, including allergic rhinitis, asthma,
inflammation, and a variety of skin disorders. Hydrocortisone is available over-the-counter (OTC)
as a 1% cream for the topical treatment of pruritus, inflammation, eczema, psoriasis, and other skin
disorders. It is also available as a variety of lipid-soluble esters, including hydrocortisone butyrate.
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FIGURE 5-19.Lipid-soluble ester prodrugs of glucocorticoids. Esters are formed using the
C17 and C21 hydroxyl groups.
The butyrate ester enhances the topical penetration of the drug through the skin and increases its
topical potency. Instead of using a 1% formulation, the lipid-soluble butyrate ester can be used as a
0.1% cream. Beclomethasone dipropionate is used for the treatment of asthma and allergic rhinitis
and is administered via oral or nasal inhalation. The two propionate esters enhance the lipid solubility of beclomethasone. Once inhaled, this prodrug is rapidly absorbed in either the pulmonary tract
or nasal sinus cavity, depending upon the route of administration. Once absorbed, the C21 ester is
rapidly cleaved to produce beclomethasone 17-monopropionate. This metabolite is pharmacologically active and can directly produce the desired therapeutic response or be subsequently converted
to beclomethasone that is also able to produce the desired response.
Strategy 3: Add or Alter Functional Groups
This strategy involves replacement of existing functional groups with those that are either more
water soluble or more lipid soluble, depending on the specific pharmaceutic or therapeutic need.
Common types of modifications include the replacement of a hydrogen atom with either a lipid- or
water-soluble functional group, replacement of a water-soluble functional group with a lipid-soluble
functional group or vice versa (e.g., replacement of a hydroxyl group with a methyl group or replacement of a methyl group with a hydroxyl group), and modification of existing functional groups (e.g.,
conversion of a –CH2CH3 group to a more water-soluble –CH2CH2OH group or conversion of a primary amine, RNH2 to a more lipid-soluble secondary amine, RNHCH2CH2CH2CH3).
There is an important difference between this strategy and the two strategies previously discussed. While salts and esters can enhance either the water or lipid solubility of the drug molecule,
once the salt or ester is administered to the patient, the parent drug molecule will eventually be
released. For example, timolol maleate (Figure 5-4) separates into its two components, and timolol
binds to its target receptor and produces the therapeutic effect. The same is true for haloperidol
150 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
decanoate (Figure 5-18). The decanoate ester is hydrolyzed, and haloperidol provides the therapeutic action. In contrast, the replacement or alteration of functional groups results in a permanent
change in the original drug molecule and the creation of an entirely new drug entity. Additionally,
and as discussed in Chapter 2, the alteration of a functional group not only changes the water/lipid
solubility but also may affect the electronics and the overall size of the drug molecule. As such, there
are limitations to the types of alterations that can be done because the altered drug molecule must
still be able to bind to its biological target.
Let us look at two examples of this strategy. As previously discussed, increasing the lipid solubility of glucocorticoids can enhance their topical, nasal, and/or pulmonary absorption. While lipidsoluble ester prodrugs can provide this advantage, another strategy involves masking the C16 and
C17 hydroxyl groups. The reaction of triamcinolone with acetone produces triamcinolone acetonide
(Figure 5-20). The acetonide analog is more lipid soluble than triamcinolone and is used topically to
treat pruritus and a variety of dermatological disorders, as a nasal inhalation to treat allergic rhinitis,
and as an oral inhalation to treat asthma. Unlike ester prodrugs, the acetonide analog is active and
is not metabolized back to triamcinolone. Other glucocorticoids that are used as their acetonide
analogs are also shown in Figure 5-20.
FIGURE 5-20.Acetonide analogs of selected glucocorticoids.
A second example involves modifications of penicillin G, a naturally occurring β-lactam antibiotic that was previously discussed in this chapter, to ampicillin and amoxicillin (Figure 5-21).
Penicillin G is useful in treating a variety of microbial infections; however, it is only active against a
limited number of bacteria and has a narrow spectrum of action. One way to extend its spectrum of
action is to add hydrophilic functional groups at the carbon atom between the phenyl ring and the
carbonyl group. This modification is seen in ampicillin. The increased water solubility attained by
the addition of this primary amine allows ampicillin to access water soluble channels, also known as
porins, that are present in gram-negative bacteria. This allows ampicillin to treat bacterial infections
that are not susceptible to penicillin G.
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FIGURE 5-21.Penicillin G and two analogs: ampicillin and amoxicillin.
While the addition of this primary amine is useful in treating specific bacterial infections, it also
converts penicillin, an acidic drug, to ampicillin, an amphoteric drug. Within the small intestine, both
the carboxylic acid and the primary amine are primarily ionized, and ampicillin will exist in what is
known as its zwitterion form. In the zwitterion form, both the acidic and basic functional groups are
ionized, and the molecule has an overall net charge of zero. In some instances, such as the example
here with ampicillin, zwitterions have inadequate water solubility, a much slower dissolution within
the GI tract, and an overall decrease in oral absorption. To enhance the oral absorption, a phenol
was added at the para position of the aromatic ring to produce amoxicillin. Amoxicillin, by virtue
of the hydrogen bonding capacity of the phenol, is more water soluble than ampicillin, contains a
better balance between lipid and water solubility, and has a much higher oral absorption. Because
the structure of amoxicillin retains the primary amine, it has an extended spectrum of action compared with penicillin G. The oral absorption of ampicillin ranges from 30% to 55% while the oral
absorption of amoxicillin ranges from 74% to 92%. It should be noted that not all zwitterions have
dissolution problems and that the key attribute is an appropriate balance between water and lipid
solubility. Amoxicillin and ampicillin both exist as zwitterions within the GI tract; however, amoxicillin has a better balance of water/lipid solubility and thus has better oral absorption.
Factors Affecting the Oral Absorption of Drug Molecules
This chapter highlights the importance of both water and lipid solubility on the oral absorption of drug molecules. It is important to recognize that other reasons, beyond an inadequate
balance between water and lipid solubility, can alter the oral absorption, oral bioavailability,
and oral efficacy of a drug molecule. The following list highlights some of the major factors
that can cause a drug molecule to be orally inactive or have poor oral absorption or oral
bioavailability.
• The drug molecule has insufficient water solubility, which results in poor dissolution
of the drug molecule in the GI tract.
• The drug molecule has insufficient lipid solubility, which results in a decreased ability
to traverse GI mucosal membranes.
152 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
• The drug molecule is unstable in the acid environment of the stomach, which can
cause a significant amount of a given dose to be destroyed or inactivated before it can
be absorbed.
• The drug molecule is subject to enzymatic degradation within the GI tract, which is
seen with insulin and other small proteins and peptides.
• The drug molecule is too large to pass through the GI mucosal membranes.
• The drug molecule undergoes extensive first-pass metabolism prior to reaching the
circulation. In this case, the drug is absorbed but a significant percentage is inactivated
prior to reaching the general circulation.
THE INFLUENCE OF SOLUBILITY ON DRUG METABOLISM
A full discussion of metabolism and metabolic pathways is provided in Chapter 8; however, it is
important to recognize that the overall water/lipid solubility of a drug molecule plays a key role in
the extent to which it is metabolized. Most drug molecules administered for therapeutic purposes
are not normally found in the human body. As such, the human body views these as foreign molecules, commonly known as xenobiotics. The two major purposes of metabolism are to detoxify
these foreign molecules and ensure that they can be eliminated from the body.
Drug molecules that possess sufficient lipid solubility are able to reside longer in the body than
drug molecules that are more water soluble. Drug molecules with sufficient lipid solubility can be
passively reabsorbed from the nephron tubule back into the blood. Additionally, drug molecules
with sufficient lipid solubility can undergo enterohepatic recycling, a process by which the drug
molecules are secreted from the liver into the small intestine and then reabsorbed into the blood.
Finally, lipid-soluble drug molecules have a greater affinity for plasma proteins than do analogous
water-soluble drugs. An example of this can be seen with pravastatin and simvastatin (Figure 5-11),
two drugs that were previously discussed in this chapter. Simvastatin is more lipid soluble than
pravastatin and is 95% bound to plasma proteins. In contrast, the more water-soluble pravastatin
is only 43% to 55% plasma protein bound. While bound to a plasma protein, a drug molecule is less
likely to be eliminated from the body.
The goals of metabolism are thus met through biotransformation reactions that enhance the
water solubility of drug molecules and make them easier to be eliminated in either the urine or the
feces. As such, drug molecules that are already highly water soluble are often eliminated unchanged
(i.e., without requiring metabolism). Examples of this are seen with alendronic acid and tobramycin
(Figure 5-9) and zanamivir (Figure 5-22). In contrast, drug molecules that are highly lipid soluble
often undergo extensive hepatic metabolism prior to entering the general circulation. This process
is known as first-pass metabolism and often significantly reduces the amount of orally administered
drug that is available (i.e., the drug’s bioavailability). An example of this can be seen with propranolol (Figure 5-22), a nonselective β receptor antagonist (or β blocker). When given orally, more than
FIGURE 5-22.Zanamivir and propranolol.
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90% of the given dose is orally absorbed; however, 50% to 70% of the absorbed drug is inactivated
through first-pass metabolism.
In general, the extent of metabolism increases as lipid solubility increases. Within a given class
of drugs, those with higher log P values often require more extensive metabolism than those with
lower log P values. An example of this can be seen with temazepam and quazepam. As previously
mentioned, quazepam has a log P value of 4.1 ± 0.8 while temazepam has a log P value of 2.2 ± 0.6.
Due to its higher lipid solubility, quazepam undergoes multiple oxidative transformations prior to
being conjugated with glucuronic acid (Figure 5-23). In contrast, temazepam requires only a single
nonoxidative metabolic transformation to be eliminated from the body.
FIGURE 5-23.The metabolism of quazepam and temazepam. Oxidative metabolic path-
ways are designated by the [O] abbreviation.
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