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154 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
As will be discussed in Chapter 8, a common type of drug interaction can occur when a coadministered drug either induces or inhibits the activity of hepatic oxidative enzymes. In looking at
the example given here, quazepam, the more lipid-soluble drug, requires oxidative metabolism and
could be subject to this type of drug interaction, whereas temazepam, the more water-soluble drug,
does not require oxidative metabolism and would not be subject to this type of drug interaction.
Thus, the overall water/lipid solubility of a drug molecule affects both the extent to which it is
metabolized and its potential to be involved in a certain type of drug interaction.
A SUMMARY OF THE ADVANTAGES OF ENHANCING EITHER
WATER OR LIPID SOLUBILITY
Throughout this chapter, examples of specific drugs have been used to illustrate specific therapeutic
benefits that can be gained through the enhancement of their respective water or lipid solubility.
These advantages are summarized here.
Therapeutic Advantages of Enhancing Water Solubility
y Water solubility enhances the solvation and dissolution of drug molecules in the GI tract,
which is required for oral absorption.
y Water solubility allows for the preparation of concentrated IV, ophthalmic, and otic
solutions.
y Water solubility allows certain drug molecules (e.g., diuretics, antibiotics) to reach ade-
quate concentrations in the urine.
y Drug molecules with higher water solubility require less metabolism and are less likely to
have drug interactions with other drugs that alter hepatic oxidative enzymes (i.e., CYP450
enzymes).
Therapeutic Advantages of Enhancing Lipid Solubility
y Lipid solubility is required for drug molecules to pass through the lipid bilayer present
within the GI mucosal membrane.
y Adequate lipid solubility is required for drug molecules to cross the blood brain barrier and
have effects within the central nervous system.
y Lipid solubility allows for the use of IM or subcutaneous depot injections. This type of
administration allows for a slow release from the injection site and an extended duration
of action.
y Drugs that are more lipid soluble have greater plasma protein binding, which may provide
a longer duration of action compared with analogous drugs that are more water soluble.
y Lipid-soluble salts and esters can be used to prepare more palatable oral suspensions.
y Lipid-soluble salts and esters can delay the dissolution of drug molecules in the stomach
and therefore decrease the degradation of acid labile drugs.
y Lipid solubility can enhance the absorption of drugs that are administered via oral or nasal
inhalation.
y Lipid solubility can enhance the absorption of drugs that are administered as topical creams
or ointments.
STRUCTURAL ANALYSIS CHECKPOINT
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Checkpoint Drug 1: Venetoclax
1. Draw the potassium salt of venetoclax.
A. In Chapter 3, you were asked to identify if venetoclax is an acidic drug, a basic drug, an
amphoteric drug, an electrolyte, or a nonelectrolyte. You should have determined that
this is an amphoteric drug. Given this information, explain why the salt is only formed
at one functional group.
B. Using the same functional group, draw a water-soluble organic salt of venetoclax.
CH 5 - SALTS AND SOLUBILITY 155
C. In comparison with the potassium salt, what advantages does the organic salt you
drew in question 1B provide?
2. Venetoclax is administered orally. Evaluate the functional groups present within the structure of venetoclax and explain how these functional groups allow venetoclax to be orally
active.
3. How could the addition of a hydroxyl group (Box A) provide opportunities to alter both the
water and lipid solubility of venetoclax?
4. If the chlorine group (Box B) is removed, how would his affect the overall solubility of venetoclax? What other chemical properties would also be affected?
Checkpoint Drug 2: Elamipretide
Elamipretide is a peptide-based drug molecule and cannot be administered orally due to instability
in the GI tract. You identified in a previous chapter that there are both acidic (substituted phenol)
and basic (guanidine and primary amine functional groups) present within the molecule.
156 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
1. This drug has not yet been formulated into a salt for drug formulation and marketing
purposes.
A. Identify two different forms of inorganic salts that could be formed with elamipretide.
B. Modify the structure below to show each of the two forms of salts that you identified.
C. Consider the parent drug and either of the salt forms of the drug from Question 1B and
determine which form of the drug will have improved solvation, dissolution, and water
solubility. Provide a brief rationale for your answer.
2. This drug will likely need to be administered via injection. Based on your structural evaluation of this molecule, determine whether formulation as a water-soluble organic salt is
beneficial. Provide a brief rationale for your answer.
3. Log P for elamipretide is calculated to be 0.3677 (Accelrys Draw 4.2).
A. Based on the cLog P values in Table 5-2 for the HMGCoA reductase inhibitors, deter-
mine if elamipretide is likely to be more water soluble or more lipid soluble than this
class of drugs.
B. Based on the structure evaluation that you conducted in Chapter 2, does your func-
tional group evaluation agree with or disagree with your answer to Question 3A?
CH 5 - SALTS AND SOLUBILITY 157
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C. Predict what types of structural modifications would be necessary to increase the lipo-
philic character of this drug.
4. Elamipretide is subject to degradation by amino and carboxy peptidases. To protect peptide-based drugs from this type of degradation, the amino and carboxy termini can be
“protected” via the use of lipid-soluble prodrugs. In this case, the carboxy terminus has
already been protected as an amide, which makes the drug resistant to degradation by
carboxy peptidases.
A. What kind of modification could occur at the amino terminus of elamipretide?
B. Identify which physicochemical properties of elamipretide will change if a lipid-soluble
prodrug is in fact developed. Don’t forget the impact on cLog P!
REVIEW QUESTIONS
1. Verapamil is marketed as a hydrochloride salt, and rosuvastatin is marketed as a calcium
salt.
A. Circle the functional group in verapamil that reacts with HCl to form a salt. Circle the
functional group in rosuvastatin that reacts with Ca(OH)2 to form a salt.
B. Modify the structures of verapamil and rosuvastatin to show the salt forms of each
drug.
C. Are the salts that are formed organic or inorganic salts?
2. Consider the structures of amlodipine besylate and loxapine succinate and determine if
they are examples of organic or inorganic salts. For each drug, modify each component of
the salt to show the form that is relevant at pH = 7.4.
158 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. Citalopram is marketed as a hydrobromide salt. Complete the following steps:
A. Complete the grid for citalopram drawn below.
B. Based on your knowledge related to the need for a drug molecule to contain a bal-
ance between hydrophobic and hydrophilic functional group character, provide a brief
rationale for why this drug can be administered via an oral route.
C. Which is more hydrophilic, citalopram or citalopram HBr? Provide a brief structural
rationale for your answer.
Contribution to
Name of Functional
Group
Hydrophilic and/or
Hydrophobic Acidic, Basic, or Neutral
Aqueous Solubility
and/or Absorption
4. Consider the two tetracyclines drawn below and their respective log P values. Compare the
structural features between oxytetracycline and doxycycline. Provide a structural rationale for the changes in log P observed.
CH 5 - SALTS AND SOLUBILITY 159
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5. Each of the following three agents is used in the treatment of acne.
Retinol is a naturally occurring vitamin A that is applied topically.
Tretinoin is a naturally occurring vitamin A that is administered topically and orally.
Adapalene is a third-generation retinoid/vitamin A analog that is applied topically.
A. For each of these drug molecules, complete the structure evaluation in the grid below.
Contribution to Aqueous
Name of Functional
Group
Retinol
Tretinoin
Adapalene
Hydrophilic and/or
Hydrophobic
Acidic, Basic, or
Neutral
Solubility and/or
Absorption
B. Based on your structural evaluation of hydrophobicity and hydrophilicity, provide a
brief structural rationale for why retinol and adapalene can be administered topically.
Why is it appropriate to treat acne with a topical agent?
160 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
C. Based on your structural evaluation of hydrophobicity and hydrophilicity, provide a
brief structural rationale for why tretinoin can be administered orally.
D. Some patients prefer to use an oral product for the treatment of acne. Isotretinoin is
an orally available isomer of tretinoin. The following statement is found within the
isotretinoin capsule package insert. Based on this statement, evaluate isotretinoin’s
structural features and provide a rationale for why it is capable of being systemically
distributed.
Package Insert Statement: “Accutane must not be used by female patients who are or may
become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Accutane in any amount, even for short periods of time. Potentially
any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Pregnancy category X.”
6. An 85-year-old patient presents you with three containers, each containing one of the
drugs shown. The patient knows that each of these medications is used to treat different
types of fungal infections and that some of them can be applied topically. Now that they
have returned from a Caribbean cruise, he and his wife both must treat the athlete’s feet
that they contracted. She wants to take a medication orally because she doesn’t like to
have messy fingers. He could not care less what type of medication he uses, as long as it
fixes the problem.
A. For each of these drug molecules, complete the structure evaluation in the grid on the
next page.
CH 5 - SALTS AND SOLUBILITY 161
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Hydrophilic and/or
Functional Group Name
Naftifine (marketed as HCl salt)
Undecylenic Acid (marketed as calcium salt [powder] or zinc salt [cream])
Fluconazole
Hydrophobic
Contribution to Aqueous
Solubility and/or Absorption
B. Using the information that you obtained in the structure evaluation process on the
previous page, provide a structural rationale for why naftifine and undecylenic acid can
be administered topically. Why is it appropriate to treat athlete’s foot with a topical
agent?
C. Fluconazole is administered orally but is not an effective treatment for athlete’s foot.
What kind of characteristics (properties) must a drug have to be given orally? Provide
a structural rationale for why fluconazole can be administered via an oral route.
D. Griseofulvin is used orally to treat superficial fungal infections (e.g., fingernail and
toenail). It does not penetrate the skin or nails if used topically. Provide a structural
rationale for why this agent cannot be used topically to treat fungal infections.
7. Hydrocortisone is marketed in a variety of forms, including as a sodium succinate C-21 ester
and a C-17 valerate ester. These agents are used in the management of several different
disease states/conditions, including systemic treatment of acute flares of inflammatory
conditions and topical treatment of dermatological inflammation and itching. Based on
your functional group evaluations of these two forms of hydrocortisone, answer the following questions:
A. Which of these forms of hydrocortisone do you anticipate can be administered via
an IM or IV route? What strategy was used to create a more water-soluble form of
hydrocortisone?
162 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
B. Provide a rationale for why the other form of hydrocortisone is available only as a topi-
cal cream or ointment. What strategy was used to create a more lipid-soluble form of
hydrocortisone?
8. Acamprosate (calcium salt) and risedronate (sodium salt) do not require systemic metabolism to be eliminated. Modify each structure below to show the salt form of the drug
and provide a brief structural rationale for why these agents are able to be “excreted
unchanged.”
9. Each of the following drugs contains one functional group that can be ionized or contains
several functional groups that are either all either basic or acidic. Based on the name of the
salt that is marketed, determine whether the parent drug molecule (in its unionized form)
is acidic or basic in character.
A. Orphenadrine citrate
B. Losartan potassium
C. Atorvastatin sodium
D. Bazedoxifene acetate
E. Abacavir sulfate
F. Enalapril maleate
G. Tetracycline phosphate
H. Omeprazole magnesium
I. Tramadol hydrochloride
J. Doxycycline calcium
K. Butaconazole nitrate
CH 5 - SALTS AND SOLUBILITY 163
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10. Both vitamin E and vitamin A (in the form of retinol) are used in the management of skin
conditions, including acne, wound healing, and the effects of aging.
A. Vitamin A has a cLog P = 4.6. Vitamin E has a cLog P = 8.4. Provide a structural ration-
ale for why these vitamins can be administered topically.
B. Oral administration of these agents is a challenge because vitamin A is considered
“insoluble” and vitamin E is only dispersible in aqueous solution. Given the information
presented in this chapter, identify two ways that each of these molecules could be
structurally modified to improve aqueous solubility.
A 25-year-old woman approaches the counter and asks for a private consultation. During
11.
the consultation, she reports that she suspects that she has a vaginal yeast infection. From
doing some Internet searching, she knows that creams, suppositories, and tablets are available and has a box of each formulation in her hands. She really wants to take the tablet
form because it is the least messy but doesn’t understand how that could possibly treat an
external infection.
Terconazole is available as a cream or suppository.
Fluconazole is available as a tablet.
Miconazole is available as a cream or ointment.
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