Chapter 6. pKa
&
Chapter 7. Solubility
2015.10.07 목희연
Chapter 6. pKa
6.1 • pKa Fundamentals
6.2
• pKa Effets
6.3
• pKa Case Studies
6.4
• Structure Modification Strategies for pKa
• Problems
Chapter 6. pKa
6.1 pKa Fundamentals
• pKa = -logKa
• For acids:
• For bases:
6.1 pKa Fundamentals
• Henderson-Hasselbach equation
6.2 pKa Effets
• Highly permeable compounds
Low solubility
Acidic compound with pKa 5
6.3 pKa Case Studies
• Effect of pKa and size on activity
6.3 pKa Case Studies
• Effect of pKa on activity of a structural series
6.3 pKa Case Studies
• Basic drugs tend to permeate the bloodbrain barrier
6.3 pKa Case Studies
• Acidity and basicity effects water solubility
6.4 pKa Case Studies
• At acids
:adding α-halogen or EWG → increase acidity
• At bases
:adding EDG → increase basicity
:adding aromatic group → decrease basicity
Problems
• 1. For acids, as pH decreases, are there: (a) more anions,
(b) more neutral molecules, (c) higher solubility, (d) lower
solubility, (e) higher permeability, (f) lower permeability?
• 2. For bases, as pH decreases, are there: (a) more cations,
(b) more neutral molecules, (c) higher solubility, (d) lower
solubility, (e) higher permeability, (f) lower permeability?
• 3. At pH 6.8, a basic compound of pKa 9.5 is mostly in
what form?: (a) ionized, (b) neutral.
Problems
• 4. For benzoic acid (pKa 4.2), estimate the degree of
ionization in the fasted state for the stomach, duodenum,
and blood. For HA=H++A−, use the relationship:
[HA]/[A−]=10(pKa−pH)
Location
pH
[HA]/[A−] = 10(pKa-pH)
Ionization
Stomach
1.5
102.7
Neutral
Duodenum
5.5
10-1.3
(-)
Blood
7.4
10-3.2
(-)
Problems
• 5. For piperazine (pKa 9.8), estimate the degree of
ionization in the fasted state for the stomach, duodenum,
and blood. For BH+ =H++B, use the relationship:
[BH+]/[B]=10(pKa−pH)
Location
pH
[BH+]/[B] = 10(pKa-pH)
Ionization
Stomach
1.5
108.3
(+)
Duodenum
5.5
104.3
(+)
Blood
7.4
102.4
(+)
Problems
• 6. If the pH is 2 units above the pKa of an acid, the
predominant species is: (a) neutral, (b) anion.
• If the pH is 2 units below the pKa of a base, the
predominant species is: (c) neutral, (d) cation.
Chapter 7. Solubility
7.1 • Solubility Fundamentals
7.2 • Effects of Solubility
7.3 • Effets of Physiology on Solubility and Absorption
7.4 • Structure Modification Strategies to Improve Solubility
7.5 • Strategies for Improving Dissolution Rate
7.6 • Salt Form
• Problems
Chapter 7. Solubility
• Solubility is one of the most important properties in drug
discovery.
• Negative effects of low-solubility compounds:
- Poor absorption and bioavailability after oral dosing
- Insufficient solubility for IV dosing
- Artificially low activity values from bioassays
- Erratic assay results (biological and property methods)
- Development challenges (expensive formulations and
increased development time)
- Burden shifted to patient (frequent high-dose
administrations)
7.1 Solubility Fundamentals
Compound structure
Physical state of compound that is introduced into solution
• Solid: Amorphous, crystalline, polymorphic form
• Liquid: Predissolved in solvent (e.g., dimethylsulfoxide [DMSO])
Composition and physical conditions of solvent(s)
• Types of solvents
• Amount (%) of co-solvents
• Solution components (e.g., salts, ions, proteins, lipids, surfactants)
• pH
• Temperature
Methods of measurement
• Equilibration time
• Separation techniques (e.g., filter, centrifuge)
• Detection (e.g., ultraviolet, mass spectrometry, turbidity)
7.1 Solubility Fundamentals
• Structural properties affect solubility
-Lipophilicity, Size, pKa, Crystal lattice energy
• Log S = 0.8 – LogPOW – 0.01(MP-25)
LogP increses by 1 unit or
Melting Point increases by 100℃
Solubility decreases
10-fold
7.1 Solubility Fundamentals
• Derivation of Henderson-Hasselbalch equation for
solubility
S = S0 (1+10(pH-pKa)) (Acid)
S = S0 (1+10(pKa-pH)) (Base)
7.2 Effects of Solubility
• Solubility classification ranges for human oral
absorption
 <10㎍/mL Low solubility
 10-60㎍/mL
 >60㎍/mL
Moderate solubility
High solubility
• Solubility for animal dosing
7.4 Structure Modification Strategies to
Improve Solubility
• How to improve solubility through structure
modification
7.4 Structure Modification Strategies to
Improve Solubility
• Add Ionizable Groups
SGF, simulated gastric fluid (pH 1.2)
PB, phosphate buffer (pH 7.4)
7.4 Structure Modification Strategies to
Improve Solubility
• Reduce Log P
Maximum concentrations in the blood
7.4 Structure Modification Strategies to
Improve Solubility
• Add Hydrogen Bonding
introducing hydrogen bond donors or acceptors
ex) OH, NH2
7.4 Structure Modification Strategies to
Improve Solubility
• Add Polar Group
7.4 Structure Modification Strategies to
Improve Solubility
• Reduce Molecular Weight
7.4 Structure Modification Strategies to
Improve Solubility
• Out-of-Plane Substitution
7.4 Structure Modification Strategies to
Improve Solubility
• Construct a Prodrug
7.5 Strategies for Improving Dissolution
Rate
Dissolution rate
how fast a compound can dissolve into solution
7.6 Salt Form
Salt forms can modify
 physicochemical properties (e.g., dissolution rate, crystallinity,
hygroscopicity)
p-amino-salicylic acid
 mechanical properties (hardness, elasticity, etc.)
Problems
• 1. A free acid (pKa4) and its sodium salt are tested for solubility.
Will they have the same solubility in water? Why? Will they
have the same solubility in pH 7.4 potassium phosphate buffer?
In pure water, the pH will change when the compound is added, so salt will be more
soluble / Same solubility
• 2. Compound A was dosed in rat as an oral suspension at 100
mg/kg, 200 mg/kg, and 300 mg/kg. Cmax and AUC of all three
doses were the same. What is the potential cause?
Solubility-limited absorption
• 3. An acidic compound has intrinsic solubility of 2 μg/mL and
pKa of 4.4. What is the approximate solubility of the compound
at pH 7.4?
S = S0 (1+10(pH-pKa))
2,000 μg/mL
• 4. Why does the solubility of subsequent analog compounds in
a lead series tend to be lower during lead optimization?
In order to improve target binding, lipophilic groups are often added to the
template, which reduces aqueous solubility
Problems
• 5. List structural properties that affect solubility.
Lipophilicity, molecular size, pKa, charge, crystal lattice energy
• 6. What is the difference between solubility and dissolution rate?
Solubility is the highest sustainable concentration;
dissolution rate is how much of the compound dissolves per unit time
• 7. Structural modifications to improve solubility often decrease
what other property?
Permeability
• 8. What usually is the most successful structure modification to
improve solubility?
Add ionizable group
• 9. Making a salt improves the: (a) intrinsic solubility, (b)
dissolution rate.
Problems
• 10. For the following lead structure, what structural
modifications could you make to improve solubility?
Remove groups not needed for
binding (reduce lipophilicity and MW)
Add amines to existing chains
Add H-bond donors and acceptors in locations that also increase binding
• 11. Low solubility can cause which of the following?: (a)
low oral bioavailability, (b) low metabolism, (c) low
permeability, (d) increased burden on patients, (e) less
expensive drug product formulation.