1. Chapter 6. pKa & Chapter 7. Solubility
목희연

2. Chapter 6. pKa 6.1 6.2 6.3 6.4 pKa Case Studies
pKa Fundamentals
6.2
pKa Effets
6.3
pKa Case Studies
6.4
Structure Modification Strategies for pKa
Problems

3. Chapter 6. pKa

4. 6.1 pKa Fundamentals
pKa = -logKa
For acids:
For bases:

5. 6.1 pKa Fundamentals
Henderson-Hasselbach equation

6. 6.2 pKa Effets Highly permeable compounds Low solubility
Acidic compound with pKa 5

7. 6.3 pKa Case Studies
Effect of pKa and size on activity

8. 6.3 pKa Case Studies
Effect of pKa on activity of a structural series

9. 6.3 pKa Case Studies
Basic drugs tend to permeate the blood- brain barrier

10. 6.3 pKa Case Studies
Acidity and basicity effects water solubility

11. 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

12. 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.

13. 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
Duodenum
5.5
Blood
7.4
102.7
Neutral
10-1.3
(-)
10-3.2
(-)

14. 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
Duodenum
5.5
Blood
7.4
108.3
(+)
104.3
(+)
102.4
(+)

15. 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.

16. Chapter 7. Solubility 7.1 7.2 7.3 7.4 7.5 7.6 Solubility Fundamentals
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

17. 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)

18. 7.1 Solubility Fundamentals
Compound structure
Solid: Amorphous, crystalline, polymorphic form
Liquid: Predissolved in solvent (e.g., dimethylsulfoxide [DMSO])
Physical state of compound that is introduced into solution
Types of solvents
Amount (%) of co-solvents
Solution components (e.g., salts, ions, proteins, lipids, surfactants) pH
Temperature
Composition and physical conditions of solvent(s)
Equilibration time
Separation techniques (e.g., filter, centrifuge)
Detection (e.g., ultraviolet, mass spectrometry, turbidity)
Methods of measurement

19. 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

20. 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)

21. 7.2 Effects of Solubility
Solubility classification ranges for human oral absorption
<10㎍/mL Low solubility
10-60㎍/mL Moderate solubility
>60㎍/mL High solubility
Solubility for animal dosing

22. 7.4 Structure Modification Strategies to Improve Solubility
How to improve solubility through structure modification

23. 7.4 Structure Modification Strategies to Improve Solubility
Add Ionizable Groups
SGF, simulated gastric fluid (pH 1.2)
PB, phosphate buffer (pH 7.4)

24. 7.4 Structure Modification Strategies to Improve Solubility
Reduce Log P
Maximum concentrations in the blood

25. 7.4 Structure Modification Strategies to Improve Solubility
Add Hydrogen Bonding
introducing hydrogen bond donors or acceptors
ex) OH, NH2

26. 7.4 Structure Modification Strategies to Improve Solubility
Add Polar Group

27. 7.4 Structure Modification Strategies to Improve Solubility
Reduce Molecular Weight

28. 7.4 Structure Modification Strategies to Improve Solubility
Out-of-Plane Substitution

29. 7.4 Structure Modification Strategies to Improve Solubility
Construct a Prodrug

30. 7.5 Strategies for Improving Dissolution Rate
how fast a compound can dissolve into solution

31. 7.6 Salt Form Salt forms can modify
physicochemical properties (e.g., dissolution rate, crystallinity, hygroscopicity)
mechanical properties (hardness, elasticity, etc.)
p-amino-salicylic acid

32. 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?
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?
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?
4. Why does the solubility of subsequent analog compounds in a lead series tend to be lower during lead optimization?
In pure water, the pH will change when the compound is added, so salt will be more
soluble / Same solubility
Solubility-limited absorption
S = S0 (1+10(pH-pKa))
2,000 μg/mL
In order to improve target binding, lipophilic groups are often added to the
template, which reduces aqueous solubility

33. Problems 5. List structural properties that affect solubility.
6. What is the difference between solubility and dissolution rate?
7. Structural modifications to improve solubility often decrease what other property?
8. What usually is the most successful structure modification to improve solubility?
9. Making a salt improves the: (a) intrinsic solubility, (b) dissolution rate.
Lipophilicity, molecular size, pKa, charge, crystal lattice energy
Solubility is the highest sustainable concentration;
dissolution rate is how much of the compound dissolves per unit time
Permeability
Add ionizable group

34. Problems
10. For the following lead structure, what structural modifications could you make to improve solubility?
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.
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