pKa
About pKa
- About pKa Methods
-
2013. 10.11. FRI
Park Sook Jin
Majority of drugs contain ionizable groups
pKa affects to,
Solubility
Permeability
About pKa
H+(수소이온, Proton)이 해리되는 정도.
 For example,
- 염산(HCl) : 거의 완전하게 H+가 해리.
- 아세트산(CH3COOH) : H+ 약간 해리.
(강산인 염산과의 상대적인 세기.)

이때 해리되는 정도를 측정할 수 있는 것 -> Ka.
K : 평형상수
a : acidity
Ka 가 크면 product 쪽으
로 치우침.( 이온화 강
도 :↑)
About pKa
Ka의 단위가 커져 –log값으로
치환한 식.
-log 값으로 치환했기때문에 Ka값이 커질수록 pKa 값은 작아진다.
# 정리
Strong acid 란?
pH ↓, Ka↑, pKa ↓
pKa ∝ pH ∝ 1/Ka
About pKa
[HA] ↑, [A-] ↓; pKa ↑
[A-] ↑; pH ↓, acidity ↑
For acids :
For bases :
[HB+] ↑, [B] ↓; pKa ↑
[B] ↑; pH ↓, weak base
Henderson-Hasselbach equation
when pH is the same as pKa, then there is an equal concentration of
ionic and neutral species in solution.
산의 이온화 상수로
부터 유도해
pH = pKa를 이용해
서 buffer solution을
만들 수 있음.
Predict pKa – Methanol & Acetic acid
>
- Acetic acid와 Methanol
모두 –OH기를 가지고 있
지만 pKa는 Acetic acid가
더 낮다.
- Acetic acid는 H+가 형성
된 후 resonance
structure를 가지기 때문에
이온화 된 후의 stability가
methanol 보다 더 높기 때
문이다.
Predict pKa - alanine
Amine
N의 비공유 전자쌍
으로 인해 전자를 주
려고 해 염기성을 띔.
- 산성 화합물과 반응
하는 site
Carboxylic acid
H가 잘 떨어져 나가
이온화가 되므로 산
성을 띔.
- 염기성 화합물과 반
응하는 site
주요 유기 화합물의 pKa value
pKa Effects
Solubility
Ionized molecules > Neutral molecules
(Because ionized molecules are more polar)
Permeability
Ionized molecules < Neutral molecules
(Because neutral molecules are much more lipophilic)
# pKa determines the degree of ionization
→ major effect on solubility and permeability ( For
determine intestinal absorption after oral dosing)
pKa Effects
# 정리
Product
▶ ionized form ▶polarity↑▶ 지방에 잘 녹지 않아 세포막통과↓
▶ nonionized form ▶polarity↓ ▶지방에 잘 녹아 세포막 통과↑
# Product가 weak acid일 경우,
용매의 Ph > pKa : 용매가 산성일수록 이온화도 감소
용매가 알칼리일수록 이온화도 증가
# Product가 weak base일 경우,
용매의 PH > pKa : 용매가 산성일수록 이온화도 증가
용매가 알칼리일수록 이온화도 감소
pKa Effects
# Highly permeable compounds → low solubility
# Highly solubility compounds → low permeability
Figure 6.3 ▶ Permeability and solubility profiles for an acidic compound
with a pKa of 5.
Permeability and solubility are pH dependent for ionizable compounds.
The properties exhibit opposite effects with pH because of the effects
of ionization.
pKa Case Studies
Commonly appear in drug molecules are listed in Table 6.1
pKa Case Studies
The pKa values of some drugs are listed in Table 6.2
pKa Case Studies
Incresing size
Added aromatic ring
-Amine’s basity ↓
-Low Activity
(much more lower
than other moieties)
Added aliphatic groups
- Little effect on pKa
- Loss activity
pKa Case Studies
Mostly, pKa ↓, pH ↓, acidity ↑ ; IC50 ↓
pKa Case Studies
▶ Basic drugs tend to penetrate the blood-brain barrier(BBB)
more effectively than acids do.
# Trifluoroperazine
-Typical antipsychotic of the phenothiazine chemical class
-Prescribe to treat Schizophrenia (조현병 : 정신분열증)
# Indomethacin
- Non-steroidal anti-inflammatory drugs(NSAID)
- Prescription medication to reduce fever, pain and swelling
pKa Case Studies
The acidity of the bile acids ↑
Water solubility ↑
pKa Case Studies
Figure 6.8 shows two SRC kinase inhibitors.
Increasing basicity increased solubility due to ionization.
Structure Modification Strategies for pKa
When synthetic modifications are planned for
1. improving the water solubility or permeability of a
structural series
2. A wide selection of substructures can be used.
▶ It is important to remember that structural modifications
that increase solubility will also decrease permeability.
pKa modifications to enhance solubility and permeability can
be found in Chapters 7 and 8, respectively.
Electron donating and withdrawing groups can be added or
removed to add electron density at the acid or base,
depending on the desired effect.
Structure Modification Strategies for pKa
▶ The strength of an acid can be increased by adding
-halogen(s) or other electron withdrawing groups (e.g.,
carboxy, cyano, Nitro).
▶ Removing electron-withdrawing groups can
decrease acid strength.
▶ Addition of aliphatic groups has little effect.
Structure Modification Strategies for pKa
▶ The strength of a base is decreased by attachment
an aromatic group (e.g., aniline). The lone pair is
delocalized into the aromatic ring.
▶ It is also decreased slightly with addition of an
aliphatic group.
▶ The basicity of an aniline can be increased with
attachment of a methoxy group, which donates
electrons, or it can be decreased with the attachment
of a nitro group, which withdraws electrons.
Conclusion
▶ The ionizability of a compound is indicated
by pKa.
▶ Ionizability is a major determinant of
solubility and permeability.
▶ When pH=pKa, the concentrations of
ionized and neutral molecules in solution are
equal.
▶ Basicity of bases increases as pKa increases;
acidity of acids increases at pKa decreases.
pKa Methods
pKa Methods
The compound set has 98 diverse real-world drug discovery
compounds that were synthesized, measured, and predicted using
ACD/pKa DB software at Wyeth Research.
The R2 for the correlation is 0.90, which is very good for in silico
predictions.
pKa Methods
# ACDLabs software provides structural assignment of which
ionization center in the molecule has which pKa.
#The different pKa values of tautomers can be predicted.
(consider pKa, solubility, permeability in order to optimize
absorption)
Experimental pKa Methods
# pKa 측정시,
1) Compound는 극소량(<0.1mg)이 필요
2) 걸리는 시간은 1 sample당 5mins
# pKa 측정 방법
1) Spectral Gradient Analysis Method for pKa(SGA)
2) Capillary Electrophoresis Method for pKa(CE)
Experimental pKa Methods
- Spectral Gradient Analysis Method for pKa(SGA)
Gradient high-performance liquid chromatography pump,
with the substitution of aqueous acidic and basic buffers for
the two mixed liquid phases.
1. The test compound is dissolved in dimethylsulfoxide
(DMSO) at 10 mM and placed in a 96-well plate.
2. Each solution in the plate is diluted with aqueous
buffer.
3. The aqueous solution then is continuously mixed into
the aqueous pH buffer.
4. Throughout the 2-minute experiment, a gradient
program is run, which starts with a high percentage of
one buffer and progresses to a low percentage of that
buffer over 2 minutes.
5. Thus, the test compound is mixed with a
continuously changing pH.
6. As the pH changes, the fraction of the compound
that is ionized changes.
7. The absorption of an ultraviolet or visible
chromophore, which is near the ionization center
(within three to four bonds), changes with ionization.
8. As the mixture flows into the diode array UV
detector/spectrometer, the ultraviolet/visual
(UV/VIS) absorption changes with pH (Figure 24.4).
9. pKa is the inflection point of this absorption curve.
The instrument can produce a pKa screen for test
compounds about every 3 to 4 minutes for high
throughput. A commercial instrument is available (Table
24.1).
Experimental pKa Methods
Experimental pKa Methods
- Capillary Electrophoresis Method for pKa
This is based on the different electrophoretic mobility of a
compound in the neutral and ionized form.
The CE pKa method can be automated using commercial CE
instruments.
1. The test compound is diluted into aqueous buffer and injected
into a CE column.
2. The compound is run several times using CE mobile phase
buffers at different pHs. Ionized molecules move through the
mobile phase faster because CE mobility is proportional to
charge. Thus, as the fraction of ionized molecules increases, the
effective mobility (retention time) is progressively shorter.
3. By plotting the effective mobility versus mobile phase pH, pKa
is calculated as the inflection point.
In-Depth pKa Methods – pH-Metric
Problems
Problems
Problems - Answer
THANK YOU