Ionic Equilibria

Qasim Allawi
Msc.Pharm.
Assistant professor
Lecturer in pharmaceutics
2024
Introduction
• Many drugs are:
• Weak acids such as acetylsalicylic acid and ibuprofen
• Weak bases such as procaine and lidocaine
• Salts such as sodium salicylate and lidocaine hydrochloride
• Ionization of drug is important in:
• Formulation: ionized drug is more soluble
• Absorption: unionized drugs easily diffuse across membrane.
• Distribution: unionized drugs have high volumes of distribution and protein
binding
• Excretion: ionized drugs excreted more readily.

2
Ionic Equilibria
Arrhenius Theory
• Arrhenius defined an acid as a substance that liberates hydrogen ions,
H+ and a base as a substance that supplies hydroxyl ions, OH− on
dissociation.
• However; Arrhenius definition could not explain the basic behavior of
many compounds that do not contain hydroxyl ions, OH− (e.g. NH3)
• NH3 + HCl ↔ NH4+ + Cl−
• Therefore; the Brönsted–Lowry theory is more useful than the
Arrhenius theory for the representation of ionization in both aqueous
and non-aqueous systems.

3
Ionic Equilibria
Brönsted–Lowry Theory
• According to the Brönsted–Lowry theory, an acid is a
substance that is capable of donating a proton, and a
base is a substance that is capable of accepting a proton
from an acid.

4
Ionic Equilibria
Brönsted–Lowry Theory
• The relative strengths of acids and bases are measured by the tendencies
of these substances to give up and take on protons.
• E.g. HCl is a strong acid in water because it gives up its proton readily
• CH3COOH is a weak acid because it gives up its proton only to a small extent.
• The strength of an acid or a base varies with the solvent.
• E.g. HCl is a weak acid in glacial acetic acid
• CH3COOH is a strong acid in liquid ammonia.
• i.e. the strength of an acid depends not only on its ability to give up a
proton but also on the ability of the solvent to accept the proton from the
acid.

5
Ionic Equilibria
Brönsted–Lowry Theory
Types of Solvent
• Solvents can be classified as protophilic, protogenic, amphiprotic, and
aprotic.
1. Protophilic or basic solvent is one that is capable of accepting
protons from the solute (e.g. liquid ammonia NH3).
2. Protogenic solvent is a proton donating compound (e.g. acetic acid
CH3COOH)
3. Amphiprotic solvents act as both proton acceptors and proton
donor (e.g. water H2O).
4. Aprotic solvents neither accept nor donate protons (e.g. methan
CH4).

6
Ionic Equilibria
Lewis Electronic Theory
• According to the Lewis theory:
• An acid is a molecule or an ion that accepts an electron
pair to form a covalent bond.
• A base is a substance that provides the pair of unshared
electrons to coordinates with an acid.

7
Ionic Equilibria
Lewis Electronic Theory
• According to Lewis definition:
• Certain compounds such as BF3 are considered acids
even when they are not proton donors (do not contain
hydrogen).
• Other compounds such as ethers and NH3 are considered
bases even in cases when they are not proton acceptors.
• Example
• BF3 + :NH3 → F3B:NH3
• Lewis acid Lewis Base

8
Ionic Equilibria
Acid–Base Equilibria
Ionization of Weak Electrolytes
Ionization of Salts
Ionization of Polyprotic Electrolytes
Ionization of Water
pH
pKa, pKb, and pKw
Ionic Equilibria 9
Ionization of Weak Electrolytes
WeakTheAcids
ionization of an uncharged weak acid, HA, in water:
HA + H2O ↔ H3O+ + A−
Acid 1 Base 1 Acid 2 Base 2
The acidity constant Ka is expressed as:
𝑯𝟑 𝑶+ [𝑨− ]
𝑲𝒂 =
[𝑯𝑨]

Note: An acid and a base in equilibrium is

termed a conjugate acid-base pair. E.g. A− is the
conjugate base of the weak acid HA

For a charged acid, BH+, the reaction is written as:

BH+ + H2O ↔ H3O+ + B
Acid 1 Base 1 Acid 2 Base 2
The acidity constant Ka is expressed as :
𝑯𝟑 𝑶+ [𝑩]
𝑲𝒂 =
[𝑩𝑯+ ] 10
Ionic Equilibria
Ionization of Weak Electrolytes
Weak Bases
The ionization of an uncharged weak base, B, in water can be
written as:
B + H2O ↔ OH − + BH+
Base 1 Acid 1 Base 2 Acid 2
The basicity constant Kb is expressed as :
𝑶𝑯− [𝑩𝑯+ ]
𝑲𝒃 =
[𝑩]
For charged base, A−, the reaction is written as:
A− + H2O ↔ OH − + HA
Base 1 Acid 1 Base 2 Acid 2
The basicity constant Kb is expressed as :
𝑶𝑯− [𝑯𝑨]
𝑲𝒃 = −]
Ionic Equilibria
[𝑨 11
Ionization of Salts
Salts are the non-water product of an acid base
neutralization.
Drug salts are often used due to their complete ionization,
and thus better aqueous solubility than weak acids and
bases.
Depending on the strength of the acid and base that form
the salt, there are four possible types:
1. Salt of strong acid and a strong base (e.g. NaCl)
This salt dissociates to give ions that practically do not
consume or release protons.
E.g. NaCl → Na+ + Cl-
12
Salt
Ionic Equilibria (Practically neither Acid or Base)
Ionization of Salts
2. Salt of weak acid and strong base (e.g. NaOAc)
This salt dissociates into ions; from which one acts as a base
and consumes a proton to give its conjugate weak acid:
E.g. NaOAc → Na+ + OAc−
Salt Base 1
• OAc− + H2O ↔ HOAc + OH−
Base 1 Acid 1 Acid 2 Base 2
3. Salt of weak base and strong acid (e.g. NH4Cl)
This salt dissociates into ions; from which one acts as an acid
and releases a proton to give its conjugate weak base:
E.g. NH4Cl → NH4+ + Cl−
Salt Acid 1
NH4+ + H2O ↔ NH3 + OH−
• Acid 1 Base 1 Base 2 Acid 2
13
Ionic Equilibria
Ionization of Salts
4. Salt of weak acid and weak base (e.g. NH4OAc)
This salt dissociates into ions; from which one acts as an
acid and the other as a base.
E.g. NH4OAc → NH4+ + OAc−
Salt Acid 1 Base 1

NH4+ + H2O ↔ NH3 + H3O+

• Acid 1 Base 1 Base 2 Acid 2
AcO− + H2O ↔ AcOH + OH−
• Base 1 Acid 1 Acid 2 Base 2

14
Ionic Equilibria
Ionization of Polyprotic Electrolytes
Polyprotic Acids
Polyprotic acids can lose more than one H+ ion.
E.g. Diprotic acids, such as H2SO4 and H2CO3, which release 2
protons, and Triprotic acids, such as H3PO4 which releases 3
protons.
Consider the ionization of the weak diprotic acid, H2CO3 that
dissociates in two steps:
H2CO3 + H2O ↔ H3O+ + HCO3−
HCO3− + H2O ↔ H3O+ + CO32−
Two acidity constants is used to describe the two equilibrium:
𝑯𝟑 𝑶+ [𝑯𝑪𝑶𝟑− ] 𝑯𝟑 𝑶+ [𝑪𝑶𝟑𝟐− ]
𝑲𝒂𝟏 = , 𝑲𝒂𝟐 =
[𝑯𝟐𝑪𝑶𝟑] [𝑯𝑪𝑶𝟑− ]
Ka1 is larger than Ka2 because the polyprotic acid lose its first proton more easily
than the second (and third) proton.
15
Ionic Equilibria
Ionization of Polyprotic Electrolytes
Polyprotic Bases
Polyprotic bases can accept more than one H+ ion.
E.g. Diprotic bases, such as CO32− which accepts 2 protons, and
Triprotic bases, such as PO43− accepts 3 protons.
Consider the ionization of the weak diprotic base, CO32 that
consumes protons in two steps:
CO32− + H2O ↔ OH− + HCO31−
HCO31− + H2O ↔ OH− + H2CO3
Two basicity constants is used to describe the two equilibrium:
𝑶𝑯− [𝑯𝑪𝑶𝟑− ] 𝑶𝑯− [𝑯𝟐𝑪𝑶𝟑]
𝑲𝒃𝟏 = 𝟐−
, 𝑲𝒃𝟐 =
[𝑪𝑶𝟑 ] [𝑯𝑪𝑶𝟑− ]
Kb1 is larger than Kb2 because the polyprotic base consumes its first proton more
easily than the second (and third) proton. 16
Ionic Equilibria
Ionization of Water
Water ionizes slightly to yield hydrogen and hydroxyl ions by reacting
with another molecule of water (autoprotolytic reaction):
H2O + H2O ↔ OH − + H3O+
The equilibrium constant is expressed as:
𝑶𝑯− 𝑯𝟑 𝑶+ 𝟐 = 𝑶𝑯− 𝑯 𝑶+
𝑲= ⟹ 𝑲 𝑯 𝟐 𝑶 𝟑
𝑯𝟐 𝑶 𝟐
[H2O]2 is considered as a constant and is combined with K to give a
new constant, Kw, known as the autoprotolysis constant, or the ion
product of water:
𝑲w = 𝑶𝑯− 𝑯𝟑 𝑶+

17
Ionic Equilibria
Ionization of Water
In pure water: 𝑶𝑯− = 𝑯𝟑 𝑶+ = 1 × 10-7 M at 25°C.
𝑲w = 𝑶𝑯− 𝑯𝟑 𝑶+ = (1 × 10−7)×(1 × 10−7)=1 × 10-14 M
When an acid is added to pure water, the increase in
hydrogen ions is offset by a decrease in the hydroxyl ions
so that Kw remains constant at about 1 × 10-14 M at 25°C.
A simple relationship exists between Ka of a weak acid
(HB) and Kb of its conjugate base (B−), and between Ka of
BH+ and Kb of B when the solvent is amphiprotic (e.g.
water).
𝑲𝒂 𝑲𝒃 = 𝑲𝒘

18
Ionic Equilibria
pH
+
[𝑯𝟑𝑶 ] varies from 1 (in a 1 M solution of a strong acid) to
1 × 10-14 (in a 1 M solution of a strong base).
Sorensen
+
suggested a simplified method of expressing
[𝑯𝟑𝑶 ] via the term pH.
+
pH is defined as the negative logarithm of [𝑯𝟑𝑶 ] :
+
𝒑𝑯 = − 𝐥𝐨𝐠[𝑯𝟑𝑶 ]
The pH of a solution is a numeric scale from 0 to 14, which
expresses the degree of acidity (7- 0) and alkalinity (7-14).
+ −
The value 7 at which [𝑯𝟑𝑶 ] = [𝑶𝑯 ] at room
temperature is referred to as the neutral point

19
Ionic Equilibria
pKa, pKb, and pKw
The term “p” is also used to express the negative
logarithm of each of [OH−], Ka, Kb, Kw as pOH, pKa, pKb,
and pKw
𝒑𝑲𝒘 = 𝒑𝑶𝑯 + 𝒑𝑯
𝒑𝑲𝒘 = 𝒑𝑲𝒂 + 𝒑𝑲𝒃
PKa and PKb values provide a mean of comparing the
strengths of weak acid and weak bases:
• Lower PKa values corresponds to stronger acids
• Lower PKb values corresponds to stronger Bases

20
Ionic Equilibria
 Calculation of pH
Strong Acids and Bases
Weak Electrolytes
Salts
Diprotic Acids and Bases

Ionic Equilibria 21
Strong Acids and Bases
A strong acid, HA, ionizes completely to H3O+ and A−.
Therefore 𝑯𝟑𝑶+ = [𝑯𝑨] and pH is calculated as:
𝒑𝑯 = − 𝒍𝒐𝒈[𝑯𝑨]
While a strong base, B ionizes completely to BH+ and OH−.
Therefore 𝑶𝑯− = [𝑩], and pOH is calculated as:
𝒑𝑶𝑯 = − 𝐥𝐨𝐠[𝑩]
Since: 𝒑𝑯 = 𝒑𝑲𝒘 − 𝒑𝑶𝑯
Then: 𝒑𝑯 = 𝒑𝑲𝒘 − (−𝐥𝐨𝐠[𝑩])
𝒑𝑯 = 𝒑𝑲𝒘 +𝐥𝐨𝐠[𝑩]
22
Ionic Equilibria
Weak Electrolytes
Weak Acids
A weak acid, HA, ionizes partially H3O+ and A−:
𝑯𝟑 𝑶+ [𝑨− ]
𝑲𝒂 = Since 𝑨− = 𝑯𝟑 𝑶+
[𝑯𝑨]
𝑯𝟑 𝑶+ 𝟐
Then 𝑲𝒂 =
[𝑯𝑨]
After rearranging and taking the negative logarithm:
𝟏
𝒑𝑯 = (𝒑𝑲𝒂 −𝐥𝐨𝐠 𝑯𝑨 )
𝟐
23
Ionic Equilibria
Weak Electrolytes
Weak Acids
Example
• Calculate the pH of a 50 mg .mL-1 solution of ascorbic acid (MW
176.1, pKa 4.17)
• 1. Convert concentration to M (or mol/L)
• C = 50 mg/mL = 50 g/L
• M = 50 / 176.1 = 0.284 mol/L ( wt/m.wt * 1/L)
𝟏
•𝒑𝑯 = (𝒑𝑲𝒂 −𝐥𝐨𝐠 𝑯𝑨 )
𝟐
1
•𝒑𝑯 = (4.17 −log 0.284)
2
1
•𝒑𝑯 = 4.17 + 0.574 = 2.36
2
24
Ionic Equilibria
Weak Electrolytes
Weak Bases
A weak base, B, ionizes partially to BH+ and OH−:
𝑩𝑯+ [𝑶𝑯− ]
𝑲𝒃 = Since 𝑩𝑯+ = 𝑶𝑯−
[𝑩]
𝑶𝑯− 𝟐
Then 𝑲𝒃 =
[𝑩]
After rearranging and taking the negative logarithm:
𝟏 𝟏
𝒑𝑶𝑯 = 𝒑𝑲𝒃 − 𝐥𝐨𝐠[𝑩]
𝟐 𝟐
Since 𝒑𝑶𝑯 = 𝒑𝑲𝒘 − 𝒑𝑯 and 𝒑𝑲𝒃 = 𝒑𝑲𝒘 − 𝒑𝑲𝐚
𝟏
Then 𝒑𝑯 = (𝒑𝑲w + 𝒑𝑲𝒂 +𝐥𝐨𝐠 𝑩 )
Ionic Equilibria
𝟐 25
Weak Electrolytes
Weak Bases
Example
• Calculate the pH of a saturated solution of codeine monohydrate
(MW 317.4, pKa 8.2, solubility at room temperature is 1 g in 120 mL
• Convert concentration to mol/L
• C = 1 g / 120 mL = 8.33 g/L
• M = 8.33/317.4 = 0.0263 mol/L
𝟏
• 𝒑𝑯 = (𝒑𝑲w + 𝒑𝑲𝒂 +𝐥𝐨𝐠 𝑩 )
𝟐
1
•𝒑𝑯 = (14 + 8.2 +log 0.0263)
2
1
•𝒑𝑯 = 14 + 8.2 − 1.58 = 10.31
2

26
Ionic Equilibria
Salts
Salts of Strong Acid and Strong Base
The salt of strong acid and strong base (e.g. NaCl) dissociates in water
into Na+ and Cl−.
NaCl → Na+ + Cl−
Neither Na+ nor Cl− ions are capable of consuming or releasing protons
from/to water (they are neither acids nor bases)
Therefore these ions have no effect on pH. The pH of the solution
remains the same as that of pure water, 7

27
Ionic Equilibria
Salts
Salts of Weak Acid and Strong Base
The salt of weak acid and strong base (e.g. Sodium acetate,
AcONa) dissociates into Na+ and AcO−.
AcONa → AcO− + Na+
S
AcO− acts as a base and consumes one proton to form AcOH
AcO− + H2O ↔ AcOH + OH−
The pH is calculated in the same way as in weak base:
𝟏
𝒑𝑯 = (𝒑𝑲w + 𝒑𝑲𝒂 +𝐥𝐨𝐠 𝑨𝒄𝑶− )
𝟐
Since [AcO−] = [AcONa] (designated as [S])
𝟏
Then 𝒑𝑯 = (𝒑𝑲w + 𝒑𝑲𝒂 +𝐥𝐨𝐠 𝑺 )
𝟐
Note: the pH is always > 7
28
Ionic Equilibria
Salts
Salts of Weak Base and Strong Acids
The salt of weak base and strong acid (e.g. ammonium
chloride, NH4Cl) dissociates into NH4+ and Cl−.
NH4Cl → Cl− + NH4+
NH4+ acts as an acid and releases one proton to form NH3
NH4+ + H2O ↔ NH3 + H3O+
The pH is calculated in the same way as in weak acid:
𝟏
𝒑𝑯 = 𝒑𝑲𝒂 −𝐥𝐨𝐠 𝑵𝑯𝟒+
𝟐
Since [NH4+] = [NH4Cl] (designated as [S])
𝟏
Then 𝒑𝑯 = (𝒑𝑲𝒂 −𝒍𝒐𝒈 𝑺 )
𝟐
Note: the pH is always < 7
29
Ionic Equilibria
Salts
Salts of Weak Acid and Weak Base
The salt of weak acid and weak base (e.g. ammonium
acetate, AcONH4) dissociates into NH4+ and AcO−.
AcONH4 → AcO− + NH4+
NH4+ acts as an acid and releases one proton to form NH3,
while AcO− acts as a base and consumes one proton to
form AcOH
NH4+ + H2O ↔ NH3 + H3O+
AcO− + H2O ↔ AcOH + OH−
The pH can be calculated by:
𝟏
𝒑𝑯 = (𝒑𝑲𝒘 + 𝒑𝑲𝒂 − 𝒑𝑲𝒃)
𝟐
Note: the pH does not depend on the concentration of the salt, but rather
depends on the strength of the weak acid and weak base 30
Ionic Equilibria
Diprotic Acids and Bases
+
For weak diprotic acid, the 𝑯𝟑𝑶 mostly comes from the
first step of dissociation. Therefore; The second step is ignored
during calculation of pH:
𝟏
𝒑𝑯 = (𝒑𝑲𝒂 −𝐥𝐨𝐠 𝑯𝑨 )
𝟐
pH is calculated the same way as
with monoprotic weak acid
−
For weak diprotic base, the 𝑶𝑯 mostly comes from the first
step of reaction. Therefore; The second step is ignored during
calculation of pH:
pH is calculated the same way as
with monoprotic weak base
𝟏
𝒑𝑯 = (𝒑𝑲w + 𝒑𝑲𝒂 +𝐥𝐨𝐠 𝑩 )
𝟐
31
Ionic Equilibria