+

Solubility and Distribution

Phenomena
Aseel Samaro

+
Objectives of the Chapter
After completion of this chapter, the student should
be able to:
1.

Understand
solutions.

the

various

types

2.

Define solubility, saturated & unsaturated solutions and

polar & non polar solvents.

3.

Understand the factors controlling the solubility of strong

& weak electrolytes.

4.

Define partition coefficient

pharmaceutical systems.

&

of

its

pharmaceutical

importance

in

+
Importance of studying the
phenomenon of solubility
Understanding the phenomenon of solubility helps the
pharmacist to:
1.

Select the best solvent for a drug or a mixture of drugs.

2.

Overcome
problems
arising
pharmaceutical solutions.

3.

Have information about the structure and intermolecular forces

of the drug.

4.

Many drugs are formulated as solutions, or added as powder or

solution forms to liquids.

5.

Drugs with low aqueous solubility often present problems related

to their formulation and bioavailability.

during

preparation

of

+
Definitions

Solution:
is a mixture of two or more components that form a
homogenous mixture. The components are referred to the solute and/or
solutes & the solvent and/or solvents .

Solute: is the dissolved agent . (less abundant part of the solution )

Solvent : is the component in which the solute is dissolved (more

abundant part of the solution).

A saturated solution: is one in which an equilibrium is established

between dissolved and undissolved solute at a definite temperature. Or

A solution that contains the maximum amount of solute at a definite
temperature

An unsaturated solution: or subsaturated solution is one containing the

dissolved solute in a concentration below that necessary for complete

saturation at a definite temperature.

+
Solubility

A supersaturated solution: contains more of the

dissolved solute than it would normally contain in a
saturated state at a definite temperature.
Solubility:

In a quantitative way: it is the concentration of

solute in a saturated solution at a certain temperature

In a qualitative way: it is the spontaneous interaction

of two or more substances (solute & solvent) to form a
homogeneous molecular dispersion

+
Degree of saturation
Unsaturated, Saturated or Supersaturated?

How much solute can be dissolved in a solution?

+
Solubility Curve

Any solution can be made saturated, unsaturated, or

supersaturated by changing the temperature.

+
Thermodynamic solubility of
drugs

The thermodynamic solubility of a drug in a solvent is

the maximum amount of the most stable crystalline
form that remains in solution in a given volume of the
solvent at a given temperature and pressure under
equilibrium conditions.

The equilibrium involves a balance of the energy of three

interactions against each other:
(1)

solvent with solvent

(2)

solute with solute

(3)

solvent and solute

Steps of solid going into solution.

1.

Step 1: Hole open in the solvent

2.

Step 2: One molecule of the solid breaks away from the bulk

3.

Step 3: The solid molecule is enter into the hole in the solvent

+
Solubility process
A mechanistic perspective of solubilization process
for organic solute in water involves the following
steps:
1.

Break up of solute-solute intermolecular bonds

2.

Break up of solvent-solvent intermolecular bonds

3.

Formation of cavity in solvent phase large enough to

accommodate solute molecule

4.

Transfer of solute into the cavity of solvent phase

5.

Formation of solute-solvent intermolecular bonds

+
Tree types of interaction in the
solution process
1. solvent solvent interaction
2. solute solute interaction
3. solvent solute interaction

sol

= H

+ H

+ H

+
Enthalpy

The enthalpy change of solution refers to the overall

amount of heat which is released or absorbed during
the dissolving process (at constant pressure).

The enthalpy of solution can either be positive

(endothermic reaction) or negative (exothermic
reaction).

The enthalpy of solution is commonly referred to as H

solution.

Expression
Molarity

M, c

Definition
Moles (gram molecular weights) of solute in 1 liter
(1000 ml) of solution.

Molality

Moles of solute in 1000 gm of solvent.

Normality

Gram equivalent weights of solute in 1 liter of

solution

Mole Fraction

Ration of moles of solute to total moles of solute+

solvent

Percentage by

% w/w

gm of solute in 100 gm of solution

%v/v

ml of solute in 100 ml of solution

% w/v

gm of solute in 100 ml of solution

Weight
Percentage by
Volume
Percentage
Weight in Volume

Solubility expressions

Symbol

+
Solubility expressions

The USP lists the solubility of drugs as: the number of

ml of solvent in which 1g of solute will dissolve.

E.g. 1g of boric acid dissolves in 18 mL of water, and in

4 mL of glycerin.

Substances whose solubility values are not known are

described by the following terms:
Term
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
Very slightly

Parts of solvent required for 1

part of solute
Less than 1 part
1 to 10 parts
10 to 30 parts
30 to 100 parts
100 to 1000 parts
1000 to 10 000 parts

+
Biopharmaceutics
Classification System (BCS)

BCS is a scientific framework for classifying Drug

substances according to their aqueous solubility and
their intestinal permeability

+
Solubility expressions: BCS
High solubility

The highest single unit dose is completely soluble in

250 ml or less of aqueous solution at pH 1 - 6.8 (37 C)

Xanax (alprazolam)
anxiety disorder

+
Solvent - Solute Interactions

In pre - or early formulation, selection of the most suitable

solvent is based on the principle of
like dissolves like

That is, a solute dissolves best in a solvent with similar

chemical properties. Or two substances with similar
intermolecular forces are likely to be soluble in each others

Polar solutes dissolve in polar solvents. E.g salts & sugar

dissolve in water .

Non polar solutes dissolve in non polar solvents. Eg.

naphtalene dissolves in benzene.

+
POLAR SOLUTE - POLAR
SOLVENT
Ammonia Dissolves in Water:

Polar ammonia molecules dissolve in polar water

molecules.

These molecules mix readily because both types of

molecules engage in hydrogen bonding.

Since the intermolecular attractions are roughly equal,

the molecules can break away from each other and
form new solute (NH3), solvent (H2O) hydrogen bonds.

Alcohol Dissolves in Water:

The -OH group on alcohol is polar and mixes with the

polar water through the formation of hydrogen bonds.

A wide variety of solutions are in this category such as

sugar in water, alcohol in water, acetic and
hydrochloric acids.

+
Solute-Solvent interactions

If the solvent is A & the solute is B, and the forces of attraction are
represented by A-A, B-B and A-B,
One of the following conditions will occur:

1.

If A-A >> A-B

The solvent molecules will be attracted to
each other & the solute will be excluded. Example: Benzene & water,
where benzene molecules are unable to penetrate the closely bound
water aggregates.

2.

If B-B >> A-A

The solvent will not be able to break the
binding forces between solute molecules. Example NaCl in benzene,
where the NaCl crystal is held by strong electrovalent forces which
cannot be broken by benzene.

3.

If A-B >> A-A or B-B, or the three forces are equal

will . form a solution. Example: NaCl in water.

The solute

+
Classification of solvents &
their mechanism of action
1.
2.
3.

Polar solvents
Non polar solvents

Semi polar solvents

+
Polar solvents

The solubility of a drug is due in large measure to the polarity

of the solvent, that is, to its dipole moment. Polar solvents
dissolve ionic solutes and other polar substances.

The ability of the solute to form hydrogen bonds is a far more

significant factor than is the polarity as reflected in a high
dipole moment

Water dissolves phenols, alcohols and other oxygen & nitrogen

containing compounds that can form hydrogen bonds with
water.

+
Polar solvents

The solubility of a substance also depends on structural

features such as the ratio of the polar to the nonpolar
groups of the molecule.

As the length of a nonpolar chain of an aliphatic alcohol

increases, the solubility of the compound in water
decreases

Straight-chain
monohydroxy
alcohols,
aldehydes,
ketones, and acids with more than four or five carbons
cannot enter into the hydrogen-bonded structure of
water and hence are only slightly soluble.

+Polar solvents

When additional polar groups are present in the

molecule, as found in propylene glycol, glycerin, and
tartaric acid, water solubility increases greatly.

Branching of the carbon chain reduces the nonpolar effect and leads to
increased water solubility.
Tertiary butyl alcohol is miscible in all proportions with water, whereas nbutyl alcohol dissolves to the extent of about 8 g/100 mL of water at
20C.

tert-Butanol

n-Butanol

+
Hydrogen bonding is the
attractive
interaction
of
a
hydrogen
atom
with
an
electronegative atom, such as
nitrogen, oxygen

Dipole-dipole forces are electrostatic

interactions of permanent dipoles in
molecules.

Non polar solvents

Non-polar solvents are unable to reduce the attraction

between the ions of strong and weak electrolytes because
of the solvents' low dielectric constants.

They are unable to form hydrogen bonds with non

electrolytes.

Non polar solvents can dissolve non polar solutes through

weak van der Waals forces

Example: solutions of oils & fats in carbon tetrachloride

Polyethylene glycol 400
or benzene.
Castor oil

Semi polar solvents

Semi polar solvents, such as ketones can induce a

certain degree of polarity in non polar solvent molecules.
For example, benzene, which is readily polarizable,
becomes soluble in alcohol

They can act as intermediate solvents to bring about

miscibility of polar & non polar liquids.

Example: acetone increases solubility of ether in

water.
Propylene glycol has been shown to increase the mutual
solubility of water and peppermint oil and of water and
benzyl benzoate

Polarity as Dielectric Constant of

Solvent, decrease , the solubility
also decrease

Polarity

The solubility of the drug substance is attributable in large part

to the polarity of the solvent, often expressed in terms of dipole
moment, related to the dielectric constant.

Solvents with high dielectric constants dissolve ionic compounds

(polar drugs) readily because of iondipole interactions,

Solvents with low dielectric constants dissolve hydrophobic

substances (non-polar drugs)

polar solvents, with examples such as water and glycerin;

non-polar solvents, with example such as oils.

Solvents with intermediate dielectric constants are classified as

semipolar.

Types of solutions
Solutions of pharmaceutical importance include:

Gases in liquids

Liquids in liquids

Solids in liquids

+ Solubility of gases in liquids

When the pressure above

the solution is released
(decreases), the solubility
of the gas decreases
As
the
temperature
increases the solubility of
gases decreases

+Solubility of liquids in liquids

Preparation of pharmaceutical solutions involves mixing of 2 or more liquids

Alcohol & water to form hydroalcoholic solutions

volatile oils & water to form aromatic waters

volatile oils & alcohols to form spirits , elixirs

Liquid-liquid systems may be divided into 2 categories:

1.

Systems showing complete miscibility such as alcohol & water, glycerin &
alcohol, benzene & carbon tetrachloride.

2.

Systems showing Partial miscibility as phenol and water; two liquid

layers are formed each containing some of the other liquid in the
dissolved state.
The term miscibility refers to the mutual solubility of the
components in liquid-liquid systems.

+
Solubility of liquids in liquids

Complete miscibility occurs when: The adhesive

forces between different molecules (A-B) >> cohesive
forces between like molecules (A-A or B-B).

Polar and semipolar solvents, such as water and

alcohol, glycerin and alcohol, and alcohol and acetone,
are said to be completely miscible because they mix
in all proportions.

Nonpolar solvents such as benzene and carbon

tetrachloride are also completely miscible.

+
Solubility of liquids in liquids

Partial miscibility results when: Cohesive forces of the constituents

of a mixture are quite different, e.g. water (A) and hexane (B). A-A
B-B.

When certain amounts of water and ether or water and phenol are
mixed, two liquid layers are formed, each containing some of the
other liquid in the dissolved state.

The effect of temperature on the miscibility of two-component liquids

is expressed by phase diagrams.

In the phase diagrams of two-component liquids, the mixture will

have an upper critical solution temperature, a lower critical solution
temperature or both.

+
Three-Component Systems
Polyethylene glycol

Peppermint oil

water

+
Three-Component Systems

Methyl salicylate

IPA

water

Solubility of solids in
liquids

Solubility
of
solids
in
liquids
+
Factors influencing solubility
1- Particle size (surface area) of drug particles
Particle size surface area Solubility

+
Solubility of solids in liquids
Factors influencing solubility

o So is the solubility of large particles

o S is the solubility of fine particles
o is the surface tension of the
particles
o V is molar volume
o T is the absolute temperature
o r is the radius of the fine particle
o R is the gas constant

+
Example

A solid is to be comminuted so as to increase its

solubility by 10%, that is s/so is to become 1.10

What must be the final particle size, assuming that the

surface tension of the solid is 100 dynes/cm and the
volume per mile is 50 cm3? The temperature is 27oC

Answer: 0.042m

+
Solubility of solids in liquids
Factors influencing solubility
2- Molecular size

Molecular size will affect the solubility.

The larger the molecule or the higher its molecular weight

the less soluble the substance.

Larger molecules are more difficult to surround with

solvent molecules in order to solvate the substance.

In the case of organic compounds the amount of carbon

branching will increase the solubility since more branching
will reduce the size (or volume) of the molecule and make
it easier to solvate the molecules with solvent

+
Solubility of solids in liquids
Factors influencing solubility
3- The boiling point of liquids and the melting point
of solids:
Both reflect the strengths of interactions between the
molecules in the pure liquid or the solid state.
In general, aqueous solubility decreases with increasing
boiling point and melting point.

+
Solubility of solids in liquids
Factors influencing solubility
4-The influence of substituents on the solubility of
molecules in water can be due to their effect on the
properties of the solid or liquid (for example, on its
molecular cohesion, or to the effect of the substituent
on its interaction with water molecules.
Substituents can be classified as either hydrophobic or
hydrophilic, depending on their polarity

+
Influence of substituents on
the solubility

Polar groups such as OH capable of

hydrogen
bonding
with
water
molecules impart high solubility

Non-polar groups such as CH3 and

Cl are hydrophobic and impart low
solubility.

Ionization
of
the
substituent
increases solubility, e.g. COOH and
NH2 are slightly hydrophilic whereas
COO and NH3 are very hydrophilic.

Influence of substituents on
the solubility
The position of the substituent on the molecule can
influence its effect on solubility, for example the aqueous
solubilities of o-, m- and p-dihydroxybenzenes

Solubility of solids in liquids

Factors influencing solubility

5-Temperature

Temperature will affect solubility. If the solution process absorbs

energy then the solubility will be increased as the temperature
is increased.

If the solution process releases energy then the solubility will

decrease with increasing temperature.

Generally, an increase in the temperature of the solution

increases the solubility of a solid solute.

A few solid solutes are less soluble in warm solutions.

For all gases, solubility decreases as the temperature of the

solution increases.

Solubility of solids in liquids

Factors influencing
solubility
6-Crystal properties
Polymorphic Crystals, Solvates, Amorphous forms

Polymorphs have the same chemical structure but different

physical properties, such as solubility, density, hardness, and
compression
characteristics
A drug that exists
as an amorphous form (non crystalline form)
generally dissolves more rapidly than the same drug in
crystalline form

+
Solubility of solids in liquids
Factors influencing
solubility
7- PH

is one of the primary influences on the solubility of most drugs that

contain ionizable groups

Large number of drugs are weak acids or weak base.

Solubility depends on the degree of ionization.

Degree of ionization depends on the pH

About 85% of marketed drugs contain functional groups

that are ionised to some extent at physiological pH (pH 1.5
8).

+Carboxylic

acids
containing more than
five
carbons
are
relatively insoluble in
water, they react with
dilute sodium hydroxide,
carbonates
and
bicarbonates
As
the
number
to form
of
soluble salts.
carbons
in a carboxylic
acid series becomes
greater,
the
boiling
point increases and the
solubility
in
water
decreases.

carboxyl group (RCO2H)

+
Carboxylic acids with 12 to 20 carbon atoms are often referred to
as fatty acids
Fatty acids containing more than 10 carbon atoms form soluble
soaps with the alkali metals. They are soluble in solvents having
low dielectric constants; for example, oleic acid (C17H33COOH) is
insoluble in water but is soluble in alcohol and in ether.
Benzoic acid is soluble in sodium hydroxide solution
Phenol is weakly acidic and only slightly soluble in water but quite
solution in dilute NaOH solution.
Organic compounds containing a basic nitrogen atom
Most of these weak electrolytes are not very soluble in water but are
soluble in dilute solutions of acids

HP H 2O H 3O P

[ H 3O ][ P ]
Ka
[ HP ]

[
P
]

log K a log[ H 3O ] log(

)
[ HP ]

[
P
]

log[ H 3O ] log K a log(

)
[ HP ]

S The total solubility of

drug ( un-ionized + ionized)

S [ HP ] [ P ]

S solubility of the un-ionized form of drug in solution

S [HP ]

S S
pH p pK a log
S

+ The equation relating the solubility, S, of

an acidic drug to the pH of the solution
is:

Acidic drugs
S S
pH pK a log
S

Henderson-Hasselbalch

S The total solubility of the drug (un-ionized + ionized)

The solubility of the un-ionized form of the drug

pH is the pH below which the drug separates from solution

as the undissociated acid.
From equation we can calculate:
If the pH of the solution is known then we can calculate the solubility of
an acidic drug at that pH.
minimum pH that must be maintained in order" to prevent precipitation
from a solution of known concentration.

BH 2OBH OH

[
BH
]
log K b log[ OH ] log(
)
[ B]

[ BH ][OH ]
Kb
[ B]

[ BH ]
log[ OH ] log K b log(
)
[ B]

[ BH ]
14 pH 14 pK a log(
)
[ B]
[ B]
pH pK a log(
)

[ BH ]

[ BH ]
pOH pK b log(
)
[ B]

K b dissociation constant or

basicity
constant for a weak base

S The total solubility of (phenobarbital) un-ionized + ionized S [ B ] [ BH ]

S concentration of the un-ionized form in solutionS [B ]

S
pH pK a log
S S

+The equation relating the solubility, S,

pK a

of

an basic drug to the pH of the solution is:

Henderson-Hasselbalch

Basic drugs

S
pH pK a log
S S

S The total solubility of the drug (un-ionized + ionized)

The solubility of the un-ionized form of the drug

The pH is the pH above which the drug begins to precipitate from

solution as the free base
From equation we can calculate:
If the pH of the solution is known then we can calculate the solubility of
an basic drug at that pH.
minimum pH that must be maintained in order" to prevent precipitation
from a solution of known concentration.

Ionization of drugs
For acidic drug
HP H 2O H 3O P
S S
pH pK a log
S
S [ HP ] [ P ]

S [HP ]

pH = pKa + log
[P ]
pH

pK

log(
)
[ionized drug]
a
[ HP ]
[un-ionized drug]

For basic drug

B H 2O BH OH
pH pK a log

S
S S

S [ B ] [ BH ]

S [B]
[ B]
pH pK a log(
)

[ BH ]
pH = pKa + log
drug]

[un-ionized
[ionized drug]

Below what pH will phenobarbital begin to separate

+
from a solution having an initial concentration of
5% (w/v)?
The molar solubility of phenobarbital, So, is 0.005
and the pKa is 7.41 at 25C.
The molecular weight of sodium phenobarbital is
254.

S S
pH p pK a log
S

5 gm

50 gm / Liter
0.1L 1L

Weight
50
Molarity

0.1968mole / Liter
Molecular .Weight 254
0.1968 0.005
pH p 7.41 log
7.41 log 38.36 7.41 158 5.826
0.005

Calculate the pHp of a 1% sodium

phenobarbital solution.
From Merck Index:

S S
pH p pK a log
S

i.e. 1% phenobarbital will precipitate at or below a pH of 8.

Example

What is the pH below which sulfadiazine (pKa =

6.48) will begin to precipitate in an infusion
fluid, when the initial molar concentration of
sulfadiazine sodium is
4X 10 -2 mol/ dm 3 and
the solubility of sulfadiazine is 3.07X 10 -4 mol/
The
below which the drug will precipitate is calculated using
dmpH3 ?
equation

S S
pH pK a log
S

Example
Example:
If 8.66 mg/ml procaine solution stable (i.e., no ppt.)
at pH 7.4 given that 1 gm dissolves in 200 ml water
and pka = 8.05.

S
pH pK a log
S S

S = 8.66 mg/ml
pka = 8.05

= 1gm/ 200ml = 1000mg/200 ml =5 mg/ ml

pH = 8.05 + log (5/ 8.66 5)

pH = 8.05 + log 1.37
pH = 8.19
This is maximum pH and 7.4 is less than 8.19,
therefore solution is stable and no ppt. occurs.

Ionization and pH

Strong vs. weak acids and bases

1. Strong ionized at all pHs
2. Weak only ionized at certain pHs (most drugs are
weak acids or weak bases
3. Ionized drugs are not very lipid soluble- only
nonionized form of drug crosses membrane readily
4. Percent ionization is pH dependent
5. pKa is the negative log of the ionization constant and
is
equal to the pH at which a drug is 50% ionized
6. Weak acids become highly ionized as pH increases
7. Weak bases become highly ionized as pH decreases

Computing Ionization Ratios

According

to the Henderson-Hasselbalch equation,

the difference between the pH of the solution and
the pKa of the drug is the common logarithm of
the ratio of ionized to unionized forms of the drug.

For

acid drugs

log(ionized/unionized) = pH - pKa, or
ratio of ionized to unionized is 10X / 1, where
X = pH pKa

[P ]
pH pK a log(
)
[ HP ]

+
Computing ionization ratios
For basic drugs, everything is the same except that the
ratio reverses:
Log(unionized/ionized) = pH pKa, or
Ratio of unionized to ionized is 10X / 1, where
X = pH pKa
[P ]
pH pK a log(
)
[ HP ]

pH pK a log(

[ B]
)

[ BH ]

Acidic drugs
[P ]
pH pK a log(
)
[ HP ]

Basic drugs
pH pK a log(

[ B]
)

[ BH ]

Lipoid diffusion- weak acids and weak

+
bases
Henderson-Hasselbalch equation
Determines

extent of ionization

pKa = pH at which 50% of drug is ionized.

WEAK

ACIDS:

[P ]
pH pK a log(
)
[ HP ]

log (ionized form/nonionized form)= pH pKa

WEAK

BASES:

pH pK a log(

[ B]
)

[ BH ]

log (nonionized form/ionized form)= pH pKa

PASSIVE DIFFUSION
water
soluble
drug (ionized or
polar) is readily
absorbed
via
aqueous
channels
or
pores
in
cell
membrane.
Lipid
soluble
drug
(nonionized
or
non polar) is
readily absorbed
via
cell
membrane

+
Examples
P weak acid, has a pKa of 5.5. Taken orally, it
is in a stomach solution of pH 3.5.
pH pKa = 3.5 5.5 = -2
Since it is an acid drug, we use the
alphabetical formula ionized/unionized.
ionized/unionized = 10-2/1= 1/100
For every 1 molecule of P that is ionized, 100
are unionized. P in the stomach is highly fat
soluble.

+
But look what happens
The highly fat soluble P readily crosses the
stomach membranes and enters blood
plasma, which has a pH of 7.5
pH pKa = 7.5 5.5 = 2
ionized/unionized = 102/1= 100/1
For every 100 molecules of P that are ionized,
only 1 is unionized. P in the blood is not very
fat soluble.
P will be subject to ion trapping.

Percent Ionization of Aspirin [Stomach]

+ pKa of Aspirin
[weak acid] = 3.4 (50% HA and A- at pH 3.4)
pH stomach = 1.4
pH blood = 7.4
pH = pKa + log (A-)/(HA) [ H-H equation]
pH - pKa = log (A-)/(HA)
1.4 3.4 = - 2 log of 0.01= -2 (stomach)
A- / HA= 0.01/ 1 so HA is 100 fold greater than A
HA moves from the stomach into the blood (good absorption)
Percent Ionization of Aspirin [Blood]
Stomach (pH=1.4)
Blood (pH=7.4)
pH - pKa = log (A-)/(HA)
7.4 3.4 = 4
log of 10,000 = 4 (blood)
A- / HA= 10,000/ 1
so A- is 10,000 fold greater than HA

+
Another example
M, a weak base with a pKa of 7.5 is dissolved in the
stomach, pH 3.5
pH pKa = 3.5 7.5 = -4
Since M is a base drug, we use the ratio backwards:
unionized/ionized.
unionized/ionized = 10-4/1= 1/10,000
In the stomach, M will be mostly ionized, and not very fat
soluble.

+
But
If we inject M intravenously into the blood, with a pH of 7.5,
pH pKa = 7.5 7.5 = 0
unionized/ionized = 100 = 1/1
In the blood, M will be equally ionized and unionized.

+
Percent Ionization of Codeine
[Stomach]

CODEINE (weak base) pKa = 7.9

Stomach pH=1.9 Blood pH =7.4

pH - pKa = log(B)/(BH+) [H-H equation]

1.9 - 7.9 = -6 log 0.0000001 = -6 [Stomach]
B/ BH+ = 0.000001/1 so BH+ is 1,000,000 fold greater than
B.
Little B (codeine) is absorbed into the blood (poor
absorption)

+
An oddity
Caffeine is a base drug, but it has a pKa of 0.5
pH pKa = 3.5 0.5 = 3
Since caffeine is a base drug, we use the ratio
backwards: unionized/ionized.
unionized/ionized = 103/1= 1000/1
In

the stomach, caffeine will be mostly unionized, and

fat soluble!

In

the blood, caffeine will be even more unionized and

fat soluble:

pH pKa = 7.5 0.5 = 7, ratio = 107/1= 10,000,000/1.

+
WEAK ACIDS
log (ionized form/nonionized form)= pH pKa

A drug is a weak acid.

pKa is 3.5.

If stomach pH is 1.5, what percentage of drug will be in

absorbable form?

pH pKa = 1.5 3.5 = - 2

pH = pKa + log
drug]
(pH) (pKa)

Weak acid
% nonionized

[ionized drug] / [un-ionized

-2 -1 0 1 2
99 90 50 10 1

Remember absorbable means

nonionized !

pH pka = -2

This (-2) in the table for weak acid matches to 99%.

And this is supposed to be the nonionized form, which

is same as absorbable form that is asked in this
problem.

Hence the absorbable form is 99%.

+
Weak bases
log (nonionized form/ionized form)= (pH)
(pKa)
A

drug is a weak base.

pKa

is 8.

At

pH 6, what percentage of drug will be in the

ionized form?
pH pKa = 6 8 = - 2

(pH) (pKa)

Weak base
% nonionized

-2 -1 0 1 2
1 10 50 90 99

Please remember ionized means

nonabsorbable !

pH pka has come as -2.

In the table for weak base, -2 matches with 1%. But

this 1% is nonionized form. What is asked is ionized.

So, ionized is 100 1 = 99%.

+
Co-solvent effect on
solubility
The
nonelectrolytes and the undissociated
molecules of weak electrolytes more soluble in a
mixture of solvents than in one solvent alone.
This phenomenon is known as cosolvency, and
the solvents that, in combination, increase the
solubility of the solute are called cosolvents.
The

presence of a co-solvent can

increase the solubility of hydrophobic
organic chemicals

Co-solvents

can completely change the

solvation properties of water

+
Fig. 9-5. The influence
of
alcohol
concentration on the
dissociation
constant
of phenobarbital.

Distribution of Solutes between

Immiscible Solvents

States that a solute will distribute itself between two

immiscible solvents so that the ratio of its
concentration in each solvent is equal to the ratio of its
solubility in each one

CO
Kd = --------CW
Co= molar conc in organic layer
Cw= molar conc in aqueous layer
Kd= distribution constant, distribution ratio,
distribution coefficient, or partition coefficient

Partition coefficients
P

Xaqueous

Xoctanol

Partition coefficient P (usually expressed as log10P or logP) is defined as:

P=

[X]octanol
[X]aqueous

P is a measure of the relative affinity of a molecule for the lipid and

aqueous phases in the absence of ionisation.
1-Octanol is the most frequently used lipid phase in pharmaceutical
research. This is because:
It has a polar and non polar region (like a membrane phospholipid)
Po/w is fairly easy to measure
Po/w often correlates well with many biological properties

Application

Extraction

Preservative action of weak acids in o/w systems

Drug absorption/distribution/action

Application

Extraction

it

is used to determine the efficiency with

which one solvent can extract a compound
from a second solvent
extract natural drugs from a solvent with
several portions of an immiscible solvent

Application

Preservative action

the concentration of preservative to be used in an emulsion

can be calculated from the distribution law to give the
effective antimicrobial concentration in the water phase

Drug
Absorption/Distribution/Action

Hydrophobic drugs (high partition coefficients) are

preferentially distributed to hydrophobic compartments
such aslipid bilayersof cells

Hydrophilic drugs (low partition coefficients)

preferentially are found in hydrophilic compartments
such asblood serum.

Example
What is the solubility of benzylpenicillin G at
a pH sufficiently low to allow only the
nondissociated form of the drug to be
present?
The pKa of benzylpenicillin G is 2.76 and the
solubility
of the drug
at pH 8.0
is Marcel
0.174
mol/
(From
R. E. Notari, Biopharmaceutics
and Pharmacokinetics,
2 edn,
Dekker,
New York, 1978.)
dm 3
nd

If only the undissociated form is present at low pH then we need

to find S0.

S S
pH pK a log
S
0.174 S
8.0 2.76 log
5.24
S
S 0 1 10 6 mol / dm 3

+
In general

solubility increases exponentially as cosolvent fraction

increases.

need 5-10 volume % of cosolvent to see an effect.

extent of solubility enhancement depends on type of

cosolvent and solute

effect is greatest for large, nonpolar solutes

more organic cosolvents have greater effect

propanol>ethanol>methanol