CEUTICS IV

lecture 10b
B) Solubility:

water ,alcohol, propylene glycol

solvent

When a solute dissolves, the substance's inter molecular forces of attraction must be overcome by
forces of attraction between solute and solvent molecules.
This involves breaking the solute-solute forces and the solvent-solvent forces to achieve the
solute-solvent attraction.
solvents

solutes
solubility

solute &solvent

Solvent Polarity:
Most important solvent is H2O to mimic body.
Like dissolves like (

non-polar

poplar

polar

solubility
non-polar

Salts of organic compounds are generally more soluble in water than are the corresponding organic
bases.
Conversely, the organic bases are generally more soluble in organic solvents, including alcohol, than are
the corresponding salt forms.
Relatively insoluble compounds often exhibit incomplete absorption, as for a drug to enter the systemic
circulation to exert a therapeutic effect; it must first be in solution.
One important goal of the pre-formulation effort is to devise a method for making solutions of the
drug.
dissolution

solubility

solubility
therapeutic effect

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particle size
Absorbance

dissolution

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CEUTICS IV

lecture 10b

Factors affecting the solubility of a drug:

1) Effect of temperature:
dosage form

Depend on being endothermic or exothermic

Most commonly, the solution process is endothermic, and thus increasing the solution
temperature increases the drug solubility.
For such solutes as lithium chloride and other hydrochloride salts that are ionized when
dissolved, the process is exothermic such that higher temperature suppresses the solubility.

2) Chemical and physical properties of both the solute and the solvent.
3) Pressure
CO2

pressure

4) The acidity or basicity of the solution.

5) The state of subdivision of the solute (i.e particle sizeMolecular level)
6) The physical agitation

applied to the solution during the dissolving process.

The solubility of a pure chemical substance at a given temperature and pressure is constant;
however, its rate of solution, that is, the speed at which it dissolves, depends upon the particle size of
the substance and the extent of agitation.
The more fine the powder, the greater the surface area that comes in contact with the solvent,
and e more rapid the dissolving process.
surface area

particle size

The greater the agitation, the more unsaturated solvent passes over the drug and the
faster the formation of the solution.
If the solubility of the drug substance is less than desirable, some methods that depend on the
chemical nature of the drug and the type of drug product can be used.

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CEUTICS IV

lecture 10b
solubility

How to increase solubility??? Methods used for enhancing drug solubility:

1.

The chemical modification of the drug through either the formation of salt or ester or the
introduction of polar groups (OH, CHO, COH, CHOH, CH2OH, COOH, NO2, CO, NH/ and SO3H) which
are capable of forming hydrogen bonds with water.

polar functional gp
H-bond
2. Selection of solubilizing agent;

a. Example: The solubility of iodine in water is 0.03%. However, through the use of an aqueous
solution of potassium or sodium iodide as the solvent, much larger amounts of iodine may
be dissolved as the result of the formation of a water-soluble complex with the iodide salt.
This reaction is taken advantage of for example, in Iodine Topical Solution, USP, prepared to
contain about 2% of iodine and 2.4% of sodium iodide.

salting in

salt
sol. Complex

KI

3. Utilization of co-solvents.
PEG or glycerin

4. The adjustment of the pH of the solvent in which the drug is to be dissolved to enhance solubility.
However, weak acidic or basic drugs... may require extremes in pH that are outside accepted physiologic
limits or may cause stability problems with formulation ingredients. Adjustment of pH usually has little
effect on the solubility of non-electrolytes.
Example: The weak bases, including many of the alkaloids (atropine, codeine, and
morphine), antihistamines (diphenyhydram ineand tripelennamine), and local anesthetics
(cocaine, procaine, and tetracaine) are not very water-soluble, so they are prepared as acid
salts to enable the preparation of their aqueous solutions.

wake base
aq. soln

sol.
acid salt

pH

acid

5. Micronization.
surface

particle size

solid crystals
area

6. Solid dispersion.
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CEUTICS IV

lecture 10b

Determination of solubility :by Equilibrium solubility method

:
xss amount of drug
filterate

25

solubility

solvent
24

10

shake

Excess of the drug is placed in a solvent and shaken at a constant temperature over a prolonged
period of time until equilibrium is obtained (in the range 60 to 72 hours).
Chemical analysis of the drug content in solution is performed to determine degree of solubility .
mg/ml W/V

Solubility and Distribution Phenomena

If a solute is added to a mixture of two immiscible liquids, it will distribute between the two phases and reach
equilibrium at a constant temperature.
The distribution of the solute (un-aggregated & un-dissociated) between the two immiscible layers can
be described as:

K=Cu/CL

application of solubility

partition coefficient = distribution coefficient

lipid

P.C
polar

membrane

K is the distribution constant or partition constant

Cu is the concentration of the drug in the upper phase
CL is the Concentration of the drug in the lower phase.

This information can be effectively used in the:

a) Extraction of crude drugs.

b) Recovery of antibiotics from fermentation broths.
c) Recovery of biotechnology-derived drugs from bacterial cultures
d) Extraction of drugs from biologic fluids for therapeutic drug monitoring
liq.liq

plasma
shake

organic solvent asCCl4 or CHCl3)

extraction

e) Absorption of drugs from dosage forms (ointments, suppositories, transdermal patches)

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CEUTICS IV

lecture 10b
base
base

f) Study of the distribution of flavoring oil between oil and water phases of emulsions.
flavoring agent

extraction

oil in water emulsion

solvent

extracted

To derive a formula showing the amount remaining unextracted after " n" no. of extractions,
suppose:

Xo = amount of drug dissolved in V1

V1

V1 = volume of solvent A

V2 = volume of solvent B (extracting solvent)

V1

X1 = amount remaining in original solvent.

extraction

V1

extraction

= [
]
+
V1 = X

V2

Xn=amount remaining after n extractions

n Xn efficacy
extraction

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CEUTICS IV

lecture 10b

Examples:remaining

extracted

1- How many gm of organic substance are extracted with 100ml of ether from 100ml of 1% aq. Solution
when these 100ml of ether were added:
a) At once
b) On 2 portions
P.C. of the organic substance between ether and H2O =20
V2 (ether) =100ml

a) at once :
extraction
P.C

ether

V1,V2,n,X0

P.C (ether & water)

water to ether

P.C=20

ether to water

20

20 1

P.C=20

Ether

water
P.C=1/20

= [

= [

extracted

] = . .

extraction

Amount extracted = 1-0.04 =-0.96 gm.

V2=50

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n=2

extraction

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CEUTICS IV

lecture 10b

a) On 2 portions

= [

] = . .

Amount extracted = 1- 0.008 =-0.992 gm.

n

extraction

extracted

extraction
remaining

2- If the partition coefficient of a substance between solvent A and B=9. How many gms of this sub.
Remains in 200ml of 4% solution in solvent B when extracted with 100ml solvent A. If these
100ml were added:

a) at once

b) on 2 equal portions

c) on 4 equal

portions.

= [

a)

]
+

=
= .

= [

b)

= [

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= [

] = . .

] = . .

] = .

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CEUTICS IV

lecture 10b

solubility

c) Partition Coefficient and Dissociation Constant (pKa):

The oil/water partition coefficient is a measure of a molecule's lipophilic character; that is, its
preference for the hydrophilic or lipophilic phase.
The partition coefficient should be considered in developing a drug substance into a dosage
form.
The partition coefficient (P) represents the ratio of the drug distribution in a two-phase system of oil
solvent and aqueous phase. Using octanol-water as an example, it is defined as:
organic layer
std.for organic layer

octanol

p.c
pKa

aq.layer

A. For non-ionizable drugs:

P ( Partition Coefficient) =

[Conc. of drug in octanol]

[Cone. of drug in water]

P is dependent on the drug concentration only if the drug molecules have a tendency to associate
in solution.

B. For an ionizable drug, the following equation is applicable:

P=

[Cone. of drug in octanol]

(1- ) [Cone. of drug in water]

Where equals the degree (extent) of ionization.

The determination of the degree of ionization or pKa value of the drug substance is an important
physical-chemical characteristic relative to evaluation of possible effects on absorption from
various sites of administration.
Dissociation constant or pKa is usually determined by potentiometric titration.

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CEUTICS IV

lecture 10b
Ka

Pka

P= -log

Ka

PKa= 4
log Ka=4 so, Ka=10000

unionized
Cell membranes are more permeable to the unionized forms of drugs than to their
ionized forms, mainly because of:

1) the greater lipid solubility of the unionized forms

more lipid soluble

lipid bilayer

membrane

2) The highly charged nature of the cell membrane binding or repelling of the ionized drug and
thereby decreases cell penetration.
ionized

charge

membranes

3) Ions become hydrated through association with water molecules, resulting in larger particles
than the undissociated molecule and again decreased penetrating capability.
ionized

membrane

unionized
ionization in basic

acidic drugs

PH

PKa ionization
medium

The degree of a drug's ionization depends both on the pH of the solution in which it is
presented to the biologic membrane and on the pKa, or dissociation constant, of the drug (whether
an acid or base).
drug

pKa

medium

pH

The concept of pKa is derived from the Henderson-Hasselbalch equation and is:
equations

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CEUTICS IV

lecture 10b

For an acid:
Ionized conc. (salt)
PH = pKa + log
Unionized conc. (acid)

acid

salt
PH

ratio

absorption

acid

base

acid or salt

pH

For a base:

Unionized conc. (base)

PH = pKa + log
Ionized conc. (salt)

Since the pH of body fluids varies (stomach, = pH I; lumen of the intestine, pH 6.6; blood; plasma,

= pH 7.4), the absorption of a drug from various body fluids will differ and may dictate to some
extent the type of dosage form and the route of administration preferred for a given drug.

By rearranging the equation for an acid:

Unionized concentration (acid)

pKa - pH = log
Ionized concentration (salt)
Thus pKa may be defined as the pH at which a drug is 50% ionized.
For example, Phenobarbital has a pKa value of about 7.4, and in plasma (pH 7.4) it is
present as ionized and unionized forms in equal amounts
phenobarbital
unionized

pKa

pH
1

log zero
& ionized

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CEUTICS IV

lecture 10b

Example:

1- If a weak acid having a pKa of 4 is assumed to be in an environment of gastric juice with a pH of I,

what is the ratio of unionized to ionized drug particles? Comment on your result.
Answer:
Unionized concentration (acid) ----pKa - pH = log
Ionized concentration (salt)
For acidic drugs with pKa 4 in stomach at PH 1 the conc. Of unionized form is
1000 times than the ionized

Acid
4-1= log
Salt
So, acid / salt = shift log 3 = 1000
stomach

acidic form

The ratio of unionized to ionized drug particles would be about 1000 to 1, and gastric absorption
would be excellent.

basic drugs
For basic drug with pKa 4 in intestine at PH 7 the conc. Of ionized form is
1000 times than the unionized

Salt
PH pKa = log
Acid
Salt
7 4=log
Acid

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CEUTICS IV

lecture 10b

So, salt/acid = 1000

pH

intestine

basic medium

lipophilicity

basic drug

esterification

enteric coating

acidity

What is the salt/acid ratio of an acetic/acetate buffer solution of pH 5? Express your

results on percentage basis. pKa acetic acid = 4.76
ratio

Ionized conc. (salt)

PH = pKa + log
Unionized conc. (acid)

5 = 4.76 + log salt / acid

1.74
Salt/Acid = 1.74/1

100X
%Salt = (1.74/2.74) X 100 = 63.47%
%Acid= (1/2.74) X 100 = 36.63%

dissolution rate

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