Solution and Solubility

Ossama sayed

Definitions
A solution: a mixture of two or more components that form
a homogeneous single phase, down to the motecular level.
Solution= solvent+ solute as molecule(as sucrose in
water) or ions (as sodium chloride in water) throughout the
solvent.
Dissolution: the transfer of molecules or ions from a solid
state into solution.
Saturated solution: is one in which the solution is in
equilibrium with excess undissolved solid at a definite
temperature.

Definitions
Unsaturated or subsaturated: is one containing be
dissolved solute in a concentration below that
necessary for complete saturation at a definite
temperature.
Supersaturated solution: is one that contains more of
dissolved solute than it would normally contain at a
definite temperature where the undissolved solute
present.

Definitions
Some salts such as sodium thiosulfate- and sodium acetate
can be dissolved in large amounts at an elevated
temperature and upon cooling, fail to crystallize from the
solution.
These solutions are meta stable and can be converted to a
soluble saturated solution (deposit their excess of solute) by:

(a) Seeding the solution with a small crystal of solute.

(b) Scratching the wall of the container in contact with the
solution.
(c) Vigorous agitation or shaking.

Definitions
Solubility is the concentration of solute in a saturated solution at
a certain temperature.
Solubility is important to the pharmacist because it helps him to:

[1] Assess the purity of the drug.

[2] Determine the possible dosage form.
[3] Qualitatively and quantitatively analyze the dug in the dosage
form.
[4] Expect bioavailability of drugs from solid dosage forms since
the most important stage is the dissolution of solid drug particles
to form a solution in die gastrointestinal tract.

Solubility Expression
1- Quantitative terms:
Molar Solution: This is the number of moles of solute
contained in 1 liter of solution. Thus, solutions of equal
molarity contain the same number of solute molecules
in a given volume of solution. (unit: mol.L-1)
Molal Solution: The number of moles of solute dissolved
in 1000 gm of solvent.
Molal solution does not depend on temperature while
molar solution being dependent on temperature.

Solubility Expression
Mole Fraction:

Percent by weight/weight:% (w/w)

The number of grams of solutes per 100 gms of solution.
Percent weight/volume:% (w/v)
The number of grams of solutes per 100 milliliters of
solution.

Solubility Expression
Percent volume/volume: % (v/v)
The number of milliliters of solutes per 100 milliliters of
solution.
** if unit is not stated: if solid in liquid means w/v %
if liquid in liquid means v/v %

Solubility Expression
Example:
The solubility of a drug in water is 41.5 gm per 1000 ml
of solution at 18 C. The density of the solution was
1.0375 and the mol. Wt of the drug is 151.9 gm.
1- Express the solubility of the drug in terms of molarity,
molality and % by weight.
2- Calculate the mole fraction and mole percent of both
components of the solution.

Solubility Expression
2- Qualitative terms:

Dissolution Process

Dissolution Process
Solvents may act as:
1- Polar solvents:
The process of solution of
ionic salt in water involves
separation of the cations
and anions of the salt with
attendant orientation of
molecules of water around
the ions.

Dissolution Process
Salvation is the orientation of solvent molecules
around the ions of the solute= hydration if the
solvent is water.
Salvation is possible only when the solvent is
highly polar where the dipoles of the solvent are
attracted to and held by the ions of the solute.
The solvent must also possess the ability to keep
the solvated, charged ions apart with a minimum
requirement of energy.

Dissolution Process
Mechanisms of salvation:
1- Formation of dipoles with which to overcome
the attractions between ions of an ionic salt.
2- Breakage of a covalent bond to produce an ionic
compound.
3- Formation of association complexes with a
solute (hydrogen bond formation).

Dissolution Process
2- Non polar Solvents:
Non polar liquids are incapable of dissolving polar
compounds.
In general they can only dissolve other non polar
substances in which the bonds between molecules
are weak.
The forces involved are usualiy of the induced
dipole-induced dipole type.

Dissolution Process
3- Semi-polar Solvents:
E.g.: Alcohols and ketones
Can induce certain degree of polarity in non polar solvent molecules.
benzene which is readily polarizable, becomes soluble in alcohol.
Alcohol molecule induces in the benzene molecule a temporary
dipole, which forms an association complex with the alcohol
molecules.
A binding force of this kind is referred to as a permanent dipoleinduced dipole force.
Semi polar compounds may as well act as intermediate solvents to
bring about miscibility of polar and non polar liquids.
Accordingly, acetone increases the solubility of ether in water.

Factors Affecting Solubility

1. Temperature:
.If the increase of temperature is accompanied by
an increase in the solubility of solid in liquid the
solubility process is endothermic as in case of
Potassium nitrate with +ve solubility coefficient.
.If the increase of temperature is accompanied by a
decrease in the solubility of solid in liquid the
solubility process is exothermic as in case of
Calcium Hydroxide with ve solubility coefficient.

Factors Affecting Solubility

Factors Affecting Solubility

2- Molecular Structure of Solute:
A) Introduction of hydrophilic groups increase the
solubility of drugs to around 100-fold
-OH, -NH3+ , -COOH > -NH2, -CHO > -OCH3, -NO2
B) Increasing the number of polar groups increasing its
solubility in water (e.g. Pyrogallol is more soluble than
phenol)
C) The relative position of the groups:

Factors Affecting Solubility

D) Isomers: branching of chains induce change in
molecular surface area change placing into solvent
cavity
E) High melting point low solubility high cohesive
force (in case of inorganic solutes)
F) Salts > base or acid in solubility.

Factors Affecting Solubility

3- Crystallization, polymorphism and solvation:
** Amorphous form is > soluble than crystalline for ???
*** Polymorphism: the phenomenon of the presence of
the drug in more than one crystal form known as
polymorphs due to the different conditions of
crystallization.
*** polymorphs are different in solubility different
energires
**** conversion of metastable forms to stable forms.

Factors Affecting Solubility

*** Solvation: or hydrate forms less soluble than
unsolvated forms ???
4) Particle size of solids:
Decreasing particle size increasing solubility ?
Suspension ???

Factors Affecting Solubility

5) Added substances ..
I- Effect of salts on solubility of nonelectrolytes: (Salting out)
* process by which solubility of the non-electrolyte
is decreased by addition of an electrolyte,

* The added electrolyte requires water for its

hydration and thus decreases the amount of water
available for hydration of the non-electrolyte,

Factors Affecting Solubility

Salting In
* process by which solubility of the non-electrolyte is increased by the addition of an
organic acid salt
e.g. Na benzoate, Na acetate and K citrate this process is also called Hydrotropy and
the salt is known as Hydrotropic salt.
Example
Na benzoate is used to increase aqueous solubility of caffeine.

Factors Affecting Solubility

II- Effect of Common Ion:* solubility of slightly soluble electrolytes is decreased by the addition of second
electrolyte having an ion in common with the salt;
e.g. solubility of Ca oxalate is decreased in presence of ammonium oxalate

Factors Affecting Solubility

Exception

* deviation may occur due to formation of a soluble complex between the two salts
thus solubility would be increased;

e.g. Addition of KI to HgI2,

2KI + HgI2 k2HgI4
Soluble complex

Factors Affecting Solubility

III- Effect of semipolar solvents on solubility of Nonpolar solutes Cosolvency:
* process by which solubility of nonpolar molecules is increased by addition of a watermiscible solvent called cosolvent in which the drug has good solubility;
e.g. Ethanol, Glycerol, Sorbitol and propylene glycol.
IV. Effect of semipolar solvents on solubility of Sparingly soluble electrolytes:
Depends on the Dielectric constant of the solvent.
solvents having High DEC like water (DEC = 80) can induce ionization of the electrolyte
and allow its dissociation.
Adding another solvent with lower DEC will decrease the ability of water to dissolve
electrolytes. (solubility of NaCl in water will decrease upon addition of alcohol)

Factors Affecting Solubility

Dielectric Requirement for solubility
* Every solute has a maximum solubility at certain DEC,
* A series of dioxane-water mixtures with known DEC are prepared;
The drug is dissolved in these mixtures and the DEC at which maximum solubility
occurs is noted.
why dioxane is used ?
1- Because it's miscible with water.
2- dioxane-water mixture would give a wide range of DEC.

Factors Affecting Solubility

For a mixture of two solvents, DEC can be calculated as follow;
e.g. mixture of 60% by weight alcohol and 40% by weight water
DECwater = 80 , DECalcohol = 25
Approximate DEC = 60
40
x 25
x80 47
100
100
Since DEC of glycerin is 46 which is close to that of the above mixture, and so it's
expected that NaCl has equal solubility in both glycerin and 60% alcohol solution.

Factors Affecting Solubility

V- Effect of Surface Active Agents ...
* when a surfactant is added to a liquid;
- At low concentration:
SAA molecules migrate to the liquid-air interface.
- At high concentration:
Molecules are forced into the bulk of the liquid and at a specific concn (CMC),
molecules begin to form aggregates or micelles.

Factors Affecting Solubility

Solubilization
* A water insoluble drug could be solubilized in the hydrophilic core of the micelle,
e.g.
- phenol is more soluble in aqueous soap solution than in water.
- cresol is dissolved in aqueous soap solution which is known as Lysol.

Factors Affecting Solubility

VI- Complex Formation:* solubility of a solute in a liquid may be increased or decreased by addition of a third
substance that form a complex with the solute
e.g. solubility of HgI2 is increased by the addition of KI due to formation of soluble
complex HgI4-- .

Factors Affecting Solubility

6) pH and solubility ...
* Basic drugs are more soluble in acidic solutions where they are ionized;
e.g. Atropine base, Caffeine base
* Total solubility of the basic drug increases as [H +] of the solution increases (i.e. as
pH decreases) according to this equation;

Total solubility = K(s1 K b [ H ] )

Kw

Factors Affecting Solubility

For a basic drug:
S : total solubility (Mole / litre)

SO
PH = pKw pKb + log
S SO

So : solubility of undissolved form in water (Mol/L)

* Acidic drugs are more soluble in basic solutions
where they are ionized,
e.g. phenobarbitol acid, sulfa, penicillin G

Factors Affecting Solubility

total solubility of the acid increases as [H+] of the solution decreases (i.e. as pH
increases);
according to this equation;

Ka
Stotal K s (1
)

[H ]

Factors Affecting Solubility

For an acidic drug :

S SO
PH PK a Log
SO
Problems:
1- what must be the pH an aqueous solution be in order to maintain in solution 10
mg/ml of a weakly acidic drug;
Mol.Wt = 200, Ka = 10-5 and Ks = 0.001 M/L

Factors Affecting Solubility

Solution
S = 10 mg/ml = 10/200 mole/litre = 0.05 mole/litre

PH PK a Log
pH = 5 + log (0.05 0.001) / 0.001 = 6.69

S SO
SO

Factors Affecting Solubility

2- Above what pH will free cocaine begin to precipitate from a solution initially
containing 0.0294 mole/L. the
pKb = 5.59 and its molar solubility is 5.6x10-3
Givens:
S = 0.0294 mole/L
So = 5.6x10 mole/L
-3

pKb = 5.59

pH pK w pK b log

So
S So

pH = 14 5.59 + log [5.6x10-3]/[0.0294 mole/L 5.6x10-3]

= 8.17

Factors Affecting Solubility

3- what is the solubility of penicillin G at a pH sufficiently low to allow the
non-dissociated form of the drug to be present ? the pKa of penicillin G is 2.76
and the solubility of the drug at pH 8 is 0.174 mole/L.
Givens:
S = 0.174 mole/L
pH = 8
pKa = 2.76
8 = 2.76 + log [0.174 So]/So
Solve for So = 1x10-5 mole/L

S SO
PH PK a Log
SO

Rate of solution (Dissolution Rate):

Definition: Rate at which a solute goes into solution
* A solid particle is surrounded by a thin layer of the solvent (stagnant layer)
having a finite thickness however small it may gets;
Note that the thickness of the stagnant layer may get smaller by stirring of the
solution
According to Fick's first law of diffusion:
* Rate of solution:
Rate at which a solute particle diffuses through the stagnant layer to the bulk solution;
The driving force for this diffution is the concentration difference between
concentration in the stagnant layer (C1)and the concentration in the bulk solution(C2).

Rate of solution (Dissolution Rate):

As this difference (C1 C2) increases, the rate of solution increases.
Rate is directly proportional to the surface area of the solid (A cm2)
Rate is inversely proportional to the diffusion path length (l );
Rate of solution =

DA(C1 C 2 )
L

Rate of solution (Dissolution Rate):

Factors Affecting Dissolution Rate:
1- particle size;
As particle size is reduced, surface area would increase and hence Rate would also increase.
2- stirring of solution;
Stirring would decrease the thickness of the stagnant layer and also l will be decreased and
hence rate increased.
* The faster the solution is stirred, the faster the solute will go into solution.
3- saturation solubility Cs:
The larger the Cs the faster the dissolution rate;
4- Viscosity:
As viscosity of the medium is increased, the rate of dissolution is slowed since D is inversely
proportional to viscosity.

THE DISTRIBUTION OF SOLUTES BETWEEN IMMISCIBLE

LIQUIDS AND THE PARTITION COEFFICIENT
If a substance is dissolved in a mixture of two immiscible liquids, the solute is
distributed between the two liquids;
Partition Coefficient is the ratio of the concentration of the solute in the liquid A to that
in liquid B:

K = C A / CB

* Note that if the solute exists as monomer in solvent A and as a dimmer in solvent B,
The partition coefficient would equal;

K = CA / (CB)1/2

* Note that if the solute dissociate into ions:

K = CA / CB(1 a)

Where a is the degree of dissociation

* If K(oil-water) = 2, then K(water-oil) = 1/2

THE DISTRIBUTION OF SOLUTES BETWEEN IMMISCIBLE

LIQUIDS AND THE PARTITION COEFFICIENT
Applications of the distribution law:
1- Extraction (removal of aditve principles from crude drugs).

mass extracted (g)

volume of phase B
K
x
volume used for extraction
remaining mass
* It's more efficient to divide the extracting liquid into a number of equal volumes that
are used successively in extraction rather than to use the total amount of solvent in
one single process.

THE DISTRIBUTION OF SOLUTES BETWEEN IMMISCIBLE

LIQUIDS AND THE PARTITION COEFFICIENT
Example:
If 5 g of drug is dissolved in 100 ml of water and it was
extracted by:
a) 100 ml chloroform
b) 2 x 50 ml chloroform
determine the amount extracted in each case.
K(chloroform-water) = 8

THE DISTRIBUTION OF SOLUTES BETWEEN IMMISCIBLE

LIQUIDS AND THE PARTITION COEFFICIENT
Solution
Suppose that x g of the drug are extracted in chloroform and 5
- x will remain in water;
K

mass extracted (g)

volume of phase B
x
volume used for extraction
remaining mass

a)
X
100
K 8
x
100
(5 x )

solve for x = 4.44 g , and 0.56 g remain in water.

THE DISTRIBUTION OF SOLUTES BETWEEN

IMMISCIBLE
LIQUIDS AND THE PARTITION COEFFICIENT
b) i.
y
100
K 8 x
50 (5 y )

solve for y = 4g and 1g remains

ii.
K 8

solve for z = 0.8 g

z
100
x
50 (1 z )

the total amount extracted by 2x50 ml chloroform = 4 + 0.8 = 4.8 g

which is greater than that extracted by 100 ml chloroform at once.

THE DISTRIBUTION OF SOLUTES BETWEEN

IMMISCIBLE
LIQUIDS AND THE PARTITION COEFFICIENT
2- Relaese of drugs from certain dosage forms:
* The rate of release of drugs from suppositories and ointments into the aqueous body fluids
in affected by the partition coefficient of the drug between the base and the body fluids.
* prolonged release of the drug could also be provided by the effect of partition
coefficient between water immiscible base and body fluids.
3- passage of drugs across membranes:
* the cell membrane acts as a lipoidal barrier surrounding the cell and hence the drug should
possess sufficient lipid solubility to pass though it .
* the partition coeff. Of the drug is important in all processes involving the transport of the
drug throughout the body; e.g
a) Absorption of drug from GIT
b) Distribution of the drug into tissues
c) Penetration of the drug into its site of action

THE DISTRIBUTION OF SOLUTES BETWEEN

IMMISCIBLE
LIQUIDS AND THE PARTITION COEFFICIENT
4- The formulation of solubilized systems:
Solubilization process:
It's the partition of the organic drug between the micelles and the surrounding
aqueous phase
* Activity of the solubilized drug is dependent on its concentration in the aqueous
phase.
5- preservation of emulsions and creams:
Emulsions and creams consists of two immiscible phase (oily and aqueous phase);
* Microorganisms usually grow and multiply in the aqueous phase and so a
preservative should exert its effect in this phase;
However preservative would be distributed between the two phases and hence its
concentration in the aqueous phase is reduced and so the overall concentration of the
preservative should be accurately calculated.