Transcript non-electrolytes - Millennium Organization

SOLUTIONS
AND
SOLUBILITY
Effect of additives
Common ion effect
Electrolytes to
non electrolytes
Semi-polar solvents
On non-electrolytes
Semi-polar solvents
On sparingly soluble
electrolytes
Effect of surfactants
(S.A.A.)
Complex formation
A- Common ion effect
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The solubility product, Ksp, of a saturated solution
of a sparingly soluble solute such as silver chloride
(AgCl) is written as:
Ksp = [Ag+][Cl–]
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Therefore, if either [Ag+] or [Cl–] concentration is
increased by adding a Ag+ or Cl– ion to the solution then
because the value of the solubility product is constant,
some of the sparingly soluble salt will precipitate.
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The solubility of the sparingly soluble solute is decreased
by adding a common ion (referred to common ion
effect).
Addition of Electrolytes to non electrolytes
B- Salting out
(Incompatibility)
N.B. salts of alkali metals
Li>Na>K>Rb>Cs
C- Salting in
(Hydrotropy)
N.B. salts of organic acids
(K citrate, Na benzoate, Na acetate).
B- Salting out (Incompatibility)
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The solubility of non-electrolytes depends primarily on
the formation of weak intermolecular bonds (hydrogen
bonds) between their molecules and those of water (like
association complex of sucrose with water).
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Addition of an electrolyte having more affinity towards
water reduces the solubility of the non-electrolyte by
competing for the aqueous solvent and breaking the
intermolecular bonds between the non-electrolyte and
water.
C-Salting in "Hydrotropy"
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An effect opposite to that of common ion effect
Several salts of organic acids which are themselves
very soluble in water result in salting in and increase
in solubility of non electrolyte.
Sodium benzoate, sodium p-toluenesulfonate, sodium
acetate, and potassium citrate are good examples of
such agents and are referred to as hydrotropic salts;
the increase in the solubility of other solutes is
known as hydrotropy.
Effect of semi-polar solvents
D-On non-polar solutes
(Co-solvency)
Increase solubility of
non polar drug in water
Increase solubility of
volatile flavour in water
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E-On sparingly
soluble (weak)
electrolytes
Decrease DEC
Decrease solubility
Supress ionization
Examples of semi-polar solvents: Ethanol - sorbitol-
glycerin- propylene glycol- polyethylene glycol (PEG).
D) Effect of semipolar solvents on the
solubility of nonpolar solutes
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The solubility of non-electrolytes depends primarily on the
formation of weak intermolecular bonds (hydrogen bonds)
between their molecules and those of water.
Non-polar solutes frequently have poor water solubility,
their solubility can be increased by the addition of water
miscible semipolar solvent such as alcohol.
This process is known as "cosolvency" and the solvent
used is known as cosolvent. This increase in solubility of
nonpolar solutes in water is due to the decrease in DEC
(polarity) of water by the addition of semipolar solvent as
alcohol.
E) Effect of semipolar solvents on the
solubility of sparingly soluble electrolytes
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The solubility of electrolytes in water primarily depends on
the dissociation of the dissolved molecules into ions.
The ease with which the electrolytes dissociate depends on
the dielectric constant (DEC) of the solvent which is a
measure of the polar nature of the solvent.
Solvent with a high DEC like water is able to reduce the
attractive forces that operate between the oppositely
charged ions produced after electrolyte dissociation.
If a water- miscible semipolar solvent such as alcohol is
added to an aqueous solution of sparingly soluble
electrolyte, the solubility of the latter decreased
Alcohol lowers the DEC of water and ionic dissociation of
the sparingly soluble electrolyte becomes more difficult.
Dielectric constant (D.E.C.):
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The dielectric constant (DEC) of the solvent is a
measure of its polarity, ↑value (water) can
↓attractive forces between the ions of an
electrolyte.
If the added semi-polar solvent (alcohol) is water
soluble, so it ↓ DEC of water, ↓ solubility of
sparingly soluble (weak) electrolyte(↓ionization).
Calculation of DEC of an isoalcoholic mixture:
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DEC of water=80, that of alcohol=25
DEC of a mixture of 60% alcohol by weight in water can be
estimated as follows: [0.6 x 25] +[0.4 x 80] = 47
F-Complex formation
Increase solubility
Decrease solubility
Soluble complex
e.g. HgI2/KI
Insoluble complex
e.g.Tetracycline/Ca2+
 Solubility may be either ↑or↓ by the formation of a complex upon
addition of a third substance forming complex with the solute.
 The solubility of the formed complex will determine the
apparent change in the solubility of the original solute.
Examples of Complexes
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Complexation is the interaction of Iodine with Povidone
to form water-soluble "Povidone-Iodine" complex.
Solution of Mercuric iodide upon addition of Potassium
iodide will yield a water soluble complex of "Potassium
mercuric iodate".
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A number of compounds, such as Beta-cyclodextrins
have been used to increase the solubility of poorly water
soluble drugs.
An insoluble complex. Tetracycline –Ca2+complex
forms an insoluble complex with calcium ions present in
milk or any preparation containing calcium salts.
G-Effect of surfactants (S.A.A.)
(Solubilization)
At low
concentration
At high
concentration
Adsorption at
air- liquid interface
Micelle formation
(CMC)
Air
Water
Oil
Water
1- At ↓conc of SAA, adsorption at air- liquid interface.
2- At ↑conc of SAA, formation of aggregates or
micelles in the bulk are formed at a concentration
called “ critical micelle concentration CMC”.
3- Solubility of poorly soluble drugs may be enhanced
by the presence of solubilising agents or
"surfactants" by a technique known as "Micellar
solubilisation" which involves the use of
surfactant for increasing the solubility.
Process of solubilization by
Micellization:
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Solubilization process occurs as the insoluble
solute dissolves into the micelle interior(4) or
adsorbed onto the micelle surface (1) or sits at
some intermediate point (2, 3) according to
its polarity e.g. fat-soluble vitamins (A,D,E and
K).
Dissolution of solid drugs:
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"Noyes–Whitney equation" the modified Fick’s law
equation may be written as:
dw/dt = K (Cs- C)
Where: k = DA/l
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dw/dt: The rate of increase of the amount of material
in solution dissolving from a solid
K: The rate constant of dissolution (time-1)
Cs: Saturation solubility of the drug in solution in the
diffusion layer
C: Concentration of the drug in the bulk solution.
A: area of the solvate particles exposed to the solvent
l: Thickness of the diffusion layer
D: Diffusion coefficient of the dissolved solute.
l
Cs
C
Factors enhancing the solution rate
[1] The↓ particle size, ↑A, the ↑ rate of solution (particle size)
[2] The ↓ diffusional path (l), the ↑ rate of solution
 The faster the solution is stirred, the faster the solute will go into
solution.
[3] The ↑ saturation solubility (Cs), the faster the dissolution rate.
A. Different polymorphs of the same drug may have different solubility,
the metastable polymorph usually have higher solubility
e.g. Riboflavin can exist in three different polymorphic forms, having a
solubility in water at 25oC of (60 mg, 80 mg, and 1200 mg per liter
respectively). The most soluble is useful for powdered parenterals.
B. Solubility of weak acids or bases can be highly increased by the use
of their respective salts, e.g. Atropine sulfate, sodium
phenobarbital sodium sulphadiazine.
[4] With a ↑ viscous liquid, the ↓ rate of solution. This is because the
diffusion coefficient (D) is inversely proportional to the viscosity of
the medium.
dw/dt = K (Cs- C)
Where: k = DA/l
From the equation, how to enhance (increase) the
solution rate?
1.Increase the surface area how? Decrease particle size .
2.Decrease the thickness of the diffusion layer how? Stirring rate.
3.Increase the saturation solubility how? If the drug has different
polymorphs, the metastable polymorph usually has higher
solubility OR use of weak acid or base salts.
4.Decrease viscosity why? Diffusion coefficient (D) is inversely
proportional to the viscosity.
Prediction of Solubility:
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Polar and weak polar solutes dissolve in polar solvents. ( polarity
measured by DEC)
Non- polar solutes dissolve in non-polar solvents.
Solubility of non-polar substances can be predicted by “solubility

parameter”
The solubility parameter ( δ1 ): It is the measure of intermolecular
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forces within the solvent , and gives us information on the ability
of the liquid to act as a solvent which is the energy required to
form cavities within the solvent, by separating other solvent
molecules, in order to accommodate solute molecules
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The solubility parameter ( δ2 ): It is the solubility parameter of the
solute, it is a hypothetical value.
(δ1 - δ2) will give an indication of solubility, a value of 2 is taken as
rough index of solubility.
Partitioning of drugs between immiscible solvents
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Drugs partitioning between aqueous phases and lipid
biophases.
Preservative molecules in emulsions partitioning
between the aqueous and oil phases.
Antibiotics partitioning into microorganisms.
Drugs and preservative molecules partitioning into
the plastic of containers.
Partitioning include the permeation of antimicrobial
agents into rubber stoppers and other closures.
If two immiscible phases are placed in contact, one
containing a solute soluble to some extent in both
phases.
 The solute will distribute itself until the chemical
potential of the solute in one phase is equal to its
chemical potential in the other phase.
Non-aqueous Solvents used to determine partition:
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Octanol
Isobutanol
hexane.