SOLUTIONSSOLUTIONSANDAND

SOLUBILITYSOLUBILITY

Effect of additives

Common ion effectSemi-polar solventsOn sparingly solubleelectrolytes

Electrolytes to non electrolytes

Effect of surfactants (S.A.A.)

Semi-polar solvents Semi-polar solvents On non-electrolytes On non-electrolytes

Complex formation

A- Common ion effectA- Common ion effect The The solubility product, Ksp,solubility product, Ksp, of a of a saturated saturated

solutionsolution of a of a sparingly soluble solutesparingly soluble solute such such as silver chloride as silver chloride (AgCl)(AgCl) is written as: is written as:

Ksp Ksp = [Ag= [Ag++][Cl][Cl––]]

Therefore, if either [Ag+] or [Cl–] Therefore, if either [Ag+] or [Cl–] concentration is increased by adding a Agconcentration is increased by adding a Ag++ or or ClCl–– ion to the solution then because the value ion to the solution then because the value of the of the solubility product is constantsolubility product is constant, some , some of the sparingly soluble salt will of the sparingly soluble salt will precipitateprecipitate. .

The solubility of the sparingly soluble solute The solubility of the sparingly soluble solute is is decreaseddecreased by adding a by adding a common ioncommon ion (referred to common ion effect).(referred to common ion effect).

Addition of Addition of ElectrolytesElectrolytes to to non electrolytesnon electrolytes

B- Salting out(Incompatibility)

C- Salting in(Hydrotropy)

N.B. salts of alkali metals Li>Na>K>Rb>Cs

N.B. salts of organic acids (K citrate, Na benzoate, Na acetate).

B- Salting out B- Salting out (Incompatibility)(Incompatibility)

The solubility of The solubility of non-electrolytesnon-electrolytes depends depends primarily on the formation of primarily on the formation of weak weak intermolecular bondsintermolecular bonds (hydrogen bonds) (hydrogen bonds) between their molecules and those of between their molecules and those of water water ((like association complex of sucrose with waterlike association complex of sucrose with water))..

Addition of an Addition of an electrolyteelectrolyte having having more affinitymore affinity

towards towards waterwater reducesreduces the solubility of the non- the solubility of the non-electrolyte by competing for the aqueous solvent electrolyte by competing for the aqueous solvent and breaking the intermolecular bonds between and breaking the intermolecular bonds between the non-electrolyte and water.the non-electrolyte and water.

C-Salting in "Hydrotropy"C-Salting in "Hydrotropy" An effect opposite to that of An effect opposite to that of commoncommon ion effect ion effect Several salts of organic acids which are Several salts of organic acids which are

themselves very soluble in water result in themselves very soluble in water result in salting in and increase in solubility of salting in and increase in solubility of non non electrolyteelectrolyte..

Sodium benzoate, sodium Sodium benzoate, sodium pp-toluenesulfonate, -toluenesulfonate, sodium acetate, and potassium citrate are sodium acetate, and potassium citrate are good examples of such agents and are good examples of such agents and are referred to as referred to as hydrotropic saltshydrotropic salts; the increase ; the increase in the solubility of other solutes is known asin the solubility of other solutes is known as hydrotropyhydrotropy..

Effect of semi-polar solventsEffect of semi-polar solvents

D-On non-polar solutes(Co-solvency)

E-On sparinglysoluble (weak)

electrolytes

Increase solubility ofnon polar drug in water

Increase solubility of volatile flavour in water

Decrease DEC

Decrease solubilitySupress ionization

Examples of semi-polar solvents:Examples of semi-polar solvents: Ethanol - sorbitol- glycerin- propylene Ethanol - sorbitol- glycerin- propylene glycol- polyethylene glycol (PEG).glycol- polyethylene glycol (PEG).

D) Effect of semipolar solvents D) Effect of semipolar solvents on the solubility of nonpolar on the solubility of nonpolar solutessolutes The solubility of The solubility of non-electrolytesnon-electrolytes depends depends

primarily on the formation of weak primarily on the formation of weak intermolecular bonds (hydrogen bonds) between intermolecular bonds (hydrogen bonds) between their molecules and those of water.their molecules and those of water.

Non-polar solutes frequently have poor water Non-polar solutes frequently have poor water solubility, their solubility can be increased by the solubility, their solubility can be increased by the addition of water miscible semipolar solvent such addition of water miscible semipolar solvent such as alcohol. as alcohol.

This process is known as This process is known as "cosolvency""cosolvency" and the and the solvent used is known as solvent used is known as cosolventcosolvent. This . This increase in solubility of nonpolar solutes in water increase in solubility of nonpolar solutes in water is due to the decrease in DEC (polarity) of water is due to the decrease in DEC (polarity) of water by the addition of semipolar solvent as alcohol.by the addition of semipolar solvent as alcohol.

E) Effect of semipolar solvents on E) Effect of semipolar solvents on the solubility of sparingly soluble the solubility of sparingly soluble electrolyteselectrolytes

The solubility of electrolytes in water primarily depends The solubility of electrolytes in water primarily depends on the dissociation of the dissolved molecules into ions. on the dissociation of the dissolved molecules into ions.

The ease with which the electrolytes dissociate depends The ease with which the electrolytes dissociate depends on the dielectric constant (DEC) of the solvent which is on the dielectric constant (DEC) of the solvent which is a measure of the polar nature of the solvent. a measure of the polar nature of the solvent.

Solvent with a high DEC like water is able to reduce the Solvent with a high DEC like water is able to reduce the attractive forces that operate between the oppositely attractive forces that operate between the oppositely charged ions produced after electrolyte dissociation.charged ions produced after electrolyte dissociation.

If a water- miscible semipolar solvent such as alcohol is If a water- miscible semipolar solvent such as alcohol is added to an aqueous solution of sparingly soluble added to an aqueous solution of sparingly soluble electrolyte, the solubility of the latter decreased electrolyte, the solubility of the latter decreased

Alcohol lowers the DEC of water and ionic dissociation Alcohol lowers the DEC of water and ionic dissociation of the sparingly soluble electrolyte becomes more of the sparingly soluble electrolyte becomes more difficult.difficult.

Dielectric constant Dielectric constant (D.E.C.):(D.E.C.):

The dielectric constant (DEC) of the The dielectric constant (DEC) of the solvent is a measure of its polarity, solvent is a measure of its polarity, ↑value (water) can ↓attractive forces ↑value (water) can ↓attractive forces between the ions of an electrolyte. between the ions of an electrolyte.

If the added semi-polar solvent If the added semi-polar solvent (alcohol) is water soluble, so it ↓ DEC (alcohol) is water soluble, so it ↓ DEC of water, ↓ solubility of sparingly of water, ↓ solubility of sparingly soluble (weak) electrolyte(↓ionization).soluble (weak) electrolyte(↓ionization).

Calculation of DEC of an isoalcoholic Calculation of DEC of an isoalcoholic mixture:mixture:

DEC of water=80, that of alcohol=25DEC of water=80, that of alcohol=25 DEC of a mixture of 60% alcohol by weight in water DEC of a mixture of 60% alcohol by weight in water

can be estimated as follows: [0.6 x 25] +[0.4 x 80] = can be estimated as follows: [0.6 x 25] +[0.4 x 80] = 4747

F-Complex formationF-Complex formation

Increase solubilityDecrease solubility

Soluble complexe.g. HgI2/KI

Insoluble complexe.g.Tetracycline/Ca2+

Solubility may be either ↑or↓ by the formation of Solubility may be either ↑or↓ by the formation of a complex upon addition of a third substance a complex upon addition of a third substance forming complex with the solute.forming complex with the solute.

The solubility of the formed complex will The solubility of the formed complex will determine the apparent change in the solubility of determine the apparent change in the solubility of the original solute.the original solute.

Examples of ComplexesExamples of Complexes Complexation is the interaction of Iodine Complexation is the interaction of Iodine

with Povidone to form water-soluble with Povidone to form water-soluble "Povidone-Iodine" complex"Povidone-Iodine" complex. .

Solution of Mercuric iodide upon addition of Solution of Mercuric iodide upon addition of Potassium iodide will yield a water soluble Potassium iodide will yield a water soluble complex of complex of "Potassium mercuric iodate". "Potassium mercuric iodate".

A number of compounds, such as A number of compounds, such as Beta-Beta-cyclodextrinscyclodextrins have been used to increase have been used to increase the solubility of poorly water soluble drugs.the solubility of poorly water soluble drugs.

An insoluble complex. An insoluble complex. Tetracycline –Tetracycline –Ca2+complexCa2+complex forms an insoluble complex forms an insoluble complex with calcium ions present in milk or any with calcium ions present in milk or any preparation containing calcium salts.preparation containing calcium salts.

G-Effect of surfactants (S.A.A.)G-Effect of surfactants (S.A.A.)(Solubilization)(Solubilization)

At low concentration

At high concentration

Adsorption at air- liquid interface

Micelle formation (CMC)

Oil

Water

Air

Water

1- 1- At ↓conc of SAA, adsorption at air- , adsorption at air- liquid interface.liquid interface.

2- 2- At ↑conc of SAA, formation of , formation of aggregates or micelles in the bulk are aggregates or micelles in the bulk are

formed at a concentration called “ formed at a concentration called “ critical micelle concentration CMC”. critical micelle concentration CMC”.

3- Solubility of poorly soluble drugs may 3- Solubility of poorly soluble drugs may be enhanced by the presence of be enhanced by the presence of solubilising agents or "surfactants" by a solubilising agents or "surfactants" by a technique known as technique known as "Micellar Micellar solubilisationsolubilisation" which involves the use which involves the use of surfactant for increasing the of surfactant for increasing the solubility. solubility.

Process of solubilization by Process of solubilization by Micellization:Micellization:

Solubilization process occurs as the Solubilization process occurs as the insoluble solute dissolves into the insoluble solute dissolves into the micelle interior(4)(4) or adsorbed or adsorbed onto the onto the micelle surface (1)micelle surface (1) or or sitssits at some intermediate point (2, 3)at some intermediate point (2, 3) according to its polarity e.g. fat-according to its polarity e.g. fat-soluble vitamins (A,D,E and K).soluble vitamins (A,D,E and K).

Dissolution of solid Dissolution of solid drugs:drugs: ""Noyes–Whitney equation"Noyes–Whitney equation" the modified the modified

Fick’s lawFick’s law equation may be written as: equation may be written as:ddww/d/dtt = = K K ((CCs- s- CC) )

Where: k Where: k = = DADA//ll

ddww/d/dtt:: The rate of increase of the amount of The rate of increase of the amount of material in solution dissolving from a solidmaterial in solution dissolving from a solid

KK:: The rate constant of dissolution (time The rate constant of dissolution (time-1-1) ) CCss:: Saturation solubility of the drug in solution Saturation solubility of the drug in solution

in the diffusion layerin the diffusion layer CC:: Concentration of the drug in the bulk Concentration of the drug in the bulk

solution. solution. AA:: area of the solvate particles exposed to the area of the solvate particles exposed to the

solvent solvent ll:: Thickness of the diffusion layer Thickness of the diffusion layer DD:: Diffusion coefficient of the dissolved solute. Diffusion coefficient of the dissolved solute.

Cs

CC

ll

Factors enhancing the solution Factors enhancing the solution raterate[1] The[1] The↓↓ particle size, particle size, ↑↑AA, the , the ↑↑ rate of solution rate of solution (particle size)(particle size)

[2] The [2] The ↓↓ diffusional path diffusional path (l),(l), the the ↑↑ rate of solution rate of solution The faster the solution is The faster the solution is stirredstirred, the faster the solute will go into , the faster the solute will go into

solution.solution.[3] The [3] The ↑↑ saturation solubility saturation solubility (Cs),(Cs), the faster the dissolution rate. the faster the dissolution rate. A.A. Different polymorphs of the same drug may have different solubility, Different polymorphs of the same drug may have different solubility,

the metastable polymorph usually have the metastable polymorph usually have higher solubilityhigher solubility e.g.e.g. RiboflavinRiboflavin can exist in three different polymorphic forms, having a can exist in three different polymorphic forms, having a

solubility in water at 25solubility in water at 25ooC of (60 mg, 80 mg, and C of (60 mg, 80 mg, and 1200 mg1200 mg per liter per liter respectively). The most soluble is useful for powdered parenterals.respectively). The most soluble is useful for powdered parenterals.

B.B. Solubility of weak acids or bases can be highly increased by the use Solubility of weak acids or bases can be highly increased by the use of their respective salts, e.g. of their respective salts, e.g. Atropine sulfateAtropine sulfate, , sodium sodium phenobarbital sodium sulphadiazine.phenobarbital sodium sulphadiazine.

[4] With a [4] With a ↑↑ viscous liquid, the viscous liquid, the ↓↓ rate of solution. This is because the rate of solution. This is because the diffusion coefficient diffusion coefficient (D)(D) is inversely proportional to the viscosity of is inversely proportional to the viscosity of the medium.the medium.

ddww/d/dtt = = K K ((CCs- s- CC) ) Where: k Where: k = = DADA//ll

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:Prediction of Solubility: Polar and weak polar solutes dissolve in polar Polar and weak polar solutes dissolve in polar

solvents. ( polarity measured by DEC) solvents. ( polarity measured by DEC) Non- polar solutes dissolve in non-polar solvents.Non- polar solutes dissolve in non-polar solvents. Solubility of non-polar substances can be predicted by Solubility of non-polar substances can be predicted by

“solubility parameter”“solubility parameter” The solubility parameter ( The solubility parameter ( δδ1 1 ):): It is the measure of It is the measure of

intermolecular forcesintermolecular forces within the solvent , and gives us within the solvent , and gives us information on the ability of the liquid to act as a information on the ability of the liquid to act as a solvent which is the energy required to form cavities solvent which is the energy required to form cavities within the solvent, by separating other solvent within the solvent, by separating other solvent

moleculesmolecules, , in order to accommodate solute moleculesin order to accommodate solute molecules The solubility parameter ( The solubility parameter ( δδ2 2 ):): It is theIt is the ssolubility olubility

parameter of the solute, it is a hypothetical value. parameter of the solute, it is a hypothetical value. ((δδ1 - 1 - δδ2) 2) will give an indication of solubility, a value of 2 will give an indication of solubility, a value of 2

is taken as rough index of solubility.is taken as rough index of solubility.

Partitioning of drugs between Partitioning of drugs between immiscible solventsimmiscible solvents

Drugs partitioning between aqueous phases Drugs partitioning between aqueous phases and lipid biophases.and lipid biophases.

Preservative molecules in emulsions Preservative molecules in emulsions partitioning between the aqueous and oil partitioning between the aqueous and oil phases.phases.

Antibiotics partitioning into microorganisms.Antibiotics partitioning into microorganisms. Drugs and preservative molecules Drugs and preservative molecules

partitioning into the plastic of containers.partitioning into the plastic of containers. Partitioning include the permeation of Partitioning include the permeation of

antimicrobial agents into rubber stoppers antimicrobial agents into rubber stoppers and other closures. and other closures.

If two immiscible phases are placed in If two immiscible phases are placed in contact, one containing a solute soluble contact, one containing a solute soluble to some extent in both phases.to some extent in both phases.

The solute will distribute itself until the The solute will distribute itself until the chemical potentialchemical potential of the solute in one of the solute in one phase is equal to its phase is equal to its chemical chemical potentialpotential in the other phase. in the other phase.

Non-aqueous Solvents used to Non-aqueous Solvents used to determine partition:determine partition:

OctanolOctanol IsobutanolIsobutanol hexane.hexane.