Solution and Solubility

Solution and SolubilityOssama 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.


• 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.


• 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 %


• 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.


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 dipole-induced

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.



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, -NO2B) 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:


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


*** Solvation: or hydrate forms less soluble than unsolvated forms ???

4) Particle size of solids:Decreasing particle size increasing solubility …?Suspension ???


5) Added substances ..I- Effect of salts on solubility of non-electrolytes: (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,


• 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.


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


• 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


III- Effect of semipolar solvents on solubility of Nonpolar solutes “Cosolvency”:

• * process by which solubility of nonpolar molecules is increased by addition of a water-miscible 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)


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.


• 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 =

• 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.

4780100

4025

100

60 xx


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.


• 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.


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-- .


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 = Ks )

][1(

w

b

K

HK


For a basic drug:

PH = pKw – pKb + log

S : total solubility (Mole / litre)

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

O

O

SS

S


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

according to this equation;

)][

1( H

KKS astotal


For an acidic drug :

• 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

O

Oa S

SSLogPKPH


• Solution

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

pH = 5 + log (0.05 – 0.001) / 0.001 = 6.69O

Oa S

SSLogPKPH


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 = 5.6x10-3 mole/L

pKb = 5.59

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

= 8.17

o

obw SS

SpKpKpH

log


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

O

Oa S

SSLogPKPH

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).


• 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 =

L

CCDA )( 21


• 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 = CA / 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


LIQUIDS AND THE PARTITION COEFFICIENT• Applications of the distribution law:

1- Extraction (removal of aditve principles from crude drugs).

* 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.

mass remaining

B phase of volume

extractionfor used volume

(g) extracted massxK


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


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

remain in water;

• a)

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

mass remaining

B phase of volume

extractionfor used volume

(g) extracted massxK

)5(

100

1008

xx

XK


LIQUIDS AND THE PARTITION COEFFICIENTb) i.

solve for y = 4g and 1g remainsii.

solve for z = 0.8 gthe 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.

)5(

100

508

yx

yK

)1(

100

508

zx

zK


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


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.

Solution and Solubility

Documents