SOLUTIONS AND SOLUBILITY

1. SOLUTIONSANDSOLUBILITY

3. A- Common ion effect • The solubility product, Ksp, of a saturated solution of a sparingly soluble solute such as silver chloride (AgCl) is written as: Ksp = [Ag+][Cl–] • 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. • The solubility of the sparingly soluble solute is decreased by adding a common ion (referred to common ion effect).

4. N.B. salts of alkali metals Li>Na>K>Rb>Cs N.B. salts of organic acids (K citrate, Na benzoate, Na acetate).

5. B- Salting out (Incompatibility) • 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). • Addition of an electrolyte having more affinity towards waterreduces the solubility of the non-electrolyte by competing for the aqueous solvent and breaking the intermolecular bonds between the non-electrolyte and water.

6. C-Salting in "Hydrotropy" • 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 ashydrotropy.

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

8. D) Effect of semipolar solvents on the solubility of nonpolar solutes 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.

9. E) Effect of semipolar solvents on the solubility of sparingly soluble electrolytes • 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.

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

11. 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.

12. Examples of Complexes • 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". • 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.

13. Air Oil Water Water

14. 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.

15. Process of solubilization by Micellization: • Solubilization process occurs as the insoluble solute dissolves into the micelle interior(4) or adsorbed onto the micelle surface (1) or sitsat some intermediate point (2, 3) according to its polarity e.g. fat-soluble vitamins (A,D,E and K).

16. Dissolution of solid drugs: • "Noyes–Whitney equation" the modifiedFick’s law equation may be written as: dw/dt = K (Cs- C) Where: k = DA/l • 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.

17. l Cs C

18. 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

19. From the equation, how to enhance (increase) the solution rate? • Increase the surface area how?Decrease particle size . • Decrease the thickness of the diffusion layer how?Stirring rate. • 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. • Decrease viscosity why?Diffusion coefficient (D) is inversely proportional to the viscosity.

20. Prediction of Solubility: 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 forceswithin 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 The solubility parameter ( δ2 ):It is thesolubility 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.

21. Partitioning of drugs between immiscible solvents • 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.

22. 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: • Octanol • Isobutanol • hexane.