SOLUBILITY OF DRUGS

1. SOLUBILITY OF DRUGS By: Ms. Santoshi Naik Assistant Professor Yenepoya Pharmacy College and Research Centre

2. What is Solubility??? Solubility of substance in a particular solvent is defined as the concentration of the substance in a saturated solution at a certain temperature.

3. Solubility expressions

4. Solubility is also expressed in terms of percentage, molarity and molality. • In pharmaceutical field 3 concentration terms are used.

5. Molarity is defined as the number of moles of solute dissolved in 1 litre of solution. • Molality is defined as the number of moles of solute dissolved in 1000g of solvent.

6. Mechanism of solute solvent interactions • The solubility of solute in solvent is predicted by the solute-solute, solvent-solvent and solute-solvent interactions. 2 Types of forces: • Cohesive forces – attraction between like molecules ie. Solute-solute or solvent -solvent molecules. • Adhesive forces – attraction between unlike molecules i.e. solute-solvent molecules.

7. 3 types of solvents

8. Solubility of Gases in Liquids • Eg. Of Pharmaceutical preparations are effervescent preparations containing dissolved CO2, Ammonia water & Hydrochloric acid.

9. Factors affecting solubility of gases in liquids 1) Effect of Pressure • Henry’s Law – states that in dilute solution, the mass of gas which dissolves in given volume of liquid at constant temperature is directly proportional to partial pressure of the gas. C = σ p • The solubility of gases increases with increase in pressure.

10. 2) Effect of Temperature Solubility of gases in solvent decreases with rise in temperature. 3) Effect of Electrolytes and Non – electrolytes Solubility of gases decreases by addition of electrolytes such as NaCl or nonelectrolytes such as sugar. This is called salting out. 4) Effect of Chemical reaction Chemical reaction between gases and solvent increases the solubility of gas in solvent.

11. Solubility of Liquids in Liquids • Egs. Of Pharmaceutical solutions containing liquid dissolved in another liquid are hydroalcoholic solutions, aromatic waters such as CHCl3 & peppermint water, spirits & elixirs, emulsions. • Raoult’s law: At definite temperature the partial pressure (PA) of a component (A) in a liquid mixture is equal to vapour pressure in the pure state (P ̊A) multiplied by the mole fraction of the component (XA) in the solution. PA = P ̊A XA

13. Ideal solutions – are those which obey Raoult’s law over the whole range of composition at all temperatures. • These solutions form when adhesive forces are equal to cohesive forces between the components. • Eg: benzene- toluene, methanol-ethanol, hexane-heptane.

14. Non ideal solutions – are also called as Real solutions which do not obey Raoult’s law. • Eg: mixture of acetone and chloroform, alcohol and water. • These solutions form when adhesive forces are stronger or weaker than cohesive forces between the components. • There may be positive or negative deviations.

15. Mole fraction

16. If positive deviation: • Adhesive forces are weaker than the cohesive forces between the components. • Thus it decreases solubility because of association of molecules to form dimer. • The vapour pressure is higher than expected from ideal solution. • Eg: alcohol-water mixture.

18. If negative deviation: • Adhesive forces are stronger than the cohesive forces between the components • Thus it increases solubility because of hydrogen bonding between the polar components. • The vapour pressure of mixture is lower than expected from ideal solution. • Eg: acetone-chloroform mixture.

20. Partially miscible liquids • Partially miscible liquids form 2 immiscible liquid layers each of which is a saturated solution of one liquid in the other. • They are completely miscible with each other at definite temperature condition • The 2 liquid phases are called conjugate liquid phases. • Eg: Solution of phenol and water Solution of triethylamine and water

21. Critical Solution Temperature(consolute temperature) It is the temperature at which complete miscibility is reached as temperature is raised as in eg. Phenol water system or when temperature is lowered as in eg. Triethylamine water system.

22. PHENOL WATER SYSTEM Upper Consolute temperature 66.8 ̊C

23. TRIETHYLAMINE WATER SYSTEM Temperature ̊ C Lower consolute Temperature 18.5 ̊C % Triethylamine in H2O

24. NICOTINE WATER SYSTEM Upper consolute Temperature 208 ̊C One phase Two phases Lower consolute Temperature 60.8 ̊C One phase

25. Applications of Critical Solution Temperature • In characterisation of polymer mixtures & study of compatibility- lower critical solution temperature. • To correlate relationship between temperature and solubility of phenol and water. • To construct mutual solubility curve. • To find concentration of impurities.

26. BINARY SOLUTION Binary solution is a mixture of two liquids or components that are completely miscible one with another In binary solution, the component which is present in smaller amount is called solute and other one is called solvent. Eg: Mixture of water and alcohol, water and aldehydes, water and milk

27. The boiling point of binary solution depends upon the solution composition and there can be three cases: • The boiling points of solutions of all compositions: 1. May lie between the boiling points of clean liquids 2. May lie above the boiling points of clean liquids 3. May lie below the boiling points of clean liquids

28. TERNARY SYSTEM • Addition of third component to a pair of partially miscible liquids produce ternary system. • If the added component is soluble in only one of the 2 components, then the mutual solubility is decreased. • If the added component is soluble in both components to same extent then mutual solubility is increased. • For eg: Addition of salt to phenol water system – salt is more soluble in water phase compared to phenol thus solubility decreases.

29. SOLUBILITY OF SOLIDS IN LIQUIDS • Eg: of Pharmaceutical preparations of solids in liquids are solutions, suspensions, syrups etc.

30. Factors affecting solubility of solids in liquids 1) Temperature • Most solids dissolve in liquids as the temperature is increased. • Effect of temperature on solubility of solids in liquids is represented by solubility curves. 2) Molecular structure • Slight modification in the molecular structure of solids leads to changes in solubility. • If weak acid is converted to salt – solubility increases. • If weak acid is esterified – solubility decreases

31. 3) Particle size • Decrease in particle size of the solid increases the solubility due to increase in surface area. • However decreasing particles to a very small size decreases solubility due to generation of electrical charge on particle. 4) Nature of solvent and cosolvent • Polar solutes dissolve in- polar solvents • Nonpolar solutes dissolve in– nonpolar solvents. • Cosolvency – the phenomenon of increasing solubility of poorly soluble substances by use of more than one solvent (cosolvents– eg: propylene glycol, sorbitol, ethanol).

32. 5) pH • Solubility of weakly acidic drugs ∝ pH. • Solubility of weakly basic drugs ∝ 1/pH. 6) Combined effect of solvent and pH. • The addition of alcohol to buffered solution affects the solubility of weak electrolytes.

33. 7) Common ion effect When slightly soluble electrolytes are dissolved to form saturated solutions, solubility is described as solubility product Ksp. The addition of compound bearing common ion reduces the solubility. 8) Effect of indifferent electrolyte on solubility product Effect opposite to common ion effect is observed.

34. 9) Effect of nonelectrolytes on the solubility of electrolytes. Addition of nonelectrolyte such as alcohol decreases solubility of electrolyte. 10) Effect of electrolytes on the solubility of nonelectrolytes. Addition of electrolyte having more affinity towards water reduces solubility of nonelectrolyte.

35. 11)Effect of complex formation The solubility of solute may be increased or decreased by complexation. 12) Effect of solubilizing agents Solubility of poorly soluble drugs may be enhanced by micellar solubilization using surfactants. CMC – is concentration of surfactants at which micelle formation starts.