1. Ionic equilibria Wan Rosalina Wan Rosli, PhD

2. Learning objectives At the end of this lecture, students should be able to: 1.Characterize electrolytes 2.List properties of acid and bases 3.Describe electrolyte ionization phenomena 4.Calculate pH and pKa equations for solutions and salts 5.Identify the importance of ionization

3. What is electrolytes? Electrolyte: a substance (acid, base or salt) that ionizes to positive ions (cations) and negative ions (anions) in aqueous solution.

4. Properties of electrolytes Exhibit anomalous colligative properties compared with nonelectrolytes irregular and inconsistent colligative properties

5. Can conduct an electric current cations and anions get distributed throughout the solution ions are free to move and carry electrons

6. Tend to show rapid chemical reaction compared with nonelectrolyte solution

7. ACID AND BASES THEORIES

8. Bronsted-Lowry concept Acid is a substance, charged or uncharged, that is capable of donating a proton. Base is a substance, charged or uncharged, that is capable of accepting a proton.

9. Strength of acids and bases The relative strengths of acids and bases depend on: The tendencies of the substances to give up or take on protons Type of solvent HCl in water vs HCl in glacial acetic acid Acetic acid in water vs acetic acid in liquid ammonia

10. Strong acids and strong bases Example: Hydrochloric acid HCl + H 2 O H 3 O + + Cl - A strong acid because it has strong tendency to ionize. Extent of ionization is pH-independent

11. Weak acids and weak bases Example: phenol in water Weak tendency to ionize. Ionization is pH-dependent

12. IONIZATION OF ELECTROLYTES

13. Ionization of weak acids Consider the following rxn HA + H 2 O H 3 O + + A - What is the rate of forward rxn, R f ? What is the rate of reverse rxn, R r ? k1 k2

14. A balance will be attained when the two rates are equal R f = R r Concentrations of products and reactants are not necessary equal at equilibrium; the speeds of the forward and reverse rxn are what are the same.

15. Try solving for the ratio k1/k2 with [H2O] constant at 55.3 moles/liter. K a = k1/ k2= ?

16. Equation for K a can be represented in a more general form: C= initial molar concentration X= represent [H 3 O + ] and [A - ] because both are formed in equimolar concentration HA + H 2 O H 3 O + + A - (c) x x

17. Now the equation becomes K a = x 2 /c Rearrangement: x 2 = K a c  x= [H 3 O + ]= √K a c

18. Rearrangement: -log [H+] = ½(-log K a –log c) pH= ½ pK a - ½ log c This equation is useful for calculating the pH of a weak acid in water if c (molar concentration) and pK a for weak acid is known.

19. Example 4 (Applied Physical Pharmacy, Amiji & Sandmann) Calculate the pH of a 0.1 M solution of a weak acid at 25°C. pK a of acid is 4.76 at 25°C

20. How to calculate pH using K a ? *Clue: take -log of equation

21. Rearrangement gives pH= pK a + log [A-] [HA] This equation can be used to calculate the ratio of ionized form to the unionized form of drug in fluids (eg physiologic fluids).

22. Example 5 (Applied Physical Pharmacy, Amiji & Sandmann) Salicylic acid is an organic weak acid with pKa of 3.0. Calculate the ratio of ionized:unionized of this drug in stomach with pH 1.2. Ratio of unionized form:ionized Percent of unionized form in stomach

23. Ionization of weak bases Consider the rxn: B + H 2 O OH - + BH + So, K b = [OH - ] [BH + ] [B] This leads to [OH - ]= √K b c

24. To change the ionization expression for bases to K a, the equilibrium is written as follows: BH + B + H + K1/k2= K a = [B] [H + ] [BH + ]

25. How to calculate pH using K a ? *Clue: take log of equation, then equate [H + ] to [B] (because they are equimolar). *pH of protonated weak base can be calculated using this equation.

26. To calculate the pH of organic weak base (free base) pH= ½ pK w + ½ pK a - ½ log [B]

27. Example 6 (Applied Physical Pharmacy, Amiji & Sandmann) Calculate the pH of a 0.1 M solution of a weak base (triethylamine) at 25°C. pK a of base is 9.72 at 25°C

28. To calculate the ratio of freebase to the ionized form of drug in fluids (eg physiologic fluids). pH= pK a + log [B] [BH + ]

29. Example 7 (Applied Physical Pharmacy, Amiji & Sandmann) Calculate the approximate percentage of codeine present as free base in the small intestine (pH 6.5). pKa codeine= 7.9.

30. IONIZATION OF SALTS

31. A salt is formed by an acid-base rxn involving proton donation or proton acceptance. When salt is added to water, the solution can be neutral, acidic or basic (depend on salt). Interaction of ions of salts with ions of water is called hydrolysis

32. Salts of strong acids and strong bases Salts of this class do not undergo hydrolysis [H + ] and [OH - ] unchanged Example: NaCl

33. Salts of weak acids and strong bases These salts completely ionize in aqueous solution. Hydrolysis rxn results in basic pH NaA  Na + + A - The conjugate ion A- interact with water, results in alkaline soln H 2 O + A - HA + OH -

34. Example of salt: Sodium acetate Calculation of pH uses the equation: pH= ½ pK w + ½ pK a - ½ log [A - ]

35. Example from Amiji and Sandmann What is the pH of a sodium acetate solution with pKa of 4.76 and concentration of salt is 0.1M?

36. Special cases For the rxn of weak acid with calcium or magnesium hydroxide (molecules with valence >1), concentration of salt is multiplied by number of moles required to react with 1 mole of strong base. MgS 2  Mg 2 + + 2S - [S - ]= 2C pH= ½ pK w + ½ pK a - ½ log nC

37. Example in Amiji and Sandmann: What is the pH of 0.01 M magnesium stearate in water. pKa= 5.75.

38. Salts of strong acids and weak bases These salts completely ionize in aqueous solution. Hydrolysis rxn results in acidic pH BHCl  BH + + Cl - The conjugate ion BH + interact with water, results in acidic soln BH + + H 2 O B + H +

39. Salt example: ephedrine hydrochloride The equation for pH calculation pH= ½ pK a - ½ log [BH + ] Example from Amiji & Sandmann Calculate the pH of 0.1M ephedrine hydrochloride in water, pKa= 9.36

40. Special cases For the rxn of weak base with sulfuric acid (molecules with valence >1), concentration of salt is multiplied by number of moles required to react with 1 mole of strong acid. (Eph) 2 SO 4  2 EpH + + SO 4 - [Eph + ]= 2C pH= ½ pK a - ½ log nC

41. Example in Amiji & Sandmann What is the pH of 0.1M epehedrine sulfate, pKa for ephedrine= 9.36

42. IONIZATION OF POLYPROTIC ELECTROLYTES

43. Polyprotic electrolyte: Polyprotic acid = capable of donating two or more protons Polyprotic base = capable of accepting two or more protons  Ionizes in stages What if capable of donating/accepting only one proton?

44. Example: ionization/ protolysis of phosphoric acid H 3 PO 4 + H 2 O = H 3 O + + H 2 PO 4 -  1 (K 1 : 7.5 x 10 -3 ) H 2 PO 4 - + H 2 O = H 3 O + + HPO 4 2-  2 (K 2 : 6.2 x 10 -8 ) HPO 4 2- + H 2 O = H 3 O + + PO 4 3-  3 (K 3 : 2.1 x 10 -13 ) The primary protolysis is the greatest and succeeding stages become less complete

45. Each of the species formed by ionization can also act as a base. In general, if the parent acid is H n A, there are n + 1 possible species in soln.

46. IONIZATION OF AMPHOTERIC ELECTROLYTES

47. Remember: phosphoric acid can function as acid and also a base. This means that it is an ampholyte/ amphoteric electrolyte a species that can function either as acid or base

48. Important ampholyte: amino acids and proteins Example: glycine hydrochloride + NH 3 CH 2 COOH + H 2 O + NH 3 CH 2 COO - + H 3 O + + NH 3 CH 2 COO - + H 2 O NH 2 CH 2 COO - + H 3 O +

49. The species + NH 3 CH 2 COO - is amphoteric as it reacts with water to form + NH 3 CH 2 COO - + H 2 O + NH 3 CH 2 COOH + OH -

50. The amphoteric species is a zwitterion because it carries both a positive and negative charge, and the whole molecule is electrically neutral + NH 3 CH 2 COO - The pH where the zwitterion concentration is maximum is known as the isoelectric point The net charge of the molecule is zero No migration of protein in applied electrical field

51. WHY LEARNING THIS IS SO IMPORTANT?

52. Importance of ionization in pharmacy Many drugs are weak electrolytes Degree of ionization is important and have physiologic implication Affect absorption, transport and excretion of drugs Generally: ionized forms are more water soluble and unionized form is more lipid soluble. pH of environment determine ratio of ionized: unionized form A small change in pH can result in big change in ratio Affect solubility, dissolution rate, stability etc.

53. CONCLUSION

54. Electrolytes is used extensively in pharmacy hence the properties must be understood. Ionization of electrolytes involve acid, base and salt. Determination of K a enable the determination of pK a, pH and concentrations of reactants. Knowledge on ionization facilitate the understanding of how drugs react in body.

55. THANK YOU