1. P HYSICAL P HARMACY SECOND STAGE B UFFER Dr. Anoosh B. Hagopian MS.c Pharmaceutics Pharmaceutics Dept. Hawler Medical University College of Pharmacy Lec. (1&2)

2. B UFFERED AND I SOTONIC S OLUTIONS Outline: Buffer solutions Buffer action The Buffer Equation Buffer Capacity Factors affecting pH of buffer solutions Buffers in Pharmaceutical and Biologic Systems Preparation of pharmaceutical buffers Buffered Isotonic Solutions Measurements of Tonicity Methods of Adjusting Tonicity and pH

3. B UFFER SOLUTIONS Buffers are compounds or mixtures of compounds that, by their presence in solution, resist changes in pH upon the addition of small quantities of acid or alkali Buffers are usually consists of a mixture of a weak acid and its salts or a weak base and its salt

4. B UFFER ACTION The ability of certain solutions to resist a change in their pH upon the addition of an acid or a base is known as the buffer action Example: Nacl in H 2 O pH of 1L Nacl is 7, if: a. 1mL of 1N Hcl, pH= 3 b. 1mL of 1N NaOH, pH= 11 Then is it a buffer solution? And why?

5. B UFFER ACTION, CONT., Example: a. w.a & its salt like acetic acid and sodium acetate H + + CH 3 COO - CH 3 COOH O H - + CH 3 COOH CH 3 COO - + H 2 O b. w.b & its salt like ammonium hydroxide and ammonium chloride H + + NH 4 OH H 2 O + NH 4 + O H - + NH 4 + NH 4 OH

6. B UFFER EQUATION a. Buffer equation for a weak acid and its salt b. Buffer equation for a weak base and its salt The pH of a buffer solution and the change in pH upon the addition of an acid- or base may be calculated by use of the buffer equation

7. B UFFER EQUATION, CONT., a. Buffer equation for a weak acid and its salt:  The pH of a buffer solution and the change in pH upon the addition of an acid- or base may be calculated by use of the buffer equation  The dissociation constant for the weak acid is given by:

8. B UFFER EQUATION, CONT., CH 3 COOH CH 3 COO - + H 3 O + K a = [CH 3 COO - ] [H 3 O + ] [CH 3 COOH] H 3 O + + CH 3 COO - CH 3 COOH + H 2 O [H 3 O + ] = K a [CH 3 COOH] [CH 3 COO - ]

9. B UFFER EQUATION, CONT., [H 3 O + ] = K a [CH 3 COOH] [CH 3 COO - ] [H 3 O + ] = K a [acid] [salt] Log [H 3 O + ] = Log K a + Log [acid]- Log [salt] -Log [H 3 O + ]=-Log K a - Log [acid]+ Log [salt] pH = pK a + Log [salt] [acid] Henderson-Hasselbalch equation for a weak acid and its salt

10. B UFFER EQUATION, CONT., b. Buffer equation for a weak base and its salt: Buffer solutions are not ordinarily prepared from weak bases and their salts, why? because of the volatility and instability of the bases and because of the dependence of their pH on p K w, which is often affected by temperature changes

11. B UFFER EQUATION, CONT., b. Buffer equation for a weak base and its salt: Pharmaceutical solutions-for example, a solution of Ephedrine base and Ephedrine hydrochloride-often contain combinations of weak bases and their salts. The buffer equation for solutions of weak bases and the corresponding salts may be derived in a manner analogous to that for the weak acid buffers, accordingly:

12. B UFFER EQUATION, CONT., OH - = K b [base] / [salt] K w = H 3 O + × OH - OH - = K w / H 3 O + K w / H 3 O + = K b [base] / [salt] Log K w -Log[H 3 O + ]=LogK b +Log[base]-Log [salt] -Log [H 3 O + ]=-Log K w +Log K b +Log[base]-Log [salt] pH= p K w - p K b + Log [base] / [salt]

13. B UFFER CAPACITY  The buffer capacity of a solution is a measure of its magnitude of resistance to change in pH on addition of an acid or a base  It is also referred to as buffer index, buffer efficiency, buffer coefficient or buffer value  The buffer capacity (ß) defined as the ratio of the increment of strong base (or acid) to the small change about this addition

14. B UFFER CAPACITY, CONT. ß= ∆B/ ∆pH Where: ∆B represents the small increment in gm /L of strong base (or acid) added to the buffer to bring about a pH change of ∆pH Therefore: Buffer capacity is the amount of a strong acid or strong base (expressed as gm/L) required to change the pH of 1L of a buffer system by one unit.

15. F ACTORS AFFECTING PH OF BUFFER SOLUTIONS a. Temperature effects b. Dilution effects c. Salt effects

16. F ACTORS AFFECTING PH OF BUFFER SOLUTIONS a. Temperature effects:  The activity coefficient and the pk a value of a buffer are dependent on the temperature  Buffer pH changes with temperature  Buffer consisting of a base and its salt show greater changes with temperature  An increase in temperature lowers the pH of a buffer solution containing boric acid and sodium borate and raises the pH of a buffer solution containing acetic acid and sodium acetate

17. F ACTORS AFFECTING PH OF BUFFER SOLUTIONS, CONT. b. Dilution effects:  Dilution of an aqueous buffer solution with water in moderate quantities shows only a small effect on the pH of the buffer solution  Dilution of an acidic buffer shows an increase in pH while dilution of a basic buffer shows a decrease  Quantification of the dilution effect can be done by the use of dilution value

18. F ACTORS AFFECTING PH OF BUFFER SOLUTIONS, CONT. b. Dilution effects:  Dilution value defined as the change in pH brought about by the dilution of a buffer solution with an equal volume of water  The dilution values for most pharmaceutical buffer systems are usually less than 0.1 pH unit

19. F ACTORS AFFECTING PH OF BUFFER SOLUTIONS, CONT. c. Salt effects:  If a neutral salt is added to a dilute buffer solution, the activity coefficients of the ions are lowered  Salt added to acidic buffers lowers its pH while to a basic buffer increases its pH  The change in pH in not greater than 0.1 pH units provided the final concentration of the neutral salt added is not greater than that of the buffer system itself

20. F ACTORS AFFECTING PH OF BUFFER SOLUTIONS, CONT. c. Salt effects: Example: Drugs as Buffers. It is important to recognize that solutions of drugs that are weak electrolytes also manifest buffer action Salicylic acid solution in a soft glass bottle, how?

21. F ACTORS AFFECTING PH OF BUFFER SOLUTIONS, CONT. c. Salt effects:  Salicylic acid solution in a soft glass bottle is influenced by the alkalinity of the glass.  It might be thought at first that the reaction would result in an appreciable increase in pH; however, the sodium ions of the soft glass combine with the salicylate ions to form sodium salicylate.  Thus, there are rises a solution of salicylic acid and sodium salicylate-a buffer solution that resists the change in pH

22. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS In Vivo Biologic Buffer Systems Blood is maintained at a pH of about 7.4 by the so-called primary buffers in the plasma and the secondary buffers in the erythrocytes. The plasma contains carbonic acid/bicarbonate and acid/alkali sodium salts of phosphoric acid as buffers.

23. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS In Vivo Biologic Buffer Systems Plasma proteins, which behave as acids in blood, can combine with bases and so act as buffers. In the erythrocytes, the two buffer systems consist of haemoglobin / oxyhaemoglobin and acid/alkali potassium salts of phosphoric acid.

24. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS In Vivo Biologic Buffer Systems Lacrimal fluid, or tears, have been found to have a great degree of buffer capacity, allowing a dilution of 1: 15 with neutral distilled water before an alteration of pH is noticed. In the terminology of Bates; this would be referred to today as dilution value rather than buffer capacity. The pH of tears is about 7.4, with a range of 7 to 8 or slightly higher.

25. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS In Vivo Biologic Buffer Systems Pure conjunctival fluid is probably more acidic than the tear fluid commonly used in pH measurements. This is because pH increases rapidly when the sample is removed for analysis because of the loss of CO 2 from the tear fluid.

26. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS In Vivo Biologic Buffer Systems Urine: The 24-hour urine collection of a normal adult has a pH averaging about 6.0 units; it may be as low as 4.5 or as high as 7.8. When the pH of the urine is below normal values, hydrogen ions are excreted· by the kidneys. Conversely, when the urine is above pH 7.4, hydrogen ions are retained by action of the kidneys in order to return the pH to its normal range of values.

27. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS Pharmaceutical Buffers: Buffer solutions are used frequently in pharmaceutical practice, particularly in the formulation of ophthalmic solutions. They also find application in the colorimetric determination of pH For research studies in which pH must be held constant

28. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS Pharmaceutical Buffers: a. Buffers in Tablet formulations b. Buffers in Ophthalmic preparations c. Buffers in Parenteral preparations d. Buffers in Creams and Ointments

29. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS Pharmaceutical Buffers: a. Buffers in Tablet formulations  Buffers are used in tab. and cap. to control the pH of the drug particles  Buffers employed in formulations containing acidic drugs to reduce gastric irritation  Buffering agents used in solid oral dosage forms include antacids such as sodium bicarbonate, magnesium carbonate and sodium citrate

30. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS Pharmaceutical Buffers: Buffers in Ophthalmic preparations  To maintain the pH within the physiological pH range of the lacrimal fluid  To adjust the pH to a value that is best with regard to the solubility and stability of the drug and which tolerated by the eye  To prevent discomfort and injury to the surface of the eye  Example: borate, phosphate, and carbonate buffers

31. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS Pharmaceutical Buffers: Buffers in Parenteral preparations  The ideal pH of a parenteral product is 7.4  Because a highly alkaline pH (above 9) can cause tissue necrosis while an acidic pH (below 3) can result in extreme pain at the site of injection

32. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS Pharmaceutical Buffers: Buffers in Parenteral preparations  Buffers in parenteral preparations compromise between the stability and solubility of medicament as well as the irritancy of the preparation  Buffers are usually added for adjusting the pH of the parenteral products to a suitable value  Example: acetate, phosphate, citrate and glutamate buffers

33. BUFFERS IN PHARMACEUTICAL AND BIOLOGIC SYSTEMS Pharmaceutical Buffers: Buffers in Creams and Ointments  Buffers are used to maintain the stability of the product, Why? Because topical products have a tendency to undergo change in pH during storage which may adversely affect the stability of the drug.  Example: citric acid and its salts or phosphoric acid and its salt

34. P REPARATION OF PHARMACEUTICAL BUFFERS The steps included are: a. A weak acid should have a pk a near to pH at which the buffer is used. Why? Because this will give maximum buffer capacity. b. The ratio of the conjugate salt and acid required to attain the desired pH calculated from the buffer equation which gives a pH range of 4-10 c. Individual concentrations of the buffer salt and acid should be considered to obtain the desired buffer capacity.

35. P REPARATION OF PHARMACEUTICAL BUFFERS Factors affecting the selection of buffer system:  Easy availability of the buffer components  Compatibility with the drug stability of the buffer and the drug on ageing  Free from toxicity  Sterility of the final solution  Cost of the material  The pH and buffer capacity of the prepared system should be determined experimentally using pH meter or pH indicator papers. Why?

36. B UFFERED ISOTONIC SOLUTIONS  Isotonic or Iso-osmotic solutions are solutions having the same osmotic pressure as that of the body fluids when separated by a biological membrane  Body fluids including blood and lacrymal fluid with osmotic pressure corresponding to 0.9% solutions of Nacl concentration of 0.9% solution of Nacl is isotonic, why?  Solutions with osmotic pressure lower than that of the body fluids or of 0.9% Nacl solution are referred to as being hypotonic and those having a higher osmotic pressure are termed as hypertonic

37. B UFFERED ISOTONIC SOLUTIONS, CONT. The effect of hypertonic and hypotonic solutions on the red blood cells: Hypotonic solutions injected into the blood stream cause haemolysis of the RBC while hypertonic solutions cause shrinkage of the RBC! Why?

38. B UFFERED ISOTONIC SOLUTIONS, CONT. The effect of hypertonic and hypotonic solutions on the red blood cells If the RBCs are suspended in a hypotonic solution, water enters the blood cells causing swelling and finally bursting of the cell with the liberation of haemoglobin This bursting of the cells is known as haemolysis

39. B UFFERED ISOTONIC SOLUTIONS, CONT. The effect of hypertonic and hypotonic solutions on the red blood cells: If the RBCs are suspended in a hypertonic solution, the water within the cells passes out through the cell membrane in order to dilute the surrounding salt solution and attain an equilibrium across the membrane This outward passage of water causes the cells to shrink and become wrinkled or crenated

40. B UFFERED ISOTONIC SOLUTIONS, CONT. The effect of hypertonic and hypotonic solutions on the red blood cells: Pharmaceutical solutions introduced into the body or applied to delicate membranes of the body should be buffered at the desired pH and isotonic with the physiological fluids (blood plasma and lachrymal secretion), why?

41. B UFFERED ISOTONIC SOLUTIONS, CONT. Paratonic solutions (hypertonic or hypotonic) if instilled into the eyes or nose may cause irritation specially if the quantity instilled is large Parenteral, ophthalmic and nasal preparations are made isotonic by adding therapeutically inert substances like sodium chloride or dextrose

42. M EASUREMENTS OF T ONICITY 1. Haemolytic method 2. Colligative methods

43. M EASUREMENTS OF T ONICITY Haemolytic method: It is done qualitatively and quantitatively: suspending the RBCs in hypertonic and hypotonic solutions Liberation of oxyhaemoglobin in direct proportion to the number of cell haemolysed

44. M EASUREMENTS OF T ONICITY Colligative method:  Tonicity of a solution may be determined by determining its colligative properties, why?  Solutions having same tonicity exhibit similar behavior with respect to their colligative properties such as: Lowering of vapour pressure and depression in freezing point

45. C ALCULATION OF TONICITY USING L ISO VALUES the depression in freezing point of solutions of weak as well as strong electrolytes may be given by: ∆T f = K f c Where, ∆T f is the depression in freezing point K f is the molal depression constant c is the molar concentration ∆T f = iK f c ∆T f = L c L= ∆T f /c

46. M ETHODS OF ADJUSTING TONICITY  Cryoscopic or freezing point depression method  Sodium chloride equivalent method  White- vincent method  Sprowls method

47. M ETHODS OF ADJUSTING TONICITY  Cryoscopic or freezing point depression method %w/v of adjusting substance = 0.52-a/b where, a represents the depression in freezing point due to unadjusted solution or substance b represents the depression in freezing point of 1% w/v of adjusting substance  Sodium chloride equivalent method E = 17 L iso / M where, M is the molecular weight of the drug

48. M ETHODS OF ADJUSTING TONICITY, CONT.  White – Vincent method: This method involves the addition of sufficient quantity of water to a drug in order to prepare an isotonic solution Then an isotonic or a buffered isotonic solution is added to this drug solution to give the final volume The volume of the water required for a particular quantity of drug to prepare an isotonic solution can be calculated from the following equation: V = w × E × 111.1

49. M ETHODS OF ADJUSTING TONICITY, CONT.  White – Vincent method: V = w × E × 111.1 Where, V is the volume in ml of an isotonic solution that can be prepared by dissolving w gram of drug in water E is the sodium chloride equivalent of the drug 111.1 is a constant representing the volume in ml of isotonic solution obtained by dissolving 1 gm of Nacl in water.

50. M ETHODS OF ADJUSTING TONICITY, CONT.  Sprowls method: It is the modification of the White-Vincent method This method uses tables listing the volume of isotonic that can be prepared by mixing 0.3 gm of a drug in water

51. Any Question?

52. The End…. Thank you…