Dr.

Doaa Hussien Hassen Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy & Pharmaceutical Manufacture Misr University or Science & Technology Email: doaa.hussien@gmail.com

Dr. Doaa Hussien Hassen

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1/28/2012 Dr. Doaa Hussien Hassen

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. alkali. The buffer action: action:

The buffer action is to resist the change in pH. pH.

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 Buffer

could be: be:

A combination of a weak acid and its conjugate base (salt) e.g. acetic acid and sodium acetate or A combination of a weak base and its conjugate acid (salt). (salt). e.g. Ammonium hydroxide and ammonium chloride
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If 1 ml of a 0.1 N HCl is added to 100 ml of pure water (pH=7 (pH=7) solution, the pH is reduced from 7 to 3. But if 1 ml of a 0.1 N HCl solution is added to 100 ml of pure water containing buffer (equal quantities of acetic acid and sodium acetate 0. 1 M solution), the pH is changed only 0.09 pH units, because the base Ac- ties up the hydrogen ions according to the reaction: reaction:

Ac- +H3O+

HAC +H2O
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 In

case of base addition: addition:

If a strong base; sodium hydroxide, is base; added to the buffer mixture, acetic acid will neutralize the hydroxyl ions

HAc

+NaOH

H2O+ NaAC

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 The

buffer equation or the HendersonHenderson-

Hasselbalch equation, for a weak acid equation, and its salt: salt:
pH=

pKa + log [Salt]/[acid]

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Importance of Buffer Equation: Equation: To calculate the pH of a buffer solution The buffer equation is important in the preparation of buffered pharmaceutical solution; it is satisfactory for solution; calculations within the pH range of 4 to 10. 10.

1.

2.

To calculate the change in pH upon the addition of an acid or base

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pH= pKw -pKb + log [base]/ [salt] Buffer solutions are not ordinarily prepared from weak bases and their salts because of: of: (1) The volatility (2) Instability of the bases (3) The dependence of their pH on pKw, which is often affected by temperature changes. changes.
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Buffer capacity is the magnitude of the resistance of a buffer to pH changes. changes. It is also known as buffer efficiency, buffer index, and buffer value. value. Van Slyke introduced the concept of buffer capacity and defined: defined: It as the ratio of the increment of strong base (or acid) added to the small change in pH brought about by this addition. addition.

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= B / pH
10

= B / pH B is the

delta, has its usual meaning, a finite change, and

small increment in gram equivalents per liter of strong base added to the buffer solution to produce a pH change of pH. pH.

The buffer capacity of a solution has a value of 1 when: the when: addition of 1 gram Eq of strong base (or acid) to 1 liter of the buffer solution results in a change of 1 pH unit. unit.

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 It

must be noted that: that:

(1) The buffer capacity is not a fixed value for a given buffer system, but rather depends on the amount of base added. added. (2) The buffer capacity changes as the ratio log [salt]/[acid] increases with added base. base. (3) The buffer has its greatest capacity when [salt]/[acid] = 1, and, therefore, pH = pKa. pKa. (4) The buffer capacity is also influenced by an increase in the total concentration of the buffer constituents, since, obviously, a greater concentration of salt and acid provides a greater alkaline and acid reserve. reserve.

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Van Slykes Equation for Buffer Capacity: Capacity:

Where: Where: C

is the total buffer concentration

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In summary, the buffer capacity depends on: on: (a) The value of the ratio [salt] / [acid], ratio approaches unity; (salt/acid=1) unity; (salt/acid=1 increasing as the

(b) The magnitude of the individual concentrations of the buffer components, the buffer becoming more efficient as the salt and acid concentrations are increased. increased. Therefore an increase in the concentration of the buffer components results in a greater buffer capacity or efficiency. efficiency. C = [salt] + [acid], obviously results in a greater value of .
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The maximum buffer capacity occurs where pH = pKa, pKa, Substituting [H3O+] for Ka in both numerator and denominator of Van Slyke equation gives

maximum = 0.576 C In which C is the total buffer concentration. concentration.

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Buffer capacity of a weak acid/salt buffer as a function of pH, showing maximum buffer capacity at pKa.
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The components of various buffer systems and the concentrations required to produce different pHs are listed in several reference books, such as the pharmacopoeias. pharmacopoeias. When selecting a suitable buffer the pKa value of the acid should be close to the required pH the compatibility of its components with other ingredients in the system should be considered. considered. The toxicity of buffer components must also be taken into account if the solution is to be used for medicinal purposes

1. 2. 3.

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A solution of ephedrine base act as a natural buffer protecting against reductions in pH. pH. When Hydrochloric acid is added to the ephedrine solution, Ephedrine hydrochloride is formed, and the buffer system ephedrine plus ephedrine hydrochloride will resist large changes in pH until the ephedrine is depleted by reaction with the acid. acid.

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A drug, in solution may often act as its own buffer over a definite pH range. Such buffer action, range. however, is often too weak to resist pH changes brought about by the carbon dioxide of the air and the alkalinity of the bottle. Additional buffers are bottle. therefore frequently added to drug solutions to maintain the System within a certain pH range. range.

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The ability to resist change in pH on adding acid or alkali is possessed also by relatively concentrated solutions of strong acids and strong bases. bases. In general, solutions of strong acids of pH 3 or less, and solutions of strong bases of pH 11 or more, exhibit this kind of buffer action due to the relatively high concentration of hydronium or hydroxyl ion present. present.
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The USP includes among its Standard Buffer Solutions a series of Hydrochloric Acid Buffer, covering the pH rang 1.2 to 2.2, which also contain potassium chloride; the salt does not participate in the chloride; buffering mechanism, as is the case with salts of weak acids, instead it serves as a non reactive constituent required to maintain the proper electrolyte environment of the solutions. solutions.
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Blood: Blood:
Blood is maintained at a pH of about 7.4 by the so-called primary buffers in sothe plasma and the secondary buffers in the erythrocytes. erythrocytes. The Primary buffer in plasma contains: contains: Carbonic acid/bicarbonate and Acid/alkali sodium salts of phosphoric acid as buffers. buffers. Plasma proteins, which behave as acids in blood, can combine with bases and act as buffers. buffers.

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The secondary buffers in the erythrocytes, The two buffer and systems consist of hemoglobin salts of /oxyhemoglobin phosphoric acid. acid. acid/alkali potassium

Usually when the pH of the blood goes below 7.0 or above 7.8, life is in serious danger. danger. The pH of the blood in diabetic coma is alleged to drop as low as about 6.8.
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Lachrymal fluid, or tears lachrymal fluid

Lachrymal fluid has been found to have a great degree of buffer capacity: capacity: allowing a dilution of 1:15 with neutral distilled water before an alteration of pH is noticed. noticed. This would be referred to as dilution value rather than buffer capacity. capacity. The pH of tears is about 7.4, with a range of 7 to 8 or slightly higher. higher.
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Buffer solutions are used frequently in pharmaceutical practice, particularly in the formulation of ophthalmic solutions. solutions.
1- Gifford suggested two stock solutions, when mixed in various proportions, yield buffer solutions with pH values from about 5 to 9 one containing boric acid and the other monohydrate sodium carbonate. carbonate. 2- Sorensen Phosphate buffer (mixture of the salts of sodium phosphate for buffer solutions of pH 6 to 8. Sodium chloride is added to each buffer mixture to make it isotonic with body fluids. fluids. 3- Boric acid, sodium borate Buffer. Buffer. It is used for ophthalmic solutions in the pH range of 7 to 9. Sufficient sodium chloride to make the mixtures isotonic
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Solutions to be applied to tissues or administered parenterally are liable to cause irritation if their pH is greatly removed from the normal pH of the relevant body fluid. fluid. Consequently, the pharmacist must consider this point when formulating ophthalmic solutions, parenteral products, and fluids to be applied to abraded surfaces. surfaces.

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Pharmacist must consider: consider: 1- The pH of the formula 2- Buffer capacity and the volume to be used in relation to the volume of body fluid with which the buffered solution will come in contact. The buffer contact. capacity of the body fluid should also be considered. considered.

3-Buffer capacity of body fluid

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Tissue irritation, due to large pH differences between the solution being administered and the physiological environment in which it is used, will be minimal if: if: (a) The lower the buffer capacity of the solution, (b) The smaller the volume used, and (c) The larger the volume and buffer capacity of the physiological fluid. fluid. The pH of solutions for introduction into the eye may vary from 4.5 to 11 .5 marked pain or damage. (This statement damage. evidently would be true only if the buffer capacity was kept low). low).
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It was found that Sorensens buffer produced irritation in the eyes of a number of subjects, whereas a boric acid solution of pH 5 produced no discomfort in the eyes of the same subjects. subjects. This can be explained partly in terms of: of: (1) The low buffer capacity of boric acid as compared to that of the phosphate buffer and (2) The difference of the physiological response to various species. species. Parenteral solutions for injection into the blood are buffered to a low capacity so that the buffers of the blood may readily bring them within the physiologic pH range. range.
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In aqueous solutions Instability may arise through the catalytic effect of acids or bases; bases; Acids: by transferring a proton Acids: Bases by accepting a proton. proton. This instability problem could be overcome by adjusting pH through the use of buffers It must be noted that pH adjustment is important for solutions that require sterilization Examples: Examples: Morphine solutions: solutions: If pH< 5.5 they will not decomposed during 60 minutes exposure at a temperature of 100oC. But they are highly unstable at neutral and alkaline solutions. solutions.

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Solutions of thiamine hydrochloride: hydrochloride: They may be sterilized by autoclaving without appreciable decomposition if the pH is below 5; above this, thiamine hydrochloride is unstable. unstable. The stability of many disperse systems, The stability of many disperse systems are especially of certain emulsions, is often pH-dependent. pH-dependent.
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Drugs are weak acids or weak bases, and hence may exist in ionized or unionized form (or a mixture of both), Often such drugs have an optimum pH range for maximum activity. activity. (1) Mandelic acid, benzoic acid, and salicylic acid have distinct antibacterial activity in unionized form but have practically no such activity in ionized form; accordingly, these substances require an form; acid environment to function effectively as antibacterial agents. agents. (2) Sodium benzoate is effective as a preservative in 4% concentration at pH 7.0, 0.06 to 0.1% concentration at pH 3.5 to 4.0, and 0.02 to 0.03% concentration at pH 2.3 to 2.4 (needs acidic pH). 03% pH).

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Rate of absorption of drugs from the gastrointestinal and their passage through cellular membranes is determined by: by: (1)The degree of ionization and (2) Lipid solubility of a drug (3) The pH of the physiological medium (gastric or intestinal fluid, plasma, cerebrospinal fluid, etc.) in which a etc. drug is dissolved. dissolved.

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 Drugs

that are weak organic acids or bases, and which in non ionized form are soluble in lipids, are absorbed through cellular membranes by virtue, of the lipid nature of the membranes. membranes. ionized drugs, on the other hand, are poorly absorbed. absorbed.
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Completely

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Not only the degree of the acidic or basic character of a drug but consequently also the pH of the physiological medium (gastric or intestinial fluid, plasma, cerebrospinal fluid, etc.) etc. in which a drug is dissolved or dispersed since this pH determines the extent to which the drug will be converted to ionic or nonionic form become important parameters of drug absorption. absorption.

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Stability versus Optimum Therapeutic Response: Response: The pH for maximum stability of a drug for ophthalmic use may be far below that of the optimum physiologic effect. effect. Under such conditions: conditions: 1- The solution of the drug can buffered at a low buffer capacity 2-A compromise pH between that of optimum stability and the pH for maximum therapeutic action must be done. done.
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