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Buffer in biological & pharmaceutical

systems

Buffer in biological & pharmaceutical systems

• I. In vivo biological buffer systemsØa) BloodØ b) Lacrimal fluid

• II. Pharmaceutical Buffers

• III. Pharmaceutical significance of

buffers

I. In vivo biological buffer systems

Øa) BloodØ b) Lacrimal fluid

:by4.7Blood is maintained at a pH of about v 1° buffers in the plasma &

v 2° buffers in the erythrocytes.

vvThe buffer capacity of bloodThe buffer capacity of blood = = 00..039 039 gram equiv. per liter/pH gram equiv. per liter/pH unit for whole blood of which: unit for whole blood of which: 00..031 031 by the cellsby the cells

00..008 008 by the plasmaby the plasma

a) Blood

a) Blood

••When the pH of the blood When the pH of the blood goes below goes below 77..0 0 or or

•• above above 77..88, life is in serious , life is in serious danger. danger.

•• The pH of the blood in The pH of the blood in diabetic coma is dropped to diabetic coma is dropped to about about 66..88

• Tears have a great degree of buffer

capacity, allowing a dilution of 1:15 with

neutral distilled water before an alteration

of pH is noticed.

• The pH of tears is about 7.4 with a range of

7 to 8

b) Lacrimal fluid

II. Pharmaceutical Buffers

• Examples• Steps of formulation• Factors considered in formulation

II. Pharmaceutical Buffers

•• Buffer solutions are used in Buffer solutions are used in pharmaceutical formulation pharmaceutical formulation particularly in ophthalmic particularly in ophthalmic preparationspreparations

•• ExamplesExamplesØØGiffordGiffordØØSorensenSorensenØØThe ClarkThe Clark--LubsLubs

Gifford bufferGifford buffer

•• suggested two stock suggested two stock solutions of:solutions of:ØØboric acid and boric acid and monohydrated sodium monohydrated sodium carbonatecarbonateØØpH values from about pH values from about 5 5 -- 99..

Sorensen bufferSorensen buffer

••proposed a mixture of salts proposed a mixture of salts of:of:ØØ sodium phosphate sodium phosphate ØØ pH pH 6 6 to to 88. .

The ClarkThe Clark--Lubs bufferLubs buffer•• mixtures and their pH rangesmixtures and their pH rangesØØa. pH a. pH 11..2 2 to to 22..22: HCl and KCl: HCl and KClØØb.b. pH pH 22..2 2 to to 44..00: HCl and potassium : HCl and potassium

hydrogen phthalatehydrogen phthalateØØc. pH c. pH 44..0 0 to to 66..22: NaOH and potassium : NaOH and potassium

hydrogen phthalatehydrogen phthalateØØd. pH d. pH 55..8 8 to to 88..00: NaOH and KH: NaOH and KH22POPO4 4 ØØe. pH e. pH 77..8 8 to to 10 10 : H: H33BB0303, NaOH and KCl , NaOH and KCl

Sodium chloride is added to buffer mixture to make it isotonic with body.

The following steps should be used in preparing buffer systems

•a. Select a weak acid having a pKa approximately equal to

• the pH wanted to insure maximum buffer capacity.

vPka= pH

Steps of preparing buffer solution

• b. From the buffer equation, calculate the ratio of salt and weak acid required to obtain the desired pH.

• The buffer equation is suitable for calculations within the pH range of 4 to 10.

• log Cu/Ci = pKa - pH


• c. Consider the individual concentrations of the buffer salt and acid needed to obtain a suitable buffer capacity.

• β = 2.3 C Ka[H3O+](Ka + [H3O+])2

• A concentration of 0.05 to 0.5 molar is sufficient and buffer capacity of 0.01 to 0.1 is sufficient.


•d. Finally, determine the pH and buffer capacity of the completed buffered solution using a pH meter.

Factors of some importance in the choice of pharmaceutical buffer

• Availability of chemicals • Sterility of the final solution.• Stability of the drug and buffer on

aging.• Cost of materials.• Freedom from toxicity. Ø For example, a borate buffer,

because of its toxic effects, cannot be used for a solution to be administrated orally or parenterally

III-Significance of pharmaceutical buffers

•Minimize Tissue irritation•Optimum Therapeutic

Response•Drug Stability•Drug solubility•Drug Activity

1-Tissue irritation

•due to large pH differences between:Øthe solution administeredØthe physiological fluid

Tissue irritation is minimized:

• (a) The lower the buffer capacity of the solution

• (b) The smaller the volume used for a given concentration.

• (c) The larger the volume and buffer capacity of the physiological fluid

Parenteral solutions for injection into theblood stream are usually not buffered or theyare buffered to a very low capacity so that thebuffers of the blood may bring themwithin the physiological pH range.

2-Influence of Buffer Capacity and pH on Optimum Therapeutic Response

•The undissociated form of a weakly acidic or basic drug has a higher therapeutic activity than the dissociated salt form WHY?


• Because: the undissociated formis lipid soluble and can penetratebody membranes, whereas theionic form is not lipid-soluble andcan only penetrate membraneswith great difficulty.


• Thus, the therapeutic response of weakly basic alkaloids (used as ophthalmic drugs) increases as the pH of the solution increases, and hence-concentration of the undissociated base, was increased.

• At a pH of about 4 these drugs are in the ionic form and penetration is slow.

• When the tears bring the pH to about 7.4, the drugs may exist in the form of the free base depending on the dissociation constant of the drug.

3-Influence of Buffer Capacity and pH onDrug Stability

• Buffer is used to prevent changes in pH due to the Øalkalinity of the glassØacidity of CO2 from dissolved air

• Solutions as Thiamine hydrochloride may be sterilized by autoclaving without decomposition if the pH is below 5 ; above this pH thiamine hydrochloride is unstable.

• The stability of emulsions is pH dependent.

¬The pH for maximum stability of a drug for ophthalmic use maybe far below that of the optimum physiological effect s

⇒1- solution of the drug can be buffered at a low buffer capacity2- adjust pH to be a compromise between that of optimum

stability and the pH for maximum therapeutic action.

¬Yet, when the solution is instilled in the eye, the tearsparticipate in the gradual neutralization of the solution and theconversion of the drug from the physiologically inactive form tothe undissociated base the base can then readily penetrate thelipoidal membrane.

¬As the base is absorbed at the pH of the eye , more of the salt isconverted into base to preserve the equilibrium, hence thealkaloidal drug is gradually absorbed.

4-PH and solubility.

• The influence of buffering on the solubility of the alkaloidal base:

• at a low pH a base is predominantly in the ionic form which is usually very soluble in aqueous media

• as the pH is raised more undissociated base is formed.

• Therefore, the solution should be buffered at sufficiently low pH

5-Influence of Buffer Capacity and pH on Drug Activity

•Drugs that are weak acids or weak bases, may exist in ionized or non ionized form. They may be active in one form but inactive in the other. Such drugs have an optimum pH range for maximum activity.

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