Pharmaceutics: Buffers And Isotonicity

Front 1

Describe factors to consider when selecting a pH buffer.

Back 1

Physiological pH is 7.4.

Ophthalmic and parenteral solutions must be properly buffered for comfort and safety (no irritations).

Ophthalmic solutions can tolerate a wide pH range (6.5 to 8.5) and still avoid corneal damage because tear fluid helps dilute and buffer the solutions.

Reasons to NOT buffer all pharmaceutical products to 7.4: Solubility, chemical stability, therapeutic activity, other formulation considerations.

Front 2

Describe how pH affects the solubility of drugs.

Back 2

Weak acids and bases are more soluble in their ionized forms than their unionized forms, so solubility is important for the solubility of weak electrolytes.

Front 3

Describe how pH affects the therapeutic activity of drugs.

Back 3

Weak acids and bases: the unionized, undissociated salt form crosses lipid membranes more readily than the ionized form. However, this is the LEAST soluble form.

Ex. Phenobarbital; only 1 gram of the drug is soluble in 1000ml of water. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.

In the STOMACH with pH of 1: weak acids and bases are PROTONATED, so the non-ionized form will predominate. Weak acids are more absorbed in the stomach.

In the INTESTINES with pH 7: Weak bases are mostly ionized so they're more readily absorbed in the intestine.

Front 4

Describe how pH affects and is used to test for chemical stability.

Back 4

Isoniazid is an example: maximal stability at pH 6. Oral liquid dosage form is no longer available. A formula for compounding an oral liquid dosage form has been reported. A study in 2005 to test the stability of isoniazid in an oral liquid dosage form: used a high performance liquid chromatographic assay method for the quantization of isoniazid. The initial pH value was 5.9. The formulation's physical appearance changed from almost colorless to light brown after 42 days of storage... 30 days is the beyond use date (pH 5.6)

Front 5

Describe how pH can affect the formulation of drug products.

Back 5

Carbopol (Carbomer gels): form acid aqueous solutions (pH around 3) but thickens at pH 5-6 so the pH must be adjusted to form the gel.

Front 6

Define buffer.

Back 6

Buffer: a substance that by its presence in solution resists change in pH of the solution upon addition of small quantities of acid or alkali, or on dilution of the solution with a solvent. The resistance is not an absolute protection from pH variation because all buffer solutions have a maximum capacity.

Front 7

Describe three types of buffer systems, recognizing common buffers and their type.

Back 7

--Weak acid and its conjugate base (MOST COMMON). Ex: acetic acid + sodium acetate, boric acid + borate, citric acid + citrate, carbonic acid + bicarbonate, disodium phosphate + mono sodium phosphate.

--Weak bases and its conjugate acid. (not as common bc of instability). Ex. ephedrine + ephedrine HCl.

--Two salts. mono basic potassium phosphate KH2PO4 and dibasic potassium phosphate K2HPO4. H2PO4- ion is the weak acid and K2HPO4 is its salt.

Front 8

Define Buffer Zone.

Back 8

The pH near the pKa is known as the buffer zone. The weak acid and the conjugate base are the buffer agents.

Front 9

Apply the Henderson Hasselbalch equation to perform buffer solution calculations.

Back 9

HH equation is also known as the pH or buffer equation. One can make a solution of a desired pH using different concentrations of the buffer agent, as long as the [base]/[acid] ratio is kept the same.

pH = pKa + log ([salt]/[acid])

Ex. What is the pH of acetic acid and sodium acetate solution where the concentration of both acid and salt are 0.1M each? the pKa of acetic acid is 4.76.

pH = 4.76 + log (0.1/0.1)

pH = pKa: equal amounts of protonated and non-protonated forms are present.

At the half-equivalents point, the pH = pKa.

Ex: What is the mole ratio, [salt]/[acid], required to prepare an acetate buffer of pH 5? pKa of acetic acid is 4.76. Also, express the salt concentration in mole percent.

(mole percent = mole fraction x 100)

5 = 4.76 + log (s/a)

10^0.24 = 1.74:1

1.74/ (1+1.74) x 100 = 63.5%

Front 10

Describe factors that influence the pH of a buffer system.

Back 10

Ionic strength: addition of neutral salts such as NaCl affect pH of a buffer solution by altering ionic strength. Dilution of an aqueous buffer solution with water in moderate quantities shows only small effect on pH of a buffer solution.

Temperature: Buffer pH changes with temperature. Acidic buffers increase pH as temperature increases, and basic buffers decrease pH as temperature increases.

Front 11

Define buffer capacity, including the unit of concentration.

Back 11

Buffer Capacity (B): The magnitude of resistance of a buffer to pH changes is referred to its buffer capacity. It is also known as buffer efficiency, buffer value, and buffer index.

The buffer capacity is proportional to the concentration of the buffer agents used.

B = 2.3 x C (Ka [H3O+]/ (Ka + [H3O+])^2)

C is the TOTAL concentration of the solution. This concentration is an indication of the amount of base needed to raise the solution pH by 1 pH unit.

Front 12

Define maximum buffer capacity.

Back 12

Bmax: The maximum buffer capacity occurs when pH = pKa (or [H3O+] = Ka).

Bmax = 0.575 x C

Front 13

Perform buffer capacity calculations.

Back 13

At a pH of 4.76, what is the capacity of a buffer containing 0.1 moles each of acetic acid and sodium acetate per liter of solution? pKa = 4.93

C: 0.1 + 0.1 = 0.2 moles/L

Ka = -log(4.93) = 1.17x10^-5

[H3O+] = 10^-pH = 10^ -4.76

B = 2.3 x C (Ka [H3O+]/ (Ka + [H3O+])^2)

B = 0.11

Front 14

Perform maximum buffer capacity calculations.

Back 14

What is the maximum buffer capacity of an acetate buffer with a total concentration of 0.02moles/liter?

Bmax = 0.575 x 0.02 = 0.0115

Front 15

Define tonicity, isosmotic, and isotonic.

Back 15

Tonicity: the osmotic pressure exerted by salts in aqueous solution. Body fluids have an osmotic pressure corresponding to that of 0.9% sodium chloride solution (290mOsm).

Isosmotic: solutions with the same osmotic pressure.

Isotonic: when a solution's tonicity (osmotic pressure) is equal to that of 0.9% sodium chloride solution.

Front 16

Define hypotonic and hypertonic solutions; describe how these solutions affect the eye and what the tolerated tonicity range is for ophthalmic preparations.

Back 16

Hypotonic: solutions with a lower osmotic pressure (tonicity) than 0.9%.

Hypertonic: solutions having a greater osmotic pressure than 0.9%.

A hypertonic solution added to the eye draws water out of the eye. Highly hypertonic solutions are used to relieve corneal edema.

Hypotonic solution added to the eye will induce passage of water from solution into the eye tissue.

The eye is much more tolerant to tonicity variations and can tolerate 0.5 to 1.8 % NaCl.

Front 17

Describe commonly used isotonicity agents.

Back 17

Tonicity agents are added to some liquid drug delivery systems to make the isotonic to the body fluid.

NaCl or dextrose: formulation of injectable, ophthalmic, and nasal solutions.

Sodium acetate or boric acid: additional tonicity agents. Boric acid can cause erythrocyte damage and is not a choice for systemic drug delivery.

Most drugs used in ophthalmic preparations are weak acids. The eye can tolerate a greater deviation from physiological pH toward alkalinity with less irritation than toward the acidic range. For these reasons, boric acid and its salt, sodium borate, have been used as tonicity agents for isotonic ophthalmic solutions.

Front 18

Apply the sodium chloride equivalent method to calculate the amount of tonicity agent needed to make pharmaceutical preparations isotonic.

Back 18

0.9% or 9mg/ml solution of NaCl is isotonic with body fluids.

A = 9mg/ml x volume of Rx

B = mg of drug x E (NaCl equiv)

Repeat for all drugs and express as B1, B2, etc.

C = A - B1- B2 etc.

See notes for example problem.