The Pharmaceutics and Compounding Laboratory
Ophthalmic Preparations

Iso-osmoticity and Isotonicity

If a semi-permeable membrane (one that is permeable only to solvent molecules) is used to separate solutions of different solute concentrations, a phenomenon known as osmosis occurs in which solvent molecules cross the membrane from lower to higher concentration to establish a concentration equilibrium. The pressure driving this movement is called osmotic pressure and is governed by the number of "particles" of solute in solution. If the solute is a nonelectrolyte, the number of particles is determined solely by the solute concentration. If the solute is an electrolyte, the number of particles will be governed by both the concentration and degree of dissociation of the substance.

Solutions containing the same concentration of particles and thus exerting equal osmotic pressures are called iso-osmotic. A 0.9% solution of NaCl (Normal Saline) is iso-osmotic with blood and tears. The term isotonic, meaning equal tone, is sometimes used interchangeably with the term iso-osmotic. The distinction between these terms comes with the realization that red blood cell membranes are not perfect semipermeable membranes, but allow passage of some solutes, such as alcohol, boric acid, ammonium chloride, glycerin, ascorbic acid, and lactic acid. Hence, a 2% solution of boric acid while physically measured to be iso-osmotic (containing same number of particles) with blood, will not be isotonic (exerting equal pressure or tone) with blood but is isotonic with tears. Practically speaking, this differentiation is rarely of significance and isotonicity values calculated on the basis of the number of particles in solution is usually sufficient.

The clinical significance of all this is to insure that isotonic or iso-osmotic solutions do not damage tissue or produce pain when administered. Solutions which contain fewer particles and exert a lower osmotic pressure than 0.9% saline are called hypotonic and those exerting higher osmotic pressures are referred to as hypertonic. Administration of a hypotonic solution produces painful swelling of tissues as water passes from the administration site into the tissues or blood cells. Hypertonic solutions produce shrinking of tissues as water is pulled from the biological cells in an attempt to dilute the hypertonic solution. The effects of administering a hypotonic solution are generally more severe than with hypertonic solutions, since ruptured cells can never be repaired. The eye can tolerate a range of tonicities as low as 0.6% and as high as 1.8% sodium chloride solution.

Several methods are used to adjust isotonicity of pharmaceutical solutions. One of the most widely used method is the sodium chloride equivalent method. The NaCl equivalent (E) is the amount of NaCl which has the same osmotic effect (based on number of particles) as 1 gm of the drug.

sample calculation: Calculate the amount of NaCl required to make the following ophthalmic solution isotonic.


Atropine Sulfate 2%
NaCl qs
Aqua. dist. q.s. ad. 30 ml
M.ft. isotonic solution

    1. Determine the amount of NaCl to make 30 ml of an isotonic solution

    X = 0.27 g

    2. Calculate the contribution of atropine sulfate to the NaCl equivalent

    30 ml × 2 g/100 ml = 0.6 g atropine sulfate - E atropine sulfate = 0.13 - 0.6 g x 0.13 = 0.078 g

    3. Determine the amount of NaCl to add to make the solution isotonic by subtracting (2) from (1)

    0.27 g - 0.078 g = 0.192 g or 192 mg

    Other substances may be used, in addition to or in place of NaCl, to render solutions isotonic. This is done by taking the process one step further and calculating the amount of the substance that is equivalent to the amount of NaCl calculated in step 3.

    For example, boric acid is often used to adjust isotonicity in ophthalmic solutions because of its buffering and anti-infective properties. If E for boric acid is 0.50, then the amount of boric acid needed to replace the NaCl in step 3 can be calculated:

      or X = 0.38 g

      or, more simply: 0.192 g ÷ 0.50 = 0.38 g

    Thus, 0.38 g or 380 mg of boric acid would be required to render the previous ophthalmic solution isotonic.