Question

Phenytoin is an extremely weak acid, pKa 8.3, with very poor water solubility. Solubility of the sodium salt in water is 15 g/L, and in ethanol it is 95 g/L. It is freely soluble in warm propylene glycol and it has a molecular weight of 274.3. We are going to prepare five 5 mL vials of this product. With its poor water solubility, how would you propose that the required concentration of 50 mg/mL be achieved and which and how much cosolvent would you use?

Answer 1

Maximum solubility of phenytoin in EtOH is = 95g/L

And that of in water it = 15g/L = 15mg/mL

So if we take all 5mL of water as solvent the total concentration of

Phenytoin in 5mL solution = 15mg/mL × 5mL = 75mg

However, we need a solution with concentration of = 50mg/mL×5mL = 250mg

Hence, only water will not be enough to make this solution.

Maximum solubility of phenytoin in EtOH = 95mg/mL

So to have 250mg of concentration we need = 250mg/95mg/mL = ~2.7 mL of EtOH.

Please note that actual volume comes to be 2.63mL, however, to ensure complete solubility we take 2.7mL of solvent.

Thus the we may use 2.7mL EtOH and add 2.3mL of water to dissolve 250mg of phenytoin.

This resulting solution is of concentration = 250mg / 5mL = 50mg/mL

The minimum solvent requirement is 2.7mL and above that you can use any amount of EtOH as a solvent and then add water as a cosolvent respectively.