Physicochemical Characteristics
Three benzodiazepine receptor agonists are commonly used in the
practice of anesthesia in the United States: midazolam, diazepam, and lorazepam
( Fig. 10-10
and Table
10-7
). All these molecules are relatively small and lipid soluble at physiologic
pH. Each milliliter of diazepam solution (5 mg) contains 0.4 mL propylene glycol,
0.1 mL alcohol, 0.015 mL benzyl alcohol, and sodium benzoate/benzoic acid in water
for injection (pH 6.2 to 6.9). Lorazepam solution (2 or 4 mg/mL) contains 0.18 mL
polyethylene glycol with 2% benzyl alcohol as a preservative. Midazolam solution
contains 1 or 5 mg/mL midazolam plus 0.8% sodium chloride and 0.01% disodium edetate,
with 1% benzyl alcohol used as a preservative. The pH is adjusted to 3 with hydrochloric
acid and sodium hydroxide. Midazolam is the most lipid soluble of the three drugs
in vivo,[363]
but because of its pH-dependent solubility,
it is water soluble when formulated in a buffered acidic medium (pH 3.5). The imidazole
ring of
*Data
from Moffet A: Clarke's Isolation and Identification of Drugs, 2nd ed. London,
Pharmaceutical Press, 1986.
†pH dependent:
pH > 4, lipid soluble; pH < 4, water soluble.
midazolam accounts for its stability in solution and rapid metabolism. The high
lipophilicity of all three accounts for their rapid CNS effect, as well as their
relatively large volumes of distribution.[364]
