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The physicochemical properties of select opioid and anilinopiperidine narcotic analgesics were investigated. The solubilities of the narcotics in hexane and water and, for morphine, in other organic solvents were determined. Regular solution theory seems to be applicable to the solubility behavior of morphine in solvents that lack strong dipoles and hydrogen bonds. A best-fit solubility parameter of 13.2 (cal/cm3)½ for morphine was determined from its solubilities in London solvents and its ideal solubility. Calculation of morphine's solubility parameter from its hexane solubility alone and its melting properties gave a corresponding δ2 value. These measured solubility parameters were appreciably larger than the solubility parameter estimated from molar attraction constants. Solubility parameters of hydromorphone, codeine, fentanyl, and sufentanil were also calculated from respective hexane solubilities, melting points, and heats effusion and were 11.7, 10.9, 9.8, and 9.7 (cal/cm3)½. For these compounds, experimental solubility parameters agreed with solubility parameters estimated from molar attraction constants. Because meperidine, fentanyl, and sufentanil exhibit low levels of intracrystalline cohesion, as reflected in low melting points and relatively modest heats of fusion, theoretically projected ideal solubilities and actual solubilities in organic solvents measured for them were considerably higher than determined for morphine and its analogues. Consistent with the solubilities, the octanol–water partition coefficients of the two 4-anilinopiperidine analogues and of meperidine were several orders of magnitude larger than those of the opioids, evidencing the fact that meperidine, fentanyl, and sufentanil are substantially more lipophilic than the opioids.