Roy S D, Flynn G L
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Pharm Res. 1988 Sep;5(9):580-6. doi: 10.1023/a:1015994030251.
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)1/2 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 delta 2 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 of fusion and were 11.7, 10.9, 9.8, and 9.7 (cal/cm3)1/2. 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.
对选定的阿片类和苯胺基哌啶类麻醉性镇痛药的物理化学性质进行了研究。测定了这些麻醉药在己烷和水中的溶解度，以及吗啡在其他有机溶剂中的溶解度。正则溶液理论似乎适用于吗啡在缺乏强偶极和氢键的溶剂中的溶解行为。根据吗啡在伦敦型溶剂中的溶解度及其理想溶解度，确定了其最佳拟合溶解度参数为13.2（cal/cm³）¹/²。仅根据吗啡在己烷中的溶解度及其熔点性质计算出的溶解度参数，得到了相应的δ₂值。这些实测的溶解度参数明显大于由摩尔吸引常数估算出的溶解度参数。还根据氢吗啡酮、可待因、芬太尼和舒芬太尼各自在己烷中的溶解度、熔点和熔化热计算出它们的溶解度参数，分别为11.7、10.9、9.8和9.7（cal/cm³）¹/²。对于这些化合物，实验溶解度参数与由摩尔吸引常数估算出的溶解度参数相符。由于哌替啶、芬太尼和舒芬太尼表现出较低的晶体内内聚力，这反映在它们较低的熔点和相对适中的熔化热上，理论预测的它们在有机溶剂中的理想溶解度和实测溶解度比吗啡及其类似物的要高得多。与溶解度一致，两种4-苯胺基哌啶类似物和哌替啶的正辛醇-水分配系数比阿片类药物的大几个数量级，这表明哌替啶、芬太尼和舒芬太尼比阿片类药物的亲脂性要强得多。
