Lipophilicity determination of psoralens used in therapy through solubility and partitioning: comparison of theoretical and experimental approaches.
The aim of this study was to determine and to compare experimental and theoretical solubilities (S) as well as partition coefficients (PC) in an octanol/water system of psoralen (P), 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5',8-trimethylpsoralen (TMP). For each psoralen, experimental results were performed in triplicate with a spectrofluorimetric technique. The measurements were achieved 10 times for each solution. The obtained order of the solubilities in pure octanol was 5-MOP approximately TMP > P > 8-MOP, while in water-saturated octanol it was expressed as follows: TMP approximately 5-MOP > P > 8-MOP. However, the following order was found for hydrophobicity: TMP > 5-MOP > 8-MOP > P. The solubility ratios (SR) in pure octanol and water were assessed (mean +/- SD): 3.13 +/- 0.01 (P), 2.60 +/- 0.01 (8-MOP), 3.75 +/- 0.01 (5-MOP), and 5.11 +/- 0.01 (TMP). In saturated phases, they were 3.27 +/- 0.01, 2.63 +/- 0.01, 3.85 +/- 0.01, and 5.32 +/- 0.01, respectively. The PCs were determined with low concentrations according to the Dearden and Bresnen32 method and they were 1.67 +/- 0.01, 1.93 +/- 0.01, 2.00 +/- 0.01, and 3.14 +/- 0.01, respectively. Solubility parameters (delta), in Hildebrand unit (H) or in (cal/cm3)1/2, were evaluated. They confirmed the polarity of psoralens, previously expressed through the PC, although the positional isomers (5-MOP and 8-MOP) revealed no difference. Hildebrand's approach to the solubility of regular solutions and Yalkowsky's concept of the solubility of nonelectrolytes and weak electrolytes in an octanol/water system permitted a comparison of the theoretical and experimental results. The perspective of this work is to use the physicochemical properties of the psoralens in practice for insuring convenient experimental assays and the prediction, in vitro, of the percutaneous absorption of these compounds.
Laboratoire de Pharmacie Galénique, Faculté de Médecine et Pharmacie, Besançon, France.
A
A
Said
S
S
Makki
P
P
Muret
J C
JC
Rouland
G
G
Toubin
J
J
Millet
D000078223:5-Methoxypsoralen; D005363:Ficusin / Q000032:analysis; D011564:Furocoumarins / Q000032:analysis / Q000737:chemistry*; D008730:Methoxsalen / Q000031:analogs & derivatives / Q000032:analysis; D008962:Models, Theoretical; D000442:Octanols / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry*
D011564:Furocoumarins; D000442:Octanols; D014867:Water; D000078223:5-Methoxypsoralen; D005363:Ficusin; D008730:Methoxsalen