Reaction #66034

ord-c327fe2a3cd64e28b5e7e204d8e172a1

Reaction equation

CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12.O=S(=O)([O-])[O-].[NH4+].[NH4+]
sildenafil ammonium sulphate
CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12.O=C(O)CC(O)(CC(=O)O)C(=O)O
sildenafil citrate
CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC
DPPC
CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
cholesterol
O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
glucose
→
CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
sildenafil

Reactants

CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12.O=S(=O)([O-])[O-].[NH4+].[NH4+]
sildenafil ammonium sulphate
CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12.O=C(O)CC(O)(CC(=O)O)C(=O)O
sildenafil citrate
CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC
DPPC
CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
cholesterol
O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
glucose

Reagents

None

Solvents

CCO
ethanol

Conditions

Detailed conditions
See reaction.notes.procedure_details.

Workup

  1. 1
    workup.ADDITIONwas added for dilution and alkalinization of the reaction mixture, i.e. of the resulting liposome suspension

Procedure

The lipids (DPPC:cholesterol=55:45 mol %) were dissolved in ethanol and the solution was injected into a sildenafil/ammonium sulphate solution (pH 3.5-4.5), whereupon, immediately after spontaneous vesicle formation, a 5% glucose solution (pH 7), which comprised further sildenafil citrate, was added for dilution and alkalinization of the reaction mixture, i.e. of the resulting liposome suspension. As a result of the production of this H+ gradient immediately after the vesicle formation, sildenafil is not only included in the liposomes in one step but is also retained there in a stable manner. The amount of sildenafil included liposomally in this manner was likewise in a range of about 160 to 230 nmol of sildenafil per μmol of total lipids (DPPC+cholesterol)—depending on the pH or H+ gradient.

Source

DOI: 10.6084/m9.figshare.5104873.v1Patent: US08524274B2uspto-grants-2013_09