Analysis of the complexation of gemfibrozil with gamma- and hydroxypropyl-gamma-cyclodextrins.
The interactions of gemfibrozil with gamma- and HP-gamma-cyclodextrin (CD) have been studied in aqueous solution by fluorescence and NMR spectroscopy and by solubility measurements and in the solid state by X-ray diffraction, thermal analysis and FTIR spectroscopy. The influence of the technique employed in the analysis of complexation is discussed. The fluorescence of gemfibrozil increased in the presence of gamma- and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), especially with the later, because the inclusion of the aromatic ring in the cavity, evidenced by 1H NMR, has a protective effect on the excited state of the drug. The fluorescence enhancement allowed the determination of the binding constants at pH 2.8. Complexation was a both entropy and enthalpy driven process. The solubility diagrams obtained with gamma-CD and HP-gamma-CD were B(s) and A(L) type, respectively. The apparent stability constants calculated from the solubility data at 25 degrees C were compared with those obtained from the fluorescence assays. It was found that drug solubilization with gamma-CD involves other contributions together with the inclusion phenomena. Solid complexes of gemfibrozil with gamma-CD (and not with HP-gamma-CD) have been obtained by kneading, coevaporation and coprecipitation methods. The solid complexes crystallised in the channel structure, in a process involving the carboxyl and aryl-ether groups.
Fernández
L
L
Departamento de Química y Edafología, Facultad de Ciencias, Universidad de Navarra, Irunlarrea s/n, Pamplona 31080, Spain.
Martínez-Ohárriz
M C
MC
Martín
C
C
Vélaz
I
I
Sánchez
M
M
Zornoza
A
A
D004347:Drug Interactions; D004355:Drug Stability; D015248:Gemfibrozil / Q000032:analysis* / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D000960:Hypolipidemic Agents / Q000032:analysis* / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011208:Powders; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction; D047408:gamma-Cyclodextrins / Q000032:analysis* / Q000737:chemistry* / Q000378:metabolism
D000960:Hypolipidemic Agents; D011208:Powders; D012996:Solutions; D047408:gamma-Cyclodextrins; D014867:Water; C023792:gamma-cyclodextrin; D015248:Gemfibrozil