Comparison of the effect of the R2 phenothiazine ring substituent on fluphenazine and perphenazine interactions with cyclodextrins.
The effect of -CF3 R2 fluphenazine (FLF) and -Cl R2 perphenazine (PF) substituents on interactions of these phenothiazine derivatives with cyclodextrins (CD) was compared. Inclusion complexes of protonated and basic forms of FLF and PF with CDs were obtained in HCl 0.01 mol/L (pH 1.9 or 2.1), in phosphate buffer (pH 5.8) and in Britton-Robinson's buffer (pH 10.2) solutions and studied using spectral method. It was established. that the uncharged forms of both phenothiazine derivatives interact with CDs stronger than protonated molecules and that the perphenazine-CD inclusion complexes characterize greater apparent stability constants in comparison to adequate fluphenazine complexes. The thermodynamic parameters, estimated from linear Van't Hoff plot, suggest that the van der Waals forces accompanied by hydrophobic effects were operating in the investigated FLF-CD and PF-CD systems. The effect of pH and presence of CD on photostability of FLF or PF was also compared. The photochemical decomposition of both phenothiazine derivatives, in the absence and in the presence of CDs, proceeds according to the first order reaction. It was also established that independent on the charge of molecule, perphenazine was more stabile than fluphenazine and that the inclusion complexation with CDs improved the photostability of both drugs. The data of 2D NMR analysis suggest, that the aromatic portion of FLF and PF molecules, without R2 substituent, tend to the interior of CD.
Lutka
Anna
A
Department of Inorganic and Analytical Chemistry, Poznań University of Medical Sciences, 6 Grunwaldzka Str., 60-780 Poznań, Poland. alutka@amp.edu.pl
Prange
Wojciech
W
D014150:Antipsychotic Agents / Q000737:chemistry*; D003505:Cyclodextrins / Q000737:chemistry*; D004355:Drug Stability; D005476:Fluphenazine / Q000031:analogs & derivatives* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D010546:Perphenazine / Q000031:analogs & derivatives* / Q000737:chemistry; D010777:Photochemistry; D013816:Thermodynamics
D014150:Antipsychotic Agents; D003505:Cyclodextrins; D010546:Perphenazine; D005476:Fluphenazine