Inclusion complexation of ziprasidone mesylate with beta-cyclodextrin sulfobutyl ether.
Ziprasidone is an antipsychotic agent indicated primarily for the treatment of schizophrenia. An intramuscular dosage form of ziprasidone was developed using beta-cyclodextrin sulfobutyl ether (SBECD) to solubilize the drug by complexation. Inclusion complexation of ziprasidone mesylate (ZM) with SBECD was studied by circular dichroism (CD) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, Monte Carlo simulations, phase-solubility studies, and counterion titration. The results of the studies indicate that ZM, of which the counterion is not fully dissociated from the drug, forms a 1:1 inclusion complex with SBECD with the benzisothiazole group positioned in the cavity. A mathematical model was developed to calculate stability constants of inclusion complexes for the ion pair (Z+M-:SBECD) and the dissociated ionic form (Z+:SBECD) of ZM; the values were 7892 and 957 M(-1), respectively. The model also allowed the dissociation constants of noncomplexed and complexed ZM to be calculated; the value of the former is 8-fold greater than the value of the latter. These results indicate that the inclusion complex formation of the ion pair is favored over that of the dissociated ionic form of ZM, and that the dissociation of ZM is suppressed by inclusion complexation with SBECD.
Kim
Y
Y
Pharmaceutical R&D Department, and Exploratory Medicinal Sciences, Pfizer Inc., Groton, Connecticut 06340, USA.
Oksanen
D A
DA
Massefski
W
W
Blake
J F
JF
Duffy
E M
EM
Chrunyk
B
B
D014150:Antipsychotic Agents / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000378:metabolism*; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy; D008962:Models, Theoretical; D015394:Molecular Structure; D009010:Monte Carlo Method; D010879:Piperazines / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism*; D047392:beta-Cyclodextrins
D014150:Antipsychotic Agents; D003505:Cyclodextrins; D010879:Piperazines; D013844:Thiazoles; D047392:beta-Cyclodextrins; C092292:ziprasidone; C031215:betadex