Inclusion complexation of ziprasidone mesylate with β-cyclodextrin sulfobutyl ether

Abstract

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.

The Utility of Sulfonate Salts in Drug Development

“…48 Kim et al 49 also reported on a combination of salt formation and formulation strategies to enhance the solubility of a drug for parenteral dosage forms. The mesylate salt of ziprasadone had an intrinsic solubility of 0.89 mg/mL; however, this was inadequate to achieve the required solubilities for intramuscular administration (20-40 mg/mL).…”

Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial

“…Ziprasidone mesylate was supplied as 30 mg sterile lyophilized powder in a 10 ml clear, glass vial. This was reconstituted with 1.2 ml sterile water, producing a 1.5 ml stock solution containing 20 mg/ml ziprasidone mesylate and 294 mg/ml of the cyclodextrin derivative, sulphobutylether betacyclodextin (SBECD), a novel excipient that enhances the solubility of ziprasidone (Kim et al 1998). The 20 mg dose was prepared by drawing 1 ml of the stock solution, and the 2 mg dose was prepared by adding 0.03 ml of the stock solution to 0.97 ml of a separately prepared SBECD solution.…”

“…The development of an IM formulation of ziprasidone, using sulfobutylether beta-cyclodextrin to solubilize the drug by forming a complex (Kim et al 1998), provides a means of administering ziprasidone to patients for whom an IM formulation is the preferred route because of acute symptoms of agitation associated with psychosis. Ziprasidone IM attains peak exposure within approximately 30 min, exposure is dose-related and there is negligible drug accumulation with multiple dosing (Miceli et al 1998).…”

Use of Solid Dispersions and Inclusion Complexation for Enhancing Oral Bioavailability of Ziprasidone in Treating Schizophrenia

“…The enhanced dissolution may be due to inclusion complex Ziprasidone in Treating Schizophrenia formation as well as raised mechanistic impinging during dissolution [60,61]. The in vitro dissolution studies of solid dispersion by spray drying with Kollidon, F-127 in 7.2 po4 buffer with 92.05%, and 73.3% drug being released within 20 min, Whereas in case of Soluplus almost 92.97%,drug was released in 20 min in 7.2 po4 buffer.…”

“…The literature data indicate that many studies are carried out for solubility enhancement of Ziprasidone focussing on utilization of various derivatives of cylodextrins [40,41]. It has been shown that different salt forms of Ziprasidone have different solubility due to the degree of ion pair formation between ziprasidone & the counterion [42].…”