Improvement of aripiprazole solubility by complexation with (2-hydroxy)propyl-β-cyclodextrin using spray drying technique

Abstract

Due to the fact that the number of new poorly soluble active pharmaceutical ingredients is increasing, it is important to investigate the possibilities of improvement of their solubility in order to obtain a final pharmaceutical formulation with enhanced bioavailability. One of the strategies to increase drug solubility is the inclusion of the APIs in cyclodextrins. The aim of this study was to investigate the possibility of aripiprazole solubility improvement by inclusion in (2-hydroxy)propyl-β-cyclodextrin (HPBCD) and simultaneous manipulation of pH of the medium and addition of polyvinylpyrrolidone. Aripiprazole-HPBCD complexes were prepared by spray drying aqueous drug-HPBCD solutions, and their properties were compared with those prepared by solvent-drop co-grinding and physical mixing. The obtained powders were characterized by thermoanalytical methods (TGA and DSC), FTIR spectroscopy, their dissolution properties were assessed, while the binding of aripiprazole into the cavity of HPBCD was studied by molecular docking simulations. The solubilization capacity was found to be dependent on pH as well as the buffer solution's ionic composition. The presence of PVP in the formulation could affect the solubilization capacity significantly, but further experimentation is required before its effect is fully understood. On the basis of solubility studies, the drug/HPBCD stoichiometry was found to be 1:3. The spray-dried products were free of crystalline aripiprazole, they possessed higher solubility and dissolution rate, and were stable enough over a prolonged period of storage. Spray drying of cyclodextrin solutions proved to be an appropriate and efficient technique for the preparation of highly soluble inclusion compounds of aripiprazole and HPBCD.

Fig. 1

(2-Hydroxy)propyl-β-cyclodextrin isomers used for the docking simulations: isomer a, with substitution only at the O6 position, and isomer b, having substituents at the O6 and O2 positions

Fig. 2

Representative DSC thermograms of aripiprazole a, HPBCD b, aripiprazole–HPBCD inclusion compound produced by spray drying at 160 mM HPBCD concentration c, physical mixture of aripiprazole with HPBCD d, and aripiprazole–HPBCD inclusion compound produced by solvent-drop co-grinding e

Fig. 3

Representative ATR-FTIR spectra of aripiprazole a, HPBCD b, aripiprazole–HPBCD inclusion compound produced by spray drying at 160 mM HPBCD concentration c, and corresponding physical mixture of aripiprazole with HPBCD d

Fig. 4

Representative docked conformations of aripiprazole in different HPBCD isomers

Fig. 5

Phase solubility diagrams for aripiprazole and HPBCD in different media

Fig. 6

Phase solubility diagram for aripiprazole in HPBCD solution in water

Fig. 7

Phase solubility diagrams for media with the most significant solubility improvement: a citrate buffer pH 3; b citrate buffer pH 3 with PVP

Fig. 8

Dissolution rate of aripiprazole from different samples, in 0.1 M HCl, agitation speed: a 60 rpm and b 50 rpm