Comparative analysis of zaleplon complexation with cyclodextrins and hydrophilic polymers in solution and in solid state

The aim of this work was to investigate the potential synergistic effect of water-soluble polymers (hypromellose, HPMC and polyvinylpyrrolidone, PVP) on zaleplon (ZAL) complexation with parent β-cyclodextrin (βCD) and its randomly methylated derivative (RAMEB) in solution and in solid state. The addition of HPMC to the complexation medium improved ZAL complexation and solubilization with RAMEB (KZAL/RAMEB = 156 ± 5 M−1 and KZAL/RAMEB/HPMC = 189 ± 8 M−1; p < 0.01), while such effect was not observed for βCD (KZAL/βCD = 112 ± 2 M−1 and KZAL/βCD/HPMC = 119 ± 8 M−1; p > 0.05). Although PVP increased the ZAL aqueous solubility from 0.22 to 0.27 mg/mL, it did not show any synergistic effects on ZAL solubilization with the cyclodextrins tested. Binary and ternary systems of ZAL with βCD, RAMEB and HPMC were prepared by spray-drying. Differential scanning calorimetry, X-ray powder diffraction and scanning electron microscopy demonstrated a partial ZAL amorphization in spray-dried binary and ternary systems with βCD, while the drug was completely amorphous in all samples with RAMEB. Furthermore, inclusion complex formation in all systems prepared was confirmed by solid-state NMR spectroscopy. The in vitro dissolution rate followed the rank order ZAL/RAMEB/HPMC > ZAL/RAMEB = ZAL/βCD/HPMC > ZAL/βCD ≫ ZAL, clearly demonstrating the superior performance of RAMEB on ZAL complexation in the solid state and its synergistic effect with HPMC on drug solubility. Surprisingly, when loaded into tablets made with insoluble microcrystalline cellulose, RAMEB complexes had no positive effect on drug dissolution, because HPMC and RAMEB acted as a binders inside the tablets, prolonging their disintegration. Oppositely, the formulation with mannitol, a soluble excipient, containing a ternary RAMEB system, released the complete drug-dose in only 5 min, clearly demonstrating its suitability for the development of immediate-release oral formulation of ZAL.

► Zaleplon (ZAL) complexation with RAMEB and HPMC enhanced its solubility about 9 times.
► βCD was less effective in ZAL solubilization, not forming ternary complexes with HPMC or PVP.
► CP-MAS confirmed the inclusion complexation for all spray dried binary and ternary samples.
► βCD complexes contained 39.8–31.1% of crystalline ZAL; RAMEB complexes were amorphous.
► ZAL/RAMEB/HPMC complex tabletted with mannitol gained immediate-release formulation.