Development and Characterization of Zaleplon Solid Dispersion Systems: A Technical Note

Abstract

Zaleplon (Fig. 1) is a pyrrazolopyrimidine hypnotic drug indicated for the short term (2 to 4 weeks) management of insomnia (1). It interacts with GABAA receptor and also shows some pharmacological properties of benzodiazepines (2). It also possesses potent anticonvulsant activity against pentylenetetrazole- and electroshock-induced convulsions (3) and is rapidly and completely absorbed after oral administration. However, it undergoes extensive first pass hepatic metabolism after absorption, with only 30% of zaleplon being systemically available (4). Zaleplon attains peak concentration (Cmax) within 1.1 h (tmax) approximately after administration, with terminal elimination half life of 1 hour (5). Cmax and area under the plasma concentration–time curve (AUC) both exhibit linear dose proportionality at doses up to 60 mg well above the 10 mg therapeutic dose (6,7). Fig. 1 Chemical structure of zaleplon Although zaleplon is rapidly absorbed after oral administration, its poor aqueous solubility (8) (practically insoluble) can make its absorption dissolution rate limited and thus delay onset of action. The dissolution of drugs is a prime determinant in the absorption of poorly water-soluble drugs and also serves as a rate-limiting step (9). No information is available on the improvement of these drug-like properties of zaleplon. In this article increasing the solubility of zaleplon has been addressed via solid dispersion technique. The formulation of poorly water-soluble drugs is one of the most challenging tasks to the formulation experts. An enhancement in the solubility and the dissolution rate can improve the oral bioavailability of such drugs, which further improves the therapeutic efficacy and patient compliance. Various techniques have been used to enhance the solubility of poorly water-soluble drugs, including the use of surfactants (10), inclusion complexation (11), use of polymorph (12), and amorphous form of drug micronisation (13) and solid dispersion (14–16). The solubilization of drug from solid dispersion systems is mainly because of the reduction in particle size, increase in the surface area and reduction in the crystallinity that improves dissolution rate. Also, no energy is required to break up the crystal lattice of a drug during dissolution process and drug solubility and wettability may be increased by surrounding hydrophilic carriers (17). The various methods used to prepare solid dispersions are the hot melt method (18,19), solvent evaporation (20), spray drying (21), hot melt extrusion (22), solvent deposition technique (23) and solvent wetting method (24). The aim of the present study was to enhance the dissolution rate of zaleplon using solid dispersion technique with various hydrophilic polymers. The solvent evaporation method was used to prepare solid dispersion particles of zaleplon. Solid dispersion systems and physical mixtures of zaleplon were prepared with poloxamer F68, polyvinylpyrrolidone K30 (PVP K30), and polyethyleneglycol 6000 (PEG 6000) each in 1:1, 1:3 and 1:5 ratios. The selection of different ratios of polymers was purely on random basis. The solid-state properties of these binary systems were studied by thin layer chromatography, Fourier transformation infrared spectroscopy, X-ray powder diffractometry and differential scanning calorimetry. The dissolution behavior of zaleplon and its binary systems were further evaluated.