Poorly water-soluble drugs often show low bioavailability when administered orally, since the absorption of the drugs in the gastrointestinal tract can usually be a rate-limiting step. Therefore, it is important for such kind of drugs to enhance their dissolution rate. Some of the dissolution-enhancing methods have been applied for the production of pharmaceutical preparations. Various studies have been reported in attempt to improve solubilities of poorly water-soluble drugs. Increasing the available surface area for dissolution via particle size reduction is one of the oldest methods for improving the dissolution rates of poorly water-soluble drugs (1
). Solid dispersion systems have been widely studied and repeatedly shown to improve the dissolution properties of poorly water-soluble drugs (2
Cyclodextrins (CyDs) comprise a family of cyclic oligosaccharides, and several members of this family are used industrially in pharmaceutical and allied applications. CyDs are potential candidates because of their ability to alter physical, chemical, and biological properties of guest molecules through the formation of inclusion complexes (4
). Recently, various kinds of CyD derivatives have been prepared so as to extend the physicochemical properties and inclusion capacity of natural CyDs as novel drug carriers (6
). 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) has superior properties (a highly soluble, amorphous powder with no detectable oral toxicity) as pharmaceutical additive. HP-β-CyD can modify the release rate of poorly water-soluble drugs, which can be used for the enhancement of drug absorption across biological barriers, serving a potent drug carrier in the immediate release formulations (10
) and be useful for inhibition of polymorphic transition and crystallization rates of poorly water-soluble drugs during storage, which can consequently maintain the higher dissolution characteristics and oral bioavailability of the drugs (13
Extrusion process is one of the processes of applying pressure to mass until it flows through an orifice or a defined opening (16
). An extruder is a mixer that operates continuously and involves processes such as kneading, shearing, heating, melting, and cooling. The extruder has been used for polymer processing and in the plastic sand food industries (17
). Melt extrusion may be applied to disperse drugs in a given matrix down to the molecular level, e.g.
, to form a true solution. It is the convenience of the technology that gives new hope to the glass or solid solution approach as a delivery system for poorly soluble drugs. The use of melts in order to obtain solid molecular dispersions, e.g.
, glass or solid solutions, is well known, and the essential advantage of a melt process in this domain is its solvent-free formation of such dispersions (19
). The melt extrusion process is capable of handling active agents of different particle sizes as well as amorphous solids or other polymorphic forms leading to the same product. Wet granulation is considered one of the most important processes in the manufacturing of solid dosage forms. Production of solid dosage forms using granules has several advantages such as enhanced flowability, improved compactability, reduced segregation, and less dust. In the pharmaceutical industry, the use of a twin-screw extruder for wet extrusion was introduced by Gamlen and Eardley (20
). Kleinebudde and Lindner (21
) performed preliminary studies with an instrumented, co-rotating twin-screw extruder. Schroeder and Steffens (22
) used rotary screw extrusion for continuous wet extrusion. Lindberg et al.
) were the first to report on the possibility of using a twin-screw extruder for the continuous granulation of an effervescent paracetamol preparation.
Recently, there were some reports about application of CyDs in extrusion process to improve stability and dissolution behavior of poorly water-soluble drugs. Rambali et al.
) used a melt extrusion process with HP-β-CyD to improve the poor solubility of itraconazole. In other studies, Fukuda et al.
) investigated the influence of sulfobutyl ether-β-CyD on the dissolution properties of ketoprofen from extrudates prepared by melt extrusion at a processing temperature close to the melting point of ketoprofen, but below the melting point of sulfobutyl ether-β-CyD, the dissolution rate of ketoprofen from extrudate was significantly higher than both the physical mixture and melt extrudate prepared with parent β-CyD.
However, no literature was presented so far on the comparison of dissolution behavior and physicochemical properties of extrudate between melt extrusion and wet extrusion with application of CyDs in extrusion process.
In this study, indomethacin (IM), which is a model for poorly water-soluble drugs, and HP-β-CyD were used. The improvement of dissolution behavior of IM by application of HP-β-CyD in extrusion process was investigated, and the mechanism of enhancing effect for dissolution properties in both melt extrusion process and wet extrusion process was evaluated.