Research paper
Novel tablet formulation of amorphous indomethacin using wet granulation with a high-speed mixer granulator combined with porous calcium silicate

https://doi.org/10.1016/j.jddst.2016.03.001Get rights and content

Abstract

Solid dispersion techniques are useful for improving the dissolution of poorly water-soluble drugs. This study aimed to produce and evaluate solid dispersion tablets improving the solubility and oral bioavailability of a poorly water-soluble indomethacin (IND) by wet granulation method with a high-speed mixer granulator combined with porous calcium silicate (PCS). A low density of PCS is a major disadvantage which is a bulky volume and scattering. So, it is necessary to prepare a high density PCS granule. Our system is very simple. At first, IND ethanol solution was added to PCS in a high-speed mixer granulator. After mixing, the granulation started the addition of the binder water solution to the PCS/IND mixture. The solid dispersion granules were obtained after drying the mixture. The dissolution rates of IND from PCS tablets were markedly enhanced compared with the dissolution rate of the pure drug. IND did not recrystallize in granules prepared using water and this formulation provided superior bioavailability in rats. Our amorphous solid dispersions have been successfully employed to enhance both solubility and oral bioavailability of IND. Though the use of PCS, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.

Introduction

Currently, most new candidate drugs show poor solubility in aqueous media [1], [2], [3], [4]. The increase in the number of poorly soluble candidate compounds is frequently attributed to improvements in synthesis technology that has enabled the design of highly complicated compounds and to the change in discovery strategy from the so-called phenotypic approach to the target-based approach [4], [5]. Poorly water-soluble drug compounds exhibit low systemic absorption and bioavailability; therefore, the development of oral formulations for increased solubility remains an important issue for pharmaceutical scientists.

Solid dispersion techniques, where the active pharmaceutical ingredient is dispersed in an inert matrix [4], are useful for improving the dissolution of poorly water-soluble drugs [6], [7], [8], [9], [10], [11], [12], [13], [14]. For example, a polymeric excipient has been used as an inert carrier for obtaining solid dispersion formulations [6], [7], [8], [9], [10]. While polymeric excipients are now most commonly used as inert carriers, many attempts have also been made to use porous materials as carriers because they offer a large area for drug adsorption [11], [12], [13], [14], [15], [16], [17]. Solid dispersions with porous materials are referred to as surface solid dispersions [17] because the drug is present on the surface of the carrier, unlike the conventional solid dispersions where the drug is trapped within the polymer network. The interactions between the carrier and the drug also play an important role in the release of the drug from the carrier.

Porous calcium silicate (PCS) exhibits a highly porous structure and a large individual pore volume, and it has been used as a liquid absorber and a compressive adjuvant of powder for tableting [18]. While PCS-based solid dispersions have been shown to be effective for improving the dissolution of poorly water-soluble drugs [11], [12], [13], PCS, owing to its low density, can easily become airborne during manufacturing. Additionally, low-density materials may not mix uniformly with other materials because of differences in density [19] and may affect the filling of rotary tableting machines [19], [20]. Development of high-density PCS granules is therefore essential. Nevertheless, little research on increasing the density of PCS granules has been reported so far.

Wet granulation is currently the most widely used granulation technique [21], [22] because of its favorable characteristics such as increased particle size, improved flow and compression properties, and improved content uniformity of low-dose (<20 mg) tablets [19]. Three main types of granulators are used in the pharmaceutical industry for wet granulation: tumbling granulators, fluidized-bed granulators, and mixer granulators [23]. In particular, high-speed mixer granulators are used extensively because they can produce small (typically less than 1 mm) and dense granules that are ideal for blending and tableting [23]. The granules formed by mixing the powder with an agitator while adding a liquid binder (mainly water) are smaller, denser, and often more spherical than those obtained using tumbling or fluidized-bed granulators [24]. It is likely that the wet granulation method will be useful for producing dense granules of low-density materials such as PCS.

Because of their high entropy, enthalpy, and free energy, amorphous drug particles in a solid dispersion generally recrystallize easily and thus are inherently unstable [4], [25], [26], [27]. Recrystallization is especially likely in the presence of water [7], [8], [9], [10] and solid dispersions are therefore generally prepared without using water, leading to a paucity of reports on solid dispersion granules prepared using water. The aim of the present study was to produce and evaluate PCS-based solid dispersion tablets that improve the solubility and oral bioavailability of poorly-water-soluble indomethacin (IND) (PubChem CID: 3715) using wet granulation with a high-speed mixer granulator.

Section snippets

Materials

IND was purchased from KONGO CHEMICAL Co., Ltd. (Toyama, Japan; purity over 99.5 w/w%). PCS (Fluorite® RE) was provided by Tomita Pharmaceutical Co., Ltd. (Tokushima, Japan) and xylitol for use as a binder was obtained from B Food Science Co., Ltd. (Tokyo, Japan). Crospovidone (Kollidon® CL) used as a disintegrant was obtained from BASF Co., Ltd. (Ludwigshafen, Germany) and silicified microcrystalline cellulose (Prosolv® SMCC90) and magnesium stearate were obtained from JRS PHARMA GMBH & Co.

Preparation of IND formulation using PCS

The flow properties of powders are important for preparing dosage forms [19], [20], and powders with poor fluidity must be improved by granulation or the addition of excipients. We therefore evaluated the bulk density, tap density, CI, angle of repose, particle size, and water content for PCS, ASD, and PCS granules, with the results shown in Table 2. The PCS porous carrier has low density and easily becomes airborne; its angle of repose, CI, and particle size were 39.5°, 35.6%, and 30.8 μm,

Conflict of interest

The authors declare that they have no conflict of interest to disclose.

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