Optimization of Tablets Containing High Dose of Spray-Dried Plant Extract: A Technical Note

Optimization of Tablets Containing High Dose of Spray-Dried Plant Extract: A Technical Note
May 23, 2005
L.A.L. Soares1,2, G. Gonz?lez Ortega2, P.R. Petrovick2, P.C. Schmidt3
1 Departamento de Farm?cia - UFRN Av. General Cordeiro de Farias s/n, 59010-180, Natal, Rio Grande do Norte, Brazil
2 Programa de P?s-Gradua??o em Ci?ncias Farmac?uticas - UFRGS Av. Ipiranga, 2752, 90610-000, Porto Alegre, Rio Grande do Sul, Brazil
3 Department of Pharmaceutical Technology, University of T?bingen Auf der Morgenstelle 8, D ? 72076, T?bingen, Germany
AAPS PharmSciTech. Accepted: May 23, 2005. Author?s final version.
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INTRODUCTION
The development and production of tablets containing high dose of active ingredients is a complex and extensive technological challenge. Dried plant extracts are often used as therapeutically active material in the manufacture of tablets. They are quite often very fine, poorly compressible and very hygroscopic powders. Additionally, tablets containing a high amount of dried extract show prolonged disintegrate times; therefore, the release of the active constituents is affected [1-3]. Some alternatives have been proposed to minimize these problems. The granulation seems to be the most appropriated technique to improve the technological properties of these products. However, due to their high hygroscopicity, extracts cannot be granulated using aqueous systems. Thus, dry granulation is a possible technique to produce granules from dried herbal extracts [2,3]. Slugging is a simple dry granulation process, by which material is compacted in tablet press with subsequent milling process. Previously work showed that the use of lubricants during direct compression of vegetable dried extracts increasing the disintegration time [2]. On the other hand, Rocksloh et al. [2] and von Eggelkraut-Gottanka et al. [3] showed that the incorporation of a high amount of magnesium stearate into the granules shortened the disintegration times compared to tablets containing the powdered mixture. Experimental design is a widely used tool for the systematic and effective evaluation of differences among formulations [4-7]. The Central Composite Design (CCD) is the most employed second-order design to study and optimize tablet formulations [8-11]. With CCD, it is possible to create response surfaces, which allow the ranking of each variable according to its significance on the responses studied. Therefore, it may be possible to predict the formulation composition to reach a desired response with a reduced time and experimental effort [12-17]. The aim of this study was to evaluate the concentration of CMC-Na and CSD on the crushing strength, disintegration time and friability of tablets containing high doses of spray dried extract dry granulations, using a CCD.
MATERIALS AND METHODS
Materials
Spray dried extract (SDE)
Maytenus ilicifolia aerial parts were extracted by maceration using distillated water (1:10, w/v). Colloidal silicon dioxide (Aerosil 200?, Degussa AG, S?o Paulo, Brazil) was added to the miscella in a ratio of 2:8 of adjuvant to dry residue [18]. The dispersion was dried using a Production Minor? spray-dryer (GEA, Copenhagen, Denmark), provided with a rotating disk. The operational conditions were 9500 rpm of the rotation disk, inlet temperature of 149 ?C, outlet temperature of 99 ?C and 140 mL/min of feed ratio.
Excipients
Microcrystalline cellulose (MCC - Avicel PH 101?; FMC Corp., Lehmannn and Voss, Hamburg, Germany), cross-linked sodium carboxymethylcellulose (CMC-Na - Lehmannn and Voss, Hamburg, Germany), colloidal silicon dioxide (CSD - Aerosil 200?; Degussa AG, Frankfurt/Main, Germany), and magnesium stearate (Otto B?rlocher GmbH, Munich, Germany), were used as received.
Methods
Slugging and Granulation [19]
The SDE from Maytenus ilicifolia (486.0 g) was blended in a Turbula mixer (Model T2C, Willy Bachofen, Basel, Switzerland) for 5 minutes, with 7.0 g of CSD and 7.0 g of magnesium stearate. Slugs of 0.8 g were produced at a compression force of 22.0 ? 1.0 kN using flat faced tooling of 17 mm in diameter on a single punch tablet press EK 0 (Korsch AG, Berlin, Germany). The upper punch was instrumented with four strain gauges (Model 3/120 LY-11; Hottinger Baldwin, Darmstadt, Germany) to measure the compression force. A Hottinger Baldwin carrier-frequency bridge was used as amplifier (Model K52 with A/D converter KWD 523D; Hottinger Baldwin, Darmstadt, Germany). The compression data were acquired and processed using a Messefix? V. 2.3 software (Dr. R. Herzog, T?bingen, Germany).
The slugs were crushed in a dry granulator (Erweka TG IIS coupled to a Erweka AR 400 multipurpose motor; Erweka GmbH, Heusenstamm, Germany) to obtain granules with a particle size < 2.00 mm. The resulting material was passed through an oscillating granulator (Erweka FGS coupled to a Erweka AR 400 multipurpose motor; Erweka GmbH, Heusenstamm, Germany) using a 1.0 mm sieve. The granulate fraction between 250 and 1000 ?m was chosen for tablet optimization.
Preparation of Tablets
Tablets were prepared from each formulation described in Table 1. The granule proportion was kept constant at 71.23 % (w/w). The amount of CMC-Na and CSD was established according to each formulation and MCC in concentration sufficient to 100 % (Table 1). The different formulations were blended for 10 min in the Turbula mixer. Then, CSD was sieved through a 315 ?m sieve onto the mix, and the final mixing was carried out for 5 min. 250.0 mg from each formulation were weighted (n = 40) and compressed at 11.0 ? 0.5 kN on a single punch tablet machine EK 0 (Korsch AG, Berlin, Germany) using a flat faced tooling of 10 mm in diameter.