Use of coarse ethylcellulose and PEO in beads produced by extrusion–spheronization

https://doi.org/10.1016/j.ijpharm.2009.10.028Get rights and content

Abstract

This study evaluated the potential of coarse ethylcellulose (CPEC) and high molecular weight polyethylene oxide (PEO) as excipients in the production of beads by extrusion–spheronization. CPEC was investigated as a diluent and PEO as an extrusion aid and a binder. Beads were manufactured with caffeine as a model drug. Release studies were conducted, and the bead size, shape, yield, and friability were determined. The effects of formulation and process variables and their interactions were studied by a sequential experimental design based on a response surface method. In the initial stage, a two level half fractional factorial design was employed as a screening design, which was subsequently augmented to a central composite design. Statistical analysis indicated that formulation variables including PEO content, microcrystalline cellulose (MCC) content, and water content, and two process variables, namely spheronizer speed and spheronization time, significantly affected the properties of the beads. Interactions between two factors have significant effects on several of the measured responses. Simultaneous optimization of the responses was conducted and validated by performing experiments at the optimal conditions. Overall, the results confirmed that immediate release, spherical beads with low friability and narrow size distribution could be produced with minimal amounts of MCC.

Introduction

Extrusion–spheronization is becoming the most popular method for the production of beads due to advantages such as production of relatively dense and homogeneous beads with low surface porosity, as well as short processing times and the resultant operator and time savings (Vervaet et al., 1995). Microcrystalline cellulose (MCC) has long been considered crucial for bead production by extrusion–spheronization (Dukic-Ott et al., 2009, Vervaet et al., 1995, Barrau et al., 1993, Ku et al., 1993). However, there are disadvantages encountered with the use of MCC, including batch-to-batch variability in the commercial material, trace microbial contamination, generation of heat during the extrusion process, and failure of the beads to disintegrate that often results in incomplete drug release (Tho et al., 2002). Several drugs have been reported to be unstable in the presence of MCC (Brandl et al., 1995, George et al., 1994, Torres and Camacho, 1994, Patel et al., 1988, Signoretti et al., 1986, Carstensen et al., 1969). Specifically, the highly water soluble drug, ranitidine, has been shown to undergo chemical degradation by a complex three way interaction with MCC and water at MCC levels greater than 60% (Basit et al., 1999). Reducing or completely removing MCC from the formulation should be a means to eliminate this problem. Nevertheless, there are few studies that address this issue using this approach (Charoenthai et al., 2007, Newton et al., 2007, Thommes and Kleinebudde, 2006, Howard et al., 2006, Agrawal et al., 2004, Tho et al., 2002, Basit et al., 1999).

MCC typically constitutes greater than 20% (w/w) of the bead formulation (Jover et al., 1996, Hileman et al., 1993). According to Kleinebudde et al. (1999), the minimal amount of MCC needed to form a continuous network is about 14%. In order to confirm that excipients other than MCC are suitable for beads produced by extrusion–spheronization, the amount of MCC in the formulation should therefore be less than 14%. In the present study, the use of two excipients in the preparation of beads with little MCC in them was investigated.

Ethylcellulose ethers are a family of inert hydrophobic polymers obtained by reacting ethyl chloride with alkali cellulose. The alkaline conditions are likely to reduce microbial contamination in comparison to that observed with MCC. Ethylcellulose manufactured by the Dow Chemical Company is available in two different size ranges. The standard form of ethylcellulose, coarse particle ethylcellulose (CPEC), is granular with an average particle size greater than 250 μm. Fine particle ethylcellulose (FPEC) is the finely milled version with an average particle size range of 6–50 μm. In addition, there is likely a lower batch-to-batch variability than observed with MCC since the ethylcellulose products from Dow Chemical Company are available at specific viscosity levels that should minimize molecular weight variability, and the ethoxy level is specified and of a narrow range (e.g., an ethoxy content of 48–49.5% is specified for the product used in the present studies).

The level of polymer and the particle size of ethylcellulose in direct compression tablets have been shown to dramatically affect the drug release rates (Dabbagh et al., 1996, Katikaneni et al., 1995a, Katikaneni et al., 1995b). Smaller particle sizes of ethylcellulose were shown to produce direct compression tablets of lower porosity and increased hardness due to differences in compactibility and compressibilty. Similar studies are lacking regarding the application of ethylcellulose in extrusion–spheronization.

Polyethylene oxide (PEO) is a nonionic, synthetic, linear polymer of ethylene oxide. It is highly water soluble and rapidly swells upon exposure to an aqueous environment to form a strong gel. The major pharmaceutical applications of PEO have been in the production of dry blends, direct compression tablets (Hong and Oh, 2008, Kojima et al., 2008, Yang et al., 1996) and in hot melt extrusion (Prodduturi et al., 2007, Repka and McGinity, 2000). Maggi et al. (2000) investigated the use of high molecular weight PEO as an alternative to HPMC as a binder in direct compression tablets. The influence of the molecular weight of PEO on study of the drug release from direct compression tablets revealed that swelling was the primary mechanism for drug release with very high molecular weight PEO while low molecular weight PEO released the drug by both erosion and swelling (Maggi et al., 2002, Kim, 1998, Apicella et al., 1993).

Pinto et al. (2004) investigated the use of high molecular weight PEO in extrusion. Different PEO levels were tested for their ability to produce an extrudate, but they do not describe the preparation of beads by a subsequent spheronization process. They report that the affinity of PEO for water is so high that the hydrogel formed dramatically affects the extrudability of a granulation or wetted mass. Low molecular weight PEO (MW 300,000) was used along with methoxy polyethylene glycol by Howard et al. (2006) in the production of extruded and spheronized beads containing pseudoephedrine HCl. In their study, MPEG reduced the tackiness of PEO and improved the lubricity of the wetted mass.

The first objective of the present study was to investigate the application of CPEC as an excipient in the production of beads with little or no MCC. High molecular weight PEO was chosen as a binder and an extrusion aid in the process. The second objective was to identify important formulation and process variables that affect the properties of the beads and to optimize those effects by using statistical experimental design.

Section snippets

Materials

CPEC (Ethocel™ Standard Premium 7 cps viscosity grade with ethoxy content of 48–49.5%) and high molecular weight PEO (HMW PEO, PolyOx™ WSR N-12K) were gifts from the Dow Chemical Company (Midland, MI). Microcrystalline cellulose (Avicel PH-101, 36,450 average molecular weight, 51.5 μm average particle size, and 1.57 g/cm3 powder density) was a gift from FMC Corporation (Philadelphia, PA). Caffeine from Sigma–Aldrich (St. Louis, MO) served as a model drug. Distilled de-ionized water was used as the

Preliminary studies

The appropriate use and level of each excipient was determined by conducting preliminary studies. Preliminary studies in our lab indicated that CPEC can be used in the production of spherical beads, although these beads, produced using a radial extruder, could be obtained only at a particular water level. However, it is desirable to have a range over which water could be varied and still be able to produce characterizable product. In the present study, conducted with an axial extruder, the

Conclusions

The results from a central composite design (alpha equal to 1.5) demonstrated the feasibility of producing high quality extruded and spheronized beads with minimal amounts of MCC by using CPEC and high molecular weight PEO. High molecular weight PEO was used as an extrusion aid and a binder. Each of the batches in the study produced beads that were highly spherical irrespective of the formulation and process variables, suggesting that CPEC is a good excipient for the production of beads by

Acknowledgments

The authors would like to thank Rick Bruce from Johnson & Johnson for his help with PS and AR assessments. The authors are grateful to Dow Chemical Company for their gifts of coarse ethylcellulose and high molecular weight PEO and to FMC Corporation for the gift of their microcrystalline cellulose product, Avicel PH 101.

References (39)

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