Purpose: The study looked into the feasibility of producing pellet using Avicel CL611 as spheronization aid by the extrusion/spheronization technique. Methods: Pellets were formulated to contain either 20% or 40% Avicel CL611 and lactose monohydrate as the other sole ingredient. Water is used as liquid binder. Quality of pellets and extrudates were analyzed for size distribution, shape, surface tensile strength and disintegration profile. Results: More water was needed when higher Avicel CL611

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... raction was used during the production of pellets. The pellets of larger size were obtained by increasing the water content. Pellets with aspect ratios of ~1.1 were produced with high spheronization speed at short residence time. Higher tensile strength was achieved when increasing the water content and the fraction of Avicel CL611 during pellet production. These pellets also took longer time to disintegrate, nonetheless all the pellets disintegrated within 15 minutes. A positive linear relationship was obtained between the tensile strength and time for pellets to disintegrate. Conclusion: Strong but round pellets that disintegrate rapidly could be produced with Avicel CL611 as spheronization aid using moderately soluble compounds such as lactose. Introduction Pelletization involves processing of fine powder into free flowing, spherical or semi-spherical pharmaceutical agglomerates known as pellets. Pellets manufactured in pharmaceutical industries normally range in size from 500 to 1500 µm1. Pellets are an attractive solid dosage form as they provide not only the therapeutic advantages but also the technological benefits2,3. Pellets can be prepared using several techniques2,3. Extrusion/ spheronization is commonly used to produce pellets due to the ability to form pellets with high drug content while maintaining narrow size distribution. Low friability of the pellets also allow for the production of controlled release formulation that can withstand coating process. Production of pellets by extrusion/spheronization involves several stages, which include powder mixing, wet massing, shaping of wet mass and cutting into extrudate and rolling of extrudates into pellet which is followed by drying and screening if necessary3. There are many factors that may affect the property of wet mass and extrudates and hence the quality of pellets. Some of the factors that were investigated included the quantity and type of liquid binder; physical properties of starting materials which include particle size and solubility of drug and excipients; type of extruder, extrusion speed and temperature; speed, residence time and loading of spheronizer as well as drying techniques3-8. Spheronization aid is usually incorporated to maintain the balance between plasticity and brittleness of the wet mass and extrudates. Due to its hygroscopic property, microcrystalline cellulose (MCC) has the ability to absorb water molecules and adsorb moisture from the surrounding. It can also retain a significant amount of water, thus provides the appropriate rheological properties to the wet mass for further processing9,10. Two models, which are "sponge" and "crystallite gel", have been proposed to explain how MCC may aid the extrusion/spheronization process11,12. MCC remains one of the most commonly used spheronization aid and many studies were based upon the application of the conventional MCC to produce pellets with ideal properties. However, the use of MCC is associated with some limitations. Prolonged or incomplete drug release profile due to the lack of disintegration has been reported, especially when combining drug with poor solubility at high level2,5. The slow release of drug will pose a problem if an immediate effect is required. Adsorption of active ingredients onto the surface of MCC fibers13 and decomposition of sensitive drugs prior to release have also been reported14. To overcome these disadvantages, several strategies have been implemented such as using water/ethanol mixture instead of water alone as liquid binder; balancing the ratio of MCC and drug with the inclusion of the water-soluble diluents such as solubilizers and disintegrants in the formulation; replacing MCC with other possible alternatives such as powdered cellulose, hydroxyethylcellulose, pectinic acid, k-carrageenan, crospovidone, chitosan and starch derivatives2,5,10,15. MCC is available in various brands and grades in the market. Different physical properties of MCC could affect the quality of the pellets16-18. Compared to Avicel PH-series, Avicel CL or RC series are seldom used in manufacturing pellets but are commonly incorporated in suspension due to their ability to form thixotropic gel. These types of Avicel consist of MCC and sodium carboxymethylcellulose (NaCMC)19. Earlier work by Newton et al.20 reported that formulations with equal amount of colloidal MCC and lactose could produce extrudates with smooth surfaces, yet the pellets formed were classified as "rounded" instead of round. The colloidal grades MCC failed to produce satisfactory pellets due to its inelasticity21. Accordingly, the coprocessed NaCMC in the colloidal grades MCC could result in sticky granules18. Recently, studies have shown that the colloidal grades MCC could produce pellets with high drug loadings (90-95%) using 5-aminosalicylic acid22,23. This was due to their abilities to better retain water, thus preventing liquid phase migration (LPM) under applied pressure22. High yield could be obtained depending on the physicochemical properties of the model drug23. Therefore, colloidal grade MCC such as Avicel CL611 has demonstrated its potential as a spheronization aid. The ability of Avicel CL611 to produce pellets of satisfactory qualities with water-soluble materials remains to be explored. This study aims to investigate the quality of pellets prepared with Avicel CL611 at 60 and 80% with lactose as the other sole ingredient. Parameters such as quantity of liquid binder, extrusion speed and spheronization speed and residence time during spheronization were adjusted during manufacture of pellets. Physical properties of pellets such as size distribution, morphology and mechanical properties were investigated. In this study, different batches of pellets with the ratios of 2:8 and 4:6 of Avicel CL611: lactose were produced by using water as liquid binder. The appropriate amount of lactose and Avicel CL611 to produce 100 g of product were weighed out using Precisa 400M balance (Precisa Balance Ltd., Dietikon, Switzerland). The raw materials were premixed in a planetary mixer (Model A901E; Kenwood Chef, UK) for 2 minutes at a speed setting of 3. Then an appropriate amount of distilled water was added gradually into the powder mixture that underwent mixing for a further 10 minutes. A spatula was used to scrap off the sides of the bowl of the mixer to ensure homogenous mixing. The wet mass was then transferred immediately into the radial extruder (Model 10 Extruder, G.B. Caleva Ltd., Sturminster Newton, UK) fitted with a screen of 150mm in diameter and die holes of 1.0 mm. The extrudates produced were then spheronized immediately in a spheronizer (Model 120; G.B. Caleva Ltd., UK) fitted with a 125mm cross hatch plate. The pellets were collected and left to