Co-processed microcrystalline cellulose and sodium carboxymethyl cellulose as spheronisation AID for disintegrating pellets

Aim of this study is the evaluation of co-processed microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (NaCMC) as a spheronisation aid, alternative to MCC, for the manufacturing of disintegrating pellets. Commercially available grades of co-processed MCCs prepared by spray-drying were taken into account: Avicel® RC591 and Avicel® CL611 (kindly provided by IMCD Italia), containing about 11 and 15 % of NaCMC, respectively. MCC is considered the golden standard for the manufacturing of pellets by extrusion/spheronisation (ES) because when wetted it shows the rheological properties, cohesiveness and plasticity needed to obtain highly resistant and spherical units [1, 2]. However, MCC is not universally applicable due to a number of possible limitations: drug adsorption onto the surface of polymeric fibers, chemical incompatibility, formation of non-disintegrating prolonged-release matrix pellets especially with poorly-soluble drugs. In the case of multiple-unit dosage forms containing drugs that need to be absorbed in the duodenum, e.g. enteric-coated pellets carrying proton-pump inhibitors, the lack of disintegration of MCC-based pellets could impair the release performance. The study involved, at first, the preparation of placebo cores made of the spheronisation aid alone, granulated with water: MCC, Avicel® PH101, was selected as the standard reference and compared to the two different grades of co-processed MCC. Based on the process yield and pellets technological characteristics, such as shape, dimensions and mechanical properties, both Avicel® RC591 and Avicel® CL611 were proven a good alternative to MCC for ES processing (NICA™ Extruder E140 and NICA™ Spheronizer S320). With respect to the disintegration performance of pellets, pharmacopoeial tests were demonstrated not able to discriminate the effect of different spheronisation aids. Therefore, a new method based on the evaluation of the mass loss, performed in a paddle dissolution-apparatus (100 rpm, 1000 mL water, 37±0.5 °C) was developed. The results obtained pointed out the disintegrating ability of pellets prepared with co-processed MCCs that was greater for those based on Avicel® CL611. ES placebo cores were also prepared from physical mixtures of standard MCC with increasing amounts of NaCMC (Blanose™ 7MF, Ashland): 3, 7, 11 or 15 % by weight. The processability by ES of MCC/NaCMC physical mixtures turned out generally critical: products obtained, in fact, were not satisfactory in terms of roundness, flowability and mechanical properties, friability in particular. Moreover, the formulation with the higher content (15 % w/w) of NaCMC could not be processed. On the contrary, the disintegration rate of pellets was increased, with respect to the co-processed MCC-based products, as a function of the amount of NaCMC. Finally, the influence of co-processed MCC on the disintegration ability of drug-containing pellets and the relevant impact on the release performance was investigated. Pellets containing model drugs (acetaminophen, mesalamine, ibuprofen or lansoprazole) and fillers (lactose or bibasic calcium phosphate) with different solubility were prepared using each of the spheronisation aids previously considered. The process yield, the technological characteristics of pellets and their disintegration as well as dissolution performance were evaluated. The overall results obtained demonstrated the potential of co-processed MCCs with NaCMC (Avicel® RC591 and Avicel® CL611 ) to be used as alternative spheronisation aids for the manufacturing by ES of disintegrating pellets with improved dissolution/release performance. [1] L. Zema, L. Palugan, A. Maroni, A. Foppoli, M.E. Sangalli, A. Gazzaniga - AAPS PharmSciTech, 9(2), 708-717 (2008) [2] G. Di Pretoro, L. Zema, A. Gazzaniga, S.L. Rough, D.I. Wilson - Int. J. Pharm., 402, 153-164 (2010)