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10 March 2014 Tablets & Capsules ment, particle deformation, particle fragmentation, and particle bonding [1]. While roller compaction seems sim- ple, the fundamental mechanisms are complex because several material attributes and process parameters are involved. These include material flow properties, com- pactablity, compressibility, roll surface, roll pressure, roll speed, and feeding method. A review of the literature indicates that roll pressure is the most critical process parameter [2], and several researchers have studied its effect on tablet dissolution [3- 6]. Sheskey and Dasbach [3] evaluated nine commonly used polymers as dry binders in the manufacture of an immediate-release tablet formulation using roller com- paction and niacinamide, a water-soluble compound, as a model API. The authors investigated the impact of roll pressure (1, 3, and 6 tons) on the physical characteristics of the granule and tablet and on dissolution using three binder levels (6.25, 12.5, and 25 percent). Tablet compres- sion force was kept at a constant 28.03 kilonewtons for all the batches, and roll pressure did not have a significant effect on tablet dissolution. In most of the reported studies, granulations prepared at varying roll pressures were com- pressed at the same tablet compression force to investigate how roll pressure affected dissolution. The expectation is that this approach would yield tablets of different hard- nesses according to the different roll pressures applied even though tablet compression force remained constant. Although many researchers have studied the effect of roll pressure on the dissolution of tablets, the effect of roll pressure on the dissolution of tablets that have been compressed to different hardness levels has not been explored. The objective of this study was to investigate the effect of roll pressure on the blend characteristics and on the properties of low-, medium- and high-hardness tablets of an immediate-release formulation, including the disintegration time (DT) and dissolution profile when indomethacin, a poorly soluble compound, was used as a model API. Experiment Materials. Indomethacin was obtained from Tokyo Chemical Industry (Tokyo, Japan). Excipients used in this study included anhydrous lactose (SuperTab 21AN, DFE Pharma, Princeton, NJ), co-processed microcrystalline cellulose (MCC) and anhydrous calcium phosphate (AvicelDG, FMC Biopolymer, Philadelphia, PA), sodium starch glycolate (Explotab, JRS Pharma, Patterson, NY), colloidal silicon dioxide (Cab-O-Sil M-5P, Cabot, Boston, MA), and magnesium stearate (Hyqual, Mallinckrodt, St. Louis, MO). Formulation and process. Table 1 shows the formula- tion used in this study. Both ductile (MCC) and brittle (anhydrous calcium phosphate and anhydrous lactose) diluents were used in order to have good compactability during roller compaction and good compressibility dur- ing the preparation of tablets. The process parameters (roll pressure range, roll speed, feeder speed, mill screen size, and mill speed) were defined based on results from preliminary studies. Each ingredient was sieved through a 20-mesh screen, except the magnesium stearate, which was sieved through a 40- mesh screen. Intragranular ingredients were placed in a V-type blender (Blend Master, Patterson-Kelley, East Stroudsburg, PA) and mixed for 10 minutes. The pre- blend was compacted into ribbons using a TFC-Lab Micro roll compactor (Freund-Vector, Marion, IA) fitted with serrated non-interlocking rolls. Three sets of ribbons were produced at roll pressures of 2 (low), 3.5 (target), and 5 megapascals (MPa) (high); a roll speed of 0.78 rpm; and a feeder speed of 9.30 rpm. Each set of ribbons was milled using a Comil 197 (Quadro Engineering, Waterloo, Ontario) fitted with a round arm impeller and a 991-micron screen (round holes). The milled granules were blended with the extra- granular ingredients in a V-type blender for 3 minutes. Three final blends, from each set of ribbons, were gener- ated for compression. Final blends were compressed into tablets of 7 (low), 10 (target) and 13 kiloponds (kp) (high) hardness using a B-10 Piccola tablet press (Riva, Buenos Aires, Argentina). Pre-blend, ribbon, and final blend characterization. Prior to roller compaction, the true density of the pre- blend was determined using an Accupyc II 1340 pyc- nometer (Micromeritics, Norcross, GA). During roller compaction, the apparent density (envelope density) of the compacted ribbons was determined using a GeoPyc 1360 pycnometer (Micromeritics). Next, the solid frac- tion—an intrinsic attribute that can be used to monitor the characteristics and physical performance of the com- pacted ribbons [7]—was determined. That required mea- suring the apparent densities of the ribbons at the begin- ning, middle, and end of roller compaction, as well as accounting for the apparent density of the compacted ribbons and the true density of the pre-blend. Monitoring the solid fraction of compacted ribbons provides insight into formulation strategy, enabling researchers to opti- mize the granules and control the roller compaction process. Table 1 Formulation composition Ingredients % w/w * Intragranular Indomethacin 10 Anhydrous lactose (SuperTab 21AN) 45 Co-processed MCC-anhydrous calcium phosphate (Avicel DG) 30 Sodium starch glycolate (Explotab) 2 Colloidal silicon dioxide (Cab-O-Sil M-5P) 0.3 Magnesium stearate (Hyqual) 0.25 Extragranular Co-processed MCC-anhydrous calcium phosphate 10 Sodium starch glycolate 2 Colloidal silicon dioxide 0.2 Magnesium stearate 0.25 Total 100 * Tablet weight = 250 mg c-Roblesart_8-17 copy_Masters 3/5/14 10:04 AM Page 10