Experiment

Materials. The authors obtained the following materials: PanExcea MHC300G, Avantor Performance Materials (formerly Mallinckrodt Baker); microcrystalline cellulose (102 RanQ, RanQ Pharmaceuticals & Excipients); microcrystalline cellulose (Emcocel 90, JRS Pharma); magnesium (Mg) stearate (Product No. 2256-05, Mallinckrodt Chemicals); stearic acid (Hystrene, PMC Biogenics); colloidal silica (RxCipients GL100, J. M. Huber); hydroxypropyl methylcellulose, USP grade (Pharmacoat, grade 603, SHIN-ETSU Chemical); crospovidone (Polyplasdone XL-10, International Specialty Products (ISP)); and ibuprofen (respectively, Product grade: Albemarle 20, Albemarle 40 and Albemarle 70, Albemarle; and Ibuprofen 50, BASF).

Methods. High-shear wet granulation (HSWG) of MCC (89%)/HPMC(2%)/CPVD (9%). In a 1-L stainless-steel bowl were placed 133.5 g MCC, 3.0 g HPMC and 13.5 g CPVD. The bowl was attached to a vector micro high-shear mixer/granulator (GMX.01, Vector). The dry mixture was mixed for 2 min at 870 rpm impeller speed and 1000 rpm chopper speed.

Following the granulation, the wet granular material was dried in a tray at 60 °C. The resulting granular material (moisture content 2.35%) was screened through a 30 mesh sieve. The yield of the granular material that passed through 30 mesh was 116.73 g (79.3 % referenced to dry starting materials and dry product).

Physical characterization. Particle-size analysis was performed using an air jet sieving instrument (Micron Air Jet Sieve, Hosokawa Micron Powder Systems). Angle of repose, aerated bulk density/tapped bulk density, and total flowability index were measured using a powder tester (Model PT-S, Hosokawa Micron Powder Systems). Particle morphology was assessed using an environmental scanning electron microscope (ESEM, XL30, FEI) using a voltage of 5 kV, spot size of 3, and SE detector. The samples were sputtered with iridium before SEM analysis (sputtering time 40 s).

Granule strength was determined using the following three methods. Method A: The particle-size distribution of 75–100 g of MHC300G was measured and the material was loaded in a 4-L V-blender (MaxiBlend, GlobePharma) and tumbled for two hours. After tumbling, the granular material was collected and analyzed again for particle-size distribution. Method B: 60 g of MHC300G were charged in a 1-L stainless-steel bowl that was attached to a vector micro high-shear mixer/granulator (GMX.01,Vector). The powder was processed by applying an impeller speed of 950 rpm and a chopper speed of 3600 rpm for 5 min. The particle-size distribution was measured before and after the high shear experiment. Method C: 100 g of MHC300G were passed through a mill (Quadro Comil model U3, Quadro Engineering) at 3000 rpm using US # 16 (1180 µm) screen.

Dilution potential of MHC300G was assessed by preparing blends of ibuprofen (IBU), MHC300G and silica. The blends were prepared in a V-blender (MaxiBlend, GlobePharma). Before blending, the powder mixture was passed through a 30 mesh sieve to break the IBU clumps. A blend containing IBU/MCC/HPMC/CPVD/silica was prepared in a similar manner. Powder characteristics as well as IBU content uniformity were analyzed for all blends.

Figure 4: Evaluation and characteristics of a new direct-compression performance excipient. Scanning electron microscope micrographs of A: MHC300G (engineered particles); B: EMB001 (engineered particles); C: EMB002 (traditional high-shear wet granulation); and D: microcrystalline cellulose. The scale bar in the images in the left column represents 100 µm, and the scale bar in the right column represents 20 µm.

The blends for the tableting studies were prepared in the following manner: all ingredients except the lubricant (Mg stearate or stearic acid), were mixed, passed through a mill (Quadro Comil model U3, Quadro Engineering) at 3000 rpm using US # 16 screen and then blended in a V-blender (MaxiBlend, GlobePharma) for 15 min at 20 rpm. The lubricant was added to the resulting mix in the V-blender and everything was blended for 3 min at 20 rpm. The final blend was discharged from the V-blender and transferred to the tableting machine.

Table I: Composition of PanExcea MHC300G, EMB001, EMB002, and EMB003 excipients.

Table II: Bulk density, compressibility index, and Hausner ratio for various grades of microcrystalline cellulose (MCC) and coprocessed excipients containing MCC.