Experiment
Materials. Magnesium stearate, from vegetable source (monohydrate, lot no. J12404; and dihydrate, lot no. J04688), and acetaminophen,
USP (APAP, lot no. 0048905C330) were provided by Mallinckrodt (St. Louis, MO) and used as received. Microcrystalline cellulose,
NF (MCC, Avciel PH 101, 102, FMC Biopolymer, Philadelphia, PA); dibasic calcium phosphate, anhydrous (DCP, Encompress, JRS
Pharma, Patterson, NY); and lactose monohydrate, spray-dried (LAC, Spectrum Chemicals, NJ) all were used as received. All
materials were delumped before mixing.
Table I: Experimental design.
|
Methods. Diluent systems. Two ratios of binary diluents were used in the study (75:25 and 50:50) for each of MCC:DCP and MCC:LAC. These binary diluents
constituted desirable solid dosage formulation systems in that the physical characteristics are unique. In the case of the
MCC:DCP system, the physical interaction between a plastically deformable material (MCC) and an abrasively brittle material
(DCP) with distinct particle–particle shapes was deemed informative. Moreover, using two grades of MCC with different particle
sizes (Avicel PH 101 had a nominal mean particle size of 50 μm, and Avicel PH 102 had a nominal mean particle size of 100
μm) could present additional valuable information through their blending behavior. With respect to the MCC:LAC system, two
plastically deformable diluents with distinct particle–particle morphology would be another opportunity to elucidate the influence
of MgSt in such widely used pharmaceutical combinations (16).
Table II: Optimized design.
|
Experiment designs. APAP was used at concentrations of 1.25, 2.5, and 5.0% w/w. MgSt was used at concentrations of 0.3, 0.5, and 1.0% w/w. The
experimental design was a modified Plackett–Burman fractional factorial having two levels with two center points. Eleven batches,
each at 10-kg batch size, were blended in a 1-ft3 twin-shell blender (Patterson-Kelley, Stroudsburg, PA). This fractionalization allowed for a reduction of input variables
or factors with the benefit of identifying the key factor variables that affected product quality. The design also enabled
the evaluation of main effects aliased with two-way interactions (17). Tables I and II show the designs and independent variables
(factors). Results from the experimental design provided information for optimization of the study (see Table I). Subsequently,
six optimization batches were processed to substantiate the preliminary findings from the 11-batch runs (see Table II). The
dependent variables (responses) included ejection force and total compression force (precompression and main compression forces).
Prelubrication blend uniformity was predicted using multiple effusivity sensors fitted to the blender as previously described
(2, 12). Prelubrication and postlubrication blend uniformity samples were collected using a sampling thief (Globe Pharma,
New Brunswick, NJ) for comparative analysis. Blend samples were analyzed for the APAP assay with an internally validated high-performance
liquid chromatography (HPLC) method.
|
