The new protocols and analyses provide accurate and precise shelf-life estimations in a reduced time from current state of the art.

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In this investigation, the potency distribution of a low-dose drug in a granulation was optimized through a two-part study using statistically designed experiments. The purpose of this investigation was to minimize the segregation potential by improving content uniformity across the granule particle size distribution, thereby improving content uniformity in the tablet. Initial operating parameters on the Gerteis 3-W-Polygran 250/100/3 Roller Compactor resulted in a U-shaped potency function (potency vs. granule particle size) with superpotent fines and large granules. The roller compaction optimization study was carried out in two parts. Study I used a full factorial design with roll force (RF) and average gap width (GW) as independent variables and Study II used a D-optimal response surface design with four factors: RF, GW, granulating sieve size (SS), and granulator speed (GS). The planned response variables for Study I were bypass weight % and potency of bypass. Response variables for Study II included mean granulation potency with % relative standard deviation (% RSD), granulation particle size, sieve cut potency % RSD, tablet potency with % RSD, compression force at 7 kP crushing strength, and friability of 7-kP tablets. A constraint on GW was determined in Study I by statistical analysis. Bypass and observations of ribbon splitting were minimized when GW was less than 2.6 mm. In Study II, granulation potency, granulation uniformity, and sieve cut uniformity were optimized when the SS was 0.8 mm. Higher RF during dry granulation produced better sieve cut uniformity and tablets with improved uniformity throughout the run, as measured by stratified tablet samples taken during compression and assayed for potency. The recommended optimum roller compaction and milling operating parameters that simultaneously met all constraints were RF = 9 kN, GW = 2.3 mm, SS = 0.8 mm, and GS = 50 rpm. These parameters became the operating parameter set points during a model confirmation trial. The results from the confirmation trial proved that the new roller compaction and milling conditions reduced the potential for segregation by minimizing the granulation potency variability as a function of particle size as expressed by sieve cut potency % RSD, and thus improved content uniformity of stratified tablet samples.

Three granulating binders in high drug-load acetaminophen blends were evaluated using high shear granulation and extrusion granulation. A polymethacrylate binder enhanced tablet tensile strength with rapid disintegration in simulated gastric fluid, whereas polyvinylpyrrolidone and hydroxypropyl cellulose binders produced less desirable tablets. Using the polymethacrylate binder, the extrusion granulation process was studied regarding the effects of granulating liquid, injection rate and screw speed on granule properties. A full factorial experimental design was conducted to allow the statistical analysis of interactions between extrusion process parameters. Response variables considered in the study included extruder power consumption (screw loading), granule bulk/tapped density, particle size distribution, tablet hardness, friability, disintegration time and dissolution.

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