The flow properties of typical tablet and capsule formulation excipients, active compounds, and representative formulation blends were tested with current and novel flow measurement techniques to identify a reliable bench test to quantify powder flow as a screening method in early tablet and capsule formulation development. Test methods employed were vibrating spatula, critical orifice, angle of repose, compressibility index, and avalanching analysis. Powder flow results from each method were compiled in a database, sorted, and compared. An empirical composite index was established and powder flow was ranked in accordance with formulator experience. Principal components analyses of the angle of repose, percent compressibility, and critical orifice of the powder materials were also performed. The first principal component accounted for 72.8% of data variability; scores associated with this principal component score can serve as an index of flowability. Data generated from vibrating spatula and avalanching methods were not reproducible and were inconsistent with formulator experience and cited vendor references for flow. Improvements of test instruments and further studies are necessary for better assessment of these approaches.

Abstract. The purpose of this research was to use inline real-time near-infrared (NIR) to measure the moisture content of granules manufactured using a commercial production scale continuous twin-screw granulator fluid-bed dryer milling process. A central composite response surface statistical design was used to study the effect of inlet air temperature and dew point on granule moisture content. The NIR moisture content was compared to Karl Fischer (KF) and loss on drying (LOD) moisture determinations. Using multivariate analysis, the data showed a statistically significant correlation between the conventional methods and NIR. The R 2 values for predicted moisture content by NIR versus KF and predicted moisture values by NIR versus LOD were 0.94 (p<0.00001) and 0.85 (p<0.0002), respectively. The adjusted R 2 for KF versus LOD correlation was 0.85 (p<0.0001). Analysis of the response surface design data showed that inlet air temperature over a range of 35-55°C had a significant linear impact on granule moisture content as measured by predicted NIR (adjusted R 2 =0.84, p<0.02), KF (adjusted R 2 =0.91, p<0.0001), and LOD (adjusted R 2 =0.85, p<0.0006). The inlet air dew point range of 10-20°C did not have a significant impact on any of the moisture measurements.

Focused beam reflectance measurement (FBRM) was used as a process analytical technology tool to perform inline real-time particle size analysis of a proprietary granulation manufactured using a continuous twin-screw granulation-drying-milling process. A significant relationship between D20, D50, and D80 length-weighted chord length and sieve particle size was observed with a p value of <0.0001 and R(2) of 0.886. A central composite response surface statistical design was used to evaluate the effect of granulator screw speed and Comil® impeller speed on the length-weighted chord length distribution (CLD) and particle size distribution (PSD) determined by FBRM and nested sieve analysis, respectively. The effect of granulator speed and mill speed on bulk density, tapped density, Compressibility Index, and Flowability Index were also investigated. An inline FBRM probe placed below the Comil-generated chord lengths and CLD data at designated times. The collection of the milled samples for sieve analysis and PSD evaluation were coordinated with the timing of the FBRM determinations. Both FBRM and sieve analysis resulted in similar bimodal distributions for all ten manufactured batches studied. Within the experimental space studied, the granulator screw speed (650-850 rpm) and Comil® impeller speed (1,000-2,000 rpm) did not have a significant effect on CLD, PSD, bulk density, tapped density, Compressibility Index, and Flowability Index (p value > 0.05).

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Abstract. Light-induced fluorescence (LIF) was evaluated as a process analytical technology to monitor blend homogeneity and establish a relationship with high-performance liquid chromatography (HPLC). Secondary aims for this study included a determination of blend steady-state, acceptable mixing time interval, and mixing end point. Also, identification of potential "dead spots" in the 124 L intermediate bulk container mixing tote was explored. Individual samples from 13 sample locations were collected at 0.25, 0.5, 0.75, 1, 2, 5, 10, and 20 min and analyzed using LIF and HPLC. LIF and HPLC methods showed similar mixing profiles. A coefficient of determination (R 2 ) of 0.86 (p value<0.0001) was obtained for a second-degree polynomial bivariate fit of LIF counts by HPLC percent label claim (%LC). A significant linear relationship was determined between LIF percent relative standard (%RSD) and HPLC %RSD (R 2 =0.97, p<0.0001). The LIF steady-state, acceptable mixing time interval, and mixing end point were determined to be 1-20, 2-20, and 2 min, respectively. The steady-state, acceptable mixing time interval, and mixing end point determined by HPLC were 1-20, 5-10, and 5 min, respectively. The Tukey-Kramer honestly significant difference analysis of HPLC %LC by sample location at 5 and 10 min mixing times showed that there was a statistical difference between the HPLC %LC group means at two blender locations.