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Tablets & Capsules March 2017 29 Pellets were prepared using the Atlas Automatic Hydraulic Press-40 Ton (set to 15 tons) equipped with a 40-mm die assembly (Premier Lab Supply). The tablet sets were prepared using a manual Model 3925 hydraulic press (Carver, Wabash, IN) equipped with both round and oblong TDP-0 tablet press punches and dies (Foshan KOS, Guangdong, China). Materials. ICP standards for Pb, As, Cd, Hg, Co, V, and Ni were purchased from Fisher Scientific (Fair Lawn, NJ). All the ICP standards had a concentration of 1,000 ppm, ±1 ppm. Cellulose was purchased from SPEX SamplePrep (Metuchen, NJ), and polypropylene cups were purchased from Premier Lab Supply. A Milli-Q water purification system (Millipore, Bedford, MA) was used to produce the deionized water used in serial dilu- tions of the elemental "cocktails." Standard preparation. Bulk powder material (cellulose matrix) was compressed into pellets and tablets so each could be analyzed and compared. Standard ICP solutions were used to prepare a cocktail of Class 1 and 2A ele- ments. Serial dilutions were made accordingly. The cellu- lose powder was then spiked with the various diluted stan- dards and dried to the desired dry-weight concentrations, which are listed in Table 2. Pellets were prepared for each concentration by placing 5 grams of powder in a 40-mm die assembly. Tablets were prepared by similar manual compression. Because each tablet contained approxi- mately 250 milligrams of the cellulose matrix, approxi- mately 20 tablets were used to constitute a 5-gram set for analysis. Tablet sets were simply poured into a polypropy- lene cup held in place by the cup holder. It was not neces- sary to use a film to keep the samples in place; the tube- above geometry of the spectrometer was sufficient. Sets of both round and oblong tablets were made to see how shape affected reproducibility and sensitivity. Results and discussion Correlation factors for all calibration curves ranged from 0.996 to greater than 0.9999 (Table 3). According to options 2 and 3 offered in ICH Q3D, it is permissible to set the detection limits according to final product daily intake. The limits of detection (LOD) listed in Table 3 were suitable for use with daily intakes equal to or greater than 5 grams of final product. The LOD for each element can be reduced by employing longer counting times, higher power, and a larger analysis area/cup size. Table 2 Standard concentration ranges of spiked powder STDS Cd Pb As Hg Co V Ni LOQ 0.4 0.4 1.2 2.4 4 8 16 0.5J 0.5 0.5 1.5 3 5 10 20 1J 1 1 3 6 10 20 40 2J 2 2 6 12 20 40 80 ULOQ 5 5 10 20 30 50 100 Tables 4 to 8 show typical validation results per USP <233>. The pellet method was initially used to demon- strate validation, and all aspects of the validation, includ- ing intermediate precision and ruggedness, were easily achieved. The goal of this study was to test whether voids and random or preferred orientation of the tablet sets affected the results relative to a pellet. We also sought to learn whether different tablet shapes affected repeatability and to what extent and whether calibrations for one tablet could be used to analyze another that had a significantly different shape. Table 3 Limit of quantitation, range, and linearity for pellets of each element of interest Elements LOD (ppm) LOQ (ppm) Target concentration** (ppm) Range (ppm) Linearity (R 2 ) Cd 0.13 0.4 1 0.4 - 5 0.998188 Pb 0.20 0.4 1 0.4 - 5 0.999468 As 0.13 1.2 3 1.2 - 10 0.999973 Hg 0.28 2.4 6 2.4 - 20 0.996066 Co 0.71 4 10 4 - 30 0.999319 V 1.17 8 20 8 - 50 0.999755 Ni 0.59 16 40 16 - 100 0.999974 * LOD may be improved with a longer counting time. ** Target concentration is based on a 5-gram dose of finished product according to USP <232> for elemental impurities. Table 4 Detectability Table 5 Precision and accuracy Sample ID (average reported) Cd (ppm) Pb (ppm) As (ppm) Hg (ppm) Co (ppm) V (ppm) Ni (ppm) Standard solution 1 1.00 (9.0) 1.11 (5.4) 2.90 (0.7) 5.92 (4.1) 9.94 (2.6) 20.60 (4.1) 40.54 (1.6) Spiked 1J 0.92 (1.1) 1.14 (5.1) 2.98 (1.2) 5.58 (5.7) 9.97 (2.7) 20.19 (1.1) 40.79 (1.5) Spiked 0.8J 0.87 (2.9) 0.95 (8.2) 2.33 (2.7) 4.35 (4.8) 8.34 (4.1) 15.86 (2.5) 32.34 (0.8) Acceptance criteria 1. 7.69 2.69 2.76 5.80 0.30 1.99 0.62 Acceptance criteria 2 Yes Yes Yes Yes Yes Yes Yes Notes: Three individual samples were prepared at the following concentrations containing the tar- get elements: Spiked 0.8J, Spiked 1J, and Standard Solution 1J. Values reported are averages of three replicate measurements. Numbers in parentheses are percentage coefficient of variation. Acceptance criteria: 1. The average value of the three replicate measurements of Spiked 1J is ±15% of the aver- age value for the three replicate measurements of the Standard solution 1J. 2. The average value of the three replicate measurements of Spiked 0.8J < Standard solu- tion 1. Sample ID Cd (ppm) Pb (ppm) As (ppm) Hg (ppm) Co (ppm) V (ppm) Ni (ppm) Nominal concentration 1.00 1.00 3.00 6.00 10.00 20.00 40.00 Accuracy-1 1.07 1.10 2.92 5.49 9.96 21.20 39.88 Accuracy-2 0.94 1.12 2.91 5.37 9.67 19.94 40.45 Accuracy-3 0.98 1.05 2.85 5.30 9.67 19.94 40.41 Mean (ppm) 1.00 1.09 2.89 5.39 9.82 20.75 40.25 Precision (%RSD) 6.68 3.31 1.31 1.78 1.48 3.39 0.79 Accuracy (%) 100 109 96 90 98 104 101 Notes: Three individual samples were prepared at the 1J concentration containing the target ele- ments. Acceptance criteria for spike recovery: 70% to 150% for the mean of three replicate preparations.