RESUMEN
PURPOSE: To evaluate the use of resonant acoustic mixing (RAM) technology for homogenous blending of a morphologically challenging model API in low-dose concentrations (<0.1% w/w), and assess the potential for blend uniformity (BU) optimization. METHODS: Caffeine (CAF) mixing was carried out using a LabRAM I benchtop mixer. Uniformity was assessed under a range of mixing conditions and sample preparation procedures in order to optimize system performance. The capacity for microscale mixing was evaluated from final parameters for 0.05% and 0.0125% CAF blends. RESULTS: Upon optimization, RAM was able to accurately prepare homogeneous mixtures of <0.1% CAF in dilutions of up to 1 part per 8,000. Results from a 0.05% blend targeting 125 µg CAF dosage amounts revealed an AV score of 8.8 while a 0.0125% w/w blend accurately prepared 25 µg of CAF with 99.3% accuracy (98.7% label claim) and AV of 10.1. Microscale mixing in the 0.05% w/w blend was confirmed from plots of BU data against sample size demonstrating a slope of 0.05 within the range of 250-10 mg sample (125-5 µg CAF). L1 BU criteria only failed at the level of 2 µg CAF, despite target precision to 26 nanograms (98.7% label claim). CONCLUSIONS: This study presents the first instance of a homogenously mixed <0.1% (w/w) blend using RAM technology and demonstrate the suitability for reproducible dosing of single-digit microgram drug amounts. Uniformity is documented for API amounts 60x smaller than a recent report has shown and 10,000x smaller than achieved previously with CAF.