Micro-mixing dynamics of active pharmaceutical ingredients in bin-blending

• Automated chemical image analysis performed to study blending dynamics.
• Micro-mixing dynamics of three cohesive active pharmaceutical ingredients compared.
• Large chlorpheniramine maleate aggregates were present even after 200 rotations.
• Micro-mixing dynamics of acetaminophen and caffeine were dependent on concentrations.

This paper compares the micro-mixing dynamics of three active pharmaceutical ingredients (APIs) varying in particle size, bulk density and cohesion. Chlorpheniramine maleate, acetaminophen and caffeine, in a common blend of excipients, were used in this study. Micro-mixing was studied in a 1-L bin-blender using in-line near infrared chemical imaging (NIR-CI) to monitor the aggregate size distribution of the APIs and excipients. A science-based calibration chemometric method was used to calculate the concentration maps of ingredients in the blends. Chlorpheniramine maleate, smallest in particle size with lowest bulk density, resulted in the highest relative standard deviation (RSD) for all concentrations. The RSDs obtained for acetaminophen and caffeine were similar and dependent on their concentrations. Chlorpheniramine remained in large aggregates throughout the blending process. Overall, other ingredients (e.g. Avicel) required longer blending times to become well dispersed in the presence of chlorpheniramine maleate, as evidenced by the aggregate size measurements. This in-line NIR-CI technique was able to approximate the number of API aggregates and their size during a common blending process. Although further development of this technique is necessary, metrics measured using this technique could potentially be used as a critical quality attributes during pharmaceutical processing.

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