Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy

Continuous manufacturing has the potential to offer several benefits for the production of oral solid dosage forms, including reduced costs, low-scale equipment, and the application of process analytical technology (PAT) for real-time process control. This study focuses on the implementation of a stream sampler to develop a near infrared (NIR) calibration model for blend uniformity monitoring in a continuous manufacturing mixing process. Feeding and mixing characterizations were performed for three loss-in-weight feeders and a commercial continuous mixer to prepare powder blends of 2.5–7.5 % w/w ibuprofen DC 85 W with a total throughput of 33 kg/h.

Highlights

• First implementation of the stream sampler using in a continuous mixing process.
• Low drug concentration monitoring in a manufacturing continuous mixing process.
• The in-line calibration model presented low predictions errors.
• The continuous mixing process was not affected after an independent experiment.

The NIR spectral acquisition was performed after the mixing stage using a stream sampler for flowing powders. A continuous mixer shaft speed of 250 RPM was selected to operate the mixing process based on a variability analysis developed with in-line spectral data acquired using the stream sampler at 6 RPM. A partial least squares regression (PLS-R) model was performed and evaluated, yielding a root-mean-square error of prediction (RMSEP) of 0.39 % w/w and a bias of 0.05 % w/w. An independent experimental run conducted two days later revealed that the continuous mixing process and the NIR calibration model presented low day-to-day variation.

The minimum practical error (MPE) and sill values through variographic analysis showed low variance associated with the sampling process using the stream sampler. Results demonstrated the promising capacity of the stream sampler coupled to an NIR probe to be implemented within continuous manufacturing processes for the real-time determination of API concentration.

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Formulation components

The formulation used in this study included ibuprofen DC 85 W® powder, Ph. Eur./USP/JP/IP (BASF Corporation/Bishop, Texas, USA) as the active pharmaceutical ingredient (API). Ibuprofen DC 85 W contains 84.66–85.34 % ibuprofen 50 (assay range of 82–88 %), and the remaining 15 % is distributed between croscarmellose sodium, microcrystalline cellulose, and colloidal silicon dioxide. The main excipients were silicified microcrystalline cellulose (Prosolv® SMCC HD90, JRS Pharma GMBH& Co.).

The following excipients are mentioned also in the study: Tablettose 70 (Meggle)

Raúl S. Rangel-Gil, Juan M. Nasrala-Álvarez, Rodolfo J. Romañach, Rafael Méndez, Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy, International Journal of Pharmaceutics, Volume 661, 2024, 124478, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124478.

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