Proof of a LOD prediction model with orthogonal PAT methods in continuous wet granulation and drying

Real-time monitoring of critical quality attributes, such as residual water in granules after drying which can be determined through loss-on-drying (LOD), during wet granulation and drying is essential in continuous manufacturing. Near-infrared (NIR) spectroscopy has been widely used as process analytical technology (PAT) for in-line LOD monitoring. This study aims to develop and apply a model for predicting the LOD based on process parameters. Additionally, the efficacy of an orthogonal PAT approach using NIR and mass balance (MB) for a vibrating fluidized bed dryer (VFBD) is demonstrated. An in-house-built, cost-effective NIR sensor was utilized for measurements and exhibited good correlation compared to standard method via infrared drying.

Highlights

• Implementation of an orthogonal process analytical technology approach for loss-on-drying monitoring using near-infrared spectroscopy and mass balance within a vibrated fluidized bed dryer-
• Loss-on-drying prediction model based on key process parameters was developed and verified.
• Demonstrated the feasibility of predicting a process parameter to achieve a desired moisture content.
• Low-cost, in-house built near infrared spectroscopy sensor correlated good with the measurement via mass balance.

The combination of NIR and MB, as independent methods, has demonstrated their applicability. A good correlation, with a Pearson r above 0.99, was observed for LOD up to 16 % (w/w). The use of an orthogonal PAT method mitigated the risk of false process adaption. In some experiments where the NIR sensor might have been covered by powder and therefore did not measure accurately, LOD monitoring via MB remained feasible. The developed model effectively predicted LOD or process parameters, resulting in an R2 of 0.882 and a RMSE of 0.475 between predicted and measured LOD using the standard method.

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Materials

Two mixtures consisting of alpha-lactose monohydrate (GranuLac® 200, MEGGLE, Wasserburg am Inn, Germany) and microcrystalline cellulose (MCC, VIVAPUR® 101, JRS PHARMA, Rosenberg, Germany) were selected as model formulations based on previous studies.6, 32 MCC is an important excipient used in the manufacturing of solid oral dosage forms and the water absorption capacity of MCC makes the formulations more challenging during drying. Polyvinylpyrrolidone K 30 (PVP, Kollidon® 30, BASF SE, Ludwigshafen, Germany) was used as binder. Further formulations were investigated containing Ibuprofen (IBU, Ibuprofen 50, BASF SE, Ludwigshafen, Germany) as an active pharmaceutical ingredient (API). Two different levels for the drug content were utilized together with alpha-lactose monohydrate and MCC. In total, four formulations were investigated in this study as described in Table 1. This allows the application of different formulation and enables the analysis of whether the methods and models for LOD are applicable. The physical characterization of the mixtures regarding particle size distribution, flowability and initial LOD is provided in the supplement (Supplement Table 1). IBU was deagglomerated before mixing using a high-speed conical mill (BTS100, L.B. Bohle Maschinen und Verfahren, Ennigerloh, Germany) with a sieve mesh of 1.0 mm. Each powder mixture was blended for 20 min at 25 rpm in a lab-scale blender (LM 40, L.B. Bohle Maschinen und Verfahren, Ennigerloh, Germany). Demineralized water was utilized as granulation liquid during TSG.

Katharina Kiricenko , Stefan Klinken , Peter Kleinebudde , Proof of a LOD prediction model with orthogonal PAT methods in continuous wet granulation and drying, Journal of Pharmaceutical Sciences (2024), doi: https://doi.org/10.1016/j.xphs.2024.07.008

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