(M1230-07-40) Optimization of Excipients Attributes of Immediate Release Tablet Formulation Using Quality by Design

Purpose: To optimize the excipients attributes for an immediate release tablet using Quality by design (QbD) strategy. QbD Tools Used: DOE - Minitab® 19

Methods: The formulation and manufacturing process were selected based on API properties and observations from development batches. The manufacturing process consists of high shear wet granulation followed by compression and coating. The binder viscosity, and particle size for the filler and the disintegrant were identified as experimental factors based on prior knowledge of the product. A 2³ full factorial Design of Experiments (DoE) was conducted for independent variables viz. hydroxypropyl cellulose (HPC) viscosity, microcrystalline cellulose (MCC) particle size, and crospovidone particle size as the excipient properties. A total of 11 trials including 3 centre-points were designed and executed. During statistical designing of the trials, randomization was used to minimize the effect of uncontrollable variables. The 3 center point batches were included to estimate curvature of the model, error, and increase statistical power. During manufacturing, the process parameters were kept constant to determine the impact of excipient attribute changes. Compression profiles were performed at 3 different compression forces. Twenty response factors (RF) were evaluated from the study, which were grouped into 3 manufacturing stages: the compression profiles, blend properties, and main compression run. Minitab^® 19 was used to obtain a full factorial analysis and a reduced model after stepwise selection of terms.

Results: Initial statistical analysis of the compression profile results confirms that MCC particle size has an impact on disintegration time and dissolution between 60 to 75 minutes. The further reduced model confirms the initial statistical analysis, and indicates an impact on tablet hardness. The further reduced model confirms crospovidone particle size has an impact on disintegration time. Both the initial statistical analysis and the further reduced model of the blend physical testing results confirm that the MCC particle size, HPC viscosity, and the MCC particle size-HPC viscosity interaction have an impact on the blend particle size. Initial statistical analysis of the compression run results confirm that the MCC particle size has an impact on tablet weight variation, HPC has an impact on tablet friability, HPC viscosity and MCC particle size have an impact on dissolution
at 30 minutes. Additionally, MCC particle size, HPC viscosity and the MCC particle size-HPC viscosity interaction have an impact on dissolution between 60 to 75 minutes. Further reduced model confirms that the MCC particle size has an impact on content uniformity and dissolution at 15 minutes, HPC has an impact on tablet friability, HPC viscosity and MCC particle size have an impact on dissolution at 30 minutes. Alongside this, MCC particle size, HPC viscosity, and the MCC particle size-HPC viscosity interaction have an impact on dissolution between 60 to 75 minutes.

Conclusion: Based on mathematical and mechanistic modeling, it is concluded that HPC viscosity, MCC particle size and crospovidone particle size are critical material attributes (CMA) as they have impact on the blend properties, content uniformity, and dissolution of the tablets. The optimum HPC viscosity, MCC particle size, and crospovidone particle size were identified. A confirmatory batch is recommended to further validate the mathematical/mechanistic modeling.