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Effect of Material Properties and Variability of Mannitol on Tablet Formulation Development

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Abstract

Purpose

Using a high level of mannitol as a diluent in oral formulations can potentially result in tablet defects (e.g., chipping, cracking) during compression. This work aims to scrutinize the linkage between the mechanical properties and material attributes of mannitol and also uncover how variations between vendors and lots can lead to significant changes in the compaction performance of tablet formulations containing mannitol.

Methods

The mechanical properties (Poisson’s ratio, fracture energy) and mechanical performance (ejection force, pressure transmission ratio, residual radial die-wall stress, and tensile strength) of mannitol compacts were assessed on a compaction simulator for four lots of mannitol from two different vendors. The variation of material attributes of each lot, including particle size distribution (PSD), crystal form, primary crystal size and morphology, specific surface area (SSA), powder flow, and moisture absorption were investigated.

Results

The variability of material attributes in mannitol lots, especially primary crystal size and SSA, can result in significant changes in mechanical properties and mechanical performance such as ejection force and residual radial die-wall stresses, which potentially led to chipping during compression.

Conclusion

The study elucidated the linkage between fundamental material attributes and mechanical properties of mannitol, highlighting their impact on tablet defects and compaction performance in compression. A comprehensive understanding of the variability in mannitol properties between vendors and lots is crucial for successful formulation development, particularly when high percentages of mannitol are included as a brittle excipient.

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Notes

  1. Details of the Flodex measurement can be found from SUPPLEMENTARY INFORMATION-Experimental section.

  2. * Details of the DVS measurement can be found from SUPPLEMENTARY INFORMATION-Experimental section.

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Acknowledgements

We acknowledge Dr. Sebastian Escotet for his contribution in conducting the mannitol PSD adjustment experiments and Dr. Meng Li for helpful scientific discussions. The authors would also like to acknowledge Fan Zhang-Plasket for her contribution in conducting several material characterization experiments and data collection.

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Authors and Affiliations

  1. Pharmaceutical Sciences, Merck & Co., Inc, 126 E. Lincoln Ave, Rahway, NJ, 07065, USA

    Jiaying Liu, Gerard R. Klinzing & Haichen Nie

  2. Center for Materials Science and Engineering, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA, 19486, USA

    Haichen Nie

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  1. Jiaying Liu
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Contributions

Haichen Nie: Conceptualization, conducting experiment, data collection and analysis, manuscript drafting, manuscript review & editing; Jiaying Liu: conducting experiment, interpretation of data, manuscript drafting, review and editing; Gerard R. Klinzing, conducting experiment, interpretation of data, manuscript review and editing.

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Correspondence to Haichen Nie.

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Liu, J., Klinzing, G.R. & Nie, H. Effect of Material Properties and Variability of Mannitol on Tablet Formulation Development. Pharm Res 40, 2071–2085 (2023). https://doi.org/10.1007/s11095-023-03577-y

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