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A Rapid 3-Day Excipient Screening Methodology and its Application in Identifying Chemical Stabilizers for Solid Formulations with Mixed Mechanisms of Degradation

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Abstract

This study outlines a practical approach for assessing chemical instability by heating the drug-excipient binary mixtures or multi-excipient formulations at 75°C for 3 days before characterization. Differentiating itself from other excipient compatibility methods, our methodology necessitates a saturated aqueous slurry rather than arbitrarily fixed water content. This allows bulk and surface water in the excipient to contribute to drug degradation. The synergistic impact of surface water and elevated temperature expedites degradation kinetics, resulting in accelerated data generation. Among excipient compatibility methods available, our method is quantitative and merges with traditionally used methodologies. The devised nomograph enables extrapolation of shelf life at 20°C from experimental data obtained at 75°C. This methodology also helped identify stabilizers for the drug NVS-1 where traditional excipient compatibility programs had failed. Incorporation of monovalent salts, such as sodium/potassium chloride and sodium bicarbonate at 5% w/w, significantly enhanced the chemical stability of NVS-1, ensuring stable tablet formulations. Our hypothesis posits that stabilization is due to increased ionic strength in the slurry, which stabilizes an induced dipole within the polar NVS-1 drug. Additionally, the presence of ions in the moisture layer is anticipated to stabilize π-π stacking of two planar aromatic NVS-1 molecules. The expedited generation of experimental data allowed the identification of inorganic salts to supplement a standard excipient compatibility screening panel. Considering the economic implications of stability testing methodologies in effort, cost, and duration, a faster turnaround in chemical stability data enhances formulation selection. This ultimately facilitates the development of drug formulations with greater efficiency without delays.

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Acknowledgements

The authors dedicate this work to late Professor Anthony (Tony) P. Simonelli (Jun 28th 1924-Jul 14th 2023) whose profound influence and guidance provided by classroom instructions and publications served as the foundation for this 3-day rapid testing methodology. The authors acknowledge Dr. Keith Flood, Dr. Thomas Eskay for assistance with design of experiments and material characterization, and Dr. Anup Ray for helpful discussions on the stabilization mechanism of NVS-1 in presence of salts. The authors also appreciate Dr. Mahendra Patel for the helpful insights and suggestions.

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  1. Amol S. Matharu

    Present address: Falcon Sterile Automation Inc., East Windsor, New Jersey, 08512, USA

  2. Yu (Jade) Cao

    Present address: Jade Pharma Consulting LLC, 3 Franklin Ct., Montville, New Jersey, 07045, USA

Authors and Affiliations

  1. Technical Research and Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, 07936, USA

    Amol S. Matharu & Yu (Jade) Cao

  2. Global Program Management, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, 07936, USA

    Sundeep S. Dhareshwar

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The authors have approved the contents of this manuscript and are accountable for the accuracy of the work presented.

YC and ASM: generation and curation of experimental data, its interpretation, drafting of the manuscript, and final approval of the publication.

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Correspondence to Sundeep S. Dhareshwar.

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Matharu, A.S., Dhareshwar, S.S. & Cao, Y.(. A Rapid 3-Day Excipient Screening Methodology and its Application in Identifying Chemical Stabilizers for Solid Formulations with Mixed Mechanisms of Degradation. AAPS PharmSciTech 25, 12 (2024). https://doi.org/10.1208/s12249-023-02730-5

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