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Quantification of Monomer Units in Insoluble Polymeric Active Pharmaceutical Ingredients Using Solid-State NMR Spectroscopy I: Patiromer

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Abstract

Although extensive precautions are taken to limit batch-to-batch variation in pharmaceutical manufacturing, differences between lots may still exist, particularly in complex formulations. When polymerization is used in the production process, the potential for varying chain lengths and incorporation of different monomers increases the likelihood of batch-to-batch variation. This poses a significant challenge for demonstrating active pharmaceutical ingredient (API) sameness between the innovator and generic drug under development. Therefore, the ability to accurately analyze and quantify the relative amounts of active ingredients present in a formulated product is critically important. Solid-state nuclear magnetic resonance (SSNMR) spectroscopy was used to identify, quantify, and compare the relative amounts of the three polymer groups in the amorphous block copolymer drug, patiromer (Veltassa®). Techniques such as cross polarization (CP) and magic angle spinning were used to quantify each polymer group while the importance of understanding CP dynamics to obtain quantitative data was also addressed. It was found that the magnetization transfer rate and chemical shift anisotropy for different functional groups present in patiromer play a large role when optimizing parameters for spectral acquisition. Once accounted for, the average patiromer lot contained 90.9%, 7.6%, and 1.5% carboxylate, aromatic, and aliphatic blocks, respectively, with little lot-to-lot variation between different dosage strengths and expiration dates. SSNMR proved to be a sensitive analytical technique for evaluating and quantifying different monomer groups present in patiromer. This procedure may serve as a guide for similar quantitation studies on complex drug products and for demonstrating API sameness during generic drug development.

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Acknowledgments

The views expressed in this paper do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

Funding

Funding for this research was made possible by a U.S. Food and Drug Administration grant (5U01FD004275-07). Dr. Li was supported in part by an appointment to the Oak Ridge Institute for Science and Education (ORISE) Research Participation Program at the Center for Drug Evaluation and Research administered by the ORISE through an agreement between the U. S. Department of Energy and CDER.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA

    Travis W. Jarrells & Eric J. Munson

  2. Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA

    Travis W. Jarrells & Eric J. Munson

  3. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States FDA, Silver Spring, Maryland, USA

    Deyi Zhang & Shaohua Li

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  1. Travis W. Jarrells
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Correspondence to Eric J. Munson.

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Conflict of Interest

The authors declare the following competing financial interest(s): E.J.M. is a partial owner of Kansas Analytical Services, a company that provides solid-state NMR services to the pharmaceutical industry. The results presented here are from academic work at University of Kentucky and Purdue University, and no data from Kansas Analytical Services are presented.

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Jarrells, T.W., Zhang, D., Li, S. et al. Quantification of Monomer Units in Insoluble Polymeric Active Pharmaceutical Ingredients Using Solid-State NMR Spectroscopy I: Patiromer. AAPS PharmSciTech 21, 116 (2020). https://doi.org/10.1208/s12249-020-01654-8

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