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In-Situ Characterization of Pharmaceutical Formulations by Dynamic Nuclear Polarization Enhanced MAS NMR Qing Zhe Ni, Fengyuan Yang, Thach V. Can, Ivan V. Sergeyev, Suzanne M. D’Addio, Sudheer K. Jawla, Yongjun Li, Maya P. Lipert, Wei Xu, Robert Thomas Williamson, Anthony Leone, Robert G. Griffin, and Yongchao Su J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b07213 • Publication Date (Web): 01 Aug 2017 Downloaded from http://pubs.acs.org on August 5, 2017
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The Journal of Physical Chemistry
In-Situ Characterization of Pharmaceutical Formulations by Dynamic Nuclear Polarization Enhanced MAS NMR Qing Zhe Ni1, Fengyuan Yang2, Thach V. Can1, Ivan V. Sergeyev3, Suzanne M. D’Addio2, Sudheer K. Jawla4, Yongjun Li2, Maya P. Lipert2, Wei Xu2, R. Thomas Williamson2, Anthony Leone2, Robert G. Griffin1,*, Yongchao Su2,* 1
Department of Chemistry and Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 2Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ 07033, USA 3Bruker BioSpin Corporation, Billerica, MA 01821, USA 4Plasma Science and Fusion Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ABSTRACT: A principal advantage of magic angle spinning (MAS) NMR spectroscopy lies in its ability to deter-
mine molecular structure in a non-invasive and quantitative manner. Accordingly, MAS should be widely applicable to studies of the structure of active pharmaceutical ingredients (API) and formulations. However, the low sensitivity encountered in spectroscopy of natural abundance APIs present at low concentration has limited the success of MAS experiments. Dynamic nuclear polarization (DNP) enhances NMR sensitivity and can be used to circumvent this problem provided that suitable paramagnetic polarizing can be incorporated into the system without altering the integrity of solid dosages. Here, we demonstrate that DNP polarizing agents can be added in-situ during the preparation of amorphous solid dispersions (ASDs) via spray drying and hot-melt extrusion so that ASDs can be examined during drug development. Specifically, the dependence of DNP enhancement on sample composition, radical concentration, relaxation properties of the API and excipients, types of polarizing agents and proton density, has been thoroughly investigated. Optimal enhancement values are obtained from ASDs containing 1% w/w radical concentration. Both polarizing agents TOTAPOL and AMUPol provided reasonable enhancements. Partial deuteration of the excipient produced 3x higher enhancement values. With these parameters, an ASD containing posaconazole and vinyl acetate yields a 32-fold enhancement which presumably results in a reduction of NMR measurement time by ~1,000. This boost in signal intensity enables the full assignment of the natural abundance pharmaceutical formulation through multidimensional correlation experiments.
INTRODUCTION The stability, solubility, and bioavailability of active pharmaceutical ingredients (APIs) are key determining factors of pharmaceutical formulation performance. Drug molecules can undergo undesired phase transformations, such as amorphous and crystalline interconversion, salt formation, and disproportionation induced by chemical, physical and pharmaceutical processes - transformations that often result in significant alterations in drug bioavailability. As a consequence analysis by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), Raman, and mass spectrometry are routinely employed to monitor the physicochemical properties of an API during drug formulation. In addition to these
techniques, magic angle spinning (MAS) NMR can shed light on atomic scale molecular structures, quantify various solid-state forms, and probe molecular dynamics and chemical interactions in a nondestructive and noninvasive manner.1-7 Although powerful, high throughput measurements by MAS are limited due to the inherently low sensitivity. Detection becomes even more challenging in enabled formulations that contain small amounts of poorly soluble API dispersed in a polymeric matrix for enhancing bioavailability. Furthermore, MAS detection on nuclei other than 1H suffers from both the low natural abundance and the low gyromagnetic ratios of 13C and 15N when compare to 1H , making it impractical to perform multidimensional correlation experiments in a reasonable amount of time for exploration of subtle molecular information.
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The Journal of Physical Chemistry
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The sensitivity of NMR can be improved by 2-3 orders of magnitude8-14 by using dynamic nuclear polarization (DNP), which transfers the high polarization of unpaired electrons to nearby nuclei such as 1H, 13C, and 15N via microwave irradiation of the electron-nuclear transitions. The maximum theoretical enhancement factor is given by εmax= γe/γn =658 where γe and γn are the gyromagnetic ratios of the electron and nuclei, respectively. Thus, even a fraction of this translates into a time saving of months or years, enabling many otherwise infeasible experiments to be performed.15, 16 The recent developments of high-power microwave sources, NMR probes for cryogenic MAS, biradical polarizing agents, and new sample preparation methods, has enabled DNP to be successfully applied to investigate the dynamics and structures of microcrystalline peptides, membrane proteins, amyloid fibrils, natural products and catalytic materials.17-29 Recent studies have demonstrated the considerable potential of DNP in applications to pharmaceutical chemistry.30-36 The major challenge to successful DNP experiments lies in developing a suitable method of introducing polarizing agents into to the sample for optimum signal enhancement without sample disruption. A number of methods for preparing DNP pharmaceutical samples have been reported, including polymer film casting and glass forming methods.34, 37. In addition, Emsley and coworkers have successfully demonstrated an innovative impregnation method on the pharmaceutical formulations with an organic solvent (1,1,2,2tetrachloroethane) containing polarizing agents.24 Enhancements in the range of 40-90 were obtained for commercial formulations containing cetirzine dihydrochloride and excipients povidone, magnesium stearate, hypromellose, and lactose. These enhancements allow rapid characterization via oneand two-dimensional MAS spectra of these formulations with drug loading
