Quantifying Pharmaceutical Formulations from Proton Detected Solid-State NMR under Ultrafast Magic Angle Spinning (original) (raw)
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Journal of Pharmaceutical Sciences, 2017
The lower detection limit for 2 distinct crystalline phases by 1 H magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) is investigated for a minority amount of cimetidine (anhydrous polymorph A) in a physical mixture with the anhydrous HCl salt of cimetidine. Specifically, 2-dimensional 1 H double-quantum (DQ) MAS NMR spectra of polymorph A and the anhydrous HCl salt constitute fingerprints for the presence of each of these solid forms. For solid-state NMR data recorded at a 1 H Larmor frequency of 850 MHz and a MAS frequency of 30 kHz on~10 mg of sample, it is shown that, by following the pair of cross-peaks at a 1 H DQ frequency of 7.4 þ 11.6 ¼ 19.0 ppm that are unique to polymorph A, the level of detection for polymorph A in a physical mixture with the anhydrous HCl salt is a concentration of 1% w/w.
Solid-state NMR in the field of drug delivery: State of the art and new perspectives
Magnetic Resonance Letters
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The journal of physical chemistry. B, 2017
A principle advantage of magic angle spinning (MAS) NMR spectroscopy lies in its ability to determine 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 API's 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 extru-sion so that ASDs can be examined during drug development. Specifically, the dependence of DNP enhancement on sample composition, radica...
Applications of solid-state NMR to pharmaceutical polymorphism and related matters
Journal of Pharmacy and Pharmacology, 2007
Magic-angle spinning NMR is now making a significant contribution to our understanding of the structure of polymorphs and solvates of pharmaceutical significance. This personal review article discusses a range of applications, with particular emphasis on information about crystallography, for which NMR can address problems that cannot be readily solved by diffraction techniques (such as dynamic disorder and non-stoichiometric hydration). Unlike diffractograms, NMR spectra yield immediate chemical information. Moreover, heterogeneous samples can be investigated and amorphous content provides no significant barrier to studies. Furthermore, NMR can be an effective technique for quantitation (down to the level of ca. 1%). Additional strength is being derived from computation of chemical shifts in solids, using a code that takes account of the spatial repetition inherent in crystalline materials.
Angewandte Chemie, 2009
Over 80% of pharmaceutical products on the market, including many biopharmaceuticals, are in various solid forms.[1-4] Solid-state NMR (SSNMR) provides atomic-resolution structural insight to such materials, and therefore is recognized as a powerful analytical approach to analyze formulation chemistry in pharmaceutical products.[1] Dramatic progress in SSNMR over the last decade has enabled the determination of structures for several proteins, with the assistance of 13 C and 15 N isotope enrichment.[5,6] However, due to limited experimental sensitivity inherent in low natural abundance of 13 C (1.07%) and 15 N (0.368%), the application in pharmaceutical SSNMR research has been limited to small molecules.[1] Furthermore, the one-dimensional 13 C spectra commonly acquired for small molecule drugs have insufficient resolution for larger peptide and protein pharmaceuticals. ** This research was supported by the National Institutes of Health (R01 GM-75937 to C.M.R). We thank John A. Stringer and Mircea Cormos (Varian, Inc.
Analytical Chemistry, 2013
The feasibility of 1 H-High Resolution-Magic Angle Spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy for the direct analysis of viscous cosmetic and pharmaceutical formulations such as creams, gels, and pastes is presented. Three examples are described: (i) the detection of chitosan in toothpaste, (ii) the analysis of dexamethasone acetate (DMA) in a cream, and (iii) the analysis of the local anesthetics, lidocaine and prilocaine, in a gel and a cream. All active components could be directly detected in their original commercial formulations without the need for laborious sample preparation steps. In addition, the possibility for HR-MAS-based quantifications and the analysis of dynamic properties of active components in different formulations applying HR-MAS diffusion-ordered NMR spectroscopy are shown.
What NMR can do in the biopharmaceutical industry
Journal of Pharmaceutical and Biomedical Analysis
Nuclear magnetic resonance (NMR) spectroscopy has a unique capability to probe the primary and higher order molecular structure and the structural dynamics of biomolecules at an atomic resolution, and this capability has been greatly fortified over the last five decades by an astonishing NMR instrumental and methodological development. Because of these factors, NMR has become a primary tool for the structure investigation of biomolecules, spawning a whole scientific subfield dedicated to the subject. This role of NMR is by now well established and broadly appreciated, especially in the context of academic research dealing with proteins that are purified and isotope-labeled in order to facilitate the necessary sophisticated multidimensional NMR measurements. However, the more recent industrial development, manufacturing, and quality control of biopharmaceuticals provide a different framework for NMR. For example, protein drug substances are not isotope-labeled and are present in a medium of excipients, which make structural NMR measurements much more difficult. On the other hand, biotechnology involves many other analytical requirements that can be efficiently addressed by NMR. In this respect the scope and limitations of NMR are less well understood. Having the non-expert reader in mind, herein we wish to highlight the ways in which modern NMR can effectively support biotechnological developments. Our focus will be on biosimilar proteins, pointing out certain cases where its use is probably essential. Based partly on literature data, and partly on our own hands-on experience, this paper is intended to be a guide for choosing the proper NMR approach for analytical questions concerning the structural comparability of therapeutic proteins, monitoring technology-related impurities, protein quantification, analysis of spent media, identification of extractable and leachable components, etc. Also, we focus on critical considerations, particularly those coming from drug authority guidelines, which limit the use of the wellestablished NMR tools in everyday practice.