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      Two-dimensional proton-detected 35Cl/1H correlation solid-state NMR experiment under fast magic angle sample spinning: application to pharmaceutical compounds

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          Abstract

          In this study, we have measured 35Cl/ 1H correlations in hydrochloride salts of active pharmaceutical ingredients (HCl APIs) using the D-HMQC pulse sequence at fast MAS.

          Abstract

          The determination of structure of hydrochloride salts of active pharmaceutical ingredients (HCl APIs) utilizing 35Cl solid-state NMR studies has been of considerable interest in the recent past. Until now these studies relied on the 35Cl direct observation method which has its own limitations in terms of the sensitivity and resolution due to the quadrupolar nature and the low gyromagnetic ratio of 35Cl. In this contribution we demonstrate the two-dimensional (2D) 35Cl/ 1H correlation measurement by using the proton detection-based (indirect observation of 35Cl via 1H) approach under fast magic angle sample spinning (MAS: 70 kHz). The main advantages of this approach over the direct observation method are highlighted in the present study. We have employed heteronuclear magnetization transfer through the recoupling of 35Cl– 1H heteronuclear dipolar interactions. The applicability of 35Cl indirect detection method is first demonstrated on hydrochloride salts of amino acids, l-tyrosine·HCl and l-histidine·HCl·H 2O following which the 2D 35Cl/ 1H correlations are obtained for HCl APIs, procainamide HCl (Proc) and aminoguanidine HCl (Amin). On the basis of separation between the central transition (CT) and satellite transition (ST) peaks, and the shape/width of CT powder patterns, it is also shown that the quadrupolar parameters which are useful for the elucidation of the molecular structure can be determined. Moreover, the 35Cl/ 1H correlations provide the precise determination of 1H chemical shifts of nearby 35Cl nuclei.

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          Most cited references 29

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          Multiple-Quantum Magic-Angle Spinning NMR: A New Method for the Study of Quadrupolar Nuclei in Solids

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            High resolution solid-state N.M.R.

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              Drug polymorphism and dosage form design: a practical perspective.

              Formulators are charged with the responsibility to formulate a product which is physically and chemically stable, manufacturable, and bioavailable. Most drugs exhibit structural polymorphism, and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf life under a variety of real-world storage conditions. There are occasional situations in which the development of a metastable crystalline or amorphous form is justified because a medical benefit is achieved. Such situations include those in which a faster dissolution rate or higher concentration are desired, in order to achieve rapid absorption and efficacy, or to achieve acceptable systemic exposure for a low-solubility drug. Another such situation is one in which the drug remains amorphous despite extensive efforts to crystallize it. If there is no particular medical benefit, there is less justification for accepting the risks of intentional development of a metastable crystalline or amorphous form. Whether or not there is medical benefit, the risks associated with development of a metastable form must be mitigated by laboratory work which provides assurance that (a) the largest possible form change will have no substantive effect on product quality or bioavailability, and/or (b) a change will not occur under all reasonable real-world storage conditions, and/or (c) analytical methodology and sampling procedures are in place which assure that a problem will be detected before dosage forms which have compromised quality or bioavailability can reach patients.
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                Author and article information

                Journal
                PPCPFQ
                Physical Chemistry Chemical Physics
                Phys. Chem. Chem. Phys.
                Royal Society of Chemistry (RSC)
                1463-9076
                1463-9084
                2016
                2016
                : 18
                : 8
                : 6209-6216
                Affiliations
                [1 ]RIKEN CLST-JEOL Collaboration Center
                [2 ]RIKEN
                [3 ]Yokohama
                [4 ]Japan
                [5 ]JEOL RESONANCE Inc.
                [6 ]Akishima
                Article
                10.1039/C5CP06042G
                © 2016
                Product
                Self URI (article page): http://xlink.rsc.org/?DOI=C5CP06042G

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