Predictive strategy for the rapid structure elucidation of drug degradants

Rourick, Robyn A.; Volk, Kevin J.; Klohr, Steven E.; Spears, Tony; Kerns, Edward H.; Lee, Mike S.

doi:10.1016/0731-7085(96)01843-2

Cited by 34 publications

(31 citation statements)

References 8 publications

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“…With experienced operators, the structures of impurities can be inferred from MS and MS/ MS experiments with a good degree of success [54]. LC-MS/MS substructural analysis methodologies and strategies have been developed for rapid and accurate elucidation of structures of impurities and degradants [36,57]. The fragmentation patterns of known structures are then used as a substructural template for interpretation of the structures of unknown impurities and degradants by association of specific product ions and neutral losses with specific substructures.…”

Section: Strengths and Limitations Of Coupling Lc To Ion Trap Msmentioning

confidence: 99%

Hyphenation of liquid chromatography to ion trap mass spectrometry to identify minor components in polypeptide antibiotics

et al. 2003

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The application of liquid chromatography-ion trap mass spectrometry for the characterization of linear and cyclic polypeptide antibiotics was investigated. The aim was on-line identification of impurities in those antibiotic complexes without recourse to time-consuming isolation and purification procedures. Hyphenated techniques, such as liquid chromatography coupled to mass spectrometry, are ideally suited for this purpose. Characterization was performed with an ion trap mass spectrometer offering MS(n) capability; this enables more structural information to be obtained. Liquid chromatography in combination with ion trap mass spectrometry was successfully applied for the characterization of impurities in gramicidin, polymyxin B, polymyxin E, and bacitracin and the study of the degradation products of polymyxins B and E.

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Section: Strengths and Limitations Of Coupling Lc To Ion Trap Msmentioning

confidence: 99%

Hyphenation of liquid chromatography to ion trap mass spectrometry to identify minor components in polypeptide antibiotics

et al. 2003

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“…In these communications from the 1960s, a thorough understanding of electron ionization mass spectra allowed one to resolve structural and stereochemical problems for steroidal molecules [90]. The relative lack of 3D structural information from MS spectra is compensated when highly automated lC-uV-MS/MS-NMR platforms are utilized, as has been shown in several examples [91][92][93][94]. As previously stated, hyphenated SFC-MS also plays an important role in these studies [95].…”

Section: The Role Of Ms In the Elucidation Of Chemical Structuresmentioning

confidence: 84%

MS Applications in Support of Medicinal Chemistry Sciences

Honing¹,

Ingelse²,

Pramanik³

2013

Mass Spectrometry for Drug Discovery and Drug Development

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In the drug discovery process, medicinal chemistry plays a crucial role in the optimal design and synthesis (production) of new chemical entities (NCEs) or new biological entities (NBEs); this is true for a single entity as well as a complete compound library. A key requirement in this field of science is the optimization of both the chemical and the biological properties of these potential drug-like compounds. Important criteria are the design of efficient synthesis routes, the balancing of the physical chemical properties with optimal in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) processes, and a profound understanding of the pharmacodynamics in the appropriate pharmacological models. In the lead optimization stage, an important step is scaling up the synthesis route as needed for the execution of toxicology studies and the screening of suitable drug formulations. In summary, medicinal chemistry support includes participating in a large variety of activities and decision making processes that play a key role in the search for either a "first in class" new drug or a "best in class" new drug [1].These "drug discovery" processes are continuously under pressure, as the research and development (R&D) costs continue to increase and more data are requested before new drug candidates are taken into (pre-)clinical development. Hence, the choice of "targeted" high-throughput screening (HTS) libraries, the process of hit appraisal, and the understanding of target-ligand interactions can be considered the starting points for a new drug discovery program [2]. Next, the main focus is on the discovery of a lead compound; typically, this is a compound showing promising data regarding target affinity, reasonable efficacy in cellular models, good physical chemical parameters (i.e., a "drug-like" compound), and acceptable oral bioavailability in Mass Spectrometry for Drug Discovery and Drug Development, First Edition. Edited by Walter A. Korfmacher.

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“…There had been numerous reports in the literature that involved LC/MS and LC/MS/MS for characterization of degradation products [1, [88][89][90][91][92][93][94][95][96][97]. An early example of the rapid structure elucidation of drug degradants induced by acid, base and heat by LC/MS was reported by Rourick et al in 1996 [90].…”

Section: Characterization Of Decomposition Products By Lc/msmentioning

confidence: 99%