Isolation, identification and characterization of novel process-related impurities in flupirtine maleate

Oxidation Potentials of N‐Modified Derivatives of the Analgesic Flupirtine Linked to Potassium KV7 Channel Opening Activity But Not Hepatocyte Toxicity

“…The formation of compound 8 was not expected, as Zhang et al only found the regioisomer with N1 and N3 acylated among the process impurities. [22] Synthesis of N-methylated derivatives following an established route for the synthesis of flupirtine Direct alkylations of flupirtine in our hands always yielded Nmethylated flupirtine derivatives with substitution at the carbamate nitrogen only. To obtain derivatives with a divergent N-alkylation pattern, multistep syntheses were required.…”

“…[38] Until now, no reports have been published concerning the effects of N-alkylation either on activity or toxicity. On the other hand, methylation at N 2 and N 6 (i.e., [20][21][22] can theoretically facilitate oxidation due to the electropositive nature of the two methyl groups on that nitrogen. All nine N-modified flupirtine derivatives were previously unreported, thus offering a unique opportunity to conduct SAR studies with respect to oxidation potential, K V 7.2/3 channel-opening activity, and hepatotoxicity of this widely used drug.…”

“…Compound 6 is a known process impurity formed during large-scale synthesis of flupirtine and was recently identified and synthesized by Zhang et al [22] Our straightforward preparation of 6 by dry heating, however, is advantageous over the method described by Zhang et al, who used 2,3-diamino-6-(4fluorobenzylamino)pyridine, a compound extremely sensitive to oxidation, as an intermediate in a multistep sequence.…”

Characterization of a novel process-related impurity in commercial bendazac lysine eye drops by LC–ESI-QTOF/MS/MS and NMR

“…1C). In addition, as NOESY spectrum could determine the configuration, it was also analyzed to comply with the assignment [12]. …”

Determination and Characterization of Two Degradant Impurities in Bendamustine Hydrochloride Drug Product

“…To simulate the impurities and degradation products which may be formed during shelf-life period, stress testing including thermal stressed testing, humidity stressed testing and photostability testing of pharmaceutical products must be conducted (11). Recently, there has been series of studies (12)(13)(14)(15) published for characterization of potential drug impurities in drug substance or drug product using ICH Q3A (2) by employing modern sophisticated analytical methods.…”