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Taxifolin stability: In silico prediction and in vitro degradation with HPLC-UV/UPLC-ESI-MS monitoring.

ABSTRACT: Taxifolin has a plethora of therapeutic activities and is currently isolated from the stem bark of the tree Larix gmelinni (Dahurian larch). It is a flavonoid of high commercial interest for its use in supplements or in antioxidant-rich functional foods. However, its poor stability and low bioavailability hinder the use of flavonoid in nutritional or pharmaceutical formulations. In this work, taxifolin isolated from the seeds of Mimusops balata, was evaluated by in silico stability prediction studies and in vitro forced degradation studies (acid and alkaline hydrolysis, oxidation, visible/UV radiation, dry/humid heating) monitored by high performance liquid chromatography with ultraviolet detection (HPLC-UV) and ultrahigh performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS). The in silico stability prediction studies indicated the most susceptible regions in the molecule to nucleophilic and electrophilic attacks, as well as the sites susceptible to oxidation. The in vitro forced degradation tests were in agreement with the in silico stability prediction, indicating that taxifolin is extremely unstable (class 1) under alkaline hydrolysis. In addition, taxifolin thermal degradation was increased by humidity. On the other hand, with respect to photosensitivity, taxifolin can be classified as class 4 (stable). Moreover, the alkaline degradation products were characterized by UPLC-ESI-MS/MS as dimers of taxifolin. These results enabled an understanding of the intrinsic lability of taxifolin, contributing to the development of stability-indicating methods, and of appropriate drug release systems, with the aims of preserving its stability and improving its bioavailability.

SUBMITTER: Stenger Moura FC

PROVIDER: S-EPMC8116214 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPiperaquine, 1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane, is an anti-malarial compound belonging to the 4-aminoquinolines, which has received renewed interest in treatment of drug resistant falciparum malaria in artemisinin-based combination therapy with dihydroartemisinin. The impurity profile of this drug product is paid an ever-increasing attention. However, there were few published studies of the complete characterization of related products or impurities in piperaquine phosphate bulk and forced degradation samples.MethodsThe impurities in piperaquine phosphate bulk drug substance were detected by a newly developed gradient phase HPLC method and identified by TOF-MS and ESI-MS. The structures of impurities were confirmed by NMR. Forced degradation studies were also performed for the stability of piperaquine phosphate bulk drug samples and the specificity of the newly developed HPLC method. In silico toxicological predictions for these piperaquine phosphate related impurities were made by Toxtree® and Derek®.ResultsTwelve impurities (imp-1-12) were detected and identified, of which eight impurities (imp-1, 2, 4, 6-10) were first proposed as new related substances. Based on TOF-MS/ESI-MS and NMR analysis, the structures of imp-2, 6 and 12 were characterized by their synthesis and preparation. The possible mechanisms for the formation of impurities were also discussed. These piperaquine phosphate related impurities were predicted to have a toxicity risk by Toxtree® and Derek®.ConclusionsFrom forced degradation and bulk samples of piperaquine phosphate, twelve compounds were detected and identified to be piperaquine phosphate related impurities. Two of the new piperaquine phosphate related substances, imp-2 and imp-6, were identified and characterized as 4-hydroxy-7-chloro-quinoline and a piperaquine oxygenate with a piperazine ring of nitrogen oxide in bulk drug and oxidation sample, respectively. The MS data of imp-1, 2, 4, 6-10 were first reported. The in-silico toxicological prediction showed a toxicity risk for piperaquine related impurities by Toxtree® and Derek®.

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Taxifolin stability: In silico prediction and in vitro degradation with HPLC-UV/UPLC-ESI-MS monitoring.

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