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

Fernanda Cristina Stenger Moura; Carmem Lúcia dos Santos Machado; Favero Reisdorfer Paula; Angélica Garcia Couto; Maurizio Ricci; Valdir Cechinel-Filho; Tiago J. Bonomini; Louis P. Sandjo; Tania Mari Bellé Bresolin

doi:10.1016/j.jpha.2020.06.008

Volume 11 Issue 2

Apr. 2021

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Article Navigation > Journal of Pharmaceutical Analysis > 2021 > 11(2): 232-240

Fernanda Cristina Stenger Moura, Carmem Lúcia dos Santos Machado, Favero Reisdorfer Paula, Angélica Garcia Couto, Maurizio Ricci, Valdir Cechinel-Filho, Tiago J. Bonomini, Louis P. Sandjo, Tania Mari Bellé Bresolin. Taxifolin stability: In silico prediction and in vitro degradation with HPLC-UV/UPLC–ESI-MS monitoring[J]. Journal of Pharmaceutical Analysis, 2021, 11(2): 232-240. doi: 10.1016/j.jpha.2020.06.008

Citation:

Fernanda Cristina Stenger Moura, Carmem Lúcia dos Santos Machado, Favero Reisdorfer Paula, Angélica Garcia Couto, Maurizio Ricci, Valdir Cechinel-Filho, Tiago J. Bonomini, Louis P. Sandjo, Tania Mari Bellé Bresolin. Taxifolin stability: In silico prediction and in vitro degradation with HPLC-UV/UPLC–ESI-MS monitoring[J]. Journal of Pharmaceutical Analysis, 2021, 11(2): 232-240. doi: 10.1016/j.jpha.2020.06.008

Citation:

Fernanda Cristina Stenger Moura, Carmem Lúcia dos Santos Machado, Favero Reisdorfer Paula, Angélica Garcia Couto, Maurizio Ricci, Valdir Cechinel-Filho, Tiago J. Bonomini, Louis P. Sandjo, Tania Mari Bellé Bresolin. Taxifolin stability: In silico prediction and in vitro degradation with HPLC-UV/UPLC–ESI-MS monitoring[J]. Journal of Pharmaceutical Analysis, 2021, 11(2): 232-240. doi: 10.1016/j.jpha.2020.06.008

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

doi: 10.1016/j.jpha.2020.06.008

a. Pharmaceutical Sciences Graduate Program, School of Health Sciences, Course of Pharmacy, Universidade do Vale do Itajaí, Itajaí, SC, 88302-202, Brazil;
b. Laboratory of Research and Development of Drugs, Pharmaceutical Sciences Graduate Program, School of Health Sciences, Course of Pharmacy, Universidade Federal do Pampa, Uruguaiana, RS, 97500-970, Brazil;
c. Department of Pharmaceutical Science, Università degli Studi di Perugia, Perugia, PG, 06123, Italy;
d. Chemistry Department, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

Funds:

This work was partially supported by CAPES (PVE, Grant No. 88887.116106/2016-00) (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), Brazil, which provided financial support in the form of a doctoral’s degree scholarship to Stenger, F. C. and financial support (Science Program Without Borders - Researcher Special Visitor – PVE), and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Edital Universal (Grant No. 88887.122964/2016-00).

Received Date: Nov. 19, 2019
Accepted Date: Jun. 29, 2020
Rev Recd Date: Jun. 28, 2020
Publish Date: Jul. 06, 2020

Abstract

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.
- Dihydroquercetin,
- In silico stability prediction,
- Forced degradation

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References(36)

References

H.M. Graham, E.F. Kurth, Constituents of extractives from douglas fir, Ind. Eng. Chem. 41 (1949) 409-414. https://doi.org/10.1021/ie50470a035

A.G. Schauss, S.S. Tselyico, V.A. Kuznetsova, et al., Toxicological and genotoxicity assessment of a dihydroquercetin-rich dahurian larch tree (Larix gmelinii Rupr) extract (Lavitol), Int. J. Toxicol. 34 (2015) 162-181. https://doi.org/10.1177/1091581815576975

F. Schlickmann, L.M. Mota, T. Boeing, et al., Gastroprotective bio-guiding of fruits from Mimusops balata, Naunyn Schmiedebergs Arch. Pharmacol. 388 (2015) 1187-1200. https://doi.org/10.1007/s00210-015-1156-8

D. Turck, J-L. Bresson, B. Burlingame, et al., Scientific opinion on taxifolin-rich extract from Dahurian Larch (Larix gmelinii), EFSA J. 15 (2017) 1-16. https://doi.org/10.2903/j.efsa.2017.4682

J.O. Teselkin, B.A. Zhambalova, I.V. Babenkova, et al., Antioxidant properties of dihydroquercetin, Biofizika. 41 (1996) 620-624

Y. Zhao, W. Huang, J. Wang, et al., Taxifolin attenuates diabetic nephropathy in streptozotocin-induced diabetic rats, Am. J. Transl. Res. 10, (2018), 1205-1210. PMCID: PMC5934579

Y. Wang, Q. Wang, X. Bao, et al., Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phopholipase A2/protaglandin E2 content, Metab. Brain. Dis. 33 (2018) 1069-1079. https://doi.org/10.1007/s11011-018-0207-5

X. Xiaobin, J. Feng, Z. Kang, S. et al., Taxifolin protects RPE cells against oxidative stress-induced apoptosis, Mol. Vis. 23 (2017)520-528. PMCID: PMC5534490

Y.J. Wang, H.Q. Zhang, H.L. Han, et al., Taxifolin enhances osteogenic differentiation of human bone marrow mesenchymal stem cells partially via NFkB pathway, Biochem. Biophys. Res. Commun. 490 (2017) 36-43. https://doi.org/10.1016/j.bbrc.2017.06.002

M.B. Plotnikov, O.I. Aliev, A.V. Sidekmenova, et al., Modes of hypertension action of dihydroquercetin in arterial hypertension, Bul. Exp. Biol. Med. 162 (2017) 353-356.https://doi.org/10.1007/s10517-017-3614-4

X. Sun, R. Chen, Z. Yang, et al., Taxifolin prevents diabetic cardiomyopathy in vivo and in vitro by inhibition of oxidative stress and cell apoptosis, Food Chem. Toxicol. 63 (2014) 221-232. https://doi.org/10.1016/j.fct.2013.11.013

Y. Zhang, Q. Jin, X. Li, et al., Modulation of AMPK-dependent lipogenesis mediated by P2x7R-NLRP3 inflammasome activation contributes to the amelioration of alcoholic liver steatosis by dihydroquercetin, J. Agric. Food Chem. 16 (2018) 4862-4871. https://doi.org/10.1021/acs.jafc.8b00944https://search.crossref.org/?q=Y.+Zhang%2C+Q.+Jin%2C+X.+Li%2C+et+al.%2C+Modulation+of+AMPK-dependent+lipogenesis+mediated+by+P2x7R-NLRP3+inflammasome+activation+contributes+to+the+amelioration+of+alcoholic+liver+steatosis+by+dihydroquercetin%2C+J.+Agric.+Food+Chem.+16+%282018%29+4862-4871

F.C. Stenger Moura, L. Perioli, C. Pagano, et al., Chitosan composite microparticles: A promising gastroadhesive system for taxifolin, Carbohydr. Pol. 218 (2019) 343-354. https://doi.org/10.1016/j.carbpol.2019.04.075

J.H.S. Gomes; G.C. da Silva; S.F. Cortes; et al., Forced degradation of L -(+)-bornesitol, a bioactive marker of Hancornia speciose: Development and validation of stability indicating UHPLC-MS method and effect of degraded products on ACE inhibition, J. Chromatogr. B 1093 (2018) 31-38.https://doi.org/10.1016/j.jchromb.2018.06.045

D.A Chernikov, T.A. Shishlyannikova, A.V. Kashevskii, et al., Some peculiarities of taxifolin electrooxidation in the aqueous media: The dimers formation as a key to the mechanism understanding, Electrochim. Acta 271 (2018) 560-566. https://doi.org/10.1016/j.electra.2018.02.179

O.N. Pozharitskaya, M.V. Karlinab, A.N. Shikov, et al., Determination and pharmacokinetic study of taxifolin in rabbit plasma by high-performance liquid chromatography, Phytomedicine 16 (2009) 244-251. https://doi.org/10.1016/j.phymed.2008.10.002

J. Winter, L.H. Moore, V.R. Dowell, et al., C-ring cleavage of flavonoids by human intestinal bacteria, Appl. Environ. Microbiol. 55 (1989) 1203-1208. PMID:2757380

M. Blessy, R.D. Patel, P.N. Prajapati, et al., Development of forced degradation and stability indicating studies of drugs-A review, J. Pharm. Anal. 4 (2014) 159-165.https://doi.org/10.1016/j.jpha.2013.09.003

M.M. Annapurna, C. Mohapatro, A. Narendra, Stability-indicating liquid chromatographic method for the determination of Letrozole in pharmaceutical formulation, J. Pharm. Anal. 2 (4) (2012) 298-305.https://doi.org/10.1016/j.jpha.2012.01.010

J. Kieffer, E. Bremond, P. Lienard, et al., In silico assessment of drug substances chemical stability, J. Mol. Struct. 954 (2010)75-79.https://doi.org/10.1016/j.theochem.2010.03.032

L.H. Mendoza-Huizar, Global and local reactivity descriptors for picloram herbicide: a theoretical quantum study, Quim. Nova 38 (2015) 71-76. https://doi.org/10.5935/0100-4042.20140283

C. Cardenas, N. Rabi, P. Ayers, et al., Chemical reactivity descriptors for ambiphilic reagents: dual descriptor, local hyper softness, and electrostatic potential, J. Phys. Chem. A. 113 (2009) 8660-8667. https://doi.org/10.1021/jp902792n

C. Morell, A. Hocquet, A. Grand, et al., A conceptual DFT study of hydrazino peptides: Assessment of the nucleophilicity of the nitrogen atoms by means of the dual descriptor Δf(r), J. Mol. Struct. Theochem. 849 (2008) 46-51. https://doi.org/10.1016/j.theochem.2007.10.014

T.R. Sharp, Calculated carbon-hydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drug substance molecules, Int. J. Pharm. 418 (2011) 304-307.https://doi.org/10.1016/j.theochem.2005.01.028

P. Lienard, J. Gavartin, G. Boccardi, et al., Predicting drugs substances autoxidation, Pharm. Res. 32 (2015) 300-310. https://doi.org/10.1007/s11095-014-1463-7

ICH, Harmonized Tripartite Guideline Specifications: Validation of analytical procedures: text and methodology Q2(R1), Current Step 5 version, 2005

ICH, Harmonised Tripartite Guideline Stability Testing: Photostability Testing of New Drug Substances and Products Q1B, Current Step 4 version, 1996

R.G. Parr, W. Yang, Functional Theory of Atoms and Molecules, Oxford Univ. Press, New York, 1989

S.J. Blanksby, G.B. Ellison, Bond dissociation energies of organic molecules, Acc. Chem. Res. 36 (2003) 255-263. https://doi.org/10.1021/ar020230d

S. Yamada, Y. Naito, M. Takada, et al., Photodegradation of hexachlorobenzene and theoretical prediction of its degradation pathways using quantum chemical calculation, Chemosphere 70 (2008) 731-736. https://doi.org/

E. Osorio, E. G. Perez, C. Areche, et al., Why is quercetin a better antioxidant then taxifolin? Theorical study of mechanisms involving activated forms, J. Mol. Model. 19 (2013) 2165-2172

S. Singh, M. Bakshi, Guidance on conduct of stress test to determine inherent stability of drugs, Pharm. Technol. 24 (2000) 1-14

H.J. An, Y. Lee, L. Liu, et al., Physical and Chemical Stability of Formulations Loaded with Taxifolin Tetra-octanoate, Chem. Pharm. Bull., 67, 1 (2019), 985-991

S. Barrek, O. Paisse, M.F. Grenier-Loustalot, Analysis of neem oils by LC-MS and degradation kinetics of azadirachtin-A in a controlled environment, Anal. Bioanal. Chem., 3 (2004) 753-763

M. Mocek, P.J. Richardson, Kinetics and mechanism of quercetin oxidation, J. Inst. Brew. 78 (1972) 459-465. https://doi.org/10.1002/j.2050-0416.1972.tb03481.x

W. Wang, C, Sun, L. Mao, et al. The biological activities chemical stability, metabolism and delivery system of quercetin: A review, Trend Food Sci. 56 (2016) 21-38. https://doi.org/10.1016/j.tifs.2016.07.004

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