Electrospray ionization tandem mass spectrometry of the two main antimalarial drugs: artemether and lumefantrine

Abstract

Ionização por electrospray no modo de íons positivos, e espectrometria de massas de alta resolução e exatidão, e em tandem, realizadas em espectrômetro de massas híbrido quadrupolo e tempo de vôo, foram utilizadas para investigar a dissociação química das moléculas intactas dos dois antimaláricos mais amplamente utilizados: artemeter e lumefantrina. As rotas de dissociação das formas cationizadas e protonadas foram claramente estabelecidas via determinações de massas de alta resolução e distribuição isotópica. Os resultados obtidos podem auxiliar a monitorização e a quantificação de artemeter e lumefantrina por LC-MS/MS, assim como de novos derivados ou outros fármacos antimaláricos estruturalmente relacionados.Electrospray ionization in the positive ion mode and high resolution and high accuracy tandem mass spectrometry performed in a hybrid quadrupole time-of-flight mass spectrometer were used to investigate the dissociation chemistry of the intact molecules of two most widely used antimalarial drugs: artemether and lumefantrine. The dissociation pathways of their cationized and protonated forms were rationalized based on high accuracy mass measurements and isotopic distributions. The obtained results should benefit LC-MS/MS monitoring and quantitation by mass spectrometry of the artemether and lumefantrine molecules, as well as of new derivatives or other structurally related antimalarial drugs. Keywords: artemether, lumefantrine, ion dissociation, tandem mass spectrometry, ESI-MS/MS IntroductionArtemether-lumefantrine is a drug association currently of wide use for malaria treatment. The registered fixed dose combination is commercialized in tablets that contain 20 mg of artemether and 120 mg of lumefantrine. 1 The World Health Organization (WHO) recommends this association as first line therapy for falciparum malaria in endemic areas, mainly when cases of resistance against traditional drugs are reported. 2 Artemether (Scheme 1) is a semisynthetic derivative of artemisinin, a natural product of the Chinese herb Artemisia annua, 3 whereas lumefantrine (Scheme 1) is a synthetic racemic fluorene derivative originally named benflumetol. 4 Counterfeiting or drugs with substandard antimalarial doses are however major problems of worldwide occurrence that dramatically affects the efficacy of malarial treatment. Ineffective or poor quality drugs is of great concern since their use may contribute to the development of plasmodium resistance in malaria endemic areas, due to the exposition to subtherapeutic doses. 5,6 The development of useful and reliable methods for the identification of antimalarials is therefore essential to evaluate the quality of the antimalarial pharmaceutical preparations. Electrospray Ionization Tandem Mass Spectrometry of the Two Main Antimalarial Drugs J. Braz. Chem. Soc. 66 Chromatographic methods for the analysis of artemether and lumefantrine have been reported, focusing on the quantitation of these drugs in pharmaceutical products 7 or biological matrices. 8,9 HPLC with UV detection ...

LC–UV/MS quality analytics of paediatric artemether formulations

“…This contrasts our observation, whereby m / z 267 and 239 are high intensity peaks, leading to the fragments with the similar characteristic m / z values of 221 and 163. Their hypothesis that artemether salt adducts undergo first isomerisation through the rupture of the peroxide ring [56] is not observed or supported by our data, as no observation was made of m / z 259 for Li + -β-artemether salt adduct, which also corresponds with m / z -values of 254 for H + , 271 for NH 4 + , 276 for Na + and 292 for K + . Also the MS-spectra of the AHA and DKA-reference (see Supplementary information ) ( Table 4 ) give extra supportive information for structure elucidation of the β-artemether fragments by their characteristic m / z values.…”

“…6 for β-artemether and Fig. 7 for artemisinin, respectively, and compared to those already described in literature [56] , [57] , [58] , [59] .…”

“…The proposed fragmentation pathway of the cationized β-artemether (Li + , Na + and K + -salt adducts) revealed by Dos Santos et al [56] differs in the first fragmentation steps, i.e. , they did not detect no significant signals for [AHA+H] + m / z 267 or [DKA+H] + m / z 239.…”

Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries

“…The detection and quantification of AMT was carried out at 163 m/z because it was the main signal obtained in the mass spectrum under chromatography conditions as show in Fig 2 . In addition, this m/z signal was used in previous methods and the fragmentation of AMT was described in literature [ 52 , 53 ].…”

Kinetics of Lumefantrine Thermal Decomposition Employing Isoconversional Models and Artificial Neural Network

“…Lumefantrine is the first choice for the treatment of uncomplicated and severe Plasmodium falciparum malaria. 33,34 The knowledge of thermal stability is fundamental to properly design the industrial process, since most unit operations require or generate heat, as can occur to obtain tablets containing lumefantrine. 1,2 It should be emphasized there are no data in the scientific literature describing the kinetic of lumefantrine thermal decomposition.…”