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Development of a Chiral RP-HPLC Method for Identification Of Pharmacia 66(1): 1–6 DOI 10.3897/pharmacia.66.e35643 Research Article Development of a chiral RP-HPLC method for identification of stereomers of newly synthesised xanthine-based hydrazide- hydrazone compound Lily Peikova1, Diana Tzankova1, Alexandrina Dineva1, Maya Georgieva1, Alexander Zlatkov1 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University-Sofia, 2 Dunav str. 1000, Sofia Bulgaria Corresponding author: Lily Peikova ([email protected]) Received 20 March 2019 ♦ Accepted 22 April 2019 ♦ Published 14 May 2019 Citation: Peikova L, Tzankova D, Dineva A, Georgieva M, Zlatkov A (2019) Development of a chiral RP-HPLC method for iden- tification of stereomers of newly synthesised xanthine-based hydrazide-hydrazone compound. Pharmacia 66(1): 1–6.https://doi. org/10.3897/pharmacia.66.e35643 Abstract A reverse phase enantio-selective high performance liquid chromatographic method was developed for enantiomeric separation of 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purine-7(6H)-yl)-N’-(3-fluorobenzylidene)-propanehydrazide isomers. The enantio- mers of 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purine-7(6H)-yl)-N’-(3-fluorobenzylidene)propanehydrazide were resolved on a ACE®Equivalence™ С18 (250 × 4.6 mm, 5 μm) column using a mobile phase system containing methanol, water, phosphate buffer рН 7.4 (50:46:4 v/v/v). The resolution between enantiomers was found to be more than 2.0. The sample solution and mobile phase were found to be stable for at least 48 h. The final optimised method was successfully applied to separate the (R)- and the (S)-enanti- omers of 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purine-7(6H)-yl)-N’-(3-fluorobenzylidene)-propanehydrazide and was prov- en to be reproducible and accurate. Keywords xanthine-hydrazone, isomers, chiral RP-HPLC Introduction velopment of new molecules with potential biological ac- Theophylline, also known as 1,3-dimethylxanthine, is a tivity (Radunsky et al. 2015). Secondly, literature reports proven bronchodilator drug used in therapy for respira- an important number of hydrazones which show interes- tory diseases such as asthma or chronic pulmonary ob- ting biological effects, such as antioxidant (Prathap et al. structive disease (COPD) (Black et al. 1990; Cazzola and 2010), antitumour (Vicin et al. 2006), anti-inflammatory Gabriella 2007; Majumdar and Sloan 2007a, b; Kawayama (Kumar and Chauhan 2014), anticonvulsive (Padmini et et al. 2008; Korzycka and Górska 2008). al. 2013), analgesic (Kheradmand et al. 2013), antimicro- Currently, the compounds with hydrazone structu- bial (Küçükgüzela et al. 1999; Singh and Raghav 2011) and re have attracted the interest of many researchers for two antiviral (Vicin et al. 2009). reasons. Firstly, based on their facile synthesis, these com- The idea of combining these two principles is inter- pounds are important intermediary products in the de- esting in order to obtain substances with diverse phar- Copyright Peikova L et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2 Peikova L et al.: Development of RP-HPLC method for identification of stereomers macological activity and improved toxicological profiles Mobile phase composition (Constantin et al. 2016). Most often, the presence of a chiral carbon atom in CH3OH:H2O:phosphate buffer pH 7.4 = 50:46:4 (v/v/v). the structure of the organic compounds is responsible for the appearance of at least two enantiomers. There is Preparation of the phosphate buffer a well-known relationship between the pharmacological with pH = 7.4 effect and the appearance of enantiomers in biologically active substances. Very often, an individual enantiom- The used buffer was prepared according to the methodo- er of a chiral compound potentially exhibits different logy described in European Pharmacopoea 7.0 (2016). pharmacology, toxicology and metabolism activities in the living system (Nguyen et al. 2006) in comparison Preparation of the test solution to the corresponding racemic mixture. Potentially only one of the two enantiomers may be responsible for the A 2 mg sample of the tested compound was weighed and desired therapeutic response. Whereas, the other enan- dissolved in 10 ml of methanol. A 2.5 ml portion of this tiomer may be inactive or may even have deleterious solution was diluted to 25.0 ml with methanol and 20 μl effect. Therefore, it is of most importance to develop of the obtained solution was injected into the apparatus. analytical methods that can identify and determine the enantiomeric purity of a chiral active biologically active substance (Zhuang et al. 2016). Results and discussion Use of chiral chromatography has proven to be immense- ly valuable for identification and quantification of chiral In the current research, 2-(1,3-dimethyl-2,6-di- compounds. However, the development of the methods oxo-2,3-dihydro-1H-purine-7(6H)-yl)-N’-(3-fluoroben- for the quantitative analysis of Chiral compounds and for zylidene)-propanehydrazide was selected as a model the assessment of enantiomeric purity is extremely challen- compound whose chemical structure revealed the possi- ging, because the same physical and chemical properties of bility of formation of optical isomers, based on the pres- the two enantiomers make discriminating and separating ence of an asymmetric carbon atom, as seen on Figure 1. them very difficult (Chimalakonda et al. 2012). The aim of this study is to develop, validate and ap- ply a chiral reverse phase liquid chromatography (RP- O H3C HPLC) method for identification of geometrical isomers O F of a newly synthesised theophylline-based hydrazide-hy- NH N drazone derivative. H3C N N Materials and methods O N N Chemicals and reagents CH3 Figure 1. Chemical structure of the evaluated 2-(1,3-dimethyl- The necessary products for preparation of the mobile 2,6-dioxo-2,3-dihydro-1H-purine-7(6H)-yl)-N’-(3-fluoroben- phase and solutions are of analytical grade, obtained from zylidene)propanehydrazide. Sigma-Aldrich, Steinheim, Germany. Instrumentation and chromatographic For identification of the possible isomers, a chiral RP- conditions HPLC method was developed and validated. The chromatographic separation was performed on Development of the chiral RP-HPLC a modular HPLC system UltiMate Dionex 3000 SD, analytical procedure Chromeleon 7.2 SR3 Systems, Thermo Fisher Scientific Inc. The separation was achieved isocratically with chi- The main purpose of this work was to develop a fast Re- ral ACE®Equivalence™ С18 (5 μm), 250 mm x 4.6 mm, verse Phase HPLC method to separate and quantify the 5 μm column eluted with a mixture of methanol, wa- two enantiomers in 2-(1,3-dimethyl-2,6-dioxo-2,3-dihy- ter and 0.5 M potassium dihydrogen phosphate buffer dro-1H-purine-7(6H)-yl)-N’-(3-fluorobenzylidene)pro- pH 7.4, 50:46:4 v/v/v, as the mobile phase at flow rate panehydrazide. During the method development, several of 1.0 ml/min. The mobile phase was filtered through a chiral HPLC columns were selected on the basis of the 0.45 μm membrane filter and degassed. Detection was chemical structure and location of the chiral centre of the carried out by absorbance at 272 nm. The analysis was analyte and also on the characteristics of the chiral phase carried out at column temperature of 25oC and injection of the analytical columns. The best chiral selectivity and volume of 20 μl. resolution were obtained on an ACE®Equivalence™ С18 Pharmacia 66(1): 1–6 3 column. Therefore, the ACE®Equivalence™ С18 column of CH3OH:H2O:phosphate buffer pH 7.4 = 50:46:4 (v/v/v) was selected for further optimisation. as mobile phase and an ACE®Equivalence™ С18 column as For optimisation of the mobile phases, the effect of a the chiral stationary phase. variety of organic modifiers such as methanol, ethanol, glacial acetic acid and phosphate buffers with different Validation of the developed chiral RP- pH were investigated. The finally selected mobile phase HPLC analytical procedure was methanol : water : phosphate buffer pH 7.4 (50:46:4, v/v/v). Table 1 summarises the final chromatographic The method was validated according to ICH Q2 (R1) conditions. The final method was then used for analysis of guidelines (ICH 2005). The system’s suitability, precision, both 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purine- linearity, accuracy and selectivity were evaluated during 7(6H)-yl)-N’-(3-fluorobenzylidene)propanehydrazide method validation. isomers in the racemic mixture. The system’s suitability requirements (blank baseline: no interfering peaks above 0.1% level at the retention time Table 1. Final chromatographic conditions of the method. of two 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-pu- rine-7(6H)-yl)-N’-(3-fluorobenzylidene)propanehydra- Chiral HPLC column ACE®Equivalence™ С18 (250 zide enantiomers, 0.2% standard solution having signal- x 4.6 mm), 5µm to-noise ratio (S/N) ≥ 10 for each enantiomer; standard Mobile phase CH3OH:H2O:phosphate buffer pH 7.4 = 50:46:4 (v/v/v) solution preparation agreement (≤ 2.0%), resolution fac- Temperature 25 oC tor (≥ 1.2), injector agreement (difference between two in- Flow rate 1.0 ml/min jections ≤ 2.0%)) were met prior to performing the meth- Wavelength 272 nm od validation experiments. Injection volume 20 μl 2-(1,3-dimethyl-2,6-dioxo-2,3-dihy- 0.2 mg/ml Specificity dro-1H-purine-7(6H)-yl)-N'-(3-flu- orobenzylidene)propanehydrazide No significant interfering peaks (peak area > 0.1%) was observed at the retention time of the two enantiomers in As indicated in Figure 2, the separation of the two blank solution.
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