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Degradation of ondansetron: Isolation and characterization impurity D ondansetron as A candidate reference standard impurity in drug
Abstract
Drug safety does not only depend on the active ingredient of the drug itself but also depends on the contamination contained in it. 1,2,3,9-Tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one, or often called impurity D ondansetron is contamination in ondansetron which can endanger human health if the value is above the minimum (0.1 %) due to its toxicity. The qualitative and quantitative methods of selective and accurate for the impurity D ondansetron need to be developed to ensure the quality of the drug. Qualitative and quantitative analysis of drug contamination is often not possible due to it is constrained by the high-price of standard contaminant. The aim of this study is to obtain impurity D ondansetron that fulfills the requirements for characterization and purity as candidate for standard impurity; and obtain a method of analysis of impurity D ondansetron both qualitatively and quantitatively in ondansetron tablet which is valid in HPLC. The research experiments were carried out by hydrolyzing ondansetron in alkaline condition with optimum concentration 1 M NaOH for 30 h at 80 °C. Impurity D Ondansetron from degradation was successfully isolated by ethyl acetate as a solvent and hexane-ethyl acetate (6:4) as an eluent. The purity of Impurity D Ondansetron was measured using HPLC-DAD and obtained the purity index of 1.0000 and purity of 99.77 %. Impurity D Ondansetron was characterized using infrared spectroscopy, mass spectroscopic gas chromatography and HPLC-DAD.
... Nevertheless, LC-MS/MS is quite expensive method and is not readily available in many facilities. High performance liquid chromatography with diode array detector (HPLC-DAD) has been widely used to determine the purity of drug substances for example it was used for the determination of related substances in chlorzoxazone, diclofenac sodium and tramadol hydrochloride [18] , in alfuzosin and solifenacin [19] , and Ondansetron [20] . However, limited studies have reported the determination of NDMA in pharmaceuticals using HPLC-DAD which is the most popular technique for quality control of APIs and products in routine analysis [ 5 , 21 ]. ...
In this study, two novel, rapid, sensitive, and specific chromatographic methods were developed and validated for the determination of N-nitrosodimethylamine (NDMA) impurity in the valsartan drug substance. The first method is a high-performance liquid chromatography method with a diode array detector (HPLC-DAD). The method was validated according to ICH Q2 (R1) guidelines and was used for the determination of NDMA in valsartan drug substances from different suppliers. Satisfactory validation results were obtained in terms of linearity with a range from 9.10 to 29.5 µg/L and R²= 0.994, precisions with a coefficient of variation of 1.2%, accuracy with recovery between 94.5 and 103.1%, limit of detection (LOD) and limit of quantitation (LOQ) were 0.0027 and 0.0091 mg kg⁻¹, respectively. Assay of NDMA in valsartan drug substances using the developed HPLC-DAD method showed that samples from Zhejiang Huahai supplier, obtained between 2012 and 2017, contained high levels of NDMA that exceed the acceptable limits with an average concentration of 59.3 mg kg⁻¹. On the other hand, the new Zhejiang Huahai samples, obtained after November 2018, did not show significant contamination with NDMA. For confirmation of our results, a second method was developed which is the liquid chromatography method with tandem mass spectrometry detection (LC-MS/MS). The new LC-MS/MS method was developed and validated for confirmation of the results of the NDMA assay in the new valsartan samples obtained from Zhejiang Huahai after November 2018. The new LC-MS/MS method has been more selective than the HPLC-DAD method with LOD and LOQ values of 0.0021 and 0.0070 mg kg⁻¹, respectively. The results of LC-MS/MS show good agreement with those obtained with the HPLC-DAD method.
Drug impurity and degradation profiling mean the detection, structure elucidation and quantitative determination of impurities and degradation products in bulk drug materials and pharmaceutical formulations. This is today one of the most important fields of activities in pharmaceutical analysis. The reason for this is that unidentified, potentially toxic impurities are health hazards, and in order to increase the safety of drug therapy, impurities should be identified and determined by selective methods.
The aim of this review is to characterise the state-of-art in the field of impurity and degradation profiling of drugs based on papers published in the last decade. The separation and determination of impurities and degradants with a known structure are discussed, but emphasis is placed on the structure elucidation and determination of new (unknown) impurities and degradation products by off-line and on-line chromatographic–spectroscopic methods. The analytical aspects of enantiomeric purity of chiral drugs are also discussed.
Serotonin 5-hydroxytryptamine (5-HT3) receptor antagonists (setron derivatives) are drugs used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. The first-generation of 5-HT3 receptor antagonists are ondansetron, dolasetron, granisetron, and tropisetron and the second-generation is palonosetron. The aim of this work is to review the analytical methods used to determine these drugs from 1990 to 2016.
Impurities will be present in all drug substances and drug products, i.e. nothing is 100% pure if one looks in enough depth. The current regulatory guidance on impurities accepts this, and for drug products with a dose of less than 2g/day identification of impurities is set at 0.1% levels and above (ICH Q3B(R2), 2006). For some impurities, this is a simple undertaking as generally available analytical techniques can address the prevailing analytical challenges; whereas, for others this may be much more challenging requiring more sophisticated analytical approaches. The present review provides an insight into current development of analytical techniques to investigate and quantify impurities in drug substances and drug products providing discussion of progress particular within the field of chromatography to ensure separation of and quantification of those related impurities. Further, a section is devoted to the identification of classical impurities, but in addition, inorganic (metal residues) and solid state impurities are also discussed. Risk control strategies for pharmaceutical impurities aligned with several of the ICH guidelines, are also discussed.
Ondansetron hydrochloride was subjected to forced degradation studies under various conditions of hydrolysis (acidic, basic and neutral), oxidation, photolysis and thermal as prescribed by International Conference on Harmonisation guideline Q1A (R2). A simple, selective, precise, and accurate high performance liquid chromatography method was developed on a Waters Xterra C18 (150 mm × 4.6 mm i.d., 3.5 μm) column using 10 mM ammonium formate (pH 3.0)/methanol as a mobile phase in gradient elution mode at a flow rate of 0.6 mL/min. The method was extended to liquid chromatography quadrupole time-of-flight tandem mass spectrometry for identification and structural characterization of stress degradation products of ondansetron. The drug showed significant degradation in base hydrolytic and photolytic stress conditions in the liquid state, while it was found to be stable in neutral, acidic, thermal, oxidative stress conditions. A total of five degradation products were characterized and most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation of the [M+H](+) ions of the drug and its degradation products. Finally, the developed method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonisation guideline Q2 (R1). This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
While the use of pharmaceuticals is always a balance of risks and benefits, the same is not true for impurities in pharmaceuticals; impurities convey only risk. A number of international guidelines and regional guidances instruct drug developers and regulatory agencies on how to evaluate and control impurities in drug substances and drug products. While impurities should always be reduced to the lowest levels that are reasonably practical, it is acknowledged that impurities cannot be reduced to zero and specifications for impurities need to be established. This chapter discusses practical and theoretical methods for qualification of different classes of impurities.