Validated stability indicating assay method of olaparib: LC-ESI-Q-TOF-MS/MS and NMR studies for characterization of its new hydrolytic and oxidative forced degradation products

Thummar, Mohit; Kuswah, Bhoopendra S.; Samanthula, Gananadhamu; Bulbake, Upendra; Gour, Jitendra; Khan, Wahid

doi:10.1016/j.jpba.2018.07.017

Cited by 12 publications

(10 citation statements)

References 13 publications

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“…Hydroxylation was initiated by chlorination in the presence of hydrochloric acid, and a similar chlorinated degradation product was observed in our earlier publications 16 . Subsequently chlorine was replaced by a hydroxyl radical, which in turn was formed by a thermally induced molecular oxygen 18,19 . DP 3 was not observed in other conditions, confirming that initially hydrochloric acid catalyzes the reaction.…”

Section: Degradation Pathway Of Dp 1 To Dpsupporting

confidence: 83%

Comprehensive degradation profiling and influence of different oxidizing reagents on tinoridine hydrochloride: Structural characterization of its degradation products using HPLC and HRMS

Dhiman

Patil

Velip

et al. 2021

Rapid Comm Mass Spectrometry

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Rationale Stress testing on tinoridine hydrochloride was carried out using a multidimensional approach. This included different conditions: hydrolytic (acidic, alkaline, and neutral conditions), different oxidative reagents, thermal, photolytic conditions, HPLC method development, and structural elucidation using high‐resolution mass spectrometry (HRMS). It provides the basis for quality control of tinoridine hydrochloride and its derivatives during storage conditions. Methods The tinoridine hydrochloride was subjected to a variety of stress conditions. A gradient reversed‐phase HPLC method was developed on a X‐Bridge C18 column (250 × 4.6 mm, 5 μm) to separate all the degradation products (DPs). HRMS studies have been performed to elucidate the structure of DPs. Results HPLC‐PDA study revealed that significant degradation products were formed in hydrolytic, AIBN (radical initiator at 40°C), thermal, and solid‐state photolight stress conditions, but the drug was stable under oxidative conditions (H2O2, Fenton's reagent at room temperature and ferric chloride at 40°C). The structure of degradation products was elucidated, and mechanism of their formation was explained. Conclusion Stress study was successfully carried out as per ICH Q1A (R2) guideline on tinoridine hydrochloride. A total of six new degradation products were characterized, DP 2 and DP 6 formed by the effect of co‐solvent. This study provides the scientifically sound basis for quality monitoring and storage conditions of tinoridine hydrochloride.

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Section: Degradation Pathway Of Dp 1 To Dpsupporting

confidence: 83%

Comprehensive degradation profiling and influence of different oxidizing reagents on tinoridine hydrochloride: Structural characterization of its degradation products using HPLC and HRMS

Dhiman

Patil

Velip

et al. 2021

Rapid Comm Mass Spectrometry

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“…Different results also emerge from the study of oxidative stress test, where some authors reported an effective degradation while others argue that the drug was stable. A general overview of the already reported studies on olaparib and its related stress impurities is summarized in Table S1 and Figure . − …”

Section: Resultsmentioning

confidence: 99%

“…Previous works have described the forced degradation of olaparib under basic, acidic, neutral, oxidative, dry heat, and photolytic stress conditions. − Sample preparation as well as the reaction conditions used to induce the drug’s forced degradation change slightly among the cited works. In addition, the DPs observed under the same conditions also differ among the reported studies.…”

Section: Resultsmentioning

confidence: 99%

MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

et al. 2023

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Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC–MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated. MassChemSite has been recently described as a promising informatics solution for LC–MS/MS and UV data analysis of forced degradation experiments and for the automated structural identification of DPs. Here, we applied MassChemSite to investigate the forced degradation of three poly(ADP-ribose) polymerase inhibitors (olaparib, rucaparib, and niraparib) under basic, acidic, neutral, and oxidative stress conditions. Samples were analyzed by UHPLC with online DAD coupled to high-resolution mass spectrometry. The kinetic evolution of the reactions and the influence of solvent on the degradation process were also assessed. Our investigation confirmed the formation of three DPs of olaparib and the wide degradation of the drug under the basic condition. Intriguingly, base-catalyzed hydrolysis of olaparib was greater when the content of aprotic-dipolar solvent in the mixture decreased. For the other two compounds, whose stability has been much less studied previously, six new degradants of rucaparib were identified under oxidative degradation, while niraparib emerged as stable under all stress conditions tested.

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“…A liquid chromatography-mass spectrometric method was found in the literature describing the quantification of OLA in either bulk form, in human plasma, or in combination with other drugs [4,5]. Thummar et al (2018), described a validated stability indicating assay method of OLA using the high-performance liquid chromatography-diode array mass-spectrometric (LC-DAD-MS) method, however, the related substances, including potential impurities, were not considered [6]. The process for the preparation of OLA, according to the published patents, showed many intermediates with a percentage yield of the final product of not more than 96% [7,8].…”

Section: Introductionmentioning

confidence: 99%

Multi-Steps Fragmentation-Ion Trap Mass Spectrometry Coupled to Liquid Chromatography Diode Array System for Investigation of Olaparib Related Substances

2019

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A high-performance liquid chromatography-diode array-mass spectrometric (LC-DAD-MS) method was developed and validated to investigate the related substances of olaparib (OLA) in bulk form. OLA was exposed to acid–base hydrolysis, boiling, oxidation with hydrogen peroxide, and UV light followed by LC-DAD-MS analysis. OLA and OLA-related substances were simultaneously and quantitatively monitored by DAD at 278 nm and triple quadrupole mass spectrometry (QQQ-MS). The investigated compounds were auto-scanned by an ion trap MS which applied positive and negative modes separately. The fragmentation pathway was confirmed by applying multi-steps fragmentation to identify the resulted cleaved ions and their parent ion. OLA was found to be sensitive to the alkaline hydrolysis and less sensitive to UV light. Two major hydrolytic degradation products, including the protonated molar ions m/z 299 and m/z 367, were identified. Three potential impurities were also characterized. The LC-MS limit of detection (LOD) and limit of quantification (LOQ) were 0.01 and 0.05 ng/µL, respectively. The quantitative results obtained by LC-DAD was comparable with that of LC-QQQ-MS. The proposed method shows good intra-day and inter-day precision with relative standard deviation (RSD) <2%.

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Validated stability indicating assay method of olaparib: LC-ESI-Q-TOF-MS/MS and NMR studies for characterization of its new hydrolytic and oxidative forced degradation products

Cited by 12 publications

References 13 publications

Comprehensive degradation profiling and influence of different oxidizing reagents on tinoridine hydrochloride: Structural characterization of its degradation products using HPLC and HRMS

Comprehensive degradation profiling and influence of different oxidizing reagents on tinoridine hydrochloride: Structural characterization of its degradation products using HPLC and HRMS

MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

Multi-Steps Fragmentation-Ion Trap Mass Spectrometry Coupled to Liquid Chromatography Diode Array System for Investigation of Olaparib Related Substances

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