Determination of polymeric impurities in asunaprevir drug substance and product using size exclusion effect of reversed-phase columns

Huang, Zhanwen; Y, Hu; Zha, Yan; Perrone, Robert; Ruan, Joan; Fish, William P.

doi:10.1016/j.jpba.2018.01.018

Cited by 5 publications

(2 citation statements)

References 12 publications

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“…These two last adsorbents can both be used in the pH range between 1 and 11. A wide number of published results in 24] and XSelect CSH C18 [25][26][27] can be found in literature. All three packings generally use alcohol:water or acetonitrile:water solvents, often with an acid or basic modifier (typically 0.1%).…”

Section: Introductionmentioning

confidence: 99%

Separation of nadolol racemates by high pH reversed-phase preparative chromatography

Arafah

Ribeiro

Rodrigues

et al. 2020

Separation and Purification Technology

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The separation of nadolol racemates under high pH reversed-phase preparative chromatography is presented for the first time.Three Waters C18 adsorbents (XBridge, Shield and XSelect) are compared for the separation of nadolol racemates using ethanol:water:diethylamine solvent mixtures. Experimental and simulation results are presented to compare the separation performances at preparative scale using both the fixed-bed and the simulated moving bed operations.The Waters XBridge C18 adsorbent and an ethanol:water:diethylamine solvent mixture are selected as a good option for the separation of nadolol racemates. The validated methodology allows the separation of a multicomponent nadolol feed mixture composed by four stereoisomers into two pure racemates (two pairs of enantiomers). This work introduces the potential of using an initial achiral separation step in the global strategy for the complete multicomponent separation of the four nadolol stereoisomers.

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Section: Introductionmentioning

confidence: 99%

Separation of nadolol racemates by high pH reversed-phase preparative chromatography

Arafah

Ribeiro

Rodrigues

et al. 2020

Separation and Purification Technology

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“…From a mass spectrometry (MS) point of view, the inherent PEG heterogeneity causes extensive numbers of polymer charge states in the electrospray process that result in highly convoluted mass spectra, preventing sensible identification and quantitation . From a chromatographic separation point of view, the intrinsic heterogeneity and HMW of complex polymer samples (e.g., branched-chain multifunctionalized PEG–maleimide molecules) often require more than one mode of separation to obtain the full impurity or degradation profile. − While size variants can be separated by size-exclusion chromatography (SEC), chemical modifications to the pendant functional groups with negligible size differences are difficult to be differentiated by SEC and require reversed-phase (RP) chromatography to provide sufficient separation . In addition to this, the multiple maleimides that attached to the PEG molecule further increase the sample multiplicity and complexity, as the readily occurring succinimide ring-opening hydrolysis can further confound the sample heterogeneity.…”

mentioning

confidence: 99%

Characterization of High Molecular Weight Multi-Arm Functionalized PEG–Maleimide for Protein Conjugation by Charge-Reduction Mass Spectrometry Coupled to Two-Dimensional Liquid Chromatography

Yang¹,

Chen²,

Wang³

et al. 2020

Anal. Chem.

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A current trend in drug development involves the use of high molecular weight, branched, and functionalized polymers for protein conjugation and drug delivery. Accurately characterizing these polymers is critical to control the product quality, to monitor the stability, and ultimately to ensure the drug efficacy and patient safety. However, due to the heterogeneity in size, the multiplicity of functional groups, and the highly convoluted charge-distribution profile in mass spectra, the characterization of these polymers is highly challenging from both chromatography and mass spectrometry perspectives. To overcome these challenges, we developed a strategy utilizing charge-reduction mass spectrometry (CRMS) coupled with two-dimensional HPLC (2D-LC). We then applied the workflow to characterize a 40 kDa 8-arm polyethylene glycol (PEG) functionalized with a maleimide terminal group for protein conjugation. The development was carried out in stages, where first we focused on the development of a CRMS method to simplify the charge profile of the polymers and then coupled it to HPLC to obtain discernible mass spectra of key impurities and degradants. Second, the CRMS method was applied to an investigation of the size-variant impurity resolved by reversed-phase size-exclusion 2D-LC. Finally, a separate size-exclusion reversed-phase 2D-LC-CRMS method was developed to capture a wider range of process-related impurities and reaction intermediates from the PEG–maleimide polymers throughout the conjugation process. The combination of these experiments using the 2D-LC-CRMS strategy enables the sensitive characterization of the entire impurity profile of the high molecular weight multifunctionalized PEG–maleimide conjugation intermediate.

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Development of simple isocratic HPLC methods for siRNA quantitation in lipid-based nanoparticles

Huang

Fish

2019

Journal of Pharmaceutical and Biomedical Analysis

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Determination of polymeric impurities in asunaprevir drug substance and product using size exclusion effect of reversed-phase columns

Cited by 5 publications

References 12 publications

Separation of nadolol racemates by high pH reversed-phase preparative chromatography

Separation of nadolol racemates by high pH reversed-phase preparative chromatography

Characterization of High Molecular Weight Multi-Arm Functionalized PEG–Maleimide for Protein Conjugation by Charge-Reduction Mass Spectrometry Coupled to Two-Dimensional Liquid Chromatography

Development of simple isocratic HPLC methods for siRNA quantitation in lipid-based nanoparticles

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