Generic gas chromatography-flame ionization detection method for quantitation of volatile amines in pharmaceutical drugs and synthetic intermediates

Graffius, Gabriel C.; Jocher, Brandon M.; Zewge, Daniel; Halsey, Holst M.; Lee, Gary; Bernardoni, Frank; Bu, Xiaodong; Hartman, Robert; Regalado, Erik L.

doi:10.1016/j.chroma.2017.08.048

Cited by 22 publications

(20 citation statements)

References 45 publications

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“…After intense literature search, we decided to focus on a newly developed volatile amine column. 13,33,34 The stationary phase is highly suitable for polar two times lower values than Zeisel et al 38 As described earlier, it is likely that DMA is present as a contaminant in EDTA plasma tubes. 26 To exclude production process related contamination with SCVA, Li-heparin tubes were filled with 10 mL PBS as negative control.…”

Section: Discussionmentioning

confidence: 99%

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Derivatization‐free determination of short‐chain volatile amines in human plasma and urine by headspace gas chromatography‐mass spectrometry

Neyer

Bernasconi

Fuchs

et al. 2019

Clinical Laboratory Analysis

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Background Short‐chain volatile amines (SCVA) are an interesting compound class playing crucial roles in physiological and toxicological human settings. Dimethylamine (DMA), trimethylamine (TMA), diethylamine (DEA), and triethylamine (TEA) were investigated in detail. Methods Headspace gas chromatography coupled to mass spectrometry (HS‐GC‐MS) was used for the simultaneous qualitative and quantitative determination of four SCVA in different human body fluids. Four hundred microliters of Li‐heparin plasma and urine were analyzed after liberation of volatile amines under heated conditions in an aqueous alkaline and saline environment. Target analytes were separated on a volatile amine column and detected on a Thermo DSQ II mass spectrometer scheduled in single ion monitoring mode. Results Chromatographic separation of selected SCVA was done within 7.5 minutes. The method was developed and validated with respect to accuracy, precision, recovery and stability. Accuracy and precision criteria were below 12% for all target analytes at low and high levels. The selected extraction procedure provided recoveries of more than 92% from both matrices for TMA, DEA and TEA. The recovery of DMA from Li‐heparin plasma was lower but still in the acceptable range (>75%). The newly validated method was successfully applied to plasma and urine samples from healthy volunteers. Detected concentrations of endogenous metabolites DMA and TMA are comparable to already known reference ranges. Conclusion Herein, we describe the successful development and validation of a reliable and broadly applicable HS‐GC‐MS procedure for the simultaneous and quantitative determination of SCVA in human plasma and urine without relying on derivatization chemistry.

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Section: Discussionmentioning

confidence: 99%

“…For short‐chain fatty acids and for SCVA, polyethylene glycol based columns were broadly used for separation. After intense literature search, we decided to focus on a newly developed volatile amine column . The stationary phase is highly suitable for polar and basic target analytes.…”

Section: Discussionmentioning

confidence: 99%

Derivatization‐free determination of short‐chain volatile amines in human plasma and urine by headspace gas chromatography‐mass spectrometry

Neyer

Bernasconi

Fuchs

et al. 2019

Clinical Laboratory Analysis

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“…1 ) used in the synthetic route of an API. Although multiple generic GC-FID methods [ [19] , [20] , [21] ] have been reported for the analysis of amines and solvents in pharmaceutical samples, superbases such as TMG were typically not included as an analyte of interest. Based on our observation, TMG tends to be more severely adsorbed on the column surface than TEA and DIPA due to its stronger basicity, which introduces more obvious peak tailing and sensitivity issues.…”

Section: Introductionmentioning

confidence: 99%

Development of a rapid GC-FID method to simultaneously determine triethylamine, diisopropylamine, and 1,1,3,3-tetramethylguanidine residues in an active pharmaceutical ingredient

Shou

Qiu

2021

Journal of Pharmaceutical Analysis

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A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine (TEA), 1,1,3,3-tetramethylguanidine (TMG), and diisopropylamine (DIPA) in the synthetic route of an active pharmaceutical ingredient (API). Due to the severe absorption of amines on GC stationary phases, GC columns with various stationary phases were evaluated for optimal peak shape and reproducibility. The final conditions used the Agilent CP-Volamine column to resolve the three amines in 12 min. Various inlet liners were also screened to further improve the sensitivity of the analysis. The Restek Siltek® liner was selected to achieve the desired detectability for the method. The quantitation limits were 4, 3, and 4 μg/mL for TEA, DIPA, and TMG in the presence of API, respectively. All three amines showed good linearity ( r > 0.999) and recoveries (> 90%) over the concentration range of 3 to 16 μg/mL. The testing of residual amines was initially performed at the penultimate stage of the synthesis. However, this work demonstrates that TMG can act as a proton sponge to react with salicylic acid, the counter ion of the penultimate, to form a volatile component that elutes at a different retention time. Consequently, in the final method, these three amines were monitored in the final API to circumvent the matrix interference. Key parameters of the method were qualified per method validation requirements in ICH guidelines. The method was successfully applied for batch testing during development and implemented as an in-process control procedure at manufacturing sites.

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“…Amine is one of the most important functional groups in the chemical industry, highly present in various industrial fields, such as pharmaceuticals [1,2,3], agrochemicals [4,5], detergents [6,7], lubricants [8] and polymer industry [9,10]. Amines act as intermediates in the synthesis of different polymers including phenolic resins [11,12], polyimides [13], polyureas, polyurethane [14] and poly(hydroxy)urethanes [15], polyamide [16,17] and epoxy thermosets [18,19].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Pluri-Functional Amine Hardeners from Bio-Based Aromatic Aldehydes for Epoxy Amine Thermosets

Mora

Tayouo²,

Boutevin

et al. 2019

Molecules

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Most of the current amine hardeners are petro-sourced and only a few studies have focused on the research of bio-based substitutes. Hence, in an eco-friendly context, our team proposed the design of bio-based amine monomers with aromatic structures. This work described the use of the reductive amination with imine intermediate in order to obtain bio-based pluri-functional amines exhibiting low viscosity. The effect of the nature of initial aldehyde reactant on the hardener properties was studied, as well as the reaction conditions. Then, these pluri-functional amines were added to petro-sourced (diglycidyl ether of bisphenol A, DGEBA) or bio-based (diglycidyl ether of vanillin alcohol, DGEVA) epoxy monomers to form thermosets by step growth polymerization. Due to their low viscosity, the epoxy-amine mixtures were easily homogenized and cured more rapidly compared to the use of more viscous hardeners (<0.6 Pa s at 22 °C). After curing, the thermo-mechanical properties of the epoxy thermosets were determined and compared. The isophthalatetetramine (IPTA) hardener, with a higher number of amine active H, led to thermosets with higher thermo-mechanical properties (glass transition temperatures (Tg and Tα) were around 95 °C for DGEBA-based thermosets against 60 °C for DGEVA-based thermosets) than materials from benzylamine (BDA) or furfurylamine (FDA) that contained less active hydrogens (Tg and Tα around 77 °C for DGEBA-based thermosets and Tg and Tα around 45 °C for DGEVA-based thermosets). By comparing to industrial hardener references, IPTA possesses six active hydrogens which obtain high cross-linked systems, similar to industrial references, and longer molecular length due to the presence of two alkyl chains, leading respectively to high mechanical strength with lower Tg.

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Generic gas chromatography-flame ionization detection method for quantitation of volatile amines in pharmaceutical drugs and synthetic intermediates

Cited by 22 publications

References 45 publications

Derivatization‐free determination of short‐chain volatile amines in human plasma and urine by headspace gas chromatography‐mass spectrometry

Derivatization‐free determination of short‐chain volatile amines in human plasma and urine by headspace gas chromatography‐mass spectrometry

Development of a rapid GC-FID method to simultaneously determine triethylamine, diisopropylamine, and 1,1,3,3-tetramethylguanidine residues in an active pharmaceutical ingredient

Synthesis of Pluri-Functional Amine Hardeners from Bio-Based Aromatic Aldehydes for Epoxy Amine Thermosets

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