The “New Polyethylene Glycol Dilemma”: Polyethylene Glycol Impurities and Their Paradox Role in mAb Crystallization

Hildebrandt, Christian; Joos, Lea; Saedler, Rainer; Winter, Gerhard

doi:10.1002/jps.24424

Cited by 19 publications

(11 citation statements)

References 30 publications

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“…PEG-coated toroids show a much stronger reaction to DIMP than ammonia or formaldehyde (Figure 4), despite ammonia being readily dissolvable in liquid PEG at sub-atmospheric pressures, 43 and formaldehyde being a significant and persistent impurity in PEG owing to the decomposition of hydroxymethyl end groups in the polymer. 44 In our experiments, we believe that the strongly polar phosphorous oxide bond in DIMP is responsible for its strong interactions with PEG as compared to those of ammonia or formaldehyde at the low concentrations employed in our gas sensing experiments. The presence of methoxy end groups, as opposed to hydroxyl end groups, in our PEG coatings suggests that the polymer is not being chemically modified by DIMP during our measurements.…”

Section: ■ Results and Discussionmentioning

confidence: 74%

Part-per-Trillion Trace Selective Gas Detection Using Frequency Locked Whispering-Gallery Mode Microtoroids

Lohrey

Nguyen

et al. 2022

ACS Appl. Mater. Interfaces

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Rapid detection of toxic and hazardous gases at trace concentrations plays a vital role in industrial, battlefield, and laboratory scenarios. Of interest are both sensitive as well as highly selective sensors. Whispering gallery mode (WGM) microresonator-based biochemical sensors are among the most sensitive sensors in existence due to their long photon confinement times. One main concern with these devices, however, is their selectivity towards specific classes of target analytes. Here, we employ frequency locked whispering gallery mode microtoroid optical resonators covalently modified with various polymer coatings to selectively detect the chemical warfare agent surrogate diisopropyl methylphosphonate (DIMP) as well as the toxic industrial chemicals formaldehyde and ammonia at parts-per-trillion concentrations. This is 1-2 orders of magnitude better than previously reported, depending on the target, except for pristine graphene and pristine carbon nanotube sensors, which demonstrate similar detection levels but in vacuum and without selectivity. Selective polymer coatings include polyethylene glycol (PEG) for DIMP sensing, accessed by the modification of commercially available materials, and 3-(triethoxysilyl)propyl-terminated polyvinyl acetate (PVAc) for ammonia sensing. Notably, we developed an efficient one-pot procedure to access 3-(triethoxysilyl)propyl-terminated PVAc that utilizes cobaltmediated living radical polymerization and a nitroxyl polymer-terminating agent. Alkaline hydrolysis of PVAc coatings to form polyvinyl alcohol (PVA) coatings directly bound to the microtoroid proved to be reliable and reproducible, leading to WGM sensors capable of the rapid and selective detection of formaldehyde vapors. The selectivity of these three polymer coatings as sensing media was predicted, in part, based on their functional group content and known reactivity patterns with the target analytes. Furthermore, we demonstrate that microtoroids coated with a mixture of polymers can serve as an all-in-one sensor that can detect multiple agents. We anticipate that our results will facilitate rapid early detection of chemical agents, as well as their surrogates and precursors.

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Section: ■ Results and Discussionmentioning

confidence: 74%

Part-per-Trillion Trace Selective Gas Detection Using Frequency Locked Whispering-Gallery Mode Microtoroids

Lohrey

Nguyen

et al. 2022

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

show abstract

“…PEG coated toroids show a much stronger reaction to DIMP than ammonia or formaldehyde (Figure 4), despite ammonia being readily dissolvable in liquid PEG at sub-atmospheric pressures, 32 and formaldehyde being a significant and persistent impurity in PEG owing to the decomposition of hydroxymethyl end groups in the polymer. 33 In our experiments, we believe the strongly polar phosphorous oxide bond in DIMP is responsible for its strong interactions with PEG as compared to those of ammonia or formaldehyde at the low concentrations employed in our gas sensing experiments. The presence of methoxy end groups, as opposed to hydroxyl end groups, in our PEG coatings suggests that the polymer is not being chemically modified by DIMP during our measurements.…”

Section: Sensitivity and Selectivity Tests Of Polymer-coated Microtor...mentioning

confidence: 70%

Part-per-trillion trace selective gas detection using frequency locked whispering gallery mode microtoroids

Lohrey

Nguyen

et al. 2022

Preprint

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Rapid detection of toxic and hazardous gases at trace concentrations plays a vital role in industrial, battlefield, and laboratory scenarios. Of interest are both sensitive as well as highly selective sensors. Whispering gallery mode (WGM) microresonator-based biochemical sensors are among the most sensitive sensors in existence due to their long photon confinement times. One main concern with these devices, however, is their selectivity towards specific classes of target analytes. Here, we employ frequency locked whispering gallery mode microtoroid optical resonators covalently modified with various polymer coatings to selectively detect the chemical warfare agent surrogate diisopropyl methylphosphonate (DIMP) as well as the toxic industrial chemicals formaldehyde and ammonia at parts-per-trillion concentrations. This is 1-2 orders of magnitude better than previously reported, depending on the target, except for pristine graphene and pristine carbon nanotube sensors, which demonstrate similar detection levels but in vacuum and without selectivity. Selective polymer coatings include polyethylene glycol (PEG) for DIMP sensing, accessed by the modification of commercially available materials, and 3-(triethoxysilyl)propyl-terminated polyvinyl acetate (PVAc) for ammonia sensing. Notably, we developed an efficient one-pot procedure to access 3-(triethoxysilyl)propyl-terminated PVAc that utilizes cobalt-mediated living radical polymerization and a nitroxyl polymer-terminating agent. Alkaline hydrolysis of PVAc coatings to form polyvinyl alcohol (PVA) coatings directly bound to the microtoroid proved to be reliable and reproducible, leading to WGM sensors capable of the rapid and selective detection of formaldehyde vapors. The selectivity of these three polymer coatings as sensing media was predicted, in part, based on their functional group content and known reactivity patterns with the target analytes. Furthermore, we demonstrate that microtoroids coated with a mixture of polymers can serve as an all-in-one sensor that can detect multiple agents. We anticipate that our results will facilitate rapid early detection of chemical agents, as well as their surrogates and precursors.

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“…Since all analytical data for the originally employed inhibitors was consistent with the given structures, we postulate that the incorporation of an additional methylene group occurred via spontaneous Pictet-Spengler cyclization [74,75,76] during crystallization. In line with this notion, PEG, which has been used in our soaking solutions, is known to generate formaldehyde traces that have been shown in the past to affect the derivatization of both, proteins and ligands [77,78,79]. To further corroborate this hypothesis, we examined whether simple exposure of 29d / e to formaldehyde would give rise to the same Pictet-Spengler products 31a / b (Scheme 5).…”

Section: Resultsmentioning

confidence: 87%

Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds

et al. 2019

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In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral “ribose-like” pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.

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The “New Polyethylene Glycol Dilemma”: Polyethylene Glycol Impurities and Their Paradox Role in mAb Crystallization

Cited by 19 publications

References 30 publications

Part-per-Trillion Trace Selective Gas Detection Using Frequency Locked Whispering-Gallery Mode Microtoroids

Part-per-Trillion Trace Selective Gas Detection Using Frequency Locked Whispering-Gallery Mode Microtoroids

Part-per-trillion trace selective gas detection using frequency locked whispering gallery mode microtoroids

Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds

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