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Fast Screening of Diol Impurities in Methoxy Poly(Ethylene Glycol)S (Mpeg)S by Liquid Chromatography on Monolithic Silica Rods

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Fast Screening of Diol Impurities in Methoxy Poly(Ethylene Glycol)S (Mpeg)S by Liquid Chromatography on Monolithic Silica Rods polymers Communication Fast Screening of Diol Impurities in Methoxy Poly(Ethylene Glycol)s (mPEG)s by Liquid Chromatography on Monolithic Silica Rods Michaela Brunzel 1,2, Tobias C. Majdanski 1,2, Jürgen Vitz 1,2,3, Ivo Nischang 1,2,* and Ulrich S. Schubert 1,2,* 1 Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany; [email protected] (M.B.); [email protected] (T.C.M.); [email protected] (J.V.) 2 Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany 3 Center for Sepsis Control and Care (CSCC), Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany * Correspondence: [email protected] (I.N.); [email protected] (U.S.S.); Tel.: +43-3641-9-48569 (I.N.); +43-3641-9-48200 (U.S.S.) Received: 30 November 2018; Accepted: 11 December 2018; Published: 16 December 2018 Abstract: The determination of diol impurities in methoxy poly(ethylene glycol)s (mPEG)s is of high importance, e.g., in the area of pharmaceutical applications, since mPEGs are considered the gold standard—based on properties of biocompatibility, stealth effect against the immune system, and well-established procedures used in PEGylation reactions. Herein, we communicate a straightforward and fast approach for the resolution of the PEGdiol impurities in mPEG products by liquid chromatography on reversed-phase monolithic silica-rods. Thus, we utilize fine, in-house prepared and narrow dispersity mPEGs (Ð ≤ 1.1) and commercial PEGdiol standards as a reference. Most efficient analysis of diol impurities becomes possible with reversed-phase liquid chromatography that results in selective elution of the PEGdiol from mPEG macromolecule populations in partition/adsorption mode. We do this by a minimum selectivity of the population of macromolecules characterizing the narrow molar mass distributions of mPEG. Control experiments with intentionally added water at the start of the well-controlled mPEG synthesis via the living anionic ring opening polymerization of ethylene oxide clearly reconciled the existence of PEGdiol impurity in chromatographed samples. The here-demonstrated methodology allows for the resolution of diol impurities of less than one percent in elution times of only a few minutes, confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) of the collected elution fractions. The unique combination of the open flow-through pore structure of the monolithic silica rods and resultant varying accessibility of C18-derivatized pore surfaces indicates beneficial properties for robust and end-group-specific adsorption/partition liquid chromatography of synthetic macromolecules. Keywords: anionic ring-opening polymerization; MALDI-TOF-MS; monolith; PEGdiol; pharmaceutical PEG; reversed-phase chromatography 1. Introduction One of the most important pharmaceutically relevant polymers and as well the gold standard in medicine for a stealth effect by the PEGylation reaction is the well-established mPEG, which is also approved by the Food and Drug Administration (FDA) for a range of applications [1–4]. However, a well-known problem of outmost significance is the existence of PEGdiol impurities, which lead to Polymers 2018, 10, 1395; doi:10.3390/polym10121395 www.mdpi.com/journal/polymers Polymers 2018, 10, 1395 2 of 8 Polymers 2018, 10, x FOR PEER REVIEW 2 of 8 well-knowncross-linking problem of proteins of oroutmost other pharmaceuticalsignificance is the components existence ofof interest,PEGdiol thus impurities, resulting which in ill-defined lead to cross-linkingspecies in PEGylation of proteins reactions or other [3 pharmaceutical]. components of interest, thus resulting in ill-defined speciesThe in PEGdiolPEGylation has reactions very similar [3]. physicochemical properties compared to the mPEG (Figure1) and,The hence, PEGdiol it is difficult has very to similar distinguish physicochemical between the prop two.erties Approaches compared to from the themPEG literature (Figure used 1) and, to hence,address it thisis difficult problem to distinguish include, e.g., between nuclear the magnetic two. Approaches resonance from (NMR) the literature spectroscopy used [ 5to–7 address], mass thisspectrometry problem include, (MS) [8], e.g., and nuclear last but magnetic not least theresonance potential (NMR) application spectroscopy of liquid [5–7], chromatography mass spectrometry [9–12], (MS)often [8], hyphenated and last withbut not suitable least the detection potential technology, application e.g., of evaporative liquid chromatography light scattering [9–12], detection often (ELSD),hyphenated MS, with etc. Commonsuitable detection analytical technology, approaches e.g., in polymerevaporative science light suchscattering as matrix-assisted detection (ELSD), laser MS,desorption etc. Common ionization analytical mass spectrometry approaches (MALDI-MS)in polymer science and NMR such alone as matrix-assisted have some inherent laser desorption drawbacks. ionizationMALDI-MS mass of spectrometry mixtures of different(MALDI-MS) species and providesNMR alone difficulties have some due inherent to the drawbacks. well-known MALDI- mass MSdiscrimination of mixtures asof different well as thespecies different provides ionization difficulties efficiencies due to the for well-known mPEG vs. mass PEG. discrimination NMR is also asnot well a very as the sensitive different and ionization precise efficiencies method for for such mP aEG purpose vs. PEG. since NMR the is also integrated not a very backbone sensitive signal and precisecompared method to the for end-group such a purpose largely since increases. the integr Theseated aspects backbone make signal liquid compared chromatography to the end-group a highly largelyinteresting increases. field of These research, aspects particularly make liquid in combination chromatography with orthogonala highly interesting detection field technology of research, used particularlyfor identification in combination purposes. with orthogonal detection technology used for identification purposes. Figure 1.1. SchematicSchematic representation representation of anof αan-methoxy α-methoxy poly(ethylene poly(ethylene glycol) gl (mPEG)ycol) (mPEG) with an with!-hydroxyl an ω- hydroxylgroup and group the corresponding and the corresponding PEGdiol. PEGdiol. According toto thethe literature,literature, thethe chromatography chromatography of of synthetic synthetic macromolecules macromolecules may may be be classified classified in inthree three modes: modes: size exclusionsize exclusion chromatography chromatography (SEC), liquid(SEC), chromatography liquid chromatography under critical under conditions critical (LCCC),conditions and (LCCC), liquid and adsorption liquid adsorption chromatography chromatography (LAC) [13 (LAC)]. LCCC [13]. LCCC as an as elution an elution mode mode may mayoffer offer macromolecule macromolecule chain chain length length independent independent elution, elution, i.e., i.e., being being determined determined byby thethe backbone respectively, end end group group only only [14–17]. [14–17 Fundamen]. Fundamentally,tally, however, however, the influence the influence of the ofmethoxy the methoxy α-end inα-end mPEG, in mPEG, as opposed as opposed to that to thatof the of thehydroxyl, hydroxyl, implies implies very very limited limited differences differences in in the the overall hydrophobic/hydrophilic properties properties of of PEG PEG macr macromoleculesomolecules (Figure (Figure 11),), makingmaking straightforwardstraightforward resolution proceduresprocedures based based on on liquid liquid chromatography chromatography a challenging a challenging and so farand unreported so far unreported endeavor. endeavor.To the best of our knowledge, there has been no overarching approach, allowing for a straightforwardTo the best resolutionof our knowledge, of PEGdiol there impurities has been in mPEG no overarching over an extended approach, molar allowing mass range.for a straightforwardIf such possibility resolution is indicated, of PEGdiol then only impurities for a very in mPEG limited over molar an massextended range molar far below mass range. 1000 g If mol such−1 possibilityof model compounds is indicated, [ 18then,19 only] or afor single a very molar limited mass molar example mass range [5,7,11 far]. Thebelow patent 1000 literatureg mol−1 of onmodel this compoundsissue suggests [18,19] that chromatographicor a single molar resolutionmass example may become[5,7,11]. possibleThe patent by theliterature modification on this ofissue the suggestshydroxyl-terminal that chromatographic chain end(s) resolution with groups may of pronounced,become possible e.g., by hydrophobic the modification character of the which hydroxyl- results terminalin functionalized chain end(s)!-ends with or grou functionalps of pronounced,α- and !-chain e.g., ends hydropho that maybic character show interaction which results with thein particularlyfunctionalized chosen ω-ends chromatographic or functional α sorbents- and ω [-chain20]. The ends efficiency that may of suchshow labelling interaction reactions with isthe a particularlyfurther issue chosen of consideration. chromatographic sorbents [20]. The efficiency of such labelling reactions is a furtherTo issue address of consideration. the quest for analyzing a very tiny difference in the end-group character of pharmaceuticalTo address mPEG the quest as opposed for analyzing to that of a thevery PEGdiol tiny
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