Diffusion-ordered NMR Spectroscopy Research Articles

Near‐Infinite‐Chain Polymers with Ge=Ge Double Bonds

Despite considerable interest in heteroatom‐containing conjugated polymers, there are only few examples with heavier p‐block elements in the conjugation path. The recently reported heavier acyclic diene metathesis (HADMET) allowed for the synthesis of a polymer containing Ge=Ge double bonds – albeit insoluble and with limited degree of polymerization. By incorporation of long alkyl chains, we now obtained soluble representatives, which exhibit degrees of polymerization near infinity according to diffusion‐ordered NMR spectroscopy (DOSY) and dynamic light scattering (DLS). Analyses of the UV/Vis absorption and the NMR spectroscopic data confirm the presence of σ,π‐conjugation across the silylene‐phenylene linkers between the Ge=Ge double bonds. Favorable intermolecular dispersion interactions lead to ladder‐like cylindrical supramolecular assemblies as confirmed by X‐ray diffraction (XRD), small angle X‐ray scattering (SAXS) and DLS. AFM and TEM images of deposited thin films reveal lamellar ordering of extended polymer bundles.

Near-Infinite-Chain Polymers with Ge=Ge Double Bonds.

Despite considerable interest in heteroatom-containing conjugated polymers, there are only few examples with heavier p-block elements in the conjugation path. The recently reported heavier acyclic diene metathesis (HADMET) allowed for the synthesis of a polymer containing Ge=Ge double bonds - albeit insoluble and with limited degree of polymerization. By incorporation of long alkyl chains, we now obtained soluble representatives, which exhibit degrees of polymerization near infinity according to diffusion-ordered NMR spectroscopy (DOSY) and dynamic light scattering (DLS). Analyses of the UV/Vis absorption and the NMR spectroscopic data confirm the presence of σ,π-conjugation across the silylene-phenylene linkers between the Ge=Ge double bonds. Favorable intermolecular dispersion interactions lead to ladder-like cylindrical supramolecular assemblies as confirmed by X-ray diffraction (XRD), small angle X-ray scattering (SAXS) and DLS. AFM and TEM images of deposited thin films reveal lamellar ordering of extended polymer bundles.

Speedy Component Resolution Using Spatially Encoded Diffusion NMR Data.

Diffusion-ordered NMR spectroscopy (DOSY) is a powerful tool to analyse mixtures. Spatially encoded (SPEN) DOSY enables recording a full DOSY dataset in just one scan by performing spatial parallelisation of the gradient dimension. The simplest and most widely used approach to processing DOSY data is to fit each peak in the spectrum with a single or multiple exponential decay. However, when there is peak overlap, and/or when the diffusion decays of the contributing components are too similar, this method has limitations. Multivariate analysis of DOSY data, which is an attractive alternative, consists of decomposing the experimental data, into compound-specific diffusion decays and 1D NMR spectra. Multivariate analysis has been very successfully used for conventional DOSY data, but its use for SPEN DOSY data has only recently been reported. Here, we present a comparison, for SPEN DOSY data, of two widely used algorithms, SCORE and OUTSCORE, that aim at unmixing the spectra of overlapped species through a least square fit or a cross-talk minimisation, respectively. Data processing was performed with the General NMR Analysis Toolbox (GNAT), with custom-written code elements that now expands the capabilities, and makes it possible to import and process SPEN DOSY data. This comparison is demonstrated on three different two-component mixtures, each with different characteristics in terms of signal overlap, diffusion coefficient similarity, and component concentration.

What Is the Molecular Weight of "High" Molecular Weight Dissolved Organic Matter?

The use of ultrafiltration to isolate high molecular weight dissolved organic matter (HMWDOM) from seawater is a fundamental tool in the environmental organic chemist's toolbox. Yet, important characteristics of HMWDOM relevant to its origin and cycling, such as its molecular weight distribution, remain poorly defined. We used diffusion-ordered NMR spectroscopy coupled with mixed-mode chromatography to separate and characterize two major components of marine HMWDOM: acylpolysaccharides (APS) and high molecular weight humic substances (HS). The molecular weights (MWs) of APS and HS both fell within distinct, narrow envelopes; 2.0-16 kDa for APS and 0.9-6.5 kDa for HS. In water samples from the North Pacific Ocean the average MW of both components decreased with depth through the mesopelagic. However, the minimum MW of APS was >2 kDa, well above the molecular weight cutoff of the ultrafilter, suggesting APS removal processes below 2 kDa are highly efficient. The MW distribution of APS shows only small variations with depth, while the MW distribution of HS narrowed due to removal of HMW components. Despite the narrowing of the MW distribution, the concentration of HS did not decrease with depth between 15 and 915 m. This suggests that HMW HS produced in surface waters was either degraded into lower MW compounds without significant remineralization, or that HMW HS was remineralized but replaced by an additional source of HS in the mesopelagic ocean. Based on these results, we propose potential pathways for the production and removal of these major components of HMWDOM.

Study of the preparation, characterization, and solubility of lidocaine complexed with 5-sulfosalicylic acid dihydrate

Objective: This study was to prepare solid dispersions of lidocaine (Lid) with 5-sulfosalicylic acid dihydrate (SSA) by freeze-drying (freeze-dried [FD] Lid/SSA = 1/1) and to evaluate their physical properties. Methods: Here, we evaluated the physicochemical properties and solubility of solid dispersions of Lid and SSA prepared by freeze-drying (freeze-dried [FD] Lid/SSA = 1/1). Results: Differential scanning calorimetry measurements showed that after freeze-drying, the endothermic peak due to Lid melting, the dehydration peak, and the endothermic peak due to SSA melting disappeared. Powder X-ray diffraction results showed that the characteristic Lid and SSA peaks disappeared after freeze-drying, indicating a halo pattern. The near-infrared spectroscopy results suggested that Lid-derived –NH and –CH groups and the Lid-derived –OH and –CH groups from the SSA peak shifted and broadened after freeze-drying, suggesting their involvement in complex formation through Lid/SSA intermolecular interactions. Nuclear Overhauser effect spectroscopy-nuclear magnetic resonance (NMR) measurements showed a cross-peak due to the interaction between the Lid-derived –CH group and the SSA-derived –OH group, suggesting hydrogen bonding. Diffusion-ordered spectroscopy NMR measurements showed that the diffusion coefficients of Lid and SSA aggregated in FD Lid/SSA, suggesting a change in Lid dispersibility in the solvent owing to the formation of a complex with SSA. The solubility of FD Lid/SSA was approximately 88 mg/mL (∼20-fold higher than that of Lid). Conclusions: These findings suggest that complex formation occurred in FD Lid/SSA; this enhanced the solubility of this dispersion.

Water Confinement on Polymer Coatings Dictates Proton-Electron Transfer on Metal-Catalyzed Hydrogenation of Nitrite.

Enzymes can precisely control the speed and selectivity of chemical reactions by modifying locally the solvent-reactant interactions. To extrapolate these attributes to heterogeneous catalysts, we have employed thermoresponsive poly n-isopropylacrylamide (p-NIPAM) brushes bonded to silica spheres containing palladium. These polymers can form hydrogen bonds with water molecules at low temperatures (<32 °C) allowing the polymer to stay swollen. Detailed reaction kinetics of nitrite hydrogenation showed that p-NIPAM decreases the apparent activation barrier by a factor of 3 at low temperatures. Diffusion-ordered spectroscopy nuclear magnetic resonance and ab initio molecular dynamics simulations showed that when p-NIPAM is present, water molecules near the surface are less mobile. This confinement perturbs the water interaction with the metal, reducing the barrier for the proton-electron transfer reduction of nitrite. Notably, this enhancement vanishes at high temperature as the polymer collapses on itself exposing the Pd to unconfined water. The fully reversible nature of this process opens the door for creating homeostatic catalysts with controlled water-confinement.

Taylor dispersion analysis for measurement of diffusivity and size of gadolinium-based contrast agents

Gadolinium-based contrast agents (GBCA) are complexes of a Gadolinium metal center and a linear or macrocyclic polyamino-carboxylic acid chelating agent. These agents are employed to enhance the visibility of deep abnormalities through MRI techniques. Knowing the precise dimensions of various GBCA is key parameter for understanding their in-vivo and pharmaco-kinetic behaviors, their diffusivity, as well as their relaxivity. However, conventional size characterization techniques fall short when dealing with these tiny molecules (≤1 nm). In this work, we propose to determine the size and diffusivity of gadolinium-based contrast agents using Taylor dispersion analysis (TDA). TDA provided a reliable measurement of the hydrodynamic diameter and the diffusion coefficient. The obtained results were compared to DOSY NMR (Diffusion-ordered Nuclear Magnetic Resonance Spectroscopy) and DFT (Density Functional Theory).

Predicting Molecular Weight Characteristics of Reductively Depolymerized Lignins by ATR-FTIR and Chemometrics.

Recent scientific advances in the valorization of lignin, through e.g., (partial-)catalytic depolymerization, require equally state-of-the-art approaches for the analysis of the obtained depolymerized lignins (DLs) or lignin bio-oils. The use of chemometrics in combination with infrared (IR) spectroscopy is one avenue to provide rapid access to pertinent lignin parameters, such as molecular weight (MW) characteristics, which typically require analysis via time-consuming size-exclusion methods, or diffusion-ordered NMR spectroscopy. Importantly, MW serves as a marker for the degree of depolymerization (or recondensation) that the lignin has undergone, and thus probing this parameter is essential for the optimization of depolymerization conditions to achieve DLs with desired properties. Here, we show that our ATR-IR-based chemometrics approach used previously for technical lignin analysis can be extended to analyze these more processed, lignin-derived samples as well. Remarkably, also at this lower end of the MW scale, the use of partial least-squares (PLS) regression models well-predicted the MW parameters for a sample set of 57 depolymerized lignins, with relative errors of 9.9-11.2%. Furthermore, principal component analysis (PCA) showed good correspondence with features in the regression vectors for each of the biomass classes (hardwood, herbaceous/grass, and softwood) obtained from PLS-discriminant analysis (PLS-DA). Overall, we show that the IR spectra of DLs are still amenable to chemometric analysis and specifically to rapid, predictive characterization of their MW, circumventing the time-consuming, tedious, and not generally accessible methods typically employed.

Metabolomics analysis using matrix-assisted diffusion-ordered spectroscopy (DOSY) and its application in acrylamide-induced cardiovascular toxicity

Untargeted NMR-based metabolomics strategies are increasingly applied for metabolite screening in a wide variety of medical conditions. However, the identification of metabolites remains a great challenge in NMR metabolomics research. Here, we used matrix-assisted diffusion-ordered spectroscopy (DOSY) to identify new biomarkers in body fluids. DOSY-based metabolomics can exploit the unique strengths of NMR and, thanks to improvements in its resolution, can be successfully used to address a significantly wider range of biological issues. In this study, a metabolite model consisting of ten common metabolites was employed to optimize the matrix-assisted DOSY experimental parameters. Polyvinylpyrrolidone (PVP), a high-molecular-weight polymer, was found to be the most appropriate matrix with which to accomplish the separation of the mixture components. 1H NMR and PVP-assisted DOSY analyses were performed to characterize the metabolic profile of serum samples from acrylamide (ACR)-treated rats and study the mechanism of ACR-induced cardiovascular toxicity. Biomarker identification by 1H NMR and PVP-assisted DOSY yielded similar results. However, multivariate statistical analysis showed that, compared with 1H NMR, PVP-assisted DOSY achieved a better discrimination of the serum samples obtained from rats treated with different doses of ACR. A total of 11 differential metabolites were identified. An enrichment analysis of the metabolic pathways showed that, in rats treated with a high dose of ACR, the glutamate and glutathione metabolic pathways and the energy metabolism pathway of the tricarboxylic acid cycle were mainly affected.

Molecular insights into fragrance release from SDS and SLES micelles

Understanding the interaction between fragrance and surfactant micelles is essential for formulators to develop performing fragrant products. The equilibrium of fragrances in micellar solution of two commonly used surfactants in home and body care industries, namely sodium dodecyl sulphate (SDS) and sodium lauryl ether sulphate (SLES), has been investigated. The difference between SDS and SLES in the release of fragrant compounds is assessed by headspace measurements and explained at a molecular level by the different solubilization sites of the perfume within the micellar systems. Diffusion-Ordered Nuclear Magnetic Resonance Spectroscopy (DOSY NMR) shows that SLES micelles solubilize less fragrance than SDS. Subsequently, a shift from fragrance positioning through the water phase from SDS to SLES system is shown with COSMOmic calculations. This study brings knowledge on fragrance/surfactant interactions and shows the interest of using a computational method to screen and compare fragranced surfactants systems allowing formulators to anticipate the performance of their products.

Using Nuclear Magnetic Resonance to Troubleshoot a Stability Issue in a Real-World Formulation Chassis-Application to Consumer Oral Healthcare.

With direct application to current and future consumer healthcare products, this research sheds light on the importance of packaging and its potential effects on both Active Pharmaceutical Ingredient (API) delivery and stability. Industrially sourced, proprietary experimental formulations (PEFs), specifically oral cleansers, based on salicylic acid and hydrogen peroxide, discolored over time at different rates, depending on packaging type used. This discoloration stemmed from an interplay of two factors, involving both spontaneous formulation degradation and the interaction of both degradants and salicylic acid with the internal surface of the packaging. This manuscript reports on the investigation to uncover the origins of discoloration. To investigate this real-world, industrial pipeline problem, we exploited the high dimensionality and simple sample preparation uniquely afforded by NMR. Using a combination of 1D/2D NMR and diffusion-ordered NMR spectroscopy (DOSY) to leverage molecular mass estimations from, we not only quickly confirmed the identities of these degradants, but also assessed their formation as a function of temperature and pH, providing insight into the mechanisms underlying their formation. We were able to identify catechol as the main source of discoloration over a period of several weeks, being formed at the ppm level. Furthermore, we evaluated the formulation-container interaction, employing NMR, ICP-MS, and ATR-IR. Despite this comprehensive analysis, the root causes of discoloration could only tentatively be assigned to a surface Ti complex of salicylic acid and other hydroxy carboxylic acids. Through the understanding of formulation degradation pathways, we were able to support further toxicology assessment, vital to both consumer safety and the manufacturer. This work underscores the invaluable role of NMR in the analysis of intricate proprietary mixtures with a consumer-centric purpose. Our findings demonstrate that conventional analytical techniques falter in the face of such complexity, requiring extensive preparation and pre-analytical processing, highlighting the novelty and crucial relevance of NMR research to manufacturers and consumers. Such an analysis is of value in the pursuit of materials within the consumer-healthcare space, which meet the requirements for successful recycling or re-use.

Effects of Drug Conjugation on the Biological Activity of Single-Chain Nanoparticles.

The field of single-chain nanoparticles (SCNPs) continues to mature, and an increasing range of reports have emerged that explore the application of these small nanoparticles. A key application for SCNPs is in the field of drug delivery, and recent work suggests that SCNPs can be readily internalized by cells. However, limited attention has been directed to the delivery of small-molecule drugs using SCNPs. Moreover, studies on the physicochemical effects of drug loading on SCNP performance is so far missing, despite the accepted view that such small nanoparticles should be significantly affected by the drug loading content. To address this gap, we prepared a library of SCNPs bearing different amounts of a covalently conjugated therapeutic drug-sulfasalazine (SSZ). We evaluated the impact of the conjugated drug loading on both the synthesis and biological activity of SCNPs on pancreatic cancer cells (AsPC-1). Our results reveal that covalent drug conjugation to the side chains of the SCNP polymer precursor interferes with chain collapse and cross-linking, which demands optimization of reaction conditions to reach high degrees of cross-linking efficiencies. Small-angle neutron scattering and diffusion-ordered spectroscopy nuclear magnetic resonance (DOSY NMR) analyses reveal that SCNPs with a higher drug loading display larger sizes and looser structures, as well as increased hydrophobicity associated with a higher SSZ content. Increased SSZ loading led to reduced cellular uptake when assessed in vitro, whereby SCNP aggregation on the surface of AsPC-1 cells led to reduced toxicity. This work highlights the effects of drug loading on the drug delivery efficiency and biological behavior of SCNPs.

Spatially encoded pure-shift diffusion-ordered NMR spectroscopy yielded by chirp excitation

Spatially-encoded diffusion-ordered NMR spectroscopy (SPEN-DOSY) has emerged as a new time-efficient tool for the analysis of mixtures of small molecules in solution. Time efficiency is achieved using the concept of spatial parallelization of the effective gradient area, instead of the sequential incrementation used in conventional diffusion experiments. The data acquired with such sequences are then usually processed to extract diffusion coefficients, but cases when peak overlap in the 1H spectrum are difficult to address. Such limitation in conventional diffusion experiments is addressed via using the Pure Shift Yielded by CHirp Excitation (PSYCHE)-iDOSY sequence. Here we have adapted the PSYCHE-iDOSY sequence by using echo planar spectroscopic imaging (EPSI) to acquire SPEN-DOSY data. The pure shift mode of PSYCHE separates the overlapped components and a modified Stejskal-Tanner equation is used to extract the corresponding diffusion coefficient. The primary results obtained with the above-mentioned mixtures seem to open the possibility of separating complex mixtures in less time than PSYCHE-iDOSY.

Synthesis, characterisation and antimicrobial activity of supramolecular cobalt-peptide conjugates.

Herein, we describe the synthesis and characterisation of four new supramolecular cobalt conjugates of antimicrobial peptides functionalised with terpyridine ligands (L). Peptides were chosen based on the well-established arginine-tryptophan (RW)3 motif, with terpyridine-derivatized lysine (Lys(tpy)) added to the sequence, or replacing tryptophan residues. Self-assembly of the antimicrobial peptides with Co(BF4)2·6H2O formed exclusively CoL2 dimers (for peptides with one tpy ligand each) and Co2L4 metallo-macrocycles (for peptides with two tpy ligands for each peptide), which could be 'locked' by oxidation of Co(+II) to Co(+III) with ammonium ceric nitrate. The Co-peptide complexes were characterised by mass spectrometry and in solution by NMR spectroscopy, including 2D diffusion ordered NMR spectroscopy (DOSY) which confirmed the proposed stoichiometries. The antimicrobial activity of the novel peptides and their metallo-supramolecular assemblies was investigated by determination of their minimal inhibitory concentration (MIC) against a panel of Gram-positive and Gram-negative bacteria. Complexation with cobalt increases the activity of the peptides in almost every case. Most of the new metal-peptide conjugates showed good activity against Gram-positive bacteria, including a multi-resistant S. aureus strain and the opportunistic pathogenic yeast C. albicans (down to 7 μmol l-1 for the most active Co2L4 derivate), a value that is increased five-fold compared to the lysine-derivatized peptide ligand alone. Interestingly, conjugates of the CoL2 type also showed decent activity against Gram-negative bacteria including the WHO-flagged problematic A. baumannii strain (down to 18 μmol l-1 for the most active derivative).

Supramolecular polymerization behavior of a ditopic self-folding biscavitand

Abstract Reported herein is the supramolecular polymerization of a mixture of a feet-to-feet connected biscavitand and a homoditopic quinuclidinium guest that is regulated by cooperativity in the host–guest association. Diffusion-ordered NMR spectroscopy (DOSY) was used to evaluate the supramolecular polymerization in toluene, CHCl3, and tetrahydrofuran (THF). Upon concentrating the solutions of the biscavitand with the quinuclidinium guest in CHCl3 and THF, the diffusion coefficient (D) values were meaningfully decreased, indicating that the host–guest complexation facilitated supramolecular polymerization. In contrast, the slight change of the D value in toluene suggests that supramolecular polymerization was suppressed, although the binding constant (K) between the cavitand and quinuclidinium guest was reported to be 105 L mol−1 in toluene. The viscosity measurements showed both the critical polymerization concentration (CPC) and entangled concentration (Ce) upon concentrating the CHCl3 solution of the mixture. Neither the CPC nor Ce was seen in the toluene solution of the mixture. Accordingly, the strong negative cooperativity in the 1:2 host–guest complexation of the biscavitand discouraged the supramolecular polymerization in toluene. These findings are valuable in deepening the understanding of host–guest association-driven supramolecular polymerization behaviors regulated by a combination of cooperativity and K value in solution.

Monitoring galactolipid digestion and simultaneous changes in lipid-bile salt micellar organization by real-time NMR spectroscopy

The use of Nuclear Magnetic Resonance spectroscopy for studying lipid digestion in vitro most often consists of quantifying lipolysis products after they have been extracted from the reaction medium using organic solvents. However, the current sensitivity level of NMR spectrometers makes possible to avoid the extraction step and continuously quantify the lipids directly in the reaction medium. We used real-time 1H NMR spectroscopy and guinea pig pancreatic lipase-related protein 2 (GPLRP2) as biocatalyst to monitor in situ the lipolysis of monogalactosyl diacylglycerol (MGDG) in the form of mixed micelles with the bile salt sodium taurodeoxycholate (NaTDC). Residual substrate and lipolysis products (monogalactosyl monoacylglycerol (MGMG); monogalactosylglycerol (MGG) and octanoic acid (OA) were simultaneously quantified throughout the reaction thanks to specific proton resonances. Lipolysis was complete with the release of all MGDG fatty acids. These results were confirmed by thin layer chromatography (TLC) and densitometry after lipid extraction at different reaction times. Using diffusion-ordered NMR spectroscopy (DOSY), we could also estimate the diffusion coefficients of all the reaction compounds and deduce the hydrodynamic radius of the lipid aggregates in which they were present. It was shown that MGDG-NaTDC mixed micelles with an initial hydrodynamic radius rH of 7.3 ± 0.5 nm were changed into smaller micelles of NaTDC-MGDG-MGMG of 2.3 ± 0.5 nm in the course of the lipolysis reaction, and finally into NaTDC-OA mixed micelles (rH of 2.9 ± 0.5 nm) and water soluble MGG. These results provide a better understanding of the digestion of galactolipids by PLRP2, a process that leads to the complete micellar solubilisation of their fatty acids and renders their intestinal absorption possible.

Review on NMR as a tool to analyse natural products extract directly: Molecular structure elucidation and biological activity analysis.

Natural products, the small organic molecules produced by plants, microbes and invertebrates, often present in the form of a mixture, this leads to the structural characterisation of natural extracts often requiring time-consuming multistep purification procedures. Nuclear magnetic resonance (NMR) technology is traditionally utilised as a tool for the structural elucidation of pure compounds. Contemporarily, an up-to-date trend in the application of NMR in natural product research is shifting to the direct NMR analysis of crude mixtures, to obtain molecular structure and biological activity information without performing cumbersome separation. To review works of literature on the evolution, principle and progress of NMR technologies for analysing mixtures, we focus on the successful application of NMR technologies in direct analysis of natural product extracts. Based on our research experience, academic tracking and extensive literature search, which involved, but not limited to, the use of various databases, like Web of Knowledge and PubMed. The keywords used, in various combinations, to retrieve recent literature on the successful application of NMR technologies to sheer natural product extracts, and excluded artificially natural product mixture and biofluid. NMR technologies for direct natural extracts analysis, including two-dimensional J-resolved spectroscopy (2D-JRES), pure shift NMR, diffusion-ordered NMR spectroscopy (DOSY), statistical correlation spectroscopy (STOCSY), concentration-ordered NMR spectroscopy (CORDY), saturation transfer difference (STD) and water-ligand observed via gradient spectroscopy (WaterLOGSY) were illustrated. By these methods, molecular structure and biological activity information will be directly obtained from NMR analysis of natural products extract, aiming to save experimental time and expenses.

Recycled PLA for 3D Printing: A Comparison of Recycled PLA Filaments from Waste of Different Origins after Repeated Cycles of Extrusion.

The objective of this work is to evaluate the reprocessing of PLA 3D printing waste from different origins, into filaments and films, and without the addition of any additive. Two types of waste were considered: a blend of different printing wastes (masks, visors, other components) of personal protective equipment coming from an association of Spanish coronamakers, and PLA waste from a single known commercial source. Both types of materials were subjected to repeated extrusion cycles and processed into films by compression molding. Samples were characterized after each cycle and their mechanical and viscosity properties evaluated. Diffusion-ordered NMR spectroscopy (DOSY) experiments were also carried out to estimate molecular weights. The results show a better performance for the PLA waste from the known origin, capable of withstanding up to three re-extrusion cycles per two for the waste blending, without significant degradation. Additionally, a model to address collection and mechanical recycling cycles under two different scenarios (full traceability and not full traceability) was proposed.

Using surface plasmon resonance, capillary electrophoresis and diffusion-ordered NMR spectroscopy to study drug release kinetics

Nanomedicines, including polymer nanocarriers with controlled drug release, are considered next-generation therapeutics with advanced therapeutic properties and reduced side effects. To develop safe and efficient nanomedicines, it is crucial to precisely determine the drug release kinetics. Herein, we present application of analytical methods, i.e., surface plasmon resonance biosensor technology (SPR), capillary electrophoresis, and 1H diffusion-ordered nuclear magnetic resonance spectroscopy, which were innovatively applied for drug release determination. The methods were optimised to quantify the pH-triggered release of three structurally different drugs from a polymer carrier. The suitability of these methods for drug release characterisation was evaluated and compared using several parameters including applicability for diverse samples, the biological relevance of the experimental setup, method complexity, and the analysis outcome. The SPR method was the most universal method for the evaluation of diverse drug molecule release allowing continuous observation in the flow-through setting and requiring a small amount of sample.

Charge transport in protic ionic liquids: Effect of protonation state in 1-methylimidazolium – acetate/trifluoroacetate mixtures

Despite the potential to overcome slow charge transport in ionic liquids by decoupling charge transport from mass transport in protic ionic liquids (PILs), the average proton distribution and the contribution of proton conduction to the overall charge transport in PILs has not been fully established. To elucidate the predominant underlying molecular species in the PILs and the molecular dynamics of the PILs, we study the dipolar response and conductivity using dielectric relaxation (DR) spectroscopy and the nucleis chemical environment and molecular mobility using nuclear magnetic resonance (NMR) spectroscopy of prototypical PILs based on 1–methylimidazolium as Brønsted base. To elucidate the effect of the acidity of the Brønsted acid we gradually vary the composition of the PILs from 1–methylimidazoliumacetate [MimH][AcO] to 1–methylimidazoliumtrifluoroacetate [MimH][TFA]. Both, 15N-NMR chemical shifts and the sample conductivities suggest that in neat [MimH][AcO] electro-neutral molecular species dominate, consistent with earlier findings. The dipolar response of these molecular species as detected via the DR spectra is stronger than what one would expect based on the molecular dipole moments estimated from density functional theory calculations, which points to the formation of an extended hydrogen-bonded network. Upon addition of [MimH][TFA], this dipolar response is reduced as the degree of protonation of 1–methylimidazolium gradually increases, which is apparent from the conductance and 15N chemical shifts. Interestingly, diffusion ordered NMR spectroscopy indicates protons to become more mobile than the constituting acid and base molecules, consistent with Grotthuss-like proton transport. To vary the immediate environment of the PILs, we study solutions of the PIL mixtures in aprotic dimethylformamide (DMF) and protic methanol (MeOH) as two limiting cases. We find that [MimH][AcO] exclusively forms electroneutral species in DMF, as evident from the negligible conductivity, while with increasing TFA content the fraction of charged molecular species increases. Although these ionic species give rise to a finite conductivity, demonstrating the presence of mobile ions, a large fraction of these ions is bound in [MimH][TFA] ion-pairs, as detected in the DR spectra. Yet, temperature dependent 1H-NMR linewidths of the acidic proton signals suggest proton exchange to occur on the NMR timescale, presumably between [MimH]+ and [Mim]. Conversely, in MeOH we find no evidence for the presence of ion-pairs, while the high conductivity of these solutions shows that MeOH can efficiently solvate ions and may participate in proton transfer. Together, our results highlight the sensitivity of protonation equilibria to the immediate environment and of proton dynamics to these protonation equilibria. Our results show that tuning these equilibria using PIL mixtures can provide routes to tailor the contribution of proton transport to charge transport in PILs.