Chloride is the most common counterion used to improve aqueous solubility and enhance stability of small molecule active pharmaceutical ingredients. While several analytical techniques, such as ...titration, HPLC with charged aerosol detection, and ion chromatography, are currently utilized to assay the level of chloride, they have notable limitations, and these instruments may not be readily available. Here, we present a generally applicable
Cl solution NMR method to assay the level of chloride in pharmaceutical compounds. The method uses KClO
as an internal standard for improved accuracy in comparison with external standard methods, and it was found to be robust, linear over three orders of magnitude, precise (<3% RSD), and accurate (<0.5% absolute error).
Density functional theory (DFT) benchmark studies of sup.1H and sup.13C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules and non-standardized data ...acquisition. To address this issue, we carefully selected and measured sup.1H and sup.13C NMR chemical shifts for 50 structurally diverse small organic molecules containing atoms from only the first two rows of the periodic table. Our NMR dataset, DELTA50, was used to calculate linear scaling factors and to evaluate the accuracy of 73 density functionals, 40 basis sets, 3 solvent models, and 3 gauge-referencing schemes. The best performing DFT methodologies for sup.1H and sup.13C NMR chemical shift predictions were WP04/6-311++G(2d,p) and ωB97X-D/def2-SVP, respectively, when combined with the polarizable continuum solvent model (PCM) and gauge-independent atomic orbital (GIAO) method. Geometries should be optimized at the B3LYP-D3/6-311G(d,p) level including the PCM solvent model for the best accuracy. Predictions of 20 organic compounds and natural products from a separate probe set had root-mean-square deviations (RMSD) of 0.07 to 0.19 for sup.1H and 0.5 to 2.9 for sup.13C. Maximum deviations were less than 0.5 and 6.5 ppm for sup.1H and sup.13C, respectively.
Isolation and chemical characterization of target components in fast-paced pharmaceutical laboratories can often be challenging, especially when dealing with mixtures of closely related, possibly ...unstable species. Traditionally, this process involves intense labor and manual intervention including chromatographic method development and optimization, fraction collection, and drying processes prior to NMR analyses for unambiguous structure elucidation. To circumvent these challenges, a foundational framework for the proper utilization of supercritical carbon dioxide (scCO2) and deuterated modifiers (CD3OD) in sub/supercritical fluid chromatography (SFC) is herein introduced. This facilitates a streamlined multicomponent isolation with minimized protic residues, further enabling immediate NMR analysis. In addition to bypassing tedious drying processes and minimizing analyte degradation, this approach (complementary to traditional reversed-phase liquid chromatography, RPLC) delivers highly efficient separations and automated fraction collection using readily available analytical/midscale SFC instrumentation. A series of diverse analytes across a wide spectrum of chemical properties (acid, basic, and neutral), combined with different stationary-phase columns in SFC are investigated using both a protic organic modifier (CH3OH) and its deuterated counterpart (CD3OD). The power of this framework is demonstrated with pharmaceutically relevant applications in the context of target characterization and analysis of complex multicomponent reaction mixtures from modern synthetic chemistry, demonstrating high isolation yields while reducing both the environmental footprint and manual intervention. This workflow enables unambiguous fast-paced structure elucidation on the analytical scale, providing results that are comparable to traditional, but time-consuming, RPLC purification approaches.
Background
Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical ...characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL).
Methods
Caregiver–patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses.
Results
The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions.
Conclusion
This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.
At the forefront of chemistry and biology research, development timelines are fast‐paced and large quantities of pure targets are rarely available. Herein, we introduce a new framework, which is ...built upon an automated, online trapping‐enrichment multi‐dimensional liquid chromatography platform (TE‐Dt‐mDLC) that enables: 1) highly efficient separation of complex mixtures in a first dimension (1D‐UV); 2) automated peak trapping‐enrichment and buffer removal achieved through a sequence of H2O and D2O washes using an independent pump setup; and 3) a second dimension separation (2D‐UV‐MS) with fully deuterated mobile phases and fraction collection to minimize protic residues for immediate NMR analysis while bypassing tedious drying processes and minimizing analyte degradation. Diverse examples of target isolation and characterization from organic synthesis and natural product chemistry laboratories are illustrated, demonstrating recoveries above 90 % using as little as a few micrograms of material.
Trapping‐Enrichment Deuterated Multidimensional‐Liquid Chromatography (TE‐Dt‐mDLC) for rapid microgram‐scale structure elucidation by NMR is introduced. This concept enables a streamlined chemical characterization of multicomponent mixtures (e.g. catalysis, natural products) while bypassing tedious drying processes with recoveries above 90 % using as little as a few micrograms of material.
INTRODUCTIONElectronic nicotine delivery system (ENDS) and liquid characteristics affect nicotine and toxicant exposure and use behaviors. Little is known about how adults who frequently use ENDS ...transition between ENDS device/liquid groupings. METHODSA total of 379 US adults (≥21 years) using ENDS frequently (≥5 days/week) self-reported and uploaded photos of their most used ENDS device and liquid in three waves of online surveys (May 2020 - November 2021). Device/liquid grouping was defined by device (i.e. disposable/refillable tank/refillable pod or cartridge/disposable pod or cartridge, adjustable/no adjustable settings) and liquid (i.e. salt/freebase) characteristics. Participants using the same grouping across waves were considered stable users. RESULTSThe most prevalent wave (W) 1 grouping was tank (freebase, adjustable settings; 36.8%). From W1 to W3, the number of disposable device (salt, no adjustable settings) users increased 156.4% and the number of disposable pod/cartridge (salt, no adjustable settings) users decreased 15.2%. In W2 and W3, compared to stable users, participants using tank (freebase, adjustable settings) in W1 and another grouping in W2 and/or W3 reported significantly higher nicotine concentrations (mg/mL) (W2: 15.1 vs 5.5, p<0.001; W3: 22.9 vs 5.6, p<0.001) and lower device power (watt) (W2: 46.8 vs 58.7, p=0.02; W3: 34.0 vs 57.2, p<0.001). CONCLUSIONSOver a 1.5-year period, a rapid growth in disposable device (salt, no adjustable settings) use and a decrease in disposable pod/cartridge (salt, no adjustable settings) use were observed. Participants who transitioned from tank (freebase, adjustable settings) to other groupings were more likely to increase liquid nicotine concentration and reduce device power compared to stable users.
This work describes the application of vibrational (VCD) and electronic (ECD) circular dichroism spectroscopy to solve the longstanding debate around the absolute configuration of (+)-frondosin B (
...). The absolute configuration of (+)-
could confidently be assigned as (
) using these spectroscopic techniques. The discrepancy in the optical rotation (OR) values obtained in previous studies can be attributed to an undetected minor impurity (
7%) that arose unexpectedly in a key step late in the synthesis. Additionally, the conditions used in the final step of the previous reports for demethylation to form the natural product proceeded with significant loss of enantiopurity. The large OR measured for the impurity at its observed level, when compared to the small rotation for the less enantiopure natural product
, led to a measured OR value for the synthetic material that had the opposite sign of the natural product.
Chronic rhinosinusitis (CRS) is known to affect around 5 % of the total population, with major impact on the quality of life of those severely affected (1). Despite a substantial burden on ...individuals, society and health economies, CRS often remains underdiagnosed, under-estimated and under-treated (2). International guidelines like the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) (3) and the International Consensus statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR) (4) offer physicians insight into the recommended treatment options for CRS, with an overview of effective strategies and guidance of diagnosis and care throughout the disease journey of CRS.
Selectfluor is one of the most widely used fluorinating agents in the pharmaceutical industry. These reactions are often scaled up in reactors made with corrosion-resistant metals such as Hastelloy ...because of the presence of fluoride in Selectfluor. Herein we report an investigation into the variable performance of a fluorination reaction in the belzutifan synthesis, which initially focused on the unexpected corrosiveness of the reaction toward the high-nickel alloys Hastelloy C-276 (N10276) and Hastelloy C-22 (N06022). This investigation identified that the corrosion, rather than being inherent to the reaction, was associated with the particular lot of Selectfluor used and could be correlated with elevated levels of chloride and iron in the lot of Selectfluor. Further investigation found that the increased aggressiveness was associated with the elevated chloride level (some chloride can be found in nearly all lots of Selectfluor), and the presence of metals does not impact the level of corrosion. A corrosion-reaction pathway involving the presence of an oxidized chloride species is proposed which accounts for both the poor reaction performance and the corrosion observed.
A method for the measurement of residual chemical shift anisotropy in one experiment using a biphasic isotropic/anisotropic lyotropic liquid crystalline medium based on poly-γ-benzyl-l-glutamate as ...the alignment medium is presented. This approach is demonstrated on the model compound strychnine and neotricone, a depsidone natural product with a questionable structural assignment based on comparison with the closely related excelsione and in-depth density functional theory calculations.
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