This study explored the use of stable light δ2H, δ13C, and δ18O isotope ratio mass spectrometry (IRMS) to identify unique isotopic signatures in 27 ibuprofen drug products and pharmaceutical 27 commonly used excipients. The 27 ibuprofen drug products were collected from six different countries containing active pharmaceutical ingredient varying from 20% to 82% of the total tablet mass and 6-18 excipients. The drug products were homogenized by ball milling, but no other sample preparation was required prior to analysis. Approximately 150 μg of sample material was encapsulated (n = 3) and analyzed through TC/EA IRMS calibrated against certified reference materials. The isotopic analyses were conducted over consecutive weeks with high data reproducibility, and the ibuprofen drug products and excipients presented the lowest isotopic variation by mass for the δ13C signal, followed by δ2H and δ18O. The isotopic standard deviations for the drug products (δ2H ≤ 5.29%, δ13C ≤ 0.37%, and δ18O ≤ 1.75%) were expectedly higher compared to monoingredient excipients but generally considered low. Unique isotopic signatures were determined for the drug products and excipients, and through the isotopic separation, it was possible to differentiate across pharmaceutical manufacturers and between drug products produced by the same manufacturer. The isotopic signal stability across pharmaceutical batches was determined through analysis (n = 3) of 9 drug products obtained from the same manufacturer having different batch numbers, expiration dates, and packaging material. The isotopic variation (δ2H = -44.78 ± 3.51‰, δ13C = -22.11 ± 0.46‰, and δ18O = 34.18 ± 1.73‰) within batches from a pharmaceutical manufacturer was lower than the isotopic variation across the different drug products making stable light isotopic analysis a powerful tool for unique identification and for health authorities and pharmaceutical manufacturers to detect falsified and substandard drug products, protect against patent infringement, and ensure high-quality drug products.

The timing and magnitude of the early Cenozoic surface uplift of the Tibetan Plateau is controversial due to a scarcity of unaltered terrestrial sediments required for palaeoaltimetry techniques. Such information is critical, however, for constraining the geodynamic and palaeoclimatic evolution of the Indian and Eurasian continents and for interpreting global climate, biodiversity and biogeochemical cycles since the Cenozoic. We find that substantial uplift occurred by 63 to 61 million years ago, before the collision of the Indian and Eurasian continental plates, based on comparison of triple oxygen isotopes of modern meteoric waters with epithermal Ag–Pb–Zn deposit quartz veins from the Palaeocene Gangdese Arc in southern Lhasa. Low δ 18 O and δ 17 O quartz values are consistent with precipitation from meteoric waters influenced by a large degree of topographic rainout. We show that by 63 to 61 Ma, the Gangdese Arc reached an elevation of ~3.5 km, suggesting that the Gangdese Arc achieved >60% of its current elevation before continent–continent collision. This uplift was probably caused by crustal shortening in response to low-angle subduction of Neo-Tethyan oceanic lithosphere. This early high palaeoelevation estimate for the Himalaya–Tibetan system challenges previous assumptions that southern Tibet uplift required continent–continent collision to achieve substantial topography.

Trace elements are found in most drugs as a result of the drug formulation and drug production methods. An inductively coupled plasma-mass spectrometry method for the determination of 24 trace elements (Mg, Ti, V, Cr, Mn, Cu, Fe, Co, Ni, Zn, As, Se, Mo, Ru, Rh, Pd, Ag, Cd, Sb, Ba, Ir, Pt, Au, and Pb) in solid ibuprofen tablets was established in relation to the ICH Q3D(R1) guideline, to evaluate the possibility of linking trace elemental profiles to drug formulation strategies, and to differentiate between drug products based on the trace elemental profiles. Ten European ibuprofen drug products were evaluated (n=3). The sample preparation was performed by microwave-assisted acid digestion using only 10 mg of homogenized sample and 900 μL of a mix of 65% HNO3, 37% HCl, and 30% H2O2. Solid residuals primarily composed of insoluble SiO2 excipients were removed by centrifugation. Only concentrations of Mg, Fe, Ti, Mn, Cr, and Ni were detected above the limits of detection and did not exceed the ICH Q3D(R1) guideline permitted daily exposure limits. The trace elemental profiles were evaluated through principal component analysis. Three principal components describing 96% of the variance were useful in grouping the ibuprofen drug products, and the detected trace elemental remnants could be related to drug formulation and drug production strategies. An in-house quality control material was used in lack of certified reference materials and was in combination with spike recoveries used for method validation. Good spike recoveries (94-119%) were obtained for all measured trace elements except Mg. Mg showed acceptable spike recoveries (75-155%) for mid and high-spike concentrations, but poor recoveries (30-223%) were detected with low spike concentrations in spike matrices containing high amounts of Mg. Overall, the method is suggested applicable for solid drugs containing insoluble SiO2 excipients and drugs comparable to ibuprofen.

The oxygen-18 isotopic composition (delta O-18) of silica preserved in oceanic sediments is an important archive of Earth's temperature and/or seawater delta O-18 from the Archean to present. Recent advances in high-precision measurements of both delta O-18 and delta O-17 values have been used to provide additional constraints on what the oxygen isotopic composition of chert reflects about past conditions. Here, we examine the effects on the triple oxygen isotopic composition of chert that occurs during transformation and recrystallization of biogenic opal-A to opal-CT to microquartz in deep sea sediments. We studied late Miocene to present samples from the Sea of Japan at ODP Site 795 and measured biogenic diatom opal-A, opal-CT, micro quartz chert, and 'altered' opal-A samples-previously measured for delta O-18 values only-for both delta O-18 and delta O-17 values. We find that delta O-18 decreases and & UDelta;0(17)O increases (where & UDelta;0(17)O = delta O-17 - 0.528 x delta O-18) with depth, coincident with the conversions from diatom opal-A to opal-CT to microquartz. Silica samples deviate from the trend expected for triple oxygen isotopic equilibrium with modern seawater. To explain these data, we developed a model that shows that local temperature gradients and pore fluid delta O-18 profiles in combination lower the measured opal-CT and microquartz delta O-18 values and raise the & UDelta;0(17)O values relative to the initial opal-A, but deviate from triple oxygen isotopic equilibrium with seawater. We find that a steeper local temperature gradient and a larger influence of hydrothermal alteration of basalt at the base of the sediment column (which lowers pore fluid delta O-18 values) in the past explain both the measured delta O-18 and & UDelta;0(17)O values of the opal-CT and microquartz. These data and our modeling show that the transformation of opal-A to microquartz in marine sediments at elevated temperatures and in the presence of lowered pore water delta O-18 values leads to an array that falls below the theoretical triple oxygen isotope line of equilibrium for SiO2 with modern seawater. Further, our model indicates that opal-CT and microquartz do form in triple oxygen isotopic equilibrium with pore fluids that are offset in their triple oxygen isotopic composition compared to seawater due to fluid-rock alteration of igneous rocks at the base of the sediment column. The diagenetic processes taking place in the Japan Sea do not explain a large portion of the existing Archean to present triple oxygen isotope chert data, which likely require either changes in the oxygen isotopic composition of the source water (i.e., ocean water) and/or alteration by meteoric fluids. Further, our data demonstrate that the triple oxygen isotopic composition of preserved chert need not represent surface conditions, but instead may reflect processes that occur in subsurface sediments at elevated temperatures and with modified pore fluid oxygen isotopic compositions.(c) 2021 Elsevier Ltd. All rights reserved.

The timing of surface uplift of the Altai Mountains in northern Central Asia—and the climatic consequences—remains controversial. Today, the Altai Mountains cast a substantial rain shadow, effectively separating the western Gobi Desert and steppe from the Siberian Taiga. We take advantage of this stark climatic gradient to trace the interaction of climate and topography in the lee of the Altai. First, we present new water stable isotope data that demonstrate that—along with this climatic gradient—the Altai modify the δ18O of precipitation via rainout on the leeward side of the range. Second, we present a new paleosol carbonate clumped isotope (Δ47) record that spans much of the Neogene from the immediate lee of the Altai in western Mongolia to address how surface temperatures may have responded to potential uplift during the Neogene. We find that Δ47-derived temperatures have, overall, declined by approximately 7 °C over the course of the Neogene, though the precise timing of this decrease remains uncertain. Third, we pair our Δ47 record with previously published stable isotope data to demonstrate that the timing of decreasing temperatures corresponds with long-term stability in paleosol carbonate δ13C values. In contrast, increases in paleosol carbonate δ13C values—linked to declining vegetation productivity—are correlated with intervals of increasing temperatures. We speculate that declines in vegetation biomass and leaf area changed the partitioning of latent and sensible heat, resulting in rising surface temperatures during Altai uplift. In contrast, long-term Neogene cooling drove the overall decline in surface temperatures. Reconstructed soil water δ18O values (based on carbonate δ18O and Δ47 values) remain surprisingly stable over our Neogene record, differing from our expectation of decreasing δ18O values due to progressive uplift of the Altai Mountains and Neogene cooling. We demonstrate that the shift in precipitation seasonality that likely accompanied Altai uplift obscured any change in lee-side precipitation δ18O that would be expected from surface elevation change alone.

In the last two decades, analytical advances and a growing interest in relevant research questions has brought a rapid increase in the amount of stable isotope data used for reconstructing terrestrial paleoclimates and environments. As the spatial and temporal resolution of proxy data continues to improve, the quantitative interpretation of these data is becoming increasingly common. These advances in data resolution and theory bring opportunities for multi-proxy comparisons, synthesis and modeling of large datasets, integration with paleoecological datasets, improved climate model benchmarking, and more. Here, in an effort to support these growing avenues of research, we present The PATCH Lab (Paleo-Analysis of Terrestrial Climate and Hydrology)—an online portal to discover, download, and quantitatively analyze Cenozoic terrestrial stable isotope data. The PATCH Lab portal includes a new database that currently includes 27009 stable isotope measurements from 211 publications spanning multiple terrestrial proxies, and quantitative models for interpreting water isotope and soil carbonate data. Data query, download, and modeling results are organized into user-friendly graphical interfaces that export datasets as .csv files. New data can be easily submitted to the PATCH Lab curators through the portal by completing a data submission template. The PATCH Lab, with the help of community engagement, serves as a resource for archiving terrestrial stable isotope data, building paleo "isoscapes", and increasing accessibility to quantitative methods of investigating terrestrial stable isotopes in paleoclimate.

The shift from denser forests to open, grass‐dominated vegetation in west‐central North America between 26 and 15 million years ago is a major ecological transition with no clear driving force. This open habitat transition (OHT) is considered by some to be evidence for drier summers, more seasonal precipitation, or a cooler climate, but others have proposed that wetter conditions and/or warming initiated the OHT. Here, we use published ( n = 2,065) and new ( n = 173) oxygen isotope measurements ( δ 18 O ) in authigenic clays and soil carbonates to test the hypothesis that the OHT is linked to increasing wintertime aridity. Oxygen isotope ratios in meteoric water ( δ 18 O p ) vary seasonally, and clays and carbonates often form at different times of the year. Therefore, a change in precipitation seasonality can be recorded differently in each mineral. We find that oxygen isotope ratios of clay minerals increase across the OHT while carbonate oxygen isotope ratios show no change or decrease. This result cannot be explained solely by changes in global temperature or a shift to drier summers. Instead, it is consistent with a decrease in winter precipitation that increases annual mean δ 18 O p (and clay δ 18 O ) but has a smaller or negligible effect on soil carbonates that primarily form in warmer months. We suggest that forest communities in west‐central North America were adapted to a wet‐winter precipitation regime for most of the Cenozoic, and they subsequently struggled to meet water demands when winters became drier, resulting in the observed open habitat expansion.

Interrupting a long‐term Cenozoic cooling trend, the Miocene Climatic Optimum (MCO; ca. 17–15 Ma) represents a time interval characterized globally by warmer than present temperatures, lower ice volume, and elevated pCO 2 levels. Establishing quantitative Neogene temperature estimates is an important element in the effort to explore the long‐term changes in the carbon cycle and associated climate feedbacks, yet terrestrial temperature records are still sparse. Here, we present a clumped isotope (Δ 47 ) temperature record of the MCO from intermontane basins in the Northern Rocky Mountain (NRM) region. Arikareean (22.7–21.5 Ma) to Barstovian (16.9–14.7 Ma) paleosol carbonates from the Hepburn's Mesa Formation (Montana), supplemented with data from fossil localities in western Idaho. These records yield Δ 47 ‐temperatures ranging from 17°C to 24°C, which are rather warm given the high elevation sites and are further relatively stable (mean of 21 ± 2°C) leading into and during the MCO until ca. 14.7 Ma. At ca. 14.7 Ma, we observe low Δ 47 ‐temperatures (8°C–10°C) concomitantly with elevated Δ 47 ‐temperatures (ca. 22°C). In line with recently suggested climate stability in the NRM region leading into the MCO, our Δ 47 ‐temperature record, combined with carbon isotope (δ 13 C) and reconstructed soil water oxygen isotope (δ 18 O sw ) values, indicates rather stable climate and environmental conditions throughout the MCO. Combining available records from inland sites in the western United States (NRM, Mojave region) points to prevailing stable continental climates even during the MCO.

Triple oxygen isotope measurements are an emerging tool in paleoclimate reconstructions. In this contribution we develop the application of triple oxygen isotope measurements to lacustrine sediments to reconstruct past elevations. We focus on a well-constrained sample set from the Eocene North American Cordillera (Cherty Limestone Formation, Elko Basin, NV, United States, 42–43.5 Ma) on the east side of the elevated Nevadaplano. We present triple oxygen isotope measurements on freshwater lacustrine chert samples from the Cherty Limestone Formation. Across an evaporation trend spanning 6.5‰ in δ 18 O values we observe a negative correlation with Δ′ 17 O ranging from −0.066 to −0.111‰ (λ RL = 0.528), with an empirical slope (λ chert , δ′ 17 O vs. δ′ 18 O) of 0.5236. Additionally, we present new carbonate clumped isotope (Δ 47 ) temperature results on the overlying fluvial-lacustrine Elko Formation, which indicate an error-weighted mean temperature of 32.5 ± 3.8°C (1σ), and evaporatively enriched lake water spanning δ 18 O values of −3.7 to +3.5‰ (VSMOW). Paired chert and carbonate δ 18 O values demonstrate that co-equilbrium among the carbonate and chert phases is unlikely. Thus, as also previously suggested, it is most likely that Elko Basin chert formed during early diagenesis in equilbirium with pore waters that reflect evaporatively 18 O-enriched lake water. Using this scenario we apply a model for back-calculating unevaporated water composition to derive a source water of δ′ 18 O = −16.1‰ (VSMOW), similar to modern local meteoric waters but lower than previous work on paired δ 18 O- δD measurements from the same chert samples. Further, this back-calculated unevaporated source water is higher than those derived using δD measurements of Late Eocene hydrated volcanic glass from the Elko Basin (average δ′ 18 O equivalent of approximately −18.4‰, VSMOW). This suggests, assuming Eocene meteoric water Δ′ 17 O values similar to today (∼0.032‰), either that: (1) the hypsometric mean elevation recorded by the lacustrine Cherty Limestone was lower than that derived from the average of the volcanic glass δD measurements alone; or (2) there was hydrogen exchange in volcanic glass with later low δD meteoric fluids. Nonetheless, our new findings support a relatively high (∼2.5–3 km) plateau recorded in the Elko Basin during the mid-Eocene.

Triple oxygen isotopes of hydrothermally altered minerals from crystalline rocks can be used to determine past elevations of mountain ranges. This method uses all three isotopes of oxygen ( 16 O, 17 O, and 18 O) to create arrays that can be extrapolated back to the meteoric water line. One advantage of this technique is that it relies only on oxygen isotopes in contrast to previous studies that use oxygen and hydrogen isotopes to determine the isotopic composition of meteoric waters. Our analysis suggests that hydrogen isotopes may exchange with ambient fluids. Triple oxygen isotopes provide an independent check on the reliability of hydrogen isotope studies.

The John Day region of central Oregon, United States contains ∼50 million years of near-continuous, fossiliferous sedimentation, representing one of the world’s richest archives of Cenozoic terrestrial ecosystems and climate. Stable isotope proxy data from this region are commonly used to infer the elevation history of the Cascades, which intercept westerly moisture in transit to the John Day region. However, the Blue Mountains, which accreted in the Mesozoic, create a region of local high topography that can confound signals of Cascades uplift. John Day deposits, including the John Day Formation, are divided into an eastern facies located within the Blue Mountains and a western facies in the adjacent plains. As a result, the Blue Mountains may have supported gradients in climate and ecology between the eastern and western facies, and constraining these gradients is necessary for reconstructing past topography and ecosystem change. In order to define the Cenozoic extent and magnitude of Blue Mountains topography we use oxygen isotopes in authigenic clay minerals to construct a spatially resolved map of local elevation. We find that the oxygen isotope composition of clay minerals within the Blue Mountains is ∼3‰ lower than in the adjacent high plains, and this offset is mostly constant throughout our record (spanning ∼50 – 5 Ma). We attribute this offset to Blue Mountains topography, either directly from upslope rainout or indirectly through the effect of elevation on local variations in precipitation seasonality. Our results highlight the importance of local topographic features in regional paleotopography reconstructions and provide important biogeographical context for the rich paleo-floral and -faunal records preserved in John Day sediments.

From the latest Cretaceous (late Campanian to Maastrichtian, -75?66 Ma) to the earliest Paleogene, fluctuations in greenhouse climate, inferred primarily from marine sediments, have been linked to volcanism, the Chicxulub asteroid impact, and the Cretaceous-Paleogene (K-Pg) mass extinction. In this paper, we summarize terrestrial climate records in mid-latitude East Asia during the latest Cretaceous and across the K-Pg boundary, based on a multi-proxy approach from the geochronologically well-constrained Sifangtai and Mingshui formations (SMF), accessed by scientific drilling of the Songliao Basin in northeastern China. Evolution of sedimentary environments is characterized by five depositional units of fluvial-deltaic-lacustrine facies. Development of four types of paleosols, including Inceptisols, Aridisols, Vertisols and Alfisols, is interpreted to primarily reflect climatic changes. Correlations among sedimentary facies, paleosol features, illite chemistry index, chemical index of alteration, as well as stable and clumped isotopes of pedogenic carbonates and clay minerals of the SMF validate their reliability for paleoclimate reconstruction, and indicate significant fluctuations in terrestrial climate and sedimentary environment. During global warming intervals possibly triggered by volcanism (e.g. -69.5?68.5 Ma), the Songliao Basin experienced a warmer and wetter climate with stronger terrestrial chemical weathering and more monsoon-derived moisture sourced from the Pacific. In contrast, during global cooling intervals (e.g. -70.5?69.5 Ma and - 68.5?66.5 Ma), the SMF record a cooler and drier climate with less intensive chemical weathering and more westerlies-derived moisture. Across the K-Pg boundary, dramatic changes in land temperatures and hydroclimate correspond to the latest Maastrichtian warming episode (-66.4?66.1 Ma), the transient cooling preceding the K-Pg boundary (-66.1?66.0 Ma), and the earliest Paleogene warming interval (-66.0?65.7 Ma). Temporal correlation of weathering index changes with the Deccan Traps volcanism suggests that volcanism and subsequent intensified weathering played a major role for climatic changes across the K-Pg boundary. The integrated records of sedimentological and geochemical datasets from the Songliao Basin robustly demonstrate that the terrestrial climate of mid-latitude East Asia responded strongly to greenhouse climate changes and to the catastrophic geological events from the latest Cretaceous to the earliest Paleogene.

The Amazon forest is increasingly vulnerable to dieback and encroachment of grasslands and agricultural fields. Threats to these forested ecosystems include drying, deforestation, and fire, but feedbacks among these make it difficult to determine their relative importance. Here, we reconstruct the central and western Amazon tree cover response to aridity and fire in the mid-Holocene—a time of less intensive human land use and markedly drier conditions than today—to assess the resilience of tree cover to drying and the strength of vegetation-climate feedbacks. We use pollen, charcoal, and speleothem oxygen isotope proxy data to show that Amazon tree cover in the mid-Holocene was resilient to drying in excess of the driest bias-corrected future precipitation projections. Experiments with a dynamic global vegetation model (LPJ-GUESS) suggest tree cover resilience may be owed to weak feedbacks that act to amplify tree cover loss with drying. We also compare these results to observational data and find that, under limited human interference, modern tree cover is likely similarly resilient to mid-Holocene levels of aridification. Our results suggest human-driven fire and deforestation likely pose a greater threat to the future of Amazon ecosystems than drying alone.

Over 20 years ago, two new ideas began to become commonplace: the "Critical Zone" and "metal isotope geochemistry." The former provides a conceptual view of the Earth's terrestrial surface, while the latter provides a means with which to study it. The progress that has been made in

We use triple oxygen isotopes of altered granitic rocks to determine the isotope composition of meteoric waters in a fossil hydrothennal system, the low delta O-18 Eocene Idaho Batholith, originally studied by Criss and Taylor (1983). In doing so we: 1) test whether meteoric water values estimated from previous delta O-18 and delta D analyses on quartz, feldspar and biotite are robust and 2) determine the palaeoelevation of the Eocene highlands that are presently constrained primarily by the delta O-18 and delta D of paired muscovite and quartz from core complexes and altered granites. Our calculated delta O-18 values of meteoric water are higher than estimates that use combined feldspar delta O-18 and biotite SD measurements in these hydrothermally altered granites and SD values from muscovite from nearby core complexes (Mulch et at., 2004). Both methods are consistent with a high elevation (similar to 3.1 to 4.7 km) Eocene highland in the northwestern U.S. Cordillera.