Insights into Factors Affecting Ethylene-Vinyl Acetate Copolymer Crystallinity in Islatravir Implant.

Islatravir, a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) for the treatment of HIV, has great potential to be formulated as ethylene-vinyl acetate (EVA) copolymer-based implants via hot melt extrusion. The crystallinity of EVA determines its physical and rheological properties and may impact the drug-eluting implant performance. Herein, we describe the systematic analysis of factors affecting the EVA crystallinity in islatravir implants. Differential scanning calorimetry (DSC) on EVA and solid-state NMR revealed drug loading promoted EVA crystallization, whereas BaSO4 loading had negligible impact on EVA crystallinity. The sterilization through γ-irradiation appeared to significantly impact the EVA crystallinity and surface characteristics of the implants. Furthermore, DSC analysis of thin implant slices prepared with an ultramicrotome indicated that the surface layer of the implant was more crystalline than the core. These findings provide critical insights into factors affecting the crystallinity, mechanical properties, and physicochemical properties of the EVA polymer matrix of extruded islatravir implants.

Cocrystal Synthesis through Crystal Structure Prediction.

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all the possible crystalline solid forms of small-molecule active pharmaceutical ingredients. We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. For MK-8876, the CSP-based cocrystal prediction was performed retrospectively and successfully predicted the maleic acid cocrystal as the most likely cocrystal to be observed. The triol is known to form two different cocrystals with 1,4-diazabicyclo[2.2.2]octane (DABCO), but a larger solid form landscape was desired. CSP-based cocrystal screening predicted the triol-DABCO cocrystal as rank one, while a triol-l-proline cocrystal was predicted as rank two. Computational finite-temperature corrections enabled determination of relative crystallization propensities of the triol-DABCO cocrystals with different stoichiometries and prediction of the triol-l-proline polymorphs in the free-energy landscape. The triol-l-proline cocrystal was obtained during subsequent targeted cocrystallization experiments and was found to exhibit an improved melting point and deliquescence behavior over the triol-free acid, which could be considered as an alternative solid form in the synthesis of islatravir.

Scalable Asymmetric Synthesis of MK-8998, a T-Type Calcium Channel Antagonist.

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.

Palladium-Catalyzed Carbon Isotope Exchange on Aliphatic and Benzoic Acid Chlorides.

An operationally simple protocol for a palladium-catalyzed 13CO and 14CO exchange with activated aliphatic and benzoic carbonyls is presented. Several 13C and 14C building blocks, natural product derivatives, and pharmaceuticals have been prepared to showcase the method for late-stage carbon isotope incorporation and its functional group compatibility.

Effects of in situ exposure to tritiated natural environments: A multi-biomarker approach using the fathead minnow, Pimephales promelas.

Aquatic ecosystems are chronically exposed to radionuclides as well as other pollutants. Increased concentrations of pollutants in aquatic environments can present a risk to exposed organisms, including fish. The goal of this study was to characterize the effects of tritium, in the context of natural environments, on the health of fathead minnow, Pimephales promelas. Fish were exposed to tritium (activity concentrations ranging from 2 to 23,000Bq/L) and also to various concentrations of several metals to replicate multiple-stressor environments. Fish were exposed for 60days, then transferred to the tritium background site where they stayed for another 60days. Tritium, in the forms of tritiated water (HTO) and organically bound tritium (OBT), and a series of fish health indicators were measured in fish tissues at seven time points throughout the 120days required to complete the exposure and the depuration phases. Results showed effects of environmental exposure following the increase of tritium activity and metals concentrations in water. The internal dose rates of tritium, estimated from tissue HTO and OBT activity concentrations, were consistently low (maximum of 0.2µGy/h) compared to levels at which population effects may be expected (>100µGy/h) and no effects were observed on survival, fish condition, gonado-somatic, hepato-somatic, spleno-somatic and metabolic indices (RNA/DNA, proteins/DNA and protein carbonylation (in gonads and kidneys)). Using multivariate analyses, we showed that several biomarkers (DNA damages, MN frequency, gamma-H2AX, SFA/MUFA ratios, lysosomal membrane integrity, AChE, SOD, phagocytosis and esterase activities) were exclusively correlated with fish tritium internal dose rate, showing that tritium induced genotoxicity, DNA repair activity, changes in fatty acid composition, and immune, neural and antioxidant responses. Some biomarkers were responding to the presence of metals, but overall, more biomarkers were linked to internalized tritium. The results are discussed in the context of multiple stressors involving metals and tritium.

Tritium uptake in rainbow trout (Oncorhynchus mykiss): HTO and OBT-spiked feed exposures simultaneously.

There is currently considerable interest in organically bound tritium (OBT) formation in edible fish. The major questions revolve around whether or not tritium can accumulate in fish after being released into aquatic environments. Since OBT formation rates in large, edible fish are poorly understood, rainbow trout (Oncorhynchus mykiss) studies, where fish were simultaneously exposed to tritiated water (HTO) and OBT-spiked feed over 130 days, were conducted to evaluate tritium uptake. The measured HTO activity concentrations in fish tissue confirmed that HTO in fish tissue equilibrates quickly with HTO in tank water. The data obtained also confirmed that OBT uptake is faster when fish are ingesting OBT-spiked feed compared to when fish are living in tritiated water (and consuming non-OBT-spiked feed). The difference between the two exposure types is such that the groups exposed to tritiated water and OBT-spiked feed simultaneously were showing the same uptake rates as OBT-spiked feed only exposures. Contrary to what was expected, the rate of OBT uptake (from OBT-spiked feed) seemed to be higher in slow growing fish compared to fast growing fish. Another observation from these studies was that OBT activity concentrations in all organs (viscera) had a tendency to be higher than OBT activity concentrations measured in fish flesh.

Organically bound tritium (OBT) formation in rainbow trout (Oncorhynchus mykiss): HTO and OBT-spiked food exposure experiments.

In order to determine the rate of organically bound tritium (OBT) formation, rainbow trout (Oncorhynchus mykiss) were exposed to tritiated water (HTO) or OBT-spiked food. The HTO (in water) exposure study was conducted using a tritium activity concentration of approximately 7000 Bq/L and the OBT (in food) exposure study was conducted using a tritium activity concentration of approximately 30,000 Bq/L. Fish in both studies were expected to be exposed to similar tritium levels assuming 25% incorporation of the tritiated amino acids found in the food. Four different sampling campaigns of HTO exposure (Day 10, 30, 70, 140) and five different sampling campaigns of OBT-spiked food exposure (Day 9, 30, 70, 100, 140) were conducted to measure HTO and OBT activity concentrations in fish tissues. OBT depuration was also evaluated over a period of 30 days following the 140 d exposure studies. The results suggested that the OBT formation rate was slower when the fish were exposed to HTO compared to when the fish were ingesting OBT. In addition, the results indicated that OBT can bioaccumulate in fish tissues following OBT-spiked food exposure.

Practical synthesis of a potent bradykinin B(1) antagonist via enantioselective hydrogenation of a pyridyl N-acyl enamide.

A practical and efficient synthesis of bradykinin B(1) antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10. The key to the success of the synthesis was the development of a fluorodenitration step to install the fluorine in pyridine 7 and a catalytic enantioselective hydrogenation of N-acyl enamide 9 to set the stereochemistry.

Synthesis of a tertiary carbinamide via a novel Rh-catalyzed asymmetric hydrogenation.

Asymmetric hydrogenation of allylic dimethylcarbinamide 2 with 1 mol % of cationic Rh(I)-Josiphos complex in THF under 500 psi of H2 generated the corresponding tertiary carbinamide 1 in 98.5% assay yield and a 94:6 enantiomeric ratio. Upon crystallization, the product was isolated in 91% isolated yield and 95:5 enantiomeric ratio.

Unlocking the potential of asymmetric hydrogenation at Merck.

This Account outlines the efforts of Merck scientists toward implementing asymmetric hydrogenation as a core competency within Merck Research Laboratories. Several key factors are discussed including (i) a focus on efficient chemical synthesis, (ii) implementation of high throughput screening (HTS) techniques, (iii) demonstration of robustness on scale, and (iv) diligence to ensure freedom of operation and catalyst supply for manufacturing. Several examples of the development of efficient asymmetric hydrogenation processes are described.

An efficient catalyst for Pd-catalyzed carbonylation of aryl arenesulfonates.

Aryl carboxylic esters were synthesized by Pd-catalyzed carbonylation of aryl p-fluorobenzenesulfonates or -tosylates. A unique Josiphos ligand was discovered through high-throughput catalyst screening, which was the key for the successful carbonylation of various substrates. This catalyst is effective and works well for both electron-rich and electron-poor aryl arenesulfonates. Isolated yields of up to 90% were obtained for aryl p-fluorobenzenesulfonates and -tosylates. [reaction: see text]

Asymmetric hydrogenation of N-sulfonylated-alpha-dehydroamino acids: toward the synthesis of an anthrax lethal factor inhibitor.

A novel and highly enantioselective Ru-catalyzed hydrogenation of N-sulfonylated-alpha-dehydroamino acids has been discovered and demonstrated in the synthesis of an anthrax lethal factor inhibitor (LFI). Herein, this methodology is used to prepare N-sulfonylated amino acids in up to 98% ee. This unprecedented hydrogenation uses a chiral Ru catalyst rather than Rh as typical for acylated dehydroamino acids and esters, and this work reports the first asymmetric hydrogenation of a tetrasubstituted dehydroamino acid derivative using a Ru catalyst. [reaction: see text]

A [2 + 2] cycloaddition route to dimethylaminomethylene vinamidinium salts.

[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).

Ectopic gastric mucosa in the oesophagus mimicking ulceration.

We report two patients with ectopic gastric mucosa in the oesophagus in whom emergency contrast medium studies after traumatic endoscopy revealed broad, flat depressions on the right lateral wall of the upper oesophagus that could initially be mistaken for ulcers or even intramural dissections. However, the appearance and location of these lesions is so characteristic of ectopic gastric mucosa that confirmation with endoscopic biopsy specimens probably is not required in asymptomatic patients.

Accidental needlestick injuries in the academic setting: a model follow-up program.

Developed in response to needlestick injuries received by university nursing students, a model for initiating a comprehensive faculty and student follow-up treatment program for incidents involving blood and body fluids is presented. Providing an overview of need and risks, the authors review the program components, such as reporting mechanisms, program initiation, use of screening tests, recommended treatment modalities, and a decision-analysis for guiding the process.

Psychological correlates of loneliness in the older adult.

Loneliness is the emotional response to the discrepancy between desired and available relationships. As people grow old, the likelihood of experiencing age-related losses increases. Such losses may impede the maintenance or acquisition of desired relationships, resulting in a higher incidence of loneliness. This pilot study examines how loneliness relates to age-related losses, hopelessness, self-transcendence, and spiritual well-being in a convenience sample of 107 adults aged 65 years or older. The collective utility of the independent variables in predicting loneliness was investigated by means of a regression decision tree with an automatic random subset crossvalidation procedure. This procedure explained 46% of the variance. Higher scores for age-related losses and hopelessness were associated with higher loneliness scores. Higher scores for self-transcendence and existential spiritual well-being were associated with lower loneliness scores.