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Drug substances and excipients must be stored in recommended storage conditions and should comply with their specifications during the retest period for their use in the manufacture of drug products. The ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) and WHO (World Health Organization) regulatory guidelines mandate that after the retest period, the drug substances must be retested for compliance with the specification and then used immediately in the manufacture of the finished product. Although these substances can be retested multiple times, an emphasis is placed on immediate use following a retest and compliance with standards. The phrase "used immediately" is ambiguous and is left for interpretation. In this article, we will look at the various processes that must be completed to determine the retest date. In addition, we present a risk-based method for establishing retest dates and the time during which material can be used.
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A computational study is reported here on the mechanism of tetrahydrofuran (THF)-diol formation from the Os(VI)-catalyzed oxidative cyclization of 5,6-dihydroxyalkene ligated with citric acid and in the presence of BroÌ·nsted acid. Initiated by Os(VI) dioxo citrate formation, coordination of co-oxidant pyridine-N-oxide (PNO) and protonation of its oxo group generate the active catalyst. The catalytic cycle commences through successive steps, including dihydroxyalkene addition to the active catalyst in a concerted mechanism to form hexacoordinated alkoxy-protonated PNO-complexed Os(VI) bisglycolate as a turnover-limiting step (TLS), cyclization to Os(IV) THF-diolate, reoxidation to Os(VI) THF-diolate, and hydrolysis via a dissociative mechanism to furnish the THF-diol and regenerate the active species, sustaining the catalytic cycle through an Os(VI)/Os(IV) cycle. Despite the overall exergonic nature of catalytic cycle (ΔGrcycle = -45.0 kcal/mol), the TLS is accelerated by the formation of an open-valence 16-electron Os(VI) intermediate but decelerated by the undesired formation of a saturated/hexacoordinate 18-electron Os(VI) intermediate. BroÌ·nsted acid plays crucial roles in the formation of Os(VI) citrate and the active catalyst, impediment of the second cycle, and the cyclization step. Additionally, besides its role as a co-oxidant, and in the presence of acid, PNO is found to assist the insertion of dihydroxyalkene and, importantly, in releasing the THF-diol to regenerate the active intermediate.
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The remote groups in N-heterocyclic carbene (NHC) ligands have a significant influence on metal-catalyzed reactions. We examine how remote bulkiness, electronic groups, and expanded-ring NHCs (ER-NHCs) influence alkene reactivity and regioselectivity toward hydrocupration using density functional theory calculations. The impact of remote steric bulkiness on the Cu-H insertion rate is analyzed, revealing a strong correlation between the steric substituent constant and rate ratio, where a bulky group increases the rate due to reduced steric effects in the transition state (TS). The steric properties of the examined catalysts (with a remote group R2 = CPh3, CHPh2, CH2Ph, CH3, and H) and their corresponding TSs are found to be modulated greatly by the remote steric substitution group and the ring size of the NHC ligand. Enhanced bulkiness enhances the nucleophilic Cu-H moiety. The remote electronic groups have a smaller impact on insertion barrier compared to that of steric hindrance. Furthermore, ER-NHC exploration indicates that NHCs with over five-membered rings have a significantly negative influence on the reaction rate. Finally, with a highly bulky group (R2 = CPh3), anti-Markovnikov insertion preference is attributed to high interaction energy and improved steric properties. Overall, our findings here provide valuable insights for the development of a more effective catalyst in metal-catalyzed reactions.
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There is a significant variation in symptoms and clinical presentation of connective tissue disorders (CTD) associated with interstitial lung disease (ILD) (CTD-ILD). This presents difficulties in the diagnosis and treatment of CTD-ILD. Early detection and treatment of CTD-ILD using a multidisciplinary approach have been shown to enhance patient outcomes. This exercise aims to explore clinical components to develop a screening tool for pulmonologists for early detection of CTD in ILD and to provide a framework for a multidisciplinary approach in managing CTD-ILD. This in turn will lead to early treatment of CTD-ILD in collaboration with rheumatologists. A panel of 12 leading rheumatologists from the Middle East and North Africa (MENA) region met virtually to select the most relevant clinical findings to aid in identifying CTD-ILD. Twelve panellists opted to investigate seven of the most common inflammatory autoimmune disorders. The panel discussed how to improve the early detection of CTD-ILD. Clinical characteristics were categorized, and a nine-item questionnaire was created. A biphasic algorithm was developed to guide early referral to a rheumatologist based on the presence of one of nine clinical features of CTD (Phase 1) or the presence of CTD-specific antibodies (Phase 2). A brief questionnaire has been developed to serve as a simple and practical screening tool for CTD-ILD detection. Additional research is needed to validate and evaluate the tool in longitudinal cohorts.
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Background Rhinoplasty, a prevalent cosmetic surgical procedure worldwide, is not exempt from associated risks and complications, as with any other surgery. In light of the surging demand for rhinoplasty amongst young adults, it is imperative to acknowledge that the procedure can engender various complications that can be classified as either early or late complications. Examples of early complications include epistaxis and periorbital ecchymosis, while late complications may manifest as enophthalmos or septal perforation. The present study endeavors to gauge the knowledge of rhinoplasty complications among adult residents of the Western region of Saudi Arabia. Methods To achieve the research objectives, a cross-sectional study design was implemented, utilizing a self-administered online questionnaire. The study targeted male and female adults aged 18 years and above residing in the Western region of Saudi Arabia. The questionnaire comprised of 14 items, categorized into socio-demographic and rhinoplasty postoperative complications sections, respectively. Results The study gathered responses from a total of 968 participants, of which 60.95% fell within the age range of 18-30 years. The majority of participants identified as female (77.89%), and Saudi citizens constituted the vast majority of the respondents (96.28%). Among the participants, 22.62% expressed a desire to undergo rhinoplasty, whereas 77.38% indicated no interest in the procedure. Of those who sought rhinoplasty, the majority favored having the surgery performed by a skilled physician (81.74%). Notably, participants exhibited a relatively high level of awareness regarding the postoperative complications of rhinoplasty, with respiratory issues being the most widely recognized complication (66.63%). Conversely, headache, nausea, and vomiting were the least familiar complications (100%). Conclusion The study findings reveal a considerable knowledge gap among adults residing in the Western region of Saudi Arabia concerning rhinoplasty's possible postoperative complications. The results underscore the pressing need to establish comprehensive educational and awareness-raising programs to equip individuals contemplating the procedure with the requisite information to make informed decisions. Future research endeavors could delve into the underlying determinants that drive the desire for rhinoplasty and assess potential interventions geared toward augmenting individuals' comprehension and knowledge of the procedure.
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In this paper, two novel dual-band bandpass filters (BPFs) and a compact quad-channel diplexer working at 1.7/3.3 GHz and 1.9/3.6 GHz are proposed. In the proposed diplexer design, triangular loop resonators and rectangular loop resonators are used together to reduce the circuit size and improve diplexer performances. Insertion loss (IL) and return loss (RL) of the proposed diplexer are better than 0.8 dB and 21 dB, respectively, at these four operating frequencies. Output ports isolation parameter is better than 30 dB. With the achieved specifications, the proposed diplexer can be used in L and S band applications.
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N-Heterocyclic carbene (NHC) Au(i)-catalyzed organic synthesis has recently been receiving increasing attention, especially with the activation of alkynes. In contrast, counteranions, being widely problematic in Au(i)-catalyzed transformations, are commonly considered as innocent partners and are not respectably included in a computational model. Herein, we report density functional theory (DFT) investigations of the Au(i)-catalyzed cyclization of propargylic amides to exploit the mechanistic effect of several counteranions to shed some light for further future developments. Among the counteranions used in this study, NTf2 -, ClO4 -, TsO-, TFA-, TfO-, MsO-, and SbF6 -, both the cyclization and protodeauration step favor the 5-exo-dig product over the 6-endo-dig product when the alkyne moiety is terminated with hydrogen. These anions reveal a crucial influence on the energy profile through lowering the barriers of the reaction. Mechanistically, the results obtained from all counteranions show that the protodeauration is slower than the cyclization. By using an energetic span model, the results clearly indicate that the rate-determining state is the protodeauration step for all counteranions, and thus protodeauration is the turnover-limiting step. The turnover frequency (TOF) results for the formation of the 5-exo-dig product show cyclization reactivity in the order of MsO- > TFA- > ClO4 - > NTf2 - > TfO- > TsO- â« SbF6 -, whereas an order of TFA- > MsO- > NTf2 - > TfO- ≈ ClO4 - > SbF6 - â TsO- is calculated for the protodeauration, suggesting that SbF6 - and TsO- are disfavored due to their slow protodeauration. In this regard, and for the 6-endo-dig pathway, our conclusions demonstrate an order of TfO- > TFA- > MsO- > NTf2 - > ClO4 - > TsO- â SbF6 - for the cyclization and TFA- > TsO- > MsO- > TfO- > NTf2 - > ClO4 - â SbF6 - for the protodeauration, advocating that the anions SbF6 -, NTf2 - and ClO4 - are unlikely partners for the 6-endo-dig pathway because of their slow protodeauration. Finally, the findings here advise that any engineering of the counteranion to increase the efficiency of catalytic system would be more effective on the protodeauration step rather than the cyclization step.
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The pincer-Co catalyzed nitrile hydroboration of nitrile has been presented as an elegant strategy to afford amine synthesis; however, ligand engineering is required. We show here a strategy to tune the catalytic behavior of the organometallic catalyst, as an alternative approach to ligand engineering, by means of computational investigations to understand the effect of partners such as (18-crown-6)K+, W(CO)3 and W(PMe3)3 on the reactivity of the pincer-Co catalyzed nitrile hydroboration reaction through π-coordination to the ligand aromatic ring. The extra additives bind the central phenyl ring of the ligand by either dispersion or chemical bonding. The electron-richness of the cobalt center is tuned by the partner, and follows the order (18-crown-6)K+ > W(PMe3)3 > no partner > W(CO)3. While the influence of the covalent W-containing partners parallels the electron-richness of the W, the non-covalent partner, (18-crown-6)K+, surprisingly increases the donor ability of the pincer ligand through the polarization effect. All the elementary steps involved in the nitrile hydroboration reaction are influenced by the partner, and the overall barrier is lowered by a surprisingly large amount of 4.9 kcal mol-1 in the presence of (18-crown-6)K+, suggesting a notable partner effect to be explored by experimentalists so that the reactivity of a catalyst can be tuned without ligand modification.
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OBJECTIVE: The objective of this study was to compare types of veneer preparations and their combination with three materials. MATERIALS AND METHODS: Two finite element models were specially prepared used representing window and wrap around preparation for veneers. The "central incisor" tooth geometry was acquired using a laser scanner, and then its surface was adjusted to form a solid model prior to the removal of each preparation separately. Three materials (Lava Ultimate, IPS e-max, and Celtra) were tested in combination with the preparation type. Bone geometry was simplified as two coaxial cylinders in all models. Each model was subjected to two loading conditions of occlusion (edge-to-edge bite and normal bite). STATISTICAL ANALYSIS AND RESULTS: It was observed that cortical, cancellous bone, and periodontal ligament are insensitive to preparation or materials. Their stresses and deformation were within physiological limits. Significant changes appeared on the central incisor tooth structure, cement layer, and veneer layer stresses and deformations under loading cases. CONCLUSIONS: Edge-to-edge bite stresses are severe with window-type preparation, and normal bite did not show any critical values on tooth structure, cement layer, or veneer layer. Veneer layer finish line and its contact with the cement layer and tooth structure play a role in the loading transfer mechanism. Preparation type alters the values of stresses on tooth structure, cement, and veneer layers. With window preparation, extreme stresses appear at finish line, while stresses appear under the loading site with wrap around preparation. Veneer and cement layers withstand the load energy with wrap around preparation and reduce tooth structure stresses. Thus, the lifetime of veneer and cement layers might be longer with window preparation.
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Resonant elastic soft X-ray magnetic scattering (XRMS) is a powerful tool to explore long-periodic spin textures in single crystals. However, due to the limited momentum transfer range imposed by long wavelengths of photons in the soft x-ray region, Bragg diffraction is restricted to crystals with the large lattice parameters. Alternatively, small-angle X-ray scattering has been involved in the soft energy X-ray range which, however, brings in difficulties with the sample preparation that involves focused ion beam milling to thin down the crystal to below a few hundred nm thickness. We show how to circumvent these restrictions using XRMS in specular reflection from a sub-nanometer smooth crystal surface. The method allows observing diffraction peaks from the helical and conical spin modulations at the surface of a Cu 2 OSeO 3 single crystal and probing their corresponding chirality as contributions to the dichroic scattered intensity. The results suggest a promising way to carry out XRMS studies on a plethora of noncentrosymmetric systems hitherto unexplored with soft X-rays due to the absence of the commensurate Bragg peaks in the available momentum transfer range.
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Studies of multiple bonding between transition metal complexes offer fundamental insight into the nature of bonding between metal ions and facilitate predictions of the physical properties and the reactivities of metal complexes containing metal-metal multiple bonds. Here we report a computational interrogation on the nature of the metal-metal bonding for neutral, oxidized, and reduced forms of dinuclear rhenium and osmium corrole complexes, [{Re[TpXPC]}2]0/1+/1- and [{Os[TpXPC]}2]0/1+/1-, using a complete active space self-consistent (CASSCF) methodology and density functional theory (DFT) calculations. For [{Re[TpXPC]}2]0, [{Ru[TpXPC]}2]0, and [{Os[TpXPC]}2]0, CASSCF calculations shows that the effective bond order is 3.29, 2.63, and 2.73, respectively. On their oxidized forms, [{Re[TpXPC]}2]1+, [{Ru[TpXPC]}2]1+, and [{Os[TpXPC]}2]1+ molecules, the results indicate an electron removal from a ligand-based orbital, where [{Re[TpXPC]}2]1+ gives slightly different geometry from its neutral form due to populating the δ* orbital. In this regard, the CASSCF calculations give an effective bond order of 3.25 which is slightly lower than in the [{Re[TpXPC]}2]0. On their reduced forms, the electron addition appears to be in the metal-based orbital for [{Re[TpXPC]}2]1- and [{Ru[TpXPC]}2]1- whereas in the ligand-based orbital for the Os-analogue which has no effect on the Os-Os bonding, an effective bond order of 3.18 and 2.17 is presented for the [{Re[TpXPC]}2]1- and [{Ru[TpXPC]}2]1-, respectively, within the CASSCF simulations. These results will further encourage theoreticians and experimentalists to design metalloporphyrin dimers with distinct metal-metal bonding.
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Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl-NH-1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with N-sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of NH-1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines. It is shown that the direction of each reaction is not only controlled by the nature of the initial enaminones and sulfonyl azides but also depends on the tested solvent. The problem of removing sulfonamides and amidines from the desired products was solved for the first time using new water-soluble enaminones. Based on the experimental and computational studies, the factors contributing to the selective course of alternative reactions were identified, and methods for the synthesis of azoloyl-NH-1,2,3-triazoles and azolyl diazoketones were developed. Density functional theory (DFT) results have shown that the 1,3-dipolar cycloaddition is totally driven toward one single regioisomer with a high asynchronous bond formation, and the introduction of an electron-deficient group in sulfonyl azides induces faster cycloaddition. Additionally, DFT calculations were used to gain further mechanistic insights on the reaction studied here.
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Although palladium-catalyzed aryl-nitro bond activation reaction has recently gained a lot of interest, it still requires rather harsh conditions. We here systematically explore the substituent effect on oxidative addition steps, known as the rate-determining step, by density functional theory simulations based on a Nakao's nitrogen heterocyclic carbene (NHC) ligand. The key aryl ring on the catalyst, ring A, acts as a π-donor and stabilizes the palladium center of the transition state, and thus an electron-rich ring A is expected to lower the barrier. However, the polarization and electrostatic effects were shown to be more important, although they were often ignored before. These effects originate from through-space interaction with a nitro group in the resting state, and the overall effect is that any polarizable or partly negative group near ortho- or meta-site of ring A is harmful for the reaction. Based on these discoveries, we proposed a list of guidelines for successful ligand developments and designed several new ligands. These ligands exhibit a significantly lower barrier than the reported Nakao's ligand by as large as â¼5 kcal/mol, in both gas phase and solvent with a moderate dipole. These candidates will promote further experimental studies and enhance the ability to improve ligands in a rational and predictive manner.
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Eletrônica , Paládio , Catálise , Ligantes , Eletricidade EstáticaRESUMO
BACKGROUND: Although aortic valve replacement (AVR) has been the standard of treatment for severe aortic stenosis, a small aortic annulus (SAA) poses significant challenges. Improvements in valve designs and evolution in surgical techniques have led to improved outcomes, however, the ideal prosthetic valve remains elusive. METHODS: We performed a comprehensive literature review to discuss the surgical management of aortic stenosis, with a special focus on patients with SAA. RESULTS: Stentless valves and root replacement techniques have been shown to overcome the hemodynamic challenges associated with conventional stented bioprostheses, but are technically challenging and require longer cross-clamp times. Sutureless and rapid deployment valves mitigate the long operative time while maintaining the hemodynamic advantages. The use of transcatheter AVR has emerged as another reasonable alternative and has shown promise among patients with SAA, however, long-term outcomes are awaited. CONCLUSION: There is no consensus regarding the type of valve prosthesis or replacement technique among patients with SAA. Consideration of patient comorbidities and valvular anatomy is paramount in planning the optimal strategy for AVR. Further long-term clinical trials are necessary to assess outcomes and achieve progress toward the development of the ideal prosthesis.
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Estenose da Valva Aórtica , Bioprótese , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Humanos , Desenho de Prótese , Resultado do TratamentoRESUMO
The interaction between the main carrier (serum albumin, SA) of endogenous and exogenous compounds in the bloodstream of different species (human, bovine, canine, rat, rabbit, and sheep) and a general anesthetic agent (propofol, PR) was investigated using an experimental technique (high-performance liquid chromatography) and computational methods (molecular docking, molecular dynamics, sequence, and phylogenetic analyses). The obtained results revealed the differences in the PR binding affinity to various homologous forms of this protein with reliable statistics (R 2 = 0.9 and p-value < 0.005), correlating with the evolutionary relationships among SAs from different species. Additionally, the protein conformational changes (root-mean-square deviation ≈ 1.0 Å) and amino acid conservation of binding sites in protein domains were detected, contributing to the SA-PR binding modes. Overall, the outcomes from this study might provide a novel methodology to assess protein-ligand interactions and to gain some interesting insights into drug pharmacokinetics and pharmacodynamics to explain its variations among different species.
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We report herein a visible-light-mediated C-H alkylation of pyridine derivatives that proceeds by simple combination of a large variety of N-alkoxypyridinium ions with alkanes in the presence of 2 mol % of fac-Ir(ppy)3 under blue illumination. The mild reaction conditions together with the high group functional tolerance make of this process a useful synthetic platform for the construction of structurally strained heterocycles. Detailed mechanistic investigations, including density functional theory calculations and quantum yield measurement, allowed us to understand factors controlling the reactivity and the selectivity of the reaction.
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A density functional theory study is presented here to offer mechanistic insights and explications of experimentally intriguing observations in the Au(I)-catalyzed cyclization of cyclic and acyclic acetals of alkynylaldehydes that leads to indenone formation. The reactivity of catalytic cycles with and without methoxy migration is clearly defined when the alkyne terminus is phenylated. The reaction mechanism of indenone formation proceeds first with the coordination of Au(I) to alkyne to initiate the reaction with 1,5-H shift as a rate-determining step (RDS), and the fastest 1,5-H shift is achieved when one phenyl ring carries an electron-donating group and the other one is substituted with an electron-withdrawing group. Following the 1,5-H shift, the reaction undergoes feasible steps that are cyclization and 1,2-H shift before elimination to persist the iterative cycle, but the reactivity of both steps is highly affected by the existence of the phenyl group on the alkyne terminus. The unreactivity of the alkyne terminus not bearing a phenyl ring is because the cyclization is thermodynamically disfavorable, subsequently deactivating the 1,2-H shift kinetically and thermodynamically. The absence of a tether in the acetal unit considerably outpaces any 1,5-H shift and instead activates 1,5-methoxy migration, giving methoxy-migrated indenone, with the 1,2-OMe shift being an RDS.
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A computational study on Pinnick oxidation of aldehydes into carboxylic acids using density functional theory (DFT) calculations has been evaluated with the (SMD)-M06-2X/aug-pVDZ level of theory, leading to an important understanding of the reaction mechanism that agrees with the experimental observations and explaining the substantial role of acid in driving the reaction. The DFT results elucidated that the first reaction step (FRS) proceeds in a manner where chlorous acid reacts with the aldehyde group through a distorted six-membered ring transition state to give a hydroxyallyl chlorite intermediate that undergoes a pericyclic fragmentation to release the carboxylic acid as a second reaction step (SRS). 1H NMR experiments and simulations showed that hydrogen bonding between carbonyl and t-butanol is unlikely to occur. Additionally, it was found that the FRS is a rate-determining and thermoneutral step, whereas SRS is highly exergonic with a low energetic barrier due to the Cl(III) â Cl(II) reduction. Frontier molecular orbital analysis, intrinsic reaction coordinate, molecular dynamics and distortion/interaction analysis further supported the proposed mechanism.
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The Ru-mediated oxidative cyclisation of 1,5-dienes to furnish 2,5-dihydroxyalkyl-substituted tetrahydrofuran-diols (THF-diols) represents a practical approach for the synthesis of many bioactive natural products. In the current study, we reported profound findings obtained by density functional theory (DFT) simulations, and they were consistent with the experimental conditions. The results set out a catalytic cycle within intermediacy of NaIO4-complexed Ru(vi) species. Importantly, the co-oxidant played a critical role in the cyclisation step and subsequently the release of THF-diols. Following the formation of Ru(vi) glycolate, cyclisation and THF-diol release proceeded through NaIO4-coordinated Ru(vi) intermediates, outpacing the Ru(viii) glycolate or THF-diolate intermediates and subsequently entering "second cycle" type pathways. The results indicated a cycle involving Ru(viii)/Ru(vi)/Ru(iv)/Ru(vi) rather than Ru(viii)/Ru(vi)/Ru(viii)/Ru(vi)/Ru(viii). Additionally, the existence of an electron-withdrawing group (EWG) on one of the double bonds of 1,5-dienes revealed that the regioselectivity of the Ru-catalysed oxidative cyclisation was predominantly initiated at the electron-rich alkene. Overall, this study offers new insights, which were ignored by earlier experimentalists and theoreticians, into the Ru-catalysed functionalizations of alkenes and 1,5-dienes.