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Herein we have reported a fluorescent probe (MB-M) based on MB derivative for Cu 2+ ions detection. The probe was well characterized by 1 H NMR, 13 C NMR and HR-MS spectrum. Probe MB-M showed naked-eyes recognition to Cu 2+ as color change from colorless to indigo. The probe exhibited promising features such as high fluorescence and UV-vis selectivity, fast response (5 mint), workable at pH 2-7, and low limit of detection (LOD = 0.33 µM). Probe MB-M was also used for Cu 2+ ions imaging in HepG-2 cells and detection in daily life (Test Strip and lake water). Moreover, non-covalent interaction (NCI) and quantum theory of atoms in molecules (QTAIM) analysis were used to study the interaction between MB-M and Cu 2+ ions. By examining the electronic characteristics of the complex using natural bond orbital (NBO), electron density difference (EDD), and frontier molecular orbital (FMO) analysis, the sensitivity of MB-M towards Cu 2+ ions were investigated. The results illustrated that the interactions between MB-M and Cu 2+ ions involved chemisorption., (© 2024. The Author(s).)

A novel series of alkaline earthides containing eight complexes based upon 3 6 adz complexant are designed by placing carefully transition metals (V-Zn) on inner side and alkaline earth metal outer side of the complexant i.e., M + (3 6 adz) Be - (M +  = V, Cr, Mn, Fe, Co, Ni, Cu and Zn). All the designed compounds are electronically and thermodynamically stable as evaluated by their interaction energy and vertical ionization potential respectively. Moreover, the true nature of alkaline earthides is verified through NBOs and FMO study, showing negative charge and excess electrons on alkaline earth metal respectively. Furthermore, true alkaline earthides characteristics are evaluated graphically by spectra of partial density state (PDOS). The energy gap (HOMO -LUMO gap) is very small (ranging 2.95 eV-1.89 eV), when it is compared with pure cage 3 6 adz HOMO-LUMO gap i.e., 8.50 eV. All the complexes show a very small value of transition energy ranging from 1.68eV to 0.89eV. Also, these possess higher hyper polarizability values up to 2.8 x 10 5 au (for Co + (3 6 adz) Be - ). Furthermore, an increase in hyper polarizability was observed by applying external electric field on complexes. The remarkable increase of 100fold in hyper polarizability of Zn + (3 6 adz) Be - complex is determined after application of external electric field i.e., from 1.7 x 10 4 au to 1.7 x 10 6 au when complex is subjected to external electric field of 0.001 au strength. So, when external electric field is applied on complexes it enhances the charge transfer, polarizability and hyper polarizability of complexes and proves to be effective for designing of true alkaline earthides with remarkable NLO response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the current work, organic cyclopenta-thiophene (CPT) based derivatives (FICR and FICD1-FICD5) were designed by the modulation of end-capped acceptor group of the reference molecule i.e., FICR, to explore their nonlinear optical (NLO) response. The effect of terminal acceptor and donor groups in the tailored compounds was explored by using DFT based quantum calculations. The UV-Vis analysis, frontier molecular orbitals (FMOs), transition density matrix (TDM), natural bond orbitals (NBOs), density of states (DOS), nonlinear optical (NLO) analyses were performed at M06/6-311G(d,p) functional. The LUMO-HOMO band gaps of FICD1-FICD5 were found to be smaller (1.75-1.92 eV) comparative to FICR (1.98 eV). Moreover, the global reactivity parameters (GRPs) were correlated with the results of other analyses. FICD2 and FICD5 with lowest band gap 1.73 and 1.75 eV showed less hardness (0.86 and 0.87 eV, respectively), high softness (0.58 and 0.57 eV -1 ), and larger absorption spectrum (815 and 813 nm) in gaseous phase and (889 and 880 nm) in solvent phase among all entitled compounds. All the designed chromophores (FICD1-FICD5) demonstrated a significant NLO response as compared to FICR. Particularly, FICD2 and FICD5 exhibited the highest average linear polarizability (<α>) [2.86 × 10 -22 and 2.88 × 10 -22 esu], first hyperpolarizability (β tot ) (8.43 × 10 -27 and 8.35 × 10 -27 esu) and second hyperpolarizability (γ tot ) (13.20 × 10 -32 and 13.0 × 10 -32 esu) values as compared to the other derivatives. In nutshell, structural modeling of CPT based chromophores with extended acceptors, can be significantly utilized to achieve potential NLO materials., (© 2024. The Author(s).)

Polysaccharides are favourable and promising biopolymers for wound care applications due to their abundant natural availability, low cost and excellent biocompatibility. They possess different functional groups, such as carboxylic, hydroxyl and amino, and can easily be modified to obtain the desirable properties and various forms. This review systematically analyses the recent progress in polysaccharides derived materials for wound care applications, emphasizing the most commonly used cellulose, chitosan, alginate, starch, dextran and hyaluronic acid derived materials. The distinctive attributes of each polysaccharide derived wound care material are discussed in detail, along with their different forms, i.e., films, membranes, sponges, nanoemulsions, nanofibers, scaffolds, nanocomposites and hydrogels. The processing methods to develop polysaccharides derived wound care materials are also summarized. In the end, challenges related to polysaccharides derived materials in wound care management are listed, and suggestions are given to expand their utilization in the future to compete with conventional wound healing materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Due to excellent biocompatibility, bioactivities, and osteoconductivity, hydroxyapatite (HAp) is considered as one of the most suitable biomaterials for numerous biomedical applications. Herein, HAp was fabricated using a bottom-up approach, i.e., a wet chemical method, and its composites with TiC, h-BN, and ZrO 2 were fabricated by a solid-state reaction method with enhanced mechanical and biological performances. Structural, surface morphology, and mechanical behavior of the fabricated composites were characterized using various characterization techniques. Furthermore, transmission electron microscopy study revealed a randomly oriented rod-like morphology, with the length and width of these nanorods ranging from 78 to 122 and from 9 to 13 nm. Moreover, the mechanical characterizations of the composite HZBT4 (80HAp-10TiC-5h-BN-5ZrO 2 ) reveal a very high compressive strength (246 MPa), which is comparable to that of the steel (250 MPa), fracture toughness (14.78 MPa m 1/2 ), and Young's modulus (1.02 GPa). In order to check the biocompatibility of the composites, numerous biological tests were also performed on different body organs of healthy adult Sprague-Dawley rats. This study suggests that the composite HZBT4 could not reveal any significant influence on the hematological, serum biochemical, and histopathological parameters. Hence, the fabricated composite can be used for several biological applications, such as bone implants, bone grafting, and bone regeneration.

Owing to the broad applications of quaternary ammonium salts (QAS), we present the synthesis of benzimidazolium-based analogues with variation in the alkyl and alkoxy group at N-1 and N-3 positions. All the compounds were characterized by spectroscopic techniques and found stable to air and moisture both in the solid and solution state. Moreover, molecular structures were established through single-crystal X-ray diffraction studies. The crystal packing of the compounds was stabilized by numerous intermolecular interactions explored by Hirshfeld surface analysis. The enrichment ratio was calculated for the pairs of chemical species to acquire the highest propensity to form contacts. Void analysis was carried out to check the mechanical response of the compounds. Furthermore, theoretical investigations were also performed to explore the optoelectronic properties of compounds. Natural population analysis (NPA) has been conducted to evaluate the distribution of charges on the synthesized compounds, whereas high band gaps of the synthesized compounds by frontier molecular orbital (FMO) analysis indicated their stability. Nonlinear optical (NLO) analysis revealed that the synthesized QAS demonstrates significantly improved NLO behaviour than the standard urea., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

The most common denture material used for dentistry is poly-methyl-methacrylate (PMMA). Usually, the polymeric PMMA material has numerous biological, mechanical and cost-effective shortcomings. Hence, to resolve such types of drawbacks, attempts have been made to investigate fillers of the PMMA like alumina (Al 2 O 3 ), silica (SiO 2 ), zirconia (ZrO 2 ) etc. For the enhancement of the PMMA properties a suitable additive is required for its orthopedic applications. Herein, the main motive of this study was to synthesize a magnesium oxide (MgO) reinforced polymer-based hybrid nano-composites by using heat cure method with superior optical, biological and mechanical characteristics. For the structural and vibrational studies of the composites, XRD and FT-IR were carried out. Herein, the percentage of crystallinity for all the fabricated composites were also calculated and found to be 14.79-30.31. Various physical and optical parameters such as density, band gap, Urbach energy, cutoff energy, cutoff wavelength, steepness parameter, electron-phonon interaction, refractive index, and optical dielectric constant were also studied and their values are found to be in the range of 1.21-1.394 g/cm 3 , 5.44-5.48 eV, 0.167-0.027 eV, 5.68 eV, 218 nm, 0.156-0.962, 4.273-0.693, 1.937-1.932, and 3.752-3.731 respectively. To evaluate the mechanical properties like compressive strength, flexural strength, and fracture toughness of the composites a Universal Testing Machine (UTM) was used and their values were 60.3 and 101 MPa, 78 and 40.3 MPa, 5.85 and 9.8 MPa-m 1/2 respectively. Tribological tests of the composites were also carried out. In order to check the toxicity, MTT assay was also carried out for the PM0 and PM15 [(x)MgO + (100 - x) (C 5 O 2 H 8 ) n ] (x = 0 and 15) composites. This study provides a comprehensive insight into the structural, physical, optical, and biological features of the fabricated PMMA-MgO composites, highlighting the potential of the PM15 composite with its enhanced density, mechanical strength, and excellent biocompatibility for denture applications., (© 2024. The Author(s).)

Multiple studies in the literature have demonstrated that synthetic compounds containing heterocyclic rings possess a reparative potential against acute and chronic inflammation. In the present study, two novel thiosemicarbazone derivatives based on l-ethyl-6-(thiophen-2-yl)indoline-2,3-dione with different phenyl substituted thiosemicarbazides were synthesized by condensation reaction and the structures of proposed target compounds (KP-2 and KP-5) were confirmed by UV-VIS, FTIR, 1 H-NMR and 13 C-NMR. In-vitro anti-inflammatory behavior of KP-2 and KP-5 was confirmed by bovine serum albumin (BSA) and ovine serum albumin (OSA) analysis. Acute and chronic anti-inflammatory potential of synthesized compounds were evaluated by using carrageenan and complete Freund's adjuvant (CFA) as inflammation-inducing agents, respectively. Inhibition of pro-inflammatory mediators and prevention of protein denaturation owing to synchronization of more electronegative flouro-groups substituted on phenyl rings along with heterocyclic indoline ring provides anti-inflammatory effects and are corroborated by radiological, histopathological analysis. Additional support was provided through density functional theory (DFT) and molecular docking. KP-5 exhibited excellent lead-likeness based on its physicochemical parameters, making it a viable drug candidate. The synthesized compounds also showed promising ADMET properties, enhancing their potential as therapeutic agents. These findings emphasize the pivotal role of new compounds for drug design and development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this work, four fluorinated α, β-unsaturated ketones named as 3-(3-bromophenyl)-1-(3-(trifluoromethyl)phenyl)prop-2-en-1-one (1), 3-(4-methoxyphenyl)-1-(3-(trifluoromethyl)phenyl) prop-2-en-1-one (2), 3-(3-bromo-5-chloro-2-hydroxyphenyl)-1-(3-(trifluoromethyl)phenyl) prop-2-en-1-one (3) and 3-(2-hydroxy-5-methylphenyl)-1-(3-(trifluoromethyl)phenyl)prop-2-en-1-one (4) were synthesized by Claisen-Schmidt reaction. The synthesized molecules were then characterized through ultraviolet-visible spectroscopy (UV-Vis), Fourier transform infrared (FTIR), 1 H-NMR, 13 C-NMR, and mass spectrometry. The antioxidant potential, Urease inhibition, and interaction of compounds 1-4 with Salmon sperm DNA were experimentally explored and supported by molecular docking studies. The synthesized compounds strongly interact with SS-DNA through intercalative mode. It was noticed that compound 1 served as potent Urease inhibitor while compound 4 as better antioxidant among synthesized compounds. Moreover, frontier molecular orbitals, nonlinear optical (NLO) properties, natural bond orbitals, molecular electrostatic potential, natural population analysis, and photophysical properties of synthesized compounds were accomplished through density functional theory and time-dependent density functional theory. The band gap of all the compounds have been worked out using Taucs method. In addition to that, a precise comparative account of UV and IR data obtained from theoretical and experimental findings showed good agreement between theoretical and experimental data. The findings of our studies reflected that compounds 1-4 possess better NLO properties than Urea standard and the band gap data also reflected their prospective use towards optoelectronic materials. The better NLO behavior of compounds was attributed to the noncentrosymmetric structure of synthesized compounds., (© 2023 Wiley Periodicals LLC.)

Hydrogen is currently considered as the best alternative for traditional fuels due to its sustainable and ecofriendly nature. Additionally, hydrogen dissociation is a critical step in almost all hydrogenation reactions, which is crucial in industrial chemical production. A cost-effective and efficient catalyst with favorable activity for this step is highly desirable. Herein, transition-metal-doped fullerene (TM@C 60 ) complexes are designed and investigated as single-atom catalysts for the hydrogen splitting process. Interaction energy analysis ( E int ) is also carried out to demonstrate the stability of designed TM@C 60 metallofullerenes, which reveals that all the designed complexes have higher thermodynamic stability. Furthermore, among all the studied metallofullerenes, the best catalytic efficiency for hydrogen dissociation is seen for the Sc@C 60 catalyst E a = 0.13 eV followed by the V@C 60 catalyst E a = 0.19 eV. The hydrogen activation and dissociation processes over TM@C 60 metallofullerenes is further elaborated by analyzing charge transfer via the natural bond orbital and electron density difference analyses. Additionally, quantum theory of atoms in molecule analysis is carried out to investigate the nature of interatomic interactions between hydrogen molecules and TMs@C 60 metallofullerenes. Overall, results of the current study declare that the Sc@C 60 catalyst can act as a low cost, highly efficient, and noble metal-free single-atom catalyst to efficiently catalyze hydrogen dissociation reaction., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Herein, present study mainly focuses on the synthesis and characterizations of boron nitride reinforced waste zirconia (wZrO 2 ) with different concentrations. Composites were prepared via a scalable solid-state reaction method. Various physical parameters such as density, ionic concentration, polaron radius, and field strength were evaluated. XRD results reveal crystalline nature with a major phase of tetragonal zirconia and as boron nitride is reinforced, the tetragonal transforms into a monoclinic zirconia. Interconnected spherical grains and nanosheets were observed using FESEM. Mechanical characterizations revealed the highest compressive strength of 266 MPa. The latent fingerprints were visualized using a composite on different surfaces, implementing the powder dusting and solution techniques. MTT assay was performed and revealed good biocompatible nature. These results reveal that composite is suitable for fabrication of bioceramics with acceptable mechanical and biological performances. The composite can also be utilized for latent fingerprint detection in forensic science., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in the present paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Y-series-based non-fullerene acceptors (NFAs) have achieved significant deliberation by chemists and physicists because the promising optical and photochemical properties associated with high-performance OSCs can be further tuned through end-capped modification. In this work, such modifications of Y-series benzothiadiazole-based NFAs were accomplished theoretically to propose new acceptors for photovoltaic cells (PVCs). The recently synthesized Y-series non-fullerene acceptor m-BTP-PhC6 was taken as a reference acceptor. We designed five new acceptors (BTP1-BTP5) through the structural modification at both ends of acceptor groups and evaluated their performance by applying DFT and TD-DFT. The newly engineered molecules exhibited a narrower bandgap (E g ) than the reference (R) resulting in better intramolecular charge transfer (ICT). Further, the designed acceptors expressed the maximum absorption in the region of 600-800 nm revealing a redshift in their absorption spectrum. Low excitation energy and low exciton binding energy were noted for designed acceptors confirming them as better candidates for high PCE of solar cells. Low reorganizational energy for the mobility of holes and electrons was also observed for the designed molecules, indicating improved charge transfer properties. The newly tailored acceptor BTP4 was found to be the promising candidate among all acceptors because of lower bandgap, lower exciton binding energy, reorganizational energy, and redshift of the absorption spectrum. The complex analysis of BTP4 with donor polymer PTB7-Th and PM6 was executed at the same DFT level. Furthermore, FMOs studies showed relatively rich electron density in the acceptor groups of LUMO as compared to the reference molecule. The overall theoretical results of this study showed that the designed acceptors played a productive and effective role in uplifting the efficiency of fullerene-free energy devices., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Proteins-derived polymeric micelles have gained attention and revolutionized the biomedical field. Proteins are considered a favorable choice for developing micelles because of their biocompatibility, harmlessness, greater blood circulation and solubilization of poorly soluble drugs. They exhibit great potential in drug delivery systems as capable of controlled loading, distribution and function of loaded agents to the targeted sites within the body. Protein micelles successfully cross biological barriers and can be incorporated into various formulation designs employed in biomedical applications. This review emphasizes the recent advances of protein-based polymeric micelles for drug delivery to targeted sites of various diseases. Most studied protein-based micelles such as soy, gelatin, casein and collagen are discussed in detail, and their applications are highlighted. Finally, the future perspectives and forthcoming challenges for protein-based polymeric micelles have been reviewed with anticipated further advances.

The performance of organic solar cells (OSCs) has been improving steadily over the last few years, owing to the optimization of device fabrication, fine-tuning of morphology, and thin-film processing. Thiophene core containing fused ring-type non-fullerene acceptors (NFAs) achieved significant proficiency for highly efficient OSCs. Quantum chemical computations are utilized herein with the motive of suggesting new NIR sensitive, highly efficient low-band gap materials for OSCs. A series of extended conjugated A-π-D-π-A architectured novel fused-ring NFAs (FUIC-1-FUIC-6) containing thieno[2,3- b ]thiophene-based donor core are proposed by substituting the end-capped units of synthesized molecule F10IC. Different properties including frontier molecular orbital analysis, density of states analysis, transition density matrix analysis, excitation energy, reorganizational energies of both holes (λ h ) and electrons (λ e ), and open-circuit voltage ( V oc ) were performed employing the density functional theory approach. Charge transfer analysis of the best-designed molecule with the donor complex was analyzed to comprehend the efficiency of novel constructed molecules (FUIC-1-FUIC-6) and compared with the reference. End-caped acceptor alteration induces the reduction of the energy gap between HOMO-LUMO (1.88 eV), tunes the energy levels, longer absorption in the visible and near-infrared regions, larger V oc , smaller reorganizational energies, and binding energy values in designed structures (FUIC-1-FUIC-6) in comparison to reference (FUIC). The designed molecules show the best agreement with the PTBT-T donor polymer blend and cause the highest charge from the HOMO to the LUMO orbital. Our findings predicted that thieno[2,3- b ] thiophene-based newly designed molecules would be efficient NFAs with outstanding photovoltaic characteristics and can be used in future applications of OSCs., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Propolis (bee glue) is a complex, phyto-based resinous material obtained from beehives. Its chemical and biological properties vary with respect to bee species, type of plants, geographical location, and climate of a particular area. This study was planned with the aim of determining the chemical composition and to investigate various properties (against oxidants and microbes) of different extracts of Saudi propolis collected from Arabian honey bee ( Apis mellifera jemenitica ) colonies headed by young queens. Chemical analysis of propolis extracts with different solvents, i.e., ethyl acetate (Eac), methanol (Met), butanol (BuT), and hexane (Hex) was done through colorimetry for the total phenolic content (TPC) and total flavonoid content (TFC) evaluation. For separation and extensive characterization of the Met extract, chromatography and 1 H NMR were deployed. Six different microorganisms were selected to analyze the Saudi-propolis-based extract's antimicrobial nature by measuring zones of inhibition (ZOI) and minimum inhibitory concentration (MIC). Molecular docking was done by utilizing AutodDock, and sketching of ligands was performed through Marvin Chem Sketch (MCS), and the resultant data after 2D and 3D clean were stored in .mol format. The highest TFC (96.65 mg quercetin equivalents (QE)/g of propolis) and TPC (325 mg gallic acid equivalents (GAE)/g of propolis) were noted for Met. Six familiar compounds were isolated, and recognition was done with NMR. Met extract showed the greatest 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging activity and Ferric Reducing Antioxidant Power (FRAP). Met showed max microbial activity against Staphylococcus aureus (ZOI = 18.67 mm, MIC = 0.625 mg/mL), whereas the minimum was observed in Hex against E. coli (ZOI = 6.33 mm, MIC = 2.50 mg/mL). Furthermore, the molecular docking process established the biological activity of separated compounds against HCK (Hematopoietic cell kinase) and Gyrase B of S. aureus . Moreover, the stability of protein-ligand complexes was further established through molecular dynamic simulation studies, which showed that the receptor-ligand complexes were quite stable. Results of this research will pave the way for further consolidated analysis of propolis obtained from Arabian honey bees ( A. m. jemenitica ).

End-capped modification is an efficient approach for enhancing the power conversion efficiency of organic solar cells (OSCs). Herein, five novel acceptor molecules have been designed by end-capper modification of the recently synthesized molecule NTIC ( R ). Different geometric and photovoltaic properties like frontier molecular orbital analysis, absorption maximum, transition density matrix analysis, reorganizational energy, binding energy, oscillator strength, energy of excitation, and charge transfer analysis of designed and reference molecules have been computed by employing density functional theory and time-dependent density functional theory. Designed molecules expressed a narrow energy band gap ( E g ) with red-shifting in the absorption spectrum. Additionally, low excitation and binding energies are also noted in designed molecules. Excellent values of hole and electron reorganizational energies suggested that designed molecules are effective contributors to the development of the active layer of the organic solar cells. Further, a complex study is also performed for evaluation of charge transfer between the acceptor molecule and the donor polymer. Results of all analyses recommended that designed molecules are effective candidates for high-performance organic solar cell applications., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Essential oils (EOs) have received attention in the food industry for developing biopolymer-derived food packaging materials. EOs are an excellent choice to replace petroleum-derived additives in food packaging materials due to their abundance in nature, eco-friendliness, and superior antimicrobial and antioxidant attributes. Thus far, EOs have been used in cellulose-, starch-, chitosan-, and protein-based food packaging materials. Biopolymer-based materials have lower antioxidant and antibacterial properties in comparison with their counterparts, and are not suitable for food packaging applications. Various synthetic-based compounds are being used to improve the antimicrobial and antioxidant properties of biopolymers. However, natural essential oils are sustainable and non-harmful alternatives to synthetic antimicrobial and antioxidant agents for use in biopolymer-derived food packaging materials. The incorporation of EOs into the polymeric matrix affects their physicochemical properties, particularly improving their antimicrobial and antioxidant properties. EOs in the food packaging materials increase the shelf life of the packaged food, inhibit the growth of microorganisms, and provide protection against oxidation. Essential oils also influence other properties, such as tensile, barrier, and optical properties of the biopolymers. This review article gives a detailed overview of the use of EOs in biopolymer-derived food packaging materials. The innovative ways of incorporating of EOs into food packaging materials are also highlighted, and future perspectives are discussed.

The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) pandemic has become a global challenge based on its replication within the host cells that relies on non-structural proteins, protease (M pro ). Flavonoids, an important class of naturally occurring compounds with medicinal importance, are frequently available within fruits and vegetables. Herein, we report the in silico studies on naturally occurring flavonoids consisting of molecular docking studies and evaluation of theoretical kinetics. In this study, we prepared a library of nine different classes of naturally occurring flavonoids and screened them on Autodock and Autodockvina. The pharmacokinetic properties of most promising compounds have been predicted through ADMET SAR, inhibition constants, ligand efficiency and ligand fit quality have been worked out theoretically. The results revealed that naturally occurring flavonoids could fit well in the receptor's catalytic pocket, interact with essential amino acid residues and could be useful for future drug candidates through in vitro and in vivo studies. Moreover, MD simulation studies were conducted for two most promising flavonoids and the protein-ligand complexes were found quite stable. The selected natural flavonoids are free from any toxic effects and can be consumed as a preventive measure against SARS CoV-2., (© 2021 Published by Elsevier B.V. on behalf of King Saud University.)

Organic materials development, especially in terms of nonlinear optical (NLO) performance, has become progressively more significant owing to their rising and promising applications in potential photonic devices. Organic moieties such as carbazole and quinoline play a vital role in charge transfer applications in optoelectronics. This study reports and characterizes the donor-acceptor-donor-π-acceptor (D-A-D-π-A) configured novel designed compounds, namely, Q3D1 - Q3D3 , Q4D1 - Q1D2 , and Q5D1 . We further analyze the structure-property relationship between the quinoline-carbazole compounds for which density functional theory (DFT) and time-dependent DFT (TDDFT) calculations were performed at the B3LYP/6-311G(d,p) level to obtain the optimized geometries, natural bonding orbital (NBO), NLO analysis, electronic properties, and absorption spectra of all mentioned compounds. The computed values of λ max , 364, 360, and 361 nm for Q3 , Q4 , and Q5 show good agreement of their experimental values: 349, 347, and 323 nm, respectively. The designed compounds ( Q3D1 - Q5D1 ) exhibited a smaller energy gap with a maximum redshift than the reference molecules ( Q3 - Q5 ), which govern their promising NLO behavior. The NBO evaluation revealed that the extended hyperconjugation stabilizes these systems and caused a promising NLO response. The dipole polarizabilities and hyperpolarizability (β) values of Q3D1 - Q3D3 , Q4D1 - Q1D2 , and Q5D1 exceed those of the reference Q3 , Q4 , and Q5 molecules. These data suggest that the NLO active compounds, Q3D1 - Q3D3 , Q4D1 - Q1D2 , and Q5D1 , may find their place in future hi-tech optical devices.

The supply of affordable, high-quality pharmaceuticals to US patients has been on a critical path for decades. In and beyond the COVID-19 pandemic, this critical path has become tortuous. To regain reliability, reshoring of the pharmaceutical supply chain to the USA is now a vital national security need. Reshoring the pharmaceutical supply with old know-how and outdated technologies that cause inherent unpredictability and adverse environmental impact will neither provide the security we seek nor will it be competitive and affordable. The challenge at hand is complex akin to redesigning systems, including corporate and public research and development, manufacturing, regulatory, and education ones. The US academic community must be engaged in progressing solutions needed to counter emergencies in the COVID-19 pandemic and in building new methods to reshore the pharmaceutical supply chain beyond the pandemic.

In this study, six compositions in the system [ x (h-BN)-(100 - x )ZrO 2 ] (10 ≤ x ≤ 90) were synthesized by a bottom up approach, i.e. , the solid-state reaction technique. XRD results showed the formation of a novel and main phase of zirconium oxynitrate ZrO(NO 3 ) 2 and SEM exhibited mixed morphology of layered and stacked h-BN nanosheets with ZrO 2 grains. The composite sample 10 wt% h-BN + 90 wt% ZrO 2 (10B90Z) showed outstanding mechanical properties for different parameters, i.e. , density (3.12 g cm -3 ), Young's modulus (10.10 GPa), toughness (2.56 MJ m -3 ), and maximum mechanical strength (227.33 MPa). The current study further checked the in vivo toxicity of composite 10B90Z and composite 90B10Z using Drosophila melanogaster . The composite 10B90Z showed less cytotoxicity in this model, while the composite 90B10Z showed higher toxicity in terms of organ development as well as internal damage of the gut mostly at the lower concentrations of 1, 10, and 25 μg mL -1 . Altogether, the current study proposes the composite 10B90Z as an ideal compound for applications in biomedical research. This composite 10B90Z displays remarkable mechanical and biological performances, due to which we recommend this composition for various biomedical applications., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Herein, we report the quantum chemical results based on density functional theory for the polarizability ( α ) and first hyperpolarizability ( β ) values of diacetylene-functionalized organic molecules (DFOM) containing an electron acceptor (A) unit in the form of nitro group and electron donor (D) unit in the form of amino group. Six DFOM 1 - 6 have been designed by structural tailoring of the synthesized chromophore 4,4'-(buta-1,3-diyne-1,4-diyl) dianiline ( R ) and the influence of the D and A moieties on α and β was explored. Ground state geometries, HOMO-LUMO energies, and natural bond orbital (NBO) analysis of all DFOM ( R and 1 - 6 ) were explored through B3LYP level of DFT and 6-31G(d,p) basis set. The polarizability ( α ), first hyperpolarizability ( β ) values were computed using B3LYP (gas phase), CAM-B3LYP (gas phase), CAM-B3LYP (solvent DMSO) methods and 6-31G(d,p) basis set combination. UV-Visible analysis was performed at CAM-B3LYP/6-31G(d,p) level of theory. Results illustrated that much reduced energy gap in the range of 2.212-2.809 eV was observed in designed DFOM 1 - 6 as compared to parent molecule R (4.405 eV). Designed DFOM (except for 2 and 4 ) were found red shifted compared to parent molecule R . An absorption at longer wavelength was observed for 6 with 371.46 nm. NBO analysis confirmed the involvement of extended conjugation and as well as charge transfer character towards the promising NLO response and red shift of molecules under study. Overall, compound 6 displayed large α and β tot , computed to be 333.40 (a.u) (B3LYP gas), 302.38 (a.u.) (CAM-B3LYP gas), 380.46 (a.u.) (CAM-B3LYP solvent) and 24708.79 (a.u), 11841.93 (a.u.), 25053.32 (a.u) measured from B3LYP (gas), CAM-B3LYP (gas) and CAM-B3LYP (DMSO) methods respectively. This investigation provides a theoretical framework for conversion of centrosymmetric molecules into non-centrosymmetric architectures to discover NLO candidates for modern hi-tech applications.

Facilitating utility of prior knowledge to accelerate evidence-based new drug development is a focus of several communities of knowledge, such as clinical pharmacology. For example, progress has been made via modeling and simulation of pharmacokinetic and pharmacodynamic relationships in the more effective use of "End of Phase 2" regulatory meetings for a New Drug Application (NDA). Facilitating utility of prior "Chemistry, Manufacturing, and Controls" (CMC) knowledge to accelerate new drug development and regulatory review process is also a topic of significant interest. This paper focuses on facilitating the utility of prior pharmaceutical formulation knowledge to accelerate drug product development and regulatory review of generic and biosimilar products. This knowledge is described as New Prior Knowledge (NPK) because research is often needed to fill ontological (i.e., the domain of connectivity between concepts and phenomena), epistemological (i.e., distinguishing knowledge or justified belief from the opinion), and methodological gaps in information derived a decade or so ago. The corporate economic advantages of such knowledge are derived, in part, when significant portions remain a trade secret. The proposed NPK seeks to generate knowledge about critical aspects of pharmaceutical quality and failure modes to place it in the public domain and to facilitate accelerated and more confident development and regulatory review of generic products. The paradoxical combination of "new" and "prior knowledge" is chosen deliberately to highlight both a distinction from proprietary and trade secret information and to acknowledge certain historical dogmas inherent in the current practices. Considerations for operationalizing NPK are also summarized.

Levothyroxine sodium pentahydrate (LEVO) tablets have been on the US market since the mid-twentieth century and remain the most highly prescribed product. Unfortunately, levothyroxine sodium tablets have also been one of the most highly recalled products due to potency and dissolution failures on stability. In 2008, the assay limits were tightened, yet the recalls did not decline, which highlights the serious quality concerns remaining to be elucidated. The aim of the present investigation was to test the hypothesis that the solid-state physical instability of LEVO precedes the chemical instability leading to product failure. The failure mode was hypothesized to be the dehydration of the crystal hydrate, when exposed to certain humidity and temperature conditions, followed by the oxidation of the API through vacated channels. It was previously reported by the authors that LEVO degradation occurred in the presence of oxygen at a low relative humidity (RH). Furthermore, powder X-ray diffractometry shows changes in the crystal lattice of LEVO initially and through the dehydration stages. Storage of LEVO at RT and 40 °C at 4-6% RH for 12 days shows a decrease in d-spacing of the (00 l) planes. Based on a structure solution from the powder data of the dehydrated material, the basic packing motif persists to varying degrees even when fully dehydrated along with disordering. Therefore, the crystal structure changes of LEVO depend on RH and temperature and are now explicable at the structural level for the first time. This exemplifies the dire need for "new prior knowledge" in generic product development.

The genus Datura comprises wild shrub plants that belong to the Solanaceae family. Naturally, they possess both medicinal and poisonous properties due to the presence of many biologically active phytochemical constituents. Traditionally, Datura had been used for mystic and religious purposes, as a natural drug to treat asthma, pain, gout, boils, abscesses, and wounds, and as psychoactive infusions and fumitories. Different Datura species exhibit diverse ethnopharmacological activities against different diseases, and many ancient and traditional cultures have used various forms of Datura to treat ailments and to prevent many diseases. In this article, we comprehensively summarize various phytochemical constituents isolated from Datura, their pharmacological properties against different diseases, parts of the plants used as traditional therapeutic agents, regions where they are located, and botanical descriptions of different Datura species. The ethnopharmacological properties of Datura may provide new insights for discovery and development of natural drugs. Further research is needed for the investigation of mechanisms of action and to develop safety profiles of the phytochemical constituents isolated from Datura species.

Hispidulin is well-known natural bioactive flavone on behalf of its pharmacological aspects. This review contains data on isolation, synthetic methodology, pharmacokinetics and bioactivities of hispidulin. The article provides a critical assessment of present knowledge about hispidulin with some clear conclusions, perspectives and directions for future research in potential applications.

Hispidulin is well-known natural bioactive flavone on behalf of its pharmacological aspects. This review contains data on isolation, synthetic methodology, pharmacokinetics and bioactivities of hispidulin. The article provides a critical assessment of present knowledge about hispidulin with some clear conclusions, perspectives and directions for future research in potential applications.

The reactions of bromomethyllithium with tert-alkylboronic esters could be of great potential for the formation of quaternary carbon centers but often give poor yields/conversions. Calculations and experimental evidence show that tert-alkyl groups migrate less effectively than other types of alkyl group in such reactions and that O-migration competes. Furthermore, slow/incomplete capture of the bromomethyl reagent by the boronic ester is a problem in more hindered systems, and an additional competing reaction, possibly Li-Br exchange on the bromomethylborate species, also leads to lower yields of migrated products. Based on this, experimental protocols have been devised in which the competing reactions are largely suppressed, leading to higher conversions to migrated product for several substrates.

In the title compound, C(16)H(13)BrFN(3)O(2)S, the dihedral angle between the aromatic rings is 2.55 (19)° and the C=N-N=C torsion angle is 178.9 (3)°. The conformation of the thia-zine ring is an envelope, with the S atom displaced by -0.811 (3) Å from the mean plane of the other five atoms (r.m.s. deviation = 0.042 Å). In the crystal, C-H⋯O inter-actions link the mol-ecules and weak aromatic π-π stacking between the fluoro-benzene and bromo-benzene rings [centroid-centroid separation = 3.720 (2) Å and inter-planar angle = 2.6 (2)°] is also observed.

In the title compound, [Cu(C(12)H(18)N(2)O(2))]·0.25H(2)O, the coordination of the O,N,N',O'-tetra-dentate ligand results in a cis-CuN(2)O(2) square-planar geometry for the metal ion and the presence of two six-membered and one five-membered chelate rings. The complete complex mol-ecule is close to planar (r.m.s. deviation = 0.047 Å). The uncoordinated water mol-ecule (O-atom site symmetry 2) was modelled as half occupied. In the crystal, C-H⋯O(w) and O(w)-H⋯O (w = water) hydrogen bonds link the components into layers parallel to ab plane.

Nine compounds have been isolated from the ethyl acetate soluble fraction of C. sinensis, namely protocatechuic acid (1), trans-caffeic acid (2), methyl rosmarinate (3), rosmarinic acid (4), kaempferide-3-O-β-D-glucopyranoside (5), kaempferol-3-O-β-D-glucopyranoside (6), quercetin-3-O-β-D-glucopyranoside (7), kaempferide-3-O-α-L-rhamnopyranosyl (1→6)-β-D-glucopyranoside (8) and kaempferol-3-O-α-L-rhamno-pyranosyl (1→6)-β-D-glucopyranoside (9), all reported for the first time from this species. The structures of these compounds were deduced on the basis of spectroscopic studies, including 1D and 2D NMR techniques. Compounds 1-9 were investigated for biological activity and showed significant anti-inflammatory activity in the carrageen induced rat paw edema test. The antioxidant activities of isolated compounds 1-9 were evaluated by the DPPH radical scavenging test, and compounds 1, 2, 4 and 7-9 exhibited marked scavenging activity compared to the standard BHA. These compounds were further studied for their anti-glycation properties and some compounds showed significant anti-glycation inhibitory activity. The purity of compounds 2-5, 8 and 9 was confirmed by HPLC. The implications of these results for the chemotaxonomic studies of the genus Cordia have also been discussed.

Quantification analysis with near-infrared (NIR) spectroscopy typically requires utilizing chemometric techniques, such as partial least squares (PLS) method, to achieve the desired selectivity. This article points out a major limitation of these statistical-based calibration methods. The limitation is that the techniques suffer from the potential for chance correlation. In this article, the impact of chance correlation on the robustness of PLS model was illustrated via a pharmaceutical application with NIR to the content uniformity determination of tablets. The procedure involves evaluating the PLS models generated with two sets of calibration tablets incorporated with distinct degree of concentration correlation between the active pharmaceutical ingredient (API) and excipients. The selectivity and robustness of the two models were examined by using a series of data sets associated with placebo tablets and tablets incorporated with variations from excipient content, hardness and particle size. The result clearly revealed that the strong correlation observed in the PLS model created by the correlated design was not solely based on the API information, and there was an intrinsic difference in the variances described by the two calibration models. Diagnostic tools that enable the characterization of the chemical selectivity of the calibration model were also proposed for pharmaceutical quantitative analysis., ((c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association)

This paper examines how one may assess spectral changes with instrument configuration (or composition), in combination with the spectral changes in the measurement that are caused by experimental effects, and subsequently select an appropriate measurement modality for tablet content uniformity determination with near-infrared (NIR) spectroscopy. Two NIR spectrometers furnished with three configurations in the sample measurement interface were evaluated. One spectrometer, Bruker MPA (multiple purpose analyzer), was equipped with two measurement modalities, diffuse transmission (DT) and diffuse reflection based on integrating sphere optics (DR/IS). The other spectrometer, Bruker StepOne, was equipped only with diffuse reflection mode based on a fiber-optic probe (DR/FO). The data were collected with each of the configurations for the tablets associated with two dosage strengths differing significantly in diameter and thickness. Spectral diagnosis was performed in terms of sensitivity and selectivity. The signal-to-noise ratio computed for the data collected with the DT and DR/IS spectrometers was approximately an order of magnitude greater than that computed for the DR/FO spectrometer. The net-analyte-signal-based selectivity analysis of NIR spectra associated with the sample tablet and the placebo tablet indicated that both transmission and reflection mode provided similar selectivity when the optimal spectral range was chosen. A partial least squares (PLS) calibration model was developed for each data set. The overall standard error of calibration for each DT and DR/IS measurement was approximately 0.3% in weight for each strength, significantly better than the value of 1.0% in weight produced by the DR/FO measurement. This result was consistent with the sensitivity analysis based on spectral noise characterization. The poor analytical performance of the DR/FO spectrometer was attributed to the small illumination spot size of the reflection probe and thus the sensitivity of the measurements to the tablet engraving. The PLS analysis and spectral diagnostics both showed that transmission and reflection modes based on the Bruker MPA provided similar measurement accuracy for each strength. However, the robustness study clearly revealed that the transmission mode would be more robust than the reflection mode when there is considerable variability in the chemical composition and physical properties of tablets.

The objective of this study was to examine the effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powders measured by the ASTM D 6940-04 segregation tester using design of experiments (DOE) approaches. The test blends consisted of 4% aspirin (ASP) and 96% microcrystalline cellulose (MCC) with and without magnesium stearate (MgS). The segregation tendency of a blend was determined by measuring the last/first (L/F) ratio, the ratio of aspirin concentrations between the first and last samples discharged from the tester. A 2(2) factorial design was used to determine the effects of measurement parameters [amount of material loaded (W), number of segregation cycles] with number of replicates 6. ANOVA showed that W was a critical parameter for segregation testing. The L/F value deviated further from 1 (greater segregation tendency) with increasing W. A 2(3) full factorial design was used to assess the effects of formulation variables: grade of ASP (unmilled, milled), grade of MCC, and amount of lubricant, MgS. MLR and ANOVA showed that the grade of ASP was the main effect contributing to segregation tendency. Principal Component Regression Analysis established a correlation between L/F and the physical properties of the blend related to ASP and MCC, the ASP/MCC particle size ratio (PSR) and powder cohesion. The physical properties of the blend related to density and flow were not influenced by the grade of ASP and were not related to the segregation tendency of the blend. The direct relationship between L/F and PSR was determined by univariate analysis. Segregation tendency increased as the ASP to MCC particle size increased. This study highlighted critical test parameters for segregation testing and identified critical physical properties of the blends that influence segregation tendency., ((c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association)

Ferric hexacyanoferrate (Fe4III[FeII(CN)6]3), also known as insoluble Prussian blue (PB) is the active pharmaceutical ingredient (API) of the drug product, Radiogardase. Radiogardase is the first FDA approved medical countermeasure for the treatment of internal contamination with radioactive cesium (Cs) or thallium in the event of a major radiological incident such as a "dirty bomb". A number of pre-clinical and clinical studies have evaluated the use of PB as an investigational decorporation agent to enhance the excretion of metal cations. There are few sources of published in vitro data that detail the binding capacity of cesium to insoluble PB under various chemical and physical conditions. The study objective was to determine the in vitro binding capacity of PB APIs and drug products by evaluating certain chemical and physical factors such as medium pH, particle size, and storage conditions (temperature). In vitro experimental conditions ranged from pH 1 to 9, to cover the range of pH levels that PB may encounter in the gastrointestinal (GI) tract in humans. Measurements of cesium binding were made between 1 and 24h, to cover gastric and intestinal tract residence time using a validated atomic emission spectroscopy (AES) method. The results indicated that pH, exposure time, storage temperature (affecting moisture content) and particle size play significant roles in the cesium binding to both the PB API and the drug product. The lowest cesium binding was observed at gastric pH of 1 and 2, whereas the highest cesium binding was observed at physiological pH of 7.5. It was observed that dry storage conditions resulted in a loss of moisture from PB, which had a significant negative effect on the PB cesium binding capacity at time intervals consistent with gastric residence. Differences were also observed in the binding capacity of PB with different particle sizes. Significant batch to batch differences were also observed in the binding capacity of some PB API and drug products. Our results suggest that certain physiochemical properties affect the initial binding capacity and the overall binding capacity of PB APIs and drug products during conditions that simulated gastric and GI residence time. These physiochemical properties can be utilized as quality attributes to monitor and predict drug product quality under certain manufacturing and storage conditions and may be utilized to enhance the clinical efficacy of PB.

Terahertz (THz) spectroscopy and chemometric analysis of resultant absorption spectra in the 30-500 cm(-1) range has been applied to perform quantitative determination of both active ingredient and excipient concentrations of tablets. Tests were performed on a series of tablets composed of various concentrations and processes of theophylline formulated with lactose, magnesium stearate, starch or Avicel, and as a function of tablet hardness. Transmission spectra of polyethylene pellets derived from each of the samples were analyzed using three approaches. Spectral superposition method was used as an indirect measure to examine whether and when the interaction among various pharmaceutical components and the tableting history could be considered insignificant for quantification purpose. Spectral characteristic peak method was able to correlate peak maxima with correction for tablets having the same hardness. Multivariate analysis (PCR and PLS 1) was capable of correlating THz spectra with tablet concentrations. The predicted concentrations of independent samples using multivariate models agreed well with nominal concentrations. The best correlations were obtained using multivariate analysis. With these studies, the advantage of using multivariate approach was demonstrated for process analytical technology (PAT) application. Further, the feasibility of integrating THz spectroscopy and chemometrics for the purpose of quantifying pharmaceutical tablet concentrations was demonstrated.

The aim of this study was to use terahertz spectroscopy to characterize pharmaceutical materials and tablets, and to understand the effects of measuring conditions and compositional variability on the data quality. Tests were performed on five formulation components (theophylline, lactose, starch, Avicel, magnesium stearate) and a series of tablets composed of various concentrations of theophylline and excipients. Transmission spectra of polyethylene (PE) disks derived from each of the samples were analyzed. Three factors (component loading, component chemistry, and disk drying time) were screened as critical factors associated with the magnitude and location of THz absorbance peaks. Applying the standard sample spectra divided by PE reference spectra ratio method revealed that, to a large extent, PE was responsible for the disk drying time dependence. Direct spectral feature analysis along with mass-transfer analysis of the disk drying process revealed THz absorption peak maxima of lactose (255 cm(-1)) and water (54 and 210 cm(-1)) which is also supported by literature values for the peak maxima assignment for water. Particle scattering due to specimen and PE was found to be also partially responsible for the observed spectral intensities. The importance of THz spectroscopy was demonstrated for characterization of pharmaceutical materials and tablet.

Transdermal drug delivery systems (TDDS), also known as "patches," are dosage forms designed to deliver a therapeutically effective amount of drug across a patient's skin. The adhesive of the transdermal drug delivery system is critical to the safety, efficacy and quality of the product. In the Drug Quality Reporting System (DQRS), the United States Food and Drug Administration (FDA) has received numerous reports of "adhesion lacking" for transdermal drug delivery systems. This article provides an overview of types of transdermals, their anatomy, the role of adhesion, the possible adhesion failure modes and how adhesion can be measured. Excerpts from FDA reports on the lack of adhesion of transdermal system products are presented. Pros and cons of in vitro techniques, such as peel adhesion, tack and shear strength, in vivo techniques used to evaluate adhesive properties are discussed. To see a decrease in "adhesion lacking" reports, adhesion needs to become an important design parameter and suitable methods need to be available to assess quality and in vivo performance. This article provides a framework for further discussion and scientific work to improve transdermal adhesive performance.

The American Medical Association has questioned whether expiration dating markedly underestimates the actual shelf life of drug products. Results from the shelf life extension program (SLEP) have been evaluated to provide extensive data to address this issue. The SLEP has been administered by the Food and Drug Administration for the United States Department of Defense (DOD) for 20 years. This program probably contains the most extensive source of pharmaceutical stability data extant. This report summarizes extended stability profiles for 122 different drug products (3,005 different lots). The drug products were categorized into five groups based on incidence of initial extension failures and termination failures (extended lot eventually failed upon re-testing). Based on testing and stability assessment, 88% of the lots were extended at least 1 year beyond their original expiration date for an average extension of 66 months, but the additional stability period was highly variable. The SLEP data supports the assertion that many drug products, if properly stored, can be extended past the expiration date. Due to the lot-to-lot variability, the stability and quality of extended drug products can only be assured by periodic testing and systematic evaluation of each lot.

The goal of this study was to assess the utility of near infrared (NIR) spectroscopy for the determination of content uniformity, tablet crushing strength (tablet hardness), and dissolution rate in sulfamethazine veterinary bolus dosage forms. A formulation containing sulfamethazine, corn starch, and magnesium stearate was employed. The formulations were wet granulated with a 10% (wt/vol) starch paste in a high shear granulator and dried at 60 degrees C in a convection tray dryer. The tablets were compressed on a Stokes B2 rotary tablet press running at 30 rpm. Each sample was scanned in reflectance mode in the wavelengths of the NIR region. Principal component analysis (PCA) of the NIR tablet spectra and the neat raw materials indicated that the scores of the first 2 principal components were highly correlated with the chemical and physical attributes. Based on the PCA model, the significant wavelengths for sulfamethazine are 1514, (1660-1694), 2000, 2050, 2150, 2175, 2225, and 2275 nm; for corn starch are 1974, 2100, and 2325 nm; and for magnesium stearate are 2325 and 2375 nm. In addition, the loadings show large negative peaks around the water band regions ( approximately 1420 and 1940 nm), indicating that the partial least squares (PLS) models could be affected by product water content. A simple linear regression model was able to predict content uniformity with a correlation coefficient of 0.986 at 1656 nm; the use of a PLS regression model, with 3 factors, had an r (2) of 0.9496 and a standard error of calibration of 0.0316. The PLS validation set had an r (2) of 0.9662 and a standard error of 0.0354. PLS calibration models, based on tablet absorbance data, could successfully predict tablet crushing strength and dissolution in spite of varying active pharmaceutical ingredient (API) levels. Prediction plots based on these PLS models yielded correlation coefficients of 0.84 and 0.92 on independent validation sets for crushing strength and Q(120) (percentage dissolved in 120 minutes), respectively.

The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUC(inf) were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUC(inf) were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUC(inf) were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.

Crystallizations of pharmaceutical active ingredients, particularly those that posses multiple polymorphic forms, are among the most critical and least understood pharmaceutical manufacturing processes. Many process and product failures can be traced to a poor understanding and control of crystallization processes. The Food and Drug Administration's process analytical technology (PAT) initiative is a collaborative effort with industry to introduce new and efficient manufacturing technologies into the pharmaceutical industry. PAT's are systems for design, analysis, and control of manufacturing processes. They aim to assure high quality through timely measurements of critical quality and performance attributes of raw materials, in-process materials, and final products. Implementation of PAT involves scientifically based process design and optimization, appropriate sensor technologies, statistical and information tools (chemometrics), and feedback process control strategies working together to produce quality products. This review introduces the concept of PAT and discusses its application to crystallization processes through review of several case studies. A variety of in situ analytical methods combined with chemometric tools for analysis of multivariate process information provide a basis for future improvements in modeling, simulation, and control of crystallization processes.

The purpose of this report was to investigate the feasibility of using disk intrinsic dissolution rate (DIDR) to determine solubility class membership. We employed a VanKel dissolution apparatus fitted with a Wood's intrinsic dissolution die. To test the robustness of the method, variations of DIDR with compression force, dissolution volume, distance of the drug disk from the bottom of the dissolution vessel, and drug disk rotation speed were studied using furosemide and metoprolol in pH 4.5 acetate buffer as a model system. The DIDRs of six low solubility and nine high solubility model drugs were then determined at pH 1.2, 4.5, and 6.8 and compared to their BCS solubility class membership. It was found that the compression force, dissolution medium volume, and die position had no significant effect on DIDR for the system studied. The proposed compression force, dissolution volume, die position, and rotation speed are 2000 psi, 900 ml, 0.5 in., and 100 rpm, respectively. The test results obtained from 15 model BCS drugs show a good relationship between the DIDR and BCS solubility classification with 0.1 mg/min/cm(2) as a class boundary unless the dose is either extremely low or high where discrepancies may exist between the solubility and DIDR methods. Therefore, more scientific research and debates are needed before considered for regulatory purpose.