Machine learning with active pharmaceutical ingredient/polymer interaction mechanism:Prediction for complex phase behaviors of pharmaceuticals and formulations

The high throughput prediction of the thermodynamic phase behavior of active pharmaceutical ingredients(APIs)with pharmaceutically relevant excipients remains a major scientific challenge in the screening of pharmaceutical formulations.In this work,a developed machine-learning model efficiently predicts the solubility of APIs in polymers by learning the phase equilibrium principle and using a few molecular descriptors.Under the few-shot learning framework,thermodynamic theory(perturbed-chain statistical associating fluid theory)was used for data augmentation,and computational chemistry was applied for molecular descriptors'screening.The results showed that the developed machine-learning model can predict the API-polymer phase diagram accurately,broaden the solubility data of APIs in polymers,and reproduce the relationship between API solubility and the interaction mechanisms between API and polymer successfully,which provided efficient guidance for the development of pharmaceutical formulations.

Reactive template-derived interfacial engineering of CoP/CoO heterostructured porous nanotubes towards superior electrocatalytic hydrogen evolution

The development of economical,efficient,and robust electrocatalysts toward the hydrogen evolution reaction(HER)is highly imperative for the rapid advancement of renewable H2 energy-associated technologies.Extensive utilization of the heterointerface effect can endow the catalysts with remarkably boosted electrocatalytic performance due to the modified electronic state of active sites.Herein,we demonstrate deliberate crafting of CoP/CoO heterojunction porous nanotubes(abbreviated as CoP/CoO PNTs hereafter)using a self-sacrificial template-engaged strategy.Precise control over the Kirkendall diffusion process of the presynthesized cobalt–aspartic acid complex nanowires is indispensable for the formation of CoP/CoO heterostructures.The topochemical transformation strategy of the reactive templates enables uniform and maximized construction of CoP/CoO heterojunctions throughout all the porous nanotubes.The establishment of CoP/CoO heterojunctions could considerably modify the electronic configuration of the active sites and also improve the electric conductivity,which endows the resultant CoP/CoO PNTs with enhanced intrinsic activity.Simultaneously,the hollow and porous nanotube architectures allow sufficient accessibility of exterior/interior surfaces and molecular permeability,drastically promoting the reaction kinetics.Consequently,when used as HER electrocatalysts,the well-designed CoP/CoO PNTs show Pt-like activity,with an overpotential of only 61 mV at 10mA cm^(−2) and excellent stability in 1.0M KOH medium,exceeding those of the vast majority of the previously reported nonprecious candidates.Density functional theory calculations further substantiate that the construction of CoP/CoO heterojunctions enables optimization of the Gibbs free energies for water adsorption and H adsorption,resulting in boosted HER intrinsic activity.The present study may provide in-depth insights into the fundamental mechanisms of heterojunction-induced electronic regulation,which may pave the way for the rational design of advanced Earth-abundant electrocatalysts in the future.

Photocatalytic activation of sulfite by N-doped porous biochar/MnFe_(2)O_(4) interface-driven catalyst for efficient degradation of tetracycline

A novel photo-catalytic system composed of N-doped biochars(NBCs),MnFe_(2)O_(4) and sulfite activation under ultraviolet(NBCs/MnFe_(2)O_(4)/sulfite/UV)was constructed to realize the efficient eliminate of tetracycline(TC).As the carrier of MnFe_(2)O_(4),NBCs were synthesized from alfalfa,which has large specific surface area,graphite like structure and hierarchical porous structure.The adsorption isotherm indicated that NBCs/MnFe_(2)O_(4)-2:1 had the best adsorption performance for TC(347.56 mg g^(-1)).Through synergistic adsorption and photocatalysis,the removal rate of TC reached 84%,which was significantly higher than that of MnFe_(2)O_(4).Electrochemical impedance spectroscopy(EIS)and Photoluminescence(PL)characterization results showed that the introduction of NBCs improved the separation efficiency of photogenerated electron and hole pairs and enhanced the photocatalytic performance.Moreover,the adsorption,degradation mechanism and degradation path of TC by the catalyst were systematically analyzed by coupling HPLC–MS measurement with the theoretical calculation.Considering the advantages of excellent degradation performance,low cost,easy separation and environmental friendliness of NBCs/MnFe_(2)O_(4),this work was expected to provide a new path for the practical application of biochar.

Injectable hydrogels for cartilage and bone tissue engineering

Tissue engineering has become a promising strategy for repairing damaged cartilage and bone tissue. Among the scaffolds for tissue-engineering applications, injectable hydrogels have demonstrated great potential for use as three-dimensional cell culture scaffolds in cartilage and bone tissue engineering, owing to their high water content, similarity to the natural extracellular matrix(ECM), porous framework for cell transplantation and proliferation, minimal invasive properties, and ability to match irregular defects. In this review, we describe the selection of appropriate biomaterials and fabrication methods to prepare novel injectable hydrogels for cartilage and bone tissue engineering. In addition, the biology of cartilage and the bony ECM is also summarized. Finally, future perspectives for injectable hydrogels in cartilage and bone tissue engineering are discussed.

Preparation, Characterization and Catalytic Behavior of 12-Molybdophosphoric Acid Encapsulated in the Supercage of Cs^＋-exchanged Y Zeolite

In order to solve the serious leaching problem of supported heteropoly acid catalysts in polar reaction media,12-molybdophosphoric acid encapsulated in the supercage of Cs+-exchanged Y zeolite was prepared by the "ship in the bottle" synthesis.The influence of ion-exchange conditions and the synthesis parameters on the encapsulation of PMo12 were investigated.The obtained solid sample was characterized by X-ray diffraction(XRD),31P magic angle spin nuclear magnetic resonance(MAS NMR) and Fourier Transform Infrared Spectroscopy(FT-IR),and its catalytic activity in the esterification of acetic acid and n-butanol was tested.The ion-exchange time,concentration of aqueous Cs+ solution,pH value,and amount of Mo added in the synthesis mixture were revealed to influence the encapsulation very remarkably.Under the optimal conditions,12-molybdophosphoric acid could be successfully encapsulated in the supercage of CsY zeolite,and the samples showed considerable catalytic activity and excellent reusability in the esterification reaction.

Synthesis and characterization of Ce_(0.8)Sm_(0.2)O_(1.9) nanopowders using an acrylamide polymerization process

Ce0.8Sm0.2O1.9(SDC) nanopowders were synthesized by an acrylamide polymerization process.The XRD results showed that SDC powders prepared at 700 °C possessed a cubic fluorite structure.Transmission electron microscopy(TEM) indicated that the particle sizes of powders were in the range of 10-15 nm.A 98.3% of theoretical density was obtained when the SDC pellets were sintered at 1350 °C for 5 h,indicating that the powders had good sinterability.The conductivity of the sintered SDC ceramics was 0.019 S/cm at 6...

Synthesis,Crystal Structure and Neuroprotection of Methyl 2-((4-(2-(2-Methylphenoxy)acetyl)-piperazin-1-yl)-methyl)benzoate

A new phenoxyacetamide derivative, methyl 2-（（4-（2-（2-methylphenoxy）acetyl）pi- perazin-1-yl）methyl）benzoate （C22H26N2O4, M, = 382.45）, has been synthesized and characterized by 1H NMR, 13C NMR, H RMS and single-crystal X-ray diffraction. The crystal is of monoclinic system, space group P21c with a = 11.145（2）, b = 13.667（3）, c = 13.998（3） A, β= 112.01（3）°, V= 1976.8（7）A3, Z = 4, Dc = 1.285 g/cm3, F（000） = 816, g = 0.089 mml, MoKa radiation （λ= 0.71073 A）, the final R = 0.0602 and wR = 0.1533 for 2343 observed reflections with I 〉 20（I）. Intramolecular C-H……O interactions as well as intermolecular C-H……O hydrogen bonds help to stabilize the crystal structure. The preliminary bioassay results show that the title compound exhibits potent neuroprotective activity.

Synthesis, Characterization and Theoretical Studies of a Novel Salt(Dexmedetomidine: Perchloric Acid = 1:1) and the Investigation of Its Stability

Dexmedetomidine and its novel salt have been synthesized and characterized by single-crystal XRD and TGA/DSG. Components of the crystalline phase have also been investigated in terms of their corresponding Hirshfeld surface. In the crystal lattice, a three-dimensional hydrogen-bonded network is observed. In this work, the salt strategy has been applied successfully to dexmedetomidine. One important parameter, i.e. stability, has also been significantly improved, which proves to be an important factor for solid dosage formulation. Furthermore, DSC/TGA analysis indicates that the salt maintains its crystallinity up to 300℃, suggesting a higher stability of the salt compared to pure dexmedetomidine.

Synthesis, Crystal Structure and Thermal Stability of a New Cadmium(II) Polymer Based on 1H-pyrazole-3-carboxylic Acid Ligand

A novel Cd（Ⅱ） coordination polymer, [CdCI（Hpc）H2O]n （1, H2pc = 1H-pyrazole-3- carboxylic acid）, was synthesized by the reaction of CdCl2·2.5H2O with H2pc, and structurally characterized by IR spectrum, UV-Vis spectrum, elemental analysis, single-crystal X-ray diffraction, as well as thermal analysis. Compound 1 crystallizes in monoclinic, P21/n space group with α = 7.0304（3）, b = 10.3047（3）, c = 10.6446（4） A, β= 107.174（4）°, F = 736.78（5） A^3, Z = 4, C4HsCdClN2O3, Mr = 276.95, Dc = 2.497 g/cm%3, F（000） = 528.0,μ= 3.281 mm^-1, R = 0.0169 and wR = 0.0387. The central metals adopt distorted octahedral geometry. Carboxyl groups of the ligand connect Cd（Ⅱ） into a one-dimensional chain, which further constructs a two-dimensional network by halogen bridging. Such two-dimensional structures are finally connected into a three-dimensional supramolecular architecture due to the hydrogen bonds and intermolecular π…π interactions. In addition, complex 1 has high thermal stability.

Integrated computer-aided formulation design:A case study of andrographolide/cyclodextrin ternary formulation

Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.

Synthesis, Crystal Structure and Neuroprotective Activity of(E)-1-(4-(4-Chlorobenzyl)piperazin-1-yl)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one

The crystal structure of the new cinnamide derivative（E）-1-（4-（4-chlorobenzyl）piperazin-1-yl）-3-（benzo[d][1,3]dioxol-5-yl）prop-2-en-1-one（C（21）H（21）ClN2O3, Mr = 384.85） was determined by single-crystal X-ray diffraction method. Compound 5 crystallizes in the monoclinic system, space group P21/c with a = 11.762（2）, b = 15.279（3）, c = 11.865（2） , β = 116.57（3）°, V = 1907.1（7） 3, Z = 4, Dc = 1.340 g/cm3, F（000） = 808, μ = 0.224 mm-1, Mo Kα radiation（λ = 0.71073 ）, the final R = 0.0565 and w R = 0.1479 for 2318 observed reflections with I 〉 2σ（I）. Intramolecular C（9）–H（9A）···O（1） interactions as well as intermolecular C（16）–H（16A）···O（1） hydrogen bonds help to stabilize the crystal structure. The bioassay results indicated that the title compound displayed promising neuroprotection in vitro and in vivo, and suppressed apoptosis of glutamate-induced PC12 cells.

Novel Perchlorate and Sulphate Salts of 2-Aminonicotinic Acid:Synthesis,Characterization,Thermal Studies and Hirshfeld Surface Analysis

Since 2-aminonicotinic acid is a zwitterionic molecule,the salt or co-crystal strategy was used for the precipitation under identical conditions and obtained two novel salts： salt 1 with 2：1：2 stoichiometry of 2-aminonicotinic acid：perchloric acid：H2O and salt 2 with 2：1：3 stoichiometry of 2-aminonicotinic acid：sulfuric acid：H2O. Their crystal structures were characterized by single-crystal X-ray diffraction,differential scanning calorimetry（DSC） and thermogravimetric analyses（TGA）. The structure determination shows that two salts are both primarily stabilized by the strong N–H…O hydrogen bonding interaction between 2-aminonicotinic acid and its corresponding acids. Constituents of the salt-crystalline phase were also investigated in terms of Hirshfeld surfaces. In the crystal lattice,a three-dimensional hydrogen-bonded network is observed,including the formation of a two-dimensional molecular scaffolding motif. Hirshfeld surfaces and fingerprint plots of two salts show that the structures are stabilized by H…H,O–H…O and C–O…π intermolecular interactions.

Synthesis and characterization of methacrylate matrix resin bearing o-nitrobenzyl group

The matrix polymer PTBCHNB bearing o-nitrobenzyl group was successfully synthesized by copolymerization of tertiary-butyl methacrylate(TBMA), cyclohexyl methacrylate(CHMA) and o-nitrobenzyl methacrylate(NBMA) via reversible addition fragmentation chain transfer(RAFT) polymerization method. PTBCHNB was characterized by FTIR, 1HNMR, GPC and DSC. After UV irradiation, the o-nitrobenzyl groups of PTBCHNB were photocleaved and the resulting carboxyl groups were highly alkali soluble, and PTBCHNB was converted to PCHIBMA bearing carboxyl groups. So, the matrix polymer could be etched by mild alkali solution with no requirements of photoacid generators and other diverse additives. The photocleavable behaviors of PTBCHNB were determined by FTIR, 1H NMR and TGA analysis. The resist formulated with PTBCHNB and cast in THF solution showed square pattern of 10 μm×10 μm using a mercury-xenon lamp in a contact printing mode and tetramethyl-ammonium hydroxide aqueous solution as a developer.

Performances of ZnO-Based Dye Sensitized Solar Cells Fabricated by Hydrothermal Synthesis and Sol-Gel Technique

ZnO is introduced as an alternative to TiO2 in dye sensitized solar cells （DSSCs） due to its band gap similar to TiO2, higher electron mobility, and flexible procedures of preparations. Several samples of ZnO films are prepared with the hydrothermal synthesis method and the sol-gel technique, respectively. These ZnO films were assembled as photoanodes in DSSCs using N3 dye as the sensitizer. The ZnO-based cells prepared by the hydrothermal synthesis show typical current source characteristics, whose fill factor （FF） is 0.44 and photo-to-electric power conversion efficiency is 0.34%. On the other hand, all the samples prepared with the sol-gel technique show accompanied source characteristics with relatively higher power conversion efficiencies （1%） but a lower FF （0.26）. X-ray diffraction （XRD） and atomic force microscopy （AFM） measurements indicate that the sol-gel samples have small particles sizes. Therefore, sol-gel samples could adsorb more dye molecules to generate high conversion efficiencies. At the same time, more grain boundaries make it more possible for injected electrons to recombine with the oxidized electrolyte. Hydrothermal samples have bigger grains, so they show poor conversion efficiency and relatively high FF.

Three-Photon Absorption and Upconversion Fluorescence Properties of Series 1,3,4-Oxadiazole Derivatives

A newly synthesized 1,3,4-oxadiazole derivatives have been studied using a femtosecond Ti：sapphire laser system. The series molecules present strong three-photon absorption and frequency upeonversion fluorescence at wavelengths from 1205 nm to 1575 nm. Furthermore, there is no proportional relationship between three-photon absorption cross sections and the chemical structure transformation from monomer, dimer to trimer. Effective charge-transfer distance by π-conjugation bonds may be the contributing factor. In the experimental design, the far-field intensity distribution of femtosecond laser beam has been taken into account. We give the optimized analytical solution of nonlinear transmission in a three-photon absorption （3PA ） process when the incident beam has a Gaussian transverse spatial profile.

Synthesis, Crystal Structure, Hirshfeld Surface Analysis and Biological Activity of 1-(Bis(4-methoxyphenyl)-methyl)-4-(2-(2-methylphenoxy)ethyl)piperazine

In this study, a novel phenoxyethylamine derivative 1-(bis(4-methoxy phenyl)-methyl)-4-(2-(2-methylphenoxy)ethyl)piperazine(C28 H35 N2O3, Mr = 454.58) has been synthesized and its structure was characterized by 1 H NMR, 13 C NMR, HRMS and single-crystal X-ray diffraction. The compound crystallizes in triclinic system, space group P1 with a = 6.1980(12),b = 12.212(2), c = 19.527(4)A,α= 93.08(3)°,β= 98.62(3)°,γ= 90.72(3)°, V = 1458.9(5)?3, Z =2, Dc = 1.035 g/cm^3, F(000)= 489,μ= 0.067 mm-1, Mo Kα radiation(λ= 0.71073 ?), the final R= 0.0693 and wR = 0.1759 for 3030 observed reflections with I > 2σ(I). The bioassay results indicated that the title compound 5 displayed effective activities against glutamine-induced neurotoxicity in PC12 cells.

Synthesis,Crystal Structure and Biological Activity of 1-(4-(4-Ethoxybenzyl)piperazin-1-yl)-2-(2-methylphenoxy)ethanone

One novel phenoxyacetamide derivative（C22H28N2O3, Mr = 368.47） has been synthesized and determined by means of NMR spectroscopy, high resolution mass spectra and single-crystal X-ray diffraction. The single crystal belongs to the monoclinic system, space group Cc with a = 14.910（3）, b = 14.592（3）, c = 38.683（8） A^°, β = 100.37（3）°, V = 8279（3） ？3, Z = 16, Dc = 1.183 g/cm^3, F（000） = 3168, μ = 0.079 mm^-1, Mo Kα radiation（λ = 0.71073A^°）, the final R = 0.0508 and wR = 0.0666 for 4120 observed reflections with I 〉 2σ（I）. There are four independent molecules in an asymmetric unit cell. The four symmetry-independent molecules have a variety of different conformations indicating considerable conformational freedom. The bioassay results indicated that the title compound displayed effective activities against glutamine-induced neurotoxicity in PC12 cells and significantly prolonged the survival time of mice subjected to acute cerebral ischemia.

Synthesis,Crystal Structure and Anti-ischemic Activity of(E)-1-(4-(Bis(4-methoxyphenyl)methyl)piperazin-1-yl)-3-(4-acetoxy-3-methoxyphenyl)prop-2-en-1-one

A new cinnamide derivative,（E）-1-（4-（bis（4-methoxyphenyl）methyl）piperazin-1-yl）-3-（4-acetoxy-3-methoxyphenyl）prop-2-en-1-one（C31H34N2O6,Mr = 530.60）,has been synthesized by the condensation of 1-（bis（4-methoxyphenyl）methyl）piperazine and（E）-3-（4-acetoxy-3-methoxyphenyl）acrylic acid.The compound was characterized by 1H NMR,13 C NMR,H RMS and single-crystal X-ray diffraction.The crystal belongs to the orthorhombic system,space group P212121 with a = 24.946（5）,b = 7.6380（15）,c = 14.555（3） A,V = 2773.3（10） A^3,Z = 4,Dc = 1.271 g/cm^3,F（000） = 1128,μ = 0.088 mm-1,Mo Kα radiation（λ = 0.71073 A）,the final R = 0.0641 and w R = 0.1170.A total of 3009 unique reflections were collected,of which 1760 with I 〉 2σ（I） were observed.Intramolecular C（17）–H（17B）···O（3） and C（22）–H（22A）···O（3） interactions as well as intermolecular C（27）–H（27A）···O（3） hydrogen bonds help to stabilize the crystal structure.The title compound was evaluated for the anti-ischemic activity in vitro and in vivo.The bioassay results indicated that the title compound displayed efficient activities against glutamine-induced neurotoxicity in PC12 cells and significantly prolonged the survival time of mice subjected to acute cerebral ischemia.

Crystal Type Iof Azilsartan Polymorphs: Preparation and Analysis

Azilsartan (2-ethoxy-1-([2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-1H-benzimidazole-7-carboxylic acid) is a new angiotensin II receptor antagonist used in the treatment of hypertension. This paper describes the preparation of type I crystal and its single crystal diffraction data, the comparison of the powder diffraction data for both type I and II crystals as well as their stability and solubility in methanol.