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.

Quantum-chemical investigation on hydrogen bonding interaction of hydrogen fluoride dimer at various mutual orientations

Hydrogen bonding interaction in hydrogen fluoride dimer has been investigated by quan- tum-chemical calculation with 6-311G^(**) basis set at various mutual orientations.Atomic charges and charge transfer have been calculated by means of potential-derived method,and decomposition of hydro- gen bonding interaction has been executed.The calculation results show that there is a variation range for the energy-stable orientations,the charge transfer in the range presents maximum value,and the charge transfer interaction plays a decisive role in the hydrogen bonding.

Molecular Dynamics Simulation Study of CIF in Water： Halogen Bonding Interaction in Liquid

Does the halogen bonding interaction co-exist in liquid when it competes with the hydrogen bonding interaction？ The classical molecular dynamics simulations for the solvation properties of CLF molecule in water are performed with the Lennard-Jones plus Coulomb electrostatic potential parameters that are optimized with ab initio interaction energy calculations for the pre-reactive H2O-CLF complex. We find that the halogen bonding interactions occur between O and CL atoms and have the comparable strength and population with respect to the hydrogen bonding interactions of C1...H.

Study on the Hydrogen Bond Interaction Between Soy Protein Isolate and Glycerol Using Two-Dimensional Correlation Fourier-Transform Infrared Spectroscopy

A series of soy protein isolate(SPI)films plasticized by glycerol(Gly)were studied using attenuated total reflectance-Fourier transform infrared spectroscopy(ATR/FTIR).Perturbation-correlation movingwindow two-dimensional(PCMW2D)and two-dimensional correlation(2DCOS)analyses were applied to the amideⅠband and thus the hydrogen bond interaction between SPI and Gly was systematically investigated.When Gly concentrations were in the range 0~35%,the hydrogen bond amongβ-sheets was replaced by the one between SPI chain and Gly molecule,which caused these protein chains being changed toα-helix.However,the transformation ofβ-sheet toα-helix was saturated and both of them tend to change to random coil when Gly concentrations were in the range 35%~60%.

Transition metal coordination polymers with flexible dicarboxylate ligand:Synthesis,characterization,and photoluminescence property

Under solvothermal conditions,six new coordination polymers(CPs)[Mn(L)(phen)(H_(2)O)]_(n)(1),[Co(L)(phen)(H_(2)O)]_(n)(2),[Cu(L)(phen)(H_(2)O)]_(n)(3),[Zn_(2)(L)_(2)(phen)2(H_(2)O)]_(n)(4),[Zn(L)(phen)]_(n)(5),and[Cd(L)(phen)2]_(n)(6)were synthesized by reactions of dicarboxylate ligand 2,2'-(1,2-phenylenebis(methylene))bis(sulfanediyl)dinobutyric acid(H_(2)L)and 1,10-phenanthroline(phen)with the corresponding metal salts.Complexes 1-6 have been structurally characterized by single-crystal X-ray diffraction analyses,elemental analysis,IR,thermogravimetric analysis,and powder X-ray diffraction.The structures of 1-6 are 1D chains,which are further connected by hydrogen bonding interac-tions to form 3D supramolecular structures.Among them,1 and 2 are isomorphic with L2-of syn-conformation,while L2-shows anti-conformation in 3-6.In addition,the solid-state photoluminescence property of 4-6 was investigated.

Hydrogen bond promoted thermal stability enhancement of acetate based ionic liquid

Acetate-based imidazolium ionic liquids(ILs)are of great importance and widely applied in biomass processing and engineering but under stability issue due to the structure self–rearrangement induced by C2–H deprotonation,by which the IL based biomass processing will be challenging.Herein,we demonstrated that the thermal stability of normal acetate-based imidazolim[C8C1Im][OAc]could be significantly improved by changing its cation and anion environment with the presence of 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide IL([C4C1Im][NTf2]).When the molar fraction of[C8C1Im][OAc]was 0.3,the thermal stability of[C8C1Im][OAc]could be significantly improved(ΔT5%dec=+43°C).Detailed information obtained from thermal gravimetric analysis(TGA)and nuclear magnetic resonance(NMR)revealed that the addition of[C4C1 Im][NTf2]played a significant role in enhancing the thermal stability of[C8C1Im][OAc].It was proposed that the formation of an anion–π+structure network between[C8C1 Im][OAc]and[C4C1Im][NTf2]via strong hydrogen bond interactions greatly affects the environment of hydrogen atom in the imidazolium ring of each IL.

Cellulose Solubility in Deep Eutectic Solvents:Inspecting Quantitative Hydrogen-Bonding Analysis

According to the Kamlet-Abraham-Taft(KAT)polarity parameters(α,β,π*),polymers and solvents can be categorized as hydrogen-bond(H-bond)acidic(α>β)or H-bond basic(α<β).Recently,we proposed a quantitative hydrogen bonding(QHB)analysis to predict the solubility of polymers in ionic liquids(ILs)using the product ofΔαΔβ<0 as an indicator,whereΔαis the difference between the H-bond acidic parameters of the polymer and IL,andΔβis the difference in their basicity,while the prerequisite of the“complementary”principle(i.e.,that one component is H-bond acidic and the other is basic)is satisfied.Here,the applicability of QHB analysis was first confirmed by testing the solubilities of carefully chosen polymer/deep eutectic solvent(DES)pairs,as the DESs were eutectic mixtures dominated by hydrogen bonding interactions.Then,our attention focused on the solubility of cellulose in DESs.Our testing results as well as the typical published results were summarized,which indicate that the potential DESs for cellulose dissolution and regeneration must be of the H-bond basic type because the“complementary”principle should be satisfied as a prerequisite.However,the H-bond basic DESs investigated in this study do not show the superior solubility of cellulose that has been commonly observed for H-bond basic ILs,even if the criterion ofΔαΔβ<0 is satisfied for both DESs and ILs.Possible reasons for this discrepancy are given to understand the varying effectiveness in cellulose dissolution for H-bond basic DESs and ILs.

The Crystallization Behavior Regulating Nature of Hydrogen Bonds Interaction on Polyamide 6,6 by Poly(vinyl pyrrolidone)

The crystallization behavior of polyamide 6,6(PA66) under complex flow field is of great importance for its final mechanical properties.Poly(vinyl pyrrolidone)(PVP) was applied as crystallization modifying agency to improve processability of PA66.The regulation nature on hydrogen bonds(H-bonds) interaction of PVP was studied upon cooling process.As revealed by in situ FTIR,the sample with 5 wt% PVP displays decreased enthalpy change(ΔH) for both the generation of H-bonds and the transition of H-bonds from “disordered” to “ordered” state,which illustrates the molecular mechanism for the regulation of crystallzation behavior.Moveover,2D-WAXD is applied to reveal the evolution of microstructure for sample under external injection field.Hermans orientation factor(f_(H)) decreases obviously with the addition of PVP,because the relaxation of chain segments is promoted as well the crystallization is retarded.The above crystallization and microstructure changes during the processing provokes the improvement of processability without the apparent sacrifice of mechanical properties.

Mechanistic insights of the controlled release capacity of polar functional group in transdermal drug delivery system:the relationship of hydrogen bonding strength and controlled release capacity

Background:Hydrogen bonding interaction was considered to play a critical role in controlling drug release from transdermal patch.However,the quantitative evaluation of hydrogen bonding strength between drug and polar functional group was rarely reported,and the relationship between hydrogen bonding strength and controlled release capacity of pressure sensitive adhesive(PSA)was not well understood.The present study shed light on this relationship.Methods:Acrylate PSAs with amide group were synthesized by a free radical-initiated solution polymerization.Six drugs,i.e.,etodolac,ketoprofen,gemfibrozil,zolmitriptan,propranolol and lidocaine,were selected as model drugs.In vitro drug release and skin permeation experiments and in vivo pharmacokinetic experiment were performed.Partial correlation analysis,fourier-transform infrared spectroscopy and molecular simulation were conducted to provide molecular details of drug-PSA interactions.Mechanical test,rheology study,and modulated differential scanning calorimetry study were performed to scrutinize the free volume and molecular mobility of PSAs.Results:Release rate of all six drugs from amide PSAs decreased with the increase of amide group concentrations;however,only zolmitriptan and propranolol showed decreased skin permeation rate.It was found that drug release was controlled by amide group through hydrogen bonding,and controlled release extent was positively correlated with hydrogen bonding strength.Conclusion:From these results,we concluded that drugs with strong hydrogen bond forming ability and high skin permeation were suitable to use amide PSAs to regulate their release rate from patch.

Syntheses and Crystal Structures of Two New Supramolecular Architectures Constructed from the Main Group Metal Chloride and Protonated 2-(3-Pyridyl)benzimidazole

The reactions of SbCl3 and HgCl2 with 2-（3-pyridyl）benzimidazole （PyBIm） in solution acidified with HCl have been investigated. The PyBIm ligands are protonated into 2-（3-pyridinio）benzimidazolium （H2PyBIm） cations and the corresponding metal ions are bonded with chloride atoms into coordination anions, forming two new coordination compounds, namely, （H2PyBIm）（SbCl5） 1 and （H2PyBIm）2（Hg2Cl8） 2. Both compounds were characterized by X-ray crystallography. Crystal data for 1： triclinic, space group P1^- with a = 5.7030（7）, b = 9.0625（11）, c = 16.5929（18） A, α = 91.808（7）°, β = 93.234（6）, γ = 99.216（7）°, C12H11N3SbCl5, Mr = 496.24, V = 844.44（17） A^3, Z = 2, Dc = 1.952 g/cm^3, μ（MoKα） = 2.419 mm^-1, F（000） = 480, the final R = 0.0496 and wR = 0.1382 for 3433 observed reflections （I 〉 2σ（I））. Crystal data for 2： monoclinic, space group P21/c with a = 7.8061（5）, b = 15.8127（9）, c = 12.2435（9） , β = 91.955（4）o, C24H22N6Hg2Cl8, Mr = 1079.26, V = 1510.40（17） 3, Z = 2, Dc = 2.373 g/cm3, μ（MoKα） = 10.889 mm-1, F（000） = 1008, the final R = 0.0293 and wR = 0.0562 for 2854 observed reflections （I 〉 2σ（I））. X-ray diffraction analysis reveals that the antimony（III） is five-coordinated, exhibiting a slightly distorted square-pyramidal coordination geometry; while in 2, a dimeric [Hg2Cl8]^4-anion consists of two trigonal bipyramids sharing two common edges. The organic cations and coordination anions are connected into a one-dimensional belt and a two-dimensional sheet through N-H···Cl hydrogen bonding interactions in compounds 1 and 2, respectively; both are further aggregated into 3D frameworks by strong π-π contacts.

Synthesis and Crystal Structure of a Two-dimensional Cadmium Complex Based on Terephthalate and 1-Methyl-2,2'-bibenzimidazole

The title complex, [Cd（MeHbibzim）（1,4-bdc）]n （1, MelToibzim = 1-methyl-2,2＇- bibenzimidazole, 1,4-bdc = terephthalate）, was synthesized with hydrothermal reactions. The compound crystallizes in monoclinic, space group C2/c with a = 9.822（4）, b = 18.510（7）, c = 22.372（9） A, β = 98.359（6）°, C23H16CdN4O4, Mr = 524.81, V= 4024（3） A3, Z = 8, Dc. = 1.733 g/cm3, μ（MoKa） = 1.126 mm-1, F（000） = 2096, the final R = 0.0597 and wR = 0.1374 for 3906 observed reflections （1 〉 2σ（I））. X-ray diffraction analysis reveals that the Cd atom is coordinated by two nitrogen atoms from the chelating MeHbibzim and three carboxyl oxygen atoms from three terephthalate ligands, thus forming a distorted square pyramidal coordination sphere, [CdN2O3]. Every two Cd atoms are linked together via two carboxyl groups into a dinuclear unit with Cd...Cd separation of 3.806（4） A. The dinuclear building units are linked by terephthalate ligands into two-dimensional layers, which are further aggregated into a 3D framework via hydrogen bonding interactions.

Solvent Effects on Spectral Property and Dipole Moment of the Lowest Excited State of Coumarin 343 Dye

Steady-state absorption and fluorescence spectra, and time-resolved fluorescence spectra of coumarin 343 （C343） were measured in different solvents. The effect of the solvent on the spectral properties and dipole moment of the lowest excited state of C343 were investigated. It was found that the absorption and fluorescence spectra red-shifted slightly and strongly with increasing solvent polarity, respectively, because the charge distribution of the excited state leaded to the increasing difference between the absorption and fluorescence spectra with increasing solvent polarity. The dipole moment of the lowest excited state of C343 was determined from solvatochromic measurements and the quantum chemical calculation, and the results obtained from these two methods were fully consistent. Investigations of the time-resolved fluorescence of C343 in different solvents indicated that the fluorescence lifetimes increased nearly linearly with 4.45 ns in water. This can be ascribed between C343 and hydrogen donating increasing solvent polarity from 3.09 ns in toluene to to the intermolecular hydrogen bonding interactions solvents

Synthesis and Crystal Structure of a Cobalt(Ⅱ)Complex Based on 2,2-Bibenzimidazole and N,N-bis(phosphonomethyl)aminoacetic Acid

The title complex, [Co2（bibzim）（H2bibzim）4]·Co2（H2bibzim）2（Hbibzim）（HL）]2- 2H2O （1） （HEbibzim = 2,2＇-bibenzimidazole, H5L = N,N-bis（phosphonomethyl）aminoacetic acid （HO2CCH2N（CH2PO3H2）2））, was synthesized with hydrothermal reactions. The compound crystallizes in triclinic, space group P1 with a = 13.71020（10）, b = 14.9165（5）, c = 20.9924（5） A, a = 86.344（9）, β = 71.214（8）, γ = 73.757（7）°, C162HI24Co6N46O18P4, Mr = 3478.52, V = 3900.55（16） A3, Z = 2, Dc = 1.482 g/cm3,μ（MoKa） = 0.747 mm^-1, F（000） = 1784, the final R = 0.0777 and wR = 0.2091 for 13598 observed reflections （I 〉 2σ（I））. X-ray diffraction analysis reveals that there are three crystallographically independent Co（II） atoms in the complex. The complex consists of binuclear coordination cation, binuclear coordination anion, as well as lattice water molecules, which further aggregate into a 3D framework via hydrogen bonding as well as π-π interactions.

Synthesis and Crystal Structure of an Infinite 1D Zigzag Chain Compound (dimbH^+)(ClO_4^-) and Its Comparison with (dimb)2H_2O (dimb = 1,3-Di(imidazol-1-ylmethyl)-5-methylbenzene)

A new imidazolium compound, C15H17N4ClO4, was prepared from a flexible bidentate ligand of 1,3-di(imidazol-1-ylmethyl)-5-methylbenzene, and characterized by X-ray analysis. It is of orthorhombic, space group Pnma with a = 8.182(2), b = 12.874(3), c = 15.611(4) ? V = 1644.4(7) 3, Dc = 1.425 g/cm3, Z = 4, Mr = 352.78, m(MoKa) = 0.944 mm-1, F(000) = 736, S = 1.036, the final R = 0.0521 and wR = 0.1187 for 1128 observed reflections (I > 2s(I)). An infinite one-dimensional zigzag chain is formed by NH…N hydrogen bonding interactions between the imidazolium salt cations.

Syntheses and Structures of Two Complexes Based on Mixing Carboxylate Ligands and Imidazole-containing Ligands

Two novel complexes, [Zn（L2-1）（L2）]（1） and [Ni（L2-3）（L4）·2H2O]（2）, have been synthesized by solvothermal reactions in different solvents through mixing the carboxylate ligand, imidazole-containing ligand and the metal salt. Compound 1 crystallizes in monoclinic, space group P21/c with a = 9.21400（15）, b = 18.1172（3）, c = 15.7669（2） A, β = 91.1769（13）o, C30H26N4O4 Zn, Mr = 571.92, V = 2631.44（7） A3, Z = 4, Dc = 1.444 g·cm-3, μ = 1.659 mm-1, F（000） = 1184, λ（Cu Kα） = 1.54178 A, the final R = 0.048, w R = 0.1442 and S = 1.139. Compound 2 crystallizes in triclinic, space group P1 with a = 7.0664（3）, b = 9.5265（4）, c = 12.8861（6） A, α = 74.066（4）, β = 87.408（3）, γ = 83.591（3）o, C34H32N6O6S2 Ni, Mr = 743.49, V = 828.83（6） A3, Z = 1, Dc = 1.490 g·cm-3, μ = 2.490 mm-1, F（000） = 386, λ（CuK α） = 1.54178 A, the final R = 0.0315, w R = 0.0861 and S = 1.022. Complex 1 is the 1D chain which is linked by C–H···O hydrogen bonding interactions to form a 2D supramolecular architecture. Meanwhile, complex 2 is a 2D（4,4） network with the ABCABC stacking mode and then generates a 3D supramolecular architecture through C–H···N and O–H···O hydrogen bonding interactions.

Synthesis and Crystal Structure of a New Zn(Ⅱ) Complex Exhibiting Strong Luminescence

The title complex,[Zn（ip）2（H2O）2][ZnCl4]·H2O·2DMF 1（ip=imidazo[4,5-f][1,10] phenanthroline）,has been synthesized via the slow evaporation of concentrated reaction solution at room temperature.It was characterized by single-crystal X-ray diffraction.Crystal data for C32H36Cl4N10O5Zn2：white prism,0.17mm×0.15mm×0.10mm,monoclinic,space group P2/c,a=11.928（8）,b=9.868（6）,c=16.520（11）,β=104.879（12）°,V=1879（2）3,Z=2,Mr=913.25,Dc=1.614 g/cm3,F（000）=932,μ=1.616 mm-1,λ（MoKα）=0.71073,GOOF=1.045,R=0.0710 and wR=0.1755 for 3055 observed reflections with I 〉 2σ（I）. X-ray diffraction study reveals that the title complex has an interesting 3D architecture via hydrogen bonding interactions and π-π interactions. The IR, TGA, XRD and luminescent properties of complex 1 were also studied.

A Novel Potassium Complex Based on the Taurine-salicylaldehyde Schiff Base:Synthesis,Crystal Structure and Spectroscopy

A novel two-dimensional self-assembly network formulated as [K（TSSB）]n （TSSB= taurine-salicylaldehyde Schiff base） has been synthesized via the reaction of salicylaldehyde with taurine at the presence of potassium hydroxide in water-methanol solution,and was structurally characterized by elemental analysis,IR,UV-VIS spectra and X-ray diffraction.It crystallizes in the monoclinic system,space group P21/c with a=20.245（3）,b=7.2905（9）,c=7.5458（10）,β= 94.1920（10）o,V=1110.8（2）3,Mr=267.34,Z=4,Dc=1.599 g/cm3,μ（MoKα）=0.663 mm-1 and F（000）=552.The units of K[TSSB] are linked into a one-dimensional double chain structure via the sulfonic groups from the taurine-salicylaldelyde Schiff base,and such chains are further extended through O-K-O bond interactions resulting in a two-dimensional supramolecular architecture.In the complex,the K（I） ion displays a slightly distorted dodecahedral geometry with an eight-coordination number.

A Novel Mononuclear Copper(Ⅱ) Complex:Crystal Structure and DNA Cleavage Ability

The reaction of N-tosylatirdine with 1,2-diaminopropane in dry benzene solution yields an intermediate H2L, N,N,N＇,N＇-tetrakis（2-（p-tolylsulfonyl）aminoethyl） propane-1,2-diamine. The mononuclear copper（Ⅱ） complex, [CuLH2O]·H2O, was synthesized by the reaction between the intermediate and copper（Ⅱ） in absolute methanol. The complex has been characterized by IR, UV-vis and X-ray diffraction technology, and its crystal crystallizes in the orthorhombic system, space group Pbca with a = 15.589（1）, b = 21.897（2）, c = 27.645（2） A, V = 9436.4（1）A^3, Dc = 1.352 g/cm^3, Z = 8, Mr = 960.68, F（000） = 4040, μ（MoKa） = 0.698 mm-1, S = 0.98, R = 0.0537 and wR = 0.1180 for 5804 observed reflections （I 〉 2σ（I））. In the crystal structure, a one-dimensional chain is formed by abundant hydrogen bond interactions. The interaction of the complex with DNA was monitored using agarose gel electrophoresis. The result shows that the complex can transform the supercoiled to nicked and liner forms, and has a concentration-dependent cleavage activity.

Synthesis and Crystal Structure of (5-Hydroxy-6-methoxybenzofuran-3-yl)-(4-methoxyphenyl)methanone

Compound 1 （5-hydroxy-6-methoxybenzofuran-3-yl）（4-methoxyphenyl）metha- none, C17H1405, as a potential anti-breast cancer agent has been synthesized under microwave irradiation, which was further converted to （5,6-dihydroxybenzofuran-3-yl）（4-methoxyphenyi）me- thanone （2）. The compounds were characterized by MS and NMR spectra. Meanwhile, the crystal of 1 was obtained and determined by X-ray single-crystal diffraction. Crystal data： monoclinic system, space group P2/n, a = 8.908（6）, b = 10.505（7）, c = 15.452（11） A, β = 105.043（9）, V = 1396.4（16） A3, Z = 4, F（000） = 624, Dc = 1.419 g/cm3, p = 0.105 mm-1, R = 0.0513 and wR = 0.1246 for 14459 independent reflections （Rint = 0.0647） and 2488 observed ones （I〉 2σ（/））. lntermolecular O-H...O and π-π stacking interactions contributed to the stability of the structure.

Synthesis and Crystal Structure of N-Benzyl-N'-(2-pyridyl)urea and Its Mononuclear Cu(Ⅱ) Complex

A new ligand of N-benzyl-N＇-（2-pyridyl）urea L and its self-assembly product with CuCl2, [Cu（Ⅱ）LCl2]∞ 1, have been synthesized and structurally characterized by IR, 1H NMR and single-crystal X-ray diffraction analysis. In the structure of L, the urea groups adopt Z,E conformation to form dimers through intermolecular hydrogen bonds; while in complex 1, it assumes Z,Z conformation to fit for the coordination sphere of the Cu（Ⅱ） ions. The coordinated units are connected through intermolecular N-H...Cl hydrogen bonds to form an extended 2D framework. Finally, a 3D structure is obtained via π-π stacking interactions between pyridyl rings