Ultrasound assisted crystallization of cephalexin monohydrate:Nucleation mechanism and crystal habit control

With the high-quality requirements for cephalexin monohydrate,developing a robust and practical crystallization process to produce cephalexin monohydrate with good crystal habit,appropriate aspect ratio and high bulk density as well as suitable flowability is urgently needed.This research has explored the influence of ultrasound on crystallization of cephalexin monohydrate in terms of nucleation mechanism and crystal habit control.The results of metastable zone width and induction time measurement showed the presence of ultrasound irradiation can narrow the metastable zone and shorten induction time.Cavitation phenomena generated by ultrasound were used to qualitatively explain the mechanism of ultrasound promoting nucleation of cephalexin monohydrate.Furthermore,on the basis of classical nucleation theory and induction time data,a series of nucleation-related parameters(such as crystalliquid interfacial tension,radius of the critical nucleus and etc.)were calculated and showed a decreasing trend under ultrasound irradiation.The diffusion coefficient of the studied system was also determined to increase by 72.73%under ultrasound.The changes in these parameters have quantitatively confirmed the mechanism of ultrasound influence on the nucleation process.In further,the calculated surface entropy factor has confirmed that the growth of cephalexin monohydrate follows continuous growth mechanism under the research conditions of this work.Through the exploration of crystallization conditions,it is found that suitable ultrasonic treatment,seeding,supersaturation control and removal of fine crystals are conducive to improving the quality of cephalexin monohydrate product.Optimizing the crystallization process coupled continuous ultrasound irradiation with fine-crystal dissolution policy has achieved the controllable production of monodisperse cephalexin monohydrate crystal with good performance.

A Cell-based High-throughput Screening Assay for Farnesoid X Receptor Agonists

Objective To develop a high-throughput screening assay for Farnesoid X receptor （FXR） agonists based on mammalian one-hybrid system （a chimera receptor gene system） for the purpose of identifying new lead compounds for dyslipidaemia drug from the chemical library. Methods cDNA encoding the human FXR ligand binding domain （LBD） was amplified by RT-PCR from a human liver total mRNA and fused to the DNA binding domain （DBD） of yeast GAL4 of pBIND to construct a GAL4-FXR （LBD） chimera expression plasmid. Five copies of the GAL4 DNA binding site were synthesized and inserted into upstream of the SV40 promoter of pGL3-promoter vector to construct a reporter plasmid pG5-SV40 Luc. The assay was developed by transient co-transfection with pG5-SV40 Luc reporter plasmid and pBIND-FXR-LBD （189-472） chimera expression plasmid. Results After optimization, CDCA, a FXR natural agonist, could induce expression of the luciferase gene in a dose-dependent manner, and had a signal/noise ratio of 10 and Z＇ factor value of 0.65, Conclusion A stable and sensitive cell-based high-throughput screening model can be used in high-throughput screening for FXR agonists from the synthetic and natural compound library.

Effects of piperacillin synthesis on the infterfacial tensions and droplet sizes

Piperacillin is a polar organic substance,and can reduce the interfacial tension of oil and water when dissolved in water.In this study,changes in dichloromethane–water interfacial tensions and microdroplet sizes during piperacillin synthesis from an aqueous solution of ampicillin and dichloromethane solution of 4-ethyl-2,3-dioxo-1-piperazine carbonyl chloride(EDPC)were observed using a pendent drop technique and a coaxial ring tube system with embedded high-speed camera,respectively.It was found that the rapid N-acylation reaction caused the piperacillin at the interface to synthesize rapidly and diffuse out slowly,resulting in the interfacial tension decreased from 19.5 m N·m-1 to 7.2 m N·m-1 rapidly and then increased slowly as the concentrations of ampicillin and EDPC were 0.05 mol·L-1 and 0.1 mol·L-1.Meanwhile,the increase in the concentration of EDPC increased the peak concentration of piperacillin at the interface,and the addition of ethyl acetate to the ampicillin solution promoted mass transfer and reduced the aggregation of piperacillin effectively.During synthesis,the interfacial tension decreased,leading to a change in droplet sizes in the micro-reaction system.The two-phase reaction was carried out in a coaxial ring tube,with ampicillin and EDPC solutions as continuous and dispersed phases,respectively.The reaction reduced the dripping flow area,and the addition of ethyl acetate to the ampicillin solution slightly affected the division of the flow pattern.Under the same flow conditions,the droplet sizes of the reaction group were smaller than those of the no reaction group.The experimental results demonstrated that the increase of the continuous phase,decrease in the dispersed phase flow rate,or increase in EDPC concentration making droplet sizes smaller,and the addition of ethyl acetate slightly affected droplet sizes.These findings are important for the design and optimization of piperacillin synthesis reactors.

Nonisothermal Kinetics of Dehydration Process of [Sm(m-ClBA)_3phen]_2·2H_2O and [Sm(p-ClBA)_3phen]_2·2H_2O

Compounds [Sm（m-CIBA）3phen]2.2H20 and [Sm（p-CIBA）3phen]2·2H20（m-CIBA=m-chlorobenzoate, pClBA=p-chlorobenzoate, phen=l,10-phenanthroline） were prepared. The dehydration processes and kinetics of these compounds were studied from the analysis of the DSC curves using a method of processing the data of thermal analysis kinetics. The Arrhenius equation for the dehydration process can be expressed as lnk=-38.65-243.90×l0^3/RT for [Sm（m-CIBA）3phen]2·2H2O, and lnk=38.70-172.22×103/RT for [Sm（p-CIBA）3phen]2·2H2O. The values of △H^1, △G^1, and △S^1 of dehydration reaction for the title comnonnds are determined respectively.

A NEW PROCESS FOR THE EXTRACTION OF PENICILLIN G FROM THE FILTRATE OF FERMENTATION BROTH WITH TBP IN BUTYL ACETATE

The mixture of neutral phosphorus esters and butyl acetate (BA) can be used, as the extractant for the extraction of penicillin G. The extraction equilibrium pH can be increased to pH3—4 due to the stronger extraction capability of the solvent mixture, instead of pH1.8—2.2 with butyl acetate as solvent. The experimental results indicate that the total recovery of penicillin G can reach 96.6% with the new extraction process, which is 5—6% higher than that obtained with the traditional process using BA as solvent at pH1.8—2.2.

Electrocatalytic NAD(P)H regeneration for biosynthesis

The highly efficient chemoselectivity,stereoselectivity,and regioselectivity render enzyme catalysis an ideal pathway for the synthesis of various chemicals in broad applications.While the cofactor of an enzyme is necessary but expensive,the conversed state of the cofactor is not beneficial for the positive direction of the reaction.Cofactor regeneration using electrochemical methods has the advantages of simple operation,low cost,easy process monitoring,and easy product separation,and the electrical energy is green and sustainable.Therefore,bioelectrocatalysis has great potential in synthesis by combining electrochemical cofactor regeneration with enzymatic catalysis.In this review,we detail the mechanism of cofactor regeneration and categorize the common electron mediators and enzymes used in cofactor regeneration.The reaction type and the recent progress are summarized in electrochemically coupled enzymatic catalysis.The main challenges of such electroenzymatic catalysis are pointed out and future developments in this field are foreseen.

Complete genome analysis of Ketogulonigenium sp. WB0104

Ketogulonigenium sp. may convert L-sorbose into 2-keto-L-gulonic acid, the vitamin C precursor. The genome of Ketogulonigenium sp. WB0104 consists of a circular 2765030 bp chromo- some with 61.69% G+C content and two circular plasmids of 267968 and 242707 bp. The genome contains 2727 open reading frames (ORFs). The systems of replication, transcription, translation, carbohydrate and energy metabolism are intact, but the repair system is incomplete. About 640 predicted ORFs have been found to encode transporter pro- teins, which account for about one fourth of total predicted ORFs, noticeably higher than other docu- mented bacteria. This may be due to the fact that WB0104 adapts to soil circumstance.

Doxorubicin-loaded zein in situ gel for interstitial chemotherapy of colorectal cancer

The aim of this research was to evaluate doxorubicin(DOX)-loaded zein in situ gels,a new drug delivery system in which a liquid state drug can be transformed into semi-solid after intratumoral injection.In vitro release of DOX-loaded zein was investigated and the pharmacokinetics,biodistribution and therapeutic efficacy of these DOX-loaded zein formulations were investigated using BAI B/c nude tumor-bearing mice.In vitro release of DOX from the gels extended up to 7 days.Efficient accumulation of DOX in the tumor with lower drug concentration in blood and normal organs was obtained resulting in effective inhibition of tumor growth and fewer off-target side effects.In conclusion,a DOX-loaded in situ gel was developed with sustained release,enhanced anti-cancer efficacy for colorectal cancer in vivo,and especially with reduced off-target side effects.

Extraction of penicillin G by aqueous two-phase system of [Bmim]BF_(4)/NaH_(2)PO_(4)

A novel approach for the extraction of penicil-lin G by aqueous two-phase system comprised of hydrophilic ionic liquid [Bmim]BF4 (1-butyl-3- methylimidazolium tetra-fluoroborate) and NaH2PO4 is reported. The effects of some important parameters involving the concentration of NaH2PO4, the concentration of penicillin G, the amount of [Bmim]BF4 on the formation of aqueous two-phase system and the extraction yield of penicillin were investigated. The primary result shows that the ATPS can take advantage of penicillin concentrated in upper phase at higher pH value for penicillin extraction from its aqueous solution without emul-sification.