主办:上海医药工业研究院
   中国药学会
   中国化学制药工业协会
ISSN 1001-8255   CN 31-1243/R   ZYGZEA

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  • 2014 Volume 45 Issue 8
    Published: 10 August 2014
      

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  • CHEN Feng1, ZHANG Shengping1, WANG Peibei1, LI Yuezhen2, LAI Yisheng1*
    2014, 45(8): 701-704.
    Abstract ( )   Knowledge map   Save
    Neratinib was synthesized from methyl 4-hydroxybenzoate by nitration, reduction, acetylation, etherification, nitration, reduction, condensation with trans-3-(dimethylamino)acrylonitrile, cyclization and chlorination to give 6-(acetylamino)-4-chloro-3-cyano-7-ethoxyquinoline(12), which was subjected to condensation with 3-chloro-4-(2-pyridinylmethoxy)aniline, deprotection and then acylation with 4-dimethylamino-2-butenoyl chloride with an overall yield of about 29%.
  • LUO Hairong, CHAI Jian, GU Rongling, YU Xufeng
    2014, 45(8): 705-707.
    Abstract ( )   Knowledge map   Save
    Regadenoson was synthesized by reaction from 2-chloroadenine and hydrazine hydrate to give 2-hydrazinoadenine, which was subjected to cyclization with ethyl 2-formyl-3-oxopropionate, amination with methylamine, glycosidation with 1,2,3,5-tetra-O-acetate-β-D-ribofuranose in the presence of trimethylsilyl triflate (TMSOTf), followed by hydrolysis with sodium hydroxide. The overall yield was about 43% with 98.6% purity.
  • CHEN Daoxin, ZHANG Chao, PAN Yi
    2014, 45(8): 708-709.
    Abstract ( )   Knowledge map   Save
    The 7-ACA was reacted with 5,6,7,8-tetrahydroquinoline and trimethylsilyl iodide(mole ratio of 1∶1.3∶1.5) by concentration reaction to give 1-[[(6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-5,6,7,8-tetrahydroquinoline hydroiodide, followed by reaction with 2-(2-amino-4-thiazolyl)-2-
    methoxyiminoacetic thiobenzothiazole ester and crystallization at 10~15 ℃ to afford antibacterial agent cefquinome sulfate. The total yield was about 50% with HPLC purity of 99.5%.
  • ZHANG Shan1, WANG Peibei1, CHEN Feng1, LI Yuezhen2, LAI Yisheng1*
    2014, 45(8): 710-713.
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    CO-1686 was synthesized from 2,4-dichloro-5-(trifluoromethyl)pyrimidine by condensation with 3-nitroaniline, reduction and amidation to afford N-[3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]acrylamide(7), which was subjected to condensation with 1-(4-amino-3-methoxyphenyl)-4-acetylpiperazine(4) obtained from 4-fluoro-2-methoxy-1-nitrobenzene by condensation with piperazine, acetylation and reduction with an overall yield of approximately 71%(based on 2,4-dichloro-5-(trifluoromethyl)pyrimidine).
  • PENG Yinsheng, PAN Qiangbiao
    2014, 45(8): 714-716.
    Abstract ( )   Knowledge map   Save
    Started from the cheap and readily available material 4'-bromomethyl-2-cyanobiphenyl and sodium azide as well as triethylamine hydrochloride, 5-[4'-(azidomethyl)-[1,1'-biphenyl]-2-yl]-1H-tetrazole was generated via the nucleophilic substitution and [3+2] dipolar cyclo-addition in a one-pot process. The above product was easily reduced by triphenylphosphine via Staudinger reaction to afford [2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methanaminium chloride, the key intermediate of sartans. The overall yield was about 72% with a purity of 99.88%. The 300 kg-scale experiment showed the process was quite suitable for industrial production.
  • LIU Ling, ZHANG Changsheng, ZHANG Ling, ZHENG Youguang, LIU Yi
    2014, 45(8): 717-718.
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    L-Citrulline was synthesized from L-ornithine monohydrochloride by chelation with ZnSO4·7H2O and carbamylation with urea to give citrulline zinc, followed by the removal of zinc ions by Na2S without filtration with an overall yield of 65% and purity of 98.7%.
  • GONG Guihua1, ZHANG Wei1*, HU Youjia1, ZHU Baoquan2
    2014, 45(8): 719-723.
    Abstract ( )   Knowledge map   Save
    The Aspergillus nidulans velvet (veA) gene homologue AcveA found in Acremonium chrysogenum encodes a global regulator which controls the expression of cephalosporin C (CPC) biosynthetic genes. In this study, an AcveA expression plasmid pYG280 was constructed by amplifying the AcveA gene from genomic DNA of A. chrysogenum, which was then transformed into a high-yield strain of A. chrysogenum. The results of real-time PCR indicated that AcveA transcriptional level in the transformant 280-5 was 165% higher than that of the original strain. Meanwhile the relative transcriptional levels of CPC biosynthetic genes pcbC, cefEF and cefG in the transformant 280-5 were increased by 825%, 353% and 25%, respectively, with the introduction of additional copy of AcveA. HPLC analysis results showed that CPC production in the transformant was also improved by 22.7%. These results demonstrated that AcveA was a positive regulator in the biosynthesis of CPC.
  • WEI Tingting, HU Haifeng*
    2014, 45(8): 724-728.
    Abstract ( )   Knowledge map   Save
    Under directional screening of the microorganisms in sixty natural soil samples, the strain SIPI-18-5 was identified which could convert the aconitine to single ester type or less toxic compounds. Preliminary study on the convert-products by the mass spectrometry analysis showed benzoylaconine and deoxybenzoylaconine were part of the products. After optimization of the fermentation and conversion processes, the fermentation medium composition was determined as glucose 10 g/L, (NH4)2SO4 1 g/L, yeast extract 10 g/L, FeSO4 0.01 g/L, CaCO3 5 g/L. The pH value before sterilization was 8.0 and inoculation amount was 5%. The optimized conversion process was transformation temperature of 30 ℃, shaking speed of 180 r/min, bottle volume of 50 ml/250 ml, aconitine addition of 0.1 g/L and adding aconitine as the inducer at 16 h. The production of benzoylaconine was 0.051 g/L under the optimal conditions, with the molar conversion rate of 54.5%.
  • LUO Fenrong, QIU Jianfang, XU Wen, HUANG Mingqing, WU Shuisheng?
    2014, 45(8): 729-733.
    Abstract ( )   Knowledge map   Save
    The pretreatment, extraction and purification methods of Alisma orientalis (Sam.) Juzep. were optimized with contents of total triterpenes (1) and alisol B 23-acetate (2) as indexes. The optimized process was as follows: the crude herbs about 10 mesh were extracted under reflux by 10 times of 85% ethanol twice, 1 h pre time. The extract containing crude drug 0.5 g/ml with the volume of 100 ml was loaded on the D101 macroporous resin column with the sample flow rate of 2 BV/h (60 ml/h). Then the column was washed by 4 BV of water, 6 BV of 40% ethanol with the rate of 4 BV/h for removing impurities and 8 BV of 80% ethanol with 2 BV/h for purifying 1. Both the laboratory scale test and pilot scale test of 50 kg showed that the optimal process was stable. Contents of 1 and 2 in the extract obtained by this process were above 50% and 8%, the yield of 1 was about 77 %.
  • LI Ling1, CHENG Liang1, CHENG Lifang1, TIAN Chenmin1, CHEN Dawei1,2*
    2014, 45(8): 734-738.
    Abstract ( )   Knowledge map   Save
    The pH-sensitive polymeric micelles based on amphiphilic block copolymer poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidenepentaerythritol carbonate) loaded with doxorubicin (1) were prepared by dialysis method. The physicochemical properties of micelles were characterized. A TEM image showed that the prepared micelles were well-distributed and regularly spherical particles. The average diameter, ζ potential, drug loading and encapsulation efficiency of the product were (163.3±2.1)nm, (-17.54±0.26)mV, 10.3% and 68.9%, respectively. The results of in vitro drug release test suggested that the pH values of medium had a significant effect on particle size and release behavior of 1 from the micelles. Particle size increased to 800 - 1 000 nm within 24 h in pH 5.0 medium. Moreover, the product had a serious burst release in 2 h and the cumulative release at 48 h was 90% in pH 5.0 medium. The results of in vitro cytotoxicity test indicated that the blank micelles had no significant toxicity on normal and cancer cells, while the drugloading micelles possessed high dose-dependent cytotoxicity against B16 melanoma cells.
  • ZHANG Lu1, CHENG Lifang1, CHENG Liang1, RUAN Yuan1, CHEN Dawei1,2*
    2014, 45(8): 739-743.
    Abstract ( )   Knowledge map   Save
    Based on the generation 4 poly(amidoamine) (PAMAM) dendrimers, the binary and ternary selfassembled gene complexes, siRNA/PAMAM and siRNA/PAMAM/HA, were prepared by successive electrostatic adsorption of PAMAM with siRNA and hyaluronic acid (HA) for active targeting of siRNA delivery. The prepared siRNA/PAMAM/HA particles were spherical. With the increase of the charge ratio of HA on surface of the ternary complexes, the mean particle size increased and the ζ potential decreased. Moreover, the complexes were able to combine and protect siRNA efficiently. The results showed that the shielding with HA could reduce the toxicity of PAMAM to MDA-MB-231 breast cancer cells significantly. Compared with siRNA/PAMAM complexes without HA coating, thesiRNA/PAMAM/HA complexes showed obviously increased uptake and active targeting ability. And the highest cellular uptake was observed when the shielding ratio of HA was 25% (charge ratio).
  • CHEN Wenrong1, LONG Xiaoying1, CHEN Bao2*, LIN Wanting1, WANG Yifan1
    2014, 45(8): 744-749.
    Abstract ( )   Knowledge map   Save
    The effects of process influence factors (shearing speed, adding speed of ethanol solution and homogeneous times) and formulation influence factors (the types of phospholipids, amounts of surfactants, electrolyte and drug) on the quality of vitamin A palmitate (1) transfersomes were investigated with particle size and ζ potential as the indexes by single factor tests. The preliminary stability of the product was also tested. The optimal preparation was as follows: dissolving phospholipids (1 g), Tween-80 (0.2 g) and 1 (0.2 g) into 0.5 ml of ethanol as oil phase, dissolving phenoxyethanol (0.5 g) into 100 ml of water as water phase, dropping the oil phase with 2 ml/min into the water phase kept the shearing speed of 13 000 r/min to obtain the primary transfersomes, then high pressure homogenization under the pressure of 1 500 bar for one times to obtain the final product. The particle size, ζ potential and entrapment efficiency of the optimized product were (100.8±16.5)nm,(-43.7±1.1)mV and (96.2±1.2)%, respectively. However, when the product was stored at 4 ℃ for 6 months, the particle size and drug content were decreased while the absolute value of ζ potential was increased.
  • TAI Yi, ZHOU Zhen, LUO Huafei, LI Zhou, GE Qinghua*
    2014, 45(8): 750-753.
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    A LC-MS/MS method was established for the determination of estradiol in rat plasma by derivatization. Plasma samples were extracted and derivatized before injection. An ESI ion source was used and operated in the positive ion mode with multiple reaction monitoring (MRM) mode. Estradiol-d3 was chosen as the internal standard and a C18 column was used. The calibration curve was linear in the concentration range of 50 - 10 000 pg/ml. The method recoveries were 94.0% - 107.2%, with RSDs less than 10%. The method was applied in the determination of estradiol in blank female rat plasma and the pharmacokinetic study of the estradiol patch in rats. The results showed that this method was selective, accurate and sensitive, and was successfully applied in pharmacokinetic study for estradiol.
  • CHEN Na, ZHANG Yijie, HAN Jichang, MA Chaonan
    2014, 45(8): 754-757.
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    The ZS1 peptide decorated liposomes loaded with paclitaxel (1) and curcumin (2) were prepared by thin film hydration method. The particle size and ζ potential of the product were (92.8±3.5)nm and (13.50±2.55)mV. The entrapment efficiency of 1 and 2 were 84.5% and 75.6%. The transmittance values of the product after incubation with phosphate buffer containing 50% fetal bovine serum for 24 h were not significantly changed, which indicated the prepared liposomes were rather stable in serum. The results of in vitro uptake test showed that the cellular uptake efficiency of the ZS1 peptide decorated liposomes by A549 cells was 3.3 times higher than that of the unmodified liposomes, while the uptake efficiencies of both liposomes by human umbilical vein endothelial cells (HUVEC) were close. It indicated that the liposomes decorated with ZS1 peptide had a potential effect of active targeting to A549 cells. The blank liposomes had no cytotoxicity on A549 cells. The cell viabilities of the title liposomes, ZS1-modified liposomes loaded with 1 or 2 and the unmodified liposomes were 11%, 36%, 51% and 61%, respectively.
  • LU Ming, WANG Linbo, SHEN Yi, CHEN Zhukang, YANG Meicheng
    2014, 45(8): 758-762.
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    The absorption coefficient-determination capacity of the laboratories was evaluated. Testing samples were prepared with homogeneity and stability meeting the requirements of proficiency-testing. The study was performed according to ISO13528:2005, protocol of International Union of Pure and Applied Chemistry (IUPAC) and procedure of China National Accreditation Service for Conformity Assessment (CNAS). The one-way ANOVA was used to evaluate the homogeneity of the test samples, whose stability was confirmed with t-test. All results conformed to the requirements. Z-scores were used to evaluate results from each laboratory with the median of all results as the indicated value. NIQR was used as the variable metricvalue (target standard deviation). Among 128 laboratories which reported their results, 101 laboratories' results were ''satisfactory'', 15 were ''questionable'' and 12 were ''unsatisfied''.
  • HAN Jihong1, WANG Lin1, XIE Junxia1 , HOU Zhifei1, JIANG Ye2*
    2014, 45(8): 763-766.
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    An HPLC method was established for the determination of calycosin-7-O-β-D-glycoside, ferulic acid, calycosin and formononetin in Danggui Buxue preparations and their contents in different preparations were compared. A Kromasil C18 column was used with the mobile phase of methanol∶0.4% formic acid by gradient elution and at the detection wavelength of 280 nm. The calibration curves of the four components were linear in the concentration ranges of 0.8 - 16, 1 - 20, 0.6 - 12 and 0.56 - 11.2 μg/ml, respectively. Their average recoveries were 99.4%, 99.6%, 96.8% and 98.2%, with RSDs of 2.1%,1.6%,1.8% and 1.9%, respectively.
  • SU Yanbin1, ZHANG Fengrong2*, SU Yanwen1, XU Yongchao1, WANG Xufeng1
    2014, 45(8): 767-770.
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    An HPLC method was established for the determination of three constituents in compound trivitamin B for injection (Ⅱ). An Agela C18 column was used with the mobile phase of phosphate buffer (0.05 mol/L potassium dihydrogen phosphate solution 1 000 ml, adjusted to pH 6.3 by 1 mol/L potassium hydroxide solution, A)∶
    methanol (B)(86∶14) at the detection wavelength of 267 nm for the determination of thiamine nitrate and pyridoxine hydrochloride, and A∶B(75∶25) at the detection wavelength of 361 nm for the determination of vitamin B12. The calibration curves of thiamine nitrate, pyridoxine hydrochloride and vitamin B12 were linear in the ranges of 2.0 - 10.1, 30.5- 152.7 and 1.2 - 6.2 μg/ml, respectively. The average recoveries were 99.63%, 99.39% and 100.60%, with RSDs of 0.31%, 0.67% and 0.58%, respectively.
  • ZHANG Xi1, WEN Fang1, GAO Li1, YU Kai,1 ZHANG Caixia2*
    2014, 45(8): 771-772.
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    An HPLC method was established according to USP 29 for the determination of natamycin eye drops and its related substances. A C18 column was used with the mobile phase of 4 mg/ml ammonium acetate solution∶ acetonitrile∶THF (76∶24∶5) at the detection wavelength of 303 nm. The calibration curve for natamycin was linear in the concentration range of 40 - 400 μg/ml. The average recovery was 100.3%, with RSD of 0.65%.
  • DU Jiaqiu1, LI Juan 2, ZHENG Guogang2
    2014, 45(8): 773-775.
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    The HPLC method was improved for the determination of the related substances in doxofylline injection. A C18 column was used, with the mobile phase of acetonitrile∶water (10∶90), at the detection wavelength of 273 nm. The calibration curves for doxofylline and its related substances A and B were linear in the range of 0.2 - 3 μg/ml. Their low limits of detection were 8.3, 16.7 and 14.8 ng/ml. The average recoveries of related substances A and B were 100.1% and 102.1%, with RSDs of 1.2% - 2.7%.
  • TIAN Huairu1, JING Shaojun1, NI Meiping2, ZHOU Rujun3, JIANG Ye1*
    2014, 45(8): 776-778.
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    A flow injection chemiluminescence (CL) method was established for the determination of dihydropyridine drugs on cleaning validation, including nitrendipine, nimodipine, felodipine, and m-nisoldipine. The calibration curves for the above dihydropyridines were linear in the concentration range of 0.2 - 4 μg/ml. Their low limits
    of detection were 0.03 - 0.06 μg/ml. The average recoveries were 96.3% - 100.9%, with RSDs less than 3.6%.
  • WANG Haixia, LIN Ping, ZHOU Wenting, JIA Canchao, JI Shengguo*
    2014, 45(8): 779-781.
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    A near-infrared spectroscpoy (NIR) method was established for the determination of extracts content in Desmodium styracifolium. The quantitative calibration models of NIR were established by the partial least squares method for the extract content and the NIR data of 109 batches of D. styracifolium samples, approved by 21 samples for model validation set validated and methodological study. The correlation coefficients, root-mean-square error of calibration, rootmean-square error of prediction and root-mean-square error of cross-validation of the calibration model were 0.979, 0.311, 0.331 and 0.568, respectively.
  • MEI Li1,2, JIN Fang3*
    2014, 45(8): 782-788.
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    Solid dispersion refers to pharmaceutical forms in which active pharmaceutical ingredient(API) is highly dispersed in a biologically inert matrix in the form of molecular, amorphous or crystalline. It is crucial for further studies and evaluations to explore the state of API in carrier, interactions between them as well as the structure of solid dispersion sufficiently. The principle, main content and recent development of several characterization methods, such as dissolution test, thermal analysis, spectrum analysis and other common methods are reviewed in this paper. The future directions of characterization technologies for solid dispersion are also prospected.
  • CHEN Shaoxiong1, ZHAN Xiaoping2, WANG Liqun1, MAO Zhenmin2*
    2014, 45(8): 789-794.
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    The drug carriers with excellent properties produce significant influences on the development of new administrations of protein drugs. The carrier materials used in the drug delivery systems for protein drugs are reviewed in this paper. Here, artificial and natural biodegradable materials, non-degradable polymer carrier materials, block copolymer materials containing PEG segments and related drug loading technologies are introduced.
  • HUANG Ke, ZHOU Ruili*
    2014, 45(8): 795-798.
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  • ZHOU Bin1,2, WU Xiaoming1*
    2014, 45(8): 799-4594.
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