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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  • 2016 Volume 47 Issue 01
    Published: 09 January 2016
      

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  • LU Shiyong1, ZHANG Xiaotian1, ZHOU Weicheng2, ZHANG Fuli2, YE Weidong1
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Ethylene glycol was reacted with tert-butylchlorodiphenylsilane, tosyl chloride and sodium bromide to give (2-bromoethoxy)(tert-butyl)diphenylsilane, which was coupled with sirolimus in the presence of silver trifluorom ethanesulfonate to give 40-O-[2-(tert-butyldiphenylsilyloxy)ethyl]rapamycin, followed by hydrolysis with hydrofluoric acid to provide everolimus with an overall yield about 43%.
  • LIU Xiangsheng, ZHANG Yi, ZHANG Jiquan, WANG Jianta, TANG Lei*
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Linagliptin was synthesized from methylurea by condensation with ethyl cyanoacetate, cyclization, nitrosation, reduction, cyclization, bromination, substitution with 1-bromo-2-butyne to give 8-bromo-7-(but-2-yn-1-yl)- 3-methyl-1H-purine-2,6(3H,7H)-dione, which was subjected to alkylation with 2-chloromethyl-4-methylquinazoline, followed by substitution with (R)-3-aminopiperidine dihydrochloride with an overall yield about 27% and optical purity of 99.8%.
  • XIA Jun1, YU Zhengye2, WANG Haiping1*
    Abstract ( )   Knowledge map   Save
    Bepotastine besilate was prepared from (S)-(4-chlorophenyl)(pyridin-2-yl)methanol via reaction with 2,2,2-trichloroacetonitrile to give (S)-(4-chlorophenyl)(pyridin-2-yl)methyl 2,2,2-trichloroacetimidate, which was subjected to condensation with ethyl 4-(4-hydroxypiperidin-1-yl)butanoate to obtain ethyl 4-[4-[(S)-
    (4-chlorophenyl)(pyridin-2-yl)methoxy]piperidin-1-yl]butanoate, followed by hydrolysis and salt formation with benzenesulfonic acid with an overall yield of 60%.
  • LI Bo, ZHANG Wenxuan*, QIU Hui, WU Song
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    D-MTX is the enantiomer of methotrexate (L-MTX) originated from the process of preparation or racemized during the shelf life under improper storage conditions. In order to control the chiral impurities of methotrexate, racemic methotrexate was synthesized from methotrexate via esterification, racemization with DBU in absolute alcohol and deprotection. The structure was confirmed by MS, 1H NMR, and the ratio of enantiomers was 1∶1. The racemic
    methotrexate could be used as a reference substance in the quality control of methotrexate.
  • ZHANG Xianyi1, LI Min1, ZHOU Xiaocong1, GAO Hongjun2*, LI Yuanqiang2
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Four related substances of axitinib were synthesized. These related substances were: N-methyl-2- [3-[2-(pyridin-2-yl)ethyl]-1H-indazol-6-ylthio]benzamide (A), 2,2'-(1H-indazole-3,6-diyl)bis(sulfanediyl)bis(Nmethylbenzamide) (B), (E)-N-methyl-2-[1-[2-(pyridin-2-yl)ethyl]-3-[2-(pyridin-2-yl)vinyl]-1H-indazol-6- ylthio]benzamide (C) and 2-(3-acetyl-1H-indazol-6-ylthio)-N-methylbenzamide (D). Their structures were confirmed by 1H NMR and MS.
  • CAI Zhenyan1, LIU Henan2, WANG Hong3, YANG Wuxin4, HE Guixia1*
    Abstract ( )   Knowledge map   Save
    3,5,7,3',4',5'-Hexaacetyldihydromyricetin(1), 3,3',4',5'-tetraacetyldihydromyricetin(2), 3,7,3',4',5'- pentaacetyldihydromyricetin(3), 3-acetyldihydromyricetin(4) and acetone adduct of dihydromyricetin(5) were synthesized from dihydromyricetin(6) with different acylating reagents under different catalytic conditions. Their structures were confirmed through MS, 1H NMR and 13C NMR. Their antioxidant activities were evaluated by the clearance effect to hydroxyl radical and superoxide anion. The results showed that the antioxidant activities of these compounds in descending order were 6>4>5>2>3>1.
  • SHI Lianyong, ZHANG Haibo, HU Tao, CHEN Lingwu
    Abstract ( )   Knowledge map   Save
    Febuxostat was synthesized from 4-hydroxybenzothioamide via Hantzsch cyclization with ethyl 2-chloroacetoacetate and Duff reaction to obtain ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (4), followed by oximation and dehydration to give ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (5), which was subjected to reaction with isobutylbromide and hydrolysis with an overall yield of 50%. Ethyl 2-(3,5-diformyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (7), the process impurity of the intermediate 4, was synthesized and the structure was confirmed.
  • FENG Jianxun, CHEN Rui, GAO Xingqiang, WEI Dongzhi, WANG Xuedong*
    Abstract ( )   Knowledge map   Save
    One strain of Mycobacterium neoaurum was screened in a previous research and it was validated that it could transform phytosterol into androstadienedione(2). In this study, the effects of Tween-80 and hydroxypropyl-β- cyclodextrin (HP-β-CD) on the efficiency of phytosterol biotransformation to drug intermediates were investigated, as well as the effects of two cosolvents on the metabolic pathways. The conversion rates reached 70.2% and 100% in the presence of Tween-80 and HP-β-CD at the phytosterols concerntration of 2.5 g/L, while that of the control group was 36.7%. When Tween-80 was added, the proportion of 2 decreased, but the proportion of androstenedione and testosterone increased. However, the proportion of 2 increased and side-chain incompletely reduced metabolites were accumulated at the addition of HP-β-CD. Besides, when two cosolvents were used together, the effect of HP-β-CD was much greater than that of Tween-80.
  • JIN Hongguang1, XU Lingling1, JIANG Shenhua1, WOO Eun-Rhan2, LIAO Liang1*
    Abstract ( )   Knowledge map   Save
    Seven compounds were isolated and purified by macroporous adsorptive resin HP-20, MCI gel, silica gel and Li Choprep RP-18 column chromatographies from the rattan of Akebia quinata Decne.. Their structures were identified by spectroscopic methods as L-threo-guaiacylglycerol 8-O-β-D-glucopyranoside (1), guaiacylglycerol 9-O-β- D-glucopyranoside (2), 3-methoxy-4-hydroxyphenol 1-O-β-D-glucopyranoside (3), 2-methoxy-4-hydroxyphenol 1-O-β- D-glucopyranoside (4), 2,6-dimethoxy-4-hydroxyphenol 1-O-β-D-glucopyranoside (5), di-O-methylcrenatin (6) and coniferin (7). Compounds 2—7 were isolated from the plant for the first time.
  • SUN Aijing1,2, PANG Suqiu1,2, WANG Guoquan1
    Abstract ( )   Knowledge map   Save
    Five compounds were isolated by gel and ODS chromatographic methods from Bletilla striata (Thunb.) Reichb.f., and were identified by spectrum analysis as 5-(hydroxymethyl)-2-furaldehyde (1), stigmasta-5,22- dien-3β-ol (2), brugnanin (3), 2-methylanthraquinone (4) and cycloneolitsol (5). Their antiproliferative effects to tumor cells were evaluated by MTT test, and their effects on the A549 cell cycle were also investigated. Compound 1 showed high antiproliferative activity against the tumor cells as it could induce G0/G1 phase arrest of A549 cells effectively. Compounds 1—4 were isolated form Bletilla striata for the first time.
  • FENG Yue 1, ZHONG Meng 2, CHEN Yue1
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    To improve the half time and bioavailability of gemcitabine hydrochloride (1), the 1 liposomes (1-LP) modified by D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared by reverse evaporation method. The properties and pharmacokinetics of the product in rats were investigated. The results showed that the average particle size, ζ potential, entrapment efficiency and drug loading were (212.6±7.2)nm, (-31.1±2.9)mV, (70.56±1.92)% and (7.41±0.05)%, respectively. The in vitro release curves of 1-LP and 1 solution in pH 7.4 phosphate buffer were drawn and the experimental data were fitted by serval commonly used models. The results showed that a biexponential model fitted the data well according to the correlation coefficient (R2) values, which were 0.996 and 0.947. After vein injection of 1-LP or commercially available injection of 1, the pharmacokinetics of both preparations in SD rats were
    investigated and compared. The drug concentration in plasma was determined by HPLC. The main pharmacokinetic parameters of 1-LP and 1 injection were as follows: t1/2 (4.12±0.73) and (1.32±0.10)h,AUC0→∞ (37.57±1.09) and (9.64±0.20)mg·L·h-1,MRT0→∞ (6.06±0.28) and (1.67±0.04)h.
  • MA Yuhua1, WANG Hong2, SUI Hong2,3,4 , WANG Wenping2,3,4*
    Abstract ( )   Knowledge map   Save
    Bovine serum albumin (BSA) or BSA-Zn complex was dissolved or dispersed in poly (L-lactic acid) (PLLA) solution, which were further loaded into microparticles by emulsion-solvent evaporation method or hydrogel template technique (with polyvinyl alcohol as a template). Then four kinds of microparticles were obtained and their properties were characterized. The average particle size of the former two (named as s/o/w and w/o/w microparticles)
    and the last two (named as s/o/t and w/o/t microparticles) were 38.13, 34.65, 49.47 and 45.82 μm, the span values were 0.77, 0.86, 0.22 and 0.26, the entrapment efficiencies were 15.62%, 7.74%, 85.87% and 81.77%, respectively. The drugloading capacities of the two kinds of microparticles prepared by the former method were significantly decreased. The results of in vitro release test showed that the burst release at the first day of the above four products were 1.3%, 13.3%, 18.9% and 55.7%, the cumulative release at 127 d were 14.1%, 83.6%, 57.5% and 60.6%, respectively. It indicated that morphology and structure of microparticles significantly affected by the preparation methods, which further impacted drug-loading efficiency and release profile.
  • LIU Shanshan1, LI Zemin2, ZHENG Lina3, ZHAO Ligang2*, HAN Gang1
    Abstract ( )   Knowledge map   Save
    Two fatty acid ester derivatives of α-terpineol, terpineol acetate butyrate (T-BUT) and terpineol acetate hexanoate (T-HEX), were synthesized. The in vitro permeability test was carried out with two-chamber cells and excised rabbit skin to investigate the penetration effects of the obtained derivatives, α-terpineol, azone and N-methylpyrrolidone (NMP) on permeation behavior of isosorbide dinitrate (1) in the isopropyl myristate (IPM) system. The results showed that all enhancers with the concentration of 5% had significant enhancing effects on the penetration of 1 compared with the control group without adding any enchancer (P<0.05). Compared with α-terpineol, the enhancement effects of NMP, T-BUT and T-HEX were more significant (P<0.05). It was clearly that these two derivatives could significantly promote the enhancing activity of α-terpineol. In the group with the combinations of 5% NMP and 5% T-HEX as enhancers, the cumulative penetration amount of 1 at 8 h were 11.24 times higher than that of the blank group.
  • LIU Yuan, LI Yi, YIN Gang, REN Jing*
    Abstract ( )   Knowledge map   Save
    The cores of the title tablets loaded with doxifluidine (1) were prepared by wet granule compression technique. Then the inner layer with pectin and sodium alginate (2∶1) as main materials and weight gain of 5%—10% and the outer layer with Eudragit S100 as the material and weight gain of 12%—15% were coated over the surface of the above cores in sequence to obtain the title tablets. The in vitro release profiles of 1 from the tablets in media with different pH values were investigated by paddle method. The results showed that 1 did not release in artificial gastric fluid (dilute hydrochloric acid) and none or a little released in artificial intestinal fluid [phosphate buffer (PBS), pH 6.8], while more than 85% of 1 could release from the tablets within 2 h in artificial colonic fluid (PBS, pH7.8). It indicated that the product had a colon targeting property.
  • ZHANG Yakun, WANG Weimei, HE Wenjuan, DONG Weichong, ZHANG Zhiqing*
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    An UPLC method was established for the determination of metoprolol tartrate in rat plasma. The influence of sarpogrelate hydrochloride on the pharmacokinetics of metoprolol tartrate in rats was also investigated. An Acquity UPLC® BEH C18 column was used, with lamotrigine as the internal standard and the mobile phase of methanol∶ 0.01 mol/L potassium dihydrogen phosphate buffer (adjusted to pH 3.6 with phosphoric acid) (31∶69), at the detection wavelength of 225 nm. Forty rats were randomly divided into two groups with 20 rats in each. Each rat in the control group was given metoprolol tartrate (27 mg/kg) by gavage, while the animal in the test group was given metoprolol tartrate (27 mg/kg) and sarpogrelate hydrochloride (10 mg/kg) by gavage. The pharmacokinetic parameters of the two groups were calculated by DAS 2.1.1 pharmacokinetic software and were compared by SPSS 13.1 software. The results showed that there were no significant differences of the AUC0→5 h, AUC0→∞, t1/2, tmax, V, CL and cmax between the control group and the test group (P>0.05). It suggested that the pharmacokinetics of metoprolol tartrate in rats had no significant difference between single administration and co-administration with sarpogrelate hydrochloride.
  • WANG Can, WU Lihong, SHAO Hong, CHEN Gang*
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    A cell growth inhibition test was used to detect the biological activity of nimotuzumab. A CE-SDS method was applied for its purity determination, and a weak cation exchange (WCX) chromatoraphy was used for the evaluation of the charge heterogeneity. Other tests were carried out according to the requirements of the registered specification and Chinese pharmacopoeia (volume Ⅲ, 2010 edition). Based on the registered specification, the key tests such as bioassay, CE-SDS, WCX chromatoraphy, as well as Tween-80 content, clarity, particulate matter and osmolality were cited into the specification. The improved specification for nimotuzumab was cited into the Chinese pharmacopoeia (2015 edition).
  • ZHOU Yimeng, ZHOU Bin*
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    An HPLC method was established for the determination of emedastine difumarate and its related substances. A Zorbax Extend-C18 column was used with the mobile phase of 0.5% triethylamine solution (adjusted to pH 7.6 with phosphoric acid)∶methanol∶acetonitrile (40∶42∶18) at the detection wavelength of 284 nm. Emedastine difumarate and its related substances were separated successfully. It was linear in the concentration range of 0.05— 1.0 mg/ml for emedastine difumarate. The average recovery was 100.3%, with RSD of 0.12%.
  • GU Guangzhi, WANG Yemu, LIU Wei, WANG Linbo*, PENG Xingsheng
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    A laser light scattering method was established for the determination of particle size and distribution of efavirenz. A Malvern Mastersizer 3000 type laser size analyzer and a Hydro MV wet autosampler were used. The determination conditions were investigated as follows: pump speed of 1 800 r/min, shading degree of 10%—20%, measurement time for background and samples of 10 s, measurement for 5 times, sample refractive index of 1.52, and sample absorbency of 0.01. The RSDs of methodological study for d(0.5) values were lower than 3%, and lower than 5% for d(0.1) and d(0.9) values. All the d(0.9) and d(0.5) values of 6 batches of efavirenz bulk drug were 8—30 μm and 1.7—12.0 μm, respectively, which were all in line with the requirements of imported drug registration standards.
  • DOU Nina1, RAN Congcong2, DU Chaohui2, JIANG Ye2*
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    A hollow fiber centrifugal ultrafiltration method was established for the sample pretreatment, an HPLC method was developed for the determination of ketoprofen gel. The macromolecule gel materials were effectively removed from the sample solutions by a hollow fiber centrifugal ultrafiltration device, thus it improved the method accuracy and repeatability. A C18 column was used, with the mobile phase of 0.05 mol/L potassium dihydrogen phosphate solution (adjusted to pH 3.5 with phosphoric acid)∶methanol(25∶75), at the detection wavelength of 255 nm. It was linear in the concentration range of 0.25—10 μg/ml. The average recoveries were 100.8%—102.6%, with RSDs no more than 1.6%.
  • WANG Hairong1,2, LI Jian3, ZHANG Yanfen2, DU Yumin1, ZHANG Lantong1*
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    An HPLC method was established for the enantiomeric separation and determination of stiripentol enantiomers. A Chiralpak AY-H column was used, with the mobile phase of n-hexane∶isopropanol (90∶10), at the detection wavelength of 270 nm. It was linear in the concentration range of 15.6—500 μg/ml for both (R)- and (S)- stiripentol. Their recoveries were 98.60% and 99.84%, with RSDs of 0.82% and 0.72%.
  • CHEN Jianqin
    Abstract ( )   Knowledge map   Save
    An HPLC method was established for the determination of hydrochlorothiazide, vitamin B6 and methyl hesperdine in compound reserpine and hydrochlorothiazide tablets. An Agilent Zorbax ODS column was used, with the mobile phase of acetonitrile∶0.1% phosphoric acid (adjusted to pH 2.7 with triethylamine)(25∶75), at the detection wavelength of 283 nm. The calibration curves were linear in the range of 4—80 μg/ml for the above three components. Their average recoveries were 100.46%, 99.35% and 99.75%, with RSDs of 0.64%, 0.52% and 0.89%, respectively.
  • MA Shuai, WEN Yingling, ZHOU Weicheng
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    The U.S. Food and Drug Administration (FDA) approved 45 new drugs into the market in 2015, including 32 chemical small molecules and 13 biological products. According to the prescription information for professionals and the related literature as well as patent information, this review describes the  descriptions, indications, mechanism of action, dosage form and strength, adverse reactions, and one synthetic route of the chemical small molecules, and brief information about biological products.
  • DAN Jixiu, YUE Pengfei*, XIE Yuanbiao, ZHENG Qin, YANG Ming
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    Spray freeze drying (SFD) is a novel technology for micronization of poorly soluble drugs. This technology can be used to prepare the particles with low-density and high specific surface area, which are useful to improve the solubility and bioavailability of poorly soluble drugs. The principle, characteristics and applications of SFD are introduced in this paper. Special emphasis is placed on the key influence factors of SFD on micronization.
  • WANG Ruyi, LIU Yi
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    Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a mixture of acetic acid and succinic acid esters of hydroxypropyl methyl cellulose so that it has an amphiphilic property. The glass transition temperature of HPMCAS is about 120 ℃. HPMCAS is commonly used as an enteric film-coating material because of its pH dependence. In recent years, the application researches of HPMCAS used as an amorphous solid dispersion carrier for poorly water soluble drugs are increasing. HPMCAS is suitable for use in common preparation methods of solid dispersions, such as solvent evaporation method, hot melt extrusion, spray (freeze) drying and milling method. Moreover, HPMCAS exhibits the ability of inhibit drug recrystallization in the processes of storage, in vitro dissolution and in vivo absorption of solid dispersions, which is beneficial for improving stability of solid dispersions. The progress of applications of HPMCAS to solid dispersions is reviewed in this paper.
  • LEI Chunhua1,2, QIU Fei1,2,3*, WANG Liqiang1,2,3
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  • CAI Zhongxi, GAN Rongfu*
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  • TAN Xiaodong, CHEN Yuwen*
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