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 7
    Published: 10 July 2014
      

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  • ZHAO Jie1, SHANG Weiding1, XUE Na2, ZHANG Kai1*, DU Yumin1
    2014, 45(7): 601-602.
    Abstract ( )   Knowledge map   Save
    Desmethylvenlafaxine was synthesized from 4-hydroxyphenylacetonitrile by etherification with benzyl bromide, condensation with cyclohexanone with NaH as base and hydrogenation catalyzed by 10% Pd/C to give 1-[2-amino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, which was subjected to N-methylation with formaldehyde and
    formic acid. The overall yield was about 46.5%.
  • WANG Kai, ZHANG Xiong, JIN Qi, ZHANG Xiulan, ZHANG Heng
    2014, 45(7): 603-605.
    Abstract ( )   Knowledge map   Save
    D-serine underwent the esterification and protection with (Boc)2O to obtain methyl (R)-3-hydroxy-2-(tert-butoxy)carbonyl aminopropanoate, from which (R)-3-hydroxy-2-[(tert-butoxycarbonyl)amino]propionyl benzylamine was prepared. In the condition of cool temperature, (R)-2-amino-N-benzyl-3-methoxypropanamide was generated with the etherification of dimethyl sulfate and deprotection by concentrated hydrochloric acid. Finally, lacosamide was prepared through acetylation with acetic anhydride, with the total yield of 39.3%.
  • WANG Jiangxia1, ZHENG Ligang2, WANG Pan1, LIU Qing1, SHANG Zhenhua1*
    2014, 45(7): 606-610.
    Abstract ( )   Knowledge map   Save
    To perform the quality control of iloperidone, six related substances: 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol(P88), 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxybenzoic acid (P95), 1,1'-[1,3-propanediylbis[oxy(3-methoxy-1,4-phenylene)]]bis-ethanone(A), (E)-(2,4-difluorophenyl)(piperidin-4-yl)methanone oxime(B), 1-[4-[3-[4-(6-ethoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone(C) and 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine-N-oxide(D) were synthesized. The chemical
    structures were confirmed by MS, 1H NMR and 13C NMR.
  • LI Qiang, LIU Junmin, FU Qingyun, LI Rong, LIU Ruibin*
    2014, 45(7): 611-612.
    Abstract ( )   Knowledge map   Save
    5-(N,N-Biscarboxymethyl)amino-4-cyano-3-carboxymethyl-thiophene-2-carboxylic acid was prepared from strontium ranelate in hydrochloric acid at low temperature, which was used to synthesize two related substances by controlling different conditions (temperature and concentration of hydrochloric acid). The related substances were 4-cyano-5-[bis(carboxymethyl)amino]thiophene-3-acetic acid and 4-methyl-3-cyano-2-[bis(carboxymethyl)amino]thiophene. Their structures were identified by IR, 1H NMR, 13C NMR and MS.
  • ZHANG Jianjun, SUN Pinghua, CHEN Yan, GENG Zhizhong, CHEN Weimin*
    2014, 45(7): 613-616.
    Abstract ( )   Knowledge map   Save
    3-Hydroxy-5-methoxystilbene-2-carboxylic acid derivatives 1a - 1e were synthesized from methyl 2-[(diethoxyphosphoryl)methyl]-4,6-dimethoxybenzoate and aromatic aldehyde, via several steps including condensation, demethylation and hydrolysis. The anti-inflammatory activities of these compounds were evaluated on lipopolysaccharide-induced RAW264.7 macrophages. The compounds 1c, 1d and 1e showed a certain degree of antiinflammatory effects with low toxicity to normal cells.
  • JIN Longlong, LEI Pingsheng*
    2014, 45(7): 617-619.
    Abstract ( )   Knowledge map   Save
    4-[4-(3-Pyridyl)-1H-imidazol-1-yl]-1-butanamine, the side chain of telithromycin, was synthesized from 3-acetylpyridine by dibromination, and cyclization with paraformaldehyde and ammonium hydroxide to give 4-(3-pyridyl)-1H-imidazole, followed by condensation with N-(4-bromobutyl)phthalimide and hydrazinolysis with an
    overall yield of 41%.
  • LIU Yongshuang, NA Ke, ZHAO Wenjie*, ZHAO Bo, WEI Xiaodong
    2014, 45(7): 620-622.
    Abstract ( )   Knowledge map   Save
    The separation and purification processes of fibrinolytic compound FGFC1 with high-purity from the fermentation broth were established. The Stachybotrys longispora FG216 mycelium was obtained by solid-liquid separation and the extract liquid containing FGFC1 was got after ethanol extraction. AmberliteTM XAD-1600 resin column was used to remove part of pigments and impurities, and Uni PS30-300 chromatographic column was used to remove the rest pigments and homologues. Then the purified liquid of FGFC1 was got. The FGFC1 powder was finally obtained after precipitation at pH 3 and vacuum freeze-drying. Its chemical structure was identified by MS and NMR. The product purity was 97% with a total yield of 48%.
  • YANG Songbai, CHEN Shaoxin*
    2014, 45(7): 623-625.
    Abstract ( )   Knowledge map   Save
    The Claviceps purpurea strain SIPI-197, a producer of α-ergocryptine, was mutated with UV and nitrosoguanidine. A mutant SIPI-11 was obtained by screening in plate containing high concentration of sucrose, which yielded 657.5 mg/L α-ergocryptine in shake flask cultures. Furthermore, the production of α-ergocryptine in a 5 L jarfermentor was investigated. The yields of α-ergocryptine were 374 mg/L and 903.6 mg/L in batch culture and fed-batch culture with sucrose feeding method, respectively.
  • LI Dingxiang, CHOU Guixin*, WANG Zhengtao
    2014, 45(7): 626-628.
    Abstract ( )   Knowledge map   Save
    The chemical constituents of the n-butanol fraction of Senecio solidagineus Hand. -Mazz. were investigated by macroporous resin, MCI, ODS and Sephadex LH-20 column chromatographies and prep-HPLC preparation. On the basis of NMR spectrum analysis, eight isolated compounds were identified as eugenyl-O-β-Dglucopyranoside (1), erigeside Ⅱ (2), (6R,7E,9R)-9-hydroxymegastigma-4,7-dien-3-one-9-O-β-D-glucopyranoside (3), crotonine (4), bidensmethoside B (5), pinoresinol-O-β-D-glucopyranoside (6), picraquassioside C (7) and 3,3'-dimethoxyl ellagic acid (8). Compounds 2 - 8 were isolated from the genus Senecio for the first time, compound 1 was isolated from Senecio solidagineus for the first time.
  • XIAO Juan, LI Ruixiang, QIN Jing, HAN Limei, WANG Jianxin*
    2014, 45(7): 629-633.
    Abstract ( )   Knowledge map   Save
    The in vitro release values (F) of self-made pramipexole hydrochloride extended-release tablets based on lipid matrix were determined by basket and reciprocating cylinder methods, respectively. The drug concentration in release media was determined by HPLC. The plasma concentration was determined by HPLC-MS/MS after oral administration of commercial tablets or self-made tablets to Beagle dogs with a single dose. The in vivo absorption fraction values (X) of self-made tablets were calculated with Loo-Riegelman method according to model fitting result of the pharmacokinetics of commercial tablets. The correlation coefficients of linear equation between X and F based on basket and reciprocating cylinder methods were calculated and then compared to the critical correlation coefficient. The results showed the two correlation coefficients were 0.97 and 0.99, while the critical correlation coefficient r(0.001, 6) was 0.92, which indicated a significant level of the in vitro-in vivo correlation (IVIVC) for both methods. But it was more significant for reciprocating cylinder method to establish the IVIVC. So reciprocating cylinder method was more
    applicable to investigate the in vitro release behavior to establish the IVIVC.
  • JIANG Dongbo1, ZHANG Weihua1, LIU Jianwen1, SHEN Xiong2, WENG Weiyu1*
    2014, 45(7): 634-640.
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    Stearyl grafted chitooligosaccharide (COS-SA) and its PEGylated derivative (PEG-COS-SA) were synthesized. Both materials could self-assemble into nanomicelles in aqueous solution. The properties of the blank and doxorubicin hydrochloride nonamicelles with COS-SA or PEG-COS-SA as carrier were investigated. The results
    showed that there was a linear correlation between the substitution degree of stearic acid (SA) in COS-SA and the feed ratio of SA to COS. The substitution degree of SA affected the critical micelle concentration (CMC). The particle size of the drug-loading nanomicelles was significantly larger than that of the corresponding blank nanomicelles. PEGylation could further increase the particle size and CMC but decrease the ζ potential. Both nanomicelles exhibited sustainedrelease profiles of doxorubicin and no significant differences in the release behavior were observed. Compared with the COS-SA nanomicelles, the PEG-COS-SA nanomicelles showed good serum stability, prolonged circulation time, but low cytotoxicity against tumor cells. It indicated that chemical composition was a decisive factor for the properties of nanomicelles with chitooligosaccharide derivatives as carriers.
  • ZHU Yuan1, ZI Peng2, CHEN Bingjie1, GU Peipei1, GU Zhengyi1*
    2014, 45(7): 641-645.
    Abstract ( )   Knowledge map   Save
    The nifedipine solid dispersions with Soluplus® as the main carrier were prepared by solvent method or melt method. The products were characterized by XRD, DSC and SEM. The solubilities and in vitro dissolution profiles of the bulk drug and different solid dispersions were investigated. The results showed that the solid dispersions prepared by both methods could significantly increase the solubility and in vitro dissolution of the bulk drug and the increase depended on the amount of the carrier. The dissolution at 2 h of nifedipine from the product prepared by solvent method was higher than that of the product prepared by melt method. However, adding an appropriate amount of poloxamer 188 into the formulation could increase the dissolution of the product prepared by melt method.
  • SHENG Yan, LI Shanshan
    2014, 45(7): 646-648.
    Abstract ( )   Knowledge map   Save
    The bovine serum albumin poly(lactic acid) nanoparticles (NPs) were prepared by a double-emulsion solvent diffusion/evaporation method. Then the NPs were surface-modified with self-made water-soluble chitosan derivative (WSC) and polyvinyl alcohol (PVA), respectively. The particle size, z potential, surface hydrophilicity and blood retention-time in mice of both NPs were investigated. The results showed that both NPs were in the size range of 100 - 200 nm. Surface modification with WSC could highly improve the surface hydrophilicity and adjust the surface charge close to neutrality (5.2 mV). The blood half-life of WSC-modified nanoparticles calculated by DAS 2.0 software was 6.9 h, which was longer than that of PVA-modified nanoparticles (0.3 h).
  • REN Tiankun, ZHANG Yurui, LIU Xiaoya, WANG Jing, YANG Caiqin*
    2014, 45(7): 649-651.
    Abstract ( )   Knowledge map   Save
    The co-crystals were prepared with a 1∶1 molar ratio of oleanolic acid (1) to fumaric acid (2) and cogrinding for 60 min by solvent-drop cogrinding method. The product was characterized by XRD and IR. The content of 1 was determined by HPLC. The phase solubility curves of 1 at 28, 37 and 45 ℃ were drawn. On the basis of the resultant equations, the stability constants and the thermodynamic parameters were calculated. The results showed that the co-crystals were formed through the O-H…O=C hydrogen bond between 1 and 2. The stability constants at 28, 37 and 45 ℃ were 960, 1 386 and 2 082 L/mol, respectively. Both entropy change and enthalpy change were in positive values, which indicated that the formation process of the co-crystals was an endothermic and entropy production process. The free energy changes in the range of 28 - 45 ℃ were all in negative values, which indicated that the reaction could proceed spontaneously. The results of thermodynamics indicated that entropy was the main driving force in the co-crystal formation between 1 and 2.
  • XIA Miaofen1, LI Shimin2
    2014, 45(7): 652-654.
    Abstract ( )   Knowledge map   Save
    The compound neostigmine methylsulfate in situ ophthalmic gel containing neostigmine methylsulfate, taurine, chlorphenamine maleate and vitamin B6 was prepared with poloxamer P407 and P188 as matrices. The product was clear and transparent solution with suitable gelation temperature an pH value, which was in accordance
    with the general requirements of ophthalmic preparations and gels in China pharmacopeia. The contents of the four ingredients and related substances in the product were determined by HPLC. The results of eye irritation in rabbits showed that the product had no significant irritation.
  • YU Xinrong
    2014, 45(7): 655-658.
    Abstract ( )   Knowledge map   Save
    The common long-circulating liposomes (LP) and RGD-modified liposomes (RGD-LP) were prepared by thin-film dispersion method, and the transferrin-modified liposomes (TF-LP) and transferrin and RGD comodified liposomes (TF/RGD-LP) were obtained by post-insertion of the corresponding ligands. The particle size and ζ
    potential of the TF/RGD-LP were (128.4±14.5)nm and (2.55±4.15)mV. The results of the in vitro uptake in A2780 cells showed that the fluorescence value of TF/RGD-LP group was 2.3- and 2.9-fold higher than that of TF-LP group and RGDLP group. The results of the A2780 tumor spheroid penetration test qualitatively proved that the penetration ability of the TF/RGD-LP was the best among the four kinds of liposomes. The heterotopic A2780 tumor model in nude mouse was established. The in vivo distribution of different liposomes in above mice were observed through the ex vivo near-infrared fluorescence images. The results also showed that the TF/RGD-LP had a good targeting therapy for ovarian carcinoma.
  • ZHAO Yazhen, GONG Liyan
    2014, 45(7): 659-662.
    Abstract ( )   Knowledge map   Save
    An LC-MS/MS method was established for the determination of 5-(3-methyl-triazen-1-yl)imidazole-4-carboxamide(MTIC), the active metabolite of temozolomide, in Beagle dog plasma. A Dikma C18 column was used, with the mobile phase of methanol∶0.1% formic acid (containing 1 nmol/L ammonium acetate)(30∶70). A tandem mass spectrometer equipped with electrospray ionization source was adopted as detector. Multiple reaction monitoring (MRM) transitions of m/z 169→m/z 109 and m/z 172→m/z 128 were measured in positive mode for MTIC and the internal standard, metronidazole, respectively. The calibration curve for MTIC was linear in the concentration range of 0.5 - 100 ng/ml. The intra- and inter-day RSDs were less than 10%.
  • ZHAO Yanyan1,2, LIU Liyan1, HAN Yuanyuan1, WANG Yan2, SHI Minjian2
    2014, 45(7): 663-670.
    Abstract ( )   Knowledge map   Save
    According to the information of HPLC, MS and NMR, the chromatographic and spectral characteristics of principal component isomers and the related substances in bulk drug of ammonium glycyrrhizate were studied. Firstly, according to the information of retention time, the validity of the substance's structure assignments of relative retention time of 1.2 in the European pharmacopoeia 7.0 version and British pharmacopoeia 2012 version was questioned. A high resolution electrospray ionization mass spectrometry (HR-ESI-MS) was used to confirm the molecular weight and formula, and the molecular unsaturation was calculated. Moreover, the 1H NMR and 13C NMR signals were completely assigned by 2D-NMR techniques including correlation spectroscopy (COSY), heteronuclear singlequantum coherence (HSQC), nuclear overhauser enhanced spectroscopy (NOESY), and heteronuclear multiple-bonds correlation (HMBC). As a result, we concluded that the principal components of ammonium glycyrrhizate were 18α,20β-glycyrrhizic acid and 18β,20β-glycyrrhizic acid, the related substance A and the compound of relative retention time of 1.2 were (18β,20β)-24-hydroxyglycyrrhizinic acid and 18β,20α-glycyrrhizic acid, respectively.
  • HU Xingping1, HU Yongmei2,3, ZHANG Lei1,3*, LUO Lingling1, XU Jianming1,3
    2014, 45(7): 671-673.
    Abstract ( )   Knowledge map   Save
    An HPLC method was established for the determination of levofloxacin in the human gastric mucosa. Thirty-seven patients with Helicobacter pylori (Hp) infection suffering from chronic gastritis participated in the study. All patients received therapy with 7 days of levofloxacin-based triple regime (esomeprazole 20 mg plus amoxicillin 1 000 mg, twice a day and levofloxacin 500 mg once a day). They received gastroscopy and were drawn three mucosal tissue from antrum after the end of treatment. The gastric mucosa were homogenized. The concentration of levofloxacin in gastric mucosa was determined by HPLC. A Hypersil ODS C18 column was used with the mobile phase of acetonitrile︰ 50 mmol/L citric acid︰1 mol/L ammonium acetate solution (27︰72︰1) at the detection wavelength of 295 nm. It was
    linear in the range of 0.5 - 10 μg/g. The recoveries for levofloxacin of low, medium and high concentrations were 96.4%, 95.2% and 102.8%. The intra- and inter-day RSDs were 6.70%, 2.01%, 1.46% and 7.40%, 4.56%, 3.62%, respectively. The concentration of levofloxacin in gastric mucosal were (6.05±2.47)μg/g in these patients.
  • GUAN Yucheng1, WANG Jianta2, TANG Lei2*, HUANG Jiayu2, XU Jie3
    2014, 45(7): 674-676.
    Abstract ( )   Knowledge map   Save
    A related substance in diacerein was obtained by semi-prepatative HPLC with the mobile phase of acetonitrile︰0.35% phosphoric acid (40︰60). Its structure was identified to be 1,8-bis(acetyloxy)-3-[(acetyloxy)methyl]-9,10-anthracenedione by UV, IR, MS, 1H NMR and 13C NMR.
  • LIN Huangjing, WU Ying, ZHANG Yilan*
    2014, 45(7): 677-670.
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    An HPLC method was established for the determination of 2,4-di-tert-butyl-phenol (DBP) in different extractants, which was the degradation product of Irgafos 168 from three-layer co-extrusion film for infusion bag. The migration of DBP to the extractants was also studied. An Agilent C18 column was used with the mobile phase
    of acetonitrile∶water∶tetrahydrofuran (45∶35∶20) at the detection wavelength of 280 nm. It was linear in the concentration range of 1 - 50 μg/ml. The average recoveries were between 90% - 105% with RSDs less than 3% in pH 3.0 solution, pH 9.0 solution and 20% ethanol, respectively.
  • MA Xinying, CHEN Meifeng
    2014, 45(7): 680-683.
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    A polyvaline modified electrode was prepared. The electrochemical behavior of ofloxacin at the electrode was investigated and drug content was determined. The strongest electrochemical signal of ofloxacin was obtained at the electrode prepared under the conditions of potential window of -1.4 - 2.5 V, scan rate of 100 mV/s and 10 scan cycles. In pH 6.0 citric acid-disodium hydrogen phosphate buffer solution and with the scan rate of 80 mV/s, the linear range for ofloxacin was 1.00×10-7 - 5.65×10-5 mol/L and its low limit of detection was 8.50×10-8 mol/L. The recoveries of samples with low, medium and high concentrations were 95.0%, 98.3% and 102.1%, with RSDs of 2.97%, 4.33% and 2.68%.
  • DU Jiaqiu1, HE Jiajia2, ZHU Peixi2, ZHENG Guogang2
    2014, 45(7): 684-686.
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    The HPLC method was improved for the determination of the related substances in ornidazole and sodium chloride injection. A C18 column was used, with the mobile phase of methanol∶water (20∶80), at the detection wavelength of 318 nm. The calibration curves for ornidazole, 2-methyl-5-nitroimidazole (2) and 2-methyl-5-nitro-1-(2,3- dihydroxypropyl)imidazole were linear in the concentration range of 0.2 - 2.0 μg/ml. The average recoveries of 2 and 3 were 100.1% and 97.9%, with RSDs of 0.9% and 1.5%, respectively. The corrective factors of UV absorption for 2 and 3 were 0.75 and 1.73, compared with ornidazole.
  • XIE Mufeng
    2014, 45(7): 687-689.
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    Dissolution test plays a very important role in the development of oral solid formulations. A critical dissolution condition for distinguishing the dissolution behaviors of the products should be found. The paper describes how to choose a critical dissolution condition for showing the inherent properties of different solid products.
  • WANG Wei1,2, LI Ling2, XU Xiangyang2, ZHOU Jianping1*
    2014, 45(7): 690-696.
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    As a special type of oral sustained- and controlled-release formulations, tablets containing coated pellets can disintegrate the coated pellets with unbroken film. This formulation has flexible choices of dose and release behavior by adjusting the proportion of pellets. To assure film integrity and content uniformity, the parameters in
    formulation and process design should be optimized and controlled. The relevant influence factors on quality of tablets containing coated pellets are reviewed in this paper in order to provide references for development of this formulation.
  • HUANG Baobin1, XU Mingzhe1, BAI Dongting1, WU Zhiang2, WU Chunfu2*
    2014, 45(7): 697-700.
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  • ZHOU Bin1,2, WU Xiaoming2*
    2014, 45(7): 4581-4583.
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  • WANG Ying
    2014, 45(7): 4584-4587.
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