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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    Perspectives & Review
  • Perspectives & Review
    ZHANG Ji1,2, ZHANG Yingjun1,2, NIE Biao1
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    In this review, the necessary background and some concepts related to genotoxic impurities are introduced. The alert structure of potential genotoxic impurities commonly found in drug synthesis are given, and the process were analyzed and classified by case studies. The use of ACP(avoid-control-purge) strategies and methods are shown for controlling and purging GTI, and some successful cases and progress from multinational pharmaceuticals are analyzed.
  • Perspectives & Review
    WU Chuanling
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    Microneedle technique is a breakthrough progress in the field of transdermal drug delivery. In the past two decades, microneedles have gradually evolved into five categories from its initial prototype: solid microneedles, coated microneedles, hollow microneedles, soluble microneedles, and hydrogel microneedles. With the dramatic increasing number of deliverable drugs and dosage forms, the application range of microneedles has also expanded from the skin to the oral mucosa, gastrointestinal mucosa, nails, eye sclera and vaginal mucosa. The clinical value of microneedles has been increasing, but challenges still exist. The present article summarizes the principles of microneedles dosing and the pros and cons of various types of microneedles, discusses measures undertaken to improve the drug delivery efficiency, reviews application expansion of microneedles technique in skin and other organs or tissues for soluble small molecules, vaccines, and biomacromolecules, and provides a general overview about the commercialization of microneedles products and the problems that need to be solved.
  • Perspectives & Review
    WANG Lijiang
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    Pharmaceutical water is the material and solvent used most widely in the process of drug production, which is of great importance to drug quality. At present, pharmacopoeia of each country has strict regulations on the quality of pharmaceutical water. However, in view of the different water system technologies adopted by enterprises, the qualities of purified water and water injection are uneven, which seriously affect the quality of drugs. In this article, the quality indexes of purified water and injection water in different pharmacopoeias are compared, such as bacterial endotoxin, electrical conductivity, total organic carbon and microbial limitation. The preparations of water for injection with the thermocompression type distillation and multi-effect distillation, preparations of deionized purified water by the double stage reverse osmosis and the combined mode of reverse osmosis and electrodeionization, as well as pharmaceutical water storage and distribution system design technology are discussed.
  • Paper
  • Paper
    HAN Zaiqi, WANG Sen, FENG Bo, YAO Lu, CHANG Sheng*
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    In this study, belinostat was synthesized according to the following route. 3-Bromobenzenesulfonyl chloride reacted with aniline to give 3-bromo-N-phenylbenzenesulfonamide. Then the latter was handled directly with ethyl acrylate via Heck coupling reaction to afford ethyl (E)-3-[3-(N-phenylsulfamoyl)phenyl]acrylate by an ''one-pot'' method. Finally, the latter reacted with hydroxylamine in the presence of sodium hydroxide to afford the target compound with a total yield of 62%, and a purity of 99.1%. This process has some advantages such as simple operation, high yield, and it has been tested in kilogram scale.
  • Paper
    CHEN Xiangfeng, ZONG Lei, ZHANG Jing, YI Chao, ZHU Haixi
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    Dexrazoxane was prepared according to the following route. (S)-Propane-1,2-diamine dihydrochloride was subjected to a nucleophilic substitution with chloroacetic acid in sodium hydroxide solution to give (S)-(+)-1,2-diaminopropane-N,N,N',N'-tetraacetic acid. The latter was reacted with methanol directly in the presence of sulfuric acid to afford tetramethyl (S)-(+)-1,2-diaminopropane-N,N,N',N'-tetraacetate, which was followed by a cyclization with formamide in the presence of sodium methoxide at room temperature to give crude dexrazoxane. After a recrystallization from 1,4-dioxane, the target compound was obtained with a total yield of 52.4%, and a purity of 99.88%. The reaction conditions in this study are mild, and the formation of impurities A and B in the process are avoided. It has been applied to commercial production.
  • Paper
    ZHOU Shiyu, LI Minyong*
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    In this study, the synthetic process of febuxostat was improved. 5-Bromo-2-isobutoxybenzonitrile (4) was obtained via a substitution of 2-hydroxybenzonitrile (2) and bromoisobutan, followed by bromination with N-bromosuccinimide at room temperature, the yield was increased from 75.7% to 95.3%. Then compound 4 reacted with bis(pinacolato)diboron via Miyaura borylation to give 3-cyano-4-isobutoxyphenylboronic acid pinacol ester. Then the latter was subjected to Suzuki coupling with ethyl 2-bromo-4-methylthiazole-5-carboxylate in dioxane/H2O to afford ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate with a yield of 72.6%, which was followed by a hydrolysis with sodium hydroxide to product the target compound with a total yield of 58.7%(based on 2).
  • Paper
    GAO Xuezhi, WANG Qinghe, TONG Qiaolin, YANG Jianwen, CHENG Maosheng*
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    The synthesis for 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine-N-oxide, the key intermediate of lansoprazole was developed. At first, sodium tungstate/hydrogen peroxide was used instead of acetic acid/hydrogen peroxide to oxidize 2,3-dimethylpyridine in water to 2,3-dimethylpyridine-N-oxide (3), the yield was increased from 85% to 91%. Subsequently, 4-bromo-2,3-dimethylpyridine-N-oxide (4) was obtained via an oxidative bromination of 3 under NaBr/NaBrO3 and H2SO4, which could avoid the formation of a large amount of waste acid during the nitration with the mixed acid. Finally, 4 reacted with trifluoroethanol in DMF in the presence of potassium tert-butoxide to afford the target compound with a yield of 89%. This improved synthetic route had some advantages, such as mild reaction conditions, simple operation and environmental protection, and the total yield was up to 56.7%.
  • Paper
    ZHANG Qiuchen, JIANG Faqin, XIE Dongsheng, YANG Fengzhi, FU Lei*
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    For the purpose of finding an aminooxy helper lipid which is structural simplified and well-suited to cationic liposomes, in this paper, a new aminooxy lipid (APCL) was synthesized using the readily available starting materials such as tetraethylene glycol, cholesterol formyl chloride and 2-[[(tert-butoxycarbonyl)amino]oxy]acetic acid. APCL is an amphipathic lipid with an aminooxy and a cholesteryloxycarbonyl groups on both ends and linked by a linker. In this study, APCL, cationic lipid and other helper lipid were dissolved together to prepare cationic liposome delivery system via membrane dispersion method. After the reporter gene was packaged, the in vitro transfection experiments were carried out. Using another commonly-used aminoxy lipid CA as a control, in vitro transfection data under the same conditions showed that, APCL cationic liposome delivery system has a higher in vitro transfection activity than CA system, and the average transfection activity is increased 3-5 times..
  • Paper
    SHEN Ruixue, ZHU Zhuangzhi, TONG Xiangliu, WU Yubo, LUO Huafei*
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    The study was to assess the feasibility of salmon calcitonin(sCT)-hyaluronic acid (HA) dissolving microneedle patches for osteoporosis (OP) treatment. The dissolving microneedles were fabricated using micromold casting method. In vitro characteristics including morphology, mechanical strength and dissolution profile were investigated. The results showed that the prepared dissolving microneedles were able to penetrate the stratum corneum to the depth of the top of dermis and completely dissolved within 2 min resulting in the rapid release of the loaded sCT. The animal study showed a similar hypocalcemic effect in rats receiving a dissolving microneedle patch and subcutaneously injecting of Miacalcic. The relative pharmacological activity of sCT in the prepared microneedle patches was (78.6± 21.7)% , implying that dissolving microneedle patches might be a painless alternative to conventional injection.
  • Paper
    BAI Lei1, LI Yingxia1, XU Hui2, LIU Dongchun1*, TANG Xing2
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    This paper investigated the stability of the ester drug triamcinolone acetonide acetate (TAA) in ionic Carbopol 940 (CP) and in nonionic hydroxypropyl methylcellulose stearoxy ether (Sangelose 90L, SGL) hydrogels to provide the basic guideline for gelling formulation. The content change of TAA (1 mg/g) dispersed in either CP (0.5%) or in SGL (0.5%) was examined during the storage at 60 ℃ for 10 d. To explore the possible reasons for the changes in content of TAA in CP and SGL gels, the stability of dissolved TAA (20 μg/ml) in respective solvents (water, phosphate buffers of pH 4.7, 5.8, 7.4 and 9.18, sodium chloride solutions of 0.01, 0.1 and 1 mol/L) containing 30% methanol was investigated during the storage at 25 ℃ for 10 d. The effects of pH value and neutral salts on the hydrolysis of TAA were studied. In the SGL and CP hydrogels, TAA decreased to 82.0% and 74.4%, respectively. In respective solutions (water, phosphate buffers of pH 4.7, 5.8, 7.4, and 9.18, sodium chloride solutions of 0.01, 0.1 and 1 mol/L), TAA reduced to 92.1%, 25.0%, 30.5%, 33.9%, 4.38%, 89.5%, 85.8% and 82.8%. TAA was stable in methanol-water but unstable in acidic, especially in alkalic solutions. The stability of TAA decreased as the ionic strengths (concentrations of sodium chloride) of the solution increased in a neutral solution. By the catalysis of H+, OH- or Lewis acid and salt effect, the ester bond could be induced to polarize and accelerate the hydrolysis. The triethanolammonium cation in CP hydrogel, as a Lewis acid, induced the ester bond of TAA polarizing and nucleophilic (OH-) attacking to the carbonyl group resulting in promoting the hydrolysis of TAA. We concluded that TAA was more stable in the nonionic SGL hydrogel than in the ionic CP hydrogel. For ester drugs, it was suggested that nonionic polymer should be considered and electrolytes should be avoided in the hydrogel formulations.
  • Paper
    LI Songlong, RU Renping
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    A new azithromycin preparation, instant configuration type azithromycin oral suspension liquid, was prepared to achieve the aim of accurate dose for a child. The formulation consisted of two parts, the mixed powder containing azithromycin and blank suspension liquid. The powder could evenly disperse and form the oral suspension liquid by shaking before use. The concentration of azithromycin was determined by HPLC method. The results showed that the content of azithromycin had no obvious changes in the mixed powder stored at 10-30 ℃ and relative humidity of 45%-75% for 12 months. The azithromycin suspension liquid was stable within 1 h after shaking, and the drug content was not significantly decreased when this suspension liquid was stored at 2-8 ℃ for 1 month. The dissolution behaviors between the self-made suspension liquid and the commercial dry suspension Zithromax were compared in pH 6.8 phosphate buffer. The results showed that the dissolution at 5 min of the self-made and marketed suspensions were (95.3±0.7)% and (87.6±0.6)% respectively.
  • Paper
    ZHENG Xiangwei1, GAO Qi2, ZHU Guoqin2, WEI Yafang2, FENG Yi1?
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    Here we reported an economical and practical preparation process of ginkgo flavonol glycosides with high purity (≥80%). Taking the transfer rate and contents of the active components as the indexes, the key parameters influencing the column chromatographic separation were investigated by single factor tests, and the optimal technological route of separating and purifying gingko flavonol glycosides from Ginkgo biloba extract (GBE) was screened out. The results showed that modified macroporous resin (LSA-12S) column chromatography was suitable for this purpose. The optimum process parameters were as follows: column packing by ways of wet method (diameter to height ratio of 1∶5), sample loading by means of wet method (loading ratio of 1∶30), and elution by water and 0.1% sodium carbonate solution (5 BV each) successively. The product eluted with 0.1% sodium carbonate solution was collected, and then concentrated in vacuum to the appropriate volume and adjusted to pH 1-3 with diluted hydrochloric acid. The acidic product was continuously wet-loaded on polyamide column chromatography (diameter to height ratio of 1∶10, loading ratio of 1∶30), eluted by water, 20% and 80% ethanol (5 BV). The portion eluted by 80% ethanol was concentrated in vacuum and dried to give the ginkgo flavonol glycosides product with purity no less than 80%. This process requires simple equipments and low production costs, and it has large sample processing capacity, with great industrialization prospects.
  • Paper
    MO Huifang, CHEN Fangjun, GUO Wei, PAN Baishen, WANG Beili*
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    A UPLC-MS/MS method was established for the determination of imatinib (IMA, 1) in human plasma. Isotope deuterated imatinib (IMA-d8, 2) was used as the internal standard. A BEH C18 column was used for separation, with the mobile phase of 0.1% formic acid∶acetonitrile by gradient elution. The detected quantification ion pairs of 1 and 2 were m/z 494.2→m/z 394.2 and m/z 502.3→m/z 394.2. The method performances were verified according to the "LC-MS clinical recommendations", including specificity, carrying pollution, linearity, repeatability, quantitative detection limits, imprecision, accuracy, and stability. The chromatographic retention times of 1 and 2 were 1.25 and 1.26 min. Their limits of quantification was 5 ng/ml, and it was linear in the range of 5-2 000 ng/ml. Due to the dilution, the reportable range extended to 5-40 000 ng/ml. The method performance was verified and it was proved to be a robust and reliable method for the clinical determination of 1 in human plasma.
  • Paper
    JIANG Zhendong, YANG Lin*, LU Wei
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    An HPLC method was established for the determination of the related substances in celecoxib. The separation was performed on a Zorbax SB-Phenyl column, with the mobile phase of acetonitrile∶0.02 mol/L potassium dihydrogen phosphate buffer (adjusted to pH 3.0 with phosphoric acid) (35∶65), at the detection wavelength of 215 nm. It was linear for celecoxib and its related substances in the range of 0.1-10 μg/ml. The recoveries for the related substances were 95.7%-99.3%, with RSDs of 1.23%-1.63%. The detection limits of the related substances were 0.01 μg/ml, and the quantitation limits were 0.03 μg/ml. The method is simple, accurate, reproducible, and suitable for the determination of related substances in celecoxib, which provides a reliable method for the quality control of celccoxib.
  • Paper
    LAI Xiudi, LIN Xiaojing, GONG Xue, JI Shengguo, WANG Dong*
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    The potential of near infrared spectroscopy (NIRS) in quality control of traditional Chinese medicine has been evaluated. Here we developed a rapid and non-destructive quantitative analysis model of andrographolide regarding the 144 batches of Andrographis paniculata by NIRS. The andrographolide contents of the Andrographis paniculata extracts were determined by HPLC and were taken as the reference values. Among them, 117 batches of samples were selected as the calibration set. The predicted values were determined by the established NIRS quantitative analysis model based on partial least squares (PLS) regression. The correlation coefficients (R2), the root-mean-square error of calibration (RMSEC), the root-mean-square error of predication (RMSEP) and the internal cross validation variance (RMSECV) of the calibration model were 0.962 7, 0.211, 0.247 and 0.605 2, respectively. The average recovery of 27 batches of samples (the validation set) was 100.14%. The calibration model can be used in the rapid quantitation of andrographolide in Andrographis paniculata and this method is fit for the on-line monitoring of production and processing of Chinese medicines using Andrographis paniculata as the raw material.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    ZHAO Yangsheng1, SUN Qing2, WANG Linlin3, CHU Shuzhen1*
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  • Pharmaceutical Management & Information
    WU Lin, WANG Yufeng, QIAO Susu, GU Xiaoxi, CHEN Yongfa*
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  • Pharmaceutical Management & Information
    ZHAO Nana1, SUN Lihua*
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  • Pharmaceutical Management & Information
    TONG Xiao, CHEN Yuwen*
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  • Pharmaceutical Management & Information
    LI Bo1,2, SUN Lihua1*
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  • Pharmaceutical Management & Information
    PAN Qi1,2, WANG Jun2, XU Xiaoyuan1*, GUO Mengjia2
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