Chinese Journal of Pharmaceuticals

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Synthesis of L-Dopa

ZHAI Ning, ZHOU Houyuan , ZHANG Fuli

2015, 46(5): 439-441. https://doi.org/10.16522/j.cnki.cjph.2015.05.001

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L-Dopa was synthesized from 3,4-dimethoxybenzaldehyde and hydantoin by condensation, hydrogenation, hydrolysis and esterification to give race ethyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate which was subjected to asymmetric transformation via salt formation with dibenzoyl-D-(+)-tartaric acid in the presence of 5-nitrosalicylaldehyde to afford ethyl (S)-(-)-2-amino-3-(3,4-dimethoxyphenyl)propanoate D-(+)-2,3- bis(benzoyloxy)succinate, followed by hydrolysis and deprotection with an overall yield of about 46.5％.

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Synthesis of Rivaroxaban

YANG Jie, HE Hongguang, SONG Yaoyao, DENG Yong*

2015, 46(5): 442-444. https://doi.org/10.16522/j.cnki.cjph.2015.05.002

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Rivaroxaban was synthesized by reaction of 4-(4-aminophenyl)-3-morpholinone with (R)- epichlorohydrin, followed by amination with ammonia to afford the key intermediate (S)-4-[4-[(3-amino-2- hydroxypropyl)amino]phenyl]-3-morpholinone, which was subsequently subjected to acylation with methyl 5-chlorothiophene-2-carboxylate and cyclization with bis(trichloromethyl)carbonate with an overall yield of about 58％.

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Synthesis of Arzoxifene Hydrochloride

FANG Fang1,2, CHEN Yong1, WANG Ping1, WANG Jiafeng1

2015, 46(5): 445-448. https://doi.org/10.16522/j.cnki.cjph.2015.05.003

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Arzoxifene hydrochloride was synthesized from 6-benzyloxybenzo[b]thiophene by oxidation, bromination to give 2,3-dibromo-6-benzyloxybenzo[b]thiophene-1,1-dioxide, which was subjected to substitution with 4-[2-(piperidin-1-yl)ethoxy]phenol, Suzuki reaction with 4-methoxyphenylboronic acid to obtain 6-benzyloxy-2-(4- methoxyphenyl)-3-[4-[2-(piperidin-1-yl)ethoxy]phenoxy]benzo[b]thiophene-1,1-dioxide, followed by hydrogenation, debenzylation, and salt formation with an overall yield of 50％.

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Synthesis of Apatinib Mesylate

ZHAO Jianhong, XU Ting, MA Lei*

2015, 46(5): 449-452. https://doi.org/10.16522/j.cnki.cjph.2015.05.004

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Apatinib mesylate, an antitumor drug, was synthesized from phenylacetonitrile (3) and 1,4-dibromobutane via alkylation-cyclization, nitration, reduction and condensation to give 2-chloro-N-[4- (1-cyanocyclopentyl)phenyl]pyridine-3-carboxamide, which was subjected to nucleophilic substitution with 4-aminomethylpyridine and salt formation with an overall yield of about 38％ (based on 3). The structure of apatinib mesylate was confirmed by 1H NMR, ESI-MS and X-Ray.

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Synthesis of 5-Bromo-4-chloroindol-3-yl-N-acetyl-β-D-galactosaminide

XIE Xi1, HE Yanling2, YANG Ruchun1, DING Haixin1, XIAO Qiang1*

2015, 46(5): 453-456. https://doi.org/10.16522/j.cnki.cjph.2015.05.005

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5-Bromo-4-chloroindol-3-yl-N-acetyl-β-D-galactosaminide, a N-acetamido-β-D-galactoside enzyme substrate for detection of Canidia albicans, was synthesized from β-bromo-2,3,4,6-tetraacetyl galactose and N-acetyl-5- romo-4-chloro-3-hydroxyindole via 7 steps. Its structure was confirmed by NMR, MS and biological test.

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Synthesis of Pasiniazide

JIN Guoyou, YAO Liuduan, ZHU Yiji

2015, 46(5): 457-458. https://doi.org/10.16522/j.cnki.cjph.2015.05.006

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Pasiniazide was prepared by the reaction of 4-amino salicylic acid with isoniazid in water and ethyl acetate in a yield of 75.8% with the purity over 99％.

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Genetic Stability of Recombinant Arginine Deiminase Engineered Strain

QIN Lina1, LIU Ying1*, HU Haifeng1, SHI Yunsong2

2015, 46(5): 459-461. https://doi.org/10.16522/j.cnki.cjph.2015.05.007

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The genetic stability of arginine deiminase (ADI) engineering strain, E. coli BL21/pET27brADI, was investigated. The engineering strain was passaged under antibiotic selective pressure (kanamycin+) on SB agar plates for 50 generations. Every ten generations were preserved and their colony morphology, plasmid stability, restriction map, ADI gene sequencing, expressing level and activity of the recombinant protein were analyzed. The results showed that the engineering strain maintained the typical characteristics after continuous passages, without significant difference in terms of growth rate compared with the parental strain. The restriction map of plasmids was correct after 50 generations. There were no DNA mutations or missing. After isopropyl β-D-1-thiogalactopyranoside induction, SDSPAGE of cell extractions showed no significant differences in the recombinant arginine deiminase expression levels.

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Production of Oritavancin Intermediate A82846B by Strain Improvement and Medium Optimization

ZHENG Linghui, HONG Yun, CHEN Xiaojing, TENG Yun, BAI Hua

2015, 46(5): 462-466. https://doi.org/10.16522/j.cnki.cjph.2015.05.008

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Nocardia orientalis HS807-N-1287 was treated with atmospheric and room temperature plasma (ARTP) mutation for production of oritavancin intermediate A82846B (1), and screened in the selective plates containing 1 and tyrosine. A mutant HS807-A-639 with high productivity of 1 was obtained. The compositions of fermentation medium, including carbon sources, nitrogen sources and trace elements, were optimized in shake flask culture. The optimized medium composition (g/L) consisted of glucose 15.0, malto-dextrin 40.0, corn starch 20.0, molasses 12.0, acid-hydrolyzed casein 6.0, tyrosine 1.0, yeast extract powder 5.0, soybean powder 20.0, pharmamedia 10.0, NaCl 0.6, CaCO3 2.8, MnSO4·4H2O 0.1, CoCl2·6H2O 0.05. In the optimized medium fed with tyrosine, the production of 1 achieved 1 671 mg/L in 50 L fermenter at 192 h by the mutant HS807-A-639.

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Spectrum-effect Correlation for Blood Coagulation Activity of Callicarpa kwangtungensis Chun

YU Jing, YANG Yifang*, HU Xiao, WU Chunzhen, LI Li

2015, 46(5): 467-472. https://doi.org/10.16522/j.cnki.cjph.2015.05.009

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A spectrum-effect correlation pattern was established for evaluating blood coagulation activity of Callicarpa kwangtungensis Chun. The samples were prepared in nine ways and analyzed by HPLC to obtain their fingerprints. Blood coagulation was observed through recording the bleeding time after tail tip amputation and the clotting time of blood samples collected after eye extirpation. A feasible mathematical model was built to correlate the HPLC fingerprint data and blood coagulation. Twenty-two correlation peaks were obtained, which consisted of twelve phenylethanoid glycosides and ten flavonoids. The deviations between the theoretical and measured hemostatic time were calculated through the mathematical model. The results showed that the standard deviation rates of 78％ samples were within 10％, and those of 28％ samples were within 5％. It demonstrated that the blood coagulation activity of Callicarpa kwangtungensis Chun was contributed mainly by phenylethanoid glycosides and partly by flavonoids.

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UPLC-PDA Fingerprint and Determination of Index Components of Supercritical CO2 Extract from Xiao-yao-san

TIAN Junsheng1,2, ZUO Yamei1,2, ZHOU Yuzhi1, GAO Xiaoxia1, QIN Xuemei1,2

2015, 46(5): 473-476. https://doi.org/10.16522/j.cnki.cjph.2015.05.010

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The fingerprints of 14 batches of supercritical CO2 extract from Xiao-yao-san and the quantitative determination of ligustilide, atractylenolide Ⅰ and atractylenolide Ⅲ were established by UPLC-PDA. A BEH C18 column was used, with the mobile phase of acetonitrile∶0.03％ trifluoroacetic acid by gradient elution. Fifteen common peaks were found, and the similarities between UPLC fingerprints of 14 batches of supercritical CO2 extract from Xiao-yao-san
were all above 0.9.

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Preparation, in vitro and in vivo Evaluation of Timolol Maleate Ophthalmic in situ Gel

GUO Jiawang, MA Yang, WANG Jian*

2015, 46(5): 477-481. https://doi.org/10.16522/j.cnki.cjph.2015.05.011

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An ophthalmic in situ gel loaded with timolol maleate was prepared with gellan gum and xanthan gum as gel matrix. The viscosities and modulus of the gel and a mixture of the gel and simulated tear fluid (STF) were measured by rotary rheometer. The zero-shear viscosity of the drug-loaded product with 0.4％ gellan gum and 0.1％ xanthan gum as gel matrix was 2.89 Pa·s, and the storage modulus (G′) was smaller than the loss modulus (G″). After mixed with STF, the G′ increased to be larger than G″, indicating phase transition occurred and the gel formed. The intraocular pressure-reducing effect of the product was investigated with healthy Beagle dogs as models. The results showed that the effect could maintain for more than 9 h after administration.

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Preparation and in vitro Evaluation of Metoprolol Succinate Osmotic Pump Capsules

LI Fangting, DANG Yunjie, WANG Xiaohui, CAO Deying, DU Qing*

2015, 46(5): 482-487. https://doi.org/10.16522/j.cnki.cjph.2015.05.012

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The osmotic pump capsule shells were prepared by solvent method with cellulose acetate as a membrane material. The contents containing metoprolol succinate (1) were prepared by wet granulation and then were filled into the above capsule shells to obtain the osmotic pump capsules. The influences of the composition and preparation method of shells and the amount of excipients in contents on in vitro release of 1 were investigated by single factor test and orthogonal test. The results showed that the optimal shells were prepared with 8％ cellulose acetate in acetone containing 1.6％ polyethylene glycol 4000. The optimal contents for one capsule were as follows: the mixture of 47.5 mg of 1, 60 mg of sodium chloride, 60 mg of polyoxyethelene, 10 mg of hypromellose K10M and 82.5 mg of glucose was granulated with 95％ ethanol as adhesive. Then the title capsules were obtained through filling these granules into the shells. The results indicated that the release of 1 from the capsules was depended on the osmotic pressure caused by sodium chloride. The drug was completely released within 24 h and the data were fitted to zero order equation. Moreover, the release behavior was not affected by the rotation speed and pH values of the medium.

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Investigation of Inclusion Complexes between Apigenin and Sulfobutyl Ether β-Cyclodextrin

LI Zhen1, JIA Yuntao2, TIAN Rui3, ZHENG Hang1, ZHANG Liangke1*

2015, 46(5): 488-491. https://doi.org/10.16522/j.cnki.cjph.2015.05.013

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The preparation methods of inclusion complexes between apigenin and sulfobutyl ether β-cyclodextrin (SBE-β-CD) as well as the process parameters were optimized with inclusion rate as index. The optimal product with inclusion rate of 79.5％ was prepared by grinding method with molar ratio of 1∶5 (apigenin to SBE-β-CD) and grinding time of 1.5 h. The solubilization effect of SBE-β-CD on apigenin at 25, 37 and 50 ℃ were investigated by phase solubility method. The results showed that the apparent solubility of apigenin was significantly increased with the increasing of temperature and SBE-β-CD concentration, and the inclusion process was spontaneous. The results of DSC and FT-IR analyses showed that a rather stable inclusion complexes had been formed.

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Preparation and Dissolution of Manidipine Phospholipid Complex

YU Botao1, SUN Weizhang1, JIN Weihua1, CHEN Hua1, ZHOU Jiping2

2015, 46(5): 492-494. https://doi.org/10.16522/j.cnki.cjph.2015.05.014

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The preparation of manidipine phospholipid complex was optimized by single factor experiment and orthogonal design test. The optimal preparation process was as follows: the weight ratio of manidipine to lecithin was 1∶1, the mixture of methanol containing 20 mg/ml of manidipine and chloroform containing 100 mg/ml of lecithin in a volume ratio of 5∶1 was incubated at 40 ℃ for 4 h. The drug concentration was determined by HPLC. Compared with the bulk drug and the physical mixture, the dissolution of phospholipid complex was significantly improved.

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Transport of Asiatic Acid Tromethamine Salt in Caco-2 Cell Monolayer Model

GU Lingling, YU Lifang, LU Weigen

2015, 46(5): 495-498. https://doi.org/10.16522/j.cnki.cjph.2015.05.015

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Caco-2 cell monolayer model was adopted to investigate the absorption behavior of asiatic acid tromethamine salt (1). The concentration of asiatic acid in cell samples was determined by HPLC-MS/MS. It showed that the transport behavior of 1 in Caco-2 cell monolayer model depended on time and concentration as well. The bidirectional apparent permeability coefficients (Papp) for 1 groups with different concentrations were all 10-6 cm/s level, which
indicated the moderate absorption of 1. Moreover, the Papp values were all decreased with the increasing of concentration, which indicated that both passive diffusion and active transport were included in the absorption behavior of 1. The efflux ratio (ER) values were all greater than 1, and the transport behavior of 1 was affected by the P-glycoprotein (P-gp) inhibitor verapamil.

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Effect of Foscarnet Sodium on the Pharmacokinetics of Cefoselis Sulfate in Rats

TAO Xinglong, WANG Weimei, GONG Ying, HE Wenjuan, ZHANG Zhiqing*

2015, 46(5): 499-501. https://doi.org/10.16522/j.cnki.cjph.2015.05.016

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The influence of foscarnet sodium on the pharmacokinetics of cefoselis sulfate in rats was investigated. Rats were randomly divided into test group and control group with 20 rats in each. Foscarnet sodium (360 mg/kg) was given to the test group by intravenous injection via vena caudalis, and then cefoselis sulfate (200 mg/kg) was given immediately by the same route. While the control group was given cefoselis sulfate (200 mg/kg) intravenously. An HPLC method was applied for the determination of cefoselis sulfate concentration in plasma. The pharmacokinetic parameters of the test and the control group for cefoselis sulfate were calculated as follows: t1/2 (1.76±0.57) and (1.22±0.51)h, cmax (1 314.37±196.70) and (1 470.18±321.38)μg/ml, AUC0→24 h (863.19±189.46) and (799.57± 203.39)μg·h·ml-1, AUC0→∞ (898.81±214.25) and (800.02±207.04)μg·h·ml-1, V (0.56±0.18) and (0.45±0.17)L/kg, CL(0.23±0.05) and (0.27±0.07)L·h-1·kg-1, respectively. The results showed that the values of t1/2 and V increased significantly when co-administered with foscarnet sodium in rats, which indicated that foscarnet sodium might inhibit the excretion of cefoselis sulfate by competing the excretion pathway in kidney.

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Determination of Elemental Impurities in Pharmaceutical Inhalation Aerosols by ICP-MS/MS

MEI Li1,2, YE Xiaoxia2, ZENG Xiangcheng3, JIN Fang4, YANG Yongjian2*

2015, 46(5): 502-507. https://doi.org/10.16522/j.cnki.cjph.2015.05.017

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An ICP-MS/MS method was established for the determination of 24 elemental impurities in inhalation aerosols. The MS/MS mode was utilized for particular elements (Si, P, S), significantly reducing polyatomic interference compared with conventional single quadrupole ICP-MS systems. The calibration curves of 23 elements were linear in the concentration range of 0 - 100 ng/ml, while that of Hg was linear in the range of 0 - 5 ng/ml. The recoveries were 80％ - 120％. Two commercially available inhalation aerosols were determined, and the concentrations of elemental impurities were all under specified limits.

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Comparison of NIR, HPLC and UV for the Determination of Dengzhanhuasu Tablets

ZHANG Yunhua, DONG Yuan, LIU Yingying, LI Zhongqiong, ZHANG Wenjie*

2015, 46(5): 508-510. https://doi.org/10.16522/j.cnki.cjph.2015.05.018

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The NIR, HPLC and UV methods were applied for the determination of 46 batches of Dengzhanhuasu tablets from different factories. Their results were analyzed by correlation and regression methods. It showed that the determination results obtained from three methods were different, but their relevance was good. The NIR method was accurate, rapid and without damage to samples, therefore it was fit for on-site rapid analysis.

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Determination of Epimer of Faropenem Sodium for Injection by HPLC

FENG Zhong, WEI Ruixia, ZHANG Liping, NIE Deping, ZHANG Guimin*

2015, 46(5): 511-513. https://doi.org/10.16522/j.cnki.cjph.2015.05.019

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An HPLC method was established for the determination of the epimer of faropenem sodium for injection. A C18 column was used, with the mobile phase A of phosphate buffer (added 6.12 g of potassium dihydrogen phosphate, 1.79 g of disodium hydrogen phosphate dodecahydrate and 1.61 g of tetrabutyl ammonium bromide to 1 L of water) and the mobile phase B of A∶acetonitrile (1∶1) by gradient elution, at the detection wavelength of 240 nm. It was linear for the epimer in the range of 0.15 - 1.80 μg/ml, with LLOD of 0.06 μg/ml and LLOQ of 0.30 μg/ml. The average recovery was 99.9％, with RSD of 1.13％.

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Uncertainty Analysis in Determination of Relative Molecular Weight of Polysaccharide by Size Exclusion Chromatography (SEC) Coupled with Multi-angle Laser Light Scattering

HU Chuanmei1,2, LU Ming2, SHAO Hong2, CHEN Gang2*

2015, 46(5): 514-518. https://doi.org/10.16522/j.cnki.cjph.2015.05.020

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A size exclusion chromatography (SEC) itself and coupled with multi-angle laser light scattering (SEC-MALLS) were both applied in the determination of the relative molecular weight (Mw) of pullulan. Mw was determined by RI (SEC method) or RI with laser light scattering detectors (SEC-MALLS method). The t-test were conducted to compare the results of the two methods, and the results revealed that SEC-MALLS was traceable to the reference method (SEC) under the studied conditions. The uncertainty of both methods was also analyzed. Through the analysis of the test process, all potential uncertainty factors of SEC and SEC-MALLS were evaluated, and the measurement uncertainty components, combined uncertainty and expanded uncertainty were also calculated. The results showed that SEC-MALLS was a stable and reliable method, and it was an alternative to SEC.

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WANG Likui, CHEN Zhongya, WANG Wei, TAO Tao*

2015, 46(5): 519-524. https://doi.org/10.16522/j.cnki.cjph.2015.05.021

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Dissolution test plays an important role in evaluating the inherent quality of solid oral dosage form and it is critical to efficient drug development. Different countries, according to their own national conditions, have different claims on dissolution testing and evaluating methods. In this paper, the similarities and differences of dissolution testing and evaluating methods at home and abroad were discussed after literature survey, and some references were provided for the quality consistency evaluation of generic products in our country.

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Advances in NAD+-dependent Histone Deacetylases, Sirtuins, and Their Modulators

WANG Lei, FANG Hao*

2015, 46(5): 525-532. https://doi.org/10.16522/j.cnki.cjph.2015.05.022

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Sirtuins belong to the third class of histone deacetylases, which are dependent on NAD+ for activity. The functions are related to gene expression, metabolic control, apoptosis and cell survival, DNA repair, inflammation, neuroprotection and longevity. Because the regulation of the human sirtuins plays an important therapeutic role in diseases, the research of small molecule modulators impacting target function becomes one of the hot fields of pharmaceutical research. This review lists some active compounds which can activate or inhibit the enzyme, and discusses the potential implications for clinical practice.

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Graphical Synthetic Routes of Vernakalant Hydrochloride

GE Ting, CHEN Guohua*, QIN Yinhui

2015, 46(5): 533-537. https://doi.org/10.16522/j.cnki.cjph.2015.05.023

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Application of Sterility Testing Isolator

WU Wenlei, CHENG Jinsheng, ZHENG Jinwang

2015, 46(5): 546-551. https://doi.org/10.16522/j.cnki.cjph.2015.05.025

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