Chinese Journal of Pharmaceuticals

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Synthesis of Sitafloxaci

CHEN Lingwu, ZHANG Haibo, LIANG Huixing, LIU Hongchang, LU Xianfeng

2014, 45(1): 1-4.

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8-Chloro-6,7-difluoro-1-[(1R,2S)-cis-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3- carboxylic acid(11) was obtained from ethyl 2,4,5-trifluoro-3-chlorobenzoacetate through the one-pot method of condensation with triethyl orthoformate, substitution with (1R,2S)-2-fluorocyclopropylamine and hydrolysis with hydrochloric acid, and then compound 11 was converted into sitafloxacin via the substitution with (S)-(–)-tert-butyloxycarbonylamino-5-azaspiro[2,4]heptane and deprotection through trifuoroacetic acid with the overall yield of about 60％ and the HPLC purity of 99.9％.

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Synthesis of Related Substance of Mirabegron

ZHANG Lei, TAN Zhimin, JIAO Huirong, QIU Pengcheng, ZHANG Fuli*

2014, 45(1): 9-12.

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The dehydroxyl impurity was found in the synthesis of overactive bladder (OAB) drug mirabegron. In order to perform the quality control of mirabegron, dehydroxymirabegron hydrochloride, i.e., 2-(2-aminothiazol-4-yl)-N-[4-[2-(phenylethylamino)ethyl]phenyl]acetamide hydrochloride, was synthesized in four steps from phenylacetic acid and nitrophenylethanamine hydrochloride by amide condensation, borane reduction, catalytic hydrogenation and condensation with 2-aminothiazol-4-acetic acid. The structure was confirmed by MS,1H NMR and 13C NMR.

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Synthesis of Aurora Kinase Inhibitor ZM-447439

WANG Gang1, ZHANG Fan1*, ZHANG Yuzhu2

2014, 45(1): 13-16.

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4-Chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (8) was prepared from 4-hydroxy-3-methoxybenzoic acid via esterification,O-alkylation, nitration, reduction, cyclization and chlorination. Meanwhile, N-(4-aminophenyl)benzamide (11) was synthesized from p-nitroaniline via acylation and reduction. Finally, ZM-447439 was synthesized by nucleophilic substitution of 8 with 11, followed by N-alkylation. The overall yield was about 31％ based on 4-hydroxy-3-methoxybenzoic acid.

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Preparation of 2-(3-Carboxymethyl-4-phenylthiophenyl)propionic Acid

CHEN Wenhua, ZHANG Hong

2014, 45(1): 17-18.

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2-(3-Carboxymethyl-4-phenylthiophenyl)propionic acid, the intermediate of zaltoprofen, was synthesized from methyl 5-propionyl-2-phenylthiophenylacetate by condensation with neopentyl glycol in the presence of p-toluenesulfonic acid and trimethyl orthoformate to give methyl 5-[1-(5,5-dimethyl-1,3-dioxan-2-yl)]propyl-2-phenylthiophenylacetate, which was subjected to bromination with Br2 to afford methyl 5-[2-bromo-1-(5,5-dimethyl-1,3-dioxan-2-yl)]propyl-2-phenylthiophenylacetate, followed by rearrangement with ZnO as catalyst and hydrolysis with an overall yield of about 81％.

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Investigation of Lipid and Lipstatin Biosynthesis in Streptomyces toxytricini by Addition of Biotin and ATP

DONG Huijun, JIANG Junyun, CHEN Fang

2014, 45(1): 19-24.

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The effects of adding biotin and ATP on the lipid metabolism were investigated. The results indicated that high concentration biotin promoted the cellular lipid production and inhibited the biosynthesis of lipstatin. For example, when 1.2 mg/L biotin was added at the beginning of cultivation, the lipstatin content decreased 28.9％, and the total lipid content increased to 15.8％ compared with the control. Contrast to biotin, ATP took adverse effect on the lipid and lipstatin production. Furthermore, the addition of ATP and biotin at the secondary metabolism period generated more obvious effects than adding at the beginning of cultivation.

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Extraction Behavior of Bitespiramycin and Selective Separation of Impurities

ZHANG Xiaojun, CHEN Kui*, ZHU Jiawen

2014, 45(1): 25-27.

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The effects of extraction time, aqueous/ester phase ratio and pH to the bitespiramycin components and impurities were investigated in the extraction process. The distribution coefficientsof isovaleryl spiramycin Ⅲ and impurities with weak polarity were analyzed respectively. Results showed that both of the distribution coefficientswere reaching towards zero along with the rise of extraction pH value. When the extraction pH value reached 4.4, the removal rate of impurities with weak polarity would be 40.6％, and the proportion of isovaleryl spiramycin Ⅲ would still be more than 30％.

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Optimization of Extraction Process of Paeoniae Radix Angelica Compound by Orthogonal Design

HE Qingjiao1, DENG Yang1, YAN Miao2*, YANG Wen3, DU Fanglu3

2014, 45(1): 28-30.

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The optimal extraction process of Paeoniae Radix Angelica compound was investigated by orthogonal test. The effects of ethanol concentration, extraction time, solvent volume and extraction times on the process were studied with the extraction rate of paeoniflorin,ferulic acid and extract yield as the indexes. The optimal extraction process was determined as follows: six volumes of 70％ ethanol and refluxextracting 3 times with 15 minutes each time. Under the above conditions, the extraction rates of paeoniforin and ferulic acid were 12.99 mg/g and 0.593 mg/g, with RSDs of 0.55％ and 2.83％, and the extract yield was 42.85％, with RSD of 1.15％.

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Comparison and Identification ofRadix Isatidis, Baphicacanthis cusiae Rhizoma and Its Adulterants

SHEN Qiongqi1, HOU Huichan2*, LI Jianming2, FENG Shiyin3

2014, 45(1): 31-34.

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Radix Isatidis, Baphicacanthis cusiae Rhizoma and its adulterants were discriminated. Samples were distinguished by character identification,microscopic identification,fluorescenceobservation at 365 nm and thin-layer chromatography. An HPLC method was also applied for the determination of (R,S)-epigoitrin, the characteristic component in Radix Isatidis. The results of above methods showed the simple, fast and specificidentificationfeatures for the distinguishment of Radix Isatidis, Baphicacanthis cusiae Rhizoma and its adulterants.

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Effect of Molecular Structures on Emulsification Capability oIndomethacin-contained Self-emulsifying Drug Delivery System

HE Rui, YIN Zongning*, LI Fanfan, SHEN Yuting

2014, 45(1): 35-40.

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Titration method was used for the research on the phase behavior of indomethacin-contained self-emulsifying drug delivery system (SEDDS). The quantitative structure-activity relationship (QSAR) models were established to describe the correlation between the molecular descriptors, such as quantum chemical, physical chemical and topological parameters, of the components and the self-emulsifying region of SEDDS loaded with indomethacin by multiple linear regression (MLR) and artifcial neural network (ANN). The results demonstrated that both models showed good predictive ability, and MLR model was superior to ANN model. The self-emulsifcation capability of oil and surfactants would be calculated from their molecular descriptors, which might guide for screening the optimal formulation.

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Preparation and Quality Evaluation of Azithromycin Resin Suspension

LI Zhe, CHENG Yingying, LAI Zhenhong, WANG Lei, ZENG Huanxiang

2014, 45(1): 41-44.

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The oral azithromycin resin suspension was prepared to mask the bitter taste and its quality was evaluated. The azithromycin resin complexes with ion exchange resin IRP64 as the carrier were obtained through ion exchange reaction, then adding some suspending agents to prepare the oral suspension. The azithromycin resin complexes were irregular particles. The results of X-ray diffraction and differential scanning calorimetry showed that azithromycin and the resin were combined through chemical bonds. The oral suspension was pseudoplastic fuid with good in vitro dissolution behavior and tasteless.

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Micromeritic Comparative Study of Co-processed Excipients of Different Proportions of Lactose and Microcrystalline Cellulose

ZHANG Chenmeng, TIAN Chao, KE Xue*, JU Mingzhu, HU Danrong

2014, 45(1): 45-48.

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The properties of two co-processed excipients composed of different ratios of lactose to microcrystalline cellulose, Disintequik MCC (D-MCC) and Disintequik MCC 25 (D-MCC 25), were investigated. From the aspects of the fluidityand compressibility, the angle of repose, Carr′s index, flowvelocity and tensile strength of D-MCC and D-MCC 25 were determined. The angle of repose of the mixed powder of co-processed excipients and different drugs and tensile strength of the tablets prepared by direct compression were also determined. The results showed that both D-MCC and D-MCC 25 had good fluidityand compressibility, and the compressibility of D-MCC 25 was slightly better than D-MCC. Both co-processed excipients could improve the fluidityand compressibility of drugs with poor fluidity and ensure the content uniformity of low-dose drugs in tablets

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Intestinal Absorption of PLGA Nanoparticles Loaded with ZL-004

ZHAO Feng1, LUAN Hansen1, MA Yinling2, ZHANG Xiaohong3, WANG Hao1*

2014, 45(1): 49-55.

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The PLGA nanoparticles loaded with ZL-004 (1) were prepared successfully by ultrasonic homoemulsificationmethod. The in vitro release rate from the product was higher than that of the bulk drug. Then the intestinal absorption of 1 PLGA nanoparticles in rats was investigated by means of in situ single pass perfusion model. The absorption was observed in the whole intestinal tract. The absorption constant (Ka) and the effective absorption coeffcient (Peff) of 1 nanoparticles were higher than those of the bulk drug (P<0.01). The Ka and Peff of 1 nanoparticles at small intestine (duodenum, jejunum and ileum) were higher than those at colon (P<0.01). In addition, the accumulative absorption amounts of 1 nanoparticles at different segments of intestinal tract were increased with the increasing of drug concentration in the range of 5 - 20 mg/ml.

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Preliminary Safety Evaluation of Seal Oil Based Lipid Emulsion for Parenteral Nutrition

SU Jianfen1,2, WU Linna1, WANG Zhouhua1, ZHANG Zhengzan1, WU Chuanbin1*

2014, 45(1): 56-59.

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The safety of seal oil based lipid emulsion (SOLE) was preliminary evaluated comprehensively through pyrogen test, in vitro and in vivo haemolysis and stimulation test in blood vessel in rabbits, allergic test in guinea pigs and acute toxicity in mice. The results showed that except slight stimulation caused by SOLE reasonably, neither pyrogen-induced fever nor haemolysis was observed. There was no allergic reaction in guinea pigs induced by SOLE, and no death was found in a week after intravenous injection of SOLE at the maximum tolerated dose of 0.04 ml/g to mice per 12 h for one day.

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Determination of Exenatide Multivesicular Liposomes by HPLC

CHEN Zhixiang, TANG Shu, YU Lifang, LU Weigen

2014, 45(1): 60-62.

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An HPLC method was established for the determination of exenatide multivesicular liposomes. A SEPAX GP-C4 column was used with the mobile phase of 0.1％ trifuoroacetic acid acetonitrile solution∶0.1％trifuoroacetic acid water solution by gradient elution at the detection wavelength of 215 nm. The calibration curve was linear in the concentration range of 2 - 50 mg/ml. The average recovery was 101.6％ with RSD of 2.7％.

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Determination of Asiatic Acid Tromethamine in Rat Plasma by LC-MS/MS

GU Lingling1, CHEN Zhixiang1, LU Weigen1, LIU Quanhai2, LIU Ying2

2014, 45(1): 63-65.

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A LC-MS/MS method was established for the determination of asiatic acid tromethamine (AAS) in rat plasma. A Kromasil C18 column was used with the mobile phase of acetonitrile∶0.1％ formic acid by gradient elution. Prednisolone acetate was used as the internal standard. Samples were detected by electrospray negative ionization mass spectrometry and multiple-reaction monitoring mode. The transitions of AAS and internal standard were m/z 533.00→487.25 and m/z 447.00→401.15, respectively. The calibration curve was linear in the concentration range of 10 - 1 000 ng/ml. The inter- and intra-assay RSDs were less than 10％. The extraction recoveries of the standard blood samples of low, medium and high concentrations were 77.3％, 81.0％ and 73.9％, with RSDs of 12.3％, 5.3％ and 3.1％.

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Comparison of the Chemical Components of Volatile Constituents fromCorydalis yanhusuo W.T.Wang and C. yanhusuo f. floribund by HS-SPME-GC-MS

SHI Huaqing1, CHEN Bin1, SHOU Jiani2, CHENG Cungui3

2014, 45(1): 66-68.

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A headspace solid-phase microextraction (HS-SPME) method was established for the extraction of volatile organic compounds from Corydalis yanhusuo W.T.Wang and C. yanhusuo f. foribunda, respectively. The chemical components of volatile constituents were analyzed by GC-MS. Thirty and ffty four compounds representing 88.24％ and 93.10％ of the volatile compounds were identifed with the result that seventeen of those components were identical. The major volatile components in C. yanhusuo W.T.Wang and C. yanhusuo f. foribunda. were higher alkanes, alkenes, alcoholes, phenols and aldehydes.

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Cleaning Validation of Manufacturing Equipment ofBenazepril Hydrochloride Tablets by HPLC

ZHENG Shukun, WU Weijia, CHEN Dan, WU Tao*

2014, 45(1): 69-72.

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An HPLC method was established for the determination of benazepril hydrochloride in swab extraction solution to verify if the residue of benazepril hydrochloride on the cleaning surface was below the safe limit. A Diamonsil C18 column was used with the mobile phase of tetrabutylammonium bromide solution (dissolving tetrabutylammonium bromide 2.25 g in water 1 L containing glacial acetic acid 0.56 ml)∶methanol (32∶68) as the mobile phase at the detection wavelength of 240 nm. The calibration curve was linear in the range of 0.14 - 2.80 mg/ml. The extraction recovery from manufacturing equipment was 87.97％, with RSD of 2.55％. The recovery of method was 103.0％, with RSD of 1.82％.

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Determination of the Dimer in Doripenem for Injection by HPLC

PENG Jie, HONG Jianwen, HUANG Wenjing

2014, 45(1): 73-75.

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An impurity in doripenem for injection was detected by HPLC and it was deduced as the dimer of doripenem by LC-MS. A C18 column was used with the mobile phase of 0.05％ trifluoroaceticacid∶acetonitrile (94∶6) at the detection wavelength of 297 nm. The calibration curve was linear in the concentration range of 0.15 - 30 mg/ml. The contents of dimer in 4 batches of samples were 0.005％ - 0.019％.

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Determination of Two Components and Related Substances in Bayaspirin Plus Vitamin C Effervesent Tablets by HPLC

Lü Xia1, HU Mingtong2, YU Xu3

2014, 45(1): 76-78.

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An HPLC method was established for the determination of two components, aspirin and vitamin C, and their related substances, salicylic acid and furfural in bayaspirin plus vitamin C effervesent tablets. A Hypersil C18 column was used with the mobile phase of methanol∶tetrabutylammonium hydroxide (adjusted to pH 4.5 with acetic acid) by gradient elusion, at the detection wavelength of 247 nm. The calibration curves for vitamin C, furfural, aspirin and salicylic acid were linear in the concentration ranges of 24 - 480, 0.5 - 10, 40 - 800 and 0.8 - 16 mg/ml. Their average recoveries were 100.2％, 100.3％, 100.2％ and 99.9％, with RSDs of 1.07％, 0.85％, 0.81％ and 0.77％, respectively.

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Resonance Rayleigh Scattering Spectra of Janus Green-Chondroitin Sulfate System and Its Analytical Application

HAN Quan1, TIAN Li2, HAO Tiantian1, ZHAI Yunhui1, HUO Yanyan1

2014, 45(1): 79-82.

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In pH 8.5 - 9.5 Britton-Robinson buffer media, a compound complex was formed between janus green and chondroitin sulfate, leading to a great enhancement of the intensity of resonance Rayleigh scattering (RRS) and giving a new RRS spectrum. The maximum scattering peak was located at 326 nm and two relatively weaker peaks were located at 407 nm and 560 nm. It was also found that the intensity of RRS was directly proportional to the concentration of chondroitin sulfate in the range of 0.1 - 5.0 µg/ml. The low limit of detection was 25.3 ng/ml.

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Application of Excipients for Oral Colon-specific Drug Delivery Syste

FANG Yongbing, CUI Shengmiao*

2014, 45(1): 83-87.

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The oral colon-specificdrug delivery system (OCDDS) has the advantages of colon-specificrelease property, increasing local drug concentration and acting on the lesion site directly, etc. The key point is the correct choice of excipients for OCDDS. The recent applications of some excipients, including Eudragits, azo-polymers and polysaccharides for OCDDS are reviewed in this paper in order to provide a reference for the further research.

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Drug Regulation in Japan and Its Implication for China

ZHANG Xuanxuan, SHAO Rong*

2014, 45(1): 88-94.

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Progress in Global Pharmaceutical R&D in August 2013

LIU Lingling

2014, 45(1): 95-98.

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