Chinese Journal of Pharmaceuticals

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Synthesis of Lixivaptan

ZHANG Dashuai1, MU Shuai2, LIU Ying3, LIU Dengke3, WANG Pingbao3*

2013, 44(12): 1201-1204.

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Lixivaptan, a selective arginine vasopressin V2 receptor antagonist, was synthesized from 2-chloro-4-nitrobenzoic acid by esterification, reduction with hydrazine hydrate, acylation with 5-fluoro-2-methylbenzoyl chloride, hydrolysis and acyl chlorination to give 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoyl chloride, which was subjected to reaction with 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine with an overall yield of about 57％ (based on 2-chloro-4-nitrobenzoic acid).

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Synthesis of Dexlansoprazole

CHEN Jia1, YUAN Huafeng1, TU Qingbo2

2013, 44(12): 1205-1206.

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Dexlansoprazole was synthesized from 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridinehydrochloride and 2-mercaptobenzimidazole by condensation to give 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio-1H-benzimidazole, followed by asymmetric oxidation and purification with the yield of 75％ and optical purity of 99.9％.

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Synthesis of Parecoxib

WANG Kai, XU Zebin, SONG Shuaihua, JIN Qi

2013, 44(12): 1207-1209.

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Parecoxib was synthesized from 1,2-diphenylethanone by reaction with chlorosulfonic acid, condensation with acetyl chloride in the presence of pyridine and cyclization with hydroxylamine hydrochloride to give 4-(5-methyl-3-phenylisoxazol-4-yl)phenylsulfonic acid, which was subjected to chlorination and ammonolysis to afford valdecoxib, followed by reaction with propionic anhydride with an overall yield of about 23％.

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Designing, Synthesis and Antimicrobial Activity of Cationic Antimicrobial Peptides Based on Histatin5

LU Jianguang1, DONG Yuanzhen1, ZHU Yuhui1, ZHANG Xiquan2, FENG Jun1*

2013, 44(12): 1210-1214.

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Nine cationic antimicrobial peptides(CAMPs) were designed and synthesized based on Histatin5 and its analogues Dhvar4 and Dhvar5 and six of them exhibited higher in vitro activities against both standard and drug-resistant strains including bacteria and fungi by broth dilution method. The relationship between the antimicrobial activities of CAMPs and α-helicity, net positive charges, hydrophobicity as well as amphipathicity was discussed.

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Synthesis of 8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepten[1,2-b]pyridine-11-one

ZHANG Guang1,2, CHEN Min2, ZHUANG Shouqun1, ZHOU Houyuan 1, WANG Guoping2

2013, 44(12): 1215-1216.

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8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepten[1,2-b]pyridine-11-one, the important intermediate of loratadine, was synthesized from 2-cyano-3-methylpyridine via Ritter reaction and alkylation to give 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridinecarboxamide, which was subjected to hydrolysis with methanesulfonic acid, treatment with sulfinyl chloride and Friedel-Crafts acylation with an overall yield of about 36％.

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Optimization of Fermentation Medium for Erythromycin by Regulation of Phosphate Content

YU Xiaoguang1, CHEN Yong1,2, ZHUANG Yingping1*, CHU Ju1, ZHANG Siliang1

2013, 44(12): 1217-1221.

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Three fermentation media with different phosphate contents were designed. The highest erythromycin titer of 11 209 μg/ml was obtained under the low level phosphate medium containing 2.0％ soybean meal, 1.0％ defatted soybean powder and 1.0％ feather peptone. In order to avoid the repression of erythromycin biosynthesis by phosphate released from the soybean meal, 1.0％ soybean meal was substituted by 0.5％ ammonium sulfate and 0.031％ potassium dihydrogen phosphate. The erythromycin production reached to 11 657 μg/ml. The broth viscosity decreased by 20％.

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Separation of Erythromycin A and C by Washing Process and Frontal Chromatography

JIN Xin, CHEN Kui*, ZHU Jiawen, WU Yanyang

2013, 44(12): 1222-1226.

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Macroporous resin SP825 was adopted to separate erythromycin A (EA) and its main impurity, erythromycin C (EC). Adsorption equilibrium experiments were carried out to investigate the effect of adjustment of aqueous solvent polarity on adsorption behaviors of EA and EC. Washing process and frontal chromatography were used to separate EA and EC. The effects of washing velocity and pH on washing curves were determined. The elution products of two separation methods were compared. The results showed that phosphate buffer containing 3％ acetic ethyl as solvent, washing flow rate of 10.5 ml/h and pH 7.0 were appropriate. Both washing process and frontal chromatography could remove EC efficiently, while frontal chromatography was better for comprehensive consideration.

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Chemical Constituents in Ethyl Acetate Fraction of Kadsura coccinea

CHENG Liang1, HE Quanquan2, YEON Jaeho2, KONG Deyun1

2013, 44(12): 1227-1231.

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MCI, silica gel and ODS column chromatography were used to investigate the chemical constituents of the ethyl acetate fraction of Kadsura coccinea. On the basis of spectral data and physicochemical properties, twelve compounds were isolated and identified as 3'-demethylicariside E3(1), propindilatone J(2), campesterol(3), lupeol(4), abietinal(5), 7α,18-dihydroxydehydroabietanol(6), tamarixetin-3-O-rutinoside(7), quercetin(8), 5,7,3',4'-tetrahydroxyflavan-
3-ol(9), (+)-catechin-7,3′-di-O-β-D-glucopyranoside(10), fortuneanoside G(11) and fortuneanoside J(12). All compounds were reported from K. coccinea for the first time.

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Preparation and Characteristics of a Novel Wound Gel

LUO Muchao1, ZHUO Yang2, YANG Yan1*, SHAN Weiguang1

2013, 44(12): 1232.

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The composite gel system based on chitosan (CS) and Bletilla striata gelatin (BSG) for wound healing was prepared and its formulation was optimized by single factor test with gelation time at 37 ℃ as the index. The gelation time of the optimal product with CS 2％, BSG 1％ and sodium bicarbonate of 0.68 mol/L was 8.3 min. The effects of the concentrations of CS and BSG on gel properties determined by physical analyzer were investigated. The results showed that the gel strength, adhesion, hardness, elasticity and cohesiveness of the optimal product were relatively higher. The microstructure of this gel system was porous. Moreover, this system had good water binding capacity and water absorbability.

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Optimization of Preparation of Aprepitant Nanosuspensions

LU Xiaojie1, DUAN Xi2

2013, 44(12): 1236-1239.

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The aprepitant nanosuspensions were prepared by high pressure homogenization method. The effects of temperature, pressure and cycle times on the particle size, polydispersion index and ζ potential of the product were investigated by Box-Behnken design combined with response surface methodology. The particle size, polydispersion index and ζ potential of the optimal product were (352.4±21.4)nm, 0.301±0.075 and (-31.3±3.3)mV, respectively. The results of transmission electron microscope showed that the product was spherical and uniform. The dissolution at 45 min of the product was 93.5％.

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Optimization of Filling Particles with Three Excipients in Sustained-release Pellets-type Tablets by CCD-RSM

LIU Qi, JIANG Liqun, ZHENG Chunli, ZHU Jiabi, LIU Jianping*

2013, 44(12): 1240-1244.

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The isosorbide mononitrate sustained-release pellets were prepared by extrusion-spheronization and fluid-bed coating method with Eudragit® NE30D as coating material. Then these pellets were mixed with filling particles containing microcrystalline cellulose (MCC) PH 200, MCC KG-802 and pregelatinized starch PC-10 to prepare pelletstype tablets. The ratios of three excipients in filling particles were optimized by central composite design-response surface
methodology (CCD-RSM) and the results were validated. The optimal particles with the ratio of MCC PH 200 to MCC KG-802 of 1.01 and PC-10 content of 23％ had good compressibility and formability so that they could effectively protect the multi-unit coating pellets. The release behaviors and microstructures of the pellets prior to and after compression were not significantly changed according to the results of similarity factor method and scanning electron microscope observation.

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Micronization of Prednisone Acetate by Rapid Expansion of Supercritical Solution

CHEN Qi1, PEI Zhanzhu2, XIE Banghai3, HU Guoqin3*

2013, 44(12): 1245-1248.

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Prednisone acetate was micronized by the rapid expansion of supercritical solution (RESS). The influence factors on the average diameter of the product were investigated by single factor test. The results showed that the average diameter of the micronized particles decreased with the increasing of extraction temperature, pre-expansion pressure or collection distance or the decreasing of pre-expansion temperature or diameter of nozzle. The product was characterized by differential scanning calorimetry and X-ray diffraction. The results showed that there was no significant difference between the prednisone acetate powders prior to and after RESS.

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Solubility Enhancement of Nitrendipine and Nifedipine with Different Carriers for Solid Dispersion

SHEN Song1, WU Lin2, QI Xueyong1, GE Yanru1, JIN Yi3*

2013, 44(12): 1249-1252.

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The solid dispersion (SD) loaded with nitrendipine or nifedipine with polyethylene glycol (PEG), polyvidone (PVP), low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose (MCC) or sodium carboxymethyl starch (CMS-Na) as carrier was prepared by fusion method or solvent method, respectively. The dissolution test of above SDs was carried out in water and 0.3％ sodium dodecyl sulfate (SDS) solution. The results showed that all prepared SDs could improve the drug dissolution. X-Ray diffraction (XRD) and scanning electron microscopy (SEM) were used to study the status of drug in SD. The results showed that the drug in SD with PVP as the carrier was in amorphous form, while in SD with other carriers was in microcrystalline form. The results indicate SEM was more visualized in phase identification compared with XRD.

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Pharmacokinetics of Galantamine Sustained-release Suspension in Beagle Dogs

CHEN Ang, SHI Ye, XI Lian, TAN Zounian, HE Fen*

2013, 44(12): 1253-1257.

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A LC-MS/MS method was established for the determination of galantamine hydrobromide in Beagle dog plasma. According to a three period crossover study, the feeding and fasting pharmacokinetics of galantamine sustained-release suspension (test preparation) in Beagle dogs were studied with galantamine hydrobromide sustainedrelease capsules (Razadyne ER) as the reference preparation. Six Beagle dogs were divided into three groups, two
groups were in fed state and another was in fasting state. Dogs in fed groups were given a single dose of test or reference preparation at the dosage of 10 mg galantamine hydrobromide, and dogs in fasting group were given test preparation at the same dosage. The main pharmacokinetic parameters of above three groups were as follows: tmax (3.3±1.0), (3.2±1.0) and (2.2±0.4)h, cmax (63.0±3.4), (69.5±6.2) and (65.1±12.0)ng/ml, t1/2 (6.8±0.7), (5.6±0.7) and (5.1±2.1)h, AUC0→t (633.5±38.3), (657.2±76.9) and (557.1±36.7)ng·ml-1·h, AUC0→∞ (691.5±34.8), (698.1±81.3) and (595.9±70.4)ng·ml-1·h, MRT (7.5±0.1), (7.3±0.6) and (6.9±0.8)h, respectively.

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Pharmacokinetics and in vitro-in vivo Correlation of Ibuprofen Sustained-release Pellet-filled Capsules in Beagle Dogs

TANG Jing1,2, ZHANG Hailong2, LIANG Feng3, ZHOU Yanbin2, DING Jinsong2*

2013, 44(12): 1258-1261.

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The pharmacokinetics of ibuprofen sustained-release pellet-filled capsules (test preparation) in Beagle dogs was investigated with Fenbid capsules as the reference preparation. The main parameters of test and reference preparations were as follows: t1/2 (4.14±1.12) and (3.84±0.77)h, cmax (81.30±24.52) and (88.81±16.87)μg/ml, AUC0→t (420.79±96.17) and (410.10±85.06)μg·h·ml-1, respectively. The self-made product showed a good sustained-release behavior and its relative bioavailability was (104.70±27.86)％. There was a significant correlation between in vitro release and in vivo absorption.

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Determination of Related Substances in Azithromycin by LC-MS

XU Zhuoni, LI Yue*, SHEN Shunyi

2013, 44(12): 1262-1267.

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A LC-MS method was established for the determination of azithromycin and its related substances. A XBridgeTM C18 column was used with the mobile phase A consisting of 0.3％ formic acid aqueous solution (adjusted to pH 8.2 by ammonium hydroxide) and mobile phase B consisting of acetonitrile and methanol (3∶1) by gradient elution. The data was acquired in positive ion mode. Good resolution of azithromycin and eleven known related substances was achieved. The specialization of the method was studied and the related substances in azithromycin were determined and elucidated after forced degradation by strong base.

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Structure Elucidation of An Unknown Impurity in Rabeprazole Sodium Bulk Drug

LIU Lu1,2, JIANG Wenming2, REN Meiting2, YAO Jinting3, YANG Yongjian2*

2013, 44(12): 1268-1271.

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Rabeprazole sodium bulk drug was analyzed by LCMS-IT-TOF and an unknown impurity was detected. By comparison its possible fragmentation pathway with rabeprazole, the structure of the impurity was referred as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-chloro-benzimidazole.

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Determination of Related Substances in Thiamazole by GC

CHEN Ning, MAO Ke, WU Yongping

2013, 44(12): 1272-1274.

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A GC method was established for the determination of related substances in thiamazole. A Varian CP7595 CP-SIL 8CB AMIN silica capillary column was used, with programmed temperature, at the injection port temperature of 150 ℃ and the FID temperature of 250 ℃. There was good resolution of the related substances and thiamazole. The contents of total impurities in 3 batches of samples were all less than 0.1％.

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Determination of the Dissolution of Ezetimibe/Simvastatin Tablets by HPLC

LAI Qingkuan, WANG Lei, XIE Ting, CHEN Fangxiao, ZENG Huanxiang

2013, 44(12): 1275-1277.

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An HPLC method was established for the determination of the dissolution of ezetimibe/simvastatin tablets. An ODS-3 column was used, with the mobile phase of 25 mmol/L sodium dihydrogen phosphate solution (adjusted to pH 4.0 with 10％ phosphoric acid)-acetonitrile (49︰51), at the detection wavelength of 231 nm. The calibration curves for ezetimibe and simvastatin were linear in the ranges of 1.0 - 12.0 μg/ml and 2.0 - 24.0 μg/ml. Their average
recoveries were 100.8％ and 100.5％, with RSDs of 1.0％ and 1.2％. The ezetimibe dissolution at 20 min of three batches of samples were 101.5％, 100.2％ and 101.9％, while that of simvastatin were 92.5％, 90.9％ and 91.5％.

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Determination of Ten Chemical Components in Sanhuang Tablets by HPLC-DAD

DU Qian1,2, TANG Daoquan1,2*, NI Luqing1, WU Xiaowen1

2013, 44(12): 1278-1280.

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An HPLC-DAD method was established for the determination of ten chemical components in Sanhuang tablets, which were scutellarin, baicalin, berberine hydrochloride, baicalein, aloe-emodin, wogonin, rhein, emodin, chrysophanol and physcione. An Zorbax SB-C18 column was used with the mobile phase of acetonitrile-0.1％ phosphonic acid (adjusted to pH 3.1 by triethylamine) by gradient elution with DAD detection. The results showed that the ten components were well separated and the linear relationships were good within wide ranges. Their recoveries were 96.8％ - 101.1％, with RSDs of 0.42％ - 1.84％.

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Application of Telescoping Approach to Pharmaceutical Process Optimization

ZHANG Ji1, ZHANG Fuli2

2013, 44(12): 1281-1291.

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This review outlines the term "Telescoping Process" and its definition and showcases its superiority when properly applied through case studies of several pharmaceutical processes during process development and optimization. This work analyzes and highlights the application of process telescoping during pharmaceutical process development and summarizes some characteristics and rules of the telescoped process.

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Progress in the Synthesis of Loratadine

ZHUANG Shouqun1, ZHANG Guang1,2, ZHOU Houyuan 1, WANG Hongbo1

2013, 44(12): 1292-1299.

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Because of the excellent clinical performance of loratadine, great attentions have been paid to its synthesis by domestic and overseas researcher. There are two important intermediates: (1-methyl-4-piperidinyl)-[3-[2-(3-chlorophenyl)ethyl]pyridine-2-yl]methanone and 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-one, in the synthesis process of loratadine. This paper reviews the synthetic routes of lorotadine based on these intermediates.

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Progress on Genetic Recombination Breeding of Actinomycetes

XIONG Lei, HU Haifeng*

2013, 44(12): 1300-1307.

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Actinomycetes are Gram-positive bacteria famous for their significant capacity for the production of natural products. Traditionally, researchers have developed many ways, which based on the mutagenesis and screen programmes, to screen the strains with high-output or with the capacity to produce novel natural products. Now, the development of the recombinant DNA technology facilitated the way of strain improvement. This review summarizes the
progress of recombinant DNA technology applied in breeding of actinomycetes in improving natural products output and producing novel products.

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Graphical Synthetic Routes of Crizotinib

SUN Yafei, SUN Zhanli, XIAO Xuhua*

2013, 44(12): 1308-1310.

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Graphical Synthetic Routes of Boceprevir

LIANG Xin, ZHAN Peng, LIU Xinyong*

2013, 44(12): 1311-1313.

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