Chinese Journal of Pharmaceuticals

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Synthesis of Donepezil Hydrochloride

SHAN Lingxing, GAO Jiasuo, HE Yuxuan, SUN Pinghua, CHEN Weimin*

2013, 44(11): 1084-1085.

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Donepezil hydrochloride was synthesized by condensation of 5,6-dimethoxy-2-ethoxycarbonylindan-1-one with 1-benzyl-4-chloromethyl piperidine to give 5,6-dimethoxy-2-[(1-benzyl-4-piperidyl)methyl]-2-ethoxycarbonyl-indan-1-one, followed by hydrolysis with NaOH in methanol with an overall yield of about 86％.

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Synthesis of Bosutinib

CHEN Hong, WANG Yingli*, LIU Tongbin

2013, 44(11): 1086-1088.

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Bosutinib was synthesized from 2-methoxy-5-nitrophenol by protection and reduction to give 3-isopropoxy-4-methoxyaniline, which was subjected to condensation with ethyl 3-ethoxy-2-cyanoacrylate, Gould-Jacobs cyclization in Dowtherm A, chlorination, reaction with 2,4-dichloro-5-methoxyaniline to afford 7-isopropoxy-6-methoxy-4-(2,4-dichloro-5-methoxyanilinyl)quinoline-3-carbonitrile, followed by deprotection, substitution and condensation with 4-methylpyperizine with an overall yield of about 21％.

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Synthesis of Cefodizime Disodium

LI Mingjie, CHAI Qian, HE Yaguan, HOU Shanbo

2013, 44(11): 1089-1090.

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Cefodizime disodium was synthesized from 7-ACA and 2-mercapto-4-methyl-1,3-thiazol-5-yl acetic acid by condensation to give 7-amino-3-(5-carboxymethyl-4-methyl-1,3-thiazolidinyl-2-mercaptomethyl)-2-cephem-2-carboxylic acid, which was subjected to reaction with 2-(2-amino-4-thiazolyl)-(Z)-2-methoxyiminoacetic acid thiobenzothiazole ester and sodium salt formation with an overall yield of about 63％.

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Synthesis of N-(4-Methoxymethylpiperidin-4-yl)-N-phenylpropionamide Hydrochloride

SHI Yubai, ZHANG Yulin, MA Shaohua

2013, 44(11): 1091-1093.

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N-(4-Methoxymethylpiperidin-4-yl)-N-phenylpropionamide, the intermediate of alfentanil and sufentanil, was synthesized from 1-benzyl-4-piperidone, aniline and trimethylsilyl cyanide by reaction to give 1-benzyl-4-phenylamino-4-cyanopiperidine, which was subjected to successively hydrolysis with concentrated
sulfuric acid and potassium hydroxide, esterification, reduction and etherification to afford 1-benzyl-4-phenylamino-4-methoxymethylpiperidine, followed by acylation and debenzylation with an overall yield of about 25％.

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Effect of Quality Optimization of Organic Nitrogen Source on the Fermentation Process of Erythromycin by Saccharopolyspora erythraea

CHANG Xiantong1,2, DUAN Feizhong2, ZHUANG Yingping1*, CHU Ju1, ZHANG Siliang1

2013, 44(11): 1096-1100.

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Based on the content analysis of amino acids in the organic nitrogen source for erythromycin fermentation by Saccharopolyspora erythraea, a new complex nitrogen source was designed, which could realize the rational combination of amino acids and optimize the quality of protein in nitrogen source. With the application of the new complex nitrogen source, the production of erythromycin reached to 4 611 u/ml, which was 22.5％ higher than that of the control in shake flask experiment. Further investigation was carried out in a 50 L fermenter. In comparison with the control, the content of the active constituent EryA increased by 9.4％ and reached to 7 901 μg/ml, while that of the byproducts EryB and EryC decreased 17.9％ and 33.1％, respectively.

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Optimization of Penicillin Fermentation Medium by Response Surface Methodology

ZHOU Liang1, FENG Tao1,2, LI Liang1, CHU Ju1, ZHUANG Yingping1*

2013, 44(11): 1101-1105.

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The original penicillin fermentation medium was optimized by response surface methodology with Penicillium chrysogenum PC-01 as the production strain. Six components of the original fermentation medium were analyzed by the factorial experiment. With the aid of Minitab16 software analysis, it was found that corn steep liquor, lactose and potassium dihydrogen phosphate were three factors affecting penicillin fermentation significantly. Then the steepest ascent experiment was carried out by varying the three significant factors and fixing the three insignificant factors at an appropriate level, and thus the range of the optimal condition was determined. Finally, the central composite design was employed to determine the optimal condition. The optimized recipe of the medium was as follows: corn steep liquor 15.9 g/L, lactose 104.8 g/L, potassium dihydrogen phosphate 5.5 g/L, ammonium sulfate 2.5 g/L, sodium sulfate 0.5 g/L and calcium carbonate 5 g/L. Under this condition, the predicted yield of penicillin was 16 996 u/ml. The verifying experiment proved that the difference between the actual yield (17 101 u/ml) and the predicted yield was only 0.62％. The yield was increased by 36.8％ compared with the initial production (12 500 u/ml). The impurity content was reduced.

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Preparation of Lansoprazole Enteric-coated Pellets-type Tablets

LIU Zhihua, FANG Yu, WU Xiaohui, CAO Deying, DU Qing*

2013, 44(11): 1106-1110.

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The lansoprazole pellet cores were prepared by extrusion-spheronization technology with microcrystalline cellulose as diluent, 15％ polyvinylpyrrolidone (PVP) K30 aqueous solution containing 1％ Tween-80 as adhesive and 6％ sodium carboxymethyl starch as disintegrant. The pellet cores were coated with alkaline solution as the insulation layer, then the above pellets were coated with Eudragit L30D-55 at the level of 60％ to obtain the entericcoated
pellets. Then the pellets were mixed with Avicel PH101, crosslinked povidone and other excipients to prepare the pellets-type tablets by direct compression method. The cumulative amounts of the pellets and the tablets in hydrochloric acid (pH 1.2) within 1 h were less than 10％, while in phosphate buffer (pH 6.8) in 45 min were over 75％. The release behaviors of pellets before and after compression had no significant difference.

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Preparation and Preliminary Investigation of in vitro Transdermal Property of Diclofenac Sodium Microemulsion-based Hydrogel

LIU Lingling, HU Qiang, SHEN Shuhui, YU Weimin, CUI Jingbin*

2013, 44(11): 1111-1114.

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The effects of three kinds of matrix, carbopol 980, HPMC (1×104 mPa·s) and Sangelose 90L, for diclofenac sodium microemulsion-based hydrogel were compared. The results showed that the transparent yellow microemulsion-based hydrogel was only available with carbopol 980 as a substrate. The viscosity and pH value of the product were (6 000±2.65)mPa·s and 6.5±0.5, respectively. The product was also rather stable. The in vitro transdermal property through excised mouse skin was investigated. Compared with the commercial hydrogel, the cumulative amount at 12 h of the microemulsion-based hydrogel was higher. The steady-state penetration rate of microemulsion-based hydrogel was (20.08±0.73)μg·cm-2·h-1, which was higher than that of commercial hydrogel [(9.47±0.41)μg·cm-2·h-1].

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Optimization of Freeze-drying Process of Tigecycline for Injection

REN Jun1,2, SHU Yusheng2, OU Ning3*, XU Jianguo2

2013, 44(11): 1115-1119.

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To shorten the freeze-drying cycle and improve the stability of tigecycline for injection, the kind and dosage of freeze-drying protective agent, the pH value of the solution and heat conducting oil temperature in pre-freezing and sublimation stage were optimized. The optimal freeze-drying process was to add lactose as the protectant with the amount of two times as much as tigecycline and adjust to pH 5.0 - 6.5 with 1 mol/L hydrochloric acid. Intermediate product should be keep for about 0.5 h at the vicinity of the eutectic point (-10 ℃) before cooled to -40 ℃, then the product should be keep for 1 h at -40 ℃. The next step was to heat the already frozen product to -10 ℃ and keep for 0.5 h. Subsequently, the temperature was decreased to -40 ℃ again and maintained for 2 h. Then the conducting oil temperature should be set at 8 ℃ for about 6.5 h before the temperature was elevated to 40 ℃ for 4.5 h. This improved freeze-drying process would significantly improve the stability of the final product and decrease the moisture content, and whereas reduce the freeze drying period to about 20 h.

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Preparation and in vitro Evaluation of Asiaticoside Ultraflexible Liposomal Gel

LIU Minmin, LI Li, MA Xiaolai*

2013, 44(11): 1120-1122.

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The asiaticoside ultraflexible liposomes were prepared by ethanol injection method with high pressure homogenization. The nanometer-sized particles with the mean diameter of (76.20±2.80)nm and polydispersity index of (0.10±0.02) were obtained. The ζ potential and entrapment efficiency of the product were (-41.40±3.20)mV and (91.94±2.56)％, respectively. The asiaticoside ultraflexible liposomal gel with methylcellulose as the gel matrix was prepared by adding above liposomes into the gel matrix. The in vitro transdermal delivery of asiaticoside from the prepared liposomal gel and common gel through the excised mouse skin were investigated. The results showed that the average steady-state fluxes of asiaticoside from the liposomal gel and common gel were 16.15 and 3.34 μg·cm-2·h-1, respectively. The skin retention of above preparations were (14.99±0.58) and (6.76±0.39)μg/cm2, respectively.

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Preparation of Capsules Filled with Gefitinib Pellets

ZHANG Anping1, JIANG Jianguo2, ZHANG Jia3, MI Zhiyuan3*

2013, 44(11): 1123-1126.

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The blank pill core was sequentially coated on the active ingredient layer and inactive ingredients layer by fluidized bed coating method to obtain the gefitinib pellets. The prepared pellets were filled into the capsules. The parameters of the coating process were optimized by orthogonal design. The in vitro dissolution behaviors in pH 1 hydrochloric acid and pH 6.8 phosphate buffer (PBS) of the product and the original preparation (Iressa) were investigated. The results showed that the dissolution at 30 min of both preparations were over 90％ in hydrochloric acid while in PBS were below 20％. The destructive test and influencing factor test were carried out to evaluate the preliminary stability of the product. The results showed that the related substances of the product after destruction by acid, alkali, oxidation or light were less than 0.6％. After storing the pellets under high temperature, light or high humidity condition for 10 d, the appearance, content, related substances and dissolution had no significant changes.

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Establishment of Immunotoxicity Evaluation Model for Memory System

LIN Man, HONG Min, MA Jing*

2013, 44(11): 1127-1131.

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Based on the T-cell dependent antibody response method, the immunotoxicity evaluation model for memory system with a dose-dependent relationship was established. The keyhole limpet hemocyanin (KLH) was injected to female SD rats at the dosage of 300 μg/kg at d1 and d22, and these rats were ig administrated with cyclophosphamide (1) at the dosage of 5 or 20 mg·kg-1·d-1 for three days (from d22 to d24). The results showed that the white blood cells, lymphocytes and neutrophils of the high-dose group of 1 were significantly decreased at d27 compared with the blank group, while the neutrophils were increased at d30 and d33. The results of ELISA showed that the serum IgG level of high-dose group of 1 were also significantly decreased(P<0.01) in a time- and dose-dependent manner.

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Pharmacokinetics of NGR Modified Brucine Liposomes in Rats

WANG Yong1, CHEN Jun1*, LIN Aihua2, FANG Yun3

2013, 44(11): 1132-1137.

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A NGR peptide derivative with multifunction of stealth and tumor targeting was synthesized and characterized by MALDI-TOF-MS method. Then the brucine-loaded liposomes modified with different ratios of the NGR peptide derivative were prepared by ammonium sulfate gradient method. The in vitro release behaviors of these formulations in blank rat plasma were also investigated. The results indicated that the in vitro release rates of above modified liposomes were slower than that of non-modified liposomes. After iv administration of brucine solution or the above liposomes at the dosage of 5 mg/kg, the drug concentrations in rat plasma were determined. The results of pharmacokinetic study showed that the AUC values of different liposomes groups were all increased to 5 to 6 times as compared with the solution group. Compared with the common stealth liposomes, the MRT of liposomes modified with 1.28％ NGR peptide derivative was significantly prolonged, while no significant differences of other pharmacokinetic parameters were observed.

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Pharmacokinetics and Tissue Distribution of Cannabidiol in Rats

CHENG Liang, XIAO Feng, QIN Yan, KONG Deyun*

2013, 44(11): 1138-1141.

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A LC-MS/MS method for determination of cannabidiol (1) in rat plasma, liver and muscle tissue was established. The pharmacokinetics and tissue distribution of 1 in rats after single-dose ig administration (20 mg/kg) or iv administration (2 mg/kg) were investigated. After ig administration of 1 suspension, the main pharmacokinetic parameters were as follows: AUC0→t(1 501.9±338.6)mg·h·L-1, t1/2(2.49±0.88)h, cmax (595.8±120.3)mg/L. The absolute bioavailability of 1 suspension was (37.7±8.4)％. The drug distribution at 15 min in liver and muscle of rats after ig administration of 1 suspension could be observed, and more in liver especially.

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Determination of Four CSPCHA028 Enantiomers by HPLC

YANG Hanyu, GUO Wenmin, WANG Binglin, BAI Xiaoxue

2013, 44(11): 1142-1144.

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An HPLC method was established for the determination of four enantiomers of CSPCHA028 [N1-benzyl-N4-[1-butyl-2-hydroxyl-2-(5-chloro-6-methoxy-2-naphthal)ethyl]piperazine], a new antidepressant drug candidate. A Chiralpak IC column was used with the mobile phase of hexane-isopropanol-diethylamine (75∶25∶0.1) at the detection wavelength of 236 nm. The resolution of CSPCHA028 enantiomers were over 2.0. The calibration curves
were linear in the range of 5 - 120 μg/ml. Their low detection limits were all 1.0 μg/ml.

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Determination of Volatile and Active Ingredients in the Ointment by Micellar Headspace Gas Chromatography

NI Meiping1, ZHANG Fucheng2, HE Xiaowen3, ZHANG Lin1, JIANG Ye1*

2013, 44(11): 1145-1147.

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A micellar headspace gas chromatography was established for the determination of camphor and menthol in the ointment. The analytes were equilibrated at oven temperation of 85 ℃ for 20 min with the 0.1％ Tween-80 as matrix medium. A separation was performed on a DM-WAX capillary column. The temperatures of column oven, injector and FID were 125, 150 and 180 ℃, respectively. Their calibration curves were linear in the range of 1 - 32 μg/ml. The recoveries of camphor and menthol were 101.3％ - 102.1％ and 97.0％ - 100.5％, with RSDs less than 2.9％ and 3.4％, respectively.

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Determination of Residual Organic Solvents in Rabeprazole Sodium by Headspace Capillary GC

LIU Lu1,2, ZHANG Shenghua2, SONG Dongmei2, YANG Yongjian2*

2013, 44(11): 1148-1150.

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A headspace capillary GC method was established for the determination of the residual organic solvents in rabeprazole sodium. A DB-624 capillary column was used, with helium as the carrier gas and FID as the detector in temperature program mode. The calibration curves of methanol, acetone, acetonitrile, dichloromethane, methyl tert-butyl ether, ethyl acetate, chloroform, n-heptane and toluene were linear. Their average recoveries were 96.8％,
103.1％, 106.5％, 102.8％, 103.4％, 105.6％, 106.5％, 107.5％ and 106.9％, with RSDs of 2.0％, 1.0％, 1.6％, 1.4％, 1.9％, 1.4％, 7.0％, 1.6％ and 2.3％, respectively.

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Determination of Residual Organic Solvents in Biotin by Capillary Gas Chromatography

HU Chuchu, CHEN Xuefan

2013, 44(11): 1151-1153.

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A capillary gas chromatography method was established for the determination of residual organic solvents including ethanol, isopropanol, tetrahydrofuran, benzene, pyridine, toluene, N,N-dimethylformamide(DMF) and xylene in biotin. A DB-624 capillary column was used with temperature program. FID was used as detector with temperature of 250 ℃, and the inlet temperature was 150 ℃. The carrier gas was nitrogen, and the flow rate was 5 ml/min. The eight residual organic solvents were completely separated. Their recoveries and linear relationship were good.

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Progress of Microneedles in Transdermal Drug Delivery System

LU Wangding1, LUO Huafei1, ZHANG Xiaohong2, ZHU Zhuangzhi1, WANG Hao1*

2013, 44(11): 1154-1159.

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The barrier function of the stratum corneum of skin limits the usage of macromolecular and hydrophilic drug in transdermal drug delivery system (TDDS). Through traditional passive diffusion dynamic way or adding penetration enhancers, the cumulative penetrative can be increased, but it may hardly reach an ideal effect. The investigation of microneedles in TDDS is one of the hot spots at present, especially in the field of macromolecular drug and transcutaneous immunization (TCI). Based on the domestic and foreign literatures in recent years, current status of microneedles application to TDDS is summarized. The conception, classification, characteristics, influence effects on microneedle-based transdermal drug delivery system and applications are introduced in this paper.

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Application of Hyperbranched Copolymers to Drug Carriers

YANG Sufang1,2, LIU Guohua2, KANG Rongrong1,2, HAN Meng1,2, XIANG Daxiong1,2*

2013, 44(11): 1160-1165.

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Hyperbranched polymers have the unique properties, such as high solubility, low viscosity and slow clearance etc. Hyperbranched copolymers with the properties of stable structure and high drug loading are obtained by grafting other polymers onto the surface of hyperbranched polymers, which can be used as drug carriers. This paper lays emphasis on the kinds of hyperbranched copolymer as well as the applications to drug carriers. And the safety of this material is briefly introduced.

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Research Progress on Analytical Methods of Residual Quaternary Ammonium Salts as Phase Transfer Catalyst in Drug Substances

LIU Xiaohui1, PAN Hongjuan1*, WEI Jingjing2

2013, 44(11): 1166-1169.

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International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) explicitly points out that it is necessary to control and define the residual quaternary ammonium salts in active pharmaceutical ingredients (APIs). Quaternary ammonium salts are commonly used as phase transfer catalyst in the drug synthesis and people pay more and more attention to their analytical methods. Several analytical methods are reviewed in this paper, including gas chromatography, high-performance liquid chromatography, ion chromatography, etc.

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Graphical Synthetic Routes of Edoxaban

PAN Linyu, LIANG Bin, ZHANG Fuli*

2013, 44(11): 1170-1173.

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Some Opinions on the Studies of Related Substances in Generic Drugs

XIE Mufeng

2013, 44(11): 1174-1183.

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