Chinese Journal of Pharmaceuticals

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Synthesis of Arformoterol Tartrate

QIU Peng-Cheng, LIAO Na, ZHANG Fu-Li*

2012, 43(9): 721-725.

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(R)-2-(4-Benzyloxy-3-nitrophenyl)oxirane(7) was synthesized from 4-hydroxyacetophenone via nitrification, protection by benzyl, bromination, reduction by BH3/CBS and cyclization. Meanwhile (R)-1-(4-methoxyphenyl)-N-[(R)-1-phenylethyl]propan-2-amine(10) was synthesized from 4-methoxyphenylacetone and (R)-α-methylbenzylamine by asymmetric reductive amination. Arformoterol tartrate, a long-acting β2-adrenergic agonist, was synthesized by condensation of compounds 7 and 10, followed by reduction, formylation, debenzylation and salification with L-tartrate acid with an overall yield of about 15％(based on 4-hydroxyacetophenone).

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Synthesis of Antitumor Drug-candidate Intedanib

SUN Min1,2, SUN Huan-Liang1, WANG Fei-Dong1, HUANG Wen-Long2

2012, 43(9): 726-729.

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Antitumor drug-candidate intedanib was synthesized from methyl 3-nitrobenzate(2) by nucleophilic substitution, reduction and ring closure, N-acetylation and condensation to give methyl (E)-1-acetyl-3-(methoxyphenylmethylene)-2,3-dihydro-1H-indol-2-oxo-6-carboxylate(5), which was subjected to condensation with
N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide(9) and deacetylation with an overall yield of about 28％(based on compound 2) and purity of 99.5％. The intermediate 9 can be obtained from N-methyl-4-nitroaniline(6) by N-bromoactylation, nucleophilic substitution and reduction.

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Microwave-assisted Synthesis of [des-Thr-ol8]-Octreotide

YANG Xiao-Xiao, LIN Hao, WANG De-Xin*

2012, 43(9): 729-733.

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[des-Thr-ol8]-Octreotide(1), a major related substance of octreotide, was successfully synthesized with 100 ml reaction tube made from centrifuge tube by microwave-assisted solid phase stepwise synthesis technique in pilot scale. Synthesis was carried out with 2-Cl-Trt resin by Fmoc strategy. After cleavage of the resin, linear peptide was oxidized in aqueous solution by air in the presence of active carbon and purified by preparative RP-HPLC subsequently
to give the target peptide 1 in 62.9％ overall yield with excellent purity. The compound 1 was confirmed by HRMS and amino acid analysis, and the conformation change between linear and cyclic peptide was investigated by CD spectra.

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Synthesis of 2-Aminoethylmethylsulfone Hydrochloride

SHI Jiao-Yang, WU Xue-Song, CEN Jun-Da*

2012, 43(9): 734-735.

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2-Aminoethylmethylsulfone hydrochloride(1) was synthesized from zinc methanesulfinate dihydrate by reaction with ethylene oxide, chlorination, substitution and then hydrolysis with the overall yield of 50％. The compound 1 was also prepared from zinc methanesulfinate dihydrate or sodium methanesulfinate by substitution with N-(2-bromoethyl)phthalimide and then hydrolysis with the overall yield of 68％ and 79％, respectively.

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Synthesis of 7-Chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

TONG Jia-Yong, ZHANG Can*

2012, 43(9): 736-738.

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7-Chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, the key intermediate of tolvaptan, was synthesized from 5-chloro-2-nitrobenzoic acid by reduction and esterification to give methyl 2-amino-5-chlorobenzoate,which was subjected to sulfonylation, N-alkylation and Dieckmann condensation, followed by simultaneous decarboxylation and desulfonation in H2SO4 with an overall yield of about 71％.

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Application of Flow Feeding Technology to Lincomycin Fermentation

LI Ji-An1, LIN Hui-Min1, NIU Jin-Gang2, ZHANG Hong-Zhou2, CHEN Dai-Jie3*

2012, 43(9): 739-742.

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According to the preliminary pre-test in shake flasks, it could be concluded that there was a glucose effect in the fermentation of lincomycin (1). Furthermore, the high oxygen consumption was found in the whole fermentation process. This event was specially strong in the prophase of the fermentation. Based on above facts, the fermentation process was optimized in a 200 L fermentor. As a result, the glucose and ammonium sulfate were fed with continuous flow to remove the glucose effect and keep a stable fermentation process in the middle and late phase of the fermentation. The process of mycelium regeneration became better in whole fermentation. This study prolonged fermentation period and increased the production of 1 in the fermentation anaphase. With the continuous flow feeding technology, the production of 1 increased by 50.3％ compared with the repeated-batch feeding. The final fermentation units of 1 was 91.1％ higher than the present average titer (7 500 μg/ml) of the other Chinese manufacturer.

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Optimization of Pichia pastoris Expression System Related to Recombinant Human Interferon β Based on Control of Protease Activity

ZHANG Dan-Dan, DOU Wen-Fang, XU Zheng-Hong*, SHI Jin-Song

2012, 43(9): 743-747.

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The effect of nutrition and environmental factors related to protease activity on the expression and degradation of exogenous protein (IFNβ-HAS) was investigated in Pichia pastoris expression system. The results suggested that pH, glutamic acid and EDTA were three key factors significantly affected the expression of IFNβ-HAS.Moreover, the optimal condition was determined as pH 5.5, glutamic acid 0.18％ and EDTA 12 mmol/L by response surface analysis of three factors and three levels. The production of IFNβ-HSA reached 24.46 mg/L. The electrophoresis results of the final fermentation product showed that the degradation of IFNβ-HSA reduced significantly and the production of target protein increased due to the activity of protease was inhibited after the optimization of nutrition and environmental factors.

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Percutaneous Penetration in vitro for Optimization of Cream Loaded with Evodia Fruit Extract

HE Qing1, WANG Ting2, CHEN Fei2, ZHOU Yan-Bin2, DING Jin-Song2*

2012, 43(9): 748-751.

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The type of cream, emulsifier and drug loading of the cream loaded with Evodia fruit extract were screened by single factor test with in vitro cumulative percutaneous penetration of evodiamine and rutaecarpine as the indexes. The optimal formulation was as follows: the oil-in-water cream with the drug loading of 0.2％ was prepared with Span-60 and Cremophor RH-40 as combinated emulsifiers. The product was a pale yellow semi-solid oil-in-water
emulsion with a uniform appearance and spherical emulsion droplet. Its pH was (6.81±0.04) and the cone penetration was between 102.4 mm and 119.7 mm. The cream after centrifugation at 1 000×g for 30 min was not stratified, and the product was fairly stable under the condition of storing at 40 and -20 ℃ for 10 d.

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Optimization of Andrographolide Solid Lipid Nanoparticles by Central Composite Design and Response Surface Methodology

YANG Tao1,2, SHENG Huan-Huan1,3, CHENG Xue-Mei1,2, WANG Chang-Hong1,2*, WANG Zheng-Tao1,2

2012, 43(9): 752-755.

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Andrographolide solid lipid nanoparticles were prepared by high pressure homogenization. The influence of the ratio of drug to lipid materials (the mixture of glycerin monostearate and Compritol ATO 888 with the ratio of 1∶1), ratio of lecithin to lipid materials and the concentration of surfactant (Tween-80) on entrapment efficiency and drug loading were investigated by central composite design. The results fit with multiple linear and binomial equation
and the optimal formulation was predicted by response surface methodology. The results showed that there was a well correlation for drug loading by multiple linear regression while for entrapment efficiency the binomial equation was superior to the multiple linear regression. The optimal formulation was as follows: the ratio of drug to lipid materials was 9％, the ratio of lecithin to lipid materials was 1.6, and the concentration of Tween-80 was 3％. The entrapment efficiency, drug loading, mean diameter and ζ potential of the product were (91.0±0.9)％, (3.49±0.03)％, (286.3±8.0)nm and (-20.6±0.2)mV, respectively.

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Preparation of Naftopidil Self-microemulsifying Drug Delivery System

JIANG Xing-Long1,2, JIA Yun-Tao,3 ZHANG Liang-Ke1*, TIAN Rui2, TENG Yong-Zhen2

2012, 43(9): 756-759.

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The components of the blank self-microemulsifying drug delivery system (SMEDDS) were screened by the results of equilibrium solubility of naftopidil in different excipients and pseudo-ternary phase diagrams. The formulation of SMEDDS loaded with naftopidil was optimized by orthogonal design and single factor experiment. The solubility of naftopidil in the optimal SMEDDS was significantly higher than in water. The mean particle size was about 23 nm after self-microemulsification. The results of the in vitro release test showed that the cumulative amount at 8 h of naftopidil SMEDDS and its suspension in pH 6.8 phosphate buffer were lower than 20％ while the former released faster and more completely in 0.1 mol/L HCl.

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Application of Fingerprinting Technology of the Fruits of Schisandra chinesis to Quality Control of Shengmai Intermediates-Schisandra Extract

ZHANG Ping, TANG Hai-Tao, MIN Wen-Lin

2012, 43(9): 764-768.

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An HPLC method was applied to compare the fingerprints of the alcohol-soluble part and watersoluble part of the fruits of Schisandra chinesis. A Waters SymmetryShieldTM RP18 column was used with the mobile phase of acetonitrile-water by gradient elution. The compounds of Schisandra chinensis were separated optimally. A chromatography fingerprinting technology was established to control the process quality from Schisandra chinensis to Shengmai intermediates-Schisandra extract.

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Determination of Praziquantel in Macrophages by HPLC

ZOU Yong-Hua1, DING Jin-Song1, HE Shi-Ying1, ZHANG Long-Gui2, MA Ning2*

2012, 43(9): 773-775.

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An HPLC method was established for the determination of praziquantel in mouse peritoneal macrophage in vitro. A Kromasil 100-5 C18 column was used, with the mobile phase of methanol-water(67︰33) at the detection wavelength of 264 nm. The calibration curve was linear in the range of 2 - 40 μg/ml. The method recoveries of low-, middle- and high-concentration quality control samples were (98.24±2.99)％, (104.49±4.27)％ and (105.13±6.05)％, with RSDs less than 10.6％.

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Determination of Human Albumin by Raman Spectroscopy

MAO Dan-Zhuo, WENG Xin-Xin, YANG Yong-Jian*

2012, 43(9): 776-779.

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A Raman spectroscopy method was established for the determination of human albumin. The linear regression (LR) and partial least square(PLS) were employed to establish calibration models. The calibration curve was linear in the range of 48.8 - 243 g/L(4.88％ - 24.30％). The r values of the LR and PLS regression model were both 0.999 7, while the root mean square error of cross validation(RMSECV) values were 0.385 and 0.153, respectively.

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Determination of Hydroxysafflor Yellow A and Emodin in Shuganquzhi Capsules by HPLC

LIU Qing-Feng1, SHI Xiao-Jin1, LI Zhong-Dong1*, WANG Xiao-Ping2, ZHONG Ming-Kang1

2012, 43(9): 782-784.

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An HPLC method was established for the simultaneous determination of hydroxysafflor yellow A and emodin in Shuganquzhi capsules. A C18 column was used with the mobile phase of methanol -1％ acetic acid by gradient elution at the detection wavelength of 254 nm. The calibration curves of hydroxysafflor yellow A and emodin were linear in the concentration ranges of 0.1 - 60 μg/ml and 0.1 - 6 μg/ml, respectively. The recoveries were over 98％, with intraand
inter-day RSDs less than 2.0％.

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Progress in Pharmaceutical Excipients with Function of Inhibition of P-glycoprotein Mediated Efflux

CUI Sheng-Miao, YE Zhen-Zhen, ZHANG Jian, LIAO Hua-Wei

2012, 43(9): 785-789.

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P-Glycoprotein (P-gp) is an ATP-dependent efflux pump that is expressed in various tissues. It can reduce the bioavailability of some drugs, and it is also one of the important causes for multidrug resistance of tumor cells. Some pharmaceutical excipients can inhibit P-gp mediated efflux, and they simultaneously have the advantages of low toxicity, no pharmacological activity and high safety. This paper emphasizes on the progress of three kinds of pharmaceutical excipients (non-ionic surfactants, polymers and lipids) with the function of inhibition of P-gy mediated efflux. Meanwhile the structure, function and research model of P-gp are briefly introduced.

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Application of Numerical Simulation to Tablet Formation

YANG Xiao-Juan, CHEN Lan*

2012, 43(9): 790-795.

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Tablet has good stability and tolerance to changes of temperature and humidity so that it is the most common dosage form. The tablet formation technology is one of the key techniques in the pharmaceutical industry.There are many researches on the important parameters of the tablet preparation process and influence factors on powder fluidity. However, tabletting process includes a series of problems, such as the complex flow of powder, structural design
of machine, microscopic and macroscopic changes of powder. Common studies are difficult to solve above problems.With the rapid development of computer technology, numerical simulation is becoming an effective tool in the tabletting process. The literatures on tablet preparation process (the process of filling and tabletting) with numerical simulation method are summarized in this paper. The application of numerical simulation to tablet formation is discussed.

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Graphical Synthetic Routes of Lapatinib

GENG Jing-Kun, ZHAO Gui-Sen*

2012, 43(9): 796-798.

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Interpretation of Common Technical Document on Pharmaceutical Development and Manufacture

WANG Ya-Min, JIANG Yu

2012, 43(9): 799-A77.

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