Chinese Journal of Pharmaceuticals

Select

Perspectives & Review

Application of Negishi Cross-coupling in the Synthesis of Bioactive Molecules

ZHANG Qingwen

2019, 50(04): 359-382. https://doi.org/10.16522/j.cnki.cjph.2019.04.001

Abstract ( ) Download PDF ( )

Knowledge map

Save

The Nobel Prize-winning Negishi cross-coupling reaction is a powerful tool for constructing carboncarbon bond. This perspective covers the general aspects and recent advances of this important organic name reaction, with emphasis on its state-of-the-art applications in the synthesis of bioactive molecules such as drugs, drug candidates and natural products, hoping to encourage Negishi reaction implementation and innovation in both academia and industry.

Select

Perspectives & Review

Application of Physiologically Based Pharmacokinetic Modeling in Pharmaceutics

LIU Hongrui1, CHEN Fang1*, XIANG Xiaoqiang2, QUAN Yingjun3, JIN Shasha2

2019, 50(04): 383-391. https://doi.org/10.16522/j.cnki.cjph.2019.04.002

Abstract ( ) Download PDF ( )

Knowledge map

Save

Physiologically based pharmacokinetics (PBPK) model is an important mathematical modeling method for drug research. It can predict the pharmacokinetic behaviors of drugs in the human by using preclinical data, explore the impacts of various physiological parameters, such as age, race or disease status on human pharmacokinetics, guide on dosage and dosing regimens and evaluate drug-drug interactions. PBPK modeling has developed rapidly in the last decade within both the fields of academia and the pharmaceutical industry, which has been widely used in all stages of drug development. In this article, the concept and methodology of PBPK modeling are briefly introduced. Several cases are discussed on its application and prospect in the research and development of pharmaceutics, including preformulation, dosage form development, food effect, prediction of population pharmacokinetics, bioequivalence of generic drugs, etc.

Select

Paper

Synthesis of Flupentixol Decanoate

CHEN Daopeng1, WANG Shengqing1, YANG Xiangping1, MA Yanqin1, ZHANG Guisen2

2019, 50(04): 392-395. https://doi.org/10.16522/j.cnki.cjph.2019.04.003

Abstract ( ) Download PDF ( )

Knowledge map

Save

A new method for the separation of (Z)-flupentixol(8) was developed. (Z/E)-Flupentixol hydrochloride (6) was synthesized from 2-(trifluoromethyl)-9H-thioxanthen-9-one(2) via Grignard reaction, dehydration and addition with a yield of 69.6％. Compound 6 was freed with aqueous ammonia, after quantitative addition of HCl/ ethyl acetate, (E)-flupentixol hydrochloride precipitated preferentially. The (E)-isomer was filtered out and the mother liquor was recovered and then re-salted to obtaine (Z)-flupentixol hydrochloride(7). Then 7 was subjected to dissociation and recrystallization to prepare 8 with a purity of 99.9％ and a yield of 29.6％. Finally, 8 reacted with decanoyl chloride to afford flupentixol decanoate in a total yield of 15.3％(based on 2).

Select

Paper

Synthesis of Pemetrexed Dialanine

GAO Ji, XU Jianguo, ZANG Chao, TANG Yunfeng, ZHANG Guimin*

2019, 50(04): 396-398. https://doi.org/10.16522/j.cnki.cjph.2019.04.004

Abstract ( ) Download PDF ( )

Knowledge map

Save

A synthetic method of pemetrexed dialanine (1) which has more stable property was reported based on the synthesis of pemetrexed disodium. 4-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)- ethyl]benzoic acid (4) reacted with acetic anhydride to give 4-[2-(2-acetamido-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]- pyrimidin-5-yl)ethyl]benzoic acid, which was followed by a condensation with diethyl L-glutamate (3) to produce diethyl N-[4-[2-(2-acetamido-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamate. Then after a hydrolysis by sodium hydroxide, the corresponding product was subjected to a salification with alanine to afford the target compound with a purity of 99.5％ and an overall yield of 69.1％ (based on 3). This synthetic route can avoid the production of self-condensation impurities of 4 sucessfully. Moreover, the use of p-toluenesulfonic acid which could produce the genotoxic impurities was avoided. The process has some advantages such as mild reaction conditions and simple operation, which can provide more choices for the development of pemetrexed formulation.

Select

Paper

Synthesis of Sonosensitizer DEG

CHEN Junlei, ZHAO Ming*, SHI Zhichun, LI Jun, ZHANG Shujun

2019, 50(04): 399-402. https://doi.org/10.16522/j.cnki.cjph.2019.04.005

Abstract ( ) Download PDF ( )

Knowledge map

Save

The synthetic process of sonosensitizer DEG was reported in the first time. Hemin(2) was subjected to an addition and demetalation with hydrogen bromide in acetic acid, which was followed by an etherification and esterification with diethylene glycol under the catalysis of concentrated sulfuric acid to obtain di(2-hydroxyethoxy)- ethyl 7,12-bis[1-[2-(hydroxyethoxy)ethoxy]ethyl]-3,8,13,17-tetramethyl porphyrin-2,18-dipropionate in 83.2％ yield. Then it reacted with anhydrous ethanol via transesterification to give diethyl 7,12-bis[1-[2-(hydroxyethoxy)ethoxy]- ethyl]-3,8,13,17-tetramethyl porphyrin-2,18-dipropionate. The latter reacted with manganese dichloride tetrahydrate via coordination to afford diethyl manganese-7,12-bis[1-[2-(hydroxyethoxy)ethoxy]ethyl]-3,8,13,17-tetramethyl porphyrin-2,18- dipropionate. Then after a hydrolysis with sodium hydroxide and an acidification with hydrochloric acid, the target compound DEG was obtained with a purity of 95.2％ and an overall yield of 73.1％(based on 2).

Select

Paper

Synthesis of Tricin by Ultrasonic Phase Transfer Catalysis

CHU Chaosen1,2, WANG Xiaoli1, HU Yutao1, LI Tianxue1,2, WANG Zheng3

2019, 50(04): 403-405. https://doi.org/10.16522/j.cnki.cjph.2019.04.006

Abstract ( ) Download PDF ( )

Knowledge map

Save

A novel synthetic method for tircin was reported. Phloroglucinol (2) reacted with chloroacetonitrile in the presence of zinc chloride in HCl/ethyl acetate to give 2-(2-chloro-1-iminoethyl)benzene-1,3,5-triol, which was followed by a hydrolysis in diluted hydrochloric acid directly to afford 2-chloro-1-(2,4,6-trihydroxyphenyl)ethan-1- one (4). Then the latter was subjected to a cyclization under ultrasonic condition with syringaldehyde in the presence of TBAB to provide the target compound with a total yield of 74.1％(based on 2). This synthetic route has advantages of low cost, mild condition and simple operation. In addition, the method for preparing the target compound from 4 has not been reported in the literature.

Select

Paper

Immobilization of Thermophilic S-Adenosylmethionine Synthetase and Preparation of S-Adenosylmethionine

HUA Haojü1, WU Yong1, HUANG Zongqing1, ZHANG Xiquan2, FENG Jun1*

2019, 50(04): 406-410. https://doi.org/10.16522/j.cnki.cjph.2019.04.007

Abstract ( ) Download PDF ( )

Knowledge map

Save

The specific activities of immobilized enzyme, recoveries of enzyme activity and stabilities of continuous reaction were compared between amino resin and epoxy resin in the immobilization of S-adenosylmethionine synthetase. The results showed that amino resin was an effective immobilized matrix for S-adenosylmethionine synthetase with good stability of continuous reaction. The specific activity of immobilized enzyme and recovery rate of enzyme activity were (27.91±1.33)U/g and (25.78±1.23)％. The optimal reaction conditions of immobilized enzyme were listed as follows: the sample volume was 20 BV with the flow rate of 3 BV/h. The salt types were potassium sulfate and magnesium sulfate. The molar conversion rate of S-adenosylmethionine was up to (61.78±1.91)％. The immobilized enzyme reaction solution was purified by DK-1 cation exchange chromatographic column. S-Adenosylmethionine with the purity more than 98％ was obtained and the yield was (71.50±1.61)％.

Select

Paper

Separation and Purification Process of Daptomycin

GUO Chaojiang, WANG Meng, LIU Zhong, LI Chunli, ZHANG Guimin*

2019, 50(04): 411-415. https://doi.org/10.16522/j.cnki.cjph.2019.04.008

Abstract ( ) Download PDF ( )

Knowledge map

Save

The separation and purification of daptomycin was processed by the reversed-phase chromatographic resins in combination with ion-exchange resins. The parameters including loading capacity, cumulative elution recovery and purification fold was compared to confirm the optimal resins. The LP20MM reversed-phase chromatographic resin, NM-Q ion-exchange resin and XT-30 reversed-phase chromatographic resin were used respectively. The parameters of the purification process were listed as follows. The pre-treatment broth was loaded into the LP20mm reversed-phase chromatographic resin column and eluted with 10％ acetonitrile aqueous solution to collect the fractions with the purity more than 80％. The resulted elutes were purified by NM-Q ion-exchange resin column with 10 g/L NaCl aqueous solution as the eluent, then the fractions with the purity greater than 90％ were collected. The elutes were further purified by XT-30 reversed-phase chromatographic resin column and washed with 50％ ethanol aqueous solution(containing 40 mmol/L ammonium acetate) to collect the fractions with purity over 99％. The final purity of daptomycin was 99.2％ with the total yield of 57.5％.

Select

Paper

Species Identification Analysis by Different Methods and Toxin Genes Detection of Staphylococcus Strains Isolated from Drug Manufacturing Enterprises

LI Qiongqiong, SONG Minghui, QIN Feng, LIU Hao, YANG Meicheng*

2019, 50(04): 416-421. https://doi.org/10.16522/j.cnki.cjph.2019.04.009

Abstract ( ) Download PDF ( )

Knowledge map

Save

The species identification accuracy of 16S rRNA sequence alignment, VITEK 2 Compact microbial identification system and RiboPrinter bacterial identification system in 92 Staphylococcus strains isolated from production environment of drug manufacturing enterprises were compared and evaluated. The distribution of 12 toxin genes in 92 Staphylococcus strains was also investigated. It revealed that all the 92 Staphylococcus strains were coagulase-negative bacteria, and could be divided into 8 Staphylococcus species. Among the 8 species, S. epidermidis had the highest isolation rate (27.2％). The 16S rRNA sequence alignment analysis could not distinguish S. capitis and S. caprae. The RiboPrinter bacterial identification system misidentified all S. pseudintermedius strains as S. intermedius. The VITEK 2 Compact microbial identification system displayed false or invalid identification results of some strains including S. capitis, S. hominis, S. pasteuri, and S. cohnii. 7 toxin genes (pvl, sea, seb, sec, sed, egc and eta) were detected in the 92 coagulasenegative strains, in which the leukotoxin gene pvl had the highest detection rate (8.70％), followed by enterotoxin gene sec (6.52％). In summary, 16S rRNA sequence alignment analysis and RiboPrinter bacterial identification system are superior to the VITEK 2 Compact microbial identification system for the identification of different Staphylococci species. Contaminated coagulase-negative Staphylococci in the production environment of drug manufacturing enterprises have a certain potential pathogenicity, so the monitoring of coagulase-negative Staphylococci should be strengthened in the future.

Select

Paper

Species Identification Analysis by Different Methods and Toxin Genes Detection of Staphylococcus Strains Isolated from Drug Manufacturing Enterprises

XU Ying1, WANG Jiaxin2, LUAN Hansen2*, WANG Hao2

2019, 50(04): 422-429. https://doi.org/10.16522/j.cnki.cjph.2019.04.010

Abstract ( ) Download PDF ( )

Knowledge map

Save

The species identification accuracy of 16S rRNA sequence alignment, VITEK 2 Compact microbial identification system and RiboPrinter bacterial identification system in 92 Staphylococcus strains isolated from production environment of drug manufacturing enterprises were compared and evaluated. The distribution of 12 toxin genes in 92 Staphylococcus strains was also investigated. It revealed that all the 92 Staphylococcus strains were coagulase-negative bacteria, and could be divided into 8 Staphylococcus species. Among the 8 species, S. epidermidis had the highest isolation rate (27.2％). The 16S rRNA sequence alignment analysis could not distinguish S. capitis and S. caprae. The RiboPrinter bacterial identification system misidentified all S. pseudintermedius strains as S. intermedius. The VITEK 2 Compact microbial identification system displayed false or invalid identification results of some strains including S. capitis, S. hominis, S. pasteuri, and S. cohnii. 7 toxin genes (pvl, sea, seb, sec, sed, egc and eta) were detected in the 92 coagulasenegative strains, in which the leukotoxin gene pvl had the highest detection rate (8.70％), followed by enterotoxin gene sec (6.52％). In summary, 16S rRNA sequence alignment analysis and RiboPrinter bacterial identification system are superior to the VITEK 2 Compact microbial identification system for the identification of different Staphylococci species. Contaminated coagulase-negative Staphylococci in the production environment of drug manufacturing enterprises have a certain potential pathogenicity, so the monitoring of coagulase-negative Staphylococci should be strengthened in the future.

Select

Paper

Preparation, Characterization and Properties of Acipimox-isonicotinamide Co-crystal

GUO Lihong1,2, XIA Xianglai1, ZHAI Lihai1,2, ZHANG Guimin1,2*

2019, 50(04): 430-435. https://doi.org/10.16522/j.cnki.cjph.2019.04.011

Abstract ( ) Download PDF ( )

Knowledge map

Save

Acipimox-isonicotinamide co-crystal, which was composed of a molecule isonicotinamide and a molecule acipimox, was prepared by solution crystallization. Acipimox and isonicotinamide were respectively dissolved in methanol at 65 ℃, then filtering and mixing under rotation (500 r/min) at 65 ℃ for 1 h. And then, the mixture was slowly cooled (0.2 ℃/min) to room temperature. After crystallization for 36 h, the white needle crystals were precipitated, the acipimox-isonicotinamide co-crystal was obtained through filtering and drying. The structure of cocrystals was characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (XRPD), synchronous thermal analysis (TGA/DSC), respectively. The stability and solubility of the co-crystal were also assessed. The results showed that the solubilities of co-crystal in various pH solutions were increased to two times as compared with acipimox. The results of anti-hypercholesterolemic evaluation showed that compared with the model group, the serum levels of triglyceride, total cholesterol, low density lipoprotein in rats were obviously decreased in positive control (acipimox capsules, Olbetam) group and co-crystal group; while there were no significant differences between the positive control group and co-crystal group (P>0.05).

Select

Paper

Evaluation of Micromeritic Properties of Anhydrous Dicalcium Phosphate for Direct Compression

YANG Qiuxia, XIAO Yan, LU Weigen, XI Quan*

2019, 50(04): 436-440. https://doi.org/10.16522/j.cnki.cjph.2019.04.012

Abstract ( ) Download PDF ( )

Knowledge map

Save

The micromeritic properties of six types of anhydrous dicalcium phosphate (DCPA), namely Fujicalin? SG, A-TAB, DI-CAFOS? A60, DI-CAFOS? A150, C1890D and Emcompress?, had been evaluated to provide theoretical bases for the direct compression technology. The particle size and morphology of six types of DCPA were determined by laser particle size analyzer and polarized light microscopy. Flowability and filling property were characterized by calculating Hausner ratio, compressibility and Kawakita equation. The tensile strength-pressure regression equation was employed to characterize the compactibility of DCPA. The results showed that the values of d(0.9) for different types of DCPA increased in the following order: DI-CAFOS? A60Emcompress?>C1890D≈A-TAB>DI-CAFOS? A150. While, the sequence of filling property was DICAFOS ? A60>Fujicalin? SG>Emcompress?>C1890D>A-TAB>DI-CAFOS? A150. Furthermore, the descending sequence of compactibility was DI-CAFOS? A60>Emcompress?>DI-CAFOS? A150>A-TAB>Fujicalin? SG>C1890D. According to the above results, it was found that different types of DCPA had different sizes and shapes, which led to different micromeritic properties. Fully understanding the powder properties was helpful for reasonable selection of direct compacting excipients.

Select

Paper

Determination of Total Tungsten Extracted from Prefilled Syringes by ICP

HOU Qingqing1,2, ZHANG Bing2, ZHU Hanchao2, ZHANG Yilan2*

2019, 50(04): 441-444. https://doi.org/10.16522/j.cnki.cjph.2019.04.013

Abstract ( ) Download PDF ( )

Knowledge map

Save

An inductively coupled plasma spectrometry (ICP) method was established for the determination of tungsten which was extracted and migrated from prefilled syringes (PFS). The extraction solvents (4％ acetic acid solution, water and 0.5％ ammonia solution), extraction sites (stainless steel needle, needle connected with the glass tip and the whole syringe) and extraction conditions (sterilized in the autoclave and ultrasound) were investigated respectively. The results showed the efficiency of tungsten extraction was the highest when extracted with 0.5％ ammonia solution to fill the whole syringe and sterilized at the condition of 121 ℃ for 1 h. The tungsten contents in the migration solutions were determined with pH 4.0 and pH 7.0 ammonium acetate buffer as the media for migration test. The method was simple, feasible, accurate, reliable and suitable for the detection of tungsten in PFS.

Select

Paper

Pharmacokinetics of Two Forms of Acotiamide Hydrochloride Hydrate in Beagle Dogs

XIAO Xiaoyang, ZHANG Guoshun, ZHANG Shuqiu*

2019, 50(04): 445-449. https://doi.org/10.16522/j.cnki.cjph.2019.04.014

Abstract ( ) Download PDF ( )

Knowledge map

Save

null

Select

Pharmaceutical Management & Information

Investigation and Analysis of the Implementation of Drug Priority Review System Based on the Perspective of Registered Applicants

LU Chengkun, WANG Yushan, JIANG Rong, SHAO Rong*

2019, 50(04): 450-455. https://doi.org/10.16522/j.cnki.cjph.2019.04.015

Abstract ( ) Download PDF ( )

Knowledge map

Save

Select

Pharmaceutical Management & Information

Validation Strategy for Legacy Systems in Computerization of Pharmaceutical Industry

ZHAO Chenyang, ZHU Jianwei*

2019, 50(04): 456-463. https://doi.org/10.16522/j.cnki.cjph.2019.04.016

Abstract ( ) Download PDF ( )

Knowledge map

Save

Select

Pharmaceutical Management & Information

Application of Six Sigma Management in Pharmaceutical Enterprises Based on GMP: A Case from BT Company

LI Dongang, LIANG Yi*

2019, 50(04): 464-469. https://doi.org/10.16522/j.cnki.cjph.2019.04.017

Abstract ( ) Download PDF ( )

Knowledge map

Save

Please choose a citation manager

Content to export

Archive