Chinese Journal of Pharmaceuticals

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Synthesis of Pacritinib Hydrochloride

HAN Chang1, GUO Yajun1, PENG Jiajuan2, ZHU Xueyan1, SHAN Hanbin1*

2015, 46(12): 1269-1273. https://doi.org/10.16522/j.cnki.cjph.2015.12.001

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Pacritinib hydrochloride was synthesized from 2-hydroxy-5-nitrobenzaldehyde by nucleophilic substitution with 1-(2-chloroethyl)pyrrolidine hydrochloride to give 5-nitro-2-[2-(pyrrolidin-1-yl)ethoxy]benzaldehyde, then followed by reduction, substitution, reduction and salification to obtain 3-[(allyloxy)methyl]-4-[2-(pyrrolidin-1- yl)ethoxy]aniline ditoluenesulfonate, which was subjected to condensation with 4-[3-[(allyloxy)methyl]phenyl]-2- chloropyrimidine, and olefin metathesis with an overall yield of about 13％(based on 2-hydroxy-5-nitrobenzaldehyde).

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Synthesis of Everolimus

LIU Shengquan1,2, YU Jingliang2,3, LIU Zhende2, GAO Heyong2, LI Kang1*

2015, 46(12): 1274-1277. https://doi.org/10.16522/j.cnki.cjph.2015.12.002

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Everolimus was synthesized from rapamycin via condensation with 2-[(tetrahydro-2H-pyran- 2-yl)oxy]ethyl trifluoromethanesulfonate in the presence of organic base to give 40-O-[[(tetrahydro-2H-pyran-2- yl)oxy]ethyl]rapamycin, which was subjected to deprotection under acidic conditions directly. The crude product was isolated and purified by prep-HPLC, and the overall yield was about 66％. This route had better selectivity, mild reaction condition, and industrial application.

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Synthesis of Nelarabine

XIA Ran1, SUN Liping2, YANG Xining3, QU Guirong4*

2015, 46(12): 1278-1279. https://doi.org/10.16522/j.cnki.cjph.2015.12.003

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Nelarabine, an anti-leukemia drug, was synthesized from guanine arabinoside via condensation with acetic anhydride to give 2',3',5'-tri-O-acetylguanine arabinoside, which was subjected to chlorination with POCl3 to obtain 6-chloro-2',3',5'-tri-O-acetylguanine arabinoside, followed by deprotection in the presence of Na2CO3-CH3OH with an overall yield of 73％.

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Synthesis of Mesalazine

LI Yunshan1, QIU Yuhua2, CHEN Bai2

2015, 46(12): 1280-1282. https://doi.org/10.16522/j.cnki.cjph.2015.12.004

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Mesalazine was synthesized from 2-chlorobenzoic acid by nitrification to give 2-chloro-5-nitrobenzoic acid, which was subjected to substitution by water to give 2-hydroxy-5-nitrobenzoic acid, followed by reduction in the presence of zinc dust and hydrazinium monoformate with an overall yield of about 88％ and an HPLC purity of 99.4％.

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Synthesis of (R)-and (S)-Naftopidil

XIAO Rong, DU Peigang

2015, 46(12): 1283-1287. https://doi.org/10.16522/j.cnki.cjph.2015.12.005

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(S)-Naphthylglycidic ether [(S)-2] and (R)-3-(α-naphthoxy)-1,2-propanediol (5), the key chiral building block, were obtained with high enantiomeric excess by means of hydrolytic kinetic resolution (HKR) of naphthylglycidic ether (2) with (R,R)-Salen Co(Ⅲ)·BF3 complex (4), and then 5 was converted into (R)-2 by “one-pot” procedure which was developed with Sharpless. Optical pure compounds 2 were further transformed into corresponding (R)- and (S)-naftopidil by treatment with 1-(2-methoxyphenyl)piperizine (3), respectively. The enantiomeric excess of (R)- and (S)-naftopidil were both 98％.

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Synthesis of the Related Substances of Lesinurad

SUN Xiangyu1,2, DU Yuelei2, SONG Bo2, YAN Hong1, YANG Yan2*

2015, 46(12): 1288-1292. https://doi.org/10.16522/j.cnki.cjph.2015.12.006

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According to the structure of lesinurad and its synthetic process, four related substances: 2-[[4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (A), 2-[[5-chloro-4-(4- cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (B), 2-[[5-hydroxy-4-(4-cyclopropylnaphthalen- 1-yl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (C) and 2-[[5-bromo-4-(1-cyclopropylnaphthalen-2-yl)-4H-1,2,4-triazol- 3-yl]thio]acetic acid (D) were prepared and confirmed by 1H NMR and LC-MS. These substances were taken as the references for the quality control of lesinurad.

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Candida rugosa Lipase-catalyzed Double Resolution for the Preparation of (S)-Naproxen

XIN Jiaying1,2, LI Haiyan1, CHEN Shuming3, SUN Lirui1, XIA Chungu2

2015, 46(12): 1293-1295. https://doi.org/10.16522/j.cnki.cjph.2015.12.007

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(S)-Naproxen was obtained from naproxen methyl ester via asymmetric hydrolysis catalyzed by Candida rugosa lipase (CRL) to give crude (S)-naproxen, then esterification with methanol and further hydrolysis by CRL catalyzed. According to the established theoretical curves, when the conversions of the first and second resolution were 46.8％ and 75.1％, respectively, (S)-naproxen was obtained with an overall yield of 31.8％ and the value of ee over 99％.

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Gene Cloning and Expression of Transaminase for the Catalytic Synthesis of Sitagliptin

HUANG Zongqing1, LU Jianguang1, ZHANG Xiquan2, FENG Jun1*

2015, 46(12): 1296-1300. https://doi.org/10.16522/j.cnki.cjph.2015.12.008

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The transaminase gene, which could be used for the catalytic synthesis of sitagliptin, was cloned into the expression vector pGEX-6p-1, then transfered into E. coli to express and obtain a high expression strain of recombinant transaminase. Its expression in four kinds of E. coli, E. coli W3110, E. coli BL21 (DE3), E. coli Rosetta (DE3) and E. coli Rosetta-gami2 (DE3), was investigated, among which E. coli BL21(DE3) had the highest expression level of transaminase in soluble forms. The specific enzyme activity of the crude product produced by E. coli BL21 (DE3) was relatively high (0.32 u/mg).

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Construction of Prokaryotic Expression Vector of TAZ and Its Expression in E. coli

XU Huijing, WANG Ningning, LIU Lei, DONG Yuan, WANG Huiyan*

2015, 46(12): 1301-1304. https://doi.org/10.16522/j.cnki.cjph.2015.12.009

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Tafazzin, the full-length gene of cardiolipin acyltransferase, was amplified by polymerase chain reaction (PCR) and inserted into expression vector pEASY. The positive clones were screened by colony PCR, and the construction of the prokaryotic expression vector pEASY-TAZ was confirmed by DNA sequencing. pEASY-TAZ was transformed into E. coli competent cells BL21(DE3), BL21(DE3)pLysS and Transetta(DE3), respectively. Recombinant TAZ proteins were induced at different IPTG concentrations and temperatures. As a result, Transetta(DE3) was selected as the engineering bacteria for its higher expression amount. The results showed that the expression of the recombinant protein increased accordingly as the IPTG concentration raised. Temperature played an important role in TAZ expression. The expression of soluble recombinant proteins could be improved at the low temperature conditions (16 ℃). A Western
blot analysis was conducted and it confirmed that TAZ protein was successfully expressed.

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Effect of Mesoporous Molecular Sieve MCM-41 on Dissolution and Bioavailability of Indometacin in Rats

ZHANG Wenjun, Lü Chunyan, REN Jungang, WANG Li, Lü Jiangwei

2015, 46(12): 1305-1310. https://doi.org/10.16522/j.cnki.cjph.2015.12.010

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The mesoporous molecular sieve MCM-41 was synthesized with tetraethyl orthosilicate as silicon source and cetyl trimethylammonium bromide as templates under basic conditions. Then the assemblies of indometacin (1) and MCM-41 were prepared by immersion method. The characteristics of MCM-41 and the assemblies were investigated by X-Ray diffraction, N2 adsorption-desorption isotherm, FT-IR spectroscopy and thermogravimetric analyses. The results proved that 1 was loaded into the pore of MCM-41 successfully. The drug loading of the assemblies was 15.9％. Compared with the bulk drug, the in vitro dissolution rate of 1 from the assemblies was significantly increased. The dissolution of the assemblies at 30 min in water was above 75％, and at 90 min was above 90％. The pharmacokinetic behaviors of 1 in rats after single intragastric administration of 1 suspension or 1/MCM-41 were compared. The drug concentrations in plasma were determined by HPLC. The main pharmacokinetic parameters of 1 suspension and 1/MCM-41 were as follows: cmax(2.85±0.41) and (4.39±0.31)μg/ml; tmax(4.50±0.55) and (3.00±1.27)h; AUC0→t (24.83±4.60) and (54.98±4.43)μg·h·ml−1; MRT (7.43±0.21) and (12.49±0.37)h, respectively. Compared with 1 suspension, the relative bioavailability of the assemblies of 1/MCM-41 was 236.9％.

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Investigation of Gel Matrix Formulation Based on Eudragit RS100 as a Novel Crosslinking Agent

YANG Huasheng, CHEN Lihua, LI Xiaoli, WU Lu*

2015, 46(12): 1311-1316. https://doi.org/10.16522/j.cnki.cjph.2015.12.011

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The yield and viscosity of sodium polyacrylate (PAA-Na) solution after adding Eudragit RS100 or aluminum chloride as the crosslinking agent were determined and compared. The results showed that there was no significant difference between this two systems. However, the drawn rheological curves showed that the system adding Eudragit RS100 had s smooth viscosity curve which was beneficial for improving the content uniformity of drug in gel matrix. Based on the above conclusion, the blank matrix of gel patches with carboxymethylcellulose sodium (CMCNa) as the thickening agent was prepared, and the formulation was optimized by the Box-Behnken design and response surface method. The optimal formulation compositions were as follows: PAA-Na 4.0％, Eudragit RS100 0.2％ and CMCNa 14.0％. Two kinds of Wushao gel patches with Eudragit RS100 or aluminum chloride as the crosslinking agent were
prepared with the extracts of Aconiti Radix Cocta and Radix Paeoniae Alba as the models. The transdermal behaviors of peoniflorin from two preparations were investigated. The results showed that the steady penetration rate and lag time of peoniflorin from two preparations had no significant difference, which indicated that Eudragit RS100 had little influence on percutaneous penetration of this gel patches.

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Investigation of Enhanced Percutaneous Penetration of Imidazolium Ionic Liquids

ZHANG Ding1,2, WANG Huaiji1,2, CUI Xiuming1,2, YANG Xiaoyan1,2, WANG Chengxiao1,2*

2015, 46(12): 1317-1322. https://doi.org/10.16522/j.cnki.cjph.2015.12.012

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The effects of eleven imidazolium ionic liquids (MILs) on percutaneous penetration of Panax notoginseng saponins were investigated with excised mouse skin as a barrier and ginsenoside Rg1 as an index. The results of confocal laser scanning microscopy (CLSM) showed that the MILs could enhance the penetration depth and penetration amount of sodium fluorescein. Furthermore, the structure-activity relationship of these MILs was preliminarily investigated. The results showed that the enhancement effect of the MILs affected by the length of side chain, number and type of substituent groups. The enhancement effects of di-substituted MILs were better than those of mono- and trisubstituted ones. When a hydroxyl group was introduced into one of the di-substituted MILs, its effect was enhanced; when a carboxyl group was introduced, its effect was weakened. Compared with the commonly used enhancers (azone, N-methyl-2-pyrrolidone and 1,2-propanediol), the enhancement effects of di-substituted MILs were similar or even superior.

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Determination of Efavirenz in Human Plasma by LC-MS/MS and Bioequivalence in Human Body

LI Zhou1, DING Cungang1, ZHOU Zhen1, GE Qinghua1*, LI Xuening2

2015, 46(12): 1323-1326. https://doi.org/10.16522/j.cnki.cjph.2015.12.013

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An LC-MS/MS method was established for the determination of efavirenz in human plasma. A tandem mass spectrometric detection was conducted using multiple reaction monitoring (MRM) under positive ionization mode with an electrospray ionization (ESI) interface. It was linear for efavirenz in the range of 0.05 - 10 μg/ml. The method recoveries were 96.9％ - 100.1％, with intra-assay RSDs≤4.6％, and inter-assay RSDs≤6.1％, respectively. The bioequivalence of the efavirenz test and reference tablets were invesigated after single oral administration to 22 healthy male volunteers under fasting conditions. There was no significant differences of AUC and cmax between the test and reference tablets. The average relative bioavailability (F) of the test preparation was (98.75±35.41)％. The result showed that the test and reference preparations were bioequivalent.

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Determination of Tiotropium Bromide and Its Related Substances by HPLC

ZHOU Yimeng, ZHOU Bin*

2015, 46(12): 1327-1329. https://doi.org/10.16522/j.cnki.cjph.2015.12.014

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An HPLC method was established for the determination of tiotropium bromide and its related substances. A Diamonsil-C18 column was used with the mobile phase of 0.03 mol/L sodium 1-octanesulfonate solution (containing 0.5％ triethylamine, adjusted to pH 3.3 with phosphoric acid)∶methanol∶acetonitrile (50∶20∶30) at the detection wavelength of 238 nm. Tiotropium bromide and its related substances were separated successfully. It was linear for tiotropium bromide in the range of 0.01 - 1.0 mg/ml. The average recovery was 100.1％, with RSD of 0.16％.

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Comparison of Microbial Limit Test Methods for Pharmaceutical Water

ZHANG Guanghua, WANG Sijin, GAO Chun, CAI Chunyan

2015, 46(12): 1330-1333. https://doi.org/10.16522/j.cnki.cjph.2015.12.015

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The test methods for microbial limit recorded in USP 37 and ChP 2010 were conducted and compared for the examination of pharmaceutical water used in Beijing pharmaceutical enterprises. The results showed that there were more kinds of colony form unit grown on R2A agar medium plate, which was recorded in USP 37. R2A agar medium was more suitable for the growth of microbes in polluted water, and the test method recorded in USP 37 for the
measurement of microbes in pharmaceutical water was proved to be more scientific and reasonable.

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Determination of Methyl p-Toluenesulfonate and Ethyl p-Toluenesulfonate in Vinpocetine by LC-MS/MS

ZHANG Wei1,2, CHEN Yihua1, ZHENG Feng1*

2015, 46(12): 1334-1336. https://doi.org/10.16522/j.cnki.cjph.2015.12.016

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A simple and sensitive LC-MS/MS method was established for determination of the genotoxic impurities methyl p-toluenesulfonate (2) and ethyl p-toluenesulfonate (3) in vinpocetine. A Waters XTerra RP-C18 column was used, with the mobile phase of 0.1％ formic acid∶methanol(27∶73). Samples were detected by selective reaction monitoring (SRM) and positive ion mode. Ethyl p-hydroxybenzoate (4) was used as the internal standard. The mass transitions of 2, 3 and 4 were m/z 186.9→m/z 91.0, m/z 201.0→m/z 91.0 and m/z 167.0 →m/z 95.0, respectively. It was linear in the range of 2.5 - 50 ng/ml for both 2 and 3. The limit of quantification was 2.5 ng/ml. Their recoveries were 102.9％ and 97.3％, with RSDs of 5.0％ and 4.2％, respectively.

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Determination of Five Effective Components in Baidu San by HPLC

ZHANG Xingguo1, ZHAO Mingzhong1, LIU Yanting2

2015, 46(12): 1337-1339. https://doi.org/10.16522/j.cnki.cjph.2015.12.017

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An HPLC method was established for the determination of five effective components, osthole, columbianadin, senkyunolide I, senkyunolide A and levistilide A, in Baidu San. A C18 column was used, with the mobile phase of acetonitrile∶0.1％ glacial acetic acid by gradient elution, at the detection wavelengths of 330 nm(0 - 28 min) and 280 nm(28 - 60 min). It was linear for the above five compounds in the ranges of 5.0 - 100.0, 2.6 - 52.0, 2.2 - 44.0, 8.5 - 170.0, and 2.0 - 40.0 μg/ml, respectively. Their average recoveries were 98.25％, 96.84％, 99.06％, 99.22％ and 97.74％, with RSDs of 1.27％, 0.81％, 1.22％, 1.05％ and 1.43％, respectively.

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Determination of Nine Phospholipid Components in Poractant Alfa Injection by HPLC-ELSD

WANG Yingchun1,2, ZHENG Luxia2,3, XU Xu1*, CHEN Gang2, CHEN Guiliang2

2015, 46(12): 1340-1342. https://doi.org/10.16522/j.cnki.cjph.2015.12.018

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An HPLC-ELSD method was established for the separation and determination of nine phospholipid components in poractant alfa injection. A silica column was used, with the mobile phase A of chloroform∶methanol∶ water∶ammonia water(78∶21∶0.2∶0.4)and mobile phase B of chloroform∶methanol∶water∶ammonia water (59∶35∶5∶0.4)by gradient elution, and detected by evaporative light scattering detector. Phospholipids in poractant alfa injection were separated completely. Their calibration curves were linear in their corresponding injection amounts. The average recoveries were 98.5％ - 101.3％, with RSDs of 0.6％ - 2.6％.

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Investigation of Quality Parameters of Pressurized Metered Dose Inhaler in Usage Process

JIN Zhixin, SHAO Qi, HONG Chen

2015, 46(12): 1343-1346. https://doi.org/10.16522/j.cnki.cjph.2015.12.019

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The concentration of salbutamol sulphate was determined by HPLC. The effects of cleaning, shaking and priming before usage of the pressurized metered dose inhaler loaded with salbutamol sulphate on the delivered dose (DD) and fine particle fraction (FPF) were investigated to compare whether these operations had influences. The results showed that after administration for 8 d and without cleaning, the residual drugs on surface of the inhaler would
progressively increase, the DD value could even reach twice as much as the labelled amount. Without sharking before usage, the fluctuation of measured DD values of the product was large and went beyond the limit requirement (in the range of 80％ - 120％ of the labelled amount); moreover, the FPF values were also below the limit requirement (>30％). The measured DD values of the first dose of the product without priming were slightly low while the values of the second dose were higher than the upper limit, and the DD values of the third and the fourth doses were in the limit range.

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Separation and Purification of 3-Methylxanthine from Crystallization Mother Liquor with Macroporous Adsorption Resin

SHI Lei1, TIAN Yumiao2, YU Wenguo1, LIU Qingtao1, ZHAO Xu2

2015, 46(12): 1347-1351. https://doi.org/10.16522/j.cnki.cjph.2015.12.020

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The optimal process was investigated and established for the separation and purification of 3-methylxanthine from crystallization mother liquor with macroporous adsorption resin. Five kinds of macroporous resins were screened by static adsorption test. The optimal purification conditions were obtained based on dynamic adsorption and desorption. The results showed that HZ16 resin was an optimal macroporous adsorbent for the separation and purification of 3-methylxanthine from crystallization mother liquor. Its adsorption capacity for 3-methylxanthine was about 18 mg/ml. 3-Methylxanthine could be effectively desorbed by 5％ and 60％ ethanol(pH 10.0). The average yield of desorption was over 92％.

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Progress in Bioactivities and Synthetic Methods of 4-Arylcoumarins

LI Na1,2,3, SUN Jie1,2,3, SUN Jingyong1,2,3, WANG Xiaojing1,2,3*

2015, 46(12): 1352-1365. https://doi.org/10.16522/j.cnki.cjph.2015.12.021

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4-Arylcoumarins, also named “neoflavones”, are present in a variety of natural products and biologically active compounds. They are verified to have many pharmacological activities such as cytotoxic, antioxidant, antimicrobial, and anti-inflammatory. Studies on synthetic methods of 4-arylcoumarins attract special interest with its development in structure-activity relationship (SAR) researches. This review puts emphasis on the analysis of various research reports involving the bioactivities and synthetic methods of 4-arylcoumarins, and then provides references for the discovery of novel lead compounds.

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Review of Rubber Stoppers for Pharmaceutical Use and Its Compatibility with Pharmaceutical Products

LI Ligen, ZHANG Yilan*

2015, 46(12): 1366-1371. https://doi.org/10.16522/j.cnki.cjph.2015.12.022

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Rubber is widely used as stoppers in the pharmaceutical packaging material system. Although it is convenient for the transport and storage of medicines, there are many adverse effects to the medicines, such as the absorption of medicines, particle contamination, chips fall when punctured the stopper and chemical reactions with medicines etc. This article introduced the ingredients of rubber stoppers for pharmaceutical use and sketched its compatibility with the pharmaceutical products.

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Graphical Synthetic Routes of Suvorexant

WEN Limin, YANG Shangyan*

2015, 46(12): 1372-1375. https://doi.org/10.16522/j.cnki.cjph.2015.12.023

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Situation Analysis of Changzhou New Pharmaceutical Industry and Countermeasure

TENG Yiwan1, CAI Zhenyi2, CHEN Rui1, ZHOU Xin1, JIANG Pengju3,4*

2015, 46(12): 1376-1379. https://doi.org/10.16522/j.cnki.cjph.2015.12.024

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