Chinese Journal of Pharmaceuticals

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Synthesis of Silodosin

LIANG Huixing, ZHANG Haibo, MIAO Shifeng, YIN Lixian, CHEN Lingwu

2015, 46(4): 328-331.

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Silodosin was synthesized from 1-acetyl-5-(2-aminopropyl)-2,3-dihydro-7-cyano-1H-indole and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate by condensation, resolution with L-mandelic acid to give (R)-1-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-7-cyanoindoline, which was subjected to protection with (Boc)2O, hydrolysis with sodium hydroxide to afford (R)-5-[2-[N-tert-butoxycarbonyl-2-[2- (2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-7-cyanoindoline, followed by cyano hydrolysis, substitution with 3-bromopropyl benzoate, hydrolysis of ester group and deprotection with an overall yield of about 6.6％.

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New Synthetic Process of Erlotinib Hydrochloride

FANG Jinhai, ZENG Hui, MENG Qingwei*

2015, 46(4): 332-335.

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Erlotinib hydrochloride was synthesized from ethyl 3,4-dihydroxybenzoate by substitution, nitrification, reduction, cyclization and chlorination to give 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, which was subjected to nucleophilic substitution with 3-aminophenylacetylene and salt formation with an overall yield of about 67％ (based on ethyl 3,4-dihydroxybenzoate). 3- Aminophenylacetylene was synthesized from acetophenone by a new procedure including nitrification, chlorination, elimination and reduction with the yield of about 48％.

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GU Honglei, WU Taizhi*, JIN Linyong, ZHU Jinjin, ZHANG Fuli

2015, 46(4): 336-342.

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According to the structural characteristics of dabigatran exetilate mesylate and its synthetic process, ten related substances: 4-[[(hexyloxy)carbonyl]carbamimidoyl]aniline (A), ethyl 2-[[[4-(carbamimidoyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-carbonylate (B), ethyl 2-[[[4-[[(hexyloxy)carbonyl]carbamimidoyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5- carbonylate (C), methyl 3-[[[2-[[[4-[[(hexyloxy)carbonyl]carbamimidoyl]phenyl]amino]methyl] 1 -me t h y l - 1H- b e n z imi d a z o l - 5 - y l]c a r b o n y l] (p y r i d i n - 2 - y l)ami n o]p r o p a n o a t e (D) , me t h y l 3 - [[[2-[[[4-[[[(hexyloxy)carbonyl]amino]carbonyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]- carbonyl](pyridin-2-yl)amino]propanoate (E), 3-[[[2-[[[4-(carbamimidoyl)phenyl]amino]methyl]- 1 - m e t h y l - 1 H - b e n z i m i d a z o l - 5 - y l ] c a r b o n y l ] ( p y r i d i n - 2 - y l ) a m i n o ] p r o p a n o i c a c i d ( F ) , 3-[[[2-[[[4-[[(hexyloxy)carbonyl]carbamimidoyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]- carbonyl](pyridin-2-yl)amino]propanoic acid (G), 3-[[[2-[[[4-[[(hexyloxy)carbonyl]carbamimidoyl]- phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propanamide (H) , e t h y l 3 - [ [ [2 - [ [ [4 - [ [ [ (h e x y l o x y) c a r b o n y l ] ami n o] c a r b o n y l ]p h e n y l] ami n o]me t h y l ] - 1 - m e t h y l - 1 H - b e n z i m i d a z o l - 5 - y l ] c a r b o n y l ] ( p y r i d i n - 2 - y l ) a m i n o ] p r o p a n o a t e ( I ) a n d 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]carbonyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]- carbonyl](pyridin-2-yl)amino]propanoic acid (J) were synthesized and confirmed by 1H NMR and MS. These
substances were taken as references for quality control of dabigatran etexilate mesylate.

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Separation, Structural Identification and Synthesis of Related Substances of Ivabradine Hydrochloride

ZHAO Aihui1,2,3, SHI Xiujuan1, SUN Jingyong1,3, DOU Chunshui1, YAO Qingqiang1,2,3*

2015, 46(4): 343-345.

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In the quality study of ivabradine hydrochloride, two new impurities were identified by HPLCMS. The structures were speculated to be 3-(3-hydroxypropyl)-7,8-dimethoxy-1,3-dihydrobenzoazepin-2-one and 3-(3-hydroxypropyl)-7,8-dimethoxy-1,3,4,5-tetrahydrobenzoazepin-2-one. They were synthesized from 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydrobenzoazepin-2-one via substitution and hydrogenation, respectively. The structures were confirmed by 1H NMR、13C NMR and MS. These compounds had the same retention time with the impurities in ivabradine hydrochloride.

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Improved Synthesis of 4α,5α-Epoxy-androst-2-eno[2,3-d]isoxzol-17β-ol

LI Yong, ZHU Tao, FAN Lingling, WANG Jianta, TANG Lei*

2015, 46(4): 346-350.

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4α,5α-Epoxy-androst-2-eno[2,3-d]isoxzol-17β-ol, the key intermediate of trilostane, was synthesized from 17β-hydroxy-4-androsten-3-one by condensation with ethyl formate in the presence of sodium methoxide to give 2-hydroxymethylene-androst-4-en-3-one-17β-ol, which was subjected to cyclization with hydroxylamine hydrochloride to afford androst-4-eno[2,3-d]isoxazol-17β-ol, followed by epoxidation with m-CPBA with an overall yield of 70％ and purity of 99.1％.

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A Chemo-enzyme Method to Synthesis of (S)-t-Butyl 3-Hydroxypiperidine-1-carboxylate

ZHU Wei, WANG Bo, WU Hui, LI Binghao

2015, 46(4): 349-350.

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(S)-t-Butyl 3-hydroxypiperidine-1-carboxylate, the chiral intermediate of ibrutinib, was synthesized from 3-hydroxypiperidine via t-butyloxocarbonyl protection, oxidation with NaOCl-TEMPO, enzyme K198 catalyzed asymmetrical reduction with an overall yield of 70％.

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Separation and Purification of Fidaxomicin

WANG Haiyan, LI Ning, LI Xiaolu, REN Fengzhi, ZHANG Xuexia*

2015, 46(4): 351-353.

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The separation and purification process of fidaxomicin was developed. A medium pressure chromatography system using polymer microsphere as the carrier was setup. The system was optimized by studying the different types of polymer microsphere and elution conditions. The results showed that when using UniPS 30 - 300 polymer microsphere as the chromatography filler, 75％ methanol (containing 0.05% acetic acid) as the eluant, and 1.0 g/100 ml
filter as the sample loading amount, the purity of the final product was higher than 95% and the yield was above 60％.

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Transdermal Permeation Investigation of Tacrolimus Ointment in vitro

WANG Xin, LI Ling, TIAN Juan, HUANG Hui, DING Jinsong*

2015, 46(4): 354-357.

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To provide a reference for the quality consistency evaluation of two brands of tacrolimus ointment, the transdermal permeation behaviors with piglet skin and nude mouse skin as barriers were investigated. The modified Franz diffusion cell was employed for the in vitro transdermal permeation test. The tacrolimus concentration in receiving liquids and skins was measured by LC-MS/MS. The results showed that when using piglet skin as the barrier, the cumulative
penetration amounts at 24 h of three batches of test ointment and the original preparation were (243.50±72.07), (247.22±66.42), (237.76±92.81) and (226.00±38.88)ng/cm2, and the cumulative retention amounts in skin at 24 h were (1 866.21±164.91), (1 686.11±176.54), (1 817.08±221.52) and (1 769.77±254.50)ng/cm2, respectively. When using nude mouse skin as the barrier, the cumulative penetration amounts at 24 h of both two brands of tacrolimus ointment were three to four times higher than those in piglet skin groups. It indicated that the in vitro transdermal behavior of the test ointment and original preparation were consistent.

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Preparation and Characteristics of Celecoxib Nanocrystals

HUANG Ting1,2, LIN Qiaoping2, QIAN Yong2, XU Xiangyang2, ZHOU Jianping1*

2015, 46(4): 358-363.

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Celecoxib nanocrystals were prepared by a combined method of antisolvent precipitation and high pressure homogenization to increase the dissolution of celecoxib. The effects of types and ratios of stabilizers, pressure and circle numbers of high pressure homogenization were investigated with appearance of initial suspension, particle size and polydisperse index (PDI) of nanocrystal suspension as indexes. The optimal nanosuspension was prepared with
the combined stabilizers of 25 mg of Polyvidone K30 and 2.5 mg of sodium dodecyl sulfate, at the pressure of 500 bar for 10 circles. The particle size and PDI of the nanosuspension were (283.67±20.84) nm and 0.16±0.01(n=3). Then the nanosuspension was spray-dried to obtain the nanocrystals of celecoxib. The spray-dried product could redisperse rapidly to form uniform suspension with the particle size of (623.33±28.71)nm. The product was also characterized by
X-ray diffraction, differential scanning calorimeter, scanning electron microscope, transmission electron microscope and saturated solubility. The results showed that the nanocrystals had the same chemical structure and crystalline form with celecoxib. The dissolution of the nanocrystals was significantly higher than that of bulk drug and physical mixture. The product stored at high temperature and high moisture condition for 10 d was still rather stable.

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Preparation and Pharmacokinetics of Exenatide-loaded Mesoporous Silica Nanoparticles

XU Junjun, WANG Guowei, GUO Manman, FEI Weidong, LI Fanzhu?

2015, 46(4): 364-368.

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The SBA-15 mesoporous silica nanoparticles were prepared, which had an average particle size of (920±120) nm, a pore diameter of (6.0±0.2)nm, a pore volume of (0.94±0.03)cm3/g and a specific surface area of (701.4±0.70)m2/g. The exenatide-loaded nanoparticles were prepared with the prepared SBA-15 as carriers. Due to the big specific surface area and pore volume of SBA-15, the drug-loading was increased to (15.2±2.0)％. The results of in vitro release test showed that the release of exenatide from the nanoparticles was nearly 35％ at d1 in pH 7.4 phosphate
buffer, and slowly increased to 40％ at d14. The exenatide solution and exenatide-loaded SBA-15 nanoparticles were subcutaneously injected to SD rats, respectively. The t1/2, AUC0→t and MRT of exenatide solution and exenatide-loaded SBA-15 nanoparticles were 0.60 and 14.53 h, 1.71 and 8.60 ng⋅ml-1⋅h, 1.14 and 21.30 h, respectively. The results showed that SBA-15 could significantly increase the drug half-life and MRT, which was expected to become a promising and ideal carrier of exenatide.

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Effect of Crystalline Drug Content on Drug Release from Risperidone Microspheres

LUAN Hansen1, XU Fenglan2, YANG Li1, ZHAO Hong1, WANG Hao1*

2015, 46(4): 369-374.

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Risperidone microspheres were prepared by the emulsion-solvent evaporation method. The scanning electron microscopy was used to observe the surface and cross-section of the microspheres. In order to investigate the effect of crystalline risperidone in microspheres on the drug release from the microspheres, an X-ray powder diffractometric method was developed to quantify the content of crystalline risperidone in the microspheres. Consequently,
the different size and quantification of crystalline risperidone in the microspheres prepared by different process were observed. With the content of crystalline risperidone increasing in the microspheres, the latent period of the drug release was prolonged.

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Determination of Anti-carcinoma Activity of Ribonucleic Acid Ⅱ

WANG Can, LIN Shangyan, WU Lihong, SHAO Hong, CHEN Gang*

2015, 46(4): 375-377.

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Seven cell lines were treated with different concentrations of RNA Ⅱ. The cell proliferation was determined by WST-8 colorimetric assay, and the sensitive cell line, human leukemia cell line K562, was chosen as the experiment object. Experiment conditions including cell density and incubation time were investigated. It was linear for RNA Ⅱ in the range of 0.02 - 100 mg/ml. The anti-carcinoma activities of 10 batches of samples were determined by this
method, and their inhibition rates to K562 cells were all over 55％.

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Determination of Micafungin by pCEC

ZHAO Qi, LIU Huimin, HU Haifeng*

2015, 46(4): 378-380.

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A pressurized capillary electrochromatogrphy (pCEC) method was established for the determination of antifungal antibiotic micafungin. An EP-100-20/45-3-C18-BP reverse phase capillary chromatographic column was used, with the mobile phase of acetonitrile∶2.5 mmol/L phosphate buffer (pH 6.5) (35∶65), at the detection wavelength of 270 nm and separation voltage of 15 kV. It was linear in the range of 62.5 - 800 μg/ml. The average recovery was 99.6％, with RSD of 1.47％.

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Quantitative Analysis of Nine Active Constituents in Yizhi Capsule by UPLC-MS/MS

LI Xuena1, OUYANG Yue2,4, LIU Xiaoyan2,3, LI Xiangjun1,2*, LIU Minyan2

2015, 46(4): 381-383.

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An UPLC-MS/MS method was established for the simultaneous determination of nine active compounds in Yizhi capsule, including protocatechuic aldehyde, chlorogenic acid, syringin, 4-dicaffeoylquinic acid, echinacoside, verbascoside, rosmarinic acid, salvianolic acid B and salvianolic acid A. A Waters Acquity UPLC BEH C18 column was used with the mobile phase of acetonitrile∶0.1％ aqueous formic acid by gradient elution. The monitoring of all analytes was achieved under the negative ionization mode. All calibration curves showed good linearity within the test ranges, and the average recoveries were in the range of 97.7％ - 101.1％, with RSDs less than 3％.

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Determination of Formaldehyde in Metered Dose Inhaler by HPLC

LIU Yuan1, YE Xiaoxia2, JIN Fang3, YANG Yongjian2*

2015, 46(4): 384.

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An HPLC method was established for the determination of formaldehyde in pressurized metered dose inhalers (pMDIs) by pre-column derivation using dinitrophenylhydrazone (DNPH). A Welch Ultimate XB-C18 column was used, with the mobile phase of acetonitrile∶water (50∶50), at the detection wavelength of 355 nm. It was linear in the range of 0.1 - 20 μg/ml. The low limit of detection was 12.5 ng/ml, and the low limit of quantity was 50 ng/ml. The recovery of formaldehyde was 102.3％, with RSD of 1.34％.

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Determination of 6-Methoxy-7-benzyloxyquinazolin-4-one and Its Related Substances by HPLC

SHAN Cuihong1, ZHANG Taisong2

2015, 46(4): 388-390.

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An HPLC method was established for the determination of vandetanib synthetic material, 6-methoxy- 7-benzyloxyquinazolin-4-one (1) and its related substances. An Agela C18 column was used, with the mobile phase of 0.01 mol/L potassium dihydrogen phosphate solution(adjusted to pH 3.0 with phosphoric acid)∶methanol by gradient elution, at the detection wavelength of 240 nm. Its low limit of detection was 11 ng. The key intermediate and degradation products generated by destructive experiments could be separated effectively with 1.

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Determination of Related Substances in (S)-Pantoprazole Sodium Enteric-coated Tablets by HPLC

SHEN Weiyang1, DOU Xiaorui1, CHEN Lingfang1, SHEN Puyi2, SHI Rui2

2015, 46(4): 391-395.

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An HPLC method was established for the determination of related substances in (S)-pantoprazole sodium (1) enteric-coated tablets, including related substances A, B, C, D&F and E. A C18 column was used, with the mobile phase of ammonium buffer (ammonium acetate 3.85 g and tetrabutylammonium hydrogen sulfate 1.1 g in 1 L water, and adjusted to pH 7.9 by ammonium hydroxide)∶acetonitrile (65∶35), at the detection wavelength of 290 nm. 1 was separated well from the above related substances and degradation products. The calibration curves for related substances A, B, C, D&F and E were linear in the ranges of 0.080 - 2.400, 0.050 - 1.500, 0.033 - 1.000, 0.080 - 2.400 and 0.033 - 1.000 μg/ml, respectively. Their average recoveries were 100.2％, 101.6％, 99.0％, 100.2％ and 104.0％, with RSDs of 1.5％, 0.64％, 3.0％, 0.91％ and 1.1％, respectively. In addition, an HPLC method using Chiralcel OJ-RH column was established for the effective determination of (R)-pantoprazole sodium (2) in 1 enteric-coated tablets.

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Research Progress of Drug Nanocrystals for Oral Delivery

TU Liangxing, HU Kaili, FENG Jianfang*

2015, 46(4): 396-403.

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Poor water-solubility is becoming a major hurdle for water-insoluble drug to reach the market. The preparation for nanocrystals has the advantages of simplicity of production, high drug loading and easy to scale-up, etc. The water-insoluble drug can be broken into samller particles easily with this technology, so that the saturation solubility and dissolution velocity as well as the oral bioavailability are improved. How to produce nanoscale particles and enhance
stability of the nanocrystals are the key point and difficulty in this field at present. This paper will summarize and make comments on these two aspects.

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Surface Modification Strategies of Nanocarriers with Antibody as Targeting Agents

LIU Shuai, LIU Jie, YANG Yani, HE Jun*

2015, 46(4): 404-411.

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In recent years, there have been many active targeted nanocarriers surface modified by antibodies occurring to overcome the limitations of nanocarriers. Most commonly used antibody surface modification methods are reviewed in this paper. It mainly includes non-covalent coupling methods based on adsorption effect and covalent coupling methods with or without coupling agent. Then this article highlights the differences between these methods, including their advantages and disadvantages. Next, surface modification methods of nanocarriers and several common antibodies are introduced. Finally, present limitations and future challenges are discussed.

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Present Situation and Development Strategy of Paediatric Formulations

WANG Wei, CHEN Zhongya, CHAI Xuyu, WANG Likui, TAO Tao*

2015, 46(4): 412-417.

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The use of medicines in children is at dangerous status due to the lack of drug safety information and paediatric formulations. While briefly introduces the reason of the deficiency and the legislative status of drug for children, this review summarizes and analyzes the strategy of development of paediatric formulations according to the features of commercial medicines for children and present research focus.

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Applications of Crispr/Cas9 in Gene Disruption of CHO Cells

SUN Tao, WANG Jiaxian, LI Chaodong, ZHU Jianwei*

2015, 46(4): 418-421.

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Crispr/Cas9 is a newly developed gene editing technology. It has been widely applied to gene manipulation in various species such as human, animal, plant cells, etc. Based on recent publications and the researches in our laboratory, we provide a basic experimental protocol for conducting Crispr/Cas9 in CHO cells. We also give examples on disruption of genes associated with protein expression in CHO cells and explanations on some issues that researchers
might encounter during implementation of this protocol. It is concluded that this novel gene editing tool is applicable in engineering of CHO cells to create an ideal host for biopharmaceuticals development and production.

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Graphical Synthetic Routes of Afatinib

LI Qingqing, ZHANG Qingwen*

2015, 46(4): 422-424.

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Graphical Synthetic Routes of Enzastaurin

LIU Longfei, LIU Xinyong*

2015, 46(4): 425-427.

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