Chinese Journal of Pharmaceuticals

Select

Synthesis of Tedizolid Phosphate

ZENG Huang1,2, ZHANG Zixue1,2, LIU Yu1,2, PAN Deng1,2, WANG Guan1,2*

2016, 47(12): 1491. https://doi.org/10.16522/j.cnki.cjph.2016.12.001

Abstract ( ) Download PDF ( )

Knowledge map

Save

5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine(7) was prepared from 5-bromo-2-pyridinecarbonitrile(5) by cyclization and methylation. Meanwhile 3-fluoro-4-bromoaniline(2) reacted with carbobenzoxy chloride following by coupling with triisopropyl borate to give 4-(benzyloxycarbonylamino)-2-fluorophenyl boronic acid(4). Then, 4 was subjected to Suzuki coupling with 7, followed by cyclization to afford (R)-3-[4-[2-(2-methyltetrazol-5-yl)pyridine-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(9), the latter was subjected to esterification with POCl3, salt formation and then acidification to give tedizolid phosphate with an overall yield of 19％ (based on 5).

Select

Synthesis of Barnidipine Hydrochloride

WANG Jianta, LI Wei, LI Shumin, ZHANG Jiquan, TANG Lei*

2016, 47(12): 1496. https://doi.org/10.16522/j.cnki.cjph.2016.12.002

Abstract ( ) Download PDF ( )

Knowledge map

Save

(R)-2,6-Dimethyl-4-(3-nitrophenyl)-5-(methoxycarbonyl)-1,4-dihydropyridine-3-carboxylic acid, a key intermediate of barnidipine, was synthesized from 3-hydroxylpropionitrile, 2,2,6-trimethyl-4H-1,3-dioxin-4-one, 3-nitrobenzaldehyde and methyl 3-aminobut-2-enoate via Hantzsch condensation, selective hydrolysis
and resolution with quinidine. Another crucial intermediate (S)-1-benzyl-3-pyrrolidinol was obtained from trans-4-hydroxy-L-proline via decarboxylation, benzylation, Mitsunobu reaction and hydrolysis. Then the two intermediates were subjected to a condensation to afford the title product with an overall yield of 10％, a purity of 99.3％ and ee value of 99.45％.

Select

Synthesis of Innovative Thrombin Inhibitor Pyrimitroban

LIU Li, XU Kui

2016, 47(12): 1500. https://doi.org/10.16522/j.cnki.cjph.2016.12.003

Abstract ( ) Download PDF ( )

Knowledge map

Save

Ethyl acetate reacted with ethyl formate in the presence of sodium methoxide to give ethyl 2-hydroxylacrylate sodium, after a cyclization with argatroban, (2R,4R)-4-methyl-1-[(2S)-2-[(3-methyl-1,2,3,4-tetrahydroquinoline)-8-sulfonamido]-5-[(6-oxo-1,6-dihydropyrimidin-2-yl)amino]pentanoyl]piperidine-2-carboxylic acid was obtained, the latter was reacted with 1-acetoxy-1-ethyl bromide via esterification to afford the innovative thrombin inhibitor candidate drug pyrimitroban with an overall yield of 65％(based on argatroban).

Select

Synthesis of Two Metabolites of Ticagrelor

ZHOU Fugang, DAO Shuo, MA Yuxiu, LIU Yang, LIU Chunlei

2016, 47(12): 1503. https://doi.org/10.16522/j.cnki.cjph.2016.12.004

Abstract ( ) Download PDF ( )

Knowledge map

Save

To perform the quality control of ticagrelor and study the metabolic pathway of the drug in vivo, two metabolites of ticagrelor, AR-C133913XX[(1S,2S,3R,5S)-3-[7-amino-5-propylthio-3H-1,2,3-triazolo [4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol] and AR-C124910XX[(1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamino]-5-propylthio-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol] were prepared. Their structures were confirmed by NMR and ESI-MS.

Select

Synthesis and Anti-tumor Effect of PEG-Epothilone B

WANG Haibo, ZHANG Wei, CHEN Tongtong, CAI Zhengjiang, ZHU Tianmin

2016, 47(12): 1507. https://doi.org/10.16522/j.cnki.cjph.2016.12.005

Abstract ( ) Download PDF ( )

Knowledge map

Save

Epothilone B was modified by the polyethylene glycol derivatives with different molecular weights (PEG-NH2 or PEG-SH) to give eleven novel Epothilone B derivatives. The structures were confirmed by NMR and MS. The inhibitory effectes of the target compounds on the human hepatoma cells HepG2 and human primary hepatocytes were detected by MTT assay. The results suggested that, the target compounds exhibited good inhibition on HepG2 celllines, lower toxicity on human primary hepatocytes, and better solubility in water.

Select

Synthesis as Well as Determination of the Antimicrobial Activities and Haemolytic Activities of Halogen-contained Cationic Antimicrobial Pepti

TANG Hanqing1,2, LI Yingchun3, DONG Yuanzhen2, WANG Yan2, FENG Jun2*

2016, 47(12): 1513. https://doi.org/10.16522/j.cnki.cjph.2016.12.006

Abstract ( ) Download PDF ( )

Knowledge map

Save

Ten pieces of novel cationic antimicrobial peptides (2—11) were designed based on the antimicrobial peptide F-K-K-L-L-K-K-L-R-K-F-NH2 (1) by replacing phenylalanine with halogen-contained phenylalanine and cyclizing with sulfide bond. These antimicrobial peptides were synthesized with solid phase method, cyclized under alkaline conditions and purified by RP-HPLC. Their antimicrobial activities were determined by the broth microlilution procedure, and haemolytic activities were determined by using sterile defidrinated sheep blood. The antimicrobial activity of 10 was higher than that of 1, whose MIC against Escherichia coli was 1 μg/ml, and the antimicrobial activity was four times as much as that of 1. Its MIC against Acinetobacter baumanii was 4 μg/ml, and the antimicrobial activity was about eight times the activity of 1.

Select

Production of Fidaxomicin by Strain Breeding and Optimization of Its Fermentation Process

YANG Zhenjiang, WU Yuanjie, ZHANG Ke, CHEN Shaoxin*

2016, 47(12): 1519. https://doi.org/10.16522/j.cnki.cjph.2016.12.007

Abstract ( ) Download PDF ( )

Knowledge map

Save

Dactylosporangium aurantiacum-18, a fidaxomicin producing strain, was mutated with UV and NTG and then screened in the plate with streptomycin. As a result, a mutant D. aurantiacum N-61 was obtained with the fidaxomicin titer of 1 141 mg/L in the shake flask. Furthermore, the fermentation process was investigated by optimizing medium composition in a 5 L fermentator. In the medium (g/L) containing lactose 75.0, glycerol 20.0, cottonseed powder 10.0, dry yeast 10.0, CaCO3 4.0, and MgSO4·7H2O 2.0, the yield of fidaxomicin could reach 3 343 mg/L.

Select

Preparation and in vitro-in vivo Evaluation of Pramipexole Dihydrochloride Diphase Sustained-release Capsules

ZHANG Lifeng, PAN Yusheng, YU Yue

2016, 47(12): 1522. https://doi.org/10.16522/j.cnki.cjph.2016.12.008

Abstract ( ) Download PDF ( )

Knowledge map

Save

The pramipexole dihydrochloride diphase sustained-release capsules were prepared by mixing two kinds of membrane-moderated pellets, which were coated with different layers by bottom spray fluid bed coating technology at certain proportion to obtain rapid- and sustained-release characteristics. The formulation was optimized by single factor experiment and central composite design-response surface methodology with the release similarity between self-made capsules and reference listed drug (Siforl) in pH 6.8 phosphate buffer (PBS). The results of validation test showed that the drug release behaviors of both preparations were similar in PBS or in pH 1.2 hydrochloric acid for first 1 or 2 h, followed by PBS, those similarity factor (f2) values were all above 50. In vivo pharmacokinetics of the self-made capsule and Siforl were investigated with Beagle dog model. The drug concentration in plasma was determined by LC-MS/MS, and pharmacokinetic parameters of these two formulations were calculated by non-compartmental model. The results showed that the self-made diphase phase sustainedrelease capsules and Siforl of cmax (1 118.3±121.9) and (1 108.6±183.2) pg/ml, AUC0→∞ (18 227.5±1 870.8) and (16 321.8±2 327.5)pg·ml-1·h, suggesting a similarity of these two preparations.

Select

Preparation of Aceclofenac-carboxylated Multiwalled Carbon Nanotubes Electro-responsive Transdermal Drug Delivery System

CUI Minghan1, DENG Yali2*

2016, 47(12): 1530. https://doi.org/10.16522/j.cnki.cjph.2016.12.009

Abstract ( ) Download PDF ( )

Knowledge map

Save

Carboxylated multiwalled carbon nanotubes were prepared by ultrasonic method or milling method and characterized by Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA) and Raman spectroscopy. The effects of different adsorption methods (oscillation method, frozen milling method and ultrasonic method) on aceclofenac adsorption on the prepared carbon nanotubes were investigated. The results showed that the frozen milling method had the best effect. The transdermal behaviors of aceclofenac from the gels loaded with the bulk drug or the complex of aceclofenac-carboxylated multi-walled carbon nanotubes were investigated by Franz diffusion cell method with dialysis membrane and excised mouse skin as barriers. The changes of transdermal rate after combining with
iontophoresis were also investigated. The results showed that the transdermal rate of the gels loaded with the complex was improved but the lag time was slightly prolonged. After combining with iontophoresis with current density of 0.2, 0.3 and 0.5 mA/cm2, the transdermal rates of the complex gels were 3.73, 6.21 and 8.72 μg·cm-2·h-1 during the rapid-release phase (1—4 h). It indicated that carboxylated multi-walled carbon nanotubes could be used as the electro-responsive transdermal drug delivery system due to its good electrical conductivity property.

Select

Blending Process of Solifenacin Succinate Tablets by Direct Compressio

CHEN Xian, LOU Chao, GONG Junqiang, JIN Xiufang, CHEN Yiqun

2016, 47(12): 1542. https://doi.org/10.16522/j.cnki.cjph.2016.12.011

Abstract ( ) Download PDF ( )

Knowledge map

Save

The small-dose solifenacin succinate tablets were prepared by direct compression. The pretreatment methods for bulk drug and excipients and blending process parameters were optimized with the content uniformity of the mixed powder as the index by single factor test and orthogonal design. According to the results, particle size of the bulk drug was confirmed as the most significant factor affecting the blending uniformity. The optimal blending process was as follows: the particle size d(0.9) should be controlled to below 120 μm; then the bulk drug was pre-blended with hypromellose, followed by adding StarLac passed through a 60 mesh sieve and mixing at blending frequency of 24 Hz for 3 min; finally magnesium stearate was blended with the mixture for 3 min before tabletting. Three batches of solifenacin
succinate (5 mg) tablets were prepared in a batch production of 10 000 tablets to investigate the segregation of the blended mixture and the content uniformity of the tablets at the different sampling time points during compression. The results showed that this blending process could ensure the materials with good homogeneity, and there was no observation of segregation in the process of tablet compression.

Select

Determination of Specific Surface Area of Magnesium Stearate by Static Volumetric Method Based on BET Adsorption Theory

WANG Miao, WU Weicong, WANG Caimei

2016, 47(12): 1546. https://doi.org/10.16522/j.cnki.cjph.2016.12.012

Abstract ( ) Download PDF ( )

Knowledge map

Save

The specific surface area of magnesium stearate was determined by static volumetric method based on BET adsorption theory with nitrogen as the adsorbate. During manufacture, processing and storage, some gases or vapours could be adsorbed by magnesium stearate, which caused fluctuations of determination results. As a result, the samples should be pretreated by heating and degassing before determination. The effects of pretreatment conditions, such as heating temperature, sampling amount and evacuation time on the determination results of specific surface area were investigated. The results showed that the optimal conditions were as follows: 3 g of magnesium stearate was heated at 75 ℃ and evacuated for 2 h. The method had good reproducibility and durability. The specific surface areas of three batches of magnesium stearate were 3.743, 4.014 and 3.857 m2/g with RSDs of 2.9％, 3.0％ and 2.5％(n=5), respectively.

Select

Determination of Nebivolol in Beagle Dog Plasma by LC-MS/MS and Its Pharmacokinetics

ZOU Lingyan1,2, GONG Huan3, ZHOU Zhen3, GE Qinghua3, LU Weiyue1*

2016, 47(12): 1549. https://doi.org/10.16522/j.cnki.cjph.2016.12.013

Abstract ( ) Download PDF ( )

Knowledge map

Save

A LC-MS/MS method was established for the determination of nebivolol in Beagle dog plasma. The detections of the analyte and the internal standard (diphenhydramine) were conducted under positive ionization mode with an electrospray ionization (ESI) interface. A multiple reaction monitoring mode was optimized with the transitions of m/z 406.2→m/z 151.0 (nebivolol) and m/z 256.1→m/z 167.0 (diphenhydramine). The calibration curve was linear in the concentration range of 40—10 000 pg/ml. The method recoveries were 85.72％—108.8％, with RSDs less than 13.2％. A single oral dose of nebivolol hydrochloride (5 mg) was administered to six Beagle dogs respectively. The main pharmacokinetic parameters under fast and fed conditions were as follows: cmax(2 897±712) and (3 714±1 209) pg/ml, t1/2(2.63±0.56) and (3.52±1.24) h, AUC0→t(9 710±2 643)and (11 892±3 547)pg·h·ml-1, AUC0→∞ (9 922±2 716) and (12 329±3 330)pg·h·ml-1. The outcome indicated that food partly promoted the absorption of nebivolol.

Select

Proficiency-testing of Pharmaceutical Nitrogen Determination

DING Wenjing, SHEN Yi*, CHEN Zhukang, SUN Mengyu, LU Ming

2016, 47(12): 1554. https://doi.org/10.16522/j.cnki.cjph.2016.12.014

Abstract ( ) Download PDF ( )

Knowledge map

Save

According to the protocol of International Union of Pure and Applied Chemistry (IUPAC) and procedure of China National Accreditation Service for Conformity Assessment (CNAS), the pharmaceutical nitrogen determination capacity of the laboratories which participated in the proficiency-testing was evaluated, and some technical analyses and advices were provided. The one-way ANOVA was used to evaluate the homogeneity of the proficiencytesting samples (glycine), whose stability was confirmed with t-test. All results conformed to the requirements. The median value and the normalized interquartile range (NIQR) of robust statistical method was adopted and Z-scores were used to evaluate the results from each laboratory. Among 84 laboratories which reported their results, 76 laboratories'
results were ''satisfactory'', four were ''questionable'', and four were ''unsatisfied''. The in-depth comprehensive technical analysis could help the laboratories to find out the causes, take measures, and improve the detection capability.

Select

Identification and Out-of-specification Survey for Contaminated Isolates from Sterility Test

YANG Yan, SUN Mengjia, JIANG Bo, LIU Hao, LIU Dongling

2016, 47(12): 1559. https://doi.org/10.16522/j.cnki.cjph.2016.12.015

Abstract ( ) Download PDF ( )

Knowledge map

Save

Two contaminated isolates from sterilized drug were identified by VITEK 2 Compact system, 16S ribosomal RNA sequencing and Ribotyping analysis, and an out-of-specification (OOS) survey was systematically analyzed referencing the latest version of Good Manufacture Practice (GMP) of drugs. Both of the isolates were
identified as Burkholderia cepacia with high homology when using biochemical and molecular biological identification methods. According to the collected environmental monitoring bacteria library, it was showed that the Burkholderia cepacia was definitely originated from the drug itself other than from the experimental process.

Select

Determination of Seven Components in Shenling Jianpiwei Granules by HPLC with Wavelength-switching

LIU Yan, LIU Zhiyang

2016, 47(12): 1564. https://doi.org/10.16522/j.cnki.cjph.2016.12.016

Abstract ( ) Download PDF ( )

Knowledge map

Save

An HPLC combined with wavelength-switching method was established for the determination of psoralen, 8-methoxypsoralen, bergapten, imperatorin, atractylenolide Ⅲ, atractylenolideⅠand atractylenolide Ⅱ in Shenling Jianpiwei granules. A Phenomenex ODS C18 column was used, with the mobile phase of acetonitrile∶0.1％
phosphoric acid by gradient elution. The detection wavelength was switched from 310 nm for psoralen, 8-methoxypsoralen, bergapten and imperatorin, to 220 nm for atractylenolide Ⅲ and atractylenolideⅠ, and then to 276 nm for atracylenolide Ⅱ, respectively. The calibration curves between the concentrations and peak areas were linear for the 7 components in the measurement ranges. Their average recoveries were 98.5％, 97.6％, 97.2％, 99.5％, 96.6％, 99.6％ and 98.4％, with RSDs of 0.93％, 1.11％, 1.26％, 1.54％, 0.65％, 1.18％ and 1.43％, respectively.

Select

Determination of Related Substances of Pidotimod Oral Solution by HPLC

MAO Ke, XU Bin, KONG Rong, CHEN Ning, LU Dingqiang,

2016, 47(12): 1568. https://doi.org/10.16522/j.cnki.cjph.2016.12.017

Abstract ( ) Download PDF ( )

Knowledge map

Save

Four determination conditions of HPLC were established based on the polarities and the stereo structures of nine specific related substances and degradation products of pidotimod oral solution. The results showed that the specific related substances and degradation products could be fully separated from pidotimod, other impurities and the excipients under the corresponding chromatographic conditions. The recoveries were 94.1％—102.6％, with RSDs of 0.64％—2.11％.

Select

Determination of the Related Substances in Ezetimibe Tablets by HPLC

LIU Qingliang, ZHAO Pihua, YANG Yan, WANG Wenf

2016, 47(12): 1573. https://doi.org/10.16522/j.cnki.cjph.2016.12.018

Abstract ( ) Download PDF ( )

Knowledge map

Save

An HPLC method was established for the determination of related substances in ezetimibe (1) tablets. A Hypersil Gold C8 column was used, with the mobile phase of methanol∶0.05％ TFA (50∶50), at the detection wavelength of 232 nm. The resolution between 1 and its diastereoisomer [6, (3R,4S)-1-(4-fluorophenyl)-3-[(3R)-3-(4-
fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one] was 1.8. It was linear for 1, the related substance 2, diastereoisomer 6 and the related substance 3 in the ranges of 12—820, 9.6—640, 12—780 and 12—780 ng/ml, respectively. Their relative correction factors were 0.8, 1.0 and 1.2. Their average recoveries were 102.5％, 104.4％ and 97.9％, with RSDs of 1.3％, 1.7％ and 2.4％, respectively.

Select

Determination of Butylated Hydroxytoluene in Rivastigmine Transdermal Patch by H

ZHANG Junyun, ZHANG Furong, WU Yubo, LUO Huafei, WANG Hao*

2016, 47(12): 1578. https://doi.org/10.16522/j.cnki.cjph.2016.12.019

Abstract ( ) Download PDF ( )

Knowledge map

Save

An HPLC method was established for the determination of 2,6-ditertbutyl-4-methylphenol (butylated hydroxytoluene, BHT) in rivastigmine transdermal patch. BHT was extracted from the patches by ultrasound with an ice water bath. An InertSustain C18 column was used, with the mobile phase of methanol∶20 mmol/L ammonium acetate buffer (80∶20), at the detection wavelength of 278 nm. It was linear for BHT in the range of 2.25—13.50 μg/ml. The limit of quantification was 90 ng/ml. The average recovery was 100.9％, with RSD of 3.17％.

Select

The Application and Development of Dose Counters in Respiratory Medication

SHAO Qi, JING Zhixin, HONG Chen, SUN Ningyun, WEN Bin*

2016, 47(12): 1582. https://doi.org/10.16522/j.cnki.cjph.2016.12.020

Abstract ( ) Download PDF ( )

Knowledge map

Save

Inhalation preparation is the choice drug of respiratory disease. Because the development of inhalation product started late, the whole market was already controlled by foreign companies. The development of formulation research, drug delivery device and dose counter also lags behind developed Europe and America. In this
article, the dose counter, mechanical or electronic, integrated to traditional inhalation device was introduced. By visual and auditory, patients can replace their finished drug when the dose counter remind them to do so. The use of dose counter not only enhance the experience of patients, but also reduce the probability of emergency when without drug.

Select

Application of Fused Deposition Molding to Pharmaceutics

CHAI Xuyu, CHAI Hongyu, YANG Jingjing, TAO Tao

2016, 47(12): 1587. https://doi.org/10.16522/j.cnki.cjph.2016.12.021

Abstract ( ) Download PDF ( )

Knowledge map

Save

The recent FDA approval of the first three dimensional (3D) printed tablets, Spritam®(levetiracetam), opens a new chapter in 3D printing for pharmaceutical applications. 3D printing is a layer-by-layer process to form 3D objects from digital designs using plastic and metal materials. It can be divided into more than ten different categories in term of raw materials and binding principles. Among them, fused deposition modeling (FDM) is the most widely used method nowadays. Based on a holistic perspective of the principles, drug-loading methods and pharmaceutical applications, this paper summarizes the advantages and disadvantages of FDM. Finally, the future development of FDM is prospected.

Select

Research Progress on Lipid-based Nanoscale Formulations for Ophthalmic Application

YANG Long, CHEN Lingyun, WEI Gang

2016, 47(12): 1592. https://doi.org/10.16522/j.cnki.cjph.2016.12.022

Abstract ( ) Download PDF ( )

Knowledge map

Save

Lipid-based nanoscale formulations, including nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers and liposomes, have made considerable progress in ophthalmic application in recent years. The purpose of this paper is to give a brief introduction of the lipid-based nanoscale formulations via summarizing
the latest literature. The characteristic and ophthalmic application of this category of formulations were elaborated. Furthermore, formulation, preparation and evaluation of the lipid-based nanoscale drug delivery systems have also been reviewed.

Select

Graphical Synthetic Routes of Brivaracetam

YU Chenggong, WU Jingde

2016, 47(12): 1600. https://doi.org/10.16522/j.cnki.cjph.2016.12.023

Abstract ( ) Download PDF ( )

Knowledge map

Save

Select

Pharmaceutical Management & Information

Critical Consideration of Quality Control in Low-dose Solid Pharmaceutical Preparation

ZHANG Junlin, HE Wu

2016, 47(12): 1604. https://doi.org/10.16522/j.cnki.cjph.2016.12.024