Chinese Journal of Pharmaceuticals

Select

Synthesis of the Anticoagulant Drug Apixaban

ZHANG Wei, WANG Xue, CHANG Xinglong, LI Yingguang, XIAO Wei*

2016, 47(10): 1216. https://doi.org/10.16522/j.cnki.cjph.2016.10.001

Abstract ( ) Download PDF ( )

Knowledge map

Save

The key intermediate 3-morpholino-5,6-dihydropyridin-2(1H)-one was obtained via dichlorination with 2-piperidone and condensation-elimination, then the intermediate reacted with 1-(4-iodophenyl)piperidin-2-one via nucleophilic substitution, 1,3-dipolar cycloaddition and aminolysis to give the anticoagulant drug apixaban with an overall yield of 30.2％(based on 2-piperidone)and a purity of 99.8％. The process was stable and easy to scale up industrially.
Key Words:

Select

Synthesis of Pimavanserin

HUO Wenge, ZHANG Hongyu, ZHU Yunjing, ZHANG Yuecheng, ZHAO Jiquan

2016, 47(10): 1219. https://doi.org/10.16522/j.cnki.cjph.2016.10.002

Abstract ( ) Download PDF ( )

Knowledge map

Save

Methyl acrylate reacted with methylamine via Michael-addition, followed by Dieckmanncyclization and decarboxylation to give N-methyl-4-piperidone, after reacting with 4-fluorobenzyl amine via reductive amination, (4-fluorobenzyl)-(1-methylpiperidin-4-yl)amine(10) was obtained. Meanwhile, 4-isobutoxyphenylacetic acid was synthesized from 4-hydroxyphenylacetic acid via esterification, electrophilic substitution and hydrolysis, then it was subjected to a Curtius rearrangement in the presence of triethylamine with acetonitrile as solvent to afford 1-isobutoxy-4-(isocyanatomethyl)benzene(6). Finally, 6 without purification, reacted with 10 via a condensation to give pimavanserin, which was purified by salt formation and recrystalization, with an overall yield of 52.5％(based on methyl 4-hydroxyphenylacetate). This new synthetic process has the advantages of low cost, convenient operation, which is suitable for industrialization.

Select

Improved Synthetic Process of Conivaptan Hydrochloride

QIU Chuanju

2016, 47(10): 1223. https://doi.org/10.16522/j.cnki.cjph.2016.10.003

Abstract ( ) Download PDF ( )

Knowledge map

Save

Methyl 2-[(4-methylphenyl)sulfonamido]benzoate(6) reacted with 4-chlorobutyronitrile via N-alkylation in the presence of the phase transfer catalyst PEG-400 and mixed bases(KOH+K2CO3) to afford methyl 2-[[N-(3-cyanopropyl)-4-methylphenyl]sulfonamido]benzoate, after condensation, cyclization, decyanation,
bromination, ring-closing with acetamidine hydrochloride and then removing the sulfonyl-group, 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine(5) was obtained. Meanwhile, [1,1'-biphenyl]-2-carboxylic acid reacted with 4-aminobenzoic acid via acid-amine condensation under the action of N,N'-carbonyldiimidazole(CDI) to give 4-[(1,1'-biphenyl)-2-yl-carboxamido]benzoic acid, after reacting with 5 via acid-amine condensation reaction and
salification with hydrochloric acid, conivaptan hydrochloride was obtained with an overall yield of 37.6％(based on 6).

Select

Synthesis of Emtricitabine

RAN Dongsheng, WANG Sumei, LI Jingu

2016, 47(10): 1226. https://doi.org/10.16522/j.cnki.cjph.2016.10.004

Abstract ( ) Download PDF ( )

Knowledge map

Save

(2R,5S)-5-(4-Amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl)-1,3-oxathiolane-2-carboxylic acid (1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl ester(6) was reduced with sodium borohydride, removed excess sodium borohydride with hydrochloric acid, pressure distillation to remove most of the ethanol, washed with toluene to remove the byproducts menthol, the benzoic acid was added for 2 hours, and then filtered to give the new compound benzoic acid emtricitabine. Benzoic acid emtricitabine mixed with triethylamine and ethyl acetate, stirred at 15～30 ℃ for 4 h, followed by filtration to give high purity emtricitabine with an overall yield of 72.2％(based on 6).

Select

Synthesis of Isomers of the Key Intermediate of Fondaparinux Sodium

GAN Hao, LI Zhenzhong, HAN Jian, ZHOU Xize, HOU Wenfeng

2016, 47(10): 1229. https://doi.org/10.16522/j.cnki.cjph.2016.10.005

Abstract ( ) Download PDF ( )

Knowledge map

Save

To conduct the quality control of fondaparinux sodium, two isomers(1a, 1b)of the fully protected pentasaccharide(1) which was the key intermediate of fondaparinux sodium were synthesized. The disaccharide which is composed of glucuronic acid and levoglucosan was used as the starting material to give the corresponding receptor by the removal of the chloracetyl group. The disaccharide receptor was coupled with a monosaccharide donor to give a
trisaccharide. After ring-opening, ammonolysis and activization, the trisaccharide donor was obtained, which was coupled with the reducing end of the disaccharide receptor to provide 1(the configuration of glycosidic bond is α-β-α-α-α in sequence)and two isomers 1a(β-β-α-α-α ) and 1b(α-α-α-α-α). The chemical structures were confirmed by 1H NMR and ESI-MS.

Select

Synthesis of Methyl 6-O-benzoyl-3-O-benzyl-2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside

CUI Xing, WANG Wei, WANG Jianta, TANG Lei

2016, 47(10): 1235. https://doi.org/10.16522/j.cnki.cjph.2016.10.006

Abstract ( ) Download PDF ( )

Knowledge map

Save

A solution of N-acetyl-D-glucosamine in methanol was heated with concentrated sulfuric acid to give methyl 2-amino-2-deoxy-α-D-glucopyranoside, followed by reacting with benzyl chloroformate to afford methyl 2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside, the latter was protected by 2,2-dimethoxypropane and benzyl-group in sequence, and then subjected to deprotection to give methyl 3-O-benzyl-2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside, after protecting the C6-hydroxy with benzoyl-group, the title compound, served as the intermediate of fondaparinux sodium, was obtained with a total yield of 52.3％.This route is simple and easy to operate, potential for industrial production.

Select

Synthesis of 2-(3-Hydroxy-1-adamantane)-2-oxoacetic acid

GAN Run, ZHANG Ming, LI Jie, JIANG Xue, HU Xiangnan

2016, 47(10): 1239. https://doi.org/10.16522/j.cnki.cjph.2016.10.007

Abstract ( ) Download PDF ( )

Knowledge map

Save

1-Adamantanecarboxylic acid was oxidized by a mixture of sulfuric acid and nitric acid to afford 3-hydroxy-1-adamantanecarboxylic acid, after using a one-pot method, including acylation, substitution by diethyl malonate, decarboxylation and hydroxylation reaction, 3-hydroxy-1-acetyladamantane was obtained. The latter was subjected to oxidation reaction with potassium permanganate to give the key intermediate of saxagliptin: 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid with an overall yield of about 61％(based on 1-adamantanecarboxylic acid). The improved route has several advantages, such as common and inexpensive reagents, mild reaction conditions, simple operations, etc.

Select

Synthesis of 3'-Amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid

LI Yanan, PAN Helin, YU Yankun, LONG Zhongzhu, CAI Shuihong

2016, 47(10): 1242. https://doi.org/10.16522/j.cnki.cjph.2016.10.008

Abstract ( ) Download PDF ( )

Knowledge map

Save

2-Amino-6-bromophenol was prepared by reduction of 2-bromo-6-nitrophenol with Raney nickel and hydrogen, then it was cyclized with di(1H-imidazol-1-yl)methanone to give 7-bromo-1,3-benzoxazol-2(3H)-one, the latter was converted to 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)benzoic acid via a Suzuki coupling reaction, after hydrolyzation with aqueous of sodium hydroxide, 3'-amino-2'-hydroxy-3-carboxylic acid, the key intermediate of eltrombopag was obtained with an overall yield of about 69％. This novel process has the advantages of short synthetic rout and lower cost with good potential for industrial application.

Select

Optimization of Seed Cultivation Conditions of Industrial Erythromycin Producing Strain

CHEN Chongchong, YANG Qi, CHU Ju*

2016, 47(10): 1245. https://doi.org/10.16522/j.cnki.cjph.2016.10.009

Abstract ( ) Download PDF ( )

Knowledge map

Save

An orthogonal design and a response surface methodology were used to optimize the seed cultivation conditions, which was evaluated by mycelium concentration, amylase activity and viscosity. The optimized medium was determined as follows: soybean meal 3.0％, (NH4)2SO4 0.15％, corn steep liquor 0.57％, starch 1.81％, dextrin 2.37％, glucose 1.0％, soybean oil 1.0％, NaCl 0.5％, CaCO3 0.4％, and antifoam 0.02％. The higher quality seed was obtained using the optimized medium, and then was inoculated into a 50 L fermenter. As a result, the erythromycin A concentration was increased from 8 057 μg/ml to 8 563 μg/ml, a 6.0％ increase compared with the original seed.

Select

Biosynthesis of Ribavirin by Immobilized Recombinant E.coli Cells

WANG Fasong, CAO Huajie, XU Qingyang, CHEN Ning, XIE Xixian

2016, 47(10): 1251. https://doi.org/10.16522/j.cnki.cjph.2016.10.010

Abstract ( ) Download PDF ( )

Knowledge map

Save

A recombinant Escherichia coli BL21 (pET-His-pupG) was constructed to express purine nucleoside phosphorylase (PNPase) efficiently. In this study, the cell immobilization experiment was conducted using different entrapment agents. The results revealed that the gelatin was the best entrapment agent for cell immobilization. Furthermore, the optimal catalytic conditions for cell immobilization were determinated as follows: the reaction temperature of 55 ℃, the entrapped cell concentration of 200 g/L, the immobilized cell dosage of 20 g/L and the reaction period of 20 h. The synthesis of ribavirin was carried out by immobilized cell with 100 mmol/L guanosine and 100 mmol/L 1,2,4-triazole-3-carboxamide (TCA) as substrates in phosphate buffer (pH 7.6). The immobilized cell was stable with
high enzymatic activity after 8 batches of consecutive reaction.

Select

Studies on the Phenolic Acids from Coreopsis tinctoria

YAN Renjie1, LI Moying1, YU Anwei2, KONG Deyun1, WU Tong1*

2016, 47(10): 1257. https://doi.org/10.16522/j.cnki.cjph.2016.10.011

Abstract ( ) Download PDF ( )

Knowledge map

Save

The phenolic acids constituents of the water extract of the capitula of Coreopsis tinctoria were isolated and purified by many kinds of chromatography. Their structures were identified according to the physical and chemical constants and spectral data as caffeic acid (1), 1-O-caffeoyl-β-D-glucopyranose (2), vanilloyl-β-D-glucopyranose (3), 5-O-caffeoylquinic acid (4), 3-O-caffeoylquinic acid (5), 4-O-caffeoylquinic acid (6), 3,4-di-O-caffeoylquinic (7), 1,5-di-O-caffeoylquinic (8), 3,5-di-O-caffeoylquinic (9), 4,5-di-O-caffeoylquinic (10), and 3,4,5-tri-O-caffeoylquinic acid (11), respectively. Compounds 2—7 and 9—11 were isolated from the genus Coreopsis for the first time.

Select

Influence of Granulation Process on Quality of Pomalidomide Capsules

WU Lingjing1, WANG Xiaofang2, YAN Chao1

2016, 47(10): 1261. https://doi.org/10.16522/j.cnki.cjph.2016.10.012

Abstract ( ) Download PDF ( )

Knowledge map

Save

The pomalidomide granules were prepared by dry granulation and wet granulation. Then these granules were respectively filled into vacant capsules to obtained two kinds of self-made capsules. To evaluate the influence of granulation process on the dissolution similarity and stability of pomalidomide capsules, the similarity
factor (f2) values between the dissolution curves of the self-made products and reference preparation (Pomalyst®) were calculated in four media (water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1 mol/L hydrochloric acid solution). The results showed that the f2 values between the dissolution curves of the self-made capsules filled with the granules prepared by dry granulation and reference preparation in four media were all above 50. However, the drug dissolution behavior from the self-made capsules filled with the granules prepared by wet granulation in water and pH 6.8 phosphate buffer were not similar to reference preparation. The stability test was carried out under the conditions of high temperature (60 ℃), high humidity (relative humidity of 95％) and illumination (4 500 lx) for 10 d. The results showed that the description, related substances and dissolution at 45 min in 0.1 mol/L HCl solution of two kinds of self-made products stored for 10 d had no significant changes compared with original capsules. However, the capsules containing wet granulation products were easily absorb moisture, and showed a new impurity at relative retention time (RRT) 1.10 of about 0.2％.

Select

Preparation and Characterization of Agomelatine Porous Adsorbents by Hot-melt Granulation

YU Hui, PENG Junqing, WANG Honglian, YU Lushan

2016, 47(10): 1265. https://doi.org/10.16522/j.cnki.cjph.2016.10.013

Abstract ( ) Download PDF ( )

Knowledge map

Save

The agomelatine (1) porous adsorbents with crospovidone (PVPP) as carriers, named as 1-PA, were prepared by hot-melt granulation and characterized by power X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The results showed that drug mainly existed in an amorphous form in porous adsorbents. The
solubilities of the bulk drug in pH 2.0 hydrochloric acid solution, pH4.5 acetate buffer and pH6.8 phosphate buffer were 0.27, 0.29 and 0.30 mg/ml, while the solubilities of 1 in 1-PA increased to 0.40, 0.41 and 0.40 mg/ml, respectively. The dissolution rate and extent of 1 from 1-PA were significantly higher than those in physical mixture and bulk drug in pH 2.0 hydrochloric acid solution within initial 30 min. Moreover, the determination results of assay and related substances
showed that almost all of the drug were adsorbed during the preparation process and its related substances were not significantly increased (P>0.05). In addition, the stability of the 1-PA packaged in aluminum bags and stored at 40 ℃ and relative humidity of 75％ for 6 months was investigated. The results showed that the solubility, dissolution, determination results of assay and related substances had no significant changes, suggesting a good physical and chemical stability.

Select

Investigation of Supercritical CO2 Fluid Technology in Preparation of Solid Dispersions of Bifendate

PEI Ying, SHAN Dongyuan, MENG Qing, CHENG Hongbo, LI Tong

2016, 47(10): 1270. https://doi.org/10.16522/j.cnki.cjph.2016.10.014

Abstract ( ) Download PDF ( )

Knowledge map

Save

To improve the in vitro dissolution of bifendate, the solid dispersions (SDs) were prepared by supercritical CO2 fluids technology. The effects of carrier type, weight ratio of drug to carrier, pressure and temperature of supercritical CO2 and reaction time on the dissolution profiles of bifendate from the SDs were investigated by single factor test to optimize the preparation process. The results showed that the rate and extent of dissolution of bifendate from the optimal SDs with fumed silica as carriers and drug-to-carrier ratio of 1∶15 prepared at 45 ℃ and 25 MPa for 2 h were significantly increased compared with the bulk drug. The dissolution at 90 min of bifendate from the optimal SDs was about 80％ in pH 6.85 medium. The results of differential scanning calorimetry and powder X-ray diffractometry showed that bifendate existed in an amorphous state in carriers in SDs with drug-to-carrier ratio of 1∶15.

Select

Transdermal Delivery of Fat-soluble and Water-soluble Drugs Based on Lecithin Reverse Micellar System

QI Xiaodan, WANG Xiaohui, HE Xiaoming

2016, 47(10): 1275. https://doi.org/10.16522/j.cnki.cjph.2016.10.015

Abstract ( ) Download PDF ( )

Knowledge map

Save

The reverse micelles consisting of lecithin and isopropyl myristate (IPM) were prepared and the critical reverse micelle concentration (CRMC) values determined by both spectrometric iodine method and water solubilization method were (2.37±0.15)％ and (1.78±0.34)％. The solubilities of fat-soluble salicylic acid in IPM or
reverse micellar system containing 0.04 or 0.15 g/ml lecithin were 35.86, 47.66 and 65.17 mg/ml, respectively. The transdermal performance of reverse micellar system loaded with fat-soluble salicylic acid or water-soluble sodium salicylate was investigated with excised mouse skin as a barrier. The results showed that with the increasing of salicylic acid content (2, 4 and 8 mg/ml) in reverse micellar system, the cumulative permeation amount and penetration rate of salicylic acid were both increased in a dose-dependent manner. In reverse micellar systems containing different concentrations of lecithin (5％—30％), the penetration coefficients of sodium salicylate were all significantly higher than that of sodium salicylate saturated solution. The penetration coefficients of sodium salicylate exhibited first increase then decrease with an increasing of lecithin, and the maximum value was observed when the concentration of lecithin was 15％ in IPM. Compared with the penetration coefficient of saturated solution group (5.58×10-5 cm/h), the maximum value reached 5.99×10-3 cm/h. It indicated that reverse micellar system had a good role in promoting the transdermal transport for fat-soluble salicylic acid and water-soluble sodium salicylate.

Select

Preparation and Quality Evaluation of Ibuprofen Hollow Type Suppositories for Pediatric Usage

CHEN Penghao, QIAO Jin, WANG Chenxi, SUI Xiaoyu, JIANG Fan

2016, 47(10): 1280. https://doi.org/10.16522/j.cnki.cjph.2016.10.016

Abstract ( ) Download PDF ( )

Knowledge map

Save

The effects of polyethylene glycol (PEG) types (PEG 400, PEG 600 and PEG 1000) and composition ratios on melting point, melting time, appearance and hardness of matrix of blank suppositories were investigated. The results showed that the melting point and melting time of the blank suppositories with PEG 400 and PEG 1000 in a weight ratio of 25∶75 as matrix were 30.3 ℃ and 19.3 min. The blank suppositories also had uniformly white appearances and appropriate hardness. Thus, the ibuprofen hollow type suppositories for pediatric usage were prepared based on above blank suppositories. Two kinds of self-made drug-loaded hollow type suppositories with the cavity diameter of 3 mm and depth of 1.8 or 2.3 cm were prepared by adding the powder of ibuprofen directly. The appearance and hardness of two products were similar to the blank suppositories, and the melting time decreased to 18.4 min. The dissolution profiles of two products were investigated with the commercial ibuprofen suppositories for pediatric usage as the control. The results showed that the dissolution of both self-made hollow type suppositories reached equilibrium within 20 min, and the dissolution amount were above 90％, while the dissolution of the commercial product at 70 min was 79％. It indicated that the hollow type suppositories could achieve the aim of quick release.

Select

Determination of the Enantiomer of Apremilast and Its Intermediate by NP-HPLC

王慧君1，黄生军2，潘红娟1*

2016, 47(10): 1284. https://doi.org/10.16522/j.cnki.cjph.2016.10.017

Abstract ( ) Download PDF ( )

Knowledge map

Save

A NP-HPLC method was established for the chiral separation and determination of the enantiomer (2) of apremilast (1). A Daicel Chiralpak IF column was used, with the mobile phase of hexane∶ethanol∶isopropanol∶ diethylamine (30∶40∶30∶0.1) at the detection wavelength of 232 nm. It was linear for 2 in the range of 1.0—10 μg/ml. Its LOD was 0.084 μg/ml, and average recovery was 99.1％, with RSD of 1.59％. In addition, a NP-HPLC method was established for the chiral separation and determination of the intermediate of the enantiomer (4) in apremilast (3). A Daicel Chiralpak IF column was used, with the mobile phase of hexane∶isopropanol∶diethylamine (50∶50∶0.1) at the detection wavelength of 232 nm. It was linear for 4 in the range of 2.0—10 μg/ml. The LOD was 1.012 μg/ml. Its average recovery was 98.9％, with RSD of 3.20％.

Select

Investigations of the Interactions of Antituberculous Candidate Compound HY152-J with the Transporter P-gp by LC-MS/MS

LI Liang, XIAO Feng, XU Lingmei, QIN Yan, TAN Qiong

2016, 47(10): 1289. https://doi.org/10.16522/j.cnki.cjph.2016.10.018

Abstract ( ) Download PDF ( )

Knowledge map

Save

HY152-J (1) is an antituberculous candidate compound. The interactions of 1 with the transporter P-gp in Caco-2 cell monolayer model were investigated by LC-MS/MS. The results showed that the ratio of Papp values for different concentrations of 1 from basolateral (BL) side to apical (AP) side and Papp from AP side to BL side were between 0.99—1.27, suggesting that 1 could not be a substrate for transport protein P-gp probably. The inhibition tests for the transport of digoxin across Caco-2 cell monolayer model did not show an obvious decrease of the efflux ratios (ER value) with different 1 concentrations (0.625—10 μmol/L) compared with the negative group. It is concluded that 1 is not an inhibitor for P-gp.

Select

Determination of Related Substances in Macitentan Bulk Drug by HPLC

PAN Deng, NI Feng, LI Jianqi, SUN Yuanyuan

2016, 47(10): 1294. https://doi.org/10.16522/j.cnki.cjph.2016.10.019

Abstract ( ) Download PDF ( )

Knowledge map

Save

An HPLC method was established for the determination of the related substances in macitentan bulk drug. A Waters Symmetry C18 column was used, with the mobile phase of 0.1％ trifluoroacetic acid (A) ∶acetonitrile (B) by linear gradient elution, at the detection wavelength of 260 nm. It was linear for macitentan and its related substances in the range of 0.1—10 μg/ml. The recoveries for the related substances were 94.20％—105.68％, with RSDs of 0.45％—1.48％.

Select

Determination of Related Substances in Agomelatine by HPLC

LUO Junqiu, LU Chunxiao, YAN Chao

2016, 47(10): 1298. https://doi.org/10.16522/j.cnki.cjph.2016.10.020

Abstract ( ) Download PDF ( )

Knowledge map

Save

An HPLC method was established for the determination of related substances in agomelatine. An Inertsil C18 column was used, with the mobile phase A of 0.01 mol/L disodium phosphate dodecahydrate solution (adjusted to pH 2.7 with phosphoric acid)∶methanol∶acetonitrile(40∶35∶25), and the mobile phase B of acetonitrile for gradient elution, at the detection wavelength of 230 nm. Agomelatine and its related substances were seperated well, and their calibration curves were linear in the concentration ranges of 0.030—0.225 μg/ml. Their average recoveries were 102.0％—102.6％, with RSDs of 1.07％—1.77％.

Select

Determination of Caffeine in Pharmaceutical Preparations by Per Aqueous Liquid Chromatography

DONG Lili, LI Min, YU Ling, LIANG Huifeng

2016, 47(10): 1301. https://doi.org/10.16522/j.cnki.cjph.2016.10.021

Abstract ( ) Download PDF ( )

Knowledge map

Save

A per aqueous phase liquid chromatography method was established for the determination of caffeine in pharmaceutical preparations. A bare silica column was used, with the mobile phase of acetonitrile∶0.03 mol/L sodium formate solution (pH 2.9)(5∶95), at the detection wavelength of 274 nm. Caffeine could be determined within 5 min. It was linear for caffeine in the range of 0.2—107 μg/ml. The average recovery was 99.3％, with RSD of 1.66％.

Select

Chiral Separation and Determination of Daclatasvir Dihydrochloride and Its Five Enantiomers by HPLC

GUO Feng, SUN Xiaowei, GUO Wenmin, WANG Yanjiao, ZHANG Wenxing

2016, 47(10): 1304. https://doi.org/10.16522/j.cnki.cjph.2016.10.022

Abstract ( ) Download PDF ( )

Knowledge map

Save

An HPLC method was established for the determination of daclatasvir dihydrochloride and its five enantiomers. A Chiralpak IC column was used, with the mobile phase of methyl tertbutyl ether (containing 0.1％ diethylamine)∶ethanol (88∶12) at the detection wavelength of 305 nm. Daclatasvir dihydrochloride and its enantiomers could be separated successfully. It was linear for the above compounds in the range of 0.1—4 μg/ml. Their recoveries were over 99.0％, with RSDs less than 1.5％.

Select

Determination of a Genotoxic Impurity and Morpholin Acetic Acid in Carfilzomib by LC-MS/MS

LI Haixia, BAI Peifeng, LIU Na, GUO Wenmin

2016, 47(10): 1308. https://doi.org/10.16522/j.cnki.cjph.2016.10.023

Abstract ( ) Download PDF ( )

Knowledge map

Save

A LC-MS/MS method was established for the determination of morpholin acetic acid (2) and genotoxic impurity (S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one (3) in carfilzomib. A Waters Xbridge Shield RP18 column was used, with the mobile phase of 1 mmol/L ammonium acetate solution (adjusted to pH
5.5 with acetic acid)∶acetonitrile (30∶70). MS/MS detection was conducted in multiple reaction monitoring (MRM) mode using positive electrospray ionization as the ionization source, and with the transitions of m/z 146.1→m/z 100.1 for 2 and m/z 172.2 →m/z 86.1 for 3. It was linear in the concentration rang of 100—3 000 ng/ml for 2 and 10—300 ng/ml for 3. Their limits of quantification (LOQs) were 100 and 10 ng/ml. Their average recoveries were 99.6％ and 99.7％, with RSDs of 1.4％ and 1.3％.
Key Words: carfilzomib; genotoxic impurity; morpholin acetic acid; (S)-2-amino-4- methyl-1-((R)-2-
methyloxiran-2-yl) pentan-1-one; LC-MS/MS; content determination

Select

Traceable Analysis of Microbial Contamination to Traditional Chinese Medicine Oral Liquid and Its Evaluation and Control

DING Bo, LIU Yan, SUN Tong, GUO Ming

2016, 47(10): 1311. https://doi.org/10.16522/j.cnki.cjph.2016.10.024

Abstract ( ) Download PDF ( )

Knowledge map

Save

Based on a drug recall case caused by microbial contamination, the detailed investigation and test process was elaborated by following the steps of production process review, positive sample analysis, optimization of culture conditions, analysis of contaminated strains, production process sampling, analysis of survey results, and establishment of solutions, so that investigation procedures and test methods for microbial contamination to traditional Chinese medicine oral liquid could be established. Furthermore, evaluation and control methods for microbial contamination could be established by the following four steps such as harmful microorganism identification, harmful microorganism characterization, critical control point and effective detection method. The investigation results showed that the recalled products, contaminated by lactobacillus carried by the crude medicinal materials, had serious quality deficiency. Isolation and characterization methods on microbial contamination of traditional Chinese medicine oral liquid played a significant role in the prevention of microbial contamination to products during production.

Select

Progress of Applications of Multi-site Microdialysis Sampling Technology to Pharmacokinetics

QIU Ruiqi, SUN Yandong, ZHANG Ranran, LU Weigen*

2016, 47(10): 1316. https://doi.org/10.16522/j.cnki.cjph.2016.10.025

Abstract ( ) Download PDF ( )

Knowledge map

Save

Microdialysis, a novel in vivo microsampling method, can be used to monitor the dynamic processes in vivo of endogenous or exogenous substances. Multi-site microdialysis sampling technology can realize the simultaneous and continuous sampling in different organs, different tissues or different sites of the same tissue. Through the realtime detection of drug concentration of target site, the in vivo characteristics of drug distribution and metabolism can be understood intuitively and accurately. So, this technology has some advantages in clarifying the ADME (absorption, distribution, metabolism and excretion), pharmacological mechanism, targeting capacity of drugs and guiding the clinical treatment. The applications and advances of multi-site microdialysis sampling technology to pharmacokinetics are reviewed in this paper.

Select

The Utilization and Advances of Traditional Chinese Medicine Dregs

LI Feng1, WANG Na2*, ZHANG Shiyu2, ZHENG Lin2

2016, 47(10): 1322. https://doi.org/10.16522/j.cnki.cjph.2016.10.026

Abstract ( ) Download PDF ( )

Knowledge map

Save

Traditional Chinese medicine dregs generated in the process of Chinese pharmaceutical production, the annual output of up to hundreds of tons. Directly discarded not only pollute the environment but also cause a huge waste. Explore the high value use of traditional Chinese medicine dregs and development of high-value added products has a very high significance and research value. Traditional Chinese medicine dregs contain cellulose, hemicellulose, lignin, fats, proteins and pharmaceutical active ingredients. By extraction, fermentation, roasting, gasification, pyrolysis and other processes, the pharmaceutically active substance, feed, plant culture, construction materials, fuel, etc. could be obtained. Then, they could applied to medicine, animal and plant breeding, energy, chemical industry, environmental protection, and advanced functional materials, in order to achieve the secondary development of waste, resulting in huge
economic benefits.

Select

Graphical Synthetic Routes of Isavuconazonium Sulfate

SONG Cheng'en, HAO Qun, ZHOU Weicheng

2016, 47(10): 1327. https://doi.org/10.16522/j.cnki.cjph.2016.10.027

Abstract ( ) Download PDF ( )

Knowledge map

Save

Select

Graphical Synthetic Routes of Roxadustat

FANG Fang, ZHANG Jinfeng, GUO Yekun, ZHONG Jingfen

2016, 47(10): 1330. https://doi.org/10.16522/j.cnki.cjph.2016.10.028

Abstract ( ) Download PDF ( )