Chinese Journal of Pharmaceuticals

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Synthesis of PI3K/mTOR Dual Inhibitor NVP-BEZ235

LEI Fei, WANG Linxiao, OUYANG Yiqiang, ZHENG Pengwu, ZHU Wufu*

2016, 47(02): 135-139. https://doi.org/10.16522/j.cnki.cjph.2016.02.001

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6-Bromo-4-chloro-3-nitroquinoline (7) was synthesized from 2,2-dimethyl-1,3-dioxane-4,6-dione by substitution with triethoxymethane, condensation with 4-bromoaniline, cyclization, nitrification and chlorination. NVP-BEZ235, the PI3K/mTOR inhibitor, was synthesized from 2-(4-nitrophenyl)acetonitrile via alkylation with iodomethane and reduction to give 2-(4-aminophenyl)-2-methylpropanenitrile (10), followed by substitution with 7 to obtain 2-[4-[(6-bromo-3-nitroquinolin-4-yl)amino]phenyl]-2-methylpropanenitrile, which was subjected to reduction, cyclization, alkylation and Suzuki-coupling reaction with an overall yield of 6％(based on 2,2-dimethyl-1,3-dioxane-4,6- dione) and purity of 99.1％. The structure of the target product was confirmed by 1H NMR and MS. This method started with cheap raw materials was of simple experimental operation and mild reaction conditions. It was suitable for largescale pilot study.

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Improved Synthesis Method of Everolimus

LIU Mingxia, JI Honghai

2016, 47(02): 140-141. https://doi.org/10.16522/j.cnki.cjph.2016.02.002

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Everolimus was synthesized from rapamycin by condensation with t-butyldimethylchloroethoxysilane to give 40-O-[2-(t-butyldimethylsilyloxyethyl)]rapamycin, followed by deprotection in the presence of trifluoroacetic acid/dichloromethane with an overall yield of about 79％.

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Synthesis of the Related Substances of Nilotinib Hydrochloride

HUANG Junjie1, LIAO Mingyi2, GUO Qi2, YOU Qidong1*

2016, 47(02): 142-146. https://doi.org/10.16522/j.cnki.cjph.2016.02.003

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To strengthen the quality control of nilotinib hydrochloride, five related substances of nilotinib were synthesized based on its synthetic process. These substances, including 3-[4-(pyridin-3-yl)pyrimidin-2- ylamino]-4-methylbenzoic acid(A), 3-[4-(pyridin-3-yl)pyrimidin-2-ylamino]-N-[3-(4-ethyl-1H-imidazol-1-yl)-5-
(trifluoromethyl)phenyl]-4-methylbenzamide(B), 3-[4-(pyridin-3-yl)pyrimidin-2-ylamino]-N-[3-(trifluoromethyl)-5- (1H-imidazol-1-yl)phenyl]-4-methylbenzamide(C), 3-[4-(pyridin-3-yl)pyrimidin-2-ylamino]-N-[3-(trifluoromethyl)- 5-(2,4-dimethyl-1H-imidazol-1-yl)phenyl]-4-methylbenzamide(D), 3-[4-(pyridin-3-yl)pyrimidin-2-ylamino]-N-[3- (trifluoromethyl)-5-(5-methyl-1H-imidazol-1-yl)phenyl]-4-methylbenzamide(E), were synthesized and their structures were confirmed by MS and 1H NMR.

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Synthesis of Vitamin K1 with Different Ratio of Cis/Trans Isomers

ZHANG Zhigang

2016, 47(02): 147-148. https://doi.org/10.16522/j.cnki.cjph.2016.02.004

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Vitamin K1 with different ratio of cis/trans isomers was synthesized from natural phytol via bromination with phosphorus tribromide in the presence of different content of water to get different ratio of (E/Z)- isomeric phytyl bromide, followed by condensation with cyclopentadiene-menadione adduct and retro-Diels-Alder reaction.

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Synthesis of 4-(Pyridin-3-yl)-2-[(2-methyl-5-aminophenyl)amino]thiazole

LIU Changchun, YAO Shunyu, WANG Ying

2016, 47(02): 149-151. https://doi.org/10.16522/j.cnki.cjph.2016.02.005

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4-(Pyridin-3-yl)-2-[(2-methyl-5-aminophenyl)amino]thiazole, the key intermediate of masitinib, was synthesized from 1-(pyridin-3-yl)ethanone by bromination with ionic liquid 1-butyl-3-methylimidazolium tribromide ([bmim]Br3) at room temperature, substitution with ammonium thiocynate and cyclization with 2-methyl-5-nitroaniline in the presence of acetic acid in one-pot to give 4-(pyridin-3-yl)-2-[(2-methyl-5-nitrophenyl)amino]thiazole, which was subjected to hydrogenation catalyzed by Pd-Fe/TiO2 under atmospheric pressure with an overall yield of 87％. The ionic liquid [bmim]Br generated by [bmim]Br3 acted as the catalyst and solvent for the following reactions and can be recycled.

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Construction of Recombinant Engineering Strains Over-producing Tacrolimus and Preliminary Optimization of Fermentation Process

WANG Ya, HUANG He, BIAN Jiaxin, ZHOU Bin, HU Haifeng*

2016, 47(02): 152-157. https://doi.org/10.16522/j.cnki.cjph.2016.02.006

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Based on the synthetic pathway and mechanism of tacrolimus, the genes encoding Streptomyces coelicolor acetyl-CoA carboxylase and Actinoplanes sp. N902-109 lysine cyclodeaminase/non-ribosomal peptide synthetase (rapL/rapP) were obtained by PCR amplification using the primers designed according to the biosynthetic gene clusters. Two recombinant engineering strains, named as SIPI-F002 and SIPI-F003, were constructed by integrating acetyl CoA carboxylase gene, or rapL/rapP gene into Streptomyces tsukubaensis No. 9993 genome, respectively. The results showed that the production of tacrolimus by recombinant strain SIPI-F002 was greatly improved through the addition of 0.1％ sodium propionate and 0.01％ oleic acid methyl ester into the fermentation medium, with a yield of 392 and 383 μg/ml in the shake flask, respectively. An optimized composite carbon source consisting of 4％ dextrin and 2％ soluble starch was verified to be effective for the promotion of the yield of tacrolimus by SIPI-F003, which could reach 694 μg/ml in the shake flask.

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Design and Screening of siRNA Targeting to Multi-drug Resistance Gene MDR1

WEN Tianjiao1, LIU Donglu2, TIAN Qin3, CUI Jingxia1*

2016, 47(02): 158-162. https://doi.org/10.16522/j.cnki.cjph.2016.02.007

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The effect of siRNA on the reversal of multi-drug resistance of cancer cells which was mediated by P-glycoprotein was investigated. The human MDR1 gene was selected as the target. siRNA candidate sequences were obtained via online design and further optimized by biological software. The chemically synthesized siRNAs were transfected into drug-resistant breast cancer cell line MCF-7/ADR. MDR1 gene expression were quantitatively analyzed by real-time PCR and Western blot, respectively. MTT experiment was carried out to assay the sensitivity of transfected cells to doxorubicin. Ultimately, eight MDR1 gene siRNA sequences were designed and synthesized, of which four sequences could effectively inhibit the expression of MDR1 gene. The siRNA1 had the highest interference efficiency and could specifically silence MDR1 gene, effectively reversing the multi-drug resistance in breast cancer.

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Comparation of HPLC Fingerprints between Fructus Gardeniae and Its Processed Products

BAO Jiake1, LIU Ling2

2016, 47(02): 163-167. https://doi.org/10.16522/j.cnki.cjph.2016.02.008

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The HPLC fingerprints of Fructu Gardeniaes, Fructus Gardeniae (stir-baked), Fructus Gardeniae roasted with ginger juice and Fructus Gardeniae preparatus were established and compared to investigate the changes before and after processing. A Diamosil C18 column was used, with the mobile phase of methanol∶0.1％ phosphate by gradient elution, at the detection wavelength of 238 nm and 440 nm, with the reference peaks of geniposide and crocin I,
respectively. Nineteen common peaks of Fructus Gardeniae and its processed products were marked at 238 nm. The total peak area of each processed products and that of Fructus Gardeniae had no significant difference(P>0.05). Seventeen common peaks of Fructus Gardeniae preparatus and fifteen common peaks of Gardenia and other processed products were detected at 440 nm. Fingerprints of Fructus Gardeniae and its processed products in the overall drawing distribution of main characteristic peaks were basically same, but there were obvious differences for the distribution of non-common peaks. Compared with Fructus Gardeniae, the total area values and crocin I peak area value in fingerprint of Fructus Gardeniae (stir-baked) and Fructus Gardeniae preparatus decreased substantially(P<0.05). But the total area values in fingerprint of Fructus Gardeniae roasted with ginger juice had no obvious change(P>0.05).

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HPLC Fingerprint of Suoquan Capsules and Correlativity with the Relevant Herbs

ZHANG Niyu1, YANG Hua1, ZHANG Feifei1,2, WANG Xionglong1, HU Gaoyun2*

2016, 47(02): 168-171. https://doi.org/10.16522/j.cnki.cjph.2016.01.009

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The chemical correlations between Suoquan capsules and the relevant herbs, Rhizoma Dioscoreae, Fructus Alpiniae Oxyphyllae and Radix Linderae were evaluated by HPLC fingerprint analysis to offer a theoretical basis for the fingerprint detecting standard of Suoquan capsules. An Agilent Zorbax SB-C18 column was used, with the mobile phase of acetonitrile∶0.1％ phosphoric acid by gradient elution, at the detection wavelengths of 280 nm(0—21 min), 260 nm(21—33 min) and 230 nm(33—50 min). There were 14 common peaks in the HPLC fingerprints of 10 batches of samples, and their similarities were all over 0.90. The results showed a consistency between Suoquan capsules and their relevant herbs.

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Effects of Solid Dispersion Technology on in vitro Release and Pharmacokinetics of Felodipine from Sustained-release Tablets in Beagle Dogs

DING Xiaoli, ZHU Yulian, REN Yuanzhi, HUANG Hua*

2016, 47(02): 172-177. https://doi.org/10.16522/j.cnki.cjph.2016.02.010

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To improve the solubility of felodipine (1), solid dispersions (SD) were prepared by solvent method with polyvidone (PVP) K29/32 as a carrier at three different drug/carrier weight ratios of 1∶2, 1∶4 and 1∶6. The results of differential scanning calorimetry and X-ray diffraction analysis indicated that the drug existed in an amorphous form in the three prepared SDs. Compared with physical mixture and the bulk drug, all SDs significantly increased the dissolution of 1. Four kinds of hydrophilic matrix sustained-release tablets based on the above three SDs and the bulk drug were respectively prepared. The similarities in release profiles between four self-made products and Plendil in 1％ Tween-80 solution were investigated. The results showed that the calculated similar factor (f2) value between the tablets based on SD with drug/carrier weight ratio of 1∶6, named as product c, and Plendil was 70. Furthermore, the f2 values between product c and Plendil were all above 50 according to the release profiles in water and media with different pH values (1.0, 4.5 and 6.8). The pharmacokinetics of these two preparations in Beagle dogs were investigated. The drug concentration was determined by LC-MS. The results showed that two preparations were bioequivalent in Beagle dogs. The relative bioavailability of product c was 103.5％.

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Preparation and Properties of Carboxymethyl Chitosan Nanoparticles Loaded with Curcumin

PENG Lin1, LI Lifeng2, HAN Gang1, JIA Jingwen3, LIU Zhanjun3*

2016, 47(02): 178-182. https://doi.org/10.16522/j.cnki.cjph.2016.02.011

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Carboxymethyl chitosan-graft-vinyl acetate copolymer nanoparticles were prepared by a free radical graft polymerization with ammonium persulfate as an initiator. The Fourier transform infrared spectrum, thermogravimetric curve, particle size and appearance of the prepared blank nanoparticles were investigated. The results showed that vinyl acetate was successfully grafted onto carboxymethyl chitosan. The thermal stability of blank nanoparticles were improved. The average particle size of the product was (179±2)nm. The curcumin nanoparticles with different feed ratios of curcumin to copolymer nanoparticles were prepared. The drug loading and encapsulation efficiency of these products were determined. The results showed that the drug-loading capacity became saturated when the ratio was 2.5∶10. When the ratio was 1∶10, the encapsulation efficiency was the highest (97.8％). In vitro release studies demonstrated a dual release phase from the nanoparticles in pH 7.4 phosphate buffer with a rapid first-phase release and a slow second-phase release of curcumin.

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Preparation of Immediate Release Pellets of Omeprazole by Centrifugal Granulation

WANG Li, MA Weiyang, ZHANG Wenjun*, Lü Chunyan, QIAO Xiaoxi

2016, 47(02): 183-187. https://doi.org/10.16522/j.cnki.cjph.2016.02.012

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Omeprazole (1) immediate release pellets were prepared by centrifugal granulation. The formulation and process parameters were optimized by single factor design. To improve the stability of 1 in acidic conditions, an antacid, sodium bicarbonate, was adding into the formulation to increase the microenvironmental pH value. Moreover, the antacid played a role in speeding up dissolution of 1 from the pellets, which was comparable to a disintegrant, sodium carboxymethyl starch. The optimal pellets were prepared with the blank pores of microcrystalline cellulose (28 mesh), 1.5％ hypromellose solution as a adhesive, and amounts of sodium bicarbonate and microcrystalline cellulose PH101 (a filler) of 200 and 60 g. After optimization, the yields of 1 immediate release pellets in size range of 18—24 mesh was (89.6±2.5)％. The dissolution of 1 from the pellets at 15 min in pH 1.2 hydrochloric acid was above 85％, and the product could maintain the stability of 1 in 1 h.

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Process Improvement of Preparation of the Compound Vitamin E Cream

DING Zhijun, XU Shigui, LUO Meilan*, LIAO Yingen, XU Rui

2016, 47(02): 188-191. https://doi.org/10.16522/j.cnki.cjph.2016.01.013

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To enhance the storage stability of hydrocortisone butyrate (1) in the compound vitamin E cream, the formulation composition was improved. The storage stability and transdermal behaviors of the products before and after improvement were compared. Three batches of the improved product and one batch of the original product were stored under the accelerated conditions [(30±2)℃, relative humidity of (65±5)％] for 6 months and the long-term conditions
[(25±2)℃, relative humidity of (60±10)％] for 12 months, respectively. The results showed that the content of 1 in the original product was significantly decreased but not remarkably changed in the improved product, which indicated that the storage stability of 1 was enhanced. The transdermal penetration of 1 and vitamin E, two active ingredients, from the products before and after improvement were investigated with mouse skin as the barriers. The results showed that the cumulative penetration amount at 18 h and the steady penetration rate of the improved product were also significantly higher than those of the original product (P<0.05).

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

XU Zhiru1, XIAO Feng1, JIANG Chunhong2, QIN Yan1, YANG Xiaoling2*

2016, 47(02): 192-197. https://doi.org/10.16522/j.cnki.cjph.2016.02.014

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An LC-MS/MS method was established for the determination of naringin (1) and neohesperidin (2), as well as their aglycones naringenin (3) and hesperetin (4), in Beagle dog plasma. Its pharmacokinetics was also investigated after oral administration of total flavanones of Fructus Aurantii Immuaturus extract to Beagle dogs. A C18 column was used with the mobile phase of methanol∶10 mmol/L ammonium formate by gradient elution via negative electrospray ionization (ESI) mass spectrometry with multiple-reaction monitoring (MRM) mode. The total flavanones of Furctus Aurantii Immuaturus extract were administrated to dogs via oral route (17, 50 and 150 mg/kg) and intravenous injection (5 mg/kg). The main pharmacokinetic parameters of 1 and 2 after oral administration were as follows: t1/2(5.32± 2.13), (5.23±3.20), (5.98±3.49) and (3.82±1.98), (3.58±1.02), (5.06±4.04) h, cmax (107±35), (310±136), (501±
269) and (101±34, 297±118, 481±240) ng/ml, AUC0→t(391±161), (605±229), (964±333) and (277±43), (684±377), (927±224) ng·ml-1·h. The bioavailabilities for 1 and 2 were (3.51±1.44)％, (1.84±0.70)％, (0.98±0.34)％ and (2.27± 0.35)％, (1.91±0.96)％, (0.86±0.21)％, respectively. The main pharmacokinetic parameters of 1 and 2 after intravenous injection were as follows: t1/2 (5.48±4.17) and (3.68±1.91) h, AUC0→t (3 590±652) and (3 281±594) ng·ml-1·h.

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Relative Bioavailability of Lurasidone Hydrochloride Tablets in Beagle Dogs

XIANG Zhixiong, ZANG Weijun, LIU Wenli

2016, 47(02): 198-201. https://doi.org/10.16522/j.cnki.cjph.2016.02.015

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A randomized single-dose cross-over design was used to evaluate the relative bioavailability of lurasidone hydrochloride tablets in ten Beagle Dogs. The drug concentration of lurasidone in plasma was determined by UPLC-MS/MS. It was linear for lurasidone in the range of 0.1 - 300.0 ng/ml. Its low limit of quantification was 0.1 ng/ml. The main pharmacokinetic parameters of the test and the reference preparations in Beagle dogs after oral administration of
lurasidone hydrochloride tablets were as follows: tmax(0.8±0.2) and (0.8±0.5) h, cmax (51.1±50.1) and (66.4±75.5) ng·ml-1, AUC0→t (162.9±97.2) and (175.9±123.7) ng·h·ml-1, AUC0→∞(178.0±99.1) and (183.9±124.3) ng·h·ml-1, t1/2 (16.6± 8.8) and (15.7±4.4) h. The relative bioavailability of the test preparation was (92.6±43.8)％. There was no significant difference between the test and the reference preparations.

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Determination of Clopidogrel and Its Active Metabolite in Human Plasma by LC-MS/MS

TIAN Xi, YANG Xiuling*, ZHANG Zhiqing, WANG Shumei, DONG Weichong

2016, 47(02): 202-206. https://doi.org/10.16522/j.cnki.cjph.2016.02.016

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A LC-MS/MS method was established for the determination of clopidogrel (1) and its active metabolite (2) in human plasma. 2-Bromo-1-(3-methoxyphenyl)ethanone (MPB) was used as a derivation agent. A Diamonsil C18 column was used, with the mobile phase of acentonitrile∶1 mmol/L ammonium acetate solution containing 0.01％ formic acid (80∶20), with ticlopidine (3) as the internal standard. An ESI source was applied in the multiple reaction monitoring (MRM) and positive ion mode, with transitions of m/z 322.2→m/z 212.0 (1), m/z 504.4→m/z 354.1 (2 derivative) and m/z 264.2→m/z 154.1 (3), respectively. It was linear for 1 and 2 (derivative) in the ranges of 0.53 — 52.50 ng/ml and 2 — 200 ng/ml. Their LLOQs were 0.53 and 2.00 ng/ml, and the intra- and inter-day RSDs were both less than 10％.

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Determination of Eighteen Pigments in Capsule Shells with Polyamide Solid Phase Extraction(PA-SPE) and UPLC

ZHENG Xiwang1, HU Qing2, SUN Jian2, CUI Yajun1, JI Shen2*

2016, 47(02): 207-211. https://doi.org/10.16522/j.cnki.cjph.2016.02.017

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An UPLC method was established for the determination of eighteen synthetic pigments in capsule shells. The extraction liquid was purified through a polyamide solid phase extraction(PA-SPE). A Zorbax SB-C18 column was used, with the mobile phase of methanol∶20 mmol/L ammonium acetate solution by gradient elution, with the application of diode array detector. It was linear in the range of 10—300 μg/ml for the above 18 pigments. Their LODs were 0.38 — 9.85 mg/kg, and recoveries were 85.9％—105.1％, with RSDs of 1.91％—14.02％.

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LU Qichun, LIU Jingling, XU Liangliang, SU Li

2016, 47(02): 212-214. https://doi.org/10.16522/j.cnki.cjph.2016.02.018

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The similarity of in vitro dissolution curves for the test and the reference propranolol hydrochloride and hydrochlorothiazide extended-release capsules was evalutated. The dissolution curves for the test and the reference preparations in four media (water, pH 1.2 artificial gastric juice, pH 4.5 and pH 6.8 phosphate buffer) and at different rotation speeds (50 and 100 r/min) were determined by HPLC. Their similarity was investigated according to the f2 factor method. The results showed f2 values of the test and the reference formulations under different conditions were all greater than 50, which indicated that their in vitro releasing behaviors were similar.

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Determination of Palladium in Tigecycline by Microwave Digestion-ICP-MS

CHEN Fengqin, SONG Xuejie, SHI Ying

2016, 47(02): 215-216. https://doi.org/10.16522/j.cnki.cjph.2016.02.019

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An inductive coupled plasma mass spectrometry (ICP-MS) method was established for the determination of palladium residue in tigecycline. The samples were pretreated by microwave digestion technology and determined by ICP-MS. It was linear for palladium in the concentration range of 10 — 250 ng/ml, with the limit of detection of 3.07 ng/g. The mean recoveries were 88.8％ — 99.2％, with RSDs of 0.9％ — 1.2％.

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Application of Freeze-drying to Solidification of Emulsion

WANG Guanru, BIAN Wei, NI Meiping, YANG Yani, HE Jun*

2016, 47(02): 217-224. https://doi.org/10.16522/j.cnki.cjph.2016.02.020

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The instable phenomena of emulsion during storage are degradation (hydrolyzation), Ostwald ripening and increasing of particle sizes, etc. In recent years, the lyophilization technique has been widely employed in the field of pharmaceutical preparation to improve stability. However, the usage of lyophilization technique in emulsion preparation is less common. The effects of pharmaceutical factors (such as emulsifiers, lyoprotectants and weight ratio of excipients) and process parameters of lyophilization on the solidification of emulsion are reviewed in this paper. Moreover, serval important evaluation parameters are briefly introduced.

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Development of Magnetosomes from Magnetotactic Bacterium

DENG Wanping, SUN Junzhong*

2016, 47(02): 225-229. https://doi.org/10.16522/j.cnki.cjph.2016.02.021

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Magnetosomes are intracellular structures produced by magnetotactic bacteria, which comprise magnetic nanoparticles surrounded by lipid bilayer membrane. They can combine different biological molecules, besides, they possess a narrow size distribution and uniform morphology, with the characteristics of high biological compatibility and hypotoxicity. Magnetosomes are widely used in biotechnology. For example, they can be used as the contrast agent of magnetic resonance imaging, or serve as the carriers for drug transportation in the treatment of cancer, taking advantage of their magnetic-heat generating in variable magnetic fields. They can also separate pathogenic bacteria and DNA, as well as immobilize proteins by utilization of their magnetism. In this paper, the characteristics and clinical applications of magnetosomes were reviewed.

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Graphical Synthetic Routes of Alogliptin and Trelagliptin

XU Shenghui, HAO Qun, ZHOU Weicheng

2016, 47(02): 230-232. https://doi.org/10.16522/j.cnki.cjph.2016.02.022

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Graphical Synthetic Routes of Fondaparinux Sodium

HOU Wenfeng, HAN Furong, LI Zhenzhong, SUN Fuliang, GAN Hao*

2016, 47(02): 233-240. https://doi.org/10.16522/j.cnki.cjph.2016.02.023

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