Chinese Journal of Pharmaceuticals

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Perspectives & Review

Application of Pressure Sensitive Adhesive in Transdermal Patch and Discussion on Its Pharmaceutical Research

LIU Mengsi, JIANG Dianzhuo, LUO Huafei, YUAN Lijia

2021, 52(07): 863-870. https://doi.org/10.16522/j.cnki.cjph.2021.07.001

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Pressure sensitive adhesive(PSA) is the key auxiliary material of transdermal patches, which is important to the efficacy, safety and quality properties of the final product. It is usually divided into acrylic PSA, polyisobutylene PSA, silicone-type PSA and thermoplastic elastomer adhesive. This paper discusses the effect of PSA on the critical quality attributes of transdermal patches, including in vitro skin permeation, in vitro release, adhesion, recrystallization and stability. At the same time, the considerations on quality control of PSA by domestic and foreign regulatory agencies were sorted out, especially the related requirements for rheological properties and safety indicators.

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Perspectives & Review

Extractables and Leachables of Single Use System Applied in Antibody Drugs manufacturing: An Overview

CAO Yanjing, HOU Wei, ZHANG Zhongli, HSU Simon Sheng-Tsiung, ZHANG Lei

2021, 52(07): 871-880. https://doi.org/10.16522/j.cnki.cjph.2021.07.002

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The single use system(SUS) is widely used in the process development and commercial production of antibody drugs due to its simplicity, flexibility, and cost advantages. However, in the production process of antibody drugs, SUS or its components will produce extractables and leachables(E&L), which can affect the quality of the product and bring risks to the health of patients. Therefore, it is necessary to conduct E&L researches on SUS before the application of the drug on the market to prove its control strategy. In recent years, with the continuous development and improvement of the antibody pharmaceutical industry, domestic and foreign laws, as well as the regulations have raised more and more requirements for E&L research. In this review, E&L-related regulations and industry requirements were summarized with the experience of successful application of antibody drugs at home and abroad. The research ideas and considerations of E&L were introduced in detail, including information collection, risk assessment, E&L researches and safety assessment.

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Perspectives & Review

New Research Progress of Pharmaceutical Cocrystals

WANG Lili, GAO Ziyao, LIU Shuyu

2021, 52(07): 881-890. https://doi.org/10.16522/j.cnki.cjph.2021.07.003

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Pharmaceutical cocrystals have the potential to adjust the physicochemical properties of active pharmaceutical ingredient(API), and have attracted increasing attention as the alternative solid forms of APIs. New synthetic strategies and advanced characterization techniques have been proposed in this hot research topic by researchers. On the basis of the research progress of pharmaceutical cocrystals over the last decade, the formation principles, preparation methods, characterization techniques, physicochemical properties and application prospects are described respectively, some research cases are also introduced. This review focuses on melting point, solubility, dissolution rate, bioavailability, stability and mechanical properties of pharmaceutical cocrystals, and summarizes the latest research progress, hoping to provide some references for the further development of pharmaceutical cocrystals.

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Paper

Improved Synthetic Process of Clobazam

PENG Chenchen, ZHANG Zhidong, LIU Qixing, LIAO Zongquan, ZHOU Haifeng

2021, 52(07): 891-894. https://doi.org/10.16522/j.cnki.cjph.2021.07.004

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N-Phenyl-N-(2-nitro-5-chlorophenyl)-2-methoxylcarbonyl acetamide(4) was obtained by an acylation reaction of 5-chloro-2-nitrobenzidine and methyl malonyl chloride. Subsequently, 1-phenyl-8-chloro-1,2,4,5- tetrahydro-1,5-benzodiazepine-2,4-dione(5) was synthesized from 4 by one-pot reaction including reduction and cyclization with zinc powder and hydrochloric acid. Finally, active pharmaceutical ingredient clobazam was obtained via methylation of 5 after recrystallization. The use of methyl malonyl chloride as an acylation reagent apparently enhanced the yields of intermediates 4 and 5, increasing the total yield from 34％ to 50％. This improved synthetic process has been successfully executed to produce active pharmaceutical ingredient clobazam.

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Synthesis of Related Substances of Vortioxe

ZHOU Chengkai, JIANG Kaiyuan, YUE Hui, FANG Hao, SUI Qiang

2021, 52(07): 895-900. https://doi.org/10.16522/j.cnki.cjph.2021.07.005

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In order to control the quality of vortioxetine, five related substances found in API, namely 1-[2-[(5-chloro-2,4-dimethylphenyl)thio]phenyl]piperazine hydrobromide (A-HBr), 1-phenyl-4-[2-[(2,4- dimethylphenyl)thio]piperazine (B), 1,2-bis[(2,4-dimethylphenyl)thio]benzene(C), 1,1'-(1,1'-Binaphthalene)-2,2'- diylbis(1,1-diphenylphosphine oxide)(D) and 2-diphenylphosphino-2'-diphenylphosphino-1,1'-binaphthyl(E), were synthesized based on the synthetic process of API. Among them, both related substance B and E have not found in the literatures. The structures of the above five compounds were confirmed by 1H NMR, MS and elemental analysis.

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Preparation and Structural Confirmation of Related Substences of Tedizolid Phosphate

YAO Songmei, ZHU Yizhong,LIU Limin, GU Hongmei, LI Yang

2021, 52(07): 901-905. https://doi.org/10.16522/j.cnki.cjph.2021.07.006

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To control the quality of tedizolid phosphate and promote the establishment of its quality standard, five impurities of tedizolid phosphate were prepared: [(R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]- phenyl]-2-oxooxazolidin-5-yl]methyltrihydrogen diphosphate(related substance A), [(R)-3-[3-fluoro-4-[6-(2-methyl- 2H-tetrazol-5-yl)pyridin-3-yl]phenyl]-2-oxooxazolidin-5-yl]methyl trihydrogen diphosphate(related substance B), bis[[(R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl]-2-oxooxazolidin-5-yl]methyl]hydrogen phosphate(related substance C), diphosphoric acid P,P'-bis[[(R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3- pyridinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ester(related substance D), (5R)-3-[3-fluoro-4-[6-(2-methyl-2Htetrazol- 5-yl)-1-oxo-3-pyridinyl]phenyl]-5-[(phosphoryloxy)methyl]-2-oxazolidine(related substance E). Among them, related substance A, D and E have not been reported in literature. The structures of the five impurities were confirmed by HRMS, 1H NMR.

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Paper

Application of Resins and Related Regulations in Gentamicin C1a Fermentation

ZHAN Jiahong, YANG Ziyan, ZHANG Jianbin, LI Ji′an, LIN Huimin

2021, 52(07): 906-911. https://doi.org/10.16522/j.cnki.cjph.2021.07.007

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In the fermentation process of gentamicin C1a(1), the resin was put into use and the fermentation conditions were optimized, and a new fermentation process was developed that could significantly increase the potency of 1 and had industrial application value. First, the static adsorption method was used to screen out the resin 001×8 suitable for 1 fermentation, with a diameter of 0.4 - 0.6 mm. At twenty four hours of fermentation, the selected 001×8 resin was put into the fermentation broth to continue the fermentation, which could increase the potency of 1 final fermentation tank to 1.58 g/L, but the resin recovery rate was only 70％. Subsequently, on the basis of adding resin, the potency of 1 fermentation was increased to 1.85 g/L, which was an increase of 54.1％ compared with the 1.20 g/L of the original process(the resin recovery rate was 95％), by reducing the stirring speed, increasing the aeration rate and tank pressure, as well as adopting the method of feeding feed.

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Preparation of Alisol G Self-microemulsion and Its Pharmacokinetic Evaluation in Rats

GAO Chenyu, XI Jianqiang, SONG Dingzhong, LI Chenglong, CHENG Zhihong

2021, 52(07): 912-919. https://doi.org/10.16522/j.cnki.cjph.2021.07.008

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Alisol G, an antagonist of cannabinoid receptor 1(CB1R), has a significant weight loss effect. But absolute oral bioavailability of its suspension in SD rats was only 5.31％. Self-microemulsifying drug delivery system (SMEDDS) of alisol G was designed to improve its oral bioavailability. The composition of the self-microemulsion was screened according to the test results of solubility, compatibility of oils and emulsifiers, and pseudo-ternary phase diagrams. Then, with saturated drug loading, particle size and polydispersity index as the main evaluation indicators, the formulation was optimized by central composite design-response surface methodology. The results showed that the optimal formulation contained alisol G 5 g, oleoyl polyoxyl-6 glycerides(Labrafil M1944CS) 19.0 g, polyoxyl 40 hydrogenated castor oil(Cremophor RH40) 30.4 g and caprylocaproyl polyoxyl-8 glycerides(Labrasol) 45.6 g per 100 g of the self-microemulsion. The absolute oral bioavailability of the optimal self-microemulsion in SD rats was 12.87％, which was 2.42 times as many as that of the suspension.

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Effect of Twin Screw Granulation Process on Formation of Traditional Chinese Medicine Compound Granules

REN Wenxia, YANG Gaopin, HUANG Yansheng, ZHAO Lijie, WANG Youjie

2021, 52(07): 920-927. https://doi.org/10.16522/j.cnki.cjph.2021.07.009

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The traditional Chinese medicine compound granules were prepared by twin screw granulation under different feeding rates(1.00 - 1.80 g/min) and liquid-to-solid(L/S) ratios(0.05 - 0.17 ml/g). Then, the yield, particle size distribution, microscopic appearance and strength of each batch were investigated to explore the relationship between feeding rate and L/S ratio. It was observed in this experiment that L/S ratio should be changed with the feeding rate to obtain the granules with best yield, distribution, shape and strength. The results of principal component analysis showed that the targeted granules, strength, the proportions of particles distributed in the ranges of 250 - 850 and 850 - 2 000 μm were important indicators that reflected the quality of the granules prepared by the twin screw granulation process. In conclusion, there was an interaction between the feeding rate and L/S ratio in the twin screw granulation process, and the optimal L/S ratio decreased with the increasing of the feeding speed. No matter weather at excessive high or low level, volumetric fill-level would impact the quality of the granules. It indicated that it is feasible for twin screw granulation in preparation of traditional Chinese medicine compound granules.

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Formulation Optimization of Andrographolide Solid Dispersion Tablets and Preliminary Stability Analysis

CAI Ping, ZENG Qingyun, ZHAO Guowei, OU Liquan, GAO Cuiyun

2021, 52(07): 928-933. https://doi.org/10.16522/j.cnki.cjph.2021.07.010

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With andrographolide(1) as a model drug, the solid dispersions(1-SDs) was prepared with polyvinylpyrrolidone(PVP K30) as a carrier, then the solid dispersion tablets(1-SDTs) were prepared. The formulation of 1-SDTs was optimized by single factor experiment and central composite design-response surface methodology with disintegration time and the dissolution rate at 120 min as the evaluation indicators. The optimal formulation was as follows: 17.4％ of α-lactose, 12％ of cross-linked povidone and 1％ of magnesium stearate. The preliminary stabilities of 1-SDs and 1-SDTs stored at (40±2)℃ and relative humidity of (75±5)％ for 90 days were investigated. The results showed that the dissolution stability profiles of 1-SD and 1-SDT stored for 60 and 90 days were significantly declined compared with the initial products (P<0.05). The recrystallization degrees of 1 from the 1-SDTs stored for 60 and 90 days were higher than those of the corresponding 1-SDs. However, there was no significant difference in dissolution rate at 120 min between 1-SDs and 1-SDTs stored for 60 and 90 days.

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Comparison of Oto- and Renal Toxicities of Four Aminoglycosides in Zebrafish

SHAO Weihao, HAN Yujie, YIN Yu, CHEN Daijie, JING Lili

2021, 52(07): 934-939. https://doi.org/10.16522/j.cnki.cjph.2021.07.011

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The clinical use of aminoglycoside antibiotics is frequently restricted by their adverse effects to the kidney and inner ears. This study was designed to compare the embryotoxicity, nephrotoxicity and ototoxicity of gentamycin C1a, dibekacin and their derivatives(etimicin and arbekacin) in zebrafish embryos. The results demonstrated that the embryonic lethalities for four drugs were in the following order: arbekacin>etimicin>gentamicin C1a and dibekacin. The order of nephrotoxicity was as follows: dibekacin>gentamicin C1a>arbekacin>etimicin. The order of ototoxicity was: dibekacin>gentamicin C1a>arbekacin and etimicin. Arbekacin and etimicin exhibited more developmental toxicities to the young embryos than dibekacin and gentamicin C1a. But at sub-minimum lethal doses, arbekacin and etimicin showed significantly reduced toxicities towards kidney and neuromast hair cells, whereas dibekacin had the strongest nephrotoxicity and ototoxicity in zebrafish embryos. Our results also supported that zebrafish could be employed as a convenient and quick platform to evaluate the toxicities of aminoglycoside antibiotics.

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Regulatory Science Research on Acceptable Intake of Nitrosamine DNA Reactive Impurities

YANG Jingshu, LI Zhuangqi, QIAO Zelin, QI Yun, YANG Yue

2021, 52(07): 940-947. https://doi.org/10.16522/j.cnki.cjph.2021.07.012

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The appearance of DNA reactive impurities in marketed drugs has gained much attention from domestic and foreign drug regulatory agencies. Based on relevant guidelines or drafts issued by different countries and regions, ICH M7(R1) put forward specific categories and control strategy for DNA reactive impurities via a decisiontree method in 2017. The scientific logic of the underlying design in ICH M7(R1) and the method for determining the acceptable intake of nitrosamine impurities was discussed in this paper. In addition, impurity limits, impurity risk prediction and the creation of toxicity database should be combined in three dimensions to investigate the supervision of DNA reactive impurities in line with China's national conditions.

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Determination of Eleven Antiepileptic Drugs in Human Plasma by UPLC-MS/MS

WANG Wei, XU Weizhe, LI Qingyan, CUI Yujing, LIU Guoru

2021, 52(07): 948-954. https://doi.org/10.16522/j.cnki.cjph.2021.07.013

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An UPLC-MS/MS method was established for the determination of eleven antiepileptic drugs in human plasma. Plasma samples were precipitated with methanol and then injected for analysis. Multiple reaction monitoring(MRM) mode was performed combined with the positive and negative ion switching and segmented scanning analysis. The results showed that it was linear for the eleven antiepileptic drugs, including acetazolamide, primidone, zonisamide, gabapentin, levertiracetam, pregabalin, lamotrigine, brivaracetam, sodium valproate, diazepam and nirazepam, in the corresponding ranges, and the LLODs were 0.53, 0.10, 0.11, 0.50, 0.50, 2.06, 0.10, 0.10, 498, 0.10 and 0.10 ng/ml, respectively. The intra-day and inter-day precision RSDs were both less than 15％, and the extraction recoveries were greater than 70％. The established method is sensitive, rapid, accurate, and highly specific, which can be used for the blood concentration determination and pharmacokinetic study of the eleven antiepileptic drugs.

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Development of the Determination Method of Letrozole Tablets Dissolution Profile

SHU Xintong, YAO Xiaomin, LUO Yan, XU Yun

2021, 52(07): 955-959. https://doi.org/10.16522/j.cnki.cjph.2021.07.014

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The second method(paddle method) in the four general rules 0931 of the Pharmacopoeia of the People's Republic of China(2020 edition) was adopted in this study, and the pH 1.0 hydrochloric acid, pH 4.5 acetate butter solution, pH 6.8 phosphate butter solution and purified water were selected as the dissolution medium. After optimization, the volume of the medium was 900 ml, the rotation speed was 50 r/min, and the dissolution curve was determined by UV spectrophotometry. The results showed that the optimized method for measuring the dissolution profile of letrozole tablet has good discrimination, which can provide a reference for the evaluation of the in vitro dissolution of letrozole tablet and the consistency evaluation of its generic drugs.

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Determination of DCC and DCU Residues in Entacapone Intermediate by GC-FID

LIU Jinyan, ZHUANG Zihan, XIA Chunyu, LI Jianqi, ZHOU Ainan

2021, 52(07): 960-963. https://doi.org/10.16522/j.cnki.cjph.2021.07.015

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A GC-FID method was established to determine the content of dicyclohexylcarbodiimide(DCC, 4) and dicyclohexylurea(DCU, 7) in the intermediate of entacapone(1). HP-5 Column(0.32 mm×30 m×0.25 μm) was used with programmed temperature rise, the FID detector temperature was 320 ℃, the injection port temperature was 300 ℃, the injection volume was 1 μl and the split ratio was 10∶1. The results showed that it was linear for 4 and 7 in the corresponding ranges, and the average recoveries were 98.75％ and 100.05％, respectively. The contents of 4 and 7 in the six batches of samples calculated by the external standard method were all lower than 0.1％. The established method is simple, accurate and reproducible, which can be used for the determination of 4 and 7 in 1 intermediates.

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Pharmaceutical Management & Information

Analysis on the Mechanism of Corporate Compliance Management Promotion and Its Enlightenment

ZHAO Yanjiao, WU Lin, CHEN Yongfa

2021, 52(07): 964-970. https://doi.org/10.16522/j.cnki.cjph.2021.07.016

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Compliance management system, as an important means of corporate self-governance, can effectively improve the ability of compliance level and thus help to avoid economic losses of enterprises and even the whole society, which has the role of compliance risk prevention and control. Promoting pharmaceutical companies to strengthen compliance management, is conducive to consolidate the main responsibility of enterprises to realize the control of drug safety risks at source, and further enhance the effectiveness of drug safety governance. Therefore, in order to promote the compliance construction of pharmaceutical enterprises, this paper systematically analyzes the external stimuli in the foreign development process of enterprises compliance management and the internal driving forces. And based on the analysis framework of motivation theory, the foreign enterprises compliance management promotion mechanism is analyzed and summarized. Finally, based on the China's pharmaceutical industry reality, some thoughts on strengthening the compliance construction of China's pharmaceutical enterprises are put forward.

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Pharmaceutical Management & Information

System of Drug Site Inspection in United States and its Enlightenment to China

ZHANG Lian

2021, 52(07): 971-974. https://doi.org/10.16522/j.cnki.cjph.2021.07.017

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Pharmaceutical Management & Information

Analysis of Patent Strategy of PDE-5 Inhibitor Sildenafil Citrate

LUO Zhibo, WANG Wei, QIN Fei, WANG Jiansong, CHEN Jiachun