主办:上海医药工业研究院
   中国药学会
   中国化学制药工业协会
ISSN 1001-8255   CN 31-1243/R   ZYGZEA
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2022 Volume 53 Issue 10   Published: 10 October 2022
  
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    Perspectives & Review
  • Perspectives & Review
    HAO Mengya, ZHU Peixi, SU Feng, SU Weike
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Natural products are physiologically active chemical components extracted from natural resources. The key issue to enhance the utilization efficiency of natural products is to explore rapid, efficient and environmentally friendly extraction technologies. Mechanochemical-assisted extraction technology has the advantages of high yield, short extraction time and environmental-friendly. Thus, it has broad application prospects in the field of natural product extraction. This paper mainly introduces the method procedure, process principle, application mode and future trend of mechanochemical-assisted extraction technology. Meanwhile, the limitations of current mechanochemistry in industrial extraction applications are also discussed. Furthermore, the countermeasures are put forward. It could provide new research ideas for promoting the improvement and industrial applications of mechanochemical-assisted extraction technology.
  • Perspectives & Review
    CHEN Wei, FENG Mingjie, XU Bo, PAN Yi, CHEN Hua, TANG Lida
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    Continuous flow chemistry is a promising new pharmaceutical technology, which has the advantages of reducing production cycle, higher automation, more environmentally friendly, energy-saving and emission reduction, and it also has the ability to perform chemical reactions that are difficult or impossible to do in batch manufacturing. It is the trend of active pharmaceutical ingredient(API) technology innovation. However, it has been slowly popularized in the pharmaceutical industry for a long time. With publication of ICH guideline Q13 on continuous manufacturing of drug substances and drug products, the key points of process development and control strategies have been put forward, and the regulatory expectation will gradually become clear. The characteristics, application scenarios and quality considerations of continuous flow chemistry are reviewed in this paper based on ICH Q13. Through literature research, the research points and control strategies of continuous flow chemistry are discussed, so as to promote the application of continuous flow chemistry in domestic pharmaceutical enterprises, improve the manufacturing level of the industry, strive to achieve carbon peaking and carbon neutrality goals.
  • Perspectives & Review
    CAO Meng, GE Yuanyuan, HU Yanchen, WANG Yamin, CAO Yi
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    With the release of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) Q13 guideline and the approval of several oral solid dosage form drug products adopting continuous manufacturing techniques, the regulatory development in this area is receiving increasing attention. Material handling is an important part of a continuous manufacturing platform. In this paper, the material handling for continuous manufacturing of oral solid dosage forms is introduced through analyzing the technical characteristics of material input, continuous feeding and continuous mixing. Also, the concerns of supervision and inspection are studied from the aspects of process validation, robustness, facilities and equipment, process control, quality assurance and cleaning. For technical consideration, process equipment should handle materials continuously and stably, with risks controlled and losses reduced as much as possible, so it is necessary to have a deep understanding of material characteristics, scientifically design process equipment and carry out qualification and verification; while regulatory inspections may focus on continuous process-specific risks and their possible effects on product quality. Hopefully this paper could accelerate the application of continuous manufacturing in pharmaceutical industry together with the aid of cooperation of regulation agencies, industrial community as well as the whole society, making full use of process analysis technology, innovative testing methods and digital quality assurance to steadily manufacture qualified products, thus promote domestic pharmaceutical industry to a high level of modernization.
  • Perspectives & Review
    ZAN Mengqing, NIU Jianzhao, XU Mingdi, LIU Qian
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    The concept of continuous manufacturing and process analysis technology is expounded, and the relevant guiding principles of continuous pharmaceutical manufacturing and the consideration of relevant control strategies are introduced. Then, the principles, characteristics and application examples of commonly used analytical tools, such as near-infrared spectroscopy, Raman spectroscopy, terahertz pulsed imaging, ultrasound technique and X-ray microscopy imaging technology, in the continuous pharmaceutical manufacturing process are summarized. Finally, the factors affecting the continuous manufacturing of pharmaceuticals and the difficulties in the application of process analysis technology are reviewed, and the development direction of continuous pharmaceutical manufacturing is prospected. It is hoped to provide a reference for the development of process analysis technology related to continuous manufacturing.
  • Perspectives & Review
    HUANG Lu, SUN Jian, WANG Mingwei, GE Fan
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    Three small molecule JAK inhibitors, namely ruxolitinib phosphate, fedratinib hydrochloride, and pacritinib citrate, for the treatment of myelofibrosis have been marketed worldwide. Their research progress and the published patents on chemical compound, crystalline form, salt form, process, formulation, drug combination, new use, and product derivatives, as well as the compounds in pharmaceutical research are unscrambled and researched in this paper. It is hoped to provide patent information and reference for Chinese pharmaceutical companies conducting project establishment and development, new patent mining, patent protection, and patent layout.
  • Paper
  • Paper
    ZHANG Xiaojie, MIAO Qingzhu, JIA Jingyang, DU Chaoyu, HE Feng
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    Five related substances of sufentanil citrate, namely N-[4-(methoxymethyl)piperidin-4-yl]-Nphenylpropionamide( related substance A), cis-4-(methoxymethyl)-4-(N-phenylpropionamido)-1-[2-(thiophen-2-yl)- ethyl]piperidine 1-oxide(related substance B), trans-4-(methoxymethyl)-4-(N-phenylpropionamido)-1-[2-(thiophen- 2-yl)ethyl]piperidine 1-oxide(related substance Ⅰ), [4-(phenylamino)-1-[2-(thiophen-2-yl)ethyl]piperidin- 4-yl]methanol(related substance C), and N-[4-(methoxymethyl)-1-[2-(thiophen-2-yl)ethyl]piperidin-4-yl]-Nphenylacetamide citrate(related substance D). Their structures were confirmed by NMR and ESI-MS. These compounds may be used as the references in the quality control of sufentanil citrate.
  • Paper
    ZHANG Jing, ZHANG Jieyu, HUI Zi, ZHU Jianwei, CHEN Junsheng
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    Split intein-mediated protein trans-splicing is a promising technique with excellent prospects in many protein engineering fields. The naturally occurring cysteine-less split intein, Aes123 PolB1, can perform transsplicing without reducing agents, which is particularly suitable for splicing proteins containing disulfide bonds. In this study, Aes123 PolB1 was used to splice proteins with the junction sequence EPK/SCD derived from the IgG hinge region in trans. The results showed that Aes123 PolB1 could successfully splice proteins with the EPK/SCD sequence without reducing agents. The factors that might affect the splicing activity, such as the concentration of sodium chloride, pH value, and temperature, were also investigated, and the results showed that the splicing reaction of Aes123 PolB1 could perform well in the EPK/SCD sequence. In this study, trans-splicing was performed under non-reducing conditions in the IgG hinge region amino acid sequences, which provided a theoretical and experimental basis for the application of split intein to seamlessly splicing antibody drugs, especially bispecific antibodies, under non-reducing conditions.
  • Paper
    XU Haiyue, WU Yong, LI Lele, HUANG Zongqing, HUA Haoju, FENG Jun
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    Ubiquitin-like protein-specific protease 1(Ulp1) is a crucial tool for protease in removing small ubiquitin-related modifier protein(SUMO) tags from the fusion protein. It has been widely used in the production of recombinant peptides and proteins. The easy aggregation of Ulp1 protein brings many challenges to the downstream separation and purification process. An S13-Ulp1 fusion protein was designed and recombinantly expressed to improve the solubility of Ulp1, reduce its aggregation, and decrease its isoelectric point for the convenient purification by anion exchange chromatography. After optimizing the parameters of fermentation and clarification, a preparation process of S13- Ulp1 fusion protein with high yield and simple purification was established. Finally, for S13-Ulp1, the fermentation yield reached 2.34 g/L, the total yield of downstream separation and purification was 64%, and the purity shown in SDS-PAGE analysis was about 95%. The enzymatic reaction assay showed that S13-Ulp1 fusion had the same specificity as Ulp1, which could efficiently remove the SUMO tag to obtain the targeted peptide.
  • Paper
    ZOU Xixi, GAO Zhenye, ZHANG Weijie, WU Fei, JIN Tuo
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    Coagulation factor Ⅷ(F8), one of the most common drug for treating hemophilia, has the disadvantage of a short half-life(10 - 14 h), and its injection needs to be administered several times a week. In order to obtain a long-acting sustained-release preparation of F8, a triblock polymer PLGA-PEG-PLGA with reverse thermosensitive properties synthesized by thermal ring-opening polymerization was used as a thermosensitive hydrogel matrix to prepare a novel long-acting sustained-release preparation loaded with F8. This thermosensitive hydrogels of F8 was an aqueous solution below 4 ℃ and turns into gel at around 37 ℃. In vitro activity and in vitro and in vivo release behaviors of F8-loaded hydrogel formulation were investigated. The results of in vitro release test showed that 17.4% of the drug loading, namely initial burst release, was observed on d1 and the drug release from the gels could maintain for 3 weeks. The cumulative amount of F8 at 22 d reached 92%. The results showed that the bioactivities of F8 in the solution before and after gelation was more than 97%, and the bioactivities of F8 in release media were all above 60% during the release process, indicating the stability of F8 in the thermosensitive hydrogels. The results of in vivo test showed that F8 quickly reached the peak plasma concentration[(113.21±14.50)ng/ml] within one hour after injection administration to the rats. During the whole release period, the plasma concentration could maintain above the lowest therapeutic concentration(10 ng/ml) for up to 15 days. In this study, we successfully developed a long-acting sustained-release formulation of F8, which had potential for clinical application.
  • Paper
    JIANG Shaobo, YANG Lei, WEI Xiaohui
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    This study aimed to establish a top spray granulation for ibuprofen arginine(Ibu-Arg) granules by fluid-bed technology based on Quality by Design(QbD) concept and approach. The quality target product profile(QTPP) and critical quality attributes(CQAs) of Ibu-Arg granules were firstly identified. The relevant CQAs for top spray granulation process were screened out by risk assessment. The percent of the labeled content and particle size distribution(PSD) were selected as the key responses. Risk assessment on critical process parameters(CPPs) was performed by failure mode and effect analysis(FMEA) methodology. By the results of FMEA, spray rate and atomization pressure were screened out as the high-risk process variables to be further studied. A center composite design(CCD) was employed for process optimization. Experimental results were analyzed by response surface methodology(RSM), process parameters model was established for exploration of design space and optimized operation conditions by Design Expert 10 software. The optimized process parameters were established as follows: inlet air volume 55 – 70 m3/h, product temperature 40 – 45 ℃, atomization pressure 80 - 120 kPa and spray rate 17.5 – 18.5 g/min. By implementing validated experiments, the process was confirmed to be robust with high yield, the product CQAs such as the percent of the labeled content and PSD complied with quality requirements.
  • Paper
    PENG Yanjie, ZHANG Lin, PANG Zheng, ZHONG Lijun, LIU Fang
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    TP25 is a highly active recombinant immunotoxin that targets human epidermal growth factor receptor 2(HER2) positive breast cancer. In this study, the lyoprotectant was selected and the lyophilization procedure of TP25 was optimized through the appearance of lyophilized products and half maximal inhibitory concentration(IC50) of reconstituted TP25 determined by tetrazolium method. The results showed that the lyophilized product in the group with 3.5 μg/ml of human albumin and 40 μg/ml of mannitol as lyoprotectant combination had a smooth and full appearance, and the activity recovery rate of the product was the highest. This study promoted the development process of TP25 industrial preparation and also provided ideas for the research of lyophilization of similar biological products.
  • Paper
    GAO Yadong, JIANG Wenming, LE Jian, DING Jingyuan, GUO Shengrong
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    The nasal mucosal permeabilities and pharmacokinetic characteristics of one formulation of budesonide nasal spray and two formulations of mometasone furoate nasal spray for the treatment of allergic rhinitis in clinical practice were compared. In this study, the solubilities of two raw material drugs, the permeabilities of the drugs from three approved nasal sprays through goat nasal mucosa and retention amounts, and the drug concentrations in plasma and main tissues of the rats were determined. The results showed that the solubility of budesonide in ultrapure water at 25 ℃ was (18.92±0.03)μg/ml, while the solubility of mometasone furoate was lower than the lower limit of linearity (5 μg/ml). The permeation rate of budesonide from the nasal spray across goat nasal mucosa was 1.07 μg·cm–2·h–1, while the permeation rates of mometasone furoate from two formulations of the nasal spray were lower than 0.77 ng·cm–2·h–1. The retention amount of budesonide in goat nasal mucosa was 19.27 μg, which was significantly higher than those of mometasone furoate from two nasal sprays(2.27 and 2.61 μg, respectively). After administration to rats(equivalent to 5 times of human daily dose), the drug concentrations in plasma and tissue samples were all lower than 1 ng/ml. It indicated that the amounts of the drugs which had been absorbed into the systemic circulation were low and the clinical safeties of three approved nasal sprays were high.
  • Paper
    SUN Jing, ZHOU Jing, LUO Jiajia, XU Yunhui, HUA Moli
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    Nine batches of hemp flowers and leaves collected from two domestic legally hemp planting bases in Yunnan and Heilongjiang provinces in 2019 and 2020 were used as the test materials. A GC-MS method was used to determine the composition of volatile components. The results showed that sixty-four components were identified by GC-MS, of which twenty-one components were found in all nine batches. And β-pinene(8), caryophyllene oxide(9), humulene(10), limonene(11) and β-caryophyllene(12) were confirmed by comparison with the reference substances. The UPLC-Q-TOF-MS method was used to determine the composition of non-volatile components. The results showed that forty-nine components were identified by UPLC-Q-TOF-MS, including twenty-seven phytocannabinoids, thirteen flavonoids, five spiro-components, two fatty acids, one dihydrophenanthrene and one phenolic component. Twentyone components were found in all nine batches, involving twelve cannabinoids. The Δ9-tetrahydrocannabinol(1), cannabidiol(2), cannabidiolic acid(3), cannabidivarin(4), cannabinol(5), cannabichromene(6) and cannabicyclol(7) were confirmed by comparison with the commercially available or self-made reference substances. This study can provide a reference for the development of medical applications of domestic hemp.
  • Paper
    WANG Xiaofeng, WANG Huijuan, ZHANG Jing, XIAO Xinyue, YANG Rui
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    The content, average degree of substitution, substitution degree distribution, acidity, moisture and particle size distribution of sodium sulfobutyl ether β-cyclodextrin(SBE-β-CD) were determined. The key factors affecting the consistency of solubilization ability of SBE-β-CD were analyzed by stepwise regression. The results showed that only the moisture variable was left in the stepwise regression analysis model of solubilization ability of SBE-β-CD, indicating that moisture had a significant negative impact on the solubilization ability, with an impact as high as –95.4%. Further stepwise regression analysis was carried out on the data of moisture and substitution degree distribution. The results showed that the relative contents of the two components, substitution degrees 3 and 10, had a high impact weight on moisture, which were respectively 58.1% and –57.3%. It was concluded that by optimizing the relative contents of the two components of substitution degrees 3 and 10, the moisture content in the final product might be adjusted, which could improve the solubilization ability of SBE-β-CD.
  • Paper
    HUANG Youxing, WANG Yuanjing, LI Guoqiong, YUN Yihui, CHEN Zelun
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    The purpose of this study was to investigate the effect of water activity(Aw) on the chemical stability of latamoxef sodium(1). Accelerated tests were carried out to investigate the generation rates of degradation impurities of 1 API and 1 for injection with different Aw during the period of 6 months, and the correlation analysis was carried out. The results showed that three degradation impurities(impurities 3, 4, 6) were significantly correlated with Aw. When the Aw value of 1 API or 1 for injection was less than 0.10, the change of each impurity in the accelerated stability test was not significant. When the Aw value of 1 API or 1 for injection was greater than 0.11, all impurities were increased, especially impurities 3, 4, and 6 increased sharply. 1 had been proved to possess strong hygroscopicity, and its legal moisture limit was set to 5.0%, which was close to the inflection point of Aw increase. In order to ensure the product quality, it is recommended to tighten the moisture control limit.
  • Paper
    SHAO Tianshu, GUO Lei, LI Xiao, ZHOU Changming
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    An HPLC method was established to determine the content of cystine(1) and cysteine(2) in compound amino acid injection(18AA). The Waters SunFire C18 column(4.6 mm×150 mm, 3.5 μm) was used, and the analysis was carried out in the gradient elution mode, with ammonium sulfate buffer∶acetonitrile(97∶3) as mobile phase A, acetonitrile as mobile phase B. The detection wavelength was 205 nm, the column temperature was 40 ℃, and the injection volume was 25 μl. The results showed that it was linear for 1 and 2 in the 0.002 - 0.040 mg/ml and 0.001 - 0.027 mg/ml, respectively. The detection limits were 0.99 and 0.67 μg/ml, respectively. The mean recoveries(n=9) of 1 and 2 were 102.3% and 100.5%, with the RSDs of 1.6% and 1.5%. The results of the simulation test on the formulation showed that the content of 1 in the sample was lower than the labeled amount, which might be related to the addition of the antioxidant sodium bisulfite. The established method is simple, rapid and accurate, which can provide a reference for the determination of 1 and 2 in compound amino acid injection.
  • Paper
    WANG Qianqian, WANG Xiaofeng, TU Jiasheng, SUN Huimin
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    A near-infrared quantitative analysis model on the glass transition temperature of polyvinyl alcohol with good accuracy was established using Fourier transform near-infrared diffuse reflectance spectroscopy technology. Both the choices of spectral preprocessing method and the model were optimized, and its feasibility was verified. The results of verification test showed that the predicted value according to the model was close to the measured value of differential scanning calorimetry, which was suitable for rapid screening of the glass transition temperature of polyvinyl alcohol.
  • Paper
    LENG Feng, LI Xiaolu, REN Fengzhi, LI Ning, YANG Zhaohui
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    The effects of the crystallization temperature, the dripping rate of antisolvent adding, the initial concentration of the crystallization and the occasion of seed crystal adding on the polymorph formation of fusidic acid(1) were investigated by the orthogonal experiment. The results showed that the crystallization temperature was the key factor affecting the polymorph formation of 1, followed by the dripping rate of antisolvent. Anhydrous 1 was formed when the antisolvent dripping rate was 0.1 ml/min and crystallized at 40 ℃, while 1 hemihydrate was obtained with more than 0.2 ml/min of dripping rate and 20 – 30 ℃ of crystallization temperature. The crystallization process of 1 was recorded online in real time with process analysis technology tools, and the transformation process of 1 crystal forms was revealed. Powder X-ray diffractometry(PXRD) and infrared spectroscopy(IR) were applied for both anhydrate and hemihydrate products. The analysis results were consistent with the literature reports. The experimental results could provide technical guidance for the large-scale production of 1 hemihydrate.
  • Paper
    LIU Yang, ZHANG Yaru, ZHOU Jiajia, ZHANG Xiaohua, XU Dan
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    The Arrhenius equation was used to predict the impurity growth trend of dexrazoxane for injection. The levels of impurities A and B were measured at 50, 60, 65, 75 and 80 ℃, and the rate constant(k) values for both was calculated. The Arrhenius equation of impurity A was lnk=–9.612–3.7/T(R2=0.953 8, P<0.000 1), and the Arrhenius equation of impurity B was lnk=–7.546–2.3/T(R2=0.959 1, P<0.000 1) by standard least squares linear regression. Then, the obtained Arrhenius equations were used to predict the levels of impurities A and B of 3 pilot batches of dexrazoxane for injection stored at 25 ℃ for 12 months, and the deviations of the predicted and measured values of impurity A were 0, 16.67% and 0, while the deviations of the predicted and measured values of impurity B were 4.76%, 5.26% and 5.56%, respectively. It was predicted that the levels of impurities A and B in dexrazoxane for injection stored at 25 ℃ were below limits in 51 months. The Arrhenius equation established in this paper can effectively predict the growth of impurities A and B of dexrazoxane for injection, which can be used as data support for the stability study of this product.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    LU Shihua, LI Shan, JIANG Mingyan, ZHAO Jie, JIANG Shoujun, ZHANG Jie
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  • Pharmaceutical Management & Information
    ZHANG Lian
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