30 November 2024, Volume 44 Issue 11

    

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Review & Monography
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  The metabolomics research progress of exploring biomarkers for colorectal cancer^*

  WANG Hua-guang, LONG Jiang, ZHANG Ying, DING Xian, ZHANG Jing-hui, LIU Xin-juan, AN Zhuo-ling, HAO Jian-yu

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1827-1841. https://doi.org/10.16155/j.0254-1793.2024-0158

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  Metabolomics, as a branch of systems biology, utilizes high-throughput omics technology to investigate metabolite changes within organisms, which enable us to explore the relationship between such alterations and disease etiology or evolution, thereby providing novel research insights for identifying relevant biomarkers and screening of diseases. In recent years, metabolomics has been widely used in the field of cancer research. At the same time, the changes of metabolic pathways can be deeply discussed by using the network shared database. Given that colorectal cancer ranks as the second most prevalent malignant tumor in China, it is crucial to search for clinically valuable tumor markers. This article will highlight the progress of recent five-year metabolomics studies in different matrices to identify potential biomarkers associated with colorectal cancer(CRC), so as to provide references for early screening of CRC.
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  Current approaches for in vitro drug release study of long-acting injectable formulations^*

  WANG Jing-wen, WEN Qiang, PENG Yu-shuai, ZHAO Wen, YIN Li-hui

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1842-1851. https://doi.org/10.16155/j.0254-1793.2024-0364

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  Long-acting injectable formulations are preferred over conventional formulations for the treatment of chronic diseases. The regulatory guidelines and pharmacopoeia have remained silent on dissolution methods for long-acting injectable formulations due to their diverse nature. The lack of compendial method for dissolution testing increases the duration of approval process for long-acting injectable formulations. This article reviews various dissolution methods used to study in vitro drug release profile of long-acting injectable formulations. Compendial as well as noncompendial methods, such as-flow-through cell method, sample and separate method, the dialysis method are used by researchers for drug release profile of long-acting injectable formulations. This review article also highlights the advantages and disadvantages of reported dissolution methods. The compiled work will help the researchers in designing the bio-relevant dissolution method and expedite the development of long-acting injectable formulations.
Ingredient Analysis
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  Flavor characterization of two kinds of Notopterygii Rhizoma et Radix volatile oils based on sensory evaluation and electronic nose technology, and establishment of nondestructive detection models

  OUYANG Hui-fa, LI Lin-zhi, WU Jia-ying, HU Hui-ling

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1852-1862. https://doi.org/10.16155/j.0254-1793.2024-0016

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  Objective: To conduct odor analysis of the main effective components, namely volatile oils, contained in two varieties, Notopterygium incisum Ting ex H.T.Chang and Notopterygium franchetii H.de Boiss, to provide a feasible method for promptly and accurately distinguishing between the differences in volatile oils of these two varieties of Notopterygii Rhizoma et Radix. This enriches the traditional evaluation content and serves as a reference for assessing the quality of extracts predominantly governed by volatile oils. Methods: The flavors of two samples of Notopterygii Rhizoma et Radix volatile oil were analyzed using electronic nose technology and sensory evaluation. The electronic nose data obtained were subjected to analysis and identification through principal component analysis (PCA) and linear discriminant analysis (LDA). Additionally, two nondestructive testing models-Fisher discrimination and multilayer perceptron (MLP) neural network discrimination were established for sample differentiation. Results: Sensory evaluation results indicated that pine resin flavor, cool flavor and woody flavor were the primary odor characteristics of both Notopterygii Rhizoma et Radix volatile oils. Additionally, the key flavor attribute influencing acceptance and differentiation was identified as spoiled yuba flavor, with the Notopterygium franchetii H. de Boiss volatile oil exhibiting a stronger presence of this attribute than the Notopterygium incisum Ting ex H. T. Chang volatile oil. The electronic nose results revealed that the nitrogen oxides’ response values in Notopterygium franchetii H. de Boiss volatile oil were significantly higher than those in Notopterygium incisum Ting ex H. T. Chang volatile oil. Meanwhile, the response values of hydrides, alcohol ether aldehydes, and ketones were slightly lower in Notopterygium franchetii H. de Boiss volatile oil compared to Notopterygium incisum Ting ex H. T. Chang volatile oil. The Fisher discriminant model demonstrated overall discrimination rates of 93.8% for the training set and 87.5% for the prediction set of the two volatile oils. In contrast, the MLP model achieved discrimination rates of 89.3% for the training set and 91.7% for the prediction set. Notably, the MLP model proved effective for identifying volatile oils, while the Fisher model exhibited greater suitability for discriminating volatile oils with broad-leaved characteristics. Conclusion: The combination of artificial senses and intelligent senses can be characterized from both subjective and objective perspectives, elucidating the flavor differences between the two kinds of Notopterygii Rhizoma et Radix volatile oils. The established Fisher discriminant function and MLP discriminant models can rapidly and accurately distinguish between the two kinds of Notopterygii Rhizoma et Radix volatiles. This lays a preliminary foundation for quality control in Notopterygii Rhizoma et Radix volatiles and offers new ideas and directions.
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  Analysis on transfer of reference value of classic prescription Daqinglong decoction^*

  MA Qi-feng, ZHANG Miao, WANG Yi-fei, LUO Jian-shun, CHU Qi, XI Qing-ju, QIU Zhi-dong, GAO Hong-mei

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1863-1874. https://doi.org/10.16155/j.0254-1793.2024-0093

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  Objective: To establish the substances benchmarks fingerprint of Daqinglong decoction and determine the content and transfer rate of 6 index components, and study the transfer rule of Daqinglong decoction substances benchmarks value, which laid the foundation for the study of Daqinglong decoction compound preparation and quality standard. Methods: Fifteen batches of substances benchmarks of Daqinglong decoction were prepared, and the paste rate was determined. To determine the contents of ephedrine, pseudoephedrine, amygdalin, and cinnamic acid, HPLC method was performed on a Dikma Platisil C₁₈ column (250 mm×4.6 mm, 5 μm). And 0.15% phosphoric acid water (A) and acetonitrile (B) were used as mobile phases with gradient elution at a flow rate of 1 mL·min^-1. The column temperature was 25 ℃, the detection wavelength was 207 nm, and the injection volume was 10 μL. To determine the contents of liquiritin and glycyrrhizic acid, 0.05% phosphoric acid water (A) and acetonitrile (B) were used as mobile phases with gradient elution. The detection wavelength was 237 nm. The transfer rate was calculated, and the transfer analysis from the decoction pieces to the substances benchmarks was carried out. Results: The fingerprint similarities of 15 batches of Daqinglong decoction substances were ≥0.921. Fifteen common peaks were identified, including 8 from Ephedrae Herba, 3 from Cinnamomi Ramulus, 2 from Glycyrrhizae Radix et Rhizoma(fried), and 2 from Armeniacae Semen Amarum(here). The contents of ephedrine, pseudoephedrine, amygdalin, liquiritin, cinnamic acid and glycyrrhizic acid were 0.94%-1.30%, 0.56%-1.02%, 0.70%-1.25%, 0.18%-0.32%, 0.05%-0.10% and 0.46%-1.23%, respectively. The transfer rates were 41.67%-59.47%, 42.66%-59.74%, 17.59%-36.34%, 21.48%-44.75%, 31.06%-48.89% and 12.95%-25.15%, respectively. The paste yields of substances benchmarks were 11.98%-13.38%. Conclusion: The fingerprint combined with the determination of paste rates and index component contents are used to study the quantitative value transfer of Daqinglong decoction substance benchmarks, and initially establish a scientific and stable substance benchmarks quality evaluation method, which can provide reference for the future research on compound preparation.
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  Characteristic chromatogram and quality evaluation of Gujing Maisiha tablets by HPLC coupled with chemometrics

  CHANG Dao-xiao, GENG Xiao-xiu, LI Hui, WEN Jin-rong, WANG Zhen

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1875-1884. https://doi.org/10.16155/j.0254-1793.2023-0565

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  Objective: To establish the HPLC characteristic chromatogram for Gujing Maisiha tablets, and evaluate the quality using chemical pattern recognition. Methods: The Welch Xtimate C₁₈ column (250 mm × 4.6 mm, 5 μm) was used and the mobile phases were acetonitrile (A) and 0.1% formic acid (B) in gradient elution (0-10 min,5%A→15%A;10-20 min,15%A;20-40 min,15%A→40%A;40-65 min,40%A→70%A; 65-66 min,70%A→90%A;66-80 min,90%A;80-81 min,90%A→5%A;81-85 min,5%A). The detection wavelength was 254 nm. The column temperature was 35 ℃ and the flow rate was 1.0 mL·min^-1. Gujing Maisiha tablets were analyzed to construct characteristic chromatogram. The quality of Gujing Maisiha tablets was assessed through similarity evaluation, cluster analysis, principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA). Results: The characteristic chromatogram of Gujing Maisiha tablets was established, which contained the twenty-eight distinct peaks, and seven compounds identified as gallic acid, chlorogenic acid, picrocrocin, isoquercitrin, crocin-Ⅰ, crocin-Ⅱ, eugenol. The similarities for the ten batches of Gujing Maisiha tablets were more than 0.98, with no significant difference observed. Cluster analysis segregated the samples into two distinct groups according to the Euclidean distance of 10, which was consistent with the results of PCA analysis. PLS-DA analysis screened out five components from Flos Caryophylli, Rosae Rugosae Flos, Olibanum that may cause differences between samples. Conclusion: The method of HPLC characteristic chromatogram of Gujing Maisiha tablets is effective, feasible and reproducible, which can provide reference for the study of quality standard of this product.
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  Quality control of Zuoyu’an San research based on fingerprint combined with chemometrics and QAMS^*

  QIN Xiang, LIANG Jie, CHEN Zhuang, LIANG Guo-cheng, HUANG Bei, HUANG Yan-qiong, YU Tong-tong

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1885-1898. https://doi.org/10.16155/j.0254-1793.2024-0167

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  Objective: To establish an HPLC fingerprint of Zuoyu’an San and conduct quality control by combining chemometrics and quantitative analysis of multi-components with a single-marker(QAMS). Methods: HPLC was used to establish the fingerprint spectra of 12 batches of Zuoyu’an San and perform similarity evaluation. Cluster analysis (CA), principal component analysis (PCA), and orthogonal partial least squares discriminant analysis (OPLS-DA) were combined to perform chemical pattern recognition analysis on different batches of Zuoyu’an San. At the same time, QAMS method was established using rhein as the internal standard reference. The relative correction factors between the internal reference and jatrorrhizine, palmatine, berberine, aloe-emodin, emodin, chrysophanol, and physcion were established. The external standard method (ESM) and QAMS method were used to determine jatrorrhizine, palmatine, berberine, aloe-emodin, rhein, emodin, chrysophanol, and physcion in Zuoyu’an San, respectively. To verify the reliability of QAMS metod results, the contents of 8 components of physcion were determined. Results: A total of 23 common peaks were calibrated in the fingerprint, and 8 components were identified by comparing with the mixed reference solution. The similarity between the samples and the control spectrum was between 0.952 and 0.994; CA divided 12 batches of Zuoyu’an San samples into 3 categories; PCA showed that there were certain differences in the chemical composition of different batches of Zuoyu’an San, and extracted 5 principal components that affected the quality evaluation of Zuoyu’an San; OPLS-DA screened out 13 potential marker components (VIP>1) among 23 common peaks that caused quality differences between different batches of Zuoyu’an San samples; There was no significant difference between the QAMS method calculated value and the ESM measured value. Conclusion: The established HPLC fingerprint and multi-index component determination method was accurate and simple, and combined with chemometric methods, could provide reference for the quality control and evaluation of Zuoyu’an San.
Bioassay·Metabolism Analysis
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  Monitoring the bioburden of oligotrophs in pharmaceutical water systems and controlled environments^*

  FAN Yi-ling, LI Qiong-qiong, WANG Pei-en, YANG Mei-cheng

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1899-1908. https://doi.org/10.16155/j.0254-1793.2024-0357

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  Objective: To screen the suitable monitoring method applicable to oligotrophs and review the bioburden and microbial species of oligotrophic environments in pharmaceutical water systems and cleanrooms. Methods: The culture conditions and detection methods suitable for microorganisms under oligotrophic conditions were optimized by comparing the counting results of microorganisms in laboratory pure water with R₂A and TSA media at different temperatures, media, and incubation times. In addition, monitoring of oligotrophs in pharmaceutical environments using both the traditional and oligotrophic assays were conducted, combining with the techniques of 16s rDNA sequencing and MALDI-TOF MS for multiphase microbial identification and analysis of the isolated microorganisms under oligotrophic conditions. Results: The colony counting methods, the type of culture media, and the incubation intervals significantly affected microbial enumeration. The isolation method using oligotrophic medium R₂A was more effective than the TSA medium in this study. The profiles of microorganisms isolated from the R₂A and TSA media were unique. The isolation rate of Gram-negative bacteria in the R₂A medium reached 37.0%, however, that of Gram-negative bacteria in the TSA medium was only 14.0%. In addition, several strains of potential pathogens initially isolated from the R₂A medium grew slowly in the TSA medium and were easily missed by the traditional monitoring method. Conclusion: With the development of the pharmaceutical industry, the contamination proportion of human-associated Gram-positive cocci might gradually decrease, the oligotrophic culture method as a powerful supplement to traditional monitoring techniques can help to detect potential objectionable microorganism contamination risks at an early stage.
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  Study on the pharmacokinetics and the correlation between distribution of puerarin-icariin and dynamic expression of proteins in mouse hippocampus after oral administration of Shenge Bushen capsules^*

  WANG Wei-hua, LEI Fan, LI Cheng-gong, SUN Hong, HU Shi-xian, XING Dong-ming, REN Bin, HAO Juan, DU Li-jun

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1909-1922. https://doi.org/10.16155/j.0254-1793.2024-0423

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  Objective: To study the dynamic changes of puerarin and icariin in plasma and hippocampus of mice, to observe the changes of depression-related protein expression in hippocampus, and to explore the pharmacokinetic changes of Shenge Bushen capsules (SBC) and its correlation with the changes of hippocampus-related protein expression. Methods: Puerarin and icariin in plasma and hippocampus of normal mice were analyzed by UPLC-MS/MS-ABSCIEX QTRAP 5500 triple quadrupole series linear ion trap mass spectrometry method using Waters Acquity HSS T3 (50 mm×2.1 mm, 1.8 μm) column with 0.05% formic acid water-acetonitrile-methanol (1∶1) containing 0.05% formic acid as mobile phases gradient elution at a flow rate of 0.2 mL·min^-1 and electrospray ion source under negative ion model. The proteins in hippocampus were expressed by Western blot assay. Results: Puerarin and icariin were detected in plasma and hippocampus after the oral administration, including plasma puerarin t_1/2 2.45 h, icariin t_1/2 3.59 h, hippocampus puerarin t_1/2 4.37 h and icariin t_1/2 8.5 h. The plasma concentration of puerarin accounts for 27.3% and that of icariin accounts for 1.34% of the dosage taken. Puerarin in hippocampus accounts for 2.47% of puerarin absorbed into blood, while icariin in hippocampus accounts for 73.56% of icariin absorbed into blood. The expressions of restrictive silencing factor (NRSF), brain-derived neurotrophic factor (BDNF) and its downstream protein tyrosine kinase B (TrkB), solute carrier transporter 6a4 (SLC6A4), glucocorticoid receptor (GR) and μ opioid receptor (MOR) in hippocampus were all up-regulated after SBC administration, in which icariin was negatively correlated with NRSF expression, puerarin was positively correlated with BDNF-TrkB and MOR, and GR had no obvious correlation with the proteins. Conclusions: Puerarin and icariin can be absorbed into the blood and distributed in the hippocampus after oral administration of SBC in mice. Icariin was easier to pass through the blood-brain barrier and distribute in the hippocampus than puerarin. The expression of hippocampus-related proteins was related to the changes of puerarin and icariin concentrations, suggesting that the targets of the two components as well as SBC were related to these proteins. This study provides an important experimental basis for the pharmacokinetic study of SBC and also provides a material basis of its antidepressant effect.
Process Evaluation·Standard Deliberation
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  Study on in-line monitoring of water content in domperidone tablets particles by near infrared spectroscopy^*

  WANG Xiao-liang, NIU Long-qing, ZHANG Bing-hua

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1923-1931. https://doi.org/10.16155/j.0254-1793.2023-0357

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  Objective: To establish a quantitative model to in-line in situ determination of the water content of domperidone tablets particles in fluidized bed granulation drying process. Methods: Using micro near infrared spectrometer, in-line collected near infrared(NIR) spectrum of domperidone tablets particles in granulation drying process, took sample at different drying time to acquire sample in different level of water content. The pretreatment method of first derivative(FD), multiplicative scatter correction (MSC) and Savitzky-Golay smoothing were selected. The modeling band was 1 100-1 600 nm, model was established by partial least square(PLS) method, and validation was executed including accuracy, precision, specificity, linearity and range, robustness. Results: The root mean square error of cross validation(RMSECV) was 0.079 7,the coefficient of determination(R²) was 0. 994 5,the root mean square error of prediction(RMSEP) was 0.092 3, the R² was 0.986 0. All validation results met predefined criteria. Conclusion: It is feasible for using micro NIR spectrometer to in-line measure the water content of domperidone tablets particles which provides an experimental basis for the in-line application of process analysis technology in pharmaceutical industry.
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  Optimization of extraction process of Impatientis Balsaminae Caulis based on network pharmacology and mixture weighting methods^*

  MU Xue-feng, WU Ming, ZHOU Chao-mei, SHI Jing, YOU Yuan-yuan

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1932-1943. https://doi.org/10.16155/j.0254-1793.2023-0717

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  Objective: To optimize the extraction process of Impatientis Balsaminae Caulis in the treatment of degenerative osteoarthritis based on network pharmacology, mixture weighting and response surface method. Methods: Network pharmacology and LC-MS techniques were used to determine the active ingredients of Impatientis Balsaminae Caulis in the treatment of osteoarthritis,and they were taken as evaluation indexes. The extraction process of Impatientis Balsaminae Caulis was optimized by analytic hierarchy process(AHP)-criteria importance through intercriteria correlation(CRITIC) mixed weighting method and Box-Behnken response surface design. Results: Scopoletin,quercetin and kaempferol were the active ingredients in the treatment of osteoarthritis. The optimal extraction process was to add 5 times of 82% ethanol and reflux twice, 35 min each time. Conclusion: The treatment of osteoarthritis can be achieved by regulating target genes and related signaling pathways through various active components. The weight coefficient determined by AHP-CRITIC hybrid weighting method is objective and reasonable, and the optimized extraction process is stable and feasible.
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  Exploration of matrix effect in drug concentration detection in biological samples

  LIU Fei-fei, WANG Yu-zhu

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1944-1950. https://doi.org/10.16155/j.0254-1793.2024-0174

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  In the process of drug development, the bioanalytical is required generally in pharmacokinetic studies. The accuracy, reliability, and scientificity of bioanalytical method validation are crucial, the investigation of matrix effects has become an important part of the validation system for bioanalytical methods. This article investigated related guidelines from ICH, NMPA, FDA and EMA, searching the related domestic and foreign literature on matrix effect, combining with the case study of matrix effect in actual review, to discuss the method of investigating the matrix effect in the methodological verification of drug concentration detection in unknown biological samples, to clarify the causes and solutions of matrix effect. So as to ensure the standardization of the methodological verification of drug concentration detection in unknown biological samples and the accuracy of the test results, to achieve the optimization of drug concentration detection methods for biological samples.
Safety Monitoring
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  Identification of Eupolyphaga Steleophaga (Eupolyphaga sinensis) formula granules by specific PCR

  LIU Shan-shan, TAN Si-yin, SONG Ye, XIAN Le-yao, FAN Yao-yao, LUO Yu-qin, LI Guo-wei

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1951-1957. https://doi.org/10.16155/j.0254-1793.2024-0075

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  Objective: To establish a specific polymerase chain reaction(PCR) method based on SNP loci for molecular identification of Eupolyphaga Steleophaga formula granules and its counterfeit. Methods: By analyzing the cytochrome oxidase Ⅰ (COⅠ) sequences of Eupolyphaga Steleophaga and its common forgeries, the SNP mutation sites of Eupolyphaga Steleophaga were searched and specifi cprimers were designed, which were TBC-F(5’-TTCTTGTTGGCAAGCAGTATAAT-3’) and TBC-R(5’-AACTACTGCTCAAACAAATAATGGA-3’). Three-step method was used to amplify specific polymerase chain reaction (PCR) and the optimal PCR reaction system was determined by optimizing the PCR reaction procedure. At the same time, in order to ensure the accuracy of the test results, the PCR amplified products were conducted by generation sequencing. Results: The PCR method with the annealing temperature of 55-57 ℃ and 37 cycles produced a single band at 237 bp for 21 batches of Eupolyphaga Steleophaga, 20 batches of standard decoction and 19 batches of its dispensing granules, while it produced no band for the adulterant or the negative control. The experimental result was consistent with the result of Sanger sequencing, which was Eupolyphaga sinensis. Conclusion: The established specific PCR method can accurately identify the medicinal materials, and standard decoction freeze-dried powder of Eupolyphaga Steleophaga, as well as final products of dispensing granules. It provides a reference for research on the quality standards of Eupolyphaga Steleophaga dispensing granules.
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  Changes of volatile components during oxidative rancidity of Scorpion analyzed by SPME-GC-MS^*

  ZUO Kai, HE Xu-feng, HUANG Xiao-lan, YANG Wen-wu, WU Rong, CAO Wei-guo

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1958-1966. https://doi.org/10.16155/j.0254-1793.2024-0162

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  Objective: To analyze the variation of volatile components during oxidative rancidity of Scorpion, and identify the main components resulting in the rancid flavor of Scorpion. Methods: Scorpion samples were subjected to accelerated oxidation experiment for 50 d, starting from 0 d, and sensory evaluation of the sample was performed every 10 d. At the same time, the volatile components were detected by solid phase microextraction GC-MS(SPME-GC-MS). Six groups of data were obtained. The volatile components obtained were searched by computer, and the results were matched with the NIST 20 database to determine the chemical structure of that. Meanwhile, the relative content of volatile components was calculated by using 2-octanol as internal standard, and the main components of Scorpion’s rancid flavor were screened out through principal component analysis and cluster analysis. Results: A total of 51 volatile components such as aldehydes, acids and furans were detected, of which 43 were common to six groups of data. There were significant differences in the content of volatile components of Scorpions in different oxidation time periods, with aldehydes being the highest, with an average content of 101.33 mg·kg^-1, accounting for 54.45%, followed by acids, with an average content of 52.01 mg·kg^-1, accounting for 27.95%. With the prolongation of the oxidation time, the Scorpion appeared to have a rancid flavor, when oxidized for 50 d, a heavy rancid flavor appeared; at the same time, the content of volatile components of all categories showed an increasing trend, among which the content of heptanal, nonanal, n-octanal, 2-butyl-2-octenal, 4-oxo-2-nonenal, hexanoic acid and 2-n-pentylfuran increased significantly, with an increase of multiples of 4 times to 44 times. Through principal component analysis, three principal components were screened out with eigenvalues above 1 value, among which the eigenvalue of principal component 1 was 40.451, and the contribution rate of that reached a 79.32%, the main influencing factors included aldehydes, acids and furans. Six groups of samples were divided into four categories by cluster analysis, which was consistent with the results of sensory evaluation. Conclusion: Seven volatile components, heptanal, nonanal, n-octanal, 2-butyl-2-octenal, 4-oxo-2-nonenal, hexanoic acid, and 2-n-pentylfuran, are the main substances in the production of rancid flavor of Scorpion. This experiment provides a new technology and new method for the development of simple and precise monitoring of the oxidative rancidity process of Scorpion, and to provide a research basis for the improvement of Scorpion quality standard.
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  Determination of two related substances in lappaconitine hydrobromide injection by HPLC-principal component self-compare with correction factor^*

  XU Shu-juan, ZHANG Lei, MA Shu-feng, FU Xia, LU Na, WU Chuan-li

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1967-1974. https://doi.org/10.16155/j.0254-1793.2024-0149

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  Objective: To establish an HPLC-principal component self-compare with correction factor method for quantification of two related substances (N-deacetyllappaconitine and ranaconitine) in lappaconitine hydrobromide injection. Methods: The analysis was performed on a Kromasil 300-5-C₁₈ (250 mm×4.6 mm,5 μm) column with a mobile phase composed of 0.04 mol·L^-1 potassium dihydrogen phosphate solution, methanol and acetonitrile (68∶17∶15). The detection wavelength was 252 nm, the flow rate was 0.8 mL·min^-1, the column temperature was 37 ℃, and the injection volume was 10 μL. The slope of linear equation was used to determine the relative correction factor between the two impurities and lappaconitine hydrobromide. The relative retention time was used to determine the position of related substances. The contents of two impurities in 25 batches of lappaconitine hydrobromide injection produced by four pharmaceutical companies were determined and compared with the results of the external standard method. Results: Lappaconitine hydrobromide and the impurities were separated well by this method. The relative retention time of N-deacetyllappaconitine and ranaconitine were 1.20 and 1.39, and the correction factors were 1.23 and 0.94, respectively. Lappaconitine hydrobromide, N-deacetyllappaconitine and ranaconitine showed good linearity in the mass concentration ranges of 0.951 7-38.07 μg·mL^-1, 1.047-41.87 μg·mL^-1 and 1.001-40.02 μg·mL^-1 with r=1.000, respectively. The average recovery rates of lappaconitine hydrobromide, N-deacetyllappaconitine and ranaconitine were 100.2%, 100.5% and 100.5% respectively, with RSD less than 2.0%. The limits of detection (LOD) of lappaconitine hydrobromide, N-deacetyllappaconitine and ranaconitine were 0.095, 0.10, 0.10 μg·mL^-1 and the limits of quantitation (LOQ) were 0.32, 0.35 and 0.33 μg·mL^-1, respectively. The content of N-deacetyllappaconitine in 25 batches of lappaconitine hydrobromide injection was in the range of 0.31%-0.82% and the content of ranaconitine was in the range of 0%-0.09%. It was consistent with the determination result of the external standard method. Conclusion: The method is proved to be simple, rapid, and accurate for the determination of related substances in lappaconitine hydrobromide injection.
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  Identification of 22 added drugs in foot-use cold compress gel and quantification of four drugs

  LU Hua, ZHU Xi, ZHONG Zhuo-ling, GAO Xiao-yan, YANG Jing

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1975-1982. https://doi.org/10.16155/j.0254-1793.2024-0114

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  Objective: To establish a method for the rapid identification of 22 illegally added drugs in foot-use cold compress gel, and to quantify the content of 4 drugs. Methods: Use ultra-performance liquid chromatography-high resolution mass spectrometry/mass spectrometry (UPLC-HRMS/MS) for qualitative analysis. Using Hypersil GOLD^TM VANQUISH C₁₈ (2.1 mm×100 mm,1.9 μm) chromatographic column, gradient elution was performed with 10 mmol·L^-1 ammonium acetate aqueous solution (A) and methanol (B) as mobile phases, column temperature was 40 ℃, flow rate was 0.2 mmol·L^-1, ESI ion source was used, and qualitative analysis was performed by switching between positive and negative scanning modes. By comparing the retention time, parent ion, and fragment ion information of the standards and sample under the same chromatographic and mass spectrometric conditions confirmed the illegal added drugs in the sample and the suitable methods were used for quantitative analysis. Results: After qualitative analysis, it was confirmed that the sample contained 4 illegally added drugs: acetaminophen,chloramphenicol,lidocaine hydrochloride and miconazole nitrate. The concentrations of these 4 drugs ranged 2.542-101.7 μg·mL^-1, 1.410-169.161 μg·mL^-1, 0.002-0.2 μg·mL^-1, 5.184-290.304 μg·mL^-1, respectively. The peak areas showed good linear relationships with concentrations, with correlation coefficients of 0.999 9, 0.999 7, 0.999 9 and 0.999 1, respectively. The limits of detection were 0.015, 0.143, 0.001,0.833 μg·mL^-1, respectively. At three concentration levels, the recovery rates ranged 98.5%-104.5%, 90.2%-99.4%, 79.5%-84.9%, 102.8%- 104.3%, with the RSD of 0.059%-0.28%, 0.20%-0.49%, 1.2%-3.1%, 0.18%-0.40%, respectively. The contents were 195.05, 264.10, 1.24, 67.00 mg per bottle, respectively. Conclusion: The qualitative method is simple, rapid, and highly accurate, while the quantitative method is specific, precise, accurate, and stable, making it suitable for the rapid identification of 22 illegally added drugs and the quantification of 4 illegal added drugs in foot-use cold compress gel.
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  Determination of 17 chemicals in medical cold compress by solid phase extraction-ultra performance liquid chromatography-tandem mass spectrometry^*

  PENG Yan, YANG Zhi, CHENG Li, LIN Li-qin, CHEN Liu-wei

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1983-1991. https://doi.org/10.16155/j.0254-1793.2024-0212

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  Objective: To establish a method for the determination of 17 kinds of anti-allergic compounds in medical cold compress by solid phase extraction-ultra performance liquid chromatography-tandem mass spectrometry(SPE-UPLC-MS/MS). Common medical cold compress matrices were suitable for this new method. Methods: Three pretreatment methods were compared: prime pass-through column purification, SPE purification including HLB and MCX solid-phase extraction. The pretreatment was optimized by focusing on the kind of solid-phase extraction, the type and volume of elution solvents. The analytes were extracted using methanol and then mixed with water at the ratio of 1∶9 in volume, purified with an Agilent Bond Elut HLB column. Waters ACQUITY UPLC BEH C₁₈(100 mm×2.1 mm,1.8 μm)column was used with 0.1% formic acid(with 0.5 mmol·L^-1 ammonium acetate)-acetonitrile as mobile phases by gradient elution for separating 17 compounds. Detection was carried out by positive and negative electrospray ionization(ESI)mass spectrometer in multiple reaction monitor (MRM) mode. Results: All the 17 kinds of compounds showed good linearity in their reasonable ranges(r)＞0.99, the limit of detection (LOD) and quantification(LOQ)were 0.01-13.32 μg·g^-1 and 0.02-26.64 μg·g^-1, respectively. The average recoveries of at three spiked levels were in range of 77.7%-108.5%, with RSDs (n=6) were 0.62%-4.7%. The content range of diclofenac sodium in positive samples was 0.09-27.55 mg per tablet. Conclusion: The method is simple, sensitive and reliable, and is suitable for determination of 17 illegally add chemical drugs in medical cold compress. Moreover, the method might provide technological support for the detection of illegal additions in medical cold compress.
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  Rapid determination of water content in certain pharmaceutical excipients by ¹H qNMR method^*

  CHEN Xin-qi, WEN Jing, LIU Hao-hui-ling, ZHANG Mei, JIAO Xiao-lin, WANG Wei

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1992-1996. https://doi.org/10.16155/j.0254-1793.2024-0258

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  Objective: To establish a quantitative nuclear magnetic resonance hydrogen spectroscopy(¹H qNMR) method for determining the moisture content in several pharmaceutical excipients. Methods: Using sodium benzenesulfonate as the internal standard and heavy water as the solvent, the water content in the blank sample was determined by absolute quantification using nuclear magnetic resonance spectroscopy. By comparing with the blank value, a quantitative calculation formula for the water content in the sample was established, and the water content in the sample was tested and calculated. Results: Methodological studies had shown that this method had a good linear relationship(r=0.999 1), with a linear range of 0.032-0.561 mg absolute water content in the sample, the precision RSD was 0.039%, repeatability RSD was 0.43%, and the average recovery was 98.7%. The ¹H qNMR method measured the water content in DMSO-1, DMSO-2, sodium benzenesulfonate, and sodium acetate to be 0.23%, 0.28%, 0.46%, and 0.28%, respectively, which were essentially consistent with the results obtained from the method described in the Chinese Pharmacopoeia(2020). Conclusion: The ¹H qNMR method established is fast, simple to operate, with a small sample size and accurate results. It can be used for the determination of water content in some pharmaceutical excipients.
Quality Control
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  Application of cyclic ion mobility mass spectrometry for conformational analysis of lasso peptide-type complex drugs^*

  ZHU Shao-zhou, FAN Li-jiao, ZHANG Tuo, SUN Jia-bei, YAO Jing, HUANG Hai-wei, ZHANG Qing-sheng

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 1997-2003. https://doi.org/10.16155/j.0254-1793.2024-0112

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  Objective: To explore the feasibility and potential applications of high-resolution cyclic ion mobility separation mass spectrometry (Cyclic IMS) for detecting the conformations (topological isomers) of complex medicines. Methods: Using MccJ25 and Rubrinodin lasso peptides as models, the compounds were subjected to heat treatment at 0, 50, and 80 ℃ for 4 h, respectively. The samples were then directly injected for separation and detection using high-resolution Cyclic IMS. Results: The two model compounds exhibited different topological structural changes at three temperatures tested. MccJ25 showed no significant conformational changes and exhibited a relatively stable topological structure across all temperatures. In contrast, Rubrinodin demonstrated significant conformational changes at each temperature. The cyclic ion mobility cell in Cyclic IMS was able to accurately identify conformational changes, such as folding and unfolding, in the complex drugs. Conclusion: Cyclic IMS can precisely analyze the conformation (topological isomers) of complex drugs, detect small conformational changes, and offers strong operability, good reproducibility, and high accuracy. It holds potential for use in the conformational determination and quality control of complex drug molecules.
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  Determination of particle size distribution of budesonide suspension for inhalation by laser diffraction method^*

  XIE Li, SU Li, XIAO Yao, ZHANG Rong-qin, ZHENG Ping

  Chinese Journal of Pharmaceutical Analysis. 2024, 44(11): 2004-2010. https://doi.org/10.16155/j.0254-1793.2023-0812

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  Objective: To establish a laser diffraction method for the determination of particle size distribution of budesonide suspension for inhalation. Methods: The Master sizer 3000 laser size analyzer with the Hydro SV wet sampler was used. The sample solution should be immediately measured after ultrasonication. The measurement conditions were as follows:refractive index of budesonide was 1.592, absorbency of budesonide was 0.01, dispersing medium was saturated solution of budesonide containing 0.5% Tween 80 with refractive index of 1.33, stirring rate was 1 000 r·min^-1,and laser obscurations were 6%-12%. Results: RSD of D₅₀ was lower than 2%, RSDs of D₁₀ and D₉₀ were both lower than 5%.The particle size distribution D₉₀ values of 3 batches of budesonide suspension for inhalation were less than 5 μm. Conclusion: The method is simple, accurate and producible, which is suitable for the particle size detection of budesonide suspension for inhalation.