A Mechanism Study on the (+)-ESI-TOF/HRMS Fragmentation of Some PPI Prazoles and Their Related Substances.

Fragmentation mechanisms of some prazoles and their related substances were newly investigated in this paper via positive mode ESI-TOF HRMS1 and HRMS2. Some novel fragmentation rules or ions were found or detected in the research. The pyridine and the benzoimidazole ring remained in most cases during the ionization, and heterolytic fragmentations often occurred near the -S(O)nCH2- linker to give the [1,3]-H migration ion or [1,7]-H migration ion rearranging across the benzoimdazole ring. Smiles rearrangement ionizations also frequently occurred, initiated by the attack of the lone pair electrons from the pyridine ring, and the sulfones gave special N-(2-benzoimdazolyl) pyridine ions (11b and 12c) by a direct extraction from SO2, and the thioethers gave similar framework ions (8c, 9c and 10c) via the rearrangement and a further homolytic cleavage of SH radicals. However, the sulfoxides were seldom detected in the corresponding Smiles rearrangement ions during our measurement, and the N'-oxides of the pyridines did not undergo the Smiles rearrangement ionization due to the absence of the lone pair electrons. The 5/6-membered chelating ions with Na+ or K+ were frequently detected as the molecular and further fragment ions. Some novel and interesting fragment ions containing bivalent (8b and 9b), tetravalent (4b, 5c and 6c) or hexavalent (15b and 16b) sulfurs were first reported here.

Evaluating the sensitivity, stability, and cross-reactivity of commercial fentanyl immunoassay test strips.

Illicit fentanyl has flooded the United States' drug market, increasing the risk of overdose and poisonings throughout the general population and accidental exposure among law enforcement officers confiscating the increasing number of seizures. Fentanyl test strips (FTS) are used to obtain presumptive information about the presence of fentanyl in a suspected sample. However, their adoption by law enforcement personnel and seized-drug analysts has been limited because most products are advertised for urine testing, not for assays using water solutions. This study presents an evaluation of four commercial FTS: Rapid Response from BTNX, Inc.; T-Dip Fentanyl (FTY) Urine Dip Cards obtained from Amazon.com; Premier BioDip FYL10 from Premier Biotech Inc.; and MobileDetect Fentanyl strips from DetectaChem, Inc. Performance characteristics curves were used to compare the products' sensitivity, showing that all can reliably detect fentanyl in aqueous solutions at concentrations below 1 µg/mL, with some of the tests able to reliably detect the drug at 200 ng/mL. A stability study demonstrates the performance of all four FTS brands was only slightly affected after 30 days of storage at two extreme environmental conditions. Fentanyl-related substances are also evaluated using the Rapid Response FTS, which showed high cross-reactivity with para-fluorofentanyl and acetylfentanyl, but lower with ortho-chlorofentanyl, carfentanil, and 4-ANPP. Users should be aware that FTS may give false-negative results even when potentially dangerous levels of carfentanil are present. When testing other common drugs, adulterants, and diluents frequently encountered in seized tablets, concentration-dependent results were obtained and multiple instances of false positives were recorded.

New Insights into Herb-Induced Liver Injury.

Significance: Herbs are widely used worldwide. However, inappropriate use of some of the herbs can lead to herb-induced liver injury (HILI). Intriguingly, HILI incidents are on the rise, and our understanding of the underlying etiologies is in progress, and hence, an update on the current status of incidents as well as our understanding on the etiologies of HILI is appropriate. Recent Advances: HILI reports due to the use of some herbs that are traditionally considered to be safe are also on the rise. Furthermore, HILI due to the use of certain herbs in combination with other herbs (herb-herb interaction [HHI]) or non-herb components (herb-drug interaction [HDI]) has also been reported, suggesting a potentially important new type of inappropriate use of herbs. Critical Issues: Updated overviews focus on the epidemiology, etiology, phenotypes, and risk factors of HILI, as well as HDI and HHI, and analysis on several types of newly reported "toxic" effects of herbs based on types of hepatotoxicity and the HILI mechanisms. Future Directions: HILI will continue to be a significant public health challenge in the near future. In the light of the lack of broadly available guidelines and regulations for proper and safe uses of herbs worldwide, raising the public awareness of HILI will remain one of the most effective measures. In particular, it should include a better understanding of the contributing factors; a more detail subclassification and description of HILI, better characterization of the components/substances that could induce HILI; and development of HILI diagnosis based on the Roussel Uclaf Causality Assessment Method (RUCAM). Antioxid. Redox Signal. 38, 1138-1149.

Occurrence characteristics of uranium mineral-related substances in various environmental media in China: A critical review.

The high demand and extensive exploitation of uranium resources resulted in the ubiquity and high detection levels of uranium mineral-related substances in various environment media in China. The potential adverse effects of uranium mineral-related substances on environment and human health have received extensive attention. Therefore, we reviewed the occurrence and spatial distribution of uranium mineral-related substances in various basins and environmental media in China to obtain an overall understanding. We collected information from over 70 papers reporting the occurrence and distribution of uranium mineral-related substances in multiple environments and 183 articles on the genesis of uranium deposits in China from 2001 to 2021. Then the occurrence of uranium mineral-related substances and corresponding correlation in different basins, environmental media and depth ranges were compared in detail. And this review assessed the uranium mineral-related pollution in China based on various environmental quality standards of China, EPA and WHO, and proposed the priority uranium mineral-related heavy metals and radioactive substances based on cluster analysis. This review showed that there were obvious differences in the occurrence characteristics of various uranium mineral-related substances in different environmental media, especially in the surrounding environment of sandstone type and hard rock type uranium deposits. These results will guide us to tackle the challenge of uranium mineral-related pollution in China. The correlation analysis of uranium mineral-related pollutants in different environmental media and the identification of priority pollutants will also provide instructions for us to control uranium mineral-related pollution. Finally, we put forward a series of urgent and practical suggestions on risk management and control of uranium mining according to the current situation of uranium mining environment in China, which is of guiding significance for the realization of "green uranium mining".

Method establishment for content determination of related substances in Oxcarbazepine tablets / 中国药房

OBJECTIVE To establish the method for content determination of related substances in Oxcarbazepine tablets. METHODS Ultra-high performance liquid chromatography （UPLC） method was adopted and the separation was performed on ZORBAX Eclipse Plus C18 column with mobile phase consisted of acetonitrile-0.01 mol/L ammonium acetate solution （pH6.0） （gradient elution） at the flow rate of 0.5 mL/min. The detection wavelength was 230 nm and column temperature was set at 35 ℃. The sample size was 10 μL. RESULTS The linear ranges of oxcarbazepine and impurity A， B， C， D， E， I， K， L and N were 0.192-1.440， 1.019-7.639， 0.208-1.559， 0.230-1.727， 0.389-2.915， 0.182-1.364， 0.393-2.945， 0.199-1.493， 0.199-1.490 and 0.200- 1.503 μg/mL， respectively （all r＞0.999）. The detection limits were 0.046， 0.037， 0.049， 0.027， 0.077， 0.040， 0.114， 0.054， 0.055 and 0.039 μg/mL. The quantitation limits were 0.152， 0.122， 0.162， 0.090， 0.258， 0.132， 0.380， 0.181， 0.185 and 0.130 μg/mL. RSDs of precision， repeatability， stability （24 h） and durability tests were all lower than 5.0%. The average recoveries were 92.8%-105.6% （RSD≤3.0%， n＝9）. Only impurity K and unknown impurity were detected in the original preparation sample， with a total content of 0.078% to 0.083%； impurities A， B， D， I and unknown impurity were detected in the generic preparations produced by domestic enterprise Ⅰ， with a total content of 0.147% to 0.163%； impurities A， B， I and unknown impurity were detected in the generic preparations produced by domestic enterprise Ⅱ， with a total content of 0.085% to 0.161%. CONCLUSIONS The established method is rapid， sensitive， accurate， stable and durable. It can be used for the content determination of 9 known impurities in Oxcarbazepine tablets.

Study on related substances of TSD-1 — a novel P2Y12 receptor antagonist / 药学学报

For quantitative analysis of related substances in TSD-1 active pharmaceutical ingredient, structures of prepared impurities were confirmed by NMR and UHPLC-MS, and a high performance liquid chromatographic method was established to determine the related substances in TSD-1. The analytical column was an Agilent ZORBAX Eclipe XDB-C8 (250 mm × 4.6 mm, 5 µm). The mobile phase A was 50 mmol·L-1 ammonium acetate solution (adjusted pH to 5.8 with acetic acid) and the mobile phase B was acetonitrile. The whole run was carried out by gradient elution at a flow rate of 1.0 mL·min-1. The detection wavelength was set at 240 nm and the column temperature was 30 ℃. The resolutions among peaks of TSD-1, impurity A, impurity B, TSD-D, and TSD-F were good. The calibration curves (n = 7) of TSD-1, impurity A, impurity B, TSD-D and TSD-F were linear in their respective weight ranges of 0.242-48.4 µg·mL-1 (r = 1.000 0), 0.244-9.75 µg·mL-1 (r = 0.999 9), 0.244-4.80 µg·mL-1 (r = 0.999 9), 0.254-1.02 µg·mL-1 (r = 0.999 9), and 0.247-0.987 µg·mL-1 (r = 0.999 9). The lower limits of quantitation were 0.244, 0.244, 0.254, and 0.247 µg·mL-1 for impurity A, impurity B, TSD-D, and TSD-F, respectively, and the average recovery of each impurity ranged from 99.08% to 103.00% with high accuracy. TSD-D and TSD-F were not detected in the three batches of TSD-1 active pharmaceutical ingredients, and impurity A and impurity B were not detected beyond the limit. The established HPLC method is simple, accurate, and suitable for determination of related substances of TSD-1, which can provide a valuable reference for the subsequent development of TSD-1.

Simultaneous determination of related substances in entecavir film-coated tablet by high performance liquid chromatography.

: To establish a high performance liquid chromatography method to simultaneously quantify eight related substances in entecavir film-coated tablets.According to USP40 and YBH33292005 standards, a high performance liquid chromatography (HPLC) method for simultaneous determination of 8 related substance in entecavir film-coated tablets was established and validated. The column was WATERS C18 (250 mm the mobile phase A was water-acetonitrile-trifluoroacetic acid (990∶10∶1), the mobile phase B was water-acetonitrile-trifluoroacetic acid (700∶300∶1) with gradient elution and ultraviolet-visible light detector, detection wavelength at 254 nm and column temperature of The resolution between entecavir and each impurity peak was more than 1.5, and each impurity had a good linear relationship with the peak area in the linear range. The limits of detection and quantification, precision, stability, durability, specificity, met the verification requirements. The HPLC method established in this study can be used for simultaneous determination of 8 related substance in entecavir film-coated tablets.

Oxidized related substance of methionine in compound amino acid injection (18AA-Ⅱ) / 中国药科大学学报

@#TA method for the content determination of methionine sulfoxide and methionine sulfone in compound amino acid injection (18AA-II) was established in order to investigate their level in 155 batches of this product, and to explore the reason for the generation of these two impurities.The determination was performed on an Agilent Poroshell 120 EC-C18 column with mobile phases of sodium acetate/tetrahydrofuran solution (A) and sodium acetate solution -acetonitrile-methanol (B, 200∶400∶400) (gradient elution) at the flow rate of 0.5 mL/min.The excitation wavelength and the emission wavelength of the fluorescence detector were 233 nm and 441 nm, respectively.The column temperature was 40 °C, and the injection volume was 8 μL.The contents of methionine sulfoxide and methionine sulfone from 155 batches of compound amino acid injection (18AA-II) was determined using this method, and the residual oxygen content was detected by headspace gas analyzer.The results showed that the linear range of methionine sulfoxide and methionine sulfone were 0.128 1-10.250 0 μg/mL (r = 0.999 9) and 0.261 0-10.440 0 μg/mL (r = 0.999 8), respectively.The limits of quantitation were 0.13 μg/mL and 0.26 μg/mL, respectively; the limits of detection were 0.04 μg/mL and 0.09 μg/mL, respectively.RSDs of precision, stability and repetitive test were all lower than 1.3%.The recoveries ranged 98.00%-100.79% (RSD = 1.15%, n = 9) and 98.19%-102.31% (RSD = 1.33%, n = 9).The content level of oxidized related substances from different manufacturers showed significant difference, showing relevance with the residual oxygen content to some extent, yet no significant correlation with the added amount of antioxygen (sodium pyrosulfite).The method is validated to be useful for the content control of methionine sulfoxide and methionine sulfone in compound amino acid injection (18AA-II).It is quite necessary to include the determination of oxidized related substance into the quality specification.Manufacturers should strengthen the control of remaining oxygen in their products.

Simultaneous Determination of 6 Carbohydrate Related Substances in Glucose by HPLC-ELSD / 中国药房

OBJECTIVE：To establish the m ethod for the simultaneous determination of 6 carbohydrate related substances in glucose as fructose ，maltose，isomaltose，maltotriose，maltotetraose and maltopentaose. METHODS ：HPLC-ELSD was adopted. The determine was performed on XBridge Amide column with mobile phase consisted of acetonitrile-water （75∶25，V/V）at a flow rate of 0.5 mL/min. The column temperature was set at 30 ℃，and the sample size was 10 L. The detector was evaporative light scattering detector ，the carrier gas was nitrogen ，the gas pressure was 40 psi，the evaporation temperature was 80 ℃，the drift tube temperature was 80 ℃，and the gain was 100. RESULTS ：The linear range of 6 carbohydrate related substances were 5.99-59.88， 9.90-98.96，9.92-99.19，5.97-59.74，4.03-40.32，5.89-58.89 μg/mL（r＞0.999 0）. The quantitation limits were 1.5，1.5，1.5，3.0， 3.0 and 3.0 μg/mL，respectively. The detection limits were 0.5，0.5，0.5，1.0，1.0，1.0 μg/mL，respectively. RSDs of precision ， stability（12 h）and reproducibility tests were all lower than 2.0％. The average recoveries were 95.87％-98.59％（RSD＝1.04％，n＝ 9），95.66％-99.84％（RSD＝1.20％，n＝9），96.11％-98.97％（RSD＝1.04％，n＝9），95.06％-99.11％（RSD＝1.25％，n＝9）， 95.69％-98.22％（RSD＝0.83％，n＝9），95.34％-98.56％（RSD＝1.01％，n＝9）. The contents of 6 carbohydrate related substances in 9 batches of glucose were 1.26-2.22，2.55-3.36，2.37-3.37，1.28-2.01，0-2.11 and 0-1.89 mg/g，respectively. CONCLUSIONS ： Established method is accurate and sensitive ，and can be used for the detection of carbohydrate related substances in glucose.

[Studies on fingerprints and efficacy-related substance of classical prescription Zhuru Decoction].

Based on fingerprint and network pharmacology,the whole process quality control of Zhuru Decoction was conducted and efficacy-related substances were predicted.The fingerprints of raw materials,decoction pieces and Zhuru Decoction were established,and 25 common peaks were identified,including 9 common chromatographic peaks of 3'-hydroxy puerarin,puerarin,3'-methoxy puerarin,puerarin,aperioside,daidzin,daidzein,liquiritin,glycyrrhizic acid and 6-gingerol, with similarity all greater than 0.95.The main groups of pharmacodynamic substances can be transferred from raw materials,decoction pieces to Zhuru Decoction step by step,with a clear affiliation relationship.Based on the testability and traceability,the active ingredients were screened,and the network relationship of "component-target-pathway" was constructed and analyzed for the nine chemical components screened by network pharmacology.The enriched pathways included energy metabolism,alcoholism,and smooth muscle contraction and relaxation-related pathways.The nine active components of Zhuru Decoction may achieve the effects of clearing heat, alleviating a hangover, harmonizing stomach and stopping vomiting through these signaling pathways.Based on transitive and traceable properties of the above 9 components as well as their close relationship to the efficacy of Zhuru Decoction,these 9 components can be identified as potential efficacy-related substances and provide basis for the overall quality control of Zhuru Decoction.

Simultaneous determination of chiral and achiral impurities of ivabradine on a cellulose tris(3-chloro-4-methylphenylcarbamate) chiral column using polar organic mode.

A high performance liquid chromatographic method was developed for the simultaneous determination of the related substances (R-ivabradine, dehydro-S-ivabradine, N-demethyl-S-ivabradine, ((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-yl-methyl)-methyl-amine) and 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-on-3-yl)-3-chloro-propane) of the heart-rate lowering drug, ivabradine. The separation capability of seven different polysaccharide-type chiral columns (Lux Amylose-1, Lux i-Amylose-1, Lux Amylose-2, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3 and Lux Cellulose-4) was investigated with a mobile phase consisting of 0.1% diethylamine in methanol, 2-propanol and acetonitrile. During the screnning experiments the best results were obtained on Lux Cellulose-2 (based on cellulose tris(3-chloro-4-methylphenylcarbamate) column with methanol with an ideal case, where all the impurities eluted before the S-ivabradine peak. Chromatographic parameters (flow rate, temperature and mobile phase constituents) were optimized by a full factorial screening design. Using optimized parameters (Lux Cellulose-2 column with 0.06% (v/v) diethylamine in methanol/acetonitrile 98/2 (v/v) with 0.45 mL/min flow rate at 12 °C) baseline separations were achieved between all compounds. The optimized method was validated according to the International Council on Harmonization Q2(R1) guideline and proved to be reliable, linear, precise and accurate for determination of at least 0.05% for all impurities in S-ivabradine samples. Method application was tested on a commercial tablet formulation and proved to be suitable for routine quality control of both chiral and achiral related substances of S-ivabradine.

Analysis of Related Substances in Biapenam by Micellar Electrokinetic Capillary Chromatography / 中国药学杂志

OBJECTIVE: To establish a method for analysis of related substances in biapenem with micellar electrokinetic capillary chromatography(MEKC). METHODS: In order to improve the separation selectivity, a zwitterionic surfactant, 3-(N, N-dimethylhexadecylammonium)-propanesulfonate(PAPS) was used. The optimal separation conditions were as follows: the total length of the capillary was 48.5 cm (the effective length was 48 cm), the buffer was 90 mmol•L-1 tris(hydroxymethyl)aminomethane (tris)-phosphate buffer containing 17 mmol•L-1 PAPS and 3 mg•mL-1 polyoxyethylene 23 lauryl ether (Brij 35), the applied voltage was 22 kV, and the capillary temperature was controlled at 30℃. Further more, the specificity, linearity, precision, repeatability, stability and durability were studied. The contents of related substances in biapenem commercial samples were analyzed. RESULTS: The MEKC method, which was a comparable analysis method to HPLC, successfully separated the adjacent impurities of biapenem by using the zwitterionic surfactant PAPS. The specific test showed that this method was especially suitable for the detection of biapenem dimers A, B and open-ring compound. CONCLUSION: In this method, MEKC with zwitterionic surfactant is for the first time applied to the analysis of related substances in biapenem (amphoteric drugs). It provides a feasible analysis method with high sensitivity, good specificity and reproducibility for the quality control of biapenem.

Determination of related substances in carbaindoline hydrochloride tablets by HPLC / 国际药学研究杂志

Objective: To establish a high performance liquid chromatography(HPLC)method for determination of the related substances of carbaindoline hydrochloride tablets. Methods: HPLC was performed on an octadecylsilane bonded silica gel column. The mobile phase was acetonitrile/0.01 mol/L KH2PO4 solution in a gradient elution. The flow rate was 1.0 ml/min. Column temperature was 25℃. Injection volume was 10 μl. The detection wavelength was 210 nm. Methodological verification was carried out and the changes of related substances under different influencing conditions were investigated using the verified method. Results: The carbaindoline hydrochloride and related substances were all well separated under the conditions of the established method. The limit of detection(LOD)and quantitation(LOQ)of the method were 0.5 ng and 1.5 ng, respectively. The calibration curve was linear in the range of 2.0-7.0 μg/ml(r=0.9995). The RSD of reproducibility was 0.05%. The carbaindoline hydrochloride tablets showed colored changes with a significant increase of related substances under light illumination or at higher temperature of 60℃. Conclusion: The established method is simple, acurate, sensitive and specific, which might be used for the determination of related substances in carbaindoline hydrochloride tablets. The carbaindoline hydrochloride tablets produced more impurities under the light illumination or at the higher temperature, which indicates that they should be stored at room temperature avoiding light.

Isolation and identification of unknown impurities of alogliptin benzoate / 中国药科大学学报

@#By silica gel column chromatography, solvent extraction and preparative high performance liquid chromatography (HPLC), four new related substance were isolated and purified from the mass production and preparation process of alogliptin benzoate. Then it was analyzed and confirmed by various spectrum identification methods such as nuclear magnetic resonance (NMR) spectroscopy, high-resolution mass spectrometry (HR-MS) and Fourier-transform infrared spectroscopy (FTIR) according to its physical and chemical properties. The chemical structures of the four related substances produced in each step of the synthesis process of alogliptin benzoate were determined, and they were named as impurities L, M, T, and V. These four related substances were new impurities which were found for the first time. The isolation and identification of these impurities are of great importance to the quality control of alogliptin benzoate, and the optimization of manufacturing process.

Content Determination of Related Substances in Paracetamol Tablets by HPLC / 中国药房

OBJECTIVE：To establish the method for content determination of related substances in Paracetamol tablets. METHODS：HPLC method was adopted. The determination was performed on Agilent 5HC-C8 column with mobile phase A consisted of methanol-water-glacial acetic acid （50 ∶ 950 ∶ 1，V/V/V）and mobile phase B consisted of methanol-water-glacial acetic acid（500 ∶ 500 ∶ 1，V/V/V）（gradient elution ）at the flow rate of 0.9 mL/min. The detection wavelength was set at 254 nm，and column temperature was 40 ℃. The sample size was 5 μL. RESULTS：Under the chromatographic condition ，the resolutions of main component （paracetamol），6 known impurities （p-aminophenol，p-chloroacetanilide，impurity A ，B，D，F），3 specific excipients（methyl hydroxybenzoate ，ethyl hydroxybenzoate ，propyl hydroxybenzoate ）and 1 unknown impurity were all higher than 1.5. The linear range of 6 known impurities were 0.539-1.617，0.026-0.384，0.237-17.799，0.257-19.271，0.239-17.955， 0.246-18.462 μg/mL（r≥0.999 8），respectively. Correction factors of impurity A ，B，D，F were 2.9，1.0，1.2，6.2. The limits of detection were 0.009 6，0.024 2，0.164 0，0.051 1，0.055 9，0.422 0 ng；the limits of quantitation were 0.032 0，0.080 6，0.546 0，0.170 0，0.186 0，1.406 0 ng. Average recoveries were 95.96％-111.09％（RSDs were 0.05％-2.42％）. The RSDs precision test were low than 15％，and the durability were good. p-aminophenol（all were 0.006％），impurity B （0.016％-0.017％）and unknown impurity（0.002 0％-0.002 1％）were detected in 3 batches of sample. p-choroacetanilide，impurity A ，D and F were not detected. CONCLUSIONS：The method is specific ，accurate and suitable for the determination of related substance in Paracetamol tablets.

Content Determination of Related Substances in Terlipressin for Injection by UPLC / 中国药房

OBJECTIVE：To establish UPLC method for the content determination of related substances in Terlipressin for injection. METHODS ：UPLC method was used to determine the contents of related substances in 5 batches of Terlipressin for injection. The separation was performed on Xtimate UPLC C 18 column with mobile phase A consisted of ammonium sulfate buffer （pH 2.3）-methanol（90 ∶ 10，V/V）and mobile phase B consisted of ammonium sulfate buffer （pH 2.3）-methanol（60 ∶ 40，V/V） （gradient elution ）at the flow rate of 0.2 mL/min. The detection wavelength was set at 210 nm，and sample size was 5 μL. RESULTS：The linear range of impurity A ，B，C，D，F，H，I，K，L and N were 0.43-3.86，0.44-3.95，0.44-3.97，0.45-4.08， 0.45-4.05，0.50-4.50，0.47-4.26，0.47-4.23，0.46-4.13，0.44-3.96 μg/mL（r≥0.999 7），respectively. The detection limits were 0.04， 0.04，0.05，0.04，0.05，0.05，0.05，0.05，0.04 μg/mL. The quantitation limits were 0.13，0.13，0.14，0.13，0.15，0.14，0.14， 0.14，0.13 μg/mL，respectively. RSDs of precision ，reproducibility and stability tests were all lower than 8％. The average recoveries were 94.95％，97.81％，101.88％，95.26％，93.40％，102.48％，104.26％，102.31％，96.42％，90.42％，with RSD s of 1.89％，1.86％，0.68％，1.30％，1.98％，3.36％，1.26％，1.30％，1.19％，1.40％（n＝9），respectively. Total contents of impurities in 5 batches of Terlipressin for injection were all lower than 4％. CONCLUSIONS ：Established method is rapid ，simple， accurate and specific ，which can be used for the quantitative analysis for related substances in Terlipressin for injection.

Determination of Related Substances in Dibasol Hydrochloride Raw Materials and Tablets and Structure Predic- tion of Maximum Unknown Impurity / 中国药房

OBJECTIVE：To establish a method for the determination of related substances in dibasol hydrochloride raw materials and tablets ， and to predict the maximum unknown impurity ’s structure. METHODS ： The related substances （o-phenylenediamine，phenylacetic acid ）in dibasol hydrochloride raw materials and tablets were determined by HPLC. The determination was performed on Kromasil C 18 column with mobile phase consisted of mobile phase-methanol-glacial acetic acid-triethylamine（45 ∶ 55 ∶ 0.5 ∶ 0.5，V/V/V/V）at the flow rate of 1.0 mL/min. The detection wavelength was set at 220 nm，and column temperature was 30 ℃. Sample size was 10 μL. UPLC-TOF-MS，1H-NMR and 13C-NMR were used for structure prediction. The determination was performed on Waters Acquity UPLC BEH C 18 column with mobile phase consisted of water-methanol （45∶55， V/V）at the flow rate of 0.2 mL/min. The column temperature was 30 ℃，and sample size was 1 μL. The ion source was electrospray ion source . The scanning mode was negative ion scanning mode. The first-order mass spectrum scanning range was m/z 100-800，the capillary voltage was 3 000 V，the source temperature was 100 ℃，the desolvent gas was nitrogen ，and the solvent free gas flow rate was 600 L/h. The flow rate of the conical orifice was 50 L/h. RESULTS： The linear range of o-phenylenediamine，phenylacetic acid and dibasol hydrochlo- ride were 0.427-4.27 μg/mL（r＝0.998 9），0.403-4.03 μg/mL（r＝ 0.998 9）and 0.82-8.20 μg/mL（r＝0.999 9），respec-tively. The limits of quantitation were 0.042 7，0.134 3，0.088 7 μg/mL. The limits of detection were 0.021 4，0.067 1，0.044 3 μ g/mL. RSDs of precision ，stability，reproducibility and durability tests were all less than 2％. The average recoveries were 98.31％- 99.78％-102.23％ for phenylacetic acid （RSD＝0.70％，n＝9）. No o-phenylenediamine was detected in 6 batches of dibazol hydrochloride raw materials ；the contents of phenylacetic acid · were 0-0.04％ ；the contents of maximum unknown impurity were 0.05％ -0.25％ ；total contents of unknown impurity were 0.05％-0.31％. In 77 batches of Dibasol hydrochloride tablets ，the contents of o-phenylenediamine were 0-0.11％，the contents of phenylacetic acid were 0-0.03％；the contents of maximum unknown impurity were 0.06％-0.51％；total contents of unknown impurity were 0.10％-0.62％. It was speculated that maximum unknown impurity was 2-（hydroxyphenylmethyl）benzimidazole （hydrobenzde）. CONCLUSIONS ：Established method is rapid ，accurate and specific ，and can be used for the determination of related substances in dibasol hydrochloride raw materials and tablets. The maximum unknown impurity may be benzimidazoles.

Studies on fingerprints and efficacy-related substance of classical prescription Zhuru Decoction / 中国中药杂志

Based on fingerprint and network pharmacology,the whole process quality control of Zhuru Decoction was conducted and efficacy-related substances were predicted.The fingerprints of raw materials,decoction pieces and Zhuru Decoction were established,and 25 common peaks were identified,including 9 common chromatographic peaks of 3'-hydroxy puerarin,puerarin,3'-methoxy puerarin,puerarin,aperioside,daidzin,daidzein,liquiritin,glycyrrhizic acid and 6-gingerol, with similarity all greater than 0.95.The main groups of pharmacodynamic substances can be transferred from raw materials,decoction pieces to Zhuru Decoction step by step,with a clear affiliation relationship.Based on the testability and traceability,the active ingredients were screened,and the network relationship of "component-target-pathway" was constructed and analyzed for the nine chemical components screened by network pharmacology.The enriched pathways included energy metabolism,alcoholism,and smooth muscle contraction and relaxation-related pathways.The nine active components of Zhuru Decoction may achieve the effects of clearing heat, alleviating a hangover, harmonizing stomach and stopping vomiting through these signaling pathways.Based on transitive and traceable properties of the above 9 components as well as their close relationship to the efficacy of Zhuru Decoction,these 9 components can be identified as potential efficacy-related substances and provide basis for the overall quality control of Zhuru Decoction.

Oxycodone-like discriminative stimulus effects of fentanyl-related emerging drugs of abuse in mice.

BACKGROUND: Fentanyl and its structurally related compounds have emerged as the most significant contributors to opioid overdose fatalities in recent years. While there is abundant information about the pharmacological effects of fentanyl, far less is known of its more recently abused analogs. The objective of this study was to determine whether fentanyl and several fentanyl-related substances would engender oxycodone-like responding in a mouse model of oxycodone discrimination. Oxycodone was selected as the training drug due to its high selectivity for mu opioid receptors. Compounds that elicited oxycodone-like responding in this procedure would likely evoke overlapping subjective experiences. METHODS: Adult male C57BL/6 mice were trained to discriminate 1.3 mg/kg oxycodone from vehicle in a food-reinforced, two-lever choice procedure. Generalization tests were conducted with fentanyl and the following fentanyl-related compounds: ocfentanil, 3-furanyl fentanyl, crotonylfentanyl, and valerylfentanyl. RESULTS: Fentanyl and each of its analogs completely generalized to the 1.3 mg/kg oxycodone discriminative stimulus and naltrexone pretreatment significantly decreased oxycodone-like responding for each compound. Rank order potency for engendering oxycodone-appropriate responding was ocfentanil > fentanyl > 3-furanyl fentanyl ≈ crotonylfentanyl > oxycodone > valerylfentanyl. Drug doses that evoked full substitution also significantly suppressed response rates compared to vehicle. CONCLUSIONS: These results indicate that the discriminative stimulus, and by extension, the interoceptive and subjective effects of the tested fentanyl analogs, overlap with those of oxycodone. These observations consequentially support the prediction that they would also engender the likelihood for abuse similar to oxycodone. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.

High Performance Liquid Chromatography Combined with Pulsed Amperometric Detection for the Analysis of Ribostamycin Sulfate / 中国药学杂志

OBJECTIVE: To establish an HPLC method combined with pulsed amperometric detection for the analysis of ribostamycin sulfate and related substance. METHODS: The HPLC was performed on Thermo AcclaimTMAmG C18 column (4.6 mm×150 mm,3 μm). The mobile phase consisted of acetonitrile and 0.2%(V/V) pentafluoropropionic acid aqueous solution containing 0.15%(V/V) trifluoroacetic acid (1∶99, V/V). The pH of the aqueous solution was adjusted to 1.5 with 50%(m/m) sodium hydroxide solution. The pulsed amperometricdetector was operated with aquadruple-potential wave form at 35 ℃ and the injection volume was 25 μL. RESULTS: Ribostamycin and its related substances were adequately separated under the established HPLC conditions. The LOD and LOQ of ribostamycin were 0.15 μg•mL-1(3.75 ng injected) and 0.375 μg•mL-1(9.38 ng injected), respectively. The linearity of ribostamycin ranged from 0.15 to 40.0 μg•mL-1 with a correlation coefficient of 0.999 3.The repeatability RSDs(n=6)for method validation of the content assay and total impurities test were 0.33% and 1.10%, respectively. CONCLUSION: The established method is characterized by high specificity, sensitivity and good stability. The established method has much lower test cost than the current Ch.P 2015 method and is hopeful to replace it.