To establish a method for determining the absolute contents of candesartan cilexetil and amlodipine besylate in candesartan cilexetil and amlodipine tablets by qNMR.

The chemical shift δ 5.51 of candesartan cilexetil and δ 5.31 of amlodipine besylate were used as the quantitative peaks. δ 6.27 of maleic acid was the quantitative peak of internal standard. DMSO-d₆ was used as the solvent.

The method was highly specific and the solvent peak，water peak and excipient peaks did not interfere with the quantitative peaks. Candesartan cilexetil showed a good linear relationship in the concentration range of 1.580 0- 9.480 2 mg·mL^-1，r=1.000，RSDs of precision，repeatability and stability were 0.070%，1.7% and 0.68%，respectively. The recoveries of low，medium and high concentration spiked were 98.1%-99.2%. The linear range of amlodipine besylate was 0.983 9-5.903 6 mg·mL^-1 (r=0.999 9). The RSDs of precision，repeatability and stability were 0.050%，1.8% and 0.79%，respectively. The recovery of amlodipine besylate was 99.1%-102.0%. This method was used to test two batches of reference preparations and one batch of sample from different sources. The results showed that the content of candesatan cilexetil was between 98.10% to 98.75%, and that of amlldipine besylate was between 98.98% to 99.60%.

This method is rapid and accurate and it is not necessary to use a single component reference substance. This method provides a new method to determine the content to candesartan cilexetil and amlodipine tablets.

To establish a quantitative ¹H-NMR (qHNMR) method for the determination of dexzopiclone tablets content.

Proton signal at δ 6.08 of 1，3，5-trimethoxybenzene and δ 8.54，8.38，8.12，7.78 of dexzopiclone were served as the internal standard and quantitative peaks，respectively. DMSO-d₆ was employed as the solvent. The qHNMR spectra were acquired at 298 K with 10 s relaxation delay and 32 scanning times.

The content of dexzopiclone was estimated to be 2.94% （RSD=0.15%）by qHNMR method，which indicated that 3.00 mg of dexzopiclone was in one tablet. The result was consistent with the description of the label.

qHNMR method can be used to determine the content of dexzopiclone. The method is accurate，simple and efficient.

To establish the ultra high performance liquid chromatography (UPLC) fingerprint of Qiye Shen’an dropping pills，and to determine the contents of 8 index components by quantitative analysis of multi-components by single marker at the same time.

Waters CORTECS^® T3 (150 mm×2.1 mm，1.6 μm) chromatography column was used for gradient elution with acetonitrile -0.1% phosphoric acid as mobile phase，flow rate was 0.40 mL·min^-1，column temperature was 35 ℃，detection wavelength was 203 nm.

The UPLC fingerprint of Qiye Shen’an dropping pills was established，8 common peaks were established，and the similarity of 15 batches of samples was greater than 0.99. Ginsenoside Rb₁，ginsenoside RC，panax notoginseng saponin FC，ginsenoside Rb₂，ginsenoside Rb₃，ginsenoside Rd，panax notoginseng saponin Fe and panax notoginseng saponin Fd were determined by quantitative analysis of multi-components by single marker method. The contents of 8 components in 15 batches were between 7.6-10.0 mg per pill. The average recoveries were 99.8%，100.6%，99.8%，101.2%，102.1%，101.9%，99.7% and 100.2% respectively，and the RSDs were 2.3%，2.2%，2.0%，1.5%，1.7%，1.2%，2.4% and 2.6% respectively.

The UPLC fingerprint of Qiye Shen’an dropping pills and the content determination method of quantitative analysis of multi-components by single marker method established in this study are simple to operation，and have good repeatability，stability and reliability，and can provide a more comprehensive basis for the quality control of Qiye Shen’an dropping pills.

To establish a method and validate its feasibility for quality evaluation of Erycibes Caulis and its processed products，and analyze the effect on the contents of the seven active ingredient before and after processing.

The contents of components were determined by ultra performance liquid chromatography (UPLC). Chlorogenic acid was chosen as the internal reference substances，the relative correction factors (RCFs) of neochlorogenic acid scopolin，scopoletin，isochlorogenic acid B，isochlorogenic acid A，isochlorogenic acid C and to chlorogenic acid were established. The contents of these seven active ingredients were determined by external standard method and quantitative analysis of multi-components by single-marker (QAMS) method. The method was evaluated by comparison of the quantitative results between external standard method and quantitative analysis of multi-components by single-marker (QAMS).

The peaks of neochlorogenic acid，scopolin，chlorogenic acid，scopoletin，isochlorogenic acid B，isochlorogenic acid A and isochlorogenic acid C in the sample showed good linear relationship between 0.028-1.420 μg·μL^-1，0.019-0.956 μg·μL^-1，0.027-1.324 μg·μL^-1，0.014-0.720 μg·μL^-1，0.017-0.824 μg·μL^-1，0.010-0.500 μg·μL^-1 and 0.013-0.672 μg·μL^-1，respectively. The average recoveries of them（n=6）were as follows 98.9%，99.0%，100.6%，101.2%，100.8%，101.7% and 100.5%，with the RSDs of 1.1%，1.7%，1.5%，1.6%，0.55%，1.6% and 1.5%，respectively. It was showed that no significant difference was found in the quantitative results of seven ingredients by external standard method and QAMS method. The content of 5 kinds of organic acids (neochlorogenic acid，chlorogenic acid，isochlorogenic acid B，isochlorogenic acid A and isochlorogenic acid C) in Erycibes Caulis with different processing technology showed the same change trend. The sample of Y₅ (boiled products with licorice sauce and brine) had the highest contents，and the sample of Y₁₀ (dried products Ⅱ soaked in licorice sauce and brine) had the lowest. The content of scopoline was the highest in Y₅(3.53 mg·g^-1)，while the lowest was Y₁₀(0.31 mg·g^-1). The content of scopoletin in Y₇(dried products Ⅰ with licorice sauce) was the highest(1.48 mg·g^-1) and that in Y₃(boiled products Ⅱ with licorice sauce) was the lowest(0.30 mg·g^-1).

The RCFs established in the QAMS methods with chlorogenic acid as the internal reference substances is accurate and feasible. It can be used to control the quality of Erycibes Caulis. Both heating and excipients preparation have a certain effect on the active ingredients in Erycibes Caulis.

To establish a pre-column derivatization high performance liquid chromatography-mass spectrometry to determine biogenic amines in osteopeptide injections and determine the changes of biogenic amines after the stability influence factor test and accelerated test.

The osteopeptide injections were separated by a ZORBAX SB-C₁₈ chromatographic column and gradient elution after derivatization by dansyl chloride. Ten kinds of biogenic amines was determined by mass spectrometry with electrospray ion source and multiple reaction monitoring in positive mode. The osteopeptide injections were placed under high temperature，strong light and accelerated experimental conditions to inspect the stability of biogenic amines.

Method validation showed that the linear relationship of 10 biological amines was good，and the correlation coefficients were higher than 0.990. The detection limits were 0.01-0.10 ng·mL^-1，the quantitation limits were 0.05-0.30 ng·mL^-1. Good accuracy，repeatability and durability were obtained. Under different conditions，the changes of biogenic amines in osteopeptide injections were significant. The accumulation of putrescine increased under high temperature，while spermine and spermidine decreased. The biogenic amines were unstable under strong light and accelerated test.

Method validation shows that the method can be applicable to simultaneous determine 10 biogenic amines in osteopeptide injections. It provided a reference to establish and improve the quality standards of biogenic amines in osteopeptide and other drugs. In addition，the research of the stability of biological amines shows that high temperature and strong light will affect the stability of biogenic amines. Therefore，quality control and supervision should be strengthened during drug production and storage to ensure the stability of drug.

To establish an HPLC analysis method for the determination of diazepam，nordiazepam and oxazepam in hair samples.

The determination of drug content and related substances was performed by high performance liquid chromatography (HPLC). Ultrasonic method combined with liquid-liquid extraction method was used as the pretreatment method. The chromatographic column was Athena C₁₈-WP column (250 mm×4.6 mm，5 μm)；the mobile phase was the mixture of methanol：0.02 mol·L^-1 sodium dihydrogen phosphate (adjusted to pH 3.4 with phosphoric acid)：acetonitrile (30:43:27，v/v/v) in an isometric elution；the column temperature was 50 ℃；the flow rate was 0.7 mL·min^-1；the running time was 30 min；the injection volume was 20 μL. The detection wavelength was 254 nm. The internal standard was clonazepam.

The linearity of all the analytes were good in the concentration range of 0.1 to 25 ng·mg^-1（r>0.995）. The limit of quantitative was 0.1 ng·mg^-1 and the limit of detection was 0.05 ng·mg^-1. The intra-batch accuracies were 88.2%-103.9% (n=6) and the inter-batch accuracies were 88.5%-106.2% with imprecisions ≤9.19%. The recoveries were stable for three anlytes，which met the requirement of methodology. The present method was applied to the authetic hair samples，in which the concentrations of diazepam，norazepam and oxazepam were (0.307±0.016) ng·mg^-1，(0.244±0.012) ng·mg^-1 and (0.478±0.053) ng·mg^-1 respectively. Besides，C_norazepam/C_diazepam was 0.795，which was in consistent with the literature reported.

The established HPLC method is fast and easy to operate，with good reproducibility，applicability，and reliability.

To evaluate the processing ability of identification，tracing and abnormal occurs in drug manufactures by the proficiency testing for microbiological identification and traceability in Shandong Province.

The proficiency test was derived from an event of drug microbial contamination，and samples including contaminated products group and production group were designed to evaluate the testing and tracing competence of 264 participants from those aspects of drug control，identification，genetic comparison and traceability. The contaminated products group was composed of five simulated samples including one positive sample which included Enterobacter cloacae and Staphylococcus aureus，and four negative samples which were sterile. The production group was composed of five simulated samples including four positive samples and one negative sample，but each of the four positive sample included only one strain of Enterobacter cloacae，Staphylococcus aureus，Staphylococous epidemidis and Pseudomons aeruginosa，respectively.

259 participants reported their results. The rate of unqualified，qualified，good and excellent results were 3.5%，49.8%，46.7% and 0，respectively. But four results reported phylogenetic tree based on 16S rRNA gene without genetic comparison at the strain level. The unqualified result indicated inaccurate inspection of positive and negative sample. The qualified result indicated accurate inspection but inaccurate species identification or not. The good result showed accurate species identification without effective tracing analysis.

The ability of most drug manufactures to contaminant microorganisms testing are acceptable. But the ability of microbiological identification and traceability，the precise judgement and the effective measures to an emergency of microbial contamination in drugs remain to be strengthened.

To establish a method for the determination of 22 mycotoxins in pharmaceutical excipients by ultra-high performance liquid chromatography-ion mobility time-of-flight mass spectrometry (UHPLC-IM TOF MS).

The samples were separated on a Waters CORTECS^® UPLC^® C₁₈(100 mm×2.1 mm，1.6 μm) column by gradient elution at a flow rate of 0.25 mL·min^-1 using 0.1% formic acid and a mixture of acetonitrile and methanol (60:40) as the mobile phase. The column temperature was maintained at 35 ℃. MSe data acquisition mode was chosen and electrospray ion source operating in the positive/negative ionization mode for data acquisition was applied. The external standard method was used for quantification.

22 mycotoxins showed good linear relationships within their respective ranges (r>0.998 5). The limits of detection were 0.1-2.0 μg·kg^-1. The recoveries of 22 mycotoxins at three levels were in the range of 80.4%-118.2%，and the RSDs were 0.20%-8.8%. The matrix effect of 22 mycotoxins was not obvious. The method was applied to the detection of 32 batches of corn starch and 167 batches of dextrin. Aflatoxin B1，fumonisins B1 and B2，and zearalenone were detected in some batches.

The method is accurate，efficient and stable. It can be used in quality control of mycotoxins in pharmaceutical excipients，and provides technical supports for the risk assessment of mycotoxins.

To establish a method for determination of 7 mycotoxin contaminants in Jianqu by ultra high performance liquid chromatography-tandem mass spectrometry（UPLC-MS/MS）.

The samples were extracted with acetonitrile aqueous solution (containing 0.1% formic acid) ，and purified by QuEChERS extraction salt bag and Oasis PRiME HLB solid phase extraction column. The column of UPLC was WATERS HSS T3（100 mm×2.1 mm，1.8 μm）. Mobile phase was acetonitrile-5 mmol·L^-1 ammonium formate solution (containing 0.1% formic acid) with gradient elution. Ionization mode was electrospray ionization(ESI) with positive mode. The work mode was multiple-reaction monitoring mode(MRM).

The developed method provided a good linearity for the 7 mycotoxins with their respective linear rangers. The correlation(r) ranged from 0.999 1 to 0.999 9. The average recoveries ranged from 83.5% to 113.8%，RSDs of 2.1% to 5.2%. Among 10 samples were selected for analysis，aflatoxin B1 was detected from 3 samples at concentration of 1.32 μg·kg^-1 to 6.15 μg·kg^-1. The results indicated that there were serious safety risks in the Jianqu products.

This paper establishes a method for the determination of 7 mycotoxins in Jianqu. The residual of mycotoxins in Jianqu can be rapid ly detected by UPLC-MS/MS which is suitable for the risk monitoring of mycotoxins in Jianqu. This article reveals the current situation of mycotoxins contamination in Jianqu，providing a research basis for the safety control of traditional Chinese medicine. It is recommended that the relevant departments should strengthen the corresponding supervision work.

To establish a method for related substances determination in timolol maleate by ultra-high performance liquid chromatography-quadrupole/orbitrap high resolution mass spectrometry（UPLC-Q/Orbitrap HRMS），by which the impurities both in active pharmaceutical ingredients（APIs） and preparations can be recognized and determined.

An ACE Excel3 C₁₈-AR column（150 mm×4.6 mm，3 μm）was used for the separation and a mixture of 0.01 mol·L^-1 ammonium acetate solution with 0.02% formic acid and methanol was employed as the mobile phase by gradient elution，at a flow rate of 0.6 mL·min^-1. The detection wavelength for UV detector was 295 nm，an HESI（heated ESI）ion source was employed in both the positive mode and negative mode. The possible fragmentation patterns prediction was conducted with the help of Mass Frontier 8.0 and Compound Discover 3.3. The related substances could be recognized and determined by means of the forced degradation of the APIs，with the calibration by the correction factors and confirmation by the mass spectrum data from UPLC-Q/Orbitrap HRMS.

The timolol impurity B[3-(tert-butylamino)-2-(4-morpholino-1，2，5-thiadiazol-3-yloxy)propan-1-ol]，timolol impurity D(4-morpholino-1，2，5-thiadiazol-2-ol)，timolol impurity E((S，Z)-4-(｛1-(tert-butylamino)- 3-[(4-morpholino-1，2，5-thiadiazol-3-yl) oxy] propan-2-yl｝oxy)-4-oxobut-2-enoic acid maleate salt) and timolol impurity C[N-(tert-butyl)-2，3-bis (4-morphloline-1，2，5-thiadiazol-3-yloxy) propan-1-amine maleate] were produced from the APIs under selected conditions and separated well in the specified HPLC condition，the limit of quantitation was 0.05 μg·mL^-1 and the limit of detection was 0.015 μg·mL^-1 for HPLC-UV. The contents of individual impurities were between 0.000 4%-0.09% and the results of total impurities were between 0.02%-0.12% for the samples from 4 different manufactures. The probable chemical structures of the 6 unspecified impurities were speculated according to the fragmentation pattern of fragment ions，combined with the fragment information，chemical structure of API and the references.

The system solution can be obtained by the degradation of the API，and be implied in the impurity analysis for the timolol maleate. The results can be used as a reference for the quality control of timolol maletae.