To establish and verify the helium mass spectrometry detection method to test the sealing integrity of the container closure system (CCS) of pressurized metered dose aerosols (pMDIs).

Determined the maximum allowable leakage limit (MALL) of pMDIs of CCS in the whole life cycle. The special test chambers and helium filling devices were designed and manufactured, and helium filling devices to test the negative and positive control samples under high pressure (absolute pressure 672 kPa) and normal pressure (absolute pressure 100 kPa) respectively. According to the requirements of methodology validation, the validation of detection limit, system suitability, precision, specificity and detection range indicators were completed.The accelerated sample sealing integrity testing for 3, 6 months and 3, 12, 24 months in the long-term stability inspection period was achieved.

Under both helium-filled pressure conditions, the methodological validation indicators were in line with the acceptable standards, and the results of the stability samples were less than the detection limits. This method can detect 100% that the equivalent pore diameter of pMDIs product CCS was 0.095 μm and above.

The helium mass spectrometry detection method can quickly and quantitatively investigate the leakage rate of pMDIs products, prove the seal integrity of CCS with high sensitivity, and meet the industry’s requirements for pMDIs product quality control.

To establish a method of UPLC fingerprint and quantitative analysis of gallic acid, protocatechuic acid, p-hydroxycinnamic acid, myricitrin and quercitrin for Frucius Aceris Fabri, and to provide a reference for the quality control of Frucius Aceris Fabri.

The determination was performed on a Waters CORTECS UPLC T3 column (150 mm×2.1 mm, 1.6 μm), with mobile phase consisting of acetonitrile -0.1% phosphoric acid by gradually elution at a flow rate of 0.20 mL·min^-1. The column temperature was 30 ℃, and detection wavelength was set at 300 nm. The quality of 10 batches of Frucius Aceris Fabri was evaluated by similarity analysis, CA and TOPSIS analysis of fingerprints.

The UPLC fingerprint of Frucius Aceris Fabri was established, and 14 peaks were selected as the characteristic fingerprint peaks. Five chemical components were identified, which were gallic acid, protocatechuic acid, p-hydroxycinnamic acid, myricitrin and quercitrin. And a quantitative method for the determination of the 5 chemical components was established. Good similarities were found in the established fingerprint through similarity analysis. CA and TOPSIS analysis showed that 10 batches of Frucius Aceris Fabri samples could be clustered into 3 groups. The sample S9 from Jiangxi was classified as class Ⅰ with best quality. The samples from Guangxi and Guangdong were classified as Class Ⅱ with medium quality. The samples S1, S4 and S6 from Jiangxi were classified as Ⅲ with worst quality. The linear relationship of the 5 chemical components was good, and the r values were all above 0.999. The contents of the 5 chemical components in 10 batches of samples were 0.236-0.356 mg·g^-1, 0.118-0.398 mg·g^-1, 0.108-0.141 mg·g^-1, 0.146-0.222 mg·g^-1 and 0.046-0.104 mg·g^-1, respectively.

The established UPLC fingerprint and quantitative analysis methods of Frucius Aceris Fabri are precise and stable, which can be used for evaluating and controlling the quality of Frucius Aceris Fabri.

To establish an HPLC method for simultaneous determination of seven components(narirutin, naringin, hesperidin, neohesperidin, naringenin, nobiletin and atractylenolide Ⅲ) in Zhizhu granules. And to provide reference for its quality evaluation by using chemometric analysis.

The chromatographic column Waters Symmetry C₁₈(250 mm×4.6 mm，5 μm) was adopted using HPLC-DAD. The mobile phase consisted of acetonitrile (A)-0.1% phosphoric acid (B) in gradient elution with flow rate of 1.0 mL·min^-1, the detection wavelength were 220 nm (atractylenolide Ⅲ), 280 nm (narirutin, naringin, hesperidin, neohesperidin and naringenin) and 332 nm (nobiletin). The column temperature was set at 30℃ and the injection volume was 10 μL. Cluster analysis, principal component analysis and orthogonal partial least squares-discrimination analysis were used to distinguish the content determination results.

The resolution of each component in 24 batches of Zhizhu granules was good, and the linear relationship between concentration and peak area was good (r>0.999 9). The average recoveries were within 87.6%-114.3%. There were some differences in 24 batches of Zhizhu granules, and 4 different components were screened out, which were naringin, hesperidin, neohesperidin and naringin. The contents of narirutin, naringin, hesperidin, neohesperidin, naringenin, nobiletin and atractylenolide Ⅲ in 24 batches of Zhizhu granules samples were 0.378 4-1.380 1 mg·g^-1, 5.125 8-18.137 6 mg·g^-1, 0.283 9-1.195 8 mg·g^-1, 4.490 3-22.585 0 mg·g^-1, 0.022 5-0.349 8 mg·g^-1, 0.063 3-0.211 4 mg·g^-1 and 0.054 7-0.137 5 mg·g^-1, respectively.

The established method is accurate, reliable and reproducible, which can provide reference for the quality control of Zhizhu granules.

To study the preparation and quality control of 3,5-dihydroxy-7,4’-dimethoxyflavone candidate chemical reference substance from Zhuang medicine Amomum paratsaoko S. Q. Tong & Y. M. Xia.

3,5-dihydroxy-7,4’-dimethoxyflavone was separated and purified consecutively by silica gel, recrystallization as well as preparative HPLC. The structure of 3,5-dihydroxy-7,4’-dimethoxyflavone was identified by IR, UV, NMR and other comprehensive spectrum analytical methods with MS spectrum. Its purity was determined by HPLC and TLC, the ash content was determined by incandescent residue method, and the content of 3,5-dihydroxy-7,4’-dimethoxyflavone was calculated by mass balance method. The method for quality analysis of 3,5-dihydroxy-7,4’-dimethoxyflavone candidate reference materials was investigated by HPLC.

The mean value determined by HPLC of 3,5-dihydroxy-7,4’-dimethoxyflavone was 98.85%, the ash value was 0.02%, and the content of 3,5-dihydroxy-7,4’-dimethoxyflavone calculated by mass balance method was 99.83%. The established analytical method was specific and precise.

3,5-Dihydroxy-7,4’-dimethoxyflavone which was prepared in this study met the quality standard requirements of chemical reference substance, and could be used as a reference substance for quality control of medicinal materials and their preparations such as Amomum paratsaoko S. Q. Tong & Y. M. Xia and others. The analysis method was accurate and reliable, which provided a scientific basis for the research and formulation of quality standard of this reference substance.

To establish an inductively coupled plasma mass spectrometry (ICP-MS) method for the determination of 25 potentially risky elemental impurities in alfentanil hydrochloride injection.

The Agilent 7800 ICP-MS inductively coupled plasma mass spectrometer was used, the conventional tuning mode was used, the RF power was 1 550 W, the plasma gas flow rate was 15 L·min^-1, the matrix effect was eliminated by external standard, and the sample was diluted for direct injection.

The method can simultaneously determine the content of 25 kinds of elemental impurities, and its linear relationship was good (r >0.99). The RSD of the repeatability test was ≤10% (n=6), and the recovery rate was 80.0%-120.0% (n=9), all of which met the requirements of methodological validation.

The content of elemental impurities in alfentanil hydrochloride injection is lower than 30% of the limit specified in ICH·Q3D, which will not bring safety risks to the drug, providing a reference for the quality control and risk assessment of elemental impurities in other similar drugs.

To evaluate the quality of honeyed Eriobotryae Folium from different habitats and to select the best habitat of honeyed Eriobotryae Folium preferentially based on high performance liquid chromatography fingerprinting and chemical pattern recognition methods.

The detection was performed on an Acclaim^TM 120A C₁₈ (250 mm×4.6 mm, 5 μm) column with the mobile phase of 0.2% aqueous phosphoric acid (A)-acetonitrile (B) in gradient elution (0-5 min, 5%B; 5-6 min, 5%B→10%B; 6-20 min, 10%B; 20-50 min, 10%B→25%B; 50-60 min, 25%B). The volume flow rate was 1.0 mL·min^-1, the detection wavelength was 327 nm, the column temperature was 30 ℃, and the injection volume was 10 μL. The fingerprint profiles of 30 batches of honeyed Eriobotryae Folium from different habitats were established, and the fingerprint profiles combined with chemical pattern recognition were used to conduct comprehensive analysis of honeyed Eriobotryae Folium from different habitats. And cluster analysis(CA), principal component analysis (PCA) and comprehensive scoring were performed on honeyed Eriobotryae Folium from different habitats. Orthogonal partial least squares-discriminant analysis(OPLS-DA) was used to screen out the differential markers of honeyed Eriobotryae Folium from different habitats, and the habitats of honeyed Eriobotryae Folium were selected based on the comprehensive scoring.

The fingerprint profiles of 30 batches of honeyed Eriobotryae Folium were established. Twelve common peaks were identified, and 4 peaks were identified as neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid and auriculoside according to the control finger. CA divided the 30 batches of Honeyed Eriobotryae Folium samples into 6 categories. By PCA, 3 principal components were extracted, with a cumulative variance contribution of 84.315%. Six differential markers were obtained according to OPLS-DA, two of which were identified as chrysoside and chlorogenic acid. The better habitats of honeyed Eriobotryae Folium were screened as Sichuan, Guangxi, Guangdong and Shaanxi according to the comprehensive score.

Good precision, repeatability and stability results are obtained for fingerprinting and content determination. The combination of fingerprinting and chemical pattern recognition can comprehensively evaluate the quality of honeyed Eriobotryae Folium, and this method is stable and reliable, which can provide an effective reference basis for the habitat study of honeyed Eriobotryae Folium.

To compare the differences in identification tests of vacant gelatin capsules and enterosoluble vacant gelatin capsules in the four national pharmacopoeias, optimize the identification test methods and improve the specificity of identification results.

The biuret method was used to identify vacant gelatin capsules and enterosoluble vacant gelatin capsules, and an appropriate amount of adsorbed activated carbon was added to eliminate the masking effect of pigments in capsules.

The identification method was optimized, the pigment in the capsule solution was adsorbed by activated carbon, and the capsule solution showed a clarified colorless solution, which could produce a distinct violet after the color development by biuret reaction.

This method can significantly improve the specificity of vacant gelatin capsules and enterosoluble vacant gelatin capsules identification compared with domestic and foreign pharmacopoeia methods. It can provide scientific and reasonable revision suggestions for the optimization and improvement of the identification test of vacant gelatin capsules and enterosoluble vacant gelatin capsules in the Chinese Pharmacopoeia.

To establish a high-performance liquid chromatography (HPLC) method for investigating the extraction of common antioxidants and extractable sulfur in medical rubber stoppers and the migration of antioxidants and extractable sulfur to propofol medium/long chain fat emulsion injection.

Waters Symmetry RP₁₈(250 mm×4.6 mm，5 μm) was used as chromatographic column with methanol-acetonitrile -1% acetic acid solution as the mobile phase. Detection wavelength, velocity of flow and column temperature were set to 277 nm, 1 mL·min^-1 and 35 ℃.

Good resolution and linear relationship (r≥0.999 6) in the range of 0.1-20 μg·mL^-1 were achieved. This method possesses superior precision, stability, repeatability, and all RSD were less than 5%. The rate of recovery was 93.3%-108.7%, and the RSD was 1.8%-12.5%. The migration of antioxidant BHT was detected in three batches of solution and the content was higher than its corresponding permitted daily exposure (PDE) value, which means there is a large safetyrisk.

The method represents high sensitivity and is easy to operate, which can effectively detect the migration of antioxidants in propofol medium/long chain fat emulsion injection.

To develop an inductively coupled plasma mass spectrometry (ICP-MS) matrix matching method for determination of migration of 11 elements in ketorolac tromethamine injection, including Al, As, B, Ca, Cd, Fe, Mn, Pb, Sb, Si, Ti.

Samples were diluted and capacitated with 1% nitric acid after precipitation with nitric acid. 2% ethanol was added into the standard solution as the matrix. The matrix effect was eliminated by the matrix matching method, and the polyatomic ion interferences were eliminated by the hydrogen collision reaction mode and the helium collision mode.

The linearity of 11 elements was good (r≥0.997 0). The limits of detection were 0. 049-133 ng·mL^-1. The average recoveries of all 11 elements were in the range of 83.8%-107.1%, and the RSD of repeatability was 2.6%-11.0%. Three batches of ketorolac tromethamine injection under acceleration were tested. The overall safety risk was low.

The established matrix matching ICP-MS method is simple, rapid and accurate. It can effectively eliminate the matrix effect and be used for the determination of eleven elemental impurities in ketorolac tromethamine injection, providing technical reference for risk assessment of drug packaging material compatibility.