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Robust and Ultrasensitive Determination of Hormones and Steroids by LCMSMS

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Robust and Ultrasensitive Determination of Hormones and Steroids by LCMSMS Robust and Ultrasensitive Determination of Hormones and Steroids by LCMSMS Sylvain Lachance, Danielle Lachance, Nadine Boudreau, Sofi Gagnon-Carignan and Ann Lévesque (inVentiv Health Clinical, Québec, Canada) Introduction Results The therapeutic use of hormones and steroids is widely known among the pharmaceutical community. They are used for many indications. More than 200 bioanalytical projects were performed with these assays. Since 2009, over 500000 study samples Contraceptive hormones and hormonal therapy are among the most common use of these compounds. The goal of this work is to were analyzed with these methods. Overall performances were excellent with 99% of the calibration standards demonstrate that the LCMSMS determination of hormones and steroids can be reliable and robust. Extraction method, chromatography (CS) and quality controls (QC) meeting the acceptance criteria. Moreover, the incurred sample reproducibility of conditions, issues encountered, performance of the assay and reproducibility are discussed below for multiple hormones and steroids such these assays was demonstrated with a mean of 98% of the reassays confirming their original values. For most of as estrone, estradiol, ethinyl estradiol, etonogestrel and levonorgestrel. the methods, co-medication interference evaluation was assessed during validation. For complete details of the overall performances by method, please refer to Table 3. Table 3. Overall Performance of the Methods Methods Summary Total Number Percent Total number of Percent Total number of Percent Most of the hormones and steroids are extracted using a liquid-liquid extraction. Analyses are performed on API 4000 or API 5000, of Samples Samples Samples Samples Samples of CS in Accepted of QC in Accepted of Drug Batches ISR Analyzed Analyzed Analyze Analyzed Analyzed depending on the expected sensitivity. For some compounds such as ethinyl estradiol, estrone and estradiol, derivatization with danzyl Accepted Batches with Accepted Batches with Accepted with 2009 2010 d 2011 2012 2013 Batches Study Samples CS Study Samples QCs chloride was mandatory to achieve low pg/mL level. For etonogestrel, a derivatization step was done with danzyl chloride to get rid of Study impurities and achieve the required sensitivity as etonogestrel cannot be derivatized. Tables1and2summarize the method of analysis of Samples different hormones and steroids. 3-a-OH-Tibolone 86 94.2 1296 99.5 648 100.0 n/ap 0 0 2197 3219 0 Chlormadinone acetate 27 100.0 432 100.0 216 100.0 n/ap 0 0 2103 1000 0 Table 1. Method Summary for Different Hormones (Single Assay) Cyproterone acetate 103 98.1 1616 99.0 808 98.9 n/ap 473 756 5625 1969 0 Desogestrel 135 97.8 2112 99.5 1055 99.2 98.53% 6713 22224 12714 3256 0 Dienogest 45 100.0 704 98.9 352 99.1 99.68% 0 9336 5442 0 0 Sample Drug Matrix Range Extraction Type LCMSMS Run Time (min) Volume (µL) Drospirenone 91 97.8 1424 99.6 712 99.3 n/ap 1976 1559 4177 2835 0 Estradiol 328 95.1 5018 99.6 2464 99.2 97.39% 0 17906 14709 3459 7358 Estrone 182 97.8 2890 98.2 1400 99.4 97.38% 0 13293 12337 0 0 3-a-OH-Tibolone Human EDTA K3 Plasma 100-40000 pg/mL 200 Liquid-Liquid and derivatization API 5000 6.7 Ethinylestradiol 1031 96.7 15786 98.5 7896 99.0 98.10% 16353 17878 65170 14031 15485 Chlormadinone acetate Human EDTA K Plasma 25-5000 pg/mL 400 Liquid-Liquid API 4000 6.0 2 Gestodene 322 98.1 5068 99.3 2520 99.6 99.11% 91 15926 26189 1427 2524 Cyproterone acetate Human EDTA K Plasma 100-50000 pg/mL 500 Liquid-Liquid API 4000 5.0 2 Levonorgestrel 123 99.0 1856 98.8 968 99.1 97.67% 4965 9331 10607 4750 2450 Desogestrel Human EDTA K Plasma 10-2000 pg/mL 300 Liquid-Liquid and derivatization API 5000 5.0 3 Methyltestosterone 12 100.0 216 100.0 96 100.0 97.56% 0 0 0 4483 0 Dienogest Human EDTA K2 Plasma 1-320 ng/mL 50 Liquid-Liquid Automated API 5000 3.2 Nomegestrol 4 100.0 64 100.0 32 100.0 n/ap 0 0 413 0 0 Drospirenone Human EDTA K2 Plasma 100-40000 pg/mL 100 Solid-Phase and derivatization API 4000 5.0 Norethindrone 107 97.9 1680 99.3 840 99.2 99.32% 918 1834 7166 0 5900 Progesterone 515 96.4 17096 99.1 4048 97.1 98.49% 6826 0 7748 8315 38500 Estradiol Human EDTA K3 Plasma 1-100 pg/mL 600 Solid-Phase and derivatization API 5000 7.5 Testosterone 231 97.5 3520 99.4 1760 98.8 96.62% 0 1231 11523 11148 7580 Estrone Total Human EDTA K3 Plasma 50-100000 pg/mL 200 Liquid-Liquid and derivatization API 4000 8.0 Tibolone 31 96.8 480 98.8 240 99.6 99.40% 2156 0 3549 2482 0 Ethinylestradiol Human EDTA K Plasma 1-250 pg/mL 600 Liquid-Liquid and derivatization API 5000 9.0 2 Triamcianolone 86 96.0 1384 97.5 856 98.0 95.60% 0 0 1814 515 5185 Ethinylestradiol Human Lithium Heparin 1-200 pg/mL 600 Solid-Phase and derivatization API 5000 3.5 Total 3459 97.7 62642 99.2 26911 99.2 98.06% 40471 111274 193483 62889 84982 Gestodene Human EDTA K3 Plasma 50-12500 pg/mL 500 Liquid-Liquid API 4000 5.0 Levonorgestrel Human EDTA K2 Plasma 25-5000 pg/mL 500 Liquid-Liquid API 5000 5.0 Methyltestosterone Human EDTA K3 Plasma 50-5000 pg/mL 150 Liquid-Liquid Automated API 5000 3.9 Nomegestrol Human EDTA K3 Plasma 50-20000 pg/mL 250 Liquid-Liquid API 4000 4.0 Norethindrone Human EDTA K Plasma 50-10000 pg/mL 500 Liquid-Liquid API 4000 4.0 3 inVentiv Health Clinical Progesterone Human EDTA K3 Plasma 20-20000 pg/mL 500 Liquid-Liquid API 5000 5.7 Testosterone Human Serum 60-12000 pg/mL 300 Liquid-Liquid Automated API 5000 5.0 Conclusion Tibolone Human EDTA K Plasma 25-5000 pg/mL 300 Liquid-Liquid and derivatization API 5000 9.5 3 Quantitation of hormones, steroids and other similar compounds can be done with robust methods by LCMSMS. Triamcianolone Human EDTA K Plasma 50-5000 pg/mL 100 Liquid-Liquid API 4000 2.5 2 Accuracy and precision of our assays were demonstrated as well as the reproducibility, as shown with the ISR. This poster clearly demonstrates that the results reported with our assays are reliable. It is possible to achieve Table 2. Method Summary for Combo Methods extremely low limits of quantitation for hormones and steroids. Optimization of the extraction process along with adequate chromatography conditions were shown to be successful. Sample Drug Matrix Range Extraction Type LCMSMS Run Time (min) Volume (µL) Ethinylestradiol/Gestodene Human Serum 2.5-125/50-20000 pg/mL 600 Liquid-Liquid and derivatization API 5000 9.0/5.0 Ethinylestradiol/Norethindrone Human EDTA K3 Plasma 1-200/100-40000 pg/mL 1000 Liquid-Liquid and derivatization API 5000 8.0/4.0 Estrone-Estradiol Unconjugated Human EDTA K3 Plasma 5-1000/2.5-500 pg/mL 600 Solid-Phase and derivatization API 5000 10.5 Testosterone/DHT Human NaF/K2C2O4 Plasma 100-20000/50-5000 pg/mL 300 Liquid-Liquid Automated API 5000 5.0 To get a PDF version of this poster please contact Testosterone Undecanoate/DHT Undecanoate Human NaF/K2C2O4 Plasma 1-500/0.5-250 ng/mL 100 Liquid-Liquid Automated API 4000 4.0 [email protected] © 2012. inVentiv Health. All rights reserved..
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