Determination of midazolam and its major metabolite 1′-hydroxymidazolam by high-performance liquid chromatography-electrospray mass spectrometry in plasma from children

A developed determination of midazolam and 1′-hydroxymidazolam in plasma by liquid chromatography–mass spectrometry: Application of human pharmacokinetic study for measurement of CYP3A activity

“…2), this method was applied to human pharmacokinetic study to 14 healthy volunteers. Therefore, our result was sensitive enough to obtain human pharmacokinetic parameters (Table 3), and various drawbacks of the previous published assay [7,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] were eliminated. To our knowledge, this is the first report that enables simultaneous determination of MDZ and 1-OHMDZ with LC-MS with SSI in human study after intravenous and oral administration of the low dose, which was validated according to FDA Guidelines [30].…”

“…Previous analytical methods have been reported for simultaneous determination of MDZ and 1-OHMDZ in human plasma with different detection systems [7,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Among them, the limits of quantifications (LOQ) in high-performance liquid chromatography with UV detection (LC/UV) [7,[13][14][15][16][17] and gas chromatography (GC) [18][19][20] methods were over 2 ng/ml for MDZ and 1-OHMDZ, and this was not adequate to characterize the pharmacokinetics of both compounds.…”

“…In addition, GC-mass spectrometry (MS) [22,23] appeared to be more sensitive than LC/UV and GC, but required lengthy extraction and derivation procedures before chromatographic analysis. Although LC-MS has replaced other detection systems, these methods also have various drawbacks, including large sample volume (2 ml) [24], uneconomical fast gradient LC procedure [24], use of expensive solid phase extraction cartridges [25], column switching procedure requiring an additional system [25], and inadequate sensitivity (LOQ; more than 1 ng/ml) [26,27]. The analytical method described by Shiran et al has LOQ of 0.65 and 0.68 ng/ml for MDZ and 1-OHMDZ, but calibration curves for both compounds were constructed over the 6.5-208 ng/ml for application to human plasma [28].…”

High-throughput assay for simultaneous quantification of the plasma concentrations of morphine, fentanyl, midazolam and their major metabolites using automated SPE coupled to LC–MS/MS

“…Previously, separate LC-MS/MS assay methods for quantification of the plasma concentrations of morphine, M3G and M6G [9][10][11][12][13]; fentanyl and norfentanyl [14][15][16][17][18][19]; midazolam, 1-OH-MDZ and 4-OH-MDZ [20][21][22][23][24][25] have been described in the literature. Here, we have successfully extracted all eight of these analytes of interest from a single 150 L plasma sample using a single polymeric cartridge and on-line SPE with subsequent LC-MS/MS quantification.…”

Synthesis of the impurities during the manufacture of bulk drug midazolam and separation of these impurities by HPLC

“…Literature survey revealed various HPLC methods for determination of midazolam and its metabolites in biological fluids (9)(10)(11)(12)(13). Based on the literature survey, an attempt was made to synthesize the proposed impurities of midazolam and to use a RP-HPLC method for separation of these eight impurities from the bulk drug midazolam.…”