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Rapid identification of drug impurities by benchtop high resolution mass spectrometry
Foreword
Impurity analysis is critical for drug development1. During the course of the study, impurity profile information can help drug chemists optimize synthetic routes and avoid potentially toxic impurities. In the development process, the identification and characterization of trace impurities is essential when a large amount of parent compound is present, which promotes the development of HR-MS instruments and intelligent structure identification software with high resolution, high sensitivity and high scanning speed.
In order to demonstrate the ability of HR-MS in impurity analysis and structure identification, the commercially available drug omeprazole was selected in this paper. In this study, Thermo Fisher Scientific's Q Exactive benchtop Orbitrap mass spectrometer and data processing software Mass Frontier were used to rapidly analyze and identify the structure of impurities in omeprazole.
method
Materials and reagents
Omeprazole (CAS # 73590-58-6) was purchased from Sigma-Aldrich, product number O104-100MG.
Acetonitrile and water from Fisher Scientific
Ammonium acetate was purchased from Sigma-Aldrich, product number 73594-25G-F.
Formic acid was purchased from Sigma-Aldrich, product number 33015-500 ml.
Sample preparation
Omeprazole solution (0.5 mg/mL) was prepared in a 1:1 acetonitrile/water mixture.
HPLC method
Chromatographic separation was performed using an Ultimate 3000 UHPLC system.
Column: Hypersil GOLD column, 2.1mm × 150mm, particle size 3 μm.
Column temperature: 35 °C, flow rate: 0.5 mL/min, injection volume: 8 μL
Mobile phase: A - water; B - acetonitrile; C - 100 mM ammonium acetate, adjusted to pH 5 with acetic acid
Gradient elution:
Mass spectrometry
Mass spectrometry was performed using an electrospray positive ion mode of a Q Exactive mass spectrometer. High-resolution full-scan first-order mass spectral data and data-dependent Top3 secondary mass spectral data were acquired at 70,000 and 35,000 resolutions of FWHM@m/z 200, respectively.
Ion source conditions:
Ionization mode: positive ion ESI
Ion source: HESI-II
Sheath gas flow rate: 45 units N2
Auxiliary gas flow rate: 10 units N2
Spray voltage (KV): +3.5
Capillary column temperature (°C): 320
S-lens RF level: 50.0
Heater temperature (°C): 400
Q Exactive method parameters:
AGC target (full scan): 3e6
AGC target (MS/MS): 1e5
NCE: 30, 35% step change
Scan range (full scan MS): 180 to 1200 amu
Results and discussion
I. High-resolution full scan- HCD MS/MS identification of impurities
The high-resolution full scan of the omeprazole and the three highest intensity data were relied upon for HCD MS/MS data. HRAM full scan and MS/MS data provides molecular weight and fragmentation information. HCD (High Energy Collision Dissociation) yields rich MS/MS fragmentation and low quality end fragmentation information. Using Mass Frontier software to work with this information, we not only quickly detected the major impurities of omeprazole, but also reliably determined the corresponding elemental composition, as shown in Figure 1 & 2 and Table 1.
Figure 1. Mass spectrometry total ion chromatogram of omeprazole
Figure 2. High-resolution accurate mass total scan and MS/MS spectra of omeprazole
Figure 3. Mass Frontier's FISh function to identify impurities
Table 1. Accurate mass and elemental composition of identified impurities
II. Mass Frontier for structural identification of unknowns
The HRAM full scan and MS/MS data is processed using Mass Frontier's Fragment Ion Search (FISh) function, as shown in Figure 3-a. FISh can easily identify compounds with the same fragment ions as the parent compound, see Figure 3-b, and infer the possible impurity structure from the fragments, see Figure 7. By searching Mass Frontier's HighChem spectrum database, Mass Frontier's "Fragment and Mechanism" feature provides references to recommended structures. The “Fragment and Mechanism†results for each recommended structure provide a good help in understanding the source of the structure. Comparing the data results with the "Fragment and Mechanism" provides more confirmation/negative criteria for the proposed structure.
Another important feature of Mass Frontier is the "Annotation Map of the Fragment Structure" for automatic prediction of debris. The structural identification of the three isomers demonstrates this function, see Figures 4 and 5.
Figure 4. Three isomers of m/z with an impurity of 376.1331
Figure 5-a. MS/MS spectrum of impurities with an m/z of 376.1331 for RT 8.1 min
Figure 5-b. MS/MS spectrum of impurities with an m/z of 376.031 at RT 8.5 min
Figure 5 - c. MS/MS spectrum of impurities with an m/z of 37.33131 for RT 11.2 min
*9' and 10' are the isomers of 9 and 10.
Figure 7. Recommended structure for omeprazole impurities
in conclusion
The Q Exactive benchtop Orbitrap system enables high-resolution accurate mass spectrometry (HRAM) of full scan and MS/MS data, providing critical molecular weight and structural information for structural identification of unknown impurities: HRAM full scan accurately determines elemental composition, HRAM MS/MS can accurately determine the impurity content.
Mass Frontier Fragment Ion Search (FISh) and the Fragment and Mechanism feature accurately identify the structure of an unknown by searching the HighChem Fragment Database.
A workflow consisting of Q Exactive HRAM data and Mass Frontier software helps researchers efficiently and accurately identify impurities in each batch of API early in drug research.
references
1.FDD Guidance for Industry, Q3A (R2) Impurities in New Drug Substances