1. What is LCMS and how does it work?
Explanation: This is a foundational question. LCMS combines liquid chromatography (LC) for separating compounds and mass spectrometry (MS) for detecting and identifying them based on mass-to-charge ratio (m/z). It is widely used in pharma, food safety, and environmental analysis.

2. What are the main components of an LCMS system?
 Interviewers want you to list and describe:

1. LC Pump: Delivers mobile phase at high pressure.
2. Injector: Introduces the sample.
3. Column: Separates analytes.
4. Ion Source: Converts eluted analytes into ions (e.g., ESI, APCI).
5. Mass Analyzer: Separates ions (e.g., quadrupole, TOF).
6. Detector: Detects ions and produces spectra.

3. What is the difference between ESI and APCI ion sources?

ESI (Electrospray Ionization): Best for polar, large biomolecules. Uses electric field to generate ions from liquid.

APCI (Atmospheric Pressure Chemical Ionization): Better for less polar compounds. Uses heat and a corona discharge to ionize the analyte.

4. How do you calibrate an LCMS system?

•  Calibration ensures mass accuracy. It typically involves:
• Using standard calibration solutions with known m/z values.
• Running the standards.
• Adjusting the instrument settings to match the expected values.

5. What are common issues with LCMS and how do you troubleshoot them?
Shows hands-on experience. Examples:

• Low signal → check ion source cleanliness.
• Poor peak shape → check LC column and flow rate.
• High background noise → check mobile phase quality and contamination.

6. What are the advantages of LCMS over GCMS?

• LCMS can analyze non-volatile, thermally labile, and polar compounds.
• No need for derivatization.
• Better suited for biological samples like peptides and drugs.

7. How do you prepare samples for LCMS analysis?
Sample prep is critical to avoid contamination and ion suppression. Steps include:

• Filtration (0.2 μm or 0.45 μm filters).
• Dilution with appropriate solvents.
• Protein precipitation (for biological samples).
• Solid-phase extraction (SPE) for cleanup.

8. What is ion suppression and how do you minimize it?
Ion suppression happens when matrix components interfere with ionization, reducing signal intensity. To minimize:

• Use proper sample cleanup.
• Optimize mobile phase composition.
• Adjust ion source parameters.

9. Explain the role of the mass analyzer in LCMS.
The mass analyzer separates ions based on m/z.

Common types:

1. Quadrupole: Selects ions by stability in an oscillating electric field.
2. TOF (Time of Flight): Separates ions based on flight time.
3. Orbitrap and Ion Trap: Offer high-resolution analysis.

10. What are MRM and SIM modes in LCMS and when are they used?

SIM (Selected Ion Monitoring): Detects specific m/z values; used for simple, targeted analysis.

MRM (Multiple Reaction Monitoring): Used in tandem MS (MS/MS) for quantifying specific compounds with high sensitivity and selectivity.

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