Troubleshooting Common Issues with High-Performance Liquid Chromatographs (HPLC)

  1. What are the possible causes of significantly high pump pressure in an HPLC?
  • Excessively high flow rate setting;
  • Mechanical impurities in the mobile phase or sample injection, causing blockage of the guard column, pre-column frit, or in-line filter;
  • Excessively high viscosity of the mobile phase;
  • Too low column temperature;
  • Crystallization of buffer salts;
  • Malfunction of the pressure sensor.
  1. What causes unstable baseline (fluctuations or drift), and how to resolve it?
  2. Dissolved gases in the mobile phase; Degas by ultrasonic treatment for 15-30 minutes or by helium sparging.
  3. Blockage of the check valve; Remove the check valve and sonicate it in pure water for approximately 20 minutes to clear the blockage.
  4. Damaged pump seal leading to pressure fluctuations; Replace the pump seal.
  5. Presence of liquid leakage points in the system; Identify the leakage location and repair it.
  6. Bubble formation after the column; Install a backpressure regulator at the outlet of the flow cell.
  7. Detector not set to the absorption wavelength; Adjust the wavelength to the absorption wavelength.
  8. Slow column equilibration, especially when the mobile phase is changed; Flush the column with a solvent of moderate strength. When changing the mobile phase, flush the column with 10-20 column volumes of the new mobile phase before analysis.
  9. Why does leakage often occur at the fittings, and how to address it?
    • Fittings not tightened properly; Loosen the fitting first, then retighten it. For hand-tight fittings, tighten only by hand (do not use tools). For stainless steel fittings, first tighten by hand, then use a dedicated wrench to tighten an additional 1/4 to 1/2 turn. Ensure the tubing inside the fitting reaches the bottom; otherwise, dead volume will be left.
    • Contaminated or worn fittings; Replace the fittings.
    • Mismatched fittings; Use accessories from the same brand.
  10. What causes leakage from the injection valve?
  11. Damaged rotor seal; Replace the rotor seal.
  12. Blockage of the sample loop; Clean or replace the sample loop.
  13. Loose injection port seal; Adjust the tightness.
  14. Inappropriate size of the injection needle (usually too short); Use a suitable injection needle (pay attention to the needle shape).
  15. Siphoning in the waste line; Empty the waste line.