Collision cross section measurement in time-of-flight mass analyser

1 . A method of operating a time-of-flight (ToF) mass analyser that is configured to determine a mass to charge ratio (m/z) of ions by determining flight times of ions along an ion path, the method comprising:

operating the time-of-flight (ToF) mass analyser in a first mode of operation, and analysing ions by determining flight times of the ions along the ion path so as to obtain a first set of data, wherein in the first mode of operation (i) the ion path has a first path length, and (ii) the ion path is maintained at a first pressure;

operating the time-of-flight (ToF) mass analyser in a second mode of operation, and analysing ions by determining flight times of the ions along the ion path so as to obtain a second set of data, wherein in the second mode of operation (i) the ion path has a second path length, and (ii) the ion path is maintained at a second pressure, wherein the second path length is different to the first path length and/or the second pressure is different to the first pressure;

comparing an intensity of an ion peak in the first set of data to an intensity of a corresponding ion peak in the second set of data; and

determining, based on the comparison and using a calibration for the time-of-flight (ToF) mass analyser, a collision cross section (CCS) of ions associated with the corresponding ion peaks.

2 . The method of claim 1 , wherein the second path length is greater than the first path length.

3 . The method of claim 1 , wherein:

the time-of-flight mass analyser comprises one or more ion reflectors;

in the first mode of operation ions are caused to make n reflection(s) in the one or more ion reflectors, wherein n is an integer ≥0; and

in the second mode of operation ions are caused to make m reflection(s) in the one or more ion reflectors, wherein m is an integer >n.

4 . The method of claim 1 , wherein the time-of-flight mass analyser is a multi-reflection time-of-flight (MR-ToF) mass analyser comprising:

two ion mirrors spaced apart and opposing each other in a direction X, each mirror elongated generally along a drift direction Y between a first end and a second end, the drift direction Y being orthogonal to the direction X;

an ion injector for injecting ions into a space between the ion mirrors, the ion injected located in proximity with the first end of the ion mirrors; and

a detector for detecting ions after they have completed plural reflections in the ion mirrors,

wherein the time-of-flight mass analyser is configured to analyse ions by injecting ions from the ion injector into the space between the ion mirrors, such that the ions follow an ion path having one or more (K) oscillation(s) between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector.

5 . The method of claim 4 , wherein:

in the first mode of operation ions are caused to make a first number K 1 of oscillation(s) between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector; and

in the second mode of operation ions are caused to make a second different number K 2 of oscillations between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector, wherein the second number of oscillations is greater than the first number of oscillation(s) (K 2 >K 1 ).

6 . The method of claim 5 , wherein:

the multi-reflection time-of-flight (MR-ToF) mass analyser further comprises a deflector or lens located in proximity with the first end of the ion mirrors; and

the method comprises controlling the numbers (K 1 , K 2 ) of oscillation(s) that ions make between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector by controlling a voltage applied to the deflector or lens.

7 . The method of claim 5 , wherein:

in the first mode of operation ions are caused to make a single (K 1 =1) oscillation between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector; and

in the second mode of operation ions are caused to make plural (K 2 >1) oscillations between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector.

8 . The method of claim 7 , wherein in the second mode of operation ions are caused to make (i) K 2 ≥5, (ii) K 2 ≥10, (iii) K 2 ≥20, or (iv) K 2 ≥30 oscillations between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector.

9 . The method of claim 7 , wherein:

the multi-reflection time-of-flight (MR-ToF) mass analyser further comprises a deflector or lens located in proximity with the first end of the ion mirrors;

the method comprises controlling the numbers (K 1 , K 2 ) of oscillation(s) that ions make between the ion mirrors in the direction X whilst drifting in the drift direction Y from the ion injector to the detector by controlling a voltage applied to the deflector or lens; and

analysing ions in the first mode of operation comprises injecting ions from the ion injector into the space between the ion mirrors, wherein the ions are reflected by one of the ion mirrors, travel to the deflector or lens, and are caused to travel from the deflector or lens to the detector via a reflection in the other ion mirror.

10 . The method of claim 9 , wherein analysing ions in the second mode of operation comprises:

injecting ions from the ion injector into the space between the ion mirrors, wherein the ions follow a zigzag ion path having plural (K 2 >1) oscillations between the ion mirrors in the direction X whilst: (a) drifting from the deflector or lens along the drift direction Y towards the second end of the ion mirrors, (b) reversing drift direction velocity in proximity with the second end of the ion mirrors, and (c) drifting back along the drift direction Y to the deflector or lens; and then

causing the ions to travel from the deflector or lens to the detector for detection.

11 . The method of claim 9 , wherein analysing ions in the second mode of operation comprises:

(i) injecting ions from the ion injector into the space between the ion mirrors, wherein the ions complete a first pass in which the ions follow a zigzag ion path having plural oscillations between the ion mirrors in the direction X whilst: (a) drifting along the drift direction Y from the deflector or lens towards the second end of the ion mirrors, (b) reversing drift direction velocity in proximity with the second end of the ion mirrors, and (c) drifting back along the drift direction Y to the deflector or lens;

(ii) using the deflector or lens to reverse the drift direction velocity of the ions such that the ions are caused to complete a further pass in which the ions follow a zigzag ion path having plural oscillations between the ion mirrors in the direction X whilst: (a) drifting along the drift direction Y from the deflector or lens towards the second end of the ion mirrors, (b) reversing drift direction velocity in proximity with the second end of the ion mirrors, and (c) drifting back along the drift direction Y to the deflector or lens;

(iii) optionally repeating step (ii) one or more times; and then

(iv) causing the ions to travel from the deflector or lens to the detector for detection.

12 . The method of claim 4 , wherein:

analysing ions in the first mode of operation comprises:

injecting ions from the ion injector into the space between the ion mirrors, wherein the ions follow a zigzag ion path having plural (K 1 >1) oscillations between the ion mirrors in the direction X whilst: (a) drifting from a deflector or lens along the drift direction Y towards the second end of the ion mirrors, (b) reversing drift direction velocity in proximity with the second end of the ion mirrors, and (c) drifting back along the drift direction Y to the deflector or lens; and then

causing the ions to travel from the deflector or lens to the detector for detection; and

analysing ions in the second mode of operation comprises:

(i) injecting ions from the ion injector into the space between the ion mirrors, wherein the ions complete a first pass in which the ions follow a zigzag ion path having plural oscillations between the ion mirrors in the direction X whilst: (a) drifting along the drift direction Y from the deflector or lens towards the second end of the ion mirrors, (b) reversing drift direction velocity in proximity with the second end of the ion mirrors, and (c) drifting back along the drift direction Y to the deflector or lens;

(ii) using the deflector or lens to reverse the drift direction velocity of the ions such that the ions are caused to complete a further pass in which the ions follow a zigzag ion path having plural oscillations between the ion mirrors in the direction X whilst: (a) drifting along the drift direction Y from the deflector or lens towards the second end of the ion mirrors, (b) reversing drift direction velocity in proximity with the second end of the ion mirrors, and (c) drifting back along the drift direction Y to the deflector or lens;

(iii) optionally repeating step (ii) one or more times; and then

(iv) causing the ions to travel from the deflector or lens to the detector for detection.

13 . The method of claim 1 , wherein the first pressure is approximately equal to the second pressure.

14 . The method of claim 1 , wherein the second pressure is greater than the first pressure.

15 . The method of claim 1 , wherein

comparing the intensity of the ion peak in the first set of data to the intensity of the corresponding ion peak in the second set of data comprises: determining a ratio of the intensity of the ion peak in the first set of data to the intensity of the corresponding ion peak in the second set of data; and

determining the collision cross section (CCS) of the ions associated with the corresponding ion peaks comprises: using the ratio and the calibration to determine the collision cross section (CCS) of the ions associated with the corresponding ion peaks,

wherein the calibration relates intensity ratios to collision cross section (CCS) values.

16 . A method of operating a time-of-flight (ToF) mass analyser that is configured to determine a mass to charge ratio (m/z) of ions by determining flight times of ions along an ion path, the method comprising:

operating the time-of-flight (ToF) mass analyser in a first mode of operation, and analysing ions by determining flight times of the ions along the ion path so as to obtain a first set of data, wherein in the first mode of operation (i) the ion path has a first path length, and (ii) the ion path is maintained at a first pressure;

operating the time-of-flight (ToF) mass analyser in a second mode of operation, and analysing ions by determining flight times of the ions along the ion path so as to obtain a second set of data, wherein in the second mode of operation (i) the ion path has a second path length, and (ii) the ion path is maintained at a second pressure, wherein the second path length is different to the first path length and/or the second pressure is different to the first pressure;

comparing an intensity of an ion peak in the first set of data to an intensity of a corresponding ion peak in the second set of data;

determining, based on the comparison, a collision cross section (CCS) of ions associated with the corresponding ion peaks; and

operating the time-of-flight (ToF) mass analyser in a mass analysis mode of operation, wherein in the mass analysis mode of operation the ion path is maintained at a third pressure, wherein the third pressure is less than the first and second pressures.

17 . A method of determining a calibration for a time-of-flight (ToF) mass analyser that is configured to determine a mass to charge ratio (m/z) of ions by determining flight times of ions along an ion path, the method comprising:

operating the time-of-flight (ToF) mass analyser in a first mode of operation, and analysing calibrant ions by determining flight times of the calibrant ions along the ion path so as to obtain a first set of data, wherein in the first mode of operation (i) the ion path has a first path length, and (ii) the ion path is maintained at a first pressure;

operating the time-of-flight (ToF) mass analyser in a second mode of operation, and analysing calibrant ions by determining flight times of the calibrant ions along the ion path so as to obtain a second set of data, wherein in the second mode of operation (i) the ion path has a second path length, and (ii) the ion path is maintained at a second pressure, wherein the second path length is different to the first path length and/or the second pressure is different to the first pressure;

determining a plurality of ratios, wherein each ratio is a ratio of an intensity of an ion peak in the first set of data to an intensity of a corresponding ion peak in the second set of data; and

using each ratio together with a known collision cross section (CCS) value for calibrant ions associated with that ratio to determine a calibration for the time-of-flight (ToF) mass analyser.

18 . An analytical instrument comprising:

a time-of-flight (ToF) mass analyser configured to determine the a mass to charge ratio (m/z) of ions by determining flight times of ions along an ion path; and

a control system configured to:

operate the time-of-flight (ToF) mass analyser in a first mode of operation, and analyse ions by determining flight times of the ions along the ion path so as to obtain a first set of data, wherein in the first mode of operation (i) the ion path has a first path length, and (ii) the ion path is maintained at a first pressure;

operate the time-of-flight (ToF) mass analyser in a second mode of operation, and analyse ions by determining flight times of the ions along the ion path so as to obtain a second set of data, wherein in the second mode of operation (i) the ion path has a second path length, and (ii) the ion path is maintained at a second pressure, wherein the second path length is different to the first path length and/or the second pressure is different to the first pressure;

compare an intensity of an ion peak in the first set of data to an intensity of a corresponding ion peak in the second set of data; and

determine, based on the comparison and using a calibration for the time-of-flight (ToF) mass analyser, a collision cross section (CCS) of the ions associated with the corresponding ion peaks.

19 . The analytical instrument of claim 18 , wherein the second path length is greater than the first path length.

20 . The analytical instrument of claim 18 , wherein:

the time-of-flight (ToF) mass analyser comprises one or more ion reflectors;

in the first mode of operation ions are caused to make n reflection(s) in the one or more ion reflectors, wherein n is an integer ≥0; and

in the second mode of operation ions are caused to make m reflection(s) in the one or more ion reflectors, wherein m is an integer >n.

21 . An analytical instrument comprising:

a mass analyser configured to determine a mass to charge ratio (m/z) of ions by determining flight times of ions along an ion path; and

a control system configured to:

operate the mass analyser in a first mode of operation, and analyse ions by determining flight times of the ions along the ion path so as to obtain a first set of data, wherein in the first mode of operation (i) the ion path has a first path length, and (ii) the ion path is maintained at a first pressure;

operate the mass analyser in a second mode of operation, and analyse ions by determining flight times of the ions along the ion path so as to obtain a second set of data, wherein in the second mode of operation (i) the ion path has a second path length, and (ii) the ion path is maintained at a second pressure, wherein the second path length is different to the first path length and/or the second pressure is different to the first pressure;

compare an intensity of an ion peak in the first set of data to an intensity of a corresponding ion peak in the second set of data; and

determine, based on the comparison, a collision cross section (CCS) of the ions associated with the corresponding ion peaks,

wherein the control system is further configured to:

operate the mass analyser in a mass analysis mode of operation, wherein in the mass analysis mode of operation the ion path is maintained at a third pressure, wherein the third pressure is less than the first and second pressures.