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Developing a Fast, Generic Method for Rapid Resolution LC with Quadrupole

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Developing a Fast, Generic Method for Rapid Resolution LC with Quadrupole Developing a fast, generic method for rapid resolution LC with quadrupole MS detection Combining the Agilent 6140 quadrupole MS and multimode source with the Agilent 1200 Series Rapid Resolution LC system Application Note Udo Huber 1600000 1400000 Disopyramide 1200000 1000000 Quinidine 800000 600000 Procainamide N-Acetylprocainamide 400000 200000 0 0.2 0.4 0.6 0.8 1 min Abstract In this Application Note the Agilent 6140 quadrupole MS, equipped with Agilent Equipment the multimode source, is combined with the Agilent 1200 Series Rapid • 1200 Series Rapid Resolution LC system Resolution LC system, to develop a fast, generic LC/MS method for: • 6140 quadrupole MS detector • Multimode Source • analysis of 35 pharmaceutical compounds from 17 compound classes • reduction of the method run time from 2.1 to 0.8 minutes Application Area • High throughput MS analysis in drug discovery Introduction Experimental • One resistive capillary (Agilent part number G1960-80060) With the introduction of the Agilent Equipment • One narrow-bore capillary 1200 Series Rapid Resolution LC The Agilent 1200 Series Rapid 1 (Agilent part number G1960- system , it is now possible to run Resolution LC/MS system con- 20310). sub-2-micron particle columns at tained the following modules: high flow rates and achieve run • Agilent 1200 Series binary pump times of less than 1 – 2 minutes. SL Results and discussion With increased temperatures, 4.6 • Agilent 1200 Series high-perfor- mm i.d. columns can be operated at mance autosampler SL Moving towards a generic method flow rates of 5 mL/min but this flow • Agilent 1200 Series thermostat- Generic methods for liquid chro- rate is too high for electrospray ted column compartment SL matography with UV detection often (ESI) or atmospheric pressure • Agilent 1200 Series diode array use trifluoro acetic acid (TFA) as chemical ionization (APCI). detector SL (micro flow cell: ion-pairing modifier to achieve small Therefore, usually 2.1 mm i.d. 2 µL, 3 mm path length) peak widths and good peak shapes columns are used in a system with • Agilent 6140 quadrupole LC/MS (figure 1A). For applications with MS detection but these columns are with multimode source MS detection TFA is usually avoided also operated at flow rates above The system was controlled using because it can lead to substantial 1 mL/min. With a conventional the Agilent ChemStation (rev. ion suppression for certain com- source the maximum flow rate is B.03.01. SR1).). The new capillary pounds and therefore modifiers around 1 mL/min (depending on the that provides fast POS/NEG such as formic or acetic acid are mobile phase composition). With switching is standard on Agilent 2 preferred. On the other hand TFA the Agilent multimode source with 6100 Series instruments shipped cannot be replaced with formic or integrated, additional drying using after August 2007. Earlier instru- acetic acid for all application to IR emitters, the maximum flow rate ments would require the following maintain chromatographic quality can be increased up to 2 mL/min. in addition to the B.03.01.SR1 or (figure 1B). Further, the multimode source later software: offers the possibility of simultane- ous ESI and APCI ionization, which makes it the ideal source for fast, generic MS detection. In combina- mAU A 250 UV chromatogram tion with the fast scanning Agilent Mobile phase B = acetonitrile 3 200 6140 quadrupole MS it is the ideal Modifier = TFA 150 solution for fast and ultra-fast LC 100 analysis with single quadrupole MS 50 detection. 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 min mAU UV chromatogram B 80 Mobile phase B = acetonitrile Modifier = Formic acid 60 40 20 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 min Figure 1 Influence of different modifiers on the chromatographic performance. 2 Whereas electrospray ionization Sample name Sample Compound Totals Monoisotopic (ESI) requires a modifier, atmos- formulae mass pheric pressure chemical ionization UH_TM_AH01 Antihypertensive drugs Captopril C H NO S (APCI) is controlled by vapor chem- 9 15 3 217.08 Enalapril C20H28N2O5 376.20 istry. The use of acetonitrile in APCI UH_TM_AA01 Antiasthmatic drugs Enprofylline C H N O can prevent ion formation in both 8 10 4 2 194.08 Theobromine C7H8N4O2 180.06 positive and negative ion polarity Theophylline C7H8N4O2 180.06 and, therefore, methanol is the pre- UH_TM_AB01 Antibacterial drugs Trimethoprim C14H18N4O3 290.14 ferred organic mobile phase for Furazolidone C8H7N3O5 225.04 Nalidixic acid C H N O maximum analyte coverage. One 12 12 2 3 232.08 Penicillin-G C16H18N2O4S 334.10 thing that has to be considered when using methanol as organic UH_TM_AH01 Antihistaminic drugs Chlorpheniramine C16H19N2Cl 274.12 Promethazine C H N S mobile phase in chromatography is 17 20 2 284.13 Tripelennamine C16H21N3 255.17 that the viscosity is higher than for UH_TM_AA02 Antiarrythmic drugs Disopyramide C H N O acetonitrile. Therefore, the maxi- 21 29 3 339.23 N-Acetylprocainamide C15H23N3O2 277.18 mum flow rate until the maximum Procainamide C13H21N3O 235.17 Quinidine C H N O system back pressure is reached is 20 24 2 2 324.18 lower than for acetonitrile. Further, UH_TM_TAD01 Tricyclic antidepressant drugs Imipramine C19H24N2 280.19 Protriptyline C H N the maximum viscosity for a 19 21 263.17 Trimipramine C20H26N2 294.21 water/methanol mixture is reached at about 50/50 v/v. This means the UH_TM_S01 Sulfa drugs Sulfadiazine C10H10N4O2S 250.05 Sulfamerazine C11H12N4O2S 264.07 maximum system back pressure is Sulfamethazine C12H14N4O2S 278.08 not reached at the beginning but UH_TM_CCB01 Calcium channel blockers Nifedipin C H N O somewhere in the middle of the run. 17 18 2 6 346.12 Nimodipin C21H26N2O7 418.17 A flow rate must be selected that Nisoldipin C20H24N2O6 388.16 Nitrendipin C H N O ensures that the system pressure is 18 20 2 6 360.13 not exceeded even later in the run. UH_TS_05 Antidepressant drugs Bupropion C13H18NOCl 239.11 Keeping the above mentioned facts UH_TS_07 Antiepileptic drugs Phenytoin C15H12N2O2 252.09 in mind, the general rules for a generic method are: UH_TS_08 Antitussive drugs Dextromethorphan C18H25NO 271.19 • To ensure ionization of the com- UH_TS_12 Analgesic drugs 4-Hydroxyantipyrine C11H12N2O2 204.09 pound, the multimode source UH_TS_15 Antianginal drugs Verapamil C H N O should be operated in mixed mode 27 38 2 4 454.28 • Use acetonitrile as organic phase UH_TS_18 Antiinflammatory drugs Naproxen C14H14O3 230.09 and formic or acetic acid as UH_TS_20 Androgen drugs Testosteron C19H28O2 288.21 modifier if possible UH_TS_23 Glucocorticoid drugs Prednisolon C H O • TFA should only be used if 21 28 5 360.19 chromatography requires it UH_TS_24 Muscle-relaxing drugs Papaverin C20H21NO4 339.15 • If ionization is done in APCI or mixed mode (Multimode source) Table 1 Analyzed pharmacological compounds. methanol should be used as mobile phase. ties to reduce the cycle time, for to antibacterial drugs, TFA was used Application example example, alternating column regen- as modifier. The multimode source To test a generic method 35 pharma- eration, however, this was not the was operated in mixed mode, and cological compounds were selected focus of this study but is described methanol was used as organic and analyzed using a fast, generic in other publications. Since the com- mobile phase. The list of analyzed method with a run time of less than pounds belong to completely differ- compounds is shown in table 1. 2 minutes. There are other possibili- ent compound classes from steroids 3 The following method was used to analyze the compounds: • Column: Agilent ZORBAX SB-C18 A B 2.1 x 50 mm, 1.8 µm • Solvents: A: water + 0.05 % TFA 1600000 Nalidixic acid Dihydroquinidine 1200000 Disopyramide Trimethoprim B: methanol + 0.045 % TFA Quinidine 1200000 (Impurity in • Gradient: 0 min, 10 %B; Procainamide Quinidine) N-Acetylprocainamide 800000 Furazolidone 1.7 min, 92.5 %B 800000 Penicillin-G • Flow rate: 1.6 mL/min 400000 400000 • Stop time: 1.7 min • Post time: 0.2 min 0 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 min 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 min • Injection volume: 1 µL C D • Column temperature: 80 °C 1 Nifedipin 4 1600000 1600000 1 • Diode array detector: 230 nm/40 2 Nitrendipin 3 1200000 1200000 3 Nimodipin (ref. 550 nm/50) 4 Nisoldipin 2 Peak width: > 0.0025 min (80 Hz) 800000 Promethazine Tripelennamine 800000 Flow cell: Micro flow cell Chlorpheniramine 400000 400000 (2 µL, 3 mm path length) 0 0 Multimode source, mixed mode, 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 min 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 min positive scan, ultra-fast scan: • Scan: 150–800 m/z Figure 2 • Step size: 0.2 (fixed) A) Antiarrythmic drugs B) Antibacterial drugs • Peak width: 0.01 min C) Antihistaminic drugs D) Calcium channel blockers • Drying gas flow: 7 L/min • Neb. pressure: 60 psig • Drying gas temp.: 350 °C • Vaporizer temp.: 250 °C • Cap. voltage: 2000 V 800000 • Corona current: 2 µA Gradient changed 600000 1.7 min • Charging voltage: 2000 V (- 19 %) 400000 Figure 2 shows four example MS 200000 chromatograms for different com- pound classes. Under the selected, 0 generic conditions only the two 0.25 0.5 0.75 1 1.25 1.5 1.75 2 min compounds phenytoin and naprox- en did not ionize very well but still Figure 3 gave good MS spectra. Only two Optimized gradient, MS chromatogram (TIC).
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