Make-up Solvent Considerations for Prep and Semi-Prep LC/MS Mass-Based ....

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systems utilizing a make-up solvent technique to provide required dilution. ... Fraction Collector, 322 H2 Prep Pump, 307 Make-up Pump, 155 UV/VIS Dual ...

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Make-up Solvent Considerations for Prep and Semi-Prep LC/MS Mass-Based Fraction Collection Application Note 206 Tim Hegeman (Gilson, Inc.) Introduction Solvent choices for electrospray ionization can be separated from those of column separation for systems utilizing a make-up solvent technique to provide required dilution. The following application note takes a look at a few common solvent systems and their effects on a set of pharmaceutical target compounds and related analytes. Materials & Methods What was Investigated Mass-based fraction collection solvent selection for electrospray positive ionization mode was tested for a limited set of solvents against a small set of analytes to show examples of solvent choice on results. Often in prep analysis, unlike analytical work, compromises are made in ionization mode and HPLC conditions to suit a broad number of compounds. In this Application Note, we will look at some of these compromises in terms of ionization. Main Components: Gilson-Thermo Finnigan NEBULA™ Prep System, consisting of a Gilson 215 Liquid Handler/Autosampler/Fraction Collector, 322 H2 Prep Pump, 307 Make-up Pump, 155 UV/VIS Dual- wavelength Detector with 0.2-mm flow cell, and Thermo Finnigan MSQ Mass Spectrometer. Experimental—HPLC/LCMS Six solutions of analytes were prepared (10 mg/mL of each compound) in DMSO, which offers at least moderate separation for most analytes. All injection volumes were 500 µL on a 2-mL loop. Column: Metachem 21*50 ODS2. Flow rate: 20 mL/min.; gradient: 5% MEOH/95%Water + 0.1% HCOOH to 95% MEOH/5% Water +0.1%HCOOH in 10 minutes. Retention time estimates from screening analysis on a ZORBAX 4.6*50-mm column at 1.5 mL/min. using the same gradient. Make-up Flow Rate: 0.4 mL/min. Splitter: Standard LC-Packings/standard ACM 10–50; UV = 254nm. MS Conditions: Electrospray positive ionization mode. Capillary voltage: 3kV; cone voltage varied for experimental purposes. Capillary temperature (525°C) was determined to give optimal signal for all solvents. Scan range: 100–900 amu; scan rate: 0.8 sec. Cone stepping runs: 20V, 40V, 65V, and 95V at 1 sec. August 2003 Page 1 of 14 319306-01
Experiments: Collections performed for all solvents were tested for all mixes. Each system was run with four cone voltages to look at solvent influence. Note: System is a solvent system identified by its organic constituent: MEOH, ACN, IPA, or MEOH/1,4 Dioxane. One representative mix from each system was chosen for the cone voltage experiment as indicated. Make-up 1 Solvent A Solvent B Acid Methanol % Water % HCOOH % 100 0 0.10 90 10 0.10 75 25 0.10 X 50 50 0.10 Make-up 2 Solvent A Solvent B Acid Acetonitrile % Water % HCOOH % 100 0 0.10 90 10 0.10 75 25 0.10 X 50 50 0.10 Make-up 3 Solvent A Solvent B Acid IPA % Water % HCOOH % 100 0 0.10 90 10 0.10 75 25 0.10 X 50 50 0.10 Make-up 4 Solvent A Solvent B Solvent Acid 1,4 Dioxane % Methanol % Water % HCOOH % X 25 25 50 0.10 Make-up flow = 0.4 mL/min. HCOOH = Formic Acid % = v/v X = Mix chosen to represent system for cone voltage change This change was a sequential step of voltages at 20, 40, 65, and 95V Table 1: Experimental—Make-up Solvents Tested Photo 1: Gilson-Thermo Finnigan NEBULA™ Prep System August 2003 Page 2 of 14 319306-01
Pump Finnigan MSQ™ Low-Mount, Low-Pressure Valve (not shown installed in spring clamp) Outlet Column Inlet NO COMM low flow to high 215 Liquid Handler NC flow mass spectro collect 819 UV/VIS Detector Outlet Injection Flow Splitter Inlet Module Make-up Inlet Pump to waste Semi-Prep Filter Assembly to waste Figure 1: Single-Injection LC/MS System Figure 2: Make-up Splitter Allows Solvent Choices Dilution Factor= mass split(1000) * make-up flow/prep flow Dilution Factor = (1000 * 0.4 mL/min.)/20 mL/min. = 20 August 2003 Page 3 of 14 319306-01
N 10mg/mL DMSO 1 O Mix 1 in DMSO NH2 Compound RT RT MW* ion MH+ S RT from screen Window O H3C CH3 HO 1 Niacinamide 0.6 1.5-2.5 122 123 2 4-Acetaminophen 2.9 2.3-3.5 151 152 O 3 Caffeine 4.9 4.7-5.4 194 195 2 4* Salicyclic acid acetate 5.8 5.6-6.3 180 none 5 Verapamil 6.7 6.5-7.5 454 455 NH CH3 6 Nifedaphine 7.9 7.7-8.1 346 347 * MW Molecular Weight * RT Retention time min. O CH3 * MH+ Protonated ion 4* Salicyclic acid acetate--not analyzed for H3C N CH3 N N H3C CH3 3 H3C O N O CH3 O N N 6 5 CH3 H3C O O CH3 O OH H H3C N CH3 O CH3 6 H3C O O CH3 4 O O O - + O N O Figure 3: Mix 1: 10 mg/mL DMSO N CH3 Mix 2 in DMSO HO 1 Compound RT RT MW* ion MH+ OH RT from screen Window 1 Pyridoxamine 0.4 0-1 168 169 NH2 2 Metropropolol 4.2 4.1-4.9 267 268 O OH 3 Quinine 5 4.5-5.5 324 325 OH 4* Salicyclic acid acetate 6 5.5-6.5 138 none 5 Cortisone 7.2 7-7.5 360 361 OH NH CH3 O 6 Clofazimine 8.5 9 472 473 7 Triprolidine 4.8 4.5-5.5 278 279 4 2 CH3 * MW Molecular Weight * RT Retention time min. 4* Salicyclic acid acetate--not analyzed for H3C O H2C O CH3 OH CH3 O OH Cl CH3 N 6 HO H3C O O N H3C 3 N N CH3 N 7 5 N N NH Cl Figure 4: Mix 2: 10 mg/mL DMSO August 2003 Page 4 of 14 319306-01
N CH3 HO 1 OH Mix 3 in DMSO Compound RT RT MW* ion MH+ RT from screen Window OH 1 Pyridoxine 0.4 0-1 169 170 O 2 8-Chlorotheophyline 4.4 4-4.9 214 215 H 3 Chlorpheniramine 5.2 5.0-6.0 274 275 H3C N 4 Doxepin 6.4 5.8-7.0 279 280 N 5 Funarizine 7.9 7.7-8.2 404 405 2 Cl * MW Molecular Weight * RT Retention time min. CH3 O N N * MH+Protonated ion N CH3 CH3 F Cl H3C N 3 4 H3C O N N 5 N F Double charged at high cone voltage (M2H+) Figure 5: Mix 3: 10 mg/mL DMSO N CH3 HO 1 Mix 4 in DMSO OH Compound RT RT MW* ion MH+ RT from screen Window O 1 Pyridoxal 0.55 0-1 167 168 2 Primidone 4.8 4.5-5.5 218 219 H 3 3-Is obutyl-1-methylxantthene 6.1 6-6.7 222 223 O N 4 Prednisone 7.2 7-7.6 358 359 2 NH 5 Desoximetasone * MW Molecular Weight 8.7 8.5-9.0 376 377 * RT Retention time min. * MH+Protonated ion O O CH3 CH3 OH O OH O CH3 4 H O OH H3C N N CH3 3 HO CH3 O O N N CH3 CH3 5 F O H3C Figure 6: Mix 4: 10 mg/mL DMSO August 2003 Page 5 of 14 319306-01
OH Mix 5 in DMSO O O 1 Compound RT RT MW* ion MH+ CH3 RT from screen Window 1 Panthothenic Acid 2 1-2.9 219 220 HO NH CH3 2 Sulfamethazine 4.5 4.0-5.0 278 279 3 Estrone 5.1 4.8-5.5 270 271 OH 4 Enalapril 6.4 6.2-6.8 376 377 * MW Molecular Weight CH3 * RT Retention time min. N * MH+Protonated ion O O S NH N CH3 2 H2N O OH CH3 O H3C O O H3C 3 N NH 4 O HO Figure 7: Mix 5: 10 mg/mL DMSO Br H3C N 1 Mix 6 in DMSO H3C Compound RT RT MW* ion MH+ RT from screen Window N 1 Bromopheniramine 4.9 4.1-5.8 318 319 2 Diltizem 6.6 6.4-7.4 414 415 3* Quininic Acid 7.9 7.7-8.1 203 none 3* Not analyzed for CH3 * MW Molecular Weight O * RT Retention time min. S 2 O N O CH3 O H3C N O OH CH3 O H3C 3 Figure 8: Mix 6: 10 mg/mL DMSO Targets Which Showed a Significant Solvent Effect Several of the target compounds studied were not influenced by the solvents chosen; these are omitted from further discussion. These primarily consisted of compounds that have very good MH+ ionization sites, such as tertiary amines, which dwarfed all other influences. August 2003 Page 6 of 14 319306-01
The following is a brief look at the different solvent systems and the compounds found to be most affected by the solvent choice. These tend to be molecules with weaker basicity (i.e., exposed oxygens). Adducts seen: MH+=(MW+1); MHACN+=(MW+42)+; MHIPA+=(MW+61)+; and MHDMSO+=(MW+79)+ N CH3 MNa + MHDM SO + (+23) (+79) HO 1 Niacinamide none low cone OH N 2 4-acetaminophen none low cone 3 Caffeine none low cone H O 4 Quinine none low cone NH2 O N 5 Pyridoxal none low cone 6 Primidone none low cone O 7 3-Isobutylxanthine none low cone NH HO 8 Panthothenic Acid All none 9 Sulfamethazine high cone none O O 10 Nifedapine (not shown) high cone none CH3 11 Cortisone high cone All NH CH3 12 Desoximetasone none All O O CH3 13 Estrone none low cone H 14 Prednisone none low cone H3C N N H3C N low cone = present at 20 and 40 volts at >10% MH+ N high cone present at high cone = 65 and 95 volts; > 10% of MH+ All = adduct present at > 10% MH+ at all cone voltages N O N H2C System test make-up solvent 50% MEOH + 0.1% HCOOH none = < 10% MH+ O N N Makeup flow 0.4mL/minute CH3 CH3 CH3 OH N O H3C O CH3 O O N HO S HO NH NH N CH3 CH3 OH O H2N H3C N Figure 9: Results (Make-up 1) 50/50 Methanol/Water + 0.1% HCOOH O CH3 OH O OH CH3 MNa + MHDM SO + (+23) (+79) 1 Niacinamide none low cone O 2 4-acetaminophen none low cone 3 Caffeine none low cone 4 Quinine none low cone O OH 5 Pyridoxal none low cone 6 Primidone none low cone CH3 7 3-Isobutyixanthine none low cone HO CH3 8 Panthothenic Acid All none 9 Sulfamethazine high cone none CH3 10 Nifedaphine (not shown) high cone none 11 Cortisone high cone All 12 Desoximetasone none All F 13 Estrone none low cone 14 Prednisone none low cone O O low cone = present at 20 and 40 volts at >10% MH+ CH3 high cone present at high cone = 65 and 95 volts; > 10% of MH+ All = adduct present at > 10% MH+ at all cone voltages System test make-up solvent 50% Water 50% MEOH + 0.1% HCOOH none =
20V 65V Panthothenic Acid MW 219, MH+ = 220 ; Na+ adduct (242) shows that unlike DMSO adduct (298)- relative abundance of Na+ adduct increases with cone voltage. (note DMSO adduct at 20V) 20V 65V 157 common DMSO solvent ion 2(DMSO) H+ from sample solvent PrednisoneMH+(359) and D MSO ( MH +78)+ adduct (438) at 20V and 65V shows that higher voltage drives off this adduct (MW 358, MH+ 359) Figures 11 & 12: Results (Make-up 1) 50/50 Methanol/Water + 0.1% HCOOH Compounds having acidic functionalities (e.g., phenols and carboxylic acids) tend to form Na+adducts, and the relative intensities tend to increase with cone voltage. DMSO adduct is generally fairly weak and can be driven off with increased cone voltage. Results (Make-up 1) 50/50 Methanol/Water + 0.1% HCOOH This system does not tend to add to the adduct problem via an intrinsic solvent adduct. This can result in a more simplified and consistent spectra and collection. Na + (M+23) is a problem for all analytes that have the ability to form these persistent adducts. Other adducts, such as the DMSO, adduct (M+1+78) can form if the species is available from the injection solvent (i.e., can be removed by increased cone voltage). The chief argument against this system may be solubility of certain classes of compounds. August 2003 Page 8 of 14 319306-01
MNa + MHACN+ MHDMSO+ (+23) (+42) (+79) 1 Niacinamide None All Low Cone 2 4-acetaminophen None All Low Cone 3 Caffeine None All None 4 Quinine None None None 5 Pyridoxal None All Low Cone 6 Primidone None All Low Cone 7 3-Isobutyixanthine none All Low Cone 8 Panthothenic Acid 10% MH+ System test make-up solvent = 50% water/50% ACETN with 0.1 HCOOH flow 0.4 mL/min. All = >10% of MH+ for all cone voltages measure (20, 40, 65, 95V) None =
Acetonitrile adducts for many compounds form resilient adducts that resist cone voltage fragmentation. These include compounds such as steroids and those with exposed carbonyls. This adduct can often form the base peak of the spectrum. (Acetonitrile adduct MW + 42 from (MH+Acet)+) The absence of Na+ may be due either to the absence of this metal ion or to the blockage by this solvent. MNa + MHACN+ MHDMSO+ (+23) (+61) (+79) 1 Niacinamide None None None 2 4-acetaminophen None None Low Cone 3 Caffeine None None Low Cone 4 Quinine None None None 5 Pyridoxal None All Low Cone 6 Primidone None All Low Cone 7 3-Isobutyixanthine None All Low Cone 8 Panthothenic Acid All None None 9 Sulfamethazine None None None 10 Nifedaphine (not shown) All None None 11 Cortisone None All Low Cone 12 Desoximetasone None All None 13 Estrone None None None 14 Prednisone None All None Low Cone = present at 20V and 40V at >10% MH+ System test make-up solvent = 50% water 50%/50% IPA with 0.1% HCOOH flow 0.4 mL/min. IPA = isopropanol All = >10% of MH+ for all cone coltages measured (20, 40, 65, 95V) None =
Results (Make-up 3) 50/50 IPA/Water + 0.1% HCOOH This system does not tend to add to the adduct problem via an intrinsic solvent adduct to the degree that acetonitrile-based systems do. IPA does form an adduct with many of the same compounds affected by acetonitrile. Na + (M+23) is a problem for all analytes that have the ability to form these persistent adducts. Other adducts, such as the DMSO adduct (M+1+78), can form if the species is available from the injection solvent. This system offers many of the same advantages as a methanol system, but can increase the solubility range. MNa + MHDX+ MHDMSO+ (+23) (+89) (+79) 1 Niacinamide None None Low Cone 2 4-acetaminophen None None Low Cone 3 Caffeine None None Low Cone 4 Quinine None None Low Cone 5 Pyridoxal None None Low Cone 6 Primidone High Cone None Low Cone 7 3-Isobutyixanthine None None Low Cone 8 Panthothenic Acid All None None 9 Sulfamethazine High Cone None None 10 Nifedaphine (not shown) All None None 11 Cortisone None All Low Cone 12 Desoximetasone None None None 13 Estrone None None None 14 Prednisone None None Low Cone Low Cone = present at 20V and 40V at >10% MH+ High cone present at high cone = 65V and 95V; >10% of MH+ System test make-up solvent = 50% water/25% methanol/25% 1,4 dioxane DX = 1,4 Dioxane None = 10% of MH+ for all cone coltages measured (20, 40, 65, 95V) Tabel 4: Results (Make-up 4) 25/25/50 MEOH/1,4 Dioxane/Water + 0.1% HCOOH 20V 65V Cortisone MH+ 361 shows 1,4 dioxane adduct (+88) at 449 amu. This is a significant but low ion at both 20 and 65 V. Note the DMSO adduct at 439 that lost at 65V. Figure 16: Results (Make-up 4) 25/25/50 MEOH/1,4 Dioxane/Water + 0.1% HCOOH August 2003 Page 11 of 14 319306-01
1,4 Dioxane can form adducts with some compounds, but not to the degree of other solvents. The Na+ adduct was present similar to the MEOH/water system. 1,4 Dioxane may provide a good alternative solvent choice if the solubility is too low for a MEOH/Water system alone. Results for Areas of the M+H+1 Ions for the Target Compounds The table shows different percentages of solvents and the measured areas, which are a crude guide to solvent choice results. Areas are considered estimates only due to fact that issues such as linearity of response are not accessed at these overload levels. Compounds strongly affected by solvent choice would be expected to show the greatest fluctuations in areas as a result of such properties as poor ionization or adduct formation shifting the target mass MH+ to MHACN+, MHDMSP+, Mna+, etc. MEOH MEOH MEOH MEOH ACETN. ACETN. ACETN. ACETN. IPA IPA DX H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O DX 100/0* 75/25* 50/50* 90/10* 50/50* 75/25* 90/10* 100/0* 100/0* 72/25* DX Area Area Area Area Area Area Area Area Area Area Area & ion *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 Compound MW MH+ Area Area Area Area Area Area Area Area Area Area Area Niacinamide x 122 123 297 870 742 1194 453 313 367 1000 1545 1119 714 1 4-Acetaminophemn x 151 152 313 257 347 241 152 76 121 99 61 177 221 1 Caffeine x 194 195 321 399 421 519 168 224 328 532 123 434 611 1 Verapamil 454 455 3369 4596 5396 4264 3630 28138 4446 5670 7077 5093 3327 1 Nifedapine x 346 347 533 272 897 149 429 244 175 112 32 254 304 1 Pyridoxamine 168 169 988 780 948 876 425 374 467 1090 945 534 257 2 Metropropolol 267 268 4500 4522 534 4452 3933 4521 5321 10581 8769 5165 2699 2 Quinine 324 325 4645 3839 5547 4297 2020 2347 3173 8380 8517 4733 2378 2 Cortisone x 360 361 188 182 397 138 5 6 8 16 66 67 177 2 Clofazimine 472 473 2707 3001 3542 2767 2508 2421 2518 4086 3356 2782 1571 2 Triprolidine 278 279 4126 3698 5742 3466 3331 2424 2714 5615 6409 3414 1985 2 Pyridoxine 169 170 2276 1534 1572 1795 1109 1119 1966 5226 4491 2163 1068 3 8-Chlorotheophyline x 214 215 26 26 43 23 0 12 29 11 0 2 29 3 Chlorpheniramine 274 275 2641 2114 3419 1957 1791 1668 2574 5368 5616 1889 1242 3 Doxepin 279 280 6064 5409 7313 5047 4915 5443 7744 1086 9660 4987 3639 3 Funarizine 404 405 2688 3059 3821 2535 2324 2146 2124 3034 3835 3074 1879 x = compounds found to be significantly influenced by solvent choices gp = group (solution containing the compound listed) DX = 1,4 Dioxane at 25%, MEOH at 25%, and water at 50%, HCOOH 0.1% MEOH = Methanol IPA = Isopropyl Alcohol 1,4DX = 1,4 Dioxane ACETN = Acetonitrile * = V/VVolume/Volume Table 5: Measured Areas of Analytes M+H Signal for All Solvents Tested (mix 1, 2, 3) August 2003 Page 12 of 14 319306-01
MEOH MEOH MEOH MEOH ACETN. ACETN. ACETN. ACETN. IPA IPA 1,4DX H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O 100/0* 75/25* 50/50* 90/10* 50/50* 75/25* 90/10* 100/0* 100/0* 72/25* 75/25* Area Area Area Area Area Area Area Area Area Area Area & ion *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 *10E6 Compound MW MH+ Area Area Area Area Area Area Area Area Area Area Area Niacinamide x 122 123 297 870 742 1194 453 313 367 1000 1545 1119 714 4 Pyridoxal 167 168 1375 1071 1221 1146 421 539 1308 2625 3318 1630 812 4 Primidone 218 219 107 89 188 73 2 19 36 8 0 15 150 4 3-Isobutyl-1-methylx** 222 223 682 507 637 543 125 224 371 307 65 413 680 4 Prednisone 358 359 251 216 461 162 96 100 90 47 16 225 304 4 Desoximetasone 376 377 200 183 319 127 65 71 53 24 9 178 190 5 Panthothenic Acid 219 220 496 430 452 294 516 431 447 562 245 463 373 5 Sulfamethazine 278 279 2126 2059 2352 1760 1742 2059 2558 3110 2438 2206 1559 5 Estrone 270 271 15 20 101 25 27 20 7 0 677 17 184 5 Enalapril 376 377 3129 3118 4191 2923 2977 3118 3348 5029 3988 3272 2464 6 Bromopheniramine 318 319 1616 1211 2161 1189 980 1082 1376 3018 3238 49 801 6 Diltiazen 414 415 4618 4861 6550 4165 4318 5083 577 10200 7536 1030 3399 x = Compounds found to be significantly influenced by solvent choices gp = group (solution containing the compound listed) DX = 1,4 Dioxane at 25%, MEOH at 25%, and Water at 50%, HCOOH 0.1% MEOH = Methanol IPA = Isopropyl Alcohol 1,4DX = 1,4 Dioxane ACETN = Acetonitrile * = V/V Volume/Volume *10E6 = Area * 10E6 Table 6: Measured Areas of Analytes M+H Signal for All Solvents Tested (mix 4, 5, 6) Cortisone 50/50 Cortisone 50/50 ACN/0.1%HCOOH MEOH/H2O/0.1%HCOOH Fraction missed Fraction success Ms signal MH+41+ = 418 MH+41+>>MH+ MH+ = 377 Figure 17: Gilson UniPoint™ System Software Collection Report August 2003 Page 13 of 14 319306-01
Figure 18: Gilson UniPoint™ System Software Collection Report Collection using four different cone voltages in one run, running sequentially at one second each. Conclusion Mass-based fraction collection with target compounds at the 1 mg and higher level usually will require a dilution-type of splitter for the mass spectrometer interface. This offers the user some choice in the solvent employed as the dilution solvent. This choice can significantly influence the ionization for LC/MS target mass ions. Solvents such as 1,4 Dioxane can increase the solubility range of a methanol make-up solvent without the detrimental adduct affect of acetonitrile make-up mixes for some compounds. If a solvent is used—for solubility or compatibility reasons which are found or speculated to produce additional adducts—the ions for all the target adducts should be added to the collection method. If using MS to check fractions for hits, keep in mind that the solvent was the mobile phase for the fraction at the time it was collected. This may cause changes in spectra when compared to that produced from the fraction itself in systems employing a make-up dilution. Gilson, Inc. World Headquarters 3000 W. Beltline Hwy., P.O. Box 620027, Middleton, WI 53562-0027 USA Telephone: (1) 800-445-7661 or (1) 608-836-1551• Fax: (1) 608-831-4451 Gilson S.A.S. 19, avenue des Entrepreneurs, BP 145, F-95400 VILLIERS LE BEL France www.gilson.com Telephone: (33-1) 34 29 50 00 • Fax: (33-1) 34 29 50 20 sales@gilson.com, service@gilson.com, training@gilson.com August 2003 Page 14 of 14 319306-01

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