Further 60 MHz NMR Applications   ISMAR 2013
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Further 60 MHz NMR Applications ISMAR 2013

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Further 60 MHz NMR Applications   ISMAR 2013 Further 60 MHz NMR Applications ISMAR 2013 Document Transcript

  • Compact, Cryogen-Free High-Resolution 60 MHz Permanent Magnet NMR Systems for Reaction Monitoring and Online/At-Line Process Control Observing 1H, 19F, and 31P John C. Edwards1, David A. Foley2, Mark T. Zell2, Brian L. Marquez2, Tal Cohen3, Paul J. Giammatteo1 1. Process NMR Associates, LLC, 87A Sand Pit Rd, Danbury, CT 06810 USA, 2. Worldwide Global Research & Development, Center for Discovery & Development Sciences, Pfizer Inc, Groton, CT, USA 3. Aspect AI, Shoham, Israel A compact high resolution NMR system will be described that can be situated on the bench-top or in the fume hood to be used as a continuous or stop-flow detector and/or an “in-situ” reaction monitoring system. The same system can be fully integrated into on-line shelters for on-line process control or utilized by engineers and technicians in an “at-line” environment. The system uses a unique 1.5 Tesla permanent magnet that can accommodate sample tube diameters of 3-10 mm with half-height spectral resolution (water resonance) approaching 1-3 Hz depending on the sample volume size and with excellent single pulse sensitivity. These systems can be utilized in a traditional NMR methodology approach or combined with chemometric approaches that allow NMR data to predict chemical and physical properties of materials via regression analyses that establish correlations between observed spectral variability and sample-to-sample property variance [1]. The systems utilized since the early 1990's are capable of single channel operation on higher sensitivity nuclei (1H, 19F, 31P, 23Na, 7Li, 11B). A new generation of NMR systems are now being manufactured featuring multi-channel operation giving the possibility to monitor two nuclei at once or to perform 1H-13C-DEPT and higher sensitivity approaches to 13C observation. In pharmaceutical applications the Aspect-AI 60 MHz system was utilized in a reaction monitoring scenario where a reaction was monitored simultaneously on a split sample loop by the 60 MHz NMR and a 400 MHz Bruker Avance III superconducting NMR spectrometer [2]. The results obtained on the two systems were virtually identical indicating that the 60 MHz NMR system can be used to transfer PAT knowledge generated on pharmaceutical reactions in the research lab to the manufacturing areas for production monitoring. 1) “Process NMR Spectroscopy: Technology and On-line Applications”, John C. Edwards, and Paul J. Giammatteo, in Process Analytical Technology: Spectroscopic Tools and Implementation Strategies for the Chemical and Pharmaceutical Industries, 2nd Ed., Editor Katherine Bakeev, Blackwell-Wiley, 2010. 2) "Application of a 60 MHz Permanent Magnet NMR System to Online NMR Reaction Development in the Pharmaceutical Industry", David A. Foley, Mark T. Zell, Brian L. Marquez, John C. Edwards, and Paul J. Giammatteo, Presented at PittCon 2013, Philadelphia, PA, March 21, 2013. Poster PDF available at www.process-nmr.com. Abstract Example Application: Steam Cracking Optimization Installed at BASF, Ludwigshaven 2000 Cracker Facility Capacity: 600,000 Tonnes per Year Control Strategy: Feed Forward Detailed Hydrocarbon Analysis to SPYRO Optimization NMR Analysis: 3-4 Minute Cycle (Single Stream) NMR PLS Outputs: Naphtha – Detailed Hydrocarbon PONA Analysis, Density C4-C10 normal-paraffin, iso-paraffin, aromatics, naphthenes 1st Generation NMR Analyzer Invensys –Foxboro - 1998-2003 2nd Generation NMR Analyzer Qualion Ltd. 2003-2011 Typical NMR Analyzer Environment Shelter House at Base of Vaccuum Tower Sample system providing 2 conditioned streams to NMR Analyzer 3rd Generation NMR Analyzer Modcon-Xentaur-Aspect AI Actual Toluene (Wt%) PredictedToluene(Wt%)(F9C1) PLS Model Toluene Wt% by PIONA GC 1 2 3 45 6 7 8 9 10 11 12 1314 15 16 17 18 19 20 21 22 2325 26 2728 29 30 31 32 33 34 35 36 37 383940 41 42 43 44 45 46 49 50 51 53 5456 58 59 62 63 66 68 69 70 71 73 75 76 77 78 79 80 82 83 84 85 86 87 88 90 91 9293 94 95 9697 98 99 101 102 103 104 105 106 108 109 110 111 112 113 114 115 116 117 118 119120 121 122123 124 125126 127 128 129130131132133134135136137 138139140141142143 144145146 147148149 150151152 156157158 159160161 162163164 165166167168169170 171172173 174175176 177 178179 180181182 183184185186187188 189190191 192193194 195196197 198199200 201202203 204205206 207208209210211212 213214215 216217218 219220221 222223224 225226227 228229230 231232233 234235236 237238 239240241242243244245246247248249250251 252253254 255256257 258259260261262263 264265266 267268269 270271272 273274275 279280281282 283284285 286287288 289290291 292293294 295296297298299300 301302303 304305306 307308309 310311312 313314315 319320321 322323324325326327 328329330 331332333334335336 337338339 340341342343344345 346347348 349350351 352353354 355356357 358359360 361362363 364365366367368369 370371372 373374375 376377378 379380381382383384 385386387 388389390391392393 394395396397398399400401402 403404405 406407408 409410411 412413414 427428429 430431432433434435 436437438 439440441 445446447 448449450 451452453454455456 457458459 460461462 463464 465 466467 471472473 477478 481482 483484485 489490493494495496 -.5 1 2.5 4 5.5 0 1.5 3 4.5 Spectral Units ( ) BetaCoefficient(F9C1) 0 10 40 70 100 130 -1.5 1.5 10 40 70 100 130 Cyclopentane Date Wt% GC NMR 0 2 4 6 8 10 12 14 16 1 147 293 439 585 731 877 1023 1169 1315 1461 1607 1753 iso-C5 iso-C6 iso-C7 iso-C8 iso-C9 Online Validation Process for PAT: 4 Month Comparison of Online NMR Prediction( (4 out of 33) and Laboratory GC Analysis Predictive Vector for Toluene PLS Model 96 Hours of Online Variability Observed by NMR Analyzer for iso-paraffin components 0 0.5 1 1.5 2 2.5 3 3.5 4 1 167 333 499 665 831 997 1163 1329 1495 1661 Benzene Toluene Ethyl-Benzene Xylenes 96 Hours of Online Variability Observed by NMR Analyzer for aromatic components Examples of the expected resolution obtained on various essential oils at 60 MHz demonstrating the resolution that is obtained on a static 5mm NMR sample. Essential Oil analysis is currently being developed to allow identification and authentification on a compact 60 MHz NMR system that requires no specialized personnel or custom laboratory space. 60 MHz NMR Reaction 5mm NMR Tube T-Butyl Alcohol Reacting with Acetic Anhydride In the presence of dilute acid. Sucrose Hydrolysis Kinetics Sucrose a-glucose b-glucose 2.5 2.0 1.5 ppm 1.0 ppm A B C D E E B D A C Esterification of t-BuOH Superimposed Spectrum Plot 2.5 2.0 1.5 1.0 ppm Esterification of t-BuOH Integral Graph And Integration Plot Acetyl Anhydride Acetic Acid T-BuOH T-Bu-Ester Ac-Ester 1-Propanol Esterification with Acetic AnhydridePure Solution – No Solvent – No Acid Catalyst - 8 Hour Reaction Profile 1,2 1 2 3 3 4 4 5 56 6 7 7 8 8,9 9 AcAn (7) Esterification of 1-Propanol by Acetic Anhydride Integral Plots for Reaction Profile Ac-Ester Acetic Acid 1-Pr-Ester 1-PrOH 1H NMR of a range of naphtha samples obtained every 3-4 minutes in a stop-flow situation – spectra variability of the integration binned and normalized spectra are regressed against primary property results obtained by GC-PIONA analysis EQUIPMENT SET-UP AT PFIZER PORTABLE ONLINE NMR  MOBILE ANALYSIS – The size, mobility and standard utility requirements facilitates analysis at the site of chemistry, at the fume-hood, kilo lab or manufacturing site.  REACTION MONITORING – Capable of monitoring multiple reaction components in solution in real-time. Reaction Processes were monitored simultaneously using an AI-60-RMS NMR Reaction Monitoring System (60 MHz) from Cosa Xentaur and Bruker 400 MHz Avance III. NMR spectra were recorded at regular intervals over the course of the reaction. Experimental conditions:  Typical reaction concentration: 0.2 mol/L.  Flow rate: 4 mL/min  Transfer time from reaction vessel to detection: <1 min. TRANSESTERIFICATION RESULTS ACKNOWLEDGMENTS The authors would like to thank Cosa Xentaur, and Aspect AI, for development and provision of the 60 MHz online and laboratory NMR systems installed at PNA and Pfizer as well as MestreLab Research for development of NMR reaction monitoring software. More details of the compact, cryogen free 60 MHz NMR systems utilized in these studies can be obtained at www.process-nmr.com Online systems are marketed by Cosa-Xentaur and/or Modcon Syst Laboratory Systems are marketed by Cosa-Xentaur and Aspect AI Application support and development is performed by Process NMR Associates. For further discussion contact : John Edwards Email: john@process-nmr.com Tel: +1 (203)-744-5905 Skype: jcepna Twitter: jcepna Web: www.process-nmr.com Blog: www.nmblog.com REFERENCES 1.. D. A. Foley, M. T. Zell, B. L. Marquez, and A. Kaerner, Pharm. Tech. S19-S21 (2011). IMINE FORMATION 0 20 40 60 80 100 0 20 40 60 80 100 120 % Time (min) Isopropanol 400 MHz Ester 400 MHz Isopropanol 60 MHz Ester 60 MHz Aldehyde Imine CDI COUPLING 0 20 40 60 80 100 0 10 20 30 40 50 60 % Time (min) Benzaldehyde 400 MHz Imine 400 MHz Benzaldeyde 60 MHz Imine 60 MHz  60 MHz NMR was used to monitor three reaction processes; imine formation, CDI mediated amide coupling and transesterification.  Each reaction was monitored at regular intervals by both 400 and 60 MHz NMR and the data was overlaid to compare the profiles obtained at the two different field strengths.  NMR data generated from these three reactions demonstrates the application of low field NMR as a PAT tool for reaction monitoring.  It is planned to utilize chemometric analysis in the future to enhance reaction profiling and investigate further complex reaction processes. 0 20 40 60 80 100 0 20 40 60 80 100 120 % Time (min) Acid 400 MHz CDI Intermediate 400 MHz Amide 400 MHz Acid 60 MHz CDI Intermediate 60 MHz Amide 60 MHz INTRODUCTION TO ONLINE NMR Online NMR is routinely employed as a reaction monitoring tool in the process development area at Pfizer. Investigation of organic reaction processes by online NMR at 400 MHz provides detailed process understanding for development chemists. Here we outline the details of expansion of this reaction monitoring platform to include a 60 MHz portable NMR. The utilization of a compact and portable 60 MHz instrument provides increased flexibility and cost benefits over traditional cryogenically-cooled super-conducting magnets. These advantages allow the analysis to be performed at the location where the chemistry is being conducted, rather than bringing the chemistry to the lab space specifically designed for online NMR. . WHAT INFORMATION CAN ONLINE NMR PROVIDE?  INFORMATION RICH DATA FROM A SINGLE EXPERIMENT – Online NMR is a powerful analytical tool that enables a plethora of information to be gathered from a single experiment. It provides a real-time, detailed picture of what is occurring in the process.  CONTINUOUS ONLINE SAMPLING1 – Stream of reaction mixture removed from vessel and returned following analysis. No sample preparation or isolation allows detection of labile species in solution.  PROTONATED SOLVENTS & REAGENTS – No necessity for expensive deuterated solvents or isotopic enhancement.  REACTION KINETICS – Quantitative nature of the technique furnishes reliable kinetic data.  REACTION CHARACTERIZATION – Structural information of individual components in the mixture is obtained at 400 MHz which aids assignment at 60 MHz.  REACTION OPTIMIZATION – Real-time analysis permits “on the fly” adjustments to reaction conditions.  MECHANISTIC INSIGHT – Combination of reaction profile and intermediate identification sheds new light on reaction mechanisms. . CH3 O O O CH3 + CH3 CH3 CH3 OH CH3 CH3 CH3 O OCH3 + CH3 O OH Comparison of 60 and 300 MHz NMR data obtained on Ibuprofen capsule content. Invertase induced conversion of sucrose to fructose and glucose followed by 60 MHz 1H NMR. CH3 O O O CH3 + O OCH3 CH3 + CH3 O OH CH3 OH Table shows the chemometric modeling Results PLS regression for naphtha PIONA. Beta Coefficients Spectral Units ( ) BetaCoefficient(F9C1) - 2 - .5 1 2. 5 10 40 70 100 130 - 2 - .5 1 2.5 10 40 70 100 130 PredictedCyclohexane(F9C1) 1 4 7 10 1 4 7 101 4 7 10 1 23 45 6 7 8 910 11 12 1314 15 16 17 18 19 2021 22 23 2425 26 27 28 29 30 3132 33 34 35 36 37 38 39 4041 42 4346 47 48 49 50 51 52 53 54 55 56 58 596067 68 69 70 71 72 73 74 75 76 77 7879 80 81 82 84 85 8687 88 89 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 108109 110111 112 113 115116 117118 119120121 122123124 125126127 128129130131132133 134135136 137138139 140 141142 143144145146147148149150151152153154 161162163164165166 167168169170171172173 174175176177178 179180181 182183184 185186187 191192193194195196 197198199 200201202 203204205 206207208 209210211 212213214 215216217 218219220 221 222 223 224225226 227228229 230231232 233234235 236237238239240241 243244 245246247248249250251252253 254255256 257258259 260261262 263264265 266267268 269270271272 273274275 276277 278 279280281 282283284 285286287288289290 291292293294295296 297298299 300301302 303304305 309310311 312313314 315316317 318319320 321322323 324325326 327328329 330331332333334335 336337338339340341 342343 345346347 348349350 351352353354355356357358359 360361362 363364365 366367368 369370371 372373374375376377 378379380 381382383 384385386 387388389390391392393394395396397398399400401 402403404 405406407408409410 414415416417418419 420421422423424425429430431432433434438439440441442443 444445446 447448449 453454455 456457 458459460 464465466 482483484485 486487488489 1 4 7 10 1 4 7 10 Actual Cyclohexane (Wt%) 60 MHz 300 MHz 60 MHz 300 MHz 60 MHz 300 MHz 60 MHz 300 MHz Polymer Application: Adhesive Prepolymers – Developing chemometric models relating 300 MHz calculated monomer concentrations to 60 MHz 1H NMR data. -1.5-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0 f1 (p p m) Kior-0 0 1-H Bio- Oil V1 20 91 3- 04 KH D T Liq.Fr ac._D O _ Low Con v 1 H NMR in DM S O JCE -P NA-Merc3 0 0 60 MHz 300 MHz Labile OH Groups and Aldehydes Water and Residual Alcohol/Ether Aromatics Olefin alpha Protons Aliphatic CH2/CH3 TMS 0.51.01.52.02.53.03.54.04.55.05.5 f1 (ppm) Omega-015-H Omega-015-H Genceutic Wild & Pure Omega-3 Fish Oil 1400mg EPA=530mg DHA=280mg 1H NMR in CDCl3 JCE-PNA-MVX300 5.32 NMR is ideally suited to petroleum and alternative energy applications where water and black samples make NIR and Raman process analytical approaches very difficult . The linear response of the NMR experiment, the spectral orthogonality of the chemistry Types, and the lack of response to sample color variability make It an excellent candidate for the development of robust and low maintenance chemometric calibrations. Biomass Pyrolysis yields bio oils that are readily analyzed by 1H NMR. Here is a comparison of the quality of data obtained on 60 and 300 MHz NMR system. 60 MHz 1H NMR of fish oils is being investigated to predict automatic omega-3 and omega-6 fatty acid concentrations as well as fatty acid distributions. 60 MHz NMR Reaction 5mm NMR Tube Normal propyl alcohol reacting with Acetic Anhydride in the presence of dilute acid. Over course of 8 hours 1H 60 MHz NMR shows great promise to be utilized in USP standard methods developed for ID and purity of small molecule excipients and API 19F NMR is straightforward on the 1.5 Tesla NMR system and is useful for authentification tagging analysis and pharmaceutical drug analysis. Fish and Edible Oils Analysis Biomass to Fuels - Process ControlLeft: examples of NMR chemometric prediction vectors obtained from partial least-squares regression models of toluene and cyclohexane. Each spectrum was a 140 point binned and normalized spectrum with each bin representing 0.1 ppm. The prediction vector represents the 140 coefficients by which the spectrum is multiplied to obtain the wt% of the molecular component. Each molecular component has an individual PLS regression calibration developed based upon primary test data (GC) provided by the customer. Right: Actual vs Predicted plots that demonstrate the correlation between 1H NMR and GC-PIONA analysis for cyclohexane and toluene content. Predictive Vector for Cyclohexane PLS Model PLS Regression Model Cyclohexane Wt% by GC-PIONA Naphtha is a light fraction of crude oil that is not utilized in fuel production due to poor octane values. Many refiners with petrochemical complexes utilize this material as a feed to produce ethylene/propylene/butylene based on market economical factors. The cracking condition for naphtha is controlled by a SPYRO kinetic model that can predict the cracking product distribution based on a detailed GC PIONA analysis.