1. 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.