ARTICLE
pubs.acs.org/OPRD
Kinetic Understanding Using NMR Reaction Profiling
Flavien Susanne,* David S. Smith, and Anna Codina*
Chemical Research and Development and Analytical Research and Development, Pfizer World Wide Research and Development,
Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
ABSTRACT: The combination of kinetic understanding and reaction modeling has been successfully applied to the development
of processes from laboratory to manufacturing plant. Although extensively used in bulk chemistry, polymers, and the oil industry
2 011_o.pdf, July 2011; Shin, S. B.; Han, S. P.; Lee, W. J.; Chae, J. H.; Lee, D. I.; Lee, W. H.; Urban, Z. Hydrocarbon Process.
2007, April, 83; Baumer, C.; Urban, Z. Hydrocarbon Process. 2007, June, 71], it has not been exploited to its full potential in the
pharmaceutical industry. We present a fast and efficient methodology for kinetic modeling of chemical reactions using 1H NMR
reaction monitoring that can be used for the process understanding and development of active pharmaceutical ingredients. The
parameters that are important for the development of a good, reliable model for the prediction and optimization of reaction
conditions are discussed. The hydrolysis of acetic anhydride was chosen to illustrate the methodology because it is mechanistically
and kinetically well established.
’ INTRODUCTION
function of the concentration of both starting material
([Ac2O]) and reagent ([H2O]), eq II. The Arrhenius eq III
gives the dependence of the rate constant (k) of hydrolysis
on the temperature (in Kelvin) and activation energy (Ea), A
being the pre-exponential Arrhenius factor and R the gas
constant.
In the conditions of a high excess of water, the hydrolysis of
acetic anhydride can be considered to be pseudo-first-order,
simplifying the kinetic parameters calculation. The integrated
rate law can be rearranged such as the eq IV where [Ac2O]0
is the initial concentration of acetic anhydride. Plotting
ln[Ac2O]/[ Ac2O]0 against time creates a straight line with
slope ꢀk. This can be repeated for different temperatures.
From the Arrhenius eq V, a plot ln k versus 1/T produces a
straight line where Ea and ln A can be determined from the
slope and the intercept.
Reaction modeling using NMR data has been the subject of
multiple research papers.5ꢀ7 NMR together with in silico meth-
ods is a powerful tool for the study of reaction kinetics. NMR
spectroscopy provides structurally rich data, from which it is
possible to confirm or elucidate the structure of starting materi-
als, intermediates, and products.8 It is intrinsically quantitative,
overcoming the need to determine response factors required by
other techniques such as HPLC. It is not intrusive, and it is
potentially able to detect every compound involved in the
reaction provided NMR active nuclei are present and there is
sufficient signal dispersion. Despite its power, NMR is not the
technique of choice in pharmaceutical process development.9
Even in the early stages of development, reaction monitoring by
NMR tends to be only sporadically used by NMR and/or
chemical engineering specialists. Nevertheless, the pharmaceu-
tical industry is giving increased levels of attention to reaction
understanding as a way to ensure the quality of the active
pharmaceutical ingredient (API) and manufacturing process
robustness throughout its entire lifecycle.
ln½Ac2Oꢁ=½Ac2Oꢁ0 ¼ ꢀ kt
ðIVÞ
The mechanism of the hydrolysis of acetic anhydride has been
extensively studied during the last century.10 The intermediate
scheme proceeds via three irreversible steps: addition of water,
elimination, and proton transfer (Scheme 1), the addition being
the rate-limiting step.11
ln k ¼ ꢀ Ea=RT þ ln A
ðVÞ
First-order reactions are rare in the pharmaceutical industry.
Therefore, in this study we treated the hydrolysis of acetic
anhydride as a second-order type of reaction to demonstrate
our methodology for more general application.
Ac2O þ H2O f 2AcOH
ðIÞ
In this contribution, the kinetic parameters A and Ea were
calculated using Dynochem12 from a series of experiments includ-
ing variation of (1) initial concentrations of reagents and (2) the
ꢀ d½Ac2Oꢁ=dt ¼ k½Ac2Oꢁ ½H2Oꢁ
3
1
¼ A eꢀE =RT ½Ac2Oꢁ ½H2Oꢁ
ðIIÞ
a
reaction temperatures. H NMR was used to monitor the
3
3
3
evolution of starting material and product concentration as a
k ¼ A eꢀE =RT
ðIIIÞ
function of time.
a
3
The overall reaction can be represented in a simplified eq I.
The rate of hydrolysis, ꢀd[Ac2O]/dt, can be expressed as a
Received: August 1, 2011
Published: October 26, 2011
r
2011 American Chemical Society
61
dx.doi.org/10.1021/op200202k Org. Process Res. Dev. 2012, 16, 61–64
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