The
transamination-chemistry-based process for sitagliptin is a
through-process, which challenges the crystallization of the active
pharmaceutical ingredient (API) in a batch stream composed of multiple
components. Risk-assessment-based design of experiment (DoE) studies of
particle size distribution (PSD) and crystallization showed that the
final API PSD strongly depends on the seeding-point temperature, which
in turn relies on the solution composition.
To determine the solution
composition, near-infrared (NIR) methods had been developed with partial
least squares (PLS) regression on spectra of simulated process samples
whose compositions were made by spiking each pure component, either
sitagliptin free base (FB), water, isopropyl alcohol (IPA), dimethyl
sulfoxide (DMSO), or isopropyl acetate (IPAc), into the process stream
according to a DoE. An additional update to the PLS models was made by
incorporating the matrix difference between simulated samples in lab and
factory batches.
Overall, at temperatures of 20–35 °C, the NIR models
provided a standard error of prediction (SEP) of less than 0.23 wt % for
FB in 10.56–32.91 wt %, 0.22 wt % for DMSO in 3.77–19.18 wt %, 0.32 wt %
for IPAc in 0.00–5.70 wt %, and 0.23 wt % for water in 11.20–28.58 wt
%. After passing the performance qualification, these on-line NIR
methods were successfully established and applied for the on-line
analysis of production batches for compositions prior to the seeding
point of sitagliptin crystallization.
see.........
Application of On-Line NIR for Process Control during the Manufacture of Sitagliptin
Global Science, Technology
and Commercialization, Merck Sharp &
Dohme Corporation P.O. Box 2000, Rahway, New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00409
Publication Date (Web): February 12, 2016
Copyright © 2016 American Chemical Society
*E-mail: george_zhou@merck.com.
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