Slurry studies are
useful for exhaustive polymorph and solid-state
stability screening of drug compounds. Raman spectroscopy is convenient
for monitoring crystallization in such slurries, as the measurements
can be performed
in situ
even in aqueous environments.
While the mid-frequency region (400–4000 cm
–1
) is dominated by intramolecular vibrations and has traditionally
been used for such studies, the low-frequency spectral region (<200
cm
–1
) probes solid-state related lattice vibrations
and is potentially more valuable for understanding subtle and/or complex
crystallization behavior. The aim of the study was to investigate
low-frequency Raman spectroscopy for
in situ
monitoring
of crystallization of an amorphous pharmaceutical in slurries for
the first time and directly compare the results with those simultaneously
obtained with mid-frequency Raman spectroscopy. Amorphous indomethacin
(IND) slurries were prepared at pH 1.2 and continuously monitored
in situ
at 5 and 25 °C with both low- and mid-frequency
Raman spectroscopy. At 25 °C, both spectral regions profiled
amorphous IND in slurries as converting directly from the amorphous
form toward the α crystalline form. In contrast, at 5 °C,
principal component analysis revealed a divergence in the detected
conversion profiles: the mid-frequency Raman suggested a direct conversion
to the α crystalline form, but the low-frequency region showed
additional transition points. These were attributed to the appearance
of minor amounts of the ε-form. The additional solid-state sensitivity
of the low-frequency region was attributed to the better signal-to-noise
ratio and more consistent spectra in this region. Finally, the low-frequency
Raman spectrum of the ε-form of IND is reported for the first
time.
Clinical trial registration: ClinicalTrials.gov, NCT04364529 This trial did not meet the definition of an applicable clinical trial (ACT) and thus, it was not registered in the Clinical Trials initially. During the conduction of the study, the authors however, saw for the best to conduct the Clinical trial registration anyway. The registration was done after the enrollment and ALS education but before analyzing the collected data.Funding and support: By JACEP Open policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist.
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