Low- versus Mid-frequency Raman Spectroscopy for in Situ Analysis of Crystallization in Slurries

Abstract

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.

The Influence of Gastrointestinal Biomolecules on Solid-State Transformations in Pharmaceutical Particulates

“…For example, Koskela et al recently highlighted the capabilities of this technique to probe solid-state (amorphous to crystalline) transformations within slurries, the results of which were directly compared with the MFR domain. Overall, the higher scattering propensity (i.e., better signal-to-noise ratio) and structural sensitivity of LFR spectroscopy allowed the detection of minority or transient crystalline forms that remained otherwise undetected by the MFR . Similar advantages of LFR spectroscopy have been shown for the in situ monitoring of polymorphic changes during wet granulation. , Two recent studies from our group have further exemplified the strengths of this technique that allowed the detection of subtle real-time changes during drug solubilization within milk or infant formula environments, the results of which could be directly correlated to synchrotron source small-angle X-ray scattering (SAXS) experiments. , In this study, indomethacin (a nonsteroidal anti-inflammatory drug (Figure ) was used as the primary model compound due to its broad polymorphism and its robust and easily procurable amorphous phase .…”

“…However, the complex interface that forms between drug particles and the physiological fluid of the gut adds an inherent level of complexity to probing this solid-state behavior. In a similar way to the extensively studied protein corona on nanoparticles in serum, adsorption of gastrointestinal biomolecules upon contact with particles in gastrointestinal fluids could also occur, potentially forming an analogous biomolecular corona on drug particles. , The multitude of interactions involved in the formation and structure of such a corona, coupled with the fast temporal dynamics of solid-state transitions where even short-lived states can have a profound effect on API performance, often means only limited information can be obtained with typically used analytical techniques such as X-ray diffraction. , …”

“…Overall, the higher scattering propensity (i.e., better signal-to-noise ratio) and structural sensitivity of LFR spectroscopy allowed the detection of minority or transient crystalline forms that remained otherwise undetected by the MFR. 8 Similar advantages of LFR spectroscopy have been shown for the in situ monitoring of polymorphic changes during wet granulation. 12,13 Two recent studies from our group have further exemplified the strengths of this technique that allowed the detection of subtle real-time changes during drug solubilization within milk or infant formula environments, the results of which could be directly correlated to synchrotron source small-angle X-ray scattering (SAXS) experiments.…”

“…5,6 The multitude of interactions involved in the formation and structure of such a corona, coupled with the fast temporal dynamics of solid-state transitions where even short-lived states can have a profound effect on API performance, often means only limited information can be obtained with typically used analytical techniques such as X-ray diffraction. 7,8 In this study, low-frequency Raman (LFR) spectroscopy was primarily used to probe solid-state phase transformations within simulated gastrointestinal environments under different pH conditions. This technique is similar to midfrequency Raman (MFR) spectroscopy (300−1800 cm −1 ), already used in the field of pharmaceutics due to a number of advantages including the nondestructive nature of the measurements, high chemical specificity, limited interference from the solvent medium, and fast measurement time.…”

Characterization of Variably Substituted Hydroxyapatites Using Low-Frequency Raman Spectroscopy

“…Low-frequency Raman spectroscopy (LFR) is the study of low-wavenumber vibrations (10–300 cm –1 ) arising from low-energy phonon modes associated with long-range order within a sample . LFR is particularly sensitive to the solid-state form of materials and its use is growing, particularly in the field of pharmaceutics. − Pharmaceutical systems reported thus far typically exhibit a signal advantage in the low-wavenumber region in comparison to that in the fingerprint region, allowing for improved qualitative-, quantitative-, and classification-based assessment . The assignment of these low-wavenumber modes is challenging and usually requires the use of computational approaches to identify the origin of the bands.…”