In Situ Monitoring of Drug Precipitation from Digesting Lipid Formulations Using Low-Frequency Raman Scattering Spectroscopy

Abstract

Low-frequency Raman spectroscopy (LFRS) is a valuable tool to detect the solid state of amorphous and crystalline drugs in solid dosage forms and the transformation of drugs between different polymorphic forms. It has also been applied to track the solubilisation of solid drugs as suspensions in milk and infant formula during in vitro digestion. This study reports the use of LFRS as an approach to probe drug precipitation from a lipid-based drug delivery system (medium-chain self-nanoemulsifying drug delivery system, MC-SNEDDS) during in vitro digestion. Upon lipolysis of the digestible components in MC-SNEDDS containing fenofibrate as a model drug, sharp phonon peaks appeared at the low-frequency Raman spectral region (<200 cm−1), indicating the precipitation of fenofibrate in a crystalline form from the formulation. Two multivariate data analysis approaches (principal component analysis and partial least squares discriminant analysis) and one univariate analysis approach (band ratios) were explored to track these spectral changes over time. The low-frequency Raman data produces results in good agreement with in situ small angle X-ray scattering (SAXS) measurements with all data analysis approaches used, whereas the mid-frequency Raman requires the use of PLS-DA to gain similar results. This suggests that LFRS can be used as a complementary, and potentially more accessible, technique to SAXS to determine the kinetics of drug precipitation from lipid-based formulations.

In Operando Analysis of Milk-Based Oral Formulations during Digestion Using Synchrotron Small-Angle X-ray Scattering Coupled to Low-Frequency Raman Spectroscopy

“…The advantageous information obtained from LFR measurements over diffraction data could be a consequence of multiple factors, including the amount of the excess solid present throughout the digestion (>2 mg/mL based on HPLC data) that may hinder the detection of certain changes, the probed sample volume differences, as well as differences in intrinsic sensitivity related to cinnarizine. As noted before, other examples established the correlation between LFR and SAXS data in respect to drug solubilization/precipitation during the digestion, − albeit done separately in a similar experimental configuration but using a flow-through capillary rather than direct immersion of the Raman probe in the digesting medium.…”

“…However, the restricted (and costly) access to synchrotron facilities, particularly for industry, precludes its use as a routine analytical tool. As an alternative, our group has recently highlighted a more widely accessible approach by utilizing low-frequency Raman (LFR) spectroscopy. − This technique inherits all the advantages of typical Raman measurements (i.e., nondestructive nature, fast data acquisition speeds, etc.) that have already been highlighted for in-line lipolysis monitoring and probes intermolecular vibrations (typically <300 cm –1 ), serving as a sensitive probe to structural characteristics with crystalline and disordered states manifesting in the LFR spectra as sharp phonon modes or broad vibrational density of states (VDOS) features, respectively .…”