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

Author:

Salim Malinda1,Fraser-Miller Sara J.2ORCID,Bērziņš Kārlis23ORCID,Sutton Joshua J.2,Gordon Keith C.2ORCID,Boyd Ben J.13ORCID

Affiliation:

1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia

2. Te Whai Ao-Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9016, New Zealand

3. Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

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.

Funder

Bill and Melinda Gates Foundation

ARC Linkage

Publisher

MDPI AG

Subject

Pharmaceutical Science

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