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DOI: 10.1007/s11095-013-0999-2Pages: 3114-3130

Insights into Drug Precipitation Kinetics during In Vitro Digestion of a Lipid-Based Drug Delivery System Using In-Line Raman Spectroscopy and Mathematical Modeling

1. School of Life Sciences, Institute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland

2. University of Basel, Department of Pharmaceutical Sciences

Correspondence to:
Martin Kuentz
Tel: +41-61-4674688
Fax: +41-61-4674701




To determine drug precipitation during in vitro lipolysis of a lipid-based drug delivery system (LBDDS) using Raman spectroscopy as a real-time monitoring technique. A second aim was to describe the kinetics of lipolysis-triggered drug precipitation using a theoretical nucleation and growth model.


A model LBDDS containing different concentration of fenofibrate was digested in vitro and drug precipitation was determined after ultracentrifugation and nanofiltration (off-line methods), as well as by Raman spectroscopy (in-line method). Subsequently, a theoretical nucleation and growth model was fitted to the obtained drug crystallization profiles by considering the lipolysis-triggered change in drug solubility.


Compared with standard off-line measurements, Raman spectroscopy enabled a more robust and highly time-resolved analysis of lipolysis-triggered drug precipitation. Although the formulation was rapidly digested, fenofibrate remained in a supersaturated state for several minutes before beginning to crystallize. The in vitro digestion results were in excellent agreement with the theoretical model (R2 > 0.976).


The combination of real-time Raman spectroscopy and mathematical modeling provided insights into the kinetics of lipolysis-triggered drug crystallization. This knowledge allows a better biopharmaceutical understanding and will, ultimately, lead to the improved development of lipid-based drug formulations.

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  • Accepted: Jan 28, 2013
  • Online: Feb 28, 2013

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