title: Insights into drug precipitation kinetics during in vitro digestion of a lipid-based drug delivery system using in-line raman spectroscopy and mathematical modeling.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 (R (2)  > 0.976).
  
  
  CONCLUSIONS
  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.
authors: University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute of Pharma Technology, Gründenstrasse 40, 4132, Muttenz, Switzerland.
authors: Cordula
authors: C
authors: Stillhart
authors: Georgios
authors: G
authors: Imanidis
authors: Martin
authors: M
authors: Kuentz
mesh_terms: D011232:Chemical Precipitation; D003460:Crystallization; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D011345:Fenofibrate / Q000008:administration & dosage* / Q000737:chemistry; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008066:Lipolysis; D008956:Models, Chemical; D012995:Solubility; D013059:Spectrum Analysis, Raman
chemical_list: D004337:Drug Carriers; D000960:Hypolipidemic Agents; D008055:Lipids; D011345:Fenofibrate