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

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.

Toward an Improved Understanding of the Precipitation Behavior of Weakly Basic Drugs from Oral Lipid-Based Formulations

“…Some FAs persist in the unionized state, according to the p K a value, leading to an underestimation of the total FAs liberation. To account for these unionized molecules, the so‐called “back‐titration” procedure was applied according to a previously described method . Briefly, at the end of the 30 min digestion period, the pH was rapidly increased to 9 by addition of 1 M NaOH for complete deprotonation.…”

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

“…The nucleation rate is a function of supersaturation (defined as the ratio of actual drug concentration to the drug solubility in the medium of interest) [196]: $$\text{Nucleation}:\hspace{1em}\hspace{1em}\frac{d{C}_{\mathit{\text{pr}}}}{dt}{k}_{\mathit{\text{nuc}}}\frac{C}{C^{\text{italiceq}}}{e}^{\frac{B}{{true(\text{italicln}\frac{C}{C^{\text{italiceq}}}true)}^2}}$$ $$\text{Growth}:\hspace{1em}\hspace{1em}\hspace{1em}G=k_{\mathit{\text{growth}}}{false(C-C^{\mathit{\text{eq}}}false)}^{\beta }$$ where C pr is the number of nuclei formed per unit volume (m −3 ), G is the rate of particle growth (m/s), C is the concentration of drug dissolved, C eq is the drug solubility, k nuc and k growth are the nucleation and growth rate constants, B is a thermodynamic constant dependent on the molecular volume of the solid phase, interfacial energy of the solid, and the solution temperature, and β is the order of particle growth. The impact of lipids on precipitation kinetics as described by this model has been taken into account by incorporating the change in effective solubility due to the presence of lipids [196]. The approach was used to model concurrent precipitation and LBF digestion.…”

“…Stillhart et al modeled simultaneous lipid formulation digestion and drug precipitation using a separate kinetic expression for each process, solved simultaneously. The solution to this system of equations was able to predict the solubilized drug concentration profile in in vitro studies [196]. In another study, in vitro studies of lipolysis and simultaneous drug release (for drug formulated in an LBF) or dissolution (for drug dosed as a solid together with lipids) were modeled.…”

Analytical technologies for real-time drug dissolution and precipitation testing on a small scale

“…A better understanding of drug precipitation kinetics was also obtained in another study that introduced Raman spectroscopy to an in‐vitro lipolysis test [103]. An in‐line probe was employed with a dispersive Raman spectrometer working at a wavelength of 785 nm.…”

“…Particularly challenging for Raman monitoring of in‐vitro lipolysis was the fact that the complex medium was changing because of the hydrolysis of formulation components. Extensive calibration work, adequate spectral preprocessing and multivariate data analysis were required here to obtain meaningful results [103]…”