Where Is the Drug? Quantitative 3D Distribution Analyses of Confined Drug-Loaded Polymer Matrices

Chiara Mazzoni; Fabio Tentor; Anastasia Antalaki; Rasmus D Jacobsen; Jacob Mortensen; Roman Slipets; Oleksii Ilchenko; Stephan S Keller; L Hagner Nielsen; Anja Boisen

doi:10.1021/acsbiomaterials.9b00495

Where Is the Drug? Quantitative 3D Distribution Analyses of Confined Drug-Loaded Polymer Matrices

ACS Biomater Sci Eng. 2019 Jun 10;5(6):2935-2941. doi: 10.1021/acsbiomaterials.9b00495. Epub 2019 May 22.

Affiliations

¹ The Danish National Research Foundation and Villum Foundation's Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN), Department of Health Technology, Technical University of Denmark, Ørsteds Plads Building 345C, Kgs. Lyngby 2800, Denmark.
² The Danish National Research Foundation and Villum Foundation's Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN), National Centre for Nano Fabrication and Characterization, Technical University of Denmark, Ørsteds Plads Building 345B, Kgs. Lyngby 2800, Denmark.

PMID: 33405596
DOI: 10.1021/acsbiomaterials.9b00495

Abstract

To enhance oral bioavailability of poorly soluble drugs, microfabricated devices can be utilized. One example of such devices is microcontainers. These are cylindrical in shape with an inner cavity for drug loading and with only the top side open for release. Supercritical CO₂ (scCO₂) impregnation is an interesting technique for loading drugs into polymeric matrices in, for example, microcontainers since it avoids the use of organic solvents and is cheap. One of the main drawbacks of this technique is the unknown three-dimensional drug distribution in the polymer matrix. The aim of this study was to investigate the loading of two poorly soluble drugs, naproxen and ketoprofen, by scCO₂ impregnation into confined polymer matrices of different sizes. Three different sizes of microcontainers (small, medium, and large) and, thereby, different surface areas accessible for impregnation were compared. From in vitro studies, the amount of naproxen and ketoprofen loaded into the different microcontainers and their corresponding release profiles were seen to be similar. A custom-made Raman microscope facilitated volumetric Raman maps of an entire microcontainer filled with polyvinylpyrrolidone (PVP) and scCO₂ impregnated with either naproxen or ketoprofen. In all microcontainer sizes, the drugs were only detected in the top layer of the polymer matrix, explaining the observed similar release profiles. Using X-ray powder diffraction and Raman spectroscopy, the solid state form of the drugs was evaluated, showing that ketoprofen was amorphous in all microcontainer sizes. Naproxen was found not to be crystalline nor amorphous but in a less ordered configuration than the crystalline state. In conclusion, volumetric Raman mapping is a powerful technology for imaging drug distribution and drug crystallinity in polymers and allowed us to conclude that (i) scCO₂ impregnation depth does not depend on surface area and (ii) impregnated drugs are noncrystalline.

Keywords: Raman spectroscopy; drug distribution; microdevices; polymer matrix; poorly soluble drug; supercritical CO2 impregnation.