Development of versatile Raman spectroscopy system for characterization of drug delivery devices and SERS applications

Research output: Book/ReportPh.D. thesis

Abstract

Global industrialization and the following wide spread of products from chemical, cosmetic, and pharmaceutical industries into our life requires precise development and control of those substances. At the same time technological improvement and miniaturization of functional components like electronics, optical sensors and microcomputers open new opportunities for development of new analytical techniques, which can be applied in e.g. health monitoring and in quality control during manufacturing of pharmaceutical products.
This PhD thesis demonstrates a versatile Raman spectroscopic system, it’s development stages and technical realizations of different modules for (i) drug characterization (microstructural chemical mapping, kinetic studies of transformation processes, crystal orientation determination), and (ii) low concentration drug detection in combination with external modules, like centrifugal microfluidics disc platform or heating/cooling microscopy stage.
The Raman system is designed as a modular platform, built with mostly elementary components with rich functionality. The system can be completely reconfigured, modified, or combined with specialized devices, with e.g. a view on a future miniaturization. The applications of the system have been focused on the development and evaluation of analytical methods for analysis of materials and devices developed within the IDUN center of excellence.
The high sensitivity and confocal possibilities of the system, as well as operation flexibility and integrated analytical tools made it possible for us to demonstrate volumetric mapping of microcontainers and multilayered tablets for oral drug delivery. The use of: (i) highly-optimized optics in the near-infrared range, (ii) fully-customizable scanning algorithm with exponential dependency of the frame exposition time and scanning order to not overheat the sample, and (iii) sample cooling stage with CO2 purging allowed us to obtain a Raman signal from a depth of up to 200 μm. The signals were then used further chemical decomposition and 3-dimensional modeling of material distribution.
The long scanning time, which is typical for weak spontaneous Raman spectroscopy, was overcome by introducing laser line illumination of the sample together with design of an aberration-corrected spectrograph. This illumination mode provides 256 (with our type of CCD camera) simultaneous spectra measurements along the laser line on a sample, which allows us to significantly speed up the process of surface scanning, and improves the possibility of studying kinetic processes in a target material. The line scanning method was applied for a study of dehydration phase transformations of nitrofurantoin monohydrate and theophylline crystals. In comparison to bulk thermal methods of analysis, we demonstrated the possibility to spatially resolve the presence of different solid forms of a drug during thermal processes of dehydration and we could visualize the dynamics of single particles related to the presence of metastable intermediates.
A method for low concentration drug detection was established by combining a microfluidic platform and surface-enhanced Raman spectroscopy (SERS). Due to the huge Raman signal enhancement by SERS-active materials and the matrix complexity of real samples, a purification procedure was required to remove all interfered components. A centrifugal microfluidic disk, integrated with substrates for SERS based sensing, was utilized for separation, filtration and accurate exposure of an analyte media on the SERS substrates. A modified “wide line” illumination mode was used for fast and accurate surface scanning, which allowed us to detect an order of magnitude lower molecule concentrations in two proof-of-concept applications, detecting melamine in raw milk and p-Coumaric acid production from E. coli bacteria culture.
Lastly, a multi-beam polarized laser illumination and multichannel analyzer unit made it possible to perform a fast crystal orientation determination. While the sample remains stagnant, it is possible to simultaneously collect Raman spectra with numerous combinations of the incident laser beam polarization and orientation of the analyzer at several on-axis and off-axis detecting directions. The orientation sample maps were obtained by fitting rotation angles to measured datasets. Crystal orientations of the surface elements could have an important effect on essential properties of drug products, like disintegration and dissolution behavior. A model tablet formulation with integration of carbamazepine dihydrate crystals was prepared in order to map crystallographic orientations on the surface for the first time by Raman-based imaging.
Original languageEnglish
PublisherDTU Health Technology
Number of pages220
Publication statusPublished - 2020

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