Pulsed laser synthesis and processing of organic drug and nutraceutical suspensions
Year: 2025
Type: dissertation
Abstract: Laser synthesis and processing of colloids (LSPC) is a versatile method for producing particle suspensions to alter particle size, shape, or for targeted post-treatment to control particle properties. To date, research has focused mainly on inorganic materials, where LSPC is wellestablished and mechanistically well-understood. Over the past two decades, there has been increasing interest in using LSPC for organic starting materials as well. For example, LSPC has been used to tune the optical properties of dyes, improve colloidal stability, and increase the solubility of drugs and nutraceuticals, thereby enhancing their bioavailability, which ultimately results in a reduction of the required bulk amounts. In initial studies, numerous organic dyes and drugs have been successfully fragmented with pulsed lasers in batch mode, however, the formation of considerable amounts of degradation products (> 23%) has been observed, which initially led to LSPC not being considered a prospective method in the pharmaceutical and food sectors. The large sample volume, which was only irradiated by a small laser spot, resulted in continuous back-mixing of the irradiated and non-irradiated medium. This caused unavoidable intensity gradients and an inhomogeneous pulse distribution with high variance. Due to the resulting undefined irradiation conditions, it was not possible to conduct a systematic investigation of the fragmentation mechanisms for process optimization or scaling up to industrial levels. In this work, therefore, innovative flow-through reactors with ultra-thin liquid jets are used, enabling precise control of the flow rate and repetition rate of the laser to achieve defined fluence and pulse-per-volume element conditions. For multi-pulse microparticle-laser fragmentation in liquids (MP-LFL) of the model drug naproxen, we were thus able to confirm a 100 times higher fragmentation efficiency of microparticles into submicroparticles in flow-through than in batch mode (sedimentation analysis and scanning electron microscopy), with minimal chemical degradation < 1% (high-performance liquid chromatography) and improved solubility (solubility assay). Our follow-up experiments with the model nutraceuticals curcumin and cannabidiol demonstrat that MP-LFL is a single-pulse event with material-dependent selectivity (submicrometer particles produced vs. amount of degradation product) and reactor-dependent concentration effects on fragmentation efficiency. Complemented by fluence- and time-resolved mechanistic studies using pump-probe imaging on single particles, we observe the fragmentation dynamics and describe the prevalence of laser-induced photoacoustic shockwave fragmentation in the stress confinement regime. Additionally, our recent experiments demonstrate that the ultrashort-pulsed irradiation of coffee suspensions produces highly aromatic extracts. This novel method is termed pulsed laser diffusion enhancement in liquids (PUDEL) for laser extraction in liquids (LEL), and works within a particular low-fluence regime of < 50 mJ/cm². Due to the low-fluence requirement (< 50 mJ/cm²), the PUDEL-LEL is particularly promising for future scale-up approaches, as the extraction conditions require laser parameters that fall within the technically standard range of conventional ultrashort-pulsed lasers. Non-targeted gas and liquid chromatography investigations, as well as comprehensive liquid-phase analyses of our samples, reveal the development of a distinctive volatile aroma profile enriched with fruity, aroma-intensive pyrazines, while simultaneously reducing acidity. We neither attribute this phenomenon to a reduction in particle size and thus an increase in the specific surface area, nor to a global heating of the medium. Based on our results, we hypothesize that local heating of the particles accelerates substance-specific extraction kinetics, resulting in an altered aroma profile without significant loss of volatile components. This work demonstrates that fundamentally different LSPC methods offer new perspectives on organic particulate materials, including drugs, nutraceuticals, and natural substances such as coffee. For instance, the MP-LFL method comminutes active ingredients to enhance solubility and, consequently, bioavailability. In contrast, the PUDEL-LEL method extracts aromatic plant compounds without altering particle size or global temperature, thus preserving volatile components. Verifying the universal applicability and successfully further developing the process-technical aspects of various LSPC methods indicates their enormous potential as a novel, innovative laser-based processing method for organic active ingredients and natural substance suspensions, which could lead to a lasting and sustainable revolution in the pharmaceutical and food industries.
Author: Friedenauer, Tina
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7105516516
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