Efficient Synthesis of Submicrometer‐Sized Active Pharmaceuticals by Laser Fragmentation in a Liquid‐Jet Passage Reactor with Minimum Degradation

Abstract

One challenge in the development of new drug formulations is overcoming their low solubility in relevant aqueous media. Reducing the particle size of drug powders to a few hundred nanometers is a well‐known method that leads to an increase in solubility due to an elevated total surface area. However, state‐of‐the‐art comminution techniques like cryo‐milling suffer from degradation and contamination of the drugs, particularly when sub‐micrometer diameters are aspired that require long processing times. In this work, picosecond‐pulsed laser fragmentation in liquids (LFL) of dispersed drug particles in a liquid‐jet passage reactor is used as a wear‐free comminution technique using the hydrophobic oral model drugs naproxen, prednisolone, ketoconazole, and megestrol acetate. Particle size and morphology of the drug particles are characterized using scanning electron microscopy (SEM) and changes in particle size distributions upon irradiation are quantified using an analytical centrifuge. The findings highlight the superior fragmentation efficiency of the liquid‐jet passage reactor setup, with a 100 times higher fraction of submicrometer particles (SMP) of the drugs compared to the batch control, which enhances solubility and goes along with minimal chemical degradation (<1%), determined by attenuated total reflection‐Fourier transform infrared spectroscopy (ATR‐FTIR), high‐performance liquid chromatography (HPLC), and X‐ray diffraction (XRD). Moreover, the underlying predominantly photo‐mechanically induced laser fragmentation mechanisms of organic microparticles (MP) are discussed.

Physical Regimes and Mechanisms of Picosecond Laser Fragmentation of Gold Nanoparticles in Water from X-ray Probing and Atomistic Simulations

“…The photomechanical processes can also contribute to the NP fragmentation, particularly under conditions of stress confinement, , when the NP heating time is shorter than the time required for the thermoelastic relaxation, i.e., expansion of the NP. While the conditions for photomechanical fragmentation are more readily satisfied in laser interactions with molecular and oxide particles, ,− the relaxation of laser-induced stresses may affect the dynamics of the thermally driven fragmentation of metal NPs as well. ,,, Finally, nonthermal processes related to the local near-field enhancement of the laser light intensity may also contribute to the femtosecond laser fragmentation of NPs through nonthermal (and directional) electron and ion emission, strong charging of NPs, and subsequent Coulomb instability. − These effects are typically amplified in close-to-resonant excitation, such as the plasmon resonance in several metallic systems. The complexity of the multiscale intertwined processes involved in LFL makes it difficult to establish clear maps of the laser fluence/intensity fragmentation regimes and mechanisms.…”

How Nanoparticle Size and Bubble Merging Is Governed by Short‐Range Spatially Controlled Double‐Beam Laser Ablation in Liquids

“…[13,14] The ability to produce nanoparticles in a single step, with controlled surface ligands, and tunable nanoparticle composition has broadened the range of LAL-synthesized nanoparticles applications to catalysis, [15] biotechnology, [16] photovoltaics, [17] nanomedicine, [18] and additive manufacturing. [19] Despite the advantages of LAL, achieving precise control over nanoparticle size distribution remains a challenge [20][21][22][23] that limits widespread adoption in fields such as metamaterials or photonics crystals. [24][25][26] Prior approaches to influence nanoparticle size distribution in LAL involve adding stabilizers such as polymers, [27] biomolecules, [28] or anions [29] during synthesis.…”