A new vapor-phase method creates solvent-free amorphous organic nanoparticles in a single step, offering precise control over morphology and improved dissolution without additives or stabilizers.
(Nanowerk Spotlight) When a promising drug compound fails during development, the problem often isn’t safety or effectiveness. More often, the obstacle is physical. Many compounds simply do not dissolve well enough to be absorbed in the body. The same limitation affects nutrients in food, pigments in textiles, and additives in cosmetics.
In these systems, what a molecule does depends not only on its structure, but also on how it is assembled at very small scales. Whether a material dissolves, disperses, or binds effectively can depend on whether it is engineered as a fine powder, a crystal, or a nanoparticle.
One of the most effective ways to improve performance in these cases is to make the material as nanoparticles: tiny solid particles small enough to alter how the substance behaves. This change in size can increase the surface area, shift how a material dissolves, or influence how it interacts with light or biological systems.
Despite this potential, producing nanoparticles from small organic molecules remains inefficient, chemically wasteful, and often unreliable. Most industrial processes rely on grinding, solvent evaporation, or additives that complicate purification and formulation. These methods are energy-intensive and difficult to scale without compromising the molecular integrity of the compound.
The core challenge lies in the chemistry and physics of the molecules themselves. Many of the materials used in pharmaceuticals, food science, and electronics are structurally complex. They may be sensitive to heat, prone to crystallization, or unstable in solvents. These properties make it difficult to process them into uniform nanoparticles, especially when trying to avoid chemical additives or preserve the amorphous state that often improves performance.
Some researchers have begun to explore an alternative approach. Instead of breaking down solids or relying on chemical precipitation, they are working to control how molecules transition from vapor into solid form. The idea is straightforward. If molecules can be guided as they condense from a vapor, their structure, size, and internal arrangement might be tuned with precision, using only temperature and flow conditions.
A new study published in Advanced Materials (“Molecular Nanosolids Generation by Vapor Jet Desublimation”) takes this approach and shows that it can work. Researchers at the University of Michigan describe a method for producing solvent-free, amorphous nanoparticles from complex organic compounds using a collimated jet of nitrogen gas.
The process, known as vapor jet desublimation, allows for control over particle formation while preserving the chemical identity of the original compound. For drug development, food formulation, and other applications where solubility and process simplicity are critical, this work opens a new pathway.
Morphology control and flow visualization. a) Key geometry features of the setup for smallmolecular organic vapor desublimation, with velocity mapping and streamlines from computational fluid dynamics (CFD) simulation; particles with 500 nm diameter were seeded to simulate trajectories entrained by vapor jet exiting the nozzle. Colored dots (simulation results) indicate positions at different time points after seeding. Inset: schematic of the vapor jet. b) Laser scattering by gas phase nucleated particles downstream of the nozzle; white dashed line indicates nozzle wall. c) Scanning electron micrographs (SEMs) of raw griseofulvin (GSF). d–h) SEMs of GSF deposited on silicon substrates, processed at different conditions: d) Nozzle temperature 170 °C, actively cooled substrate, nozzle navigation speed 200 mm min−1. e) Nozzle temperature 230 °C, substrate with active cooling, nozzle navigation speed 200 mm min−1. f) nozzle temperature 230 °C, substrate without active cooling, nozzle movement speed 200 mm min−1. g) Nozzle temperature 230 °C, substrate without active cooling, nozzle movement speed 25 mm min−1. h) Same condition as g) plus hot nitrogen jet annealing. (Image: Reprinted from DOI:10.1002/adma.202510419, CC BY) (click on image to enlarge)
The method begins by heating a solid compound until it vaporizes. The vapor is carried by nitrogen gas through a narrow nozzle and released into ambient conditions. A cooled surface is placed in the path of the vapor jet. As the vapor cools, it reaches a supersaturated state and begins to condense. Under the right conditions, the molecules nucleate into nanoparticles before they touch the surface. These particles then deposit onto the substrate, forming a thin layer or structured assembly. No solvents, additives, or additional processing steps are required.
To study how this process unfolds, the team developed a detailed model of vapor flow, temperature gradients, and particle formation near the nozzle. They found that most nucleation occurs in a narrow boundary layer less than 0.2 millimeters thick, just above the cooled surface. In this region, the vapor becomes sharply supersaturated, and nucleation rates reach as high as one trillion particles per cubic centimeter per second. The simulations match experimental observations, including the narrow size distribution of the resulting nanoparticles.
The researchers used griseofulvin, a poorly soluble antifungal drug, as a model compound. The raw material consisted of large, polydisperse crystalline particles several microns across. After processing, the material was recovered as uniform, amorphous nanoparticles between 100 and 800 nanometers in diameter.
By changing the nozzle temperature, the speed of the jet, or the cooling of the substrate, they were able to control the size and morphology of the particles. These findings were confirmed by electron microscopy and X-ray diffraction.
The structural transition from crystalline to amorphous form was especially important. Amorphous materials tend to dissolve faster than their crystalline equivalents. In simulated intestinal fluid, the processed griseofulvin dissolved at two to three times the concentration of the raw material. These gains were achieved without the use of polymer stabilizers, which are normally required to prevent recrystallization. This simplified process could reduce costs and eliminate several steps in conventional pharmaceutical manufacturing.
The technique proved effective for other compounds as well. The team produced nanoparticles from atovaquone, a drug used to treat malaria, along with saccharin, indigo blue dye, and the organic semiconductor Alq₃. While some of these formed amorphous nanoparticles, others crystallized more easily, depending on their structure and vaporization properties. T
he main constraint was that each compound needed to have enough vapor pressure at temperatures below its decomposition point. The researchers noted that applying a mild vacuum could expand the range of compatible materials.
One strength of the system is its simplicity. The entire process occurs at or near atmospheric pressure. No liquid-phase solvents are involved. No stabilizing polymers are required. The nanoparticles form and deposit in a single step, using only heat, carrier gas, and controlled cooling. Because the molecules remain intact, the method is suitable for fragile pharmaceuticals or complex functional materials that might degrade under harsher conditions.
The study also highlights the importance of modeling. The simulations helped identify where and how the nanoparticles form, and provided insight into how supersaturation and flow conditions interact. These data could be useful in refining theories of nucleation, especially for small organic molecules in dynamic gas-phase environments. The findings suggest that controlling boundary layer dynamics and cooling rates may be just as important as chemical factors in determining particle outcomes.
Scaling the system remains a challenge. The process currently operates at laboratory scale, and producing pharmaceutical-grade material in meaningful quantities would require new equipment or parallelization. Predicting vapor pressure for complex molecules also remains difficult, though future work may benefit from data-driven approaches.
Still, the results demonstrate a solvent-free, additive-free path to making organic nanoparticles with defined structure and size. In pharmaceutical applications, where solubility, stability, and purity are critical, this could provide a cleaner and more controllable way to deliver active ingredients.
In other industries, it may offer a route to process-sensitive materials without the burden of solvents or complex formulations. By focusing on how molecules behave as they cross the vapor-solid boundary, this work opens the door to a new phase of precision particle design.
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