Researchers have developed stable, high-payload amorphous drug nanoparticles that successfully survive thermal drying and maintain high biological membrane permeability, offering a potential solution to a persistent formulation bottleneck in pharmaceutical science. Amorphous solid dispersions, which disperse poorly soluble active molecules within hydrophilic polymer matrices, represent a major commercial approach for increasing drug solubility in the digestive tract. However, these conventional dispersions frequently fail at higher drug loadings, where the formulations experience delayed and incomplete drug dissolution that restricts systemic absorption and forces manufacturers to produce unwieldy, oversized dosage forms. Writing in AAPS Open, a research team led by Akshay Narula, Ajay Lale, Paroma Chakravarty, and Na Li demonstrated that precipitating drug-rich amorphous nanoparticles via liquid-liquid phase separation can circumvent these conventional payload limitations. By systematically evaluating diverse molecular stabilizers during solvent removal, the investigators confirmed that dried amorphous nanoparticles can be reconstituted without compromising membrane permeability, matching the transport rates of fast-releasing amorphous solid dispersions.
When poorly water-soluble compounds exceed their thermodynamic miscibility thresholds in aqueous media, liquid-liquid phase separation causes active molecules to spontaneously condense into concentrated, submicron amorphous droplets typically spanning two hundred nanometers to several micrometers in diameter. These amorphous nanoparticles serve as concentrated reservoirs capable of sustaining maximum achievable supersaturation levels while drastically reducing diffusional resistance across the unstirred aqueous boundary layer adjacent to absorptive biological membranes. Nevertheless, transforming dilute aqueous nanosuspensions into viable solid oral pharmaceuticals requires removing the aqueous solvent through drying without causing the fragile nanoparticles to destabilize. The authors emphasized that amorphous drug nanoparticles possess an intrinsic structural softness that makes them especially vulnerable to physical degradation during solvent evaporation. Prior evaluations demonstrated that droplet coalescence represents the primary destabilization mechanism during thermal drying, whereas Ostwald ripening plays a negligible role. In addition to particle aggregation and enlargement, the persistent threat of drug crystallization during drying poses a major technical hurdle, necessitating an in-depth understanding of how excipient properties govern particle integrity.
To explore how stabilizer mechanisms interact with varied active pharmaceutical ingredients, the researchers selected a diverse suite of small-molecule compounds exhibiting poor water solubility, high lipophilicity values, relatively low crystallization tendencies, and widely divergent glass transition temperatures. The initial stabilizer screening evaluated clotrimazole, felodipine, and tolnaftate, which were chosen because of their contrasting ionization behaviors at physiological intestinal conditions and broad thermal properties. In a fifty millimolar sodium phosphate buffer at pH 6.5, representing human intestinal fluid, clotrimazole becomes partially ionized, whereas felodipine and tolnaftate remain unionized. To probe the specific influence of electrostatic interactions between drug molecules and polymeric stabilizers, the investigation incorporated five additional therapeutic compounds: four weakly basic drugs comprising atazanavir, bifonazole, miconazole, and loratadine, alongside the neutral protease inhibitor lopinavir. Under the experimental pH of 6.5, bifonazole, miconazole, and loratadine acquire positive charges through protonation, whereas atazanavir and lopinavir maintain neutral, unionized profiles. This deliberate structural array enabled the researchers to isolate the distinct roles of drug ionization and electrostatic bonding during particle processing.
The team evaluated a broad spectrum of pharmaceutical excipients featuring distinct physicochemical modes of colloidal protection, dividing them functionally into core materials and interfacial wall materials. Among the tested candidates, zein, a plant protein characterized by a high glass transition temperature of 164 degrees Celsius, was examined as a core-partitioning stabilizer capable of co-dissolving with hydrophobic drugs in organic solvent streams. In contrast, hydrophilic wall materials designed to reside at the particle-liquid interface included the anionic methacrylic acid copolymer Eudragit L100, which possesses a glass transition temperature of 195 degrees Celsius, alongside hydroxypropyl methylcellulose Methocel E5, bovine milk casein, and gum arabic. To prepare the nanoparticle suspensions, the authors utilized an antisolvent precipitation method maintaining organic solvent levels below two percent by volume, thereby preventing solvent-induced Ostwald ripening. The drug solutions were titrated into continuously stirred buffer at one thousand revolutions per minute before thermal solvent removal was conducted using a rotary evaporator operating at 45 degrees Celsius and a reduced pressure of 150 millibars.
Reconstitution experiments using dynamic light scattering and polarized light microscopy revealed stark differences between excipient categories regarding their drying efficiency. Zein performed with remarkable efficiency as a core-solidifying material, successfully stabilizing clotrimazole, felodipine, and tolnaftate nanoparticles across thermal drying at an economical one-to-one drug-to-polymer mass ratio without significant particle growth. Because zein is insoluble in water and miscible within the hydrophobic drug phase, it incorporates directly into the nanoparticle matrix, raising the overall glass transition temperature and imparting vital mechanical rigidity that prevents droplet coalescence. Conversely, conventional wall materials required vastly greater quantities to build adequate interfacial physical barriers upon the removal of the continuous aqueous phase. Hydroxypropyl methylcellulose necessitated a substantial drug-to-polymer ratio of one to twenty to prevent extensive particle enlargement, and even at this elevated level, tolnaftate nanoparticles underwent measurable growth. Similarly, gum arabic failed to prevent particle growth at an optimized one-to-ten ratio, whereas casein uniquely maintained post-drying particle diameters around four hundred nanometers at a one-to-one ratio through Pickering emulsion stabilization.
The stabilizing capacity of Eudragit L100 illuminated the decisive role of drug-polymer electrostatic complementarity in mitigating nanoparticle coalescence during thermal drying. When paired with neutral lopinavir or weakly basic atazanavir, Eudragit L100 failed to preserve colloidal stability, resulting in marked particle growth and broad polydispersity indices even when the polymer proportion was elevated to a one-to-five ratio. In sharp contrast, Eudragit L100 achieved robust stabilization at a lean one-to-one mass ratio for the weakly basic drugs clotrimazole, bifonazole, miconazole, and loratadine, which yielded monomodal size distributions with low polydispersity indices between 0.05 and 0.35. At pH 6.5, the carboxylic acid groups of the anionic polymer undergo deprotonation, allowing them to form intermolecular salt bridges with the partially protonated basic drugs at the nanoparticle boundary. This localized ionic crosslinking generated a dense, mechanically resilient polymeric shell around each droplet, establishing that interfacial ionic interactions can dramatically lower the excipient volume required to preserve soft amorphous particles during the thermal evaporation of water.
Advanced analytical electron microscopy confirmed that the successfully stabilized formulations retained their intended amorphous nanoscale architecture following solvent evaporation and redispersion. The researchers performed dark-field transmission electron microscopy, high-angle annular dark-field scanning transmission electron microscopy, energy-dispersive X-ray spectroscopy, and electron diffraction on three representative systems: clotrimazole and bifonazole stabilized with Eudragit L100, and lopinavir stabilized with hydroxypropyl methylcellulose. Dark-field micrographs showed discrete, non-aggregated nanoparticles evenly dispersed across carbon-coated copper grids. Elemental mapping through energy-dispersive X-ray spectroscopy verified uniform, drug-rich cores, detecting chlorine signals localized within clotrimazole particles and distinct nitrogen signals confined within bifonazole and lopinavir structures, while background sodium signals mapped residual phosphate buffer salts. Fast Fourier transform analyses and electron diffraction patterns across all three formulations exhibited broad, diffuse scattering halos completely lacking discrete diffraction spots or crystalline rings, confirming that the high-payload active molecules remained entirely in the disordered amorphous state throughout rotary evaporation.
To determine whether drying and reconstitution altered biopharmaceutical performance, the researchers measured drug transport across synthetic lipophilic barriers within Franz diffusion cells. The testing apparatus utilized a 15-millimeter orifice separating five-milliliter donor and receiver compartments, with a lipophilic barrier formed by applying soy lecithin dissolved in dodecane over hydrophilic polyvinylidene fluoride membranes, and bovine serum albumin added to the receiver fluid. Dried nanoparticles reconstituted in buffer were directly compared against freshly generated wet amorphous nanoparticles prepared in situ. For bifonazole stabilized with Eudragit L100 at a one-to-four ratio, reconstituted dried nanoparticles demonstrated membrane flux values identical to their wet in situ counterparts across multiple donor concentrations. When the donor buffer was shifted to pH 8.0—where 99.5 percent of bifonazole is unionized and ionic interactions vanish—the hydrodynamic particle diameter increased slightly to between 316 and 326 nanometers, yet the observed membrane flux remained virtually indistinguishable from measurements collected at pH 6.5.
In evaluating clotrimazole and lopinavir systems during membrane transport studies, the authors uncovered critical operational constraints linking thermal drying duration to batch volume. While two-milliliter batches dried within thirteen minutes during initial microstructural screening, scaling the liquid volume to six milliliters prolonged rotary evaporation beyond thirty minutes. This extended heat exposure triggered drug crystallization and particle aggregation in clotrimazole formulations stabilized at a minimal one-to-one polymer ratio, demonstrating that scale-dependent thermal history can destabilize marginally protected systems. To overcome crystallization during the production of solvent-free lopinavir particles for transport assays, the team implemented flash-freezing in liquid nitrogen followed by benchtop lyophilization. Lyophilized lopinavir nanoparticles achieved an average diameter of 401 nanometers, closely mirroring the 412-nanometer diameter of wet in situ controls, and yielded equivalent membrane flux profiles across all concentrations tested. These findings proved that drying methods do not inherently impair particle dissolution kinetics, provided that active crystallization is suppressed during water removal.
The study provides practical design principles for advancing amorphous drug nanoparticles from laboratory curiosities toward commercial oral dosage forms capable of delivering poorly water-soluble therapeutics. By acting as concentrated reservoirs that drift within the unstirred aqueous boundary layer and continuously replenish solute supersaturation, amorphous nanoparticles match the high membrane permeability of low-dose solid dispersions while carrying substantially higher drug fractions. However, successful translation into finished tablets or capsules demands careful excipient pairing and modern continuous processing strategies. The authors noted that batch rotary evaporation introduces severe thermal vulnerabilities, suggesting that rapid industrial dehydration techniques, such as spray drying, could shorten thermal exposure and prevent crystallization. Furthermore, incorporating water-soluble, enteric core-forming polymers such as hypromellose acetate succinate could provide dual protection by imparting core rigidity during downstream tablet compression and accelerating dissolution in the intestine. These molecular insights establish a rational framework for engineering resilient, high-potency amorphous nanomedicines that maintain stability throughout processing and storage.
Subject of Research: Drying stability and membrane permeability of amorphous drug nanoparticles
Article Title: Drying stability and permeability advantages of amorphous drug nanoparticles
Article References: Narula, A., Lale, A., Chakravarty, P., & Li, N. (2026). Drying stability and permeability advantages of amorphous drug nanoparticles. AAPS Open, 12(1), Article 46. https://doi.org/10.1186/s41120-026-00185-z
Image Credits: AI Generated
DOI: 10.1186/s41120-026-00185-z
Keywords: amorphous nanoparticles, drug loading, thermal drying, membrane permeability, liquid-liquid phase separation, stabilizers, amorphous solid dispersions, bioavailability, Drying, stability, permeability, advantages
News Source: Ophelia Keating. (November 13, 2026). Engineered Amorphous Drug Nanoparticles Overcome Solubility Limits While Preserving Membrane Permeability. Scienmag.
