Liquid Antisolvent Precipitation Research Articles

Fabrication of Nanocrystals for Enhanced Distribution of a Fatty Acid Synthase Inhibitor (Orlistat) as a Promising Method to Relieve Solid Ehrlich Carcinoma-Induced Hepatic Damage in Mice.

Orlistat (ORL) is an effective irreversible inhibitor of the lipase enzyme, and it possesses anticancer effects and limited aqueous solubility. This study was designed to improve the aqueous solubility, oral absorption, and tissue distribution of ORL via the formulation of nanocrystals (NCs). ORL-NC was prepared using the liquid antisolvent precipitation method (bottom-up technology), and it demonstrated significantly improved solubility compared with that of the blank crystals (ORL-BCs) and untreated ORL powder. The biodistribution and relative bioavailability of ORL-NC were investigated via the radiolabeling technique using Technetium-99m (99mTc). Female Swiss albino mice were used to examine the antitumor activity of ORL-NC against solid Ehrlich carcinoma (SEC)-induced hepatic damage in mice. The prepared NCs improved ORL's solubility, bioavailability, and tissue distribution, with evidence of 258.70% relative bioavailability. In the in vivo study, the ORL-NC treatment caused a reduction in all tested liver functions (total and direct bilirubin, AST, ALT, and ALP) and improved modifications in liver sections that were marked using hematoxylin and eosin staining (H&E) and immunohistochemical staining (Ki-67 and ER-α) compared with untreated SEC mice. The developed ORL-NC could be considered a promising formulation approach to enhance the oral absorption tissue distribution of ORL and suppress the liver damage caused by SEC.

Pre-formulation of an additive combination of two antimicrobial agents, clofazimine and nisin A, to boost antimicrobial activity.

According to the World Health Organization, antimicrobial resistance is one of the top ten issues that pose a major threat to humanity. The lack of investment by the pharmaceutical industry has meant fewer novel antimicrobial agents are in development, exacerbating the problem. Emerging drug design strategies are exploring the repurposing of existing drugs and the utilization of novel drug candidates, like antimicrobial peptides, to combat drug resistance. This proactive approach is crucial in fighting global health threats. In this study, an additive combination of a repurposed anti-leprosy drug, clofazimine, and an antimicrobial peptide, nisin A, are preformulated using liquid antisolvent precipitation to generate a stable amorphous, ionized nanoparticle system to boost antimicrobial activity. The nanotechnology aims to improve the physicochemical properties of the inherently poorly water-soluble clofazimine molecules while also harnessing the previously unreported additive effect of clofazimine and nisin A. The approach transformed clofazimine into a more water-soluble salt, yielding amorphous nanoparticles stabilized by the antimicrobial peptide; and combined the two drugs into a more soluble and more active formulation. Blending pre-formulation strategies like amorphization, salt formation, and nanosizing to improve the inherent low aqueous solubility of drugs can open many new possibilities for the design of new antimicrobial agents. This fusion of pre-formulation technologies in combination with the multi-hurdle approach of selecting drugs with different effects on microbes could be key in the design platform of new antibiotics in the fight against antimicrobial resistance.

Hydrodynamics and Transport Mechanism of Microfluidic Mixing in Precipitation of Nanodrugs: A Review

AbstractPoor aqueous solubility drugs are a concern of pharmaceutical industries due to low dissolution rates and low bioavailability. Various approaches and techniques address these issues by customizing drug micro–nanonization, as investigated by many researchers. Establishing a compelling synthesis of tailored nanoparticles with highly variable qualities intended for therapeutic applications needs the flexibility to vary particle size, content, crystallinity, and shape. Such an approach necessitates getting to the desired yield and developing a synthetic process that is durable, reproducible, and scalable. However, precipitation techniques to produce nanoparticles are more convenient than other approaches. Liquid antisolvent precipitation is one of the robust crystal manipulation approaches extensively used for producing nanoparticles, where mixing sets the basis to create supersaturation followed by corresponding quality precipitation. Various process intensification equipments are in use for adequate mixing‐based precipitation. Nowadays, microfluidic precipitation system is gaining interest in the production of nanodrugs. Further, the use of ultrasound in a microfluidic system improves the mixing quality by cavitation phenomena. This review focuses on the transport phenomena and hydrodynamics involved in mixing to enhance the mass transfer during antisolvent precipitation of synthesized nanodrugs in the microfluidic system.

Impact of chitosan and/or transglutaminase treatment on the colloidal stability and air-water interfacial properties of gliadin based nanoparticles

Wheat gliadin nanoparticles (GNPs) hold great potential as food ingredients. However, they have limited stability in aqueous systems as they precipitate rapidly in the presence of salt or at certain pH values. GNP modification strategies can increase their applicability in food systems. In this work, GNPs and hybrid gliadin-chitosan nanoparticles (GCNPs) were produced by liquid anti-solvent precipitation. For the first time ever, the impact of chitosan addition, both as such and in combination with microbial transglutaminase (TG) treatment to covalently conjugate protein and chitosan, on gliadin based NP stability and foaming properties was investigated. GCNPs had excellent colloidal stability over the course of 17 days of storage and in the presence of 1.5 M NaCl. This was attributed to the high chitosan-induced surface charge of GCNPs. Size exclusion HPLC revealed that TG treatment resulted in gliadin-chitosan conjugation, although no additional positive impact on GCNP stability was noted. At pH 4.5, the addition of charged chitosan resulted in worse GNP foaming properties, and TG had only a limited positive impact on the functionality. The worse foaming properties were attributed to the chitosan charged groups reducing mutual interactions of nanoparticle constituents resulting in a weaker adsorbed interfacial film. Even though GCNPs possessed poor foaming properties, they still hold great potential due to their excellent colloidal stability under food-system relevant conditions.

Enrichment of the flavonoid fraction from Eucommia ulmoides leaves by a liquid antisolvent precipitation method and evaluation of antioxidant activities in vitro and in vivo.

Eucommia ulmoides leaves originate from the dry leaves of the Eucommia ulmoides plant. Flavonoids are the main functional components of Eucommia ulmoides leaves. Some flavonoids such as rutin, kaempferol and quercetin are rich in Eucommia ulmoides, and they have outstanding antioxidant efficacy. However, the poor water solubility significantly affects the bioavailability of flavonoids. In this study, we used a liquid antisolvent precipitation (LAP) method to enrich the main flavonoid fractions in Eucommia ulmoides leaves, and prepared nanoparticles by the LAP method to increase flavonoids' solubility and antioxidant properties. The technological parameters were optimized by Box-Behnken Design (BBD) software and were displayed as follows: (1) total flavonoids (TFs) concentration: 83 mg mL-1; (2) antisolvent-solvent ratio: 11; (3) deposition temperature: 27 °C. Under optimal processing conditions, the purity and recovery rate of TFs were 88.32% ± 2.54% and 88.08% ± 2.13%, respectively. In vitro experiments showed that the radical scavenging IC50 values for DPPH, ABTS, hydroxyl radicals and superoxide anions were 16.72 ± 1.07, 10.76 ± 0.13, 227.68 ± 18.23 and 335.86 ± 15.98 μg mL-1, respectively. In vivo studies showed that the obtained purified flavonoid (PF) (100, 200, 400 mg kg-1) treatment is able to improve CCl4-induced liver and kidney damage through adjusting, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) levels. These results demonstrated that the LAP method is capable of extracting TFs from Eucommia ulmoides leaves with high bioaccessibility.

The Preparation of Apigenin Nanoparticles and the Study of Their Anti-Inflammatory and Anti-Tumor Activities In Vitro

Apigenin (API) has many biological activities, but its poor solubility limits its clinical application. In this research, API nanoparticles were prepared by the liquid antisolvent precipitation (LAP) technique, which effectively improved the solubility and bioavailability of API. Through the design of a single-factor test, the effects of the type and dosage of surfactants, API concentration, the antisolvent to solvent volume ratio, the speed and time of stirring, the temperature of precipitation, and the dropping speed on the MPS (mean particle size) of API nanosuspension were carried out. The optimum technological conditions were determined as follows: 5 mg/mL of tween 80 as a surfactant, 20 mg/mL of API, an antisolvent/solvent volume ratio of 10, a 1200 r/min stirring speed for 5 min, a 45 °C precipitation temperature, and a 1 mL/min dropping speed. Under the optimum conditions, we obtained API nanosuspension with 170.5 nm MPS and then it was freeze-dried to obtain the API nanoparticles. Moreover, we characterized the API nanoparticles by SEM, FTIR, XRD, DSC, and TG. Results showed that although API nanoparticles transformed into an amorphous form, their internal chemical structure had not been changed and had a higher solubility. Finally, API nanoparticles’ anti-inflammatory activities were evaluated by observing the effect of API on nitric oxide (NO) production and IL-10 production toward RAW264.7 cells induced by lipopolysaccharide (LPS). Moreover, the anti-tumor effect of API was determined by testing cell viability and apoptosis. The results suggested that API nanoparticles exhibited much better anti-inflammatory and anti-tumor activities compared to raw API.

A Brief Review of the Supercritical Antisolvent (SAS) Technique for the Preparation of Nanocatalysts to Be Used in Biodiesel Production

In an era where sustainability is becoming the main driving force for research and development, supercritical fluids-based techniques are presented as a very efficient alternative technology to conventional extraction, purification, and recrystallization processes. Supercritical antisolvent (SAS) precipitation is a novel technique that can replace liquid antisolvent precipitation techniques. Additionally, through the optimization of precipitation operating conditions, morphology, particle size, and particle size distribution of nanoparticles can be controlled. As an antisolvent, supercritical carbon dioxide (scCO2) is far more sustainable than its conventional liquid counterparts; not only does it have a critical point (304 K and 73.8 bar) on its phase diagram that allows for the precipitation processes to be developed so close to room temperature, but also its recovery and, consequently, the precipitated solute purification stage is considerably simpler. This technique can be used efficiently for preparing nanocatalysts to be used in biodiesel production processes.

Optimization of Betulin Colloidal Aqueous Suspension Pretreatment for Determination of Particle Characteristics

Dynamic light scattering (DLS) is a well-established technique to analyze particle size in a liquid medium and sample preparation is an essential step of the analysis to obtain reliable data. In this study, the pretreatment of an aqueous suspension containing betulin particles was studied to characterize the colloidal betulin particles in supramolecular hydrogels obtained by the liquid antisolvent precipitation from purified and unpurified betulin samples. Parameters of two-step homogenization process using rotor and ultrasonic homogenizer, particle concentration, and pH were systematically varied to obtain stable aqueous suspensions that meet the requirements of DLS technique for good particle size analysis. It was found that the purified betulin particles have a higher tendency to agglomerate and their suspension is stable in a narrower concentration and pH range than unpurified. Particle size analysis in suspensions prepared independently shows good reproducibility of sample preparation.

Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation.

Long-acting injectables are a unique drug formulation strategy, providing a slow and sustained release of active pharmaceutical ingredients (APIs). In this study, a novel approach that combines liquid antisolvent precipitation with seeding to obtain a stable form of the API indomethacin while achieving the desired particle size distribution is described. It was proven that when a metastable form of indomethacin was initially nucleated, the rate of its transformation to the stable form was influenced by the presence of excipients and seeds (17.10 ± 0.20 μm), decreasing from 48 to 4 h. The final particle size (D50) of the indomethacin suspension produced without seeding was 7.33 ± 0.38 μm, and with seeding, it was 5.61 ± 0.14 μm. Additionally, it was shown that the particle size distribution of the seeds and the time point of seed addition were critical to obtain the desired solid-state form and that excipients played a crucial role during nucleation and polymorphic transformation. This alternative, energy-efficient bottom-up method for the production of drug suspensions with a reduced risk of contamination from milling equipment and fewer processing steps may prove to be comparable in terms of stability and particle size distribution to current industrially accepted top-down approaches.

Impact of deamidation on the physicochemical properties and air-water interfacial behaviour of gliadin nanoparticles

Gliadin due to its low water solubility is excellently suited to make biopolymeric nanoparticles through liquid antisolvent precipitation. These gliadin nanoparticles (GNPs) can be utilized to populate and stabilize interfaces. Gliadin, by nature a protein that carries a low charge, can be altered by deamidation. Deamidation effectively alters the physicochemical properties of gliadin through decreasing the protein’s isoelectric point (IEP). The objective of this study is to explore the effect of different degrees of deamidation on gliadin nanoparticle (interfacial) characteristics. Besides altering the physical stability of GNP suspensions, deamidation did alter the functionality of GNPs as interfacial agents. GNP behaviour at the air-water interface is substantially impacted by pH. Particles made with untreated and deamidated gliadin exhibited a greater tendency to adsorb and form strong viscoelastic films at the air-water interface and better foam structures closer to their IEP. The combination of SEM, confocal Raman microscopy and drop tensiometry provides unique insights in the dominant gliadin structures and interactions at the interfacial film. This study provides crucial insights into the potential of deamidation to tailor gliadin and GNP properties for specific food applications.

Quality by design-based optimization of formulation and process parameters for berberine nanosuspension for enhancing its dissolution rate, bioavailability, and cardioprotective activity.

Berberine (BER) possesses dissolution rate limited oral bioavailability. The present study deciphers the formulation of nanosuspension loaded with BER for enhancing its cardioprotective potential. The nanosuspension was prepared by a liquid antisolvent precipitation technique using sodium lauryl sulfate as a surfactant and polyvinyl pyrrolidone K30 (PVP K30) as a polymer. The optimized formulation showed a particle size of 251.32 ± 4.18 nm, zeta potential of -24.10 ± 1.16 mV, and drug loading capacity of 98.22 ± 2.24%. The results showed about 6.01-fold and 3.54-fold enhancement in the dissolution rate and permeability, respectively, upon loading berberine into nanosuspension. About 8.44-fold increase in Cmax , 27.22-fold increase in AUC0-t , and 27.38-fold increase in AUC0-∞ were observed in the case of BER nanosuspension, compared to its naïve form. The results of particle size, zeta potential, and drug loading showed a nonsignificant change in the response of fresh and aged nanosuspension, which indicated that the formulation was stable. In vitro results on H9C2 cell line indicated a lower cellular proliferation rate after treatment with BER nanosuspension with decreased cytoplasmic expression of angiotensin converting enzyme (ACE) protein. Overall, the results indicated the successful development of BER nanosuspension with an enhanced dissolution rate, permeability, bioavailability, and cardioprotective activity. Practical applications The present study provides the evidence that the formulation of nanosuspension loaded with berberine enhance the cardioprotective activity of berberine. The results of the study supports the improved bioavailability of nanosuspension of berberine showed enhanced cardioprotective activity.

Polymeric micelles loaded with glyburide and vanillic acid: I. Formulation development, in-vitro characterization and bioavailability studies

The co-formulation of glyburide (Gly) and vanillic acid (VA) as such in the form of nanomedicine has never been explored to treat metabolic diseases including type 2 diabetes mellitus. Both the drugs possess dissolution rate-limited oral bioavailability leading to poor therapeutic efficacy. Hence, co-loading these drugs into a nanocarrier could overcome their poor oral bioavailability related challenges. Owing to this objective, both drugs were co-loaded in amphiphilic polymeric micelles (APMs) and evaluated for their biopharmaceutical outcomes. The APMs were prepared using mPEG-b-PCL/CTAB as a copolymer-surfactant system via the liquid antisolvent precipitation (LAP) method. The design of these APMs were optimized using Box Behnken Design by taking various process/formulation based variables to achieve the desired micellar traits. The release of both the drugs from the optimized co-loaded APMs was compared in different media and displayed a remarkable sustained release profile owing to their hydrophobic interactions with the PCL core. The in vitro cytotoxicity study of co-loaded APMs on Caco-2 cells revealed 70 % cell viability in a concentration-dependent manner. The preventive effects of Gly and VA co-loaded in APMs on glucose uptake was studied in insulin-responsive human HepG2 cells treated with high glucose. The co-loading of both the drugs in optimized APMs exhibited synergistic glucose-lowering activity (p < 0.001) than raw drugs with low cytotoxicity on HepG2 cells within the test concentration. This could be attributed to an increase in the relative oral bioavailability of both the drugs in APMs i.e., 868 % for Gly and 87 % for VA respectively.

Quality by design-based optimization of formulation parameters to develop quercetin nanosuspension for improving its biopharmaceutical properties

The present study describes the formulation, optimization and characterization of quercetin loaded nanosuspension. The formulation was prepared using liquid antisolvent precipitation technique. Optimization of formulation was done using Box-Behnken design by varying the concentration of sodium lauryl sulfate and polyvinyl pyrrolidone that were used as solubilizers. The processing parameters varied in this study were mixing speed and solvent to antisolvent ratio. The optimized formulation showed particle size of 202.15 ± 3.56 nm, zeta potential -20.26 ± 1.32 mV and drug loading 95.22 ± 2.45%. The results of dissolution and permeability studies showed about 26 folds enhancement in dissolution rate and 3.35 folds enhancement in permeability of quercetin through nanosuspension as compared to its raw form. The results of cell viability studies performed on Caco2 cells indicated more than 90% cell viability upon using nanosuspension, indicating safety of developed formulation. Furthermore, the formulation was found stable at accelerated stability conditions indicating the marketing potential of the developed formulation. Overall results showed the appropriateness of the developed formulation in enhancing the biopharmaceutical properties of quercetin.

Ultrasound-Assisted liquid antisolvent precipitation for the production of nanoparticles

Controlling the particle size during therapeutic synthesis in the crystallization/precipitation process is a challenge as the size influences the solubility, dissolution rates, and flowability. The current study demonstrates the effect of ultrasonic energy on the size and homogeneity of precipitated Albendazole drug particles under various parametric conditions such as organic to aqueous phase ratio, drug concentration, pulse rate, height of beaker from the ultrasonic surface, and frequency. The experiment was performed using One Factor at a Time (OFAT) method. The minimum particle size was obtained 564.3 nm with corresponding Polydispersity Index (PDI) 0.389 resulted under the optimum condition: (32 kHz) frequency, (99:1) pulse rate, and (30 mm) height of beaker from the ultrasonic surface for (10 mg/mL) drug concentration, (1:4) organic to aqueous phase ratio, (30 min) sonication time, and at a temperature of (25 °C) in comparison with the precipitation without ultrasonic energy having particle size 1320 nm and PDI 0.716. Hence ultrasound-assisted precipitation promotes micromixing and accelerates the nucleation from diffusion-controlled to integration-controlled continuing to form smaller monodispersed nanoparticles.

A Systematic Approach to the Development of Cilostazol Nanosuspension by Liquid Antisolvent Precipitation (LASP) and Its Combination with Ultrasound

Nanosizing is an approach to improve the dissolution rate of poorly soluble drugs. The first aim of this work was to develop nanosuspension of cilostazol with liquid antisolvent precipitation (LASP) and its combination with ultrasound. Second, to systematically study the effect of bottom-up processing factors on precipitated particles’ size and identify the optimal settings for the best reduction. After solvent and stabilizer screening, in-depth process characterization and optimization was performed using Design of Experiments. The work discusses the influence of critical factors found with statistical analysis: feed concentration, stabilizer amount, stirring speed and ultrasound energy governed by time and amplitude. LASP alone only generated particle size of a few microns, but combination with ultrasound was successful in nanosizing (d10 = 0.06, d50 = 0.33, d90 = 1.45 µm). Micro- and nanosuspension’s stability, particle morphology and solid state were studied. Nanosuspension displayed higher apparent solubility than equilibrium and superior dissolution rate over coarse cilostazol and microsuspension. A bottom-up method of precipitation-sonication was demonstrated to be a successful approach to improve the dissolution characteristics of poorly soluble, BCS class II drug cilostazol by reducing its particle size below micron scale, while retaining nanosuspension stability and unchanged crystalline form.

Preparation of Daidzein microparticles through liquid antisolvent precipitation under ultrasonication

In this study, daidzein microparticles (DMP) were prepared using an improved ultrasound-assisted antisolvent precipitation method. Preliminary experiments were conducted using six single-factor experiments, and principal component analysis (PCA) was adopted to obtain the three staple elements of the ultrasonic power, solution concentration, and nozzle diameter. The response surface Box-Behnken (BBD) design was used to optimize the level of the above factors. The optimal preparation conditions of the DMP were obtained as follows: the flow rate was 4 mL/min, the concentration of the daidzein solution was 16 mg/mL, the ratio of antisolvent to solvent (liquid-to-liquid ratio) was 9, the nozzle diameter was 300 μm, the ultrasonic power was 180 W (665 W/L), and the system speed was 760 r/min. The minimum average particle size of DMP was 181 ± 2 nm. The properties of daidzein particles before and after preparation were analyzed via scanning electron microscopy, X-ray diffraction analysis, Differential scanning calorimetry and Fourier transform infrared spectroscopy, no obvious change in its chemical structure was observed, but crystallinity was reduced. Compared with daidzein powder, DMP has a higher solubility and stronger antioxidant capacity. The above results indicate that the improved method of ultrasonication combined with antisolvent can reduce the size of daidzein particles and has a great potential in practical production.

Solubility Determination of c-Met Inhibitor in Solvent Mixtures and Mathematical Modeling to Develop Nanosuspension Formulation.

The solubility and dissolution thermodynamics of new c-Met inhibitor, ABN401, were determined in eleven solvents and Transcutol® HP–water mixture (TWM) from 298.15 to 318.15 K. The experimental solubilities were validated using five mathematical models, namely modified Apelblat, van’t Hoff, Buchowski–Ksiazaczak λh, Yalkowsky, and Jouyban–Acree van’t Hoff models. The experimental results were correlated and utilized further to investigate the feasibility of nanosuspension formation using liquid anti-solvent precipitation. Thermodynamic solubility of ABN401 increased significantly with the increase in temperature and maximum solubility was obtained with Transcutol® HP while low solubility in was obtained water. An activity coefficient study indicated that high molecular interaction was observed in ABN401–Transcutol® HP (THP). The solubility increased proportionately as the mole fraction of Transcutol® HP increased in TWM, which was also supported by a solvent effect study. The result suggested endothermic and entropy-driven dissolution. Based on the solubility, nanosuspension was designed with Transcutol® HP as solvent, and water as anti-solvent. The mean particle size of nanosuspension decreased to 43.05 nm when the mole fraction of ABN401 in THP, and mole fraction of ABN401 in TWM mixture were decreased to 0.04 and 0.1. The ultrasonicated nanosuspension appeared to give comparatively higher dissolution than micronized nanosuspension and provide a candidate formulation for in vivo purposes.

Nucleation Rate Prediction of Curcumin Particles in Microfluidic‐Assisted Nanoprecipitation

AbstractA hybrid computational model was developed to interpret the formation of curcumin particles via liquid antisolvent precipitation (LASP) in three microchannel reactors (MCRs) with different confluence angles. The computational fluid dynamics (CFD) model was numerically combined with a discretized population balance approach. The nucleation kinetics were computed using an expression obtained from the nucleation rate and supersaturation equation from previous experimental data. A quantitative comparison of the particle size distributions (PSDs) demonstrated that the particles with the smallest diameters are observed right after the intersection of the three streams. Besides, the large confluence angle of 135° in the MCR presented higher population density as a result of the smaller size of the precipitated curcumin particles. These findings illustrate the efficient applicability of the hybrid model.

Amorphous silibinin nanoparticles loaded into porous starch to enhance remarkably its solubility and bioavailability in vivo

In the present study, the silibinin (SLB) was loaded into porous starch (PS) in the form of nanoparticles (SNPS) by the liquid antisolvent precipitation (LAP) method, so as to improve its solubility and bioavailability. Firstly, the different experimental parameters on drug loading (DL) of the SLB in the LAP process were optimized through the single-factor experiments. Under the optimum conditions, the DL and the encapsulation efficiency (EE) of the SNPS were 9.49 ± 0.37 % and 89.93 ± 0.64 %, respectively. Compared with free SLB and SLB nanoparticles (SN), the SNPS had a higher solubility, and was about 180.81 ± 5.32 μg/mL in artificial gastric juice (AGJ) and was about 88.91 ± 4.14 μg/mL in artificial intestinal juice (AIJ), respectively. The in vitro release study demonstrated a slow and sustained ± release of SLB from the SNPS with the SN and free SLB as controls. The pharmacokinetic results showed that the Cmax and AUC(0–t) of the SNPS (87.71 ± 7.24 μg/L, 439.55 ± 8.76 μg/L*h) increased when compared with the SN (60.31 ± 8.98 μg/L, 206.51 ± 12.24 μg/L*h) and free SLB (26.08 ± 1.43 μg/L, 102.63 ± 7.15 μg/L*h), showing its ability to improve SLB’s pharmacokinetic properties.

Interface between Water-Solvent Mixtures and a Hydrophobic Surface.

The mechanism behind the stability of organic nanoparticles prepared by liquid antisolvent (LAS) precipitation without a specific stabilizing agent is poorly understood. In this work, we propose that the organic solvent used in the LAS process rapidly forms a molecular stabilizing layer at the interface of the nanoparticles with the aqueous dispersion medium. To confirm this hypothesis, n-octadecyltrichlorosilane (OTS)-functionalized silicon wafers in contact with water-solvent mixtures were used as a flat model system mimicking the solid-liquid interface of the organic nanoparticles. We studied the equilibrium structure of the interface by X-ray reflectometry (XRR) for water-solvent mixtures (methanol, ethanol, 1-propanol, 2-propanol, acetone, and tetrahydrofuran). The formation of an organic solvent-rich layer at the solid-liquid interface was observed. The layer thickness increases with the organic solvent concentration and correlates with the polar and hydrogen bond fraction of Hansen solubility parameters. We developed a self-consistent adsorption model via complementing adsorption isotherms obtained from XRR data with molecular dynamics simulations.