Tracking colloidal silica particles to evaluate their dispersion and interactions in concentrated suspensions under shear force applications.

This study aimed to characterize interactions within colloidal silica particles in their concentrated suspensions, using rheo-confocal measurements and imaging, followed by image analysis. We studied the effect of shear rate (0-500 s-1) and solution pH (6, 10) on the dispersion degree of colloidal silica particles via the determination and comparison of interparticle distances and their modeling. Images corresponding to different shear rates were analyzed to identify the coordinates of the particles. These coordinates were further analyzed to calculate the distance among the particles and then their surface-to-surface distance normalized by the particle diameter (H/D). It was found that the population of the particles per unit area of the image and H/D varied with increasing shear rate. The comparison between experimentally measured and theoretically calculated H/D identified that for some particles, the former was shorter than the latter, indicating the unexpected attractions among them against the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. Then, the modification of previously reported equations for H/D was suggested and confirmed its validity. Assuming pair potential interaction and hydrodynamic interaction were the main non-DLVO interactions, their magnitudes were calculated and confirmed the significance of pH and shear application strength on particle dispersion/coagulation.

Modelling the effects of charge on antibiotic diffusion and adsorption in liquid crystalline virus suspensions.

We develop a microscopic model of antibiotic diffusion in virus suspensions in a liquid crystalline state. We then approximate this with an effective homogenised model that is more amenable to analytical investigation, to understand the effect of charge on the antibiotic tolerance. We show that liquid crystalline virus suspensions slow down antibiotics significantly, and that electric charge strongly contributes to this by influencing the effective diameter and adsorptive capacity of the liquid crystalline viruses so that charged antibiotics diffuse much slower than neutral ones; this can be directly and efficiently derived from the homogenised model and is in good agreement with experiments in microbiology. Charge is also found to affect the relationship between antibiotic diffusion and viral packing density in a nontrivial way. The results elucidate the effect of charge on antibiotic tolerance in liquid crystalline biofilms in a manner that is straightforwardly extendable to other soft matter systems.

Viscosity of Suspensions of Strongly Bonded Spherical Particles of Nickel-Manganese-Cobalt Mixed Oxides (NMC) in Molten Poly(Ethylene Carbonate) for Batteries.

Ionically conductive polymers highly filled with active materials, such as metal oxides are increasingly studied for their potential use in all solid-state batteries. They offer the desirable processing ease of polymers for mass production despite interfacial issues that remain to be solved. In this study, it is shown that spherical particles of transition metal oxides can be introduced in co-polymers of alkene carbonate and ethylene oxide at loading close to the maximum packing fraction, without imparting the processability in the melt of the material. In particular, the viscosity does not show any yield stress and the increase of viscosity shows that the intrinsic viscosity of the filler does not match with the usual 2.5 value in the limit of the Einstein's equation. Conversely, rheological data show that the value is rather close to unity consistently with theoretical arguments that predicted that this scaling factor should be unity when particle rotation is precluded. In the present case, this behavior is attributed to strong bonding between polymer and filler that is proved by electronic microscopy and by dynamical mechanical spectroscopy showing a relaxation due to bound polymer.

Dynamics of an aqueous suspension of short hyaluronic acid chains near a DPPC bilayer.

The synergy between hyaluronic acid (HA) and lipid molecules plays a crucial role in synovial fluids, cell coatings, etc. Diseased cells in cancer and arthritis show changes in HA concentration and chain size, impacting the viscoelastic and mechanical properties of the cells. Although the solution behavior of HA is known in experiments, a molecular-level understanding of the role of HA in the dynamics at the interface of HA-water and the cellular boundary is lacking. Here, we perform atomistic molecular dynamics simulation of short HA chains in an explicit water solvent in the presence of a DPPC bilayer, relevant in pathological cases. We identify a stable interface between HA-water and the bilayer where the water molecules are in contact with the bilayer and the HA chains are located away without any direct contact. Both translation and rotation of the interfacial waters in contact with the lipid bilayer and translation of the HA chains exhibit subdiffusive behavior. The diffusive behavior sets in slightly away from the bilayer, where the diffusion coefficients of water and HA decrease monotonically with increase in HA concentration. On the contrary, the dependence on HA chain size is only marginal due to enhanced chain flexibility as their size increases.

Preparation and Evaluation of Clarithromycin Taste-Masking Dry Suspension Using Hot Melt Extrusion Based on Solid Dispersion Technology.

Clarithromycin (CLA) is the preferred drug for treating respiratory infections in pediatric patients, but it has the drawbacks of extreme bitterness and poor water solubility. The purpose of this study was to improve solubility and mask the extreme bitterness of CLA. We use Hot Melt Extrusion (HME) to convert CLA and Eudragit® E100 into Solid Dispersion (SD). Differential scanning calorimetry (DSC) and Powder X-ray diffraction (PXRD) were used to identify the crystalline form of the prepared SDs, which showed that the crystalline CLA was converted to an amorphous form. At the same time, an increase in dissolution rate was observed, which is one of the properties of SD. The results showed that the prepared SD significantly increased the dissolution rate of crystalline CLA. Subsequently, the SD of CLA was prepared into a dry suspension with excellent suspending properties and a taste-masking effect. The bitterness bubble chart and taste radar chart showed that the SD achieved the bitter taste masking of CLA. Principal components analysis (PCA) of the data generated by the electronic tongue showed that the bitter taste of CLA was significantly suppressed using the polymer Eudragit® E100. Subsequently, a dry suspension was prepared from the SD of CLA. In conclusion, this work illustrated the importance of HME for preparing amorphous SD of CLA, which can solve the problems of bitterness-masking and poor solubility. It is also significant for the development of compliant pediatric formulations.

Design of Experiments-Driven Optimization of Spray Drying for Amorphous Clotrimazole Nanosuspension.

This study employed a Quality by Design (QbD) approach to spray dry amorphousclotrimazole nanosuspension (CLT-NS) consisting of Soluplus® and microcrystallinecellulose. Using the Box-Behnken Design, a systematic evaluation was conducted toanalyze the impact of inlet temperature, % aspiration, and feed rate on the criticalquality attributes (CQAs) of the clotrimazole spray-dried nanosuspension (CLT-SDNS). In this study, regression analysis and ANOVA were employed to detect significantfactors and interactions, enabling the development of a predictive model for the spraydrying process. Following optimization, the CLT-SD-NS underwent analysis using Xraypowder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), Dynamic Scanning Calorimetry (DSC), and in vitro dissolution studies. The resultsshowed significant variables, including inlet temperature, feed rate, and aspiration rate,affecting yield, redispersibility index (RDI), and moisture content of the final product. The models created for critical quality attributes (CQAs) showed statistical significanceat a p-value of 0.05. XRPD and DSC confirmed the amorphous state of CLT in theCLT-SD-NS, and FTIR indicated no interactions between CLT and excipients. In vitrodissolution studies showed improved dissolution rates for the CLT-SD-NS (3.12-foldincrease in DI water and 5.88-fold increase at pH 7.2 dissolution media), attributed torapidly redispersing nanosized amorphous CLT particles. The well-designed studyutilizing the Design of Experiments (DoE) methodology.

A combined rheometry and imaging study of viscosity reduction in bacterial suspensions.

Suspending self-propelled "pushers" in a liquid lowers its viscosity. We study how this phenomenon depends on system size in bacterial suspensions using bulk rheometry and particle-tracking rheoimaging. Above the critical bacterial volume fraction needed to decrease the viscosity to zero, [Formula: see text], large-scale collective motion emerges in the quiescent state, and the flow becomes nonlinear. We confirm a theoretical prediction that such instability should be suppressed by confinement. Our results also show that a recent application of active liquid-crystal theory to such systems is untenable.

Active Controlled and Tunable Coacervation Using Side-Chain Functional α-Helical Homopolypeptides.

We report the development of new side-chain amino acid-functionalized α-helical homopolypeptides that reversibly form coacervate phases in aqueous media. The designed multifunctional nature of the side-chains was found to provide a means to actively control coacervation via mild, biomimetic redox chemistry as well as allow response to physiologically relevant environmental changes in pH, temperature, and counterions. These homopolypeptides were found to possess properties that mimic many of those observed in natural coacervate forming intrinsically disordered proteins. Despite ordered α-helical conformations that are thought to disfavor coacervation, molecular dynamics simulations of a polypeptide model revealed a high degree of side-chain conformational disorder and hydration around the ordered backbone, which may explain the ability of these polypeptides to form coacervates. Overall, the modular design, uniform nature, and ordered chain conformations of these polypeptides were found to provide a well-defined platform for deconvolution of molecular elements that influence biopolymer coacervation and tuning of coacervate properties for downstream applications.

Linking In Vitro Intrinsic Dissolution Rate and Thermodynamic Solubility with Pharmacokinetic Profiles of Bedaquiline Long-Acting Aqueous Microsuspensions in Rats.

Pharmacokinetic (PK) profiles of a range of bedaquiline (BDQ) long-acting injectable (LAI) microsuspensions in rats after parenteral (i.e., intramuscular and subcutaneous) administration were correlated with the in vitro intrinsic dissolution rate (IDR) and thermodynamic solubility of BDQ in media varying in surfactant type and concentration to better understand the impact of different nonionic surfactants on the in vivo performance of BDQ LAI microsuspensions. All LAI formulations had a similar particle size distribution. The investigated surfactants were d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), poloxamer 338, and poloxamer 188. Furthermore, the relevance of medium complexity by using a biorelevant setup to perform in vitro measurements was assessed by comparing IDR and thermodynamic solubility results obtained in biorelevant media and formulation vehicle containing different surfactants in varying concentrations. In the presence of a surfactant, both media could be applied to obtain in vivo representative dissolution and solubility data because the difference between the biorelevant medium and formulation vehicle was predominantly nonsignificant. Therefore, a more simplistic medium in the presence of a surfactant was preferred to obtain in vitro measurements to predict the in vivo PK performance of LAI aqueous suspensions. The type of surfactant influenced the PK profiles of BDQ microsuspensions in rats, which could be the result of a surfactant effect on the IDR and/or thermodynamic solubility of BDQ. Overall, two surfactant groups could be differentiated: TPGS and poloxamers. Most differences between the PK profiles (i.e., maximum concentration observed, time of maximum concentration observed, and area under the curve) were observed during the first 21 days postdose, the time period during which particles in the aqueous suspension are expected to dissolve.

Phase separation in mixed suspensions of bacteria and nonadsorbing polymers.

The shapes of bacteria can vary widely; they may, for instance, be spherical, rod-like, string-like, or curved. In general, bacilli are highly anisotropic. For research and (bio)technological purposes, it can be useful to concentrate bacteria, which is possible by adding nonadsorbing polymers. The induced phase separation originates from a polymer-mediated depletion interaction, first understood by Asakura and Oosawa. Here, it is shown that free volume theory (FVT) can semi-quantitatively describe the phase transitions observed when adding sodium polystyrene sulfonate polymers to E. coli bacteria [Schwarz-Linek et al., Soft Matter 6, 4540 (2010)] at high ionic strength. The E. coli bacteria are described as short, hard spherocylinders. FVT predicts that the phase transitions of the mixtures result from a fluid-ABC crystal solid phase coexistence of a hard spherocylinder-polymer mixture.

Development of Novel Bead Milling Technology with Less Metal Contamination by pH Optimization of the Suspension Medium.

To develop novel contamination-less bead milling technology without impairing grinding efficiency, we investigated the effect of the formulation properties on the grinding efficiency and the metal contamination generated during the grinding process. Among the various formulations tested, the combination of polyvinylpyrrolidone and sodium dodecyl sulfate was found to be suitable for efficiently pulverizing phenytoin. However, this stabilization system included a relatively strong acid, which raised the concern of possible corrosion of the zirconia beads. An evaluation of the process clearly demonstrated that acidic pH promoted bead dissolution, suggesting that this could be suppressed by controlling the pH of the suspension. Among the various pH values tested, the metal contamination generated during the grinding process could be significantly reduced in the optimized pH range without significant differences in the particle size of the phenytoin suspension after pulverization. In addition, the contamination reduction by pH optimization in the presence of physical contact among the beads was approximately 10-times larger than that without bead contact, suggesting that pH optimization could suppress not only bead dissolution but also the wear caused by bead collisions during the grinding process. These findings show that pH optimization is a simple but effective approach to reducing metal contamination during the grinding process.

Rhamnolipids as Effective Green Agents in the Destabilisation of Dolomite Suspension.

In this paper, we describe an application of mono- and dirhamnolipid homologue mixtures of a biosurfactant as a green agent for destabilisation of a dolomite suspension. Properties of the biosurfactant solution were characterised using surface tension and aggregate measurements to prove aggregation of rhamnolipids at concentrations much lower than the critical micelle concentration. Based on this information, the adsorption process of biosurfactant molecules on the surface of the carbonate mineral dolomite was investigated, and the adsorption mechanism was proposed. The stability of the dolomite suspension after rhamnolipid adsorption was investigated by turbidimetry. The critical concentration of rhamnolipid at which destabilisation of the suspension occurred most effectively was found to be 50 mg·dm-3. By analysing backscattering profiles, solid-phase migration velocities were calculated. With different amounts of biomolecules, this parameter can be modified from 6.66 to 20.29 mm·h-1. Our study indicates that the dolomite suspension is destabilised by hydrophobic coagulation, which was proved by examining the wetting angle of the mineral surface using the captive bubble technique. The relatively low amount of biosurfactant used to destabilise the system indicates the potential application of this technology for water treatment or modification of the hydrophobicity of mineral surfaces in mineral engineering.

Preparation of Cellulose/Laponite Composite Particles and Their Enhanced Electrorheological Responses.

Cellulose, as a natural polymer with an abundant source, has been widely used in many fields including the electric field responsive medium that we are interested in. In this work, cellulose micron particles were applied as an electrorheological (ER) material. Because of the low ER effect of the raw cellulose, a composite particle of cellulose and Laponite was prepared via a dissolution-regeneration process. Scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) were used to observe the morphologies and structures of the composite particles, which were different from pristine cellulose and Laponite, respectively. The ER performances of raw cellulose and the prepared composite were measured by an Anton Paar rotational rheometer. It was found that the ER properties of the composite were more superior to those of raw cellulose due to the flake-like shapes of the composite particles with rough surface. Moreover, the sedimentation stability of composite improves drastically, which means better suspension stability.

In vitro and in vivo Evaluation of Ibuprofen Nanosuspensions for Enhanced Oral Bioavailability.

INTRODUCTION: The objectives were to prepare, characterize, and evaluate different ibuprofen (IBU) nanosuspensions. METHODS: The nanosuspensions produced by ultrahomogenization were compared with a marketed IBU suspension for particle size, in vitro dissolution, and in vivo absorption. Five groups of rabbits were orally administered with 25 mg/kg of IBU nanosuspension, nanoparticles, unhomogenized suspension, marketed product, and untreated suspension. A sixth group received 5 mg/kg IBU intravenously. Blood samples obtained were analyzed by chromatography. RESULTS: The nanosuspensions showed significant decrease in particle size. Polyvinylpyrrolidone (PP) K30 profoundly increased aqueous solubility of IBU. Addition of Tween 80 (TW), in equal amount as PP (IBU:PP:TW, 1:2:2 w/w), resulted in much smaller particle size and better dissolution rate. The Cmax values achieved were 14.8 ± 1.64, 11.1 ± 1.37, 9.01 ± 0.761, 7.03 ± 1.38, and 3.23 ± 1.03 µg/mL, and the tmax values were 36 ± 8.2, 39 ± 8.2, 100 ± 17.3, 112 ± 15, and 105 ± 17 min for the nanosuspension, nanoparticle, unhomogenized suspension, marketed IBU suspension, and untreated IBU suspension in water, respectively. Bioavailability of the different formulations relative to the marketed suspension was found to be in the following sequence: nanosuspension > unhomogenized suspension > nanoparticles > untreated IBU suspension. CONCLUSION: IBU/PP/TW nanosuspension showed enhanced in vitro and in vivo performance as compared to the marketed product. Nanosuspensions prepared by the ultrahigh-pressure homogenization technique can be used as a good formulation strategy to enhance the rate and extent of absorption of poorly soluble drugs.

A suspension-based assay and comparative detection methods for characterization of polyethylene terephthalate hydrolases.

Enzymatic breakdown of plastic has emerged as a promising green technology, and its implementation will require assays that are accurate, reliable and convenient. Here, we assess two principles to monitor the hydrolysis of the common polyester, polyethylene terephthalate (PET). Hydrolysis of PET gives rise to heterogeneous products of different sizes and solubility, and as a result, specific experimental methods detect different activity levels. To avoid errors and to get a thorough picture of enzyme reactions, it is beneficial to combine several detection techniques. The two methods described herein are quantitative and complementary, and detect respectively the amount of soluble aromatic products and the formation of the constitutive aromatic monomers. A combined quantification approach identifies pitfalls in the characterization of these enzymes and provides mechanistic insight, but for screening and/or comparative studies of PET hydrolases we recommend a plate reader-based assay with suspended PET powder. This assay is rapid and simple, but still provides a good measure of the initial rates, which may be used in comparative biochemical analyses of these enzymes.

Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats.

PURPOSE: Lipid-based formulations (LBF) have shown oral bioavailability enhancement of lipophilic drugs, but not necessarily in the case of hydrophobic drugs. This study explored the potential of lipid vehicles to improve the bioavailability of the hydrophobic drug nilotinib comparing a chase dosing approach and lipid suspensions. METHODS: Nilotinib in vivo bioavailability in rats was determined after administering an aqueous suspension chase dosed with blank olive oil, Captex 1000, Peceol or Capmul MCM, respectively. Absolute bioavailability was determined (relative to an intravenous formulation). Pharmacokinetic parameters were compared to lipid suspensions. RESULTS: Compared to the lipid suspensions, the chase dosed lipids showed a 2- to 7-fold higher bioavailability. Both long chain chase dosed excipients also significantly increased the bioavailability up to 2-fold compared to the aqueous suspension. Deconvolution of the pharmacokinetic data indicated that chase dosing of nilotinib resulted in prolonged absorption compared to the aqueous suspension. CONCLUSION: Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for 'brick dust' molecules such as nilotinib. Graphical Abstract The potential of bio-enabling lipid vehicles, administered via chase dosing and lipid suspensions, has been evaluated as an approach to enhance oral bioavailability of nilotinib.

Novel application of synchrotron x-ray computed tomography for ex-vivo imaging of subcutaneously injected polymeric microsphere suspension formulations.

PURPOSE: Subcutaneously or intramuscularly administered biodegradable microsphere formulations have been successfully exploited in the management of chronic conditions for over two decades, yet mechanistic understanding of the impact of formulation attributes on in vivo absorption rate from such systems is still in its infancy. METHODS: Suspension formulation physicochemical attributes may impact particulate deposition in subcutaneous (s.c.) tissue. Hence, the utility of synchrotron X-ray micro-computed tomography (µCT) for assessment of spatial distribution of suspension formulation components (PLG microspheres and vehicle) was evaluated in a porcine s.c. tissue model. Optical imaging of dyed vehicle and subsequent microscopic assessment of microsphere deposition was performed in parallel to compare the two approaches. RESULTS: Our findings demonstrate that synchrotron µCT can be applied to the assessment of microsphere and vehicle distribution in s.c. tissue, and that microspheres can also be visualised in the absence of contrast agent using this approach. The technique was deemed superior to optical imaging of macrotomy for the characterisation of microsphere deposition owing to its non-invasive nature and relatively rapid data acquisition time. CONCLUSIONS: The method outlined in this study provides a proof of concept feasibility for µCT application to determining the vehicle and suspended PLG microspheres fate following s.c. injection. A potential application for our findings is understanding the impact of injection, device and formulation variables on initial and temporal depot geometry in pre-clinical or ex-vivo models that can inform product design. Graphical abstract.

Organogel Nanoparticles as a New Way to Improve Oral Bioavailability of Poorly Soluble Compounds.

PURPOSE: The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. METHODS: Organogel nanoparticles loaded with EFV were formulated with sunflower oil, 12-hydroxystearic acid (HSA) and polyvinyl alcohol (PVA). Various parameters have been investigated in the current study such as (i) the release profile of organogel assessed by USP 4 cell flow dialysis, (ii) the impact of organogel on intestinal absorption, using Caco-2 cells as in vitro model and jejunum segments as ex vivo assay and (iii) the bioavailability of organogel following oral pharmacokinetic study. RESULTS: 250-300 nm spherical particles with a final concentration of 4.75 mg/mL drug loading were obtained, corresponding to a thousand fold increase in EFV solubility, combined to a very high encapsulation efficiency (>99.8%). Due to rapid diffusion, drug was immediately released from the nanoparticles. The biopharmaceutical evaluation on ex vivo jejunum segments demonstrated an increased absorption of EFV from organogel nanoparticles compare to a native EFV suspension. In vitro assays combining Caco-2 cell cultures with TEM and confocal microscopy demonstrated passive diffusion, while paracellular integrity and endocytosis activity remain expelled. Oral pharmacokinetics of EFV organogel nanoparticles improve oral bioavailability (Fr: 249%) and quick absorption compared to EFV suspension. CONCLUSION: Organogel nanoparticles increase the bioavailability of BCS Class II drugs. The main phenomena is simply oil transfer from the gelled particles through the cell membrane.

Potential role of resveratrol-loaded elastic sorbitan monostearate nanovesicles for the prevention of UV-induced skin damage.

This study was aiming to improve the effect of the water-insoluble drug, resveratrol, by encapsulating it in surfactant-based elastic vesicles (spanlastics). Spanlastics (SLs) were prepared by thin film hydration method using different ratios of Span 60 (S60) and edge activators (EAs). The prepared SLs were subjected to full in-vitro evaluation. All the SLs showed improved properties compared to the drug suspension (p < 0.05). SL5 composed of S60: Brij 35 (7:3) attained the highest drug entrapment efficiency (79.10%±5.56), the smallest particle size (201.30 nm ± 2.45), the best in-vitro anti-oxidant effect and a fast drug release pattern, thus was selected for further investigation. Based on the Draize test, the selected spanlastics (SL5), as well as the drug suspension, showed to be safe to be applied on the skin (PII <2). In-vivo studies were done to test the photoprotective effect of the designed nanovesicles compared to the drug suspension. Evaluation was done based on visual examination and analysis of some anti-oxidant markers (CAT, GSH and SOD), anti-inflammatory markers (IL-6, IL-8 and NF-κB) and anti-wrinkling markers (MMP-1 and GM-CSF) after UVB-irradiation. The drug showed a good prophylactic effect, however, that of SL5 was superior compared to that of the drug suspension as recorded by the level of all biochemical markers (p < 0.05). These results were also confirmed by histopathological examination. This study proves that elastic nanovesicles seem to be a promising approach to overcome the low drug solubility and to improve its efficacy.

Study on the stabilization mechanisms of wet-milled cepharanthine nanosuspensions using systematical characterization.

Objectives: Stability issues are inevitable problems that are encountered in nanosuspension (NS) technology developments and in the industrial application of pharmaceuticals. This study aims to assess the stability of wet-milled cepharanthine NSs and elucidate the stabilization mechanisms of different stabilizers.Methods: The aggregation state was examined via scanning electron microscopy, laser diffraction, and rheometry. The zeta potential, stabilizer adsorption, surface tension, and drug-stabilizer interactions were employed to elucidate the stabilization mechanisms.Results: The results suggest that croscarmellose sodium (CCS), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), or polyvinyl pyrrolidone VA64 (PVP VA64) alone was able to prevent nanoparticle aggregation for at least 30 days. Attempts to evaluate the stability mechanisms of different stabilization systems revealed that CCS improved the steric-kinetic stabilization of the NSs, attributed to its high viscosity, swelling capacity, and physical barrier effects. In contrast, the excellent physical stability of TPGS systems was mainly due to the reduced surface tension and higher crystallinity. PVP VA64 can adsorb onto the surfaces of nanoparticles and stabilize the NS via steric forces.Conclusion: This study demonstrated the complex effects of CCS, TPGS, and PVP VA64 on cepharanthine NS stability and presented an approach for the rational design of stable NSs.