Preparation Of Nanosuspensions Research Articles

Preparation of Piroxicam nanosuspensions by high pressure homogenization and evaluation of improved bioavailability

Objective Inflammation is a natural response of the organism, involving events responsible for releasing chemical mediators and requiring treatments of symptoms such as pain, redness, heat, swelling, and loss of tissue function. Piroxicam (PRX) is a non-steroidal anti-inflammatory drug with the effect of nonselective COX inhibitor activity; however, it shows poor bioavailability caused by the poor and slow water solubility. In this study, we developed PRX nanosuspensions with 200–500 nm in diameter to increase the bioavailability of PRX by improving its solubility. Methods PRX nanosuspensions were fabricated by High pressure homogenization method with PVA, SDS and Tween 80. The nanosuspensions were characterized by XRD, FTIR, DSC, and in vitro release. In vivo pharmacokinetic properties and anti-inflammatory effects were also investigated in rabbits. Results PRX nanosuspensions significantly increased the solubility (14.89 ± 0.03 mg/L for pure PRX and 16.75 ± 0.05 mg/L for PRX nanosuspensions) and dissolution rate as compared to the pure PRX (p < 0.05). Orally administered PRX nanosuspension (AUC 0-t is 49.26 ± 4.29 μg/mL × h) significantly improved the bioavailability of PRX (AUC 0-t is 28.40 ± 12.11 μg/mL × h). The anti-inflammatory effect of PRX nanosuspension was also investigated in rabbits and it was observed that PRX nanosuspension treatment significantly improved the inhibition of COX-2 and NFκB expression as compared to the PRX treatment (p < 0.05). Conclusions The results in this study indicate that PRX nanosuspension is a promising nanomedicine for enhancing the anti-inflammatory activity of PRX and has a high potential for the treatment of inflammation.

Oral bioavailability enhancement of doxazosin mesylate: Nanosuspension versus self-nanoemulsifying drug delivery systems.

Doxazosin mesylate (DOX) is an antihypertensive drug that possesses poor water solubility and, hence, poor release properties. Both nanosuspensions and self-nanoemulsifying drug delivery systems (SNEDDS) are becoming nanotechnology techniques for the enhancement of water solubility of different drugs. The study's goal was to identify the best drug delivery system able to enhance the release and antihypertensive effect of DOX by comparing the physical characteristics such as particle size, zeta potential, entrapment efficiency, release rate, and main arterial blood pressure of DOX-loaded nanosuspensions and SNEDDS in liquid and solid form. DOX nanosuspension preparation had a particle size of 385±13 nm, poly-dispersity index of 0.049±3, zeta potential of 50 ± 4 mV and drug release after 20 min (91±0.43 %). Liquid SNEDDS had a droplet size of 224±15 nm, poly-dispersity index of (0.470±0.01), zeta potential of -5±0.10 mV and DR20min of 93±4 %. Solid SEDDS showed particle size of 79±14 nm, poly-dispersity index of 1±0.00, a zeta potential of -18 ±0.26 mv and DR20min of 100 ±2.72 %. Finally, in terms of the mean arterial blood pressure lowering, solid SNEDDS performed better effect than both liquid SNEDDS and nanosuspension (P >0.05).

Preparation of nanosuspensions of a 1,4-dihydropyridine-based mixed L-/T-type calcium channel blocker by combined precipitation and ultrasonication methods

Preparation of nanosuspensions of a 1,4-dihydropyridine-based mixed L-/T-type calcium channel blocker by combined precipitation and ultrasonication methods

Combined Amphiphilic Silybin Meglumine Nanosuspension Effective Against Hepatic Fibrosis in Mice Model.

Silybin (SLB) as an effective hepatoprotective phytomedicine has been limited by its hydrophobicity, poor bioavailability and accumulation at lesion sites. Additionally, present drug loading methods are impeded by their low drug loading capacity, potential hazard of materials and poor therapeutic effects. Consequently, there is a pressing need to devise an innovative approach for preparing nanosuspensions loaded with both SLB and Silybin Meglumine salt (SLB-M), as well as to investigate the therapeutic effects of SLB nanosuspensions against hepatic fibrosis. The SLB nanosuspension (NS-SLB) was prepared and further modified with a hyaluronic acid-cholesterol conjugate (NS-SLB-HC) to improve the CD44 targeting proficiency of NS-SLB. To validate the accumulation of CD44 and ensure minimal cytotoxicity, cellular uptake and cytotoxicity assessments were carried out for the nanosuspensions. Western blotting was employed to evaluate the anti-hepatic fibrosis efficacy in LX-2 cells by inhibiting the secretion of collagen I. Hepatic fibrosis mouse models were used to further confirm the effectiveness of NS-SLB and NS-SLB-HC against hepatic fibrosis in vivo. Uniform nanosuspensions were prepared through self-assembly, achieving high drug loading rates of 89.44% and 60.67%, respectively. Both SLB nanosuspensions showed minimal cytotoxicity in cellular environments and mitigated hepatic fibrosis in vitro. NS-SLB-HC was demonstrated to target activated hepatic stellate cells by receptor-ligand interaction between HA and CD44. They can reverse hepatic fibrosis in vivo by downregulating TGF-β and inhibiting the secretion of α-SMA and collagen I. Designed as a medical excipient analogue, SLB-M was aimed to establish an innovative nanosuspension preparation method, characterized by high drug loading capacity and a notable impact against hepatic fibrosis.

Nanosuspension: A Novel Approach to Improve the Solubility, Bioavailability and Pharmacokinetics of Poorly Soluble Drugs

Solubility is an essential factor for drug effectiveness, independent of the route of administration. Poorly water soluble drugs show major problems for drug formulation. Many conventional methods exist to address the issues of poor solubility and bioavailability, but they have many drawbacks. Nanotechnology is employed to address the issues related to these traditional methods for improving solubility and bioavailability. Pharmaceutical nanosuspension is a very finely colloid, biphasic, dispersed, solid drug particles in an aqueous vehicle, size below 1µm, without any matrix material, stabilised by surfactants and polymers, prepared by suitable methods for Drug Delivery applications, through various routes of administration such as oral, topical, parenteral, ocular and pulmonary routes. This article covers the advantages, disadvantages, properties, preparation of nanosuspension by bottom up technology, top down technology, melt emulsification, emulsification- solvent evaporation and supercritical fluid with their advantages and disadvantages, evaluation, and their drug delivery applications.

Continuous Monitoring of the Agglomeration and Sedimentation of Indomethacin Nanosuspensions Using T2 Relaxation Time with Time-Domain NMR.

The time-domain NMR technique was utilized to monitor precisely the physicochemical stability of indomethacin (IMC) nanosuspensions using T2 relaxation time (T2). We investigated whether T2 values can distinguish between agglomeration and sedimentation. Nanosuspensions of IMC were prepared using aqueous wet bead milling with polyvinylpyrrolidone as a stabilizer. Prepared nanosuspensions were divided into two fractions: one was stored in the NMR equipment for continuous T2 measurements and the other was stored in the dispersion analyzer. Measurements of both nanosuspensions were carried out, without dilution, over a period of 24 h at 10-min intervals. Transmission profiles based on multilight scattering technology showed that agglomeration predominantly occurred at 25 and 35 °C immediately after wet bead milling up to 4 h, followed by sedimentation from 4 to 24 h. Upon measuring the T2 relaxation, T2 values at both 25 and 35 °C showed a two-step change-there was a significant prolongation in T2 values immediately after preparation of nanosuspensions up to approx. 4 h and a gradual prolongation in T2 values from approx. 4 to 24 h. Considering the results of transmission profiles, these two-step T2 changes correspond to agglomeration and sedimentation. In other words, this study established that monitoring the T2 values of nanosuspensions could be used to evaluate the agglomeration and sedimentation of contained drug particles. This technique does not directly observe the nanoparticles themselves, but the water molecules. Thus, measurement of T2 relaxation is considered to be a general-purpose technique, independent of the type of drug or polymer.

Research progress on the preparation and application of flavonoid nanocrystals.

Flavonoids have been reported to possess significant pharmacological activities,such as antioxidant, anti-inflammatory and anticancer effects. However, the low solubility and low bioavailability limits their clinical application. Nanocrystal technology can solve the delivery problems of flavonoids by reducing particle size, increasing the solubility of insoluble drugs and improving their bioavailability. This article summaries nanosuspension preparation methods and the stabilizers for flavonoid nanocrystals, and reviews the drug delivery routes including oral, Injection and transdermal of flavonoid nanocrystals, to provide information for further research on nanocrystal delivery system of flavonoids.

Extraction of rutin from tagetes erecta (Marigold) and preparation of peroral nano-suspension for effective antitussive/expectorant therapy

The present study narrates the extraction of rutin from Tagetes erecta (Marigold) via maceration followed by ultrasonication. The extracted rutin was further fabricated into nanoparticles by high-pressure homogenization (HPH) and assessed by HPLC, DSC, XRD, TEM, and FTIR spectroscopy. The optimized batch of nanoparticles obtained using 32 central composite design (CCD) which exhibited particle size 209±14 nm, PDI 0.234±0.06, and 92±1.3% entrapment efficiency. The lyophilized rutin nanoparticles were further converted into nano-suspension. Interestingly, the rutin nano-suspension exhibited a similar antitussive effect in vivo as that by standard treatment pentoxyverine and reduced the coughing times within 2 min. Also, the phlegm showed high UV absorbance, implying its better expectorant activity than the standard and control. The rutin nano-suspension was highly stable and shelf life was found to be ∼29.1 months. The present study, for the first time, paves a way for the use of rutin nano-suspension to overcome chest congestion, shortening of breath, and in the management of cough.

Review on Nanosuspension as a Novel Method for Solubility and Bioavailability Enhancement of Poorly Soluble Drugs

The formulation development of a drug is majorly based on the solubility of drugs. Nearly 40% of newly developed drugs show poor water solubility. Several approaches are used for the increasing solubility of such drugs for formulation development. Nanosuspension is one such attractive tactic which can be used for the enhancement of solubility, stability as well as bioavailability of such drugs. Nanosuspension can be defined as a two-phasic dosage form where solid drug particles of size less than 1 μm are dispersed in an aqueous phase with the help of a stabilizer. Particle size reduction in the nanoscale causes an increase in the surface area leading to an increase in dissolution rate and ultimately bioavailability is increased. A variety of excipients are used for the formulation of nanosuspension. Stabilizers, surfactants, co-surfactants, natural as well as organic solvents, buffers, salts, polyols, osmogents, and cryoprotectants are used in the formulation of nanosuspension. Various methods used in the formulation of nanosuspension can be classified into top-down and bottom-up approaches. Wet milling, high-pressure homogenization, anti-solvent techniques, melt emulsification, supercritical fluid extraction and ultrasonic homogenization are some of the methods for the preparation of nanosuspension. These methods are easy and appropriate for all poor water-soluble drugs. Nanosuspensions technology can be applied for the preparation of oral, pulmonary, injectable, ocular as well as targeted drug delivery. This review emphasizes various advantages and disadvantages of nanosuspension, its methods of preparation, formulation approaches, evaluation parameters, pharmaceutical applications, marketed products and patents of nanosuspension.

Formulation Development and Optimization of Rosuvastatin Loaded Nanosuspension for Enhancing Dissolution Rate

Background: Nanotechnology has been considered an auspicious approach over the last twenty years and numerous researchers are making efforts to extend its applications in pharmaceuticals. Recently, various nano-based drug delivery systems, such as nanoparticles, nanoemulgel, nanosuspension, and nanoemulsion, have been developed to deliver varieties of hydrophobics to target sites. Rosuvastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase enzyme. The application of rosuvastatin is compromised because of its poor aqueous solubility and low oral bioavailability. Objective: This research work aimed to develop and characterize nanosuspension formulation for enhancement of the dissolution rate of rosuvastatin. Methods: Nanosuspension of rosuvastatin was prepared by using PVP K-30 and tween 80 as a stabiliser via the high-pressure homogenization method. The nanosuspension formulation was optimised by a factorial design to determine the effect of PVP K-30 (A), the concentration of tween 80 (B) and the number of the cycle (C) of high-pressure homogenizer on particle size (Y1), polydispersity index (Y2) and zeta potential (Y3) of the developed formulation. The optimised nanosuspension formulation of rosuvastatin was assessed for particle size, zeta potential, PDI, pH, % encapsulation efficiency of the drug, solubility study and comparative in vitro dissolution study. The optimised formulation passed the stability studies in terms of physical stability (sedimentation) for three months. Results: Results: The optimised formulation resulted in 92.79 nm of particle size with a 0.201 polydispersity index. The nanosuspension of rosuvastatin showed higher dissolution rate as compared to the pure drug. Conclusion: This investigation demonstrated that nanosuspension preparation could be a promising approach for improvement of the dissolution rate of BCS II class drugs

Preparation and in vitro evaluation of quercetin nanosuspension stabilized by gypenosides

This study was designed to explore the potential of gypenosides as a novel natural stabilizer for the production of nanosuspensions. The gypenosides-stabilized quercetin nanosuspensions(QUE-NS) were prepared using the high-speed shearing and high-pressure homogenization method with quercetin as a model drug, followed by their in vitro evaluation.Based on the measured mean particle size and polydispersity index(PDI) of QUE-NS,the single factor experiment was conducted to optimize the preparation process parameters.The freeze-drying method was used to transform QUE-NS into freeze-dried powders, whose storage stability and saturation solubility were then studied.Moreover, the effects of pH and ionic strength on the physical stability of the nanosuspension system were examined.According to the results, the optimized process parameters were listed as follows: shear rate 13 000 r·min~(-1),shear time 2 min, homogenization pressure 100 MPa, and homogenization frequency 12 times.The mean particle size of QUE-NS prepared under the optimum process conditions was(461.9±2.4) nm, and the PDI was 0.059±0.016.During the two months of storage at room temperature, the freeze-dried QUE-NS powders remained stable.The saturation solubility of freeze-dried QUE-NS powders was proved higher than those of quercetin and the physical mixture.The results of stability testing demonstrated that QUE-NS stabilized with gypenosides exhibited good stability within the pH range of 6 to 8,while coalescence was prone to occur in the presence of salt.Overall, gypenosides is expected to become a new natural stabilizer for the preparation of nanosuspensions.

Preparation of polydopamine-modified celastrol nanosuspension and its anti-liver cancer activity in vitro

Celastrol (CEL) is one of the main effective components of traditional Chinese medicine Tripterygium wilfordii Hook.f, which has high antitumor activity. However, its low solubility and low bioavailability limit its clinical use. In this study, a CEL nanosuspension (PDA@CEL-NS) with near-infrared photothermal properties was prepared. PDA@CEL-NS contained spherical nanoparticles with an average particle size of 189.67 nm, zeta potential of −30.23 mV, and 60.33% drug loading. X-ray diffraction showed that PDA@CEL-NS had an amorphous structure. PDA@CEL-NS had good stability after storage at 4 °C and 37 °C for 30 days, and there was no aggregation or sedimentation in a 5% glucose solution or culture medium. The highly dispersed nanoparticles greatly improved dissolution in vitro, and the cumulative release rate of PDA@CEL-NS over 72 h was as high as 60.10%. It demonstrated both high release and a good sustained-release effect. Cell experiments showed that PDA@CEL-NS had stronger efficacy than CEL-NS or CEL, and the efficacy was further enhanced after laser application. Nuclear rupture and deformation and the induction of apoptosis were potential toxic mechanisms, and they also inhibited cell migration. In conclusion, PDA@CEL-NS is expected to become a nano-drug delivery system for the treatment of cancer.

Nanosuspension as Promising and Potential Drug Delivery: A Review

In the last decade, nanosuspensions have gained considerable interest as a method for formulating poorly soluble drugs. Because of their cost-effectiveness and technological simplicity compared to liposomes and other colloidal drug carriers, nanoscale systems have recently received a lot of attention as a way of solving problems of solubility. Nanosuspensions are biphasic systems comprising of pure drug particles dispersed in an aqueous vehicle, stabilized by surface active agents. Fabrication of nanosuspension is simple and more advantageous than other approaches. Nanosuspension is a very finely single solid drug particle in an aqueous vessel, stabilized by surfactants for either oral or topical use or for parenteral and pulmonary administration, it can also be used for targeted drug delivery when incorporated in the ocular inserts and mucoadhesive hydrogels, with reduced particle size resulting in increased dissolution rate. This article covers the preparation of nanosuspension by bottom up technology, top down technology, melt emulsification, emulsification- solvent evaporation and supercritical fluid with their advantages and disadvantages, aspects of structure, classification and their drug delivery applications. Nanosuspension can be processed for the drugs which are of hydrophobic in nature quite easily employing stability enhancers, solvents that are of organic and additional ingredients including buffering agents, salts, PEG, osmotic agents and anti-freeze compounds.

Facile Preparation of Paclitaxel Nano-Suspensions to Treat Lung Cancer

Lung cancer is a worldwide issue which account for the death of thousands every year. Paclitaxel (PTX) as the first line chemotherapy drug to treat lung cancer, its clinical applications is largely limited by its poor solubility. The facile preparation of pharmaceutical formulations to increase the solubility as well as targetability of PTX is of vital importance in lung cancer treatment. Herein, we introduced a facile method to prepare PTX nano-suspensions (NSs), which have high drug loading as well as well-dispersed particle size. The in vitro cell experiments revealed its capability to enhance the drug accumulation in A549 cells than free PTX. Moreover, in vivo animal assay suggested its better tumor accumulation and antitumor efficacy than PTX injection (Taxol).

Preparation and Characterization of Nanosuspensions of Triiodoaniline Derivative New Contrast Agent, and Investigation into Its Cytotoxicity and Contrast Properties.

Iodine-based contrast agents have limitations such as rapid clearance, potential renal toxicity, non-specific blood pool distribution, headache, and adverse events. Nowadays, it is quite common to work with nanosized systems in order to eliminate the side effects of contrast agents. This study aims to synthesize a new iodinated contrast agent, prepare its nanosuspension by using the nanoprecipitation method, investigate its cytotoxicity, and compare its contrast properties with iohexol and iopromide through in-vitro experiments. The values of nanosuspension particle size and zeta potential have been found to be ~ 400 nm and ~ (-) 15 mV, respectively. In-vitro cellular viability findings indicated that the nanosuspension has lower cytotoxicity than the iohexol and iopromide. In the computed tomography (CT) imaging study of contrast features of nanosuspensions and two commercial agents, which involved 86 CT examinations using 31 parameters and two different devices, it was found that iodine had a stronger presence in its nanosuspension form than in iohexol and iopromide, which were the other two commercial contrast agents, when used in equal amounts. Thus in the case of nanosuspensions contrast brightness was achieved by using less iodine, while the same brightness could be obtained with higher doses of iohexol and iopromide. CT imaging therefore be done without much chemical use, which indicates that it may witness fewer side effects in the future.

Mechanochemical Preparation, Characterization and Biological Activity of Stable CuS Nanosuspension Capped by Bovine Serum Albumin.

The biocompatible nanosuspension of CuS nanoparticles (NPs) using bovine serum albumin (BSA) as a capping agent was prepared using a two-stage mechanochemical approach. CuS NPs were firstly synthetized by a high-energy planetary ball milling in 15 min by milling elemental precursors. The stability of nanoparticles in the simulated body fluids was studied, revealing zero copper concentration in the leachates, except simulated lung fluid (SLF, 0.015%) and simulated gastric fluid (SGF, 0.078%). Albumin sorption on CuS NPs was studied in static and dynamic modes showing a higher kinetic rate for the dynamic mode. The equilibrium state of adsorption was reached after 90 min with an adsorption capacity of 86 mg/g compared to the static mode when the capacity 59 mg/g was reached after 2 h. Then, a wet stirred media milling in a solution of BSA was introduced to yield the CuS-BSA nanosuspension, being stable for more than 10 months, as confirmed by photon cross-correlation spectroscopy. The fluorescent properties of the nanosuspension were confirmed by photoluminescence spectroscopy, which also showed that tryptophan present in the BSA could be closer to the binding site of CuS than the tyrosine residue. The biological activity was determined by in vitro tests on selected cancer and non-tumor cell lines. The results have shown that the CuS-BSA nanosuspension inhibits the metabolic activity of the cells as well as decreases their viability upon photothermal ablation.

Preparation of Naringenin Nanosuspension and Its Antitussive and Expectorant Effects.

Naringenin (NRG) is a natural flavonoid compound abundantly present in citrus fruits and has the potential to treat respiratory disorders. However, the clinical therapeutic effect of NRG is limited by its low bioavailability due to poor solubility. To enhance the solubility, naringenin nanosuspensions (NRG-NSps) were prepared by applying tocopherol polyethylene glycol succinate (TPGS) as the nanocarrier via the media-milling method. The particle size, morphology, and drug-loading content of NRG-NSps were examined, and the stability was evaluated by detecting particle size changes in different physiological media. NRG-NSps exhibited a flaky appearance with a mean diameter of 216.9 nm, and the drug-loading content was 66.7%. NRG-NSps exhibited good storage stability and media stability. NRG-NSps presented a sustainable release profile, and the cumulative drug-release rate approached approximately 95% within 7 d. NRG-NSps improved the antitussive effect significantly compared with the original NRG, the cough frequency was decreased from 22 to 15 times, and the cough incubation period was prolonged from 85.3 to 121.6 s. Besides, NRG-NSps also enhanced expectorant effects significantly, and phenol red secretion was increased from 1.02 to 1.45 μg/mL. These results indicate that NRG-NSps could enhance the bioavailability of NRG significantly and possess a potential clinical application.

Fabrication of Stable Apigenin Nanosuspension with PEG 400 as Antisolvent for Enhancing the Solubility and Bioavailability.

The purpose of this paper is to prepare a stable apigenin nanosuspension with a drug concentration of 1.11mg/mL through green and efficient antisolvent method. Compared with the traditional preparation process that may use toxic reagents, in this study, a green and effective strategy was applied for the preparation of stable apigenin nanosuspension by using an antisolvent method with PEG 400 as antisolvent to improve the solubility and bioavailability. It was found that the particle size of apigenin nanosuspension was about 280nm, and the solubility and dissolution of the nanosuspension were 33 and 3 times higher than that of the apigenin, respectively. Pharmacokinetic study showed that the Cmax and AUC 0-8h values of the nanosuspension in fasting rats achieved about 6- and 2.5-fold enhancement than that of the apigenin, respectively. Stability test showed that the apigenin nanosuspension could be stored stably for 12months at 25℃. Taken together, the antisolvent method with PEG 400 was proven to be a green and effective method to prepare the stable nanosuspension of poorly soluble drugs.

Preparation and characterization of quercetin nanosuspensions using gypenosides as novel stabilizers

To study the potential of gypenosides as natural stabilizers for the production of nanosuspensions, quercetin (QUE) was chosen as a model drug to prepare nanosuspensions stabilized by gypenosides. Here, high-speed shearing and high-pressure homogenization were used to obtain QUE nanosuspensions (QUE-NS). Different QUE-NS were prepared by changing the concentration and type of stabilizer to evaluate the stabilization efficiency of gypenosides. The results showed that the ability of gypenosides to stabilize nanosuspensions was superior to that of the conventional stabilizers at low concentrations. Using transmission electron microscopy, QUE-NS were observed to have the nanosized particles (less than 500 nm) and present a lumpy morphology. Due to the reduction of particle size, the in vitro dissolution rate and antioxidant activity of QUE-NS were significantly higher than that of QUE coarse drug. Powder X-ray diffraction and fourier-transform infrared spectroscopy showed that there was no significant difference in the chemical structure and crystal state of QUE during the production process. According to the results of stability studies, QUE-NS stabilized with gypenosides exhibited good storage stability. In conclusion, preparation of the nanosuspensions was feasible using gypenosides as novel stabilizers. Nanosuspensions stabilized by gypenosides could be used as a potential strategy for improving the solubility of poorly water-soluble drugs.

Impact of solvents during wet stirred media milling of cross-linked biopolymer suspensions

The aim of this study was to examine the impact of solvents during the wet stirred media milling of cross-linked biopolymers considering breakage kinetics, physical stability of the suspensions, and microhydrodynamics. To this end, a model cross-linked biopolymer, sodium starch glycolate (SSG), was milled in acetone and water wherein SSG was non-swellable and swellable, respectively. Suspensions containing SSG particles with and without two stabilizers, i.e., hydroxypropyl cellulose and sodium dodecyl sulfate, were prepared. The temporal evolution of the SSG particle size during the milling was tracked by laser diffraction. Swelling of the SSG particles in water was independently characterized using microscopy and laser diffraction, which revealed fast swelling within a few minutes. Results also suggest that SSG particles were broken faster in water than in acetone, and stabilizers could not prevent severe aggregation in acetone. Despite the greater viscous dampening in water, water was more favorable for faster production of stable suspensions than acetone. The superior performance of aqueous milling was primarily attributed to favorable nanoparticle stabilization in water and secondarily to swelling-induced softening and coarsening of SSG particles. Hence, also being environmentally benign and safe, it is preferred over organic solvent-based milling for the preparation of cross-linked biopolymer nanosuspensions.