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Inhibition of asparagine endopeptidase (AEP) has been implied to be effective for treating tau- and amyloid-beta-mediated neurodegenerative diseases, although a method for targeted intracerebral delivery of AEP inhibitors has not yet been achieved. Here, we fabricated ultrasound-responsive nanobubbles (NBs) to load AEP inhibitor RR-11a, and modified the NB surface with either AEP recognizable peptide AAN or pro-transendothelial transversal motif RGD, i.e. NB(11a)-A and NB(11a)-R, for AEP-targeted treatment of Alzheimer's disease (AD). The developed NBs were uniform, small in size (50.1 ± 1.5 nm), with strong echogenicity and high drug loading efficiency (∼91.97%). When intravenously co-injected in the APP/PS1 mouse model, NB(11a)-R could adhere to endothelial cells and enhance transient opening of the blood-brain barrier (BBB) upon focused ultrasound oscillations, allowing the rest NBs/localized released RR-11a molecules to enter the brain, and then NB(11a)-A could selectively bind with the impaired neurons and deposit RR-11a molecules at the AD lesion. As a result, co-administration of NB(11a)-A and NB(11a)-R significantly promoted accumulation of RR-11a in the mouse brain, and substantially alleviated both tau cleavage and amyloid plaques deposition in the hippocampus. Most strikingly, the cognitive ability of the AD model mice was dramatically improved, achieving a level close to the normal mice. Overall, this unique AEP-targeted nanobubble design provides an efficient intracerebral drug delivery strategy and significantly enhances treatment efficacy of AD. Asparagine endopeptidase (AEP) is an innovative therapeutic target simultaneously involved in Aβ and tau-mediated Alzheimer's disease (AD) pathology, but targeted delivery of AEP inhibitors has not been achieved yet. Here we developed an efficient strategy to deliver AEP inhibitor RR-11a towards impaired neurons. We fabricated RR-11a-loaded ultrasound-responsive nanobubbles (NBs) and modified the NB surface with RGD peptide to promote BBB crossing upon focused ultrasound oscillations, or with AAN peptide to increase binding of NBs on the neurons. Our results indicated that, co-administration of the NB(11a)-A and NB(11a)-R significantly enhanced accumulation of RR-11a molecules at the AD lesion, alleviated both tau cleavage and amyloid plaques deposition in the hippocampus, and consequently restored cognitive function of the AD model mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Different contents of A-INDO in INDO binary mixtures were quantified by Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) and Near-Infrared (NIR) analytical techniques combined with chemometrics methods. Different pretreatment methods pretreated ATR-FTIR and different resolutions NIR data were used to establish PLSR models to quantify A-INDO content. [Display omitted] • Different contents of A-INDO in INDO binary mixtures were quantified. • The ATR-FTIR spectral data was selected to establish the PLSR models for quantify the content of A-INDO in binary mixtures. • A-INDO content PLSR models of different resolutions of NIR data were established to quantify the content of A-INDO. Pharmaceutical corporations prefer amorphous active pharmaceutical ingredients (APIs) because of their high apparent solubility and bioavailability, which are caused by long-range disorder, large unit surface free energy, and easily wetted particle surfaces. APIs in amorphous form tend to recrystallize into crystalline form during production, transportation, and storage, leading to differences in safety and clinical efficacy, which has been a major obstacle to development of amorphous drugs. In this study, rapid and nondestructive methods for quantitative analysis of amorphous indomethacin (A-INDO) content in A-INDO and γ-indomethacin (γ-INDO) binary mixtures were established based on Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR) and Near-Infrared spectroscopy (NIR) combined with chemometrics methods. Partial least squares regression (PLSR) was used to establish quantitative analysis models of A-INDO content ranging from 0.000 % to 10.000 % w/w %. A variety of spectral pretreatment methods were used to pretreat the spectral, reducing the influence of inconsistent particle size and uneven mixing, and highlighting the sample component information. The two analytical techniques' best PLSR models were selected, and the performance of the best models was confirmed by the validation samples. The most effective PLSR model based on ATR-FTIR was Y = 0.99456 X + 0.21526, R2 = 0.99456, the limit of detection (LOD) was 0.714 % and the limit of quantification (LOQ) was 2.164 %. The optimal PLSR model based on NIR was Y = 0.99950 X + 0.07465, R2 = 0.99950, with LOD = 0.246 % and LOQ = 0.747 %. The results showed that the PLSR models established by ATR-FTIR and NIR solid-state analytical techniques combined with stoichiometric method could be used to detect the content of amorphous APIs and to control the production quality of APIs. [ABSTRACT FROM AUTHOR]

Caking of crystals leads to a great deal of negative impact on the quality of products leading to extra cost to restore the products to its original state before caking. It is therefore an undesired phenomenon that should be investigated and inhibited. This review considers particle issues (particle science and technology) in a crystallization view (crystallization science and engineering). 1. Characterization. Caking indices and the relevant characterization methods are classified. Their advantages and disadvantages are summarized. Particularly, potential novel characterization methods, e.g. image analysis technique and its application in analysis of caking ratio, are discussed. 2. Mechanisms. Caking process is organized into three stages: moisture sorption, then liquid bridge, and finally crystal bridge. The mechanisms are reconsidered with recent studies (e.g. mass transfer, adhesion effect of liquid bridge, kinetic of crystal caking) and crystallization science (e.g. nucleation and growth theory, polymorphism, and phase transition). 3. Prevention. Based on particle and crystal engineering, prevention of crystals caking is discussed through controlling ambient conditions (relative humidity, temperature, liquids screening, and pressure) and improving anticaking property of crystals (particles size, particles shape, impurity, and anticaking agent). A potential method of simulating crystal caking behavior based on discrete element method (DEM) and caking mechanisms is presented. With the aid of simulation, the enhanced design of particle and crystal engineering would be available, which could be a key to control these factors systematically. [ABSTRACT FROM AUTHOR]

Caking is a common phenomenon of maltitol that causes problems of separation, processing and transportation. To study the mechanism of caking, method of capillary rise was used to measure the contact angles between maltitol particles and relevant liquids. Based on the calculation of adhesion free energy of maltitol particles in different liquids by Lifshitz–van der Waals acid-base theory, the relationship between adhesion free energy and the maltitol particles size has been established. It is concluded that the adhesion free energy of maltitol with rinsing liquid plays a key role in caking. When the adhesion free energy is higher than a critical value (about 60 mJ/m 2 ), the repulsion between the particles can avoid caking. In general, the adhesion free energy depends on the rinsing liquid used and maltitol particles size. The adhesion free energy increases with increasing the particles size of maltitol and type of liquids (water, ethyl acetate, formamide, ethylene glycol, ethanol, methanol in sequence). Hence, controlling particles size distribution and screening of rinsing liquid are crucial factors to avoid caking. [ABSTRACT FROM AUTHOR]

Abstract: Measurements of the metastable zone and solubility for flunixin meglumine–ethanol system were obtained. The solubility was measured within the temperature range from 288.15 to 328.15K. The mole fraction solubility was correlated satisfactorily with the temperature by the equation: x eq =2.35×10−12 e 0.07121T . The value of enthalpy of dissolution, enthalpy of fusion and enthalpy of mixing were determined to be 49.04, 64.03 and −14.99kJmol−1 respectively. The metastable zone width of flunixin meglumine was measured by an electric conductivity method. A comparison of the nucleation temperatures from electric conductivity measurement and from focused beam reflectance measurement (FBRM) shows that both detection techniques give almost the same results for flunixin meglumine. The nucleation parameters of flunixin meglumine in ethanol were determined from the metastable zone data. Over the equilibrium temperature range from 312.28 to 325.55K, the nucleation rate constant was varied from 0.00001 to 0.00120#/m2 min, whereas the nucleation order was varied from 2.23022 to 3.39299. The obtained high values of nucleation order indicated a high rate of nucleation. [Copyright &y& Elsevier]

[Display omitted] • Mechanochemical synthesis of multi-component crystals of the natural antibiotic magnolol. • Enhanced dissolution properties lead to increased antibacterial activity. • Construct of structure–activity relationship and managing of multi-component crystal on physicochemical properties. • Design of isostructural cocrystal and evaluation of pharmaceutical properties. Antibiotic is one of the most important discoveries in human and animal medicine. However, the inefficient use of antibiotics has caused widespread and persistent contamination of ecosystems, setting off microbial resistance storms. Magnolol is a botanical antibiotic, but poor physicochemical properties result in low bioavailability. Increasing solubility of magnolol can help to reduce the doses of medications to patients, minimize bothersome side effects. In this work, three novel multicomponent crystalline solids were synthesized from magnolol and isomeric coformers by mechanochemistry. It was found that the multicomponent crystalline solids achieved the customizable release profile of magnolol by manipulating the substituent positions of the isomers and complexation. Antibacterial activity test showed that bioactivity on two bacteria was considerably improved by designed MGN multicomponent crystals. In addition, the coformers controlled the dissolution behavior and further stabilized the improvement according to the variable statistical analysis. In conclusion, the properties of antibiotic multicomponent solids can be manipulated through the coformers. This provides an effective strategy for managing the release of drugs to meet individual biological differences and diverse therapeutic needs. [ABSTRACT FROM AUTHOR]

Lysozyme (LYS) and hyaluronan with low (HA1: 3 kDa), medium (HA2: 120 kDa), and high (HA3: 1200 kDa) molecular weights were used to fabricate lysozyme-hyaluronan colloidal nanoparticles using a green self-assembly method. Fourier transform infrared spectroscopy indicated that hydrogen bonding, hydrophobic and electrostatic interactions promoted the formation of the colloidal nanoparticles. The hydrophobic area of prepared colloidal nanoparticles was quantified using a pyrene fluorescent probe, and the results showed that the LYS-HA3 nanoparticles had the strongest hydrophobic capacity. Furthermore, 5-fluorouracil (5-Fu) was used to evaluate encapsulation performance, demonstrating that the LYS-HA3 nanoparticles had the highest encapsulation ability (>90 %). All prepared 5-Fu-loaded lysozyme-hyaluronan (5-Fu@LYS-HA) colloidal nanoparticles exhibited excellent long-term storage stability at 4 °C for 60 days. Cellular uptake and in vitro release results indicated that the LYS-HA2 nanoparticles exhibited the highest cellular uptake efficiency, and the LYS-HA3 nanoparticles had the best slow-release effect, while the release process was mainly controlled by the combination of Fickian diffusion and structural relaxation, respectively. This study demonstrates the influence of molecular weight on the conformational and structural properties of colloidal nanoparticles, which has implications for the design of insoluble drug self-assembly systems. • The 5-Fu@LYS-HA composite nanoparticles were prepared using the self-assembled method. • The conformation, cellular uptake, and release kinetic of nanoparticles were evaluated. • The nanoparticles had excellent long-term stability. • The nanoparticle improved the in vitro bioavailability of 5-Fu. [ABSTRACT FROM AUTHOR]

[Display omitted] • Revealing the property and mechanism of asymmetric growth of organic polar crystals. • Correlated with surface roughness and crystal growth rate. • The MAE model was used to analyze the solvent effect mechanism. • Correlated solvent-crystal face interactions and crystal growth rates. Organic polar crystals (OPCs) are the foundation for photonic and non-linear optical applications in advanced materials. High-quality crystals are a key in achieving efficient performance for OPCs. This work explores the properties and mechanisms of OPC growth along the polar axis. Melt microdrop growth experiments confirm that asymmetric growth is an inherent property of OPCs and relates to the intrinsic crystal structure. Notably, the solvent also plays a non-negligible role in OPCs growth. Solvent-crystal face interactions are strongly influenced by the crystal face structure. A rough surface has a slower growth rate, and a specific recognition of the solvent molecules. Asymmetric growth correlates with the modified attachment energy model and reveals the role of the solvent in inhibiting of crystal growth. Finally, the growth pattern in different solvents is explained by the interfacial adsorption model. This work will further enrich the asymmetric growth mechanism of OPCs and provide guidance for obtaining high-quality OPCs in solution. [ABSTRACT FROM AUTHOR]

Abstract The solubility of dapsone (DAP) in twelve mono solvents (methanol, ethanol, 1‑butanol, 2‑butanol, n ‑pentanol, isobutanol, methyl acetate, ethyl acetate, ethyl propionate, isopropyl acetate, butyl acetate, acetone) was determined at the temperature from 283.15 to 323.15K using a gravimetric method. The measurement results show the solubility are positively correlated with temperature. The accuracy of experimental results was examined by the modified Apelblat model, λh equation and NRTL model. They show good correlation with all the ARD% lower than 5%. Furthermore, the mixing thermodynamic properties of DAP were study in these twelve solvents based on the nonrandom two-liquid model for further understanding of the mixing process. Graphical abstract Unlabelled Image Highlights • The solubility of dapsone in twelve mono solvents was measured and discussed. • The experimental data was well correlated by different models. • The thermodynamic properties of the mixing process were calculated. [ABSTRACT FROM AUTHOR]

Potassium chloride crystals are cubic, which often leads to caking and greatly limits their applications. This caking can be overcome by modifying the crystal shape toward sphericity. Spherical particles have a high anti-caking ability and flowability. In this work, spherical KCl particles were prepared using a simple cooling crystallization process designed to function without additives. Among the four main processes in the crystallization of spherical particles, i.e., nucleation, growth, agglomeration, and attrition, agglomeration is the greatest contributor to the formation of spherical KCl particles, which were prepared following the principle that the adhesion force must be larger than the dispersion force. The adhesion free energy between KCl particles and solvents (i.e., water, n -hexane, formamide, diazomethane, methanol, ethanol, ethyl acetate, ethylene glycol, and dimethyl sulfoxide) was calculated using the Lifshitz–van der Waals acid–base approach, and water was found to be the most appropriate solvent because of its attractive interaction with the crystals. According to the relationship between the adhesion force and dispersion forces, we found that the stirring rate should be lower than 1300 rpm. Additionally, the effects of stirring rate and cooling rate on the KCl products were investigated and optimized, and the optimal conditions were found to be 400–500 rpm and 10–15 min/ ° C, respectively. All of the spherical KCl products prepared under the optimal conditions show a better morphology, flowability, and anti-caking performance than the original crystals. [ABSTRACT FROM AUTHOR]

• Model-based design for anti-caking function of water-soluble crystals. • Development of the Caking-Size-Crystallization (CSC) model. • First model coupling between front-end crystallization and post-end caking process. • Model validation and optimal solution by case study of ammonium persulfate. • High efficiency and product quality with CSC model on comparison of model-free. Water-soluble crystals with anti-caking function have become high-end products, whereas they are prepared by trial and error due to the lack of quantitative correlation between particle size and caking tendency, as well as the absence of the models for global consideration between caking and crystallization. This work presents a coupled Caking-Size-Crystallization (CSC) model, which connects the front-end crystallization process and the post-end caking process to achieve the closed-loop design of the anti-caking function for the first time. The CSC model can directly generate the optimal cooling trajectory to crystallize the product free of caking. The introduction of the caking constant term, the mean particle size and the Mullin-Nyvlt's theory improve the design efficiency by an order of magnitude with the precision guaranteed. This model-based approach presents an opportunity to find optimal crystallization operating profiles with diverse crystal seed loading strategies that meet both product function and manufacturability demands. [ABSTRACT FROM AUTHOR]