Application of Convolutional Neural Network in Motor Bearing Fault Diagnosis.

In the field of mechanical and electrical equipment, the motor rolling bearing is a workpiece that is extremely prone to damage and failure. However, the traditional fault diagnosis methods cannot keep up with the development pace of the times because they need complex manual pretreatment or the support of specific expert experience and knowledge. As a rising star, the data-driven fault diagnosis methods are increasingly favored by scholars and experts at home and abroad. The convolutional neural network has been widely used because of its powerful feature extraction ability for all kinds of complex information and its outstanding research results in image processing, target tracking, target diagnosis, time-frequency analysis, and other scenes. Therefore, this paper introduces a convolutional neural network and applies it to motor-bearing fault diagnosis. Aiming at the shortcomings of fault signal and convolutional neural network, a large-scale maximum pooling strategy is proposed and optimized by wavelet transform to improve the fault diagnosis efficiency of motor bearing under high-voltage operation. Compared with other machine learning algorithms, the convolution neural network fault diagnosis model constructed in this paper not only has high accuracy (up to 0.9871) and low error (only 0.032) but also is simple to use. It provides a new way for motor bearing fault diagnosis and has very important economic and social value.

Overcoming Bioavailability Challenges of Dasabuvir and Enabling a Triple-Combination Direct-Acting Antiviral HCV Regimen through a Salt of Very Weak Acid for Oral Delivery.

Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pKa = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 µg/mL at pH 1-6.8, dose number of 1.31 × 104), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

Role of Surfactants on Release Performance of Amorphous Solid Dispersions of Ritonavir and Copovidone.

PURPOSE: To understand the role of different surfactants, incorporated into amorphous solid dispersions (ASDs) of ritonavir and copovidone, in terms of their impact on release, phase behavior and stabilization of amorphous precipitates formed following drug release. METHODS: Ternary ASDs with ritonavir, copovidone and surfactants (30:70:5 w/w/w) were prepared by rotary evaporation. ASD release performance was tested using Wood's intrinsic dissolution rate apparatus and compared to the binary drug-polymer ASD with 30% drug loading. Size measurement of amorphous droplets was performed using dynamic light scattering. Solid state characterization was performed using attenuated total reflectance-infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy. RESULTS: All surfactant-containing ASDs showed improvement over the binary ASD. Span 85 and D-α-tocopheryl polyethylene glycol succinate (TPGS) showed complete release with no evidence of AAPS or crystallization whereas Span 20 and Tween 80 showed < 50% release with amorphous amorphous phase separation (AAPS). Span 20 also induced solution crystallization. Sodium dodecyl sulfate (SDS) showed very rapid, albeit incomplete (~ 80%) release. AAPS was not observed with SDS. However, crystallization on the dissolving solid surface was noted. Span 20 and TPGS formed the smallest and most size-stable droplets with ~ 1 µm size whereas coalescence was noted with other surfactants. CONCLUSIONS: Surfactants improved the release performance relative to the binary ASD. Different surfactant types impacted overall performance to varying extents and affected different attributes. Overall, Span 85 showed best performance (complete release, no crystallization/AAPS and small droplet size). Correlation between physicochemical properties and surfactant performance was not observed.

Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

OBJECTIVE: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. METHODS: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. RESULTS: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. INTERPRETATION: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.

Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performance.

Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.

Insights into the Dissolution Behavior of Ledipasvir-Copovidone Amorphous Solid Dispersions: Role of Drug Loading and Intermolecular Interactions.

The generation of a colloidal drug-rich phase by dissolving an amorphous solid dispersion (ASD) is thought to have a positive impact on oral absorption and bioavailability. Thus, understanding which formulations generate these species is important. In this study, ledipasvir-copovidone ASDs, with and without surfactants, were prepared, and their release performance was examined at different drug loadings. An intrinsic dissolution rate assembly was used to limit potential surface area variations among formulations, and the release of both polymer and drug was monitored as a function of time. Drug-rich colloids only formed when the drug loading (DL) was at or below 5%; at a DL of 7.5% or above, drug release became negligible. The drug and polymer released congruently at and below 5% DL and incongruently at higher DLs. Thus, the limit of congruency (LoC) is between 5 and 7.5% DL. X-ray photoelectron spectroscopy (XPS) of partially dissolved tablet surfaces revealed that a drug-rich layer formed on the surface of the tablet. This was most evident for the higher DL ASDs and led to amorphous drug-controlled dissolution. Consequently, the surface drug-enriched layer physically hindered the polymer from further release. Evidence is provided that the extent of drug-polymer interactions as a function of DL plays a central role in dictating the observed release behavior. Some surfactants were found to promote the formation of drug-rich colloids at considerably higher DLs, providing a formulation strategy to increase the LoC.

Insights into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance.

The aim of this study was to probe the dissolution mechanisms of amorphous solid dispersions (ASDs) of a poorly water-soluble drug formulated with a hydrophilic polymer. Ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) were used as the model drug and polymer, respectively. ASDs with drug loadings (DLs) from 10 to 50 wt % were prepared by solvent evaporation. Surface-normalized dissolution experiments were carried out using Wood's intrinsic dissolution apparatus, and both drug and polymer release were quantified. ASDs at or below 25% DL showed rapid, complete, and congruent (i.e., simultaneous) release of the drug and polymer with dissolution rates similar to that of the polymer alone. The highest drug loading at which congruent release was observed is termed the limit of congruency (LoC) and occurred at 25% DL for RTV-PVPVA. The ASD with 30% DL showed an initial lag time, followed by a period of congruent release. At later times, the release of drug and polymer became incongruent with polymer releasing faster than drug. Higher DL ASDs (40 and 50%) showed slow release of both drug and polymer, whereby the drug release rate was similar to that of the neat amorphous drug. In cases where the release of the ASD components was congruent or close to congruent, the drug concentration exceeded the amorphous solubility, and liquid-liquid phase separation (LLPS) occurred with the formation of colloidal, drug-rich species. Solid state analyses of the ASD tablet surface by infrared spectroscopy and scanning electron microscopy revealed that the partially dissolved tablet surface remains smooth, and drug-polymer miscibility is retained at low DLs; whereas, at a very high DL, the surface is porous and enriched with amorphous drug. In concert, these observations suggest that ASD dissolution and drug release at low DLs is governed primarily by hydrophilic polymer; whereas, at high DLs, amorphous drug controls dissolution. Fluorescence microscopy images of thin ASD films suggested that ASDs at or below the LoC remain homogeneous even after exposure to water. In contrast ASDs with DL above LoC undergo, to various extents, water-induced amorphous-amorphous phase separation (AAPS) leading to demixing of the drug and polymer. Correlating the observations of the dissolution study with the solid state data suggest that the ASDs with DLs higher than the LoC undergo AAPS in the hydrating matrix on the surface of the dissolving solid during dissolution, leading to separation of drug and polymer, the formation of a drug-rich interface, and hence, incongruent and/or slow release of the components. In contrast, low DL ASDs dissolve before AAPS occurs. The competition between these two parallel and competing processes on the surface of ASD solids, i.e., dissolution and AAPS, thus dictates the overall release characteristics of the ASD formulations, which is one of the most important considerations in designing formulations with superior dissolution and absorption.

Relationship between amorphous solid dispersion in vivo absorption and in vitro dissolution: phase behavior during dissolution, speciation, and membrane mass transport.

Enzalutamide is a fast crystallizing, hydrophobic compound that has solubility limited absorption in vivo. Given the low aqueous solubility of this compound, it was of interest to evaluate amorphous formulations in vitro and in vivo. Amorphous solid dispersions (ASD) of enzalutamide were prepared with the hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone (PVPVA). A side-by-side diffusion cell was developed as an in vitro characterization tool to discriminate enzalutamide ASDs based upon the solute thermodynamic activity achieved during dissolution and its impact on the subsequent membrane transport rates, phase behavior, and drug speciation. The same formulations were then tested in vivo in rats using oral dosing of ASD suspensions. Different levels of plasma exposure were observed between the ASDs, which could be correlated to the phase behaviors of the ASDs following dissolution. Unsurprisingly, ASDs that underwent crystallization show lower plasma exposures. However, differences were also observed between ASDs that dissolved to form nanosized amorphous drug aggregates versus those that dissolved to yield only supersaturated solutions, with the former outperforming the latter in terms of the plasma exposure. These observations highlight the importance of thoroughly understanding the phase behavior of an amorphous formulation following dissolution and the need to discriminate between different types of precipitation, specifically crystallization versus glass liquid phase separation to form nanosized amorphous aggregates.

Co-crystals of caffeine and hydroxy-2-naphthoic acids: unusual formation of the carboxylic acid dimer in the presence of a heterosynthon.

A group of caffeine-containing co-crystals of hydroxy-2-naphthoic acids were synthesized and analyzed via single-crystal X-ray diffraction and IR analysis. The imidazole-carboxylic acid synthon was observed in co-crystals involving 1-hydroxy-2-naphthoic and 3-hydroxy-2-naphthoic acid. In the case of 6-hydroxy-2-naphthoic acid, the co-crystal exhibits a hydrogen-bonded carboxylic acid dimer in the presence of a hydroxyl-caffeine heterosynthon.

Efficient co-crystal screening using solution-mediated phase transformation.

We have extended the established physical stability treatment for hydrates/solvates to co-crystals with solid co-crystal formers. Based on the proposed treatment, a suspension/slurry screening technique is developed and tested in sixteen pharmaceutical co-crystal systems with success. The theoretical treatment and the practical screening technique should benefit the researchers in the field of co-crystallization in improving the screening efficiency.

A "hidden" co-crystal of caffeine and adipic acid.

Co-crystal formation between caffeine and adipic acid has been explored over the years without success; utilizing the newly developed co-crystal screening method, we have finally discovered this "hidden" caffeine and adipic acid co-crystal.