REMA: A Rich Elastic Mixed Attention Module for Single Image Super-Resolution.

Detail preservation is a major challenge for single image super-resolution (SISR). Many deep learning-based SISR methods focus on lightweight network design, but these may fall short in real-world scenarios where performance is prioritized over network size. To address these problems, we propose a novel plug-and-play attention module, rich elastic mixed attention (REMA), for SISR. REMA comprises the rich spatial attention module (RSAM) and the rich channel attention module (RCAM), both built on Rich Structure. Based on the results of our research on the module's structure, size, performance, and compatibility, Rich Structure is proposed to enhance REMA's adaptability to varying input complexities and task requirements. RSAM learns the mutual dependencies of multiple LR-HR pairs and multi-scale features, while RCAM accentuates key features through interactive learning, effectively addressing detail loss. Extensive experiments demonstrate that REMA significantly improves performance and compatibility in SR networks compared to other attention modules. The REMA-based SR network (REMA-SRNet) outperforms comparative algorithms in both visual effects and objective evaluation quality. Additionally, we find that module compatibility correlates with cardinality and in-branch feature bandwidth, and that networks with high effective parameter counts exhibit enhanced robustness across various datasets and scale factors in SISR.

Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder.

Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.

Application of melt granulation technology using twin-screw extruder in development of high-dose modified-release tablet formulation.

Development of modified-release oral tablets of drug products usually requires release-modifying polymers at the level of above 50% of the total weight. This makes the development of high-dose products, especially with doses in the range of 750-1000 mg, difficult because the tablet size becomes unacceptably high. This report presents the development of high-dose modified-release formulation of an active pharmaceutical ingredient (API), imatinib mesylate, with a drug load of approximately 90%, by melt granulation using a twin-screw extruder. For an 800 mg dose, 956 mg of drug substance (salt) was needed and the final weight of tablet was approximately 1074 mg. By carefully selecting polymers based on their physicochemical properties, the release rate could be modified between desired times of 4 to >10 h for the total drug release. Mixtures of API and polymer were melt granulated at 185 °C, which is below the melting point of API (212 °C) but above the glass transition temperatures of polymers used. The confocal Raman microscopic imaging revealed that the API remained as unmelted, crystalline particles, and polymers were finely distributed on the surface and in between API particles. The formulations were found to be robust as no change in tableting and drug release properties was observed when manufacturing parameters were altered to challenge the process. The in vivo modified-release properties of formulations were demonstrated in human pharmacokinetic studies.

Application of melt granulation technology to enhance tabletting properties of poorly compactible high-dose drugs.

Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug-polymer-powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C). MG was compared with modified wet granulation (WG) and solvent granulation (SG) processes. Under identical compression force, the hardness of tablets produced was MG>SG>WG and the friability was MG

Phase behavior of amorphous molecular dispersions II: Role of hydrogen bonding in solid solubility and phase separation kinetics.

PURPOSE: To determine the factors influencing "solid solubility" and phase separation kinetics of drugs from amorphous solid dispersions. METHODS: Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single Tg were exposed to 40 degrees C/69% RH for 90 days. Drug solid solubility in the polymer and phase separation rates were determined from changes in Tg of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively. RESULTS: Freshly prepared solid dispersion of up to 30% w/w griseofulvin and indoprofen were molecularly miscible with PVP. Hydrogen bonding was evident in indoprofen-PVP, but not in griseofulvin-PVP dispersions. When exposed to 40 degrees C/69% RH, griseofulvin phase separated completely, whereas the solid solubility of indoprofen was determined as 13% w/w. The first-order rate constants of phase separation for 10%. 20%, and 30% w/w griseofulvin dispersions were estimated as 4.66, 5.19, and 12.50 (x10(2)) [day(-1)], and those of 20% and 30% w/w indoprofen dispersions were 0.62 and 1.25 (x10(2)) [day(-1)], respectively. CONCLUSIONS: Solid solubility of griseofulvin and indoprofen in PVP is approximately 0% w/w and approximately 13% w/w, respectively. Drug-polymer hydrogen bonding in indoprofen-PVP dispersions favors solid solubility. Phase separation rate of drug from the solid dispersions depends on the initial drug content and the nature of drug-polymer interactions.

Phase behavior of amorphous molecular dispersions I: Determination of the degree and mechanism of solid solubility.

PURPOSE: To understand the phase behavior and the degree and mechanism of the solid solubility in amorphous molecular dispersions by the use of thermal analysis. METHODS: Amorphous molecular dispersions of trehalose-dextran and trehalose-PVP were prepared by co-lyophilization. The mixtures were exposed to 23 degrees C, 40 degrees C, and 50 degrees C [75% relative humidity (RH)] and 23 degrees C (69% RH) storage conditions, respectively. Thermal analysis was conducted by modulated differential scanning calorimeter (MDSC). RESULTS: Upon exposure to moisture, two glass transition temperatures (TgS), one for phase-separated amorphous trehalose (Tg1) and the other for polymer-trehalose mixture (Tg2), were observed. With time, Tg2 increased and reached to a plateau (Tg(eq)), whereas Tg1 disappeared. The disappearance of Tg1 was attributed to crystallization of the phase-separated amorphous trehalose. It was observed that Tg(eq) was always less than Tg of pure polymer. The lower Tg(eq) when compared to Tg of pure polymer may be the result of solubility of a fraction of trehalose in the polymers chosen. The miscible fraction of trehalose was estimated to be 12% and 18% wt/wt in dextran at 50 degrees C/75% RH and 23 degrees C/75% RH, respectively, and 10% wt/wt in PVP at 23 degrees C/69% RH. CONCLUSIONS: Mixing behavior of trehalose-dextran and trehalose-PVP dispersions were examined both experimentally and theoretically. A method determining the "extent of molecular miscibility," referred to as "solid solubility," was developed and mechanistically and thermodynamically analyzed. Solid dispersions prepared at trehalose concentrations below the "solid solubility limit" were physically stable even under accelerated stability conditions.

Impact of solid state properties on developability assessment of drug candidates.

Solid state properties including polymorphism, solvate and salt formation can have a profound impact on two of the most important properties that are essential to the successful development of drug candidates: solubility and stability. To enable meaningful evaluations of drug candidates for their development risks, often referred to as developability, and provide input to the molecular design regarding the "drug-like" properties, one must take into account the impact of solid state properties on solubility and stability. This review examines the importance of solid state properties and their relationship to developability criteria. Phase appropriate characterization strategies and appropriate salt and crystal form screening and selection processes are discussed. These strategies and processes should balance the need for speed and throughput of modern discovery with the quality of data essential to the adequate developability assessment. Specific examples are given to illustrate the importance of understanding the solid state properties and their impact on developability.