Molecular complexes of drug combinations: A review of cocrystals, salts, coamorphous systems and amorphous solid dispersions.

As the advancements in the medical technology and healthcare develop through the years, combinational therapy has evolved to be an important treatment modality in many disease settings, including cancer, cardiovascular disease and infectious diseases. In an effort to alleviate "pill burden" and improve patient compliance, fixed dose combinations (FDCs) have been developed to be used as effective therapeutics. Among all FDCs, the category of drug-drug molecular complexes has been proven an efficient methodology in designing and treating diseases, with many drugs being approved. Among all drug-drug molecular complexes, drug-drug cocrystals, salts, coamorphous systems and solid dispersions have been successfully developed and many have been approved by the FDA. In this review, we dwell deeply into the molecular mechanisms behind the different types of drug-drug molecular complexes, including the key functional groups involved in the intermolecular interactions, the applications of each category of molecular complexes, as well as the advantages and challenges thereof. This comprehensive review provides useful insights into the practical design and manufacture of drug-drug molecular complexes and points out the future direction for the development of new advantageous combinational therapies that benefit more patients.

Urinary Nickel Was Associated with the Prevalence of Diabetes: Results from NHANES.

The study aimed to investigate the association between nickel exposure and the presence of diabetes (DM). The participants were analyzed from the National Health and Nutrition Examination Surveys (NHANES) 2017-2018. Urinary nickel exposure was measured using inductively coupled-plasma mass spectrometry. DM was diagnosed based on the WHO standards. The association between nickel and DM or fasting glucose was examined using multivariable linear regression models and logistic regression models. A total of 1899 participants (933 men and 966 women) were included in our study, of whom 342 (18.0%) were diagnosed with DM. There was a significant positive association between nickel level and DM (OR: 1.27, 95%CI: 1.04-1.56) after adjusting for potential confounding factors. Comparing with the lowest quartile, the highest quartile independently increased a 0.66-fold higher risk of DM (OR: 1.66, 95%CI: 1.13-2.44]). In addition, nickel exposure was independently related to the level of fasting glucose. The exposure to nickel was associated with a higher risk of DM in general population.

The clinical characteristics of Chinese elderly patients with different durations of type 2 diabetes mellitus.

Aims: To explore the clinical characteristics among elderly (aged ≥60 years) patients with type 2 diabetes (T2DM) of different durations. Methods: Clinical characteristics were investigated in 3840 elderly T2DM patients according to their different durations of diabetes (< 1 year, 1~5 years, 5~10 years, and ≥ 10 years). Kruskal-Wallis and Dunn tests were used to assess the differences among groups for continuous variables. The chi-square and post hoc tests were carried out for dichotomous variables. The logistic regression was adopted to investigate the relationships between various durations of diabetes and the control rates of achieving the control targets for T2DM as well as diabetic vascular complications. Results: There were 972, 896, 875 and 1097 patients with a duration of diabetes of <1, 1~5, 5~10 and ≥10 years, respectively. In logistic regression models adjusted for age, sex, education, BMI, smoking and family history of diabetes, elderly T2DM patients with a duration of diabetes of ≥10 years were more likely to reach the comprehensive control targets for TC (ORTC = 1.36, 95% CI =1.14-1.63), LDL-C (ORLDL-C = 1.39, 95% CI =1.17-1.66), TG (ORTG = 1.76, 95% CI =1.46-2.12) and BMI (ORBMI = 1.82, 95% CI =1.52-2.18). Elderly T2DM patients with a duration of diabetes of 1~5 years were more likely to achieve the HbA1c control target (ORHbA1c = 1.92, 95% CI = 1.59-2.31) than elderly T2DM patients with a duration of diabetes of <1 year. Furthermore, in elderly T2DM patients with a duration of diabetes of 5~10 years or ≥ 10 years, the duration of diabetes was positively associated with diabetic macrovascular complications (coronary heart disease and peripheral artery disease). In elderly T2DM patients with a duration of diabetes of over 10 years, the duration of diabetes was associated with diabetes kidney disease (all P < 0.05). Conclusions: It is worth noting that the clinical characteristics of elderly patients with type 2 diabetes in different durations of diabetes are different.

Direct compression tablet formulation of celecoxib enabled with a pharmaceutical solvate.

Celecoxib, an anti-inflammatory drug for pain and arthritis, is currently only available in capsule form. To reduce the onset time for a faster action and to lower the manufacturing cost, the tablet dosage form is more preferred. However, the commercial celecoxib (Form III) is not suitable for direct compression (DC) tablet manufacture due to poor flow, low bulk density, and tablet lamination. In this work, we overcome these challenges using a pharmaceutically acceptable dimethyl sulfoxide (DMSO) solvate of celecoxib. Aided with the DMSO solvate, an acceptable DC tablet formulation was successfully developed to manufacture tablets containing 200 mg celecoxib, with satisfactory manufacturability, disintegration, and in vitro dissolution performance.

The achievement of comprehensive control targets among type 2 diabetes mellitus patients of different ages.

OBJECTIVE: To evaluate achievement of comprehensive controls among patients with type 2 diabetes mellitus (T2DM) in different age groups. RESULTS: The elderly patients had higher control rates for BMI (44.36%), TC (50.83%) and LDL-C (48.27%) than those aged 60-80 years and younger patients (all P <0.05). Multiple logistic regression revealed that elderly patients were more likely to achieve control targets for HbA1c (odd ratio (OR) = 2.19), TC (OR = 1.32), HDL-C (OR = 1.35), and TG (OR = 1.74) than younger patients. This effect was stronger in males (ORHbA1c = 2.27; ORTC = 1.41; ORHDL-C = 1.51; ORTG = 1.80). By contrast, elderly females were only more likely to achieve HbA1c < 7.0% (OR=1.88). CONCLUSIONS: Our findings suggest that comprehensive control strategies still should be strengthened. METHODS: A total of 3126 T2DM patients were included, and detected blood pressure (BP), body mass index (BMI), glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C). We divided patients into three age groups (<60, 60-80 and ≥ 80 years), to assess the differences in achieving the control targets.

Reduction of Punch-Sticking Propensity of Celecoxib by Spherical Crystallization via Polymer Assisted Quasi-Emulsion Solvent Diffusion.

Punch-sticking during tablet compression is a common problem for many active pharmaceutical ingredients (APIs), which renders tablet formulation development challenging. Herein, we demonstrate that the punch-sticking propensity of a highly sticky API, celecoxib (CEL), can be effectively reduced by spherical crystallization enabled by a polymer assisted quasi-emulsion solvent diffusion (QESD) process. Among three commonly used pharmaceutical polymers, poly(vinylpyrrolidone) (PVP), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC), HPMC was the most effective in stabilizing the transient emulsion during QESD and retarding the coalescence of emulsion droplets and the initiation of CEL crystallization. These observations may arise from stronger intermolecular interactions between HPMC and CEL, consistent with solution 1H NMR analyses. SEM and X-ray photoelectron spectroscopy confirmed the presence of a thin layer of HPMC on the surfaces of spherical particles. Thus, the sticking propensity was significantly reduced because the HPMC coating prevents direct contact between CEL and the punch tip during tablet compression.

Reduced Punch Sticking Propensity of Acesulfame by Salt Formation: Role of Crystal Mechanical Property and Surface Chemistry.

Powder adhesion or sticking onto punches is one of the outstanding issues in pharmaceutical tablet manufacturing. We show in this work that, at comparable particle sizes, the acesulfame potassium exhibited pronouncedly reduced propensity to punch sticking than acesulfame. Detailed analyses revealed strong correlation between sticking propensity and crystal mechanical properties and surface chemistry. The free acid was highly plastic with high cohesive strength, while the salt form was brittle. During compaction, surfaces of acesulfame in contact with the punch face are abundant in electronegative functional groups, while those of the salt consist of mainly hydrophobic groups. Thus, acesulfame underwent stronger interactions with the electron-deficient punch. Consequently, the strikingly different onset and severity of sticking propensity between the two solid forms of acesulfame could be clearly explained based on their different crystal mechanical properties and surface characteristics. By providing molecular insight into the outstanding problem of punch sticking in tablet manufacturing, this work expands the list of pharmaceutical applications of crystal engineering.

Association of Thyroid Function With the Estimated Glomerular Filtration Rate in a Large Chinese Euthyroid Population.

BACKGROUND/AIMS: We aimed to explore whether thyroid function within a normal range is associated with the estimated glomerular filtration rate (eGFR) and the incidence of chronic kidney disease (CKD) in a large Chinese population. METHODS: We conducted a cross-sectional study that included 10,859 euthyroid individuals who underwent an annual regular health checkup in Jiangsu Province Official Hospital between August 2012 and August 2013. We measured the thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels using a Roche modular analytics E170 and then calculated the eGFR using the Chinese modified Modification of Diet in Renal Disease (CMDRD) equation. RESULTS: In multiple linear regression models, TSH was negatively associated with eGFR after adjusting for confounding factors (ß = -0.072, P = 1.994×10-22). The significance remained in both males and females. No significant association was observed between FT4 and eGFR. In the logistic regression model, we did not observe significant associations of TSH or FT3 with CKD. Participants in the highest quartile of FT4 versus the lowest quartile (reference) had an increased risk of CKD (OR = 1.763, P = 0.012). The risk of CKD was more pronounced in females with the highest quartile of FT4 (OR = 2.424, P = 0.029). CONCLUSION: Our findings suggest that TSH is associated with eGFR in euthyroid individuals and that higher FT4 is associated with an increased risk of CKD. More cohort studies are warranted to confirm whether the association is causal.

Comparative analyses of flow and compaction properties of diverse mannitol and lactose grades.

Appropriate selection of excipient grade during tablet formulation development depends on thorough knowledge in their compaction and flow properties. Each chemically unique pharmaceutical excipient is usually available in several commercial grades that are widely different in powder properties, which influence their performance for a specific formulation application. In this work, 11 grades of mannitol were systematically characterized, in terms of their particulate, flow and tableting properties, and compared against 5 grades of lactose. Principal component analysis (PCA) identified significant correlations among selected variables, such as particle size, surface area, flowability, wall friction, plasticity parameter, tensile strength, and tablet brittleness. PCA also revealed similar grades of the two excipients, which may be used to select replacement grade, if needed, based on similarity in their overall properties.

Dependence of Punch Sticking on Compaction Pressure-Roles of Particle Deformability and Tablet Tensile Strength.

Punch sticking is a complex phenomenon influenced primarily by particle size, tooling surface roughness, tooling design, and tooling construction material. When particle and environmental factors are controlled, compaction pressure has a distinct effect on punch sticking behavior for a given active pharmaceutical ingredient (API). This research focuses on the effect of compaction pressure on punch sticking using 5 compounds with different sticking propensities. The results collectively show that sticking tends to be more problematic under higher compaction pressures and for more ductile compounds. This is attributed to the greater punch surface coverage by the API and the stronger cohesion of API to the existing API layer on the punch.

Single-layer nanosheets with exceptionally high and anisotropic hydroxyl ion conductivity.

When the dimensionality of layered materials is reduced to the physical limit, an ultimate two-dimensional (2D) anisotropy and/or confinement effect may bring about extraordinary physical and chemical properties. Layered double hydroxides (LDHs), bearing abundant hydroxyl groups covalently bonded within 2D host layers, have been proposed as inorganic anion conductors. However, typical hydroxyl ion conductivities for bulk or lamellar LDHs, generally up to 10-3 S cm-1, are considered not high enough for practical applications. We show that single-layer LDH nanosheets exhibited exceptionally high in-plane conductivities approaching 10-1 S cm-1, which were the highest among anion conductors and comparable to proton conductivities in commercial proton exchange membranes (for example, Nafion). The in-plane conductivities were four to five orders of magnitude higher than the cross-plane or cross-membrane values of restacked LDH nanosheets. This 2D superionic transport characteristic might have great promises in a variety of applications including alkaline fuel cells and water electrolysis.

Recent Developments in Graphene-Based Membranes: Structure, Mass-Transport Mechanism and Potential Applications.

Significant achievements have been made on the development of next-generation filtration and separation membranes using graphene materials, as graphene-based membranes can afford numerous novel mass-transport properties that are not possible in state-of-art commercial membranes, making them promising in areas such as membrane separation, water desalination, proton conductors, energy storage and conversion, etc. The latest developments on understanding mass transport through graphene-based membranes, including perfect graphene lattice, nanoporous graphene and graphene oxide membranes are reviewed here in relation to their potential applications. A summary and outlook is further provided on the opportunities and challenges in this arising field. The aspects discussed may enable researchers to better understand the mass-transport mechanism and to optimize the synthesis of graphene-based membranes toward large-scale production for a wide range of applications.

High Detectivity Graphene-Silicon Heterojunction Photodetector.

A graphene/n-type silicon (n-Si) heterojunction has been demonstrated to exhibit strong rectifying behavior and high photoresponsivity, which can be utilized for the development of high-performance photodetectors. However, graphene/n-Si heterojunction photodetectors reported previously suffer from relatively low specific detectivity due to large dark current. Here, by introducing a thin interfacial oxide layer, the dark current of graphene/n-Si heterojunction has been reduced by two orders of magnitude at zero bias. At room temperature, the graphene/n-Si photodetector with interfacial oxide exhibits a specific detectivity up to 5.77 × 10(13) cm Hz(1/2) W(-1) at the peak wavelength of 890 nm in vacuum, which is highest reported detectivity at room temperature for planar graphene/Si heterojunction photodetectors. In addition, the improved graphene/n-Si heterojunction photodetectors possess high responsivity of 0.73 A W(-1) and high photo-to-dark current ratio of ≈10(7) . The current noise spectral density of the graphene/n-Si photodetector has been characterized under ambient and vacuum conditions, which shows that the dark current can be further suppressed in vacuum. These results demonstrate that graphene/Si heterojunction with interfacial oxide is promising for the development of high detectivity photodetectors.

Intrinsic high water/ion selectivity of graphene oxide lamellar membranes in concentration gradient-driven diffusion.

Although graphene oxide lamellar membranes (GOLMs) are effective in blocking large organic molecules and nanoparticles for nanofiltration and ultrafiltration, water desalination with GOLM is challenging, with seriously controversial results. Here, a combined experimental and molecular dynamics simulation study shows that intrinsic high water/ion selectivity of GOLM was achieved in concentration gradient-driven diffusion, showing great promise in water desalination. However, in pressure-driven filtration the salt rejection was poor. This study unveils a long-overlooked reason behind the controversy in water desalination with GOLM and further provides a fundamental understanding on the in-depth mechanism concerning the strong correlation of water/ion selectivity with the applied pressure and GO nanochannel length. Our calculations and experiments show that the applied pressure weakened the water-ion interactions in GO nanochannels and reduced their permeation selectivity, while the length of nanochannels dominated the mass transport processes and the ion selectivity. The new insights presented here may open up new opportunities for the optimization of GOLMs in this challenging area.

Perovskite solar cell using a two-dimensional titania nanosheet thin film as the compact layer.

The compact layer plays an important role in conducting electrons and blocking holes in perovskite solar cells (PSCs). Here, we use a two-dimensional titania nanosheet (TNS) thin film as the compact layer in CH3NH3PbI3 PSCs. TNS thin films with thicknesses ranging from 8 to 75 nm were prepared by an electrophoretic deposition method from a dilute TNS/tetrabutylammonium hydroxide solution. The TNS thin films contact the fluorine-doped tin oxide grains perfectly. Our results show that a 8-nm-thick TNS film is sufficient for acting as the compact layer. Currently, the PSC with a TNS compact layer has a high efficiency of 10.7% and relatively low hysteresis behavior.

Role of hydrogen in the chemical vapor deposition growth of MoS2 atomic layers.

Hydrogen plays a crucial role in the chemical vapor deposition (CVD) growth of graphene. Here, we have revealed the roles of hydrogen in the two-step CVD growth of MoS2. Our study demonstrates that hydrogen acts as the following: (i) an inhibitor of the thermal-induced etching effect in the continuous film growth process; and (ii) a promoter of the desulfurization reaction by decreasing the S/Mo atomic ratio and the oxidation reaction of the obtained MoSx (0 < x < 2) films. A high hydrogen content of more than 100% in argon forms nano-sized circle-like defects and damages the continuity and uniformity of the film. Continuous MoS2 films with a high crystallinity and a nearly perfect S/Mo atomic ratio were finally obtained after sulfurization annealing with a hydrogen content in the range of 20%-80%. This insightful understanding reveals the crucial roles of hydrogen in the CVD growth of MoS2 and paves the way for the controllable synthesis of two-dimensional materials.

Graphene/polyaniline woven fabric composite films as flexible supercapacitor electrodes.

We report the design and preparation of graphene and polyaniline (PANI) woven-fabric composite films by in situ electropolymerization. The introduction of PANI greatly improves the electrochemical properties of solid-state supercapacitors which possess capacitances as high as 23 mF cm(-2), and exhibit excellent cycling stability with ∼ 100% capacitance retention after 2000 cycles. The devices have displayed superior flexibility with improved areal specific capacitances to 118% during deformation.

All carbon coaxial supercapacitors based on hollow carbon nanotube sleeve structure.

All carbon coaxial supercapacitors based on hollow carbon nanotube (CNT) sleeve structure are assembled and tested. The key advantage of the structure is that the inner core electrode is variable from CNT sleeve sponges, to CNT fibers, reduced graphene oxide fibers, and graphene woven fabrics. By changing core electrodes from sleeve sponges to CNT fibers, the electrochemical performance has been significantly enhanced. The capacitance based on sleeve sponge + CNT fiber double the capacitances of double-sleeve sponge supercapacitors thanks to reduction of the series and internal resistances. Besides, the coaxial sleeve structure possesses many other features, including high rate capacitance, long cycle life, and good flexibility.

Ultrafast liquid water transport through graphene-based nanochannels measured by isotope labelling.

Based on isotope labelling, we found that liquid water can afford an ultrafast permeation through graphene-based nanochannels with a diffusion coefficient 4-5 orders of magnitude greater than in the bulk case. When dissolving ions in sources, the diffusion coefficient of ions through graphene channels lies in the same order of magnitude as water, while the ion diffusion is slightly faster than water, indicating that the ions are mainly transported by water flows and the delicate interactions between ions and nanocapillary walls also take effect in the accelerated ion transportation.

Structure evolution of graphene oxide during thermally driven phase transformation: is the oxygen content really preserved?

A mild annealing procedure was recently proposed for the scalable enhancement of graphene oxide (GO) properties with the oxygen content preserved, which was demonstrated to be attributed to the thermally driven phase separation. In this work, the structure evolution of GO with mild annealing is closely investigated. It reveals that in addition to phase separation, the transformation of oxygen functionalities also occurs, which leads to the slight reduction of GO membranes and furthers the enhancement of GO properties. These results are further supported by the density functional theory based calculations. The results also show that the amount of chemically bonded oxygen atoms on graphene decreases gradually and we propose that the strongly physisorbed oxygen species constrained in the holes and vacancies on GO lattice might be responsible for the preserved oxygen content during the mild annealing procedure. The present experimental results and calculations indicate that both the diffusion and transformation of oxygen functional groups might play important roles in the scalable enhancement of GO properties.