Application of Population Balance Model to Simulate Precipitation of Weak Base and Zwitterionic Drugs in Gastrointestinal pH Environment.

The purpose of the present study was to evaluate whether the population balance model (PBM) could be a suitable model for the precipitation of weak base and zwitterionic drugs in the gastrointestinal pH environment. Five poorly soluble drugs were used as model drugs (dipyridamole, haloperidol, papaverine, phenazopyridine, and tosufloxacin). PBM consists of the equations for primary nucleation, secondary nucleation, and particle growth. Each equation has two empirical parameters. The pH shift (pH-dumping) precipitation test (pH 3.0 to 6.5) was used to determine the model parameters for each drug. It was difficult to determine all six parameters by simultaneously fitting them to the precipitation profiles. Therefore, the number of model parameters was reduced from six to three by neglecting the secondary nucleation process and applying a common exponent number for the particle growth equation. Despite reducing the parameter number, PBM appropriately described the precipitation profiles in the pH shift tests. The constructed PBM model was then used to predict the precipitation profiles in an artificial stomach-intestine transfer (ASIT) test. PBM appropriately predicted the precipitation profiles in the ASIT test. These results suggested that PBM can be a suitable model to represent the precipitation of weak base and zwitterionic drugs in the gastrointestinal pH environment for biopharmaceutics modeling and simulation.

The Role of Bioinformatics and Imaging Models in Tumorigenesis and Treatment Response of Brain and Spinal Cord Neoplasm.

This chapter focuses on the division and location of brain deformities such as tumors in magnetic resonance imaging (MRI) through Chan-Vese active contour segmentation. Brain tumor division and identification is a major test in the area of biomedical picture processing. To detect the size and location of the tumor, various techniques are available, but active contour gives accurate knowledge of the region for segmentation. Chan-Vese Active contour method provides independent, robust and more flexible segmentation. In this chapter, firstly we used preprocessing technique in which noise and unused parts of the brain and skull are removed, for this we proposed the skull stripping method. Then, we applied feature extraction to enhance the image intensity and quality, and lastly, used Chan-Vese active contour with a level set image segmentation technique to detect the tumor. The tumor area was calculated after tumor detection.

Noniridescent Biomimetic Photonic Microdomes by Inkjet Printing.

Certain bird species have evolved spectacular colors that arise from organized nanostructures of melanin. Its high refractive index (∼1.8) and broadband absorptive properties enable vivid structural colors that are nonsusceptible to photobleaching. Mimicking natural melanin structural coloration could enable several important applications, in particular, for noniridescent systems with colors that are independent of incidence angle. Here, we address this by forming melanin photonic crystal microdomes by inkjet printing. Owing to their curved nature, the microdomes exhibit noniridescent vivid structural coloration, tunable throughout the visible range via the size of the nanoparticles. Large-area arrays (>1 cm2) of high-quality photonic microdomes could be printed on both rigid and flexible substrates. Combined with scalable fabrication and the nontoxicity of melanin, the presented photonic microdomes with noniridescent structural coloration may find use in a variety of applications, including sensing, displays, and anticounterfeit holograms.

Mechanochromic and Thermochromic Sensors Based on Graphene Infused Polymer Opals.

High quality opal-like photonic crystals containing graphene are fabricated using evaporation-driven self-assembly of soft polymer colloids. A miniscule amount of pristine graphene within a colloidal crystal lattice results in the formation of colloidal crystals with a strong angle-dependent structural color and a stop band that can be reversibly shifted across the visible spectrum. The crystals can be mechanically deformed or can reversibly change color as a function of their temperature, hence their sensitive mechanochromic and thermochromic response make them attractive candidates for a wide range of visual sensing applications. In particular, it is shown that the crystals are excellent candidates for visual strain sensors or integrated time-temperature indicators which act over large temperature windows. Given the versatility of these crystals, this method represents a simple, inexpensive, and scalable approach to produce multifunctional graphene infused synthetic opals and opens up exciting applications for novel solution-processable nanomaterial based photonics.

Strategies to address low drug solubility in discovery and development.

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Non-channeled Video Laryngoscopy as an Alternative to Conventional Laryngoscopy for Intubating Adult Patients in the Intensive Care Unit.

Background Endotracheal intubation in the intensive care unit (ICU) is often a risky procedure due to the emergency situation, unstable condition of the patient, and technical problems such as inadequate positioning. Several new techniques, such as video laryngoscopy, have been developed recently to improve the success rate of first-pass intubations and reduce complications. We conducted this study to compare a non-channeled reusable video laryngoscope BPL VL-02 (manufactured by BPL Medical Technologies, Bangalore, India) with a conventional laryngoscope for intubation of adult patients in the ICU. Methodology A total of 72 ICU patients were randomly allocated to be intubated with either conventional direct laryngoscopy via Macintosh blade (group A) or video laryngoscopy with BPL VL-02 (group B). All patients were intubated by the primary investigator and the assistant noted the following parameters: the total number of intubation attempts, total duration of intubation, assistance or alternative technique required, Cormack Lehane grading, and any complications. Results There was no significant difference in the Cormack Lehane grading, number of attempts, or complications between the two groups. On comparing the assistance required during intubation in patients, it was observed that four (11.11%) patients in group A and seven (19.44%) patients in group B needed backward, upward, and rightward pressure on the larynx assistance during intubation. In five (13.89%) patients in group B, Stylet was required during intubation. The difference was statistically significant (p = 0.0308). The video laryngoscopy group (group B) had a longer mean duration of intubation (64.36 ± 6.28 seconds) compared to group A (45.72 ± 11.45 seconds), and the difference was statistically significant (p < 0.0001). Conclusions Non-channeled video laryngoscope (BPL VL-02) is not a suitable alternative to conventional direct laryngoscopy with a Macintosh blade in terms of successful first-pass intubation, total duration of intubation, and assistance required.

Simultaneous determination of five metabolites of nitrofurans including the metabolite nifursol in shrimp and fish by UPLC- MS/MS: in-house method validation according to commission implementing regulation (EU) 2021/808.

For the simultaneous identification and quantification of five nitrofurans metabolites in farmed shrimp and fish, 3-amino-2-oxazolidinone (AOZ), 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), 1-aminohydantoine (AHD), semicarbazide (SEM), and 3,5-dinitrosalicylic acid hydrazide (DNSH), an accurate, precise, and specific method was developed. The mixture of water and methanol (60/40; v/v) was found to be the final optimised solvent for injection. The analytical run duration was 7 min, and the mobile phase included 2 mM methanol and ammonium formate. The new reference point for action (RPA) of 0.50 µg kg-1 as per EC/1871/2019 was taken into consideration and evaluated for the performance characteristics as per the CIR (EC)/2021/808 criteria. Specificity, relative retention time (≤0.25%) relative ion ratio (≤40%), linearity (0.25 to 2.0 µg kg-1), trueness (between 82.8 and 118.1%), repeatability (RSDr ≤14%), within lab reproducibility (RSDwr ≤16.9%), CCα (0.32-0.36 µg kg-1), ruggedness and relative matrix effect (≤14.26%) achieved acceptable values.

Binary isobaric phase diagrams of stearyl alcohol-poloxamer 407 formulations in the molten and solid state.

Multiparticulate formulations allow for the design of specialized pharmaceutical dosage forms that cater to the needs of a wide range of patient demographics, such as pediatric and geriatric populations, by affording control over the release rate and facilitating the formulation of fixed-dose combination drugs. Melt spray-congealing (MSC) is a method for preparing multiparticulate dosage forms from a suspension or solid solution of active pharamaceutical ingredients (API) and a molten carrier matrix. Stearyl alcohol and poloxamer 407 mixtures are widely used as carrier matrices in MSC microsphere formulations. In this report, the phase equilibria of stearyl alcohol-poloxamer 407 mixtures were investigated by generating binary phase diagrams of composition, i.e. weight/weight percent of poloxamer 407 in stearyl alcohol, and temperature in the molten form and the solid state. The phase equilibria of the molten state were characterized by 1H NMR measurements. The miscibility curves of stearyl alcohol-poloxamer 407 molten mixtures revealed that stearyl alcohol and poloxamer 407 are not miscible in all proportions and that miscibility substantially increases with temperature. The phase equilibria of the solid state were characterized by DSC and PXRD experiments. The phase diagrams of the solid state indicate that stearyl alcohol and poloxamer 407 crystallize and melt separately and, thus, do not form a eutectic or a single phase. The phases equilibria of the bulk mixtures were compared to the phases observed in placebo MSC microspheres and it was determined that the microspheres consist of a mixture of thermodynamically stable and metastable stearyl alcohol crystals immediately after manufacture.

Aqueous solubility of crystalline and amorphous drugs: Challenges in measurement.

Measurement of drug solubility is one of the key elements of active pharmaceutical ingredient (API) characterization during the drug discovery and development process. This report is a critical review of experimental methods reported in the literature for the measurement of aqueous solubility of amorphous, partially crystalline and crystalline organic compounds. A summary of high-throughput automated methods used in early drug discovery research is also provided in this report. This review summarizes the challenges that are encountered during solubility measurement and the complexities that are often overlooked. Even though there is an advantage in using the amorphous form of a drug due to its higher solubility, measurement of its solubility with useful accuracy is still a practical problem. Therefore, this review provides recommendations of preferred methods and precautions in using these methods to determine the aqueous solubility of amorphous and crystalline new molecular entities, with emphasis on the physico-chemical characterization of the solid state of the test substance.

Dynamically Tuneable Reflective Structural Coloration with Electroactive Conducting Polymer Nanocavities.

Dynamic control of structural colors across the visible spectrum with high brightness has proven to be a difficult challenge. Here, this is addressed with a tuneable reflective nano-optical cavity that uses an electroactive conducting polymer (poly(thieno[3,4-b]thiophene)) as spacer layer. Electrochemical doping and dedoping of the polymer spacer layer provides reversible tuning of the cavity's structural color throughout the entire visible range and beyond. Furthermore, the cavity provides high peak reflectance that varies only slightly between the reduced and oxidized states of the polymer. The results indicate that the polymer undergoes large reversible thickness changes upon redox tuning, aided by changes in optical properties and low visible absorption. The electroactive cavity concept may find particular use in reflective displays, by opening for tuneable monopixels that eliminate limitations in brightness of traditional subpixel-based systems.

Photoresponsive and Polarization-Sensitive Structural Colors from Cellulose/Liquid Crystal Nanophotonic Structures.

Cellulose nanocrystals (CNCs) possess the ability to form helical periodic structures that generate structural colors. Due to the helicity, such self-assembled cellulose structures preferentially reflect left-handed circularly polarized light of certain colors, while they remain transparent to right-handed circularly polarized light. This study shows that combination with a liquid crystal enables modulation of the optical response to obtain light reflection of both handedness but with reversed spectral profiles. As a result, the nanophotonic systems provide vibrant structural colors that are tunable via the incident light polarization. The results are attributed to the liquid crystal aligning on the CNC/glucose film, to form a birefringent layer that twists the incident light polarization before interaction with the chiral cellulose nanocomposite. Using a photoresponsive liquid crystal, this effect can further be turned off by exposure to UV light, which switches the nematic liquid crystal into a nonbirefringent isotropic phase. The study highlights the potential of hybrid cellulose systems to create self-assembled yet advanced photoresponsive and polarization-tunable nanophotonics.

Tunable Structural Color Images by UV-Patterned Conducting Polymer Nanofilms on Metal Surfaces.

Precise manipulation of light-matter interactions has enabled a wide variety of approaches to create bright and vivid structural colors. Techniques utilizing photonic crystals, Fabry-Pérot cavities, plasmonics, or high-refractive-index dielectric metasurfaces have been studied for applications ranging from optical coatings to reflective displays. However, complicated fabrication procedures for sub-wavelength nanostructures, limited active areas, and inherent absence of tunability of these approaches impede their further development toward flexible, large-scale, and switchable devices compatible with facile and cost-effective production. Here, a novel method is presented to generate structural color images based on monochromic conducting polymer films prepared on metallic surfaces via vapor phase polymerization and ultraviolet (UV) light patterning. Varying the UV dose enables synergistic control of both nanoscale film thickness and polymer permittivity, which generates controllable structural colors from violet to red. Together with grayscale photomasks this enables facile fabrication of high-resolution structural color images. Dynamic tuning of colored surfaces and images via electrochemical modulation of the polymer redox state is further demonstrated. The simple structure, facile fabrication, wide color gamut, and dynamic color tuning make this concept competitive for applications like multifunctional displays.

Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals.

PURPOSE: To quantitatively assess the solubility advantage of amorphous forms of nine insoluble drugs with a wide range of physico-chemical properties utilizing a previously reported thermodynamic approach. METHODS: Thermal properties of amorphous and crystalline forms of drugs were measured using modulated differential calorimetry. Equilibrium moisture sorption uptake by amorphous drugs was measured by a gravimetric moisture sorption analyzer, and ionization constants were determined from the pH-solubility profiles. Solubilities of crystalline and amorphous forms of drugs were measured in de-ionized water at 25°C. Polarized microscopy was used to provide qualitative information about the crystallization of amorphous drug in solution during solubility measurement. RESULT: For three out the nine compounds, the estimated solubility based on thermodynamic considerations was within two-fold of the experimental measurement. For one compound, estimated solubility enhancement was lower than experimental value, likely due to extensive ionization in solution and hence its sensitivity to error in pKa measurement. For the remaining five compounds, estimated solubility was about 4- to 53-fold higher than experimental results. In all cases where the theoretical solubility estimates were significantly higher, it was observed that the amorphous drug crystallized rapidly during the experimental determination of solubility, thus preventing an accurate experimental assessment of solubility advantage. CONCLUSION: It has been demonstrated that the theoretical approach does provide an accurate estimate of the maximum solubility enhancement by an amorphous drug relative to its crystalline form for structurally diverse insoluble drugs when recrystallization during dissolution is minimal.

The mechanism of lymphatic access of two cholesteryl ester transfer protein inhibitors (CP524,515 and CP532,623) and evaluation of their impact on lymph lipoprotein profiles.

PURPOSE: To explore the mechanism of lymphatic access of the CETP inhibitors (CETPi) CP524,515 and CP532,623 and probe their potential effect on lymph lipoprotein development. METHODS: Lymphatic access mechanisms were examined via correlation of lymphatic drug transport profiles with drug affinity for lymph lipoproteins and drug solubility in representative combinations of lipoprotein lipids. The effects of the CETPi on lymph lipoprotein profiles were evaluated by ultracentrifugation and flow cytometry. RESULTS: Both CETPi were highly lymphatically transported (22-28% of dose), and lymphatic transport was closely correlated with drug affinity for ex-vivo lymph lipoproteins or triglyceride emulsions and poorly related to solubility in mixtures of lipoprotein core and/or surface lipids. Both CETPi altered the kinetics of lymph lipid transport and decreased lymph lipid transport in chylomicrons. CONCLUSION: Lymphatic transport of the CETPi appears to reflect high affinity for the interface of lymph lipoproteins rather than solubilisation in the lipoprotein core and confirms that triglyceride solubilities >50 mg/g are not necessarily a pre-requisite for lymphatic transport. The CETPi also led to changes to lipoprotein processing in the enterocyte including a reduction in lipid transport in chylomicrons. Changes to intestinal lipoprotein profiles may contribute to the changes in systemic lipoprotein levels seen during CETPi therapy.

The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623).

PURPOSE: To evaluate the potential role of intestinal lymphatic transport in the absorption and oral bioavailability of members of an emerging class of anti-atherosclerosis drugs (CETP inhibitors). CP524,515 and CP532,623 are structurally related with eLogD(7.4) >5; however, only CP524,515 (and not CP532,623) had sufficient solubility (>50 mg/g) in long-chain triglyceride (LCT) to be considered likely to be lymphatically transported. METHODS: CP524,515 and CP532,623 were administered intravenously and orally to fasted or fed lymph-cannulated or non-cannulated dogs. Oral bioavailability and lymphatic transport of drug (and triglyceride) was subsequently quantified. RESULTS: Both CETP inhibitors were substantially transported into the lymphatic system (>25% dose) in fed and fasted dogs. Food enhanced oral bioavailability (from 45 to 83% and 44 to 58% for CP524,515 and CP532,623, respectively) and the proportion of the absorbed dose transported via the lymph (from 61 to 86% and from 68 to 83%, respectively). Lymphatic triglyceride transport was significantly lower in fed dogs administered CP532,623. CONCLUSION: Intestinal lymphatic transport is the major absorption pathway for CP524,515 and CP532,623, suggesting that a LCT solubility >50 mg/g is not an absolute requirement for lymphatic transport. The effect of CP532,623 on intestinal lipid transport may suggest a role in the activity/toxicity profiles of CETP inhibitors.

Highly Stretchable Sound-in-Display Electronics Based on Strain-Insensitive Metallic Nanonetworks.

The growing importance of human-machine interfaces and the rapid expansion of the internet of things (IoT) have inspired the integration of displays with sound generation systems to afford stretchable sound-in-display devices and thus establish human-to-machine connections via auditory system visualization. Herein, the synchronized generation of sound and color is demonstrated for a stretchable sound-in-display device with electrodes of strain-insensitive silver nanowires (AgNWs) and emissive layers of field-induced inorganic electroluminescent (EL) phosphors. In this device, EL phosphors embedded in a dielectric elastomer actuator (DEA) emit light under alternating-current bias, while audible sound waves are simultaneously generated via DEA actuation along with input sound signals. The electroluminescence and sound-generation performances of the fabricated device are highly robust and reliable, being insensitive to stretch-release cycling because of the presence of the AgNW stretchable electrodes. The presented principle of integrating light emission and acoustic systems in a single stretchable device can be further expanded to realize sound-in-display electronics for IoT and human-machine interface applications.

A Hierarchical Nanoparticle-in-Micropore Architecture for Enhanced Mechanosensitivity and Stretchability in Mechanochromic Electronic Skins.

Biological tissues are multiresponsive and functional, and similar properties might be possible in synthetic systems by merging responsive polymers with hierarchical soft architectures. For example, mechanochromic polymers have applications in force-responsive colorimetric sensors and soft robotics, but their integration into sensitive, multifunctional devices remains challenging. Herein, a hierarchical nanoparticle-in-micropore (NP-MP) architecture in porous mechanochromic polymers, which enhances the mechanosensitivity and stretchability of mechanochromic electronic skins (e-skins), is reported. The hierarchical NP-MP structure results in stress-concentration-induced mechanochemical activation of mechanophores, significantly improving the mechanochromic sensitivity to both tensile strain and normal force (critical tensile strain: 50% and normal force: 1 N). Furthermore, the porous mechanochromic composites exhibit a reversible mechanochromism under a strain of 250%. This architecture enables a dual-mode mechanochromic e-skin for detecting static/dynamic forces via mechanochromism and triboelectricity. The hierarchical NP-MP architecture provides a general platform to develop mechanochromic composites with high sensitivity and stretchability.

Calorimetric relaxation in pharmaceutical molecular glasses and its utility in understanding their stability against crystallization.

Glassy states of three pharmaceuticals, acetaminophen, griseofulvin, and nifedipine, and an acetaminophen-aspirin (1:1 mol) alloy were made by slow cooling of the melt and studied by calorimetry. Measurements were performed by cooling and heating at significantly slow rates of 20 K/h, which were comparable to the rate used in adiabatic calorimetry. The results were modeled in terms of a nonexponential, nonlinear structural relaxation. The calorimetric relaxation of all four pharmaceutical samples were less nonexponential than those of polymeric or inorganic glasses, and this finding was attributed to additional contributions to energy change that would arise from temperature and time dependent variation in the hydrogen bond population, the extent of isomerization, and/or the ionic equilibria that exist in these materials. Four calculated and relevant parameters for the pharmaceutical samples were, ln A = -183, beta = 0.75, x = 0.4, and Delta h* = 457 kJ/mol for acetaminophen, ln A = -170, beta = 0.75, x = 0.45, and Delta h* = 516 kJ/mol for griseofulvin, ln A = -189, beta = 0.69, x = 0.39, and Delta h* = 503 kJ/mol for nifedipine, and ln A = -160, beta = 0.70, x = 0.50, and Delta h* = 363 kJ/mol for the acetaminophen-aspirin alloy. The significance of these parameters and, in particular, their values are discussed in the context of the stability of the pharmaceuticals against crystallization and compared against the significance of the localized motions of the JG relaxation in the same context. Acetaminophen was found to be significantly more prone to crystallization on heating than the other two pharmaceuticals as well as the acetaminophen-aspirin alloy.

Drug-induced movement disorder and confusion associated with duloxetine.

A 60-year-old woman with major depressive disorder, developed high blood pressure, confusion and dyskinesias of face, neck and jaw, following an increase in her dose of duloxetine. Routine blood tests including toxic, infective and metabolic workup were unremarkable. Cerebrospinal fluid analysis and electroencephalogram were also normal. MRI brain showed bilaterally symmetrical diffusion-restricted areas in deep cerebral white matter. Duloxetine was held on suspicion of drug adverse effect. She had complete resolution of symptoms within 48 hours and resolution of MRI brain changes over 6 weeks. Serotonin norepinephrine reuptake inhibitors such as duloxetine may have the potential to cause drug-induced movement disorders, confusion and high blood pressure and should be used cautiously especially in elderly.

Transparent and conductive nanomembranes with orthogonal silver nanowire arrays for skin-attachable loudspeakers and microphones.

We demonstrate ultrathin, transparent, and conductive hybrid nanomembranes (NMs) with nanoscale thickness, consisting of an orthogonal silver nanowire array embedded in a polymer matrix. Hybrid NMs significantly enhance the electrical and mechanical properties of ultrathin polymer NMs, which can be intimately attached to human skin. As a proof of concept, we present a skin-attachable NM loudspeaker, which exhibits a significant enhancement in thermoacoustic capabilities without any significant heat loss from the substrate. We also present a wearable transparent NM microphone combined with a micropyramid-patterned polydimethylsiloxane film, which provides excellent acoustic sensing capabilities based on a triboelectric voltage signal. Furthermore, the NM microphone can be used to provide a user interface for a personal voice-based security system in that it can accurately recognize a user's voice. This study addressed the NM-based conformal electronics required for acoustic device platforms, which could be further expanded for application to conformal wearable sensors and health care devices.