Understanding the mechanical behaviour of organic molecular crystals is essential for their reliable handling, processing, and performance in solid-state applications. Benzoic acid crystals have been reported to be brittle in previous studies. However, in this work, the benzoic acid crystals grown using slow evaporation and sublimation processes exhibited plastic bending upon the application of force on a wider (001) crystallographic face. Single-crystal X-ray diffraction analysis and pairwise interaction energy calculations revealed the presence of a slip plane along the (001) direction, which was formed mainly due to the herringbone packing arrangement of the benzoic acid molecules and a weak edge-to-edge aromatic interaction. A low-energy (001) slip plane with an interlayer separation of approximately 0.896 & Aring; facilitates the plastic deformation of benzoic acid crystals. Nanoindentation analysis of the (001) face yielded elastic modulus (E) and hardness (H) values of 4.26 +/- 0.68 GPa and 128.03 +/- 38 MPa, respectively, which fall within the range of values reported for plastic organic crystals.

Plastic crystals are a unique class of dynamic crystalline materials that combine long-range order with partial molecular mobility, resulting in remarkable mechanical properties, such as plasticity and flexibility. These crystals have emerged as promising candidates for advanced flexible devices and pharmaceutical applications. In this study, we investigate the plastic behavior of 3-bromo-5-chlorobenzoic acid (3B5CBA), a globular halogenated aromatic compound. Crystals of 3B5CBA grown via a fast evaporation technique exhibited plastic bending when stressed along the (001) plane. Thermal analysis of crystals revealed a sublimation onset at approximately 70 degrees C and a melting point of 195.3 degrees C. Single-crystal X-ray diffraction (SCXRD) analysis and energy framework calculation revealed strong 2D sheet-like interactions parallel to the (001) plane (-299.9 kJ/mol) and weaker interlayer C-BrO interactions (-79.6 kJ/mol) forming low-energy slip planes. Nanoindentation on the (001) face confirmed homogeneous plastic deformation with a moderate hardness of 217.48 +/- 19.87 MPa and a Young's modulus of 2.94 +/- 0.35 GPa. Furthermore, shape analysis using Hirshfeld surface parameters showed high globularity (G = 0.808) and low asphericity (Omega = 0.108). Together, these results showed that 3B5CBA being an organic aromatic compound with a nearly globular shape, hydrogen and halogen synthon-forming functional groups on its periphery can show long-range disordered crystal structure, sublimation ability, and irreversible plastic deformation, offering new insights into the design of aromatic plastic molecular solids.

This study explored the extensive use of In-Situ Raman spectroscopy combined with molecular dynamics simulations to understand the polymorphic behavior of L-Glutamic acid during cooling crystallization, combined cooling and antisolvent crystallization, and solvent-mediated polymorphic transformation studies. During combined cooling and antisolvent crystallization, the effect of various antisolvents and mixing conditions were examined. Ultrasound was found to influence polymorph selection differently under cooling and combined cooling–antisolvent crystallization conditions, leading to distinct polymorphic outcomes. In addition, solvent-mediated polymorphic transformation studies revealed that additives can delay the transformation of metastable α-LGA to stable β-LGA. Molecular dynamics simulations were also performed to understand how intermolecular interactions affect the polymorphic behaviour of LGA. The results presented in this work provide deeper insights into achieving a better polymorphic control during the crystallization of LGA.

Cooling cocrystallization of 1:1 sulfamethazine-acetylsalicylic acid (SMZ-ASA) cocrystal from acetonitrile is investigated based on the ternary phase diagrams (TPDs) established at 5, 15, 25, and 35 degrees C. Nucleation kinetics of the cocrystal and pure coformers analyzed using classical nucleation theory (CNT) revealed that the nucleation rate of the cocrystal is significantly lower, approximately 1/111 times that of pure ASA and 1/21 times that of SMZ at similar supersaturations. Cooling cocrystallization was scaled up from 20 mL to 2 L, transitioning from a magnetically stirred to an overhead-stirred system. This scale-up facilitated the study of nucleation and the successful production of cocrystals in larger volumes. Cooling in the stable cocrystal region in the TPD produced pure cocrystals. Cooling crystallization in the SMZ + cocrystal region near the SMZ invariant point in TPD led to the formation of pure cocrystal instead of SMZ-cocrystal mixture due to the influence of nucleation kinetics. Conversely, in the ASA + cocrystal region near the ASA invariant point, a mixed solid phase was obtained. In-situ Raman spectroscopy revealed that pure ASA nucleated first, followed by cocrystal formation approximately 30 min later.

Pharmaceutical compounds contaminating water bodies is a threat to public health. It is therefore necessary to remove these pharmaceutical residues from sewage water. In order to effectively remove traces of pharmaceutical pollutants, various techniques such as oxidation ozonation, photocatalysis, membrane filtrations, and activated carbon adsorption have been employed by many researchers. However, the aforementioned techniques do not effectively remove traces of pharmaceutical pollutants from water completely. In the current work, magnetic catalyst nanoparticles loaded ozone microbubbles were synthesized for the efficient degradation of trace quantities of pharmaceutical pollutants in sewage water. Ozone microbubbles, typically smaller than 100 mu m, were used for the effective degradation of ciprofloxacin, a commonly used antibiotic drug. The degraded intermediates of ciprofloxacin produced during the treatment process were estimated using Liquid Chromatography Mass Spectrometry (LCMSMS), which enabled the formulation of pathway for fragmentation/degradation of ciprofloxacin using magnetic nanoparticle-coated ozone microbubbles. The catalyst nanoparticles could be retrieved completely without any traces left behind in the treated water. This method of purification can be easily scaled up and can be used in large-scale water treatment plants. Toxicity studies were performed using zebrafish larvae to confirm the safety of water obtained after treatment of sewage water using catalyst-coated ozone microbubbles.

Fenofibrate is a pharmaceutical drug of the fibrate class, which is used to lower abnormal lipid levels in the blood. However, fenofibrate suffers from poor bioavailability due to its hydrophobic nature and negligible water solubility. The generation of nanosuspension with increased surface area is one of the mechanisms to minimize this challenge. In this work, fenofibrate nanosuspension was formulated to improve the solubility of the drug. A method of hot melt emulsification followed by precipitating the hot melt into a cold aqueous medium was employed to generate the nanosuspension. Ultrasound energy and stabilizers such as Hydroxymethyl cellulose (HPMC), Polyvinyl Pyrrolidone (PVP), and Bovine Serum Albumin (BSA), along with surfactants including Tween 80 (T80) and Sodium Lauryl Sulphate (SLS), were used to control particle growth and improve the stability of the resulting suspension. Sunflower oil was used as a co-additive agent. The effects of surfactants, ultrasound energy and sonication time, drug to surfactant ratio, and sunflower oil on particle size and suspension stability were investigated. The use of ultrasound sonication during both the hot-melt formation step and the precipitation step produced smaller particle sizes. A ground mixture of fenofibrate with BSA and SLS, in the presence of 3 mL sunflower oil, produced a nanosuspension with particle sizes below 100 nm, exhibiting a relatively lower particle growth rate and improved stability. Using a lower molecular weight BSA surfactant and incorporating sunflower oil produced substantial improvement in the particle size reduction and enhancement of the suspension's stability.

Microfluidic devices are becoming increasingly popular for producing microbubbles, as these devices provide much greater control over microbubble size compared to traditional methods such as sonication and amalgamation. Recent developments in microfabrication technologies have prompted several modifications in conventional microfluidic devices, which allow one to “engineer” microbubbles relevant to specific biomedical applications. The pursuit of improvements in microbubble engineering requires a detailed understanding of fluid flow behavior in microfluidic systems, which is where the motivation for this work originates from. This work provides an extensive review of the theoretical, experimental, and numerical investigations reported in the literature to understand microbubbles formation using microfluidic devices. The evolution of gas–liquid interfaces during microbubble formation, the pinch-off mechanism, and the confinement effect on microbubble size and production rate have been discussed. The scaling laws for the prediction of microbubble diameter and microbubble formation regimes maps providing details about the interplay of different forces have also been reviewed. Furthermore, the developments in CFD simulations based on different interface tracking schemes for microbubble formation in microfluidic devices, along with the recent developments and strategies to upscale microbubble production rate in microfluidic devices, have also been discussed. We conclude this review by outlining the need for current modifications in microfluidic systems to produce microbubbles, which can pave the way to new research in the field of microfluidics for microbubble engineering.

This study explores the structural and dynamic disorder in the nanoporous organic cocrystal carbamazepine-oxalic acid, synthesized via liquid-assisted grinding, using a combination of broadband dielectric spectroscopy and molecular dynamics simulations. Notably, the oxalic acid molecules within the channel-like cocrystalline structure exhibit both translational and rotational dynamic disorder. These oxalic acid molecules are arranged as one-dimensional, interrupted single files within the channels. Their translational motion occurs through small hops, characterized as single-file diffusion at short timescales, transitioning to classical Fickian diffusion over longer times. Rotational dynamics involve jumps between preferred orientations, altering the molecular dipole moments, which are detectable through dielectric relaxation spectroscopy. Despite this disorder, it appears only partial due to hydrogen bonding between the oxalic acid and carbamazepine molecules, which imparts some degree of order within the channels. These findings underscore the value of disordered channel-like cocrystals as model systems for studying dynamics in nanoconfined environments.

Vaporizable double emulsions, characterized by a central aqueous core, have demonstrated effectiveness in encapsulating hydrophilic drugs. This study aims to investigate the potential of incorporating an additional oil- layer in the double emulsions to encapsulate hydrophobic drugs. Vaporizable multi-layered emulsions were produced in three steps using perfluoropentane (PFP), phosphate-buffered saline (PBS), and sunflower oil. Curcumin, a natural anti-inflammatory drug, was dispersed in the oil phase. Krytox, polyglycerol polyricinoleate, and bovine serum albumin (BSA) were used as surfactants. PFP was sonicated in PBS (1:6) for 1 minute to create emulsion-1. Subsequently, emulsion-1 (1:4) was homogenized in oil to make emulsion-2. Emulsion-2 was homogenized in BSA (1:4) to yield emulsion-3 at 8000 rpm for 30 seconds. The vaporization pressure threshold was determined using 2 MHz focused ultrasound with a single-element transducer (f/# of 1.27, 0.5% duty cycle). B-mode imaging was conducted using a Verasonics Vantage 128 system with an L11-5v array to determine the droplet vaporization threshold, which was found to be 6.7 MPa. Curcumin-loading (0.87 ± 0.1 mg) was significantly higher in the multi-layered emulsions than in single-layered BSA-shelled microbubbles (0.019 ± 0.004 mg) (p < 0.00001), indicating that multi-layered emulsions exhibit higher drug loading capacity.

Altering the route of uptake by the cells is an attractive strategy to overcome drug-receptor adaptation problems. Carbon nanoparticles (CNPs) with emission beyond tissue autofluorescence for imaging biological tissues were used to study the phenomenon of uptake by the cells. In this regard, red-emitting carbon nanoparticles (CNPs) were synthesized and incorporated onto lipid microbubbles (MBs). The CNPs showed red emissions in the range of 640 nm upon excitation with 480 nm wavelength of light. Atomic force microscopic and confocal microscopic images showed the successful loading of CNPs onto the MB. Carbon nanoparticle loaded microbubbles (CNPMBs) were treated with NIH 3 T3 cells at different concentrations. Confocal microscopic imaging studies confirm the presence of CNPs inside the treated cells. Cytotoxicity studies revealed that the CNPs showed minimal toxicity towards cells after loading onto MBs. The CNPs are usually taken up by the cells through the clathrinmediated (CME) pathway, but when loaded onto MBs, the mechanism of uptake of CNPs is altered, and the uptake by the cells was observed even in the presence of inhibitors for the CME pathway. Loading CNPs onto MBs resulted in the uptake of CNPs by the cell through micropinocytosis and sonophoresis in the presence of ultrasound. The in vivo uptake CNP-MBs were performed in Danio rerio (Zebrafish larvae). This study provides insights into altering the uptake pathway through reformulation by loading nanoparticles onto MBs.

Successful production of 1:1 sulfamethazine-acetylsalicylic acid (SMZ-ASA) cocrystal was achieved through slow solvent evaporation, liquid-assisted grinding, and slurry conversion method. SCXRD, PXRD, DSC, FTIR, and Raman spectroscopy were employed to characterize the cocrystal. Ternary phase diagrams (TPD) for SMZ and ASA in acetonitrile (ACN) and deionized water (DIW) has been constructed at 25 degree celsius. Using TPD of the incongruent system, slurry compositions for stable production of cocrystal was determined in both the solvents. The cocrystal conversion process in slurry was monitored using in-situ Raman spectroscopy. Intermittent sampling was also carried out to determine the purity of the solid phase from the slurry using offline PXRD. In-situ Raman and offline PXRD measurements confirmed fast conversion of the pure coformer crystals to the cocrystal in ACN, within a span of 5 minutes. However, the conversion in DIW was much slower and the in-situ Raman measurements significantly underpredicted the transformation time in comparison to offline PXRD analysis. The study highlights the utilization of TPD for developing the cocrystallization process and the need for multiple characterization techniques for monitoring cocrystallization.

Liquid marbles (LMs) are droplets encapsulated with powders presenting varied roughness and wettability. These LMs have garnered a lot of attention due to their dual properties of leakage-free and quick transport on both solid and liquid surfaces. These droplets are in a Cassie-Baxter wetting state sitting on both roughness and air pockets existing between particles. They are also reminiscent of the state of a drop on a superhydrophobic (SH) surface. In this review, LMs and bare droplets on SH surfaces are comparatively investigated in terms of two aspects: interfacial and dynamical. LMs present a fascinating class of soft matter due to their superior interfacial activity and their remarkable stability. Inherently hydrophobic powders form stable LMs by simple rolling; however, particles with defined morphologies and chemistries contribute to the varied stability of LMs. The factors contributing to this interesting robustness with respect to bare droplets are then identified by tests of stability such as evaporation and compression. Next, the dynamics of the impact of a drop on a hydrophobic powder bed to form LMs is studied vis-à̀-vis that of drop impact on flat surfaces. The knowledge from drop impact phenomena on flat surfaces is used to build and complement insights to that of drop impact on powder surfaces. The maximum spread of the drop is empirically understood in terms of dimensionless numbers, and their drawbacks are highlighted. Various stages of drop impact-spreading, retraction and rebound, splashing, and final outcome-are systematically explored on both solid and hard surfaces. The implications of crater formation and energy dissipations are discussed in the case of granular beds. While the drop impact on solid surfaces is extensively reviewed, deep interpretation of the drop impact on granular surfaces needs to be improved. Additionally, the applications of each step in the sequence of drop impact phenomena on both substrates are also identified. Next, the criterion for the formation of peculiar jammed LMs was examined. Finally, the challenges and possible future perspectives are envisaged.

This study focuses on synthesizing a catalyst that can quickly degrade micropollutants in water with minimal ozone exposure. While ozone is an effective oxidizing agent, it can harm the environment at higher concentrations if released in gaseous form. Thus, due to their efficiency and non-toxicity, researchers prefer to use hydroxyl radicals as oxidizing agents. In this study, Fe magnetite nanoparticles (FeNPs) have been synthesized to generate hydroxyl radicals for ozonation. The stability and effectiveness of the FeNPs as an ozonation catalyst were tested under different pH levels and ozone doses. Promising results have been obtained showing complete degradation of the model pharmaceutical compound within 10 min for the catalytic ozonation process. The parameters have been optimized for the holistic picture of the process, and their significance on the % degradation has been evaluated thoroughly. The energy requirement of the process has been evaluated to compare the proposed work with the available AOPs. It was found that the heterogenous catalytic ozonation process projects a much lower energy requirement as compared to many other AOPs.

Drugs have been classified as fast, moderate, and poor crystallizers based on their inherent solid-state crystallization tendency. Differential scanning calorimetry-based heat-cool-heat protocol serves as a valuable tool to define the solid-state crystallization tendency. This classification helps in the development of strategies for stabilizing amorphous drugs. However, microscopic characteristics of the samples were generally overlooked during these experiments. In the present study, we evaluated the influence of microscopic cracks on the crystallization tendency of a poorly water-soluble model drug, celecoxib. Cracks developed in the temperature range of 0-10 °C during the cooling cycle triggered the subsequent crystallization of the amorphous phase. Nanoindentation study suggested minimal differences in mechanical properties between samples, although the cracked sample showed relatively inhomogeneous mechanical properties. Nuclei nourishment experiments suggested crack-assisted nucleation, which was supported by Raman data that revealed subtle changes in intermolecular interactions between cracked and uncracked samples. Celecoxib has been generally classified as class II, i.e., a drug with moderate crystallization tendency. Interestingly, classification of amorphous celecoxib may change depending on the presence or absence of cracks in the amorphous sample. Hence, subtle events such as microscopic cracks should be given due consideration while defining the solid-state crystallization tendency of drugs.

In recent years, there has been a notable increase in the interest toward microfluidic devices for microbubble synthesis. The upsurge can be primarily attributed to the exceptional control these devices offer in terms of both the size and the size distribution of microbubbles. Among various microfluidic devices available, capillary-embedded T-junction microfluidic (CETM) devices have been extensively used for the synthesis of microbubbles. One distinguishing feature of CETM devices from conventional T-junction devices is the existence of a wall at the right-most end, which causes a backflow of the continuous phase at the mixing zone during microbubble formation. The back flow at the mixing zone can have several implications during microbubble formation. It can possibly affect the local velocity and shearing force at the mixing zone, which in turn can affect the size and production rate of the microbubbles. Therefore, in this work, we experimentally and computationally understand the process of microbubble formation in CETM devices. The process is modeled using computational fluid dynamics (CFD) with the volume-of-fluid approach, which solves the Navier-Stokes equations for both the gas and liquid phases. Three scenarios with a constant liquid velocity of 0.053 m/s with varying gas velocity and three with a constant gas velocity of 0.049 m/s at different liquid velocities were explored. Increase in the liquid and gas velocity during microbubble formation was found to enhance production rates in both experiments and simulations. Additionally, the change in microbubble size with the change in liquid velocity was found to agree closely with the findings of the simulation with a coefficient of variation of 10%. When plotted against the time required for microbubble generation, the fluctuations in the pressure showed recurrent crests and troughs throughout the microbubble formation process. The understanding of microbubble formation in CETM devices in the presence of backflow will allow improvement in size reduction of microbubbles.

Limited work has been reported on the acoustic and physical characterization of protein-shelled UCAs. This study characterized bovine serum albumin (BSA)-shelled microbubbles filled with perfluorobutane gas, along with SonoVue, a clinically approved contrast agent. Broadband attenuation spectroscopy was performed at room (23 ± 0.5 °C) and physiological (37 ± 0.5 °C) temperatures over the period of 20 min for these agents. Three size distributions of BSA-shelled microbubbles, with mean sizes of 1.86 μm (BSA1), 3.54 μm (BSA2), and 4.24 μm (BSA3) used. Viscous and elastic coefficients for the microbubble shell were assessed by fitting de Jong model to the measured attenuation spectra. Stable cavitation thresholds (SCT) and inertial cavitation thresholds (ICT) were assessed at room and physiological temperatures. At 37 °C, a shift in resonance frequency was observed, and the attenuation coefficient was increased relative to the measurement at room temperature. At physiological temperature, SCT and ICT were lower than the room temperature measurement. The ICT was observed to be higher than SCT at both temperatures. These results enhance our understanding of temperature-dependent properties of protein-shelled UCAs. These findings study may guide the rational design of protein-shelled microbubbles and help choose suitable acoustic parameters for applications in imaging and therapy.

Long-term stability of microbubbles is crucial to their effectiveness. Using a new microfluidic device connecting three T-junction channels of 100 μm in series, stable monodisperse SiQD-loaded bovine serum albumin (BSA) protein microbubbles down to 22.8 ± 1.4 μm in diameter were generated. Fluorescence microscopy confirmed the integration of SiQD on the microbubble surface, which retained the same morphology as those without SiQD. The microbubble diameter and stability in air were manipulated through appropriate selection of T-junction numbers, capillary diameter, liquid flow rate, and BSA and SiQD concentrations. A predictive computational model was developed from the experimental data, and the number of T-junctions was incorporated into this model as one of the variables. It was illustrated that the diameter of the monodisperse microbubbles generated can be tailored by combining up to three T-junctions in series, while the operating parameters were kept constant. Computational modeling of microbubble diameter and stability agreed with experimental data. The lifetime of microbubbles increased with increasing T-junction number and higher concentrations of BSA and SiQD. The present research sheds light on a potential new route employing SiQD and triple T-junctions to form stable, monodisperse, multi-layered, and well-characterized protein and quantum dot-loaded protein microbubbles with enhanced stability for the first time.

Microbubbles are tiny gas-filled bubbles that have a variety of applications in ultrasound imaging and therapeutic drug delivery. Microbubbles can be synthesized using a number of techniques including sonication, amalgamation, and saline shaking. These approaches can produce highly concentrated microbubble suspensions but offer minimal control over the size and polydispersity of the microbubbles. One of the simplest and effective methods for producing monodisperse microbubbles is capillary-embedded T-junction microfluidic devices, which offer great control over the microbubble size. However, lower production rates (∼200 bubbles/s) and large microbubble sizes (∼300 μm) limit the applicability of such devices for biomedical applications. To overcome the limitations of these technologies, we demonstrate in this work an alternative approach to combine a capillary-embedded T-junction device with ultrasound to enhance the generation of narrow-sized microbubbles in aqueous suspensions. Two T-junction microfluidic devices were connected in parallel and combined with an ultrasonic horn to produce lipid-coated SF6 core microbubbles in the size range of 1-8 μm. The rate of microbubble production was found to increase from 180 microbubbles/s in the absence of ultrasound to (6.5 ± 1.2) × 106 bubble/s in the presence of ultrasound (100% ultrasound amplitude). When stored in a closed environment, the microbubbles were observed to be stable for up to 30 days, with the concentration of the microbubble suspension decreasing from ∼2.81 × 109/mL to ∼2.3 × 106/mL and the size changing from 1.73 ± 0.2 to 1.45 ± 0.3 μm at the end of 30 days. The acoustic response of these microbubbles was examined using broadband attenuation spectroscopy, and flow phantom imaging was performed to determine the ability of these microbubble suspensions to enhance the contrast relative to the surrounding tissue. Overall, this approach of coupling ultrasound with microfluidic parallelization enabled the continuous production of stable microbubbles at high production rates and low polydispersity using simple T-junction devices.

Liquid marbles (LMs) are droplets of liquid enwrapped by hydrophobic particles. LMs can float on a liquid substrate but collapse after a certain time period. In this work, stability of LMs on a liquid substrate has been investigated. LMs were formed by rolling water drops over polytetrafluorethylene (PTFE) powder bed. Collapse patterns and times recorded for these LMs were found to be a function of the core liquid and supporting liquid substrate. Flower-shaped patterns were obtained when there was no surface tension gradient between the core liquid of LM and supporting liquid substrate. However, in case of a finite surface tension difference between the two, extremely porous patterns were formed. In order to capture process of LM collapse, aqueous solutions of methylene blue (MB) were used to form LMs. Surprisingly, these LMs made out of MB solutions exhibited very high stability against collapse. Typically, LMs collapse within a few seconds to a few minutes but LMs made out of MB solutions exhibited stability up to 6 h. The stability of LMs floating on a liquid substrate was found to be directly proportional to the effective surface tension (gamma(eff)) or more specifically to the capillary interaction between particles signified by gamma(int).

Porphyrin is known to enable the photodynamic effect during cancer drug delivery and molecular imaging. However, its hydrophobicity and tendency to aggregate in an aqueous medium create a significant hurdle for its use as an anticancer drug. Loading porphyrin onto biocompatible delivery vehicles can enhance its efficacy. This can be achieved by using gas-filled microbubbles that can be administered intravenously. This study aimed at developing near-infrared (NIR)-active porphyrin-loaded lipid microbubbles with anticancer activity enhanced by sonodynamic and photodynamic effects. The porphyrin-loaded microbubbles were studied for their cell toxicity, cellular uptake of porphyrin, and effect on cellular three-dimensional (3D) invasion of breast cancer cells (MDA-MB-231) in cellulo. Toxicity studies in zebrafish larvae (Danio rerio) in the presence and absence of photodynamic and sonodynamic therapy were also conducted. The results suggest that with a higher concentration of porphyrin loaded on microbubbles, the porphyrin-loaded microbubbles display a higher therapeutic effect facilitated by photodynamic and sonodynamic therapy, which results in enhanced cellular uptake and cellular toxicity. A lower concentration of loaded porphyrin microbubbles exhibits high cellular viability and good fluorescence intensity in the NIR region, which can be exploited for bioimaging applications.