Engineered microbubbles decorated with red emitting carbon nanoparticles for efficient delivery and imaging.

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 (CNP-MBs) 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 clathrin-mediated (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.

Microscopic Cracks Modulate Nucleation and Solid-State Crystallization Tendency of Amorphous Celecoxib.

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.

Experimental and Computational Investigation of Microbubble Formation in a Single Capillary Embedded T-junction Microfluidic Device.

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.

Effect of temperature on the acoustic response and stability of size-isolated protein-shelled ultrasound contrast agents and SonoVue.

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.

Generating Lifetime-Enhanced Microbubbles by Decorating Shells with Silicon Quantum Nano-Dots Using a 3-Series T-Junction Microfluidic Device.

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.

NIR-Active Porphyrin-Decorated Lipid Microbubbles for Enhanced Therapeutic Activity Enabled by Photodynamic Effect and Ultrasound in 3D Tumor Models of Breast Cancer Cell Line and Zebrafish Larvae.

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.

Combining Ultrasound and Capillary-Embedded T-Junction Microfluidic Devices to Scale Up the Production of Narrow-Sized Microbubbles through Acoustic Fragmentation.

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.

Enhancing In Vitro Stability of Albumin Microbubbles Produced Using Microfluidic T-Junction Device.

Microfluidics is an efficient technique for continuous synthesis of monodispersed microbubbles. However, microbubbles produced using microfluidic devices possess lower stability due to quick dissolution of core gas when exposed to an aqueous environment. This work aims at generating highly stable monodispersed albumin microbubbles using microfluidic T-junction devices. Microbubble generation was facilitated by an aqueous phase consisting of bovine serum albumin (BSA) as a model protein and nitrogen (N2) gas. Microbubbles were chemically cross-linked using dilute glutaraldehyde (0.75% v/v) solution and thermally cross-linked by collecting microbubbles in hot water maintained at 368 (±2) K. These microbubbles were then subjected to in vitro dissolution in an air-saturated water. Microbubbles cross-linked with a combined treatment of thermal and chemical cross-linking (TC & CC) had longer dissolution time compared to microbubbles chemically cross-linked (CC) alone, thermally cross-linked (TC) alone, and non-cross-linked microbubbles. Circular dichroism (CD) spectroscopy analysis revealed that percent reduction in alpha-helices of BSA was higher for the combined treatment of TC & CC when compared to other treatments. In contrast to non-cross-linked microbubbles where microbubble shell dissolved completely, a significant shell detachment was observed during the final phase of the dissolution for cross-linked microbubbles captured using high speed camera, depending upon the extent of cross-linking of the microbubble shell. SEM micrographs of the microbubble shell revealed the shell thickness of microbubbles treated with TC & CC to be highest compared to only thermally or only chemically cross-linked microbubbles. Comparison of microbubble dissolution data to a mass transfer model showed that shell resistance to gas permeation was highest for microbubbles subjected to a combined treatment of TC & CC.

Effectiveness of Oil-Layered Albumin Microbubbles Produced Using Microfluidic T-Junctions in Series for In Vitro Inhibition of Tumor Cells.

This work focuses on the synthesis of oil-layered microbubbles using two microfluidic T-junctions in series and evaluation of the effectiveness of these microbubbles loaded with doxorubicin and curcumin for cell invasion arrest from 3D spheroid models of triple negative breast cancer (TNBC), MDA-MB-231 cell line. Albumin microbubbles coated in the drug-laden oil layer were synthesized using a new method of connecting two microfluidic T-mixers in series. Double-layered microbubbles thus produced consist of an innermost core of nitrogen gas encapsulated in an aqueous layer of bovine serum albumin (BSA) which in turn, is coated with an outer layer of silicone oil. In order to identify the process conditions leading to the formation of double-layered microbubbles, a regime map was constructed based on capillary numbers for aqueous and oil phases. The microbubble formation regime transitions from double-layered to single layer microbubbles and then to formation of single oil droplets upon gradual change in flow rates of aqueous and oil phases. In vitro dissolution studies of double-layered microbubbles in an air-saturated environment indicated that a complete dissolution of such bubbles produces an oil droplet devoid of a gas bubble. Incorporation of doxorubicin and curcumin was found to produce a synergistic effect, which resulted in higher cell deaths in 2D monolayers of TNBC cells and inhibition of cell proliferation from 3D spheroid models of TNBC cells compared to the control.

Biomedical application, drug delivery and metabolic pathway of antiviral nanotherapeutics for combating viral pandemic: A review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a neoteric virus belonging to the beta coronavirus class has created a global health concern, responsible for an outbreak of severe acute respiratory illness, the COVID-19 pandemic. Infected hosts exhibit diverse clinical features, ranging from asymptomatic to severe symptoms in their genital organs, respiratory, digestive, and circulatory systems. Considering the high transmissibility (R0: ≤6.0) compared to Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, the quest for the clinical development of suitable antiviral nanotherapeutics (NTPs) is incessant. We are presenting a systematic review of the literature published between 2003 and 2020 to validate the hypothesis that the pharmacokinetics, collateral acute/chronic side effects of nano drugs and spike proteins arrangement of coronaviruses can revolutionize the therapeutic approach to cure COVID-19. Our aim is also to critically assess the slow release kinetics and specific target site chemical synthesis influenced competence of NTPs and nanotoxicity based antiviral actions, which are commonly exploited in the synthesis of modulated nanomedicines. The pathogenesis of novel virulent pathogens at the cellular and molecular levels are also considered, which is of utmost importance to characterize the emerging nano-drug agents as diagnostics or therapeutics or viral entry inhibitors. Such types of approaches trigger the scientists and policymakers in the development of a conceptual framework of nano-biotechnology by linking nanoscience and virology to present a smart molecular diagnosis/treatment for pandemic viral infections.

Enhancing Aqueous Solubility and Antibacterial Activity of Curcumin by Complexing with Cell-Penetrating Octaarginine.

Bacterial resistance to antimicrobial drugs is one of the biggest threats to human health and novel drugs, and strategies are needed to obviate this resistance crisis. An innovative strategy for designing novel antimicrobial drugs is based on the hybridization of an antimicrobial agent with a second functional entity. Here, we use a cell-penetrating peptide-octaarginine (R8) as the second functional entity and develop a complex or hybrid of R8 and curcumin that possibly targets the bacterial cell membrane. Minimum inhibitory concentration assays show that the antibacterial activity of the complex is enhanced in a synergistic manner and rapid killing kinetics are obtained, emphasizing a bactericidal mode of action. In addition, electron microscopy images reveal bacterial membrane disruption by the complex. The R8-curcumin complex also displays activity against HeLa cells.

Role of solvent in differential phase behavior of celecoxib during spray drying.

Spray drying is an industrially viable technique that can be used for modulation of the physical form of Active Pharmaceutical Ingredients (API), which is governed by inherent crystallization tendency and processing parameters during spray drying. In the current study, we investigated the role of solvent in differential phase behavior of celecoxib, a poor crystallizer, during spray drying and unveiled the underlying mechanisms. 1% w/v solutions of celecoxib in three different compositions of methanol (M)-water (W) solvent system were spray dried using a laboratory spray dryer. The proportions were 0, 5 and 10% v/v of water in methanol (MW0, MW5, and MW10, respectively). Percentage crystallinity of the spray dried products were evaluated using modulated differential scanning calorimetry and was in the order MW10 > MW5 > MW0 (i.e. 18.52% > 8.13% > 0%). Solution-state and solid-state crystallization events responsible for the experimental observations were probed using microscopy, Raman spectroscopy, and non-isothermal crystallization studies. An intermediate amorphous phase was generated for the studied samples, which underwent crystallization under the influence of chamber temperature for MW5 and MW10. Additionally, liquid-liquid phase separation (LLPS) at very high level of supersaturation led to relatively higher crystallinity for MW10. Insights from this work provide the basis for understanding of probable phase behavior of poor crystallizers during spray drying.

Kinetics of albumin microbubble dissolution in aqueous media.

The effectiveness of microbubbles as ultrasound contrast agents and targeted drug delivery vehicles depends on their persistence in blood. It is therefore necessary to understand the dissolution behavior of microbubbles in an aqueous medium. While there are several reports available in the literature on the dissolution of lipid microbubbles, there are no reports available on the dissolution kinetics of protein microbubbles. Moreover, shell parameters such as interfacial tension, shell resistance and shell elasticity/stiffness which characterize microbubble shells, have been reported for lipid shells but no such data are available for protein shells. Accordingly, this work was focused on capturing the dissolution behavior of protein microbubbles and estimation of shell parameters such as surface tension, shell resistance and shell elasticity. Bovine serum albumin (BSA) was used as a model protein and microbubbles were synthesized using sonication. During dissolution, a large portion of the protein shell was found to disengage from the gas-liquid interface after a stagnant dissolution phase, leading to a sudden disappearance of the microbubbles due to complete dissolution. In order to estimate shell parameters, microbubble dissolution kinetic data (radius vs. time) was fit numerically to a mass transfer model describing a microbubble dissolution process. Analysis of the results shows that the interfacial tension increases drastically and the shell resistance reduces significantly, as protein molecules leave the gas-liquid interface. Furthermore, the effect of processing conditions such as preheating temperature, microbubble size, and core gas and shell composition on the protein shell parameters was also evaluated.

Predictive Framework for the Spreading of Liquid Drops and the Formation of Liquid Marbles on Hydrophobic Particle Bed.

In this work, we have developed a model to describe the behavior of liquid drops upon impaction on hydrophobic particle bed and verified it experimentally. Poly(tetrafluoroethylene) (PTFE) particles were used to coat drops of water, aqueous solutions of glycerol (20, 40, and 60% v/v), and ethanol (5 and 12% v/v). The experiments were conducted for Weber number ( We) ranging from 8 to 130 and Reynolds number ( Re) ranging from 370 to 4460. The bed porosity was varied from 0.8 to 0.6. The experimental values of ßmax (ratio of the diameter at the maximum spreading condition to the initial drop diameter) were estimated from the time-lapsed images captured using a high-speed camera. The theoretical ßmax was estimated by making energy balances on the liquid drop. The proposed model accounts for the energy losses due to viscous dissipation and crater formation along with a change in kinetic energy and surface energy. A good agreement was obtained between the experimental ßmax and the estimated theoretical ßmax. The proposed model yielded a least % absolute average relative deviation (% AARD) of 5.5 ± 4.3 compared to other models available in the literature. Further, it was found that the liquid drops impacting on particle bed are completely coated with PTFE particles with ßmax values greater than 2.

Microbubble Formulations: Synthesis, Stability, Modeling and Biomedical Applications.

Microbubbles are increasingly being used in biomedical applications such as ultrasonic imaging and targeted drug delivery. Microbubbles typically range from 0.1 to 10 µm in size and consist of a protective shell made of lipids or proteins. The shell encapsulates a gaseous core containing gases such as oxygen, sulfur hexafluoride or perfluorocarbons. This review is a consolidated account of information available in the literature on research related to microbubbles. Efforts have been made to present an overview of microbubble synthesis techniques; microbubble stability; microbubbles as contrast agents in ultrasonic imaging and drug delivery vehicles; and side effects related to microbubble administration in humans. Developments related to the modeling of microbubble dissolution and stability are also discussed.

Microbubble-Mediated Enhanced Delivery of Curcumin to Cervical Cancer Cells.

The major bottleneck in the current chemotherapy treatment of cancer is the low bioavailability and high cytotoxicity. Targeted delivery of drug to the cancer cells can reduce the cytotoxicity and increase the bioavailability. In this context, microbubbles are currently being explored as drug-delivery vehicles to effectively deliver drug to the tumors or cancerous cells. Microbubbles when used along with ultrasound can enhance drug uptake and inhibit the growth of tumor cells. Several potential anticancer molecules exhibit poor water solubility, which limits their use in therapeutic applications. Such poorly water soluble molecules can be coadministered with microbubbles or encapsulated within or loaded on the microbubbles surface, to enhance the effectiveness of these molecules against cancer cells. Curcumin is one of such potential anticancer molecules obtained from the rhizome of herbal spice, turmeric. In this work, curcumin-loaded protein microbubbles were synthesized and examined for effective in vitro delivery of curcumin to HeLa cells. Microbubbles in the size range of 1-10 µm were produced using perfluorobutane as core gas and bovine serum albumin (BSA) as shell material and were loaded with curcumin. The amount of curcumin loaded on the microbubble surface was estimated using UV-vis spectroscopy, and the average curcumin loading was found to be ∼54 µM/108 microbubbles. Kinetics of in vitro curcumin release from microbubble surface was also estimated, where a 4-fold increase in the rate of curcumin release was obtained in the presence of ultrasound. Sonication and incubation of HeLa cells with curcumin-loaded BSA microbubbles enhanced the uptake of curcumin by ∼250 times. Further, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed ∼71% decrease in cell viability when HeLa cells were sonicated with curcumin-loaded microbubbles and incubated for 48 h.

Effect of PEGylation on performance of protein microbubbles and its comparison with lipid microbubbles.

Aqueous suspensions of microbubbles are being used in various biomedical applications such as contrast imaging, targeted drug and gene delivery, delivery of drugs through blood brain barrier (BBB) and IV O2 delivery etc. Major microbubble formulations use either proteins or lipids as their shell material. Protein microbubble formulations mainly consist of serum albumin, lysozyme etc., while lipid microbubble formulations consist of phospholipids like 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), etc. This work focuses on comparing performance of protein and lipid microbubbles in terms of their shelf life and in vitro performance. Protein microbubbles were produced using Bovine serum albumin (BSA) as main ingredient and N-acetyl-dl-tryptophan (Tryp) as an additive. Lipid microbubbles were produced using a mixture of DSPC as main ingredient and PEG40S (90:10molar ratio) as emulsifier. A narrow sized range (3-5µm) microbubble suspension was produced using sonication method followed by size isolation using centrifugation. These microbubbles were stored in a (PGO) solution containing 10% 1,2 propanediol (P), 10% glycerol (G) and 80% original solution used to make microbubbles (O) and were studied for their shelf stability, in vitro stability, immunogenicity and ability to produce contrast. For a 4weeks of observation period, a least reduction in concentration of around 18% was observed for PEGylated BSA microbubbles whereas highest reduction of 38% was observed for DSPC-PEG40S microbubbles. In-vitro persistence performance for PEGylated BSA microbubbles was found to be better than non-PEGylated BSA microbubbles as well as DSPC-PEG40S microbubbles. Non-PEGylated BSA microbubbles were found to be immunogenic whereas PEGylated BSA and DSPC-PEG40S microbubles were found to be non-immunogenic.

Ultrasound-assisted modulation of concomitant polymorphism of curcumin during liquid antisolvent precipitation.

Curcumin polymorphs were found to precipitate concomitantly during liquid antisolvent precipitation. While, commercially available curcumin exists in a monoclinic form, the curcumin particles when precipitated in presence of additives and ultrasound were either found to be the mixtures of orthorhombic (Form 3) and monoclinic form (Form 1) or were found to be in orthorhombic form (Form 3) or monoclinic form (Form 1). The experimentally observed particle morphologies did not match clearly with the predicted BFDH morphologies of curcumin and the experimentally observed morphologies were more elongated as compared to the predicted BFDH morphologies. At lower ultrasonic irradiation times, the monoclinic form (Form 1) was found to dominate the mixture of particles. However, an increase in ultrasonic irradiation time was found to increase the percentage of orthorhombic form (Form 3) in the particles indicating that the increase in ultrasonic energy facilitates formation of orthorhombic form over the monoclinic form, irrespective of the additive used. These results therefore suggest that the ultrasonic energy can be effectively used to manipulate the polymorphic outcome of the precipitation.

Modeling of microbubble dissolution in aqueous medium.

A mathematical model for microbubble dissolution in an aqueous medium containing dissolved gases is presented. None of the models available in the literature take into account the influence of shell elasticity (Es), variation in surface tension (σ) at the gas-liquid interface and shell resistance (Ω) on the kinetics of microbubble dissolution. Moreover, values of these shell parameters are not known/available and hence arbitrary values for these variables have been assumed in many of the reports for estimation of dissolution kinetics. Therefore, in this work, a mathematical model is developed to describe microbubble dissolution which takes into account the effect of shell elasticity (Es), shell resistance (Ω), surface tension (σ) and their variation, on the microbubble dissolution. The values of these shell parameters have then been estimated using the proposed model and the experimental data available in literature. The proposed model accurately predicts the experimental microbubble dissolution data using estimated values of shell parameters. Analysis of the results further show that the surface tension and shell resistances change drastically during the microbubble dissolution process and the variation in these parameters during the dissolution process is highly dependent on the shell elasticity which in turn affects the microbubble dissolution times. The methodology developed in this work can be used to estimate shell parameters for any microbubble formulation, to accurately predict in-vitro/in-vivo dissolution of microbubbles, and hence to design a microbubble system with desired characteristics and performance.

Effect of ultrasound and stabilizers on nucleation kinetics of curcumin during liquid antisolvent precipitation.

Nucleation kinetics of liquid antisolvent precipitation of a poorly water soluble drug curcumin in presence of ultrasound and surfactants have been estimated. Ultrasound and stabilizers were found to have opposing effects on induction time (τ ind), metastable zone width (MSZW) and nucleation rates (J) of curcumin during antisolvent precipitation. The use of ultrasound (in presence or absence of stabilizers) was found to decrease τ ind and MSZW drastically while the values of nucleation rates were found to increase. In contrast to these observations, use of stabilizers (in presence or absence of ultrasound) were found to increase MSZW, increase τ ind and lower the nucleation rates (J) of curcumin. The solid-liquid interfacial energies (γSL) for curcumin in aqueous ethanolic solutions (with and without stabilizers) have also been calculated using experimentally estimated induction time (τ ind) and supersaturation data. The values of solid-liquid interfacial energies were found to be in the range of 1.5-3.5 mJ/m(2). In comparison to these values, the values of γSL predicted by Mersmann equation and equation proposed by Bennema and Sohnel were found to be significantly higher and were in the range of 10-30 mJ/m(2).