Probe Liquids Research Articles

Characteristics of Polypeptide/Phospholipid Monolayers on Water and the Plasma‐Activated Polyetheretherketone Support

AbstractPolyetheretherketone (PEEK) is a highly biocompatible polymer widely used in medicine as an implant production material. In this article, the PEEK surface was characterized in terms of its wettabillity properties after the physicochemical modifications by treatment with the low‐temperature air plasma and covering with the Langmuir–Blodgett (LB) monolayers of polypeptide (cyclosporine A, CsA) and/or phospholipid (1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine, DPPC). The LB deposition was preceded by the analysis of miscibility and morphology of monolayers at the air/water interface by means of the Langmuir technique and Brewster angle microscopy (BAM). Then, wettability of the polymer‐supported films was evaluated by the contact angle measurements of three probe liquids of different characters (two polar—water and formamide, one apolar—diiodomethane). The measured contact angles allowed for determination of the surface free energy and its components based on the Lifshitz‐van der Waals/acid–base (LWAB) approach. Some relations between the kind and magnitude of interactions within the model membranes on the water subphase and those of the PEEK‐supported membranes with the liquids were found out. The results allowed obtaining the interesting models of biological coatings with potential applications.

Self-doped SnO2:F synthesis by aerosol-spray deposition technique and their application in relative humidity sensor devices

Fluorine-doped tin-oxide (SnO2:F) thin films were prepared by aerosol-spray deposition technique on soda lime glass substrate by one-step deposition process. Tin (II) fluoride (SnF2) was used as source of tin (Sn) and doping element fluorine (F), to synthesis a self-doped transparent conducting electrode. The doping concentration of the thin films was controlled by varying deposition temperature and the molar concentration of the SnF2 solution. Electrical resistivity of the samples was measured by Van Der Pauw method and the mobility was calculated by Hall measurement technique. SnO2:F thin films grown under optimum condition showed 1.2 × 10−4 Ω-cm resistivity and 6.5 × 1020/cm3 carrier concentration. Surface-free energy of the deposited thin films was calculated from the measurement of contact angle for three different probe liquids using the Wendt theory. Sample grown at optimum condition showed the lowest surface-free energy of 63.55 mJ/m2 with dominating polar component. Reduced graphene oxide was used to produce a resistive humidity-sensing device to study the effectiveness of FTO thin film as back electrode. Maximum of 18.27% responsivity was observed for the relative humidity of 90% along with the sensitivity of 1.16 Ω/% RH.

NMR cryoporometry of polymers: Cross-linking, porosity and the importance of probe liquid

The morphology of cross-linked polymers plays an important role in their physical and chemical properties. NMR cryoporometry allows for the investigation of these structures over different length scales, through appropriate choice of probe liquid. The different structures of two different polymeric samples, one a cross-linked polymer hydrogel, the other a pore-expanded ion-exchange polymer, are analysed here. The ability for NMR cryoporometry to analyse both polymeric materials in the swollen state is successfully demonstrated, as is the importance of probe-liquid choice for the analysis of different regions of the pore structure. In both cases, water is used to identify populations of pores smaller than ca. 5 nm. The use of t-butanol and menthol reveals the presence of additional mesoporous structures in the ion-exchange resin as well as the responsiveness of the pore structure to the liquid used to swell it.

Experimental methods in chemical engineering: Contact angles

AbstractThe contact angle (CA) formed at equilibrium at the three‐phase line of contact between a liquid, a solid, and a gas may be expressed as a function of both the interfacial and surface tensions. Young first derived this thermodynamic relationship in 1805. In practice, multiple CA values are observed due to kinetic phenomena induced by evaporation, vapour adsorption, or swelling, and thermodynamic ones induced by roughness and surface chemical heterogeneities, even at molecular‐scale. These non‐ideal conditions result into an hysteresis, i.e., a difference between wetting and dewetting behaviours, and Young's equation rarely applies. Three measuring methods stand out for their applicability and reliability. In the sessile drop method, a syringe deposits a liquid drop on a flat surface and the contact angle is measured through optical means based on the drop shape. In the Wilhelmy balance method, the force required to immerse a solid plate in a bath of liquid is indirectly related to the contact angle. In the Washburn capillary rise method, the contact angle is derived from the rate at which a liquid rises by capillarity through a packed bed of powder. Employing probe liquids of various polarities, the free surface energy of the solid may be estimated. Over the last two years, 8600 published articles mentioned “contact angle” in their topic. Their main focus was either to develop the fundamental understanding of wetting science, or to assess the success of surface modification methods for the production of novel surfaces, composites, and membranes with enhanced wetting, adhesive, and filtration properties.

Determination of pore structures and dynamics of fluids in hydrated cements and natural shales by various 1H and 129Xe NMR methods

Cements and shales play a vital role in the construction and energy sectors. Here, we use a set of advanced NMR methods to characterize the porous networks and dynamics of fluids in hydrated cement and shale samples. We compare the properties of cements from two different manufacturers, BASF and Portland, as well as shales brought from USA and China. 129Xe NMR spectra of xenon gas adsorbed in the samples indicate that the capillary mesopores are smaller and the exchange between free and confined gas is slower in the Portland than in the BASF cement samples. The pores probed by xenon in the shale samples from USA are significantly smaller than in the cement samples, partially in the micropore region. There is a substantial difference in between the 129Xe spectra of shales from USA and China. Whereas the latter show a clear signature of paramagnetic impurities by exhibiting large negative 129Xe chemical shifts (referenced to the free gas), the samples from USA lack the negative chemical shifts but feature large positive shift values, which may indicate the presence of micropores and/or paramagnetic defects. 1H NMR cryoporometry measurements using acetonitrile as probe liquid allowed the observation of mesopores in the shale samples as well, and T2-T2 relaxation exchange experiment enabled the quantification of the exchange rates between free and confined acetonitrile.

Optical fibre liquid sensor for cryogenic propellant mass measurement

The authors report a one-piece flexible liquid level optical fibre sensing probe in this Letter, which is meant to measure the liquid level inside the cryogenic propellant tanks of spacecraft and rockets. The ultra-lightweight sensing probe can be used in both aerospace vehicles and in any type of cryogenic fluid storage system. In contrast to current liquid gauging technologies such as Delta-P pressure sensor, capacitance probe, ultrasonic sensor, and silicon diode liquid level sensing probe, the fibre optic continuous liquid level sensor has unique advantages in terms of gauging accuracy, reliability, simplicity, and maintenance. The sensor uses one single optical fibre probe to measure the liquid level and the liquid distribution of cryogenic propellant. Every point of the sensing fibre is a ‘point sensor’ that is able to distinguish liquid and vapour. The physical location of each ‘point sensor’ can be determined with 1 mm spatial resolution or better. The optical fibre probe can be installed in a propellant tank with the same manner as currently used silicon diode liquid level sensing probe via only one single feed-through to connect to an optical signal interrogation unit located outside the tank. Experiments on measuring liquid nitrogen level are demonstrated.

Influence of Multiple Factors on the Wettability and Surface Free Energy of Leaf Surface

The wettability of plant leaves directly reflects leaf hydrophilicity, which is the key factor that influences the adhesion of liquid pesticide as well as affects plant protection products (PPP) efficacy. Generally, the wettability of leaf surface is quantified by the contact angle and surface free energy (SFE), which are mainly dependent on leaf surface properties, liquid properties and other spraying parameters. Therefore, the aim of this paper was to investigate the SFE of rice and rape leaves with the variation of leaf status, leaf surface, and probe liquid as well as the influence of droplet falling height, solid surface, and PPP concentration on the wettability. The results showed that: (1) the dispersive components of SFE of rice and rape account for a large proportion which are closely related to their hydrophobicity—the abaxial of rape new leaf and the adaxial of rape old leaf are easier to wet comparing with rice and rape leaves in other statuses; (2) the increase of droplet falling height had a significant effect on improving the wettability between wax surface and adjuvant solution, while it had little improving effect on the wettability between wax surface and water; (3) the wettability of different solid surface varied greatly, and the order of wettability from good to bad is water-sensitive paper (WSP), wax, rape leaf, and rice leaf; (4) the effect of PPP concentration on the leaf surface wettability is significant, the contact angle decreased with the increase of PPP concentration, and the wettability of microemulsion is better than that of suspending agent and wettable powder. In conclusion, the SFE and wettability of crop leaf surface determine the suitable type of PPP, studying the influence of multiple factors on leaf surface wettability can provide a reliable reference for providing scientific guidance as well as improving the effective utilization of PPP.

Wettability of DPPC Monolayers Deposited from the Titanium Dioxide–Chitosan–Hyaluronic Acid Subphases on Glass

The investigations were carried out to determine wettability of the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monolayers transferred from the liquid subphases containing chitosan (Ch), hyaluronic acid (HA), and/or titanium dioxide (TiO2) to a glass support by means of the Langmuir–Blodgett (LB) technique. For comparative purposes, the analysis of the plates surfaces emerged from the analogous subphases without the phospholipid film was also made. Characterization of the DPPC monolayers was based on the contact angle measurements using three test liquids (water, formamide, diiodomethane) and a simulated body fluid (SBF) solution in which the concentration of ions was close to that of human plasma. After deposition of the DPPC monolayers on the glass plates, a significant increase in the contact angles of all the probe liquids was observed compared to the plates pulled out from the given subphase without floating DPPC. The presence of phospholipid monolayer increased the hydrophobic character of the surface due to orientation of its molecules with hydrocarbon chains towards the air. In addition, the components of the subphase attached along with DPPC to the glass support modify the surface polarity. The largest changes were observed in the presence of TiO2.

Wetting hysteresis of atomically heterogeneous systems created by low energy inert gas ion irradiation on metal surfaces: Liquid thin film coverage in the receding mode and surface interaction energies

Atomically heterogeneous systems, which are created by low energy (0.5 keV) inert gas ion irradiation on metallic surfaces exhibit wetting properties that are characteristically different from those containing physical or patchwise chemical heterogeneities. The wetting properties of such systems are dictated by modification of intermolecular forces by near-surface implanted impurities, leading to a modified effective Hamaker constant. In the present study, special attention is devoted to look at the wetting hysteresis of such systems. It is found that the contact angle is almost a constant in the advancing mode and a finite hysteresis is observed during the receding process, which is believed to arise from liquid retention in the receding mode. We conclude that the nanoscale roughness and the atomic-scale heterogeneities induce negligible pinning and in the receding mode, the solid exhibits a modified effective Hamaker constant which is dependent on the probe liquid. In the advancing mode, however, the effective Hamaker constant is independent of the liquid and depends only on the solid and the embedded ionic species. The evidence of liquid retention has been further validated by a model involving the effective enhancement of surface free energy due to coverage of a thin liquid film.

Predicting the adhesion strength of thermoplastic/glass interfaces from wetting measurements

To evaluate compatibility between a substrate and a thermoplastic polymer, the established methodology is to estimate their surface composition in terms of surface energy components, utilizing the results of contact angle measurements of probe liquids onto substrate and polymer surfaces at room temperature. Using this methodology, polymer surfaces are studied in solid state, however, during spreading of polymers on a substrate, polymers are in molten state and at high temperature, having different surface energies and more complex polymer/substrate interactions due to polymer chain mobility.This paper presents a model study with practical relevance to predict polymer/substrate compatibility including contact angle measurements at high temperature directly performed between molten thermoplastics; polypropylene (PP), polyvinylidene fluoride (PVDF) and maleic anhydride-grafted polypropylene (MAPP), on smooth glass fibres and plates. The values of total surface energy of thermoplastics at high temperature (260 °C) are down to 57% of that measured at room temperature, which has a strong influence on the wetting prediction. Surface energies of both the polymer and the substrate were found not to be the only factor controlling the wetting behaviour of molten polymers and the level of adhesion with the substrate, but also some intrinsic characteristics of the polymer melt play a role. We also observed that the wetting behaviour of molten MAPP is affected by the maleic anhydride (MA) content, demonstrating dramatically different results to room temperature measurements, which is suspected to be due to the formation of covalent bonds of MA groups with the glass surface enhancing the interface strength beyond the shear strength of MAPP.

Wettability, surface free energy and cellulose crystallinity for pine wood (Pinus sp.) modified with chili pepper extracts as natural preservatives

Fresh chili peppers (Malagueta, Red Savina and Bhut Jolokia) were used as natural finishing agents for Pinus sp. (Pinus). The solvent extraction of dried peppers produced a viscous liquid primarily containing capsicin, a pungent, lipophilic compound, and known as oleoresin capsicum (OC). Changes in surface wettability were monitored by the sessile-drop technique for samples treated with OC. The contact angles for untreated and treated Pinus provided the values of surface energy, with its polar and dispersive components, and polarity ratios. When treated with OC extracted from more pungent peppers, such as Bhut Jolokia, Pinus showed higher contact angles in non-polar probe liquids and higher polarity. The protective efficacy of OC was investigated against two wood-decay fungi, Paecilomyces variotii (soft-rot fungus) and Pycnoporus sanguineus (white-rot fungus). The treated samples, when submitted to fungal decay, exhibited reduced percentage of mass loss, which indicated that OC can afford surface protection under the conditions studied here. Changes in cellulose crystallinity were observed owing to distinct contributions from amorphous and crystalline zones of Pinus after fungal decay.

Assessing omniphobicity by immersion

HypothesisCoating-free approaches to achieve liquid repellent, or omniphobic, surfaces could exploit inexpensive intrinsically wetting materials, such as polyethylene terephthalate and nylon, for applications such as liquid-vapor extraction and drag reduction. However, it is not clear whether the existing criteria for assessing coating-based omniphobicity, based on contact angles, would be reliable for coating-free approaches, especially considering localized defects/damages during manufacturing and usage. ExperimentsWe assessed the omniphobicity of silica surfaces adorned with arrays of doubly reentrant pillars, cavities, and hybrid designs with sessile drops and on immersion in water and hexadecane through contact angle goniometry and confocal microscopy. FindingsWe demonstrate that the assessment of omniphobicity of surfaces derived from intrinsically wetting materials can be misleading, if solely based on the measurement of contact angles. Specifically, localized defects in microtextures consisting of pillars may lead to the spontaneous loss of omniphobicity and detecting them through contact angles can be difficult. We also demonstrate that the immersion of those surfaces into probe liquids may serve as a simple and quick ‘litmus’ test for omniphobicity. Thus, immersion as the additional criterion for omniphobicity might prove itself useful in the context of large-scale manufacturing.

Scalable novel PVDF based nanocomposite foam for direct blood contact and cardiac patch applications

Scalable novel beta phase polyvinylidene fluoride-poly(methyl methacrylate) (PVDF-PMMA) polymer blend based nanocomposite foam with hydroxyapatite (HAp) and titanium dioxide (TiO2) as nanofillers (β-PVDF-PMMA/HAp/TiO2) (β-PPHT-f), was prepared by using salt etching assisted solution casting method. The prepared β-PPHT-f nanocomposite material was characterized using XRD, FT-IR, SEM-EDS. The XRD and FTIR results confirmed the formation of β phase of β-PPHT-f. The SEM and EDS results confirmed the formation of high porous structured closed cell type morphology of β-PPHT-f. It also, confirmed the uniform distribution of Ti, Ca, P, N and O, in β-PPHT-f. Contact angle measurements performed using sessile drop method with water and EDTA treated blood (EDTA blood) as probe liquids revealed that β-PPHT-f is hydrophilic with contact angle of 48.2° as well as hemophilic with contact angle of 13.7°. Porosity, fluid absorption and retention investigation by gravimetric analysis revealed that β-PPHT-f was 89.2% porous and can absorb and retain 139.15% and 87.05% of water and blood, respectively. The hemolysis assay performed as per ASTM F756 procedure revealed that β-PPHT-f is non hemolytic. Also, the Leishman stained blood smears prepared from whole blood incubated with β-PPHT-f for 3, 4, 5 and 6 h at 37 °C revealed that the blood cells were not affected by β-PPHT-f, its surface morphology and elemental composition. H9c2 cell line studies on a transparent film prepared using β-PPHT-f revealed that the elemental composition of the nanocomposite favored H9c2 cell adhesion and differentiation. All the characterization results indicate that the newly developed scalable novel β-PPHT-f is hemocompatible and cardiomyocyte compatible, suggesting it as a useful material for direct blood contact and cardiac patch applications.

Dual Superlyophobic Aliphatic Polyketone Membranes for Highly Efficient Emulsified Oil-Water Separation: Performance and Mechanism.

Efficient treatment of difficult emulsified oil-water wastes is a global challenge. Membranes exhibiting unusual dual superlyophobicity (combined underwater superoleophobicity and underoil superhydrophobicity) are intriguing to realize high-efficiency separation of both oil-in-water and water-in-oil emulsions. For the first time, a robust polymeric membrane demonstrating dual superlyophobicity to common apolar oils was facilely fabricated via a simple one-step phase separation process using an aliphatic polyketone (PK) polymer, thanks to a conjunction of intermediate hydrophilicity and re-entrant fibril-like texture upon the prepared PK membrane. Further chemical modification to improve surface hydrophilicity slightly can enable dual superlyophobicity to both apolar and polar oils. It is found that a nonwetting composite state of oil against water or water against oil was obtainable on the membrane surfaces only when the probe liquids possess an equilibrium contact angle (θow or θwo) larger than the critical re-entrant angle of the textured surfaces (73°), which can explain the existences of dual superlyophobicity and also the nonwetting to fully wetting transitions. A simple design chart was developed to map out the operational windows of material hydrophilicity and re-entrant geometry, that is, a possible zone, to help in the rational design of similar interfacial systems from various materials. Switchable filtrations of oil-in-water and water-in-oil nanoemulsions were achieved readily with both high flux and high rejection. The simplicity and scalability of the membrane preparation process and the well-elucidated underlying mechanisms illuminate the great application potential of the PK-based superwetting membranes.

Extending the range of liquids available for NMR cryoporometry studies of porous materials

Abstract Nuclear magnetic resonance (NMR) cryoporometry, although well established, can be limited by the inability of any one liquid to probe a broad range of pore sizes, a relatively small number of commonly-used probe liquids and the requirement to match the probe liquid to the chemistry of the material being studied. Here we demonstrate, for the first time, the use of menthol and t-butanol as probe liquids in NMR cryoporometry measurements. Using appropriate estimates for the values of the melting point depression constant, kc, and the non-freezing surface layer, 2sl, NMR melting data was converted into pore size distributions. The melting point depression constant for t-butanol is similar to that of cyclohexane; however due to its functionality, t-butanol may be the preferred liquid used to study the porosity of hydrophilic materials. Menthol, having a larger value of kc, can accurately analyze larger pore sizes up to 100 nm. This represents the first use of menthol and t-butanol to accurately probe pore dimensions in NMR cryoporometry.

Surface-wetting characterization using contact-angle measurements.

Wetting, the process of water interacting with a surface, is critical in our everyday lives and in many biological and technological systems. The contact angle is the angle at the interface where water, air and solid meet, and its value is a measure of how likely the surface is to be wetted by the water. Low contact-angle values demonstrate a tendency of the water to spread and adhere to the surface, whereas high contact-angle values show the surface's tendency to repel water. The most common method for surface-wetting characterization is sessile-drop goniometry, due to its simplicity. The method determines the contact angle from the shape of the droplet and can be applied to a wide variety of materials, from biological surfaces to polymers, metals, ceramics, minerals and so on. The apparent simplicity of the method is misleading, however, and obtaining meaningful results requires minimization of random and systematic errors. This article provides a protocol for performing reliable and reproducible measurements of the advancing contact angle (ACA) and the receding contact angle (RCA) by slowly increasing and reducing the volume of a probe drop, respectively. One pair of ACA and RCAmeasurements takes ~15-20 min to complete, whereas the whole protocol with repeat measurements may take ~1-2 h. This protocol focuses on using water as a probe liquid, andadvice is given on how it can be modified for the use of other probe liquids.

The Wilhelmy method: a critical and practical review

A brief history of the Wilhelmy technique for surface tension and contact angle measurements introduces the equation and the methods necessary to apply this modern and automatic procedure correctly. Many simple practices may avoid systematic errors and allow reliable results to be obtained for both quantities. The paper analyzes not only simple runs – that is, applications to standard shapes such as cylinders and parallelepipeds, rigid, non-porous samples immersed in probe liquids of low viscosity – but also non-simple runs – that is, applications to non-standard samples such as disk-shaped samples, porous and flexible samples, planar samples with different contact angles on their two opposite faces, and to the case of more viscous fluids. Many experimental details such as the size ratio of specimens to the liquid container may be extremely important; their role and the history of discussion about these topics are reviewed and discussed herein. Also, the possible determination of contact angles other than the usual advancing and receding ones is addressed.

An Optical Configuration of Crossed-Beam Photothermal Lens Spectrometer Operating at High Flow Velocities and Its Application for Cysteine Determination in Human Serum and Saliva.

Photothermal lens spectrometry (TLS) is a high sensitive technique for trace determination of nonfluorescent materials. Previous photothermal lens spectrometers suffer from operating limitations at high flow velocities, arising from taking the heated element off the probe beam direction, which results in a decrease in the thermal lens (TL) signal. Herein, we describe an optical configuration of the crossed-beam photothermal lens in transversal flow mode in which the propagating direction of the probe beam and liquid sample flow azimuth are concentric (CBTC). The system consists of a microfluidic cell with a volume of lower than 3 μL. In the current optical configuration, using 1-(2-pyridylazo)-2-naphthol (PAN) in ethanol as a test solution, by increasing the sample flow velocity and without increasing chopping frequency, the reduction in sensitivity is less pronounced. Under a 15 Hz chopping frequency, the optimum sample flow velocity is about 2 cm s-1, which is among the highest reported values achieved to date for photothermal lens spectrometers. Although the system operates at higher flow velocities and lower chopping frequencies compared to the collinear configuration, it provides a comparable analytical limit of detection. This optical configuration has been successfully employed for highly sensitive and selective determination of cysteine in human serum and saliva samples through a competitive complexation reaction with Cu-PAN as a colorimetric probe. The detection limit of this method (9.5 nM) shows a significant enhancement (726-times) in comparison to UV-vis measurements.

Different methods of selecting probe liquids to measure the surface free energy of asphalt binders

The present study evaluates two different methods for selection of probe liquids to determine the surface free energy (SFE) of asphalt binders: (i) Condition Number (CN) of probe liquids, and (ii) plot between cosine of total SFE (ϒL Cosθ) and total SFE of probe liquids (ϒL). Five different probe liquids, i.e. Water (W), Formamide (F), Ethylene Glycol (E), Diiodomethane (D), and Glycerol (G) were selected. Overall, ten different combinations of probe liquid triplets (W-G-F, W-G-E, W-G-D, W-F-E, W-F-D, W-D-E, G-F-E, G-F-D, F-E-D, and D-E-G) were formed to examine CN and plot of ϒL Cosθ versus ϒL. Three asphalt binders, namely unmodified (VG30), SBS polymer modified binder (PMB40) and crumb rubber modified (CRMB60) binders were selected for the present study. The contact angle of asphalt binders was measured using sessile drop method, and SFE of each of the selected asphalt binders was determined for all ten combinations of probe liquids. Thereafter, CN of probe liquid triplets was determined using Singular Value Decomposition (SVD) method. In addition, ϒL Cosθ versus ϒL plot was made for triplets using the measured contact angles of probe liquids. The CN approach and ϒL Cosθ versus ϒL plot were compared based on binder’s total SFE to identify a better approach for selecting appropriate probe liquid triplets. CN approach was observed to be superior compared to the plot of ϒL Cosθ versus ϒL. In fact, it was observed that the plot approach may not be valid for asphalt binders.

Wettability of plasma modified glass surface with bioglass layer in polysaccharide solution

Wetting properties of glass surface covered with a bioglass layer in the hyaluronic acid (HA), alginate (AL) or mixed solution were determined from the contact angle measurements by the sessile drop method. Air plasma modification of plates to increase adhesion was performed in the low-temperature plasma system. Adhesion of bioglass in the polysaccharide solution on the original glass plates usually increases hydrophobic character of glass surface insignificantly in such a way that hydrocarbon chains are directed outwards and the polar part towards the glass surface. However, after the plasma action hydrophilic character of glass (and glass with biological layer) surface increases again. The changes of glass surface wettability are evidently dependent on the kind of used probe liquid and concentration of bioglass in the polysaccharide solution. Using an optical profilometer, the surface roughness of the plates was determined. An effective smoothing of the bioglass/polysaccharide surface was obtained on the plasma treated surface. The correlation between the hysteresis of water (and/or simulated body fluid) wetting angles and the topography of the surface was found for such mixed systems. However these results are somehow preliminary, it seems that cold plasma modification is an interesting tool for the development of the effect of bioglass adhesion and change of hydrophobicity/hydrophilicity character of glass materials in order to increase the spectrum of its pharmaceutical application.