N-vinyl Caprolactam Research Articles

Biophysical study on the phase transition behaviour of biocompatible thermoresponsive polymer influenced by tryptophan-based amino acid ionic liquids

Biocompatible thermoresponsive polymers are known to have numerous biomedical applications as they are capable of exhibiting a change in conformational states on changing the solution temperature. Poly(N-vinyl caprolactam) (PVCL) is one such polymer assessed frequently on conformational changes with biomolecules due to its amphiphilic nature. The goal of this work is to explore the impact of two tryptophan-based amino acid ionic liquids (AAILs), such as cholinium tryptophan ionic liquid ([CHO][Trp]IL) and tetraethylammonium tryptophan ionic liquid ([TEA][Trp]IL) on phase transition behaviour of aqueous PVCL solution. Biophysical techniques like steady-state fluorescence spectroscopy, thermal fluorescence spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS) and differential scanning calorimetry (DSC) are used to investigate the phase transition behaviour of aqueous PVCL-AAILs solution. The lower critical solution temperature (LCST) of PVCL was elevated by 4 and 2 °C on increase in the concentration from 1 to 5 mM of [CHO][Trp]IL and [TEA][Trp]IL, respectively. On comparing both AAILs, [CHO][Trp]IL has shown higher LCST (near to human physiological temperature) with aqueous PVCL solution than [TEA][Trp]IL due to its additional hydrogen bonding ability and its higher hydrophilicity compared to [TEA][Trp]IL. The structural functionalities of the cholinium cation like hydroxyl group and methyl substituents make it more advantageous than tetraethylammonium cation. This is the first time study on the phase transition behaviour of biocompatible thermoresponsive polymer PVCL influenced by tryptophan-based AAILs. These findings could be exploited for the development of biocompatible polymer to use in drug delivery and other biomedical applications.

Biocompatible thermo-responsive N-vinylcaprolactam based hydrogels for controlled drug delivery systems

The treatment of several diseases requires drugs commonly administered orally or intravenously. Said administration has several drawbacks, such as low control of the necessary drug levels in plasma, making the treatment ineffective and, furthermore, side effects and low compatibility with the patient. Recently, the use of stimuli-responsive hydrogels in controlled Drug Delivery Systems (DDSs) has been considered an excellent alternative because of its inherent biocompatibility, responsiveness to physiological changes in the body, and diversity of both natural and synthetic material options. The present work focuses mainly on the synthesis, characterization, and drug release capacity of poly (N-vinyl caprolactam) (PVCL) and poly (N-vinyl caprolactam) microgels crosslinked with various concentrations of poly (ethylene glycol) diacrylate (PEGDA), which show temperature stimuli-responsiveness near the physiological temperature of the human body. For that reason, changes in the average hydrodynamic particle diameter at different temperatures are estimated and correlated with the drug release rate. The model drug chosen for releasing studies is colchicine, a potential drug for gout disease treatment, currently in disuse because of its low therapeutic index. It is expected that the use of the control release procedure by drug encapsulation in this polymer overcomes this drawback. The synthesis of PVCL homopolymer and three VCL-co-PEGDA hydrogels varying the PEGDA crosslinker concentration was successfully carried out by emulsion polymerization. Their characterization was performed by DLS and FTIR spectroscopy. Polymerization yields were estimated by total solids analysis, and UV-VIS determined the cloud points. Finally, the drug loading and release over time were monitored by HPLC and UV-VIS spectroscopy showing that drug release profiles obtained corresponded to a sustained drug delivery system.

Rational Design and Experimental Research on the Self-Assembled System of Thermosensitive Molecularly Imprinted Polymers Formed by α-Lipoic Acid and N-Vinyl Caprolactam

In this paper, the main work was to study the theoretical self-assembly process of thermosensitive molecularly imprinted polymers (MIPs) for α-lipoic acid and to investigate thermosensitive functional monomers through density functional theory calculations (DFT) and intermolecular weak interaction analysis. The M06-2X/6-311+G (d, p) level was used to study the structural parameters, bonding sites, natural population analysis, binding energies ( Δ E ), atom in molecules (AIM), independent gradient model (IGM), and imprinted molar ratio. The results revealed that α-lipoic acid mainly interacted with N-vinyl caprolactam (NVCL) by weak hydrogen bonds, and the best conditions for MIP synthesis were an optimum molar ratio of 1 : 4 (α-lipoic acid/NVCL). The thermosensitive properties showed that the highest adsorption was at 40°C and the lowest adsorption was at 20°C; also, the MIPs released the intercepted α-lipoic acid inside polymers, and the lower critical solution temperatures (LCST) of MIPs and nonimprinted polymers (NIPs) are 25.7°C and 19.4°C, respectively. In this study, the thermosensitive MIPs displayed a different adsorption capacity towards NVCL, which could be applied for controlled separation and release of α-lipoic acid in different temperatures in a complex matrix.

Gold nanorods-encapsulated thermosensitive drug carriers for NIR light-responsive anticancer therapy

Thermoresponsive polymers incorporated with photo-absorbing agents have been widely utilized for controlled drug delivery using light as an external stimulus. However, previously developed thermoresponsive drug carriers have disadvantages such as low biocompatibility and implantation failure. In the present study, gold nanorods (GNRs)-encapsulated poly(N-vinyl caprolactam) (PVCL) (GNR-PVCL) microparticles were synthesized by the stop-flow lithography (SFL) method. The SFL method enabled the fabrication of near-infrared (NIR) light-responsive GNR-PVCL microparticles of uniform size, which can allow localized injection. Doxorubicin (DOX) was encapsulated into GNR-PVCL microparticles to achieve NIR light-responsive anticancer therapy. DOX-loaded GNR-PVCL (DOX-GNR-PVCL) microparticles exhibited NIR light-triggered drug release due to the photothermal effect of GNRs, which increases the local temperature above the volume phase transition temperature of GNR-PVCL microparticles. In addition, DOX-GNR-PVCL exhibited controlled DOX release in response to the periodic irradiation of NIR light. Moreover, we demonstrated the efficient intracellular release of DOX upon NIR light exposure, and thus, NIR light-responsive anticancer activity. This study demonstrates that DOX-GNR-PVCL microparticles have significant potential as implantable drug carriers enabling NIR light-triggered drug release.

Preparation of poly(N-vinyl caprolactam) with various end groups using chain transfer agents and evaluation of their effects on kinetic hydrate inhibition

Poly(N-vinylamide) derivatives were synthesized to improve the performance of kinetic hydrate inhibitors (KHIs). In this work, we synthesized poly(N-vinylformamide) (PNVF) and poly(N-vinylcaprolactam) (PVCap) by free radical polymerization with several commercial chain transfer agents (CTAs), which afforded a few thousand Mn. The structures of synthesized PNVF and PVCap were then investigated by 1H NMR and MALDI-TOF/MS spectrograms. KHI properties of the synthesized PNVF and PVCap polymers were also evaluated by the high-pressure slow constant cooling KHI test method. Some of the tested polymers showed a better KHI effect than PVCap.

UV-C를 이용한 빠른 N-Vinyl Caprolactam 광중합 연구

Different polymerization techniques of poly(N-vinyl caprolactam) (PNVCL) have been reported including the photo polymerization via ultraviolet (UV). However, photo polymerization of PNVCL via UV-C (wavelength of 254 nm) has not been reported. In this study, N-vinyl caprolactam was polymerized via UV-C irradiation at different time periods. Fouirer transform infrared spectroscopy (FTIR) analysis showed that the PNVCL has been successfully synthesized via the photo polymerization method. The optimum conversion time was found as about 70 min and the conversion was found as 71.2%. Gels displayed different swelling behavior at temperatures above and below lower critical solution temperature (LCST), and swelling analysis, dynamic light scattering (DLS) and differential scanning calorimetry (DSC) were performed to investigate the phase change behavior. It was observed that LCST of the synthesized gels occurs between 31 and 35 oC determined by DSC analysis, which is also consistent with DLS and swelling analysis results. In conclusion, a facile and short time period polymerization technique is reported via use of UV-C photo polymerization technique.

Computational Study of the Formation Reaction of Polyacid Precursors of Glass-Ionomer Materials

The formation of polyacids in a glass-ionomer cement was computationally modeled. The polyacid modelled is an oligomer made up of three molecules: acrylic acid, itaconic acid and an additional molecule that acts as a spacer group between the previous two. Acryloyl and meta-acryloyl derivatives of some amino acids and related molecules such as N-vinyl pyrrolidone and N-vinyl caprolactam were used as spacer groups. Some of these molecules have been previously used experimentally as spacer groups. In this work the spacer behaviour of 15 different molecules was investigated. To our knowledge, this is the first computational attempt to model some promising molecules to be incorporated into glass-ionomer dental cements. The results revealed the best structural arrangement for the investigated molecules.

Physicochemical aspects of inorganic nanoparticles stabilized in N-vinyl caprolactam based microgels for various applications.

The vinyl caprolactam (VCL) based microgel system has become the center of great attention due to its versatile properties. Copolymerization of VCL with an ionic monomer imparts pH responsive properties into the microgel system in addition to thermo-sensitivity. Stimuli responsive behavior of VCL-based microgels makes them prospective and appealing candidates for practical applications covering the fields of drug delivery, catalysis and optical devices. In the last few years, VCL-based microgels have been used as microreactors and stabilizers for the synthesis and stabilization of inorganic nanoparticles to obtain hybrid microgels. The present review article provides a summary of the present-day progress of fabrication, stabilization, categorization and analysis of VCL-based microgels and their hybrids with different morphologies. The stimuli responsive properties and applications of VCL-based hybrid microgels have been reviewed critically. The remaining problems which need to be addressed have been pointed out for further advancement in this field.

Development of a methodology for the study of polymer wound coatings for application characteristics

This paper reports a research methodology for characterizing wound dressings in order to assess the application properties of medical devices as a whole. Wound dressing was based on grafting polymerization of N-vinyl caprolactam and 2-hydoxyethyl acrylate on polyvinyl alcohol. The obtained copolymer was characterized by FTIR. Cross-linked films of wound dressings were obtained by radiation treatment of the copolymers. The physico-mechemical properties of wound dressings were investigated. Testing included degree of swelling, elastic modulus, tensile strength and elongation at break. The radiation doses of the reaction affected physico-mechanical properties of wound dressings. As the dose of radiation increased, the yield of gel increased, degree of swilling and tensile strength decreased. Also, the results indicated that the yield of the crosslinked fraction increases, and the swelling capacity of polymer mesh decreases with increasing 2-hydroxyethyl acrylate content in the graft copolymer

Synthesis and characterization of SSS/MA/NVCL copolymer as high temperature oil well cement retarder

Oil well cement additives applied in high-temperature environments play an increasingly important role in well cementing work. In this study, a ternary copolymer LNS-1 consisting of sodium styrene sulfonate (SSS), maleic acid (MA), and N-vinylcaprolactam (NVCL) was designed and synthesized using potassium persulfate as an initiator via free radical aqueous solution copolymerization, which was then used as a retarder additive for oil well cement under high-temperature conditions. The structure and performance of copolymer LNS-1 was assessed via gel permeation chromatography, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance hydrogen spectrum, Thermogravimetric analysis, and scanning electron microscopy analysis. To study the effect of the retarder on cement slurry properties, the performance of the slurry with LNS-1 was tested. The experimental results demonstrate that LNS-1 was successfully synthesized with excellent retarding ability, thermal resistance, and outstanding suspension; thus, the copolymer can serve as an excellent retarder for oil well cement. Through exploration, it is found that the mechanism of the retarder mainly includes adsorption – membrane layer mechanism and chelation – covering mechanism. NVCL exhibits good complexation, adsorption, hydrolysis stability, and thermal stability. It contains three lone pairs of electrons, which allow the NVCL to chelate Ca2+ that in the liquid phase of the cement. The number of calcium ions is therefore reduced in the cement liquid phase, and cement hydration is inhibited to a certain extent, contributing to a longer hydration process.

Evaluation of Nonelectrolyte Hydrogel Swelling and Its Pressure Effects with Simple Equation of State and Mechanical Models Using Liquid–Liquid Equilibrium Data

From the liquid–liquid equilibrium (LLE) data of a linear polymer, an investigation of the Sanchez and Lacombe equation of state (SL-EOS) is performed with the goal of describing the swelling of three hydrogels: poly(N-isopropylacrylamide), PNIPA; poly(N-vinyl caprolactam), PVCL; and poly(N-diethylacrylamide), PNDEA. The phantom theory is applied to describe the elastic contribution of the network structure. Using SL-EOS with its binary interaction parameter as a linear temperature function is sufficient to describe the lower critical solution temperature (LCST) of non-cross-linked polymers. The results demonstrate that this function is also suitable for modeling the swelling/shrinking and the transition temperature of the corresponding hydrogel. We demonstrate that a simple mechanical model and a simple EOS are sufficient to adequately describe nonelectrolyte hydrogel swelling using LLE data and only one piece of swelling data. In addition, the pressure effects on the hydrogel swelling are analyzed without the need for new parameter estimation, an analysis scarcely found in the literature.

N-Vinylcaprolactam grafting onto cotton gauze by gamma radiation for loading and controlled release of antibacterial silver nanoparticles

AbstractTo contribute to the development of new alternatives in the area of polymers for biomedical applications, the surface modification of a cotton gauze grafted with a N-vinylcaprolactam (NVCL) by ionizing gamma radiation was developed, in to provide it with more physical and chemical properties. To verify that the grafting was successful, the samples were analyzed and characterized by attenuated total reflectance, by Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The grafted samples showed greater hydrophilicity and affinity with drugs, as well as a critical solution temperature between 33 and 40 °C; therefore, this material was implemented as administrator of AgNPs in controlled doses, thus obtaining a material with greater absorption, anti-inflammatory and with antimicrobial characteristics.

Free Volume Effect via Various Chemical Structured Monomers on Adhesion Property and Relative Permittivity in Acrylic Pressure Sensitive Adhesives.

Acrylic pressure-sensitive adhesives (PSAs) are used as fixatives between layers of a display. PSAs’ function is an important factor that determines the performance of the display. Of the various display types available, the touch screen panel (TSP) of smart devices is firmly related to the relative permittivity of the elementals. Therefore, adjusting the relative permittivity of the PSA is indispensable for driving the TSP. Accordingly, selected acrylic pre-polymers were polymerized and the pre-polymer was blended and cross-linked with monomers with different chemical structure to adjust the relative permittivity. The monomers were hexametyldisiloxane (HMDS), N-vinylcaprolactam (NVC), tert-butyl acrylate (TBA), and isooctadecyl acrylate (ISTA). The gel fraction and transmittance as a function of the monomers show a similar result to the pure acrylic PSA. However, the gel fraction value decreased to about 90% and the transmittance decreased to about 85%, due to the immiscibility between nonpolar HMDS and acrylic PSA. On the other hand, the adhesion properties were improved when NVC was added because of the polarity of the nitrogen group. In addition, the relative permittivity of the PSA decreased regardless of the monomer chosen. There was, however, a difference in the optimal content of each monomer, and NVC decreased from 4 phr content to about 3.4 in reducing relative permittivity. Through the above results, it was confirmed that NVC having a nitrogen group is most advantageous in lowering adhesion properties and relative permittivity, and necessitates further research based on the findings.

Different Strategies for the Preparation of Galactose-Functionalized Thermo-Responsive Nanogels with Potential as Smart Drug Delivery Systems.

Different synthetic strategies were tested for the incorporation of galactose molecules on thermoresponsive nanogels owing to their affinity for receptors expressed in cancer cells. Three families of galactose-functionalized poly(N-vinylcaprolactam) nanogels were prepared with the aim to control the introduction of galactose-moieties into the core, the core-shell interface and the shell. First and second of the above mentioned, were prepared via surfactant free emulsion polymerization (SFEP) by a free-radical mechanism and the third one, via SFEP/reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthetic recipes for the SFEP/free radical method included besides N-vinylcaprolactam (NVCL), a shell forming poly(ethylene glycol) methyl ether methacrylate (PEGMA), while the galactose (GAL) moiety was introduced via 6-O-acryloyl-1,2,:3,4-bis-O-(1-methyl-ethylidene)-α-D-galactopiranose (6-ABG, protected GAL-monomer): nanogels I, or 2-lactobionamidoethyl methacrylate (LAMA, GAL-monomer): nanogels II. For the SFEP/RAFT methodology poly(2-lactobionamidoethyl methacrylate) as GAL macro-chain transfer agent (PLAMA macro-CTA) was first prepared and on a following stage, the macro-CTA was copolymerized with PEGMA and NVCL, nanogels III. The crosslinker ethylene glycol dimethacrylate (EGDMA) was added in both methodologies for the polymer network construction. Nanogel’s sizes obtained resulted between 90 and 370 nm. With higher content of PLAMA macro-CTA or GAL monomer in nanogels, a higher the phase-transition temperature (TVPT) was observed with values ranging from 28 to 46 °C. The ρ-parameter, calculated by the ratio of gyration and hydrodynamic radii from static (SLS) and dynamic (DLS) light scattering measurements, and transmission electron microscopy (TEM) micrographs suggest that core-shell nanogels of flexible chains were obtained; in either spherical (nanogels II and III) or hyperbranched (nanogels I) form.

Molecular dynamics study of the thermosensitive properties of poly (N-vinyl caprolactam) in water

In this work, we present molecular dynamics (MD) simulations of single poly (N-vinyl caprolactam) (PNVCL) in the water at different temperatures, from 275 to 335 K with a gradient of 10 K. The force fields of OPLS-AA and SPC model were used for PNVCL and water molecules, respectively. Simulations with durations of 200 ns were performed at each temperature for a 20-mer PNVCL chain in an isothermal-isobaric (NPT) and canonical (NVT) ensembles. The results showed that the phase transition of PNVCL chain during heating is driven by H-bonding transformation of amide groups, followed by the hydrophobic dehydration of CH group in the caprolactam ring. PNVCL exhibited a coil-to-globule transition at 305 K, corresponding to its low critical solution temperature (LCST). Below LCST, H-bonding predominated while hydrophobic interaction was dominant above LCST. PNVCL collapsed at elevated temperatures due to the weakening of the attractive forces between its hydrophobic/hydrophilic group and water molecules. The analysis of the H-bonds formation showed that PNVCL is hydrophilic and only carboxyl oxygen (C = O) in the amide group formed H-bonds with water molecules. In the collapsed state, PNVCL formed no intra H-bonds between its residues and the globule conformation was mainly due to the hydrophobic interactions between PNVCL residues. The H-bond formation played an important role in the coil-to-globule transition of PNVCL and is believed to be the key factor of its solubility.

Molecular insights into the kinetic hydrate inhibition performance of Poly(N-vinyl lactam) polymers

The inhibition mechanism and the inhibition performance of four typical kinetic hydrate inhibitors (KHIs), poly(N-vinyl pyrrolidone) (PVP), poly(N-vinyl piperidone) (PVPip), poly(N-vinyl caprolactam) (PVCap) and poly(N-vinyl azacyclooctanone) (PVAco), have been studied using first-principle calculations and simulations. The results show that the inhibitors can disturb the local water structure, but also can adsorb onto the open hydrate cage, exhibiting the features of both the perturbation-inhibition and the adsorption-inhibition. By analyzing the molecular reactivity, KHI-water interactions, and adsorption ability of KHIs, it is found that the inhibition performance of the inhibitor increases with the increase of the lactam ring size, that is, PVP < PVPip < PVCap < PVAco. This study would be helpful to understand the inhibitor working mechanism as well as to promote the inhibitor screening.

Interfacially stable MOF nanosheet membrane with tailored nanochannels for ultrafast and thermo-responsive nanofiltration

Two-dimensional nanosheet membranes with responsive nanochannels are appealing for controlled mass transfer/separation, but limited by everchanging thicknesses arising from unstable interfaces. Herein, an interfacially stable, thermo-responsive nanosheet membrane is assembled from twin-chain stabilized metal-organic framework (MOF) nanosheets, which function via two cyclic amide-bearing polymers, thermo-responsive poly(N-vinyl caprolactam) (PVCL) for adjusting channel size, and non-responsive polyvinylpyrrolidone for supporting constant interlayer distance. Owing to the microporosity of MOF nanosheets and controllable interface wettability, the hybrid membrane demonstrates both superior separation performance and stable thermo-responsiveness. Scattering and correlation spectroscopic analyses further corroborate the respective roles of the two polymers and reveal the microenvironment changes of nanochannels are motivated by the dehydration of PVCL chains.

Thermal and enzymatic dual‐stimuli responsive linear‐dendritic block copolymers based on poly(N‐vinylcaprolactam)

The first‐ and second‐generation well‐defined thermal and enzymatic dual‐stimuli responsive amphiphilic linear‐dendritic block copolymers (LDBCs) based on hydrophilic linear poly(N‐vinylcaprolactam) (PNVCL) and a hydrophobic Fmoc‐terminated dendron derived from an aliphatic polyester of 2, 2′‐dimethylolpropionic acid (bis‐MPA) have been synthesized via a combination of reversible addition fragmentation chain transfer (RAFT) polymerization of N‐vinylcaprolactam (NVCL) and “chain‐first” strategy. The copolymers were characterized by 1H NMR spectra and gel permeation chromatograph (GPC) analyses, showing controlled molecular weight and narrow molecular weight distribution (PDI ≤1.27). They self‐assemble in water into vesicles that are able to disrupt and release encapsulated cargos upon papain treatment. Their thermal‐responsive property was highly dependent on the generation and concentration of copolymers, and enzyme‐responsive behavior was affected by the generation of dendritic aliphatic polyester block. Moreover, papain influenced the thermal‐responsive behavior of the copolymers. Such smart copolymers could be efficiently used in drug delivery systems or biosensors.

Intrinsic viscosity of poly(N-vinylcaprolactam) with varying the architecture

Five CTA’s xanthate-type were synthesized and characterized and used in the controlled polymerization of N-vinylcaprolactam (NVCL) via reversible addition-fragmentation chain transfer (RAFT) polymerization. The CTA’s are linear (bifunctional), with three arms (from cholic acid or trimethylolpropane tris[poly(propylene glycol), amine terminated] ether), with six arms (from DPERT) and nine arms (from glycerol functionalized with cholic acid). Three of the synthesized CTA’s are reported for the first time. The intrinsic viscosity [η] and the Mark-Houwink-Kuhn-Sakurada (MHKS) constants were estimated in ethanol at 35 °C for each PNVCL polymer group. The η values for star-shaped polymers were lower compared with the linear analogues with similar molecular weights. Interestingly, the intrinsic viscosity values of two groups of polymers having three arms shown a noticeable difference, probably due to starting material used to prepare the CTA (rigid or flexible core). The MHKS exponents ranged from 0.68 to 0.82 indicates that all polymers behave as a flexible expanded conformation. The hydrodynamic diameter (Dh) of the polymers in ethanol solution was measured using DLS. The Dh values decreased significantly with the molecular weight (Mn) decreasing. The Dh values of linear polymers were higher compared with the stars one with similar molecular weights. Star-shaped PNVCL polymers containing cholane skeleton shown remarkable lower viscosity values.

Comparison of the effect of poly(N-vinyl caprolactam) and poly(N-isopropyl acrylamide) trimers on the stability of hydrated Na-montmorillonite: A molecular dynamics study

In the present study, we performed a molecular dynamics simulation of the intercalation of poly( N-isopropyl acrylamide) (NIPAM)3 and poly( N-vinyl caprolactam) (NVCL)3 trimers into Na-montmorillonite (Na-Mt) to evaluate their effects on the interlayer structure and the stability of hydrated Na-Mt. The impact of both trimers on the interlayer species and their dynamics properties at different temperatures in a canonical ensemble (NVT) were investigated. The results showed that the electrostatic forces exerted by Na cations on H2O molecules and the interlayer H2O molecular arrangement are not affected by the rise in temperature after adding both trimers. Trimer addition reinforced the structure of interlayer H2O molecules so that the effect of temperature increase on them became negligible. The structural dynamics evolution of the radius of gyration of both trimers showed the existence of conformation changes when temperature increased. These conformational changes are more complex in the case of (NVCL)3 than (NIPAM)3 due to its large monomers. Both trimers reduced the mobility of interlayer particles with a better inhibition effect obtained for (NVCL)3 compared to (NIPAM)3. The concentration profile of interlayers’ species showed the affinity of Na cations for clay mineral surfaces while H2O molecules moved away. Compared these two trimers, the most stable state of Na-Mt is achieved with (NVCL)3. These results could help highlight the inhibition properties of (NIPAM)3 and (NVCL)3 on hydrated Na-Mt and to predict its stability against changes in environmental conditions.