Influence of Plasticizers and Drugs on the Physical-Mechanical Properties of Hydroxypropylcellulose Films Prepared by Hot Melt Extrusion

Hydroxypropylcellulose (HPC) films containing drugs or hydrophilic or hydrophobic plasticizers were prepared by a hot melt extrusion process. Polyethylene glycol 8000 (PEG 8000) 2%, triethyl citrate (TEC) 2%, acetyltributyl citrate (ATBC) 2%, and polyethylene glycol 400 (PEG 400) 1% were the plasticizing agents studied. In addition, either hydrocortisone (HC) 1% or chlorpheniramine maleate (CPM) 1% was incorporated into the films as a model drug. The physical-mechanical properties of the films that were investigated included tensile strength (TS), percentage elongation (%E), and Young's modulus (YM). Differential scanning calorimetry (DSC) was utilized to determine glass transition temperatures (T_g' s). These parameters were studied as a function of time and temperature. The glass transition temperatures initially decreased with the inclusion of the drugs and plasticizers. However, after 6 months aging, films containing PEG 400 and HC showed a marked increase in T_g. The films containing PEG 400 showed physical-mechanical instability in all parameters studied. All extruded films exhibited a marked decrease in TS in contrast to a large increase in %E when testing was performed perpendicular to flow versus in the direction of flow. In addition, a consistent film of HPC in the absence of drugs or plasticizers could not be extruded due to the excessive stress on the equipment. Although the theoretical percentage of CPM on aging remained fairly constant over the processing temperature ranges in this study, the HC levels remaining in the extruded films during storage were a function of time and temperature.     

The influence of different plasticizers and polymers on the mechanical and thermal properties, porosity and drug permeability of free shellac films

The effect of triethyl citrate (TEC) and different molecular weights and concentrations of polyethylene glycol (PEG), in addition to the effect of different water-soluble polymers and dispersions at different levels, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), carbomer 940, polyvinyl alcohol (PVA), ethyl cellulose (EC), on the mechanical and thermal properties, drug permeability, and porosity of free shellac films were investigated. Shellac films were cast from aqueous solutions, and their mechanical properties were studied by tensile test. Thermal analyses were performed using differential scanning calorimetry (DSC).

The results showed that the addition of plasticizer caused a decrease in both elastic modulus and glass transition temperature (T_g) and an increase in elongation at break of free shellac films. This effect was related to the concentrations of plasticizers. Different molecular weights of PEGs have different plasticization mechanisms.

Moreover, the incorporation of different amounts of HPMC, MC, or carbomer in free shellac films caused an increase in the flexibility, decrease in T_g, and a marked increase in drug permeability of free shellac films, whereas the addition of PVA caused a decrease in flexibility and drug permeability and an increase in T_g. Addition of EC resulted in a slight decrease of the elasticity and a small decrease in drug permeability. However it does not show a considerable effect on the T_g. In addition, it was found that the drug permeability is directly related to the mechanical properties and T_g of shellac films.     

The effects of plasticizers on the release of metoprolol tartrate from granules coated with a polymethacrylate film

For coating metoprolol tartrate granules, coating dispersions of Eudragit RS 30 D containing 6%, 12%, or 18% (based on polymer weight) of one of the following plasticizers were used: polyethylene glycol 400 (PEG400), propylene glycol (PG), tributyl citrate (TBC), and triethyl citrate (TEC). The release of metoprolol tartrate from these coated granules was determined at pH 1.2 and 7.4. Slower release resulted from the use of each plasticizer, being slower with increasing concentration of the plasticizer. Release was faster with the more water soluble PEG400 and PG than with TBC and TEC. pH-dependent release was observed with PEG400, PG, and TBC, while TEC gave pH-independent release of drug.     

Influence of Aging on the Physical-Mechanical Properties of Acrylic Resin Films Cast from Aqueous Dispersions and Organic Solutions

The physical-mechanical properties of the enteric copolymers, poly(methacrylic acid, ethyl acrylate) Eudragit® L100-55, and Eudragit® L30D have been investigated. Free films of the copolymer containing varying levels of glyceryl triacetate (triacetin) and citrate ester (Citroflex®) plasticizers were prepared by both aqueous and solvent casting techniques. Conditioned films were stored at different humidities and temperatures for predetermined time periods prior to testing. Free films with plasticizer concentration ranging from 0 to 30% by weight of the polymer demonstrated that physical aging at room temperature resulted in physical-mechanical changes as the stress-strain curves indicated a decrease in the percent elongation with increases in the tensile strength. Films prepared from the aqueous latex approached a constant state of equilibrium at a faster rate than films prepared from isopropyl alcohol, where the mechanical properties approach a relatively constant value. Free films containing varying amounts of the plasticizer, triethyl citrate, were stored under different humidity and temperature conditions. In addition, a headspace-gas chromatography (HSGC) method was developed to correlate solvent residues with mechanical properties. The results indicated that an increase in temperature and humidity accelerated the rate of solvent evaporation as a function of time. High vacuum and low humidity conditions were demonstrated to be ineffective conditions for solvent removal. Solvent residues were found in all films after 48 hours of exposure to temperatures up to 60°C and/or exposure to relatively high humidity conditions. A direct relationship between plasticizer content and rate of solvent evaporation from the film was established. Higher concentrations of the plasticizer were found to augment the evaporation of the solvents. This enhanced evaporation was due to the stronger molecular interaction forces between the polymer and the plasticizer than between the polymer and the solvent.     

Variation of composition of an enteric formulation based on Kollicoat MAE 30 D

Using a formulation described previously with Kollicoat MAE 30 D as the film-forming agent, the effect of variations in plasticizer type and quantity and talc concentration on the preparation and processing of spray-coating suspensions and the properties of isolated films and film-coated caffeine tablets prepared using them was investigated. In the preparation and processing of spray-coating suspensions, the plasticizers polyethylene glycol (PEG) 400, PEG1500, and TEC (triethyl citrate) tended to coagulate at all concentrations investigated, while Cremophor RH 40 coagulated above 10% (expressed as a percentage of the mass of the film-forming agent used). Analogous preparations using propylene glycol (PG), PEG6000, and Lutrol F 68, on the other hand, were found to be stable at all concentrations. The instability was not caused by the Kollicoat MAE 30 D polymer dispersion as such, but by interactions between the finely dispersed pigments and other formulation ingredients. Equivalent nonpigmented preparations are stable and do not coagulate. With all the plasticizers investigated, the minimum film-forming temperature (MFT) fell, albeit to differing degrees, as the amount of plasticizer increased. Similarly, the tensile strength of isolated films declined as plasticizer concentration increased, while the reverse was true as regards their elongation at break. Whereas neither the subsequent disintegration time nor the rate of release of active ingredient at pH 6.8 was significantly affected by the various plasticizer additives, the different film-coated tablet formulations with a core containing a powerful disintegrant exhibited varying degrees of permeability to simulated gastric fluid. With PEG6000, permeability increased as the plasticizer concentration increased, while Lutrol F 68 provided an optimum barrier at 20%, and PG provided a good barrier between 10% and 30%. No gastroresistance was obtained with TEC at 10%. Only the best plasticizer formulations were used in the trials with different talc concentrations, namely, those formulations with 20% PEG6000, 20% Lutrol F 68, 20% PG, and 10% PG. When talc was added, the MFT rose, reaching its maximum at 13% talc (as a proportion of the film-forming agent). In the test for gastroresistance, film-coated caffeine tablets without talc absorbed distinctly more acid than those containing talc. Above 27% talc, the acid resistance improved only insignificantly. On the other hand, during this test, only a maximum of 3% of the active ingredient was released into the gastric juice. Of the variants investigated, the formulation with 20% PG and 27% talc performed best.     

Influence of tartaric acid on the bioadhesion and mechanical properties of hot-melt extruded hydroxypropyl cellulose films for the human nail

The objective of this study was to investigate the influence of tartaric acid (TTA) on the bioadhesive, moisture sorption, and mechanical properties of hot-melt-extruded (HME) hydroxypropyl cellulose (HPC) films containing polymer additives. Two Klucel® EF and LF batches (HPC, MW: 80000 and 95000, respectively) containing the model antifungal drug ketoconazole (one batch of each MW with and without TTA 4%) were prepared into films by HME using a Killion extruder (Model KLB-100). The bioadhesive properties of the HPC films, with and without TTA, were investigated ex vivo on the human nails. The parameters measured were work of adhesion and peak adhesion force (PAF). A statistically significant increase in both the area under the curve (AUC) and PAF was seen for the HME films containing TTA than those without TTA. Moisture content of hot-melt extruded HPC films was determined using thermogravimetric analysis (TGA). TGA data collected at the two-week interval (25°C/60% RH), measured higher moisture content for the TTA-containing films than those without TTA. Tensile strength and percent elongation were determined utilizing a TA.XT2i Texture Analyzer® equipped with a 50-kg load cell, TA-96 grips, and Texture Expert™ software. TTA functioned as an effective plasticizer, increasing percent elongation and decreasing tensile strength of the HPC films. TTA could potentially be a candidate for transnail applications in film devices prepared by hot-melt extrusion technology.     

Investigations Regarding the Determination of Glass Transition Temperatures from Moisture Sorption Isotherms

Moisture sorption isotherm and glass transition temperature (T_g data on polyvinylpyrrolidone (PVP) of molecular weights less than or equal to 40,000 as well as PVP containing added plasticizers were collected to examine the possibility of extracting T, values from moisture sorption data. Moisture sorption isotherms generated for PVP of various molecular weights were similar to those previously reported. The moisture sorption isotherm for PVP-K15 containing added vinylpyrrolidone (VP) and methylpyrrolidone (MP) were predicted reasonably well by simple addition of their respective isotherms with that of PVP-K15. The T_g values for PVP as a function of moisture was similar to that found previously. Decreasing polymer molecular weight or the addition of plasticizers (VP or MP) reduced the T_g of the polymer system, displacing the T_g to lower temperatures. When the moisture content to give a T_g of 25°C (W_g) was indicated on the isotherm, W_g shifted downward with decreasing molecular weight or increasing plasticization by VP or MP while the shape of the isotherm was not distinguishably altered. Consequently, W_g, and thus T_g, would be difficult to extract from the moisture sorption isotherm.     

Combined Effects of Heat Treatment and Plasticizers on Polyvinyl Alcohol Films

The effects of heat treatment on PVA films containing water soluble plasticizers were investigated. Propylene glycol, glycerol and polyethylene glycol were used as plasticizers. There was synergism between heat treatment and the presence of plasticizers in enhancing the water resistance of PVA films. In the absence of heat treatment, however, the plasticizers increased the aqueous solubility of PVA films. The plasticized films further showed a lower permeability to propranolol HC1 compared to the unplasticized films following heat treatment.     

Influence of Tartaric Acid on the Bioadhesion and Mechanical Properties of Hot-Melt Extruded Hydroxypropyl Cellulose Films for the Human Nail

ABSTRACT

The objective of this study was to investigate the influence of tartaric acid (TTA) on the bioadhesive, moisture sorption, and mechanical properties of hot–melt-extruded (HME) hydroxypropyl cellulose (HPC) films containing polymer additives. Two Klucel® EF and LF batches (HPC, MW: 80000 and 95000, respectively) containing the model antifungal drug ketoconazole (one batch of each MW with and without TTA 4%) were prepared into films by HME using a Killion extruder (Model KLB-100). The bioadhesive properties of the HPC films, with and without TTA, were investigated ex vivo on the human nails. The parameters measured were work of adhesion and peak adhesion force (PAF). A statistically significant increase in both the area under the curve (AUC) and PAF was seen for the HME films containing TTA than those without TTA. Moisture content of hot-melt extruded HPC films was determined using thermogravimetric analysis (TGA). TGA data collected at the two-week interval (25°C/60% RH), measured higher moisture content for the TTA-containing films than those without TTA. Tensile strength and percent elongation were determined utilizing a TA.XT2i Texture Analyzer® equipped with a 50-kg load cell, TA-96 grips, and Texture Expert? software. TTA functioned as an effective plasticizer, increasing percent elongation and decreasing tensile strength of the HPC films. TTA could potentially be a candidate for transnail applications in film devices prepared by hot-melt extrusion technology.     

The rheological properties and characterization of bentonite dispersions in the presence of non-ionic polymer PEG

The effect of poly(ethylene glycol) on the flow behavior of Ca-bentonite and soda activated bentonite dispersions was characterized by the plastic viscosity, the relative viscosity and the yield values. In the range 0.025–12.5 mol/m³, poly(ethylene glycol) (PEG400, PEG3000, PEG8000) was added to bentonite-water systems in different concentrations. Three layered phases with different basal spacings for each Ca- and Na-bentonites were obtained, as shown by XRD studies. The maximum swelling had a basal spacing at 1.82 nm for both PEG400 containing Ca- and Na-bentonites. In addition, expanded basal spacings are displayed at 1.91 nm for Ca- and 2.08 nm for PEG8000 containing Na-bentonites. After the PEG addition, some significant changes in rheological properties were observed; corresponds changes were also found during XRD and IR studies. The results are interpreted according to the type of bentonites, molecular weight of PEG and their concentrations.     

聚乳酸片材增塑改性研究

分别采用乙酰柠檬酸三正丁酯(ATBC)和聚乙二醇400(PEG400)为增塑剂对聚乳酸片材进行改性。拉伸性能测试表明,增塑改性后的聚乳酸片材塑性增强,在ATBC和PEG400质量分数为15%时断裂伸长率分别达到25.6%和38.13%;毛细管流变仪测试表明,其非牛顿指数分别为0.7206和0.9152;通过紫外分光光度法,测得聚PEG400增塑剂增塑改性的聚乳酸片材更易析出,改性的聚乳酸60 d后降解率为14.3%,较纯聚乳酸和ATBC增塑改性片材降解率高。     

Controlled release of pranoprofen from the ethylene-vinyl acetate matrix using plasticizer

An ethylene-vinyl acetate (EVA) matrix containing pranoprofen was prepared using the casting method and the release patterns of pranoprofen were observed. The solubility of pranoprofen was determined to be a function of the volume fraction of polyethylene glycol 400. The release of the drug from the matrix was examined as a function of temperature and drug concentration. Plasticizers such as the citrates and the phthalates were added to prepare the membrane in order to increase the flexibility of the EVA matrix. The solubility of pranoprofen was the highest when the PEG 400 concentration was 20% (v/v). The rate of drug release from the EVA matrix increased with increasing temperature and drug loading dose. There was a linear relationship between the flux of pranoprofen and the square root of the loading dose. The activation energy of release (Ea), which was measured from the slope of the log P versus 1000/T plots, was estimated to be 17.44, 16.14, 14.88, and 14.78 kcal/mol for loading doses of 0.5, 1, 1.5, and 2%, respectively. Among the plasticizers used such as the citrate and the phthalate groups, diethyl phthalate had the best enhancing effects on drug release. In conclusion, the application of an EVA matrix containing a plasticizer might be useful in the development of a controlled drug delivery system.     

The Effect of Plasticizers on the Properties of Polyvinyl Alcohol Films

Abstract

The effect of water-soluble plasticizers viz propylene glycol (PG), glycerol and polyethylene glycol 600 (PEG) on the morphology and water resistance of polyvinyl alcohol (PVA) films was investigated. Polyvinyl alcohol films were cast from aqueous solutions, and their morphology studied using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Water resistance was characterized by the extent of film dissolution and the water uptake capacity of remnant films after immersion of the films in distilled water for 3 days at 37° C. DSC thermograms showed that crystallite formation in the PVA films was affected to different extent by addition of the three plasticizers. The plasticizers not only reduced the degree of crystallinity in the films, but also lowered the crystalline melting temperatures probably by introducing defects into the crystal lattice. This factor, coupled with leaching of the water-soluble plasticizers from the films when immersed in distilled water, lowered the water resistance of the plasticized PVA films. The influence of plasticizers on the properties of PVA films was further related to the degree of compatibility between the plasticizers and PVA.     

Effects on Oxygen‐barrier Properties of Pretreating Paperboard with a Starch–Poly(Vinyl Alcohol) Blend before Polyethylene Extrusion

Polyethylene (PE) extrusion coating was performed on paperboard pre‐coated with water‐borne barrier coatings based on starch–poly(vinyl) (PVOH)–plasticizer blends in order to investigate that how the addition of a plasticizer to the pre‐coating affects the oxygen‐barrier properties of the board after PE extrusion coating. The plasticizers used were glycerol, polyethylene glycol (PEG) and citric acid (CA). Photomicrographs showed that the barrier coating layers were rather smooth, but defects were observed in the starch–PVOH layers when a plasticizer was added. Starch–PVOH layers had oxygen‐barrier properties similar to those of pure PVOH without plasticizers. When a sufficient number of layers (four layers) were applied to cover defects, the starch–PVOH layers containing CA showed oxygen transmission rate (OTR) values similar to those of starch–PVOH layers without plasticizer. The adhesion of PE to pre‐coated paperboard decreased when a plasticizer was added to the pre‐coating recipes. PE extrusion coating resulted in a reduction in the OTR in the case of pre‐coating formulations containing plasticizers. A lower OTR after polyethylene extrusion was observed with PEG as plasticizer than with CA as plasticizer. This could be explained by the increase in brittleness due to cross‐linking under the high temperature load during the extrusion process. Dynamic mechanical analysis of the films showed a substantial increase in storage modulus between 100°C and 200°C for CA‐containing starch–PVOH films. The contact angle of diiodomethane on the pre‐coating layer decreased when a plasticizer was added to the coating recipe indicating an increase in wetting of the PE melt. Addition of PEG to the pre‐coating led to a greater wetting than the addition of CA, and this may have sealed some defects in the pre‐coating leading to lower OTR values.     

四种多元醇增塑剂对淀粉-壳聚糖复合膜的性能研究

目的探究多元醇作为增速剂对淀粉-壳聚糖薄膜材料性能的影响,评估4种多元醇的增塑效果,并选出最优。方法将4种不同的多元醇作为增塑剂,通过流延法制备壳聚糖-淀粉薄膜,分析增塑剂含量对材料力学性能的影响,并通过扫描电镜、傅里叶红外、X-射线衍射、静态接触角对复合膜的结构和性能进行表征。结果将单一多元醇作为增塑剂加入淀粉-壳聚糖溶液,当添加质量分数为15%的甘露醇时,拉伸强度为最大值,为53.39 MPa;当添加质量分数为60%的甘油时,断裂伸长率最大,为45.11%。当甘油质量分数为50%时,综合效果较好,拉伸强度为21.36 MPa,断裂伸长率为35.33%。结论复合膜中淀粉与壳聚糖具有良好的相容性,添加增塑剂有利于改善复合膜的力学性能。多元醇增塑剂处于低浓度或中等浓度范围时,不具有有效的增塑作用。在4种多元醇增塑剂中,甘油的综合效果最好,所制备的膜具有较优的综合性能。     

Controlled Release of Pranoprofen from the Ethylene-Vinyl Acetate Matrix Using Plasticizer

ABSTRACT

An ethylene-vinyl acetate (EVA) matrix containing pranoprofen was prepared using the casting method and the release patterns of pranoprofen were observed. The solubility of pranoprofen was determined to be a function of the volume fraction of polyethylene glycol 400. The release of the drug from the matrix was examined as a function of temperature and drug concentration. Plasticizers such as the citrates and the phthalates were added to prepare the membrane in order to increase the flexibility of the EVA matrix. The solubility of pranoprofen was the highest when the PEG 400 concentration was 20% (v/v). The rate of drug release from the EVA matrix increased with increasing temperature and drug loading dose. There was a linear relationship between the flux of pranoprofen and the square root of the loading dose. The activation energy of release (Ea), which was measured from the slope of the log P versus 1000/T plots, was estimated to be 17.44, 16.14, 14.88, and 14.78 kcal/mol for loading doses of 0.5, 1, 1.5, and 2%, respectively. Among the plasticizers used such as the citrate and the phthalate groups, diethyl phthalate had the best enhancing effects on drug release. In conclusion, the application of an EVA matrix containing a plasticizer might be useful in the development of a controlled drug delivery system.     

Dissolution rate enhancement,in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions.     

Study of mechanical properties,oxygen permeability and AFM topography of zein films plasticized by polyols

The use of plastic for packaging has grown extensively in recent years. In this context, biodegradable films can be a source of energy saving and an important issue for environmental protection. Zein protein (prolamin of corn) is one of the best biopolymers for edible film making and polyols are convenient plasticizers for biopolymers. Polyols (sorbitol, glycerol and mannitol) at three levels (0.5, 0.7 and 1g/g zein) were used as plasticizers and the tensile properties, oxygen permeability (OP) and AFM topography of zein films were studied. Films plasticized by sorbitol had a relatively higher ultimate tensile strength (UTS) than films containing glycerol and mannitol at low levels of plasticizers (0.25, 0.7g/g zein). There was no significant difference between the strain at break values (SB) of films plasticized by sorbitol and glycerol at low levels of plasticizers, while films plasticized by sorbitol had higher SB than the films containing glycerol and mannitol at a high level of plasticizer (1g/g zein). Pure zein films had low oxygen permeability (OP), and increasing the plasticizer level to 0.5g/g zein decreased OP values in films containing sorbitol and glycerol. Films containing sorbitol and mannitol had the lowest and highest OP values, respectively. AFM images were used to evaluate the surface morphology (qualitative parameter) and roughness (quantitative parameter) of zein films. Films plasticized by glycerol had smoother surfaces and a lower roughness parameter (Rq). No relationship between OP values and the roughness of the zein films was observed. Copyright © 2006 John Wiley & Sons, Ltd.     

Evaluation of hydroxypropyl methylcellulose phthalate 50 as film forming polymer from aqueous dispersion systems

Hydroxypropyl methylcelluose phthalate 50 (HPMCP 50) was evaluated as a film forming polymer from aqueous dispersion systems. The influence of plasticizer type and level on the elasticity of HPMCP 50 free films prepared by the casting method was studied by measuring Young's modulus using an Instron Material Testing System. The release of a water soluble drug in various dissolution media from pellets coated with HPMCP 50 with 30% plasticizer containing various levels of hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC) was also studied. The influence of coating level on drug release from pellets was also investigated. Results showed that HPMCP 50 alone without a plasticizer does not form a film. However, when a plasticizer was added HPMCP 50 did form a film. Also, as the concentration of the plasticizer triethyl citrate was increased the elasticity of HPMCP 50 films was increased. Similar results were obtained with the plasticizer diethyl phthalate. For pellets a high coating level was required to achieve adequate protection in 0.06 N HCl. Drug release from coated pellets was found to be dependent upon the type and the level of the water soluble polymer incorporated with HPMCP 50. Drug release was increased as the percentage of HPC was increased. Higher release rates were obtained with HPMC compared to HPC. Coating level significantly influenced drug release in 0.06 N HCl; however, less of an effect was observed at pH 5.5.     

Drug release from heat-treated polyvinyl alcohol films

Polyvinyl alcohol (PVA) films containing 10% w/w of a model drug, sulphathiazole, were cast from aqueous solutions and subjected to heat treatment at specific temperatures for known periods of time. Heat treatment at temperatures above the T_g of the PVA films slowed down the rate of drug release from the films. Increasing the temperature of heat treatment from 120°C to 160°C further decreased the rate of drug release. On the other hand, if the heat treatment were conducted at a temperature below the T_g e.g. at 80°C, there were insignificant differences between the release profile of sulphathiazole from heat-treated films and that from untreated films. The duration of heat treatment affected the rate of drug release to a smaller extent compared to the temperature of heat treatment. These results correlated with the heat induced changes in the morphology of, and in the extent of water uptake by the PVA films.