HPMC K100 Research Articles

Mucoadhesive buccal tablets of domperidone: formulation evaluation and effects of process variables

The aim of the present work was to develop and evaluate buccal adhesive tablets of domperidone and study the effect of diluents. Tablets were prepared by direct compression method using different polymer and excipients combinations. Formulations batches were evaluated for physical parameter, swelling studies, bioadhesion studies and in vitro drug release. Formulation batch F2 was most promising composition of 1:5 ratio of HPMC K4 M/Sodium alginate. Effect of formulation variables such as diluents i.e. lactose (water soluble) and di-calcium phosphate (DCP) (water insoluble) studied on swelling index, bioadhesive performance and in vitro drug release. Bioadhesive force was drastically decreased in presence of DCP; it was concluded that DCP more significantly affected the swelling index than did lactose. Both Lactose and DCP similarly affect the bioadhesive strength of buccal adhesive tablets. Dissolution profiles have shown non-fickian drug release mechanism, which indicated that the drug was released by diffusion and erosion mechanism. Thereby buccal adhesive tablets offer a promising strategy for drug delivery of domperidone.

Development of pellets of nifedipine using HPMC K15 M and κ-carrageenan as mucoadhesive sustained delivery system and in vitro evaluation

Polymeric mucoadhesive pellets of nifedipine were designed using computer software and they were prepared by extrusion-spheronization using HPMC K15M and κ-carrageenan with microcrystalline cellulose. A randomized rotatable two factor central composite design was applied for assessment of influence of two independent variables such as concentration of κ-carrageenan and HPMC K15M on dependent variables. Pellets were characterized by FTIR, DSC, SEM, flow properties, particle size, abrasion resistance, sphericity, drug content, percent production yield, in vitro drug release, ex vivo mucoadhesion, stability studies and similarity factor. The optimized formulation was selected based on criteria of sphericity nearest to 1.0 with maximum cumulative drug release percentage. Formulation NF6 exhibited sufficient porous spheres, free flowing and smooth surface mucoadhesion of 91.34 % and drug content 98.22 ± 0.37 %. Kinetic modeling revealed that the formulation followed the Higuchi model and showed the Quassi-Fickian drug release mechanism. The similarity factor, F2 value, was found to be 74 ± 6 and there was no significant change in drug content and ex vivo mucoadhesion after 90 days at 40 ± 2 °C, and 75 ± 5 % RH clearly indicated the optimized batch NF6 was stable. Thus, it can be concluded that use of κ-carrageenan, microcrystalline cellulose and HPMC K15M at the 20:35:10 w/w ratio could provide an effective carrier for enhancement of sphericity and sustained release of matrix pellets.

DEVELOPMENT AND EVALUATION OF BILAYERED GASTRO-RETENTIVE TABLET CONTAINING METFORMINHCL SR AND PIOGLITAZONEHCL IR

To get advantage of novel drug delivery in treatment of diabetes mellitus is centered aim of this work.Bi-layered gastro-retentive tablet containing MetforminHCl and PioglitazoneHCl for treatment of type-II diabetes mellitus has been formulated . To make the system more effective, combination of immediate layer, PioglitazoneHCl 15mg and sustained release layer of MetforminHCl 500mg were prepared. The core tablet of MetforminHCl was prepared by using different swellable polymers like HPMC E15, HPMC K100 and carbopol by wet granulation method and evaluated for swelling index, total floating time and floating lag time. In vitro release studies were carried out with 0.1N HCl using USP dissolution apparatus 2 (paddle). Tablet thus formulated using HPMC K100M and E15 provided sustained release of Metformin HCl over a period of 10 hours. The immediate release layer of PioglitazoneHCl was prepared by using crosspovidone,a super disintegrant by direct compression method and evaluated for disintegration time and dissolution also. Then bilayered tablet was prepared with the selected core tablet batch of MetforminHCl followed by compression coating with the selected immediate release layer of PioglitazoneHCl. The present study concluded that bilayered tablet can be a good way to treat diabetic patients with combination therapy.

Formulation and Evaluation of Fast Dissolving Buccal Patch of Olmesartan Medoxomil

Now days tablet dosage forms are supplanted by new drug delivery system because of problems like hepatic metabolism, GI toxicity and enzymatic degradation which leads to non-compliance and ineffective therapy. These problems can be overcome by formulating the drug into fast dissolving buccal patches for oromucosal absorption with fast onset of action and improved bioavailability. In present work the fast dissolving buccal patches of Olmesartan medoxomil was prepared by solvent casting method using HPMC E5, HPMC 3cps and HPMC K100 as a film formers and PEG 400 as plasticizer. The prepared patches were evaluated for weight, thickness, folding endurance, surface pH, disintegration time, in-vitro drug release and stability studies on optimized formulation. The thickness of the all patches was found in the range of 0.22 to 0.30 mm. The disintegration time was found up to 60 sec. and the folding endurance was up to 200. The in-vitro drug release was found to be up to 100% within 2 minutes. Thus the fast dissolving buccal patch of Olmesartan medoxomil was successfully formulated to achieve a safe, rapid and effective dosage form with enhanced drug dissolution and rapid antihypertensive therapy.

FORMULATION AND IN-VITRO EVALUATION OF TRANSDERMAL FILMS OF AN ANTI HYPERTENSIVE DRUG

In the present study was made to develop a suitable matrix type transdermal patch of Candesartan Cilexetil, using blends of t wo different types of polymeric combinations viz. HPMC K100 and Eudragit RL100 prepared formulations were subjected to various p hysiochemical evaluation tests like moisture content loss, moisture absorption, flatness to study the stability of the formulations, in vitro dissolution was performed to determine the amount of Candesartan present in the patches. Drug excipient interactio n studies were carried out using Fourier transform infrared (FTIR) spectroscopy technique. The in vitro release of the drug from the formulations was studied using commercial semi permeable membrane. All the formulations were found to be suitab le for formu lating in terms of physiochemical characteristics and there was no notification in significant interaction between the drug and polymer used. In vitro dissolution data showed that formulation of F11 showed faster release of drug than the F14 formulations d uring dissolution studies. Skin irritation studies revealed that the batch containing HPMCK100 - Eudragit RL100 has no erythema and edema. Based on the observation, we can reveal that HPMCK100 - eudragit RL100 polymers are better suited for the development of Candesartan cilexetil transdermal patches.

EFFECT OF HYDROPHILIC POLYMERS ON CONTROLLED RELEASE MATRIX TABLETS OF ACYCLOVIR

Acyclovir was formulated as oral controlled release matrix tablets using natural and synthetic polymers separately or in combinations. Tablets were prepared by direct compression method. The tablets were evaluated to thickness, weight variation test, drug content, hardness, friability and in vitro release studies.All the formulations showed compliance with pharmacopoeal standards. The tablets prepared with various combination of hydroxy propyl methylcellulose (HPMC K100), locust bean gum (LBG) and karaya gum (KG) failed to produce the desired controlled release. Dissolution studies indicated that formulation F5 was most successful of the study. The formulation F5 exhibited anomalous (non-Fickian) diffusion mechanism. Based on the results of in-vitro studies it was concluded that the hydrophilic polymers canbe used as an effective matrix former to provide controlled release of acyclovir. SEM images of tablet after dissolution showed pore formation. FT-IR and DSC study did not show any possibility of interaction between acyclovir and excipients.

Formulation and Evaluation of Colon Targeted Drug Delivery System of Levetiracetam using Pectin as Polymeric Carrier

Article history: Received on: 10/12/2012 Revised on: 29/12/2012 Accepted on: 15/01/2013 Available online: 28/01/2013 The aim of the present work was to develop and evaluate colon specific sustained release tablet using levetiracetam (LEV), microbially degradable polymeric carrier (pectin), coating material and matrix forming polymers. The colon targeted tablet was prepared by wet granulation technique using different percentage of pectin as matrix carrier, starch mucilage as a binding agent, HPMC K-100 as swellable polymer and coated with Eudragit polymers. Pectin, drug and physical mixture were evaluated for incompatibility study by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). All the batches of matrix tablet (F1-F4) were subjected for in-vitro dissolution in various simulated gastric fluids for suitability for colon specific drug delivery system. Tablets were evaluated for micromeritic properties of granules, physical properties, drug content, water uptake and erosion characteristics. F2 was optimized and subjected to coating based on evaluation results. The dissolution study of F2 revealed, in simulated intestinal fluid (SIF) release was 40.48% at the end of 6h and in simulated colonic fluids (rat caecal content) was 102.88% after degradation at the end of 8h. The colon targeted matrix tablet of LEV showed no change either in physical appearance, drug content or dissolution pattern after performing stability study for 3 months. The studies confirmed that, the designed formulation could be used potentially for colon delivery by controlling drug release in stomach and the small intestine.

Dissolution Rate Enhancement, Design and Development of Buccal Drug Delivery of Darifenacin Hydroxypropyl β-Cyclodextrin Inclusion Complexes.

Darifenacin is a urinary antispasmodic. The oral absorption of darifenacin is poor due to its low solubility and poor bioavailability (15–19%). Darifenacin was complexed with hydroxylropyl beta-cyclodextrin (Hpβ-CD). The best results were obtained with the coevaporation that interacts in a 1 : 1 drug : cyclodextrin molar ratio. The solid inclusion complexes were found to be amorphous in the characterization. The dissolution rate of darifenacin from the Hpβ-CD solid inclusion complex was increased compared to the powdered drug. The controlled release buccoadhesive patches for the delivery of darifenacin were prepared using HPMC K100M CR and HPMC K15. The coevaporation complex of the drug was used in the formulation due to its increased saturation solubility and increased ease of dissolution. The patches were evaluated for their surface pH, folding endurance, swelling, mucoadhesive properties, in vitro residence time, vapour transmission test, and in vitro and ex vivo release studies. Formulations Hb2 (2%) and Pb4 (4%) were found to be optimized. These two formulations can be used for buccal delivery of darifenacin which avoids first pass effect and leads to increased bioavailability of darifenacin.

Programmed delivery of verapamil hydrochloride from tablet in a capsule device

The aim of the present work was to develop a programmed drug delivery system which would be able to release the drug after 6 h of lag time by use of hydrophilic polymers. The capsule body was made impermeable by use of formaldehyde vapor treatment, while the cap was untreated. The capsule was filled with two layered tablets (tablet-in-capsule), followed by a sodium bicarbonate:citric acid mixture (SBCM) and lactose as bulking agent. Sodium alginate, chitosan, HPMC K15 and chitosan:sodium alginate complex (CSAC) were used as the rate modulating layer. Through combined use of HPMC K15 and adjusting the ratio of CSAC, the desired lag time of 6 h was obtained. The effect of the bulking agents on the lag time were also studied and it was found that the lag time was decreased with higher amounts of lactose, and delayed dissolution and decreased lag time was observed at higher amount of effervescent mixture.

Formulation and evaluation of chondroitin sulphate tablets of aceclofenac for colon targeted drug delivery.

The aim of the present study was to develop a single unit, site-specific matrix tablets of aceclofenac allowing targeted drug release in the colon with a microbially degradable polymeric carrier, chondroitin suphate (CS) and to coat the optimized batches with a pH dependent polymeric. The tablets were prepared by wet granulation method using starch mucilage as a binding agent and HPMC K-100 as a swellable polymer. Chondroitin Sulphate and drug and physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The tablets were tested for their in-vitro dissolution characteristics in various simulated gastric fluids for their suitability as a colon-specific drug delivery system and also the tablets were evaluated for physicochemical properties, drug content, water percentage swelling and erosion characteristics. The dissolution data demonstrates that the 10% w/w increase in coating level of the pH dependent polymer (Eudragit L-100 and Eudragit S-100 in a ratio of 1 : 4 prevented the drug release in the simulated gastric fluid (pH 1.2-SGF) and the simulated intestinal fluid (pH 7.4-SIF). The dissolution rate of the tablet is dependent upon the concentration of Chondroitin sulphate in the simulated colonic fluid (SCF). The rapid increase in release of aceclofenac in SCF was revealed as due to the degradation of the Chondroitin sulphate membrane by bacterial enzymes. The studies confirmed that, the designed system could be used potentially as a carrier for colon delivery of aceclofenac by regulating drug release in stomach and the small intestine.

Enhancing and Sustaining AMG 009 Dissolution from a Bilayer Oral Solid Dosage Form via Microenvironmental pH Modulation and Supersaturation

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.

Formulation and evaluation of floating oral in situ gelling system of amoxicillin.

Purpose. Effective Helicobacter pylori eradication requires delivery of the antibiotic locally in the stomach. High dose of amoxicillin (750 to 1000 mg) is difficult to incorporate in floating tablets but can easily be given in liquid dosage form. Keeping the above facts in mind, we made an attempt to develop a new floating in situ gelling system of amoxicillin with increased residence time using sodium alginate as gelling polymer to eradicate H. pylori. Methods. Floating in situ gelling formulations were prepared using sodium alginate, calcium chloride, sodium citrate, hydroxypropyl methyl cellulose K100, and sodium bicarbonate. The prepared formulations were evaluated for solution viscosity, floating lag time, total floating time, and in vitro drug release. The formulation was optimized using a 32 full factorial design. Dissolution data were fitted to various models to ascertain kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. Results. All formulations (F 1–F 9) showed floating within 30 s and had total floating time of more than 24 h. All the formulations showed good pourability. It was observed that concentration of sodium alginate and HPMC K100 had significant influence on floating lag time, cumulative percentage drug release in 6 h and 10 h. The batch F 8 was considered optimum since it showed more similarity in drug release (f 2 = 74.38) to the theoretical release profile. Conclusion. Floating in situ gelling system of amoxicillin can be formulated using sodium alginate as a gelling polymer to sustain the drug release for 10 to 12 h with zero-order release kinetics.

Formulation and evaluation of transdermal patch of repaglinide.

Repaglinide has the half life of 1 hour, and bioavailability in the body is 56% due to first-pass metabolism. The total daily dose of Repaglinide is 16 mg (e.g., 4 mg four times daily depending on meal patterns); hence, it required frequent dosing. Transdermal patch of Repaglinide was prepared to sustain the release and improve bioavailability of drug and patient compliance. Different formulations were prepared by varying the grades of HPMC and concentration of PVP K30 by solvent casting method. The prepared formulations were evaluated for various parameters like thickness, tensile strength, folding endurance, % elongation, % moisture content, % moisture uptake, % drug content, in vitro drug release, in vitro permeation, and drug excipient compatibility. A 32 full factorial design was applied to check the effect of varying the grades of HPMC (X 1) and PVP concentration (X 2) on the responses, that is, tensile strength, percentage drug released in 1 hr (Q 1), 9 hr (Q 9), and diffusion coefficient as a dependent variables. In vitro release data were fitted to various models to ascertain kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. The results of the F2 statistics between factorial design batches and theoretical profile were used to select optimized batch. Batch F6 was considered optimum batch which contained HPMC K100 and PVP (1.5%), showed release 92.343% up to 12 hr, and was more similar to the theoretical predicted dissolution profile (f 2 = 69.187).

Development of Topical Niosomal Gel of Benzoyl Peroxide

Benzoyl peroxide is macrolide antibiotic used commonly for the treatment of acne either alone or in combination. But it suffers from side effects like skin redness, irritation, itching, and edema. Niosomes, a nonionic surfactant vesicular formulation, have been explored extensively for topical application to enhance skin penetration as well as to improve skin retention of drugs. In the present study, Benzoyl peroxide was entrapped into niosomes by thin film hydration technique, and various process parameters were optimized by partial factorial design. The optimized niosomal formulation was incorporated into HPMC K15 gel and extensively characterized for percentage drug entrapment (PDE) and in vitro release performance. The stability of above formulation was studied at different temperatures. The present study demonstrated prolongation of drug release, increased drug retention into skin, and improved permeation across the skin after encapsulation of benzoyl peroxide into niosomal topical gel.

Symbolic regression via genetic programming in the optimization of a controlled release pharmaceutical formulation

Symbolic regression via genetic programming (GP) was used in the optimization of a pharmaceutical zero-order release matrix tablet, and its predictive performance was compared to that of artificial neural network (ANN) models. Two types of GP algorithms were employed: 1) standard GP, where a single population is used with a restricted or an extended function set, and 2) multi-population (island model) GP, where a finite number of populations is adopted. The amounts of four polymers, namely PEG4000, PVP K30, HPMC K100 and HPMC E50LV were selected as independent variables, while the percentage of nimodipine released in 2 and 8 h (Y 2h, and Y 8h), respectively, and the time at which 90% of the drug was dissolved (t 90%), were selected as responses. Optimal models were selected by minimization of the Euclidian distance between predicted and optimum release parameters. It was found that the prediction ability of GP on an external validation set was higher compared to that of the ANNs, with the multi population and standard GP combined with an extended function set, showing slightly better predictive performance. Similarity factor ( f 2) values confirmed GP's increased prediction performance for multi-population GP ( f 2 = 85.52) and standard GP using an extended function set ( f 2 = 84.47).

Design and optimization of mucoadhesive nasal in situ gel containing sodium cromoglycate using factorial design

Nasal in situ gel of sodium cromoglycate was prepared for sustained release and improvement of drug bioavailability. Carbopol 940 was used as a key ingredient which gives pH-induced sol to gel conversion of the formulations. Different formulations were prepared by varying the concentrations of carbopol 940 and different grades of Hydroxyl Propyl Methyl Cellulose (HPMC K100, HPMC K4M and HPMC K15M). These formulations were evaluated for parameters like pH, drug content, viscosity, gel strength, in vitro drug release and drug excipient compatibility. In this study, the release profile depends on the concentration of carbopol 940 and grade HPMC. A 32 factorial was applied to check the effect of varying the concentration of carbopol 940 (X1) and different grades of HPMC (X2) on the dependent variable i.e. viscosity, mucoadhesive strength, cumulative percentage drug released in 1 h (Q1), 4 h (Q4) and 8 h (Q8) as dependent variables. In vitro release data was fitted to various models to ascertain the kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables.The results of the F-statistics were used to select the most appropriate model. Formulation F6 was considered optimum which contained carbopol 940 (0.75%) and HPMC K4M (0.50%) and was more similar to the theoretical predicted dissolution profile (f2=70.99). The studies indicate that the formulation was effective in providing in vitro release, in vitro permeation of drug and the mucoadhesion which increases the residence time of drug.

Development and Evaluation of Intranasal Mucoadhesiv Microspheres of Neostigmine Bromide

Purpose: Neostigmine bromide, a cholinesterase inhibitor is conventionally given by oral route for the treatment of myasthenia gravis. However, it is very poorly absorbed from gastro-intestinal tract. Intranasal administration is an ideal alternative to the parenteral route for systemic drug delivery. Formulating multiparticulate system with mucoadhesive polymers may provide a significant increase in the nasal residence time. The aim of the present approach was to overcome the drawbacks of the conventional dosage forms of Neostigmine Bromide by formulating intranasal microspheres with Carbopol 974P NF and HPMC K15 M along with film forming polymer ethyl cellulose. Methods: The microspheres were prepared by emulsion solvent evaporation method. The prepared microspheres were characterized for encapsulation efficiency, drug loading, particle size, and surface morphology, degree of swelling, in-vitro mucoadhesion, drug release, in-vivo studies and stability studies. Results: Formulations IN 1 and IN 5 displayed the best results for Carbopol and HPMC based microspheres respectively. Entrapment efficiency was 75.74±0.50% and 70.27±0.61%; mucoadhesion was 98.5% and 85.3%; and drug release up to 8 h was 87.86% and 84.5% for IN 1 and IN 5 respectively. In-vivo studies revealed that the formulations IN 1 and IN 5 showed good bioavailability compared to oral drug administration. Conclusion: Both in-vitro and in-vivo studies conclude that Carbopol based microspheres are better than HPMC based microspheres for the delivery of Neostigmine Bromide.

Formulation and Evaluation of Mucoadhesive Tablet: Influence of Some Hydrophilic Polymers on the Release Rate and In Vitro Evaluation

Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. The objective of this study was to extend the GI residence time of the dosage form and control the release of Tramadol HCl using mucoadhesive tablet to achieve controlled plasma level of the drug which is especially useful for 12 hrs. Matrix tablets of Tramadol HCl were formulated using different mucoadhesive polymers namely guar gum, xanthan gum and Methocel (HPMC K15M and HPMC K100M). Formulations were evaluated for preformulation parameters, in vitro drug release profile and release kinetics. The formulations were found to have good preformulation characteristics. FTIR spectroscopy indicated the absence of any significant chemical interaction within dug and excipients. The release mechanism of Tramadol HCl from matrix tablets indicated anomalous (non-Fickian) transport mechanism and followed zero order kinetics. The retention time of the mucoadhesive tablet on the mucous membrane were investigated to develop a bioadhesive polymer-based controlled release delivery system and to evaluate the performance of such a delivery devices. The combination of HPMC K15: HPMC K100: Xanthan gum (1:2:1) and HPMC K 100: Xanthan gum (2:2) showed a greater bioadhesive strength as compared to single gum and other hydrophilic polymer combination tablet. The stability studies were performed on optimized formulation as per ICH guideline, result showed that there was no significant change in physical characteristic, adhesive strength and In vitro release.

Artificial neural networks in the optimization of a nimodipine controlled release tablet formulation

Artificial neural networks (ANNs) were employed in the optimization of a nimodipine zero-order release matrix tablet formulation, and their efficiency was compared to that of multiple linear regression (MLR) on an external validation set. The amounts of PEG-4000, PVP K30, HPMC K100 and HPMC E50LV were used as independent variables following a statistical experimental design, and three dissolution parameters (time at which the 90% of the drug was dissolved, t 90%, percentage of nimodipine released in 2 and 8 h, Y 2h, and Y 8h, respectively) were chosen as response variables. It was found that a feed-forward back-propagation ANN with eight hidden units showed better fit for all responses ( R 2 of 0.96, 0.90 and 0.98 for t 90%, Y 2h and Y 8h, respectively) compared to the MLR models (0.92, 0.87 and 0.92 for t 90%, Y 2h and Y 8h, respectively). The ANN was further simplified by pruning, which preserved only PEG-4000 and HPMC K100 as inputs. Optimal formulations based on ANN and MLR predictions were identified by minimizing the standardized Euclidian distance between measured and theoretical (zero order) release parameters. The estimation of the similarity factor, f 2, confirmed ANNs increased prediction efficiency (81.98 and 79.46 for the original and pruned ANN, respectively, and 76.25 for the MLR).

Designing, Optimisation & Characterization of Sustained Release Matrix Pellets Prepared by Extrusion Spheronization Containing Mixture of Proteolytic Enzymes

A method for developing sustained release multiple unit dosage form consisting of pellets of a proteolytic enzyme blend using extrusion spheronization as a process is demonstrated in this paper. Effect of Cellulose and Methacrylate based polymers and plasticizers on stability of the enzyme blend are determined. The effect of type & concentration of the sustained release polymer, spheronization rpm and plasticizer on the yield & sphericity of pellets is studied. The results indicated that the SR pellets could be formulated for this enzyme blend using both HPMC K15 and EUDRAGIT RSPO. The best rpm for spheronization turned out to be 1200 rpm. Use of plasticizer improved yield and sphericity. Triethyl citrate was better over polyethylene glycol 400 and EUDRAGIT RSPO was better over HPMC K15 with respect to yield and sphericity of pellets. The pellets could be suitably enteric coated for protection of enzyme blend in lower pH of GIT. The in vitro release profile indicated release extension could be extended up to 12 hours in intestinal condition postulating to an acceptable bioavailablity in vivo.