Formulation and Characterization of Microemulsion System

Formulation and Characterization of Microemulsion System Abstract Formulation of a new oil-in-water (o/w) microemulsion composed of Castor oil/Tween 80/Ethanol/Phosphate buffer for enhancing the loading capacity of an anti-inflammatory drug piroxicam has been accomplished. The pseudo-ternary phase diagram has been delineated at constant surfactant/cosurfactant ratio (1:2). The internal structure of so created four-component system was elucidated by means of an analysis of isotropic area magnitudes in the phase diagram. Conductivity (?), kinematic viscosity (kh) and surface tension (g) studies with the variation in ?w (weight fraction of aqueous phase) show the occurrence of structural changes from water-in-oil (w/o) microemulsion to oil-in-water (o/w). Along with the solubility and partition studies of piroxicam in microemulsion components, the changes in the microstructure of the microemulsion after incorporation of drug have been evaluated using pH, ?, g, kh and density studies. Piroxicam, a poorly water soluble drug, displayed high solubility (1 .0%) in an optimum microemulsion formulation using Ethanol (55.0%), Tween 80 (26.5%), Castor oil (7.5%), and Phosphate buffer (11.0%). The results have shown that the microemulsion remained stable after the incorporation of piroxicam. Fluorescence spectra analysis taking pyrene as fluorescent probe was performed and the results showed that pyrene was completely solubilized in the oil phases of the bicontinuous microemulsions. The fluorescence spectrum of model drug piroxicam was used to probe the intramicellar region of nonionic microemulsion. The results showed that the piroxicam was localized in the interfacial film of microemulsion systems more deeply in the palisade layer with ethanol as the co-surfactant. Keywords: Microemulsion; Piroxicam; Isotropic area; Spectroscopy; Structural changes Introduction Piroxicam is a non-steroid anti-inflammatory compound with analgesic and antipyretic effects, used for the treatment of rheumatoid arthritis, osteoarthritis and traumatic contusions. However, it has been associated with gastrointestinal side effects. It is possible to minimize these problems by developing drug carriers to prevent the direct contact of drug with gastric mucosal or that allow the topical administration of drug (1, 2). Microemulsions are optically isotropic, transparent and thermodynamically stable homogeneous solutions of oil and water, stabilized by addition of a surfactant and usually a cosurfactant (3, 4). These structures have been considerably investigated as drug delivery and carrier system for a wide range of drugs including analgesics and anti-inflammatory and also used to dissolve lipophilic drugs in aqueous medium or hydrophilic drugs in lipophilic medium (4, 5). Oil in water microemulsions have been described as a reservoir system that can inhibit drug release, increasing the topical effect (6). Several mechanisms have been proposed to explain the advantages of microemulsion or the transdermal delivery of drugs (7). First, a large amount of drug can be incorporated in the formulation due to the high solubilizing capacity, with increased thermodynamic activity towards the skin. Second, the permeation rate of a drug from microemulsion may be increased, since the affinity of the drug to th e internal phase in microemulsion can be easily modified, to favor partitioning, using different internal phases and changing the composition of the microemulsion. Third, the surfactant and cosurfactant used in the microemulsion may reduce the various diffusional barrier by acting as penetration enhancers (8, 9). For the selection of components of a biocompatible microemulsion system, the use of non-ionic surfactants has been widely accepted, since these are compatible and retain its utility over a broad range of pH values and may affect the skin barrier function (10-12). Microemulsion comprises different structures (water-in-oil (w/o), oil-in-water (o/w) and bicontinuous) and these help in releasing the drug (13, 14). It is necessary to characterize the microstructure of pure and drug-loaded microemulsion. The changes in the internal structure of a microemulsion can be monitored by analyzing conductivity, viscosity, density, surface tension and the fluorescence probe studies, etc. (15-17). The incorporated drug may or may not influence the microstructure. o/w and w/o microemulsions may show different behavior for the release of both hydrophilic and lipophilic drugs. In the present work, an attempt has been made to construct a microemulsion system, for poorly water soluble non-steroid anti-inflammatory drug piroxicam, comprising castor oil, a non-ionic surfactant Tween 80, a short chain alkanol cosurfactant (ethanol) and phosphate buffer (PB) pH 7.4. The pseudo-ternary phase diagram has been constructed for the chosen system at a constant surfactant:cosurfactant ratio (1:2). The reason for the selection of the particular oil chosen was that the castor oil has a hydroxyl group in addition to unsaturation, making it more polar. Ricinoleic acid is the main component of castor oil and it exerts anti-inflammatory effects (18). Polyoxyethylene fatty acid, stearic acid, oleic acid are used in emulsifiers in oil/water type creams and lotions. Conductivity, viscosity, surface tension and the fluorescence behavior of the pyrene is employed to investigate the gradual changes occurring in the microstructure of microemulsion. Pyrene is popular fluorescent probe which is used to study the microheterogeneous media. The fluorescence spectrum of Pyrene was used to sense the micropolarity of the o/w microemulsion. In this study, it is analyzed that how stability, optical texture and microstructure of microemulsion formulation, is influenced by piroxicam. To improve the solubility of piroxicam, an effort has been made to develop an optimum o/w microemulsion. It is therefore expected that the use of microemulsion formulation may enhance the solubility of piroxicam and prevent its degradation. Materials and Methods Materials Tween 80 (polyoxyethylene sorbitan monooleate), absolute ethanol (99.8 ? %) and castor oil were purchased from Fluka. Pyrene (98 %) was purchased from Sigma-Aldrich. Piroxicam was generously provided by Amson Vaccines Pharma (PVT) Ltd and used without further purification. Phosphate buffer (0.01 M, pH 7.4) was used as the hydrophilic phase. Buffers were prepared using NaH2PO4/Na2HPO4. 0.1M NaOH and HCl were used to maintain the pH of the solution. Methods Microemulsion Preparation The pseudo-ternary phase diagram was mapped (as shown in Fig. 1) using oil (castor oil), surfactant (Tween 80; HLB = 15), cosurfactant (ethanol) and aqueous phase PB (pH 7.4) at 25 ±0.01 ?C with constant surfactant:cosurfactant mass ratio (1:2). The temperature was kept at 25 ±0.01 ?C and was maintained by a Lauda M-20 thermostat. Castor oil was first mixed with Tween 80/ethanol mixture; PB was then added to obtain the desired microemulsion compositions. Transparent, single-phase mixtures were designated as microemulsions. All the samples were stable for over 10 months, remaining clear and transparent. Drug incorporation in Microemulsion Eight microemulsions differing from each other by Fw, were selected from the single-phase region of phase diagram (Fig. 2) with compositions mentioned in table I, to study their potential as drug delivery system. All of them show stability over 10 months and remain clear and transparent. Piroxicam was dissolved into the pre-weight oil component of the system at a concentration of 1% (w/w) under stirring followed by addition of remaining components. Microemulsion Characterization Optical Transparency The homogeneity and optical isotropy of pure and drug loaded microemulsions were examined by a Polarimeter (ATAGO, AP-100 Automatic Polarimeter) and visual examination at room temperature. Centrifugation Thermodynamic stability of pure and drug-loaded microemulsions was tested by carrying out centrifugation at 5500 rpm for 20 min using (Hermle Z200) centrifuge. Surface Tension Surface Tension measurements were made at 25  ±0.010C under atmospheric pressure by Torsion Balance (White Elec. Inst. Co. Ltd.) equipped with a ring having circumference of 4.0 cm. The experimental error was about  ±0.05 mNm-1. Density and Specific Gravity Densities and Specific Gravity of pure and drug loaded microemulsions were measured by making use of an Anton Paar (Model DMA 5000) density meter at 25  ±0.01 ?C. The density meter was calibrated before and after each set of density measurement using the density of air and pure water. Refractive Index The refractive indices of the formulations were determined using a refractometer (ATAGO, RX-5000) by placing 1 drop of solution on the slide. pH The apparent pH of all the selected microemulsions and the drug loaded microemulsion was determined using a pH Meter (WTW 82362 Weilheim) fitted with a pH electrode (WTW A061414035). The temperature was maintained at 25 ±0.01 ?C by a Lauda M-20 thermostat. Conductivity Measurements The effect of the amount of water phase of microemulsion was monitored quantitatively by measuring the electrical conductivity. The electric conductivity (?) was measured by means of a Microprocessor Conductivity Meter (WTW 82362 Weilheim) fitted with an electrode (WTW 06140418) having a cell constant of 1.0 cm-1. The temperature was kept at 25 ±0.01 ?C and was maintained by a Lauda M-20 thermostat. Conductivity measurements were carried out by titration of oil and surfactant/cosurfactant mixture with buffer (along the dilution line AB in Fig. 1). Further the conductivity of selected and drug loaded microemulsions was also measured. The error limit of conductance measurements was  ±0.02 ?scm-1. Viscosity Measurements Viscosities were measured with calibrated Ubbelhode viscometer at 25 ±0.1 ?C. For each measurement, the viscometer was washed, rinsed and vacuum dried. To follow the viscous behavior of the microemulsions, flow time was measured for all the selected and drug-loaded microemulsions (1 wt% drug). The error limit of viscosities measurements was  ±3%. Absorption and Steady-State Emission Measurements The absorption and steady-state fluorescence spectra were recorded using a Perkin Elmer Lambda 20 spectrophotometer and a Perkin Elmer LS 55 luminescence spectrometer, respectively, both with an external temperature controlled cell holder at a temperature of 25.0 ±0.1 °C. The fluorescence emission spectrum of pyrene (excitation at 340 nm) was used to obtain the ratio of intensities of the first to the third vibronic peaks (I1/I3). Good resolution of the bands was obtained at the slit width (ex. 5.0nm, em. 5.0 nm). The scan range used was from 350-500 nm. The Photo Multiplier tube voltage was kept at 665V. The concentration of pyrene was 1.0 ?M. The intensities for I1 and I3 are taken at 373 and 384 nm, respectively. The fluorescence emission spectrum of piroxicam at ?exc 370 nm was obtained where the emission and excitation slits were fixed at. 7.0 nm. The scan range used was from 390-650 nm. The concentration of piroxicam was 10.0 ?M. To quantify the solubilization of piroxicam in micellar media of Tween 80-Ethanol system, differential absorbance measurements were made in such a way that drug (piroxicam) solution of a particular concentration (1.0-10-5M) was kept on reference side and the Tween 80-Ethanol-Piroxicam solution on the sample side in the spectrophotometer. Partition Coefficients Oil/buffer partition coefficient was determined by dissolving 20 mg piroxicam in 2ml Castor Oil. Buffer was added in 1:1 ratio (v/v). The mixture was shaken for 10 min and centrifuged for 2 hours. The two layers were separated and the content of piroxicam in aqueous layer (PB) was assayed by UV-Visible spectrophotometer at 371 nm. The final content of drug in the lipophilic phase was calculated by subtracting the content of piroxicam in aqueous phase from initial loaded content of drug in the lipophilic phase. Further, the effect of presence of Tween 80 and ethanol on the partition of piroxicam in oil/buffer was studied by adding 5% (w/v) of each Tween 80 and ethanol. Results and Discussion In the present system, microemulsion was prepared using Castor oil (fatty acid), which induces highly permeable pathways in the stratum corneum (18-20). Tween-80 is a widely accepted non-ionic surfactant, used in many pharmaceutical formulations (21-23). The cosurfactant (ethanol) is used to study the one phase microemulsion region. The presence of alcohol overcomes the need for any additional input of energy. These properties make the components useful as vehicles for drug delivery (24-26). In the absence of aqueous phase, a solution-like oily phase consisting only of surfactant, oil, and ethanol exists. Ethanol interacts with the ethoxylated head groups of the Tween 80 by hydrogen bonding and affects its critical packing parameter (CPP). When water is progressively added to the concentrate it facilitates the organization of the hydrated head groups of the surfactant into a polar core while the fatty acid tails are immersed in the oil continuous phase. The ethanol suppresses formation of lyotropic liquid crystals. Any free aqueous phase is entrapped in the microstructures. Thus, w/o microstructures are formed. Upon further dilution, the reversed nanostructures grow and convert into a bicontinuous phase and finally invert into o/w microstructures without phase separation. Phase Studies Fig. 1 shows the pseudo-ternary phase diagram and area of existence of microemulsion for Tween-80/ethanol/castor oil/phosphate buffer. Microemulsion in the present study formed spontaneously at ambient temperature when their components were brought in contact. Phase behavior investigations of this system demonstrated the suitable approach of determining the water phase, oil phase, surfactant concentration, and cosurfactant concentration with which the transparent, 1-phase low-viscous microemulsion system was formed. The phase behavior, as shown by figure 1, manifests a two-phase region, a three-phase region and a large single-phase region which gradually and continuously transformed from buffer rich side of binary solution (buffer/surfactant micellar phase) of pseudo-ternary phase diagram towards the oil rich region. This stresses a continuous transition from a water rich compositions to oil swollen micelles. The phase study revealed that the maximum proportion of oil was incorporated in microemulsion systems when the surfactant-to-cosurfactant ratio was 1:2. From a formulation viewpoint, the increased oil content in microemulsions may provide a greater opportunity for the solubilization of piroxicam. Eight microemulsions (1-8) were selected from the single-phase isotropic region (Fig. 2), with compositions mentioned in table I. Selected Microemulsion (ME) was further analyzed by conductivity, viscosity, density, surface tension, refractive index and pH. The values of measured parameters have been presented in table II. Conductivity Measurements Conductometry is a useful tool to assess microemulsion structure. Conductivity studies have explained the existence of a characteristic zone with an isotropic microemulsion domain in a continuum. Determination of electric conductivity (s) as a function of weight fraction of aqueous component Fw (% wt) for the oil, surfactant/cosurfactant mixture along the dilution line AB (shown in Fig. 2) has been carried out. The results of variation of s vs Fw (% wt) are shown in Fig. 3 (a). The behavior exhibits profile characteristic of percolative conductivity (27-29). The conductivity is initially low in an oil-surfactant mixture but increases with increase in aqueous phase. As the volume fraction of water increases, the electrical conductivity of the system slightly increases as well, until the critical Fw is reached. At this stage, a sudden increase in conductivity is observed. This phenomenon is known as percolation, and the critical Fw at which it occurs is known as percolation threshold Fp (27). The value of conductivity below Fp suggests that the reverse droplets are discrete (forming w/o microemulsion) and have little interaction. Above Fp the value of s increases linearly and steeply till it touches the value of Kb. The interaction between the aqueous domains becomes progressively more important and forms a network of conductive channel (bicontinuous microemulsion) (30). Rapid increase in conductivity beyond the percolation threshold (Fp ? 6%) up to approximate value of 20% of Fw indicates the existence of network of conductive channels, which corresponds to the formation of water cylinders or channels in an oil phase due to the attractive interactions between the spherical micro-droplets of water phase in the w/o microemulsion. Increasing water content above Fb (Fw > 20%), the s shows a dip in the measured values which may be due to strong attractive forces as system becomes more viscous (16, 30).Fig. 3 (b) depicts the variation of log s vs weight fraction of water (Fw). The change in the slope of log s can be attributed to the structural transition to bicontinuous from w/o (23), nearly at Fw = 6%. The transition takes place once the aqueous phase becomes continuous phase i.e. at Fb. This is in line with the observation made in phase study. Figure 3(a) illustrates occurrence of three different structures (namely w/o, bicontinuous, o/w). The conductivity of the microemulsions containing more than 20 wt% water decreased significantly, probably due to the higher viscosity. The percolation threshold can be determined from the plot (ds/dFw), as a function of the water weight fraction, Fw (% wt) (30). A maximum in the first derivative of conductance Fw at ~12wt % water is observed (Fig. 4) confirming the presence of percolation behavior (bicontinuous microstructure) in this region (31). The electric conductivity of pure selected and drug loaded microemulsion (1.0%) is given in table II. A comparison of two systems shows that drug incorporation does not affect the microstructure of the microemulsion. Viscosity Measurements To avoid the ambiguity of non-Newtonian flow behavior of microemulsion the flow time has been used as an index of viscosity (32). Flow time of oil, surfactant/cosurfactant mixture along the dilution line AB (shown in Fig. 2), was measured as a function of weight fraction of water Fw (wt %) and is shown in Fig. 5. Similar trend has been observed for the viscosity of oil, surfactant/cosurfactant mixture as a function of Fw (Fig. 6). The rapid change in the viscosity is probably due to the change in the microstructure of the microemulsion. The change in the internal structure could be due to either the change in the shape of droplets or may be due to the transition from w/o to bicontinuous microemulsion. It is well known that increase of volume fraction of dispersed phase in microemulsion increases viscosity of the system (33). For the system studied viscosity increases with increase in Fw (wt% of aqueous phase). Difference in the viscosities is more profound for lower water content values in comparison to the dilute system. The microemulsion system is turning to be more viscous with addition of water and thus may help in the slow diffusing of drug at infinite dilution. The microemulsion system thus, shows a structural change from oil continuous system to water continuous, which has higher viscosities than the former (34). The plots of hk (kinematic viscosity), d2?/d2Fw and 1/? d?/dFw versus Fw reflect that the transition occurs at ~11% weight fraction of aqueous phase (Fig. 6). The transition point of surface tension, conductivity and viscosity plots coincides well at ~11% weight fraction of aqueous phase and confirms the presence of percolative behavior. Surface Tension The surface tension increases linearly over the same range of water content (Fig. 7), but two breaks (at ~7.0 and ~20 wt% water) suggest that structure changes occur at these compositions. The surface tension measurements showed increment, when measured as a function of weight fraction of aqueous component, except for the ~12% weight fraction where the value suddenly decreased and thereafter a regular increase was observed. This low surface tension value showed the presence of bicontinuous microemulsion between oil and water rich system, which is because of presence of self-assembled organize microstructure in it (14, 35). The results coincide well with the electric conductivity and viscosity measurements. It can be assumed that the added alcohol (ethanol) is incorporated in the interfacial structure in such a way that more water is on the outside of the oil drops, causing the increase in surface tension. Incorporation of drug showed a negligible change in the surface tension measure ments, therefore indicting the possibility of piroxicam molecules into the palisade layer on the inner side of microemulsion. Fluorescence Measurements In the case of oil-in-water microemulsions, the steady-state fluorescence technique was successfully applied (36). Fluorescence measurements of the hydrophobic probe mainly depend on the polarity of the medium and hence in bicontinuous microemulsions it is a good indication of the polarity of the microenvironment in the microemulsion structure (37). The fluorescence spectra for pyrene molecule in water, individual oil phase, in alcohols, in ethanol/oil and in all the selected microemulsions are shown in Figure 8. There are four principal vibronic bands in the fluorescence spectrum (Fig. 8a), labeled I to IV. The peak intensity ratio I1/I3 in the steady-state fluorescence spectra is a measurement of the relative polarity of pyrenes environment (17). Since pyrene reactant is substantially more soluble in oil phases, I1/I3 is expected to be lower in these phases (38). In the present work, for oil phase, the I1/I3 value is 0.68. In relatively polar methanol and ethanol media, I1/I3 values were found to be 1.20 and 1.09 respectively. Water is a highly polar solvent; the solubility of pyrene in this solvent is less than 2 ?M. Hence the possibility of formation of excimer leading to I3 signal is extremely low in water. Experimentally I1/I3 value is 1.70 was obtained for this medium. Plot of I1/I3 versus weight fraction of aqueous component composition in microemulsion is shown in Figure 9. The value of I1/I3 varies between 0.85 and 0.91, which is comparable to a change from oil to water (0.68 and 1.70, respectively). The I1/I3 fluorescence ratios of pyrene strongly suggest that this probe resides in microenvironments of polarity much lower (oil phase) than that of water or alcohol (39). The polarities of these microphases are similar to those of cosurfactant/oil mixtures (0.94). The following generalizations may be made regarding the fluorescence probe behavior in bicontinuous microemulsions. The I1/I3 values obtained by fluorescence measurements for all the stable bicontinuous microemulsions are closer to 0.88. These results suggest that pyrene is efficiently segregated from the water phase (40). The I1/I3 values in bicontinuous microemulsions systems are closer to the respective pure oil phase. This is due to complete solubility of pyrene in oil phases of the bicontinuous microemulsions. We conclude that all the microemulsions have separate oil microphases, in which pyrene resides. Fluorescence Behavior of Piroxicam The fluorescence spectra for piroxicam molecule in water, individual oil phases, in surfactant/cosurfactant mixture (1:2) and in the optimum microemulsion system are shown in Figure 10. For oil phase the emission maxima (lem) is 465nm. In S/CoS (1:2) system lem is 451nm. Water is a highly polar solvent; the solubility of piroxicam in this solvent is low than 10 ?M. The lem of piroxicam in water is 442nm. The emission maximum in bicontinuous microemulsion system is (462nm) closer to the respective pure oil phase. The results showed that the piroxicam was localized in the interfacial film of microemulsion systems more deeply in the palisade layer. Partition Coefficient Partition coefficients influence drug transport characteristics which involve drug absorption, retention, distribution and elimination. Since drugs are distributed by the blood, they must penetrate and traverse many cells to reach the site of action. Hence, partition coefficients will determine what tissues a given compound can reach. Oil/buffer Partition Coefficients The partition coefficient (log p) of piroxicam in oil/buffer is 5.03 ±0.20. The presence of ethanol (5% in buffer) does not affect the partition coefficient (data shown in table III) whereas Tween 80 (5% in buffer) reduces the log p. The presence of surfactant reduces the concentration of drug in oil. Thus, solubility and partition studies indicate that piroxicam may be present at interface. The drug is entering into the palisade layer on the inner side of droplet which may help to increase the solubility of piroxicam. The partition coefficients were calculated using equation 1 (41); where A(org) is the absorbance of the organic layer, A(aq) is the absorbance of the aqueous layer, Vf(org) is the final volume of the sample from the organic layer, V(org) is the volume of the aliquot from the organic layer, Vf(aq) is the final volume of the sample from the aqueous layer, V(aq) is the volume of the aliquot of the aqueous layer. Micelle/buffer Partition Coefficient Figure 11 shows the differential absorption spectra of drug (piroxicam) in presence of various concentrations of Tween 80 having constant S/CoS ratio (1:2). The buffer-micelle partition coefficient Kc (dm3 mol-1), a useful parameter to quantify the solubilization of piroxicam in micellar media of Tween 80-Ethanol system, can be calculated by using equation 2 (42). Here Ca is the drug concentration (1.0-10-5M), Csmo represents Cs-CMC0 (CMC0 is the CMC of Tween 80 in water i.e. 11.0mM), ?A? is the differential absorbance at the infinity of Cs. Kc can be obtained through intercept and slope values of the straight line plot of 1/?A against 1/ (Ca+ Csmo), as shown in Figure 12. The value of Kc is given in table IV. The dimensionless partition coefficient p is related to Kc as p = Kc.nw, where nw is the number of moles of water per dm3 (55.5 mol dm-3), and is reported in table IV. The standard free energy change of the transfer of additive, from bulk water to micelle can be calculated using the following relation (equation 3): Here T is absolute temperature and R is the gas constant. The value of ?G °p for the piroxicam, using p is reported in table IV. High negative value of indicates the ease of penetration of drug inside the micelles. This is clearly exhibited by the higher values of p and more negative for piroxicam, as shown in table IV. Tween 80 is nonionic surfactant and there is no electrostatic interaction, the hydrogen bonding between the polyoxyethylene groups of Tween 80 and piroxicam makes the complex (Tween 80-piroxicam) more hydrophobic, which corresponds to high ?G °p value. Conclusion The pseudo-ternary phase diagram and area of existence of microemulsion for Tween 80/ethanol/castor oil/buffer was delineated. The conductivity and viscosity studies along the dilution line (in phase diagram) depict the structural transition from w/o to o/w via bicontinuous phase at ~11% ?w (wt% fraction of aqueous phase). Among the eight selected microemulsions, ME was found to be optimum for the incorporation of piroxicam. After the incorporation of the drug, microemulsion remained stable and optically clears with no phase separation. The surface tension and fluorescence studies indicated that the drug may reside at the interface of oil and aqueous phase. The drug is entering into the palisade layer on the inner side of the droplet, resulting in controlled release of drug. Thus, we can conclude that this microemulsion system helps in increasing the solubility of a highly hydrophobic drug, with the help of hydrophobic component of microemulsion and lipophilic part of surfactant. In addition, the formulation can be explored with high concentration of drug. Pharmaceutically usable microemulsion system was prepared from water and castor oil with a constant amount of Tween-80 and ethanol at a mass ratio of 1:2. Its type and structure was examined by measuring surface tension, viscosity, electric conductivity, and the fluorescence techniques were assessed. Results of conductivity, viscosity, density and surface tension measurements confirm the prediction of a percolation transition to a bicontinuous structure. In future, the ability to determine type and structure of such microemulsion system could enable partitioning and release rates of drugs from microemulsion to be predicted. Acknowledgement The financial support of Quaid-i-Azam University and Higher Education Commission of Pakistan is duly acknowledged. References Lopes LB, Scarpa MV, Pereira NL, De Oliveira LC, Oliveira AG. Interaction of sodium diclofenac with freeze-dried soya phosphatidylcholine and unilamellar liposomes. Revista Brasileira de Ciencias Farmaceuticas/Brazilian Journal of Pharmaceutical Sciences. 2006;42(4):497-504. Park ES, Cui Y, Yun BJ, Ko IJ, Chi SC. Transdermal delivery of piroxicam using microemulsions. Arch Pharmacal Res. 2005;28(2):243-8. Yuan Y, Li Sm, Mo Fk, Zhong Df. Investigation of microemulsion system for transdermal delivery of meloxicam. Int J Pharm. 2006;321(1-2):117-23. Sarciaux JM, Acar L, Sado PA. Using microemulsion formulations for oral drug delivery of therapeutic peptides. Int J Pharm. 1995;120(2):127-36. Ristsehel WA. Experimental and Clinical Pharmacol. 1991. Mehta SK, Kaur G, Bhasin KK. Analysis of Tween based microemulsion in the presence of TB drug rifampicin. Colloids and Surfaces B: Biointerfaces. 2007;60(1):95-104. Sebastien H, Devin VM, Mark GA, Mark RP. Microfabricated microneedles: A novel approach to transdermal drug delivery. J Pharm Sci. 1998;87(8):922-5. Sintov AC, Botner S. Transdermal drug delivery using microemulsion and aqueous systems: Influence of skin storage conditions on the in vitro permeability of diclofenac from aqueous vehicle systems. Int J Pharm. 2006;311(1-2):55-62. Spernath A, Aserin A. Microemulsions as carriers for drugs and nutraceuticals. Adv Colloid Interface Sci. 2006;128-130:47-64. Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Adv Drug Delivery Rev. 2000;45(1):89-121. Là ³pez A, Llinares F, Cortell C, Herrà ¡ez M. Comparative enhancer effects of Span ®20 with Tween ®20 and Azone ® on the in vitro percutaneous penetration of compounds with different lipophilicities. Int J Pharm. 2000;202(1-2):133-40. Fang JY, Yu SY, Wu PC, Huang YB, Tsai YH. In vitro skin permeation of estradiol from various proniosome formulations. Int J Pharm. 2001;215(1-2):91-9. Krauel K, Davies NM, Hook S, Rades T. Using different structure types of microemulsions for the preparation of poly(alkylcyanoacrylate) nanoparticles by interfacial polymerization. J Controlled Release. 2005;106(1-2):76-87. Mehta SK, Kaur G, Bhasin KK. Incorporation of antitubercular drug isoniazid in pharmaceutically accepted microemulsion: Effect on microstructure and physical parameters. Pharm Res. 2008;25(1):227-36. He D, Yang C, Ma M, Zhuang L, Chen X, Chen S. Studies of the chemical properties of tri-n-octylamine-secondary octanol-kerosene-HCl-H2O microemulsions and its extraction characteristics for cadmium(II). Colloids Surf A. 2004;232(1):39-47. Podlogar F, GasÃÅ'Å’perlin M, TomsÃÅ'Å’icÃÅ'Å’ M, Jamnik A, RogacÃÅ'Å’ MB. Structural characterisation of water-Tween 40 ®

Alphabet of Lines

Alphabet of Lines The â€Å"Alphabet of Lines† refers to the different styles of lines used in drafting to show different features about an object that is drawn. There are eleven main line types – visible, hidden, center, dimension, extension, leader, section, cutting-plane, phantom, viewing plane and break. Each line has a definite form and line weight. The standard thick line weight varies from . 030 to . 038 of an inch whereas the standard thin line weight varies from . 015 to . 022 of an inch. Visible lines are dark and heavy lines. They show the outline and shape of an object. They define features that can be seen in a particular view. Hidden lines are light, narrow, short, dashed lines. They show the outline of a feature that cannot be seen in a particular view. They are used to help clarify a feature but can be omitted if they clutter a drawing. Section lines are thin lines usually drawn at a 45 degree angle. They indicate the material that has been cut through in a sectional view. Center lines are thin lines consisting of long and short dashes. They show the center of holes, slots, paths of rotation and symmetrical objects. Dimension lines are dark, heavy lines. They show the length, width, and height of the features of an object. They are terminated with arrowheads at the end. Extension lines are used to show the starting and stopping points of a dimension. There should be at least a 1/16 space between the object and the extension line. Leader lines are thin lines used to show the dimension of a feature or a note that is too large to be placed beside the feature itself. Cutting plane lines are thick broken lines that terminate with short 90 degree arrowheads. They show where a part is mentally cut in half to better see the interior detail. Break lines are used to break out sections for clarity or for shortening a part. There are three types of break lines with different line weights. These are short breaks, long breaks and cylindrical breaks. Short break lines are thick wavy lines used to break the edge or surface of a part for clarity of a hidden surface. Long break lines are long, thin lines used to show that the middle section of an object has been removed so it can be drawn on a smaller piece of paper. Cylindrical break lines are thin lines used to show round parts that are broken in half to better clarify the print or to reduce the length of the object. Phantom lines are thin lines made up of long dashes alternating with pairs of short dashes. Their purpose is to show the alternate position of moving parts, relationship of parts that fit together and repeated detail. They can show where a part is moving to and from. They eliminate the confusion of thinking there may be two parts instead of just one. They also show how two or more parts go together without having to draw and dimension all. They show repeated details of an object and hence, provide efficiency and less chance of drafter error. Reference: An Alphabet of Lines. (2003). Retrieved July 21, 2011, from http://www. wisc-online. com/objects/ ViewObject. aspx? ID=mtl17903 Line Weights Line weights, or the varying line thicknesses used in engineering drawing, are essential in creating a drawing that communicates effectively. Line weights are a vital part of conventional technical graphics language. They are embodied to the extent of being defined in national and international standards. Line types and line weights allow drawings to communicate information that would otherwise be very difficult to convey. For example: hidden outlines, paths of motion, planes of symmetry, fictitious outlines such as major and minor diameters of screw threads, dimensions and projections, materials (hatching), and centers and imaginary intersections. Conventional practice is that only two different line weights be used on any one drawing. This is subject to discretion and some disciplines regularly use three, and occasionally four, different line weights. Consistency and clarity of communication are the deciding factors. Continuous thick lines range from 0. 35-0. 50 mm and are used for visible outlines, existing features, cut edges and general line work. Continuous medium lines are 0. 25-0. 35 mm and used when another level of line weight would assist the delineation e. g. internal line work, notes. Continuous thin lines vary from 0. 18 to 0. 25 mm. They are applied in fictitious outlines, imaginary intersections and projections, hatching, dimensions and break lines. Dashed thick lines are 0. 35-0. 50 mm while dashed thin lines are 0. 18-0. 25 mm. They are used in hidden outlines and edges. Chain thick lines are0. 35-0. 50 mm and they indicate special surface requirements or sometimes with a text component to indicate pipelines and services. Chain thin lines, 0. 18-0. 25 mm, are for center lines, motion paths and indication of repeated detail. Engineering drawings made on A4, A3 and A2-sized pages are at the smallest end of the range of document sizes that would reasonably be used. The appropriate pen group is from the fine end of the scale – 0. 18, 0. 25 and 0. 35mm pen widths. Reference: Line Weight. (n. d). Retrieved July 21, 2011, from http://www. cadinfo. net/intellicad/ line-weight Orthographic Drawing Orthographic projection (or orthogonal projection) is a means of representing a three-dimensional object in two dimensions. It is a form of parallel projection, where all the projection lines are orthogonal to the projection plane. It is further divided into multiview orthographic projections and axonometric projections. A lens providing an orthographic projection is known as an (object-space) telecentric lens. The term orthographic is also sometimes reserved specifically for depictions of objects where the axis or plane of the object is also parallel with the projection plane, as in multiview orthographic projections. With multiview orthographic projections, up to six pictures of an object are produced, with each projection plane parallel to one of the coordinate xes of the object. The views are positioned relative to each other according to either of two schemes: first-angle or third-angle projection. In each, the appearances of views may be thought of as being projected onto planes that form a 6-sided box around the object. Both first-angle and third-angle projections result in the same 6 views; the di fference between them is the arrangement of these views around the box. First-angle projection is as if the object were sitting on the paper and, from the â€Å"face† (front) view, it is rolled to the right to show the left side or rolled up to show its bottom. It is standard throughout Europe (excluding the UK) and Asia. First-angle projection used to be common in the UK, and may still be seen on historical design drawings, but has now fallen into disuse in favor of third-angle projection. Third-angle is as if the object were a box to be unfolded. If we unfold the box so that the front view is in the center of the two arms, then the top view is above it, the bottom view is below it, the left view is to the left, and the right view is to the right. It is standard in the United Kingdom, USA, Canada, and Australia. A great deal of confusion has ensued in drafting rooms and engineering departments when drawings are transferred from one convention to another. On engineering drawings, the projection angle is denoted by an international symbol consisting of a truncated cone labeled FR for first-angle and US for third-angle. Axonometric projection is a type of parallel projection, more specifically a type of orthographic projection, used to create a pictorial drawing of an object, where the object is rotated along one or more of its axes relative to the plane of projection. There are three main types of axonometric projection: isometric, dimetric, and trimetric projection. â€Å"Axonometric† means to measure along axes. Axonometric projection shows an image of an object as viewed from a skew direction in order to reveal more than one side in the same picture. Whereas the term orthographic is sometimes reserved specifically for depictions of objects where the axis or plane of the object is parallel with the projection plane, in axonometric projection the plane or axis of the object is always drawn not parallel to the projection plane. With axonometric projections the scale of distant features is the same as for near features, such pictures will look distorted, as it is not how our eyes or photography work. This distortion is especially evident if the object to view is mostly composed of rectangular features. Despite this limitation, axonometric projection can be useful for purposes of illustration. Reference: Orthographic projection (n. d. ). In Wikipedia. Retrieved July 21, 2011, from http://en. wikipedia. org/ wiki/Orthographic_projection

Beowulf Literary Analysis Essay

Ronis Aba September 27th, 2012 Period 6th â€Å"No better king had ever lived, no prince so mild, no man so open to his people, so deserving of praise. † This is an ultimate description of the heroic events of Beowulf, an old Anglo-Saxon poem about a warrior who battles and destroys three horrifying monsters. Although written long ago, the emotions expressed within this work, emotions of bravery, valor, and ethics still speak to us centuries later. The anonymous author of the poem convinces us through the masterful use of various literary elements that emphasize its meaning and message.Conflict, imagery and setting are three literary elements that contribute to the effectiveness of the poem. The use of conflict aids us to visualize the struggles between Beowulf and his opposing forces. To begin with, we are first introduced to Beowulf’s strength as we read lines 390-392; â€Å"and the bleeding sinew deep in [Grendel’s] shoulder snapped, muscle and bone split and broke. † This first battle exemplifies the readers respect towards Beowulf; this clearly demonstrates that the readers are in fact in awe of Beowulf’s strength and capability to fight Grendel with his bare hands.Furthermore in the story, we learn that Grendel’s mother â€Å"rose at once† and â€Å"repaid [Beowulf] with her clutching claws† (lines 513-517). This passage shows the readers, not only the struggle but, the effort Beowulf put forward to defeating Grendel’s mother in the hopes of glorification to his people and maintaining his pride. Finally, in lines 768-775, we read, â€Å"I swear that nothing ever did deserve an end like this†¦. As he dove through the dragon’s deadly fumes. † This final battle grants the readers with the logic of suspense.This is an epic scene because it is shown to the readers that Beowulf is indeed aware that this is his final battle meaning, with or without help, he would have to go to ulti mate ends in order to complete his mission of defeating the dragon. Finally, these are just some of the many conflicts that help us understand the fights between Beowulf and his differing opponents. Another literary element that offer meaning to the poem is imagery, by simply allowing the readers to envision the events of the story.In the first part of the story (129-134), Beowulf is described as coming over â€Å"seas beating at the sand† while â€Å"the ship foamed through the sea like a bird. † This scene truly guides the readers to admire the vivid description of how proud and tough the ship looks. This ship in this case, becomes a metonymy for Beowulf himself, who is certainly proud and strong, resulting in the readers’ admiration. Additional imagery is used describing the mere, or lake, discussed above, with â€Å"storms [an] waves splash[ing] towards the sky, as dark as the air as black as the rain that the heavens weep† (440-442).This clearly illu strates how dreadful Grendel and his mothers’ home is. It intensely aids us to picture how grotesquely unpleasant the lake actually is. Near the end of the tale (lines 651-653], Beowulf â€Å"[strides] with his shield at his side and a mail shirt of his breast†¦.. Toward the tower, under the rocky cliffs. † While Beowulf awaits the battle, the description of his armor and the details of each entry help us to respect how ready he is for his concluding battle. Even as an elderly man, Beowulf is a hero beyond compare.In closing, the use of imagery greatly enriches the readers’ experience of this heroic epic. Evidently, the setting of Beowulf helps the readers to better understand the cultures and events that occur in the story. In lines 60-63, the mead hall (Herot) is described as â€Å"[standing] empty, and stay[ing] deserted for years, twelve winters. † This makes the readers feel and understand the seriousness of Grendel’s attack. Before Grend el, Herot was described as a beautiful and happy place, and so the readers feel terrible regret when it is destroyed by the creature.Later in the story, we are shown the lair under which Grendel and his mother lives: â€Å"secret places, windy cliffs† and a lake which â€Å"at night†¦.. Burns like a torch† (424-433). This passage shows the readers the monstrous, awful conditions of where the monsters lived. It also causes us to feel disgust and revulsion at their horrible habitat. Finally, in the episode with the dragon, its cave is depicted as a â€Å"hidden entrance† with â€Å"a streaming current of fire and smoke block[ing] the passage† (lines 659-661). The cave is intimidating, helping the readers to believe that the upcoming battle will be a real challenge for Beowulf.And it turns out to be so as the powerful dragon ultimately causes the hero’s death. Evidently, these settings, along with others, make the stories come alive for the reade rs. The poet effectively combines the literary elements conflict, imagery and setting to show the reader the qualities of an Anglo-Saxon warrior and hero. To the old English people, no one was more praise worthy than Beowulf, Despite it being written over a thousand years ago, Beowulf shows one important detail of what it takes to truly be a hero, a standard to which we can still relate to today, perhaps more powerfully than ever.

Women in the Military Essay - 4227 Words

In Women in the Military, Janette Mance explores the debates and problems faced by the increasing number of women involved in the military. After examining issues such as pregnancy, sexual harassment, and rape, Mance concludes that as a society we must continue to strive for gender equality. From the storm lashed decks of the Mayflower to the present hour, women have stood like a rock for the welfare and glory of the history of our country . . . and one might well add: unwritten, unrewarded, and unrecognized. William Cohen, â€Å"On Women in the Military,† 1997 Throughout our nation’s history, women have played an important role in the military. It has not been until recently however, that women have been able to fully†¦show more content†¦I realized that although in theory women in the armed forces seemed like a good idea, there are many obstacles that make that reality very difficult to achieve. In writing this paper I am not proposing that either position is more valid or right than the other. I only hope to present each side in an equal light to help others to understand the issues involved. History of Women in the Military General Jeanne Holm was one of the very first women in the Air Force to achieve the rank of General. Although in retirement now, she still is an important military figure. Her book, Women in the Military: An Unfinished Revolution, gives an impressive account of the roles that women have thus far played in the military. It was my primary source when researching the history surrounding women in the military. Due to the fact that Holm’s book is so detailed and in depth, I also used a book by Dorothy and Carl J. Schneider entitled Sound Off: American Military Women Speak Out. This book provides a timeline detailing the major points of women’s military history, so when writing, I tried to follow that guideline. According to Holm, Women in point of fact, have been serving their country since it began - Molly Pitcher fired her cannon in 1778 without congressional sanction. In the Revolutionary and Civil Wars, women fought disguised as men. In World War One. their medical services were indispensable. During the crises of World War Two, when women wereShow MoreRelatedWomen and the Military1125 Words   |  5 PagesWomen and the Military Statistics show that the U.S. armed forces currently employ over 229,000 women in its various branches (Donnelly 8). This figure had been increasing exponentially for over 30 years. It s no surprise to men that women are becoming an important factor in the U.S. military and now occupy every position expect those on the front lines. With the infiltration of women in the services in 1972, great controversy has arisen and has become a highly argued issue (DonnellyRead MoreWomen in the Military1458 Words   |  6 PagesGender integration in the military has always faced the question of social acceptance, whether society can accept how women will be treated and respected in the military. Throughout the history of the military, our leadership has always sought ways in how to integrate without upsetting the general public if our females were captured as prisoners of war, raped, discriminated or even blown up in combat. My paper will discuss three situations pertaining to the fi rst female submariner, fighter pilotRead MoreWomen in the Military1453 Words   |  6 PagesWomen have done incredible things within the history of the world. They have proven time and time again that they are equal in just about every way with the opposite gender. 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I chose this topic in order to get a full view on how women in the military are thought of. I have done some research and have learned a lot more then I originally expected. According to the U.S. Constitution, all men are created equal, this also includes women. I believe that a woman in the military is just as capable as any man. Some people will argue this because they feel as though it is not right to have women wounded or killedRead More Women in the Military Essay1112 Words   |  5 PagesShould women be allowed in the military? My answer was at first a resounding â€Å"no.† However, once I started my research, my opinion changed. In 1948, Congress passed the combat exclusion law that prohibited women in the Air Force, Marines, and Navy to hold combat positions; however, the Army can assign these duties as they see fit (Schroeder). 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