THE EFFECT OF SOLUTE AND MEMBRANE POLARITY IN CREATING A PSEUDO-ZERO-ORDER CONTROLLED RELEASE PROCESS

Transcription

1 THE EFFECT OF SOLUTE AND MEMBRANE POLARITY IN CREATING A PSEUDO-ZERO-ORDER CONTROLLED RELEASE PROCESS Ruchita Balasubramanian, Sakshum Chadha, Charmaine Chew, Joseph Da, Sona Dadhania, Abhinav Karale, Grace Kresge, Meilin Lu, Victoria Ou, Ram Vellanki, Peter Zhou ABSTRACT Advisor: Dr. David Cincotta Assistant: Tony Chen In a pseudo-zero-order controlled release, the rate of diffusion is independent of time and concentration. In this experiment, the team analyzed the rate of diffusion for strong electrolytes (NaCl and CaSO 4 ), weak electrolytes (citric acid, ascorbic acid, and acetylsalicylic acid), and various alcohols (propanol, ethanol, and methanol) across polymer membranes of varying compositions of ethylene-vinyl acetate (EVA). The change of concentration in the target area was recorded using changes in conductivity (strong electrolytes), ph (weak electrolytes), and gravimetric analysis (alcohols). Increasing the percent composition of EVA in the films increased the polarity of the film, which should have theoretically increased the membranes permeability to polar substances. The experiments showed that no ionic salts tested passed through the membranes for up to 40% EVA composition, and only citric acid was able to diffuse for weak electrolytes. All the moderately polar alcohols diffused successfully. These data suggest that only substances with intermolecular forces comparable to that of EVA can dissolve into the membrane and therefore diffuse through it. INTRODUCTION Zero-Order Controlled Release Ideally, the controlled release of a specific substance should be a zero-order process, which describes when the rate at which a substance is transported into its surroundings remains constant and independent of the concentration. This type of process is often sought after in pharmacy; medicines should be delivered to the body at a constant rate over a period of time. However, this is hard to achieve in practice, as the rate of delivery often slows and ultimately levels off with time as the concentration of the substance in the surroundings increases (1). This concentration-dependent process is considered first-order. Achieving zero-order controlled release requires one to disregard the concentration component and release the same amount of substance at the same rate over time. Active zero-order controlled release is often achieved using a mechanical pump, as in intravenous medical fluids. However, there is an increasing urgency to achieve passive zeroorder controlled release that has no mechanical component, because mechanical pumps tend to be large and inconvenient. Previous mechanisms for such results have included reservoir systems in which materials diffuse constantly through a polymer matrix when placed in an aqueous environment (1). Other mechanisms include a pseudo-zero-order release mechanism that relies on a first-order release kept at a constant concentration through compartmentalization. [5-1]

2 Figure 1: Representation of Uncontrolled Release versus Controlled Release This representation, produced by Alzet (2), shows the difference between uncontrolled release of chemicals, as normally done by pills, and the controlled release of chemicals achieved through pseudo-zero-order diffusion. Zero-order processes are often sought after in medicine because to be effective, drugs should be delivered to a patient at a constant rate. Most medicines, however, are given in doses that create an initial spike in concentration at the time of the dose, and then fall off until the time of the next dose (Figure 1). Occasionally this dosage system can bring the concentration of the drug into a cytotoxic range, which can harm the patient. A zero-order controlled release mechanism is most ideal for such situations in order to keep the medication at a therapeutic constant (1). Fick s Law and Diffusion Diffusion constitutes the movement of a specific substance through a membrane along a concentration gradient until the process reaches equilibrium. This process is governed by Fick s Law of Diffusion, as stated in the equation (1) where J is the flux, D is the diffusion constant, and is the change in concentration over the thickness of the membrane. As long as the concentration of the substance remains constant, D is proportional to the flux, and simplifies to the following equation: In this particular equation, J is the diffusion constant, the C represents the concentration gradient, and the x represents the thickness of the membrane. This equation provides the relationship between the concentration gradient, the thickness, and the rate of diffusion. By (2) [5-2]

3 maintaining a constant concentration gradient the rate of diffusion remains constant and pseudozero-order controlled release is effectively achieved. Polymer Membrane Films Ethylene vinyl acetate (EVA) is a copolymer that was used to create the membranes used in this experiment. It is comprised of polyethylene and vinyl acetate, which can form a uniform polymer membrane when cast using a solution of toluene (3). This makes a semipermeable membrane that can filter particles based on a variety of parameters, such as particle size, polarity, crystallinity, and intermolecular forces between membrane and particle (4). This flexibility allows us to collect a wide range of data by testing different variables. Polarity Polarity describes the presence of a dipole with opposite charges on each end of the molecule. The difference of polarity between a molecule and the polymer membrane affects the rate of diffusion across the membrane, because polar substances will only diffuse through polar membranes and the same with nonpolar substances and membranes. This phenomenon can be attributed to the solution-diffusion model, where the solute must first dissolve into the membrane and then move down its concentration gradient (6). Furthermore, when the polarities of substances are similar, the rate of diffusion across a membrane is faster, and vice versa. Polyethylene by itself is nonpolar due to its lack of polar groups, such as acetyl or alcohol groups (3). Increasing the concentration of vinyl acetate in ethylene vinyl acetate, EVA, (Figure 2) increases the polarity of the copolymer. As the polarity of the membrane approaches the polarity of the solute, the diffusion rate is expected to increase (7). Since electrolytes have a net ionic charge, a more polar membrane would allow for a greater chance of diffusion, and would increase the rate of diffusion. Figure 2: Structure of Polymer Membranes These polymers were used to make semipermeable membranes in this experiment. (a) The molecular structure of polyethylene, which is a nonpolar molecule. (b) The molecular structure of the copolymer ethylene vinyl acetate (EVA). EVA is made of polyethylene and vinyl acetate. Because vinyl acetate is a polar side chain, as [5-3]

4 the percentage of vinyl acetate increases in an EVA mixture, the polarity of the mixture increases as well (6). However, more polar membranes are more difficult to manage because of the adhesive properties of pure EVA. Therefore, the concentration of EVA must be optimized to allow for the maximum rate of diffusion without sacrificing manageability. Adding copolymers such as polyethylene vinyl alcohol or polyethylene glycol can also vary polarity; this would ideally allow more polar substances to diffuse through them more polar membrane. However, in order to add these copolymers, they must be compatible with the EVA solvent (toluene) and with the EVA itself in order to create a uniform, workable membrane (3). Hansen Solubility Parameters To predict which polymers could create a solution needed to cast a film, the team referred to the Hansen Solubility Parameters by Dr. Charles Hansen. The Hansen Solubility Parameters describes all molecules in terms of their primary intermolecular forces: dispersion forces, dipoledipole interactions, and hydrogen bonding. A molecule, with its collection of the three intermolecular interactions, can be mapped as a spherical volume on a three-dimensional plane based on the values of the forces (8). An equation developed by Dr. Klemen Skaarup calculates the solubility difference between two molecules given their respective solubility parameter components (8). (R a ) 2 = 4(δ D1 -δ D2 ) 2 + (δ P1 -δ P2 ) 2 + (δ H1 -δ H2 ) 2 (3) The relative energy difference, or RED, is used to predict the solubility of two different molecules. Using the R a value calculated above, the RED can be calculated using the equation: RED = R a /R o (4) where Ro is the experimentally determined radius of the sphere of solubility for the solvating compound (8). If the RED is less than 1, the two compounds will form a solution. If the RED is equal to 1, the two compounds will be partially soluble with one another. If the RED is greater than 1, the two compounds will not form a solution. The Hansen Solubility Parameters are an attempt to quantify and predict solubility and may not always be accurate. Solutions were experimentally tested in order to support or refute its predicted solubility (8). Previous Research Team 5 of the New Jersey Governor s School in the Sciences has been experimenting with controlled release kinetics for several years. The 2012 team diffused saturated citric acid through two different types of membranes: 10% EVA and 12% EVA (7). The concentration and diffusion of citric acid was kept constant due to the continuous dissolution of the extraneous solid citric acid added to the saturated solution. The solid citric acid continuously dissolved into the saturated solution as the aqueous solution diffused across the membrane, maintaining a [5-4]

5 constant saturated concentration. Although there were some inconsistencies in their data, the 2012 team showed that it was possible to achieve a controlled release using this method (7). However, during their first experiment, the team found that NaCl and maleic solutions were unusable as solutes due to their irregular diffusion rates through the 10% EVA film. In 2013, the team started to produce EVA films as opposed to the factory-made ones in 2012 (5). EVA was dissolved into solutions; 12% EVA was dissolved in xylene while 25% and 40% EVA were dissolved in toluene. Films were casted onto silicon paper attached to glass, and a doctor blade was used to ensure consistency for width of the film. The 2013 team performed experiments that tested the effects of polarity and crystallinity; they concluded that non-polar substances will diffuse through polymer membranes using a vapor pressure analysis (5). Hypothesis A semi-permeable polymer membrane can be used to model the diffusion of a substance (electrolytes or alcohols) with a controlled constant concentration at pseudo-zero-order controlled release. Furthermore, increasing the membrane polarity will allow more polar molecules to dissolve into the membrane and therefore diffuse down the concentration gradient at a faster rate. METHODS & MATERIALS Membranes For this experiment, it was essential to adjust the polarity of a membrane in order to control the rate of diffusion. EVA is a copolymer composed of two monomers, ethylene and vinyl acetate. Ethylene is a nonpolar molecule, while vinyl acetate is a polar molecule. The varied monomers give EVA an interesting property; the regions with ethylene are nonpolar while the regions with vinyl acetate are polar. By increasing the percentage of vinyl acetate in a membrane, the polarity of the membrane increases. Therefore, in order to change the polarity of the membranes, the percentage of vinyl acetate can be increased or decreased (5). Several semipermeable EVA membranes were created with percentages of vinyl acetate varying from 25 to 40%. In order to increase polarity, there was speculation about the addition of 99%+ Polyvinyl Alcohol (PVA) in low concentrations to allow electrolytes to diffuse through the membrane at a greater rate. However, a proper solvent for both 40% EVA and 99%+ PVA was not found and as a result, films were not made with PVA additive. The application of Hansen Solubility Parameters further confirmed that PVA and EVA are incompatible in terms of solubility. In addition to the potential of PVA, there was also potential for polyethylene glycol (PEG) to serve as an additive to the membrane. Both a 1:2 mass ratio of PEG to EVA in addition to a 50% solid solution of PEG and a lower percentage by solids of EVA have been tested for membrane integrity and evenness. All films containing PEG had more cracks than membranes containing only EVA, and also displayed clusters of PEG due to its low molecular weight. As a result, varying concentrations of membranes containing only EVA were used to create membranes. Several techniques exist to create membranes. In this experiment, a mixture of 30% EVA by mass was dissolved with toluene in order to create a gel-like substance. This solution was [5-5]

6 loaded into a Doctor Blade, an apparatus used to cast the film at a uniform thickness. The Doctor Blade could produce films at 25, 30, 40, and 50 thousandths of an inch in thickness, which allowed the team to create versatile membranes. Prior to being loaded, however, it was determined through trial and error that the mixture of EVA and toluene had to be stirred rapidly and subjected to heat to prevent the mixture from solidifying. This was accomplished by occasionally heating the covered solution. In order to cast the film, a sheet of release paper was clipped onto a sheet of glass to provide a flat surface. The Doctor Blade was then set to the appropriate width, and the solution was slowly poured into the Doctor Blade as it was dragged across the release sheet to create an even film. Through experimentation, it was also determined that the Doctor Blade and release paper needed to be heated to prevent the liquid from solidifying as it was poured into the Doctor Blade. This was accomplished by placing the Doctor Blade and release paper into an oven that was heated to approximately 80 degrees Celsius before use. The membranes themselves had two properties that could be tested; polarity and thickness. However, dealing with two variables in the membrane proved to be difficult in experimentation, and thicknesses lower than 40 thousandths of an inch proved to exhibit more pinholes and more stickiness than 40 thousandths of an inch. Therefore, thickness was kept constant at 40 thousandths of an inch. Only membranes of various polarities (30%, 35%, or 40% EVA) were tested with various solutes. Solutions Choosing Electrolytic Solutions In order to test the capacity of a membrane to achieve pseudo-zero order kinetics, it is important to use a solute that allows for a slow release mechanism. The experiment required the creation of a saturated solution in the petri dish. The following solutes were chosen and tested in the apparatus: NaCl: This highly soluble ionic compound is relatively small in size and has some medical applications in that 0.9% sodium chloride is the most common intravenous medical infusion solution. CaSO 4 : Although it is still considered a strong electrolyte, it is less soluble and has less intramolecular ionic attractions as most highly soluble electrolytes. Acetylsalicylic Acid (Aspirin): This molecule has a lower solubility and polarity that should make it diffuse more easily. It also has medical applications. Ascorbic Acid: This is highly polar and more soluble in comparison to other organic weak electrolytes, but should still diffuse efficiently through a polymer membrane. Citric Acid: This is a much more polar weak organic electrolyte, so this should display the variation between molecules of varying polarity. [5-6]

7 All the weak organic acids have a similar size and molecular mass, so any change in diffusion rate should be strictly based on solute and membrane polarity. After creating saturated solutions from these solutes, the solid solute particles in the saturated solution effectively replenished the diffused solute particles by consistently dissolving into the solution until the saturation point was reached. This system maintained a constant concentration gradient in the petri dish and thus achieved pseudo-zero-order kinetics in accordance with Fick s Law. Choosing Alcohols to test with Gravimetric Analysis In a test to determine if mostly nonpolar substances would diffuse through a polymer membrane, certain alcohols with high vapor pressures and low boiling points were also tested using a gravimetric analysis of vapor pressures. Since the vapor pressure of a liquid in a closed container is kept constant at a constant temperature, it will still establish an analogous concentration gradient as that of a saturated aqueous solution, in which the evaporated vapor will diffuse through the polymer membrane at a constant rate. The following organic alcohols were tested using vapor pressure gravimetric analysis: Methanol: Methanol is a very small and polar organic alcohol that should diffuse through a polymer membrane rather easily. It has a high vapor pressure (13.02kPa at 20 C), and a low boiling point such that it can form a distinct concentration gradient. Ethanol: Although it is still polar, this molecule is much larger and has a lower vapor pressure (5.95kPa at 20 C). It has a lower polarity, so it should diffuse more easily through less polar membranes. Propanol: This is a mostly non-polar molecule with a slightly polar hydroxyl group on a larger molecule. It also has a much lower vapor pressure, so it should diffuse faster through less polar membranes. Because the team used pure alcohols for diffusion, vapor pressures were kept constant by Raoult s Law. Thus, any amount that diffuses out of the container through the membrane will be replaced by the evaporation of the liquid, keeping a constant concentration gradient of the gaseous alcohol across the membrane. This will correlate to pseudo-zero-order controlled release according to Fick s Law. Apparatus The stable apparatus suspended the petri-dish/membrane mechanism in the reservoir beaker at a chosen height. Using two straight wires, the team created a cage for the petri-dish (Figure 3). The wire segments were intentionally longer than the diameter of the reservoir to bend them over the reservoir edges and maintain further stability. Also, the hanging wire could be adjusted for any height in the reservoir. Then, initially with silicon glue, the team fastened the membrane to the petri-dish. However, it was later determined that the silicon glue released ammonia, which affected the ph readings. As a result, the team substituted the silicon glue with the 40% EVA polymer as a glue. The part of the cage that was below the petri-dish was slightly [5-7]

8 depressed, so that it did not touch the membrane itself. The entire mechanism, pictured below, was inserted into the reservoir. To create the concentration gradient between the solution in the petri dish and the reservoir, the apparatus was adjusted such that the mechanism was barely in contact with the water. Conductivity/pH probes were placed in the side of the reservoirs to take measurements. Water was poured in until both the petri-dish and reservoir had the same water level to avoid the effects of hydrostatic pressure. Figure 3: Aqueous Diffusion Apparatus The membrane was glued to a petri dish using excess 40% EVA solution (a), and then submerged into a beaker and suspended by metal wires such that the membrane is in contact with deionized water (b). Conductivity and/or ph probes were placed into the beaker and connected to a Vernier device (c) so data could be collected over time. Gravimetric Vapor Pressure Apparatus A similar apparatus was also used to prepare the alcohols for gravimetric vapor pressure analysis. About 25 ml of the selected alcohol was sealed into a plastic petri dish using liquid EVA as an adhesive, thus creating a closed container with a constant vapor pressure. The petri dishes were kept in an incubation oven at a constant temperature of 30 C. The entire apparatus was massed periodically so as to plot the change in mass in the container, which directly correlates to the rate of diffusion over time. [5-8]

9 Measurements Conductivity/pH Because the dissociated ions of the electrolytic solutes had charge, their presence after diffusing through the membrane could be detected by a Vernier conductivity probe. A maximum of four probes were connected to a Vernier, which was set to record conductivity and/or ph readings every 5 minutes for a maximum of 100 hours. By recording the change in conductivity at five-minute intervals, the team could track the changing concentration of the electrolytic solution in the reservoir. If the change in conductivity was linear, the solute diffused at a pseudozero-order rate. In the case of weak electrolytic solutions (including organic acids), conductivity could not be accurately measured because the organic molecules did not dissociate into ions to a significant extent. Thus, ph was measured using a Vernier ph probe, because ph directly correlated to an increase in internal concentration of the acid. The probe had to be calibrated to the team s electrolytic solutions because expected reading values found online did not account for the team s specific lab conditions. First, the ph and conductivity probes were calibrated with stock solutions of known ph/conductivity to maintain consistency among all of the probes. Then, the team performed serial dilutions for the various electrolytic solutions. The maximum concentration used was 0.1M because the probe was unable to accurately measure concentrations greater than 0.15M. The team checked the readings for various concentrations, from 0.1M to M. Conductivity readings in microsiemens per centimeter were plotted against molarity on Microsoft Excel, and a line of best fit was derived. A similar test was done for ph. (a) Calibration Curve for Sodium Chloride [5-9]

10 (b) Calibration Curve for Calcium Sulfate Dihydrate Figure 4: The Calibration Curves for Sodium Chloride and Calcium Sulfate Dihydrate These calibration curves for sodium chloride NaCl (a) and calcium sulfate dihydrate CaSO 4 CaSO 4 2H 2 O (b), which were made prior to the experiments, relate concentration of solution to conductivity in microsiemens per centimeter. If there was an increase in concentration, the conductivity should increase linearly. Vapor Pressure Gravimetric Analysis In a separate experiment, nonpolar alcohols had also been tested to diffuse through the polymer membrane using a vapor pressure gradient. By Raoult s Law, the vapor pressure of a liquid in a closed container will stay constant at a constant temperature, thus creating a concentration gradient of gaseous alcohols across the polymer membrane. The vapor will diffuse through the polymer membrane at a constant rate, thus losing mass to the atmosphere. Hence, a gravimetric method was used to affirm that the vapor diffused at zero-order controlled release. The sample was massed periodically and plotted on an Excel graph to display the decrease in mass. If the average change in mass was linear, the process occurred at zero-order controlled release. Technical Limitations Membranes Errors during the making of the membranes may lead to unexpected failures during the experiment. Since the EVA solutions used to cast the films solidify easily at room temperature, the solutions, along with the Doctor Blade and the glass plates, had to be kept warm at all times. If anything was cold, the film turned out uneven or solidified during the casting process. Sometimes, holes appeared in the films; these holes could be caused by several factors, including drawing the films on uneven release paper. If there were air bubbles trapped in the EVA solutions, those bubble sometimes were visible in the finished films. Also, if the films were too [5-10]

11 thin or sticky, they caused leakages in the apparatus. Membrane makers were very careful to avoid these problems. Apparatus The wires that constructed the cages of each apparatus were not completely straight due to the limitations of mechanical equipment. Also, the glue that held the membrane to the petri dish did not always make the seal airtight, so some of the solution may have diffused out through a leak. Another error in the conductivity readings could have resulted from the fact that the apparatus could not be sealed off from its surroundings. The minimal increase in the concentration, despite the lack of diffusion of solute through the membrane, may be a result of the CO 2 in the air reacting with water to create H 2 CO 3. For the ph tests, the main problem was that the ph increased, which contradicted the predicted decrease in ph. The team later discovered that the silicon glue that bound the membrane to the petri dish was increasing the ph of the solution by releasing NH 3 into the solution. Thickness Even though each slide was put into the oven with the same thickness, each was removed from the oven at varying thicknesses because each stock solution of 30%, 35%, and 40% EVA had slightly different amounts of toluene added. Since varying thicknesses affect the diffusion rate of molecules, thickness is a moderately significant variable. [5-11]

12 RESULTS Strong Electrolytes (a) Kinetics of Sodium Chloride Diffusion (b) Kinetics of Calcium Sulfate Dihydrate Diffusion Figure 5: Strong Electrolyte Diffusion Experiments The figures refer to the change in conductivity in the reservoir for NaCl (a) and CaSO 4 2H 2 O (b) in microsiemens per centimeter vs. hours. The general erratic pattern can be attributed to chatter in the conductivity probe. Generally, this data does not display a linear increase in conductivity that would have been present in a zero-order release. [5-12]

13 Weak Electrolytes (a) Kinetics of Ascorbic Acid Diffusion (b) Kinetics of Acetysalisylic Acid Diffusion [5-13]

14 (c) Kinetics of Citric Acid Diffusion, Experiment 1 (d) Kinetics of Citric Acid Diffusion, Experiment 2 Figure 6: Diffusion of Weak Electrolytic Solutions The increase in hydronium ion concentrations in the beaker for ascorbic acid (a), acetylsalicylic acid (b), and citric acid (c,d) were calculated based on the change in ph in the general reservoir. Citric acid was conducted twice for reproducibility. [5-14]

15 (a) Zero Order Representation of Citric Acid Diffusion (30% EVA) (b) Zero Order Representation of Citric Acid Diffusion (40% EVA) Figure 7: Citric Acid Trend Lines The change in hydronium ion concentrations for citric acid diffusing through 30% EVA membranes (a) and 40% EVA membranes (b) were shown to be a linear. This suggests that the release of citric acid into the beaker was pseudo-zero-order rate. [5-15]

16 Gravimetric Analysis of Alcohols Figure 8: Gravimetric Analysis of Alcohols The change in mass of alcohols was shown to be linear, thus correlating to a constant rate of release. Hence, all alcohols are shown to successfully model pseudo-zero-order controlled release. DISCUSSION The readings of NaCl were on the low range of 0-14 μs/cm and erratic, and based on Figure 5a, NaCl also did not appreciably diffuse through the membranes. Regarding CaSO 4 2H 2 O, the conductivity readings were on the low range of μs/cm and extremely erratic (Figure 5b). These results can be considered as noise, because if CaSO 4 2H 2 O did diffuse, the conductivity readings should have consistently increased linearly and have been at least in the hundreds (Figure 5b). Thus, CaSO 4 2H 2 O did not appreciably diffuse through the membranes. The testing of NaCl and CaSO 4 2H 2 O with several membranes composed of up to 40% EVA yielded essentially no change in the conductivity of the solution. Looking at Figure 6a, the lack of an increase in the concentration of hydronium ion indicates that ascorbic acid did not diffuse through any of the membranes. Thus, ascorbic acid does not diffuse through membranes on the range of 30-40% EVA. Acetylsalicylic acid also did not increase in hydronium ion concentration, so acetylsalicylic acid did not diffuse through any membranes ranging from 30% to 40% EVA (Figure 6b). The decrease of H 3 O + concentration may be attributed to off-gassing of dissolved CO 2 from the water, which increased the ph. This off-gassing is noticed slightly in the citric acid 30% EVA trial (Figure 7c). [5-16]

17 The citric acid diffusion data (Figure 6c) exhibits pseudo-zero-order controlled release as the graph shows linear data. The R 2 value for the citric acid placed in the 30% and the 40% membranes (Figure 7a and 7b) are both above.90 after 12 hours and 5 hours respectively. Evidently, the diffusion was pseudo-zero order since the H 3O + concentration increased at a constant rate. Figure 6d displays another trial of citric acid that did not diffuse through the membrane. For this second set of trials, the thickness of the dry membrane may have prevented the citric acid from diffusing at all, since thickness may vary after the film is cast. The citric acid diffusion data (Figure 7) exhibits pseudo-zero-order controlled release as the graph shows linear data after approximately 5 hours. Figure 8 displays the gravimetric tests using alcohols. All of the tests with alcohols exhibited diffusion at a pseudo-zero-order rate because the graph displays a linear relationship. In addition, the rate of diffusion is generally correlated with the polarity of the membranes. The higher polarity membranes yielded larger diffusion rates. There is one possible explanation as to why ionic salts did not diffuse. As ionic salts dissolve, they undergo solvation and develop ion-dipole attractions with water molecules. This may prevent salts from diffusing through the membranes. Thus, membranes can only allow ionic salt diffusion by exhibiting stronger intermolecular forces with the solutes than the water molecules do. As for the weak electrolytes, citric acid, ascorbic acid, and acetylsalicylic acid mostly differ in polarity and solubility (Figure 5). Citric Acid Ascorbic Acid Acetylsalicylic Acid Solubility: g/100 ml 33.0 g/100 ml 0.30 g/100 ml Molar mass: g/mol g/mol g/mol pk a : Figure 9: Comparison between Citric Acid, Ascorbic Acid, and Acetylsalicylic Acid based on structure, solubility, and acidity This figure shows the differences in structure, solubility, and acidity between the three weak electrolytes which may explain differences in diffusion through the membrane. [5-17]

18 Our results show that citric acid was the only weak electrolyte that diffused through the membranes. This can be explained by the fact that citric acid is the most polar of the three because it has three carboxylic acid groups. Its polarity may enable its dissolution and diffusion through the membrane. In addition, citric acid is much more soluble than ascorbic acid and acetylsalicylic acid (Figure 5), so more citric acid is present in solution than ascorbic acid or acetylsalicylic acid. Therefore, its concentration gradient is greater and more detectable than that of the other two acids. The concentration gradients of both ascorbic acid and acetylsalicylic acid are so small that if they diffused, it may take weeks, or even months, for a discernible change to be detected. The gravimetric analysis of several organic alcohols was unique compared to both the weak and strong electrolytes, since each of the four alcohols tested produced a zero-order rate of diffusion. Methanol, ethanol, and propanol are significantly smaller than the electrolytes in the proceeding experiments; this could provide an explanation as to why this group of molecules was the only one to consistently diffuse through the EVA membrane. CONCLUSION Impermeability of Ionic Salts Multiple experiments with membranes of varying polarity have provided strong evidence against the hypothesis that ionic salts can pass across moderately polar membranes. The most polar membrane tested, which was 40mils in thickness and 40% EVA by composition, did not allow ionic salts to diffuse into deionized water any better than the less polar membranes tested. Hence, these extremely polar molecules cannot diffuse through a polymer membrane regardless of the increased membrane polarity. It is speculated that these ions were too polar in comparison to the moderately polar membrane. The Polarity of the Solute Influences Diffusion Although many weak, moderately polar organic acids were tested, only citric acid could successfully diffuse across the membrane. Citric acid, acetylsalicylic acid, and ascorbic acid had similar molar masses but varying solubility in water. Furthermore, citric acid has a polarity closer to that of EVA. The innate intermolecular compatibility between EVA and citric acid allows for citric acid molecules to dissolve into the membrane, and therefore diffuse through it. The Polarity of Alcohols is Comparable to that of EVA Alcohols were able to diffuse through membranes of varying polarity consistently. This can be attributed to the fact that the alcohol molecules are smaller and less polar than the weak organic electrolyte solutions tested previously. The hydroxyl functional group is less polar than the carboxyl group, thus the polarity of alcohols is more comparable to EVA, allowing it to diffuse. Zero-Order Controlled Release Can Be Achieved Through Diffusion Methanol, ethanol, propanol, and citric acid were able to successfully diffuse through the EVA membrane. Regardless of the percent composition of EVA, the flux of the sampled [5-18]

19 substance was kept at a constant rate because the concentration gradient of the selected substance was kept constant across the membrane using saturated aqueous solutions or vapor pressure constants. Hence, the apparatuses modeled a pseudo-zero-order controlled release process. FUTURE STUDIES The team found that ionic salts do not diffuse through membranes composed of up to 40% EVA, but was unable to conclude about greater polarities due to limitations of lab equipment. It may be possible that increasing the polarity of the membrane, or even changing the membrane composition itself, may yield positive results. Creating an ionic membrane, perhaps through cross-linking ionic substances, may be the best method to dissolve ionic substances. It may be important to determine if intermolecular forces between the solute and the membrane can overcome those between the solutes and the water molecules. Finding a membrane s polarity or material that diffuses ionic salts would have strong applications in the medical field, especially for the diffusion of electrolytic solutions into the body. Moreover, the weak electrolytes used were relatively large in size, which may have affected the diffusion rate. Future teams should consider choosing solutes that vary in molecular size. Decreasing molecular size may increase diffusion through interstitial spaces. Using molecules like acetic acid, which is smaller in size, may be better. Molecular size and membrane polarity may be two variables that can be tested to determine a relationship for rate of diffusion. Another variable to consider is membrane thickness. Thinner membranes may allow solutes to diffuse faster. However, this variable may be difficult to test because it is not easily controllable due to the limitations of lab equipment. Currently, the membranes are limited to a range of 30-40% EVA because the films cannot stay intact outside of these ranges. This issue limits the extent of our research because it is impossible to accurately predict the behavior of solutes through polarities outside these ranges. For example, citric acid diffuses through 12% EVA membranes and 30% EVA membranes, but not through 40% EVA membranes. This potentially suggests that citric acid only diffuses in a range of approximately 12-30% EVA. Thus, the high and low extremes of membrane polarity prevent citric acid diffusion. The rate of diffusion may follow a bell curve shape with respect to membrane polarity. Perhaps future groups should mathematically model diffusion of substances through membranes before performing experiments. Testing this theory would require experimenting with one solute and a wide range of membrane polarities, above 40% EVA. It is also important that future groups can study the wide-ranging applications of zeroorder kinetics. For example, the zero-order principle can be applied in the pharmaceutical industry to diffuse drugs at a rate that prevents underdose or overdose by supplying only a therapeutic amount. Moreover, implementing zero-order diffusion in the agricultural industry can allow nutrients to diffuse at a constant rate, eliminating the need to actively give nutrients to the plants. Similarly, in the cosmetic industry, zero-order diffusion can be used to send fragrance uniformly through a space. Nevertheless, prior years of research have provided a myriad of results and conclusions about zero-order rates and the diffusion of various substances through different membranes. The team encourages future scientists to enhance this field by further learning how to diffuse ionic [5-19]

20 salts, small or large weak electrolytes, or multicomponent solutes, and seek to find an even stronger relation between membrane polarity and diffusion rates. REFERENCES 1. Ward C.J., Dewitt, M, and Davis, E.W. Halloysite Nanoclay for Controlled Release Applications. Nanomaterials for Biomedicine, [Internet] [cited 2014 Jul 24] Available from: 2. Injection vs. Infusion. [Internet] [cited 2014 Jul 27] Available from: 3. Andrew J.P. Handbook of polyethylene: structures, properties, and applications. [Internet] [cited 2014 Jul 27] Available from: =structure+of+polyethlyene&ots=vstmhfcxeu&sig=i7zrfiih_qnnfvsvmtrln7cztf Q#v=onepage&q=structure%20of%20polyethlyene&f=false 4. Polymeric membranes. [Internet] [cited 2014 Jul 27] Available from: 5. Dormier A et al. Relative influences of polarity and crystallinity on zero-order kinetic release through a polymer membrane. New Jersey Governor's School in the Sciences, [Print] [cited 2014 Jul 27]. 6. Wijmans J., and Baker, R. W. The solutions-diffusion model: A review. Journal of Membrane Science, [Internet] [cited 2014 Jul 30] 107: Available from: Model-A-Review 7. Aquino J et al. Pseudo-zero-order kinetics across a polymer membrane using a saturated solution reservoir system. New Jersey Governor s School in the Sciences, [Internet] [cited 2014 Jul 27]. Available from: 8. Hansen C. Hansen s Solubility Parameters: A User s Handbook. [Print] New York: CRC Press, [cited 2014 Jul 27]. 9. Harper CA, Edward MP. Plastics materials and processes: a concise encyclopedia. [Print] New York: Wiley-Interscience, [cited 2014 Jul 27]. 10. Ascorbic Acid. [Internet]. [cited 2014 Jul 30] Available from: Citric Acid. [Internet]. [cited 2014 Jul 30] Available from: Aspirin. [Internet]. [cited 2014 Jul 30] Available from: The solution process. [Internet]. [cited 2014 Jul 31] Available from: [5-20]