Modified flow-through ring electrode module for oxidation, reduction, and / or capture of electroactive species in solution

Abstract

A chemically-modified flow-through ring electrode module allows for controlled changes to the solution flowing through the electrodes. The flow-through ring electrode module consists of two or more flow through ring electrodes with an electroactive coating on the surface of one or more of the flow through ring electrodes that allows for targeted oxidation, reduction, and / or capture of electroactive species from liquids or gaseous solutions. The coating is used in conjunction with an electric current or voltage to alter the rate of kinetics of a specific reaction within the solution. The target atoms or molecules in solution may be undesirable and need to be oxidized, reduced or captured for depletion or removal from the solution. Or, the atoms or molecules targeted may be useful and their oxidation, reduction, and or capture would allow for them to be concentrated for future use.

Description

A Chemically-Modified Flow-Through Ring Electrode Module for Oxidation, Reduction, and / or Capture of Electroactive Species in Solution Cross-Reference to Related Applications

[0001] This international application claims priority to U.S. provisional application 63 / 776,417 filed March 24, 2025. Such application is incorporated by reference herein.Statement Regarding Federally Sponsored Research or Development

[0002] This invention was made with government support under SBIR grant number R44DK 137702 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention.Field of the Invention

[0003] This invention describes a chemically-modified flow-through ring electrode module that allows for oxidation, reduction, and / or capture of electroactive species in solution.Background

[0004] The reference mentioned in this background section is not admitted to be prior art with respect to the present invention.

[0005] According to the American Diabetes Association, almost 2 million Americans have Type 1 Diabetes (T1D). These patients require multiple injections of insulin every day to control their blood glucose. The daily burden of T1D can be alleviated by the use of Continuous Subcutaneous Insulin Infusion (CSII) pumps that discretely deliver insulin to a patient continuously throughout the day. Recent advances in CSII pump therapy, such as wirelessly communicating with Continuous Glucose Monitors (CGMs) and dosing algorithms, have allowed unprecedented control of blood glucose, with real -worldpatients maintaining their blood glucose time-in-range (70 mg / dL to 180 mg / dL) over 75% of the time on average over 4100 users of Medtronic’s MiniMed 780G.

[0006] Even with the impressive gains in convenience and time-in-range, a substantial limitation of wearable CSII patch pumps is a maximum 3-day wear time at each infusion site location. CSII sites must be moved on the body every three days due in part to a slowing of insulin absorption, caused by inflammation and fibrosis that is induced by cytotoxic phenolic preservatives. This can eventually lead to complete loss of functionality of a site. Phenolic preservatives are a required component of pump-stable insulin formulations, acting both as a bacteriostatic and to stabilize insulin’s hexameric structure, preventing fibrillation.

[0007] Studies have shown that as pump stable insulin is delivered subcutaneously, the cytotoxic effects of the phenolic preservatives cause inflammation and fibrosis that make infusion into that site less effective over time. This site loss requires the rotation of the infusion site to various parts of the body every three days, and some patients struggle to find a suitable spot for the cannula, especially after long-term CSII use. For commercially available wearable patch pumps with internal insertion mechanisms, the 3- day wear time requires that the patch pump be removed, disposed of, and replaced at a new location every three days, a process that is both inconvenient and expensive.Extending the useful life of patch pumps would reduce the overall cost of insulin therapy and increase customer appeal and compliance with this beneficial therapy.

[0008] In addition to causing inflammation, the phenolic preservatives present in pumpstable insulin formulations preclude the integration of a CGM into the CSII device to realize a single-device, wearable Artificial Pancreas for two reasons. First, the 3-day lifetime of wearable CSII devices is too short to allow a cost-effective integrated solution. CGMs can be worn for 7 days or more which results in a mismatch between the wear times of CSII devices and CGMs. Second, the phenolic preservatives found in all pumpstable insulin formulations are electrochemically active and disrupt the electrochemical signals that CGMs use to measure glucose, preventing a CGM from being used in close proximity to the infusion site of a CSII. By depleting phenolics from the insulin formulation prior to subcutaneous injection, interference of phenolics with CGM signalmay be greatly reduced or eliminated and allow a CGM to be placed in close proximity to the injection site (i.e. creating an integrated body-worn artificial pancreas).

[0009] A device and method to remove phenolic preservatives and other target atoms and molecules from liquid or gaseous solutions is needed.Summary of the Invention

[0010] The present invention is directed to a chemically-modified flow-through ring electrode module that allows for controlled changes to the solution flowing through the electrodes. The adjective “chemically-modified” is used herein to describe electrodes that have been coated with an electroactive film (molecular, polymeric or inorganic) that alters the function of that electrode. The flow-through ring electrode module in certain embodiments consists of two or more ring electrodes configured so the electrodes are in contact with a fluidic path that goes through the ring formed by the electrodes, and the chemical-modification is an electroactive coating on the surface of one or more of the flow through ring electrodes that allows for targeted oxidation, reduction, and / or capture of electroactive species from liquids or gaseous solutions. The coating is used in conjunction with an optimal electric current or voltage to alter the rate of kinetics of a specific reaction within the solution, which results in oxidation, reduction, and / or capture of target atoms or molecules in the solution. The target atoms or molecules in solution may be undesirable and need to be oxidized, reduced or captured for depletion or removal from the solution. Or, the atoms or molecules targeted may be useful and their oxidation, reduction, and or capture would allow for them to be concentrated for future use.Additional operational parameters such as diameter and surface areas of the flow-through ring electrodes (both the coated and the uncoated electrodes) can be customized to allow modules to be designed for a particular application, such as but not limited to removal of contaminants from wastewater / drinking water / bev erages, reuse of high value components, removal of dangerous gases, or removal of preservatives from liquid therapeutics. In addition to customizing the surface areas of the ring electrodes; designing specific coatings for oxidation, reduction, and / or capture of specific atoms or molecules; and using optimal electric voltages or currents, multiple flow-through ringelectrodes can be stacked to increase the amount of target species that are oxidized, reduced, and / or captured.

[0011] The coating used for chemical-modification of the flow-through ring electrodes can be functionalized to oxidize, reduce, and / or capture specific atoms or molecules under specific conditions, including without limitation pH, temperature, hydrophobicity, viscosity, flow rate, conductivity, and more. The coating can be designed to maintain function of the flow through ring electrodes over time. The coated flow-through ring electrodes may allow for full or partial oxidation / reduction of the electroactive target or may allow for capture of part or all of the electroactive target from solution.Brief Description of the Drawings

[0012] Figure 1. Cross-sectional view of a preferred embodiment of the present invention. A chemically-modified flow-through ring electrode module (101) with unmodified reference electrode (102) and counter electrode (103) and a modified working electrode (104). The chemical modification is an electroactive coating (105) that is represented by an aromatic ring structure pattern in the drawing. This embodiment is tailored for the removal of benzene from contaminated well water.

[0013] Figure 2. Cross-sectional view of a second preferred embodiment of the present invention. A chemically-modified flow-through ring electrode module (201) with unmodified reference electrode (202) and counter electrode (203) and a modified working electrode (204). The chemical modification is an electroactive coating (205) that is represented by an aromatic ring structure pattern in the drawing. This embodiment is tailored for the removal of phenolic preservatives from insulin formulations.

[0014] Figure 3 : A graph depicting the fouling of an unmodified flow-through ring electrode by oxidation of phenol into polyphenol and subsequent deposition of polyphenol onto the surface of the bare electrodes. After only one cycle so much polyphenol is deposited that the electrode is fouled and no longer functions.

[0015] Figure 4. Example pathway of oxidative polymerization of aniline to polyaniline.

[0016] Figure 5. Mechanism of the transition between redox states of polyaniline. The top configuration is the fully reduced leucoemeraldine, the middle is emeraldine, and the bottom fully oxidized form is pemigraniline.

[0017] Figure 6. Mechanism of phenol oxidation to benzoquinone / hydroquinone when catalyzed by an electrode coated with polyaniline.

[0018] Figure 7. Depiction of the TT-TT stacking that is responsible for the adsorption and capture of phenol onto the polyaniline ring.

[0019] Figure 8. A graph showing CV readings obtained using the second preferred embodiment before (solid) and after (dashed) trapping phenolic preservatives from the diluent of a commercially available insulin formulation. The curves have been overlayed to visualize differences. The oxidative peak at 0.5 V is resultant from the reversible redox reaction of hydroquinone to benzoquinone. Oxidative currents are defined as positive.Detailed Description of the Preferred Embodiments of the Invention

[0020] The principal mechanism allowing the targeting of specific species is the combination of applied current / voltage and the change in reaction kinetics resulting from the choice of a particular coating for chemical-modification of one or more flow through ring electrodes. Similar to how electrodes of different metals have differing kinetics for the same redox species, coatings chosen based on preference of a specific reaction can favor or disfavor that reaction. Often in the case of unmodified electrodes the redox potential of a desired reaction is above (or below) that of an undesired reaction, which can make the targeting of one reaction in a system impossible. When operating the present invention in solutions containing several electroactive components, the surface of the electrode is chemically-modified with a coating that favors the kinetics of a specific reaction, that reaction can be targeted in combination with an optimal applied current or voltage. As reactions are often kinetics-limited, the inclusion of these catalysts in the coating can reduce the need for overpotential and allow the isolation of reactions in a solution. The coating can also be used to modify the reaction pathway to a desired product. Often the electrochemical redox products on unmodified electrodes result in themost stable configuration of products, but by catalyzing a desired pathway, a specific reaction product can be favored. The coatings can include, but are not limited to, free radicals, enzymes, oxidizers / reducers, and aromatic ring structures.

[0021] Flow through ring electrodes can be made by alternating layers of an insulating material and a conductor. One non-limiting example of inexpensive flow-through ring electrodes are made of alternating layers of plastic and carbon. These flow-through ring electrodes can also be made from low temperature co-fired ceramic techniques. These are both well-known methods of manufacturing three dimensional circuits by using conductive traces to form circuits on ceramic / plastic substrates, stacking these ceramic / plastic substrates, and connecting the traces through conductor-filled vias. The geometry of the ring electrodes provides high ratio of electrode surface area to volume of fluid held within, providing excellent fluidic contact and low diffusion times. The surface area to volume ratio is 2nrl Area of walls of a cylinder') -- nr2l volume contained by that cylinder). This simplifies to 2 / r and shows that the surface area to volume ratios is dependent on the radius of the electrode. This property lends itself well, but is not limited to, microfluidics as the surface area to volume ratio increases as the radius of the ring electrode decreases. Since the radius of the electrode also affects the linear velocity of the solution for any given flow rate, it is important to coordinate configuration and operational parameters such as diameter, length and flow rate of the flow-through ring electrode module to get the desired diffusion and reaction characteristics for a specific application.

[0022] Once designed and sized for a specific application, one or more of the flow- through ring electrodes is modified with a specific coating. The electrodes can be coated physically or electrochemically by oxidizing or reducing a monomer solution of the desired coating. The coating is generally applied, but not limited, to the working electrode as this provides the most control when using standard potentiostatic equipment. While the most practical method of depositing a coating is electrochemical adsorption by direct oxidation / reduction; chemical oxidation / reduction, spin coating, and vapor disposition techniques are also possible. The present invention is not limited in the respect to how the electrodes are chemically-modified or what materials they are modified with. The coating is selected based on electrochemical and chemical propertiesof the coating and the desired compound or reaction to target as well as other system properties, i.e. pH, temperature, solvents, etc. Common conductive coatings include, but are not limited to, polyaniline, polypyrrole, poly(3,4-ethylenedi oxythiophene), polyaspartic acid, activated carbon, enzyme functionalized coatings, ion exchange resins, electroactive antibodies, or any molecular structure that can participate in electrochemical reactions. The coatings can be further functionalized to enhance the operational range for a specific application.

[0023] The chemical modifications are specifically chosen to increase the activity of certain desired reactions. The advantage of increased kinetics for a desired product or reaction can be used for sensing a specific compound or atom, oxidizing or reducing a specific compound or atom, absorbing / adsorbing a specific compound or atom, or otherwise interacting with a target compound or atom. The reactions are controlled using standard potentiostatic techniques and applying a current or voltage that selectively induces the desired reaction. A specific coating and electric signal will selectively target the desired compound since the other species in solution will have less favorable reaction kinetics, which reduces the need for overpotential and makes the reduction / oxidation of specific compounds more selective. It is important to point out that care needs to be taken in selecting the operational parameters for a solution with multiple electroactive species to make sure that non-target species will not significantly be oxidized, reduced, captured or otherwise altered by the coating at the operating current or voltage.

[0024] In the case of using the chemically-modified ring electrode to trap target species, there are a few ways the electrodes can be scrubbed for reuse. One is to use opposite voltage or current signals than those used to trap the target species. For example, if the target species was oxidized to remove it from solution, its reduction could cause it to be readsorbed / reabsorbed back into the same solution or a different solution. Other methods include exploiting the redox characteristic of conductive polymers often used in the modified ring electrodes including, but not limited to, changing the pH values, temperature changes, and the use of different solvents or electrolytes. By removing a spent modified ring electrode module and placing it into a secondary solution that lowers the adsorption / absorption of the target species, the target species can be pulled from the modified electrode into the secondary solution. Once the modified electrode has beencleaned of its target species it may be used in the same method as before to trap target species.

[0025] Some possible applications of the present invention are to remove cytotoxic preservatives from therapeutics, trap trace products of chemical manufacturing to increase yields, pretreatment of commercial wastewater to reduce burden on municipal wastewater plants, and removal of trace elements in laboratory samples. For example, activated carbon modified electrodes could be used to oxidize biological material from wastewater, especially trace compounds that are otherwise difficult to break down.Modules could also be designed for use near the end step in drinking water purification processes.

[0026] A flow-through ring electrode module tailored for use to decontaminate water is shown in Figure 1. Benzene has been found to contaminate ground water and well water in U.S. states where fracking is common, like Texas, Oklahoma, and Wyoming. A flow- through ring electrode module could be sized to be large enough for under-the-sink decontamination of well-water prior to consumption. In this embodiment, the working electrode is modified with a coating specifically designed to capture benzene and the module is operated at the optimal electric voltage or current for capture of benzene as the contaminated well water flows through the module. Then, once the maximum amount of benzene is captured on the working electrode, an opposing electric current or voltage could be used to release the trapped benzene back into solution for disposal. In this manner, the same module could be reused multiple times.

[0027] Although in many electrochemical setups the counter electrode usually has an equal or larger surface area as compared to the other electrodes, the module (101) shown in Figure 1 has a small reference electrode (102) and counter electrode (103) and a much larger working electrode (104). In this embodiment, the coating (105) on the larger working electrode (104) can be designed to experience a low instantaneous current and be used for long periods of time. Therefore, this embodiment does not need a counter electrode of equal or larger size to reduce the risk of counter electrode limitations. In this embodiment any increased current density that results from a smaller counter electrode isnot important, since after the removal of the target analyte the increased current density at the counter electrode will only be exposed to water.

[0028] Configuration of the individual electrodes and the chemically-modified flow- through ring electrode module is an important aspect of the present invention. Factors to consider when configuring a set of chemically-modified flow-through ring electrodes for a particular application includes, but is not limited to, order of placement of the reference, working, and counter electrodes; number, diameter, and length of the individual electrodes; surface areas of the individual electrodes; spacing between the individual electrodes; diameter and length of the overall module, and thickness of the coating used to modify one or more of the electrodes.

[0029] The discussion thus far overviews the many possible uses of the present invention, the remaining discussion focuses on the non-limiting use of the present invention in trapping phenolic preservatives from a liquid therapeutic, specifically insulin formulations.

[0030] In a second preferred embodiment, the bare flow-through ring electrodes can be chemically-modified with a conducting polymer, such as polyaniline or polypyrrole, that is specifically designed to oxidize and adsorb phenolic preservatives from drug formulations such as commercially available insulin, glucagon, and pramlintide formulations. This preferred embodiment has been named a Phenolics Depletion Chip (PDC) by the inventors hereof. Cytotoxic preservatives are used as a bacteriostatic to help preserve the drug formulation and to maintain the drug molecules in a stable state during shipment and storage. A PDC placed in the fluidic path of a continuous subcutaneous insulin infusion (CSII) pump just before the cannula will allow the cytotoxic preservatives to be removed immediately prior to subcutaneous delivery, reducing the inflammation and cellular death response to the toxic phenolic preservatives. Use of chemically-modified ring electrodes works in this case because the reduction potential of insulin is much higher than that of the phenolic preservatives in solution. Therefore, the insulin will not be affected by the coatings and voltages used by the PDC. There are numerous advantages to removing the phenolic preservatives immediately prior to subcutaneous injection, including reduced inflammation at the insertion site, reducedneed to change out and relocate a body worn patch pump, and use of concentrated insulin formulations to increase wear time without increasing insulin reservoir size. Longer wear time also improves the economic efficiency of integrating a continuous glucose monitor into a body-worn patch pump and reduces the physical and mental burden for use of these systems.

[0031] In the case of the PDC, it is logical to size the diameter to match that of standard medical tubing to reduce the risk of bubble trapping and minimize any hindrance to the flow of insulin. Therefore, the inside diameter of the ring electrode used in this preferred embodiment is approximately 0.6 mm. The length of the flow-through ring electrode module can then be sized to accommodate the phenolic load to be captured. For the preliminary data presented herein, a miniature PDC was used that had an approximate length of 0.2 mm. However, the invention is not limited to this size, and the use of the Randles-Sevcik equation (shown below) can be used to find the necessary surface area for any given coating including the polyaniline coating discussed.

[0032] Figure 2 is a cross-sectional view of the PDC embodiment of the present invention. The chemically-modified flow-through ring electrode module (201) has an unmodified reference electrode (202) and counter electrode (203) and a modified working electrode (204). The modification is an electroactive coating (205) that is represented by a ring structure pattern in the drawing. As seen in Figure 2 the working electrode (204) and the counter electrode (203) have greater surface areas than the reference electrode (202). Additionally, the counter electrode (203) has a greater surface area than the working electrode (204). Having a larger counter electrodes in this embodiment helps ensure that insulin and other species in solution are not damaged by high current density at the counter electrode following removal of phenolic preservatives from solution.

[0033] Electrochemical adsorption of phenol from aqueous solutions has previously proved difficult due to the nature of the phenolic oxidation products and the resultant fouling of bare electrodes. To illustrate this property unmodified ring electrodes were cycled in a 3 mg / mL phenol solution. The resultant CV is shown in Figure 3. The reduced peak current in successive scans is explained by polyphenol fouling of theelectrode. During the first scan, as the potential reaches the oxidation potential of phenol, polyphenol begins to form, and this polymer is known to adhere strongly to the surface of metal electrodes. Polyphenol is insulating when it adheres to the electrode’s surface, which results in the fouling of the electrode. The first cycle reaches a peak of 7 pA while the next cycle is orders of magnitude lower, demonstrating rapid fouling of the electrode due to easy access to the phenol in the solution from the ring electrode configuration. However, this is an ineffective method of electrochemically removing phenol from solution as the fouling of the electrode drastically increases resistance and limits further phenol removal. This is because on bare, unmodified, electrodes phenol is oxidized to polyphenol which is deposited directly on the bare electrode. Polyphenol is insulating to further electrochemical reaction even when deposited in very thin layers. Therefore, when the first layer forms, polyphenol blocks subsequent layers from forming. The electrode chemical-modification described in this embodiment of the present invention (Figure 2) prevents this fouling and allows continued adsorption of phenol oxidation products onto the coating on the surface of the electrode.

[0034] There are many modifying substances that could assist in the adsorption / absorption of phenol, including but not limited to: polyaniline, polypyrrole, activated carbon, poly aspartic acid, and poly-l-lysine. The benefits of these electrode chemical modifications, for the removal of phenol, are two pronged. The first is the catalyzed oxidation of phenol by the free radical from polyaniline. This allows for faster removal of the phenol. The second is the ring structure of polyaniline which not only allows for an active site assisting in the oxidation reaction but thermodynamically favors the benzoquinone / hydroquinone oxidation products. These products are more favored when phenol is oxidized on a polyaniline electrode because benzoquinone / hydroquinone can form TC-TI stacking with the ring structure of the polymer backbone. This stabilizes the products and adsorbs the phenolic products onto the surface of the electrode. Unlike polyphenol these reaction products and subsequent adsorption do not foul the electrode, and further oxidation can be performed.

[0035] There are several methods to coat polyaniline onto the working electrode, including but not limited to electrochemical polymerization, spin coating and constant current deposition. In this non-limiting example of the PDC, polyaniline was coatedelectrochemically onto the surface of a gold ring electrode. The polymerization was done in a solution of aniline monomers using cyclic voltammetry. The gold ring electrode was used as the working electrode and successive scans were used to polymerize aniline onto the electrode. The reaction shown in Figure 4 is one possible pathway that describes the polymerization of aniline to polyaniline. The resultant CV of a successful aniline polymerization can be seen in the solid line in Figure 8 (discussed in detail below); the characteristic peaks formed are from the oxidation / reduction of the polymer backbone itself. Polyaniline can switch between three distinct forms with the addition or subtraction of electrons: Leucoemeraldine, Emeraldine, and Pemigraniline. Figure 5 is one proposed mechanism of the transition of redox state of the polyaniline backbone. Since the second redox reaction involves a hydrogen ion it is affected by the pH of solution, and this quality can be used to manipulate the redox form that polyaniline takes at a given voltage. This is one method of specializing the polyaniline coating for a specific use. In the case of the PDC, the addition of long chain organic acids, among others, into the polyaniline matrix can be used to extend the pH range of the emeraldine form of polyaniline. This is vital to increasing its ability to oxidize phenol as the free radial, present only in the emeraldine form, catalyzes the oxidation of phenol to the desired benzoquinone / hydroquinone oxidation products.

[0036] The polyaniline electrode can then be further functionalized with surfactants, long chain organic acids, metal complexes, or other chemicals to improve its operational range under specific conditions. One non-limited example is to attach carboxylic acid to the chain which has been shown to improve functionally under higher pH conditions. Once any desired changes have been made, this polyaniline electrode can be used for the capture of phenolics from solutions. In one case of the PDC, it is used to capture phenolics from commercial insulin solutions. One possible pathway for the oxidation of phenol to benzoquinone / hydroquinone oxidation products on a polyaniline electrode is shown in Figure 6. As seen in Figure 6, the benzoquinone reaction products have reversible redox chemistry similar to that of the polyaniline backbone itself. Thus, unlike polyphenol formed on unmodified electrodes, these benzoquinone reaction products allow for the transfer of electrons and the continued adsorption of phenol. These benzoquinone / hydroquinone reaction products are adsorbed onto the electrode via 7t-7istacking. The 7t-7t stacking occurs due to the overlapping of the ring structures present in both the polyaniline backbone and benzoquinone / hydroquinone reaction products. This overlapping is generally thought to be staggered slightly so that the electrostatic attraction occurs between the electrons in the it orbital of one ring with the slight positive change of the surrounding hydrogens of the second ring. A visual depiction of TI-TI stacking can be seen in Figure 7.

[0037] Subsequent testing demonstrated that chemical-modification of the flow-through ring electrodes (the present invention) resulted in successful capture of phenolic preservatives from the dilutant of a commercially available insulin formulation containing both phenol and meta-cresol. The prototype PDC used in this experiment has reference, working, and counter electrodes of the same size. The working electrode was coated with polyaniline and underwent a series of exposure and wash steps to show that phenolic compounds were captured within the poly-aniline coating. Briefly: Step 1) After production, the PDC was washed in an aqueous solution to remove any contamination. Step 2) The PDC was then interrogated using cyclic voltammetry to obtain the baseline reading for polyaniline (solid lines in Figure 8), and Step 3) cleaned again with an aqueous solution. Step 4) The clean PDC was cycled in the dilutant (with standard phenolic content) to oxidize and adsorb the phenolics, and then Step 5) cleaned again with an aqueous solution. Step 6) The clean PDC was finally interrogated in the same manner as Step 2, resulting in the reading which clearly shows polyaniline plus captured phenolics (dotted line in Figure 8). The new peak is present at approximately 0.5 V and lies between the two redox reaction peaks from the polyaniline backbone itself. This new peak is a result of the redox property of hydroquinone / benzoquinone shown in Figure 6. Because the PDC was thoroughly cleaned after each step, the new peak signals in the dashed line in Figure 8 demonstrate capture of the phenolics in Step 4.

[0038] Electrodes chemically-modified with polyaniline are the focus of this preferred embodiment because they are inexpensive, easy to create, biocompatible, stable, and can be used under physiological conditions. When used to oxidize phenols, polyaniline electrodes first oxidize the phenol to hydroquinone / benzoquinone then bond it to its surface using n- K bonding that does not foul the electrode. In fact, these electrodes have been shown to work better as they are “filled” with the benzoquinone / hydroquinoneoxidation products which effectively work to enlarge the electrode. The capture of the benzene ring of phenolic preservatives using the benzene ring of polyaniline is shown in the cartoon in Figure 7. Nonfunctionalized polyaniline works well but has the limitation that it loses its conductivity at pH>4, reducing effectiveness for use with physiological systems. The low pH dependance of polyaniline can be alleviated by functionalizing the polyaniline with surfactants or long chain organic acids that help to keep the polymer in its protonated state. One of the most promising is carboxylic acid functionalized polyaniline, which operates well at physiological pH.

[0039] Similarly, polypyrrole is one of the most utilized conducting polymers and provides one possible alternative to polyaniline due to its remarkable environmental and thermal stability, excellent intrinsic conductivity, and easy synthesis. Additionally, polypyrrole is non-toxic, biocompatible, and can be stabilized electrochemically by oxidation of monomer solutions, polypyrrole has been shown to oxidize and adsorb phenolic compounds under physiological conditions. Polypyrrole has similar properties to polyaniline but shows higher conductivity at higher pH; the addition of surfactants during the polymerization process has been shown enhance its operation at a higher pH range. Additionally, copper-doped polypyrrole electrodes have been shown to lower phenolic concentration in solutions at 0.15 M by >50%. Pump stable insulins contain much lower concentrations, around 0.03 M. polyaniline and polypyrrole are non-limiting examples of coatings that can be used to chemically-modify the working electrode of a set of flow-through ring electrodes to remove phenolic preservatives from insulin formulations.

[0040] The amount adsorption / absorption of phenol onto the electrode can be confirmed and determined by the Randles-Sevcik equation for adsorbed and / or absorbed species.

[0041] i = —vAV0

[0042] Where ipis the peak current in amps, n is the number of electrons transferred in the redox reaction, F is the faraday constant, R is the gas constant, T is the temperature, v is the scan rate, A is the surface area of the electrode, and T* o is the molar coverage of the analyte. When plotting the peak current against the scan rate (ipvs v) the resultant plot should be linear if the analyte has been adsorbed and / or absorbed onto the electrode andthe slope of this line can be used to determine the moles of analyte adsorbed and / or absorbed. Once the amount of phenol adsorbed / absorbed onto the working electrode has been determined, a ratio of adsorbed and / or absorbed phenol to surface area can be obtained. This ratio can then be used to approximate the size of a modified electrode needed to deplete phenolics from the required amount of insulin for a particular use case. It is important to note here that care must be taken when extrapolating the peak current signal from the baseline current to get the most accurate assessment of the adsorbed and / or absorbed analyte. Only the faradic current here is included in the Randle-Sevcik equation, so using polynomial fitting to base line is the best practice to get accurate peak current readings. This method of determining the amount of analyte adsorbed and / or absorbed is not limited to this use case and is extremely useful in optimizing the size of a chemically-modified ring electrode module for its intended use.

[0043] Other nonlimiting examples of the use of a PDC for injectable therapeutics include removal of phenolic preservatives from glucagon, pramlintide, pain medications, and vaccines. The size of the chemically-modified flow-through ring electrode module, the surface area of the flow-through ring electrodes, the type and properties of electroactive coating, and the properties of electric current and voltage would all need to be customized for removal of phenolic preservatives without causing significant change to the therapeutic species in solution. Bacteriostatic saline solution is often used in hospitals when multiple doses need to be taken from the same vial. This ensures that the solution remains safe but limits its use case especially with children as there are known adverse effects of the benzyl alcohol preservatives. A chemically-modified ring electrode system could be used here to remove the possibly harmful preservatives immediately prior to injection while ensuring the larger batch of saline solution remains bacteria free. This use case would be well-suited and the flow rate of saline solution is slow enough that the chemically-modified ring electrodes could remove the benzyl alcohol during the drip injection method commonly used in hospitals.

Claims

ClaimsThe invention claimed is:

1. A chemically-modified flow-through ring electrode module, comprising:two or more ring electrodes arranged such that a fluidic path passes through each ring electrode;an electroactive coating deposited on at least one of the ring electrodes; andelectrical connections configured to apply a voltage or current between two or more of the ring electrodes;wherein the electroactive coating is selected to alter the rate of a specific electrochemical reaction when the voltage or current is applied, resulting in oxidation, reduction, or capture of a target species from a solution passing through the fluidic path.

2. The chemically-modified flow-through ring electrode module of claim 1, wherein the electroactive coating comprises a conductive polymer.

3. The chemically-modified flow-through ring electrode module of claim 2, wherein the conductive polymer comprises polyaniline, polypyrrole, poly(3,4-ethylenedioxythiophene), or a combination thereof.

4. The chemically-modified flow-through ring electrode module of claim 3, wherein the conductive polymer is functionalized with one or more of surfactants, long-chain organic acids, or metal complexes to extend operational range.

5. The chemically-modified flow-through ring electrode module of claim 1, wherein the electroactive coating comprises an aromatic ring structure configured to capture aromatic target species through n-n stacking interactions.

6. The chemically-modified flow-through ring electrode module of claim 1, wherein the target species comprises a phenolic compound.

7. The chemically-modified flow-through ring electrode module of claim 6, wherein the phenolic compound is a preservative in a drug formulation.

8. The chemically-modified flow-through ring electrode module of claim 7, wherein the drug formulation comprises insulin, and wherein the operational parameters are selected such that insulin molecules in the drug formulation are not significantly altered by the electrochemical reaction.

9. The chemically-modified flow-through ring electrode module of claim 1, wherein the two or more ring electrodes comprise a working electrode, a counter electrode, and a reference electrode, and wherein the electroactive coating is selectively deposited on the working electrode.

10. The chemically-modified flow-through ring electrode module of claim 9, wherein surface areas, relative size, and configuration of the electrodes are optimized for a specific application.

11. The chemically-modified flow-through ring electrode module of claim 1, wherein an inner diameter of the ring electrodes is sized to provide an optimal ratio of electrode surface area to fluidic volume for a specific application.

12. The chemically-modified flow-through ring electrode module of claim 1, wherein the electroactive coating is selected such that oxidation or reduction products of the target species do not foul the electroactive coating.

13. A system comprising two or more chemically-modified flow-through ring electrode modules according to claim 1 arranged in series along a common fluidic path.

14. The system of claim 13, wherein each chemically-modified flow-through ring electrode module is configured to target a different species.

15. A method of selectively removing a target species from a solution, the method comprising:providing a flow-through ring electrode module comprising two or more ring electrodes, wherein at least one of the ring electrodes has an electroactive coating deposited thereon; passing the solution through a fluidic path defined by the ring electrodes; andapplying a voltage or current between two or more of the ring electrodes to alter the rate of an electrochemical reaction that oxidizes, reduces, or captures the target species;wherein the electroactive coating alters the electrochemical reaction of the target species preferentially over other species in the solution.

16. The method of claim 15, further comprising releasing the captured target species by applying a different voltage or current than that used to capture the target species.

17. The method of claim 15, further comprising releasing the captured target species by exposing the electroactive coating to a secondary solution having a different pH, temperature, or composition than the solution from which the target species was captured.

18. The method of claim 15, wherein the target species is a phenolic preservative and the solution is a drug formulation, and wherein the method further comprises delivering the drug formulation to a patient after removal of the phenolic preservative.

19. The method of claim 18, wherein the drug formulation is an insulin formulation and delivering comprises subcutaneous delivery through a cannula of a continuous subcutaneous insulin infusion pump, and wherein the flow-through ring electrode module is positioned in a flow path upstream of the cannula.

20. The method of claim 15, wherein the electroactive coating comprises a conductive polymer having aromatic ring structures, and wherein the target species comprises an aromatic compound that is captured through 7i-7t stacking interactions with the aromatic ring structures of the conductive polymer following oxidation or reduction of the aromatic compound.

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