Gamma-irradiated reference gel

Abstract

A gel for use in a pH or ORP sensor, the gel comprising water, a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent as components thereof, the gel not degrading upon exposure to gamma radiation.

Description

[Technical field]

[0001] The present application relates to a viscous, biocompatible, gamma radiation stable reference gel that can be used in pH and oxidation-reduction potential (ORP) sensors.

[0002] pH sensors that use a liquid reference electrolyte in the reference electrode can experience undesirable response variations when subjected to positive process pressure. This behavior is illustrated in Figure 1, where two pH sensors with a reference electrode filled with a liquid reference solution were subjected to various process pressures ranging from 0 to 90 psi. As the process pressure was increased from 0 psi to 30 psi, the two pH sensors began to show response variations. When the process pressure reached 90 psi, significant response variations of up to 1 pH unit were observed. Such variations would cause significant measurement errors and are unacceptable.

[0003] This unwanted pressure sensitivity is caused by the impeded diffusion of ions from the reference electrode through the reference junction into the process, resulting in an unstable reference liquid junction potential and subsequent sensor response. As a result, this issue precludes the use of pH sensors filled with liquid reference electrolyte in downstream pharmaceutical applications where process pressures can fluctuate and reach up to 90 psi.

[0004] One approach to address this issue is to counter the effect of the external process pressure by applying internal pressure to the sensor's reference electrode and forcing the reference electrolyte through the contacts. Several U.S. patent documents, including U.S. Pat. No. 7,704,359, U.S. Patent Application Publication No. 2017 / 0176371, and U.S. Pat. No. 9,134,266, describe designs and manufacturing processes that introduce internal pressure to the reference electrode. The minimum required internal sensor pressure is determined by the external process pressure and the sensor's reference fill electrolyte, and can be very high when the external process pressure is high (e.g., 90 psi). This requirement for high internal reference chamber pressure can pose challenges in mechanical design, validation, and subsequent manufacturing process development.

[0005] Another approach to address this issue is to use a high-viscosity reference electrolyte instead of a water-like, low-viscosity reference solution in the reference electrode. The high viscosity of the gel mitigates the disruption of critical ion diffusion processes by external flow and pressure fluctuations. As a result, the minimum pressure required in the reference electrode may be reduced or even eliminated. There are several viscous reference gel formulations using silica, cellulose, and polysaccharides as gelling agents. Although these gels are widely used in industrial pH sensors, they are not stable to gamma irradiation. It has been observed that gamma irradiation can degrade these gels by changing their physical and chemical properties, resulting in a significant decrease in the gel's viscosity and a change in the pH value. As a result, conventional reference gels are not suitable for use in disposable pharmaceutical pH sensors, where gamma irradiation is the standard process used for sterilization. Summary of the Invention

[0006] The present application includes a gel for use in a pH or ORP sensor, the gel comprising as components thereof water, a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent, the gel not degrading upon exposure to gamma radiation.

[0007] In another embodiment, the polymeric gelling agent comprises polyethylene glycol having a molecular weight of 15,000 or less.

[0008] In another embodiment, the viscosity of the gel is adjusted by varying the concentration of the gelling agent, or the molecular weight of the gelling agent, or both.

[0009] In another embodiment, the buffer system comprises a phosphate-based buffer or a carbonate-based buffer.

[0010] In another embodiment, the reference electrolyte salt comprises potassium chloride at a concentration between 0.01 M and saturation or lithium acetate at a concentration between 0.01 M and saturation.

[0011] In another embodiment, the concentration of the gelling agent is about 2-90% by weight.

[0012] In another embodiment, each of the components of the gel is biocompatible.

[0013] In another embodiment, the polymeric gelling agent comprises polyethylene glycol derivatives, such as methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate.

[0014] In an alternative embodiment, the present disclosure includes a pH sensor comprising a housing and a gel, the gel comprising a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent, wherein the gel does not degrade upon exposure to gamma radiation within the housing.

[0015] In this alternative embodiment, the polymeric gelling agent is a polyethylene glycol having a molecular weight of 15,000 or less.

[0016] In this alternative embodiment, the viscosity of the gel is adjusted by varying the concentration of the gelling agent, or the molecular weight of the gelling agent, or both.

[0017] In this alternative embodiment, the buffer system may be a phosphate-based buffer or a carbonate-based buffer.

[0018] In this alternative embodiment, the reference electrolyte salt comprises potassium chloride at a concentration between 0.01 M and saturation or lithium acetate at a concentration between 0.01 M and saturation.

[0019] In this alternative embodiment, the concentration of the gelling agent is about 2-90% by weight.

[0020] In this alternative embodiment, each of the components of the gel is biocompatible.

[0021] In this alternative embodiment, the polymeric gelling agent comprises polyethylene glycol derivatives such as methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 is a graph of the pressure sensitivity of a prior art sensor. [Diagram 2] FIG. 2 is a graph of the pressure sensitivity of a sensor filled with a gamma-irradiated PEG8000 40 wt % reference gel. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] This application describes a viscous, biocompatible reference gel that retains its physical and chemical properties after gamma irradiation. The reference gel retains a high viscosity, which can significantly reduce or eliminate undesirable sensor response variations when the sensor is subjected to process pressures. The novel reference gel disclosed herein is particularly suited for disposable pH sensor products designed for sanitary processes with process pressure variations.

[0024] In order for the gels to provide solutions to the problems associated with prior art gels, the gels of the present disclosure are composed of biocompatible components, have a stable yet tunable viscosity, have a stable and tunable pH, and are stable under gamma irradiation without undergoing significant physical and chemical changes.

[0025] Preferably, the reference gel of the present disclosure comprises the following four main chemical components, all of which are biocompatible:

[0026] 1. Water acts as a solvent. 2. A reference electrolyte salt that provides a stable, sample-independent liquid junction potential at the reference junction. If the reference electrode is constructed in a single-junction configuration, the salt also determines the potential of the reference electrode that is connected to the Ag / AgCl wire. A suitable salt may be potassium chloride at a concentration from 0.01 M to saturation. If the reference electrode is constructed in a multi-junction configuration, the salt may be another suitable salt, such as lithium acetate. 3. The buffer system used to adjust the pH of the gel. Since the present reference gel may come into contact with biological processes, a controllable pH is highly desirable. Common buffer systems used in biotechnology are suitable for this purpose as long as the pH is stable without significant changes even under gamma irradiation. Suitable buffer systems can be phosphate-based or carbonate-based buffers. 4. A polymeric gelling agent is used to control the viscosity of the gel, which is important for the performance of the sensor under pressure. The viscosity of the gel can be controlled by varying the concentration of the polymeric gelling agent, or the molecular weight of the polymeric gelling agent, or both.

[0027] The gelling agent must also be stable under gamma irradiation so that the physical properties of the gel do not change significantly. A successful gelling agent used in this disclosure can be polyethylene glycol (PEG) with a molecular weight of 15,000 or less. Reference gels prepared using such PEG polymers will remain liquid after gamma irradiation. Gels prepared with PEGs of molecular weights of 20,000 or more will change from a liquid state to a solid state after gamma irradiation. Gels prepared using silica or other common gelling agents may experience a significant decrease in viscosity after gamma irradiation.

[0028] The gels of the present disclosure may be useful in a variety of pH and oxidation-reduction potential (ORP) sensors, whether or not the gel is illuminated.

[0029] All four components of the sensor of the present disclosure are biocompatible, making the sensor useful for hygiene applications, although the disclosure should not be so limited and other non-hygienic applications are envisioned.

[0030] The buffer system of the gel contains an appropriate pair of an acid and its conjugate base, such as a phosphate-based buffer or a carbonate-based buffer. The pH of the gel can be adjusted by controlling the concentration ratio of the acid-base pair in the buffer system. For example, the pH of the gel can be adjusted by changing the concentration ratio of NaH2PO4 and NaOH.

[0031] The initial viscosity of the gel is 1 cP to 10,000 cP, preferably 10 cP to 5,000 cP, and more preferably 10 cP to 1,000 cP, when measured with a rotational viscometer using the measurement method specified in ASTM D2196. The viscosity of the gel can be controlled by changing the concentration and molecular weight of the gelling agent. The higher the concentration and molecular weight, the higher the viscosity.

[0032] Working Example Several prototypes of the reference gel were prepared by mixing all chemical components with water at room temperature under stirring until all components were completely dissolved. A typical gel contains a buffer system with 0.106 M NaH2PO4 and 0.04 M NaOH, a reference electrolyte of 1 M KCl, and a polyethylene glycol (PEG) gelling agent with a molecular weight of 8,000 and a concentration of 40% by weight. After all components were dissolved, the gel was in a liquid state with a viscosity of 122.4 cP at 22 °C as measured using ASTM D2196 method with a Brookfield DVE viscometer and LV-1 spindle. The pH of the gel was 6.805 as measured using a two-point calibrated pH meter.

[0033] To determine the stability of gamma irradiation, the gel samples were gamma irradiated at a dose of 55 kGy and the viscosity and pH value of the gel after gamma irradiation were examined. After gamma irradiation, the viscosity of the gel did not decrease but increased to 181.4 cP at 22°C, and the gel remained a viscous liquid. The pH of the gel after gamma irradiation was 6.692, indicating a minimal pH change of less than 0.2 pH. This indicates that the reference gel is physically and chemically stable after gamma irradiation. It is believed that the gel of the present disclosure can withstand irradiation of up to 100 kGy without degradation.

[0034] In another example, a gel was prepared using 0.106 M NaH2PO4 and 0.04 M NaOH, a reference electrolyte of 1 M KCl, and a polyethylene glycol (PEG) gelling agent of molecular weight 4,000 and concentration of 20 wt %. The initial viscosity obtained was 12.1 cP at 22° C., and the pH of the gel was 6.422. After exposure to gamma radiation at a dose of 55 kGy, the viscosity of the gel was measured to be 13.4 cP at 22° C., and the pH of the gel was 6.381. Both the viscosity and pH of the gel did not change significantly.

[0035] Other derivatives or possible gelling agents include, but are not limited to, polyethylene glycol derivatives, including methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate. Although polyethylene glycol and its derivatives are specifically listed as gelling agents, other polymers may be used as long as aqueous solutions of the polymer do not degrade upon gamma irradiation. Other suitable gelling agents include, but are not limited to, polypropylene glycol and its derivatives, and polyalkylene glycol and its derivatives.

[0036] For gels made with the higher molecular weight PEG-20000, the liquid gel transformed into a solid after gamma irradiation.

[0037] The PEG molecular weight is an important factor in determining the final morphology of the reference gel after gamma irradiation. In the present disclosure, PEG with a molecular weight of 15,000 or less will result in a suitable liquid gel.

[0038] A gamma irradiated PEG8000 40% by weight reference gel was filled into the reference chamber of the sensor body. No additional internal pressure was applied to the sensor's reference electrode. The sensor was calibrated and subjected to an external process pressure ranging from 0 to 80 psi. The process pressure is represented by the dashed line. As shown in FIG. 2, no significant pressure sensitivity was observed. This demonstrates that the reference gel of the present disclosure can reduce or eliminate undesirable sensor pressure sensitivity without the need for internal pressure within the sensor's reference electrode. The use of the present reference gel in conjunction with a pressurized sensor's reference electrode may reduce the minimum required pressure applied to the sensor's internal reference electrode. [1] A gel for use in a pH or ORP sensor, the gel comprising water, a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent as components thereof, the gel not degrading upon exposure to gamma radiation. [2] The gel according to [1] above, wherein the polymeric gelling agent is a polyethylene glycol having a molecular weight of 15,000 or less. [3] The gel according to [1], wherein the viscosity of the gel is adjusted by varying the concentration of the gelling agent, or the molecular weight of the gelling agent, or both. [4] The gel according to [1], wherein the buffer system comprises a phosphate-based buffer or a carbonate-based buffer. [5] The gel according to [1] above, wherein the reference electrolyte salt contains potassium chloride at a concentration of 0.01 M to saturation or lithium acetate at a concentration of 0.01 M to saturation. [6] The gel according to [1] above, wherein the concentration of the gelling agent is about 2 to 90% by weight. [7] The gel according to [1] above, wherein each of the components of the gel is biocompatible. [8] The gel according to [1] above, wherein the polymeric gelling agent is a polyethylene glycol derivative including methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate. [9] A pH sensor comprising a housing and a gel within the housing, the gel comprising a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent, wherein the gel does not degrade upon exposure to gamma radiation.

[10] The pH sensor according to [9], wherein the polymeric gelling agent is polyethylene glycol having a molecular weight of 15,000 or less.

[11] The pH sensor according to [9], wherein the viscosity of the gel is adjusted by varying the concentration of the gelling agent, or the molecular weight of the gelling agent, or both.

[12] The pH sensor according to [9], wherein the buffer system comprises a phosphate-based buffer or a carbonate-based buffer.

[13] The pH sensor according to [9] above, wherein the reference electrolyte salt contains potassium chloride at a concentration of 0.01 M to saturation or lithium acetate at a concentration of 0.01 M to saturation.

[14] The pH sensor according to [9] above, wherein the concentration of the gelling agent is about 2 to 90% by weight.

[15] The pH sensor according to [9], wherein each of the components of the gel is biocompatible.

[16] The pH sensor according to [9], wherein the polymeric gelling agent is a polyethylene glycol derivative including methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate.

Claims

1. A gel for use in a pH or ORP sensor, the gel comprising as components thereof water, a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent; Does not deteriorate when exposed to gamma rays, the polymeric gelling agent has a molecular weight of 15,000 or less; A gel, wherein the polymeric gelling agent is a polyethylene glycol derivative, including methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate.

2. A pH sensor comprising a housing and a gel within the housing, the gel comprising a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent; The gel does not deteriorate when exposed to gamma rays. the polymeric gelling agent has a molecular weight of 15,000 or less; A pH sensor, wherein the polymeric gelling agent is a polyethylene glycol derivative including methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate.

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