Gamma irradiation compatible reference gel

Abstract

A gel for a pH or ORP sensor, the components of the gel comprising water, a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymeric gelling agent, and the gel does not degrade under gamma irradiation.

Description

[0001] This application is a divisional application of the Chinese application No. 202110353122.9, with a filing date of March 31, 2021 and an invention name of “γ-irradiation compatible reference gel”. Technical Field

[0002] The present application relates to a viscous, biocompatible and gamma irradiation stable reference gel that can be used in pH and oxidation reduction potential (ORP) sensors. Background Art

[0003] pH sensors using a liquid reference electrolyte in the reference electrode may exhibit undesirable fluctuations in response when exposed to positive process pressure. This behavior is Figure 1 As shown, two pH sensors with reference electrodes filled with liquid reference solutions were exposed to various process pressures from 0psi to 90psi. As the process pressure increased from 0psi to 30psi, the two pH sensors began to exhibit response fluctuations. When the process pressure reached 90psi, significant response fluctuations of up to 1 pH unit were observed. Such fluctuations would result in significant measurement errors, which is unacceptable.

[0004] This undesirable pressure sensitivity is caused by the diffusion of interfering ions from the reference electrode through the reference junction into the process, resulting in an unstable reference liquid junction potential and subsequently an unstable sensor response. Therefore, this problem prevents the use of pH sensors filled with liquid reference electrolytes in downstream pharmaceutical applications where process pressures may vary and reach 90 psi.

[0005] One approach to addressing this problem is to apply internal pressure to the sensor reference electrode, thereby counteracting the effects of the external process pressure by pushing the reference electrolyte through the junction. Several U.S. patent references describe the design and manufacturing process of introducing internal pressure to the reference electrode, including US 7,704,359, US2017 / 0176371, and US 9,134,266. The minimum internal pressure required for the sensor depends on the external process pressure and the sensor reference fill electrolyte, and can be very high when the external process pressure is high (e.g., 90 psi). Higher internal reference chamber pressure requirements can lead to challenges in mechanical design, validation, and subsequent development of the manufacturing process.

[0006] Another approach to address this problem is to use a high viscosity reference electrolyte to replace the aqueous low viscosity reference solution in the reference electrode. The high viscosity of the gel mitigates the interference of external flow and pressure fluctuations on the critical ion diffusion process. Therefore, this can lead to a lower minimum required pressure inside the reference electrode, or even no internal reference electrode pressure is required. There are several viscous reference gel formulations that rely on silica, cellulose and polysaccharides as gelling agents. These gels are widely used in industrial pH sensors, but are unstable under gamma irradiation. It has been observed that gamma irradiation can break down these gels by changing their physical and chemical properties, resulting in a significant decrease in gel viscosity and changes in pH. Therefore, traditional reference gels are not suitable for use in disposable pharmaceutical pH sensors, and gamma irradiation is a standard process used for sterilization. Summary of the invention

[0007] The present patent application includes a gel for a pH or ORP sensor, wherein the components of the gel include water, a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymer gelling agent, and the gel does not degrade under gamma irradiation.

[0008] In another embodiment, the polymeric gelling agent comprises polyethylene glycol having a molecular weight of 15,000 or less.

[0009] 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.

[0010] In another embodiment, the buffer system comprises a phosphate or carbonate based buffer.

[0011] In another embodiment, the reference electrolyte salt comprises potassium chloride at a concentration of 0.01 M to saturation or lithium acetate at a concentration of 0.01 M to saturation.

[0012] In another embodiment, the concentration of the gelling agent ranges from about 2 wt % to about 90 wt %.

[0013] In another embodiment, the components of the gel are biocompatible.

[0014] In another embodiment, the polymeric gelling agents include polyethylene glycol derivatives, such as methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate.

[0015] In an alternative embodiment, the present disclosure includes a pH sensor including a housing and a gel comprising a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymer gelling agent, and the gel does not degrade under gamma irradiation within the housing.

[0016] In this alternative embodiment, the polymeric gelling agent is polyethylene glycol having a molecular weight of 15,000 or less.

[0017] 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.

[0018] In this alternative embodiment, the buffer system may be a phosphate or carbonate based buffer.

[0019] In this alternative embodiment, the reference electrolyte salt comprises potassium chloride at a concentration of 0.01 M to saturation or lithium acetate at a concentration of 0.01 M to saturation.

[0020] In this alternative embodiment, the concentration of the gelling agent ranges from about 2% to about 90% by weight.

[0021] In this alternative embodiment, the components of the gel are biocompatible.

[0022] In this alternative embodiment, the polymeric gelling agent includes polyethylene glycol derivatives such as methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 A graphical view of the pressure sensitivity of a prior art sensor.

[0024] Figure 2 is a graphical view of the pressure sensitivity of a sensor filled with a γ-irradiated PEG 8000 40 wt % reference gel. DETAILED DESCRIPTION

[0025] This patent application describes a viscous, biocompatible reference gel that maintains its physical and chemical properties after gamma irradiation. The reference gel, while maintaining its high viscosity, can significantly reduce or eliminate undesirable sensor response fluctuations when the sensor is exposed to process pressure. The novel reference gel disclosed herein is particularly suitable for disposable pH sensor products designed for sanitary processes with process pressure variations.

[0026] In order for the gel to provide a solution to the problems associated with prior art gels, the gel of the present disclosure is made of biocompatible components, has a stable but adjustable viscosity, a stable and adjustable pH, and is stable under gamma irradiation without undergoing significant physical and chemical changes.

[0027] Preferably, the reference gel of the present disclosure comprises the following four main chemical components, all of which are biocompatible.

[0028] 1. Water used as a solvent.

[0029] 2. A reference electrolyte salt that provides a stable and sample-independent liquid junction potential at the reference junction. When the reference electrode is configured as a single junction configuration, the salt also determines the reference electrode potential coupled to the Ag / AgCl wire. A suitable salt may be potassium chloride in a concentration of 0.01 M to saturation. When the reference electrode is configured as a multi-junction configuration, the salt may also be other suitable salts, such as lithium acetate.

[0030] 3. Buffer system for adjusting the pH of the gel. Since the 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 they remain stable under gamma irradiation without significant changes in pH. Suitable buffer systems may be phosphate-based buffers or carbonate-based buffers.

[0031] 4. The polymer gelling agent is used to control the viscosity of the gel, which is important for the sensor performance under pressure. The viscosity of the gel can be controlled by varying the concentration and / or molecular weight or both of the polymer gelling agent.

[0032] In addition, the gelling agent should be stable under gamma irradiation so that the physical properties of the gel do not change significantly. A successful gelling agent for use in the present disclosure can be polyethylene glycol (PEG) with a molecular weight equal to or less than 15,000. Reference gels prepared with such PEG polymers will remain in liquid form after gamma irradiation. Gels prepared with PEG with a molecular weight equal to or greater than 20,000 will change from liquid form to solid form after gamma irradiation. Gels prepared with silica or other commonly used gelling agents may experience a significant loss in viscosity after gamma irradiation.

[0033] The gels of the present disclosure can be used in a variety of pH sensors and oxidation-reduction potential (ORP) sensors, whether or not the gels are irradiated.

[0034] All four components of the disclosed sensor are biocompatible, which makes the sensor useful in sanitary applications, but other applications beyond sanitary are also contemplated and the disclosure herein should not be so limited.

[0035] The buffer system of the gel comprises a pair of suitable acids and their conjugate bases, 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 to NaOH.

[0036] As measured by a rotational viscometer using the measurement method specified in ASTM D2196, the initial viscosity of the gel is between 1 cP and 10,000 cP, preferably between 10 cP and 5,000 cP, and more preferably between 10 cP and 1,000 cP. The gel viscosity 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.

[0037] Example

[0038] Several reference gel prototypes were prepared by mixing all chemical components with water at room temperature under stirring until all components were completely dissolved. A typical gel contained a buffer system provided by 0.106 M NaH2PO4 and 0.04 M NaOH, 1 M KCI reference electrolyte, and a polyethylene glycol (PEG) gelling agent having a molecular weight of 8,000 and a concentration of 40 wt%. After all components were dissolved, the gel was in liquid form with a viscosity of 122.4 cP at 22°C as measured using ASTM D2196 method using 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.

[0039] To determine the gamma irradiation stability, the gel samples were gamma irradiated at a dose of 55 kGy, and the gel viscosity and pH were checked after gamma irradiation. After gamma irradiation, the gel viscosity 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 demonstrates 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.

[0040] In another example, a gel was prepared using a reference electrolyte of 0.106 M NaH2PO4 and 0.04 M NaOH, 1 M KCI, and a polyethylene glycol (PEG) gelling agent having a molecular weight of 4,000 and a concentration of 20 wt%. The resulting initial viscosity was 12.1 cP at 22°C, and the gel pH was 6.422. After gamma irradiation at a dose of 55 kGy, the gel viscosity was measured at 22°C to be 13.4 cP, and the gel pH was 6.381. Neither the gel viscosity nor the pH changed significantly.

[0041] Other derivatives or possible gelling agents include, but are not limited to, polyethylene glycol derivatives, which may include, but are not limited to, methoxypolyethylene glycol and poly(ethylene glycol) methyl ether methacrylate. Although polyethylene glycol and its derivatives are specifically mentioned as gelling agents, other polymers may be used as long as the aqueous solution of the polymer does not degrade under gamma irradiation. Other suitable gelling agents may include, but are not limited to, polypropylene glycol and its derivatives and polyalkylene glycols and their derivatives.

[0042] For gels made with higher molecular weight PEG-20000, the liquid gels turned into solid form after gamma irradiation.

[0043] PEG molecular weight is an important factor in determining the final form of the reference gel after gamma irradiation. For the present disclosure, PEG with a molecular weight equal to or less than 15,000 will produce a suitable liquid gel.

[0044] A gamma-irradiated PEG 8000 40 wt% reference gel was filled into the reference cavity of the sensor body. No additional internal pressure was applied to the sensor reference electrode. The sensor was calibrated and exposed to external process pressures ranging from 0 to 80 psi. The process pressure is represented by the dashed line. Figure 2 As shown, 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 internal pressure within the sensor reference electrode. When this reference gel is used in conjunction with a pressurized sensor reference electrode, it may reduce the minimum required pressure applied to the sensor internal reference electrode.

Claims

1. A gamma-irradiation-resistant gel for 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 polymer gelling agent, The polymer gelling agent is used to control the viscosity of the gel and is stable under gamma irradiation, and the buffer system is stable under gamma irradiation, so that after gamma irradiation, the viscosity of the gel does not decrease but increases, while the gel remains a viscous liquid, and the change in pH of the gel is less than 0.2 pH.

2. The gel according to claim 1, wherein the polymer gelling agent is polyethylene glycol having a molecular weight of 15,000 or less.

3. The gel of claim 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 of claim 1, wherein the buffer system comprises a phosphate or carbonate based buffer. 5 . The gel according to claim 1 , wherein the reference electrolyte salt comprises 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 of claim 1, wherein the concentration of the gelling agent is about 2 wt% to 90 wt%.

7. The gel of claim 1, wherein the components of the gel are biocompatible.

8. The gel of claim 1, wherein the polymer gelling agent is a polyethylene glycol derivative including methoxy polyethylene glycol and poly(ethylene glycol) methyl ether methacrylate.

9. A gamma-irradiation resistant pH sensor, the sensor comprising a housing and a gel within the housing, wherein the gel comprises a reference electrolyte salt, a buffer system for adjusting the pH of the gel, and a polymer gelling agent, The polymer gelling agent is used to control the viscosity of the gel and is stable under gamma irradiation, and the buffer system is stable under gamma irradiation, so that after gamma irradiation, the viscosity of the gel does not decrease but increases, while the gel remains a viscous liquid, and the change in pH of the gel is less than 0.2 pH.

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

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

12. The pH sensor of claim 9, wherein the buffer system comprises a phosphate or carbonate based buffer. 13 . The pH sensor according to claim 9 , wherein the reference electrolyte salt comprises potassium chloride having a concentration of 0.01 M to saturation or lithium acetate having a concentration of 0.01 M to saturation.

14. The pH sensor of claim 9, wherein the concentration of the gelling agent is about 2 wt% to 90 wt%.

15. The pH sensor of claim 9, wherein the components of the gel are biocompatible.

16. The pH sensor of claim 9, wherein the polymer gelling agent is a polyethylene glycol derivative including methoxy polyethylene glycol and poly(ethylene glycol) methyl ether methacrylate.

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