Patent Description:
The present disclosure generally relates to fluid leaks in chromatography systems.

Chromatography systems perform separations using various fluids and mobile phases flowing through multiple components within the system. For example, solvents under low pressure can be delivered to a pump. The pump can deliver a controlled high pressure mobile phase to a column to effect a separation. The high pressure mobile phase exiting the column can be delivered to a detector for determining the separated components. Chromatography systems also use various other fluids, such as wash solutions and needle washes to clean retained compounds from the system. Chromatography systems also have waste stream(s) to collect the used fluids and mobile phase.

A leak in any one of these flows or streams can be detrimental. A leak in the high pressure mobile phase can interfere with the separation results, e.g., accuracy and reproducibility. A leak in the high pressure mobile phase can also be dangerous. Exposure to solvents can be harmful. Each component within the chromatography system should be sealed in order to prevent leaks and maintain desired pressure and temperature levels within the system. Any leaks in the connecting tubes, fittings, or other components of a chromatography system should be identified and corrected. It can be difficult to detect leaks in chromatography systems, especially chromatography systems with low flow rates where fluid or mobile phase leaks are small.

The following documents are known: <CIT> disclosing a sealing assembly for use in chromatography systems, <CIT> disclosing a sealing component coated with a hydrogel to form a seal, and <CIT> disclosing a chromatography system which comprises a sensor material conforming to a component of the system, wherein said material changes conductivity when contacted by leaking fluid.

The present disclosure relates to devices and methods to stop or reduce leaks in a chromatography system, including small leaks.

The present disclosure generally relates to chromatography systems. In particular, the current disclosure provides for a coating that is applied to a component of a chromatography system in order to stop or both detect and stop leaks in the chromatography system. According to the invention in a first aspect, there is provided a chromatography system as recited by Claim <NUM>. According to the invention in a further aspect, there is provided a method of stopping or reducing a fluid leak in a chromatography system as recited by Claim <NUM>.

The present disclosure relates to an apparatus for reducing or stopping a leak including a coating disposed to conform to a component of a chromatography system, and a responsive material disposed within the coating and configured to respond by creating a physical change when in contact with a fluid or mobile phase. The responsive material is disposed to change at least one physical property. The responsive material is a physically responsive material that becomes stiffer (as claimed) in order to stop or reduce a leak (e.g., prevent passage of the fluid or mobile phase), in response to being contacted by the fluid or mobile phase. In another example, not falling under the scope of the present invention, the responsive material can be a chemically reactive material that changes in chemical structure or catalytic nature in response to being contacted by the fluid or mobile phase.

Also disclosed is a method of stopping or reducing a leak in a chromatography system including applying a responsive material to at least one component of the chromatography system wherein the responsive material is disposed to change at least one physical property, i.e. stiffness.

The various leak detection systems, methods, and devices disclosed can provide a number of advantages. For example, the systems, methods, and devices can facilitate identification of leak(s) in a chromatography system. The detected leaks may be smaller in scale than those detectable with conventional leak detection sensors. The systems, methods, and devices can also identify one or more specific areas of a chromatography system where a leak is present, such as when the coating or responsive material is applied to a chromatographic housing or instrument. The systems, methods, and devices can identify the fluid or mobile phase, as well as characteristics of the fluid or mobile phase, leaking Finally, the systems and methods according to the present invention can stop or prevent the leak(s) by creating a sealant layer or barrier around a detected leak that can prevent passage of the fluid or mobile phase.

The skilled artisan will understand that the drawings are primarily for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale, and in some instances, various aspects of the inventive subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features, e.g., functionally similar and/or structurally similar elements.

Certain arrangements will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the systems, methods, and devices disclosed herein. One or more such arrangements are illustrated in the accompanying drawings. Those skilled in the art will understand that the systems, methods, and devices specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present technology is defined solely by the claims. The features illustrated or described in connection with one embodiment may be combined with the features of other embodiments, insofar as such modifications and variations fall under the scope defined by the appended claims. One skilled in the art will recognize that the systems, devices, and methods described herein can be used in numerous contexts and have useful applications outside of the field of chromatography systems. For example, any field where leak detection and prevention is important can potentially benefit from the techniques described herein.

Chromatography systems use various fluids, solvents, modifiers, mobile phases, etc. to perform separations via chromatography columns and other system components. These systems can use wash solutions to clean retained compounds from the system. These systems can also have waste stream(s) to collect these various fluids, solvents, mobile phases, etc. after a separation. The different system components including the columns, connecting tubes, fittings, etc. should be properly sealed. Any leaks in the system should be identified and stopped in order for the system to function efficiently. It can be particularly difficult to detect leaks in micro-fluidic chromatography systems due to low flow rates of the mobile phase.

The chromatography systems can include, but are not limited to, liquid chromatography, gas chromatography, supercritical fluid chromatography, carbon dioxide based chromatography in nanoscale, microscale, analytical scale, and prep scale.

The components of these chromatographic systems that can be coated (or otherwise treated) include tubing, fittings, connectors and various system components, e.g., pump, column, column case, column heater, detector. Any type or size tubing can be coated including <NUM> - <NUM>. Any type or size fitting, connector, and fluidic devices appropriate for the above tubing size can be coated.

In exemplary embodiments, the leak detection device, e.g., coating or contact material, can be used in connection with connecting tubes, fittings, or fluidic devices commonly used in chromatography systems. In some embodiments, the coating can be a wrap, a sleeve, a material that is applied or sprayed onto a component, a material that is placed in close proximity to a component, etc.. The coating at least partially conforms to a component, The various components can be made of metallic or non-metallic materials, such as stainless steel, titanium, alloys, brass, ceramics, glass, fused silica, silicon, plastics (e.g., acrylonitrile butadiene styrene (ABS), polyvinyl chloride (PVC), high impact polystyrene (HIPS), HDPE, LDPE, PP, PETE, PEEK, Teflon), viscous liquids, etc..

The system components, e.g., pump, column, column case, column heater, detector, themselves can be coated, or otherwise treated. Alternatively, the bottom, corners, or sides of the component, e.g., pump, can be coated, or any opening where leaked fluid or solvent may exit the component.

The pressure of the flows or streams in the chromatography system can be, at times, lower than atmospheric pressure, e.g., when a vacuum is created within the system. The pressure can be, at times, high. Low pressure can occur before the pump. High pressure can be after the pump and through the column. The pressures of the chromatography system can be <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> psi, wherein <NUM> psi = <NUM>,<NUM> Pa. These values can define a range, such as about <NUM>,<NUM> Pa (<NUM> psi) to about <NUM>,<NUM> kPa (<NUM><NUM> psi).

In some embodiments, leaks can be detected and stopped in systems with flow rates of about <NUM> nL/min, <NUM>µL/min, <NUM>. 05µL/min, <NUM>µL/min, <NUM>µL/min, <NUM>µL/min, <NUM>µL/min, <NUM>µL/min, <NUM>µL/min, <NUM>µL/min, <NUM>µL/min, <NUM>/min, <NUM>/min, <NUM>/min, <NUM>/min, <NUM>/min, <NUM>/min, or <NUM>/min.

Additionally, a leak may be difficult to detect because the fluid, solvent or mobile phase evaporates before accumulating sufficient volume to visibly pool or drip from the component. Prior leak detection techniques use sensors that need significant volumes of leaked fluid to operate. These techniques often cannot detect smaller scale leaks or vapor leaks. The coating of the present disclosure can be placed directly on or in close proximity of the potential leak, e.g., fitting, connector. The direct placement or close proximity of the coating can identify a leak prior to significant evaporation, pooling or dripping. The coating can be placed directly on the components, e.g., fitting, connector, or can be placed within about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or about <NUM> from the component or the site of future leak. These values can be used to define a range, such as about <NUM> to about <NUM>. In some embodiments, the coating can be made of a flexible or pliable material that can conform to one or more components of a chromatography system.

A leak detection device is disclosed that contains a responsive material and is coated or wrapped around one or more components of a chromatography system. In some embodiments, the coating is the responsive material such that the entirety or bulk of the coating is the responsive material. In other embodiments, the responsive material is a component of the coating. For example, the coating can include about, or less than about, or more than about, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or about <NUM>% of the responsive material or materials. These values can be used to define a range, such as about <NUM>% to about <NUM>%. When a leak occurs through any portion of the so coated or wrapped chromatography system, such as the connecting tubes or fittings, the leaking fluid triggers a response from the responsive material in the leak detection device, producing a change in the material, for example, a change that can be detected through external means. The coating can contain other components, including adhesives, matrices, structural elements, embedded components, etc..

The responsive material can respond differently depending on the fluid or solvent that leaks and makes contact with the responsive material. Thus, a change in the responsive material can also indicate what type of fluid or solvent is leaking. A number of different types of solvents may be used within a chromatography system. For example, systems may require one, two, or more mobile phase supplies, strong and weak wash solutions, or cleaning and rinse solutions, and may require additional fluids for maintenance purposes. The responsive material can be designed to indicate differences between various fluids or solvents, including differences in pH, aqueous content, organic content, ionic strength, functional groups (e.g., amines, aldehydes, etc.), aromaticity, evaporation energy, polarity, etc. In some embodiments, the responsive material can also indicate which fluid is leaking by means of a specific color change. For example, in a system using two different solvents, solvent A and solvent B, a responsive material can be selected which responds to solvent A by changing its color from red to blue, but an interaction with solvent B results in no such color change.

To address a leak of fluid, e.g., aqueous or semi-aqueous fluid, the responsive material can include a highly absorbent material, such as a hydrogel, silica gel, Drierite® (color-indicating variant of calcium sulfate), magnesium sulfate, hygroscopic compounds, etc. In some embodiments, the responsive material can include a material, such as a hydrogel or other polymeric material(s), that can be cross-linked or polymerized when exposed to a leaked fluid. The responsive material changes in stiffness to prevent passage of fluid or mobile phase, in order to act as a sealant for a detected leak.

The responsive material can be a water soluble material, a polar solvent soluble pigment, or a non-polar solvent soluble pigment. Any shapes or patterns printed with the pigments will be moved with the spread of the compatible fluid to change the appearance (smearing) or location (simple movement), thus indicating the presence of the leak and the identity of the leaked liquid. One example arrangement, which is not independently claimed as such, is described below in reference to <FIG>. In other arrangements, which are not independently claimed as such, leaked fluid transports one reactant to another reactant to initiate a chemical reaction that may create an easily detectable product.

To indicate a leak wherein the pH of the leaking fluid or solvent can be indicated, the responsive material can include a pH indicator, such as litmus. For example, if the leak detection device is coated with a coating containing litmus, or some other halochromic material, a solvent with specific pH ranges can change the color of the device at the leaking point.

In some arrangements, which are not independently claimed as such, a color change of the responsive material, or coating containing the material, can be permanent. The color change can also change from one color to a second color. Depending on the severity of the leak, the coating/material can also change to a third (or more) color as an indication of the magnitude of the leak. The color change can have various degrees of intensity. The intensity of the color change can also indicate the magnitude of the leak.

In some embodiments, a change in state of the responsive material can be reversible. For example, the responsive material may regenerate when exposed to a particular solvent or fluid. In some embodiments, a change in the responsive material can be reversed by flushing or otherwise exposing the responsive material to a neutralizing chemical. One example of a reversible leak detection scheme, which is not independently claimed as such, could employ the use of a desiccant, such as calcium sulfate impregnated with cobalt(II) chloride, that changes colors between blue and pink when liquids are detected. Nitrogen drying can return the indicator to its original color. Another example of a reversible detection technique, not independently claimed as such, involves the use of thermo-chromic materials that change color in response to changes in temperature. A detectable temperature change can happen, for example, as a result of solvent evaporation, and the thermo-chromic material can return to its default color after the temperature change. Yet another example of a reversible detection technique involves the use of hydrogel forming materials that swell upon exposure to fluid. The hydrogel material can be returned to a dry state when the leak is stopped.

The color change can be visually detectable, or be detectable by other detection mechanisms. Examples of visually detectable changes include a color change, a change in size or thickness, a change in clarity or opacity, a foaming action, a dissolving or disintegrating reaction, etc. In some arrangements, which are not independently claimed as such, a change in the responsive material can be detected via electromagnetic waves of various wavelengths in the range of <NUM> pm to <NUM>, such as gamma rays, X-rays, ultraviolet (UV), visible light, infrared (IR), microwaves, radiowaves, etc. Other example detection techniques, which are not independently claimed as such, can employ water soluble inks or fluorescent inks that are detectable using a black light. Such techniques allow for detection of even minor leaks, including leaks in vapor form, in the connecting tubes or components of a chromatography system. In some examples, which are not independently claimed as such, detection can be automated using one or more cameras installed in strategic locations. In such examples, the camera or cameras can perform a wide range of detection, including IR and UV detection. A system including a camera or cameras taking images repeatedly and an imaging processor can detect the changes in physical appearance, such as shape, color, volume, area, in a time-dependent manner. The changes over time provides information about the rate of fluid leak. When system components are replaced, new tubing or components can come with fresh responsive coatings applied to them. Other sensors, including sensors capable of measuring the conductivity of a coating, the weight of a coating, the thickness of a coating, etc., could also be used to detect various responses of the coating.

The choice of material, weight percent, thickness, etc. can affect the sensitivity and dynamic range of the coating. The coating can be applied to a component at various thicknesses. The thickness of the coating can be <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>.

In embodiments of the invention, the coating of the present disclosure is used to stop or seal a detected leak. The responsive material becomes more stiff in response to contact by a fluid. An increase in stiffness performs a sealing function to seal a detected leak in the chromatography system.

To seal a leak wherein the fluid contains an aqueous solution, the responsive material can include an absorbent material such as a hydrogel, a water-curable material, or other suitable water-responsive material.

In exemplary embodiments, the responsive material can respond to aqueous and organic solvents, including water, methanol, ethanol, acetonitrile, propanol, tetrahydrofuran, dimethoxyethane, chlorobutane, dichlorobenzene, pentanone, acetone, chloroform, cyclohexane, diethyl ether, ethyl acetate, pentane, hexane, heptane, toluene, and combinations or mixtures thereof. The responsive material can also include acids and bases, including formic acid, acetic acid, trifluoroacetic acid, ammonia, amines, and combinations or mixtures thereof.

In exemplary embodiments, the responsive material in the coating can respond differently based on the solvent or rinse solution used in the chromatography system. For example, the responsive material can be configured to undergo a first change in response to a first solvent and undergo a second change in response to a second solvent. In this way, the leak detection device provides an indication that a leak is present, and also indicates what type of substance is leaking. In other embodiments, the responsive material can be primed to only respond to a particular chemical or type of chemicals.

In exemplary embodiments, the leak detection device can be made of rigid materials, as long as a leaking solvent, either in liquid or vapor form, can be absorbed on a surface of the leak detection device. In some embodiments, a change in the responsive material can be reversed by flushing or otherwise exposing the responsive material to a neutralizing chemical.

In another embodiment of the present disclosure, the leak detection device can be a sleeve or strip made of a flexible material that can be applied to or tightly wrapped around a portion of a component used in a chromatography system. The sleeve can be made of a responsive material or can contain a responsive material that undergoes a detectable change when exposed to a fluid. In another example embodiment, the leak detection device is a coating that can be applied to at least a portion of a component used in a chromatography system. The coating can be made of or include a responsive material that undergoes a detectable change when exposed to a fluid. The sleeve, strip, or coating can be applied to the component in various ways in order to detect a leak in a system including the component. For example, the leak detection device can be applied to the component using an adhesive material, or the leak detection device can be a coating that is applied to the device like paint. For example, the coating and/or responsive material can be applied by spray application.

In some embodiments, the liquids that can be detected can be broken down into two general groups. These groups include aqueous (acids, bases, neutrals) and organic solvents (polar and non-polar). Multiple stripes or coatings containing different indicator materials for detecting leaks of aqueous solutions or organic solvents can be placed on components of a chromatography system. In some examples, different coatings, tapes or strips containing responsive materials configured to detect the presence of polar solvents, non-polar solvents, and/or aqueous solutions can be applied to components or regions within a chromatography system. The responsive material can be located, for example, on the outer diameter of sections of tubing of a chromatography system or on the inner diameter of heat-shrink tubing sleeves. The responsive material can be applied as thin lines, strips, dots, or any other suitable configuration. In some embodiments, the responsive material can be included in a polymer coated tubing which isolates a stainless steel tube, and the responsive material could dissolve or disintegrate, thus effecting tube conductivity.

<FIG> shows an apparatus <NUM> for detecting a leak, according to an arrangement, which is not independently claimed as such. As can be seen in this arrangement, the apparatus <NUM> includes one or more chromatography components <NUM>, which are covered by a coating <NUM> that includes a responsive material. The coating <NUM> can cover the entirety of one or more of the components, or the coating <NUM> can cover strategic portions of one or more of the components, e.g., <NUM> and <NUM>. In this particular example, the responsive material is configured to change in color when exposed to a fluid, and a darkened portion of the coating covering <NUM> indicates that there is a leak in the chromatography system at or near <NUM>. In some examples, the size and/or darkness of the darkened portion <NUM> indicates the severity or size of the leak. Similar to litmus paper, the coating <NUM> can undergo a color or appearance change detectable by a UV light source, for example, when exposed to fluid.

In various arrangements, the apparatus <NUM> can be operated online, offline, or both. For online operation, the responsive coating <NUM> can be responsive to one or more of the solvents that can be used during a regular chromatographic operation. In such an arrangement, any leaking solvent will respond to the responsive coating <NUM> and indicate the presence of a leak. For offline operation, the responsive coating <NUM> can be responsive to a leak detection reagent. In such an arrangement, the system can be flushed with a reagent, such as one with a lower viscosity and/or surface tension that is more prone to leaking from a system, and the responsive coating <NUM> can be scanned for any change that can indicate a leak. As discussed above, the responsive coating <NUM> can change in color in response to being exposed to a fluid.

Alternatively, the responsive coating <NUM> can be made to harden, or otherwise physically change, upon contact with a fluid. According to the present invention, the responsive coating <NUM> hardens to form a sealant layer around a detected leak.

In exemplary embodiments, the responsive coatings of the present disclosure, can be applied using various techniques, including using an adhesive, painting, powder coating, baking, or other deposition methods. Exemplary deposition techniques can be used to apply a responsive coating, on various diameters of tubing or components, including small components where visible detection would no longer be applicable.

<FIG> shows a perspective view of a responsive coating <NUM> applied as a strip on the outside portion of a tube <NUM>, according to an arrangement, which does not fall under the scope of the present invention. As discussed above, the leak detection device can be a responsive coating <NUM> and can be used to coat all or a portion of the connective tubing <NUM> of a chromatography system. In this exemplary arrangement, the connecting tube <NUM> can be produced with a continuous strip of a responsive coating <NUM> along the length of the tube <NUM>. Similar to litmus paper, the coating <NUM> can undergo a color or appearance change when wetted or exposed to a fluid. In exemplary embodiments, the change in the responsive coating can be detected visually or by a UV light source. In one arrangement, the coating applied to the length of the tubing can detect a leak anywhere along the entire length, including where the leak occurs. In some arrangements, all or substantially all of the tubing in a chromatography system uses tubing having leak detection capability, e.g., a strip. If insufficient amounts of the leaked fluid remains present at the point of the leak, the leak can still be identified if the section of tubing at the lowest point (where the leak may travel to and accumulate) is so coated. In some arrangements, the tubing can have multiple strips of different coatings so that different leaked fluids can be independently sensed.

<FIG> shows a cross sectional view of two responsive coatings <NUM> applied to a portion of a tube <NUM>, according to an arrangement, which does not fall under the scope of the present invention. As discussed above, the leak detection device can include more than one responsive coating <NUM> and can be used to coat all or a portion of a connective tube <NUM> of a chromatography system. In this exemplary arrangement, the tube <NUM> can be produced with two responsive coatings <NUM>, or strips, along the length of the tube <NUM> on opposing portions of the tube <NUM>.

<FIG> shows an exemplary perspective view of a responsive coating applied in lines <NUM> to a portion of a tube <NUM>, according to an arrangement, which does not fall under the scope of the present invention. As will be appreciated, the responsive coating can be applied to the tube <NUM> as lines, dots, or other geometric shapes, to all of or a portion of a connective tube <NUM>. In some embodiments, lines <NUM> of the responsive coating may be short in length or be applied for the entire length of the tube. The various lines <NUM> can be configured for one type of detection (solvent, water, etc.) or may vary line to line, to detect leaks of acids, bases, water, etc. For example, four of the lines <NUM> could be configured to detect leaks of water, four of the lines <NUM> could be configured to detect leaks of a solvent, and four lines could be configured to detect leaks of an acid.

<FIG> shows an exemplary perspective view of the tube <NUM> of <FIG>. The responsive coating is applied to the tube <NUM> in the form of a number of lines <NUM>, as discussed above, and a smear <NUM> in the lines <NUM> shows the detection of a leak on a portion of the tube <NUM>. In this particular arrangement, a leak in the tube <NUM> can smear the lines <NUM> at or near the location of the leak, thus facilitating identification of a leak.

Claim 1:
A chromatography system comprising an apparatus (<NUM>) for stopping or reducing a fluid leak in the chromatography system, the apparatus comprising:
a coating (<NUM>) conforming to a component of the chromatography system; and
a responsive material disposed within the coating (<NUM>), wherein the responsive material is configured to increase stiffness in response to being contacted by the leaking fluid, wherein the component comprises tubing, a fitting, a connector, a pump, a column, a column case, a column heater, or a detector.