Patent Description:
There is a large range of fluid handling systems e.g. in laboratories. Such systems comprise a number of fluid handling units, e.g. one or more pumps, valves, mixers, sensor units etc of different types. Said fluid handling units are interconnected by fluid conduits in the form of rigid or flexible tubes or the like. Even though some systems may be designed for a specific type of application with a specific flow path, there often exists a need for flexibility and ability to alter or optimize the fluid flow path of the system. Moreover, upgrading is often restricted to specific kits provided by the manufacturer, and upgrade kits often is supplied as external add-on equipment to be arranged besides the original system, thus enlarging the foot print of the system and that need to be connected to the system both fluidically and electrically (i.e. to a system control bus or the like). Moreover, replacement of defect fluid handling units is a time consuming and delicate task.

One type of liquid handling system is liquid chromatography systems which is a standard method in laboratories, and there are a broad range of liquid chromatography systems available on the market. Common to most of the present systems is the lack of flexibility in adapting the instrument to a variety of different applications. <CIT>, <CIT>, <CIT>, <CIT> and <CIT> show prior art. <CIT> discloses a chromatographic apparatus with a mounting panel on which pumps, valve, a branch block, a damper, and a mixer can be provided.

The object of the invention is to provide a new automated liquid chromatography system, which system overcomes one or more drawbacks of the prior art. This is achieved by the automated liquid chromatography system as defined in the independent claim.

One advantage with such an automated liquid chromatography system is that the system may easily be upgraded without need for add-on equipment, and that the flow path may be easily optimized for new experimental setups.

The invention will be described in detail below with reference to the drawings, in which:.

The invention is directed to the automated liquid chromatography system of claim <NUM>. The dependent claims refer to preferred embodiments. According to one embodiment, there is provided an automated fluid handling system comprising a housing and two or more fluid handling units arranged as interchangeable modular components with an external fluidics section and an internal non fluidics section, and wherein the housing comprises a liquid handling panel with two or more of component positions for receiving said interchangeable modular components such that the external fluidics section is separated from the non fluidics section by the liquid handling panel.

According to another embodiment, there is provided a fluid handling system in the form of a liquid chromatography system comprising a housing, two or more high pressure pumps, at least one sensor unit and a plurality of fluid control valves of at least two different configurations, wherein at least the fluid control valves are arranged as interchangeable modular components and the housing comprises a liquid handling panel with a plurality of component positions for receiving said modular components.

<FIG> shows one embodiment of an automated fluid handling system modular in the form of a liquid chromatography system, with a plurality of interchangeable modular components arranged in a liquid handling panel wherein the reference numbers denotes:.

The disclosed embodiment is supplied with three high precision pumps <NUM>, <NUM>, <NUM>. There are two System pumps <NUM>, <NUM>, System pump A <NUM> and System pump B <NUM>, and one Sample pump <NUM>. The System pumps <NUM>, <NUM> may be used individually, or in combination to generate isocratic or gradient elution in purification methods. The Sample pump <NUM> is dedicated for direct loading of sample onto a column, or for filling of sample loops.

Function of the pumps:
Each pump module consists of two pump heads (not shown). The individual heads are identical but actuated in opposite phase to each other by individual stepper motors, controlled by a microprocessor. The two pistons and pump heads work alternately to give a continuous, low pulsation, liquid delivery. The flow rate of the two System pumps may be varied between about <NUM>/min and <NUM>/min and the maximum operating pressure is about <NUM> MPa. The flow rate of the Sample pump may e.g. be varied between <NUM> and <NUM>/min and according to one embodiment the maximum operating pressure is <NUM> MPa.

According to one embodiment, the plurality of fluid control valves of at least two different configurations are valves of rotary type. Such a motorized rotary valve may consist of a Valve head with a number of defined bores with channels to the inlet and outlet ports of the valve. The Rotary disc, mounted on the motor, has a number of defined channels. The pattern of channels of the Rotary disc together with the pattern and location of the ports of the Valve head, define the flow path and function of each type of valve. When the Rotary disc turns, the flow path in the valve changes.

One embodiment of fluid control valves are Inlet valves A and B (<NUM>, <NUM> respectively) that are used to select which buffers or samples to use in a run, and Sample inlet valve <NUM> that is located before Sample pump <NUM>. Inlet valve A <NUM><NUM> is located before System pump A <NUM>, Inlet valve B <NUM> is located before System pump B <NUM>, and Sample inlet valve <NUM> is located before Sample pump <NUM>. Inlet valve A and Inlet valve B are connected to another embodiment of a fluid control valve in the form of a Quaternary valve <NUM>. The Quaternary valve is used for automatic buffer preparation, and for formation of quartenary gradients. The number of inlets can be increased by installing component modules with extra inlet valves. Inlet valve A and Inlet valve B enable automatic changing between different buffers and wash solutions, and can be used to generate gradients by mixing buffer A and buffer B. The air sensors integrated in Inlet valve A and Inlet valve B can be used to prevent introduction of air into the pumps and columns.

The Quarternary valve is used for automatic mixing of four different solutions. The Quaternary valve opens one inlet port at a time, and the diffent solutions are mixed in a Mixer <NUM> to form the desired buffer. The opening time in the switching valve is controlled by the system. The volume for each inlet port opening increases stepwise when the flow increases. To obtain a homogeneous buffer composition, one has to make sure to use a mixer chamber volume suitable for the flow rate of the method.

The Quaternary valve can be used to create a gradient using four different solutions simultaneously in any combination. The percentage of each solution is controlled by instructions in the method. It is possible to form gradients that changes the percentage of two, three or four solutions linearly over time. This is useful when advanced methods are developed.

The Sample inlet valve <NUM> enables automatic loading of different samples when using the Sample pump <NUM> to inject sample directly onto the column or to fill a sample loop. The Sample inlet valve has an inlet dedicated for buffer. This Buffer inlet is used in methods to fill the Sample pump with solution before sample is introduced. The Buffer inlet is also used to wash the Sample pump with buffer between runs. The air sensor integrated in the Sample inlet valve is e.g. used when sample is applied from a vessel onto a column by selecting Inject all sample using air sensor in the Sample application phase of a method. This function uses the Buffer inlet is used to finalize sample injection and to remove air from the Sample pump.

Still another embodiment of fluid control valve may be an Injection valve <NUM>, which is used to direct sample onto the column. The valve enables usage of a number of different sample application techniques. A sample loop can be connected to the Injection valve and filled either automatically using the Sample pump or manually using a syringe. The sample can also be injected directly onto the column using the Sample pump.

Still another embodiment of fluid control valve may be a Column valve <NUM> that is used for connection of columns to the system, and to direct the flow onto the column. Up to five columns can be connected to the disclosed embodiment of said valve simultaneously. The valve also has a built-in bypass capillary that enables bypassing of connected columns.

The number of column positions can be increased by installing an extra Column valve. Both top and bottom of each column shall be connected to the Column valve. The top of the column shall be connected to one of the A ports (e.g., 1A), and the bottom of the column shall be connected to the corresponding B port (e.g., 1B). The flow direction can be set either from the top of the column to the bottom of the column, Down flow, or from the bottom of the column to the top of the column, Up flow. In the default flow path of the Column valve the columns are bypassed. Pressure monitors that measures the actual pressure over the column are integrated into the inlet and outlet ports of the Column valve.

Still another embodiment of fluid control valve may be a pH valve <NUM> that has an integrated flow cell where a pH electrode can be installed. This enables in-line monitoring of pH during the run. A flow restrictor is connected to the pH valve and can be included in the flow path to generate a backpressure high enough to prevent formation of air bubbles in the UV flow cell. The pH valve is used to direct the flow to the pH electrode and to the flow restrictor, or to bypass one or both.

Still another embodiment of fluid control valve may be an Outlet valve <NUM> that is used to direct the flow to a Fraction collector (not shown), to any of e.g. <NUM> outlet ports, or to waste. The number of outlets can be increased by installing an extra Outlet valve.

A Mixer <NUM> may e.g. be located after System pump A and System pump B and before the Injection valve. The purpose of the Mixer is to make sure that the buffers from the System pumps are mixed to give a homogenous buffer composition. The Mixer has a built-in filter that prevents impurities from entering the flow path.

To fulfill a desired purpose, with the disclosed liquid chromatography system it is possible to adapt and extend the flow path in a simple and a flexible way. Up to three extra fluid control valves or the like can be installed using the free valve positions. Dummy modules are installed in these positions at delivery. To obtain an optional flow path, it is also possible to move the standard fluid control valves to other positions. There are also two types of extra air sensors available which can be installed before Sample inlet valve or after Injection valve.

In the configuration disclosed in <FIG>, <FIG> inlets are available for each inlet valve. To increase the number of inlets, an extra inlet valve can be installed which increases the number of inlets to <NUM> for one of the valves. This optional configuration can be convenient for example when a larger number of samples will be used. There is also a general type of inlet valve, Valve X, which can be used to increase the number of inlets to for example the Quaternary valve.

In the configuration disclosed in <FIG> with one column valve, <NUM> column positions are available. To increase the number of column positions to <NUM>, an additional column valve can be installed in the instrument. An application can be to evaluate a number of different columns in method optimization.

In the configuration disclosed in <FIG> with one outlet valve, <NUM> outlet positions are available. To increase the number of outlets, one or two extra outlet valves can be connected, adding up to a total of <NUM> or <NUM> outlet positions. This optional configuration is convenient when collecting a number of large fractions outside the fraction collector.

Optional modules are easy to install in the disclosed modular liquid chromatography system. The dummy module is removed with a hexagon wrench and a bus cable is disconnected. The bus cable is connected to the optional fluid control valve or the like which is assembled in the instrument. The module is then added to the System properties in the control software. The available optional modules may e.g. be preconfigured to give the desired function. However, the function of a valve may e.g. be changed by changing the Node ID.

<FIG> is a schematic illustration of a housing <NUM> with a liquid handling panel <NUM> of the fluid handling system in the form of a modular liquid chromatography system <NUM> of <FIG>. In <FIG> some components have been removed for clarity reasons. In the disclosed configuration, as disclosed in detail above, the modular liquid chromatography system <NUM> comprises a plurality of fluid control valves in the form of: Injection valve <NUM>, Column valve <NUM>, Quaternary valve <NUM>, Inlet valve B <NUM>, Inlet valve A <NUM>, Sample inlet valve <NUM>, pH valve <NUM>, and Outlet valve <NUM>. The chromatography system <NUM> further comprises UV monitor <NUM>, System pump B <NUM>, System pump A <NUM>, Sample pump <NUM>, Mixer <NUM>, and three Dummy modules <NUM>. According to one embodiment, all liquid handling components and sensors arranged at the liquid handling panel <NUM> are designed to be readily interchangeable. The interchangeability provides improved service and upgrade possibilities and also a possibility to customize the positions of the respective liquid handling components, such as the fluid control valves, e.g. in order to optimize the fluid path for a specific experimental setup. As is illustrated in <FIG>, there are three large component positions e.g. for pump modules, one UV-sensor position and <NUM> standard component positions, e.g. for fluid control valves or the like. The component positions are given a standardized size and shape to provide simple interchangeability. According to one embodiment, each modular component is retained in a mating component position by a single screw, and it is connected to the master control unit by a single bus cable providing both communication and system power to each component. <FIG> is a schematic illustration of the housing with the liquid handling panel of <FIG> with the modular components of the liquid chromatography system removed.

<FIG> are schematic illustrations of examples of fluid handling units in the form of modular component of the fluid handling system removed. <FIG> shows a standard interchangeable modular component <NUM>, e.g. a fluid control valve or the like. The standard component module <NUM> comprises a panel member <NUM>, an external fluidics section <NUM> and an internal non-fluidics section <NUM>. According to one embodiment, the panel member <NUM> essentially separates the fluidics in the external fluidics section <NUM> from electronics and control means in the internal non-fluidics section <NUM>.

<FIG> shows a Dummy module <NUM>, which is intended to be placed in non used standard component positions. In the disclosed embodiment, the Dummy modules are provided with mounting grooves for attachment of accessories to the system. In the disclosed embodiment the dummy module is shown as a panel member <NUM> without any internal section. <FIG> shows a pump module and an UV-module, respectively, each having an external fluidics section <NUM> and an internal non-fluidics section <NUM>.

As is disclosed in <FIG>, the interchangeable modular component <NUM> comprises a panel member arranged to separate the fluidics section from the non fluidics section and for attachment to a component position in the liquid handling panel. Said panel attachment member may be arranged so that all fluid connections of said modular component are arranged on a wet side of the panel attachment member separating them from electrical components that are arranged on a dry side thereof, hence providing a high degree of liquid resistance at the external part of the fluid handling panel, and so that the liquid resistance requirements for the internal sections may be somewhat lightened. According to one embodiment, the interchangeable modular components are sealed against the liquid handling panel by a sealing member. According to another embodiment, not shown, the modular component does not comprise any panel member, but there is provided a suitable sealing arrangement between the component position openings of the liquid handling panel and the external surface of the interchangeable modular components <NUM>. In the disclosed embodiments, the component position openings of the liquid handling panel and the interchangeable modular components <NUM> are shown to have an essentially rectangular crossectional shape, but other shapes may be equally applicable.

According to one embodiment, there is provided a general fluid handling system comprising a housing and two or more fluid handling units arranged as interchangeable modular components as is schematically disclosed in <FIG>. As discussed above such a system may be configured for essentially any type of automated liquid handling operations provided that suitable fluid handling units are provided as interchangeable modular components for the system. According to one embodiment there is provided an automated fluid handling system comprising at least one fluid pump, at least one sensor unit and two or more fluid control valves of at least two different configurations, wherein at least the fluid control valves are arranged as interchangeable modular components.

The liquid handling panel <NUM> of the fluid handling system may e.g. be designed in any suitable manner to allow the modular components to be arranged in an efficient manner.

<FIG> shows a schematic embodiment of an automated fluid handling system wherein the housing <NUM> comprises an internal climate panel <NUM> arranged at a distance behind the liquid handling panel <NUM> defining an air inlet compartment <NUM> and air outlet compartment <NUM> in the housing <NUM>, the climate panel <NUM> being provided with complementary component positions <NUM> for receiving the internal non fluidics section <NUM> of the interchangeable modular components <NUM>, and wherein the non-fluidics section <NUM> of at least one interchangeable modular component is provided with one or more air inlet openings <NUM> located in the air inlet compartment <NUM> and one or more air outlet openings <NUM> located in the air outlet compartment <NUM> when the interchangeable modular component arranged in position in the component position. <FIG> shows the fluid handling system of <FIG> in a schematic cross sectional view. As is indicated by inlet vent <NUM> and outlet vent <NUM>, air for cooling interchangeable modular components <NUM> provided with air inlet and outlet openings <NUM>, <NUM> is preferably arranged to enter the air inlet compartment <NUM> at a distance from the outlet vent <NUM> in order to avoid recirculation of air. The air circulation in the system may be achieved by a system cooling unit (not shown) providing a flow of air from the air inlet compartment <NUM> to the air outlet compartment <NUM>, through the at least one interchangeable modular component <NUM>. Alternatively, the at least one interchangeable modular component <NUM> is provided with a local cooling unit (not shown) providing a flow of air from the air inlet compartment <NUM> to the air outlet compartment <NUM>. As is indicated, the complementary component positions <NUM> are arranged to provide a relatively air flow tight fit with respect to the internal non fluidics section <NUM> of the interchangeable modular components <NUM>, and according to one embodiment, this may be achieved by a sealing arrangement. In <FIG>, there is shown a sealing member <NUM> for sealing the interchangeable modular components <NUM> with respect to the liquid handling panel <NUM>, as discussed above. Other sealing member arrangements may be envisaged by a person skilled in the art. According to one embodiment, fluids are strictly restricted to the fluidics section <NUM> of the interchangeable modular component <NUM>, but in alternative embodiments, only fluid connections are restricted to the fluidics section <NUM> allowing fluid to "cross" the fluid handling panel inside the non-fluidics section <NUM> of the interchangeable modular component <NUM>.

In <FIG> there is further shown a master control unit <NUM> and bus connectors <NUM> for connecting the interchangeable modular components <NUM> to the master control unit <NUM>. According to one embodiment, the component positions including the bus connectors <NUM> and the interchangeable modular components <NUM> are of plug and play configuration with respect to each other.

<FIG> is a schematic illustration of an embodiment of a housing <NUM> with a modular liquid handling panel <NUM> with the modular components of the liquid chromatography system removed. In the disclosed embodiment, also the layout of the liquid handling panel <NUM> is configurable by means of two interchangeable panel sections <NUM> which may be selected in accordance with the desired layout of the system. In <FIG> two different layouts of the interchangeable panel sections are disclosed, but the layout may include any suitable configuration.

<FIG> are schematic illustrations of an embodiment of a modular housing with a liquid handling panel with the modular components of the liquid chromatography system removed. In the disclosed embodiment, the modular housing is comprised of a main housing <NUM> that comprises the master control unit including power supply and climate control for the whole housing, two expansion housing modules <NUM> and a side member <NUM>. This approach provides very flexible expansion possibilities for the chromatography system, while preserving the benefits of a single master control unit including power supply and climate control.

<FIG> is a schematic illustration of an embodiment of the system architecture of one embodiment of a modular liquid chromatography system according to the present invention. As mentioned above, the chromatography system comprises a master control unit <NUM> arranged to communicate with all modular components e.g. <NUM>-<NUM>, over a system bus <NUM> such as a CAN-bus or the like. According to the invention, each modular component is provided with a dedicated CPU unit allowing the component to independently perform operations in response to instructions over the BUS <NUM>. In order to minimize the number of connectors to be attached to each modular component, the bus <NUM> further comprises power feed for the modular components. The Bus <NUM> may be connected to any suitable number of modular components arranged in the housing <NUM>, but also to one or more modular components <NUM> outside of the housing <NUM> or the like. As is mentioned briefly above, the master control unit may further be arranged to control the climate in the housing. In addition to the disclosed modular components, other components of the chromatography system, e.g. a fraction collector or the like, may be arranged in the housing and the controlled climate therein.

According to one embodiment, different component modules are automatically identified by the master control unit, whereby they may be moved essentially freely between different positions. Moreover, the master control unit may be arranged to provide said information to Chromatography control software whereby experimental setup and planning may be performed. The control system may be arranged to provide an optimized layout of the component modules with respect to the present layout of the liquid handling panel and available component modules for a specific experimental setup.

According to one embodiment, the interchangeable panel sections <NUM> of <FIG> and the expansion housing modules <NUM> of figs. 6a and 6b may be provided with means for automatic detection of the same to allow automatic configuration of the system by the master control unit <NUM>. In one embodiment, each interchangeable panel section <NUM> and expansion housing module <NUM> comprises a hub (not shown) for connection to the system bus <NUM> in order to expand the system bus <NUM> network to the number of component modules in each interchangeable panel section <NUM> or expansion housing module <NUM>.

<FIG> is a schematic illustration of an embodiment of a master control unit of one embodiment of a modular liquid chromatography system according to the present invention. The master control unit <NUM> comprises a system controller <NUM> for communicating with internal and external components and control computers (not shown) etc. According to one embodiment, the system controller comprises a suitable CPU <NUM>, a bus controller <NUM>, an external communications controller <NUM>, such as a LAN unit, and a storage device <NUM>. The bus controller <NUM> is providing communication with the component modules. The master control unit may further comprise a Power supply <NUM> and a climate controller <NUM> arranged to keep the internal climate in the housing <NUM> at a predetermined level as discussed above.

Claim 1:
An automated liquid chromatography system (<NUM>) comprising:
a housing (<NUM>); and
two or more fluid handling units (<NUM>-<NUM>), each having a fluidics section (<NUM>),
at least two of the fluid handling units being arranged as interchangeable modular components, the interchangeable modular components comprising fluid control valves (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) of at least two different configurations,
wherein the housing (<NUM>) comprises a liquid handling panel (<NUM>) with two or more component positions to receive the interchangeable modular components so as to allow for customization of the position of the respective interchangeable modular component, such that the respective fluidics section (<NUM>) is external to the housing (<NUM>),
wherein a fluid flow path is formed by a fluidic interconnection arrangement between the interchangeable modular components and configured to be adapted,
wherein the system further comprises a system bus (<NUM>) and a master control unit (<NUM>) for communication with the interchangeable modular components over the system bus (<NUM>), and
each interchangeable modular component includes a CPU (<NUM>) for the interchangeable modular components to independently perform operations in response to instructions over the system bus (<NUM>).