System for mixing container contents and related methods of use

Abstract

To provide a system suitable to mix contents of containers and a related use method.SOLUTION: A method for mixing fluids in containers may include performing a mixing procedure on a plurality of containers (128, 130) on a container support (110), at least a portion of the plurality of containers being differently sized. The mixing procedure may include a plurality of mixing phases, wherein in each mixing phase, the container support may be subjected to a mixing motion at a single rate for a period of time of about 5 seconds or longer, and wherein a single rate for at least one mixing phase of the plurality of mixing phases may differ from the single rate for at least another mixing phase of the plurality of mixing phases. The mixing procedure also may include at least one non-mixing phase, wherein the container support may not be subjected to the mixing motion.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Patent Application No. 62 / 476,364, filed March 24, 2017, which is incorporated herein by reference in its entirety.

[0002] SUMMARY The present disclosure is directed to a system for mixing the contents of a container and related methods of use. [Background technology]

[0003] Automated analytical procedures for determining the presence of an analyte in a sample typically require the use, processing, and / or manipulation of fluid solutions and / or fluid suspensions. Such fluid solutions and suspensions are often stored in containers that can be accessed by a fluid extraction device (e.g., a robotic pipettor) with a probe tip. The fluid extraction device with a probe tip can remove a precise amount of the fluid contents of the container. While the fluid contents of the container may be accessed through an open end (e.g., uncapped and exposed to the atmosphere) of the container during operation of the fluid extraction device with a probe tip, it may be necessary to access the contents of the container through a pierceable seal, filter, and / or septum. Summary of the Invention [Problem to be solved by the invention]

[0004] Fluid solutions in containers may require mixing to maintain solutes in solution. Fluid suspensions in containers may require mixing to maintain substances, such as solid or semi-solid particles, in suspension. If the process for mixing the fluid solution and / or fluid suspension in a container is improper, the fluid extraction device with a probe tip may extract a volume of the fluid solution and / or fluid suspension that does not have the desired amount of solutes and / or suspended substances. On the other hand, the mixing process may result in the formation of bubbles on the surface of the fluid contents. Detergent-based fluid contents are particularly prone to forming bubbles when agitated. Bubbles may make it difficult for the fluid extraction device with a probe tip to extract an accurate amount of the fluid contents. For example, the presence of bubbles may cause the device to sense more fluid contents than are actually present in the container, resulting in inaccurate level sensing by the fluid extraction device with a probe tip. Bubbles may also enter the fluid extraction device with a probe tip, resulting in the fluid extraction device aspirating less of the fluid contents of the container and not obtaining the desired amount. All of these factors may affect the results obtained from performing an analytical procedure using the fluid contents. [Means for solving the problem]

[0005] In one aspect, the present disclosure is directed to a method for mixing fluids in containers. The method may include performing a mixing procedure on a plurality of containers on a container support, at least some of the plurality of containers being differently sized. The mixing procedure may include a plurality of mixing stages, in each mixing stage, the container support may be subjected to a mixing motion at a single rate for a duration of about 5 seconds or more, and the single rate for at least one mixing stage of the plurality of mixing stages may be different from the single rate for at least one other mixing stage of the plurality of mixing stages. The mixing procedure may also include at least one non-mixing stage, in which the container support is not subjected to a mixing motion.

[0006] Subjecting the vessel support to a mixing motion may include rotating the vessel support about an axis offset from a center of the vessel support. Subjecting the vessel support to a mixing motion may include rotating the vessel support about an axis extending through a center of the vessel support. Each of the single rates may be a velocity of the vessel support, and the velocity of the vessel support may vary from one mixing stage to an adjacent mixing stage of the plurality of mixing stages. Each of the single rates may be a frequency of rotation of the vessel support about the axis of rotation, and the frequency of rotation may vary from one mixing stage to an adjacent mixing stage of the plurality of mixing stages. Subjecting the vessel support to a mixing motion may result in vortices of the fluid within the vessel. The vortices of the fluid may result in the formation of waves within the fluid, and the amplitude of the waves may reach one or more predetermined thresholds. Feedback may be obtained after performance of the mixing procedure, and the mixing procedure may be modified based on the feedback. The feedback may be indicative of the effectiveness of the plurality of mixing stages in mixing one or more fluids within one or more of the plurality of vessels. The feedback may be indicative of an amount of foam formed in one or more fluids in one or more of the plurality of containers. The mixing procedure may include a first cycle of a mixing stage and a second cycle of a mixing stage, wherein the single rate of the mixing stage of the first cycle is the same as the single rate of the mixing stage of the second cycle and the duration of the mixing stage of the first cycle is longer than the duration of the mixing stage of the second cycle. During at least one non-mixing stage, the container support may be stationary. During at least one non-mixing stage, the container may be moved. The mixing procedure may be repeated at least once.

[0007] In another aspect, the present disclosure is directed to a method for mixing fluids in containers. The method may include performing a mixing procedure on a plurality of containers on a container support, at least some of the plurality of containers being differently sized. The mixing procedure may include a first mixing stage including a mixing motion of the container support at a first rate for a first duration of about 5 seconds or more. The mixing procedure may include a second mixing stage performed after the first mixing stage, including a mixing motion of the container support at a second rate for a second duration of about 5 seconds or more, the first rate being different from the second rate and the first duration being different from the second duration. After the second mixing stage, any of the mixing motions may not be performed for a third duration.

[0008] The mixing motion may include rotation of the container support. The rotation of the container support may include rotation of the container support about an axis of rotation offset from the center of the container support. The rotation of the container support may include rotation of the container support about an axis of rotation extending through the center of the container support. At least one of the first rate and the second rate may include a speed of the container support. At least one of the first rate and the second rate may include a frequency of rotation of the container support. The first rate may be greater than the second rate. The first duration may be shorter than the second duration. The mixing procedure may be repeated at least once.

[0009] In yet another aspect, the present disclosure is directed to a method for mixing fluids in containers. The method may include performing a mixing procedure on a plurality of containers on a container support. The mixing procedure may include a first stage including moving the container support at a first rate for a first duration greater than about 5 seconds, where the first rate and first duration may be selected to substantially uniformly mix the fluids in a first container of the plurality of containers, and the first container may have a first size. The mixing procedure may also include a second stage performed after the first stage, where the second stage may include moving the container support at a second rate for a second duration greater than about 5 seconds, where the first rate is different from the second rate. The second rate and second duration may be selected to substantially uniformly mix the fluids in a second container of the plurality of containers. The second container may have a second size different from the first size. The mixing procedure may also include a third step performed after the second step, which may include not moving the container support for a third duration, which may be selected to allow bubbles formed in the fluid in at least one of the first container and the second container to dissipate.

[0010] Moving the container support may include rotating the container support. Rotating the container support may include rotating the container support about an axis of rotation offset from the center of the container support. Rotating the container support may include rotating the container support about an axis of rotation extending through the center of the container support. At least one of the first rate and the second rate may include a speed of the container support. At least one of the first rate and the second rate may include a frequency of rotation of the container support. The first rate may be greater than the second rate. The first duration may be different from the second duration. The first duration may be shorter than the second duration. The mixing procedure may be repeated at least once. The mixing procedure may further include a fourth stage performed after the third stage, the fourth stage including moving the container support at the first rate for a fourth duration shorter than the first duration. The fourth duration may be half the duration of the first duration. The mixing procedure may further include a fifth step performed after the fourth step, the fifth step including moving the container support at the second rate for a fifth duration that is shorter than the second duration.

[0011] In yet another aspect, the present disclosure is directed to a method for mixing fluids in containers. The method may include identifying a first set of rates at which a first container can move to produce a first set of values indicative of the degree of mixing of the fluids in the first container and identifying a second set of rates at which a second container can move to produce a second set of values indicative of the degree of mixing of the fluids in the second container. The method may also include selecting a first rate from the first set of rates based at least in part on the first set of values and selecting a second rate from the second set of rates based at least in part on the second set of values. The method may also include subjecting a container support to a mixing motion, the mixing motion being performed at the first rate for a first duration greater than about 5 seconds and at the second rate for a second duration greater than about 5 seconds, and the first container and the second container may be disposed on the container support during the mixing motion. The method may also include subjecting the container support to a state without mixing motion for a third duration, during which the first container and the second container may be disposed on the container support.

[0012] The first set of rates and the second set of rates may include a speed of the vessel support. The first set of rates and the second set of rates may include a frequency of rotation of the vessel support. The first set of values and the second set of values may correspond to the movement of fluids in the first vessel and the second vessel. The first rate may be different from the second rate. The first rate may be a minimum rate corresponding to a value of the first set of values that reaches at least a predetermined value threshold for mixing of the fluids in the first vessel. The first rate may result in a maximum value of the first set of values. The second rate may be a minimum rate corresponding to a value of the second set of values that reaches at least a predetermined value threshold for mixing of the fluids in the second vessel. The second rate may result in a maximum value of the second set of values. Selecting the first rate from the first set of rates may be based at least in part on the second set of values.

[0013] In yet another aspect, the present disclosure is directed to a method for mixing fluids in containers. The method may include performing a mixing procedure on a plurality of containers on a container support. The mixing procedure may include ordered steps. The ordered steps may include moving the container support at a first rate for a first duration greater than about 5 seconds, moving the container support at a second rate for a second duration greater than about 5 seconds, the first rate being different from the second rate, stopping the container support, and not moving the container support for a third duration. The method may also include determining the extent to which bubbles appear in fluid contained in at least one of the plurality of containers as a result of moving the container support. The method may also include modifying one or more aspects of the mixing procedure based on the determined extent.

[0014] Determining the extent to which bubbles appear in the fluid may include inserting a sensing device into the fluid, the sensing device configured to detect bubbles in the fluid. Modifying one or more aspects of the mixing procedure may include reducing the first rate. Modifying one or more aspects of the mixing procedure may include reducing the first duration. Modifying one or more aspects of the mixing procedure may include reducing the second rate. Modifying one or more aspects of the mixing procedure may include reducing the second duration. Modifying one or more aspects of the mixing procedure may include increasing the third duration.

[0015] In yet another aspect, the present disclosure is directed to a method for mixing fluids in containers. The method may include performing a mixing procedure on a plurality of containers on a container support. The mixing procedure may include ordered steps. The ordered steps may include moving the container support at a first rate for a first duration greater than about 5 seconds, moving the container support at a second rate for a second duration greater than about 5 seconds, the first rate being different from the second rate, stopping the container support, and not moving the container support for a third duration. The method may also include determining the effectiveness of mixing the fluids contained in at least one of the plurality of containers as a result of moving the container support. The method may also include modifying one or more aspects of the mixing procedure based on the determined effectiveness.

[0016] Determining the effectiveness of mixing the fluids may include taking optical density measurements of different portions of the fluids and comparing the optical density measurements to determine whether a difference between the optical density measurements meets a predetermined threshold. Modifying one or more aspects of the mixing procedure may include increasing a first rate. Modifying one or more aspects of the mixing procedure may include increasing a first duration. Modifying one or more aspects of the mixing procedure may include increasing a second rate. Modifying one or more aspects of the mixing procedure may include increasing a second duration. Modifying one or more aspects of the mixing procedure may include decreasing a third duration.

[0017] In yet another aspect, the present disclosure is directed to a method for mixing fluids in containers. The method may include performing a mixing procedure on a plurality of containers on a container support, the mixing procedure including ordered steps. The ordered steps may include subjecting the container support to a mixing motion at a first rate for a first duration greater than about 5 seconds, the first rate and first duration selected to substantially uniformly mix fluids in a first container of the plurality of containers, and the first container may have a first size. The ordered steps may also include subjecting the container support to a mixing motion at a second rate for a second duration greater than about 5 seconds, the first rate may be different from the second rate, the second rate and second duration selected to substantially uniformly mix fluids in a second container of the plurality of containers, and the second container may have a second size different from the first size. The ordered steps may also include not performing a mixing motion on the container support for a third duration. The method may also include determining a value indicative of the extent to which bubbles appear in at least one of the fluid in the first container and the fluid in the second container. The method may also include modifying one or more aspects of the mixing procedure if the value differs from a threshold value, where modifying the one or more aspects of the mixing procedure may include modifying one or more of the first rate, the first duration, the second rate, the second duration, and the third duration, where the modifications may be selected to move the value toward the threshold value.

[0018] Determining a value indicative of the extent to which bubbles appear in at least one of the fluids in the first container and the second container may include inserting a sensing device into at least one of the fluids, the sensing device configured to detect bubbles in at least one of the fluids. Modifying one or more aspects of the mixing procedure may include reducing the first rate. Modifying one or more aspects of the mixing procedure may include reducing the first duration. Modifying one or more aspects of the mixing procedure may include reducing the second rate. Modifying one or more aspects of the mixing procedure may include reducing the second duration. Modifying one or more aspects of the mixing procedure may include increasing the third duration.

[0019] In yet another aspect, the present disclosure is directed to a system for mixing fluids in a plurality of differently sized containers. The system may include a container support for receiving the plurality of differently sized containers thereon. The system may also include a drive system operably coupled to the container support, the drive system may be configured to move the container support in a mixing motion. The system may also include a controller operably coupled to the drive system, the controller may be configured to control operation of the drive system to perform a mixing procedure using the container support. In the mixing procedure, the container support may be moved in a mixing motion at a first rate for a first duration greater than about 5 seconds, the container support may be moved in a mixing motion at a second rate for a second duration greater than about 5 seconds, the first rate being different from the second rate, and the container support may not be moved in any mixing motion for a third duration.

[0020] The drive system may be configured to rotate the container support about an axis offset from the center of the container support. The drive system may be configured to rotate the container support about an axis extending through the center of the container support. At least one of the first rate and the second rate may include a speed of the container support. At least one of the first rate and the second rate may include a frequency of rotation of the container support. The first rate may be greater than the second rate. The first duration may be different from the second duration. The first duration may be shorter than the second duration. In the mixing procedure, the container support may be moved in a mixing motion at one or more rates other than the first rate and the second rate for other durations. The controller may further be configured to repeat the mixing procedure at least once. For example, the present invention provides the following items: (Item 1) 1. A method for mixing fluids in a container, comprising: performing a mixing procedure on a plurality of containers on a container support, wherein at least a portion of the plurality of containers are differently sized; and the mixing procedure comprises: a plurality of mixing stages, wherein in each mixing stage, the container support is subjected to a mixing motion at a single rate for a duration of about 5 seconds or more, and wherein the single rate for at least one mixing stage of the plurality of mixing stages is different from the single rate for at least one other mixing stage of the plurality of mixing stages; at least one non-mixing stage, wherein said container support is not subjected to said mixing motion. (Item 2) 2. The method of claim 1, wherein subjecting the container support to the mixing motion comprises rotating the container support about an axis offset from the center of the container support. (Item 3) 3. The method of any one of items 1 and 2, wherein subjecting the vessel support to the mixing motion comprises rotating the vessel support about an axis extending through a center of the vessel support. (Item 4) 4. The method of any one of items 1 to 3, wherein each of the single rates is a velocity of the container support, and the velocity of the container support varies proceeding from one mixing stage to an adjacent mixing stage of the plurality of mixing stages. (Item 5) 4. The method of any one of items 1 to 3, wherein each of the single rates is a frequency of rotation of the container support about an axis of rotation, and the frequency of rotation varies from one mixing stage to an adjacent mixing stage of the plurality of mixing stages. (Item 6) 6. The method of any one of items 1 to 5, wherein subjecting the vessel support to the mixing motion results in a vortex of fluid within the vessel. (Item 7) 7. The method of claim 6, wherein the vortex in the fluid leads to the formation of waves within the fluid, and the amplitude of the waves reaches one or more predetermined thresholds. (Item 8) 8. The method of any one of items 1 to 7, further comprising obtaining feedback after performing the mixing procedure, and modifying the mixing procedure based on the feedback. (Item 9) 9. The method of claim 8, wherein the feedback indicates the effectiveness of multiple mixing stages in mixing one or more fluids in one or more of the multiple vessels. (Item 10) 10. The method of any one of items 8 and 9, wherein the feedback is indicative of an amount of foam formed in one or more fluids in one or more of the plurality of containers. (Item 11) 11. The method of any one of items 1 to 10, wherein the mixing procedure comprises a first cycle of a mixing stage and a second cycle of a mixing stage, the single rate of the mixing stage of the first cycle is the same as the single rate of the mixing stage of the second cycle, and the duration of the mixing stage of the first cycle is longer than the duration of the mixing stage of the second cycle. (Item 12) 12. The method according to any one of items 1 to 11, wherein in the at least one non-mixing step, the container support is stationary. (Item 13) 12. The method according to any one of items 1 to 11, wherein the container moves during the at least one non-mixing step. (Item 14) 14. The method according to any one of items 1 to 13, further comprising repeating the mixing step at least once. (Item 15) 1. A method for mixing fluids in a container, comprising: performing a mixing procedure on a plurality of containers on a container support, wherein at least a portion of the plurality of containers are differently sized; and the mixing procedure comprises: a first mixing stage comprising mixing movement of the container support at a first rate for a first duration of at least about 5 seconds; a second mixing stage performed after the first mixing stage, the second mixing stage including the mixing movement of the container support at a second rate for a second duration of at least about 5 seconds, the first rate being different from the second rate and the first duration being different from the second duration; after said second mixing step, not performing any mixing motion for a third duration. (Item 16) Item 16. The method of item 15, wherein the mixing motion comprises rotation of the vessel support. (Item 17) 17. The method of any one of items 15 and 16, wherein rotating the vessel support comprises rotating the vessel support about an axis of rotation that is offset from the center of the vessel support. (Item 18) 18. The method of any one of items 15 to 17, wherein rotating the container support comprises rotating the container support about an axis of rotation extending through the center of the container support. (Item 19) 19. The method of any one of items 15 to 18, wherein at least one of the first rate and the second rate comprises a velocity of the vessel support. (Item 20) 19. The method of any one of items 15 to 18, wherein at least one of the first rate and the second rate comprises a frequency of rotation of the vessel support. (Item 21) 21. The method according to any one of items 15 to 20, wherein the first rate is greater than the second rate. (Item 22) 22. The method of any one of items 15 to 21, wherein the first duration is shorter than the second duration. (Item 23) 23. The method according to any one of items 15 to 22, further comprising repeating the mixing step at least once. (Item 24) 1. A method for mixing fluids in a container, comprising: performing a mixing procedure on a plurality of containers on a container support, said mixing procedure comprising: a first step including moving the container support at a first rate for a first duration greater than about 5 seconds, the first rate and the first duration being selected to substantially uniformly mix fluid within a first container of the plurality of containers, and the first container having a first size; a second step performed after the first step, comprising moving the container support at a second rate for a second duration greater than about 5 seconds, the first rate being different from the second rate, and the second rate and second duration being selected to substantially uniformly mix fluids in a second container of the plurality of containers, the second container having a second size different from the first size; a third step performed after the second step, the third step including not moving the container support for a third duration, the third duration being selected to allow bubbles formed in fluid in at least one of the first container and the second container to dissipate. (Item 25) 25. The method of claim 24, wherein moving the container support comprises rotating the container support. (Item 26) 26. The method of any one of items 24 and 25, wherein rotating the container support comprises rotating the container support about an axis of rotation that is offset from the center of the container support. (Item 27) 27. The method of any one of items 24 to 26, wherein rotating the container support comprises rotating the container support about an axis of rotation extending through the center of the container support. (Item 28) 28. The method of any one of items 24 to 27, wherein at least one of the first rate and the second rate comprises a velocity of the vessel support. (Item 29) 28. The method of any one of items 24 to 27, wherein at least one of the first rate and the second rate comprises a frequency of rotation of the vessel support. (Item 30) 29. The method according to any one of items 24 to 28, wherein the first rate is greater than the second rate. (Item 31) 31. The method of any one of items 24 to 30, wherein the first duration is different from the second duration. (Item 32) 32. The method of any one of items 24 to 31, wherein the first duration is shorter than the second duration. (Item 33) 33. The method according to any one of items 24 to 32, further comprising repeating the mixing step at least once. (Item 34) 35. The method of any one of items 25 to 34, wherein the mixing procedure further comprises a fourth stage performed after the third stage, the fourth stage comprising moving the container support at the first rate for a fourth duration that is shorter than the first duration. (Item 35) Item 35. The method of item 34, wherein the fourth duration is half the duration of the first duration. (Item 36) 36. The method of claim 35, wherein the mixing procedure further comprises a fifth step performed after the fourth step, the fifth step comprising moving the container support at the second rate for a fifth duration that is shorter than the second duration. (Item 37) 1. A method for mixing fluids in a container, comprising: Identifying a first set of rates at which the first vessel can move to produce a first set of values indicative of the degree of mixing of the fluids in the first vessel, and identifying a second set of rates at which the second vessel can move to produce a second set of values indicative of the degree of mixing of the fluids in the second vessel; selecting a first rate from the first set of rates based at least in part on the first set of values; and selecting a second rate from the second set of rates based at least in part on the second set of values. subjecting a container support to a mixing motion, the mixing motion being performed at the first rate for a first duration greater than about 5 seconds and at the second rate for a second duration greater than about 5 seconds, the first container and the second container being disposed on the container support during the mixing motion; and subjecting the container support to a state without mixing motion for a third duration during which the first container and second container are disposed on the container support. (Item 38) Item 38. The method of item 37, wherein the first set of rates and the second set of rates comprise a velocity of the vessel support. (Item 39) 39. The method of any one of items 37 and 38, wherein the first set of rates and the second set of rates comprise a frequency of rotation of the vessel support. (Item 40) 40. The method according to any one of items 37 to 39, wherein the first set of values and the second set of values correspond to the movement of the fluid in the first container and the second container. (Item 41) 41. The method according to any one of items 37 to 40, wherein the first rate is different from the second rate. (Item 42) 42. The method according to any one of items 37 to 41, wherein the first rate is a minimum rate corresponding to a value of the first set of values that reaches at least a predetermined threshold for mixing of the fluids in the first container. (Item 43) 43. The method of any one of items 37 to 42, wherein the first rate results in the maximum value of the first set of values. (Item 44) 44. The method according to any one of items 37 to 43, wherein the second rate is a minimum rate corresponding to a value of the second set of values that reaches at least a predetermined threshold for mixing of the fluids in the second container. (Item 45) 45. The method of any one of items 37 to 44, wherein the second rate results in the maximum value of the second set of values. (Item 46) 46. The method of any one of items 37 to 45, wherein selecting the first rate from the first set of rates is based at least in part on the second set of values. (Item 47) 1. A method for mixing fluids in a container, comprising: 1. Performing a mixing procedure on a plurality of containers on a container support, said mixing procedure comprising the following ordered steps: moving the container support at a first rate for a first duration greater than about 5 seconds; moving the container support at a second rate for a second duration greater than about 5 seconds, the first rate being different from the second rate; stopping the container support and holding the container support motionless for a third duration; determining the extent to which bubbles appear in fluid contained in at least one of the plurality of containers as a result of moving the container support; and modifying one or more aspects of the mixing procedure based on the determined extent. (Item 48) Item 48. The method of item 47, wherein determining the extent to which bubbles appear in the fluid includes inserting a sensing device into the fluid, the sensing device configured to detect bubbles in the fluid. (Item 49) 49. The method of any one of items 47 and 48, wherein modifying one or more aspects of the mixing procedure comprises reducing the first rate. (Item 50) 50. The method of any one of items 47 to 49, wherein modifying one or more aspects of the mixing procedure comprises reducing the first duration. (Item 51) 51. The method according to any one of items 47 to 50, wherein modifying one or more aspects of the mixing procedure comprises reducing the second rate. (Item 52) 52. The method according to any one of items 47 to 51, wherein modifying one or more aspects of the mixing procedure comprises reducing the second duration. (Item 53) 53. The method of any one of items 47 to 52, wherein modifying one or more aspects of the mixing procedure comprises increasing the third duration. (Item 54) 1. A method for mixing fluids in a container, comprising: 1. Performing a mixing procedure on a plurality of containers on a container support, said mixing procedure comprising the following ordered steps: moving the container support at a first rate for a first duration greater than about 5 seconds; moving the container support at a second rate for a second duration greater than about 5 seconds, the first rate being different from the second rate; stopping the container support and holding the container support motionless for a third duration; determining the effectiveness of mixing fluids contained in at least one of the plurality of containers as a result of moving the container support; and and modifying one or more aspects of the mixing procedure based on the determined effectiveness. (Item 55) Item 55. The method of item 54, wherein determining the effectiveness of mixing the fluids comprises taking optical density measurements of different portions of the fluids and comparing the optical density measurements to determine whether a difference between the optical density measurements meets a predetermined threshold. (Item 56) 56. The method of any one of items 54 and 55, wherein modifying one or more aspects of the mixing procedure comprises increasing the first rate. (Item 57) 57. The method of any one of items 54 to 56, wherein modifying one or more aspects of the mixing procedure comprises increasing the first duration. (Item 58) 58. The method of any one of items 54 to 57, wherein modifying one or more aspects of the mixing procedure comprises increasing the second rate. (Item 59) 59. The method of any one of items 54 to 58, wherein modifying one or more aspects of the mixing procedure comprises increasing the second duration. (Item 60) 60. The method of any one of items 54 to 59, wherein modifying one or more aspects of the mixing procedure comprises reducing the third duration. (Item 61) 1. A method for mixing fluids in a container, comprising: 1. Performing a mixing procedure on a plurality of containers on a container support, said mixing procedure comprising the following ordered steps: subjecting the container support to a mixing motion at a first rate for a first duration greater than about 5 seconds, the first rate and the first duration being selected to substantially uniformly mix fluid within a first container of the plurality of containers, and the first container having a first size; subjecting the container support to the mixing motion at a second rate for a second duration greater than about 5 seconds, wherein the first rate is different from the second rate, the second rate and the second duration are selected to substantially uniformly mix fluids in a second container of the plurality of containers, and the second container has a second size different from the first size; not performing the mixing motion on the container support for a third duration; determining a value indicative of the extent to which bubbles appear in at least one of the fluid in the first container and the fluid in the second container; and modifying one or more aspects of the blending procedure if the value differs from a threshold value, wherein modifying one or more aspects of the blending procedure includes modifying one or more of the first rate, the first duration, the second rate, the second duration, and the third duration, wherein the modifications are selected to move the value toward the threshold value. (Item 62) Item 62. The method of item 61, wherein determining the value indicative of the degree to which bubbles appear in at least one of the fluids in the first and second containers includes inserting a sensing device into the at least one of the fluids, the sensing device configured to detect bubbles in the at least one of the fluids. (Item 63) 63. The method of any one of items 61 and 62, wherein modifying one or more aspects of the mixing procedure comprises reducing the first rate. (Item 64) 64. The method of any one of items 61 to 63, wherein modifying one or more aspects of the mixing procedure comprises reducing the first duration. (Item 65) 65. The method according to any one of items 61 to 64, wherein modifying one or more aspects of the mixing procedure comprises reducing the second rate. (Item 66) 66. The method according to any one of items 61 to 65, wherein modifying one or more aspects of the mixing procedure comprises reducing the second duration. (Item 67) 67. The method of any one of items 61 to 66, wherein modifying one or more aspects of the mixing procedure comprises increasing the third duration. (Item 68) 1. A system for mixing fluids in a plurality of differently sized containers, comprising: a container support for receiving said plurality of differently sized containers thereon; a drive system operably coupled to the container support, the drive system configured to move the container support in a mixing motion; a controller operably coupled to the drive system, the controller configured to control operation of the drive system to perform a mixing procedure using the container support; the container support is moved in the mixing motion at a first rate for a first duration greater than about 5 seconds; the container support is moved in the mixing motion at a second rate for a second duration greater than about 5 seconds, the first rate being different from the second rate; The system wherein the container support does not move with any mixing motion for a third duration. (Item 69) Item 69. The system of item 68, wherein the drive system is configured to rotate the container support about an axis offset from the center of the container support. (Item 70) 70. The system of any one of items 68 and 69, wherein the drive system is configured to rotate the container support about an axis extending through the center of the container support. (Item 71) 71. The system of any one of items 68-70, wherein at least one of the first rate and the second rate comprises a velocity of the vessel support. (Item 72) 71. The system of any one of items 68-70, wherein at least one of the first rate and the second rate comprises a frequency of rotation of the vessel support. (Item 73) 73. The system of any one of items 68 to 72, wherein the first rate is greater than the second rate. (Item 74) 74. The system of any one of items 68 to 73, wherein the first duration is different from the second duration. (Item 75) 75. The system of any one of items 68 to 74, wherein the first duration is shorter than the second duration. (Item 76) 76. The system of any one of items 68 to 75, wherein in the mixing procedure, the container support is moved with the mixing motion at one or more rates other than the first rate and the second rate for other durations. (Item 77) 77. The system of any one of items 68 to 76, wherein the controller is further configured to repeat the mixing procedure at least once.

[0021] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various embodiments and, together with the description, serve to explain the principles of embodiments of the present disclosure. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is a top perspective view of a fluid container mixing device according to an embodiment of the present disclosure. [Figure 2] FIG. 2 is a bottom perspective view of the device of FIG. [Figure 3] FIG. 3 is a schematic diagram of the power and control system of the device of FIG. [Figure 4] FIG. 4 is a schematic diagram of the orbital motion of a portion of the apparatus of FIG. [Figure 5] FIG. 5 is a cross-sectional view of an insert and container partially filled with fluid contents according to an embodiment of the present disclosure. [Figure 6] 6 is a cross-sectional view of the insert, container, and fluid contents of FIG. 5 and a pipette tip according to an embodiment of the present disclosure. [Figure 7] FIG. 7 is a flowchart of a method according to an embodiment of the present disclosure. [Figure 8] FIG. 8 is another flowchart of a method according to an embodiment of the present disclosure. [Figure 9A] FIG. 9A is a graph illustrating data associated with steps in the flowchart of FIG. 8, according to an embodiment of the present disclosure. [Figure 9B] FIG. 9B is a graph illustrating data associated with steps in the flowchart of FIG. 8, according to an embodiment of the present disclosure. [Figure 9C] FIG. 9C is a graph illustrating data associated with steps in the flowchart of FIG. 8, according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0023] Reference will now be made in detail to the embodiments of the present disclosure, which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. In the following discussion, relative terms such as "about," "substantially," and "approximately" are used to indicate a variation of ±10%, in some cases, in a stated value, numerical value, or otherwise.

[0024] mixing device A fluid container mixing apparatus 100 is shown in Figures 1-3. The apparatus 100 may include a container support platform 101 configured to hold one or more containers. In the illustrated embodiment, the container support platform 101 is rotatable, for example, about an axis of rotation at the center of the platform 101. The container support platform 101 may include a container tray 110 configured to hold a plurality of fluid containers 126, 128, 130, and a turntable 150 (shown in Figure 2) to which the container tray 110 is mounted, otherwise attached, or integrated therewith.

[0025] Platform 101 is also configured to be capable of moving in an orbital path, for example, about an orbital center offset from the center of platform 101. In the context of this specification, when used to describe the movement of platform 101 (fluid container tray 110 and turntable 150), orbit, orbital, or like terms may refer to a path of movement whereby the entire platform 101 moves about the orbital center, independent of the rotation or spin of platform 101 about the central axis of rotation of platform 101. Figure 4 illustrates the orbital motion of turntable 150. During orbital motion, turntable 150 moves such that the center of turntable 150 is aligned with orbital center C. O Circle C with center at V As the turntable 150 moves through positions 1501, 1502, 1503, and 1504, the center of the turntable 150 moves through positions C1, C2, C3, and C4.

[0026] 2, turntable 150 may include a circular disk configured to rotate about a central axis. In other embodiments, turntable 150 may have another shape configured to rotate about an axis generally perpendicular to the plane of turntable 150. Turntable 150 may be formed of any suitable material having sufficient strength, rigidity, and machinability, and may also be lightweight. Suitable exemplary materials include aluminum, stainless steel, or a suitable plastic (e.g., polystyrene, polyvinyl chloride (PVC), polypropylene, polyethylene, among others).

[0027] Apparatus 100 may also include a rotational drive system 200 (shown in FIG. 2 ) coupled to platform 101. Rotational drive system 200 is configured and arranged to cause rotation or indexing of platform 101, as described in connection with FIG. 3 . In the illustrated embodiment, rotational drive system 200 may rotate platform 101 about an axis of rotation at the center of platform 101. Apparatus 100 may also include an orbital drive system 300 coupled to platform 101. Orbital drive system 300 is configured to cause orbital motion of platform 101, as described in connection with FIG. 4 . Alternatively, apparatus 100 may include any other suitable drive system(s), orbital, rotational, or otherwise, for moving platform 101. For example, apparatus 100 may include motors and / or actuators similar to those in vortex mixers, orbital mixers, rocking mixers, overhead mixers, rolling mixers, and swing mixers.

[0028] As shown in FIGS. 1 and 2 , container tray 110 may include multiple cup-like, generally cylindrical container receptacles of various sizes, such as larger container receptacle 112, smaller container receptacle 113, and even smaller container receptacle 116, configured to receive and hold containers of various sizes (e.g., bottles). For example, receptacles 112, 113, 116 may receive and hold large fluid container 128, medium fluid container 130, and small fluid container 126, respectively. Additionally, separate drop-in adapters may be provided for receptacles 112, 113, 116 to accommodate different container sizes. The adapters may allow introduction and secure placement within receptacles 112, 113, 116 of containers having diameters smaller than those of receptacles 112, 113, 116. Container tray 110 may be circular in shape, and container receptacles 112, 113, 116 may be symmetrically arranged about a central axis of container tray 110. Container tray 110 may be formed from any suitable material, and in one embodiment is formed from molded plastic.

[0029] FIG. 3 is a schematic diagram of a control system for controlling the operation of the apparatus 100. As described above, the apparatus 100 may be configured to independently or simultaneously provide rotation about a central axis of a container and / or orbital motion of the container to agitate the fluid contents of the container. Rotation of the turntable 150 is indicated in FIG. 3 by arrow R, which represents rotation of the turntable 150 about center C. The rotation of the turntable 150 may be powered by a drive system 200, and more specifically, by a drive motor 202. The orbital motion is powered by the drive system 300, which includes a drive motor 302. The drive motors 202, 302 may be coupled to and controlled by a controller 802, which is also connected to a controllable power source 814. The controller 802 may provide power and operational control signals to the drive motors 202, 302. The controller 802 may also receive data from the drive motors 202, 302 in the form of rotary encoder counts as well as other feedback sensor signals. Feedback sensors 808 may be coupled to the device 100 and may include, for example, a rotation home flag, a position home flag, etc. The sensors 808 may be connected to the controller 802 to provide position or other status feedback used to generate control signals for operation of the drive motors 202, 302.

[0030] Rotary drive system 200 and orbital drive system 300 may operate independently of one another to independently rotate platform 101 (container tray 110 and turntable 150) about a central rotational axis or move platform 101 about one or more orbital axes. Rotary drive system 200 and orbital drive system 300 may also operate simultaneously to simultaneously rotate and move platform 101 about an orbital path, which may facilitate improved mixing of the fluid contents within the containers in container tray 110. Rotary drive system 200 may be substantially similar to the turntable drive system described in U.S. Patent Application Publication No. 2014 / 0263163. Orbital drive system 300 may be substantially similar to the vortex drive system described in U.S. Patent Application Publication No. 2014 / 0263163.

[0031] Aspects of the present disclosure, such as the controller 802 and one or more of the components controlled thereby, are implemented through control and computing hardware components, user-written software, data input components, and data output components. The hardware components include computing and control modules (e.g., system controller(s)), such as microprocessors and computers, configured to receive one or more input values, execute one or more algorithms (e.g., software) stored on non-transitory machine-readable media that provide instructions for manipulating or otherwise acting on the input values, and output one or more output values to produce computational and / or control processes. Such output may be displayed or otherwise indicated to a user to provide information to the user (e.g., information regarding the status of the equipment or the process performed thereby), or such output may comprise input for other process and / or control algorithms. Data input components include elements by which data is input for use by the control and computing hardware components. Such data inputs may include position sensors, motor encoders, as well as manual input elements (keyboards, touchscreens, microphones, switches, manually operated scanners, etc.). The data output components may include a hard drive or other storage medium, a monitor, a printer, indicator lights, or audible signaling elements (e.g., buzzers, horns, bells, etc.). The software includes instructions stored on a non-transitory computer-readable medium that, when executed by the control hardware and computing hardware, cause the control hardware and computing hardware to perform one or more automated or semi-automated processes.

[0032] Containers and Inserts The fluid contents of the containers 126, 128, and 130 transported on the container tray 110 of the mixing device 100 may include fluid solutions and / or fluid suspensions. Exemplary fluid contents may include reagents containing solid supports, such as silicon or magnetically responsive particles or beads. See, e.g., U.S. Pat. Nos. 5,234,809 and 6,534,273. The solid supports may have diameters of about 0.68 to about 1.00 μm. Such solid supports may be useful for immobilizing nucleic acids in sample processing procedures to remove amplification and / or detection inhibitors. Other suitable reagents include, for example, target enrichment reagents used in alkaline shock treatments, as described in U.S. Pat. No. 8,420,317. As discussed elsewhere in this disclosure, mixing of the fluid contents (e.g., by agitating the containers containing the fluid contents) may be useful for maintaining suspended materials and / or resuspended materials that have precipitated or otherwise fallen out of solution / suspension in suspension within the fluid. Other suitable reagents may include those used in the ChargeSwitch® Nucleic Acid Purification Kit offered by Thermo Fisher Scientific® and those described in U.S. Patent Application Publication No. 2006 / 0084089. Even in the absence of suspended particles or solid supports, one or more components of a fluid solution may precipitate out of solution, potentially affecting the concentration of the solution withdrawn from the container. Even small changes in concentration can adversely affect tests or assays performed on such solutions.

[0033] The containers may be delivered in an open state to allow a probe-tip fluid extraction device, such as a robotic pipettor, to access the fluid contents of each container. In other embodiments, the containers may be sealed and / or include a filter or septum to limit aerosolization of reagents and to further control evaporation of reagents. The probe-tip fluid extraction device may access the fluid contents of the containers to aspirate or otherwise extract fluid from the container and / or dispense additional fluid into the container. The probe-tip fluid extraction device may include a pipettor configured to detect a fluid surface within the container, for example, to determine or verify the height of fluid within the container, which can be used to calculate the volume of fluid remaining in the container. A suitable pipettor for this purpose is disclosed in U.S. Pat. No. 6,914,555. Level sensing, including, for example, capacitive level sensing, may also be used to signal that an aspiration process may be initiated or to signal the initiation of an aspiration process to aspirate at least a portion of the container's fluid contents. For example, once the liquid surface is detected, the pipettor may continue along a downward path as liquid is aspirated from the container. Alternatively, after the liquid surface is detected, the pipettor may descend a predetermined distance before aspiration begins. In the latter approach, the pipettor may remain stationary during aspiration. The pipettor may employ at least one of capacitive liquid level detection (cLLD) and pressure-based liquid level detection (pLLD). Capacitive liquid level detection may be implemented through the use of conductive disposable pipette tips mounted on the pipettor's tip holder. Additionally or alternatively, the pipettor may include one or more sensors for identifying irregularities, such as the presence of bubbles, in the dispensed or aspirated fluid by detecting discontinuities in the fluid flowing through the pipettor and / or by detecting irregularities in the pressure signal as disclosed in U.S. Pat. No. 6,914,555.

[0034] When a container is in an open state, the fluid contents of the container are exposed to the atmosphere and are therefore susceptible to evaporation. Mixing can exacerbate this problem because it results in increased exposure of the fluid contents' fluid surface to the atmosphere, thereby potentially accelerating the evaporation rate. An evaporation-limiting insert 400 for reducing the amount of evaporation from a container (e.g., container 600) is shown in FIGS. 5 and 6. Insert 400 may include features of the inserts disclosed in U.S. Provisional Application No. 62 / 466,856, filed March 3, 2017. Use of insert 400 is optional in some cases.

[0035] The insert 400 may include a body 402 having a wall 403 extending from a first (upper) end 404 to a second (lower) end 406. A lumen 408 may extend through the body 402 from the first end 404 to the second end 406. Each of the first end 404 and the second end 406 may be open and in communication with the lumen 408. The body 400 may include a plurality of openings extending through the wall 403. Each of the plurality of openings may extend into the lumen 408. The body 400 may include, for example, one or more rows of openings 414, 416. The openings 414, 416 may have different sizes and / or shapes. The openings may be through-holes. Any suitable number of openings 410 may be included on the insert 400. However, while a greater number of openings may improve mixing of the reagents in the insert 400 and the container 600, a greater number of openings may also increase evaporation compared to designs with fewer openings. It is also contemplated that at least one opening may be located below the upper fluid line of the reagent in the container 600 to facilitate mixing of the reagents.

[0036] The insert 400 may include one or more axial slots 430 extending from the second end 406 toward the first end 404. In various embodiments, the insert 400 may include one or more resilient tabs 436 defined by one or more slits 438 extending from the first end 404 toward the second end 406. The tabs 436 may be configured to bend radially inward in response to a radially inwardly directed force (e.g., when the insert 400 is inserted into the opening of the container 600). When bent radially inward, the tabs may apply a radially outwardly directed force that may help secure the insert 400 within the container 600. Additionally or alternatively to the tab and slit arrangements described above, the insert 400 may include one or more detents (not shown) that may engage the interior surface of the container 600, including the detents described in U.S. Patent Application Publication No. 2014 / 0263163. For example, one or more detents may engage corresponding recesses located on the interior surface of the container 600. Other suitable retention features are also contemplated, including, for example, snap-fit configurations, friction-fit configurations, latches, and the like. In some embodiments, one or more of the tabs 436 may include a chamfered top surface 439. The chamfered top surface 439 may aid in inserting a pipette tip or other device of substance into the container 600. Even without the chamfer, the pipette tip 700 may be able to contact a ledge on the top of the insert 400 when orienting the pipette tip 700 into the insert 400.

[0037] In FIG. 6 , the insert 400 is shown positioned within the container 600. The insert 400 may be inserted into the container 600 through an opening 602 in the top of the neck 604 of the container 600. As shown in FIGS. 5 and 6 , the first end 404 of the insert 400 may be positioned adjacent the neck 604 of the container, and the second end 406 of the insert 400 may contact the bottom surface 606 of the container 600. The slot(s) 430 in the container insert 400 may prevent the bottom second end 406 of the insert 400 from forming a sealing contact with the bottom surface 606 of the container 600.

[0038] In various embodiments, when the insert 400 is fully inserted into the container 600, the lower end of each slit 438 separating the pair of tabs 436 may extend below the neck 604 of the container 600, thereby creating a small vent hole just below the neck 604 of the container 600. The small vent hole may help prevent a vacuum from forming within the container 600 and may allow air to escape from the container 600 when filled with liquid. The resilience of the tabs 436, or the bias of the tabs in a radially outward direction, may press the tabs 436 against the inner surface 605 of the neck 604 of the container 600 to secure the insert 400 within the container 600.

[0039] The openings 414, 416 and slot 430 of the insert 400 may allow fluid within the vessel 600, including the solid supports in suspension, to flow between the space inside the insert 400 (e.g., the lumen 408) and the space outside the insert 400 within the vessel 600. The second opening 416 may be resistant to the formation of a thin film, which may help prevent a vacuum from forming inside the vessel 600. This may help ensure that the upper fluid level 610 inside the insert 400 is substantially the same height as the upper fluid level 612 outside the insert 400 and within the vessel 600. As used herein, a "solid support" may refer to a solid substance or object of any geometric shape sufficient to pass through the first opening 414 of the insert 400. A solid support may include any material that does not appreciably dissolve in the fluid medium in which it is contained. Examples of solid support materials include metal, silicon, glass, rubber, and plastic. In some embodiments, the solid support is formed from or includes a magnetically responsive material. In other embodiments, the solid support may be adapted to bind an analyte of interest. The solid support may be in the form of particles or beads.

[0040] Fluid levels 610, 612 may define the fluid surface of the fluid contents within vessel 600. Rest height 613 may be the distance between the bottom of vessel 600 and the fluid surface. During mixing, the fluid contents within vessel 600 may swirl within vessel 600 in the form of waves that propagate in circular paths along the interior walls of vessel 600. Such waves are indicated in FIG. 5 by dashed lines 615. An upper end 617 of wave 615 is above the rest height 613 of the fluid contents. The distance between upper end 617 and rest height 613 is the amplitude 619 of wave 615. The magnitude of amplitude 619 indicates the level of mixing the fluid contents experience, with a larger amplitude indicating more movement / agitation of the fluid contents than a smaller amplitude.

[0041] method Method 800 according to the present disclosure is shown in FIG. 7. Method 800 may begin at step 801, where insert 400 may be positioned inside container 600. Method 800 may proceed to step 804, where container 600 is filled with a reagent. It is contemplated that the order of steps 801 and 804 may be interchangeable. Method 800 may optionally proceed to step 805, where container 600 is sealed and shipped, for example, to a distributor or end user. Steps 801, 804, and 805 may be performed by the manufacturer before the steps are performed by an end user or by a machine operated by an end user. Thus, the following steps of method 800 may be separate steps of a method independent of steps 801, 804, and 805.

[0042] Method 800 may proceed to step 806, where container 600 and insert 400 may be positioned in container tray 110 (see FIG. 1). Alternatively, container 600 with insert 400 may be positioned in container tray 110 without containing any fluid therein. In this example, container 600 may be filled with reagent after being positioned in container tray 110. Container tray 110 may have multiple containers thereon of different sizes and / or fill levels.

[0043] Method 800 may then proceed to step 807, where the fluid contents of one or more containers 600 in container tray 110 may be mixed and / or agitated by rotating, orbiting, inverting, vibrating, and / or another suitable mixing motion. After mixing, the concentration of the fluid and / or the distribution of solid supports within the fluid may be substantially the same (uniform) both inside and outside of insert 400. Alternatively, the concentrations may not necessarily be substantially uniform, but rather may be partially mixed. Mixing effectiveness may be evaluated empirically, for example, by taking optical density measurements using aliquots of the fluid contents taken from within the container insert after agitation of the container. The optical density measurements of these aliquots will be similar if the solutes are dissolved and / or if the solid supports are uniformly distributed within the fluid contents. Mixing effectiveness may also be performed using chemical reaction methods and other suitable processes. For example, samples of the fluid contents may be taken from different regions of the container and tested for their absorbance using spectrophotometry. The absorbances may then be compared to determine whether there are concentration differences between the samples.

[0044] As used herein, "desired mixing effectiveness" applies to situations in which a substantially uniform concentration (e.g., homogeneity) is achieved for the fluid contents of a container, as well as other situations in which a substantially uniform concentration is not achieved but a threshold level of mixing is reached. The threshold level of mixing of materials may, for example, exhibit a concentration (or concentration profile) that differs from homogeneity only to the extent that it does not significantly affect the results (i.e., beyond an acceptable margin of error (e.g., ±5% of the true value, although the margin may vary in different situations) when the material is in its intended use). If the desired mixing effectiveness is not reached, a suboptimal concentration of solute may form inside the bottle 600 and / or insert 400 and / or a suboptimal concentration of solid support may form inside the bottle 600 and / or insert 400. As used herein, the phrase "suboptimal concentration" refers to a concentration that is either too high or too low, potentially resulting in a result that falls outside the acceptable margin of error. For example, if a reagent is not mixed properly / well, samples processed using this reagent will receive different concentrations of the reagent, which can lead to differences in assay performance. It is desirable for each sample to receive the same concentration of reagent so that the assay results are comparable.

[0045] On the other hand, if excessive agitation is performed (i.e., agitation occurs beyond the point where desired mixing effectiveness is achieved), excessive agitation may result in higher rates of evaporation, sloshing (i.e., fluid material swirling outside the container), and / or a higher potential for bubble formation inside the container 600 and / or insert 400. Suboptimal concentration, evaporation, sloshing, and bubble formation may adversely affect level sensing and / or accurate aspiration. For example, if pipettor-based level sensing is employed, contact between the pipette tip and bubbles that may form on the fluid surface of the fluid contents within the insert 400 may signal an inaccurate location of the fluid surface, and an associated analyzer may prematurely initiate the aspiration process before the pipette tip actually contacts the fluid surface. Additionally, the presence of bubbles may cause the bubbles to be drawn into the pipettor along with the fluid, thereby inhibiting accurate aspiration of a volume of fluid.

[0046] The method 800 may proceed to step 808, where the pipette tip 700 and an associated fluid extraction device (e.g., an automated pipettor) having a probe tip may be inserted into the container 600. The method 800 may then proceed to step 809, where level sensing may be performed to signal that the pipette tip 700 has contacted a reagent in the container 600. Upon determining that the pipette tip 700 has contacted a reagent, the pipette tip 700 and an associated fluid extraction device having a probe tip may aspirate a quantity of reagent from one of the containers 600. The pipette tip 700 may aspirate reagent from the container 600 in the same location each time an aliquot of reagent is aspirated. The aspirated reagent may be used in one or more assays or other analytical procedures performed by an automated analyzer. The analytical procedures may include any procedure for determining the presence of an analyte in a sample, including, for example, nucleic acid-based assays, immunoassays, chemical assays, and the like. Examples of automated analyzers include those described in U.S. Patent No. 9,598,723 and U.S. Patent Application Publication No. 2016 / 0060680 A1.

[0047] After a quantity of reagent is aspirated in step 810, method 800 may proceed to an optional step (not shown in FIG. 7 ) in which a determination is made whether the sensed fluid level in container 600 is above a minimum threshold fluid level (corresponding to a dead volume below which the container is no longer useful). The determination may be made by any suitable mechanism, such as one or more fluid level sensing techniques, including, for example, capacitive level sensing and / or any of the techniques described in U.S. Pat. No. 6,914,555. If the sensed fluid level is above the minimum threshold, method 800 may return to step 807 and mix and / or agitate the contents of container 600. If the sensed fluid level is below the minimum threshold, container 600 may be refilled with reagent or replaced with a new container 600.

[0048] In step 806, container 600 may be positioned in container tray 110 along with one or more other containers. For example, container 600 may be one of containers 126, 128, 130 (shown in FIG. 1 ) in container tray 110. In some cases, container tray 110 may be completely filled with containers (i.e., each receptacle 112, 113, 116 contains a container 126, 128, 130). Because the containers in container tray 110 have one or more different characteristics (e.g., geometry, fill level, fluid content viscosity, fluid content composition, etc.), simultaneously mixing the fluid contents of all of the containers in a manner that produces a desired mixing efficacy for the fluid contents of one container may result in improper mixing and / or excessive agitation of the fluid contents of another container. In such cases, the containers may be subjected to a multi-stage mixing procedure in step 807 to achieve a desired overall mixing efficacy (e.g., a condition in which a desired mixing efficacy is achieved for the fluid contents of each container). The multi-stage mixing procedure may be optimized to minimize the amount of mixing required to achieve a desired overall mixing effectiveness, thereby minimizing evaporation, sloshing, and / or foam formation of the fluid contents being mixed.

[0049] Method 812 shown in FIG. 8 describes exemplary steps for performing a multi-stage mixing procedure. Method 812 may be performed separately from or in conjunction with all or a portion of method 800. For example, step 814 of method 812 may be performed at any time before step 807 of method 800. Step 814 includes identifying aspects of a stage of the multi-stage mixing procedure. This may include, for example, identifying a first set of rates at which one container can be moved in a mixing motion, resulting in a first set of values indicative of the effectiveness of the mixing motion in mixing the fluid contents in that container. Step 814 may also include identifying at least one additional set of rates at which at least one other container can be moved in a mixing motion, resulting in at least one additional set of values indicative of the effectiveness of the mixing motion in mixing the fluid contents in the at least one other container. The set of rates at which containers in container tray 110 can be moved in a mixing motion may include, for example, a plurality of frequencies (including individual frequencies and / or ranges of frequencies) at which containers can be rotated by one or more of orbital drive system 300 and rotary drive system 200 (shown in FIGS. 2 and 3 ). Additionally or alternatively, the set of rates may include a plurality of speeds and / or frequencies (including individual values and / or ranges) at which containers can be moved by vortex mixers, orbital mixers, rocking mixers, overhead mixers, rolling mixers, swing mixers, and the like. The set of values indicative of the effectiveness of the mixing motion in mixing the fluid contents in the container may include, for example, a plurality of amplitudes 619 (shown in FIG. 5 ) of waves propagating around the interior of the container as a result of the mixing motion.

[0050] 9A-9C illustrate graphs showing examples of the sets of rates and values described above. More specifically, FIG. 9A illustrates along its x-axis frequencies 824 ranging from 3 Hz to 6 Hz, where a target capture reagent (TCR) in a large vessel (e.g., a 280 mL bottle having a diameter of 72 mm) containing a magnetically responsive solid support material can be moved with a mixing motion by orbital drive system 300. FIG. 9A illustrates along its y-axis amplitude values 826 indicating the effectiveness of the mixing motion in agitating the fluid contents of the large vessel. Curve 828 illustrates amplitude as a function of frequency for the large vessel when the fluid contents of the large vessel are at different fill heights 830 ranging from 11 mm to 70 mm. 9B and 9C show graphs similar to that of FIG. 9A, where curve 832 in FIG. 9B shows amplitude as a function of frequency for a medium container (e.g., a 125 mL bottle having a 50 mm diameter) at different fill heights 834 ranging from 12 mm to 59 mm, and curve 836 in FIG. 9C shows amplitude as a function of frequency for a small container (e.g., a 60 mL bottle having a 35 mm diameter) at different fill heights 838 ranging from 11 mm to 48 mm. The x value of the curve in each of the graphs can be considered as a set of rates for one of the container sizes (i.e., large, medium, or small), and the y value of the curve can be considered as a set of rates for a container of that size.

[0051] Some or all of the data shown in FIGS. 9A-9C and / or similar data for any other container may be received by or otherwise stored within controller 802. For example, data may be programmed into controller 802 before mixing device 100 is provided to a user. Additionally or alternatively, data may be entered into controller 802 by a user. Additionally or alternatively, data may be electronically transmitted (e.g., uploaded) to controller 802 from an external source over a network such as the Internet. Additionally or alternatively, data may be captured from the container itself by controller 802 using a scanner, sensor, or similar device to read data from a label or transmitter on the container. Additionally or alternatively, controller 802 may generate data by performing a mixing motion on the container at multiple frequencies and tracking the resulting amplitude of their swirling liquid contents, then storing the generated data for later use.

[0052] Step 814 may also include selecting, identifying, or otherwise establishing a rate from each of a set of rates for performing the mixing motion. The rate may be, for example, a frequency of the mixing motion that results in an amplitude that reaches a maximum value or a predetermined threshold indicative of a desired mixing effectiveness. Multiple rates may be used when different types of containers are present. For example, a different rate may be used to mix the fluid contents of each type of container in the container tray 110. Containers may be grouped into types based on their size. Alternatively, containers may be grouped into types based on any combination of their size, fill height, and / or contents.

[0053] Additionally or alternatively, the rate may be, for example, a frequency of mixing motion that results in a maximum amplitude for the fluid contents in two or more types of containers, a maximum amplitude for one or more of the container types, an amplitude that reaches a predetermined threshold for one or more other types of containers, or an amplitude for two or more types of containers that meets a predetermined threshold. Additionally or alternatively, the rate may be a frequency of mixing motion that results in a maximum amplitude for the fluid contents of as many types of containers as possible. In cases where a single rate is inappropriate, multiple rates may be used. One example of this is when a first desired mixing effectiveness is achieved for a first type of container at a first rate, the first desired mixing effectiveness is not achieved for the first type of container at a second rate different from the first rate, a second desired mixing effectiveness is achieved for a second type of container at a second rate, and the second mixing effectiveness is not achieved for the second type of container at the first rate, whereby the first and second rates are part of a multi-stage mixing procedure. Additionally or alternatively, the rate may be a frequency of mixing motion that is, for example, an average (e.g., mean, median, or mode) of two or more frequencies of mixing motion. In many cases, the magnitude of the rate may be directly proportional to the size of the container. In other words, the fluid contents of a larger container tend to be more uniformly mixed at a lower rate, while the fluid contents of a smaller container tend to be more uniformly mixed at a higher rate. Each of the rates may be associated with a mixing stage of the mixing procedure.

[0054] Step 814 of method 812 may also include selecting, specifying, or otherwise establishing a time period for each rate, which defines how long the mixing motion is performed at each rate. The time period may, for example, include the minimum time necessary to ensure a desired mixing effectiveness is achieved when mixing the contents of the container at a certain rate. The magnitude of the time period may be inversely proportional to the magnitude of the rate. In other words, the time period may be shorter for higher rates and longer for lower rates. Together, the rates and their corresponding time periods define the mixing phase of the mixing procedure. The time period may, for example, be about 5 seconds or more, during which the frequency and / or speed of rotation of the container may remain substantially constant at that rate.

[0055] While the examples outlined above describe using a single rate associated with each type of container, it is contemplated that method 812 may include using multiple rates, such as multiple discrete rates and / or a continuous range of rates, for any given type of container. During the mixing stage, the mixing motion may be performed at multiple discrete rates and / or over a continuous range of rates for an established period of time (e.g., a duration of 5 seconds or more). The decision of whether to use a single rate for a container or multiple rates for that container may be based on factors including the container volume, the viscosity of its fluid contents, and the like.

[0056] Step 814 may also include establishing a time period for a non-mixing phase of the multi-stage mixing procedure. During a non-mixing phase, the mixing motion may be stopped (there is no mixing motion). For example, the orbital drive system 300 may be stopped and not started again until the next mixing phase. Even when there is no mixing motion, the controller 802 may perform non-mixing movements of the container (e.g., movements that do not constitute mixing movements), such as positioning the container for pipetting and / or moving the container to a pipetting station. For example, non-mixing movements may include movements that do not follow the path of the mixing motion and / or may occur at a slower rate and for a shorter duration than movements of the mixing motion.

[0057] The top surface of the fluid contents of the container may have an amplitude of about 0 during the unmixing motion. The unmixing phase may be a single continuous phase of a multi-stage mixing procedure that occurs after all of the mixing phases have been performed. Alternatively, there may be multiple unmixing phases within a multi-stage mixing procedure, with at least one of these unmixing phases occurring between two mixing phases. The unmixing phases may have the same or different durations, depending on how much time is needed to aspirate the fluid contents from the container and / or how much time is needed to reduce the amount of foam in the fluid contents.

[0058] Step 814 may also include establishing an order for performing the mixing and non-mixing steps of the multi-step mixing procedure. In one example, a mixing step using a higher rate may be performed before a mixing step using a lower rate. One reason for this is that bubbles formed during mixing at a higher rate may move to the periphery of the fluid surface while mixing at a lower rate, resulting in fewer bubbles in the central region of the fluid surface where the pipettor may aspirate a volume of fluid material.

[0059] In some cases, a multi-stage mixing procedure may include different mixing cycles, each cycle including multiple mixing stages and at least one non-mixing stage. For example, a mixing procedure may include a first cycle of mixing stages and at least one non-mixing stage, where the mixing stage has characteristics selected to perform initial mixing of the fluid contents in the vessel. The mixing procedure may include a second cycle of mixing stages and one or more non-mixing stages, where the mixing stage is selected to mix the fluid contents of the vessel pre-mixed in the first cycle (e.g., preferably before any solutes have precipitated out of solution and / or before the solid support has settled). The rate and duration of the stages in the first cycle may result in a greater degree of agitation of the fluid contents of the vessel than in the second cycle. One or more aspects of the second cycle may differ from the first cycle to ensure unnecessary mixing is avoided. For example, in the second cycle, one or more of the mixing stage rates may be reduced, one or more of the mixing stage durations may be reduced, and / or the duration(s) of one or more non-mixing stages may be modified. An appropriate cycle may be selected and used when the mixing procedure is performed in step 816. It is also contemplated that a similar change between mixing cycles may be performed in response to any change in the fluid level of any container during the aspiration of fluid contents from any container during the non-mixing phase of the earlier of the two cycles.

[0060] Step 816 of method 812 can be performed during step 807 of method 800, in which a multi-stage mixing procedure is performed. If multiple types of containers are present in container tray 110, performance of the multi-stage mixing procedure may include performing multiple mixing stages and at least one non-mixing stage. The stages may be performed by controller 802, for example, through control of motors and / or actuators similar to those in rotary drive system 200 and / or orbital drive system 300, or alternatively, vortex mixers, orbital mixers, rocking mixers, overhead mixers, rolling mixers, and swing mixers.

[0061] Step 818 of method 812 can be performed at any point during or downstream of step 808 of method 800, at which time feedback indicating the effectiveness of the multi-step mixing procedure may be obtained. The feedback may be provided by one or more sensors either on the pipettor, on a separate device, or otherwise positioned in the environment surrounding the vessel. The feedback may include, for example, data regarding the formation of precipitates and / or the degree to which the solid support is uniformly dispersed within the fluid. Additionally or alternatively, the feedback may include data regarding the formation or presence of bubbles within the vessel.

[0062] Step 820 of method 812 can also be performed at any time during or after step 808 of method 800, in which controller 802 may be programmed to modify the multi-step mixing procedure based on feedback data. For example, if the feedback data indicates that the degree of homogeneity (e.g., solutes in solution and / or solid supports in suspension) and / or bubble formation in the vessel does not meet one or more thresholds, the multi-step mixing procedure may be modified (“Yes”) by cycling back to step 814. As described above, the degree of bubble formation may be determined by one or more sensors to identify irregularities, such as the presence of bubbles in the dispensed or aspirated fluid, by detecting discontinuities in the fluid flowing through the pipettor and / or by detecting irregularities in the pressure signal. Additionally or alternatively, the degree of bubble formation may be determined visually, by height level detection by the pipettor, and / or by image analysis using a camera, one or more of which may provide real-time, on-the-fly adjustment of mixing rates and duration. If the degree of homogeneity is below a predetermined threshold, step 814 may increase the rate and / or duration of one or more of the mixing steps to enhance mixing and / or decrease the duration of one or more of the non-mixing steps to allow less time for solutes to precipitate out of solution and / or solid supports to precipitate out of suspension. If the amount of foam is excessive (i.e., greater than a predetermined threshold), step 814 may decrease the rate and / or duration of one or more of the mixing steps and / or increase the duration of one or more of the non-mixing steps to generate less foam during mixing and / or to allow time for foam to dissipate during the non-mixing steps.

[0063] Additionally or alternatively, fill height may be a factor taken into consideration when designing a multi-stage mixing procedure, so that a change in the fill height of one or more of the containers as a result of fluid contents being aspirated from the containers may warrant modification of the multi-stage mixing procedure. The controller 802 may monitor the fill height of the containers by comparing the current fluid level sensed by the pipettor with past fluid levels, tracking the number of aspirations into the pipettor, and / or tracking the volume aspirated by the pipettor. Additionally or alternatively, fill height may be monitored using a capacitive sensor external to the container, a vision / imaging system, a scale or similar weighing device for weighing the container and its contents, an in-container float sensor, an ultrasonic or Doppler-based sensor, and the like. Modifying the multi-stage mixing procedure may include modifying one or more of the rates of the mixing stages and / or one or more of the durations of the mixing and non-mixing stages, and feedback data to bring the feedback data into compliance with one or more thresholds. On the other hand, if the feedback data adheres to one or more thresholds, the multi-stage mixing procedure may be repeated without adjustment ("No") as method 812 returns to step 816 for subsequent mixing. Repeating the multi-stage mixing procedure helps keep the fluid contents in the container properly mixed over an extended period of time.

[0064] In one particular example, involving inserting one or more large TCR containers (bottles having a volume of 280 mL and a diameter of 72 mm), one or more medium TCR containers (bottles having a volume of 125 mL and a diameter of 50 mm), and one or more small TCR containers (bottles having a volume of 60 mL and a diameter of 35 mm) into container tray 110 (shown in FIG. 1 ) and using the data associated with the graphs of FIGS. 9A-9C , a first cycle of a multi-stage mixing procedure may include performing a 30-second mixing motion using orbital drive system 300 (shown in FIGS. 2 and 3 ) operated at a frequency of 5 Hz, followed by a 60-second mixing motion at a frequency of 3 Hz, and ceasing to perform the mixing motion until 30 minutes have elapsed since the start of the first cycle. Subsequent maintenance cycles of the multi-stage mixing procedure may be performed at regular time intervals (e.g., every 30 minutes) and may include performing two mixing stages at the same frequency as the two mixing stages of the first cycle, but for half the duration (e.g., 15 seconds at 5 Hz and 30 seconds at 3 Hz).

[0065] Additional and / or alternative mixing methods are described in U.S. Patent No. 7,135, 145. Each of the U.S. patent application publications and U.S. patents referenced herein is hereby incorporated by reference in its entirety.

[0066] It will be apparent to those skilled in the art that various modifications and variations can be made in the disclosed systems and processes without departing from the scope of the present disclosure. Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only.

Claims

1. 1. A method for mixing fluids in a container, comprising: performing a mixing procedure on each of a plurality of containers positioned on a container support platform, the container support platform including a container tray defining a plurality of recesses for holding the plurality of containers, the mixing procedure comprising: a first mixing stage, the first mixing stage including rotating the container support platform with the container tray about an axis at a first rate for a first duration greater than 5 seconds, the first rate and the first duration being selected to uniformly mix fluid within a first container of the plurality of containers, the first container having a first size; a second mixing stage performed after the first mixing stage, the second mixing stage comprising rotating the container support platform with the container tray about the axis at a second rate for a second duration greater than 5 seconds, the first rate being different from the second rate, the second rate and the second duration being selected to uniformly mix fluids in a second container of the plurality of containers, the second container having a second size different from the first size; a third non-mixing step performed after the second mixing step for a third duration, the third duration being selected to allow bubbles formed in the fluid in at least one of the first and second containers to dissipate; the axis extends perpendicular to the container tray, the axis is located at a center of the container support platform or is located offset from the center of the container support platform, and the plurality of recesses are centered about the center of the container tray; each of the first rate and the second rate comprises a velocity of the container support platform or a frequency of rotation of the container support platform; the second rate is lower than the first rate when the second size is larger than the first size; The method, wherein the second rate is higher than the first rate when the second size is smaller than the first size.

2. The method of claim 1 , wherein the container support platform is not rotated about the axis during the third non-mixing stage.

3. The method of claim 1 , wherein the axis is offset from the center of the container support platform.

4. The method of claim 1 , wherein the axis extends through the center of the container support platform.

5. The method of claim 1 , wherein the first rate is greater than the second rate.

6. The method of claim 1 , wherein the first duration is different from the second duration.

7. The method of claim 1 , wherein the first duration is less than the second duration.

8. 10. The method of claim 1, further comprising repeating said mixing step at least once.

9. 2. The method of claim 1, wherein the mixing procedure further includes a fourth mixing stage performed after the third non-mixing stage, the fourth mixing stage including rotating the container support platform with the container tray at the first rate for a fourth duration that is shorter than the first duration.

10. The method of claim 9 , wherein the fourth duration is half the duration of the first duration.

11. 10. The method of claim 9, wherein the mixing procedure further comprises a fifth mixing stage performed after the fourth mixing stage, the fifth mixing stage comprising rotating the container support platform at the second rate for a fifth duration that is shorter than the second duration.

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