Abstract:
Liquid blending systems and methods of blending liquids are provided. In particular, systems and methods for compensating binary inlet buffers during inline buffer dilution are provided. The systems and methods can provide blends of diluent, a first buffer concentrate containing a majority of a tempering component, and a second buffer concentrate containing a minority of a tempering component. The flow of the first buffer concentrate can be adjusted based upon the total amount of the tempering component being added to the blend through the first and second buffer concentrates.

Description:
CLAIM OF PRIORITY 
       [0001]    This application claims priority to U.S. Provisional Application No. 62/118,355, filed on Feb. 19, 2015, the content of which is incorporated herein by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates generally to liquid blending systems and methods and, in particular, to a system and method for compensating binary inlet buffers during inline buffer dilution. 
       BACKGROUND 
       [0003]    The combining of two or more liquids together to a desired concentration and/or other characteristics or properties, such as pH, conductivity, optical density, refractive index, etc., of the constituent liquids is fundamental to many industrial processes and commercial products. This combining of liquids may be referred to as blending and is common in many industrial segments. In addition, blending systems find use in the field of liquid chromatography where blended liquids are provided to chromatography columns to permit the separation of mixtures for analysis or for purification purposes. 
         [0004]    On site blending systems provide many advantages over purchasing pre-mixed chemicals. By using a blending system, a single quantity of feedstock concentrate can be used to produce many times its volume in diluted solution, depending on the desired concentration of the dilution. Thus, a single feedstock concentrate, used to produce the equivalent of many feedstocks of dilute liquid via, a blending system can greatly reduce facility costs associated with fabrication of large tanks, floor space required, validation and quality control costs to confirm makeup, as well as spoilage and disposal costs of non-compliant out of date or unused blended solutions. Freight costs associated with chemical delivery can also be reduced. In addition, onsite dilution and blending increases the variety of chemical concentrations and mixtures that are immediately available, without requiring a corresponding increase in the number, of feedstocks and chemicals that must be purchased, thereby reducing facility and operating costs and providing the logistical and administrative advantage of reduced inventory. 
         [0005]    High accuracy in terms of concentration for blending systems providing liquids to liquid chromatography systems is desirable. In addition, quality control concerns favor increased blending accuracy for liquids that are provided to industrial processes and that are used to create commercial products. Indeed, Six Sigma quality control principles dictate that lower variability in an industrial process results in a greater percentage of higher quality products being produced by the industrial process. 
         [0006]    It is well known, however, that there will be variations in concentration within a feedstock. For example, it is common for different portions of a large feedstock tank filled with a solution to have different proportionate mixtures of the constituent liquids. Gradients exist in large feedstocks in terms of both concentration and temperature. As a result, liquid provided from the feedstock will vary in terms of concentration, which poses challenges for accurate analysis, quality control analysis, and uniform delivery to a process. Feedstock solvents, commercially supplied, have variations in actual concentration from batch to batch, as well as innate impurities, which prevents 100% pure concentrations from being available in bulk supply. In response, systems and methods for accurately blending liquids from such feedstocks, such as the Inline Buffer Dilution systems and methods using Process Analytical Technology (PAT) in commonly assigned U.S. Pat. Nos. 7,072,742; 7,515,994 and 8,271,139, all to Bellafiore et al., have been developed. 
         [0007]    When a blend is simply a dilution of a buffer concentrate with water or other diluent, it is known as a binary blend. When a blend is accomplished by way of dilution of multiple buffer concentrates with water or other diluent, it is known as a ternary blend when it has three components, a quaternary blend when it has four components, and so on with names indicating the number of components being blended. A common example of ternary blending is when two concentrate solutions are simultaneously diluted with water or other diluent to form a specific ternary blend. The inlet concentrates may be of any form, such as salts or conjugate forms of a buffer, or a form of a buffer (concentrate) that is to be tempered with a form of an acid or base. 
         [0008]    A less common example of ternary blending is the incorporation of refractive index (RI) inline process measurement with conductivity inline process measurement. Temperature control can be incorporated in such examples (and in other cases) in order to reduce the matrix effect of temperature to two measures, two variables. 
         [0009]    Factors such as target conductivity, pH, and/or other component concentration of the blend can be significant with respect to the process application to which the blend is applied. The processes these blends are used for are greatly diversified but in general, may be used to feed a final product manufacturing process, biological growth, separation or purification process, etc. 
         [0010]    As described in the commonly assigned U.S. Pat. Nos. 7,072,742; 7,515,994 and 8,271,139, the special purpose of the Inline Buffer Dilution equipment using PAT is the ability to consistently obtain the target conductivity and/or pH and/or other component concentration of the blend independent of upstream variability which may occur in the inlet concentration of the buffer concentrates or diluent composition. Due to the limitations of the analytical technologies available for PAT feedback/control, however, it is sometimes necessary to construct blends using flow control and flow meters as the feedback (to the programmable logic controller) to proportion two or more components in the blend. A drawback of the Inline Buffer Dilution equipment using flow control is the flow meter&#39;s inability to compensate for the potential/inherent variability of the inlet buffer (or diluent) concentration. Specifically, flow control fundamentally cannot be used to target desired pH within commonly acceptable precision. Thus, in a ternary blend where flow control is used to accomplish the target blend between the first concentrate buffer and the diluent, and pH control is desired, pH feedback/control of the second concentrate buffer must be used to accomplish pH tempering to a high degree of precision. 
         [0011]    In some circumstances in the above scenario, the second inlet buffer concentrate being used for pH tempering (or tempering of conductivity or other property) must be a binary mixture containing as its minority component the compound which is the majority component of the first buffer concentrate. As a result, when the diluent and the first buffer concentrate must be proportioned by flow control, the proportion between the diluent and the first concentrate being controlled by flow would, by the addition of the (for example) pH tempering solution, with its minority component being the same as the first buffer concentrate, be unaccounted for in volume added to the final solution and spoil the proportion intended between the first buffer concentrate and the diluent. A need therefore exists for a system and method that addresses these issues. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIGS. 1A and 1B  together form a schematic illustrating one embodiment of a system of the present technology. 
           [0013]      FIG. 2  is a flow chart showing a method of operating the system of  FIG. 1 . 
       
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       [0014]    Systems and methods of the present technology can be used for compensating binary inlet buffers during inline buffer dilution. 
         [0015]    In accordance with some embodiments of the present technology, as explained in greater detail below, a flow meter monitors the flow of the pH tempering solution, but the system does not have it feedback to the control of the pH tempering. The feedback to control the pH tempering solution (binary mixture) is from the pH meter or sensor in a feedback loop. The flow meter monitoring the flow of the pH tempering solution is used in conjunction with the known concentration of the minority component in a calculation to compensate the flow quantity of the first buffer concentrate to produce the desired flow-based final blend with feedback-based pH tempering. 
         [0016]    While examples of the present technology are described below primarily in terms of ternary blending with feedstock and a binary pH tempering solution, the present technology can be used in other applications. For example, the present technology may also be used with blending a feedstock with a conductivity binary tempering solution, a refractive index binary tempering solution, or a binary solution for tempering another property in place of the these example tempering solutions. In addition, the system and method of the present technology may be used with a greater number of components than ternary blending (e.g., quaternary blending, etc.), such as blending two or more feedstocks with at least one tempering solution. 
         [0017]    One embodiment of a system of the present technology is indicated in general at  10  in  FIGS. 1A and 1B . As shown, a diluent  12 , such as, for example, compendial water, is connected to the system  10  at a first port or inlet  14 . The a first port  14  is adapted to receive the diluent  12 , and the diluent  12  then travels through line  16  to inlet valve  18 , which can be opened to allow flow into a first pump  20 . Pump  20  is driven by first speed control  22 , which is controlled by a programmable logic controller  24 . The first pump  20  can have an inlet in communication with the first port  14  and an outlet in communication with the inlet  90  of the mixer  32 . For example, as illustrated, from pump  20 , the diluent can be driven through line  26 , and into line  28  when valve  30  is opened. The diluent can flow through line  28  and into mixer  32  through the inlet  90  of the mixer  32 . 
         [0018]    As shown in in  FIG. 1B , the product stream from the mixer flows out of the mixer  32  through outlet  92  of the mixer, and then through product line  34 , which can include at least one property sensor for measuring a desired property of the product stream. The at least one property sensor is in communication with the outlet  92  of the mixer. In the illustrate example, the property sensors can include: conductivity sensor  36 , pH sensor  38 , refractive index sensor  40 , a first flow meter  42  and a pressure transmitter  44 . The first flow meter  42  can be in communication with the outlet  92  of the mixer. At the pressure transmitter  44 , the product stream in product line  34  interacts with a backpressure regulator  46 , and then flows into a series of outlet valves  48   a - d,  which can be opened as appropriate for directing the blend. 
         [0019]    As also shown in  FIGS. 1A and 1B , a first buffer concentrate  50  having a majority component is connected to the system  10  by at least one second port or inlet, which as illustrated includes inlets  52   a,    52   b,  and  52   c.  The second port  52   a - c  is adapted to receive the first buffer concentrate, and the first buffer concentrate  50  travels from the at least one second port  52   a - c  through at least one line  54   a,    54   b,    54   c  (respectively) to an inlet valve  56   a,    56   b,    56   c  (respectively) which can be opened to allow flow through line  58  into a second pump  60 . The first buffer concentrate  50  can be driven through the pump  60  by a second speed control  62  that is controlled by the programmable logic controller  24 . The second pump  60  can have an inlet in communication with the second port  52   a - c  and an outlet in communication with the inlet of the second flow meter  66 . For example, as illustrated, after passing through the pump  60 , the first buffer concentrate  50  can pass through line  64  to a second flow meter  66 , and then to valve  68  which can be opened to allow flow through line  28  and into mixer  32  through the inlet  90  of the mixer  32 . 
         [0020]    As further shown in  FIGS. 1A and 1B , a second buffer concentrate  70 , which is a binary mixture having a minority component that is the same as the first buffer concentrate  50 , is connected to system  10  by at least one third port or inlet, which as illustrated includes inlets  72   a,    72   b,  and  72   c.  The second buffer concentrate  70  travels from the at least one third inlet through at least one line  74   a,    74   b,    74   c  (respectively) to an inlet valve  76   a,    76   b,    76   c  (respectively) which can be opened to allow flow through line  78  into a third pump  80 . The second buffer concentrate  70  can be driven through the pump  80  by a third speed control  82  that is controlled by the programmable logic controller  24 . The third pump  80  can have an inlet in communication with the third port and an outlet in communication with the inlet of the third flow meter  86 . For example, as illustrated, after passing through the pump  80 , the second buffer concentrate  70  can pass through line  84  to a third flow meter  86 , and then to valve  88  which can be opened to allow flow through line  28  and into mixer  32  through the inlet  90  of the mixer  32 . The third flow meter  86  can have an inlet in communication with the third port  72   a - c  and an outlet in communication with the inlet  90  of the mixer  32 . 
         [0021]    In some embodiments, as shown in  FIG. 1A , a fourth flow meter  94  can be placed such that it has an inlet in communication with the first port  14  and an outlet in communication with the inlet  90  of the mixer  32 . As illustrated, after passing through the pump  20 , the diluent  12  can pass through line  26  to the third flow meter  94 , and then to valve  30  which can be opened to allow flow through line  28  and into mixer  32  through the inlet  90  of the mixer  32 . 
         [0022]    A programmable logic controller  24  can be in communication with at least each of the flow meters, each of the speed controls for the pumps, and each property sensor. The programmable logic controller  24  can be programed, through computer readable instructions stored on a non-transient medium such as a memory, to operate the system. For example, the programmable logic controller  24  can perform the following functions:
       i) adjust the first pump based on the first and/or fourth flow meter;   ii) adjust the third pump based on the sensor; and   iii) adjust the second pump based on the second flow meter and the third flow meter.       
 
         [0026]    The systems and system operation methods of the present technology can achieve a continuous blend at a target total flowrate, at a target flow dilution between the diluent and the first buffer concentrate by flow feedback/control, with a target pH adjustment in the final product by pH feedback/control, with the pH adjustment solution being a binary mixture containing as its minority component the same majority component as the first buffer concentrate. As noted previously, while pH is used as a example of a target property, other properties including, but not limited to, conductivity and refractive index may be used as the target property. 
         [0027]    One method of operating a system of the present technology is shown in  FIG. 2 , with reference to system  10  as shown in  FIGS. 1A and 1B . The method can be carried out by programmable logic controller  24 , which controls and receives feedback from the components of the system  10 . It is to be understood that the steps illustrated in in  FIG. 2  do not necessarily have to be performed in the order illustrated. 
         [0028]    The system operation method is indicated generally at  100 . As indicated at step  102 , the programmable logic controller  24  receives a target total flowrate for the first pump  20 , which can be entered as the set point into a proportional-integral-derivative (PID) feedback loop controller of programmable logic controller  24 , and the PID loop for the first pump  20  can be set to flow feedback/control. 
         [0029]    As indicated at step  104 , the programmable logic controller  24  receives a target dilution of the first buffer concentrate, which can be entered as the set point in a PID feedback loop controller of programmable logic controller  24  for second pump  60 , and the PID loop for second pump  60  can be set to flow feedback/control. 
         [0030]    As indicated at step  106 , the programmable logic controller  24  receives the specifications for the desired target property of the product stream, which can be entered as the set point in a PID feedback loop controller of programmable logic controller  24  for the third pump  80 , and the loop for the third pump  80  can be set to feedback/control for the target property. As discussed above, the target property can be pH, or alternatively other properties such as conductivity and refractive index. 
         [0031]    In addition, as indicated at step  108 , the programmable logic controller  24  receives a concentration of the minority component of the second buffer concentrate  70 , which can be entered as a variable X defined as the ratio given by the weight of the minority component in second buffer concentrate  70  over total weight of second buffer concentrate  70 . 
         [0032]    At step  110 , the system  10  can be started based on the target total flow rate, target dilution of the first buffer concentrate, and the target property. The programmable logic controller  24  can drive first pump  20  and the second pump  60  to their respective speeds to accomplish their respective set points based on flow feedback control from first flow meter  42  and second flow meter  66 , respectively. The second flow meter  66  has an inlet in communication with the second port  52   a - c  and an outlet in communication with the inlet  90  of the mixer  32 . The product pH sensor  38  in the feedback/control loop with the third pump  80 , can drive the third pump  80  to accomplish the pH set point. Alternatively, the conductivity sensor  36  and/or the refractive index sensor  40  in the feedback/control loop with the third pump  80  can drive the third pump  80  to accomplish the conductivity or refractive index set point. In alternative embodiments, other product property sensors may be used. 
         [0033]    As indicated previously, without consideration of the concentration of the minority component in the second buffer, binary solution (second buffer concentrate  70  of  FIG. 1A ), addition of the pH tempering solution (to adjust pH) would add an unknown amount of the minority component of the second buffer, binary solution (which contains a small portion of the majority component of the first buffer concentrate  50  of  FIG. 1A ) to the final product exiting the system through valves  48   a - d  and spoil the intended flow based dilution between the first buffer concentrate  50  and the diluent  12 . In other words, the minority component in the second buffer, binary solution (second buffer concentrate  70 ) would generally act as an undesired additional amount of first buffer concentrate  50 . 
         [0034]    As indicated at step  112 , the programmable logic controller  24  can perform a compensation calculation to compensate for the additional amount of the minority component of second buffer concentrate  70  added to the final product as the pH is accurately tempered to the set point by the pH feedback/control loop with the third pump  80 . In the compensation calculation, set forth below, flow from third flow meter  86 , referred to in the equation below as F3, can be monitored by the programmable logic controller  24  and multiplied by X to give V, which is the additional amount of the component added per unit time (V): 
         [0000]        F 3× X=V  
 
         [0035]    As indicated at step  114 , the programmable logic controller  24  can determine the actual amount of the tempering component being added by adding V to the flow measured from the second flow meter  66 , defined as F2 in the equation below, to obtain actual tempering component concentrate flow (F2+): 
         [0000]        F 2+ V =F 2+ 
         [0036]    As indicated at step  116 , by using F2+ as the measured flow of the tempering component concentrate in the feedback/control loop, the programmable logic controller  24  can adjust the speed of the second pump  60  by controlling the second speed control  62 . The adjustment of the speed of the second pump can be based on the value of F2+ to establish the target flow based dilution for the final solution independent of the pH which is being adjusted by the pH feedback/control loop with the third pump  80  (as previously mentioned). 
         [0037]    The programmable logic controller  24  can determine the flow setpoint of the first pump  20  based on feedback received from fourth flow meter  94 , the flow F2 measured from the second flow meter  66 , and the flow F3 flow measured from third flow meter  86 . 
       Example 1 
       [0038]    It is desired to make a phosphate buffered saline solution at physiological pH and seawater concentration. Buffer  1  contains the sodium salt concentrate. When Buffer  1  is diluted to the desired saline (sodium salt) concentration, the pH in the final solution must be tempered to achieve physiological (pH) conditions. Buffer  2  is the tempering solution (phosphate buffer) that for shelf life purposes has a minority component of sodium salt 10%. 
         [0000]        X= minority component weight of Buffer 2/total weight of Buffer 2=0.1 
         [0000]    The above amount is entered for X into the programmable logic controller  24 . 
         [0039]    In addition, the following set points are entered into the programmable logic controller  24 : 
         [0040]    Total flowrate desired is 5 liter a minute; 
         [0041]    Buffer 1 is 5 times concentrate saline. 
         [0042]    When the flow based dilution starts, first flow meter  42  or the fourth flow meter  94  can be used to control the first pump  20  to the set point 4 times the flowrate F2 of the second flow meter  66  as established by the second pump  60 : 
         [0000]      F2=1 liter per minute. 
         [0043]    The third pump  80  will begin to adjust the pH by pH feedback/control adding tempering solution  70  (Buffer  2 ) which is counted as water by the first flow meter  42  by virtue of its position in the flow path. Thus the flow proportion between first and second flow meters  42  and  66  is automatically maintained, but Buffer  2 , being added by third pump  80 , has a minority component of saline which is not accounted for by first flow meter  42 —just the volume flow is accounted for. If the saline component (10% minority component of sodium salt) in Buffer  2  is not accounted for, it would corrupt the intended proportion between the first flow meter  42  and the second flow meter  66 , that is, 5 times dilution. 
         [0044]    To account for the sodium salt minority component in Buffer  2 , the third flow meter  86  is interrogated by the programmable logic controller  24 , which then adds the volume of the minority component to the flow recorded by the second flow meter  66 . For example: flow F3 may be 1/10 of flow F2 to obtain target pH: 
         [0000]        F 3=0.1×1 =0.1 liter per minute
 
         [0045]    The additional Buffer  1  component added per unit time V therefore is: 
         [0000]        V=F 3× X= 0.1×0.1=0.01
 
         [0046]    The contribution of saline added to F2 therefore results in: 
         [0000]        F 2+=1+0.01=1.01 liter per minute. 
         [0047]    The programmable logic controller  24  would then back off/lower the speed of the second pump  60  so that F2+ is controlled at 1 liter per minute in order to maintain the desired ratio between the first and second flow meters  42  and  66  and the final concentration of saline desired is obtained while the pH desired is maintained. 
         [0048]    While the preferred embodiments of the invention have been shown and described, it will be apparent to those skilled in the art that changes and modifications may be made therein without departing from the spirit of the invention.