Patent Application
20110036453
The present invention is directed to the field of dynamic nuclear polarization (DNP). More specifically, the present invention is directed to a component for dynamic nuclear polarization equipment. Even more specifically, the present invention is directed to a feature of the dissolution equipment for a DNP polarizer, namely a nozzle as part of the dissolution device. This nozzle provides for more efficient dissolution of the solid polarized sample, thereby enabling a rapid and complete dissolution.
Polarization by DNP in the solid state, i.e. at very low temperatures and a moderate to high magnetic field, followed by dissolution with a dissolution medium has been demonstrated to yield highly enhanced nuclear polarizations, which in turn enable a range of novel MR applications. Pyruvate for instance is a compound that plays a role in the citric acid cycle and DNP-polarized (hyperpolarized) pyruvate can be used as an MR agent for in vivo MR studying of metabolic processes in the human body. Hyperpolarized pyruvate may for instance be used as an MR imaging agent for in vivo tumour imaging as described in detail in WO-A-2006/011810 and for assessing the viability of myocardial tissue by MR imaging as described in detail in WO-A-2006/054903. To produce hyperpolarized pyruvate, pyruvic acid is DNP polarized and the solid frozen polarized pyruvic acid is dissolved and neutralized in a hot dissolution medium containing an aqueous buffer solution and a base. WO-A-2006/011809, which discloses the DNP polarization and dissolution of pyruvic acid, is hereby incorporated by reference as if provided in full herein.
The dissolution process itself has to be extremely rapid and complete. This generally requires a hot dissolution medium to be injected into a vial containing the frozen solid sample with the expectation that the thermal energy and flow of the dissolution medium will be sufficient to completely dissolve the sample and carry it to another container, see for instance WO-A-02137132 which is incorporated by reference herein. In the following the terms “solid frozen sample, solid sample and frozen sample” are used interchangeably. However, in actually reducing this process to practice a number of unexpected problems were observed. One possible failure mode was that the system freezes before the solid sample is dissolved, resulting in an ice plug either partially or completely blocking flow into and out of the system. A second failure mode was that the thermal energy transferred to the solid sample was not sufficient to dissolve all of it, resulting in some amount of solid sample being left in the vial. In addition to operating pressure and temperature it was determined that the inlet tube design and placement may play an important role in obtaining satisfactory dissolutions.
One prior approach to address this problem involves heating the dissolution media to a very high temperature and operating at very high pressures. By using this approach it is possible to rapidly dissolve a cryogenically frozen sample. Unfortunately, the pressures and temperatures required by this approach may also require expensive components made of heat and pressure resistant material and/or lead to safety issues. Furthermore, very high temperatures easily may lead to steaming of the dissolution medium, depending on the pressure. Steam is however less efficient in transferring heat to the frozen solid sample and thus to dissolve it than the liquid dissolution medium. Means to prevent steaming of the hot dissolution medium is therefore critical.
Moreover, a lengthy dissolution will inadvertently affect the nuclear polarization since polarization in the dissolved sample decays over time and variations in timing will result in a non-robust dissolution process yielding variable polarization. Additionally, incomplete dissolution will impact on the process yield. Moreover, in case of polarizing a free acid such as pyruvic acid that has to be neutralized upon dissolution, incomplete dissolution is detrimental for controlling the pH of the resulting solution. It is therefore desirable to implement features that contribute to a robust and expedient dissolution process.
As used herein, the term “sample” refers to a polarized material, which is typically provided in a sample container, at a low temperature in a frozen solid state. The term “dissolution medium” refers to a liquid provided to melt and dissolve the sample material, thereby forming a “solution” of the melted and dissolved sample material and possibly also at least some of the dissolution medium. The temperature of the dissolution medium is generally higher than the temperature of the sample. The temperature of the sample is about 1 to 5 K while the temperature of the dissolution medium is at least room temperature, i.e. about 295 K but preferably a heated, i.e. hot dissolution medium is used. If an aqueous dissolution medium is used, e.g. an aqueous buffer solution, such an aqueous buffer solution may be heated to a temperature of about 355 K or more. Thus when the dissolution medium gets into contact with the sample, the sample is melted and dissolved. The terms “sample container” and “sample vial” is contemplated as holding the sample in both its frozen solid form and in its solution form.
Dissolution stick 10 includes an elongate tubular outer housing 16 having open opposed first open end 18 and second open end 20. Housing 16 provides an interior surface 22 defining an elongate cavity 25 extending in fluid communication between open first end 18 and open second end 20. Dissolution stick 10 supports a first elongate conduit 24 having opposed first open end 26 and second open end 28 and an elongate flowpath 30 extending in fluid communication between open ends 26 and 28. Second open end 28 is provided connected to a source of a liquid dissolution medium (not shown). Dissolution stick 10 further includes a second elongate conduit 30 having opposed first open end 32 and second open end 34 and an elongate withdrawal path 36 extending in fluid communication between open ends 32 and 34. Withdrawal path 36 provides a route for conducting the dissolution medium and the dissolved sample material originally provided by container 12.
Sample container 12 typically includes a planar base 40 supporting an upstanding open cylindrical wall 42 defining a sample receptacle 44 in which the sample material is provided. When container 12 is inserted into open end 18 of dissolution stick 10, wall 42 sealingly engages interior surface 22 of housing 16 so as to prevent fluid leakage therebetween. Dissolution stick 10 and container 12 define a sample cavity 50 into which the sample material is held as dissolution medium is provided from first open end 26 of first conduit 24. The mixture of the dissolution medium and the dissolved sample material is withdrawn from cavity 50 through withdrawal path 36 of second conduit 30 to a receiver location where it can be further processed for providing a hyperpolarized material suitable for in vitro NMR analysis or for in vivo use.
The present invention provides for the incorporation of a nozzle adjacent to the sample cavity so as to increase the flow velocity of the dissolution medium onto the sample material. Desirably, the nozzle of the present invention also directs the flow of the dissolution medium so as to provide efficient dissolution of the sample material in the sample cavity. As will be more fully described hereinbelow, the design and placement of the nozzle may be optimized to obtain complete and rapid dissolution of the sample material. Desirably, the nozzle provides fluid flow through the sample cavity that promotes the conduct of the dissolved sample material through the withdrawal conduit and does not form eddies or vortices where dissolved sample material becomes entrapped in the cavity.
Thus, the present invention provides the ability to fully dissolve a cryogenically frozen sample in a closed fluid path. The present invention also provides the ability to transfer the dissolved product from a vial to a receiver. Additionally, the present invention provides the ability to modify the placement of a nozzle/inner tube such that complete dissolution may be obtained regardless of the amount of material in the vial. The present invention further provides the ability to modify the size and shape of a nozzle to improve dissolution at varying operating temperatures and pressures. Additionally, the present invention provides the ability to use a larger diameter inner tube to maintain high mass flow rates while still achieving high fluid velocity at the exit.
As seen in
One of skill in the art will appreciate that the design of the nozzle affects the efficiency of the dissolution. Here, a conically tapering inner surface of the nozzle will greatly improve the performance of the dissolution, both in terms of clearing the entire solid sample content of the sample container, and in terms of providing an expedient dissolution process that preserves the nuclear polarization during the transition. As will be seen, however the present invention contemplates additional designs for the nozzle of the present invention. Additionally, the present invention contemplates that the nozzle will be formed from a material, which does not react with the materials with which it will come into contact and which will not adversely affect the polarization levels of the sample material.
While
It has been demonstrated that the end orifice diameter of the nozzle is critical to the dissolution efficiency. The optimal diameter will of course depend on a number of parameters such as the depth and shape of the sample container, amount of sample and the chosen pressure for the dissolution medium.
Dissolution stick 210 provides a constriction member 232 having opposed first and second ends, 234 and 236, respectively. Constriction member 232 is supported on interior surface 218 of housing 212. First end 234 of constriction member 232 extends into first open end 224 of conduit 222 so as to reduce the available cross-sectional area of flowpath 230 at first open end 224. Constriction member 232 will thus cause an acceleration of the dissolution medium through open end 224 as compared to its flow rate in conduit 222 upstream thereof. Constriction member 232 further includes an exterior surface 238 which may be shaped, or angled, relative to flowpath 230 so as to direct fluid flowing out of first open end 224 of conduit 222 towards a location of choice within cavity 220. The particular direction for dissolution medium flow from conduit 222 will be influenced by the dimensions and geometry of cavity 220 as well as the desired flow rate of the dissolution medium entering cavity 220.
Dissolution stick 210 also supports a second elongate conduit 240 having opposed first and second open ends 242 and 244, respectively. Conduit 240 defines an elongate withdrawal path 246 extending in fluid communication between open ends 242 and 244. Second open end 244 of conduit 240 is connectable to a collector or receiver for the solution withdrawn from cavity 220.
First open end 624 of first conduit 622 is positioned within cavity 618 of outer housing 612 upstream from first open end 632 of second conduit 630. First open end 632 of second conduit 630 is centrally-supported within cavity 620 of outer housing 612 by annular support 638. As seen in
Dissolution stick 810 further supports a second elongate conduit 840 having opposed first and second open ends 842 and 844, respectively, and an elongate withdrawal path 846 extending in fluid communication therebetween. Second open end 844 of second conduit 840 is positionable in fluid communication with a withdrawal destination for the dissolution medium.
Vial cap 910 further defines a single flow port 928 therethrough, which accommodates both a dissolution medium conduit 930 and a solution conduit 932. Dissolution medium conduit 930 is concentrically supported within solution conduit 932 so that dissolution medium provided through dissolution medium conduit 930 into sample cavity 925 causes the frozen sample material to dissolve and flow out the annular withdrawal path 934 about dissolution medium conduit 930.
Dissolution medium conduit 930 further includes a first open end 936 having a nozzle 935. Nozzle 935 is a constriction in the dissolution medium flowpath 938 defined by dissolution medium conduit 930, which causes an acceleration in fluid flow therethrough as compared to the fluid flowrate in conduit 930 upstream of nozzle 935. The central location of nozzle 935 over sample cavity 925 provides the fluid flow characteristics which rapidly and completely dissolve a cryogenically frozen product in cavity 925, as well as which fully displace the product solution through withdrawal path 934 to a final location where it is collected into receiver vessel 988, as shown in
Referring again to
Referring now to
Dissolution device 1010 includes an outer housing 1028 having an outer housing wall 1030 which defines a sample cavity 1032 for holding a frozen polarized sample. Sample cavity 1032 is in fluid communication with nozzle port 1024. Outer housing wall 1030 defines a fluid withdrawal port 1034 in fluid communication with sample cavity 1032. Outer housing 1028 further includes an elongate outer tubular wall 1036 extending from outer housing wall 1030. Outer tubular wall 1036 defines an elongate withdrawal passageway 1038 extending in fluid communication with fluid withdrawal port 1034.
First elongate tube 1012 extends within withdrawal passageway 1038 of outer tubular wall 1036. Outer housing wall 1030 further defines an access port 1040 for accommodating first elongate tube 1012 therethrough. Outer tubular wall 1036 further defines an outlet port 1042 in fluid communication with withdrawal passageway 1038. The present invention further contemplates that first elongate tube 1012 may be slideably mounted by a mounting sleeve 1044 which maintains the fluid integrity of withdrawal passageway 1038 while also allowing first elongate tube 1012 to be extended and retracted within withdrawal passageway 1038 so as to selectively position nozzle 1022 with respect to sample cavity 1032.
Outer housing wall 1030 further includes an elongate cylindrical sample retaining wall 1046 extending from a transversely-oriented endwall 1048. A tapering frustroconical wall 1050 extends between elongate cylindrical sample retaining wall 1046 and elongate outer tubular wall 1036. While walls 1036, 1046, and 1050 are shown in
Similar to the depiction of
Through experimentation and modeling it was discovered that in order to accomplish this reliably it was advantageous to place a nozzle at the end of the inner tube and to locate that nozzle within a certain distance of the frozen sample,
In the preferred embodiment the nozzle diameter is 0.9 mm and the standoff is set to be 5 mm. This is with an outer tube inner diameter of 2.69 mm and an inner tube outer diameter of 1.83 min, resulting in a ratio of flow areas of approximately 1.6 in favor of exiting the system.
To further assist the formation of nozzle 935, heating block 952 may define a conduit-receiving depression 960 into which open end 936 is first inserted. Pin 950 would be centrally supported in depression 960. It is further contemplated that the heating of block 952 may occur simultaneously to the step of deforming conduit 930. Alternatively, conduit 930 may be provided to an already heated block 952 to cause the deformation. By this method, a nozzle with a certain length and diameter has been formed in conduit 930. This technique has been utilized to form orifices with a range of diameters and depths.
While the particular embodiment of the present invention has been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the teachings of the invention. The matter set forth in the foregoing description and accompanying drawings is offered by way of illustration only and not as a limitation. The actual scope of the invention is intended to be defined in the following claims when viewed in their proper perspective based on the prior art.
A demonstration of the impact of a nozzle on the dissolution process in shown in
2.2 grams of pyruvic acid was dissolved with 50 mL of water (dissolution medium) that is heated to 130° C. and pressurized to 250 PSI. Red food coloring was added to the pyruvic acid to aid in the visualization of this dissolution process.
By completing the melting process before the dissolution medium is consumed, the acid recovery efficiency of this system was enhanced relative to a system without a nozzle.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2008/061197 | 8/27/2008 | WO | 00 | 10/25/2010 |
| Number | Date | Country | |
|---|---|---|---|
| 60968320 | Aug 2007 | US |
