METHODS AND SYSTEMS FOR ADJUSTING THE pH OF MEDICAL BUFFERING SOLUTIONS

(1. Technical Field) The present invention generally relates to methods and systems for adjusting and controlling pH. More specifically, the present invention relates to methods and systems for adjusting the pH of buffers and other medical solutions to achieve uniformity between multiple individual containers.

A buffer is a substance that minimizes changes in the pH of a solution when an acid or base is added to the solution. Medical buffer solutions often contain bicarbonate ions for numerous medical applications, including antidotes, dialysates, body exchange fluids, body perfusate solutions, cardiac perfusate, and many other purposes. Used for One of the most commonly used medical bicarbonate buffer solutions is sodium bicarbonate (LVDS) mixed with water.₃), And above all, can be used to buffer the injection to a more physiological pH prior to injection. Of particular note in this application is that buffering acidic local anesthetic injections with a bicarbonate solution can improve the effectiveness of anesthesia, reduce injection pain, and limit tissue trauma. .. Precision sodium bicarbonate solution to a specific known pH or its vicinity for other medical uses, including, but not limited to, the use of sodium bicarbonate to buffer local anesthesia, as well as the treatment of acidemia. It is desirable to keep it at. By using a buffer solution with a known pH, the medical practitioner achieves precise control of the pH resulting from the parenteral solution by mixing a predetermined ratio of the buffer solution with the parenteral solution. It is possible to have a significant effect over the use of parenteral solutions when the pH is not precisely known.

As an example, when a 8.4% sodium bicarbonate buffer solution is combined with a commercially available cartridge of 2% lidocaine and epinephrine 1: 100,000, the pH of the buffer solution is almost universally the pH combination of the commercially available anesthetic cartridge. The pH is driven and relatively small volumes of buffer solution tend to have a disproportionately large effect on the pH of the combined solution. Therefore, it is important that the pH of the buffer solution is precisely known and controlled in order to achieve a parenteral solution with a predictable pH.

Commercially produced sodium bicarbonate buffers do not provide a buffer package with a precisely controlled pH. For example, commercially available buffer solutions list a very wide pH range on their label, and sodium bicarbonate solutions are generally labeled pH 7.0 to pH 8.5. Assays for commercially available sodium bicarbonate solutions performed by the inventors showed a pH range of 7.62 to 8.26 on several commercially available bicarbonate buffer cartridges. The actual range of products available on the market is expected to be even broader than the range shown in this assay.

In this context, it must be recognized that a medical buffer with an actual pH of 7.0 can function significantly differently than a medical buffer with an actual pH of 8.5. This is because the medical buffer is designed to buffer the pH of body fluids, for example in the treatment of acidemia, or the medical buffer is the pH of the parenteral solution prior to its use. Corresponds to whether it is designed to buffer. In an example in which the practitioner uses a sodium bicarbonate solution to buffer the anesthetic to achieve a physiological pH, the ratio of the buffer solution to the anesthetic solution is such that the pH of the bicarbonate solution is 8.5. Compared to one time, it will be very different from when the pH is 7.0. Therefore, the prior art method of combining a buffer solution with a parenteral solution, which depends on the addition of the same proportion of the buffer solution to the parenteral solution (regardless of the actual pH of the buffer), is for the buffered parenteral agent. Will not consistently reach the desired pH of.

For these reasons, it would be desirable for the pH within each individual package to be approximately equal and consistent by providing the packaged buffer with a precisely controlled pH. In addition, a packaged buffer solution that allows the preparation of an unlimited number of packages, such as cartridges, capsules, carples, vials, and other containers, each containing a stable and precisely known pH. It would be desirable to provide methods and systems for production. Such methods and systems provide an economical preparation of such buffer packages and allow long-term storage of such packages while maintaining pH stability and sterilization protocols and systems. It should also be compatible with. At least some of these objectives will be met by the present invention described below.

(2. Description of background technology) Glass vials and cartridges for storing medical solutions are described in Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5, Patent Document 6, and Patent Document 7. , Patent Document 8 and Patent Document 9. An injection pen that employs a drug cartridge is described in Patent Document 10. An exemplary disposable drug cartridge that can be loaded with a buffer solution according to the present invention is described in Japanese Patent Application Laid-Open No. 11 and co-owned and co-owned application US 2009/0292271 (USSN12 / 406,670), both. , Incorporated herein by reference. A device for delivering a buffer into an anesthetic cartridge using a transport needle is described in Patent Document 11. Devices for maintaining the dissolved gas in the solution in the pouch are described in Patent Document 12, Patent Document 13, Patent Document 14, and Patent Document 15. Other patents and applications of interest include Patent Document 16, Patent Document 17, Patent Document 18, Patent Document 19, Patent Document 20, Patent Document 21, Patent Document 22, Patent Document 23, Patent Document 24, Patent Document 11, and Patent Document. 25, Patent Document 26, and Patent Document 27. Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3; Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 5 6; Non-Patent Document 7; Non-Patent Document 8; Non-Patent Document 9; Non-Patent Document 10; Non-Patent Document 11; Non-Patent Document 12; and Non-Patent Document 13.

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<p num="0010"> The present invention is for preparing a container stock of bicarbonate medical buffer solution (buffer) having a precisely controlled pH and minimal variability between solutions in any individual container. Methods and systems are provided. By providing a stock of such buffer containers, the buffers in each container have the same pH (very small tolerance, generally within ± -0.03). A volume buffer can be used in combination with the medical solution to control the pH of other medical solutions, such as local anesthetics, to a predictable physiological pH. Thus, the buffered pH of the combined buffer and medical solution is also precisely controlled and predictable, which means that the pH of the buffer solution itself is precisely controlled and predictable. If it is not possible, it will not be possible.</p><p num="0011"> The medical bicarbonate buffer solution is an acidic buffer and is a hydrogen ion (H).⁺) And bicarbonate ion (HCO)₃^-) And carbonic acid (H)₂CO₃) Forming carbon dioxide (CO)₂) And water combination.</p><p num="0012"> For buffered medical solutions containing local anesthetics such as lidocaine, articain, prlocaine, and mepivakine, both the amount of buffer solution and the pH of the buffer solution have a significant effect on the "buffered" pH of the combined solution. It is possible to exert. From a different perspective, the amount of buffer solution required to stabilize the medical solution to a particular target pH will depend on the pH of the buffer solution itself. Therefore, when the actual pH of the buffer solution is significantly different from its nominal pH, it is not possible for a measured volume of buffer solution to rely on adjusting the pH of the medical solution to the target pH. The stabilized pH of the buffered medical solution can differ significantly from the target value. Conversely, by providing an inventory of medical buffer solutions according to the invention that have a precisely controlled and highly predictable pH value, the user places a predetermined or calculated volume of buffer. Combined with a given volume of medical solution, the pH of the topical anesthetic or other medical solution can be adjusted in a highly predictable manner.</p><p num="0013"> In the first aspect of the present invention, the method for adjusting the pH of the bicarbonate buffer in the plurality of buffer containers is the step of arranging each of the containers in the chamber, where each container is each. The buffer inside the vessel is provided with a step that is open to expose to the carbon dioxide-containing atmosphere in the chamber. Pressure, temperature, carbon dioxide (CO) in the chamber₂) Levels, and generally relative humidity, are controlled to levels selected to provide the target equilibrium pH of the buffer. Maintaining a high relative humidity level will limit evaporation from the vessel. "Equilibrium" means that the equilibrium is CO dissolved in a buffer solution in a container.₂And gaseous CO in the chamber atmosphere₂It means that it exists between the partial pressures of and. As mentioned above, the pH of the bicarbonate buffer solution is CO.₂, Carbonate, hydrogen ion, and bicarbonate ion, which depend on four directions parallel. Virtually unlimited CO in the chamber at controlled pressures and temperatures₂By providing the source, the amount of carbonate and bicarbonate ions in the buffer solution in each container is at equilibrium values that are precise and even within ± 0.05, preferably ± 0.03, more preferably ± 0.02. Driven. To achieve such accuracy, CO₂Concentration of and the temperature in the atmosphere in the chamber must be carefully controlled. The atmosphere will preferably be mixed as expected to be substantially constant over the entire area within the chamber. Such mixing can be achieved by introducing and / or recirculating fresh carbon dioxide gas through the chamber and then mechanically mixing the gas in the chamber, as detailed below. Optionally, the vessel can be vibrated, shaken, or otherwise displaced during equilibration to mix the solutions in the vessel and prevent the formation of a pH gradient in the vessel.</p><p num="0014"> The vessel is kept in the controlled atmosphere of the chamber for a time sufficient for the buffer in each of the vessels to equilibrate with the carbon dioxide atmosphere and reach the target pH. In general, the carbon dioxide atmosphere will be at least 99% by volume, preferably 99.9% by volume, and most preferably essentially pure carbon dioxide (100% by volume). These CO₂Values are based on a "dry" analysis with water vapor removed. However, in use, the atmosphere will generally have a high relative humidity, as described below. In all vessels, the time required to equilibrate and reach the target equilibrium value will generally be about 36 hours, more generally about 40 hours, often 42 hours or more. At a temperature of about 72.5 ° F (22.5 ° C), when using 100% carbon dioxide, pH 7.68 ± 0.05 can be achieved under atmospheric pressure. After sealing, the steam sterilization process (high-pressure steam sterilization of the vessel) can further affect the pH, resulting in a slight increase of, for example, about 0.03, but such changes are predictable. , Can be calculated in determining the final pH of the buffer in a closed container.</p><p num="0015"> The atmosphere in the chamber is generally as close to 100% as possible, generally at least 80%, preferably at least 90%, generally 95% relative humidity or higher. Will be humidified. As detailed below, the atmosphere is CO through the water column prior to introducing the gas into the chamber.₂Humidification is possible by passing the contained gas. The temperature in the chamber will generally be maintained in the range of 72 ° F to 74 ° F, preferably 72 ° F to 73 ° F. An open container of water, the chamber is CO₂High humidity may be achieved more efficiently by being placed in the chamber for a period of time filled with. Alternatively, the vessel may contain an amount of liquid water that is expected to evaporate during the equilibration process.</p><p num="0016"> In an exemplary embodiment, the carbon dioxide-containing gas is introduced into and discharged from the chamber at a substantially constant flow rate. The actual flow rate depends on the volume of the chamber, and the constant flow rate per hour is generally about 25% to about 150% of the volume of the chamber, and generally about 40% to 75% of the volume of the chamber. Will be within the range of. Generally, the carbon dioxide carrier gas is "primed" before the chamber accepts the container by circulating through the chamber prior to placing the buffer container in the chamber. Will be. The carbon dioxide-containing gas will generally be introduced to the bottom of the chamber and discharged from the top of the chamber. Humidified carbon dioxide gas is about twice as heavy as the air initially present in the chamber, so carbon dioxide covers the bottom of the chamber, driving the air upwards and discharging it through the discharge port at the top of the chamber. Finally, prior to the start of processing of the individual containers, a highly uniform gas composition within the chamber will be established.</p><p num="0017"> The container may be sealed after the buffer solution in the container has been balanced by the carbon dioxide atmosphere in the chamber to suppress changes in pH during transport and storage prior to use. The container is preferably CO₂Is generated from the solution and can enter the headspace that changes the pH of the solution in the container, there is no gas in the container. More preferably, the pressure is maintained on the buffer solution in the vessel and the pH can be varied as well, CO from the solution.₂To prevent the occurrence of. Devices and methods for storing buffers while applying pressure are described in co-owned application US 2009/029271, the full disclosure of which is incorporated herein by reference.</p><p num="0018"> In a more preferred aspect of the invention, the container may have a small diameter neck, which may provide an opening for the gas to equilibrate with the buffer solution. In such cases, cervical area reduction would limit the surface area of buffer available for molecular exchange required for equilibration. In such cases, the level of the buffer can be lowered to a larger diametrical region of the vessel, which results in a larger area to allow the equilibration reaction to occur. Larger areas will then reduce the time required to achieve equilibrium. After equilibrium is achieved, the level of buffer in the vessel is generally to advance the prab or other support member in the vessel, push the buffer solution upwards and fill the neck. Can be raised to eliminate headspace. Other means for raising the surface of the solution, such as introducing an inert volume (eg, a bead) that reduces the width of the vessel into the chamber and displacing the fluid, are also available.</p><p num="0019"> As described above, an inventory of buffer containers in which the buffers in each container have substantially the same pH can be prepared. In general, inventories will include containers of approximately equal shape and volume, which will then be packaged in larger boxes or other storage and / or shipping enclosures. In general, such inventories will include at least four containers, but will sometimes include hundreds, thousands, or even tens of thousands.</p><p num="0020"> The container may be sealed while remaining in the controlled environment of the chamber. However, in general, the open vessel will be removed from the chamber and sealed outside the chamber. Due to the sealing, it is possible to maintain a controlled environment even outside the chamber, but in general it will not be necessary. Exposure of the open vessel to the normal atmosphere (without high levels of carbon dioxide) has little effect on the vessel as long as the air-liquid interface is small relative to the fluid volume of the vessel, and exposure is short and general. It takes less than 10 minutes.</p><p num="0021"> In a further aspect of the invention, the system for adjusting the pH of multiple buffer containers comprises a chamber having a peripheral wall and an interior. The system also has a compressed CO connected to one or more regulators.₂One or more tanks, etc., CO₂Equipped with a supply section (source), CO inside the chamber₂Delivering gas flow, the gas flow comprises at least about 99% carbon dioxide by volume, generally approximately pure carbon dioxide, but water vapor is equilibrium as discussed in any of the specification. During the conversion process, it may be present as an amount sufficient to raise sufficient relative humidity to limit or prevent evaporation. Multiple isolated supports within the interior of the chamber removably accept multiple buffer containers or carriers that can hold a small number of containers, generally shelves on a rotating carousel or other movable frame. It is adapted to be. A number of pneumatically stable passages are formed through the peripheral walls and are located so as to allow the placement of the buffer container on each of the supports through the passage and the removal of the buffer container from it. The pneumatically stabilized passage generally allows the physical entry and exit of the buffer container on the carrier through the wall, while suppressing the exchange of gas and the external environment from within the chamber. An exemplary pneumatic stabilization passage includes a valve structure, a curtain structure, and a port hole with a closed door. CO₂The source is a constant flow of CO₂Is maintained in the chamber and the pneumatic passage is located below the level of the discharge port, so any inflowing air will travel to the top of the chamber and CO₂The continuous flow of gas will drive into the chamber and therefore will reestablish and maintain elevated carbon dioxide levels in the chamber.</p><p num="0022"> Generally, the chamber comprises a stand-alone cabinet, but the chamber may comprise a room or other structure constructed within a larger structure. The gas flow is generally free to flow from the discharge ports at the bottom of the chamber and at the top of the chamber, which is large enough to prevent any buildup of pressure in the chamber. Optionally, the supply line can be adapted to maintain the temperature of the gas introduced into the chamber, but in general the temperature inside the chamber is the temperature of the room or other ambient environment in which the chamber is maintained. Will be reached. Therefore, temperature control within the chamber will be affected by temperature control within the room or surroundings containing the chamber. Yet another option would be to construct one or more of the walls from the bilayer material, with a space in between that is heated or cooled to produce the desired temperature. In general, the system will further include a water tank or water column, most commonly a series of water columns, through which the intake carbon dioxide gas flow passes before the gas flows into the chamber. Optionally, the last water column can be maintained at a temperature slightly above the chamber temperature so that the relative humidity of the gas does not decrease as it flows into the chamber. In an exemplary embodiment, the support comprises a rotary carousel with a plurality of stacked circular shelves, by rotating the shelves adjacent to a number of adjacent pneumatically stable aisles, thereby providing different parts of the shelves. Each of the pneumatically stabilized passages will be accessible, facilitating loading and unloading of the buffer container support. Optionally, the carousel may oscillate to suppress the formation of a pH gradient, which can oscillate and mix the solution in the vessel over time, limiting uniform equilibration.</p><p num="0023"> In a still further aspect of the present invention, the stock of buffer containers comprises a plurality of containers filled with an aqueous solution of a bicarbonate buffer solution, and each container in the stock is in the range of 2.5 ml to 3.1 ml. It has a pH variation of less than ± 0.05 compared to the volume of the bicarbonate solution in it and the pH of other containers in stock. The pH container may comprise any conventional medical solution container, including bottles, syringes, tubes, etc., but generally a glass cartridge with a cap with a cervical and needle punctureable bulkhead. Will prepare. Such cartridges, sometimes referred to as carples, preferably further include a bottom support that allows the hydrous buffer to be dispensed through the neck under positive pressure by advancing within the cartridge. Such containers are exemplified, for example, in co-owned application US 2009/0292271, the full disclosure of which is incorporated herein by reference. On the preferred side, the bicarbonate solution in each container will be maintained at a pressure above atmospheric pressure to control the generation of carbon dioxide during storage. Containers will generally be maintained in storage containers such as boxes, trays, etc. for storage, shipping, etc.</p><p num="0024"> The fluid in the container is CO₂May be held under pressure by a spring or other structure that provides sufficient force to prevent it from emanating from the solution. If the cartridge is steam sterilized as an alternative to aseptic filling, the force applied by the spring must be sufficient to prevent the sodium bicarbonate from boiling during the pressure sterilization process. However, the spring force should not be increased to the extent that the fluid is not subjected to thermal expansion if the container can fail. Finally, the spring force should not increase the pressure in the vessel to the extent that it separates the bicarbonate from the solution.<u style="single">The present specification also provides, for example, the following items.</u><u style="single">(Item 1)</u><u style="single"> A method of adjusting the pH in a plurality of buffer containers.</u><u style="single"> By arranging each of the containers in the chamber, the containers are open to expose the buffer to the atmosphere in the chamber.</u><u style="single"> The pressure, temperature, and CO of the atmosphere</u>_{<u style="single">2</u>}<u style="single">Controlling the level to a value chosen to provide the target equilibrium pH of the buffer,</u><u style="single"> Keeping the container in the controlled atmosphere of the chamber for a time sufficient for the buffer in each of the containers to reach the target pH.</u><u style="single"> Sealing each of the containers to control changes in pH over time</u><u style="single"> Including methods.</u><u style="single">(Item 2)</u><u style="single"> The method of item 1, further comprising moving a container in the chamber to facilitate mixing of the atmosphere and mixing of the buffer solution.</u><u style="single">(Item 3)</u><u style="single"> Atmospheric pressure, temperature, and CO</u>_{<u style="single">2</u>}<u style="single">The method of item 1, wherein controlling the level comprises introducing, circulating, and removing gas from the chamber.</u><u style="single">(Item 4)</u><u style="single"> The method of item 3, wherein the gas is introduced and removed at a substantially constant flow rate.</u><u style="single">(Item 5)</u><u style="single"> The method of item 4, wherein the flow rate is in the range of 0.1 V to 1 V per hour, where V is the open internal volume of the chamber.</u><u style="single">(Item 6)</u><u style="single"> The method of item 1, wherein the open container is held in the chamber for at least 24 hours.</u><u style="single">(Item 7)</u><u style="single"> The method of item 6, wherein the open container is held in the chamber for a time in the range of 24 to 96 hours.</u><u style="single">(Item 8)</u><u style="single"> The temperature is in the range of 70 ° C to 74 ° C, the pressure has 1% of atmospheric pressure, and the CO</u>_{<u style="single">2</u>}<u style="single">The method of item 1, wherein the content is at least 97% by volume and provides a pH in the range of 7.63 to 7.75.</u><u style="single">(Item 9)</u><u style="single"> The method of item 1, wherein the gas has 100% relative humidity when introduced into the chamber.</u><u style="single">(Item 10)</u><u style="single"> The first item, wherein at least some of the containers contain a volume of water that evaporates during a period of time during which the container is held in the chamber and raises the relative humidity in the chamber. Method.</u><u style="single">(Item 11)</u><u style="single"> The method according to item 1, wherein the container is sealed after sealing so that no head space remains.</u><u style="single">(Item 12)</u><u style="single"> 11. The method of item 11, wherein the container is entirely filled while in the chamber.</u><u style="single">(Item 13)</u><u style="single"> The method of item 11, wherein the container is partially filled to increase the available open surface area while in the chamber, and is fully filled prior to sealing.</u><u style="single">(Item 14)</u><u style="single"> 13. The method of item 13, wherein the container is completely filled by reducing the volume within the container.</u><u style="single">(Item 15)</u><u style="single"> The method of item 1, wherein all containers are of equal shape and volume.</u><u style="single">(Item 16)</u><u style="single"> The method of item 1, wherein the container is sealed while in the chamber.</u><u style="single">(Item 17)</u><u style="single"> The method of item 1, wherein the container is removed from the chamber and then sealed.</u><u style="single">(Item 18)</u><u style="single"> A system that regulates the pH of multiple buffer containers.</u><u style="single"> With a chamber with a peripheral wall and interior,</u><u style="single"> A gas supply unit connected to deliver gas flow into the interior of the chamber, wherein the gas flow unit contains at least about 97% carbon dioxide by volume.</u><u style="single"> With a plurality of isolated supports within the chamber,</u><u style="single"> With a number of pneumatically stable passages formed through the peripheral wall and located to allow the buffer container to be placed on and removed from each of the supports.</u><u style="single"> Including the system.</u><u style="single">(Item 19)</u><u style="single"> The system of item 18, wherein the chamber comprises a stand-alone cabinet.</u><u style="single">(Item 20)</u><u style="single"> The system of item 18, wherein the mechanism applies vibration to the container and mixes the contents of the container during pH adjustment.</u><u style="single">(Item 21)</u><u style="single"> The system of item 18, further comprising a water tank that receives and humidifies the gas flow.</u><u style="single">(Item 22)</u><u style="single"> The system of item 18, wherein the support resides on a rotary carousel present in the chamber.</u><u style="single">(Item 23)</u><u style="single"> 22. The system of item 22, wherein the carousel comprises a plurality of stacked circular shelves.</u><u style="single">(Item 24)</u><u style="single"> It is a stock item of the buffer container,</u><u style="single"> Each container in the inventory comprises a plurality of containers filled with an aqueous solution of sodium bicarbonate solution.</u><u style="single"> With a volume of sodium bicarbonate solution in the range of 1.0 ml to 50.0 ml,</u><u style="single"> With pH fluctuations below ± .05 when compared to the pH of all other containers in the inventory</u><u style="single"> Have, in-stock items.</u><u style="single">(Item 25)</u><u style="single"> The stock item according to item 24, wherein the sodium bicarbonate solution in each container is maintained at a pressure above atmospheric pressure during storage to suppress the generation of carbon dioxide.</u><u style="single">(Item 26)</u><u style="single"> Each container has an open interior filled with the sodium bicarbonate solution, a needle puncture partition, a plunger, and a compression member, which pressurizes the sodium bicarbonate solution and carbon dioxide. The in-stock item according to item 25, which imparts sufficient force to the plunger to suppress the generation of carbon.</u><u style="single">(Item 27)</u><u style="single"> 24. The inventory of item 24, further comprising a box holding the plurality of containers.</u></p>

<figref num="1">FIG. 1 illustrates a medical solution container useful in the practice of the present invention.</figref><figref num="2">FIG. 2 illustrates the plurality of containers of FIG. 1 held on a carrier used for placement in a chamber for processing according to the principles of the present invention.</figref><figref num="3">FIG. 3 illustrates an exemplary processing chamber according to the principles of the present invention.</figref><figref num="4">FIG. 4 illustrates a useful humidification system with the processing chamber of FIG.</figref><figref num="5">Figures 5A-5C illustrate the placement of the container carrier in the processing chamber through the pneumatically stable port.</figref><figref num="6">FIG. 6 is a schematic representation of the pH regulation protocol of the present invention.</figref>

A buffer container 10 useful in the systems and methods of the present invention is illustrated in FIG. The buffer container 10 comprises a cartridge 12 including a glass cylindrical body having an open bottom surface 14. The small neck 16 is above the opening 18 and can be covered and sealed by a cap 20 having a needle punctureable septum 22. The bottom surface of the cartridge 12 is pushed upwards (indicated by the arrow) and pressure can be applied to the water content buffer held in the chamber 12 between the plunger and the opening 18 in the neck 16. Defined by the movable plunger 24. As just described, the configuration of the buffer container 10 is conventional in the art.

The buffer container 10 includes a plurality of sockets 32, each of which receives an individual container 10 and holds the container in an upright orientation with the opening 18 in the neck 16 exposed upward in the carrier 30. May be held in. The carrier may have a variety of configurations, but generally has an elongated structure and is conveniently inserted into the tray through a pneumatically stable port in the equilibration chamber, as detailed below. And will allow removal. For example, the carrier 30 is arranged in a linear fashion with a minimum spacing, generally 3 mm to 3.5 mm, between adjacent sockets, some, generally 1-32 sockets. 32 may be provided. A typical buffer container 10 will have a diameter in the range of 11 mm to 12 mm.

Next, referring to FIG. 3, the processing chamber 40 comprises a housing having a peripheral wall 42, a top surface 44, and a bottom surface 46. Peripheral walls may allow access to the interior of the chamber by including one or more large doors (not shown). The walls, top surface, and bottom surface will provide an atmosphere-controllable inclusion interior. The chamber does not need to be hermetically sealed and a small amount of leakage from the container is acceptable, provided that the flow rate of gas into the chamber exceeds the amount of leakage. The gas flow introduced (as described below) continuously replenishes the atmosphere, maintains substantially constant conditions in the atmosphere, and achieves the desired equilibration of the buffer container 10 as described below. There will be. The discharge port 58 is sized enough to allow the gas to escape freely and prevent any buildup of pressure in the chamber.

A plurality of horizontal supports 50 are provided inside the chamber 40, but are generally part of a rotary carousel 52 adapted to rotate at speeds in the range of 2 rpm to 5 rpm. A plurality of pneumatically stable ports 54 are provided on one or more of the peripheral walls 42 and generally support for introducing and removing the buffer container 10 by passing the carrier 30 through the port. Will provide access to each of the 50. The port will be designed to minimize the loss of gas from within the chamber during the transit process.

The carbon dioxide processing gas will be introduced through the intake port 56 near the bottom of the chamber and exhausted through the exhaust port 58 at or near the top of the chamber. The gas humidification and supply assembly 60 (FIG. 4) may generally be mounted and provided on the side of the chamber, as shown in FIG. The gas humidification and supply assembly includes a gas supply 62 that supplies carbon dioxide gas to a series of water columns 64. Generally, the gas will pass through a pressure regulator 65, where the gas flows through the columns and chambers and maintains sufficient pressure to achieve the aforementioned flow rates. The valve 66 is provided so that it can be shut off and the water filling lines 68 on each of the columns 64 are provided to allow filling to the appropriate level. Optionally, the last column may include a heating element, such as an incandescent light bulb, to ensure that the gas flowing into the processing chamber 40 is slightly above the control temperature for the chamber. By maintaining a slight temperature rise, generally 1-2 ° C, the relative humidity of the gas rises as its temperature drops to the chamber temperature, thus the relative humidity reaches the target level. It will guarantee that it will remain above. In another configuration, one of the first columns contains a heating element, such as an incandescent light bulb, which slightly raises the temperature of this column, which generally causes the cooler gas flowing into the water column. The temperature of the other water columns may not be lowered until it falls below the room temperature. Thus, the water in the last column, like the chamber, is very close to or equal to the temperature of the room, causing the relative humidity of the gas to flow out of the last column and into the chamber. Little or no change. Generally, a flow meter 70 will be provided on the line leading to the processing chamber 40 and a gas filter 72 will be useful in removing any contaminants and maintaining a clean sterile environment in the chamber. Let's go.

Next, with reference to FIG. 5A-5C, the passage of the carrier 30 having the container 10 into the processing chamber 40 through the pneumatically stabilized port 54 is described. Each of the pneumatically stabilized ports 54 present within the peripheral wall 42 has a gas barrier 76 in the form of a large flap valve, port hole door, curtain or the like. When nothing passes through port 54, the gas barrier 76 is closed to reduce gas loss from inside the processing chamber, as shown in FIG. 5A. However, the gas barrier 76 can be opened by simply passing the carrier 34 through it, as shown in FIG. 5B. This allows the carrier to be quickly introduced and placed on the support 50 with only minimal loss of gas from within the processing chamber 40. After the carrier 30 is placed on the support 50, the gas barrier 76 self-closes and restores the barrier against gas loss, as shown in FIG. 5C. Even if some gas loss occurs, the gas flow is maintained above the volume of loss due to any leakage, so that the gas is lost from the internal chamber to the outside and therefore the gas in the chamber. Will have little or no effect on the composition, pressure, and temperature of the.

Next, with reference to FIG. 6, a method for processing according to the present invention can be described. First, the individual buffer containers 10 are filled with the hydrous bicarbonate buffer B and settled in the vicinity of the meniscus M. Generally, the volume of buffer B introduced is such that the upper surface of the buffer or the meniscus M is located below the small diameter neck 16 so that the meniscus M is present within the neck. Selected to have a larger area than the one. With this larger area, the carbonic acid in the buffer can reach equilibrium with carbon dioxide in the atmosphere in the chamber 40 more quickly than if the area were reduced. The vessel 10 is then generally introduced into the processing chamber 40 after being placed on the carrier 30, as described above with reference to FIGS. 5A-5C. After being loaded onto the support 50, the container 10 is left in equilibrium with a carbon dioxide environment that is continuously replenished with carbon dioxide gas for several hours under the conditions described above. After sufficient time for the buffer in the vessel to equilibrate with the carbon dioxide in the processing chamber 40, the vessel is removed, the plunger 24 is advanced and the buffer level is opened in the neck 16. Raised to part 18. The cap 20 is then placed on top of the neck 16 with little or no headspace left, and then the individual sealed containers 10 are provided by the spring 82 being engaged with the plunger 24. , The buffer is pressurized and placed in a storage tray 80 capable of suppressing the generation of carbon dioxide gas from the buffer solution. By limiting such occurrence, the pH of the buffer will be maintained more stable. The processing tray 80 is also suitable for high pressure steam sterilization of the container to ensure sterility. The containers may then be stored and dispersed in tray 80, or may be stored and dispersed in separate containers.

The above is a complete description of preferred embodiments of the invention, but various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention as defined by the appended claims.