The invention pertains to process and a container for dissolving salt, such as pharma-grade NaCI, and the use of such salt-containing containers (cartridges) in a process wherein the salt is dissolved, e.g., a haemodialyzing process.

In various processes an aqueous solution of one or more salts, particularly NaCI, is required and various dissolution processes for the corresponding salt are known. During dissolution, however, often problems with the dissolution of the salt are encountered. Conventionally, circulation systems, very coarse forms of salt, mechanical stirrers, and/or vibrating equipment are used to make sure the salt dissolves well.

However, for applications wherein a smaller amount of a salt solution is required, such as in haemodialysing equipment, such conventional solutions are impractical. For such applications, the salt is therefore typically dissolved by flowing water through a smaller container containing the salt. For haemodialysis equipment the salt in the container has to be of pharma-grade, meaning it has to fulfil the requirements as laid down in Pharmacopoeia. Preferably, the containers are small in size, meaning they contain less than 5 kg of salt, such that the quantity is sufficient for making the required amount of salt solution. For haemodialysis equipment, the containers typically comprise up to 2 kg of salt, which is an amount sufficient for one haemodialysis treatment. Such containers are typically designed such that they have couplings attached to them so that they can be easily connected to a haemodialysis apparatus. In a suitable set-up the haemodialyser feeds water at the top of the salt container, the water flows downward through the container, dissolving salt that is in the container, resulting in a salt solution that is flowing from the bottom of the container. Such a haemodialysis machine is the Gambro® AK 100 (monitor), which works with salt containers (cartridges), the cartridges are inserted between two clamps in such a way that the side with the larger diameter points upward. The direction of flow through the cartridge is from top to bottom and indicated with arrows (water inflow at the top, outflow of the salt solution at the bottom). The inflow and outflow ports are protected against the escape of undissolved salt by means of fine screens. The cartridges that are conventionally used in this type of equipment are tapered in the direction of the flow of the liquid, so they are wider at the top than at the bottom. However, it was found that the conventional small salt containers, when used in such conventional dissolving equipment, do not always provide a salt solution with the desired concentration of the salt. It was found that this is largely due to the fact that during the dissolution step the salt bed is not always uniform, but develops layers of varying density whereby also channels are formed through the salt bed, in the direction of the flow of the liquid, through which water flows without that it is in intimate contact with the salt. As a result a salt solution is obtained that has a too low salt concentration. Typically, such a phenomenon is only observed when already more than 40% of the salt has been dissolved. The low salt concentration in the salt solution is undesired. For haemodialysis equipment typically the conductivity of the salt solution is being measured as a way to monitor the salt concentration in the solution during the dialysis. A too low conductivity will sound an alarm and corrective action is to be taken, which is particularly undesired when the dialysis is performed during the night. Therefore, there is a clear need for a system wherein a small amount of salt is dissolved over a period of time in a way that results in a delivery of a salt solution with a concentration of salt which is more constant over the delivery period. Preferably the concentration of the salt in the solution is such that it is almost or fully saturated, for NaCI this means that the amount dissolved in the water is from 4500 - 5500 mmol/l, preferably from 5000-5500 mmol/l. Accordingly, an object of this invention is the development of process and a salt container, or cartridge, which is particularly suitable for use in a haemodialysis apparatus and optionally in other equipment, which enables to obtain delivery over time of a more constant concentration of the salt in the solution, whereby the salt solution is almost or fully saturated. Preferably the salt concentration in the solution is constant till more than 90% w/w, preferably more than 95%w/w of the salt is dissolved.

Surprisingly it was found that a process according to claim 1 solved all of the problems.

More specific embodiments of the invention include processes of claim 1 using one or more pharma-grade salts, preferably pharma-grade NaCI.

Water is forced through the container containing the salt. The water can for instance be forced by pumping.

The object of the invention is also achieved with equipment in which the containers containing the salt are used to produce a salt solution, and the use of the containers containing salt to produce a salt solution.

The container can be designed in such a way that it comprises an inflow port (inlet) and an outflow port (outlet), which ports are preferably in line at opposite ends of the container, whereby the container comprises one or more salt chambers between said ports in which one or more salts can be stored. The container comprises at least one salt chamber that has a cross-sectional area perpendicular to an axis running from the inlet to the outlet, which cross sectional area expands in the direction of the outflow port. Preferably, such a section that is widening in the direction that the liquid is flowing, is located near the outflow port. The container comprises filters or screens between the salt chamber and the ports to prevent undissolved salt particles from escaping the container. Preferably, screens are used with holes having a diameter of from 50 to 100 micrometer.

Preferably the salt chamber of the container has a size such that it can hold a preferred maximum of 2 kg of salt, more preferably a maximum of 1.5 kg and most preferably a maximum of 1.3 kg and a minimum of 0.5 kg, preferably a minimum of 1 kg, and most preferably a minimum of 1.1 kg. Suitably the container can hold an amount of about 1 .2 kg of salt. The overall volume of the container is preferably not more than .5 times the volume of the salt, so that they are easily handled. It is noted that such containers can contain enough salt for one haemodialysis treatment session and, as such, can be used in small equipment without the necessity to use larger batch containers and circulation pumps as described in DE 19931077.

Preferably the salt chamber comprises a widening section which can hold at least 40% of all salt in the container, more preferably at least 60% of all salt, and most preferably at least 70% of all salt.

When used in accordance with the present invention, prior art containers typically show channelling of the water flow through the salt mass after partial dissolution of the salt. There appears to be a relation with the particle size of the salt particles and the containers of the invention are particularly beneficial for salt with a smaller particle size. Although they can be used for all salt particles, they are particularly suited for salt with a particle size having a d50 (as determined by the conventional sieving techniques as defined in ISO 2591 -1 ) of less than 0.8 mm, preferably less than 0.6 mm, even down to 0.4 mm. In view of the risk of salt dust leaving the outflow port, the salt preferably has a particle size distribution with a d50 of at least 0.2, preferably 0.3 mm.

The salt that is to be used in accordance with the invention can be any salt. Preferably it is a salt, or a combination of salts. In a preferred embodiment of the invention, the salt is selected from one or more of NaCI, NaHC0 ₃ , Na ₂ C0 ₃ , KCI, CaCI ₂ , MgCI ₂ , and salts of acetic acid, gluconic acid, citric acid, ascorbic acid. Preferably the salt is pharma-grade NaCI. Optionally, the salt may contain other additives as long as they are acceptable for use in the process wherein the salt solution is used, e.g. because they are inert and/or do not dissolve in the dissolution step.

In order to achieve the desired dissolution process without the channelling through the salt occurring, the widening container proved to be practical. For a good performance, the cross sectional expansion is preferably progressive, e.g. linear or non-linear, over at least a part of the distance between the inlet and the outlet, preferably at a section directly upstream the filter near the outlet. In a refinement, the progression of the cross-sectional expansion may be above a certain minimum. For salt chambers with a circular cross-section near the outlet filter, which is preferred, the delta-d/l ratio preferably is >= 0.070, more preferably >0.075, even more preferably >0.08, and most preferably >0.085, whereby d stand for the diameter, the delta-d is the difference in the diameter of the cross section near the outlet filter (in mm) over the length I (in mm) of the section of cross- sectional expansion (the bottom section). For salt chambers with a non-circular cross-section, the cross-sectional expansion should be such that the change in surface of the cross-section over the length of the bottom section is the same as defined for the containers with a circular cross-section. For ease of production, different sections of the salt chamber preferably all have the same linear progression of widening, which allows for easy demoulding and simple shapes.

For containers having a circular cross-section near the outlet filter, which is preferred, the l/average-d of the bottom section is preferably >=1 , more preferably >1.5, even more preferably >2, and most preferably >2.2, whereby l/(average-d) is typically below 20 for practical reasons. (Average-d) is the average diameter of the bottom section (in mm) over the length I (in mm) of the bottom section. For container having a non-circular cross-section near the outlet filter, the ratio of I and the averaged surface of the cross section should be the same as defined for the containers with a circular cross-section.

The outlet of the container is at a distance below the inlet. In a refinement, the inlet is at the top end of the container. In a further refinement, the outlet is at the bottom end of the container. The inlet and the outlet can be arranged in line with each other with a linear flow path running from the inlet to the outlet. The flow path is downward, preferably vertical.

The container can for instance be of a flexible or collapsible material, or it can be a rigid container or cartridge, i.e., with a stable shape, For all embodiments of the invention it is preferably a rigid container.

In order to strengthen the containers, they may have ridges, ribs and/or other means to reinforce them.

The inflow and outflow ports of the container are preferably designed in such a way that they comprise connectors which allow for an air and liquid-tight connection with the equipment during the dissolution of the salt. The connectors of the container are preferably designed such that they allow only one way of connecting the container to the equipment. This prevents the containers from being connected upside-down. The container can for instance be a removable cartridge, which can be easily placed and removed by a user.

In the dissolution process the cartridges (the containers containing salt) are fed at the top, through the inflow port with water, preferably purified water, while the salt solution is pushed through, or pumped from, the bottom outflow port. Preferably the dissolution process starts by filling the cartridges with water so that air is expelled. It may be preferred to expel all air, but good results may be obtained when at least the air so much air is expelled that all salt is below the water level in the container.

During the dissolution process, the cartridges may be pressurized or not by regulating the feed and/or removal rate. Preferably the process is operated such that the pressure inside the container is from atmospheric to 6 bara, preferably up to 3 bara, more preferably up to 1.5 bara. Higher pressures are undesired for risk of bursting and a heavier construction of the cartridge being required. Preferably, the feed and removal rate of the process is controlled such that the flow is from 8 to 15 ml/min.

In the dissolution process, the water that is fed to the cartridge is preferably from room temperature up to 55 degrees, preferably up to 40 degrees Celsius. A higher temperature is undesired for the risk of burns. For haemodialysis equipment, the feed temperature is preferably up to 39 degrees Celsius, so that a salt solution results, which is at about body temperature.

The salt containing sections, screens, ports, and the parts of the container between screens and ports can have any shape, form, or size, as long as the essential requirements as presented above are fulfilled and the desired flow of water and salt solution can be achieved.

The containers can be produced using conventional techniques, particularly injection moulding techniques, whereby preferably two or more parts are produced such that one part contains one port, one screen, and one or more sections that will contain the salt, and the other part contains the other port and screen, and optionally another section, or part thereof, that will contain the salt. Such a process allow filling of one or both parts with salt, after which the parts are joined in an air and water-tight way, e.g. using clamping, welding or gluing techniques. Preferably the containers are made of plastic, more preferably of polypropylene. The invention also relates to an apparatus for carrying out the disclosed process, wherein the apparatus comprises a receiving unit for a container according to the present disclosure. The apparatus can for instance be a haemodialysis apparatus. To connect the container with the apparatus, the apparatus may comprise a first connector for cooperation with a corresponding connection element of the container inlet, and a second connector for cooperation with a corresponding connection element of the container outlet. The connectors should preferably provide a leak tight connection. To prevent erratic positioning of the container, the first and second connectors are preferably configured such to allow only a single positioning of a container in the apparatus. The apparatus may comprise one or more pumps for forcing water from a water supply or water source into the salt container and through the salt contained in the salt container.

The term "cross sectional area" is meant to refer to the cross section perpendicular to the flow direction.

The invention is elucidated by the following examples.

Examples

The pharma-grade NaCI that was used in the examples below was Sanal® P that complied the Pharmacopoeia. Batch 4101460801. Properties: Poured Bulk Density 1260 kg/m3. Tapped Bulk Density 1480 kg/m3. Angle of repose 48°. Mean particle size 378 μηη.

Comparative

A tapered circular glass vessel with a bottom diameter of 4 cm, a top diameter of 7.5 cm, a length of 34 cm, a bottom outlet, and fitted with a glass frit 2 cm above the bottom outlet, was suspended and filled 1.2 kg of pharma-grade NaCI. The glass vessel was capped with a glass top having an inlet and a glass frit 1 cm below the inlet. The top was clamped on the vessel such that vessel and top were connected in a leak-free way. Water was poured in the glass vessel, while closing off the bottom, so that the salt was covered with liquid. At the start of the process, water was fed to the inlet on the glass top, using a regular tap water supply and a Fischer Porter® flow meter with regulator, which was set at a flow of about 500 cm ³ /h.

The brine flowing from the bottom was collected at atmospheric pressure in a graduated cylinder.

Already within one hour after starting the flow of the water, layers were seen at about 2 cm below the top of the salt mass. After one hour a layer of salt had formed which bridged the vessel, resulting in a space with just water between said layer and the salt mass below. Also layering was seen at a height of 10 cm below the top of the salt mass. After 1.5 hour said space consisted partially of air, partially of water, and the second layer had disappeared. After two hours, probably due to channelling, the conductivity of the water had reduced from 233 mS/cm to 207 mS/cm. It was only till after 3.5 hours that the salt bridging the vessel had collapsed. After 5 hours all salt had been dissolved.

Example 1

A container consisting of a tapered circular glass vessel, glass top and clamp, as used in the previous example was filled with 1.2 kg of pharma-grade NaCI and mounted such that a container resulted with a narrow top and a wide bottom, whereby the top diameter was 4 cm, the bottom diameter was 7.5 cm, and the length 34 cm, a top inlet, a glass frit 2 cm under the inlet, a bottom outlet, and fitted with a glass frit 1 cm above the bottom outlet. Water was poured in the glass vessel, while closing off the bottom, so that the salt was covered with liquid. At the start of the process, water was fed to the inlet on the glass top, using a regular tap water supply and a Fischer Porter® flow meter with regulator, which was set at a flow of about 500 cm ³ /h.

The brine flowing from the bottom was collected at atmospheric pressure in a graduated cylinder.

After starting the flow of the water, no layers were seen and the conductivity of the water varied from 224 to 234 mS/cm. After 4.5 hours all salt was dissolved.

The invention is further explained with reference to the drawing. In the drawing: Figure 1 : shows schematically a haemodialysis apparatus with a cartridge according to the invention;

Figure 2: shows an alternative embodiment of a cartridge;

Figure 3: shows a third embodiment of a cartridge. Figure 1 shows schematically a haemodialysis apparatus 1 comprising a main body 2 and a receiving unit 3 holding a replaceable cartridge 4 containing 0,5 - 2 kg of a pharma-grade salt. The cartridge 4 has an inlet 5 at its top end and an outlet 6 at its bottom. The receiving unit 3 of the apparatus 1 comprises a first connector 7 for cooperation with a corresponding connection element 8 at the inlet 5 of the cartridge 4. The receiving unit 3 further has a second connector 9 for cooperation with a connection element 0 at the outlet 6 of the cartridge 4.

A water supply line 1 1 leads from the main body 2 of the apparatus 1 to the receiving unit 2 and is operatively connected to the inlet 5 of the cartridge 4. The water supply line 1 1 can selectively be opened and closed by means of a valve 12.

A return line 15 is operatively connected to the outlet 6 of the cartridge 3 and leads back to the main body 2 of the apparatus 1 for controlled delivery to a patient or a buffer container for temporary storage. The return line 15 comprises a valve 16 for selectively opening and closing the return line 15. The cartridge 3 comprises a salt chamber 17 between the inlet 5 and the outlet 6. All undissolved salt in the cartridge is contained in the salt chamber 17. Filters 18, 19 separate the salt chamber 17 from the inlet 5 and the outlet 6, respectively. The filters 18, 19 are configured to retain undissolved salt particles within the salt chamber 17 and are permeable for aqueous salt solutions. The salt chamber 17 confines a flow path from the inlet 5 downwards to the outlet 6. The flow path is indicated with the arrows F in the drawing. The salt chamber 17 - and consequently also the flow path F - has a cross-sectional area linearly expanding in the direction towards the outlet 6 over the full length of the flow path F. The cross sectional expansion is such that the delta-d/l ratio is >0.085, with delta-d being the difference in diameter relative to the cross sectional diameter near the outlet filter (in mm) over the length I (in mm) of the section of cross-sectional expansion.

The salt chamber 7 is wider at the position of the filter 19 near the outlet 6 than at the position of the filter 18 near the inlet 5. The filter 19 near the outlet 6 is positioned in the widest part of the salt chamber 17. Figure 2 and 3 how alternative embodiments of the cartridge 3. In Figure 2 the salt chamber 17 comprises an upper section 20, a middle section 21 and a bottom section 22. The upper section 20 has a cross sectional area which is cylindrical or slightly narrowing down towards the outlet 6. The upper section 20 is continued by the middle section 21 which has a cross sectional area expanding in downward direction. The upper section 20 is continued by the substantially cylindrical bottom section holding the outlet filter 19. The cartridge shown in Figure 3 comprises a salt chamber 30 with sectional area expanding non-linearly in downward direction.