MXPA06004045A - Activated carbon treatment - Google Patents

Abstract

The present invention relates to a process for purification of a compound using an activated carbon treatment. In the process according to the present invention several filter units containing activated carbon immobilized in a matrix are operating in series and in a counter current mode. After passing a suitable volume of feed, a filter unit from the first series of filter units is disconnected at a particular position number, and an additional filter unit is connected at another particular position number herewith obtaining a next series of filter units where over the passing of a next volume of feed is continued. This process overcomes the problem of loss of yield of the purified compound as occurs during conventional activated carbon treatment.

Description

CARBON TREATMENT ACTIVATED FIELD OF THE INVENTION The present invention relates to a process for the purification of a compound by the use of activated carbon treatment.

BACKGROUND OF THE INVENTION For decades, in processes for the purification of valuable compounds, treatments with activated charcoal are applied where the powder of activated carbon in bulk is used to remove impurities such as colored species of valuable compounds. However, the problem when using bulk activated carbon powder is that activated carbon particles always migrate downstream causing contamination with carbon in the subsequent recovery steps. Also, working with bulk coal in industrial scale purification processes does not benefit health and safety. More recently, activated carbon cartridges have been developed to overcome these problems. In these cartridges, activated charcoal is immobilized in a filter medium .. The use of an activated carbon cartridge is described for the purification of penicillin V (R. Jansson and M. eaver, Manufacturing Chemist, March 2002, p. 30). However, despite the fact that the use of carbon cartridges also eliminates the consumption of time in the recovery processes and leads to an improved quality of the final product, the cartridges have not been widely implemented in industrial processes, despite of the deep effort to achieve an improvement in the conventional treatment of coal. One of the problems is that the yield of the desired compound is not always favorable enough to perform the purification with activated carbon cartridges at a commercially efficient industrial level.

SUMMARY OF THE INVENTION The object of the present invention is to overcome this problem of insufficient yield of the desired compound. This problem is solved by the present invention by passing a supply containing the desired compound through a series of filtration units containing activated carbon, operating in series and in a counter current mode.

DETAILED DESCRIPTION OF THE INVENTION The present invention thus relates to a process for the purification of a compound, said process comprises a treatment with activated carbon using a filtration unit containing activated carbon immobilized in a matrix, the treatment comprises: a) The passing an appropriate volume of a supply containing the compound over a first series of n connected filtering units operating in series to obtain an effluent, where n is at least 2 of said filtration units that have been assigned a number position 1 an in the series and position number 1 being the first provided with the supply, b) Disconnection of a filtration unit from the first series of filtration units in any position between 1 to n-1 after passing an appropriate volume supply, and the connection of a fresh filtration unit in any position that has a number greater than the number of position of the filter unit disconnected, resulting in a next series of filtration units, c) Step to an appropriate next volume of supply containing the compound on the next series of filtration units to obtain a following effluent, d) Optional combination of the effluents obtained in a and c, and e) recovery of the effluent compound.

Use of a carbon treatment according to the present invention which results in an increase in the yield of the purified compound. Also, use of carbon treatment according to the present invention which results in a complete or almost complete utilization of the available adsorption capacity of the activated carbon. In addition, application of the activated carbon treatment according to the present invention provides a high capacity purification system. A high capacity implies shorter processing times and improved logistics. This produces an increase in the capacity to produce more valuable compound on an industrial scale. further, the yield in the purified compound is increased, especially in processes for the purification of unstable compounds. The carbon treatment according to the invention is applicable to any purification process of a compound of interest where a conventional treatment with activated carbon is used. In the present invention, the compound to be advantageously purified may be an unstable compound, i.e. a compound that decomposes and / or degrades as soon as the process and / or the storage time increase. The compound may comprise secondary metabolites or proteins. Secondary metabolites may comprise antibiotics, vitamins, carotenoids or polyunsaturated fatty acids (PUFAs). The proteins may comprise enzymes, such as proteases, amylases, cellulases, xylanases, lactases, or their precursors. Streptomycin antibiotics may comprise, chloramphenicol, actinomycin, tetracycline, natamycin, ß-lactam compounds like clavulanic acid, penicillin G, penicillin-V, cephalosporin C, cephamycin, 6-aminopenisilínico (6-APA), 7- aminodeacetoxi cephalosporin (7-ADCA) acid, 7- aminocephalosporanic (7-ACA), semisynthetic penicillins such as amoxicillin, cloxacillin, flucloxacillin, methicillin, oxacillin, carbenicillin, ampicillin and semisynthetic cephalosporins such as cephalexin, cefadrina, cephaloridine, cephalothin, cefaclor, cefadroxil. The carotenoids may comprise β-carotene. In a particular embodiment of the present invention, the compound is produced by fermentation using a microorganism. The micro-organism may be prokaryotic or eukaryotic or a cell or a cell line of plant or mammalian origin that is capable of producing a compound of interest during fermentation. Preferably, the microorganism is a bacterium, a fungus or a yeast. The bacterium can be a strain of E. coli, Streptomyces, Bacillus or Propionibacterium. The fungus can be a strain of Penicillium, Aspergillus or a strain of Mucor. The yeast can be a strain of Saccharoxpyces, Kluyveromyces or Pichia. In a preferred embodiment of the present invention, the compound is obtained by fermentation using a micro-organism of the Streptomyces species. The compounds obtained by fermentation of Streptomyces species are particularly suitable to be purified using the carbon treatment according to the present invention since the fermentation broth obtained from Streptoiriyces species, and also obtained the compound containing a colored species and other impurities They can notably be manifested with a color from yellow to red / brown. In accordance with the present invention, these colored species and other impurities are very efficiently removed from the compound with a surprisingly high yield of the purified compound. The preferred Streptomyces species may be Streptomyces clavuligerus, S. coelicolor, S. griseus, S. Venezuela, S. aureofaciens. The compounds produced by these strains can be clavulanic acid, streptomycin, icina cefa, Amphenicol clora, tetracycline, actinomycin or -carotene. Preferably, the compound is clavulanic acid. The fermentation fluid comprising the compound of interest can be separated from the biomass in the fermentation broth by filtration. Optionally, the fermentation fluid comprising the compound can be concentrated and / or the compound can be precipitated or purified using techniques known in the art, before treatment with activated carbon. The supply that is subject to the treatment with activated carbon according to the present invention contains the compound and includes a solvent. The solvent that is typically used will depend on the compound of interest. It can be water, an alcohol, a ketone, an ester, an ether or a mixture of them. Preferably, it comprises an ester such as an alkyl acetate, more preferably ethyl acetate or methyl acetate. The filtration units contain activated carbon immobilized in a matrix. The matrix can be any porous filter media permeable to the supply containing the compound. Preferably, the matrix comprises a support material and / or a joining material. The support material in the matrix can be a synthetic polymer or a polymer of natural origin. The synthetic polymer may include polystyrene, polyacrylamide, polymethyl methacrylate. The naturally occurring polymer may include cellulose, polysaccharide, dextran, agarose. Preferably the support polymer material is in the form of a fiber network to provide sufficient mechanical stiffness. The bonding material can be a resin. The matrix can have the shape of a membrane sheet.

Preferably, the activated carbon immobilized in a matrix can be in the form of a cartridge. A cartridge is a self-containing and easily replaceable entity that contains the powdered activated carbon immobilized in the matrix and prepared in the form of a membrane sheet. The membrane sheet can be captured on a plastic permeable support to form a disc. Alternatively, the membrane sheet can be spiral wound. To increase the surface area of filtration, several discs can be stacked side by side. Preferably, the stacked disks have a central tube tube in the form of a tube to collect and remove the carbon-treated supply from the filtration unit. The configuration of stacked discs can be lenticular. It is also possible to add cartridges to an existing filtration unit, either by putting additional cartridges in the same collector shaft (and increasing the height of the stack) or accommodating a parallel stack of cartridges in the same filtration unit and, optionally, connecting the separate collector axes in an outlet at the base of the filtration cover. The coal can be used from different sources of raw material such as peat, lignite, wood or coconut shells. The choice of carbon source depends on the compound to be isolated and can be determined according to methods known in the art. Any process known in the art, such as chemical or steam treatment, can be used to activate the coal. In the present invention, the activated carbon immobilized in a matrix can be placed in a cover to form an independent filtration unit. Each filtration unit has its own input and output for the supply containing the compound to be purified. Examples of filtration units that are usable in the present invention are the carbon cartridges of Cuno Inc. (Meriden, USA) or Pall Corporation (East Hill, USA). In the process of the invention, after passing an appropriate volume of supply through a filtration unit at any position number between na n-1 it is disconnected from the series of 1 an connected filtering units and a fresh filtration unit is connected to any position that has a position number greater than the position number of the filter unit disconnected (switching filtration unit). The size of the "appropriate volume of supply" (or the time of the switching of the filtration unit) depends on several parameters and can be determined by optimization of the normal process. For example, the volume of supply may depend on the required quality of the effluent and / or the number of filtration units used. Thus, the switching of the filtration unit can occur at the moment that a used filter unit is substantially saturated with impurities. The time when a used filter unit is substantially saturated with impurities can, for example, be visible by the color of the effluent which reaches a value which is not acceptable. In a preferred embodiment, the delivery volume that passes through the first series of connected filtration units n is of the same size as the next supply volume that passes over the next series of filtration units. In this way, the logistics of the process remain as simple and reproducible as possible. In another preferred embodiment of the invention, a filtration unit can be disconnected in the position number 1 and a fresh filtration unit can be connected in the position number n + 1. To decrease losses of the compound of interest, the filtration unit can be rinsed with solvent before commutating the filtration unit, preferably using the same solvent in which the compound is dissolved. Rinse with solvent can be preceded and / or followed by purging with a gas, preferably nitrogen. In this way the residual product adsorbed to the coal and / or the residual product in the remaining supply volume within the matrix can be recovered. In the process according to the present invention a supply containing the compound is passed through at least 2 connected filtration units operating in series, i.e. n is at least 2. Preferably n is 2 to 10. More preferably, n is 2 to 4, much more preferably n is 3. Also, several filtering units operating in series can additionally be connected in parallel in order to process large streams of the supply comprising the compound to be purified. In a particular embodiment of the invention, wherein a series of 2 connected filtering units is used, the filtering unit in the number one position, i.e. at the head of the series, it is supplied with a supply containing the compound to be purified and the effluent from this filtration unit is passed over a second filtering unit at position number two. When an appropriate volume of supply has passed through the filtration units, a commutation in use of the filtration units is made by disconnecting the filtration unit in position number 1 and connecting a fresh filtration unit in the position number 3, resulting in a re-numbering of the positioning numbers since the original filtering unit in position number 2 is now first supplied with the supply and assigned position number 1 and the filtration unit previously in position number 3 is now assigned to the position number 2. In another embodiment of the invention, when a series of 3 connected filtering units is used, the filtering unit in the number one position, ie at the head of the series, it is supplied with the supply containing the compound to be purified and the effluent from this filtration unit is passed through a second filtering unit at position number two, and the effluent from this filtration unit it is passed through a third filtering unit at position number three. When an appropriate volume of supply has been passed through the three filtration units, a switch in use of the filtration units is made by disconnecting the filtering unit in the number one position and connecting a fresh filtration unit in the number position. four, which results in a subsequent re-numbering of the position numbers since the original filtering unit in position number two is now first supplied with the supply and assigned the number one position and the filtration unit previously in the position number three is now assigned to position number two and the fresh filtration unit connected to position number four is now assigned to position number three. Alternatively, instead of disconnecting the first filtering unit, the second (ie at position number two) can be disconnected, resulting in the filtering unit at position number one remaining here since it is still supplied first with the supply and filter unit in position number three is now assigned to position number two and the fresh filtration unit connected to position number four is assigned to position three in the second series. The filter unit disconnected from the series is a filtration unit containing used activated carbon, i.e. the supply containing the compound to be purified has been passed through the activated carbon. The fresh filtration unit that is connected to the series is a filtration unit that may contain unused activated carbon (i.e. activated carbon not used before) or may contain activated carbon used before and regenerated. The fresh filtration unit can be moistened with solvent and subsequently purged with nitrogen before use. The regenerated activated carbon has been subjected to a regeneration process to recover the adsorption capacity of activated carbon. The regeneration may be accompanied by rinsing with a solvent according to the processes known in the art. Typical solvents for regeneration can be methanol, ethanol, acetone or ethyl acetate. Regeneration can occur in situ. With in situ is meant that the filtration unit containing the activated carbon that is regenerated is rinsed with a solvent without the need to physically remove the filtration unit from its position in the series or physically move the activated carbon from the filtration unit . During regeneration the activated carbon may be subject to the operations of rinsing with the solvent present in the previous supply, and / or rinsing with the regeneration solvent, and / or soaking with the solvent present in the next supply. Between the rinsing and / or soaking operations the activated carbon can be purged with a gas, preferably nitrogen. In the processes according to the present invention, each filtration unit can be connected and disconnected from the series of filtration units by physical movement of the unit. Preferably, the filtration unit can be connected and disconnected from the series of filtration units without physical movement of the unit. This can be facilitated by a flow distribution system. This flow distribution system can be fully automated. Preferably, the flow distribution system may comprise multi-functional and multi-port valves preferably of the blocking-and-bleeding type. The operation of said valves can be controlled by software. More preferably, the connection and disconnection of the filtration units takes place simultaneously. In the present invention, the process can be operated in batches, in continuous or semi-continuous mode. With the operation in the batch mode it is undoubtedly a process in which an appropriate volume of supply is passed through the connected filtering units operating in series and where said supply is terminated at the moment in which a filtration unit is disconnected and / or a fresh filtration unit is connected to the series. Subsequently, after disconnection and connection (switching of the filtration unit) has taken place, the flow of supply is continued with an appropriate next volume of supply.

With the operation in continuous mode it is undoubtedly a process where the flow of the supply is not interrupted at the moment in which a filtration unit is disconnected and a fresh filtration unit is connected, i.e. it is not interrupted at the time of switching the filtration unit. Thus an appropriate volume of supply and any appropriate next volume of supply are continuously passed through the series of n connected filtering units, with the switching of the filtering unit occurring at appropriate time intervals. The operation in the continuous mode is preferably done in a situation where it is known that the delivery volume can be passed from the series of filtration units before the switching of the filtering unit occurs. This knowledge can be obtained by experience or, for example, on-line measurements. A prerequisite of operation in the continuous mode is that the time necessary for the operation of the switching of the filtration unit must be shorter than the time necessary to substantially saturate a filter unit with impurities. A continuous process can be terminated, for example, when a change to a new protocol (tanda) is desired or for reasons of cleaning or maintenance. With the operation in semi-continuous mode it is undoubtedly a process where the supply is not interrupted at the moment when a filter unit is disconnected and a fresh filtration unit is connected, i.e. it is not interrupted at the time of switching of the filtration unit, but where the supply is interrupted to prevent substantial saturation of a filter unit with impurities. The last thing that can happen when the time necessary for the commutation of the filtration unit is longer than the time necessary to substantially saturate a filter unit with impurities. The process according to the present invention can be carried out in a variety of modalities, all aimed at increasing the performance of the compound. In a first embodiment, the supply flow rate is 0.05 to 400 L / min, preferably 20 to 100 L / min, more preferably 30 to 40 L / min. The flow velocity of the supply is at least 0.05 L / min. Preferably the flow rate is at least 20 L / min, more preferably the flow rate is at least 30 L / min. The flow rate can have a maximum of 400 L / min. Preferably the flow rate is not above 100 L / min, more preferably, the flow rate is not above 40 L / min. In another embodiment, when the activated carbon immobilized in a matrix is in the form of a membrane sheet with a given surface area in square meters (m2), the flow of the supply is from 1 to 50 L / m2 / min. , preferably 1.5 to 20 L / m2 / min., more preferably 1.5 to 10 L / m2 / min. Preferably, the flow is at least 1 L / m2 / min. More preferably, the flow is at least 1.5 L / m / min. The flow can have a maximum of 50 L / m2 / min., Preferably the flow is not greater than 20 L / m2 / min., More preferably the flow is not greater than 15 L / m2 / min. By flow is meant the flow rate of the supply per square meter of the surface area of the membrane sheet. In yet another embodiment, the residence time of the supply containing the compound in a simple filtration unit is at least 15 seconds and maximum 60 minutes. The residence time of the supply containing the compound in a simple filtration unit is at least 15 seconds, preferably it is at least 30 seconds, more preferably it is at least 60 seconds, much more preferably it is 2 minutes. The residence time of the compound in a single filtration unit is maximum 60 minutes, preferably it is not more than 30 minutes, more preferably it is not more than 15 minutes. The residence time of the supply containing the compound in a simple filtration unit can be determined by measuring the difference between the supply to the inlet and the supply to the outlet through a simple filtration unit. When a supply containing the compound is passed through n filtration units connected in series, the total residence time of the supply in the series is n times the residence time in a single filtration unit.

In yet another mode, the process can be operated at a temperature between minus 10 to +40 ° C. It can be clear that the temperature is chosen in such a way that the supply containing the compound is in the liquid phase before and after passing through the filter units. The temperature can be dependent on the type of solvent present in the supply, and the thermostability of the compound. The temperature is at least -10 ° C, preferably it is at least 2 ° C, preferably it is no more than 25 ° C, more preferably it is no more than 15 ° C. After application of the activated carbon treatment according to the present invention, the compound is recovered from the effluent according to the process known to a person skilled in the art. The processes that are used for recovery will typically depend on the type of compound and / or the intended use. The recovery may include one or a combination of at least two of: stabilizing the compound in the effluent with appropriate stabilizing agents, concentrating the effluent, drying the effluent, subjecting the effluent to a granulation process, purifying the compound out of the effluent by e.g. crystallization and / or column chromatography. The recovered compound can then be converted into a pharmaceutically acceptable salt or a food grade product.

Example 1 An aqueous broth of clavulanic acid obtained by fermentation of Streptomyces clavuligerus was filtered, extracted and concentrated at 30g / l before treatment with activated charcoal. 500 ml of concentrated extract were added to a beaker containing 50 g of powder activated charcoal in bulk and a magnetic stirrer. After a reaction time of 90 minutes, the activated carbon was separated from the extract using a Buchner funnel. The percentage of discoloration was determined by measuring the differences in extinction of the extract in a colorimeter before and after the treatment with activated charcoal. The discoloration was 90%. The yield of clavulanic acid after treatment with activated charcoal was 86%. Example 2 An aqueous fermentation broth obtained from clavulanic acid was filtered, extracted and concentrated at 3 g / 1 before treatment with activated charcoal. 500 ml of the concentrated extract was passed through a simple filtration unit containing an activated carbon filtration plate (Zetacarbon® R35, 090 mm from CUNO Ltd.) with an effective surface area of approximately 0.0057 m2. The flow of the supply with the concentrated extract through the filtration unit was set at 0.03 L / min. The flow was 5.0 L / min / m2. The discoloration was of. 90% The yield of clavulanic acid after the treatment with charcoal was 90%. Example 3 A 37.5 liter supply containing concentrated clavulanic acid (25 g / L) was passed through 3 connected filtration units operated in series, each filtration unit containing fresh activated carbon cartridges (Zetacarbon® C08DB; R35S from CUNO Ltd .) with approximately 0.29 2 effective surface area. The flow rate of the supply was 1.0 L / min and the flow was 3.5 L / min / m2. The filtration unit in position number 1 was first supplied with the supply containing the impure extract. The filtration unit in position number 2 was exposed to the effluent of filtration unit 1. The filtration unit in position number 3 was exposed to the effluent of filtration unit 2. A fourth additional filtration unit was interconnected in the series in position number 4 but not in service since it is not connected to the series of the 3 units of filtrations. After having passed the 37.5 liters of extract through the 3 filtration units, filtration unit number 1 was then supplied with the supply that was disconnected from the series and an additional filtration unit previously in position number 4 was connected to the series resulting in a new assignment of the position numbers: the unit previously in position number 4 is now assigned with the position number 3; the unit previously in the position number 3 is now assigned to the position number 2; the unit previously in the position number 2 is now assigned in the position number 1, to form a second series of 3 units of filtration operating in series, where the first and the second unit in the series have been used and the third unit of Filtration in the series is fresh. After disconnecting the filtration unit and connecting the fresh unit, the supply was continued by passing 37.5 liters of untreated charcoal supply containing the concentrated extract of clavulanic acid through the second series of 3 connected filtering units. In this second filtration the discoloration was 94%. The total yield in clavulanic acid was 94%. EXAMPLE 4 The activated carbon treatment of Example 3 was repeated with the following difference: The filtration units in the first and second series of connected filtration units respectively contained two cartridges used in the number 1 position, a cartridge used in the number position 2 and a fresh cartridge in position number 3. In the second filtration the discoloration was 93%. The yield of clavulanic acid in the total decolorized extract was 97%. Example 5 The treatment with activated carbon was carried out according to example 4. After passing the supply with clavulanic acid through the second series of filtration units, the cartridges with activated carbon contained in the filtration units were washed by passing them through. 1 of ethylacetate through the filtration units. The discoloration was 94%. The total bleached extract yield collected was 98%.

Claims (19)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS

1. A process for purifying a compound comprising an activated carbon treatment using a filtration unit containing immobilized activated carbon in a matrix, the treatment comprising: a. passing an appropriate volume of a supply containing the compound through a first series of connected n filtration units operating in series to obtain an effluent, where n is at least two, said filtration units have been assigned in number position 1 an in the series and position number 1 being the first one supplied with the supply, b. disconnection of a filtration unit from the first series of filtration units at any position number between 1 to n-1 after the passage of an appropriate volume of supply, and the connection of a fresh filtration unit in any position having a number greater than the position number of the filter unit disconnected, resulting in a subsequent series of filtration units, c. passing an appropriate volume of supply containing the compound through the following series of filtration units to obtain a following effluent, d. optional combination of the effluents obtained in a and c, and e. recovery of the effluent compound.

2. The process according to claim 1, wherein the filtration unit is disconnected at the position number between 1 to n-1 and wherein the fresh filtration unit is connected at the n + 1 position.

3. The process according to claim 1, wherein the filtration unit is disconnected from the position number 1 and wherein the fresh filtration unit is connected in the position n + 1.

4. The process according to any of claims 1 to 3 wherein the number n of filtering units connected operating in series is from 2 to 10.

The process according to any of claims 1 to 4, wherein The treatment is operated in batch, semi-continuous or continuous mode.

The process according to any of claims 1 to 5, wherein the flow rate of the supply is 0.05 to 400 L / min, preferably 20 to 100 L / min, more preferably 30 to 40 L / min.

The process according to any of claims 1 to 6 wherein the activated carbon immobilized in a matrix is in the form of a membrane sheet.

The process according to claim 7, wherein the flux on the membrane sheet is 1 to 50 L / m2 / min., Preferably 1.5 to 20 L / m2 / min., More preferably 1.5 to 10 L / m2. / min.

The process according to any of claims 1 to 8, wherein the residence time of the supply containing the compound in a simple filtration unit is at least 15 seconds and maximum 60 minutes.

10. The process according to any of claims 1 to 9, wherein the process is operated at a temperature between -10 ° C to 40 ° C.

The process according to any of claims 1 to 10, wherein at least one disconnected filtration unit is regenerated in situ by rinsing with a solvent.

12. The process according to any of claims 1 to 11, wherein the compound is an unstable compound.

13. The process according to claims 1 to 12, wherein the compound is a secondary metabolite or a protein.

The process according to claim 13, wherein the secondary metabolite is selected from the group consisting of an antibiotic, a vitamin, a carotenoid or a PUFA.

15. The process according to any of claims 1 to 14, wherein the compound is obtained by fermentation using a microorganism.

16. The process according to claim 14, wherein the microorganism is a Streptomyces species.

17. The process according to claim 15, where the Streptomyces species is selected from the group consisting of S. clavuligerus, S. coelicolor, S. griseus, S. Venezuela, S. jumonj inensis, S. katsurahamanus or S. aureo faciens.

18. The process according to claims 14 to 17, wherein the compound is selected from the group consisting of clavulanic acid, streptomycin, chloramphenicol, tetracycline or β-carotene.

19. The process according to any of the preceding claims, further comprising the step of converting the compound into a pharmaceutically acceptable salt or a food grade product.