Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-11-22
2003-02-04
Leary, Louise N. (Department: 1627)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S016800
Reexamination Certificate
active
06515115
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for isolating a desired water-soluble product from a fermentation broth.
BACKGROUND OF THE INVENTION
Nowadays fermentation processes for preparing chemical compounds play an increasing role in chemistry. As this kind of process is highly selective, environmentally attractive and leads to high product yields, even industrial preparations are carried out this way.
After a fermentation is completed, the desired product needs to be isolated from the fermentation broth. Conventionally, this is done by first separating the aqueous phase from the cell material in a cake filtration step, followed by an extraction or adsorption of the product from the filtrate. Often, however, such a cake filtration step is accompanied by a significant loss of desired product. This is mainly due to the fact that the filter cake cannot be washed out sufficiently and that a rather large amount of the product remains in the filter cloth. In practice, it is observed that the efficiency and the capacity of the filtration process strongly depend on the quality of the fermentation broth. In addition, “dissolved” proteins and cell debris present in the filtration broth are insufficiently removed from the aqueous phase of the fermentation broth by the cake filtration. This has the effect that subsequent downstream processes suffer from contamination with proteins, and their capacity is diminished.
In order to overcome the above problems in the work up procedure of fermentation broths, it has been proposed to make use of other filtration methods, such as membrane filtration. The membranes used for these purposes are usually polymeric membranes, such as polysulfone membranes.
The advantage of membrane filtration is, that by design less product is lost and a more pure filtrate (permeate) is obtained. The permeate contains significantly less proteins and/or remains of cell material than the filtrate obtained in a conventional cake filtration technique. As a result, the extraction step can be carried out more conveniently, and the overall efficiency of the process is increased.
In the East German patent application DD-A-277 088, a process for isolating benzylpenicillin from a microbiological broth is described. The process involves a conventional cake filtration step to remove the biomass, and a subsequent ultrafiltration step, wherein the proteins present in the filtrate of the first filtration are separated. The product of the ultrafiltration is concentrated to 5% of its volume, and the desired benzylpenicillin is isolated therefrom by extraction.
A membrane filtration process for broth filtration usually comprises three steps. In practice, particularly in a continuous process, the transition from one step to another may not be so clearly discernible. It often happens that two or all of these steps are carried out at the same time. However, for clarity's sake it is useful to draw this distinction. The first step is a concentration of the composition that is to be filtered. Such a concentration step can suitably be carried out, by circulating the broth along the membrane surface while a pressure gradient is maintained over the surface (often referred to as cross-flow filtration). In the second step, the obtained concentrated product is washed during cross-flow filtration in a dialysis step. This means that a flow of solvent is added to the circulating flow of broth. In case the filtered product is a fermentation broth this solvent will generally be water. In the third step, the obtained filtered permeate is concentrated further during cross-flow filtration to a suitable extent.
In a process involving a membrane filtration step, it is necessary to control the flow conditions of the retentate (the residue of the filtration) along the membrane by applying a high cross-flow velocity (i.e. a linear flow velocity parallel to the plane of the membrane), in order to maximise the flux (capacity) of the process. However, in practice a number of problems arises upon trying to maintain a fast flow of the retentate after it has been concentrated. These problems are particularly encountered in case a fermentation broth having high contents (3-10%) of cell debris and proteins is to be filtered.
Due to an increased viscosity, which is observed at high concentration factors, the axial pressure drop, which is a measure for the energy required in the process, increases as well. In large scale applications, centrifugal pumps are applied and the capacity thereof decreases as a result of the increased axial pressure drop. Due to the pseudoplastic nature of the involved materials under these conditions, the viscosity increases even more, which in its turn amplifies the flow decrease further. Furthermore, a lot of heat is generated which is undesired in cases wherein the desired product is unstable at high temperatures. Therefore, in order to keep the temperature low and to avoid product degradation, a large and expensive cooling device is necessary.
Also, it is desired to minimise the time needed to complete the filtration process in order to prevent degradation and contamination of the desired product. The available measures to minimise the filtration time are increasing the filter membrane surface, or demanding an increasing specific capacity. The specific capacity indicates how much of the desired product permeates a certain surface area of the membrane per time unit (l/m
2
·h). Said capacity may be increased by applying a high trans-membrane pressure, which is the driving force behind the filtration. A disadvantage of applying a high trans-membrane pressure is that it usually leads to a higher retention of the desired product, i.e. a large amount of product that does not permeate the membrane, which leads to an inefficient process. Furthermore, the application of tubular polymeric membranes in such cases may not be possible, as this type of membrane wears out too much under these conditions.
It has presently been found that the above problems can be overcome by using a ceramic membrane and by controlling the process conditions in a surprising manner.
The use of ceramic membranes has been reported in the prior art for diverse separations of desired products from a fermentation broth.
In EP 0 522 517 A1 an &agr;-alumina microporous membrane is used for the separation of methyl glucoside from a fermentation broth. In a first step the broth is concentrated, whereafter the water-insoluble methyl glucoside is dissolved by the addition of methanol, whereafter the methyl glucoside containing solution passes the membrane and the antibiotic is recovered.
A similar technique is described in U.S. Pat. No. 5,616,595 for the separation of cyclosporin A from a fermentation broth.
According to the Russian patent publication No. 2090598 ceramic filter elements can be applied for the filtration of must in the production of wine.
DESCRIPTION OF THE INVENTION
The present invention relates to a process for isolating a desired water-soluble product from a fermentation broth wherein the broth is circulated along a ceramic membrane, and wherein a trans-membrane pressure of at least 1.5 bar is applied, whereupon an aqueous solution containing the desired product traverses the membrane, and is subsequently collected.
The process according to the invention has the advantage that a very short filtration time can be realised without the known problem of a high retention of the desired product. Thus, the present filtration process is highly efficient. Surprisingly, a high trans-membrane pressure can be applied in a process according to the invention without encountering a high retention of the desired product. Also, the temperature can very suitably be controlled at a desired value without leading to viscosity problems and without leading to breakdown of the, often thermally unstable, desired product. Moreover, in a process according to the invention it is not necessary to carry out a conventional filtration of the fermentation broth, prior to subjecting it to the membrane filtration, as has been des
De Zwarte Pieter Johannes Gerrit
Kwant Gerard Jan
DSM N.V.
Leary Louise N.
Morrison & Foerster / LLP
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