Title of Invention

"PROCESS FOR THE CONTINUOUS MANUFACTURE OF HYDROLYSED, STARCH DERIVATIVES OR SUBSTITUTED STARCH DERIVATIVES AND APPARATUS THEREFOR"

Abstract The present invention relates to a process for the continuous manufacture of hydrolysed starch derivatives, optionally substituted, by conversion with a hydrolysis agent in an aqueous medium and subsequent neutralisation for terminating the hydrolysis, wherein a solution or suspension containing the starch, optionally substituted, to be hydrolysed is passed continuously through a reaction zone, essentially without intermixing and counter to gravity in the hydrolysis stage.
Full Text The present invention relates to a process for the continuous manufacture of hydrolysed starch and apparatus therefor.
The invention relates to a process for the continuous manufacture of hydrolysed starch or hydrolysed substituted starch products. More particularly, the invention relates to a process for the manufacture of hydrolysed starch or hydrolysed substituted starch products such as hydroxyethyl starch or hydroxypropyl starch, the use of the products manufactured according to the invention in the medical field, in particular as plasma extenders as well as an apparatus for the manufacture of hydrolysed starch or hydrolysed substituted starch products.
It is known to hydrolyse starch and substituted starch products such as hydroxyethyl or hydroxypropyl starch. Thus in DE-OS 30 000 465 a process is described for the manufacture of a starch hydrolysate in which a-amylase is used. The process described there operates in a very complicated manner and cannot readily be performed continuously. Moreover, it has only limited applicability.
In DE-A1-33 13 600 as well a process for the hydrolysis of starch is described in which a-amylase, ß-amylase or pullulanase are employed and in which the starch prior or after the hydrolysis may be substituted for example with ethylene oxide.
The hydrolysis of hydroxyethyl starch to form a product which may for example be employed as a plasma extender is described inter alia in EP-A1-0 402 724.
It is not readily possible to adapt such processes to a continuous operation. Accordingly, there exists a need for a continuous process which operates economically and which results in products which can be employed in the most varied fields.
It will be appreciated that particularly products which are to be employed in the medical sector are subject to high requirements. On the one hand products are required which do not give rise to allergies in the patients, on the other hand it is desired that the metabolic elimination rate, i.e. the concentration drop within the first 24 hours in the patient should be very high and that the half life times within organs should be short. Moreover, the clinical usability of hydrolysed starch products depends greatly on their physical chemical properties. In this context reference is made to the publications of Klaus Sommermeyer et al which have inter alia been published in Krankenhauspharmacie 8 (8271/8) (1987) and Starch/Starke 44 (5), 173-9(1992).
A need has now been recognised to provide a process for the continuous manufacture of hydrolysed starch or hydrolysed substituted starch products, which can be performed economically, by means of which the properties of the hydrolysed products can be set to desired standards, which for its performance requires little investment in terms of apparatus and engineering and which results in products which can be employed in particular in the medical field and in food technology.
Accordingly, there is provided a process for the continuous manufacture of hydrolysed starch derivatives, optionally substituted, by conversion with a hydrolysis agent in an aqueous medium and subsequent neutralisation for terminating the hydrolysis, wherein a solution or suspension containing the starch, optionally substituted, to be hydrolysed is passed continuously through a reaction zone, essentially without intermixing and counter to gravity in the hydrolysis stage.
The present invention provides a process for the continuous manufacture of hydrolysed
starch derivatives, optionally substituted, by conversion with a hydrolysis agent in an aqueous medium and subsequent neutralisation for terminating the hydrolysis, wherein
characterized is that a solution or suspension containing the starch, optionally substituted,
to be hydrolysed is passed continuously through a reaction zone, essentially without
intermixing and counter to gravity in the hydrolysis stage.
In addition, the invention relates to the use of the products manufactured in a process as set out above as plasma extenders or for the manufacture of dialysis solutions. The invention furthermore relates to an apparatus for performing a process for the continuous manufacture of hydrolysed starch derivatives, more particularly for carrying out the process according to the invention comprising a feed means for starch solution, a vessel for a hydrolysing agent,
a mixing and heating station for mixing the starch solution with the hydrolysing agent
and heating the mixture to a predetermined temperature,
a pump means for feeding the mixture into at least one reactor,
a pipeline connecting all units to one another,
as well as a neutralising station for neutralising the mixture,
wherein the reactor in its operating position is in a substantially vertical position and
comprises an inlet spigot at its bottom end and an outlet spigot at its top end and the
pump means is so operated as to feed the starch solution to the bottom end inlet spigot
continuously at a predetermined pumping rate, so that the starch solution is conveyed
through the reactor to the outlet spigot counter to gravity.
In order to perform the process according to the invention, conventional starches may be employed such as, for example potato starch, wheat starch, manioc starch and the like. Starches having a high amylopectin content are particularly suitable such as the wax-like milo (sorghum) starch, maize starch or rice starch. These starches can be employed in modified or non-modified form; the starch may also be employed in the form of already partly hydrolysed starch. In particular, hydroxypropyl and preferably hydroxyethyl starch are employed as modified starches.
The modification may be performed prior to hydrolysis or even after the hydrolysis. It is, however, preferred to modify in particular ethoxylate prior to the hydrolysis.
The modified or non-modified starch to be hydrolysed is advantageously employed as an aqueous solution or suspension, the term suspension denoting also starch-containing granules in water. The concentration of starch or modified starch in the solution or suspension can be set up within wide limits.
The concentration may be adjusted even prior to the hydrolysis, having regard to the desired usage of the final product; furthermore, it is possible by the selection of the concentration in conjunction with further parameters such as hydrolysis temperature, residence times etc., to influence the property profile of the final product. Preferably, the concentration amounts to 25-30% based on the overall weight.
After the addition of a hydrolysing agent, in particular a mineral acid such as hydraulic acid, heating or cooling proceeds to the desired temperature, preferably by means of heat exchangers.
The suspension or solution is then passed into a tubular temperature controlled reactor, the term reactor also including a plurality of reactor units, connected in series. The reactor is controlled to the desired hydrolysing temperature, preferably to 70-80°C. The material to be hydrolysed is fed into the tubular reactor from below, i.e. counter to gravity so that the suspension or solution moves from the bottom to the top, i.e. in an upwards direction. If a plurality of reactor units are employed, all reactor units are set up in parallel orientation, each being fed from below.
In principle it is possible to perform the major part of the hydrolysis in a single tube. However, it is also possible for a plurality of tubular reactor units to be set up in series, for example next to one another or one above the other, which is preferred for manufacturing and handling reasons. The transfer of the material being hydrolysed from one reactor unit into the next reactor unit may take place in a simple manner, e.g. by way of pipe connections, optionally with the inter-position of variable speed pumps.
The tubular reactors are so designed or the flow rate therethrough is so dimensioned that at least a major part of the hydrolysis, i.e. at least 60%, preferably 85-95% of the hydrolysis takes place in the tubular temperature controlled reactors. Accordingly, this hydrolysis advantageously proceeds - as will be further explained further below - as the first stage in the form of a crude hydrolysis. Preferably, the tubular reactors contain no mixing elements whatsoever in order to ensure a uniform, forward movement of the suspension during the hydrolysis without mixing. Sampling positions may be provided at the connecting pipes.
The product which has already been hydrolysed for the greater part, for example to 90% may then be transferred into one or more further reactors in which the hydrolysis is performed to the desired extent (second stage in the form of a fine hydrolysis).
Preferably, the balance of the hydrolysis in the fine hydrolysis stage is performed in reactors comprising static mixing elements.
By means of these reactor units it is also possible to perform the hydrolysis up to a predetermined final degree and to perform the fine adjustment of the process. Accordingly, these reactors are preferably provided with means for temperature control. In this manner it is possible to adjust accurately the desired degree of hydrolysis. The degree of hydrolysis is preferably monitored by means of viscosity measurements.
According to the invention it is preferred to perform a dual stage continuous hydrolysis process comprising a crude and a fine hydrolysis. On the other hand it is also possible to perform a single stage hydrolysis process in accordance with the crude hydrolysis if the hydrolysis needs not necessarily be taken to an accurately predetermined degree of breakdown but may fluctuate within certain limits.
The flow of the liquid material to be hydrolysed counter to gravity has the advantage that the layers of the solutions/suspension present in a reactor will practically not mix. The reason is that the hydrolysis results in the continuous formation of starch splitting products of decreasing chain length which results in the liquid layers, viewed from the bottom of the reactor upwards, having an ever decreasing viscosity. Accordingly, the reactor contains layers having a progressively decreasing viscosity gradient from the bottom upwards, viewed counter to gravity.
The solution to be treated is moved during the hydrolysis through the reactor at a rate which substantially permits an undisturbed development of a viscosity profile. Bearing in mind that the length of the reactor, i.e. the reaction time, is fixed for the continuous process, the conveyance rate determines the overall reaction period which is determined as a function of the selected degree of hydrolysis.
If a multiple tube reactor plant is employed, the cross-sections of the connecting pipes are so selected that the layers can be transferred with a uniform viscosity from one to
the other reactor essentially without disturbance, i.e. without mixing of the layers so that in the next reactor unit the hydrolysis treatment can be performed counter to gravity. It is possible to influence the property profile of the hydrolysate obtained also by selecting the concentration of the starting solution or starting suspension as well as the molecular weight of the starch or starch derivatives employed, the degree of substitution, the hydrolysis temperature, the acid concentration and the like.
If modified hydrolysed starch products are to be manufactured the modification of the starch is preferably performed prior to the hydrolysis. In the process according to the invention it is possible and preferred to be perform both the modification process as well as the hydrolysis process fully continuously.
Thus it is possible to add to the starch, in particular hydrolysed starch, for example ethylene oxide for ethoxylation, there being added to the mixture an amount of caustic soda to attain the desired pH. This pH is preferably in the basic region and may, for example amount to 13. The mixing and the reaction may be performed continuously, such that the conversion takes place preferably in one or more series-connected tubular reactors provided with static mixers. The ethoxylated product is then, as described above, mixed with hydrochloric acid for performing the hydrolysis and brought to the desired temperature and passed to the hydrolysis.
It was particularly surprising that it is possible, with the aid of the process according to the invention, to hydrolyse starch and/or modified starch continuously, attaining a uniform profile in the final product. Moreover, it was particularly surprising that in the tubular reactors without any mixing of the solution by means of static mixers or moving mixers a hydrolysate is attained having a favourable molecular rate distribution, in particular that a very broad molecular rate spectrum does not form as one would normally have feared as a result of channelling.
The process according to the invention results in a substantial simplification of the hydrolysis process and accordingly results in considerable cost savings since for acid
hydrolysis processes only special steels (for example HASTELLOY) can be employed which is very expensive in apparatus in which static mixers are present.
By means of the process according to the invention, it is possible in a pre-directed and reproducible manner, to produce a hydrolysate having specific properties. It is thus possible to pre-set accurately defined parameters such as molecular weight, molecular weight distribution, degree of substitution and the like. These parameters may be attained reproducibly and constant in the long term, whereas in the so-called batch operation the fluxtions are very large and can be controlled only with great difficulty. This applies not only to the hydrolysis to starch but also to the hydrolysis of modified products so that it is possible to produce, in combination with a modification process, preparations for the various fields of employment with the desired properties.
The process if very flexible and can be automatised to a far-reaching extent.
The process according to the invention can be performed with a plant which is illustrated diagramatically in the drawing.
In the drawing 10 denotes an apparatus for the continuous hydrolysis of starch or starch derivatives. From the station 12 hydroxyethyl starch solution which is to be hydrolysed in a continuous manner is fed to a mixer/heat-exchanger 14 connected to a vessel 16 which, for example contains hydrochloric acid serving as a hydrolysing agent. In the mixer/heat-exchanger 14 a pH adjustment to 1-2 takes place as well as a temperature adjustment of the solution to a preselected hydrolysis temperature, for example 70-80°C.
Thereafter the hydrolysis solution is fed by means of a pump 18 at a predetermined pumping rate through a first pipeline 20 to a reactor 22 (according to the drawing three reactor units 24-28) constituting a reaction line (main or course hydrolysis station) in such a fashion that the hydrolysis solution rises counter to gravity from the bottom upwards as indicated by the direction of the arrow in the reactor units 24-28. For this purpose the reactor unit 24 in its operating position comprises at its bottom
end an inlet spigot 23 and at the top end an outlet spigot 25. These spigots 23 and 25 are provided in the same manner on the remaining reactor units 26 and 28. In this connection the pipeline 20 has a cross-section so dimensioned that whatever hydrolysis layers arrive from the reactors 24-28 substantially do not mix with one another.
On the other hand, it may also be sufficient for only one reactor unit 24 to be employed as the main hydrolysis station (shown in dashed line denoted as 22) provided its volume is adequately dimensioned. From an invention point of view it is essential in this context that the slowly rising hydrolysis solution does not suffer intermixing of its individual layers, i.e. the individual layers having their different states of hydrolysis must not intermix, in a manner similar to the plates in fractional distillation. As a result, it is possible at the upper outlet position of the reactor units 24-28 to in each case withdraw a solution having a defined degree of hydrolysis, it being possible for a fine adjustment of the hydrolysis to take place subsequently. Accordingly, the reactor units 24-28 are denoted as main hydrolysis station. In particular, the reactor units 24-28 are not equipped in their interior with mixer elements which might affect a mixing of the entire hydrolysis solution. Thus, the hydrolysis gradient, which is correlated with viscosities of the individual layers, is to remain substantially unchanged, i.e. no mutual intermixing of the individual layers is to take place.
The reactor units 24-28 advantageously comprise a temperature adjustment jacket 27 as shown symbolically in the drawing as in the case of the reactor unit 26. A temperature control liquid, usually water, kept at a predetermined temperature flows through this temperature control jacket and thereby maintains the contents of the respective reactor units 24-28 at a desired temperature. The latter is determined from case to case in that at particular positions of the reactor units 24-28, liquid samples are withdrawn for determining the prevailing viscosity i.e. the prevailing degree of hydrolysis, and from this the final degree of hydrolysis is determined by way of tables and the known conveyance rate.
The dimensioning of the reactor units 24-28 is so designed that a minimum flow rate therethrough at a predetermined viscosity is ensured in order to avoid mixing of the
respective layers due to defusion. The latter depends inter alia essentially on the viscosity. Thus, the lower limit of the flow velocity is at approximately 3 cm/min, if the viscosity of the solution to be hydrolysed amounts to about 20 mPa x s. Advantageously the flow velocity is between 5 and 20, in particular between 10 and 15 cm/min.
The ratio of length to diameter of the reactor units 24-28 is also determined by the throughput of the solution to be hydrolysed. Advantageously this ratio is between 10:1 and 20:1.
Advantageously the main hydrolysis station 22 is connected by a second line 30 to a fine hydrolysis station 52 (shown in broken lines) as represented by the reactor units 34-40. These reactor units 34-40 are advantageously connected to a temperature control unit 42, for example a temperature control jacket through which flows a temperature control liquid, kept at a predetermined temperature flows, and which corresponds to the temperature control jacket 27. In this manner the temperature suitable for the hydrolysis may be set, which is advantageously monitored and controlled by way of the viscosity of the hydrolysis solution which results at any particular time. In addition, the reactor units 34-40 are equipped with diagramatically illustrated mixing elements 44 so that within the reactors a uniform mixing takes place in order to ensure a uniform hydrolysis. The temperature control unit 42 is illustrated in the drawing solely in conjunction with the reactor unit 34, but it can obviously also be provided in the remaining reactor units 36-40. Moreover it is fed from a conventional temperature control liquid source, not shown.
There may, for example, take place in the main hydrolysis station 22 a hydrolysis up to 95% whereas in the fine hydrolysis station 32 a mere 5% of the degree of hydrolysis aimed at are attained.
As previously mentioned, it is not essential according to the invention for the fine hydrolysis station 32 to be provided, because that merely serves to produce a narrow
molecular weight range. If such a narrow range is not required such fine hydrolysis station 32 may be dispensed with.
As shown in the drawing, the fluid to be hydrolysed in the fine hydrolysis station 32 is preferably likewise fed from the bottom upwards in order to substantially eliminate gravitational effects.
In order to stop the hydrolysis, the solution is mixed at the end of the hydrolysis, with caustic soda supplied from the storage vessel 48, in a neutralisation station 46. For that purpose the vessel 46 is connected to the fine hydrolysis station 32 by a third pipeline 15.
Thereafter for further processing, for example diafiltration and spraydrying, the mixture is passed from the vessel 46 into further processing apparatus, not illustrated.
The invention will be further elucidated by way of the following example. Example 1
A 30% starch solution is produced by the addition of liquid and caustic soda. From this hydroxyethyl starch having a molecular weight of 1,4 million Dalton is produced in a continuous starch ethoxylation plant by means of ethylene oxide, and is fed at a flow rate of about 11,3 1/h into a tube reactor devoid of mixing elements. The reactor has a size of approximately 2,6m x DN 100. The oxylation is not part of the invention since for the following hydrolysis an ordinary starch may likewise be employed.
0,2 1/h 25% Hcl are metered into the hydroxyethyl starch solution prior to its entry into a hydrolysis reactor; furthermore, by means of the heat exchanger, the reaction solution is brought to a temperature of 70°C while the pH value is adjusted to approximately 1,0. By temperature control the hydrolysis reactor is maintained at 70°C, it being important that the untreated solution passes through the reactor which makes do without any mixing elements from the bottom upwards (counter to gravity).
The residence time of the solution amounts to about 2 hours. In the course thereof the molecular weight was reduced from 1,4 million to about 300 000 Dalton.
In an advantageously provided downstream fine hydrolysis sector composed of a plurality of reactors having static mixing elements, a final molecular weight (mean molecular weight) of about 250 000 Dalton is set up. The hydrolysis is then terminated by neutralisation. The mixture is purified by diafiltration using a membrane having an exclusion limit of 50 000 Dalton. The product, when dried, is excellently suited as a plasma extender.
The claims which follow are to be considered an integral part of the present disclosure. Reference numbers (directed to the drawings) shown in the claims serve to facilitate the correlation of integers of the claims with illustrated features of the preferred embodiment(s), but are not intended to restrict in any way the language of the claims to what is shown in the drawings, unless the contrary is clearly apparent from the context.



WE CLAIM :
1. A process for the continuous manufacture of hydrolysed starch
derivatives or hydrolysed substituted starch derivatives, by conversion
with a hydrolysis agent of the kind as herein described, in an aqueous
medium of the kind as herein described and subsequent
neutralisation for terminating the hydrolysis, characterized in that a
solution or suspension containing the starch or substituted starch, to
be hydrolysed is passed continuously through a reaction section,
essentially without intermixing and counter to gravity in the
hydrolysis stage.
2. Process as claimed in claim 1, wherein said reaction section comprises
at least one tubular reactor (24-28) which in its operating position
comprises an inlet spigot (23) as its bottom end and an outlet spigot
(25) at its top.
3. Process as claimed in claims 1 to 2, wherein, the main hydrolysis is
followed by a fine hydrolysis, if desired, in which the coarsely
hydrolysed starch solution is fed at a predetermined temperature into
a tubular reactor (34) with static mixing elements (44).
4. Process as claimed in any one of claims 1 to 3, wherein the tubular
reactors (24-28 and 34-40) in their operational condition are set up
essentially vertically and the product to be hydrolyzed is fed from the
bottom upwards.
5. Process as claimed in any one of claims 1 to 4, wherein the tubular
reactors are temperature controlled to a predetermined temperature of
25-100 °C.
6. Process as claimed in any one or more of claims 1 to 4, wherein the
main hydrolysis is performed in the tubular temperature controlled
reactor (22) to an extent of 60-95%.
7. Process as claimed in any one or more of claims 1 to 5, wherein
etherised starch, preferably a starch etherised with ethylene oxide
and/or propylene oxide, in particular waxy maize starch is employed.
8. Process as claimed in any one or more of claims 1 to 7, wherein
partially hydrolysed starch is continuously ethoxylated with ethylene
oxide in a basic medium, the ethoxylated product is acidified with
mineral acid, the main hydrolysis is performed at a reaction
temperature of 60-100°C and the hydrolysis is terminated by
neutralisation with caustic liquor and cooling.
9. Process as claimed in any one of claims 1 to 8, for manufacture of
hydrolysed starch derivatives for preparing plasma extender or
dialysis solution.
10. Apparatus for carrying out the process as claimed in claim 1,
comprising
a feed means (12) for starch solution,
a vessel (16) for a hydrolysing agent,
a mixing and heating station (14) for mixing the starch solution with
the hydrolysing agent and heating the mixture to a predetermined
temperature,
a pump means (18) for feeding the mixture into at least one reactor ~
(22),
a pipeline (20) connecting all units to one another,
as well as a neutralising station (46) for neutralising the mixture,
characterized in that the reactor (22) in its operating position is in a
vertical position and comprises an inlet spigot (23) at its bottom end
and an outlet spigot (25) as its top end and the pump means (18) is so
operated as to feed the starch solution to the bottom end inlet spigot
(23) continuously at a predetermined pumping rate, so that the starch
solution is conveyed through the reactor (22) to the outlet spigot (25)
counter to gravity.
11. Apparatus as claimed in claim 10, wherein the reactor (22) serving as
a main hydrolysis station, is followed downstream by a fine hydrolysis
station (32) in the form of at least one reactor unit (34-40), each
having mixing elements (44).
12. Apparatus as claimed in claim 10-11, wherein the reactors (24-28 and
34-40) are in each case, provided with a temperature control unit (27,
42).
13. Process for the continuous manufacture of hydrolysed starch
derivatives substantially as herein described with reference to the
accompanying drawings.
14. Apparatus for carrying out the process substantially as herein before
described with reference to the accompanying drawings.

Documents:

2217-del-1998-abstract.pdf

2217-del-1998-claims.pdf

2217-del-1998-correspondence-others.pdf

2217-del-1998-correspondence-po.pdf

2217-del-1998-description (complete).pdf

2217-del-1998-form-1.pdf

2217-del-1998-form-13.pdf

2217-del-1998-form-19.pdf

2217-del-1998-form-2.pdf

2217-del-1998-form-3.pdf

2217-del-1998-form-4.pdf

2217-del-1998-form-6.pdf

2217-del-1998-gpa.pdf

2217-del-1998-petition-138.pdf


Patent Number 243110
Indian Patent Application Number 2217/DEL/1998
PG Journal Number 40/2010
Publication Date 01-Oct-2010
Grant Date 27-Sep-2010
Date of Filing 29-Jul-1998
Name of Patentee FRESENIUS AG
Applicant Address GLUCKENSTEINWEG 5, 61350 BAD HOMBURG V.D.H., GERMANY.
Inventors:
# Inventor's Name Inventor's Address
1 MICHAEL GORG WIESENSTRASSE 3, 61197 FLORSTADT, GERMANY
2 THOMAS MAUL FRIEDBERGSTRASSE 62, 61169 FRIEDBERG-OCKSTADT, GERMANY
3 KLAUS SOMMERMEYER IN DER LAUBACH 26, 61191 ROSBACH V.D.H., GERMANY.
4 KLAUS HENNING LANDRAT-BECKMANN-STRASSE 21, 61250 USINGEN, GERMANY.
PCT International Classification Number A23L 1/09
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 197 44 353 1997-10-08 Germany
2 197 34 370 1997-08-08 Germany