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WO2014148966A1 - Process for manufacturing porous polysaccharide particles and particles thereby obtained. - Google Patents

Process for manufacturing porous polysaccharide particles and particles thereby obtained. Download PDF

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Publication number
WO2014148966A1
WO2014148966A1 PCT/SE2014/000019 SE2014000019W WO2014148966A1 WO 2014148966 A1 WO2014148966 A1 WO 2014148966A1 SE 2014000019 W SE2014000019 W SE 2014000019W WO 2014148966 A1 WO2014148966 A1 WO 2014148966A1
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WO
WIPO (PCT)
Prior art keywords
particles
process according
temperature
disc
polysaccharides
Prior art date
Application number
PCT/SE2014/000019
Other languages
French (fr)
Inventor
Ingemar Jonsson
Ralf Andersson
Original Assignee
HB Ijorari
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Filing date
Publication date
Application filed by HB Ijorari filed Critical HB Ijorari
Publication of WO2014148966A1 publication Critical patent/WO2014148966A1/en

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B12/00—Arrangements for controlling delivery; Arrangements for controlling the spray area
    • B05B12/08—Arrangements for controlling delivery; Arrangements for controlling the spray area responsive to condition of liquid or other fluent material to be discharged, of ambient medium or of target ; responsive to condition of spray devices or of supply means, e.g. pipes, pumps or their drive means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
    • B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/262—Synthetic macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. obtained by polycondensation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/282—Porous sorbents
    • B01J20/285—Porous sorbents based on polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B3/00—Spraying or sprinkling apparatus with moving outlet elements or moving deflecting elements
    • B05B3/001—Spraying or sprinkling apparatus with moving outlet elements or moving deflecting elements incorporating means for heating or cooling, e.g. the material to be sprayed
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B3/00—Spraying or sprinkling apparatus with moving outlet elements or moving deflecting elements
    • B05B3/02—Spraying or sprinkling apparatus with moving outlet elements or moving deflecting elements with rotating elements
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0036—Galactans; Derivatives thereof
    • C08B37/0039—Agar; Agarose, i.e. D-galactose, 3,6-anhydro-D-galactose, methylated, sulfated, e.g. from the red algae Gelidium and Gracilaria; Agaropectin; Derivatives thereof, e.g. Sepharose, i.e. crosslinked agarose
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/12—Agar or agar-agar, i.e. mixture of agarose and agaropectin; Derivatives thereof

Definitions

  • the present invention pertains to a process for the manufacturing of porous particles of narrow particle size distribution consisting of one or more
  • polysaccharides and optionally a neutralizing buffer where a water solution holding one or more polysaccharides-is being transferred onto a heated spinning disc, the temperature of which is continuously controlled, droplets of said solution are being ejected at the periphery of the disc, and said droplets are solidifying to particles during descent into a water catch, whereby the process takes place within an enclosure without opening and whereby no water vapor is added within said enclosure.
  • Polysaccharide particles made from agar, preferably from agarose, are used for chromatography.
  • said particles need to be porous in order to allow large molecules, preferably molecules with a size up to 1 000 000 Daltons, to diffuse into the particles.
  • Polysaccharide particles are traditionally produced with an emulsion process. Thereby an aqueous polysaccharide solution is vigorously stirred in an organic medium, which may comprise e g toluene and other additives e g salts and
  • US 5,643,594 discloses an apparatus for gelling the coating on particles, such coating being e g agarose or saccharose.
  • the coated particles are non-gelled introduced into the apparatus whereupon the particles are centrifuged into gelling basins for gelling the coating.
  • Another process for production of polysaccharide particles is a continuous process disclosed in US 6,841 ,097 (Amersham Biosciences). It resides in feeding an aqueous polysaccharide solution onto a spinning disc, preferably towards the center of the disc. Thereupon is formed a thin film, which under the disc rotation is radially moving towards the periphery of the disc.
  • This process takes place under monitoring and adjusting of the humidity and of the temperature of the atmosphere surrounding the production equipment, said adjustment being achieved by injection of tempered dry steam in the vicinity of the particle production.
  • This results in an ambient atmosphere with up to 100% relative humidity and a temperature of up to 100°C. Said ambient atmosphere is said to be necessary for achieving porous polysaccharide particles.
  • the film Upon leaving the disc periphery the film forms droplets, which are ejected into an atmosphere adjusted as per the preceding paragraph.
  • the droplets solidify as they descend through the temperature/humidity controlled gradient obtained from the steam and the elevated temperature of the atmosphere on their way into a water catch, in which the temperature of the water is from about 16 °C to about 23°C, where the particles are stabilized.
  • the particles are collected and fractionated over suitable vibrating sieves to remove potential debris and fines.
  • US 6,841 ,097 discloses that particles produced according to the process described therein have porosities that allow diffusion of globular proteins of large molecular weights, up to more than 670 000 Dalton, e g the commonly used test molecule Thyroglobuline. Particles produced according to a process, being like the one just described with the exception that the atmosphere in the vicinity of the production area is neither monitored nor adjusted, only allow diffusion of considerably smaller molecules, with molecular weights being less than 250 000 Dalton.
  • US 7,207,499 discloses a manufacturing process similar to the one disclosed in US 6,841 ,097.
  • US 7,207,499 as well as US 6,841 ,097 disclose the formation of a non-wanted film, a surface skin, on the droplets, which remains on the final particles. Said surface skin is caused by desiccation. The surface skin results in less porous particles. See e g US 6,841 ,097, column 5, lines 3 - 4. To avoid formation of said surface skin it was believed that both the relative humidity and the temperature of the atmosphere around the site of the production of particles need be significantly raised.
  • the inventors of US 6,841 ,097 therefore developed a technology for reducing the formation of said surface skin, such technology being disclosed in US 7,341 ,682 (Amersham Biosciences). This technology encompasses techniques for reduction of the increase in vapor pressure caused by the addition of dry steam, e g by the addition of vapor pressure reducing agents, such as glycerol.
  • Spinning disc technology is used.
  • the temperature of the spinning disc is kept at 50 - 60 °C, preferably by indirect heating.
  • the temperature of the aqueous polysaccharide solution is also kept at 50 - 60 °C, preferably by indirect heating. See e g US 2005/0006496 (Prometic).
  • US 6,841 ,097 teaches that if droplets are not ejected in an atmosphere with up to 100% relative humidity and in a temperature of up to 100°C, then the particles obtained get a low porosity. This finding is confirmed by US 7,207,499 and US 7,341 ,202, which both further teach that steam need be injected in the atmosphere surrounding the equipment where the droplets are produced.
  • Fig 1 schematically shows in cross-section a spinning disc with an upper disc part (1) and a lower disc part (2).
  • a polysaccharide solution (3) is fed via a nozzle (4) on to the center of the lower disc part (2).
  • the path followed by the polysaccharide solution is indicated by the dashed line (5).
  • a thin film (6) in a channel (7) between the upper disc part (1) and the lower disc part (2).
  • the film (6) is ejected into the surrounding atmosphere, whereby are created droplets (9), which form particles (11) (not shown in Fig 1) during their descent into a water catch (10) (not shown in Fig 1), where the particles (11) stabilize.
  • Fig 2 schematically shows in cross-section a spinning disc as per Fig1 and the water catch (10). Fig 2 also shows that the production of the particles takes place inside an enclosure (12) having no opening.
  • porous and essentially spherical polysaccharide-containing particles of narrow particle size distribution whereby preferably >90% of the particles have a size being within +/- 15% of the mean particle size, may be formed from aqueous polysaccharide solutions using a process being simpler and more efficacious than processes known to date.
  • inventive process takes place without steam injection, without elevating the atmosphere temperature and without adding vapor pressure reduction agents.
  • disc is synonymous with the term “upper disc part and lower disc part” and similar expressions as explained in the Legend of figures.
  • an aqueous solution comprising one or more polysaccharides is being transferred, preferably continuously through a nozzle onto a heated spinning disc, preferably close to the center of said disc.
  • the disc may comprise an upper and a lower part.
  • the concentration of polysaccharides in the solution is preferably between 3 % (w/w) and 8 % (w/w).
  • the temperature of said disc is continuously monitored and adjusted if needed.
  • the upper and the lower part are both preferably heated by electromagnetic induction, and/or hot gas, preferably an inert gas, and more preferably nitrogen, infrared radiation, thermofoil heating, flexible heating, built- in electrical heating coils, via current collector and/or via a current pantograph.
  • Said nozzle is stationary and the polysaccharide solution is applied onto the lower part of the disc close to the center of the lower part.
  • the polysaccharide solution is transported from the center towards the periphery of the lower part of the disc.
  • the solution is thereby following a continuous channel between the upper disc and the lower disc.
  • the solution forms a continuous thin protected film on the surface of the lower disc part.
  • the film breaks up into droplets, which are ejected into the surrounding atmosphere and descend into a water catch.
  • the temperature of the upper part and of the lower-part is feedback controlled, preferably by contact free temperature sensors, such as IR sensors.
  • the temperature of the upper disc and of the lower disc and the temperature of the solution comprising one or more polysaccharides may both reach between 60°C and 90°C. No steam is injected.
  • the polysaccharide film reaches the periphery of the lower disc part, where it disintegrates and forms droplets, which form particles during descent into a water catch, where the particles solidify.
  • the temperature of the water in the water catch is preferably below the gelling temperature of the
  • polysaccharide/s which means from 16 °C to 24°C.
  • the inventive process takes place inside an enclosure surrounding the production area.
  • the enclosure according to the present invention has no opening. See Fig 2.
  • the inventive process for manufacturing porous polysaccharide particles have the following main characteristics, which are novel and inventive over prior art processes. • Only the temperature of the spinning disc upper and lower parts is monitored and adjusted if needed.
  • spherical particles having a porosity being such that molecules with a weight of > 700 000 Dalton, e g Thyroglobuline, may diffuse into the particles. This results in a Kav ⁇ 0,40.
  • the present process makes it possible to control and optimize the process of using a polysaccharide solution for making porous, homogeneous, essentially spherical particles with a narrow particle size distribution, whereby at least a fraction of the particles have the size of . >90% of the particles are within +/-15 % of the mean particle size.
  • a disc with 20 cm diameter up to 1.5 liter of spherical particles with narrow particle size distribution may be produced per hour.
  • By increasing the volume fed per hour more particles may be produced per hour, though resulting in a broader particle size distribution.
  • Spherical particles of narrow particle size/diameter distribution where > 90% of the particles are within +/-15 % of the mean particle size, implies high production capacity, high utilization degree and reducing or eliminating the need for sieving.
  • the size of the particles being according to the present application is conveniently measured by light microscopy in a way known by a person skilled in the art.
  • Example 1 The below examples are non-limiting and for illustrating the invention.
  • Example 1
  • the solution was equilibrated to 80°C in a water jacked container under mixing and was pumped at 28 ml/min onto a spinning disc with diameter 20 cm, rotating with 5 000 rpm, having a continuously feedback controlled temperature of about 80°C.
  • the droplets formed descended 0,5m through an atmosphere
  • the particles so produced were collected and fractionated on a sieve.
  • the particles were subsequently packed in a 0, 5 cm diameter column being 22 cm high. They were found to be porous for globular proteins larger than 670 000 Dalton, e g Thyroglobulin resulting in a Kav « ⁇ 0,4 Particles collected after sieving over 50 pm and 25 pm sieves showed narrow particle size distribution fractions, one showing that > 90% of the particles lie within a size range of 70 pm +/-10pm, and another one showing that > 90% lie within a size range of 30 pm +/-5 pm.
  • Example 2 110 g agar, was fully dissolved in 2 000 ml distilled water by heating and stirring. Alkaline hydrolyzation to 100 cP (centipoise Pascal sec) was accomplished upon full solubilization.
  • the solution was equilibrated to 80°C in a water jacked container under mixing and was pumped at 28 ml/min onto a spinning disc with diameter 20 cm, rotating with 5 000 rpm, having a continuously feedback controlled temperature of about 80°C.
  • the droplets formed descended 0,5m through an atmosphere
  • the particles so produced were collected and fractionated on a sieve.
  • Particles collected after sieving over 50 ⁇ and 25 ⁇ sieves showed narrow particle size distribution fractions, one showing that > 90% of the particles lie within a size range of 70 ⁇ +/-10 ⁇ , and another one showing that > 90% lie within a size range of 30 ⁇ +/-5 ⁇ .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Analytical Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Manufacture Of Porous Articles, And Recovery And Treatment Of Waste Products (AREA)

Abstract

A process for manufacturing essentially spherical, porous particles of narrow particle size distribution, where a water solution containing one or more polysaccharides is being transferred onto a heated spinning disc, the temperature of which is continuously controlled, droplets of said solution are being ejected at the periphery of the disc, and said droplets are solidifying to particles during descent into a water catch, whereby the process takes place in an enclosure without opening and whereby no water vapor is added within said enclosure.

Description

Process for manufacturing porous polysaccharide particles and
particles thereby obtained.
Field of invention
The present invention pertains to a process for the manufacturing of porous particles of narrow particle size distribution consisting of one or more
polysaccharides and optionally a neutralizing buffer where a water solution holding one or more polysaccharides-is being transferred onto a heated spinning disc, the temperature of which is continuously controlled, droplets of said solution are being ejected at the periphery of the disc, and said droplets are solidifying to particles during descent into a water catch, whereby the process takes place within an enclosure without opening and whereby no water vapor is added within said enclosure.
Background of the invention
Polysaccharide particles, made from agar, preferably from agarose, are used for chromatography. For such use said particles need to be porous in order to allow large molecules, preferably molecules with a size up to 1 000 000 Daltons, to diffuse into the particles.
Polysaccharide particles are traditionally produced with an emulsion process. Thereby an aqueous polysaccharide solution is vigorously stirred in an organic medium, which may comprise e g toluene and other additives e g salts and
detergents. Thereby droplets are formed. These droplets are stabilized by cooling the emulsion. Then the particles are separated from the medium. This manufacturing technology is old. It is time-consuming and requires lots of energy and space. Further this manufacturing is environmentally unfriendly. It may only be performed batch- wise. See "Studies on Structure and Properties of Agarose", A.S. Medin, PhD thesis, Uppsala University, 1995.
US 5,643,594 discloses an apparatus for gelling the coating on particles, such coating being e g agarose or saccharose. The coated particles are non-gelled introduced into the apparatus whereupon the particles are centrifuged into gelling basins for gelling the coating. Another process for production of polysaccharide particles is a continuous process disclosed in US 6,841 ,097 (Amersham Biosciences). It resides in feeding an aqueous polysaccharide solution onto a spinning disc, preferably towards the center of the disc. Thereupon is formed a thin film, which under the disc rotation is radially moving towards the periphery of the disc. This process takes place under monitoring and adjusting of the humidity and of the temperature of the atmosphere surrounding the production equipment, said adjustment being achieved by injection of tempered dry steam in the vicinity of the particle production. This results in an ambient atmosphere with up to 100% relative humidity and a temperature of up to 100°C. Said ambient atmosphere is said to be necessary for achieving porous polysaccharide particles. Upon leaving the disc periphery the film forms droplets, which are ejected into an atmosphere adjusted as per the preceding paragraph. The droplets solidify as they descend through the temperature/humidity controlled gradient obtained from the steam and the elevated temperature of the atmosphere on their way into a water catch, in which the temperature of the water is from about 16 °C to about 23°C, where the particles are stabilized. Subsequently the particles are collected and fractionated over suitable vibrating sieves to remove potential debris and fines.
US 6,841 ,097 discloses that particles produced according to the process described therein have porosities that allow diffusion of globular proteins of large molecular weights, up to more than 670 000 Dalton, e g the commonly used test molecule Thyroglobuline. Particles produced according to a process, being like the one just described with the exception that the atmosphere in the vicinity of the production area is neither monitored nor adjusted, only allow diffusion of considerably smaller molecules, with molecular weights being less than 250 000 Dalton.
US 7,207,499 (Prometic) discloses a manufacturing process similar to the one disclosed in US 6,841 ,097.
US 7,207,499 as well as US 6,841 ,097 disclose the formation of a non-wanted film, a surface skin, on the droplets, which remains on the final particles. Said surface skin is caused by desiccation. The surface skin results in less porous particles. See e g US 6,841 ,097, column 5, lines 3 - 4. To avoid formation of said surface skin it was believed that both the relative humidity and the temperature of the atmosphere around the site of the production of particles need be significantly raised. The inventors of US 6,841 ,097 therefore developed a technology for reducing the formation of said surface skin, such technology being disclosed in US 7,341 ,682 (Amersham Biosciences). This technology encompasses techniques for reduction of the increase in vapor pressure caused by the addition of dry steam, e g by the addition of vapor pressure reducing agents, such as glycerol.
State of the art on production of porous polysaccharide-containing particles suitable for chromatography is essentially as follows.
Spinning disc technology is used. The temperature of the spinning disc is kept at 50 - 60 °C, preferably by indirect heating. The temperature of the aqueous polysaccharide solution is also kept at 50 - 60 °C, preferably by indirect heating. See e g US 2005/0006496 (Prometic). US 6,841 ,097 teaches that if droplets are not ejected in an atmosphere with up to 100% relative humidity and in a temperature of up to 100°C, then the particles obtained get a low porosity. This finding is confirmed by US 7,207,499 and US 7,341 ,202, which both further teach that steam need be injected in the atmosphere surrounding the equipment where the droplets are produced. In order to maintain and adjust said increased humidity and temperature an enclosure is placed around the site of production of the particles. To accomplish said adjustment the enclosure is provided with an opening, the purpose of which primarily is to let excess vapor escape. US 7,341 ,202 also teaches that a substance for lowering the vapor pressure, e g glycerol, need be added.
It is a long felt need to produce polysaccharide-containing particles, especially porous ones, using a simpler and more efficient method than any of the methods known today.
Legend of figures
Fig 1 schematically shows in cross-section a spinning disc with an upper disc part (1) and a lower disc part (2). A polysaccharide solution (3) is fed via a nozzle (4) on to the center of the lower disc part (2). The path followed by the polysaccharide solution is indicated by the dashed line (5). Thereupon is created a thin film (6) in a channel (7) between the upper disc part (1) and the lower disc part (2). At the periphery (8) of the lower disc part (2) the film (6) is ejected into the surrounding atmosphere, whereby are created droplets (9), which form particles (11) (not shown in Fig 1) during their descent into a water catch (10) (not shown in Fig 1), where the particles (11) stabilize.
Fig 2 schematically shows in cross-section a spinning disc as per Fig1 and the water catch (10). Fig 2 also shows that the production of the particles takes place inside an enclosure (12) having no opening.
Description of the invention
The present inventors have surprisingly found that porous and essentially spherical polysaccharide-containing particles of narrow particle size distribution, whereby preferably >90% of the particles have a size being within +/- 15% of the mean particle size, may be formed from aqueous polysaccharide solutions using a process being simpler and more efficacious than processes known to date. Specifically the inventive process takes place without steam injection, without elevating the atmosphere temperature and without adding vapor pressure reduction agents.
In the present application the term "disc" is synonymous with the term "upper disc part and lower disc part" and similar expressions as explained in the Legend of figures.
According to the present invention an aqueous solution comprising one or more polysaccharides is being transferred, preferably continuously through a nozzle onto a heated spinning disc, preferably close to the center of said disc. The disc may comprise an upper and a lower part. This process is schematically illustrated in Fig 1 The concentration of polysaccharides in the solution is preferably between 3 % (w/w) and 8 % (w/w). The temperature of said disc is continuously monitored and adjusted if needed. The upper and the lower part are both preferably heated by electromagnetic induction, and/or hot gas, preferably an inert gas, and more preferably nitrogen, infrared radiation, thermofoil heating, flexible heating, built- in electrical heating coils, via current collector and/or via a current pantograph. Said nozzle is stationary and the polysaccharide solution is applied onto the lower part of the disc close to the center of the lower part. By means of
centrifugal force obtained by rotation of the disc, the polysaccharide solution is transported from the center towards the periphery of the lower part of the disc. The solution is thereby following a continuous channel between the upper disc and the lower disc. Thereby the solution forms a continuous thin protected film on the surface of the lower disc part. At the periphery of the lower disc part the film breaks up into droplets, which are ejected into the surrounding atmosphere and descend into a water catch. The temperature of the upper part and of the lower-part is feedback controlled, preferably by contact free temperature sensors, such as IR sensors. The temperature of the upper disc and of the lower disc and the temperature of the solution comprising one or more polysaccharides may both reach between 60°C and 90°C. No steam is injected. Finally the polysaccharide film reaches the periphery of the lower disc part, where it disintegrates and forms droplets, which form particles during descent into a water catch, where the particles solidify. The temperature of the water in the water catch is preferably below the gelling temperature of the
polysaccharide/s, which means from 16 °C to 24°C.
The inventive process takes place inside an enclosure surrounding the production area. In contrast to the state of the art process the enclosure according to the present invention has no opening. See Fig 2.
In contrast to state of the art processes according to the inventive process just one parameter need be monitored and adjusted, namely the
temperature of the spinning disc parts. "Gel Filtration, Principles and Methods", 18-1022-18, GE Healthcare Life
Sciences Handbooks from GE Healthcare mainly on pages 111-114 provides the following information on the parameter Kav, which is referred to further below.
The inventive process for manufacturing porous polysaccharide particles, have the following main characteristics, which are novel and inventive over prior art processes. • Only the temperature of the spinning disc upper and lower parts is monitored and adjusted if needed.
• No steam is injected in the atmosphere around the site of particle production.
• No glycerol or equivalent substance for reducing the vapor pressure is used. · The enclosure around the production area has no opening while particles are being produced.
• The particles do not acquire surface skin effecting performance.
• By raising the temperature of the spinning disc is produced essentially
spherical particles having a porosity being such that molecules with a weight of > 700 000 Dalton, e g Thyroglobuline, may diffuse into the particles. This results in a Kav < 0,40.
• No organic solvents are used during the process.
The present process makes it possible to control and optimize the process of using a polysaccharide solution for making porous, homogeneous, essentially spherical particles with a narrow particle size distribution, whereby at least a fraction of the particles have the size of . >90% of the particles are within +/-15 % of the mean particle size. Using a disc with 20 cm diameter up to 1.5 liter of spherical particles with narrow particle size distribution may be produced per hour. By increasing the volume fed per hour more particles may be produced per hour, though resulting in a broader particle size distribution.
Spherical particles of narrow particle size/diameter distribution, where > 90% of the particles are within +/-15 % of the mean particle size, implies high production capacity, high utilization degree and reducing or eliminating the need for sieving. The size of the particles being according to the present application is conveniently measured by light microscopy in a way known by a person skilled in the art.
Examples
The below examples are non-limiting and for illustrating the invention. Example 1
110 g agarose, was fully dissolved in 2 000 ml distilled water by heating and stirring. Alkaline hydrolyzation to 100 cP (centipoise Pascal sec) was
accomplished upon full solubilization. The solution was equilibrated to 80°C in a water jacked container under mixing and was pumped at 28 ml/min onto a spinning disc with diameter 20 cm, rotating with 5 000 rpm, having a continuously feedback controlled temperature of about 80°C. The droplets formed descended 0,5m through an atmosphere
established in an enclosed system above a water catch with a water temperature of about 22°C. No steam injection took place.
The particles so produced were collected and fractionated on a sieve. The particles were subsequently packed in a 0, 5 cm diameter column being 22 cm high. They were found to be porous for globular proteins larger than 670 000 Dalton, e g Thyroglobulin resulting in a Kav« < 0,4 Particles collected after sieving over 50 pm and 25 pm sieves showed narrow particle size distribution fractions, one showing that > 90% of the particles lie within a size range of 70 pm +/-10pm, and another one showing that > 90% lie within a size range of 30 pm +/-5 pm.
Example 2. 110 g agar, was fully dissolved in 2 000 ml distilled water by heating and stirring. Alkaline hydrolyzation to 100 cP (centipoise Pascal sec) was accomplished upon full solubilization.
The solution was equilibrated to 80°C in a water jacked container under mixing and was pumped at 28 ml/min onto a spinning disc with diameter 20 cm, rotating with 5 000 rpm, having a continuously feedback controlled temperature of about 80°C. The droplets formed descended 0,5m through an atmosphere
established in an enclosed system above a water catch with a water temperature of about 22°C. No steam injection took place.
The particles so produced were collected and fractionated on a sieve. The particles were subsequently packed in a 0,5 cm diameter column being 22 cm high. They were found to be porous for globular proteins larger than 650 000 Dalton, e g Thyroglobulin resulting in a Kav« < 0,4. Thyroglobulin is retarded upon gel filtration as compared to Blue Dextran having a Mw of > 106 Dalton and Kav = 0
Particles collected after sieving over 50 μιη and 25 μηι sieves showed narrow particle size distribution fractions, one showing that > 90% of the particles lie within a size range of 70 μηι +/-10μηι, and another one showing that > 90% lie within a size range of 30 μηι +/-5 μητι.

Claims

Claims
1. Process for manufacturing particles consisting of one or more
polysaccharides, characterized in that an aqueous solution comprising one or more polysaccharides is being transferred onto a spinning disc, the temperature of which is continuously controlled, whereby the humidity of the atmosphere is not controlled, that droplets of said solution are being ejected from the periphery of the disc, and that said droplets are solidified to particles during descent into a water catch, whereby the process takes place in an enclosure without opening during the process, and whereby no water vapor is added within said enclosure.
2. Process according to claim ^characterized in that said particles
further include a neutralizing buffer.
3. Process according to any preceding claim, characterized in that he spinning disc comprises an upper part and a lower part.
4. Process according to any preceding claim, characterized in that the one or more polysaccharides is/are chosen among agar and agarose.
5. Process according to any preceding claim, characterized in that the particles have a large enough porosity to allow diffusion of substances with a molecular weight of up to 1000000 Daltons.
6. Process according to any preceding claim, characterized in that the concentration of polysaccharides in said water solution is between 3% (w/w) and 8% (w/w).
7. Process according to any preceding claim, characterized in that the temperature of the spinning disc is continuously monitored and adjusted to be between 60 °C and 90°C.
8. Process according to any preceding claim, characterized in that the spinning disc is heated by electromagnetic induction, and/or hot gas, preferably an inert gas, and more preferably nitrogen, infrared radiation, thermofoil heating, flexible heating, built-in electrical heating coils, via current collector and/or via a current pantograph.
9. Process according to any preceding claim, characterized in that the temperature of the water in the water catch is below the gelling temperature of the polysaccharide/s, preferably between 16°C and 24°C.
10. Process according to any preceding claim, characterized in that at least a fraction of the particles have a size being such that at least 90% of the particles have an average diameter, which is within the range of 15% larger than the average diameter of the particles of said fraction, and 15% smaller than the average diameter of the particles of said fraction.
11. Process for manufacturing particles comprising one or more polysaccharides according to any preceding claim, characterized in that that the temperature of the spinning disc is feed-back controlled.
12. Process according to any preceding claim, characterized in that the temperature of the spinning disc is monitored using a contact-free IR-sensor.
13. Porous particles, characterized in that the particles are manufactured according to any preceding claim.
PCT/SE2014/000019 2013-03-19 2014-02-18 Process for manufacturing porous polysaccharide particles and particles thereby obtained. WO2014148966A1 (en)

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SE1300203 2013-03-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106546629A (en) * 2016-10-21 2017-03-29 上海工程技术大学 A kind of urban rail catenary node failure method for early warning and device

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643594A (en) * 1992-05-29 1997-07-01 The Regents Of The University Of California Spin encapsulation apparatus and method of use
US20030052426A1 (en) * 1999-12-01 2003-03-20 Andersson Ralf Goran Method of producing porous spherical particles
US20100298548A1 (en) * 2008-02-05 2010-11-25 Ge Healthcare Bio-Sciences Ab Method for production of separation media

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643594A (en) * 1992-05-29 1997-07-01 The Regents Of The University Of California Spin encapsulation apparatus and method of use
US20030052426A1 (en) * 1999-12-01 2003-03-20 Andersson Ralf Goran Method of producing porous spherical particles
US20100298548A1 (en) * 2008-02-05 2010-11-25 Ge Healthcare Bio-Sciences Ab Method for production of separation media

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106546629A (en) * 2016-10-21 2017-03-29 上海工程技术大学 A kind of urban rail catenary node failure method for early warning and device

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