CN100445745C - Method of analyzing granular composition by fluorescene analysis - Google Patents
Method of analyzing granular composition by fluorescene analysis Download PDFInfo
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- CN100445745C CN100445745C CNB028044266A CN02804426A CN100445745C CN 100445745 C CN100445745 C CN 100445745C CN B028044266 A CNB028044266 A CN B028044266A CN 02804426 A CN02804426 A CN 02804426A CN 100445745 C CN100445745 C CN 100445745C
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Images
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
- G01N21/85—Investigating moving fluids or granular solids
-
- 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
- B01J2/006—Coating of the granules without description of the process or the device by which the granules are obtained
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
- G01N33/54346—Nanoparticles
Abstract
The present invention relates to a method for fluorescence analysis comprising illuminating a granular composition comprising a purified biologically active compound with light capable of fluorescence excitation of a fluorescent marker comprised in the granular composition, detecting light emitted from the fluorescent marker and predicting the amount of fluorescent marker in the granular composition accessible to fluorescence excitation.
Description
Invention field
The present invention relates to method by particulate composition being carried out fluorescence analysis and then the character of the particulate composition that contains bioactive compound being analyzed.The invention still further relates to the method that is used for the production specific product, comprising product is carried out fluorescence analysis.The present invention relates in addition be applicable to that preparation contains the granulation and/or the dressing equipment of the particulate composition of bioactive compound, described equipment comprises the device of fluorescence analysis.
Background of invention
Sending this phenomenon of fluorescence when utilizing some compound (fluorophore) by optical excitation, the chemical compound in the sample is analyzed (fluorescence analysis) is well known in the art.Fluorescence analysis has sensitive and accurate advantage in the sample that composition is determined very much, but it also has serious defective.For example, in complex sample, the fluorescence of fluorophore is often changed (being called cancellation) by other compound in the fluorophore surrounding environment, and this makes and is difficult to quantitatively complexity and/or the very not clear and definite sample of composition be carried out fluorescence analysis.This especially meets the situation in heterogeneous or the solid phase sample, and also must consider scattering of light this moment.
Along with the development of electronics, occurred utilizing the shooting detecting device to carry out the more ripe method of fluorescence imaging in recent years, this makes it possible to photograph the emission light of fluorescigenic sample, and two-dimensional image can demonstrate the space distribution of fluorophore in the sample thus.
Excite the example that carries out fluorescence imaging can be from Dexter etc. to being used for the refining aleuron tissue of flour through ultraviolet (UV)., Cereal Chemistry (cereal chemistry), vol.70 (1), 90-95 recognizes in 1993.
Kaufman etc., Powder Technology (becoming the powder technology), vol.78 (3), 239-246,1994) utilize fluorescence microscopy that coal Particle Distribution in the liquid fluidized bed has been carried out the original position video picture.
More generally the example of imaging analysis can be at Buydens etc., Analytical Chimica Acta, vol.361 (1-2), 161-176,1998 find, and he has reported based on online classification and the polynary imaging analysis of near infrared ray imaging to plastics in the discarded object.
Watano etc., Pharmaceutical Bulletin (pharmacy bulletin), vol.48 (8), 1154-1159,2000 have reported by the imaging processing system the generation carrying out of the particle in high-shear granulation process on-line monitoring.
At US 5,497, Watano etc. has reported and has utilized camera particle is generated to carry out imaging as being used in CCD type camera in the video camera in fluidized bed or cooking-pot type granulator in 232.
Summary of the invention
The present invention relates to the method for carrying out fluorescence analysis and then the character of this particulate composition is analyzed by to the particulate composition that contains bioactive compound.Usually chemical compound need be made finished product, especially make particle,, can make them have more commercial appeal like this with the performance of improved products.Yet for bioactive compound, the work that the producer normally of granulating must carry out is because reactive compound must separate to guarantee the safe operation of product with surrounding environment before being intended to use.Can must be reduced to from the amount that granulated product discharges as the bioactive compound of dust form minimum can be with the operator who guarantees product owing to the contact bioactive compound affect adversely.Vice versa, must protect reactive compound to prevent that it is subjected to the influence of particle external environment, so that still maintain stability and activity when it is used.In case reactive compound is by granulation, the known particle that can also utilize the coating material bag to be contained bioactive compound can further suppress reactive compound like this and come out and further improve the stability of reactive compound the particle from particle release.General by increasing the thickness of coatings, might further improve the particle performance.
An object of the present invention is to provide method,, be used to measure the nature parameters of the particulate composition of the bioactive compound that contains purifying especially with the form of imaging system.Such parameter can be the amount as the reactive compound that comes out from particle release with the active dust form in the process of preparation particulate composition or afterwards.Another parameter is that dust forms and the thickness and/or the integrality of the coatings of raising reactive compound stability to suppress on the particle as being added in, and can or measure this parameter afterwards in the process of adding dressing for the particle that contains bioactive compound among the present invention.Another object of the present invention is that a kind of facility for granulating of design and system of selection constitute, so that the method can online or in series be applied in the production of this kind particulate composition, and make this method that the information of the amount of the relevant dust that contains bioactive compound can be provided in the process of particulate composition in real time.
We find the particulate composition for the bioactive compound that contains purifying, the reactive compound that not only is limited in the reactive compound in particle surface zone but also is present in the grit (for example because the release of reactive compound or because insufficient generation of granulating in the particle) of composition all can be by can cause fluorescence labeling, the rayed composition that excites as the bioactive compound autofluorescence, and detect fluorescently-labeled emission light and estimate.Therefore, first aspect, the invention provides a kind of method of fluorescence analysis, this method comprises with can be to being included in the particulate composition that rayed that fluorescence labeling in the particulate composition carries out fluorescence excitation contains the bioactive compound of purifying, detect fluorescently-labeled emission light, and be subjected to the fluorescently-labeled amount of fluorescence excitation in the prediction particulate composition.But the amount of excited fluorescent mark can interrelate with the character of particulate composition such as dust level and/or coating thickness or dressing integrality.
In addition, second aspect, the invention provides a kind of being used for comprises the bioactive compound, fluorescence labeling of purifying and the method for the particle of auxiliary granulation agent randomly in facility for granulating preparation, and described method comprises the step (on seeing) of the fluorescence analysis of carrying out first aspect present invention.
Further; the third aspect; the invention provides a kind of granulation or dressing equipment; it comprises that (a) comprises at least one to material evolution granulation or granulate material is carried out the granulation or the coating device of the chamber of dressing; (b) at least one can detect radiative detecting device; (c) radiation source is projected device on the part material in the processing with the light beam form, (d) guiding is reached the device of detecting device by the light of launching according to material and (e) at least one is used to select the device of irradiates light or wavelength of transmitted light.
At last, fourth aspect the invention provides the particle that fluorescence analysis is applied to contain the bioactive compound of purifying.
Brief Description Of Drawings
Fig. 1: an example of optical devices, 1=detecting device (CCD camera) wherein, the 2=light source, the 3=bandpass filter, 4=dichronic mirror beam splitter, the 5=lens, the 6=funnel, 7=is by the particle that fluoresces of illumination beam
Fig. 2 a: example of online optical devices, the radiative photo of particle under the 1=CCD camera record wherein, 2=CCD camera, 3=light source, the particle on the 4=travelling belt.
Detailed Description Of The Invention
Fluorescence analysis
As described, the present invention relates to the particulate composition that contains reactive compound is carried out fluorescence analysis Method.
The first step of the method comprises with exciting the fluorescently-labeled light beam in the particulate composition to shine Penetrate particulate composition. In this step, the photon in the irradiation light will be absorbed by fluorescence labeling, thereby glimmering Electronics in the optical compounds obtains energy and enters a specific rising energy level. At the beginning of returning it with electronics Primordium attitude energy level, the fluorescence labeling that is stimulated subsequently by the photon of launching characteristic wavelength discharge to The energy that small part obtains, described wavelength is by the energy level that raises and the energy difference table between the initial level Levy.
The second step of the method comprises that utilization can be converted into utilizing emitted light the detector of the signal of telecommunication, detects Utilizing emitted light from particulate composition.
The 3rd step of the method comprises processes the signal of telecommunication, is subjected to the particle of fluorescence excitation by prediction Fluorescently-labeled amount in the composition makes one or more character of radiative amount and particulate composition Be associated.
Explanation and meaning to whole terms of relevant fluorescence analysis basic principle are the art technology people The member is known.
The irradiation of particulate composition
The irradiation of particulate composition can be radiated with any and can be excited in the particulate composition the suitable light source of fluorescently-labeled light to carry out.Light source can be as common glow lamp, the xenon lamp or the stroboscopic lamp of specialty.
The optical property of fluorescence labeling compound can be known and in order to optimize known fluorescently-labeled exciting, optimized light source is the light source that quite most of light wavelength of its transmission is applicable to the fluorescence excitation mark.Avoid or limit exciting and launching (this may interference analysis) of other compound except that fluorescence labeling if want (this is possible when using known fluorescence labeling), so just need filtered beam, so that have only the light of selected wavelength can shine particulate composition.This can utilize one or more beam splitters and one or more bandpass filter such as height and/or low band pass filter, or the grating monochromator that only allows the light of specific wavelength to pass through is finished.These parts are incorporated into commercial usually, in the fluorescence analyser from U.S. Perkin Elmer.Bandpass filter and monochromator can make narrow wavelength coverage (usually at several nm, in 0.5-10nm) light pass through, and this is known to the skilled.Therefore the light in the term monochromatic light narrow wavelength coverage that is interpreted as determining by passband bandpass filter and monochromator.
In a particular, the light of irradiation particulate composition is by 1-10 discontinuous monochromatic wavelength, and preferred 1-4 discontinuous monochromatic wavelength formed.Especially, the light of irradiation particulate composition can be made up of 1 discontinuous monochromatic wavelength.In the step of irradiation particulate composition, can use aptly to comprise as catoptron, beam splitting from (as dichronic mirror) and/or fibre-optic optical devices so that irradiates light project on the particulate composition.
Radiative detection
Emission light can be fluorescence labeling be included in chemical group in the fluorescence labeling or component institute distinctive.Because fluorescence labeling is only launched the light in one or more narrow wavelength coverages usually, thus preferably emission light is filtered, so that only the emission light in these close limits just can reach detecting device.This can finish by utilizing one or more bandpass filter or monochromator to filter emission light as mentioned above, sees above.Simultaneously this can avoid may interference analysis other compound except that fluorescence labeling emit light into the amount that reaches detecting device or limit its arrival.Therefore, in a particular, have only the emission light of 1-10 discontinuous monochromatic wavelength to be detected, preferred 1-4 discontinuous monochromatic wavelength.Especially, the emission light that arrives detecting device can be made up of 1 discontinuous monochromatic wavelength.
In addition, the same with when irradiation, in detecting radiative step, can use aptly comprise as catoptron, beam splitter (as dichronic mirror), light transmitting fiber and/or focus on radiative means (as lens) optical devices so that emission light project on the detecting device.
Many kinds of detecting devices can be applied to detect emission light.Detecting device can be a photomultiplier transit type detecting device, photodiode or photodiode array, and line scan camera, CCD camera, ICCD camera or any are applicable to and detect radiative other type.Particularly, detecting device can be the camera type detecting device, as being selected from grayscale cameras, line scan camera, photodiode array, CCD (charge-coupled image sensor) camera and ICCD (strengthening CCD) camera.Especially, detecting device can be CCD camera and ICCD camera, thereby because they are sensitiveer and can form 2 dimension images and demonstrate the space distribution of light-emitting particles or grit.This is called fluorescence imaging according to specialty analysis personnel's term.In a particular, can use two or more detecting devices to write down two or more selected wavelength or two or more wavelength coverage simultaneously.If, just need such operation if measure the light that more than one fluorescence labeling or specific fluorescence labeling are launched different wave length.This especially can utilize the optical devices that comprise one or more beam splitters and two or more bandpass filter or monochromator to finish.In an embodiment the most special, utilization be the optical devices that comprise CCD camera, dichronic mirror and bandpass filter and lens that show as signal in the accompanying drawing 1.
The processing of detection signal
Owing to carry out the extensive application of the fluorescence analyzer of fluorescence analysis, to launch phototransformation in detecting device is that electric signal is converted into value with this signal again, as numerical value (can dope radiative amount thus and infer the fluorescently-labeled amount that is stimulated), this is known to the skilled.This prediction can be aptly undertaken by the radiative data of the known particulate composition of the radiative amount of more unknown particulate composition and character, and then dopes the fluorescence labeling amount that is stimulated in the unknown particulate composition.Most of detecting devices, as type or some types based on photodiode based on photomultiplier transit, output be simulating signal.Most of detecting devices so multi-camera (comprising numerous monochromatic light electric diode detecting devices) all have the built-in simulation-digital converter can be with the digital signal of analog-signal transitions for being applicable to that more computerized data is handled.For character and radiative amount with fluorescence labeling and particulate composition connect, can handle the numerical data that produces self-emission light.This processing is suitable for being utilized as this software of handling design and carries out in computer system.This software has the LabView software that for example is used for this paper embodiment and has handles any other software that desired data makes the pre-requisite abilities that the character of radiative amount and particulate composition interrelates.The operation that data processing can comprise has counting micro particles, measures pattern match (gray scale and colour), statistics, threshold value, polynary imaging analysis, AMT, point analysis, area calculates, rim detection, morphological analysis, convolution, fold and launch, FFT, it is known that various filtering techniques such as medium filtering-all technology are the specialty analysis personnel, is the data processing function that is included in the commercial software.With data transmission in the process of calculation element, calculation element need be equipped with usually and can be used for data storage at calculation element from the hardware that detecting device obtains data.This kind hardware as the data capture card, is well-known.When utilizing CCD or other type camera to produce 2 dimension images of fluorescent grain, in calculation element, also preferred use can be tieed up the software of images with the form record 2 of discontinuous digital rest image.This software is called frame and obtains program.The speed of this software records image depends on the speed of calculation element usually, and for the purposes of most fluorescence analyses, speed is that about 15 frames of per second are just enough.This expression per second writes down 15 width of cloth two dimensional images.
Particulate composition
Physical property
Particulate composition of the present invention be a kind of be processed to particulate or particle contain bioactive compound, itself may be exactly the composition of the fluorescence labeling of this bioactive compound and randomly auxiliary granulation agent and coating agent.Therefore, finished particle is the result who implements operation of the present invention and method.Term " particle " can be understood as a kind of remarkable sphere of big molecular dimension or the structure of almost spherical, and the average-size of its longest diameter is preferably between 20-2000 μ m, more preferably between 100-1000 μ m, most preferably between 200-800 μ m.The ratio that spheric grain has (a): (b), promptly the diameter (a) of the shortest dimension of particle and the ratio between the diameter (b) of long dimension be preferably 1: 1 to 1: 5, more preferably 1: 1 to 1: 3.
" size distribution " of particle (PSD) can be represented with the mass mean diameter of each particulate.Mass mean diameter D50 represents that 50% particle has the diameter more less than this diameter by mass, and the particle of 50% quality has than major diameter.Value D10 and D90 represent respectively that by mass the diameter of 10% and 90% particle is littler than mentioned value." span " refers to the width of PSD, can be expressed as: (D90-D10)/and D50.For the purposes of the present invention, the PSD of particle is narrow more usually good more after the granulation.In the present invention, utilize fluorescence analysis control pelletization can help to reduce PSD, the span of particulate composition especially can be less than about 2.5 after therefore granulating, preferably less than about 2.0, be more preferably less than about 1.5, most preferably less than about 1.0,
Especially can form one with coating agent, preferred homogeneous, consistent and continuous layer wraps by particle around particle.Term coating agent used herein can be regarded as the single dressing compound or the potpourri of dressing compound.Therefore the tool coated granules is made up of granular core and granule coating.Especially, coatings can relatively thick stability with further minimizing dust formation and increase bioactive compound.Coating thickness can by the mean diameter of tool coated granules core and not the ratio (hereinafter to be referred as DG/Dc) between the mean diameter of coated granules core be described, just have the mean diameter of coated granules divided by the mean diameter of independent granular core.If for example the granular core pericardium of diameter 100 μ m is by the thick dressing of one deck 200 μ m, then the diameter of particle is (200+100+200)=500 μ m and DG/Dc is 500 μ m/100 μ m=5.The DG/Dc of tool coated granules of the present invention preferably is at least 1.1, this means that the thickness of dressing is at least 5% of average grain core diameter.More preferably DG/Dc is at least 1.5, is more preferably at least 2, is more preferably at least 2.5, is more preferably at least 3, most preferably is at least 4.But it is about 100 that DG/Dc preferably is lower than, and preferably is lower than approximately 50, more preferably less than 25, most preferably is lower than 10.The most preferred range of DG/Dc is about 4 to about 6.
In addition, dressing is substantially devoid of enzyme in the present invention, and the term of relevant dressing used herein " is substantially devoid of enzyme " and is meant in every gram coating material and contains the enzyme that is less than 5mg.
For the material (as follows) that constitutes particle of the present invention, these materials, opposite with material transparent such as glass, generally can not see through visible light, for instance, a people can not see through this particle usually and look thing.Yet, when the particle of the bioactive compound that contains this area is accepted the irradiation of exciting light, we find that this exciting light can penetrate particle surface and excite on the particle surface or near suitable fluorescent chemicals, and can escape out particle so that can be received by detecting device of the emission light of this fluorescent chemicals.
In addition, the moisture in the particle preferably less than 15 (w/w) %, is more preferably less than 10 (w/w) %, as in 4 to 8 (w/w) % scope less than 20 (w/w) % usually.
Make up
Can make up particle by any method of granulating known in the art.
The construction method of particle of the present invention can be divided into following non-limiting classification:
A) spray-dried granules, the fluid solution that wherein will comprise bioactive compound in the spray dryer formation droplet that atomizes, droplet is the dry particulate matter that contains bioactive compound that forms in the way that falls along exsiccator.This method can be produced very little particle (Michael S.Showell (editor); Powdered detergent; Surfactant science magazine (Surfactant ScienceSeries); 1998; Vol.71; The 140-142 page or leaf; Marcel Dekker).For these particles, bioactive compound can be closely with fluid solution in any other auxiliary granulation agent mix mutually.
B) laminar particle, wherein center on preformed core particle bag by one deck bioactive compound, in this technology, usually can carry out in the fluid unit of fluidisation preformed core particle, to comprising bioactive compound and preferably assisting the solution of granulation agent to atomize, it is also dry up to the bioactive compound layer that forms one deck drying on the core particle surface that the solution that contains bioactive compound is adhered on the core particle.Just can utilize the method to obtain the particle of required size if can access the useful core particle of required size.To the explanation of this series products referring to as WO97/23606.
C) absorption core granule, wherein be not around the core bag by one deck bioactive compound, but bioactive compound is adsorbed on the core surfaces and/or within.To the explanation of the method referring to WO 97/39116.
D) extrude or ball shape particle, the pastel that wherein will contain bioactive compound in mould is pressed into particle, or it is pressed through little perforate under pressure and is cut into particle, carries out drying subsequently.Usually the size of this kind particle is quite big, and this is can allow applied pressure to fall on the extruded hole because the material (plate that normally has boring) of preparation extruded hole has limited.In addition, if use little perforate, very high extruder pressure can make the heat generation in the pastel increase, and this may be harmful to (Michael S.Showell (editor) to bioactive compound; Powdered detergent; Surfactant science magazine (Surfactant Science Series); 1998; Vol.71; Page 140-142; MarcelDekker).
E) spraying cooling particulate, wherein with the bioactive compound powder suspension in molten wax, and for example through spinning-disc atomizer, gained suspending liquid sprayed enter cooling chamber, drop solidifies (Michael S.Showell (editor) rapidly in cooling chamber; Powdered detergent; Surfactant science magazine (Surfactant Science Series); 1998; Vol.71; Page 140-142; MarcelDekker).For these particles, bioactive compound closely mixes with wax phase, rather than concentrates on its surface.Document US 4,016,040 and US 4,713,245 also relate to this technology.
F) high shear mixer particle, wherein the liquid that contains bioactive compound is added in the dry powder composite with auxiliary granulation agent, liquid and powder mix with proper proportion, and along with the moisture in the liquid is absorbed in the dry powder, each composition in the dry powder begins bonding cohesion, particle increases, and has so just formed the particle that contains bioactive compound.For these particles, reactive compound closely mixes with auxiliary granulation agent.US 4 is seen in the explanation of the method, 106,991 (NOVONORDISK) and pertinent literature EP 170360 B1 (NOVO NORDISK), EP 304332 B1 (NOVO NORDISK), EP 304331 (NOVO NORDISK), WO 90/09440 (NOVO NORDISK) and WO 90/09428 (NOVO NORDISK).
Grit in the particulate composition
May be present in the grit in the particulate composition, it is characterized in that the fragment of complete particle, usually have much smaller size and do not have the peculiar spherical form of particle than particle.Grit generally has irregular non-spherical fault structure such as clavate or thin slice shape.Grit generally is far smaller than the mean size of particle, and according to different particulate compositions, most of grit diameters are less than 20 μ m.
As the fragment of complete particle, grit has same opacity with complete particle and contains approximately identical water cut usually, sees above.
Compound in the particulate composition
Bioactive compound
Particulate composition of the present invention comprises bioactive compound, especially the bioactive compound of purifying.Term bioactive compound used herein can be understood as any and have active compound in biosystem, as disturbing and/or change the compound of biological pathway or biologically.It before term used herein " purifying " can be understood as and granulates the bioactive compound of removing as unnecessary material and/or concentrated reactive compound process one or many purifying.Utilizing microbial fermentation processes to prepare under the situation of reactive compound, purifying especially comprises and is selected from following step: filter, ultrafiltration, flocculation, sedimentation, evaporation is extracted etc., removing biomass and other unwanted material (comprising water), and then produce the potpourri that is rich in bioactive compound.
Bioactive compound comprises especially organic compound such as biocatalyst, therapeutic agent, herbicide, pesticide and fungicide.Especially this bioactive compound can be produced by the microorganism that fermentation energy is produced this reactive compound.
Especially, compound can be protein and peptide, more preferably catalytic proteins, i.e. enzyme because protein such as enzyme are applied in the commercial production in large quantities, and known they can cause harmful allergic reaction to the human and animal who is exposed to this protein.In addition, enzyme is widely used in household products as being used for removing the detergent of biogenic property spot, and many industrial processs also relate to the manual operations of enzyme.Described enzyme can be any enzyme that need it be separated with surrounding environment by the pelletization of enzyme.
The foundation that is applied to the enzyme classification in this specification and claims book is the suggestion (1992) of international biological chemistry and NK of molecular biology association, (Recommendation (1992) of theNomenclture committee of the International Union of Biochemistry andMolecular Biology Academic Press, Inc., 1992).
Therefore, the type that is suitable for being combined in the enzyme in the particle of the present invention comprises oxidoreducing enzyme (EC1.-.-.-), transferase (EC2.-.-.-), hydrolytic enzyme (EC3.-.-.-), lyases (EC4.-.-.-), isomerase (EC5.-.-.-) and ligase (EC6.-.-.-).
In the context of the invention, oxidoreducing enzyme especially can be a peroxidase (EC.1.11.1), laccase (EC1.10.3.2) and glucose oxidase (EC1.1.3.4)], and preferred transferase can be the transferase that belongs to following any subclass:
A) transferase (EC2.1) of the single carbon-based group of transfer;
B) transferase (EC2.2) of transfer aldehydes or ketones residue; Acyltransferase (EC2.3);
C) glycosyl transferase (EC2.4);
D) transferase (EC2.5) of the alkyl or aryl group of transfer except that methyl group; And
E) transferase (EC2.6) of transfer nitrogen-containing group.
Most preferred transferase type is a transglutaminase (protein-glutamine gamma glutamyltransferase in the context of the invention; EC2.3.2.13).
Other example of the transglutaminase that is suitable for is referring to the explanation of WO 96/06931 (Novo NordiskA/S).
Preferred hydrolytic enzyme is in the context of the invention: carboxylic ester hydrolases (EC3.1.1.-) is as lipase (EC3.1.1.3); Phytase (EC3.1.3.-) is as 3-phytase (EC3.1.3.8) and 6-phytase (EC3.1.3.26); Glycosidase (EC3.2, it belongs to alleged " carbohydrase " herein) is as AMS (EC3.2.1.1); Peptase (EC3.4 is also referred to as proteinase); And other carbonylic hydrolase.
Among the present invention, term " carbohydrase " not only be used in reference to and can rupture and have especially the sugar chain of 5 and 6 ring structures (as, starch) enzyme (is a glycosidase, EC3.2), but also refer to make the isomerized enzyme of carbohydrates, for example 6 ring structures such as D-glucose isomerase are turned to 5 ring structures such as D-fructose.
Suitable carbohydrase comprises following (being the EC numbering in the bracket): AMS (3.2.1.1), beta amylase (3.2.1.2), glucosan 1,4-alpha-Glucosidase (3.2.1.3), cellulase (3.2.1.4), inscribe-1,3 (4)-1,4 beta-glucanases (3.2.1.6), inscribe-1,4-beta-xylanase (3.2.1.8), glucanase (3.2.1.11), chitinase (3.2.1.14), polygalacturonase (3.2.1.15), lysozyme (3.2.1.17), β-Pu Tangganmei (3.2.1.21), alpha-galactosidase (3.2.1.22), beta galactosidase (3.2.1.23), amylo-1:4,1:6-transglucosidase, 6-glucosidase (3.2.1.33), xylan 1,4-xylobiase (3.2.1.37), glucosan inscribe-1,3-β-D-glucosidase (3.2.1.39), schardinger dextrin inscribe-1,6-alpha-Glucosidase (3.2.1.41), sucrose alpha-glucosidase (3.2.1.48), glucosan inscribe-1,3-alpha-Glucosidase (3.2.1.59), glucosan 1,4-β-Pu Tangganmei (3.2.1.74), glucosan inscribe-1,6-β-Pu Tangganmei (3.2.1.75), araban inscribe-1,5-α-L-arabinose glycosides enzyme (3.2.1.99), lactase (3.2.1.108), chitosanase (3.2.1.132) and xylose isomerase (5.3.1.5).
Commercial oxidoreducing enzyme (EC1.-.-.-) comprises for example GLUZYME
TM(from NovoNordisk A/S).The example of commercial proteinase (peptase) comprises KANNASE
TM, EVERLASE
TM, ESPERASE
TMALCALASE
TM, NEUTRASE
TM, DURAZYM
TM, SAVINASE
TM, PYRASE
TM, PANCREATIC TRYPSINNOVO (PTN), BIO-FEED
TMPRO and CLEAR-LENS
TMPRO (all from Novo Nordisk A/S, Bagsvaerd, Denmark).
Other commercial proteinase comprises MAXATASE
TM, MAXACAL
TM, MAXAPEM
TM, OPTICLEAN
TMAnd PURAFECT
TM(from GenencorInternational Inc. or Gist-Brocades).
The example of commercial lipase comprises LIPOPRIME
TM, LIPOLASE
TM, LIPOLASE
TMULTRA, LIPOZYME
TM, PALATASE
TM, NOVOZYM
TM435 and LECITASE
TM(all from Novo Nordisk A/S).
Other commercial lipase comprises LUMAFAST
TM(pseudomonas mendocina of Genencor InternationalInc. (Pseudomonas mendocina) lipase); LIPOMAX
TM(pseudomonas pseudoalcaligenes (Ps.pseudoalcaligenes) lipase of Gist Brocades/Genencor Int.Inc; And the bacillus of Solvay Enzymes (Bacillus) lipase.
The example of commercial carbohydrase comprises ALPHA-GAL
TM, BIO-FEED
TMALPHA, BIO-FEED
TMBETA, BIO-FEED
TMPLUS, BIO-FEED
TMPLUS, NOVOZYME
TM188, CELLUCLAST
TM, CELLUSOFT
TM, CEREMYL
TM, CITROZYM
TM, DENIMAX
TM, DEZYME
TM, DEXTROZYME
TM, FINIZYM
TM, FUNGAMYL
TM, GAMANASE
TM, GLUCANEX
TM, LACTOZYM
TM, MALTOGENASE
TM, PENTOPAN
TM, PECTINEX
TM, PROMOZYME
TM, PULPZYME
TM, NOVAMYL
TM, TERMAMYL
TM, AMG
TM(amyloglucosidase NOVO), MALTOGENASE
TM, SWEETZYME
TMAnd AQUAZYM
TM(all from Novo Nordisk A/S).Other carbohydrase can be from other dealer.
The enzyme amount in the particle of the present invention of being combined in depends on the intended purpose of particle.Concerning many application, enzyme content should be as far as possible or feasible ground high.
The content of the enzyme in the particle of the present invention (calculating with pure zymoprotein) generally accounts for about 0.5% to 50% of enzyme containing granule weight.
Auxiliary granulation agent
Particle of the present invention especially comprises auxiliary granulation agent, and purpose is for for example, helps particle to form, the density and the volume of regulation and control particle, the content of reactive compound in the regulation and control particle, stabilizing active compound etc.
Auxiliary granulation agent can include but not limited to:
A) filling agent such as routine are applied to the filling agent in the field of granulating, the alkali-metal sulfate of water miscible and/or insoluble inorganic salts as grinding is very carefully arranged for instance, alkali-metal carbonate and/or alkali-metal chloride, clay such as porcelain earth (SPESWHITE for example
TM, the potter's clay of Britain), bentonitic clay, talcum, zeolite, and/or silicate.
B) bonding agent such as routine are applied to the bonding agent in the field of granulating, and have high-melting-point for instance or do not have the bonding agent of the non-wax character of fusing point fully, as polyvinylpyrrolidone, dextrin, polyvinyl alcohol (PVA), cellulose derivative, hydroxypropyl cellulose for example, methylcellulose or CMC.Suitable bonding agent is sugared bonding agent as can be from the Glucidex 21D of French Roquette Freres.
C) fibrous material such as routine are applied to the fiber in the field of granulating.Pure or the impure cellulose of fibers form can be the pure or impure fibrous cellulose of sawdust, pure fibrous cellulose, cotton or other form.Can also use filtration aid based on fibrous cellulose.The fibrous cellulose of several brands puts goods on the market, as CEPO and ARBOCELL.Point out that at " Cepo cellulose powder (Cepo CellulosePowder) " literary composition that SvenskaTramjolsfabrikerna AB delivers maximum fibre length approximately is 500 μ m for Cepo S/20 cellulose, average fiber length is about 160 μ m, maximum fiber width is approximate to be 50 μ m, and the average fiber width is approximate to be 30 μ m.Equally, point out that also CEPO SS/200 cellulose has the approximate maximum fibre length of 150 μ m, the approximate average fiber length of 50 μ m, the approximate maximum fiber width of 45 μ m, and the approximate average fiber width of 25 μ m.Cellulose fibre with these yardsticks is highly suitable for purpose of the present invention.Word " Cepo " and " Arbocel " are trade marks.Preferred fibrous cellulose is Arbocel
TMBFC200.Can use described synthon in addition, and exemplary synthetic fibers can be by tygon as EP 304331 B1, polypropylene, polyester, especially nylon, polyvinyl formate, poly-(methyl) acyclic compound is made.
D) liquid reagent such as routine are applied to the liquid reagent in the field of granulating.Liquid reagent is used for conventional mixing granulation method to be made the particulate increase of conventional granulation composition or builds up the formation particle.Liquid reagent is water and/or ceroidlike material.In pelletization, liquid reagent is generally used in the liquid phase, but can solidify after a while; Therefore,, both can make its dissolving or be dispersed in the water, also can make its thawing if ceroidlike material is arranged.Term used herein " ceroidlike material " is meant the material with all following features:
1) fusing point is between 30 and 100 ℃, especially between 40 and 60 ℃, 2) this material flexible is non-friable, and 3) this material at room temperature has certain plasticity.Water and ceroidlike material can be as liquid reagents, and promptly the two can both work in the forming process of particle; Ceroidlike material is stayed in the finished particle as a kind of component, and most of water is removed in dry run.The example of ceroidlike material has polyglycols, fatty alcohol, ethoxylized fatty alcohol, the list of higher fatty acid, two and glyceryl ester, for example glycerin monostearate, alkyl aryl ethoxylates and coconut monoethanol amide.
As use the ceroidlike material of a large amount, and then need add the water of relatively small amount, vice versa.Therefore, liquid reagent both can be independent water, and independent wax sample thing also can be the potpourri of water and wax sample thing.If make the potpourri of water and wax sample thing, water and wax sample thing can add according to any order, for example add water earlier and add wax sample thing again, or add wax sample thing earlier and add water again or form solution or the suspending liquid of wax sample thing in water.And when making the potpourri of water and wax sample thing, wax sample thing can be soluble or insoluble (but dispersible) in water.If water is as liquid reagent, water usually can be as the part of finished product composite grain, because most of water can be dried up in the dry run of subsequently composite grain.
E) enzyme stabilizers or protective agent such as routine are used to those of the field of granulating.Stabilizing agent or protective agent can be divided into following a few class: alkalescence or neutral substance, reductive agent, antioxidant and/or first transition are the salt of metallic ion.Each class can be united use with similar or inhomogeneous other protective agent.The protectant example of alkalescence has alkali-metal silicate, carbonate or supercarbonate, and they provide the chemical scavenging effect by neutralizing actively as oxygenant.The example of restitutive protection's agent has sulphite, thiosulfite or thiosulfate, and the example of antioxidant has methionine, butylated hydroxytoluene (BHT), fourth hydroxyanisol (BHA).Most preferred reagent is thiosulfate, as sodium thiosulfate.Enzyme stabilizers can also be borate, borax, formates, binary and tricarboxylic acid and reversible enzyme inhibitor as the organic compound that contains mercapto groups or the boric acid of alkylating or arylation.
F) crosslinking chemical such as routine are used to those of the field of granulating.Crosslinking chemical can be the surfactant of enzyme-compatibility, and ethoxylated alcohol for example especially has the ethoxylated alcohol of 10 to 80 ethoxy groups.
In addition, suspending agent, medium (being used for using the medium of the discoloration after improving particle dissolution or the medium of enzyme as washing) and/or solvent can be mixed as auxiliary granulation agent.
Coating agent
Dressing comprise one or more routines as WO 89/08694, WO 89/08695, among EP 270608 B1 and/or the WO 00/01793 record the coating agent composition.Other example of coating agent can be at US 4,106,991, and EP 170360, and EP 304332, and EP 304331, EP 458849, and EP 458845, and WO 97/39116, WO 92/12645A, and WO 89/08695, WO 89/08694, and WO 87/07292, and WO 91/06638, and WO 92/13030
WO 93/07260, and WO 93/07263, and WO 96/38527, and WO 96/16151, WO97/23606, and US 5,324,649, US 4,689,297, and EP 206417, EP 193829, and DE 4344215, DE 4322229 A, and DD 263790, find among JP 61162185 A and/or the JP 58179492.Especially, the saliferous dressing of record can be used for dressing of the present invention among the WO 00/01793.
Coating agent can be selected from auxiliary granulation agent listed above.Other coating agent is optional from the following non-limiting thing of listing: polymkeric substance, chlorine scavengers, plastifier, pigment, lubricant (as surfactant or antistatic agent) and aromatic.
Be applicable to that the polymkeric substance in the coatings comprises ethene polymers or ethylene copolymer such as polyvinyl alcohol (PVA) (PVA) and/or polyvinylpyrrolidone or the derivant of the two.Also comprise the m-phthalic acid polymkeric substance.
In the context of the invention, be applicable to that the plastifier in the coatings comprises, for example: polyol is lower than 1000 polyglycol (PEG) as sugar, sugar alcohol or molecular weight; Urea, the dibutyl ester of phthalic ester such as phthalic acid or dimethyl ester; And water.
Suitable pigment includes, but not limited to whitening agent in small, broken bits, as titania and porcelain earth, and coloured pigment, water-soluble colorant, and the combination of one or more pigments and water-soluble colorant.
As used herein, term " lubricant " is meant any reagent that can reduce the fragility of mantle friction, lubricated granules surface, the tendency that reduces the static increase and/or minimizing particle.Lubricant also can play dependent interaction by reducing the viscosity of bonding agent in the dressing in the improvement that adds coating method.Therefore, lubricant can be used as anticoalescent and wetting agent.The example of suitable lubricant has polyglycol (PEGs) and ethoxylized fatty alcohol.
In the embodiment of the particle that mainly is conceived to be used for the detergent preparation, can be with different " function " component such as TAED, CMC, bleaching agent, OBA, surfactant, spices and other function ingredients that is used for the detergent preparation well known by persons skilled in the art add in the dressing.Dressing can also randomly be included as them in pharmacy industry, agricultural, and grocery trade bakes industry, adjuvant industry, feed industry, detergent industry or other can use the special purpose in the industry that contains the bioactive compound particle and the function ingredients selected.
In a particular of the present invention, particle of the present invention is had the protectiveness dressing of at least 81% high constant humidity to be sealed, and illustrates referring to the WO 89/08694 that incorporates into herein as a reference.Therefore, in certain embodiments, dressing can serve as the barrier of moisture and/or bleaching agent with stable nucleus bioactive compound in the heart.In addition, in other embodiments, dressing partly serves as mechanical barrier in as mechanical processing process such as preparation and compressing tablets.In some embodiments, thus dressing partly no matter still has enough compressibilities with regard to the biologically active of reactive compound on structural meaning and pliability can be processed core through pressed sheets.This point is best suited for the detergent preparation potentially.
In a particular, coating agent can absorb the light of launching from fluorescence labeling in the light of excitation source and/or the particle, and therefore when a zone of particle surface was sealed by this coating agent, from then on regional detected emission light will reduce.
Fluorescence labeling
The fluorescence labeling that is included in the particulate composition of the present invention can be the compound that can send fluorescence after any is shone.Fluorescence labeling especially can be organic compound and can send fluorescence when light (for example light of wavelength between 10-700nm, more preferably ultraviolet region, the i.e. light of the 10-380nm) irradiation of the X-ray, ultraviolet ray and/or the visibility region that are subjected to electromagnetic wave spectrum.
In addition, be included in fluorescence labeling in the particulate composition of the present invention, i.e. the light of 185-2600nm aptly through exciting the light that to launch the ultraviolet that is arranged in electromagnetic spectrum, visible and/or near infrared region.
Fluorescence labeling can belong to the cohort of bioactive compound, auxiliary granulation agent and coating agent, and perhaps fluorescence labeling can be only to add compound in the particulate composition to for carrying out fluorescence analysis of the present invention.Yet from cost saving, prefer fluorescent labels is bioactive compound self or auxiliary granulation agent.
According to the character of the particulate composition for the treatment of to estimate, as the character or the coating thickness of grit, can select different fluorescence labelings for instance by fluorescence analysis.For the evaluation of grit character, for example be more suitable for selecting bioactive compound, because the amount of potential harmful reactive compound is essential in the grit of evaluation particulate composition as fluorescence labeling; And, can select suitable auxiliary granulation agent as fluorescence labeling for the evaluation of coating thickness.
When bioactive compound is a fluorescence labeling, especially fluorescent emission is under the fluorescence marked situation of the protein that caused by aromatic amino acid such as tyrosine and tryptophane and/or peptide, the preferred light source of sending out ultraviolet light (UV-light) that utilizes in fluorescence analysis, the wavelength of the most of light that especially sends (UV-light) is positioned at 10-380nm, more preferably be positioned at 200-400nm or 200-300nm, the light source that most preferably is positioned at 260-280nm shines particulate composition.In such cases, also preferably only detect scope, as emission light, the especially 280-360nm of 400-700nm or 300-400nm or the light of 325-375nm at 200-700nm.In such cases, also need to select to detect radiative detecting device, as the CCD camera with these wavelength.
If fluorescence labeling is one of auxiliary granulation agent, in fluorescence analysis, the preferred light wavelength of sending of utilizing is positioned at 350-550nm, and more preferably the light source between 375-425nm shines particulate composition.Equally in such cases, also need to select the detecting device that can detect, as the CCD camera to emission light with these wavelength.In pelletization, can also add the fluorescence labeling that only is used for fluorescence analysis.A large amount of suitable fluorescent chemicalses can for example (Molecular Probes USA) obtains from U.S. molecular probe mechanism.
Fluorescence analysis in granulation and the dressing process
The present invention also is included in the character of utilizing above-mentioned fluorescence analysis method prediction particulate composition in the facility for granulating and controls and improve the preparation method, and then preparation contains bioactive compound and randomly assists the method for the particulate composition of granulation agent.Therefore; the invention provides and be used for preparing the method that contains bioactive compound and randomly assist the particulate composition of granulation agent at facility for granulating; described method comprises step: when particle forms in granulator, the fluorescence labeling that is included in the particulate composition is as mentioned above carried out fluorescence analysis.
In a particular, fluorescence analysis is carried out during granuloplastic in pelletization, and preferably online carrying out this means the fluorescence analysis more than carrying out once in real time with suitable repetition rate in pelletization.Repetition rate especially depends on the data processing that the data of coming self-detector are carried out.In the particular of utilizing CCD or ICCD camera, in pelletization, note about 15 emission light measurement value with the form per second of two dimensional image.Term " formation of particle " has also comprised with the coatings bag by particle.In this embodiment, the method especially can also comprise step: the result according to fluorescence analysis changes at least one method parameter.Method parameter to be changed can be the arbitrary parameter that influences pelletization and/or shaped granule character.These parameters can be granulated material in the granulator; be the supply of bioactive compound and/or auxiliary granulation agent and/or coating agent, the donor of gas in the granulator, the temperature in the granulator; pressure in the granulation, pH in the granulator and the mechanical force that imposes on granulated material.Method parameter can change by manual or automated system, referring to, facility for granulating.
In another embodiment, fluorescence analysis of the present invention also is applicable to the control granulation dirt voltinism matter of finished particle composition afterwards.Therefore, the present invention also provides the method for the active dust in the particulate composition that contains bioactive compound being carried out fluorescence analysis.Utilize this kind method, the particulate composition that does not satisfy the quality requirements of relevant grit can be abandoned or reprocess.
In another embodiment, fluorescence analysis of the present invention also is applicable to regulation and control the granulation thickness and/or the homogenieity of the dressing of finished particle composition afterwards.Therefore, the present invention also provides the method that the thickness to the dressing in the coated granule composition that contains bioactive compound carries out fluorescence analysis.With this kind method, the particulate composition that does not satisfy the quality requirements of relevant coating thickness can be abandoned or reprocesses.
Imaging system can, as described, be used for the evaluation of Q factor such as active dust value or coating thickness.For example carrying out online evaluation in the dressing process in one embodiment.Can be subjected to the emission light image of the particle that excitation source shines by record (especially by shooting method), and the document image of the sample (with reference to sample) that document image and Q factor value is known compares, to finish evaluation.Fluoroscopic image and corresponding Q factor with reference to sample can be used for providing a master pattern, are applicable to the modeling of the master pattern that makes up view data as offset minimum binary side's model (PLS) or any other.Can utilize model to dope the estimated value of Q factor from the fluoroscopic image of unknown sample like this.
Therefore, the present invention also comprises the method that the Q factor of the particulate composition of the bioactive compound that contains purifying is estimated, step comprises:
A) provide a master pattern, mode is that utilize can be to being contained in the known particulate composition that contains the purifying biological reactive compound of rayed Q factor that fluorescence labeling in the particulate composition carries out fluorescence excitation, one or more emission light images of the particulate composition that the record quality is known are also preferably carried out data processing to produce a master pattern according to processing form to document image with the offset minimum binary number formulary
B) utilize the particulate composition that contains the purifying biological reactive compound that can carry out rayed the unknown of fluorescence excitation to the fluorescence labeling that is contained in the particulate composition, at least one emission light image of the particulate composition that record is unknown,
C) at least one image and the master pattern with unknown particulate composition compares also
D) estimate the Q factor of unknown particulate composition.
Facility for granulating
Containing with good grounds the present invention carries out the means of fluorescence analysis to particulate composition granulation and/or dressing equipment is also included within the scope of the invention equally.Therefore, the invention provides and granulate or dressing equipment, it comprises:
(a) comprise granulation or the coating device that at least one is used for materials processing is become the Processing Room of particle or coated granule,
(b) be used to carry out the optical devices of fluorescence analysis, it comprises the light source that is used to shine machined material, at least one can detect the radiative detecting device of machined material, irradiates light is projected device on the machined material partly, the emission light of illuminated material is projected device and at least one filtering apparatus of detecting device.
Granulation or coating device can be that any conventional granulation device, especially this device can be selected from fluidised bed granulator or dressing machine, high shear force mixer-granulator, spray dryer, spraying cooler and extruder.
In optical devices, light source especially can be common glow lamp, professional xenon lamp or stroboscopic lamp, preferably can send the light of wavelength 10-700nm, more preferably ultraviolet region, the i.e. light of 10-380nm.
In the optical devices, detecting device especially can be the image pick-up type detecting device, more preferably line scan camera, CCD or ICCD camera.
Optical devices can randomly comprise the radiative device of focusing, as lens.
Be used for irradiates light is projected the device on the machined material and the device that the emission light of described material projects detecting device comprised one or more light transmitting fibers, catoptron, lens, beam splitter etc.
Optical devices comprise that at least one is used to filter irradiates light and/or radiative filtration unit.In a specific embodiment, this device is bandpass filter or grating monochromator.In one embodiment, place one or more filtering apparatus, could arrive detecting device so that only emission light is filtered and make emission light must pass through light filter.In another embodiment, place at least two filtering apparatus, so that irradiates light and emission light are all filtered.The light filter of the wavelength of being addressed when most preferably those can select above at the specific fluorescent mark (seeing above).If use two detecting devices then optical devices also comprise at least one beam splitter such as dichronic mirror.
In a most preferred embodiment, optical devices comprise a stroboscopic light source, two CCD shooting detecting devices, a bandpass filter that is used to filter irradiates light, two are used to filter radiative bandpass filter, lens and two dichronic mirror beam splitters, as shown in Figure 1.
In a particular, grenade instrumentation comprise be used to make the perforate of irradiates light by Processing Room to project the device on the material partly processed in the Processing Room and be used for will the processing indoor material emission light project the device of detecting device.
In a more preferred embodiment, the device that is used to provide from the removing stream of the material of Processing Room also is provided facility for granulating.Optical devices are placed on and can carry out fluorescence analysis to the material of removing in the stream in the case, rather than on the position that the material in the Processing Room is analyzed.A reason of preferred this embodiment is the wearing and tearing that pelletization is usually directed to the quite big degree of facility for granulating.When a kind of bioactive compound of granulation such as enzyme, some auxiliary granulation agents may be clay or other inorganics.These materials have tangible abrasive action to facility for granulating.Therefore, when in mixer-granulator for example, granulating, can observe facility for granulating internal part surface every year usually and be paved with several millimeters steel sand.Such wear intensity may be very harmful to the Sensitive Apparatus of optical devices.Particle in the removing stream can carry out recycle aptly and such fluorescence analysis can not disturbed pelletization.Remove stream and can guide the light transmission part (be light can be projeced into herein) of particle aptly by removing stream.For example, remove stream and can be sent to optical devices from the granulation chamber by transfer system, wherein said transfer system can comprise and for example is selected from skewed slot, pump, pipeline, travelling belt, one or more devices of cyclone etc.Fluorescence analysis can be placed on aptly on the some sites in the transfer system, can illuminated optical excitation in this site granulated product, and from then on emission light arrive detecting device in the site.For example, this site can be for example such site, and the section of tubing material is replaced by transparent material herein, as glass, quartz or polymeric material.Especially,, provide the means of removing stream to comprise the means that are used to form monolayer of particles in the position of carrying out fluorescence analysis, overlapping with regard to can or not occurring the detection that overlapping each other of when detecting particle cause hardly like this.This can realize by becoming granule product to be loaded on the vibration surface (as the vibration skewed slot) of an inclination (non-level), wherein to the speed of this surperficial area, particle loaded and particle through the transfer rate at the surface that vibrates (angle of inclination) regulate so that the surperficial area that vibrate always greater than the area that is present in this lip-deep particle.Particle will form a particle individual layer basically through surperficial transmission like this.Fluorescence analysis can be carried out in any site of this particle individual layer.Preferably when particle from one or more edges on the surface that vibrates when falling (as waterfall); particle can also leave the vibration surface with an individual layer; and for fear of the surperficial reflection of vibration; fluorescence analysis is preferably left vibration certain behind the surface at particle and is carried out on a bit, and particle still remains an individual layer on this aspect.Owing to measure is to carry out on the particle that forms individual layer, therefore can avoid overlapping, and because the distribution of particle mainly only is a Two dimensional Distribution, so the emission light of particle can focus on more accurately.Like this, can utilize the sharply focused image of two-dimensional detector such as CCD camera acquisition by nearly all individual particle in this fluorescence analysis site.
As mentioned above, optical devices are suitable to be connected with granulation or coating device, so that can online (on-line) or connect and particulate composition is carried out fluorescence analysis (at-line).Online (on-line) analyzes can be understood as the particle that in fact carries out granulation analyzed, and for example analyzes the particle in the removing stream of granulator or recycle.Series connection (At-line) is analyzed the downstream (as in outlet) that can be understood as after pelletization and is analyzed or the acyclic sample particle of taking from granulator during granulating is analyzed.
Facility for granulating can comprise other device as being used to handle the data computing device of self-detector, and it can randomly be equipped with expert data processing hardware and software.Facility for granulating can also comprise that the control device that links to each other with calculation element is used for regulating and control method of granulating according to the fluorescence analysis result.Opertaing device can be PLC or miscellaneous equipment, and it can accept to become output signal from the data of calculation element and with these data-switching and then control one or more hardware units to influence pelletization (as incoming flow, speed, temperature, air-flow etc.).
In following experiment, carry out illustration to implementing method of the present invention.These experiments are the embodiment of one embodiment of the invention just, and limits the scope of the invention never in any form.
Embodiment
The fluorescence analysis of raw material to the preparation enzyme granulate:
On LS50B (Perkin Elmer) instrument, eight kinds of different starting material and the enzyme concentrate that is used to make enzyme granulate carried out fluorescence analysis.With 10nm is the endogenous optical excitation starting material of step-length with the 230-500nm different wave length, is the material emission light of step-length recording wavelength 270-700nm then with 1nm.The slit separation that is used in LS50B (Perkin Elmer) instrument to excite and launches all is 4nm.Place the starting material of quartz container (cup) according to the requirement of instruments design by irradiation, then in the goniometry starting material emitted fluorescence that becoming 22.5 degree with the irradiates light direction to realize fluorometric assay.
Several starting material send fluorescence significantly but the enzyme concentrate has unique very strong emission at about 350nm.
The fluorescence analysis of enzyme granulate:
On LS50B (Perkin Elmer) instrument to the enzyme granulate of dressing not and add coated granules and carry out fluorescence analysis and measure.With the endogenous optical excitation particle of 10nm step-length, launch light with the material of 1nm step-length recording wavelength 270-700nm then with the 230-500nm different wave length.The slit separation that is used to excite in this PerkinElmer instrument and launches is 4nm.Place the starting material of quartz container (cup) according to the requirement of instruments design by irradiation, then in the raw-material fluorescent emission of goniometry that becoming 22.5 degree with the irradiates light direction to carry out fluorometric assay.
Emission peak appears in about 350nm that the result is presented at corresponding to the enzyme concentrate.Another strong peak occurs between the 450-500nm, and this is to be caused by the fluorescent chemicals in the granulation auxiliary agent.The result shows that there is feasibility in the enzyme that detects in the particle.
The online fluorescence analysis of particle:
Utilize as shown in Figure 1 optical devices to the enzyme granulate of dressing not and add coated granules and carry out fluorescence analysis and measure." detecting device of taking pictures of ITCCD 782 (H) * 582 (V) type imports the site at sample and has the additional 35mm lens of a CCIR to utilize two Donpisha " camera assembly line by line " XC-8500CE1/2.Light source is Oriel xenon flash lamp 60000w/Oriel annex 60008 and Oriel power supply 68826.The bandpass filter of utilizing irradiates light filters to produce the light of a branch of wavelength 450nm.Emission light was split into two bundles by the dichronic mirror beam splitter before arriving camera, every Shu Doujing bandpass filter filters.A light filter (green color filter) allow 530nm light by and another light filter (Red lightscreening plate) permission 620nm light passes through.
Irradiation and radiative detection are to allow in the funnel that particle passes through by enzyme granulate being loaded proportion of imports to exports, and analyze and just leave from hopper outlet that the particle of funnel carries out.
The data acquisition hardware (DAQ and SCB-68 breakboard construction) that comes the signal of self-detector to be transmitted to be equipped with and the calculation element (ordinary individual's computing machine) of imgae processing software (Labview 4.1.1 IMAQ video and general Labview) from national instrument (NationalInstruments), the instantaneous digital picture when producing fluorescent grain by illumination beam.
These are measured and produce a series of images, and it can be reset as film to be recorded the back.Coated granules form and the shape of sending bright fluorescence and particle clearly do not depicted, and this proof utilizes fluorescence analysis to have feasibility in preparation enzyme granulate process.For coated granule, fluorescence obviously weakens, and shows that coatings has reduced fluorescently-labeled accessibility.Therefore the darker zone indication particle of record has thicker dressing, and this utilizes fluorescence analysis to have feasibility when having proved the preparation coated granule.
Fluorescence analysis has the enzyme granulate of various enzyme concentrates:
The enforcement of this experiment is whether also to can be used as fluorescence labeling in order to estimate bioactivator.In the Lodge mixer, make the purifying protein enzyme concentrate of four batches of different contents.The content of proteinase is respectively 0 (reference), 1,4 and 12 KPNU, wherein KPNU is the abbreviation with respect to the NOVO proteinase kilounit of standard protein enzymatic determination, and the basis of described mensuration is: standard conditions, promptly 50 ℃, pH8.3,9 minute reaction time, under 3 minutes minutes, the digestion that proteolytic enzyme carries out dimethyl casein (DMC) solution.Sample excites with Oriel xenon flash lamp 60000w/Oriel annex 60008 and Oriel power supply 68826.Utilize bandpass filter that irradiates light is filtered to produce the light beam in 300-400nm district.Utilize the 3-CCD camera of JAI (M-90) that emission light is detected.This camera is furnished with a Computar55 telecentric mirror head.Come the signal of self-detector to be transmitted to be equipped with the calculation element (ordinary individual's computing machine) of IFC51 frame grabber and Image-Pro.Plus 4.5 editions.
The particle fluoroscopic image of record is from visually demonstrating: along with the purifying protein enzyme concentration increases, emission light mean intensity also significantly increases.
Utilize standard P EG-dressing (PEG4000) bag that contains porcelain earth and titania by these four batches of particles subsequently.The fluoroscopic image of the coated granule of record is from visually demonstrating: along with the purifying protein enzyme concentration increases, emission light mean intensity also increases.
This shows bioactivator, and promptly the proteinase in this experiment also can be used as fluorescence labeling.
Fluorescence analysis has the enzyme granulate of various different coating thicknesses:
The enforcement of this experiment is in order to study between coating thickness and the radiative intensity whether have correlativity.Utilization contains standard P EG-dressing (PEG4000) bag of porcelain earth and titania by the enzyme containing granule of a collection of standard.Dressing spraying is added on the particle (Huttlin), when the dressing that adds 10%, 25% and 50% respectively, from process, extracts sample.Sample excites with Oriel xenon flash lamp 60000w/Oriel annex 60008 and Oriel power supply 68826.Utilize bandpass filter that irradiates light is filtered to produce the light beam in 300-400nm zone.Utilize the 3-CCD camera of JAI (M-90) that emission light is detected.This camera is furnished with a Computar55 telecentric mirror head.Come the signal of self-detector to be transmitted to the calculation element (ordinary individual's computing machine) that is equipped with IFC51 frame grabber and Image-Pro.Plus4.5 version.The fluoroscopic image of the coated granule of record increases (promptly for 10%, 25% and 50% dressing that adds) from visually demonstrating with dressing concentration, and emission light mean intensity weakens.
This shows that radiative fluorescence intensity can be used to predict coating thickness.
Embodiment 6
Fluorescence analysis has the enzyme granulate of the enzymatic activity grit of different content:
The enforcement of this experiment is in order to study the amount whether fluorescence analysis can be used for estimating grit.Previously known has the enzyme granulate of the tool dressing of spot the problem of enzymatic activity dust can occur on dressing.To proteinase activity dust value is that protein enzyme 29ng carries out fluorescence analysis to eight samples of 2420ng in every gram grit.Sample excites with Oriel xenon flash lamp 60000w/Oriel annex 60008 and Oriel power supply 68826.Utilize bandpass filter that irradiates light is filtered to produce the light beam in 300-400nm zone.Utilize the 3-CCD camera of JAI (M-90) that emission light is detected.This camera is furnished with a Computar55 telecentric mirror head.The signal of detecting device is transmitted to the calculation element (ordinary individual's computing machine) that is equipped with IFC51 frame grabber and Imag-Pro Plus 4.5 editions.Sample is transmitted to the approximately interior imaging system of 10cm of distance.The fluoroscopic image of the particulate composition of record is from visually showing the increase with proteinase activity dust value, and the radiative mean intensity of composition strengthens.
This shows that the fluorescent emission light intensity can be used for estimating the amount of particulate composition biologically active dust.
Claims (45)
1. the method for a fluorescence analysis; be included in granulate or the dressing process in online or in series with can fluorescence excitation being included in the particulate composition that fluorescently-labeled rayed in the particulate composition contains enzyme; detect fluorescently-labeled emission light; and predict the fluorescently-labeled amount that is subjected to fluorescence excitation in the described particulate composition, wherein the average-size of the longest diameter that has of the particle of particulate composition is between 100-1000 μ m.
2. the method for claim 1, it may further comprise the steps:
A) provide a master pattern, mode is: utilization can be to being contained in the known particulate composition that contains enzyme of rayed Q factor that fluorescence labeling in the particulate composition carries out fluorescence excitation, one or more emission light images of the particulate composition that the record quality is known, and document image carried out data processing to produce master pattern
B) utilize the particulate composition that contains enzyme that can carry out rayed the unknown of fluorescence excitation to the fluorescence labeling that is contained in the particulate composition, at least one emission light image of the particulate composition that record is unknown,
C) at least one image and the master pattern with unknown particulate composition compares also
D) estimate the Q factor of unknown particulate composition.
3. method as claimed in claim 2 is wherein also carried out data processing with the offset minimum binary number formulary according to processing form to one or more emission light images of the known particulate composition of the quality that writes down in the step a), to produce master pattern.
4. method as claimed in claim 1 or 2, wherein particulate composition shines with the light source that can produce the ultraviolet light of wavelength between 10-380nm.
5. method as claimed in claim 4, wherein ultraviolet light is made up of 1-10 discontinuous monochromatic wavelength.
6. method as claimed in claim 5, wherein ultraviolet light is made up of 1 discontinuous monochromatic wavelength.
7. the method for claim 1, the fluorescently-labeled emission light of wherein said detection is formed by detecting 1-10 discontinuous monochromatic wavelength emission light.
8. method as claimed in claim 7, wherein fluorescence labeling is a bioactive compound, and the fluorescently-labeled emission light of described detection is formed by detecting a discontinuous monochromatic wavelength emission light.
9. the method for claim 1, wherein detecting is that the detecting device that utilizes at least one emission light can be converted to electric signal carries out.
10. method as claimed in claim 9, wherein detecting is to utilize the CCD or the ICCD camera that emission light can be converted to digital two dimensional image to carry out.
11. method as claimed in claim 10, wherein detecting is to utilize at least two CCD or ICCD cameras that emission light can be converted to digital two dimensional image to carry out.
12. the method for claim 1, wherein prediction is to compare with the emission light with fluorescently-labeled particulate composition of known quantity by the emission light with described particulate composition to carry out.
13. method as claimed in claim 12, wherein said prediction is carried out in real-time mode.
14. the method for claim 1, wherein said enzyme is selected from hydrolytic enzyme and oxidoreducing enzyme.
15. the method for claim 1, wherein particulate composition also comprises auxiliary granulation agent.
16. method as claimed in claim 15, wherein auxiliary granulation agent is selected from fibrous material, bonding agent, filling agent, liquid reagent, enzyme stabilizers, suspending agent, crosslinking chemical, medium and/or solvent.
17. method as claimed in claim 16, wherein fluorescence labeling is a kind of auxiliary granulation agent, and fluorescently-labeled radiative detection is formed by detecting 1 discontinuous monochromatic wavelength emission light.
18. the method for claim 1, wherein said particle comprises core, and enzyme closely mixes with auxiliary granulation agent in this core.
19. the method for claim 1, wherein said particle comprises core granule, is coated with the dressing that one deck contains enzyme on this core granule.
20. the method for claim 1, wherein the mean size of particle is 200-800 μ m.
21. the method for claim 1, wherein said particle adds dressing with coating agent.
22. a method that is used for containing in the facility for granulating preparation enzyme, fluorescently-labeled particle, described method also comprises step: carry out fluorescence analysis by each described method among the claim 1-21.
23. method as claimed in claim 22, wherein fluorescence analysis is online and carry out in real time in pelletization, and more than in pelletization, repeating once.
24. method as claimed in claim 22, it also comprises step: the result according to fluorescence analysis changes at least one method parameter.
25. method as claimed in claim 24, wherein method parameter is selected from the supply of enzyme, supply, the supply of coating agent, supply, temperature, pressure, the pH of gas and the mechanical force that imposes on granulated material of auxiliary granulation agent.
26. as each described method among the claim 24-25, its feature is that also it is a coating method, the particle that wherein contains enzyme wraps quilt with coating agent, and described parameter is the coating agent supply in the facility for granulating.
27. method as claimed in claim 26, wherein said particle also contains auxiliary granulation agent.
28. method as claimed in claim 22, wherein fluorescence analysis is connected after pelletization and is carried out in real time, and more than being repeated once.
29. facility for granulating, it comprises:
(a) comprise the granulation apparatus of laundry that at least one is used for materials processing is become the Processing Room of particle,
(b) optical devices, comprise the light source that is used to shine processed particle, at least one can detect the radiative detecting device of processed particle, and irradiates light is projected device on the processed particle of part, the emission light of illuminated particle is projected device and at least one filtering apparatus of detecting device;
Wherein granulation device is connected with optical devices, so that can be online or in series according to each described method among the claim 1-21 particulate composition is carried out fluorescence analysis.
30. equipment as claimed in claim 29, wherein facility for granulating is selected from fluidised bed granulator, high shear force mixer-granulator, spray dryer, spraying cooler and extruder.
31. equipment as claimed in claim 29, wherein light source is selected from glow lamp, xenon lamp or stroboscopic lamp.
32. equipment as claimed in claim 29, wherein detecting device is a camera.
33. equipment as claimed in claim 32, wherein said camera are selected from line scanning camera, CCD or ICCD camera.
34. equipment as claimed in claim 29 wherein is used for irradiates light projected on the processed particle and the device that the emission light of described particle projects detecting device is selected from one or more light transmitting fibers, catoptron, lens and beam splitter.
35. equipment as claimed in claim 29 is wherein placed filtering apparatus, so that only filter emission light and make emission light could arrive detecting device by light filter.
36. equipment as claimed in claim 35 is wherein placed at least two filtering apparatus, so that irradiates light and emission light are all filtered.
37. equipment as claimed in claim 29, wherein optical devices comprise that a stroboscopic light source, two CCD shooting detecting device, one are used to filter the bandpass filter of irradiates light, two and are used to filter radiative bandpass filter, lens and two dichronic mirror beam splitters.
38. equipment as claimed in claim 29, the processed particle of wherein said part is present in the Processing Room.
39. equipment as claimed in claim 29, device that is used to provide from the removing stream of the particle of Processing Room also is provided for it, and wherein optical devices are placed on the position that can carry out fluorescence analysis to the particle of removing in the stream.
40. equipment as claimed in claim 39 wherein is used to provide the device of removing stream to comprise the device that is used to form monolayer of particles.
41. equipment as claimed in claim 40, the device that wherein is used to form monolayer of particles comprises the vibration surface of an inclination.
42. equipment as claimed in claim 41, wherein the placement location of optical devices makes the monolayer of particles after can falling one or more edges on self-excited oscillation surface carry out fluorescence analysis.
43. equipment as claimed in claim 29, it also comprises one or more devices that are selected from calculation element and control device.
44. dressing equipment, it comprises:
(a) comprise the coating device that at least one is used for materials processing is become the Processing Room of coated granule,
(b) optical devices, comprise the light source that is used to shine processed particle, at least one can detect the radiative detecting device of processed particle, and irradiates light is projected device on the processed particle of part, the emission light of illuminated particle is projected device and at least one filtering apparatus of detecting device;
Wherein coating device is connected with optical devices, so that can be online or in series according to each described method among the claim 1-21 particulate composition is carried out fluorescence analysis.
45. equipment as claimed in claim 44, wherein dressing equipment is selected from fluidized-bed coating machine, spray dryer and spraying cooler.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200100157 | 2001-01-31 | ||
| DKPA200100157 | 2001-01-31 |
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| Publication Number | Publication Date |
|---|---|
| CN1613013A CN1613013A (en) | 2005-05-04 |
| CN100445745C true CN100445745C (en) | 2008-12-24 |
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| CNB028044266A Expired - Fee Related CN100445745C (en) | 2001-01-31 | 2002-01-31 | Method of analyzing granular composition by fluorescene analysis |
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|---|---|
| EP (1) | EP1358483A1 (en) |
| JP (1) | JP4198996B2 (en) |
| CN (1) | CN100445745C (en) |
| WO (1) | WO2002061427A1 (en) |
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| US9482397B2 (en) | 2010-03-17 | 2016-11-01 | Once Innovations, Inc. | Light sources adapted to spectral sensitivity of diurnal avians and humans |
| CN102565015A (en) * | 2011-12-24 | 2012-07-11 | 浙江大学 | Method for quickly and quantitatively determining residual sulfonylurea weedicide in water sample |
| WO2015017655A1 (en) | 2013-08-02 | 2015-02-05 | Once Innovations, Inc. | System and method of illuminating livestock |
| EP3091832A4 (en) | 2014-01-07 | 2017-10-04 | Once Innovations, Inc. | System and method of enhancing swine reproduction |
| DK178701B1 (en) * | 2015-04-01 | 2016-11-21 | Spx Flow Tech Danmark As | A method and a system for monitoring spray nozzles in a spray drying or spray cooling chamber |
| BR112017028514A2 (en) * | 2015-07-02 | 2018-08-28 | Once Innovations Inc | method for increasing poultry feed intake, and method for feeding aquatic life |
| WO2017172869A1 (en) | 2016-03-29 | 2017-10-05 | Zdenko Grajcar | System and method of illuminating livestock |
| WO2018129055A1 (en) * | 2017-01-05 | 2018-07-12 | Virgin Instruments Corporation | Ligand binding assays using maldi-tof mass spectrometry |
| JP6929712B2 (en) * | 2017-06-19 | 2021-09-01 | アズビル株式会社 | Fluorescent particle manufacturing system and fluorescent particle manufacturing method |
| JP6986452B2 (en) * | 2018-01-04 | 2021-12-22 | 浜松ホトニクス株式会社 | Fluorescence measuring device and fluorescence measuring method |
| MX2022002044A (en) * | 2019-08-20 | 2022-04-06 | Basf Coatings Gmbh | Device for monitoring rotational atomization of a coating material composition. |
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Also Published As
| Publication number | Publication date |
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| WO2002061427A1 (en) | 2002-08-08 |
| JP2004518140A (en) | 2004-06-17 |
| CN1613013A (en) | 2005-05-04 |
| JP4198996B2 (en) | 2008-12-17 |
| EP1358483A1 (en) | 2003-11-05 |
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